Background: Types: ~90% of head & neck cancers are squamous cell carcinoma (HNSCC). ~10% are salivary gland tumors, lymphomas, sarcomas, mucosal melanomas Risk factors: HPV infection (16, 18, 33, 35) HPV 16 is by far the dominant subtype (>80% of HPV-positive HNSCC) HPV 18 is the second most common but plays a much smaller role than in cervical cancer (~2.5% of all HNSCC) Smoking Alcohol use (synergistic with smoking) EBV esp in nasopharyngeal carcinoma Betel nut chewing Genetic factors such as Fanconi Anemia (avoid alkylating agents and radiation due to increased toxicity in these patients) Sites of tumors: Nasal cavity and paranasal sinuses Oral cavity cancers: Mucosal lip, Buccal mucosa, anterior tongue, hard palate Oropharyngeal cancers: Upper throat, tonsil, base of tongue, soft palate, pharyngeal wall Nasopharyngeal cancers (NPC): Pharyngeal recess (fossa of Rosenmüller), posterior/lateral/superior walls NPC is often discussed separately from other HNSCC because it is a distinct entity in terms of atiology and biology and treatment. Hypopharyngeal cancer (lower throat) Laryngeal cancers: Supraglottis, glottis, subglottis Treatment: Principles of concurrent chemo-RT: RT is typically over 6-7 weeks Chemo is not curative single modality in H&N cancer Concurrent chemotherapy options: Cisplatin 40 mg/m2 weekly (preferred) High dose cisplatin 100 mg/m2 q3 weeks (may have more side effects) Carboplatin/5FU Consider cetuximab if cisplatin contraindicated though it is inferior Consider against cetuximab in HPV+ disease Follow up: Clinical assessment about 4-8 weeks after completion of chemo/RT or RT alone. FDG PET-CT at a minimum of 12 weeks after completion of chemoRT Recurrent/Residual Disease after chemo-RT: Indication for salvage surgery (if feasible) Re-radiating is typically not an option. Post surgery: If adverse pathologic features (lymphovascular invasion, T3/4, N2/N2, perineural invasion, etc): adjuvant RT If extranodal/extracapsular extension or positive margins: adjuvant chemo-RT Oropharyngeal Cancer Presents with oral mass, weight loss, loose teeth, ill fitting dentures, submental nodes, neck mass, dysphagia, odynophagia, bleeding Most primary tumors identified with head and neck SCC are located in the oropharynx, with 70% being HPV-positive. Associated with HPV 16 and 18. HPV 31 and 33 are responsible for the vast majority of the remaining fraction. Encodes for E6 and E7 protein. E6 attaches to p53 (tumor suppressor) and E7 attaches to RB protein. Together they inhibit p53 and RB allowing for tumor formation. Patients with HPV-associated H&N cancers tend to be younger. HPV positive tend to have a better prognosis (compared to smokers). Localized p16+ tumors can only go up to stage 3 Example: Patient with a T4 N0 HPV+ Oropharyngeal cancer will be considered to have Clinical Stage III disease, while a T4a N0 Non-HPV Oropharyngeal cancer will be considered to have Stage IVA disease Base of tongue tumors: No surgical options for these patients. Automatically requires chemo-RT even if early stage Treatment: Treatment of cancers in oral cavity: For T1 and T2: Resection is preferred + elective neck LN dissection, can consider adjuvant RT if adverse features (positive/close margins, extranodal extension, LVI, PNI, upstaged to pT3/T4 or pN2/N3) Treatment of cancers of the oropharynx: If T1-2, N0-1 tumor: Resection + LN dissection is preferred (if surgical candidate) Can offer definitive RT If adverse features seen: adjuvant chemo-RT If locally advanced disease (N+): Treated with concurrent chemoRT If recurrence: Consider surgical resection, neck dissection Hypopharyngeal Cancer Treatment: T2/T3, N0-3 or T1N+ (locally advanced disease): Treatment options: Induction chemotherapy (TPF: Docetaxel, Cisplatin, Fluorouracil) Chemo-RT Partial or total laryngopharyngectomy + neck dissection + thyroidectomy + pretracheal and ipsilateral paratracheal LN dissection Clinical trial Induction chemotherapy typically followed by definitive therapy depending on response Partial response → surgery → adjuvant RT Complete response → adjuvant RT T4: T4aN0: Surgery with neck dissection → adjuvant RT T4bN0: Concurrent chemo-RT Induction chemo → RT or chemo-RT Treatment for recurrent/unresectable/metastatic disease: Consider regimen based on tumor burden and performance status: If high tumor burden and good PS: consider chemo + pembrolizumab. If high tumor burden and poor PS: consider single agent IO. If no rapidly progressive disease: CPS >20: Single agent pembrolizumab CPS 1-20: pembro + platinum chemo (or pembro alone if poor PS) CPS<1: platinum chemo +/- pembro First Line: Pembrolizumab + platinum + 5FU Keynote-048: proved this regimen is superior to EXTREME regimen Single agent IO (Pembrolizumab or Nivo) Cetuximab + 5FU + Platinum (EXTREME trial) Consider if IO is contraindicated Locoregional treatment (surgery, RT, ablative therapies) for oligometastatic disease Subsequent Lines: IO (nivolumab or pembro) if IO not previously used. Category 1 option for patients with recurrent and/or metastatic SCC of the head and neck who progressed on platinum based chemo. Platinum/cetuximab/5FU: combination or single agents (if not previously used) Taxanes Methotrexate Capecitabine Afatinib: if progressed on platinum therapy Erdaftinib: for FGFR mutation/fusion Fam-trastuzumab deruxtecan (Enhertu): for HER2+ (if no other options) Supraglottic Laryngeal Cancer Presents with hoarseness, dysphagia, hemoptysis Treatment: T1-T2, N0 (or select T3, N0): If patient prefers larynx-preserving surgery: can undergo either RT or partial laryngectomy (endoscopic or open resection) and neck dissection. If surgery is pursued: consider adjuvant RT if any high risk features present T3: Induction chemotherapy, surgery or concurrent chemo-RT If induction chemotherapy given subsequent steps depend on response: CR → definitive RT PR → RT or chemoRT Less than PR → laryngectomy T4: Surgery preferred If surgery declined or not feasible in T4b: chemo-RT or induction chemo Locoregional recurrence, persistent disease, second primary, prior RT: If resectable: Surgery +/- postoperative reirradiation, chemo-RT, clinical trial If unresectable: chemo-RT, chemotherapy, clinical trial Nasopharyngeal Cancer Presents with hearing loss, tinnitus, nasal obstruction/pain, posterior neck nodes Associated with EBV High levels of EBV DNA are associated with poor disease outcomes following RT or chemoRT Treatment: T1N0M0 (EBV negative): Definitive RT to nasopharynx and elective RT to neck T2N0M0: If EBV negative: definitive RT If EBV positive: definitive RT + chemo T3N0M0: Chemo-RT T4 or any N+, M0 (locally advanced): Chemo-RT Chemo-RT followed by chemo Induction chemo (cisplatin/gemcitabine) followed by chemo-RT Clinical trial Recurrent/unresectable/metastatic disease Cisplatin + 5-FU Platinum + Taxane Carboplatin + Cetuximab Gemcitabine + Carboplatin Cisplatin + Gemcitabine + toripalimab (or any other PD-1 inhibitor) Subsequent line: Can use nivolumab or pembrolizumab (needs to be PDL1 positive) or Tislelizumab Salivary Gland Tumor < 2% of all head and neck cancers They have positive androgen receptors Initial Treatment: surgical resection + LN dissection Consider adjuvant RT if: T3/T4 disease Intermediate or high grade Close or positive margins Perineural invasion Lymphovascular invasion LN metastases Systemic therapy for metastatic disease: Combination regimens: cisplatin, doxorubicin, and cyclophosphamide Single agents: vinorelbine or mitoxantrone If adenoid cystic carcinoma histology: Taxanes are normally avoided due to lack of effectiveness. If patient progress on initial therapy and remain candidates for treatment, one can offer therapy with VEGF tyrosine kinase inhibitors (Lenvatinib, Sorafenib, or Axitinib) Thymoma/ Thymic Cancer Causes anterior mediastinal mass Associated with myasthenia gravis and pure red cell aplasia Treatment: If localized disease: Surgical resection (leads to improvement of associated paraneoplastic syndrome) If R0 resection: Surveillance If R1/R2: Consider adjuvant RT (might consider chemo-RT for R2) Preferred chemo regimen for thymoma: CAP (Cisplatin, Doxorubicin, Cyclophosphamide) If chemotherapy is given with RT: Cisplatin + Etoposide Subsequent line for thymoma: Pemetrexed Preferred chemo regimen for patients with thymic cancer: Carboplatin/Paclitaxel Subsequent line for thymic cancer: Lenvatinib/Sunitib NUT Carcinoma Highly aggressive subset of SCC, found in head and neck or mediastinum Hallmark is the rearrangement of NUT gene: located on chromosome 15 Initial treatment: surgery followed by chemo-RT

Background: NSCLC (85%): Adenocarcinoma (~60%) Squamous (~25%) Large cell carcinoma and other less common histologies (~15%) SCLC (15%) Staging: Recommend to memorize TNM staging (questions will not always state what stage but may provide size, nodal involvement, etc) T: High-yield size cutoffs: T2 begins at 3 cm Each T goes up by 2 cm: T2 (3 cm) → T3 (5cm) → T4 (7cm) N1: Ipsilateral peribronchial Ipsilateral hilar Intrapulmonary LN N2: Ipsilateral mediastinal Subcarinal LN N3: Contralateral hilar Contralateral mediastinal Scalene LN Supraclavicular LN Treatment: Stage IB-IIIA require biomarker testing: EGFR (particularly exon 19 del/L858R), ALK, RET, PD-L1 Stage I: Curative intent: Surgical resection (preferred) If positive margins: Re-resection Postoperative radiation if re-resection is not feasible If negative margins: Surveillance Definitive radiation (if inoperable) Stage IA: No routine adjuvant chemotherapy. Stage IB: Consider adjuvant chemotherapy ONLY in selected high-risk patients. High risk features: Poorly differentiated tumors, lymphovascular invasion, wedge resection, visceral pleural involvement, unknown LN status. Surgery → adjuvant chemo Regimens: Platinum/Taxol x4 Platinum/Pemetrexed x4 (nonsquamous only) Surgery → adjuvant chemo → adjuvant osimertinib x3 years if EGFR Exon 19 del/L858R (ADAURA) Surgery → adjuvant chemo → adjuvant alectinib if ALK mutated (ALINA) Surgery → adjuvant chemo → adjuvant IO Atezolizumab x1 year if PD-L1% or higher (IMPower-010) Pembrolizumab x1 year regardless of PDL-1 (Keynote-091/PEARLS) Stage II: Surgery → adjuvant chemo Regimens: Platinum/Taxol x4 Platinum/Pemetrexed x4 (nonsquamous only) Surgery → adjuvant chemo → adjuvant osimertinib x3 years if EGFR Exon 19 del/L858R (ADAURA) Surgery → adjuvant chemo → adjuvant alectinib if ALK mutated (ALINA) Surgery → adjuvant chemo → adjuvant IO Atezolizumab x1 year if PD-L1% or higher (IMPower-010) Pembrolizumab x1 year regardless of PDL-1 (Keynote-091/PEARLS) Stage III: Treatment with curative intent even if it is unresectable. If resectable: Neoadjuvant therapy → Surgery Neoadjuvant options: Chemotherapy Concurrent chemo-RT Chemo-IO (preferred) Chemo+Nivolumab x3 cycles → surgery (Checkmate 816) Chemo+Nivolumab x3 cycles → surgery → adjuvant nivolumab (NADIM) Chemo+Pembrolizumab x4 cycles → surgery → adjuvant pembrolizumab (Keynote-671) Chemo+Durvalumab ×4 cycles → surgery → adjuvant durvalumab (AEGEAN) Surgery → Adjuvant therapy Surgery → adjuvant chemo Regimens: Platinum/Taxol x4 Platinum/Pemetrexed x4 (nonsquamous only) Surgery → adjuvant chemo → adjuvant osimertinib x3 years if EGFR Exon 19 del/L858R (ADAURA) Surgery → adjuvant chemo → adjuvant alectinib if ALK mutated (ALINA) Surgery → adjuvant chemo → adjuvant IO Atezolizumab x1 year if PD-L1% or higher (IMPower-010) Pembrolizumab x1 year regardless of PDL-1 (Keynote-091/PEARLS) If unresectable: Definitive concurrent chemo-RT → (if no progression of disease) consolidation based on EGFR exon 19 del/L858R status Regimens: Platinum/Taxol x4 Platinum/Pemetrexed x4 (nonsquamous only) Consolidation If EGFR+: Consolidation Osimertinib 80 mg PO once daily until progression or toxicity (LAURA) PFS 39.1 months with osimertinib vs 5.6 months with placebo Consolidation If EGFR-: Consolidation durvalumab for up to 12 months (PACIFIC) PFS 16.8 months with Durvalumab vs 5.6 months with placebo Stage IV: NGS: check for driver mutations and PD-L1 TPS, EGFR (20-25%), ALK (5-7%), ROS1, RET, MET, BRAF V600E, KRAS G12C (13%), HER2 (ERBB2) If waiting for NGS, can start with chemo backbone and add in IO during C2 Chemo + IO: Indications: No driver mutations Large burden of disease End organ damage/visceral crisis Regimen: Platinum/Taxol + Pembrolizumab (Keynote-407) Addition of pembrolizumab resulted in significantly longer OS and PFS than chemotherapy alone. Platinum/Pemetrexed (nonsquamous only) + Pembrolizumab (Keynote-189) The survival benefit for chemo+IO was observed across all categories of PD-L1 expression. Pembrolizumab: Pembrolizumab monotherapy can be used if high PD-L1 >50% (Keynote-024) and can be extended as first-line therapy even with low PDL-1 TPS (1-49%) (Keynote-042) Second Line agents: EGFR Exon19 del/L858R: Osimertinib (FLAURA) Osimertinib + chemo (FLAURA-2) Amivantamab + Lazertinib Afatinib Dacomitinib Erlotinib +/- Bev Erlotinib +/- Ramicurumab Gefitinib EGFR Exon 20 insertion mutation: Amivantamab (CHRYSALIS) Amivantamab + chemo (PAPILLON) ALK fusion 5-7%: Can pre-screen with ALK IHC and confirm with FISH or PCR ALK TK inhibitors (Alectinib, Brigatinib, Crizontinib, Lorlatinib) are category 1 for first line therapy. They are superior to chemo in 1L and 2L setting 1G ALK TKI: Crizotinib 2G ALK TKI: Ceritinib, Alectinib, Brigatinib, Ensartinib 3G ALK TKI: Lorlatinib (CROWN trial) 4G ALK TKI: NVL-655 RET fusion: Selpercatinib ROS1 fusion: Repotrectinib, Entrectinib, Crizontinib, Lorlatinib KRAS G12C: Sotorasib, Adagrasib Both approved for 2L after 1+ systemic therapy MET Exon 14 Skipping Mutation: Capmatinib, Crizotinib, Tepotinib BRAF V600E: Dabrafenib/Trametinib HER2: Fam-trastuzumab deruxtecan (Enhertu) NTRK Repotrectinib Larotrectinib Entrectinib Nivolumab Atezolizumab Docetaxel + Ramucirumab/Pemetrexed/Gemcitabine/Abraxane/Vinorelbine Enhertu Telisotuzumab (cMET/MET >/= 50% IHC 3+ and EGFR wild type) Datopotamab deruxtecan: Trop-2 directed ADC (TROPION-Lung-01) EGFR exon 19 del/L858R

Background: SCLC is a poorly differentiated neuroendocrine carcinoma. Small blue cells, scant cytoplasm, high N:C ratio, granular chromatin Types: Limited-Stage SCLC (LS-SCLC): Stages I–III confined to the ipsilateral hemithorax that can be safely encompassed within a radiation field Some stage III tumors are considered extensive-stage when the disease burden is too extensive to be safely encompassed in a tolerable radiation field. Extensive-Stage SCLC (ES-SCLC): Stage IV disease/Metastatic, beyond the ipsilateral hemithorax, including malignant pleural or pericardial effusion Stage I–III disease that cannot be safely encompassed within a definitive thoracic radiation field. Median overall survival: LS-SCLC: ~15–30 months with treatment ES-SCLC: ~10–13 months with treatment Five-year survival: LS-SCLC: ~20–30% ES-SCLC: <5% May present with SVC Syndrome IR consult: Obtain tissue diagnosis before treatment whenever feasible and safe SVC stenting in patients with severe/life-threatening symptoms for rapid relief Rad Onc consult: Urgent radiotherapy when indicated Work up: Biopsy or cytology EBUS-guided biopsy of the primary or thoracic nodes, or biopsy of a metastatic lesion Labs: CBC, electrolytes, LFTs, BUN/creatinine Unexplained hyponatremia → require SIADH work up Hypokalemia, metabolic alkalosis, new or refractory hyperglycemia → ectopic ACTH/ Cushing syndrome Almost all of these patients have weight loss (unlike classic Cushing) so absence of the cushingoid habitus does not exclude it. LDH Elevated LDH may reflect greater disease burden and is associated with worse prognosis. Imaging: CAP CT scan Brain MRI with contrast ~15% have brain metastases at diagnosis Consider FDG-PET/CT when limited-stage disease is suspected to identify occult distant metastases and assist with radiation planning. If PET CT scan is unavailable, bone scan may be used. PET/CT does not replace brain MRI. Smoking cessation counseling Consider biomarker testing: Extensive-stage in never- smoker or light-smokers Remote smoking history Diagnostic or therapeutic dilemma Relapse Palliative care integration Treatment: LS-SCLC Curative-intent therapy Stage I-IIA (T1-2 , N0): lobectomy mediastinal lymph node dissection/sampling + adjuvant chemotherapy (Carboplatin/cisplatin + Etoposide) Invasive mediastinal staging is mandatory before resection. Patients with pathologic nodal involvement should be managed as stage IIB–IIIC disease. Stage IIB-III: Concurrent chemo-RT → consolidation Durvalumab (ADRIATIC) OS was 55.9 months (durvalumab) vs 33.4 months (placebo) PFS was 16.6 months (durvalumab) vs 9.2 months (placebo) Thoracic RT should begin with cycle 1 or 2 of chemotherapy. Do not delay RT until completion of induction chemotherapy. Myeloid growth factors are not recommended during concurrent chemo-RT. Consider prophylactic cranial irradiation (PCI) in patients with a good response to definitive therapy, which reduces the incidence of brain metastases and has demonstrated an overall survival benefit. PCI should be completed before initiating consolidation durvalumab. Brain surveillance imaging is recommended for all patients regardless of PCI status. ES-SCLC Systemic therapy is the backbone of treatment. No role for surgery Brain RT is used selectively rather than routinely. If asymptomatic: give systemic therapy first and defer brain RT If symptomatic: give brain RT + steroids before systemic therapy Consider consolidative thoracic RT after systemic therapy in selected responders with residual thoracic disease. Chemo-IO options: (Carboplatin/cisplatin + Etoposide) + Durvalumab x4 cycles → Maintenance: Durvalumab (CASPIAN) (Carboplatin/cisplatin + Etoposide) + Atezolizumab x4 cycles → Maintenance: Atezolizumab (IMPOWER-133) (Carboplatin/cisplatin + Etoposide) + Atezolizumab x4 cycles → Maintenance: Atezolizumab+lurbinectedin (IMforte) Relapsed cases The important questions is: 'When did the relapse occur?' Relapse > 6 months after platinum exposure (Platinum-sensitive relapse): Repeat original regimen (Carboplatin/cisplatin + Etoposide) Relapse ≤ 6 months after platinum exposure (Platinum-resistant relapse): Lurbinectedin Topotecan Tarlatamab: bispecific Ab (DeLLphi-301) Clinical Trial

Here are some points that can make your Hem/Onc life easier- The earlier you learn them, the better. Lesson Number 1 Below is a list of anticancer agents for which the category and mechanism of action can be recognized by their names: Chemotherapy: ...rubicin: Anthracycline ...tecan: Topoisomerase I inhibitors ...mustine: Alkylating agents ...carbazine: Alkylating agents ...taxel: Taxens (Microtubule-targeting agent) Vin...stine: Vinca alkaloids (Microtubule-targeting agent) ...platin: Platinum compounds ...trexed: Antifolates (Antimetabolites) ...citabine: Pyrimidine analogues (Antimetabolites) Immunotherapy: ...limab: PD-1 inhibitor ...limumab: CTLA-4 inhibitors ...tamab: Bispecific T-cell engager (BiTE) ...alidomide: Immunomodulators ...cabtagene ...leucel: CAR T-cell therapy Targeted therapy: ...rafenib: BRAF inhibitors ...metinib: MEK inhibitors ...rolimus: mTOR inhibitor ...tinib: TK inhibitor ...brutinib: BTK inhibitor ...rasib: KRAS inhibitors ...trectinib: NTRK inhibitors ...zomib: Proteasome inhibitors ...lisib: PI3Kδ inhibitors ...sidenib: IDH inhibitor Antibody-drug conjugate (ADC): ... Vedotin ... Ozogamicin Lesson Number 2 Antibody-drug conjugate (ADC): ADCs are composed of three main components: Monoclonal antibody targeting a tumor-associated antigen Cytotoxic payload Chemical linker Antibody binds to a specific antigen on the cancer cell surface → ADC is internalized → release the cytotoxic drug in cancer cells → targeted cell death Bispecific antibody (BsAb): Engineered Ab that have two distinct binding domains → recognize and bind two different antigens or two different epitopes (most commonly a tumor antigen and CD3 on T cells) → redirect immune cells toward malignant cells → facilitating targeted cytotoxicity The most clinically relevant BsAB in hematology are those that engage a tumor-associated antigen (CD19, CD20, BCMA, GPRC5D) and a T cells (CD3). Lesson Number 3 Route of administration: All TKI agents are administered orally. All immunotherapy medications are administered IV, except for immunomodulatory agents (lenalidomide, thalidomide, pomalidomide) which are given orally. Lesson Number 4 Assessment of treatment efficacy in hematology/oncology: Complete response (CR): Disappearance of all evidence of disease. In lymphomas (Lugano criteria): No abnormal FDG uptake on PET (Deauville score 1-3), regression of all lesions to normal size, and no new lesions. In acute leukemias: No circulating blasts, no extramedullary disease, trilineage hematopoiesis in BM with <5% blasts, and recovery of blood counts (ANC ≥1000, platelets ≥100k) Partial response (PR): Significant but incomplete reduction in disease burden. In lymphomas: ≥50% decrease in the sum of the product of diameters of target lesions, with no new lesions and reduced FDG uptake compared to baseline (Deauville score 4-5 with decreased avidity). In leukemias: PR is less commonly used, but may refer to a substantial reduction in blast percentage or disease burden without meeting all CR criteria. Progressive disease (PD): Worsening or growth of disease. In lymphomas: >50% increase in the size of existing lesions, appearance of new lesions, or increased FDG uptake (Deauville score 5). In leukemias: Increase of at least 25% in the absolute number of circulating or BM blasts, or development of new extramedullary disease. Lesson Number 5 Prostate Cancer: Castrate-sensitive prostate cancer (CSPC): Also termed "hormone-sensitive" or "androgen-sensitive" prostate cancer. Responds to androgen deprivation therapy (ADT), with tumor growth suppressed when serum testosterone is reduced to castrate levels (typically <50). Castrate-resistant prostate cancer (CRPC): Prostate cancer that progresses clinically, radiographically, or biochemically (rising PSA) despite ongoing ADT and maintenance of castrate levels of serum testosterone (<50). This resistance can occur in both non-metastatic (M0 CRPC) and metastatic (M1 CRPC) disease. Confirm castrate testosterone levels before diagnosing CRPC, and continue ADT even after resistance develops. Lesson Number 6 Measurable Residual Disease (MRD): Residual malignant cells that persist after treatment but are undetectable undetectable by conventional morphologic examination (light microscopy). After a patient achieves complete remission by standard criteria (no detectable disease by microscopy), more sensitive lab techniques (multiparameter flow cytometry, real-time quantitative PCR, NGS) can identify very low levels of leukemic cells that persisted. Patients who are MRD-positive after induction or consolidation therapy have a significantly higher risk of relapse and worse overall survival compared to those who are MRD-negative. MRD positivity at key time points (end of induction, end of consolidation) identifies patients at higher risk for relapse and may prompt consideration of therapy intensification or allo-HSCT. Lesson Number 7 Liver biopsy: Liver mass + Cirrhosis: biopsy is generally not indicated for a patient with cirrhosis who has a liver mass if the lesion meets established imaging criteria for HCC on CT or MRI. In this setting, imaging features (arterial phase hyperenhancement, washout, capsule appearance) has high specificity, and biopsy is not routinely required. Consider biopsy if: Imaging is inconclusive Lesion does not meet criteria for definite HCC (LI-RADS 5) Suspicion for a non-HCC malignancy (cholangiocarcinoma) Atypical risk factors (cirrhosis due to congenital or vascular causes) Tumor markers suggest alternative diagnoses Liver mass, No cirrhosis: Biopsy is recommended to confirm malignancy and guide management Systemic therapy in HCC: Generally indicated for patients with HCC and Child-Pugh class A or ≤B7, while it is not recommended for Child-Pugh class >B7 or C. Lesson Number 8 Basics of radiotherapy (RT): RT application ranges from definitive therapy in localized disease, to consolidation after chemotherapy, palliation of symptoms, and as part of conditioning regimens for HSCT. NCCN emphasize the use of involved-site radiotherapy (ISRT) to limit exposure to adjacent uninvolved organs, thereby reducing long-term complications such as hypothyroidism, cardiac toxicity, and secondary malignancies. Treatment planning requires CT-based simulation and often incorporates PET and MRI for precise target delineation. NCCN provides specific dose and fractionation recommendations based on histology, disease stage, and treatment intent. For example, follicular lymphoma is typically treated with 24–30 Gy, while DLBCL may require 30–36 Gy for consolidation after chemotherapy. Lesson Number 9 Anticoagulation use in renal and hepatic dysfunction: Direct oral anticoagulants (DOAC): Mixed renal and hepatic clearance Renal clearance: Dabigatran (80%) > Edoxaban (50%) > Rivaroxaban (35%) > Apixaban (27%) Indirect inhibitors: Renal clearance increases as the molecule gets smaller: UFH → least renal dependence LMWH → mostly renal Fondaparinux → almost completely renal Lesson Number 10 You can stare at this table to strengthen your visual memory and learn about lymphomas! Black cells: Positive For example: CLL has CD5 + White cells: Negative For example: FL has CD5 – Gray cells: Weak/dim For example: CLL has weak/dim CD20 Black cells with white circles: Positive, occasionally negative For example: FL often has positive CD10, but can be negative as well. Lesson Number 11 Terminal deoxynucleotidyl transferase (TdT): Template-independent DNA polymerase expressed in immature lymphoid cells Normally present in precursor B and T lymphoblasts Hallmark of lymphoblastic neoplasms, including ALL and lymphoblastic lymphoma Occasionally seen in the blast phase of CML (when transformation is lymphoid rather than myeloid) Lesson Number 12 Key distinguishing features of leukemias: CLL: CD5+ and CD23+ co-expression on B-cells (unique among leukemias). CML: BCR-ABL1 fusion; immunophenotype less diagnostic ALL: TdT+, lymphoid markers CD10+ in B-ALL CD3+ in T-ALL AML: TdT−, MPO+, myeloid markers (CD13, CD33, CD117) IN PROGRESS...!

Chemotherapy Anthracyclines: 💉 Intercalate into DNA, inhibit topoisomerase II, generate free radicals → DNA damage → cell death Doxorubicin (Adriamycin) Daunorubicin Epirubicin Idarubicin (Idamycin) Topoisomerase inhibitors: 💉 Interfere with DNA unwinding and replication → cell death Topoisomerase I inhibitors: Irinotecan Topotecan Topoisomerase II inhibitors: Doxorubicin (Adriamycin) (Anthracycline and Tomoisomerase II inh) Etoposide Alkylating agents: DNA cross-linking → inhibits replication → cell death Cyclophosphamide 💊 💉 Ifosfamide 💉 Busulfan 💉 Melphalan 💊 💉 Bendamustine 💉 Carmustine 💉 Lomustine 💊 Temozolomide (Temodar) 💊 Procarbazine 💊 Dacarbazine 💉 Microtubule-targeting agents: 💉 Disrupt mitotic spindle formation → mitotic arrest → cell death Taxanes: Paclitaxel (Taxol) Docetaxel Cabazitaxel Vinca alkaloids: Vincristine (Oncovin) Vinblastine Platinum compounds: 💉 DNA cross-linking → inhibits replication → cell death Cisplatin Carboplatin Oxaliplatin Antimetabolites: Hypomethylating agents (DNA hypomethylation→ reactivation of tumor suppressor gene): Acacitidine -SubQ Decitabine 💉 Decitabine/cedazuridine (Inqovi) 💊 Antifolates: Methotrexate 💊 💉 Pemetrexed (Alimta) 💉 Raltitrexed 💉 Purine analogues: 6-mercaptopurine 💊 6-thioguanine 💊 Fludarabine 💉 Cladribine 💉 Pyrimidine analogues: Cytarabine 💉 5-fluorouracil (5-FU) 💉 Gemcitabine (Gemzar) 💉 Capecitabine (Xeloda) 💊 Floxuridine 💉 Immunotherapy PDL-1 inhibitors: 💉 Atezolizumab Durvalumab (Imfinzi) Avelumab PD-1 inhibitors: 💉 Pembrolizumab (Keytruda) Nivolumab (Opdivo) Tislelizumab Cemiplimab Dostarlimab Retifanlimab Toripalimab CTLA-4 inhibitors: 💉 Ipilimumab Tremelimumab Bispecific T-cell engager (BiTE): 💉 Binds two targets simultaneously (CD3 on T cells and Tumor-associated antigen on cancer cells) → directs T cells to the tumor → T-cell mediated cytotoxicity Blinatumomab Teclistamab Tarlatamab Immunomodulatory imide drugs (IMiDs): 💊 Lenalidomide Thalidomide Pomalidomide Targeted Therapy BRAF inhibitors: 💊 Vemurafenib Dabrafenib Encorafenib Sorafenib Regorafenib is technically a BRAF inhibitor, but it is not a clinically effective BRAF-targeted therapy (BRAF inhibitory activity is weak compared to selective BRAF inhibitors) MEK inhibitors: 💊 (Often combined with BRAF inhibitors) Trametinib Cobimetinib mTOR inhibitors: Sirolimus 💊 Everolimus 💊 Temsirolimus 💉 VEGF inhibitors: 💉 Monoclonal antibodies Target the extracellular circulating ligand (VEGF protein) → preventing it from binding to its receptors → inhibit tumor angiogenesis → reduce tumor growth Bevacizumab (Avastin) Ramucirumab Aflibercept VEGFR inhibitors: 💊 Small-molecule TKIs Target the intracellular tyrosine kinase domain of VEGF receptors → blocking downstream signaling even after ligand binding → inhibit tumor angiogenesis → reduce tumor growth Sunitinib Sorafenib (VEGFR and BRAF inhibitor) Regorafenib Pazopanib Axitinib Cabozantinib Lenvatinib Fruquintinib KRAS inhibitors: 💊 Sotorasib Adagrasib Daraxonrasib BCR-ABL inhibitors: 💊 Imatinib Dasatinib Nilotinib Ponatinib EGFR inhibitors: 💊 Erlotinib Gefitinib Osimertinib (Tagrisso) NTRK inhibitors: 💊 Larotrectinib Entrectinib Repotrectinib BTK inhibitors: 💊 Ibrutinib Zanubrutinib Pirtobrutinib Remibrutinib ROS1 inhibitors: 💊 Entrectinib (NTRK and ROS1 inh) Repotrectinib (NTRK and ROS1 inh) Crizotinib (ALK and ROS1 inh) Lorlatinib (ALK and ROS1 inh) ALK inhibitors: 💊 Crizotinib Lorlatinib Alectinib Brigatinib RET inhibitors: 💊 Selpercatinib Pralsetinib JAK-2 inhibitors: 💊 Ruxolitinib Fedratinib Pacritinib Momelotinib HER-2 inhibitors: Tyrosine kinase inhibitor: 💊 Lapatinib Neratinib Monoclonal antibody: 💉 Trastuzumab (Herceptin) Pertuzumab (Perjeta) Margetuximab Antibody-drug conjugates: 💉 Ado-trastuzumab emtansine Trastuzumab deruxtecan (Enhertu) Proteasome inhibitors: Bortezomib (Velcade) 💉 Carfilzomib 💉 Ixazomib 💊 Phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors: 💊 Idelalisib Umbralisib Zandelisib Linperlisib Leniolisib CD20 inhibitors: 💉 Rituximab Ublituximab Obinutuzumab Ofatumumab Ocrelizumab IDH inhibitor: 💊 IDH1 inhibitor: Ivosidenib Olutasidenib IDH2 inhibitor: Enasidenib

*** A list of abbreviations is provided at the end of this note. Background: Most commonly diagnosed non-cutaneous malignancy in men Second leading cause of cancer death among men in the US Key risk factors: Age: mostly in men >50 (median age at diagnosis ~66) Family history: first-degree relative increases the risk 2-3 times Race: significantly higher incidence in African American, earlier onset and 2× mortality No biological differences in tumor genomics Germline mutations: BRCA2 (most significant), BRCA1, HOXB13, ATM Early detection: Individualized informed decision-making for prostate cancer screening (PSA ± DRE) Discuss risks and benefits: Age 45–75 for average risk Age 40–75 for high risk (African American, family history, high risk germline mutations) Based on PSA level: PSA <1 → Rescreen every 2-4 years PSA 1–3 → Rescreen every 1-2 years PSA >3 or PSA >4 for age >75 or suspicious DRE → mpMRI and consider biomarkers If high suspicion → Biopsy If low suspicion → follow up in 6-12 months with PSA ± DRE Definitive diagnosis: Requires prostate biopsy, Gleason grading, and TNM staging. Clinical Pearls: Think of Prostate Cancer treatment on a "spectrum": Localized Disease → Biochemical recurrence (BCR) → Non-metastatic castrate resistant prostate cancer (nmCRPC) OR Metastatic Castrate Sensitive Prostate Cancer (mCSPC) → Metastatic Castrate Resistant Prostate Cancer (mCRPC) PSA after radical prostatectomy (RP) should be undetectable. Radiation kills prostate cells gradually, so PSA declines slowly rather than immediately. It may continue falling for 18-36 months before reaching its lowest value (PSA nadir). Monitor for the nadir to determine BCR. BCR is defined as: After RP: PSA ≥ 0.2 after RP or 2 rising PSA’s from nadir after RP After RT: PSA increase by ≥2 above nadir PSA after radiation (Phoenix Criteria) Consider PSA doubling time of ~ 6-10 months. Grading: Gleason pattern = Primary (most predominant) pattern + Secondary (second most predominant) pattern Although both 3+4 and 4+3 equal 7, 4+3 is more aggressive because pattern 4 is the predominant component. This classification applies adenocarcinoma and squamous carcinomas but not to sarcoma or transitional cell carcinomas. Staging: T1 = clinically inapparent (not palpable); T1c = found on needle biopsy T2 = palpable, organ-confined T3 = extraprostatic extension T4 = invades adjacent structures N1 = regional LN metastases M1a = nonregional LN metastases; M1b = bone; M1c = other sites (visceral) Risk stratification: Risk stratification of localized prostate cancer based on NCCN guideline: Very low risk T1c + Grade Group 1 + PSA <10 + Fewer than 3 prostate biopsy fragments/cores positive, ≤50% cancer in each fragment/core + PSA density <0.15 Low risk T1–T2a + Grade Group 1 + PSA <10 Intermediate risk No high- or very-high-risk features + one or more intermediate risk factors: T2b–T2c Grade Group 2 or 3 PSA 10–20 Favorable intermediate: Intermediate risk factors and Grade Group 1-2 and <50% biopsy cores positive Unfavorable intermediate: 2-3 intermediate risk factors and/or Grade Group 3 and/or ≥ 50% biopsy cores positive High risk T3a OR Grade Group 4-5 OR PSA > 20 Very high risk T3b–T4 OR Primary Gleason pattern 5 OR 4 cores with Grade Group 4-5 Androgen Deprivation Therapy (ADT): ADT achieves castrate testosterone levels (<50 ng/dL) via: LHRH agonist (leuprolide, goserelin, triptorelin) Causes initial testosterone surge (start bicalutamide before Lupron to prevent tumor flare) GnRH antagonists (degarelix, relugolix) No flare risk Consider relugolix if patient has cardiovascular comorbidities Bilateral orchiectomy (surgical castration) Side effects: hot flashes, weight gain, sexual dysfunction, mood changes, cardiovascular risk, DVT, hypertension, osteoporosis. Monitor DEXA scans q2 years Androgen Receptor Pathway Inhibitor (ARPI): Target androgen signaling by either: Blocking the androgen receptor Enzalutamide Can cause falls and lower seizure threshold Apalutamide Darolutamide Suppressing androgen synthesis Abiraterone (CYP17 inhibitor) Abiraterone also inhibits cortisol synthesis (unintended effect) → low cortisol → high ACTH → stimulates the adrenal cortex → mineralocorticoid excess/ hyperaldosteronism Abiraterone should be given with prednisone (low-dose prednisone replaces the missing cortisol) Side effects: Hepatotoxicity: needs LFT monitoring Mineralocorticoid excess: HTN, hypokalemia and fluid retention, cardiovascular events (worsening heart failure, arrhythmias, ischemic events) Prednisone-related adverse effects: hyperglycemia, adrenal suppression/insufficiency (if stopped abruptly after chronic use) Non-Metastatic Prostate Cancer Treatment: Very low risk localized prostate cancer: Active surveillance (if >10 years anticipated survival) Observation (if <10 years anticipated survival) Low risk localized prostate cancer: Active surveillance RT RP Observation (if <10 years anticipated survival) Intermediate risk localized prostate cancer: Favorable: Active surveillance RT RT + PLND (if >10 years survival) Unfavorable: Baseline bone & soft tissue imaging RT + 4-6 months ADT (if 5-10 years survival) RP + PLND (if >10 years survival) Observation (5-10 years survival) High Risk/Very High Risk localized prostate cancer: Baseline bone and soft tissue imaging needed >5 years survival or symptomatic: RT + ADT ± Abiraterone/Prednisone (if very-high risk) for 2 years RP + PLND <5 years survival and asymptomatic: Observation ADT EBRT Node positive, M0: >5 years survival or symptomatic: EBRT + ADT + Abiraterone (preferred) < 5 years survival and asymptomatic: Observation or ADT Biochemical Recurrence: Obtain imaging to rule out local recurrence or distant metastasis: If negative: Salvage RT + ADT x2 years If positive for pelvic recurrence: RT + ADT + Abiraterone/Prednisone x2 years If distant metastasis: Treat as M1 disease Non-metastatic castrate resistant prostate cancer (nmCRPC): Definition of castrate resistance: Elevated PSA despite testosterone <50 ADT + ARPI If patient had RP: Check adverse features on final pathology: Positive margins Extraprostatic extension (T3a) Seminal vesicle invasion (T3b) Check PSA: PSA after RP should be undetectable. If detectable or recurrent PSA develops: If life expectancy ≤5: Observation/ Palliative therapy If life expectancy >5: Obtain imaging to rule out local recurrence or metastasis: No evidence of M1: EBRT ± ADT (based on pathologic features and recurrence risk) Evidence of M1: Work up and treatment of mCSPC Metastatic Prostate Cancer Treatment: Metastatic castrate-sensitive prostate cancer (mCSPC): Low volume mCSPC: Metachronous oligorecurrent: MDRT MDRT + short-term ADT (6 months) Synchronous (de novo) oligometastatic: ADT + ARPI (preferred option) ADT + Abiraterone/Enzalutamide/Apalutamide (category 1) ADT + darolutamide (category 2B) ADT + EBRT to the primary tumor ADT + ARPI + EBRT to the primary tumor ADT + ARPI + docetaxel (triplet therapy) (category 2B) High volume mCSPC: presence of visceral mets or 4+ bony mets with at least 1 beyond vertebra or pelvis (CHAARTED) Docetaxel + ADT + Abiraterone (PEACE-1) Docetaxel + ADT + Darolutamide (ARASENS) If poor PS (not able to tolerate triplet therapy) can use ADT + ARPI Metastatic castrate-resistance prostate cancer (mCRPC): Cabazitaxel if progressed on Docetaxel (TROPIC) Olaparib (if BRCA positive) Rucaparib (if BRCA positive) PARP inhibitor + ARPI Olaparib + Abiraterone Talazoparib + Enzalutamide Pembrolizumab (If MSI-high/MMRd) Radium-223 (Xofigo, for bone only disease) Lutetium-PSMA (if fails Docetaxel) Radioligand delivers beta-particle radiation to PSMA-expressing cells (VISION) Approved for patients with symptomatic bone metastases but no signs of visceral disease Causes bone marrow toxicity Sipuleucel-T recommended if: Asymptomatic/minimally symptomatic No liver metastases Life expectancy > 6 months ECOG 0-1 Clinical Pearls If patient has rapid progression of disease discordant from PSA, consider neuroendocrine differentiation Treat with with cisplatin/etoposide Bisphosphonate decreases skeletal related events in patients with castration-resistant prostate cancer and bone mets No clear benefit to using bisphosphonate in patients with castration sensitive disease as it has not shown to reduce skeletal related events Germline testing may be considered in patients with: Intermediate risk prostate cancer with intraductal/cribriform histology History of prostate cancer + history of pancreatic, colon, gastric, melanoma, urothelial, glioblastoma multiforme, bile duct cancers, small intestinal cancer High risk/very high risk/node positive/metastatic prostate cancer *** Abbreviations: ADT: Androgen Deprivation Therapy ARPI: Androgen Receptor Pathway Inhibitor BCR: Biochemical Recurrence EBRT: External Beam Radiation Therapy MDRT: Metastasis-Directed Radiation Therapy mCRPC: Metastatic Castrate Resistant Prostate Cancer mCSPC: Metastatic Castrate Sensitive Prostate Cancer nmCRPC: Non-metastatic Castrate Resistant Prostate Cancer PLND: Pelvic Lymph Node Dissection RP: Radical Prostatectomy RT: Radiation Therapy

CBC & differential See "How to interpret a CBC with differential" lecture for a detailed discussion. Retic Reticulocytes are immature red blood cells that spend ~3 days maturing in the bone marrow, followed by 1–2 days in the peripheral blood before becoming mature RBCs. Retic count is a real-time indicator of bone marrow erythropoietic activity. Corrected reticulocyte count = % Retic × (Patient's Hct / Normal Hct) Reticulocyte production index (RPI) = Corrected retic count / Maturation factor You do not need to calculate RPI yourself! Use Mdcalc.com. Interpretation: RPI >2 : Appropriate BM response to anemia (hemolysis, acute blood loss) RPI ≤2 : Inadequate erythropoiesis (iron deficiency, BM suppression, chronic disease) Peripheral Blood Smear (PBS) *** SchistoSite will feature a separate lecture on peripheral blood smear (PBS) interpretation with a more detailed discussion and representative pathology images. Marked increase of mature-appearing lymphocytes: Consider CLL (particularly in older adults; correlate with flow cytometry) Other cause: Reactive lymphocytosis in viral infections EBV, CMV, acute HIV infection Granulocytes at all stages of maturation + basophilia + eosinophilia Consider CML (confirm with BCR-ABL1 testing) >20% blasts in blood or BM: Acute leukemia: Predominantly lymphoblasts → Consider ALL Predominantly myeloblasts → Consider AML Smudge cells → Suggest CLL Auer rods → Suggest AML, particularly acute promyelocytic leukemia (APL) Hematologic emergency until APL is excluded. Hairy cells → Hairy cell leukemia Sézary cells → Sézary syndrome Hypersegmented neutrophils → Vitamin B12/folate deficiency Consider vitamin B12 deficiency before folate replacement. Schistocytes → Evaluate urgently for thrombotic microangiopathy (TTP/HUS, DIC), and mechanical valve Spherocytes → Autoimmune hemolytic anemia or hereditary spherocytosis. Platelet clumping → Exclude pseudothrombocytopenia before initiating a thrombocytopenia workup Repeat the lab but collect the blood sample in a heparin or citrated tube (EDTA in the collecting tubes can cause platelet clumping) Rouleax formation → Consider plasma cell disorders Target cells → Consider liver disease and thalassemia Mixing study When PT and/or aPTT is prolonged, mixing study can help to differentiate between factor deficiency or presence of an inhibitor. Technique: Mix patient plasma 1:1 with normal pooled plasma (NPP) NPP supplies ~50% of every factor and ~50% activity (sufficient to normalize the PT and aPTT) Immediately repeat the prolonged lab test (PT and/or aPTT) on the mixture. Interpretation: If the factor is deficient: Mixing study corrects PT and aPTT. If an inhibitor presents: Inhibitor neutralizes the added normal factor in NPP as well as the patient's factor, so the clotting time stays long. IN PROGRESS...

Introduction: NHL is categorized into two groups of B-cell lymphomas and T-Cell lymphomas: B-cell lymphomas (85–90%): High-grade B-cell lymphoma (HGBL): Diffuse large B-cell lymphoma (DLBCL) HGBL with MYC and BCL2/BCL6 rearrangements "Double-hit" lymphoma: MYC and BCL2 rearrangements "Triple-hit" lymphoma: MYC and BCL2 and BCL6 rearrangements Burkitt lymphoma (BL): Highly aggressive Derived from germinal center B cells Low-grade B-cell lymphomas (LGBL): Follicular lymphoma (FL): Indolent Derived from germinal center B cells Marginal zone lymphoma (MZL): Subtypes: Extranodal, Nodal, Splenic Mantel cell lymphoma (MCL): More aggressive compared to FL and MZL Derived from mantle zone B cells Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) Lymphoplasmacytic lymphoma (LPL) T-cell lymphomas (10-15%): (discussed in a separate post T-Cell Non-Hodgkin lymphoma) Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS): The most common subtype of mature T-cell lymphomas A of aggressive lymphoproliferative disorders arising from mature T cells that do not fit into other defined T-cell lymphoma categories Cutaneous T-cell lymphoma (CTCL): Mycosis Fungoides Sézary Syndrome Anaplastic large cell lymphoma (ALCL): Can be ALK-positive or ALK-negative Enteropathy-associated T-cell lymphoma (EATL): Rare, aggressive peripheral T-cell lymphoma of the small intestine Strongly associated with celiac disease Hepatosplenic T-cell lymphoma (HSTCL) Adult T-cell leukemia/lymphoma (ATLL) Extranodal NK/T-cell lymphoma (ENKTL) T-cell large granular lymphocytic leukemia (T-LGLL): Less common, often with extranodal involvement 'High grade B-Cell NHL' Diffuse Large B-Cell Lymphoma (DLBCL) Background: Most common aggressive lymphoma (30% of NHL cases) Immunophenotype: Expression of pan–B-cell markers (CD19, CD20, CD22, CD79a, PAX5) Classified by cell of origin: Germinal center B-cell (GCB) Associated with better outcomes Activated B-cell (ABC) Work up: Lab tests: CBC, CMP, LDH, Hep B/C and HIV screening Molecular profiling for MYC/BCL2/BCL6 rearrangements FDG-PET for staging and response assessment CNS International Prognostic Index (CNS-IPI) score: Estimate the risk of CNS relapse in patients with DLBCL treated with R-CHOP-based therapy Clinical factors, each get 1 point: Age >60 Elevated LDH ECOG >1 Ann Arbor stage III-IV >1 extranodal site of involvement Kidney/adrenal involvement Risk stratification: Low risk: 0-1 risk factors 5 year overall survival rate 96% Intermediate risk: 2-3 risk factors High risk: 4-6 risk factors OR kidney/adrenal/testis involvement 5 year overall survival rate 40-50% 2 year CNS relapse rate is 10% Testicular involvement is not part of the formal CNS-IPI score, but it is still recognized as an independent high-risk factor for CNS relapse. Consider CNS prophylaxis if: High risk of CNS relapse Specific extranodal involvement (kidney, adrenal, testis) Suggested CNS prophylactic therapy: Intrathecal MTX and/or Cytarabine (Ara-C) for 4-8 doses High-dose systemic MTX 3-3.5 g/m2 for 2-4 cycles Treatment: Limited stage (30%): Stage I and stage II excluding extensive mesenteric disease Non-bulky: R-CHOP x3 cycles → PET restaging → 1-3 additional cycles ± involved-site radiotherapy (ISRT) R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Vincristine (Oncovin), Prednisone Bulky (≥7.5 cm): R-CHOP x3-4 cycles → PET restaging → 2-3 additional cycles ± ISRT Advanced stage (70%): Stage II including extensive mesenteric disease and Stage III/IV R-CHOP x6 cycles Interim PET or CT after 2-4 cycles to guide further management R-miniCHOP R-CHOP in lower dose For frail or elderly patients Pola-R-CHP Polatuzumab vedotin, Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Prednisone Polatuzumab increases risk of PJP, HSV/VZV reactivation. Prophylaxis is required. Relapsed/refractory disease: If transplant-eligible AND relapse occurred >12 months after initial R-CHOP: Platinum-based therapy → auto-HCT R-DHAP: Rituximab, Dexamethasone, High-dose cytarabine (Ara-C), Cisplatin R-GDP: Rituximab, Gemcitabine, Dexamethasone, Cisplatin/Carboplatin RICE: Rituximab, Ifosfamide, Carboplatin, Etoposide If transplant-ineligible OR relapse occurred <12 months after initial R-CHOP: CAR-T cell therapy Axi-cel or Liso-cel Preferred treatment but need bridging therapy Pola-BR Polatuzumab vedotin, Bendamustine, Rituximab R-GemOx Rituximab, Gemcitabine, Oxaliplatin CD20 x CD3 Bispecific antibodies: Epcoritamab Glofitamab Mosunetuzumab Glofitamab + GemOX Mosunetuzumab + Polatuzumab vedotin Tafasitamab (Anti-CD19 mAb) + Lenalidomide Special consideration: DLBCL of paranasal sinus: R-CHOP x3 cycles → ISRT Testicular DLBCL: R-CHOP + RT to contralateral testes ± CNS intrathecal (IT) treatment Surveillance: H&P q3-6 months for 5 years, then annually CT CAP with contrast q6 months for 2 years, then as indicated HGBL with MYC, BCL2/BCL6 rearrangements Background: Aggressive with a significantly poorer prognosis High risk of CNS involvement Confirm MYC and BCL2 ± BCL6 rearrangements by FISH or cytogenetics Treatment: CNS prophylaxis: Preferably with systemic high-dose MTX Regimens: R-EPOCH (R-CHOP + Etoposide) DA-EPOCH-R (Dose Adjusted R-EPOCH) Preferred regimen R-CHOP Inferior outcomes Consider for frail, elderly or low-risk patients Pola-R-CHP Clinical trial Burkitt Lymphoma (BL) Background: Aggressive Lymphoma, originates from mature germinal center B cell Immunophenotype: CD5-, CD10+, CD19+, CD20+, CD22+, CD23- TdT-, BCL2-, BCL6+, CD79a, PAX5, surface Ig+ (with light-chain restriction) Extremely high Ki-67 index (~100%) is a hallmark feature High risk for TLS Associated with MYC rearrangement: t(8;14), t(2;8), t(8;22) Subtypes: Endemic: Typically in patients from equatorial Africa More associated with EBV Involves extranodal sites (breast, ileum, jaw bone, ovaries, kidneys) Sporadic: Often in the ileocecal area Not as commonly associated with EBV Immunodeficiency: Patients with HIV, post-transplant, or congenital immunodeficiency Treatment: Intense chemotherapy regimens: R-HyperCVAD with alternating high dose MTX and Cytarabine DA-EPOCH-R R-CODOX-M/IVAC + IT CNS prophylaxis 2-4 cycles alternating R-CODOX-M and R-IVAC R-CODOX-M: Rituximab, Cyclophosphamide, Vincristine (Oncovin), Doxorubicin, High-dose Methotrexate R-IVAC: Rituximab, Ifosfamide, Etoposide (VP-16), high-dose Ara-C (Cytarabine) No need for maintenance therapy 'Low grade B-Cell NHL' Follicular Lymphoma (FL) Background: Low grade lymphoma, originates from mature germinal center B cell Immunophenotype: CD5-, variable CD10, CD19+, CD20+, CD22+, variable CD23 Characteristic Chromosome Abnormality: t(14;18) translocation → translocates the BCL2 gene on chromosome 18 to the Ig heavy chain (IgH) locus on chromosome 14 → places BCL2 under the regulatory control of the highly active IgH enhancer elements → over-expression of the BCL2 protein in B cells → blocks the normal apoptotic program Positive BCL2 helps to distinguish FL from BL and other germinal center lymphomas Typically presents with multistation LAP, BM involvement, and splenomegaly "Bulky" mass: typically ≥7.5 cm, some studies use 10 cm Staging: Limited stage: Stage I: Single LN region Single group of adjacent nodes Single extranodal lesion without nodal involvement Stage II contiguous: ≥2 adjacent nodal groups on the same side of the diaphragm Advanced stage: Stage II non-contiguous: ≥2 non-adjacent nodal groups on the same side of the diaphragm Stage III: Involvement of LN regions on both sides of the diaphragm May include spleen involvement. Stage IV: Additional non-contiguous extralymphatic involvement. Treatment: Most patients can be observed Monitor for Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria: Used to assess tumor burden in FL and guide the decision to initiate therapy vs observation. Treatment should be initiated when the patient meets ≥1 GELF criteria: Any nodal/extranodal tumor mass ≥7 cm ≥3 nodes involvement, each ≥3 cm B symptoms Splenomegaly Pleural effusion, peritoneal ascites Leukemic phase (>5000 malignant cells) Cytopenias (WBC <1000, platelets <100k) Guidelines recommend starting treatment when there is threatened end-organ function, including compression syndromes, regardless of GELF status. First Line Treatment: R-CHOP or Obinutuzumab (Obi)-CHOP R-CVP or Obi-CVP BR: Bendamustine, Rituximab Bendamustine + Obi R-Squared (R²): Rituximab + Lenalidomide (Revlimid) Rituximab If low tumor burden or frail patient Radiation therapy If localized, small tumor burden, Stage I or contiguous Stage II Consider rituximab maintenance q2-3 months for 2 years If high tumor burden Second Line Treatment: Bendamustine/Rituximab (or Obi): Not recommended if bendamustine already used R-CHOP or Obi + CHOP R-CVP or Obi-CVP R-Squared Third Line Treatment: CD20 x CD3 bispecific Ab: Epcoritimab Mosunetuzumab CAR-T cell therapy: Axi-cel Tisa-cel Liso-cel Tazemetostat (EZH2 inhibitor) Zanubrutinib + Obi Clinical Pearls: If B symptoms, sudden change in size of LN, rise in LDH, etc: Consider transformation, may need imaging and biopsy Treat grade IIIB follicular lymphoma like DLBCL Marginal Zone Lymphoma (MZL) Background: Indolent (median survival often >10 years) but risk of transformation to aggressive lymphoma exists MZL often arises in the context of chronic immune stimulation from infections or autoimmune diseases: Gastric MALT- H. Pylori Infection Splenic MZL- Hepatitis C infection Small Bowel- Campylobacter jejuni Thyroid- Hashimoto’s disease Parotid- Sjogren’s syndrome Ocular adnexa- Chlamydia psittaci Diagnosis: Tissue biopsy Immunophenotyping: CD5–, CD10–, CD19+, CD20+, CD22+, CD23– Molecular studies: MYD88 mutation Ig Heavy Chain Variable region (IGHV) sequencing Cytogenetic studies: Trisomy 3 and trisomy 18 Deletion of 7q: Highly specific for SMZL (30% of cases) t(11;18): Most common in gastric and pulmonary MALT lymphoma Confers resistance to H. pylori eradication. Subtypes: Extranodal (EMZL) or Mucosa-Associated Lymphoid Tissue (MALT): Most common MZL Involves stomach (~60% of cases), lung, ocular adnexa, skin, salivary glands Treatment: For gastric MALT, H. pylori eradication is first-line if infection is present. For localized non-gastric EMZL, ISRT is preferred. Systemic therapy (rituximab ± chemo) if advanced, multifocal, or symptomatic disease. Nodal (NMZL): Most patients present with advanced-stage but non-bulky disease Treatment: Similar to follicular lymphoma: Observation for low burden disease Rituximab-based regimens for symptomatic or high burden disease. Splenic (SMZL): Prominent splenomegaly and BM involvement, but peripheral LAP is uncommon Treatment: Observation is appropriate for asymptomatic patients. Rituximab monotherapy is preferred for symptomatic disease Antiviral therapy is considered if hepatitis C is present. Mantle Cell Lymphoma (MCL) Background: Subtypes: Classical/conventional MCL Leukemic/non-nodal MCL Typically presents with LAP, splenomegaly, BM and GI involvement. t(11;14) translocation → Cyclin D1 over-expression (essential for diagnosis) TP53 status is an important prognostic and predictive marker Disease course ranges from indolent (especially in leukemic/non-nodal MCL) to aggressive. Most patients require therapy soon after diagnosis. Diagnosis: Tissue biopsy Immunophenotyping: CD5+, CD10–, CD19+, CD20+, CD22+, CD23–, cyclin D1+ Confirmation of t(11;14) translocation by FISH or IHC SOX11 and Ki-67 For subtyping and prognostication TP53 mutation testing Predicts poor response to standard therapy Treatment: Indolent/ asymptomatic: Observation Fit, younger patients (typically ≤65 years): Intensive regimens (alternating R-CHOP, R-DHAP, cytarabine-containing regimens) → auto-HCT + Rituximab maintenance (NORDIC regimen) Older or transplant-ineligible patients: Less intensive regimens (BR, R-CHOP, VR-CAP) + Rituximab maintenance VR-CAP: Bortezomib (Velcade), Rituximab, Cyclophosphamide, Doxorubicin (Adriamycin), Prednisone Relapsed/refractory disease: Covalent BTK inhibitors (zanubrutinib, acalabrutinib) R-squared Bortezomib (Velcade) CAR T-cell therapy Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) Discussed in a separate post "Chronic Lymphocytic Leukemia (CLL)/ SLL" Lymphoplasmocytic Lymphoma (LPL)/ Waldenstrom Macroglobulinemia (WM) Background: Rare, indolent B-cell NHL characterized by BM infiltration with monoclonal Ig secreting lymphoplasmacytic cells. Waldenström Macroglobulinemia (WM) is a variant and most common presentation of LPL. Associated with monoclonal IgM paraprotein The diagnosis requires exclusion of other small B-cell lymphomas with plasmacytic differentiation (particularly MZL) Associated with MYD88 mutation Present in ~90% LPL/WM cases Also is a predictor of response to treatment Associated with hyperviscosity syndrome Treatment: Indications for treatment: Symptoms attributable to lymphoma (not limited to B symptoms) Hyperviscosity syndrome Threatened end-organ function Significant or progressive cytopenia (BM involvement >10%) Significant bulky disease Cryoglobulinemia Steady or rapid progression of disease First line regimens: BR Bendamustine + Obinutuzumab R-CHOP or Obi-CHOP R-CVP or Obi-CVP R-squared

Gallbladder Cancer Background: Most common biliary tract malignancy (~80–95% of all biliary tract cancers) yet it remains relatively rare. ~3 times more common in women Incidence increases with age (peak 70–75 years) Symptoms are often indistinguishable from cholelithiasis/cholecystitis. ~50% of cases are discovered incidentally on post-cholecystectomy pathologic review Risk factors: Cholelithiasis, obesity chronic Infections (Salmonella typhi, Helicobacter species), chronic cholecystitis, porcelain gallbladder Cholelithiasis is the most strongly associated risk factor, present in 70–90% of gallbladder cancer cases, though only 1–3% of gallstone patients develop cancer. Survival: 5-year survival by stage: Stage I ~87%, Stage II ~73%, Stage IIIA ~32%, Stage IIIB ~24%, Stage IVB ~10% If unresectable/metastatic disease: Median OS is ~10–13 months with systemic therapy Staging: T1a: lamina propria invasion; T1b: muscular layer invasion T2a (peritoneal side); T2b (hepatic side, higher rates of nodal involvement and hepatic metastases, inferior survival) N1 = 1–3 positive nodes; N2 = ≥4 positive nodes Stage IVB: ≥N2 disease or distant metastases Treatment: T1a + negative surgical margins → simple cholecystectomy is curative → observation Routine bile duct resection increases morbidity without proven survival benefit; reserve for margin positivity. T1a + positive surgical margins or T1b or cystic duct LN positive → Re-staging workup (CAP CT scan or staging laparoscopy) If resectable: Radical cholecystectomy (hepatic resection + portal lymphadenectomy ± bile duct excision) If unresectable or Metastatic cancer: Requires adjuvant therapy: First Line: Capecitabine for 6 months (BILCAP) Capecitabine/Gemcitabine Cisplatin/Gemcitabine + Durvalumab (TOPAZ-1) Second line: FOLFOX/CAPEOX Clinical trial Cholangiocarcinoma Risk factors: Primary sclerosing cholangitis (PSC) IBD (especially ulcerative colitis) Choledochal cysts Chronic Hep C, Cirrhosis Liver fluke infection (Opisthorchis viverrini, Clonorchis sinensis) Classification: Intrahepatic cholangiocarcinoma (iCCA) Often incidental or found on HCC surveillance in cirrhosis, symptoms (pain, weight loss) signal advanced disease. Diagnosis requires core needle biopsy Extrahepatic cholangiocarcinoma (eCCA) Painless jaundice is the most common presentation. Work up: MRI/MRCP outperforms CT for biliary invasion (~85% sensitivity and specificity) ERCP allows brushings for cytology + FISH Check serum IgG4 to exclude IgG4-related sclerosing cholangitis. Types: Perhilar cholangiocarcinoma (pCCA) Distal cholangiocarcinoma (dCCA) Tumor Markers: CEA and CA 19-9 for baseline tests but they should not be used to confirm the diagnosis. CA 19-9 is unreliable in obstruction. for jaundiced patients, obtain the baseline CA 19-9 after biliary decompression. CA 19-9 >1000 U/mL may suggest metastatic disease. Treatment: Non-metastatic disease: Surgery: iCCA: Resection of ≥1 segments + regional lymphadenectomy Fewer than 40% are resectable at diagnosis. Recurrence 50–70%, most within the liver. Surgery contraindications: Decompensated cirrhosis, portal HTN, LN beyond the hepatoduodenal/gastrohepatic ligament pCCA: Major hepatectomy (≥3 segments) + caudate lobectomy, extrahepatic bile duct resection, hepaticojejunostomy, portal lymphadenectomy Requires future liver remnant ≥30% Recurrence risk is ~80% dCCA: Pancreaticoduodenectomy Liver transplant: Indications: Unresectable pCCA ≤3 cm radial diameter No intra/extrahepatic metastases, node-negative PSC-associated disease (transplant is preferred over resection) Adjuvant Therapy: Capecitabine (category 1) for up to 6 months (BILCAP) Gemcitabine Gemcitabine/capecitabine Cisplatin/gemcitabine 5-FU/leucovorin Metastatic/unresectable disease: Systemic therapy: First line: Cisplatin/gemcitabine + durvalumab (TOPAZ-1) Cisplatin/gemcitabine + pembrolizumab (KEYNOTE-966) Second line: FOLFOX (ABC-06) FOLFIRI 5-FU/liposomal irinotecan Regorafenib If MSI-H/dMMR, TMB >10: Pembrolizumab (If not received in first line) If FGFR2 mutation: Futabitinib (FOENIX-CCA2) Pemigatinib (FIGHT 202) If IDH1 mutation: Ivosidenib (ClarIDHy) If BRAF V600E mutation: Dabrafenib/trametinib If RET gene fusion: Selpercatinib Pralsetinib If KRAS G12C mutation: Adagrasib If HER2+: Enhertu (fam-trastuzumab deruxtecan-nxki) Trastuzumab/Pertuzumab Tucatinib/Trastuzumab Zanidatamab

Risk factors: History of cryptorchidism (undescended testis) Family history of testicular cancer Personal history of testicular cancer Initial work up: Testicular ultrasound Tumor markers: AFP, hCG, LDH Radical inguinal orchiectomy (through inguinal incision, not scrotum) Do not biopsy testis. Isochromosome 12p: Hallmark cytogenetic abnormality in testicular germ cell tumors It is a somatic genetic abnormality/ Not considered a hereditary predisposition factor Types: Seminoma: More likely to present with localized disease, indolent growth, less likely to be metastatic beyond RP nodes Non seminoma: Embryonal Carcinoma, Choriocarcinoma, Yolk Sac Tumor (endodermal sinus tumor), Teratoma Tumor Markers: Check tumor markers immediately prior to initiation of treatment for risk stratification. AFP: NOT produced by seminomas (if high, assume non-seminoma) Half life ~5-7 days May be elevated due to liver disease/toxicity. Generally ignore if <20-25 ng/mL B-HCG: Can be made by any germ cell tumor. Half life ~3 days. False positives from: Marijuana consumption Hypogonadism from pituitary HCG production (can test this by administering testosterone. if coming down, then not from cancer). Hyperthyroidism was mentioned in older literature but it is not in the current NCCN guideline. LDH: Very non-specific. used for staging purposes, but not very important in response to treatment or relapse. Risk Stratification: Risk Status Nonseminoma Seminoma Good Risk Testicular or retroperitoneal primary tumor + No nonpulmonary visceral metastases + Post-orchiectomy markers (all): AFP <1000, hCG <5,000, LDH < 1.5 ×ULN Any primary site + No nonpulmonary visceral metastases + Normal AFP, any hCG, any LDH Intermediate Risk Testicular or retroperitoneal primary tumor + No nonpulmonary visceral metastases + Post-orchiectomy markers (any): AFP 1,000–10,000, hCG 5,000–50,000, LDH 1.5–10 ×ULN Any primary site + Nonpulmonary visceral metastases + Normal AFP, any hCG, any LDH Poor Risk Mediastinal primary tumor OR Nonpulmonary visceral metastases OR Post-orchiectomy markers (any): AFP >10,000, hCG >50,000, LDH >10 ×ULN No patients classified as poor prognosis Seminoma Testicular Cancer Brain MRI is recommended if: Post-orchiectomy beta-hCG >5,000 IU/L Neurologic symptoms Extensive lung metastases Non-pulmonary visceral metastases Treatment: Stage I (confined to testes): Radical inguinal orchiectomy followed by: Surveillance (preferred approach) Adjuvant Carboplatin (Area Under Curve 7) x1-2 cycles Adjuvant RT to to the para-aortic ± ipsilateral pelvic LN Monitor tumor markers to to confirm an appropriate post-orchiectomy decline Stage IS (limited to testis but have persistent elevation of tumor markers after orchiectomy) Tumor marker elevation after orchiectomy generally indicates presence of metastatic disease despite radiographic evidence of disease, thus treat like stage III (see below) Treat as good/intermediate risk based of how high tumor markers are CAP CT with contrast Stage II: Stage IIA (LN size ≤2 cm) and nonbulky Stage IIB (LN size 2–3 cm): RT to para-aortic and ipsilateral iliac LNs BEP x3 or EP x4 BEP: Bleomycin + Etoposide + Cisplatin Avoid bleomycin in patients with underlying lung disease, elderly, reduced GFR If bleomycin toxicity develops: complete course with EP or change to VIP Nerve sparing RPLND (category 2B) Carboplatin + RT (category 2B) (SAKK 01/10) Bulky Stage IIB (LN size 3-5 cm): BEP x3 or EP x4 (the only option) Stage IV: Treatment is same for seminomas and nonseminomas Chemo regimen based on risk stratification (Table above): Good risk: BEP x3 cycles, or EP x4 cycles Intermediate/Poor risk: BEP x4 cycles, or VIP x4 cycles (if contraindication to Bleomycin) Residual Masses >3 cm: PET CT and resect if FDG avid If residual mass is present after completion of treatment: perform PET/CT and likely surgery (if FDG avid). The mass may be teratoma vs fibrosis/necrosis. About 10-15% of resected residual masses harbor viable germ cell tumor Late relapse (> 2 years after completion of chemo) Consider surgery if resectable Consider VeIP or TIP x 4 Consider high dose chemotherapy Non-Seminoma Testicular Cancer Brain MRI is recommended if: AFP >10000 Predominant choriocarcinoma component Treatment: Stage I: Radical inguinal orchiectomy followed by: Surveillance (preferred) BEP x 1 RPLND RT is NOT an option for non-seminoma. Consider adjuvant treatment if “high risk” features for recurrence, specifically lymphovascular invasion, predominant embryonal carcinoma >50%, histology, Invasion of spermatic cord or scrotum Monitor tumor markers to ensure downtrended Stage II: RPLND → if malignant nodes, consider adjuvant EP x2 BEP x3 or EP x4 Stage IV: Treatment is same for seminomas and non-seminomas Chemo based on risk stratification (Table above): Good risk: BEP x3 cycles, or EP x4 cycles Intermediate/Poor risk: BEP x4 cycles, or VIP x4 cycles (if contraindication to Bleomycin) Later Line therapies: TIP: Paclitaxel, Ifosfamide, Cisplatin VeIP: Vinblastine, Ifosfamide, Cisplatin High-Dose chemo: Carboplatin/Etoposide x2 cycles Paclitaxel/Ifosfamide/Carboplatin/Etoposide x3 cycles HSCT (autologous stem cell rescue) Residual Masses >3 cm: Resect RPLND: all NSGCT residual masses MUST be resected.

Chondrosarcoma Background: Most common bone cancer in adults (40%) Most frequent sites of origin: Pelvis and proximal femur Characterized by malignant cartilage matrix production without osteoid Bony destruction + calcification Very chemoresistant Subtypes: Conventional (90%) Non-conventional (10%) Clear cell Dedifferentiated Mesenchymal Myxoid Juxtacortical Treatment: Conventional chondrosarcoma: Wide surgical excision with negative margins Consider radiation therapy for: Borderline resectable tumors Unresectable tumors Selected skull base/spinal tumors when surgery is not feasible Chemotherapy is not routinely recommended. Non-conventinal chondrosarcoma: Dedifferentiated chondrosarcoma: If resectable: Surgery Treat like osteosarcoma Mesenchymal chondrosarcoma: Treat like ewing sarcoma because this subtype is chemotherapy-sensitive If metastatic/not resectable: Radiation Surgery Systemic therapy Ivosidenib (If IDH1 mutation) Pazopanib Dasatinib Pembrolizumab (if TMB >10 or MSI-H) If recurrence: Reexcision Surveillance: Long-term due to risk of late recurrence and metastasis Chest imaging for at least 10 years Osteosarcoma Background: Bimodal distribution: 10-20 and 60-80 years old Presents as hard mass and bone pain Prognostic factors: Tumor site (axial location is associated with worse prognosis compared to extremity) Tumor size Age (older age is associated with worse prognosis) Presence and number of metastases at diagnosis Histologic response to neoadjuvant chemotherapy ≥90% tumor necrosis after treatment is a good response and strongly predicts improved survival Negative/positive margin of surgical resection Diagnosis: Lytic/blastic features on X-Ray “Sunbursting” (Buzz word) Require core needle biopsy/excisional biopsy Treatment: Low grade: Surgery if localized High grade: Always chemo x3 cycles → surgery → chemo x3 cycles Regardless of how much necrosis was present on surgical pathology Regimen: MAP: Methotrexate+ Doxorubicin (Adriamycin) + Cisplatin Especially preferred for patients <40 years with excellent ECOG AP: if patient cannot tolerate high dose Methotrexate Metastatic: If oligometastatic Surgery particularly for lung mets: Potentially curative Medications: AP (if not already given) Ifosphamide Gemcitabine Regorafenib Cabozantinib Ewing Sarcoma Background: Presents with “onion skinning” pattern on xray (Buzz word) PET/CT scan for staging Consider BMBx to see if bone marrow involvement Treatment: Chemo regimens: VDC/IE: Vincristine, Doxorubicin, Cyclophosphamide alternating with Ifosfamide and Etoposide VIDE: Vincristine, Ifosfamide, Doxorubicin, Etoposide VAIA: Vincristine, Dactinomycin (Actinomycin D), Ifosfamide, Doxorubicin (Actinomycin) Localized disease: Chemo → restaging → If stable/improved: → RT or Surgery If progressive: → RT ± surgery → Chemo Metastatic Disease: Oligometastatic: Surgery or chemoRT (same as localized disease) Widely metastatic: Chemo First line: VDC/IE (best response) VIDE VAIA Second line: Temodar + Irinotecan Topotecan + cyclophosphamide Cabozantinib High dose ifosfamide Chordoma Background: Arising from notochordal remnants Mostly in age 40–75 Typically located in the sacrum, skull base and spine Slow-growing but locally aggressive Treatment: Surgery (resection with wide margins) and adjuvant high-dose RT Generally chemoresistant Adjuvant high-dose radiation is recommended for positive margins or unresectable disease If recurrent: Surgery ± RT ± systemic therapy (same as medications for chondrosarcoma) Pazopanib Dasatinib Pembrolizumab (if TMB >10 or MSI-H) Giant Cell Tumor of Bone (GCTB) Background: rare (5%), mostly affecting adults aged 20–40 years Locally aggressive with high rate of local recurrence Rarely metastasize to the lungs or undergo malignant transformation to high-grade sarcoma, especially after radiation therapy Typically arising in the meta-epiphyseal regions of long bones (distal femur and proximal tibia) Neoplastic stromal cells and numerous osteoclast-like giant cells, driven by RANKL overexpression, which leads to bone resorption and local destruction. Treatment: If resectable: Surgery Preferably intralesional curettage with local adjuvants (phenol, liquid nitrogen, cement) If unresectable: Denosumab (RANKL inhibitor)

Background: Types: Pancreatic ductal adenocarcinoma (PDAC): 85–95% KRAS mutations are found in ~90% of PDAC Neuroendocrine tumors, Acinar cell carcinomas, Cystic neoplasms: 1-5% Rare Variants: Adenosquamous carcinoma, colloid carcinoma, etc: <1% Work up: EUS/ERCP for biopsy and stent placement Consult GI for ERCP if bilirubin high (prior to giving chemotherapy) CT Chest/Abdomen/Pelvis CA 19-9 (baseline) CA19-9 is a good marker but should not be used to determine need for treatment alone Elevated CA 19-9 prompts further evaluation/imaging Germline genetic testing: ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, EPCAM, PALB2, STK11, TP53 Tumor/somatic molecular profiling (preferably via NGS): Fusions (ALK, NRG1, NTRK, ROS1, FGFR2, RET) Mutations (BRAF, BRCA1/2, KRAS, PALB2) Amplifications (HER2) and HER2 over-expression MSI/dMMR, TMB If high risk features present (listed below), consider staging laparoscopy to rule out occult metastatic disease. Markedly elevated CA19-9 Large primary tumor Large regional LNs Excessive weight loss Extreme pain Indeterminate/equivocal imaging findings Treatment: Pain control: Opioids Consider celiac plexus block Localized/Resectable Pancreatic Cancer: If tumor located at head or uncinate process: Whipple surgery which removes the pancreatic head, duodenum, distal common bile duct, and sometimes the gastric antrum or pylorus) If tumor located in tail: Distal pancreatectomy + en bloc splenectomy If entire pancreas involved: Total pancreatectomy Unresectable pancreatic cancer is defined by: locally advanced disease: Arterial involvement: Solid tumor contact >180° with the SMA or CA, or aortic involvement. Venous involvement: Complete occlusion of the SMV or portal vein without a suitable vessel for reconstruction. Distant metastasis including non-regional LNs Neoadjuvant therapy: If high risk features present Regimens: mFOLFIRINOX +/- subsequent chemoRT Gem/Abraxane +/- subsequent chemoRT If BRCA or PALB2 mutation: mFOLFIRINOX +/- subsequent chemoRT Gemcitabine/Cisplatin +/- subsequent chemoRT Adjuvant therapy: mFOLFIRINOX 5FU Gemcitabine Gemcitabine/Capecitabine Gemcitabine/Cisplatin Borderline Resectable Pancreatic Cancer: Always needs neoadjuvant chemotherapy. Typically given at least 6 months followed by serial CT scans to monitor resectability Reconsider for surgery after neoadjuvant therapy if: Vascular reconstruction is feasible No distant metastasis Patients who have response/stable disease after 4-6 months of chemotherapy may undergo a chemotherapy holiday or maintenance therapy Metastatic Pancreatic Cancer: First line: mFOLFIRINOX Gem/Abraxane NALIRIFOX: NanoLiposomal Irinotecan + 5-FU + Oxaliplatin NAPOLI-3 Trial: NALIRIFOX > Gem/Abraxane. OS 11.1 months vs 9.2 months, respectively. Plus less side effects Gemcitabine monotherapy (if poor PS) if BRCA or PALB2 mutation: (m)FOLFIRINOX Gemcitabine/Cisplatin Maintenance after induction chemo Maintenance Olaparib if germline BRCA/PALB2 mutated (POLO trial) Subsequent Lines: NALIRI (Nanoliposomal Irinotecan) + 5-FU + leucovorin NAPOLI-1 Trial: consider if previously received gemcitabine monotherapy or gem/abraxane in first line setting Rucaparib if germline or somatic BRCA or PALB2 mutated Gemcitabine +/- erlotinib Capecitabine (if poor PS) If NTRK gene fusion positive: Entrectinib, larotrectinib, Repotrectinib If RET gene fusion positive: Selpercatinib If TMB >10, dMMR/MSI-high: Pembrolizumab If BRAF V600E mutated: Dabrafenib, trametinib If progressed more than 6 months after completion of initial therapy: Clinical trial (preferred) Rechallenge with initial systemic therapy If progressed less than 6 months after completion of initial therapy: Clinical trial (preferred) Changing to treatment different from the initial systemic therapy Use gemcitabine based regimen if 5FU used previously and vice-versa If MSI-high or dMMR: Dostarlimab If TMB >10: Ipilimumab/nivolumab If KRAS mutation: Adagrasib or Sotorasib KRAS G12C mutation (~2% of PDAC) Daraxonrasib (RASolute 302): Previously treated RAS-mutated PDAC If HER2 positive: Enhertu If NRG1 gene fusion: Zenocutuzumab

Normal ranges varies slightly by labs. WBC Elevated WBC (>11k) Common causes of significant leukocytosis (>15k): Sepsis/ bacterial infection C.difficile C. diff detected in ~25% of patients with WBC >30k without hematologic malignancy Leukocytosis can even precede diarrheal symptoms If no obvious source, test for C. diff even without diarrhea Malignancy (hematologic malignancy, neoplastic syndrome from solid malignancies) Medication (steroid, G-CSF) Physiologic stress (surgery, trauma, critical illness) Autoimmune diseases typically produce only mild-to-moderate elevations Vasculitis causes neutrophil-driven inflammation (high neutrophil-to-lymphocyte ratio) Low WBC (<4k) Look at the differential: which cell line is low? Neutropenia: Absolute Neutrophil Count (ANC) <1500 Degree of neutropenia: 1000< ANC <1500: Mild neutropenia: 500< ANC <1000: Moderate neutropenia ANC <500: Severe neutropenia Febrile neutropenia (fever + ANC <500) is a medical emergency and requires emergent blood cultures and IV broad-spectrum antibiotics before any workup. Common causes: Medication: Antipsychotic, anticonvulsants, antithyroid agents, chemotherapy, etc The medication list is the single most important thing to review. Autoimmune diseases Infections: Viral infections (EBV, parvo B19, CMV, hepatitis B/C, HIV) Bacterial sepsis through BM reserve exhaustion Hematologic malignancies: MDS, Acute leukemia Benign ethnic neutropenia: Mild neutropenia Common in individuals of African and Middle Eastern Does not increase risk of infection Hypersplenism Aplastic anemia: Pancytopenia with hypocellular bone marrow Lymphopenia: Absolute Lymphocyte Count (ALC) <1000 Common causes: HIV, steroids, lymphoma Neutropenia + Lymphopenia: Common causes: Bone marrow failure, MDS, Severe systemic illness RBC Elevated RBC: Erythrocytosis (elevated RBC/hemoglobin/hematocrit) Is this real or relative? True erythrocytosis: Increased red cell mass Relative erythrocytosis: Normal red cell mass but reduced plasma volume (eg. dehydration, diuretic use) If it is real erythrocytosis: Is it medication induced? Testosterone/anabolic steroids Erythropoietin-stimulating agents (ESAs) SGLT2 inhibitors Typically raise hemoglobin by 0.5–1.0 g/dL Is erythrocytosis primary or secondary? Primary (high RBC → low EPO): Intrinsic bone marrow defect such as Polycythemia Vera independent of EPO Secondary (high/inappropriately normal EPO → high RBC): Hypoxia-driven: OSA, smoking, chronic lung disease EPO secreting tumor Renal causes: Renal artery stenosis, polycystic kidney disease None? Consider: Congenital/hereditary: EPO receptor (EPOR) mutations Low RBC: It is a marker of anemia, but it should always be interpreted alongside hemoglobin, hematocrit, and RBC indices (MCV, MCHC) Etiology: Impaired RBC production: Nutritional deficiencies (Iron, folate, B12) Chronic inflammation (Anemia of chronic disease) Clonal disorders in bone marrow (Myelodysplastic syndrome, Aplastic anemia) RBC loss: Acute bleeding Accelerated RBC destruction: Sickle cell anemia, hemolytic anemia Hb (Hemoglobin) Normal Hb ranges are approximately: 14-18.5 g/dL for males 12-16.5 g/dL for females Elevated Hb See the "Erythrocytosis" section above. First rule out Hemoconcentration (relative erythrocytosis) Low Hb Anemia Evaluation Clinical symptoms: Mild or chronic anemia causes weakness, low concentration and pallor Severe or acute anemia causes tachycardia, hypotension and syncope Check MCV to differentiate different causes of anemia See the "MCV" section below. Check retic count to evaluate bone marrow (BM) response Calculate Reticulocyte Index (RI) = %Retic × (Patient Hct/ Normal Hct​) RI <2% → Inadequate BM response Iron deficiency Vitamin B12 or folate deficiency Anemia of chronic disease Bone marrow disorders RI ≥2% → Appropriate BM response Hemolysis Acute blood loss (after several days) Recovery from nutritional deficiency HCT (Hematocrit) Definition: Percentage of whole blood volume occupied by RBC: HCT = (Volume of RBCs / Total blood volume​) ×100% Normal HCT ranges are approximately: 38- 48% for males 35- 45% for females Elevated Hct See the "Erythrocytosis" section above. Low Hct See the "Low RBC" and "Low Hb" sections above. MCV Definition: The average size (volume) of an individual RBC. Normal MCV range is 80-100 fL. Elevated MCV Macrocytosis (>100 fL) Common causes: Vitamin B12 and folate deficiency, Alcohol use, liver disease, Hypothyroidism Low MCV Microcytosis (<80 fL) Common causes: Iron deficiency, Thalassemia, Lead poisoning Mentzer index: Calculated as MCV divided by RBC count. Differentiate iron deficiency anemia from beta-thalassemia trait in microcytic anemia. Mentzer index >13 suggests iron deficiency anemia Mentzer index < 13 suggests beta-thalassemia trait Should be used as a screening tool rather than a definitive diagnostic test. RDW Measures variation in red blood cell size Elevated RDW: Anistocytosis: Common causes: Nutritional deficiency anemias: Iron deficiency anemia: Newly produced microcytes coexist with older normocytic cells → dimorphic RBC population → high RDW RDW may be the earliest CBC abnormality in iron deficiency, appearing before MCV drops. Elevated RDW is sensitive for iron deficiency, but not specific. B12 and folate deficiency: Macrocytes coexist with normal-sized cells → dimorphic RBC population → high RDW Elevated RDW is less sensitive for B12/folate deficiency than it is for iron deficiency. Sickle cell disease: Anisocytosis from sickling, reticulocytosis, and fragmentation of RBCs. Post-transfusion: Donor RBCs of different size mix with the recipient's cells. Low/Normal RDW: A low/normal RDW indicates a homogeneous RBC population and has limited established clinical significance. Differential: Common causes (beside malignancies): Elevated monocytes: Chronic infections Rheumatologic conditions Elevated eosinophils: Parasitic infections Allergic reactions Connective tissue disorders Elevated neutrophils: Infection Inflammation Stress response Splenic sequestration Asplenia Elevated lymphocytes: Viral infection (EBV, CMV, etc) Pertussis Tuberculosis Splenic sequestration Asplenia Elevated basophils: Viral infections Inflammatory conditions IN PROGRESS...

Screening (American Cancer Society): Average Risk: 40 - 44 years old: have the option to start screening with a mammogram every year. 45 - 54 years old: should get mammograms every year. 55 and older: Can switch to a mammogram every other year, or they can choose to continue yearly mammograms. Screening should continue as long as a woman is in good health and is expected to live at least 10 more years. High Risk: Definition: Women with lifetime risk of breast cancer of 20% or higher BRCA1 or 2 mutation First degree relative with BRCA 1/2 mutation and patient has not had genetic testing themselves RT to chest before 30 years old Have Li-Fraumeni Syndrome, Cowden Syndrome, Bannayan-Riley-Ruvalcaba syndrome 30 and older: Breast MRI and mammogram every year No mammogram for women younger than 30 Indications for screening with Breast MRI: High-risk women (mentioned above) with age 30 and older Women with history of breast cancer who were diagnosed at age 50 or less Women with history of breast cancer and have dense breasts Workup: Diagnostic bilateral mammogram Ultrasound as necessary Suspicious examination but negative mammogram Biopsy of suspicious lesion (core biopsy preferred) ER/PR/HER2 status Ki67 status Grading Systemic imaging for patients with clinical stage I - III breast cancer should be performed largely based on whether patient has concerning signs/symptoms suggestive of having metastatic disease Breast MRI may be helpful if: Breast cancer evaluation before and after preoperative systemic therapy to define extent of disease Identifying primary cancer in women with axillary nodal adenocarcinoma or occult primary cancer, with Paget’s disease, or invasive lobular carcinoma poorly defined on mammography, ultrasound or physical exam Staging evaluation to define extent of cancer or presence of multifocal/multicentric cancer in the ipsilateral breast Screening for contralateral breast at time of initial diagnosis Defining menopause: 12 months or more of amenorrhea Need to establish menopause status in women age < 60 at the beginning of chemotherapy to decide on endocrine regimen High Risk/Non-Malignant Breast Lesions Types: Lobular Carcinoma In Situ (LCIS) Atypical Ductal Hyperplasia (ADH) 15-30% chance of progression to invasive breast cancer If noted on biopsy, should be excised to rule out any invasive component Require breast examination q4-12 months Treatment: Surgery + ET (Tamoxifen if premenopause, Aromatase inhibitor if postmenopause) Ductal Carcinoma In Situ (DCIS) DCIS: non-invasive stage 0 breast cancer Treatment of LCIS and DCIS are similar. No need for PET or CT scan. Axillary LN evaluation and HER2 test are not recommended. Options for treatment: Breast conserving surgery without LN surgery Lumpectomy → radiation therapy (RT) If HR+: Consider endocrine therapy (ET) x5 years Total mastectomy + sentinel LN biopsy (in case there is an invasive component) No need for adjuvant RT or ET No ET is indicated. Lumpectomy → Adjuvant ET x5 years + RT x5 years Endocrine therapy (ET): Premenopause: Tamoxifen 5 mg/day x3 years Postmenopause: Raloxifen, Aromatase inhibitor Surgery goal is 2 mm margin upon resection. Trastuzumab and chemo play no role as adjuvant treatment for DCIS. HR+ HER2- Breast Cancer HR+ is defined as ER and/or PR ≥ 1% Localized HR+ Breast Cancer: Neoadjuvant chemo: Indications: Inoperable breast cancer: Inflammatory breast cancer bulky or matted cN2 axillary nodes (>4 LN+) cN3 nodal disease cT4 tumors Operable breast cancer: large primary tumor relative to breast size in patient who desires breast conservation cN+ disease (likely to become cN0 with neoadjuvant chemo) Options for HR+ neoadjuvant chemo: ddAC-T (Dose-dense Doxorubicin and Dose-dense Cyclophosphamide + Paclitaxel) TC x4-6 (Docetaxel + Cyclophosphamide) Mastectomy (generally without adjuvant RT) RT is recommended in: Tumor > 5cm Inflammatory breast cancer Positive axillary LN+ If positive margins but re-excision is not possible Lumpectomy + RT Contraindications: (they require mastectomy) Inflammatory breast cancer Multifocal or multi centric disease Diffuse microcalcifications on mammogram Positive pathologic margin Pregnancy that cannot be completed or terminated before RT delivery Relative contraindication: previous RT to breast/chest RT can be deferred if: >70 yo AND Stage pT1, cN0 AND ER+/HER2- AND ET is planned > 65 yo AND Stage pN0, pT AND < 3cm AND ER+/HER2- AND ET is planned Sentinel LN Biopsy (SLNB) or Axillary LN dissection (ALND)? ALND may be safely omitted if clinically LN- disease who are found to have 1-2 positive SLNs Adjuvant chemo: Usually TC x4-8 cycles Consider Oncotype in HR+ HER2- localized breast cancer if T1b or higher (tumor size >5 mm) Indications to use Oncotype first: All LN- breast cancer (TAILORx) Postmenopausal with 1-3 LN+ (RxPonder) Oncotype Dx Recurrence Score: ≤15 (low risk): No chemo 16-25 (intermediate risk): If >50 yo: No chemo If ≤50 yo: May consider chemo + ET (TAILORx) ≥ 26 (high risk): chemo + ET Adjuvant ET: Premenopausal: Tamoxifen Side effects: DVT/PE, lower risk of osteoporosis, endometrial cancer (50+), hot flashes. Postmenopausal: Aromatase inhibitor Side effects: hot flashes, joint pains, osteoporosis Consider Breast Cancer Index at 5 years to determine 5 vs 10 years adjuvant ET Adjuvant Ovarian Function Suppression (OFS) x2 years: For higher risk patients (LN+ patients, patients needing chemo) can add OFS (Goserelin, Lupron) x2 years Based on SOFT and TEXT trials Adjuvant CDK 4/6: For higher risk, ER+ HER2- LN+ breast cancer: >4+ LN 1-3 LN with one of following: Ki-67>20% Grade 3 disease tumor size >5 cm (T3) Abemaciclib x2 years (MonarchE) Side effects: Diarrhea, neutropenia Ribociclib x3 years (NATALEE) Palbociclib Adjuvant PARP inhibitor: Olaparib (OlympiA) Metastatic HR+ Breast Cancer: First line: CDK4/6 inhibitor + AI Abemaciclib (MONARCH-3) Ribociclib (MONALEESA) Palbociclib (PALOMA-2: Palbociclib improved PFS but not OS) CDK4/6 inhibitor + fulvestrant Subsequent lines: CDK4/6 inhibitor + fulvestrant (Switch to another CDK 4/6 inhibitor) Everolimus + ET Alpelisib + Fulvestrant (If PIK3CA mutated) Capivasertib + Fulvestrant (if PIK3CA or AKT1 mutations or PTEN alteration) PARP inhibitor (If BRCA 1/2 mutation) Fam-trastuzumab deruxtecan (Enhertu) Sacituzumab govetican Datopotamab deruxtecan Elacestrant (if ESR1 mutated) Larotrectinib, entrectinib, or repotrectinib (if NTRK fusion) Pembrolizumab (if TMB-H [>10 mut/Mb], MSI-H/dMMR) Dostarlimab (if MSI-H/dMMR) Selpercatinib (if RET-fusion) Abemaciclib (only CDK4/6 inhibitor that can be used as monotherapy) Single agent systemic chemotherapy (capecitabine, doxil, taxol) HER2+ Breast Cancer HER2+ is defined as HER2 3+ in IHC or FISH ratio >2 Localized HER2+ Breast Cancer: Neoadjuvant chemotherapy: Indications: >2 cm (T2), LN+ TCHP x6 cycles TCHP: Docetaxel + Carboplatin + Trastuzumab (Herceptin) + Pertuzumab Adjuvant chemotherapy: If pCR after neoadjuvant chemo AND HR-: complete HP x1 year If pCR after neoadjuvant chemo AND HR+: complete HP x1 year + ET x5-10 years If residual disease after neoadjuvant chemo: adjuvant trastuzumab emtansine/TDM-1 x14 cycles or 1 year (KATHERINE) adjuvant trastuzumab emtansine/TDM-1→ Neratinib x1 year If HR+ HER2+ breast cancer with a perceived high risk of recurrence If did not receive neoadjuvant chemo : TH x1 year If N+ prior to treatment: will require adjuvant RT Metastatic HER2+ Breast Cancer: First Line THP (CLEOPATRA) if chemo is stopped at some point, can add ET to HP (if HR+) HP + Eribulin (EMERALD) ET +/- HER2 targeted therapy Generally for patients not candidates for chemotherapy +/- lapatinib (restores/enhances sensitivity to endocrine agents) Subsequent Lines Enhertu Enhertu → T-DM1 Tucatinib + Capecitabine + Trastuzumab Consider in patients with brain mets (HER2CLIMB) Neratinib + Capecitabine Lapatinib + Trastuzumab +/- Capecitabine Margetuximab-ckmb + chemo (Capecitabine, Gemcitabine, Eribulin, Vinorelbine) Triple Negative Breast Cancer (TNBC) Needs NGS for multiple high penetrance cancer susceptibility genes Associated with BRCA 1/2 mutations Also check for CDH1, PALB2, PTEN, STK11, and TP53 Non-metastatic disease: Neoadjuvant chemotherapy: Indications: >2 cm (T1c) or LN+ Treatment: Platinum based chemo + IO Neoadjuvant Pembrolizumab + Carboplatin + Paclitaxel → Pembrolizumab + Cyclophosphamide + Doxorubicin → Adjuvant pembrolizumab to complete 1 year (Keynote-522) Adjuvant chemotherapy: If pCR: continue adjuvant pembro to complete 1 year (Keynote-522) If residual disease after neoadjuvant chemo: Adjuvant capecitabine (CREATE-X) If residual disease after neoadjuvant chemo + BRCA 1/2 mutation: Adjuvant Olaparib (OlympiA) If did not receive neoadjuvant chemo: Adjuvant ddAC-T or TC Metastatic disease: Must check PD-L1 CPS score First line: Single agent chemo: Taxanes (Paclitaxel, Docetaxel, Nab-paclitaxel), Eribulin, Anthracyclines, Capecitabine, Ixabepilone, platinums, Gemcitabine, Vinorelbine If PD-L1 CPS<10 + visceral crisis: Consider ddAC-T If PD-L1 CPS>10: Chemo + Pembrolizumab (Keynote-355) Subsequent lines: Sacituzumab govitecan (ASCENT) Black Box Warning: Diarrhea and Neutropenia Needs 2 prior lines of therapy If BRCA mutation: PARP inhibitor PARP inhibitor + Platinum based chemo Local/Regional Recurrence: Consider initial treatment that patient received Surgical approach: If previous lumpectomy + RT: consider mastectomy If previous mastectomy: consider re-excision If stage III disease (LN+): consider neoadjuvant chemo CALOR Trial: If HR-: Surgery → Adjuvant chemo If HR+: Surgery → Adjuvant ET Cancer in pregnancy Newly diagnosed breast cancer in the 1st trimester: Mastectomy + axillary staging + can begin adjuvant chemotherapy in the 2nd trimester (if chemo is warranted) Radiation and anti-estrogen therapy should begin in the postpartum setting. Chemo is contraindicated in the first trimester, can be safely administered starting in the second trimester. Breast conserving surgery, requiring adjuvant RT is not recommended HER2 directed therapy and anti-estrogen therapy are contraindicated in pregnancy Male Breast Cancer Associated with: Family history of breast cancer Black ethnicity Exposure to RT to breast/chest Genetic predisposition: BRCA1/BRCA2/CHEK2, PALB2 Exogenous estrogen use Diseases associated with hyperestrogenism 90% of male breast cancers are invasive ductal carcinomas Treatment: Mastectomy + Tamoxifen If progression: LHRH analog therapy + Aromatase inhibitor LHRH analog therapy + Cyclin 4/6 inhibitor Inflammatory Breast Cancer Treatment: Neoadjuvant chemo even if resectable upfront Considered T4d lesion Paget Disease of the breast Presents with crusting, itching of nipple with discharge Typically occurs in women >50 yo Important to undergo mammogram and breast US to rule out DCIS or IDC Treatment: Endocrine Chemotherapy Radiation Bone Health Clinical Trial Phyllodes Tumor Excisional biopsy → Wide excision Consider adjuvant RT if borderline or malignant phyllodes tumor completely excised No adjuvant chemo or ET in phyllodes tumor

Anemia of chronic disease: Mediated by IL-6 Promotes hepcidin expression → decreased intestinal absorption and storage of ferritin in macrophages Transferrin downregulated Erythropoiesis becomes iron restricted (since iron not accessible) May eventually lead to iron deficiency due to lack of GI absorption Hemolytic anemia (Separate section below) Iron deficiency anemia (Separate post "Iron Metabolism and Diseases") Iron refractory iron deficiency anemia (IRIDA): Inherited order of systemic iron balance in which both absorption and utilization of iron is impaired Significant microcytosis (MCV 45-65) and anemia (Hb 6-8) Associated with TMPRSS6 gene Atransferrinemia/ Hypotransferrinemia: Autosomal recessive Causes iron overload and microcytic/hypochromic anemia Treatment: FFP infusion, iron chelation Paroxysmal Nocturnal Hemoglobinuria (PNH): Acquired mutation in PIGA gene → loss of GPI anchored cell surface proteins (which help attach other surface proteins, such as CD55/CD59) RBCs lacking CD55/CD59 → complement activation + IgG against P antigen on RBCs → intravascular hemolysis + venous and/or arterial thrombosis (common cause of death) Associated with paroxysmal cold hemoglobinuria (PCH) Typically only develop symptoms or requirement treatment with PNH clones >30% of blood cells AA may have small PNH populations ~1% HSCT is the only cure More commonly treated with complement inhibitors Patients need meningococcal+pneumococcal vaccination before starting complement inhibitors Lifelong therapies, expensive Eculizumab: C5 inhibition, blocks intravascular hemolysis (IV) Weekly loading x 4, followed by q2 week maintenance Ravulizumab: C5 inhibition, blocks intravascular hemolysis (IV) q2 week loading x 2, followed by q8 week maintenance Pegcetacoplan: C3 inhibition, blocks intravascular and extravascular hemolysis (PEGASUS) Increases baseline Hb SQ injection, patient administered, q2 weeks Sideroblastic anemia: Presence of ringed sideroblast in bone marrow Most patients have iron overload Respond to Vitamin B6 Erythropoietic Porphyria: Subtypes: Congenital erythropoietic porphyria (CEP) Erythropoietic protoporphyria (EPP) (Porphyria is discussed in a separate lecture "Iron Metabolism and Diseases") Myelonecrosis/Serous Atrophy: Associated with anorexia/ Cachexia, HIV or autoimmune diseases. Causes hypoplasia, fat atrophy, gelatinous transformation of bone marrow Treat underlying cause, generally reversible Nutritional Deficiency/Excess: Folate deficiency B12 deficiency: Associated with megaloblastic/macrocytic anemia, hypersegmented neutrophils Due to dietary deficiency or poor GI absorption (pernicious anemia) Low retic count Can be associated with metformin Due to metformin’s interaction with Ca dependent membrane action Treat with Vit B12 +/- calcium supplementation Copper/ceruloplasmin deficiency: Necessary to convert iron from ferric to ferrous Common after gastric bypass Associated with neurotoxicities and neutropenia BMbx shows vacuoles in RBC precursors/Ringed sideroblasts/can mimic MDS Labs can look like iron deficiency Excessive zinc: Found in a lot of over the counter supplements Mechanism: Zinc competes with copper for absorption → copper deficiency, microcytic anemia Abnormal oxygen affinity hemoglobin: Diagnosed with p50 (normal is 26mmg Hg) High affinity/low p50 (<24 mmHg) → Hb not dropping off oxygen to tissues → polycythemia Low affinity/high p50 (>30 mmHg) → Hb is dropping off excess oxygen to tissues → anemia (feedback loop) Acute megaloblastosis: Typically young patient using recreational drugs or N2O (nitrous oxide) → inactivates B12 Can causes neurological defects (like B12 deficiency) Treat with b12/folate VEXAS syndrome: Vacuolization in marrow cells E1 ubiquitin activating enzyme (encoded by UBA1 gene) X-linked Autoinflammatory Somatic mutation Sign/Symptoms: Anemia, rash, cartilaginous structures affected, lungs, joints, vasculature Loxoscelism: Severe reaction to a Brown recluse spider bite Causes hemolysis and skin necrosis Hemolytic Anemia Premature destruction of red blood cells: Numerous mechanisms: Immune vs. non-immune mediated Hereditary vs. acquired Intravascular vs. extravascular Intrinsic vs. Extrinsic Membrane shedding and activation of coagulation complexes can increase risk of thrombosis Labs: low haptoglobin (binds free Hb), high LDH, high indirect bili, elevated retic count/polychromasia Urine hemosiderin (usually with intravascular hemolysis) Intrinsic Hemolytic Anemia PNH Hemoglobinopathy (Separate post "Red Cell Disorders"): Sickle cell disease Thalassemia Hemoglobin C (beta chain) Hemoglobin E (beta chain) Hemoglobin Lepore (beta chain) Hemoglobin M Enzymatic defects: G6PD deficiency: More common in mediterranean (more severe) or african descent X-Linked (typically male patient) Enzyme defect in the pentose phosphate pathway → generation of reducing agents in cells Coombs negative/ non-immune mediated Triggers which cause hemolysis: Food: Fava beans Medications: Sulfa drugs, Rasburicase, Dapsone, Nitrofurantoin, Primaquine Infectious: hepatitis, CMV, enterovirus, dengue, coronavirus, bacterial infections Treatment is supportive DO NOT test for G6PD deficiency during acute episode (can be falsely normal) Send the test (direct gene sequencing) after 1-2 weeks Pyruvate kinase deficiency: Autosomal recessive Caused by mutations in the PKLR gene Lack of pyruvate kinase → depletion of ATP → disturbs cation gradient, loss of H2O and potassium → cell dehydration → echinocytes (Buzzzz word) Signs and symptoms: splenomegaly, jaundice, gallstone, leg ulcers Treatment: Red cell transfusions Mitapivat (Pyruvate kinase activator) Splenectomy (historical, in severe cases) Membrane abnormalities: Spherocytosis: Mild anemia, gallstones Diagnosed with Eosin-5-maleimide testing Osmotic fragility test is outdated and not routinely used Direct antiglobulin test (DAT) negative/ non-immune mediated Most mutations are in ankyrin, spectrin, Band 4.2 Managed with splenectomy Elliptocytosis: Autosomal dominant Most mutations in spectrin Pyropoikilocytosis is more severe form (MCVs in 30-50s) Acanthocytosis: Associated with McLeod Syndrome X-linked Lack of Kell expression on RBCs Echinocytes: Associated with uremia, liver disease, and hyperlipidemia Extrinsic Hemolytic Anemia Immunologic Diagnosed with Coombs test/DAT Detects IgG and/or complement (C3) on surface of RBC Warm Agglutinin Disease: Associated with autoimmune diseases, viruses and Evan’s syndrome IgG Ab weakly activate complement, but do not agglutinate spontaneously Typical pattern is IgG++, C3+/- Mostly extravascular hemolysis (in spleen) Treatment (in order of preference): Glucocorticoids ± Rituximab Prednisone 1-2 mg/kg for 2-3 weeks and then slow taper dose Rituximab weekly x 4 doses Glucocorticoids and/or IVIG Splenectomy Azathioprine, cyclosporine A, cyclophosphamide, MMF Cold Agglutinin Disease: Primary clonal B cell disorder (Waldenstrom Macroglobulinemia, lymphoma) vs. secondary to underlying condition (EBV, mycoplasma, autoimmune diseases) Consider imaging or BMBx to find underlying cause Smear shows RBC clumping IgM Ab agglutinate RBCs at lower temperatures (0-30 degrees) and activate complement (fixes C3 onto red cells) Typical pattern is IgG- and C3+ Targets the I or i antigen on RBC surfaces Mostly intravascular hemolysis, liver (not spleen) removes the C3b coated RBCs Treatment: Treat underlying cause (steroids, antibiotics, antivirals) Bendamustine/Rituximab Fludarabine/Rituximab Rituximab alone Sutimlimab (Ab that targets C1s protein) Consider PLEX in acute setting if urgent (ACS, stroke) Splenectomy is not helpful (Liver is the organ of RBC destruction) Cryoglobulin is a cold antibody (cold reacting IgM, IgG, or IgA) but cryoglobulinemia is a vasculitis (may present with purpura) and is not typically associated with hemolysis Usually underlying process: hepatitis C, HIV, autoimmune, lymphoma, vaccination Medication induced hemolysis: Various mechanisms: Alteration of antigen on normal membrane Hapten reactions Medication (Penicillins, cephalosporins, tetracyclines) binds to RBC membrane (now is a part of the antigen) → antibody reacts → RBC destruction Infectious hemolysis: Malaria: Associated with anopheles mosquito (female) Treatment: chloroquine, hydroxychloroquine, quinine, atovaquone, doxycycline Babesia (Babesiosis): Associated with tick bite (incubation 1-4 weeks) Previous history of splenectomy causes more severe cases Associated with “maltese cross” seen on RBC smear Treat with atovaquone/azithromycin with RBC exchange Mechanical hemolysis: Microangiopathic hemolytic anemia (MAHA) Small vessel platelet microthrombi Some medications can cause TTP-HUS Quinine, gemcitabine, oxaliplatin, bactrim, quetiapine Valve hemolysis (typically mechanical aortic valve) Mild hemolysis is normal due to shearing Severe hemolysis may be associated with paravalvular leak Schistocytes seen on smear, urine hemosiderin Chemical hemolysis: Lead poisoning → acquired deficiency of pyrimidine-5-nucleotidase → accumulation of pyrimidine-containing nucleotides in RBCs → chronic hemolysis + basophilic stippling

Background: Rectal cancer is a subtype of colorectal cancer, but clinically behaves differently from colon cancer (its pelvic location creates unique challenges related to local recurrence, resection margins, sphincter preservation, and radiation planning) Accounts for ~40% of all colorectal cancers Most rectal cancers are adenocarcinoma Key risk factors overlap with colorectal cancer: Age, prior adenomas/CRC, family history, Lynch syndrome/FAP, IBD, obesity, smoking, alcohol, diet high in red/processed meat, low physical activity. The rectum extends from the rectosigmoid junction to the anal canal and is approximately 15 cm long. Clinically, rectal tumors are categorized based on the distance of the tumor from anal verge: 0 - 5 cm from anal verge: Low rectal cancer More likely to involve the sphincter complex and levator muscles, making sphincter preservation more challenging. >5 - 10 cm from anal verge: Mid rectal cancer Often amenable to sphincter-preserving surgery depending on response to neoadjuvant therapy and tumor extent. >10 - 15 cm from anal verge: High rectal cancer Behave more like colon tumors and may lie above the peritoneal reflection. Lymphatic drainage of rectum: Proximal rectal tumors: often drain upward through the mesorectal/superior rectal pathway. Distal rectal tumors: likely have both upward and lateral lymphatic drainage, which affects surgical/radiation planning. Very low rectal tumors (extended into the anal canal below the dentate line): may involve the inguinal lymph nodes (require consideration of inguinal nodal evaluation and/or treatment) Work-up: CBC, CMP, CEA Colonoscopy with biopsy Pelvic MRI Gold standard for local staging Also reports circumferential resection margin (CRM), extramural vascular invasion (EMVI), and mesorectal fascia involvement, which strongly influence treatment decisions. Endorectal ultrasound if MRI is contraindicated if lesion is superficial Universal MMR/MSI testing on all newly diagnosed rectal cancers Testing for somatic PI3K pathway alterations (stage II–III) Chest/abdomen CT or MRI PET scan is NOT indicated for non-metastatic disease If metastatic disease: Requires additional biomarker testing including KRAS, NRAS, BRAF V600E, HER2 (ERBB2) overexpression/amplification, MMR/MSI status Staging: T stage: T1: Invades submucosa T2: Invades muscularis propria T3: Invades perirectal tissues T4: Invades visceral peritoneum or adjacent organs N stage: N1: 1–3 positive regional LN N1c: No positive LN but tumor deposits are present in the perirectal tissues N2: ≥4 positive regional LN M stage: M1a: Metastasis to 1 distant site (No peritoneal metastasis) M1b: Metastasis to ≥2 distant sites (No peritoneal metastasis) M1c: Peritoneal metastasis (± other organ metastases) IN PROGRESS...

Hemoglobinopathy Sickle Cell Disease (discussed below) Thalassemia (discussed below) Hemoglobin C Substitution of lysine for glutamic acid in 6th position of the beta globin chain Subtypes: Hb AC (Hb C trait): No symptoms Hb CC (Hb C disease): Causes HbC crystals Symptoms: anemia, mild hemolytic anemia (prone to gallstone), splenomegaly Hb SC: less sickling and vaso-occlusive events compared to Hb SS More retinopathy, priapism and ischemic necrosis of bones Hemoglobin E Substitution of lysine for glutamic acid in 26th position of the beta globin chain Common in India, Southeast Asia, Bangladesh Heterozygous: No anemia but microcytosis Homozygous: microcytic anemia with large target cells Hemoglobin Lepore Hemoglobin M Genetic cause of methemoglobinemia Can cause cyanosis, otherwise asymptomatic Can be due to mutations in alpha, beta or gamma globin genes, but normal methemoglobin reductase level Heme iron is locked in ferric state Methemoglobin level is 15-30% Life expectancy is unaffected Sickle Cell Disease (SCD) Due to 6th amino acid in beta chain changed from glutamate (charged) to valine (hydrophobic) Less soluble in hypoxic conditions → sickling in affected individuals Less common in individuals with Sickle Cell Trait (heterozygous) Electrophoresis for trait: ~40% Hb S, ~60% Hb A2 Associated with medullary RCC Protects against malaria, hence its geographic distribution Other variants: Hgb SC disease Sickle trait with HbC disease Slightly worse phenotype than sickle cell trait alone, less anemic than Hgb S More retinopathy, priapism and ischemic necrosis of bones 50% HgbS, 50% HbC (runs like Hgb A2) Sickle Beta Thalassemia Heterozygous state involving one sickle cell gene (HbS) and one beta thalassemia gene Types: Sickle beta zero thalassemia (S-β⁰) : No beta globin production from the thalassemia allele, so no HbA is produced. The clinical presentation is indistinguishable from sickle cell anemia (HbSS). Sickle beta plus thalassemia (S-β⁺) : Some beta globin is produced, resulting in variable amounts of HbA. Clinical severity is generally milder than S-β⁰ or HbSS. Electrophoresis: ~60% Hb S, 4-30% Hb A2, <20% Hb A Clinical features include: Chronic Pain Pain Crises Infection Encapsulated organisms (due to splenic dysfunction) S. pneumoniae , H. influenzae  type b and N. meningitidis Salmonella osteomyelitis Most probably due to Salmonella Long term sequelae affecting multiple organ systems Long term hemolysis → free Hb binds NO → Pulmonary hypertension, leg ulceration, priapism, stroke No role for sildenafil in patients → more pain crises Vaso-occlusion → pain crises, acute chest syndrome, osteonecrosis, retinal vessel occlusion/neovascularization Thrombosis risk (more PE than DVT) Aplastic crisis Associated with parvovirus infection Binds P antigen Hyperhemolysis Almost immediately after transfusion Avoid further transfusions if possible Splenic sequestration crisis Extensive trapping of RBCs in spleen → rapid anemia, hypovolemic shock The size of spleen regress after patient receives blood transfusion Helps to differentiate it from hypersplenism which size of spleen does not regress after blood transfusion. Splenectomy should be considered due to risk of recurrent sequestration Acute chest syndrome Fever, cough, chest pain, hypoxia, infiltrate on XR chest Caused by acute stressors: infection, hypoxia, PEs, etc.  Treated with O2, antibiotics, transfusion (simple vs. exchange), and incentive spirometry Stroke Treat with exchange transfusion in acute setting Recommended to perform chronic transfusion therapy for prevention (goal Hb S <30%) Renal papillary necrosis Can cause hematuria and flank pain Vaccination: S. pneumonia, N. meningitides, Haemophilus influenzae Seasonal flu Hepatitis B Treatments: Hydroxyurea Decreased vaso-occlusive pain, ACS, transfusion needs, priapism Improved survival and quality of life For all patients regardless of age and history of vaso-occlusive episodes. Can start during infancy Exceptions: pregnancy and time of conception (both males and females) Increases fetal hemoglobin (goal Hb F >20%) and therefore less Hgb S Complications: bone marrow suppression (most common), GI upset L-glutamine (Endari) Oral Amino acid leads to decreased oxidative stress → less acute pain episodes Indication: If patient has ≥ 2 pain episodes per year despite hydroxyurea Crizanlizumab Monoclonal antibody against p-selectin Reduces frequencies of vaso-occlusive crises IV given at 0, 2, and 4 weeks Indication: If patient has ≥ 2 pain episodes per year despite hydroxyurea (or if they cannot receive hydroxyurea) Voxelotor Oral  Binds Hb S and stabilizes the oxygenated form → reducing sickling Increases hemoglobin values, reduces hemolysis Can’t be stopped suddenly Transfusions: Simple:  Any acute need for increased O2 carrying capacity Symptomatic anemia Hb goal around 10 Beta4 tetramers present Forms Heinz bodies, which cause “bite cells” Acute chest syndrome Prior to/during major surgery (if needed) Exchange:  Goal is to reduce Hb S% quickly: Goal Hb S is 30% (STOP trial) Used for stroke treatment/prevention, life/organ threatening vaso-occlusive event (severe acute chest syndrome), acute severe cholestasis/RUQ syndrome NOT for pain crisis Possibly helps prevent iron accumulation Avoid transfusing blood with C, E, and Kell antigens Transfusion is NOT indicated for: Anemia, uncomplicated pain, infections, minor surgery, avascular necrosis, uncomplicated pregnancies Excess transfusion can lead to alloimmunization and iron overload Gene therapy Casgevy: Exagamglogene autotemcel Lyfgenia: Ovotibeglogene autotemcel ACE inhibitor/ARB Reduce proteinuria Pain management Morphine, hydromorphone and fentanyl Avoid meperidine (increases risk of seizure) and ketorolac  Thalassemia Normal Hgb Electrophoresis: Hb A (95-98%), Hb A2 (2-3%), HbF (~1%) Hgb A: alpha2, beta2 Hgb A2: alpha2, delta2 Hgb F: alpha2, gamma2 Also provides protection against malaria, hence its geographic distribution Typically we can find full deletions of alpha genes and point mutations in beta genes Alpha thalassemia Hb F and Hb A2 are usually normal Normally 4 alleles (2 on each chromosome) One alpha deletion  (silent carrier): Phenotypically silent, normal electrophoresis Two alpha deletions  (Alpha thal trait): Microcytic, mild anemia Three alpha deletions ( Hemoglobin H): More anemic, variable severity (some transfusion dependent) Beta4 tetramers present Forms Heinz bodies, which cause “bite cells” Four alpha deletions  (Hydrops fetalis): Causes gamma tetramers (in utero): Hemoglobin Barts Typically causes intrauterine death Can be treated by in utero exchange transfusions followed by HSCT Constant spring mutation:  “Non-deletional” type of alpha thal mutation (caused by a point mutation) leads to more severe phenotype in Hgb H MCV is near normal  Concurrent alpha thalassemia and sickle cell has milder SS phenotype due to unbalanced globin chain synthesis leading to deficiency in Hb per cell (less sickling) Also associated with ATRX (alpha thalassemia/mental retardation syndrome) Regulates expression of HBA1 and HBA2 (alpha genes) Craniofacial features, genital anomalies, severe developmental delays, alpha thalassemia Beta thalassemia Multiple types of mutations:  B0 = absent beta globin synthesis for that allele B+ = decreased, but still present beta globin synthesis Beta thalassemia major (Cooley’s Anemia): B0, B0 Much more severe phenotype Beta thalassemia intermedia: contains at least 1 B+ allele Likely not transfusion dependent B+/B+ might require occasional transfusions Associated with osteoporosis  Infants are typically okay at birth due to Hb F but starts to become evident around age 1 Electrophoresis will show alpha tetramers Symptoms: Microcytic anemia Splenomegaly Bony deformities (bossing) Iron overload (due to transfusions, increased absorption from gut) Extramedullary hematopoiesis due to ineffective erythropoiesis/hemolysis Treatments: Luspatercept (BELIEVE) Decreases blood transfusion requirement Gene therapy:  Betibeglogene autotemcel Exagamglogene autotemcel (CRISPR/Cas9 gene-edited cell therapy) Erythrocytosis/Polycythemia Generally defined as: Males: Hb >16.5 and HCT >49 Females: Hb >16 and HCT >48 Work up: First check EPO level If EPO high/inappropriately normal → secondary polycythemia Due to physiological stressor (smoking, obesity, sleep apnea, living in high elevations) or EPO secreting tumor If patient with history of renal transplant, consider post transplant erythrocytosis (PTE) Treat with ACE/ARB If unable to tolerate higher doses, then consider phlebotomy If EPO low → primary polycythemia Consider polycythemia vera (PV) or another myeloproliferative neoplasm (MPN) PV is associated with headache, dizziness, pruritus (after shower), early satiety Related mutations: JAK2 V617F mutation : If positive, consider BMBx MPL, CALR: Also associated with essential thrombocythemia/myelofibrosis BCR/ABL: Associated with Chronic Myeloid Leukemia VHL gene (Chuvash): mutations in EPO receptor Methemoglobinemia Congenital/Acquired Due to deficiency of cytochrome b5 reductase Type 1: only affects RBCs Type 2: affects all cells Associated with development abnormalities, most infants die in the first year of life Methemoglobin level: If >20%: patient will develop clinical symptoms (respiratory depression, confusion) If >40%: life threatening Prevention: Avoid agents that may induce methemoglobinemia (nitrates, dapsone, benzocaine) Treatment:  Methylene blue 1% with dose 1-2 mg/kg IV in 5 min Allows iron in Hb to become ferrous (2+) Ascorbic acid Blood transfusion or exchange transfusion if symptoms are severe

Myeloid cells: Granulocytes (neutrophils, eosinophils, basophils) Neutrophils maturation in BM: 7-10 days, circulates in blood: 1 day, duration in tissue: 2-3 days Monocytes Macrophages Gaucher’s Disease:  Autosomal recessive lysosomal storage disorder Caused by a deficiency of the enzyme glucocerebrosidase (GBA gene) Cells accumulate in the liver, spleen, and bone marrow Classic “crumpled tissue paper” appearance (Buzz word) Dendritic cells Mast cells Lymphocytes: B cells T cells NK cells Leukocytosis Mechanism: Demargination (acute)- Changes in production or release from storage (long term) Causes: Infection Stress Drug induced (steroids, beta agonists, lithium) Chronic inflammation Post-splenectomy Non-hematologic malignancy Marrow stimulation Primary hematologic disease CML (BCR/ABL) Hereditary neutrophilia Down’s syndrome Leukocyte adhesion deficiency Defective integrin receptor (LAD1) Loss of expression of LFA1, Mac-1, gp150;95 Inability to ingest and kill microbes opsonized by C3bi Elevated WBC, recurrent infections (cutaneous abscesses), delayed umbilical cord separation Treated with HSCT Neutropenia Mechanism: Defect in WBC production, increased margination, peripheral destruction Drug induced agranulocytosis: Methimazole, Propothiouricil, Cephalosporins, Penicillins, Sulfa drugs, Chloramphenicol, Carbamazapine, Valproic Acid Significant morbidity and mortality Remove offending agent Causes: Benign neutropenia (Duffy null associated neutropenia): Constitutional neutropenia Usually a story of non-white individual with mildly decreased WBC without any problematic symptoms Severe congenital neutropenia (SCN): Severe infections, survival improved with GCSF High incidence of AML ELANE mutation Kostmann’s Syndrome: Autosomal recessive HAX1 mutation → disrupts mitochondrial function → defective neutrophil differentiation Cyclic neutropenia: Usually benign, “cyclic” every 15-35 days Myelocyte arrest on BMBx May require GSCF in certain circumstances Mutation in ELA2  Not associated with AML Autoimmune Neutropenia: Primary (more common in children) Moderate to severe neutropenia, caused by anti neutrophil antibodies Spontaneous remission over 2 years: 95% Treated with ppx abx, GCSF with severe/recurrent infection Secondary (more common in adults) Large granular lymphocytic leukemia (LGL) Treated with MTX Autoimmune diseases Neutropenia can be a marker of disease activity Felty Syndrome: Rheumatoid arthritis, neutropenia, splenomegaly Treated with steroids, IVIG Chediak-Higashi Syndrome: Autosomal recessive Lysosomal trafficking regulator protein  Increased bacterial infections, albinism and neuropathy Blood smear: giant cytoplasmic granules in the leukocytes and platelets Consider HSCT Chronic granulomatous disease: Defects in NADPH oxidase → Cells are unable to produce reactive oxygen compounds Prone to develop infections with catalase producing bacteria Staphylococcus aureus, Serratia, E. Coli, Klebsiella, Nocardia, Burkholderia cepacia, Aspergillus Diagnosis: Nitroblue tetrazolium or dihydrorhodamine 123 (DHR) Treatment: Lifelong antifungal and antibacterial prophylaxis with or without immunomodulatory (interferon gamma) therapy Hemophagocytic Lymphohistiocytosis (HLH) Life threatening syndrome characterized by excessive immune activation and hyperinflammation Primary: More common in children, rare in adults Secondary: Due to infection (frequently EBV), malignancy, autoimmune disease Macrophage activation syndrome (MAS) is a subtype of secondary HLH, triggered by rheumatic or autoimmune diseases. Diagnostic criteria: Fever  Splenomegaly  Bicytopenia  Hypertriglyceridemia or hypofibrinogenemia Hemophagocytosis  Ferritin >500 Low/absent NK cell activity  Soluble CD25 elevation Treatment: HLH-94 protocol: Etoposide + Dexamethasone (taper) Treat underlying cause

Types of transplant: Allogeneic HCT: Infusion of hematopoietic cells ( CD34⁺ ) from a HLA-compatible donor after cytotoxic conditioning to eradicate disease and enable engraftment. Used in order to deliver high doses of chemotherapy + “graft vs. tumor” (GVT) effect GVT affect: immune-mediated cytotoxic effect exerted by donor-derived immune cells against the recipient’s neoplastic cells following allo-HCT ~30-50% of allo-HCT develops with acute GVHD (aGVHD) Most commonly used for high-risk or relapsed hematologic malignancies ( high-risk AML, high-risk MDS, ALL) and non-malignant uses include severe aplastic anemia, Hemoglobinopathies (sickle cell disease, β-thalassemia major) , congenital immunodeficiencies, etc. Leads to 5-year disease free survival rates of 30-55% when done during 1st remission Autologous HCT: Hematopoietic cells collected from the patient prior to high-dose chemo are infused back into the patient after administration of the preparative regimen, with the primary goal of "rescuing" hematopoietic function that is damaged by the chemotherapy GVHD is rare Most commonly used for chemosensitive diseases such as multiple myeloma, followed by NHL and HL, and some solid tumors (neuroblastoma and testicular germ cell tumors) Leads to 5-year disease free survival rates of 45-65% when done during 1st remission Auto-HCT is associated with less morbidity and mortality but greater risk of disease relapse compared to allo-HCT Pre-Transplant Evaluation: Confirmation of diagnosis and disease status Cytogenetics/molecular testing, MRD, etc. ABO/Rh typing ABO incompatibility is not a contraindication to transplantation Performance status (ECOG/KPS) Comorbidity index: Hematopoietic Cell Transplantation- Comorbidity Index ( HCT-CI) Organ function (pulmonary, cardiac, renal, hepatic) Infectious disease screening (CMV, HBV, HCV, HIV) Psychosocial evaluation/ support systems Human leukocyte antigens (HLA) typing for allogeneic candidates Donor Selection (for allo-HCT): The preferred donor is an HLA-matched sibling. If unavailable, matched unrelated donors, haploidentical family members, or umbilical cord blood may be considered. Donor age and health are important predictors of outcome. HLA matching: Critical to minimize graft failure and GVHD. Major Histocompatibility Complex (MHC) Locus is a region on the short arm of chromosome 6 that contains genes encoding cell surface glycoproteins including the HLA class I (HLA-A, HLA-B, HLA-C) and HLA class II (HLA-DR, HLA-DQ, HLA-DP). Related donor: HLA genes are inherited as haplotypes (one from each parent). T herefore, there is a 25% chance that full sibling would be HLA matched. HLA-matched sibling donors are preferred over HLA-matched unrelated donors because they share more non-HLA genetic background → fewer minor histocompatibility antigen differences → lower risks of GVHD and improved outcomes Haploidentical means half-matched HLA genotype Parent is 100% and sibling is 50% likely to be a haploidentical donor. Unrelated donor: ~30- 75% of patients find an optimal (8/8) HLA-matched unrelated donor Highest rates: white non-Hispanic/European descent Lowest rates: Black and minority populations ABO Blood Groups: Hematopoietic stem cells do not express ABO, therefore, ABO matching is not required for transplantation. Residual donor RBCs or plasma antibodies can still lead to incompatibilities, resulting in hemolysis (immediate or delayed) or delayed RBC recovery (pure red cell aplasia). Sources of graft/stem cells: Graft source is chosen based on disease, patient comorbidities, and urgency. Peripheral Blood: Requires plerixafor (CXCR4 antagonist) ± GCSF/GMCSF (mobilize CD34+ cells) followed by leukapheresis Preferred source of graft ( ease of collection, reduced cost, better safety, faster engraftment) Similar rate of aGVHD, higher rate of cGVHD Hypocalcemia and cramping may occur due to citrate toxicity Supplemental calcium is typically given during leukapheresis  Bone Marrow: Requires multiple BM aspirations from bilateral posterior iliac crests Generally quick turnaround time to transplant (from donor to recipient) Cryopreservation is possible, but not preferred Umbilical Cord Blood (UCB): Has less mature T cells (HLA matching is less stringent) → less risk of GVHD lower hematopoietic cells ( CD34⁺) → Higher rate of graft rejection/failure Engraftment time is longer Use of two cords (to achieve adequate number of CD34+ cells) reduces risk of failure/rejection and shortens engraftment time Conditioning Regimens: Conditioning intensity is tailored to disease type, patient age, comorbidities, and remission status. Eradicate any remaining disease, create space for engraftment, and immunosuppress the host to prevent graft rejection (for allo-HCT). Patients with severe combined immunodeficiency (SCID) often require no preparative regimen before HCT because they lack a functional immune system Categories: Myeloablative regimens: Cause irreversible marrow aplasia and requires replacement stem cells Preferred for younger, fit patients with aggressive disease. Common regimens: Cyclophosphamide + Total body irradiation (TBI) Cyclophosphamide + Busulfan Fludarabine + Busulfan Non-myeloablative regimens/ low-intensity: Less myelosuppression For older or frail patients, or those with indolent disease. Provide a graft vs. tumor (GVT) effect, with similar anti-cancer outcomes and less toxicity compared to myeloablative regimens Lower non-relapse mortality but higher relapse rates compared to myeloablative regimen Transplant Procedure: After conditioning, donor hematopoietic cells (from peripheral blood/BM/UCB) are infused. Engraftment is monitored by blood counts and chimerism analysis (for allo-HCT). Chimerism analysis is a test used after HCT to determine what proportion of a patient’s blood or BM cells come from the donor vs the recipient. Post-Transplant Care: Intensive supportive care is required until engraftment. Monitoring for GVHD (in allo-HCT), infections and organ toxicities. Long-term follow-up to address late adverse effects, cGVHD and disease relapse. Complications: GVHD: Mediated by B cells (mostly in cGVHD) and T cells reacting against host cells Major cause of non-relapse mortality. Acute GVHD: Usually develops within the first 100 days after HCT (mostly in 2-6 weeks) Commonly affects the skin (maculopapular rash), GI tract (N/V, anorexia, diarrhea, ileus), and liver (jaundice, hyperbilirubinemia) May be diagnosed with biopsy, not absolutely required if clinical findings are classic Treatment: Prednisone 1-2 mg/kg/day ± topical steroids for skin or GI disease Steroid-refractory aGVHD : Ruxolitinib (JAK-2 inhibitor): T he only FDA-approved category 1 agent Antithymocyte globulin ( ATG) is listed as an alternative option Chronic GVHD: Presents more indolently Clinical features that mimic autoimmune/connective tissue diseases: Sclerotic skin changes, lichen planus-like oral lesions, dry eyes, bronchiolitis obliterans, esophageal involvement Treatment: Prednisone ± calcineurin inhibitor ± topical/inhaled steroids May need to re-escalate immunosuppression if had been tapering Steroid-refractory cGVHD : Ruxolitinib  (category 1) Ibrutinib, Belumosidil, Axatilimab (FDA-approved) May need to re-escalate immunosuppression if had been tapering Prophylaxis: Immunosuppression with calcineurin inhibitor (cyclosporine, tacrolimus) + antimetabolite (MTX, M ycophenolate Mofetil ) ± post transplant cyclophosphamide (PTCy), ATG, abatacept Autoimmune: Common autoimmune complications: Autoimmune cytopenias (Hemolytic anemia, ITP, neutropenia) Thyroid disorders Neuromuscular diseases (Myasthenia gravis) Rheumatologic diseases (RA, vasculitis, scleroderma-like syndromes) Skin manifestations (Vitiligo, psoriasis) Treatment: Immunosuppression  Infection: Significant cause of morbidity and mortality due to immunosuppression from transplant or GVHD ppx/treatment Vaccination: Normal Ab titers from previous vaccinations usually downtrends post transplant, will need revaccination. Live vaccines are usually given after 2 years to avoid complications. Bacterial: Before engraftment: Fluoroquinolone is often given if prolonged (> 7–10 days) or high‐risk neutropenia is expected After engraftment: Consider Bactrim (+ PJP ppx) and penicillin if at risk for infection Fungal: Antifungal ppx is standard, typically with fluconazole Typically continued until 75 days post transplant Consider mold coverage ( voriconazole/posaconazole ) for higher risk patients ( GVHD, prolonged neutropenia ) Viral: HSV: Prophylaxis: Acyclovir, valacyclovir, Famciclovir Begin with conditioning and continue during neutropenia or until mucositis resolves (typically at least 30 days post-HCT) Consider extended prophylaxis for those with ongoing immunosuppression or cGVHD. Treatment: Acyclovir, valacyclovir, Famciclovir, Foscarnet (for refractory/resistant infections) VZV: Consider VZV prophylaxis for at least 1 year after allo-HCT If cGVHD or ongoing immunosuppression: Zoster vaccine may be administered after the end of antiviral prophylaxis 12–18 months after allo-HCT 3–12 months after auto-HCT CMV: Mostly involves GI tract or lungs Prophylaxis with Letermovir for up to day 100-200 post-HCT in CMV seropositive allo-HCT recipients Not associated with bone marrow suppression (unlike ganciclovir or valganciclovir) Treatment: Ganciclovir Maribavir: for refractory/resistant infections Foscarnet: Nephrotoxic and requires monitoring of electrolytes Iatrogenic (due to conditioning regimen): Hemorrhagic cystitis ← Cyclophosphamide Parotiditis ← Total body irradiation Oral mucositis Usually requires analgesia Veno-Occlusive Disease/ Sinusoidal Obstruction Syndrome (VOD/SOS): Life-threatening complication of HCT/certain chemo regimens Toxic injury to the liver sinusoidal endothelial cells →  necrosis and detachment →  obstruction of small hepatic venules and sinusoids → post-sinusoidal portal HTN and impaired hepatic blood flow Associated with Antibody Drug Conjugates (ADC) with calicheamicin Inotuzumab ozogamicin Gemtuzumab ozogamicin Prophylaxis: Urosodiol Recommended for all patients undergoing allo-HCT Start before conditioning and continue for several months post-HCT. Treatment: Defibrotide: Only FDA-approved treatment for moderate-severe cases Pulmonary complications: Idiopathic pneumonia syndrome Restrictive lung disease Cryptogenic organizing pneumonia (COP) Treated with steroids Obstructive lung disease Bronchiolitis obliterans Treated with increased immunosuppression Timeline of common complications: Pre-engraftment (less than 30 days following HCT) Neutropenia: Leukocyte co unt starts to recover after 1-3 weeks post-HCT (usually later if UCB is used) Administration of GCSF post-HCT reduces the duration of neutropenia and often shortens hospitalization but does not improve overall survival or infection-related mortality. Platelet count usu ally lags behind by days to weeks. Engraftment syndrome: Occurs during neutrophil recovery after HCT d ue to release of pro-inflammatory cytokines (TNF, IL-1) Common symptoms: Fever, skin rash, pulmonary infiltrates or edema, diarrhea, and hepatic or renal dysfunction Must be differentiated from aGVHD and infectious complications Steroids are mainstay of treatment Mucositis Infections: HSV, gram- bacteria, gram+ bacteria from GI tract, Candida, Aspergillus Post-engraftment (days 30 to 100) aGVHD tends to occur here Drugs used for GVHD ppx (cyclosporine/tacrolimus) can cause TMA Characteristic infections: CMV, PJP, aspergillus Late phase (>100 days)  cGVHD tends to occur here Characteristic infections: VZV, aspergillus, PJP, other encapsulated bacteria Graft Failure: Usually due to host immune system rejecting donor marrow  The greater disparity in HLA antigens, the higher chance of rejection Other potential causes: Prior exposure to stem cell poisons Marrow damage during processing/storage Drug toxicity after HCT Viral infections Prognosis of hematologic malignancies that relapse after HCT is extremely poor Post-HCT maintenance therapies: Multiple myeloma: Lenalidomide Hodgkin Lymphoma: Brentuximab Vedotin

Background: Proliferation of immature myeloid blasts with differentiation arrest The median age at diagnosis is late ~60s May present with pancytopenia, hyperleukocytosis (>100K), leukostasis, DIC, TLS Symptoms of leukostasis: Lung: SOB, DAH, respiratory failure CNS: Confusion, coma, delirium, focal neurologic deficits Eye: Impaired vision, retinal hemorrhage Vascular: Priapism Work up: Peripheral blood: CBC with diff, PBS, coagulation panel (DIC risk in APL) BMBx: A marrow or blood blast count of 20% or more is required, except for AML with t(15;17), t(8;21), inv(16) or t(16;16) Myeloblasts, monoblasts, and megakaryoblasts are included in the blast count Flow cytometry: Confirm myeloid lineage (CD13, CD33, CD34, MPO, etc.) Cytogenetics: Karyotype is essential for risk stratification. Molecular panel: FLT3, NPM1, CEBPA, IDH1/2, TP53 Two clinically important FLT3 mutations: FLT3-ITD (Internal Tandem Duplication) Most common, more aggressive FLT3-TKD (Tyrosine Kinase Domain) Risk classification: The European LeukemiaNet (ELN) 2022 classification categorizes AML based on cytogenetic and molecular abnormalities: Favorable t(8;21); RUNX1 inv(16) or t(16;16); CBFB–MYH11 Mutated NPM1  (without FLT3–ITD high) bZIP in-frame mutated CEBPA Interme diate Mutated NPM1  with FLT3–ITD Wild-type NPM1  with FLT3–ITD t(9;11); MLLT3–KMT2A Cytogenetic abnormalities not classified as favorable or adverse Adverse t(6;9); DEK–NUP214 t(v;11q23.3); KMT2A rearranged t(9;22); BCR–ABL1 inv(3) or t(3;3); GATA2, MECOM (EVI1) t(3q26.2;v); MECOM(EVI1) rearranged −5 or del(5q); −7; −17/abn(17p) Complex karyotype, monosomal karyotype Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2 Mutated TP53 Treatment: Induction therapy: Fit/younger patients: Preferred: Cytarabine for 7 days + Idarubicin/daunorubicin for 3 days (7+3 regimen) Alternative: Cytarabine for 7 days + Mitoxantrone  for 3 days Unfit/older patients: Hypomethylating agents (azacitidine/decitabine) + venetoclax Single agent Reduced-intensity options Cardiac dysfunction/ anthracycline-ineligible: Cytarabine for 7 days + Mitoxantrone  for 3 days If FLT3-mutated: 7+3 regimen + Midostaurin ( FLT3 inhibitor) FLT3 inhibitors: FLT3-ITD and FLT3-TKD inhibitors: Midostaurin Gilteritinib Selective FLT3-ITD inhibitors: Sorafenib Quizartinib If CD33+ and favorable-risk cytogenetics AML: 7+3 regimen + Gemtuzumab ozogamicin Relapsed/refractory AML: Hypomethylating agents (azacitidine/decitabine) + venetoclax FLAG-IDA Fl udarabine, High-dose Cytarabine ( A ra-C), G -CSF (filgrastim)- Ida rubicin CLAG-M Cl adribine, High-dose Cytarabine ( A ra-C), G -CSF (filgrastim)- M itoxantrone Follow up BMBx at 14-21 days to determine if in remission Hypoplasia defined as <20% cellularity with <5% residual blasts Repeat BMBx after recovery LP after remission: Indications: If neurologic symptoms If asymptomatic but high risk for developing CNS disease Monocytic differentiation (FAB M4/M5) Mixed Phenotype Acute Leukemia (MPAL) WBC >40,000 at diagnosis Extramedullary disease (eg. gingival infiltration, leukemia cutis ) High-risk APL FLT3 mutations t(9;11) MLLT3:KMT2A fusion If circulating blasts in the CSF ( confirmed by flow cytometry ) → Intrathecal (IT) chemotherapy Consolidation therapy: Post-remission treatment given after induction achieves complete response (CR). Work up before starting consolidation therapy: Bone marrow biopsy confirming CR MRD assessment (flow cytometry ± molecular markers) MRD positivity pushes toward allogeneic transplant Review cytogenetic/molecular risk (ELN classification) Assess: Performance status Organ function Transplant eligibility HLA typing if transplant is a possibility Regimens: Favorable risk:  HiDAC: Hi gh D ose Cytarabine ( A ra- C ) Only if transplant is not planned Requires cerebellar exam before each dose Allogeneic transplant NOT routinely recommended Consider only for patients who are unable to complete consolidation therapy or who have high-risk features such as MRD-positivity or KIT mutation. Intermediate Risk: HiDAC Cytarabine (Ara-C) + Idarubicin/daunorubicin + Gemtuzumab ozogamicin (if CD33+ and given during induction) If FLT3-mutated: Cytarabine  + FLT3 inhibitor ( Midostaurin or Quizartinib) Allo-HSCT in CR1 only if: MRD-positive High-risk molecular features Adverse Risk: Allo-HSCT if young and achieved a CR (preferred) Chemotherapy alone has high relapse rates Consolidation chemo is usually a bridge to transplant, not definitive therapy Older/unfit patients: Reduced-intensity consolidation Continuation of lower intensity regimen used for induction Hypomethylating agent-based approaches (if used in induction) Some may go directly to maintenance rather than intensive consolidation Maintenance therapy: Low-intensity, prolonged therapy given after induction ± consolidation in patients: In complete response after induction therapy Completed or cannot tolerate intensive consolidation Not candidates for allo-HSCT Purpose: Suppress MRD Prolong relapse-free survival (RFS) (± OS depending on agent) Older adults: Maintenance more commonly used due to inability to tolerate prolonged intensive consolidation MRD-positive but transplant-ineligible: Maintenance may be used as disease suppression (not curative) Treatments: Oral azacitidine is used for maintenance therapy in patients ineligible for allo-HSCT Used regardless of cytogenetic risk FLT3 inhibitors: Only for FLT3-mutated AML and if FLT3 inhibitor was part of induction/consolidation Patients ineligible for intensive induction: With IDH1 mutation: Azacitidine/Decitabine + Venetoclax Azacitidine + Ivosidenib Ivosidenib Low dose Ara-C + Venetoclax Hypomethylating Agent Alone (Azacitidine/Decitabine) Without IDH1 mutation: Azacitidine/Decitabine + Venetoclax (preferred) Low dose Ara-C + Venetoclax +/- cladribine Low dose Ara-C + glasdegib (Hedgehog pathway inhibitor) Gilteritinib (if FLT3 mutated) +/- azacitidine Enasidenib (if IDH2 mutated) +/- azacitidine Gemtuzumab ozogamicin (if CD33 positive) Acute Promyelocytic Leukemia (APL) Background: AML subtype with t(15;17) → PML-RARA fusion Characterized by promyelocyte accumulation and severe coagulopathy Associated with DIC on presentation Peripheral smear may shows Auer Rods High risk APL: Classified as having >10,000 WBCs Associated with increased risk of: Early death Hemorrhage Differentiation syndrome Subtypes: Microgranular Hypergranular Treatment: Start All-Trans-Retinoic Acid ( ATRA) immediately if APL is suspected, before genetic confirmation Arsenic Trioxide (ATO) is relatively contraindicated in ventricular arrhythmia and prolonged QTc Induction Therapy: Low risk APL: ATRA + ATO If arsenic is not available or contraindicated : ATRA + Gemtuzumab ozogamicin ATRA + Idarubicin High risk APL: ATRA + ATO + Gemtuzumab ozogamicin ATRA + ATO + Idarubicin If arsenic is not available or contraindicated: ATRA + Gemtuzumab ozogamicin ATRA + Idarubicin ATRA + Daunorubicin + Cytarabine Requires BM assessment at day 28 to document remission before proceeding with consolidation Consolidation Therapy: Low risk APL: ATRA + ATO If arsenic is not available or contraindicated: ATRA + Gemtuzumab ozogamicin ATRA + Idarubicin High risk APL: ATRA + ATO If arsenic is not available or contraindicated : ATRA + Gemtuzumab ozogamicin ATRA + Idarubicin Daunorubicin + Cytarabine If relapse/refractory: If relapses >6 months after initial CR: ATRA + ATO again If relapses <6 months after initial CR: ATRA + ATO + Gemtuzumab ozogamicin ATRA + ATO + Idarubicin If arsenic is not available or contraindicated : ATRA + Gemtuzumab ozogamicin ATRA + Idarubicin Daunorubicin + Cytarabine If 2nd remission achieved, consodilation: If transplant candidate: PCR negative in CR2 → auto-HSCT If PCR positive in CR2 → allo-HSCT If not transplant candidate → ATO consolidation x6 cycles Consider CNS ppx with IT chemo

Below is a list of common chemotherapy regimens in alphabetical order: ABVD: Doxorubicin ( A driamycin), B leomycin, V inblastine, D acarbazine Hodgkin lymphoma AC: Doxorubicin ( A driamycin), C yclophosphamide Breast cancer AD: Doxorubicin ( A driamycin), D acarbazine Soft tissue sarcoma (esp leiomyosarcoma) AIM: Doxorubicin ( A driamycin), I fosfamide, M esna Soft tissue sarcoma BEP:   B leomycin + E toposide + Cis p latin Testicular cancer Ovarian malignant germ cell tumors BR: B endamustine + R ituximab CLL BrECADD: Br entuximab vedotin, E toposide, C yclophosphamide, Doxorubicin ( A driamycin), D acarbazine, D examethasone Hodgkin lymphoma BV-AVD: B rentuximab V edotin, Doxorubicin ( A driamycin), V inblastine, D acarbazine Hodgkin lymphoma BV-CHP: B rentuximab V edotin, C yclophosphamide, H ydroxydaunorubicin (Doxorubicin) , P rednisone CD30-positive peripheral T-cell lymphomas CAPOX: Cap ecitabine, Ox aliplatin GI cancers CLAG-M: Cl adribine, High-dose Cytarabine ( A ra-C),   G -CSF (filgrastim)- M itoxantrone AML CMF: C yclophosphamide, M ethotrexate, 5- F luorouracil Breast cancer DA-EPOCH-R (dose adjusted R-EPOCH): D ose A djusted E toposide,  P rednisone, Vincristine ( O ncovin), C yclophosphamide, H ydroxydaunorubicin (Doxorubicin), R ituximab DLBCL DCF: D ocetaxel, C isplatin, 5- F luorouracil Esophageal/ GEJ cancer Gastric cancer Head and neck cancer Anal SCC DDGP: D examethasone, Cisplatin ( D DP), G emcitabine, P egaspargase Extranodal NK/T-cell lymphoma (ENKTL) ddMVAC: d ose- d ense M ethotrexate, V inblastine, D oxorubicin, C isplatin Muscle invasive bladder cancer DeVIC: De xamethasone, Etoposide ( V P-16), I fosfamide, C arboplatin Extranodal NK/T-cell lymphoma (ENKTL) DHAP: D examethasone, H igh-dose cytarabine ( A ra-C), Cis p latin Hodgkin lymphoma EC: E pirubicin, C yclophosphamide Breast cancer EP: E toposide, Cis p latin Small cell lung cancer Germinal cell testicular cancer (If BEP is contraindicated) FLAG-IDA: Fl udarabine, High-dose Cytarabine ( A ra-C), G -CSF (filgrastim)- Ida rubicin AML FLOT: F luorouracil (5-FU), L eucovorin (Folinic acid) , O xaliplatin, Doce t axel Esophageal and EGJ cancers Gastric cancers FOLFCIS: Leucovorin ( Fol inic acid), F luorouracil (5-FU) , Cis platin Anal SCC FOLFIRI: Leucovorin ( Fol inic acid), F luorouracil (5-FU) , Iri notecan GI cancers FOLFIRINOX: Leucovorin ( Fol inic acid), F luorouracil (5-FU) , Iri notecan, Ox aliplatin GI cancers FOLFOX: Leucovorin ( Fol inic acid), F luorouracil (5-FU) , Ox aliplatin GI cancers FRC: F ludarabine + R ituximab + C yclophosphamide CLL GDP: G emcitabine, D examethasone, Cis p latin/Carboplatin DLBCL GELAD: G emcitabine, E toposide, Pegaspargase ( a form of L - a sparaginase ), D examethasone Extranodal NK/T-cell lymphoma (ENKTL) GVD: G emcitabine, V inorelbine, Liposomal D oxorubicin Hodgkin lymphoma ICE I fosfamide, C arboplatin, E toposide Hodgkin lymphoma DLBCL MAP: M ethotrexate, Doxorubicin ( A driamycin), Cis p latin Osteosarcoma Urothelial (bladder) carcinoma NALIRIFOX: Na no L iposomal Iri notecan, F l uorouracil (5-FU) , Ox aliplatin Pancreatic adenocarcinoma P-GEMOX: P egaspargase, Gem citabine, Ox aliplatin Extranodal NK/T-cell lymphoma (ENKTL) Pola-BR: Pola tuzumab vedotin, B endamustine, R ituximab DLBCL Pola-R-CHP: Pola tuzumab vedotin, R ituximab, C yclophosphamide, H ydroxydaunorubicin (Doxorubicin), P rednisone DLBCL POMP: Mercapto p urine, Vincristine ( O ncovin), M ethotrexate, P rednisone ALL R-CHOP: R ituximab, C yclophosphamide, H ydroxydaunorubicin (Doxorubicin), Vincristine ( O ncovin), P rednisone DLBCL R-CODOX-M/IVAC: R ituximab, C yclophosphamide, Vincristine ( O ncovin) , Dox orubicin, High-dose M ethotrexate/ I fosfamide, Etoposide ( V P-16), high-dose A ra-C ( C ytarabine) Burkitt lymphoma R-DHAP (Rituximab + DHAP): R ituximab, D examethasone,  H igh-dose cytarabine ( A ra-C), Cis p latin DLBCL Mantle Cell Lymphoma R-EPOCH (R-CHOP + Etoposide): R ituximab, E toposide, P rednisone, Vincristine ( O ncovin), C yclophosphamide, H ydroxydaunorubicin (Doxorubicin) DLBCL R-GDP (Rituximab + GDP): R ituximab, G emcitabine, D examethasone, Cis p latin/Carboplatin DLBCL R-GemOx: R ituximab, Gem citabine, Ox aliplatin DLBCL RICE (Rituximab + ICE): R ituximab, I fosfamide,  C arboplatin,  E toposide DLBCL SMILE: S teroid (Dexa), M ethotrexate, I fosfamide, L -asparaginase, E toposide Extranodal NK/T-cell lymphoma (ENKTL) TAC: Doce t axel, Doxorubicin ( A driamycin), C yclophosphamide Breast cancer TCHP: Doce t axel, C arboplatin, Trastuzumab ( H erceptin), P ertuzumab Breast cancer TIP: Pacli t axel, I fosfamide, Cis p latin Testicular cancer Cervical cancer Transitional cell carcinoma /Urothelial cancer TPF: Doce t axel, Cis p latin, 5- F luorouracil SCC of head and neck cancers VAIA: V incristine, Dactinomycin ( A ctinomycin D), I fosfamide, Doxorubicin ( A ctinomycin) Ewing sarcoma Rhabdomyosarcoma VDC/IE: V incristine, D oxorubicin (Adriamycin), C yclophosphamide alternating with I fosfamide and E toposide Ewing sarcoma VeIP: V inblastine , E toposide,  I fosfamide, Cis p latin Testicular cancer VIDE: V incristine, I fosfamide, D oxorubicin, E toposide Ewing sarcoma VR-CAP: Bortezomib ( V elcade) , R ituximab, C yclophosphamide, Doxorubicin ( A driamycin), P rednisone Mantle Cell lymphoma IN PROGRESS..!

Increased risk of CRC: Personal history of adenoma, Sessile Serrated polyp (SSP)/ lesion (SSL), CRC, IBD, Cystic fibrosis, childhood cancers Positive family history of CRC Screening: Average risk adults: Age 45–75 years with a life expectancy of ≥10 years Screening between ages 76–85 should be individualized based on comorbidity status, life expectancy, and prior screening history. Colonoscopy Every 10 years Flexible sigmoidoscopy Every 5-10 years CT Colonoscopy Every 5 years High-sensitivity guaiac test Annually Quantitative FIT Every 3 years DNA and RNA Every 3 years Increased risk adults: For individuals with ≥1 first-degree relative with CRC at any age, screening should begin with colonoscopy at age 40 OR 10 years before the earliest diagnosis of CRC, whichever is first, with repeat colonoscopy every 5 years. Work-up: All newly diagnosed: CBC, BMP, CEA CAP CT scan Colonoscopy Check MSI/MMR : If Microsatellite Instability-High/deficient Mismatch Repair ( MSI-H/dMMR): Failure of the DNA mismatch repair system → unstable microsatellite DNA ~15% of all CRCs  and ~5% of metastatic CRCs Either due to Lynch syndrome or sporadic mutations Improved prognosis in stage II Do not benefit from 5-FU adjuvant therapy alone Methods: Immunohistochemistry (IHC) for MMR proteins (MLH1, PMS2, MSH2, MSH6) Molecular testing: PCR , NGS Respond exceptionally well to immunotherapy All metastatic diseases: Check KRAS (45%), NRAS (5%), and BRAF V600E (8%), HER-2 amplification (4%) Consider PET scan if surgically curable M1 in selected areas PET scan is not indicated for stage II/III Consider Lynch Syndrome Autosomal dominant hereditary cancer syndrome Caused by mutations in MMR genes (MLH1, PMS2, MSH2, MSH6) Most common genetic cause of colorectal cancer ~3% of all CRC cases and ~10% of cases diagnosed before age 50 Germline testing recommended in patients diagnosed <50 Treatment: Non-Metastatic Colorectal Cancer: Stage I/II (Any T, N0): Surgical resection → Observation Consider adjuvant chemo for Stage IIC (T4b, N0) If >70 years: Only give 5FU, no benefit with addition of oxaliplatin (MOSAIC) Stage III (N+): Surgical resection → Adjuvant therapy Adjuvant therapy: Low risk stage III (T1-3, N1): Preferred: FOLFOX + Atezolizumab CAPEOX + Atezolizumab CAPEOX ( 3 months) FOLFOX ( 3-6 months) Category 2B: Capecitabine (6 months) 5-FU (6 months) High Risk Stage III (T4 or N2): Preferred: FOLFOX + Atezolizumab CAPEOX + Atezolizumab CAPEOX ( 3-6 months) FOLFOX ( 6 months) Category 2B: Capecitabine (6 months) 5-FU (6 months) If stage II/III and positive PIK3CA mutation: Add Aspirin 100-162 mg daily for 3 years to the treatment Metastatic Colorectal Cancer: Oligometastatic to liver (if resectable): Preferred: Primary colon surgery + Resection of liver mets Other options: Neoadjuvant chemo for 2-3 months → Surgery Colectomy → Chemo → Resection of liver mets Right sided cancers have worse outcomes (~1.5 years). Left sided cancers are more likely to benefit from EGFR inhibitors. Check NGS for RAS, BRAF V600E, RET, HER2, MSI, PD-L1 First line Treatment: FOLFOX or FOLFIRI Consider oxaliplatin for 3-6 months → 5-FU maintenance Consider FOLFIRINOX if rapid tumor shrinkage required Needs good performance status If KRAS/NRAS mutated: Add bevacizumab (or another VEGF-targeted agent) to chemo. If RAS/BRAF wild type + left sided: Add EGFR inhibitors such as Cetuximab or Panitumumab (CALGB 80405, PRIME) If MSI-H: Pembolizumab (Keynote-177) Nivolumab Ipi/Nivo (Checkmate-142) Subsequent Lines: If BRAF V600E mutated: Encorafenib + Cetuximab (BEACON) Can monitor BRAF mutations with ctDNA assays If KRAS G12C mutated: Adagrasib + Cetuximab (KRYSTAL) Sotorasib + Panitumumab (CodeBreaK 300) If NTRK-fusion positive: Larotrectinib Entrectinib If HER2 amplified: Enhertu Trastuzumab + Tucatinib TAS-102 (Lonsurf) + Bevacizumab (SUNLIGHT) TAS-102 is an oral combination of Trifluridine (a thymidine-based nucleoside analog) + Tipiracil (a thymidine phosphorylase inhibitor) VEGFR inhibitor Fruquintinib FRESCO-2 Trial → mOS was 7.4 months (fruquintinib) vs 4.8 months (placebo) Regorafenib CORRECT Trial → mOS 6.4 months (regorafenib) vs 5.0 months (placebo) Surveillance: H&P and CEA: q 3–6 M for 2 y, then q 6 M for a total of 5 y CAP CT scan: q 6–12 M for up to 5 y Colonoscopy: 1 year after surgery If normal: Repeat in 3 years, then q 5 y If advanced adenoma: Repeat in 1 year Recurrence: If serial CEA elevation → Colonoscopy + CAP CT scan If negative: PET scan Reevaluate with CAP CT scan in 3 months If positive: Treatment depends on whether the disease is surgically resectable.

Work up: CT CAP with IV and oral contrast EGD with biopsy Endoscopic Ultrasound (EUS) If no M1 unresectable disease Bronchoscopy for tumors at/above the carina to rule out fistula PET/CT scan Consider staging laparoscopy: To assess peritoneal metastases (mostly in signet ring histology) At least 15 LNs need to be removed during surgery Biomarker testing: MSI/MMR in all newly diagnosed patients PD-L1 in all newly diagnosed patients HER-2 if advanced/metastatic adenocarcinoma is documented/suspected CLDN18.2 if advanced/metastatic adenocarcinoma is documented/suspected NGS should be considered Staging: T1a: Tumor invades the lamina propria or muscularis mucosae T1b: Tumor invades the submucosa T2: Tumor invades the muscularis propria T3: Tumor invades the adventitia T4: Tumor invades the adjacent structures Pathology: SCC: Usually in the upper part of esophagus Predominates in Eastern Europe and Asia Associated with tobacco use, EtOH use, achalasia, lye ingestion, plummer-vinson syndrome Adenocarcinoma: Usually in the lower part of the esophagus/GE Junction Common in North America and Western Europe Associated with obesity, GERD and Barrett's esophagus Treatment: High-grade dysplasia/ Barrett's esophagus: Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) → radiofrequency ablation (RFA) Complete eradication of intestinal metaplasia in ~73% of patients + Anti reflux therapy → repeat EGD in 6-12 months Esophagectomy is reserved for patients with characteristics unfavorable for endoscopic therapy Localized/ Locally Advanced Resectable: Carcinoma in situ (Tis) , T1a: ESD or esophagectomy T1b: Esophagectomy T2N0 (if low risk, <3 cm, well diff, not located in cervical esophagus): Esophagectomy T2N0 (if high risk, LVI, >3 cm, poorly diff, located in cervical esophagus) or anyTN+: Neoadjuvant chemoRT (Carbo/taxol) → Surgery ( CROSS trial) If residual pathologic disease after neoadjuvant chemoRT → adjuvant Nivolumab x1 year (Checkmate-577) Preferred approach for SCC (SCC is more radiosensitive) Perioperative FLOT ± durvalumab → Surgery ( ESOPEC, Matternh orn trial ) Perioperative FLOT: 4 cycles pre-op + 4 cycles post-op FLOT: F luorouracil (5-FU), L eucovorin, O xaliplatin, Doce t axel Preferred approach for adenocarcinoma (s uperior overall survival) If not candidate for FLOT: Replace with perioperative FOLFOX or CAPEOX FOLFOX: Leucovorin ( Fol inic acid), F luorouracil (5-FU ) , Ox aliplatin CAPEOX: Cape citabine, Ox aliplatin Definitive chemoRT: Those who decline surgery Preferred for cervical esophagus Consider IO if MSI-H/dMMR Metastatic Disease/Locally Advanced Unresectable: If SCC: Immunotherapy is independent of PD-L1 status. First line: ChemoIO: Preferred FOLFOX (or CAPEOX) + PD-L1 inhibitor (Nivo, Pembro, Tislelizumab) If IO is contraindicated: FOLFOX (or CAPEOX) Carboplatin (or Cisplatin) ± Taxol If MSI-high/dMMR ( independent of PD-L1 status ): Pembrolizumab Dostarlimab Nivolumab + Ipilimumab If NTRK gene fusion positive: Entrectinib Larotrectinib Repotrectinib: Subsequent line: Nivolumab Docetaxel/ Paclitaxel Irinotecan +/- 5FU Tislelizumab-jsgr Dabrafenib/Trametinib (if BRAF V600E mutated) Selpercatinib (if RET positive) If adenocarcinoma: Immunotherapy depends on PD-L1 status, unlike SCC. HER-2 positive: If PD-L1 CPS ≥1: FOLFOX (or CAPEOX) + Trastuzumab + Pembro If PD-L1 CPS 0 or IO is contraindicated: FOLFOX (or CAPEOX) + Trastuzumab HER-2 negative: If PD-L1 CPS ≥ 1: FOLFOX (or CAPEOX) + PD-L1 inhibitor (Nivo, Pembro, Tislelizumab) If PD-L1 CPS 0 or IO is contraindicated : FOLFOX (or CAPEOX) If CLDN 18.2 positive: FOLFOX (or CAPEOX) + Zolbetuximab If MSI-high/dMMR ( independent of PD-L1 status ): Pembrolizumab Dostarlimab Nivolumab + Ipilimumab If NTRK gene fusion positive: Entrectinib Larotrectinib Repotrectinib: Subsequent line: Ramucirumab + Paclitaxel Enhertu (if HER-2 positive) Docetaxel/ Paclitaxel Irinotecan ± 5-FU Dabrafenib/ Trametinib (if BRAF V600E mutated) Selpercatinib (if RET positive) Lonsurf (trifluridine/Tipiracil): 3rd line

Risk Factors: Cirrhosis of any cause (viral, alcoholic, metabolic, autoimmune, genetic etiologies) Cirrhosis present in over 80% of HCC cases Chronic HBV and HCV infection (with or without cirrhosis, especially with high viral load or active replication) Screening: At-risk populations requiring screening: Child-Pugh Class A or B cirrhosis of any etiology Child-Pugh Class C cirrhosis patients who are transplant candidates Hepatitis B carriers without cirrhosis Screening using ultrasound and AFP every 6 months. If a nodule ≥1 cm or rising AFP is detected → CT or MRI are indicated Diagnosis: AFP alone lacks sufficient specificity and sensitivity for HCC diagnosis Calculate Child-Pugh for all cirrhotic patients Imaging: CT multiphase shows “Hyperenhancement on arterial phase, delayed washout” Diagnostic imaging criteria apply only to high-risk patients (Cirrhosis, Chronic hep B, current/prior HCC) Liver biopsy: Indications: Non-cirrhotic patients (imaging alone is insufficient) Cirrhotic patients with inconclusive imaging/ if lesion does not meet criteria for definite HCC (LI-RADS 5) Biopsy is generally not indicated for a patient with cirrhosis who has a liver mass if the lesion meets established imaging criteria for HCC on CT or MRI. Paraneoplastic hypoglycemia, hyperlipidemia, hypercalcemia, erythrocytosis is possible BCLC (Barcelona Clinic Liver Cancer) staging system: Integrating criteria: Tumor burden Patient performance status (PS) Liver function (bilirubin and portal pressure) Stages: 0 (very early): 1 nodule ≤2 cm, PS 0, preserved liver function A (early): 1-3 nodules each ≤3 cm, PS 0, preserved liver function B (intermediate): Multinodular, PS 0, preserved liver function C (advanced): Portal vein invasion/ extrahepatic spread, PS 1-2, preserved liver function D (terminal): Any tumor burden, PS 3-4, end-stage liver function Treatment: BCLC stage A or B: Res ection: If solitary lesion with preserved liver function + appropriate Future liver remnant (FLR) FLR: To determine surgical candidacy and preventing post-hepatectomy liver failure Required FLR volume is based on underlying liver parenchymal status: Non-cirrhotic liver: ≥20% of liver volume Cirrhotic liver (Class A) and Chemotherapy-exposed liver: ≥30% of liver volume No adjuvant treatment Post-op observation is preferred (though high recurrence risk) Treat Hep B or C if present Transplant: MILAN Criteria: Patient is eligible for liver transplant if they have either: one HCC lesion ≤5 cm 1-3 HCC lesions each ≤3 cm No evidence of vascular invasion/ extrahepatic disease Contraindicated in portal vein thrombosis Radiofrequency Ablation (RFA): For small (≤3 cm) and accessible lesions in patients with adequate liver function who are not surgical or transplant candidates Transarterial radioembolization (TARE), Transarterial chemoembolization (TACE): For large lesion (>4cm) with no extrahepatic disease/ vascular invasion Relative contraindications: Child-Pugh Class C Portal vein thrombosis Bilirubin >3 TARE is beneficial in patients with solitary HCC <8 cm (LEGACY) BCLC stage C: First line: Atezolizumab + Bevacizumab (IMBrave-150) Needs EGD to rule out esophageal varices prior to starting Durvalumab + Tremelimumab-actl ( HIMALAYA) Does not need EGD prior to starting Durvalumab Lenvatinib Sorafenib Tislelizumab Nivolumab + Ipilimumab Subsequent line (if disease progression): Cabozantinib (CELESTIAL) Regorafenib (RESOURCE) Ramucirumab (REACH-2): Consider in patients with AFP>400 If NTRK gene fusion positive: En trectinib Larotrectinib Repotrectinib BCLC stage D: Hospice/ supportive care Systemic therapy is generally indicated for patients with Child-Pugh Class A or ≤B7 N ot recommended for Child-Pugh Class >B7 or C

Background: Types: Pleural mesothelioma (~85%) Peritoneal mesothelioma (~15%) Histology: Epithelioid Mesothelioma: Epithelioid-to-round cells Better prognosis Non-Epithelioid Mesothelioma: Sarcomatoid: Spindle cells with tapered nuclei Biphasic: Contains both epithelioid and sarcomatioid components in various proportions (each at least 10% of the tumor) Diagnosis: Immunohistochemical panels are essential for diagnosis, requires both criteria: 2 positive mesothelial markers: WT1, calretinin, D2-40 2 negative markers: TTF-1, CEA, claudin-4 (these are typically positive in adenocarcinoma) Broad molecular profiling to identify rare driver alterations (e.g. ALK or NTRK fusions), for which targeted therapies may be available. Pleural Mesothelioma Background:  Predominantly affects males (median age 72) with prior asbestos exposure Highly aggressive cancer, typically unresectable at diagnosis.  2-year survival rate is 30-40% and 5-year survival rate is ~10% Treatment: Surgery: Consider only for stage I-IIIA disease with epithelioid histology Systemic therapy: First line: Cisplatin + Pemetrexed ± Bevacizumab Cisplatin + Pemetrexed + Pembrolizumab (IND227 trial) 21% reduction in risk of death compared to chemotherapy alone Ipilimumab + Nivolumab (Checkmate-743) Survival benefit is most pronounced in non-epithelioid histology Second line:  If immunotherapy used in first line: use chemo If chemo used in first line: use ipi/nivo Peritoneal Mesothelioma Background: Affects males and females equally and occurs in younger patients (age ~60s) Better overall prognosis compared to pleural mesothelioma. 5-year survival is around 20% Treatment: Surgery: Complete cytoreductive surgery (CRS) + Hyperthermic intraperitoneal chemotherapy (HIPEC) The goal is macroscopic complete resection of tumor Often require total parietal peritonectomy with visceral resections as needed. Systemic therapy: Regimens are the same as pleural mesothelioma

Types: Urothelial carcinoma/ Transitional cell (90%) Risk Factors: Occupational exposures (dye manufacturers, rubber aluminum factories), smoking SCC of the bladder (5%) Associated with chronic inflammation (schistosoma, chronic UTI, chronic foley use) Treatment: Surgery Adenocarcinoma of bladder (2%) Treatment: Cystectomy Small cell bladder cancer (1%) Treatment: Cisplatin + Etoposide (like regimen for SCLC) →  RT or cystectomy Plasmacytoid: Associated with CDH1 gene mutation Diagnosis: Cystoscopy with biopsy . Once confirmed, needs TURBT (Transurethral resection of bladder tumor)  Ensure muscle is present in the biopsy specimen. If no muscle: Repeat TURBT PET/CT to ensure no distant metastases Staging: T2 (invades muscularis propria) determines need for neoadjuvant therapies Treatment: Non-Muscle Invasive Bladder Cancer (cTa, cT1, Tis) : Tx: TURBT → single dose intravesical mitomycin C or epirubicin Risk stratification for Non-Muscle Invasive Bladder Cancer: Low risk - Papillary urothelial neoplasm of low malignant potential - Low-grade urothelial carcinoma + (Ta + ≤3 cm + Solitary) Intermediate risk - Low-grade urothelial carcinoma + (T1 or  >3 cm or  Multifocal or Recurrence within 1 year) - High grade urothelial carcinoma + (Ta + ≤3 cm + Solitary) High risk - High-grade urothelial carcinoma + (T1 or  >3 cm or  Multifocal or CIS) - Very high-risk features (any of the following): BCG unresponsive Variant histologies Lymphovascular invasion Prostatic urethral invasion Treatment based on risk stratification: Low risk: Followed by surveillance Intermediate Risk: Intravesicular Therapy vs. Surveillance High risk: Very High Risk: Cystectomy preferred over BCG No very high risk features: weekly intravesical BCG x6 doses If CR (negative cytology, no residual cancer): maintenance BCG up to 3 years If no CR (BCG unresponsive/intolerant): Cystectomy (preferred) Pembrolizumab (Keynote-057): if unwilling to undergo surgery Intravesicular chemo: Valrubicin, docetaxel, mitomycin, gemcitabine Nadafaragene firadenovec-vncg Nogapendekin alfa inbakicept-pmln If recurrence of non-invasive bladder tumor: Treatment based on new tumor’s AUA risk group Muscle Invasive Bladder Cancer: Stage II (cT2, N0) - Stage IIIA (up to T1-T4a and N1) If cystectomy candidate: Need to ask if the patient is “cisplatin eligible?” Galsky criteria for cisplatin ineligible: CrCl <50-60 NYHA 3-4 ECOG 3-4 Grade 2+ neuropathies Grade 2+ ototoxicity If “cisplatin eligible”: neoadjuvant chemo → cystectomy +/- adjuvant nivolumab Neoadjuvant ddMVAC ( d ose- d ense M ethotrexate, V inblastine, D oxorubicin, C isplatin ) prefered over Cis/Gem, but more toxic (VESPER) Neoadjuvant Cis/Gem + Durva (NIAGARA) Consider adjuvant Nivolumab/Pembro x1 year If upstaged to T3/4, N+ or residual disease If “cisplatin ineligible”: upfront cystectomy If not cystectomy candidate: TMT (Trimodal therapy): Maximal TURBT followed by chemo-RT Can consider chemo-RT if: <T4 “Not next to tubes” (ureters or urethra)- not at UJV or bladder base Not multiple tumors Chemo-RT options: High-Dose Cisplatin 5-FU + Mitomycin Gemcitabine If not candidate for cystectomy or definitive chemoRT RT or TURBT Stage IIIB (T1-T4, N2, N3 and M0) Downstaging systemic therapy: If CR/PR: followed by cystectomy or chemo-RT If no response/progression: treat as metastatic disease Concurrent chemo-RT: If PR: consider BCG, surgical consolidation, treat as metastatic disease If progression: treat as metastatic disease Metastatic Bladder Cancer: Preferred : Pembro + Enfortumab Vedotin (EV) EV side effects: Dermatologic side effects, peripheral neuropathies, hyperglycemia, ocular side effects, pneumonitis/ILD, myelosuppression. EV needs eye exam prior to starting and monitoring for DKA. Other options: Gem + Cis ddMVAC Gem + Cis + Nivo followed by nivolumab maintenance If not cisplatin eligible: Gem Gem + Carbo Gem + Carbo → avelumab Gem + Paclitaxel Pembrolizumab Atezolizumab If SD or CR after chemotherapy: adjuvant avelumab ( JAVELIN Bladder 100) Later Line options: Pembrolizumab: preferred post-platinum Enfortumab vedotin: after IO, if not received previously Chemotherapy: Gem/Cis, Gem/Carbo, ddMVAC Erdafitinib: if FGFR mutation present Side effects: hyperphosphatemia, hyponatremia, and retinal pigment epithelial detachment (needs baseline ophtho evaluation → monthly for first 4 months → q3 months thereafter.  Sacituzumab govitecan (TROPHY-U-01) Disatamab Vedotin (anti-HER2 with MMAE taxane payload) Fam-trastuzumab deruxtecan-nxki (HER2 positive, IHC 3+) Urachal Cancer If localized: Partial or complete cystectomy with en bloc resection of urachal ligament with umbilicus and LN dissection

Hodgkin lymphoma (HL): B-cell lymphoma Non-Hodgkin lymphomas (NHL): B-cell lymphomas (85–90%): DLBCL: The most common, aggressive Follicular lymphoma (FL): Indolent, arising from germinal center B cells Marginal zone lymphoma (MZL): Extranodal, Nodal, Splenic Mantel cell lymphoma (MCL): More aggressive, Derived from mantle zone B cells Burkit lymphoma (BL): Highly aggressive, germinal center origin Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) Lymphoplasmacytic lymphoma (LPL) Hairy cell leukemia High-grade B-cell lymphomas (LGBL) T-cell lymphomas (10-15%): Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS): Most common Angioimmunoblastic T-cell lymphoma (AITL): Often presents with systemic symptoms and immune dysregulation Anaplastic large cell lymphoma (ALCL): Can be ALK-positive or ALK-negative Enteropathy-associated T-cell lymphoma (EATL): Associated with celiac disease Hepatosplenic T-cell lymphoma Adult T-cell leukemia/lymphoma T-cell large granular lymphocytic leukemia (T-LGLL): Less common, often with extranodal involvement Immunophenotype characteristics: Black cells: Positive For example: CLL has CD5 + White cells: Negative For example: FL has CD5 – Gray cells: Weak/dim For example: CLL has weak CD20 Black cells with white circles: Positive, occasionally negative For example: FL often has positive   CD10, but can be negative as well. IN PROGRESS...

Background: 25% of all leukemias Morphologically mature but immunologically incompetent B lymphocytes Incidence increase with age Male/Female: 2 Predominantly found in caucasians, less common in African-Americans, Hispanics and Asians Positive family history: 2-8 fold increased risk Work-up: CBC: Clonal B-lymphocytes >5000 Anemia and thrombocytopenia are common PBS:  Small lymphocytes with round nuclei, clumped chromatin, scant cytoplasm Medium/large sized cells: less than 10% of the lymphocytes Smudge cells (bare nuclei that appear squashed) Flow Cytometry: Positive CD19, CD5, CD23 Weak expression of CD20, CD22, surface Ig Negative FMC7, CD10, CD103 DAT: Conversion of the DAT from negative to positive may herald the onset of AIHA LDH: Typically normal in indolent CLL High or rapidly rising LDH may be a sign of disease transformation Beta-2 microglobulin: Associated with inferior treatment response and survival CT scan:  Captures the extend of LN involvement Preferred imaging to evaluate response to treatment LN biopsy: Can distinguish between CLL and other lymphomas Help to exclude transformation in patients with rapidly enlarging LNs Differential diagnosis: Small Lymphocytic Lymphoma (SLL) Monoclonal B-cell lymphocytosis (MBL) Follicular lymphoma (FL) Mantle cell lymphoma (MCL) Marginal zone lymphoma (MZL) CLL SLL MBL Monoclonal B-cell Count ≥ 5000 ≤ 5000 < 5000 LAP, organomegaly May be present Required None (all nodes <1.5 cm) B symptoms, Cytopenias May be present May be present if due to tissue involvement Absent Diagnosis Flow cytometry LN or tissue biopsy Flow cytometry + stable B cell count over 3 months Immunophenotype CD5+, CD19+, CD23+, weak CD20 and surface Ig, negative CD10 and cyclin D1 Same as CLL Same as CLL Distinguishing Feature High B-cell count Tissue-based disease, low B-cell count No symptoms, low B-cell count, no tissue involvement RAI staging system: Low risk: 0: Lymphocytos is ( >5000 clonal B cells in blood and/or >40% lymphocytes in BM) Intermediate risk: I: Lymphocytos is + LAP II: Lymphocytos is ± LAP + splenomegaly ± hepatomegaly High risk: III: Lymphocytosis + a nemia (Hb <11 or hematocrit <33% ) IV: Lymphocytosis + t hrombocytopenia (plt <100,000) Prognostic Factors: Ig variable region heavy chain gene mutation: Unmutated IGHV genes (U-IGHV) causes a more rapid progression of disease than mutated genes (M-IGHV).  FISH: 11q, 13q, 17p, and 12 abnormalities are identified in approximately 80% of cases. Inferior outcome with del 17p (p53 locus) or 11q (ATM locus). High B2 microglobulin ZAP-70: Median OS is 9 years in ZAP-70 positive and 25 years in ZAP-70 negative patients. CD38 CD49d: Worst outcome: CD49d > ZAP-70 > CD38 Lymphocyte doubling time (LDT): LDT <12 months indicates progressive disease and is associated with decreased survival independent of stage. Treatment: Watchful waiting: Standard of care for patients with early stage Monitor labs q 3-6 months Treatment indications: B symptoms Symptomatic/massive LAP (>10 cm)  Symptomatic/massive splenomegaly (>6 cm below costal margin) Worsening anemia and/or thrombocytopenia LDT <6 months Autoimmune cytopenias poorly responsive to corticosteroid (ITP, AIHA, pure red cell aplasia)  Chemoimmunotherapy: 1st line for CLL without  del 17p with good ECOG Needs prophylaxis for pneumocystis and herpes infections Regimens: FRC: F ludarabine + R ituximab + C yclophosphamide FCR causes better PFS and ORR (CLL8 trial) Causes grade 3-4 hematologic toxicities in 50% of patients BR: B endamustine + R ituximab Preferred regimen for patients >65 years Ofatumumab (anti-CD20 Ab) + Chlorambucil Obinutuzumab (anti-CD20 Ab) + Chlorambucil Targeted therapies:  BTK inhibitors: Ibrutinib: Dose: 420 mg PO once daily Can cause a transient lymphocytosis  Side effects: bruising, rash, diarrhea, arthralgia, myalgia, A-fib Acalabrutinib Zanubrutinib Pirtobrutinib Selective and noncovalent (reversible) BTK inhibitor BCL-2 inhibitor: Venetoclax Can cause serious TLS PI3K α inhibitor: Idelalisib Mostly in combination with Rituximab for relapsed/refractory CLL Can cause a transient lymphocytosis  Black box warning for hepatotoxicity, severe diarrhea/colitis, pneumonitis, serious infections, intestinal perforation. Cellular Therapies: Preferred option in double-refractory, high-risk CLL. Treatment approaches: CLL ± del 17p : Acalabrutinib ± Obinutuzumab Zanubrutinib Venetoclax + Obinutuzumab Relapsed/refractory CLL after both BTK and venetoclax-based regimens : Relapsed/refractory CLL without del 17p: Chemotherapy-based regimens such as BR, FCR or Obinutuzumab Relapsed/refractory CLL with  del 17p: Chemotherapy-based regimens are not effective. Preferred treatments: Targeted agents (BTKi, BCL2i, PI3Ki), CAR-T cell therapy CAR-T cell therapy and pirtobrutinib (BTKi) are the most promising options for double-refractory, high-risk CLL. Summary of treatment approach: First line → covalent BTK inhibitors or venetoclax-based regimen If relapse with BTK inhibitors → BCL-2 inhibitor (Venetoclax)  All BTK inhibitors share common resistance mechanism (do not switch to another BTK inhibitors in case of relapse) If relapse with both covalent BTK inhibitors and Venetoclax-based regimen → noncovalent BTK inhibitor (Pirtobrutinib) is effective (BRUIN trial) Complications: Autoimmune hematologic manifestations Such as ITP and AIHA pure red cell aplasia and autoimmune neutropenia are rare Mostly in advanced diseases or during treatment with purine analogs (Fludarabine) Often respond to prednisone or cyclosporine Infections Hypogammaglobulinemia typically found in advanced disease. If recurrent infections and IgG level <500 → IVIG 0.3-0.5 g/kg monthly to maintain IgG level >500 Rituximab increases risk of Hep B reactivation. All CLL patients should be immunized and avoid live vaccines. Richter’s Transformation: Transformation of CLL to large B-cell lymphoma or Hodgkin lymphoma Findings: B symptoms, rapid LN enlargement, LDH elevation, highly active nodal disease on PET

Introduction: NHL is categorized into two groups of B-cell lymphomas and T-Cell lymphomas: B-cell lymphomas (85–90%): (discussed in a separate post B-Cell Non-Hodgkin lymphoma ) Low-grade B-cell lymphomas (LGBL): DLBCL: The most common, aggressive Follicular lymphoma (FL): Indolent, arising from germinal center B cells Marginal zone lymphoma (MZL): Extranodal, Nodal, Splenic Mantel cell lymphoma (MCL): More aggressive, Derived from mantle zone B cells Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) Lymphoplasmacytic lymphoma (LPL) Hairy cell leukemia High-grade B-cell lymphoma (HGBL): Burkit lymphoma (BL): Highly aggressive, germinal center origin HGBL with MYC and BCL2 ("double-hit" lymphoma) HGBL with MYC and BCL2 and BCL6 rearrangements ("triple-hit" lymphomas) HGBL-not otherwise specified (HGBL-NOS) T-cell lymphomas (10-15%): Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS): The most common subtype of mature T-cell lymphomas A of aggressive lymphoproliferative disorders arising from mature T cells that do not fit into other defined T-cell lymphoma categories Cutaneous T-cell lymphoma (CTCL): Mycosis Fungoides Sézary Syndrome Anaplastic large cell lymphoma (ALCL): Can be ALK-positive or ALK-negative Enteropathy-associated T-cell lymphoma (EATL): Rare, aggressive peripheral T-cell lymphoma of the small intestine Strongly associated with celiac disease Hepatosplenic T-cell lymphoma (HSTCL) Adult T-cell leukemia/lymphoma (ATLL) Extranodal NK/T-cell lymphoma (ENKTL) T-cell large granular lymphocytic leukemia (T-LGLL): Less common, often with extranodal involvement T-Cell Non-Hodgkin Lymphomas Adult T-Cell Leukemia/Lymphoma (ATLL) Background: Immunophenotype: Positive CD2, CD3, CD4, CD5, CD25, CCR4 Negative CD7, CD8, cytotoxic markers (TIA-1, granzyme B, perforin) Variable CD30 CD30 is a marker of activated/mature lymphocytes Presence of > 5% T lymphocytes with abnormal immunophenotype is required for diagnosis Associated with HTLV-1 Can have skin lesions or osteolytic bone lesions (which leads to hypercalcemia) Peripheral smear shows atypical lymphocytes with multilobulated “flower” cells Treatment: BV-CHP B rentuximab V edotin + C yclophosphamide, H ydroxydaunorubicin (Doxorubicin) , P rednisone First-line treatment of CD30-positive peripheral T-cell lymphomas Dose adjusted EPOCH Zidovudine + interferon Anaplastic Large-Cell Lymphoma (ALCL) Background: Positive CD30 Subtypes: ALK-positive ALCL: Systemic, often younger patients, better prognosis ALK-negative ALCL: Systemic, older patients, worse prognosis Primary cutaneous ALCL: Localized to skin, excellent prognosis Breast implant–associated ALCL: Localized to capsule/implant, distinct management Treatment: Localized disease be cured with complete excision Consider RT +/- systemic therapy if residual disease Systemic therapy: First Line: BV-CHP First-line for systemic CD30+ ALCL Brentuximab Brentuximab + Cytoxan, Doxorubicin, Prednisone CHOP EPOCH Subsequent Lines: Brentuximab or clinical trial preferred Bendamustine Bortezomib Cyclophosphamide ALK inhibitors (alectinib, crizotinib, brigatinib, ceritinib, lorlatinib) Only for relapsed/refractory ALK-positive ALCL Mycosis Fungoides (MF) /Sezary Syndrome (SS) Background: Primary cutaneous Lymphoma that involves T cells MF generally affects the skin but may progress to affect the internal organs over time. SS is defined by blood involvement and having clonal rearrangement of TCR in the blood Requires systemic treatment Treatment: Skin directed therapies: Local RT Phototherapy Topical corticosteroids Topical Imiquimod Topical Nitrogen Mustard Topical Retinoids Topical Mechlorethamine Systemic Therapies: Mogalizumab Romidepsin Interferon alfa Retinoids Bexarotene Brentuximab vedotin Gemcitabine Methotrexate Extranodal NK/T-Cell Lymphoma (ENKTL) Background: Very aggressive Typically difficult to diagnose due to necrosis Typical phenotype of NK cell: CD2+, CD7+, surface CD3- ( may express cytoplasmic CD3ε) , CD56+ ( characteristic NK cell marker), CD4 and CD8 are usually absent. Typical phenotype of T-Cell: CD2+, CD7+, surface CD3+ (defining factor), EBER-, CD56 variable, rearranged TCR T Helper: CD3+, CD4+, CD8- T cytotoxic: CD3+, CD4-, CD8+ EBV-encoded RNA (EBER) in situ hybridization is characteristically positive in ENKTL. May present with major GI bleed if involved Subtypes: Nasal ENKTL Extranasal ENKTL Aggressive NK-cell leukemia Treatment: ChemoRT: RT concurrently with 3 cycles of DeVIC DeVIC: De xamethasone, Etoposide ( V P-16), I fosfamide, C arboplatin SMILE x 2-4 cycles → RT SMILE: S teroid (Dexa), M ethotrexate, I fosfamide, L -asparaginase, E toposide P-GEMOX x2 cycles → RT → P-GEMOX P-GEMOX: P egaspargase, Gem citabine, Ox aliplatin GELAD x2 cycles → RT → GELAD x 2 cycles GELAD: G emcitabine, E toposide, Pegaspargase ( a form of L - a sparaginase ), D examethasone If treated with chemo alone: Modified SMILE → allo-HSCT consolidation P-GEMOX → allo-HSCT consolidation DDGP → allo-HSCT consolidation DDGP: D examethasone, Cisplatin ( D DP), G emcitabine, P egaspargase

Background: Risk factor: HPV (high risk) > HIV, smoking Mostl y SCC Work-up: DRE Anoscopy LN biopsy/FNA HIV test Chest/abd CT scan Staging: T1: ≤ 2cm T2: 2-5 cm T3: > 5cm T4: Any tumor size invaded to adjacent organs Perianal SCC Non-metastatic disease (M0): Local excision/surgery: Indications: T1 N0 well/moderately differentiated T2 N0 with no sphincter involvement ChemoRT: Indications: T1 N0 poorly differentiated T2-4 N0 Any T N+ ChemoRT can cure without requiring an abdominoperineal resection (APR) 1st line: 5-FU + Mitomycin + RT Capecitabine + Mitomycin + RT Category 2B: 5-FU + Cisplatin + RT The 5-year survival rate ~90% If a patient did not achieve CR 6 months after chemoRT → definitive surgery (APR) Metastatic disease: First line:  Carbo/taxol + Retifanlimab (preferred) Carbo/taxol mFOLFOX6 FOLFCIS Leucovorin ( Fol inic acid), 5- F U , Cis platin Category 2B: 5FU/Cisplatin DCF D ocetaxel,  C isplatin, 5- F U Subsequent line:  PD-1 inhibitors (if no prior immunotherapy received) Anal SCC Non-metastatic disease (M0) : ChemoRT (regimens mentioned above) If good response to chemoRT but residual mass: R eassess in a few months (up to 6 months after chemoRT) If progression after chemoRT → t ypically receive APR Metastatic disease: (Regimens mentioned above)