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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...

Genetics: Consider VHL, Tuberous sclerosis, Birt-Hogg-Dube (spontaneous pneumothorax is a hallmark) Genetic testing in patients with: Multiple renal masses, bilateral or multifocal tumors, diagnosis age < 45, family history of RCC (more than one first/second degree relatives with RCC) Types: Clear cell RCC: 75% Non-Clear Cell RCC: 25% Papillary RCC is associated with MET mutation.  Collecting Duct RCC Chromophobe RCC Associated with Birt-Hogg-Dube Medullary RCC Associated with sickle cell trait Clear Cell Renal Cell Carcinoma Treatment: Stage I: T1a and T1b (size < 7cm): Nephron sparing partial nephrectomy (preferred) Size < 3cm: Consider radiofrequency ablation Stage II or III: Partial or radical nephrectomy Consider adjuvant pembrolizumab x1 year if high risk (Keynote-564) High risk features: pT2 with WHO G4 or sarcomatoid features stage III (pT3/4) N1 stage IV oligometastatic disease with metastasectomy NED Stage IV metastatic: Risk stratify with IMDC or MSKCC criteria (1-2 intermediate risk, 3+ poor risk): IMDC: <1 year from diagnosis to systemic therapy, Karnofsky PS <80%, Anemia (Hb <12), Hypercalcemia, Neutrophilia, Thrombocytosis MSKCC: <1 year from diagnosis to treatment, Karnofsky PS <80%, LDH >1.5 ULN, Hypercalcemia, Hb LLN Low risk: They will NOT ask you to pick between IO + TKI options Oligometastatic disease: Nephrectomy + metastasectomy Nephrectomy + SBRT Pembrolizumab+Axitinib (Keynote-426) Pembrolizumab+Lenvatinib (CLEAR) Cabozantinib+Nivolumab (Checkmate-9ER) Intermediate/Poor risk: Pembrolizumab+Axitinib Pembrolizumab+Lenvatinib Cabozantinib+Nivolumab Dual IO: Ipi+Nivo NOT triple therapy (Ipi+Nivo+Cabo) per COSMIC-313 trial Second Line IO if Naive Cabozantinib Axitinib Pazopanib Tivozanib (after at least 2 prior lines of therapy) Everolimus Belzutifan: HIF-alpha inhibitor Side effects: Hypoxia, Anemia Lenvatinib/Everolimus Sunitinib Bevacizumab High-dose IL-2 Temsirolimus Non-Clear Cell Renal Cell Carcinoma First line: Clinical trial Cabozantinib Also can consider: Lenvatinib + Everolimus Nivolumab Nivolumab + Cabozantinib Pembrolizumab Sunitinib Sarcomatoid RCC Treatment: Ipi + Nivolumab Medullary Renal Carcinoma Treatment: Carboplatin + Gemcitabine Carboplatin + Paclitaxel Cisplatin + Gemcitabine Gemcitabine + Doxorubicin

Iron Metabolism: ~ 4000 mg of iron per person Mostly stored in the erythrocytes ( ~ 2700 mg) and liver ( ~ 1000 mg) Homeostasis is balance between absorption vs. loss Absorption is regulated Intestinal absorption can fluctuate in response to Iron status Erythropoietic demand Hypoxia  Inflammation Normally absorb 1-2 mg iron/day Loss is unregulated Physiologic exfoliation (hair, skin) Bleeding (physiologic, hemorrhage) Reproductive (iron needed to make a new human) Transferrin and ferritin solubilize iron in aqueous environments and minimize reactivity of iron. Transferrin carries iron thru circulation Ferritin stores iron within cells Intestinal iron absorption occurs in enterocytes in the duodenum. Heme iron is most easily absorbed Elemental iron needs to be reduced from ferric (Fe 3+ ) to ferrous (Fe 2+ ) for absorption. Hepcidin , a liver-derived peptide hormone, regulates systemic iron homeostasis by down regulating the ferroportin 1 ( FPN1 ) receptor on the basolateral side of enterocytes.  High hepcidin levels (in response to iron overload or inflammation) → hepcidin binds to FPN1 → FPN1 degradation → blocks iron export → reducing iron absorption. Therefore iron stored within the cell as ferritin (or goes back into the intestine and excreted) Low hepcidin levels → allow FPN1 to remain on the membrane → facilitating iron absorption. Macrophage iron recycling is a major source of iron From old or damaged RBCs Iron recovered by macrophages may be stored as ferritin or exported into the plasma Also mediated by hepcidin, which inhibits macrophage iron release into blood stream via ferroportin Iron Deficiency Early: No anemia, but may see changes in RDW Late: Frank anemia Microcytosis, anisopoikilocytosis, pencil/target cells Inadequate absorption can be through: Poor bioavailability Cows milk in infants High pH due to gastrectomy Excess Fe3+ (not enough heme iron) Absorption surface dysfunction Duodenectomy Celiac Disease Hepcidin excess (anemia of chronic disease) Iron replacement: Ganzoni equation: Formula to calculate total iron deficit in patients who require IV iron therapy Total iron dose (mg)= Weight (kg) ×[Target Hb−Actual Hb] ×2.4 +500 Route of administration: Oral (preferred) Low dose, no more than daily preferred Too much iron can lead to upregulation of hepcidin → reduce absorption Parenteral In pregnancy: IV Iron generally does not start until the second or third trimester (and in case of severe anemia and oral iron intolerance). Medications: Iron Dextran Category C  for pregnancy Can give up to 1000 mg in one dose Requires test dose Low price Iron Gluconate (Ferrlecit) Category B  for pregnancy Max dose of 125 mg No test dose required Iron Sucrose (Venofer) Category B  for pregnancy Max dose of 300 mg Can be given in short intervals Ferumoxytol (Feraheme) Category C  for pregnancy Max dose of 510 mg Can be given in short intervals Expensive Iron Carboxymaltose (Injectafer) Category C  for pregnancy Max dose of 750 mg Can be associated with hypophosphatemia Iron Isomaltoside Dosed 20 mg/kg up to 1000 mg Can be associated with hypophosphatemia Iron Overload Primary: Hereditary hemochromatosis: Chronic inappropriate increase in intestinal absorption of dietary iron Pathophysiology: Excess iron due to relative hepcidin deficiency phenotype Associated with HFE gene mutation (C282Y, H63D polymorphism, S65C polymorphism)  H63D: Less severe phenotype, lower penetrance Diagnosed by: High transferrin High ferritin >800 Liver biopsy Gene testing Symptoms: Depression, arthritis, liver disease, endocrinopathies (bronze diabetes, hypogonadism), cardiomyopathy Symptoms are more common and severe in males Physiologic blood loss in females Testosterone mediated suppression of hepcidin in males Other related diseases: TFR2 found in hepatocytes: Autosomal recessive Leads to increased intestinal absorption of iron Earlier onset HJV (Juvenile hemochromatosis): Autosomal recessive Younger presentation, more severe phenotype, full penetrance Ferroportin hemochromatosis: Autosomal dominant Associated with high hepcidin levels Affects iron egress into bloodstream thru FPN1 Treatment: Goal is prior to onset of irreversible organ dysfunction Phlebotomy (goal ferritin <100) Diet: avoiding iron supplementation, vitamin C intake, alcohol consumption Avoiding raw shellfish (Vibrio vulnificus) If infected, need antibiotic therapy (tetracycline and third-generation cephalosporin) Also at risk for infections with Yersinia enterocolitica (liver abscess) Chelation generally not done, unless phlebotomy contraindicated If chelation: goal ferritin <1000 IVIG in pregnancy prevents complications of neonatal hemochromatosis Secondary: Excess transfusion: Monitor volume of RBCs transfused Each unit of RBCs contains 200-250 mg of iron Keep in mind: Normally absorb 1-2 mg of iron per day Serum ferritin every 1-3 months Hepatic MRI (q6-12 months) Cardiac MRI (q6-24 months depending on severity) Clinical Pearls: Iron related cardiac complications are the most common cause of death in thalassemia Endocrinopathy and liver disease more common in thalassemia than sickle cell disease Iron loading anemias (Thalassemia intermedia, MDS, Sideroblastic anemia) Pathophysiology: Erythroferrone is a hormone produced by proliferating erythroblasts Regulates iron metabolism by inhibiting hepcidin expression Iron staining shows iron in macrophages Treatment: Chelation Prevents excess iron accumulation, removes excess stored iron, reverse iron-related organ dysfunction Usually implemented when: Serum ferritin >1000 ng/ml MRI liver iron concentration of >3 mg/g dry weight Cardiac T2 is less than 20 milliseconds After patient receives 10 units of pRBCs (or greater than 100 cc/kg/year)  Goal ferritin <1000-500 ng/ml, liver iron concentration 2-7 mg/g dry weight Medications: Deferoxamine (SubQ or IV) Dose adjustment in renal disease Deferiprone (Oral, TID) Side effects: GI symptoms, elevated hepatic enzymes Causes neutropenia/agranulocytosis No dose adjustment in renal disease Deferasirox (Oral, daily) Side effects: GI symptoms, elevated hepatic enzymes, renal toxicity Contraindicated in patients with eGFR <40 Atransferrinemia /Hypotransferrinemia: Autosomal recessive Causes iron overload and microcytic/hypochromic anemia Treatment: FFP infusion, iron chelation Sideroblastic anemia: Ringed sideroblast in bone marrow Most patients have iron overload Respond to Vitamin B6 Porphyria Genetic enzymatic defects in the heme biosynthetic pathway Erythropoietic Porphyria: Anemia is a hallmark of the erythropoietic porphyrias Congenital erythropoietic porphyria (CEP) Erythropoietic protoporphyria (EPP) Hepatic Porphyrias: Four subtypes of porphyria present with acute hepatic features: Acute intermittent porphyria (AIP) Hereditary coproporphyria (HCP) Variegate porphyria (VP) δ-ALA dehydratase porphyria Hepatic porphyrias and porphyria cutanea tarda do not usually present with anemia. Porphyria subtypes: Acute Intermittent Porphyria: Autosomal dominant disorder that affects production of heme Deficiency of the enzyme porphobilinogen deaminase Symptoms: nausea/vomiting, abdominal pain, dark urine, photosensitivity, peripheral neuropathy, headache, seizures Diagnosis involves: urine porphobilinogen and total porphyrin If elevated: plasma and fecal porphyrins should be measured Treatment: Dextrose Hemin (repression of ALAS1 synthesis) in severe cases Givosiran (small interfering RNA directed against 5-ALA synthase-1 which results in decreased delta DLA and porphobilinogen) Associated with risk for HCC Hereditary coproporphyria: Autosomal dominant Variegate porphyria: Autosomal dominant δ-ALA dehydratase porphyria: Only acute porphyria that is inherited in autosomal recessive manner δ-ALA dehydratase deficiency in the absence of lead poisoning Erythropoietic Protoporphyria: Most commonly seen in children Results from ferrochelatase gene mutation Congenital erythropoietic protoporphyria: Autosomal recessive Due to deficiency in uroporphyrinogen III synthase Severe cutaneous photosensitivity and deposition of porphyrins in teeth (reddish brown teeth) Treat with transfusion and discuss HSCT Porphyria cutanea tarda: Deficiency in uroporphyrinogen decarboxylase (UROD) Associated with blistering photosensitivity, especially on backs of hands/sun-exposed areas Should receive phlebotomy or chelation to keep ferritin <50 Treat Hep C if associated (can be initial triggering factor) Some patients treated with hydroxychloroquine and not require phlebotomy Subtypes: Sporadic (Type 1) UROD deficiency seen in liver cells Also with HFE deficiency Familial (Type 2) UROD reduced throughout the body (autosomal dominant) Type 3 (familial) Due to familial inheritance without UROD mutation Likely other etiology such as HFE mutation or shared acquired factors

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: Screening for high risk populations using ultrasound and AFP every 6 months. If a nodule ≥1 cm or rising AFP is detected, further imaging with CT or MRI is indicated. Diagnosis: AFP alone lacks sufficient specificity and sensitivity for HCC diagnosis Typically diagnosed with imaging: CT multiphase shows “Hyperenhancement on arterial phase, delayed washout” Liver biopsy: Indications: Non-cirrhotic patients (imaging alone is insufficient) Cirrhotic patients with inconclusive imaging- 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. Calculate Child-Pugh for all patients Paraneoplastic hypoglycemia, hyperlipidemia, hypercalcemia, erythrocytosis is possible BCLC (Barcelona Clinic Liver Cancer) staging system: Integrating tumor burden, liver function, and patient performance status (PS) Classifies HCC into five stages: 0 (very early): 1 nodule, size ≤2 cm, preserved liver function, PS 0 A (early): 1-3 nodules, each size ≤3 cm, preserved liver function, PS 0 B (intermediate): Multinodular, preserved liver function, PS 0 C (advanced): Portal vein invasion or extrahepatic spread, preserved liver function, PS 1-2 D (terminal): Any tumor burden, end-stage liver function, PS 3-4 Treatment: BCLC stage A or B: Res ection: If solitary lesion, preserved liver function (normal bilirubin and portal pressure) Future liver remnant >20% No adjuvant treatment, observation 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 or extrahepatic disease Contraindicated in those with portal vein thrombosis Radiofrequency Ablation (RFA): For small (≤3 cm) and accessible HCC 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 or 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 HCC and Child-Pugh class A or ≤B7 , while it is not recommended for Child-Pugh class >B7 or C.

Background: B-cell lymphoid malignancy, characterized by Reed-Sternberg cells ( resemble owl’s eyes ) Most commonly affecting young adults Presenting with painless LAP and sometimes B symptoms Types: Classic Hodgkin Lymphoma: CD15+, CD30+ and CD20- Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL): CD15-, CD30- and CD20+ Deaville Scoring System: Used to interpret FDG-PET scans for response assessment in HL and aggressive NHLs: 1 = No uptake 2 = Uptake ≤ mediastinum 3 = Uptake > mediastinum but ≤ liver 4 = Uptake moderately higher than liver 5 = Uptake markedly higher than liver and/or new lesions Scores 1–3 are PET-negative (complete metabolic response) Scores 4–5 are PET-positive (residual active disease) Stages: Stage IA/IIA favorable: Favorable disease: Stage IA/IIA + n on-bulky disease + no unfavorable risk factors Treatment: ABVD x2 cycles → PET/CT If Deauville 1-2: Involved-site radiation therapy (ISRT) ABVD x 2 additional cycles (total 4) Doxorubicin ( A driamycin), B leomycin, V inblastine, D acarbazine Stage I/II unfavorable: Unfavorable disease: S tage I/II + any of the following factors: B symptoms Bulky disease (mediastinal mass ratio >0.33, any mass >10 cm) Extranodal involvement ESR ≥50 (or ≥30 if B symptoms are present) >3 nodal sites Treatment: ABVD x2 cycles → PET/CT If Deauville 1-3: ABVD x2 additional cycles + ISRT AVD x4 additional cycles If Deauville 4-5: ABVD x2 additional cycles or BrECADD → PET/CT BrECADD: Br entuximab vedotin, E toposide, C yclophosphamide, doxorubicin ( A driamycin), D acarbazine, D examethasone If Deauville 1-4: ISRT 30 Gy If Deauville 5: Biopsy - If negative: ISRT 30 Gy - If positive: Treat as primary refractory Stage III-IV: International Prognostic Score (IPS) 1 point per factor: Albumin <4 Hb <10.5 Male gender Age ≥ 45 Stage IV disease WBC >15000 Lymphocytopenia (Lymphocyte <8% of WBC and/or ALC < 600) Treatment: AVD-Nivo x6 cycles → PET/CT BrECADD + GCSF x 2 cycles (age 18-61) → PET/CT Deauville 1-3: BrECADD + GCSF x 2 cycles (total 4) -> PET/CT Deauville 4-5: Biopsy If negative: BrECADD + GCSF x 4 cycles (total 6) If positive: Treat as primary refractory disease BV-AVD x6 cycles → PET/CT BV-AVD: B rentuximab V edotin, Doxorubicin ( A driamycine), V inblastine, D acarbazine Deauville 1-3: Follow up Deauville 4-5: Biopsy If negative: Follow up If positive: Treat as primary refractory disease BV-AVD provides a significant overall survival advantage compared to ABVD (ECHELON) BV-AVD causes neuropathy and neutropenia than ABVD ABVD x2 cycles → PET/CT Deauville 1-3: AVD x 4 cycles Deauville 4-5: BrECADD + GCSF x3 cycles → PET/CT Deauville 1-3: BrECADD + GCSF x1 cycle Deauville 4-5: Biopsy If negative: BrECADD + GCSF x1 cycle → PET/CT If positive: Treat as primary refractory disease Surveillance: H&P every 3-6 months for first 1-2 years, then every 6-12 months until year 3, then annual. CT imaging (not PET) is optional, no more than q6 months in the first 2 years. Primary Refractory Disease: Treatment: I/O containing regimen is preferred followed by Auto-HSCT BV-Nivolumab BV: Brentuximab Vedotin GVD-Pembro GVD: G emcitabine, V inorelbine, Liposomal D oxorubicin ICE-Nivolumab ICE: I fosfamide, C arboplatin, E toposide ICE-Pembro Non I/O containing regimen BV BV-Bendamustine DHAP: D examethasone, H igh-dose cytarabine, Cis p latin GVD Gem/Benda/Vinorelbine ICE +/- BV IGEV: I fosfamide, Ge mcitabine, V inorelbine Consider post-autoHSCT brentuximab vedotin for patients ≥ 2 of the following risk factors: Remission duration <1 year Extranodal involvement PET+ response at the time of transplant B symptoms >1 salvage/subsequent therapy regimen Third line options: Bendamustine Benda/Carbo/Etoposide Gem/Cis/Dex Everolimus Lenalidomide Nivolumab Vinblastine Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) Immunophenotype: CD15-, CD30- and CD20+ Risk of transformation to aggressive large B-cell lymphoma Treatment: Stage IA/IIA (non-bulky) ISRT Observation Usually if node is completely excised Stage IB/IIB or IA-IIA (bulky) Chemotherapy + Rituximab + ISRT Stage IIA (non-contiguous) Chemotherapy + Rituximab +/- ISRT Rituximab Stage III/IV Observation: if asymptomatic Chemotherapy + Rituximab +/- ISRT Rituximab Local RT PET/CT after treatment to assess response

Background: Allogeneic HSCT is generally reserved for high-risk or relapsed hematologic malignancies, while autologous HSCT is used for chemosensitive diseases such as multiple myeloma and certain lymphomas. Allo-HSCT: Infusion of hematopoietic cells from a HLA-compatible donor after cytotoxic conditioning to eradicate disease and enable engraftment. Common indications of HSCT in classic hematology: Severe aplastic anemia Hemoglobinopathies (sickle cell disease, β-thalassemia major) Inherited BM failure syndromes Congenital immunodeficiencies Pre-Transplant Evaluation: Confirmation of diagnosis and disease status Cytogenetics/molecular testing, MRD, etc. Performance status (ECOG/KPS) Comorbidity index: HCT-CI: Hematopoietic Cell Transplantation- Comorbidity Index Organ function (PFTs, cardiac, renal, hepatic) Infectious disease screening (CMV, HBV, HCV, HIV) Psychosocial evaluation/ support systems HLA typing for allogeneic candidates Donor Selection: The preferred donor is an HLA-matched sibling. If unavailable, matched unrelated donors, haploidentical family members, or umbilical cord blood may be considered. Graft source (peripheral blood, bone marrow, umbilical cord blood) is chosen based on disease, patient comorbidities, and urgency. Peripheral blood is most common but increases chronic GVHD risk. HLA matching is critical to minimize graft failure and GVHD. Donor age and health are important predictors of outcome. Conditioning Regimens: Conditioning intensity is tailored to patient age, comorbidities, disease type, and remission status. Myeloablative regimens (cyclophosphamide + TBI, busulfan-based): Preferred for younger, fit patients with aggressive disease. Non-myeloablative regimens/ Reduced-intensity: For older or comorbid patients, or those with indolent disease. Transplant Procedure: After conditioning, donor hematopoietic cells (from peripheral blood, bone marrow, or UCB) are infused. Peripheral blood is most common due to ease of collection and rapid engraftment, but is associated with higher chronic GVHD risk. UCB is reserved for patients lacking other donors and requires specialized expertise. Engraftment is monitored by blood counts and chimerism analysis (for allo-HSCT). Post-Transplant Care: Intensive supportive care is required until engraftment. Monitoring includes surveillance for GVHD (unique to allo-HSCT), infections, organ toxicities, and disease relapse. Veno-Occlusive Disease/ Sinusoidal Obstruction Syndrome (VOD/SOS) : Life-threatening complication of HSCT and certain chemotherapy regimens Characterized by toxic injury to the sinusoidal endothelial cells of the liver → their necrosis and detachment → obstruction of small hepatic venules and sinusoids → post-sinusoidal portal HTN and impaired hepatic blood flow GVHD is a major cause of non-relapse mortality. Long-term follow-up addresses late effects, chronic GVHD, and survivorship issues.

Risk factors: HPV infection (16, 18, 33, 35) Smoking Alcohol use (synergistic with smoking) Betelnut chewing Genetic factors such as Fanconi Anemia (avoid alkylating agents and radiation due to increased toxicity in these patients) Sites of tumor: Oral Cavity: mucosal lip, Buccal mucosa, anterior tongue, hard palate Oropharyngeal Cancer: upper throat, tonsil, base of tongue, soft palate, pharyngeal wall Hypopharyngeal Cancer (lower throat) Laryngeal Cancer 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 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 Hypopharyngeal Cancer Treatment: T2/T3, N0-3 or T1N+ (locally advanced disease): Treatment options: Induction chemotherapy (TPF: Doce t axel, Cis p latin, F luorouracil) 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) 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

Erythropoiesis Stimulating Agent (ESA) Mechanism: Regulates RBC production Produced in liver in fetus, kidney is primary site in adults Regulated by the HIF transcription factors Functions by stabilizing CFU-e and promotes terminal differentiation of erythroid cells Ensure iron stores is adequate before using EPO Medications: Erythr o poietin / E poetin alfa (Epogen) Darbo poietin alfa Biosimilars Indications: Chronic Kidney Disease Start when Hb <10 Lowest dose necessary to reduce transfusion Reduce/stop if Hb >11 Check iron stores (goal ferritin >100) Escalate over 12 week period Chemotherapy associated anemia (palliative intent) Lowest dose necessary to reduce transfusion Associated with increased risk for thrombosis Stop if: Hb increases by >1 in 2 week period No longer requiring transfusions Chemotherapy is done Check iron stores (goal ferritin >100) Escalate over 6-8 week period Reduction of RBC transfusion in elective non-cardiac, non-vascular surgery Given for 2 week course, starting 10 days prior to surgery DVT ppx recommendeded MDS ( Discussed in separate post) HIV Not indicated in: Immediate correction of anemia Chemotherapy associated anemia when anticipated outcome is cure It shorten OS and time to progression in curable malignancies Cardiac/vascular surgery Adverse events: Allergic reactions Hypertension Seizures Thrombosis Decreased overall survival in cancer patients Neutralizing antibodies can lead to pure red cell aplasia HIF prolyl-hydroxylase inhibitors: Dapro dustat , vada dustat , roxa dustat Increase transcription of HIF responsive genes → increase EPO levels Granulocyte Colony Stimulating Factor (G-CSF) Indications: Myelosuppressive chemotherapy with >20% neutropenic fever risk Prophylactic if: >20% risk of neutropenic fever Therapeutic if: Neutropenic fever + high-risk for infection-related complications + have not received prophylactic G-CSF (otherwise, routine use is not recommended) High-risk features: age >65, sepsis, ANC <100, anticipated neutropenia >10 days, pneumonia, hospitalization at the time of fever, prior episodes of febrile neutropenia If the patient is already receiving prophylactic G-CSF, it should be continued. AML induction/consolidation Hematopoietic Stem Cell Transplantation Reduces engraftment time Blood progenitor cell collection Goal is 5 million CD34+ cells/kg recipient weight Bone marrow failure syndromes Theoretically not as beneficial in aplastic anemia (progenitor cells are not present) Administer 24-72 hours after completion of chemotherapy Adverse effects: Allergic reactions Bone pain (treat with NSAID and/or antihistamines) ARDS Splenic Rupture Sickle Cell Crises Sweet syndrome, cutaneous vasculitis MDS/AML (0.4% absolute risk) Medications: Filgrastim (Neupogen) Recombinant protein made in E. coli Half-life 3-4 hours 5 mcg/kg (rounded to nearest vial size) TBO- filgrastim Biosimilars: Filgrastim -sndz ( Zarxio) Peg filgrastim (Neulasta) Half-life of 15-80 hours Only approved for: Myelosuppressive chemotherapy with >20% neutropenic fever risk Bone marrow failure syndromes Single 6 mg subQ dose per cycle Metabolized by neutrophils Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) Indications: Induction chemotherapy in older patients (>55) with AML Mobilization and following transplantation of auto-HSCT Accelerate recovery following auto or allo-HSCT Contraindicated if blasts 10% or more Medications: Sar gramostim (Leukine) Mol gramostim Adverse effects: Allergic reaction Edema/ capillary leak syndrome Pleural/pericardial effusion Supraventricular tachycardia Clinical pearl: Used with sipuleucel-T in prostate cancer or TVEC in melanoma Thrombomimetics (TPO) TPO made in liver and kidneys Binds to MPL receptor on platelets and marrow precursors El trombopag (Promacta): oral, non-peptide Indicated for: Chronic ITP HCV-associated thrombocytopenia to allow use of interferon based therapy Severe aplastic anemia when immune suppression fails Dose: 50mg daily 25mg daily for east asian or moderate/severe hepatic insufficiency Adverse effects: Nausea/vomiting, menorrhagia, arthralgia/myalgia, rare hepatic toxicity Ava trombopag (Doptelet): oral, non-peptide 4x more potent than eltrombopag Indicated for: ITP and treatment of thrombocytopenia associated chronic liver disease who are scheduled to undergo a procedure (start 10-13 days before procedure) Adverse effects: Nausea, abdominal pain, fever, headache, arthralgia/myalgia, peripheral edema, thromboembolism Romiplostim (Nplate): peptide Indicated for: Chronic ITP with insufficient response to first line therapy Severe thrombocytopenia with increased bleeding/risk of bleeding Radiation injury Starting dose at 1mcg/kg subq weekly Adverse effects: Bone marrow reticulin (myelofibrosis), thrombosis (not correlated with platelet count), increase in blasts (in patients with MDS)

Work up for staging: CT CAP with IV and oral contrast Endoscopic Ultrasound Bronchoscopy for tumors at/above the carina to rule out fistula Upper GI endoscopy/biopsy Consider staging laparoscopy: Best test to assess peritoneal metastases (mostly seen in signet ring histology). At least 15 LNs need to be removed during surgery 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 Associated with tobacco use, EtOH use, achalasia, lye ingestion, plummer-vinson syndrome Adenocarcinoma: usually in the lower part of the esophagus/GE Junction Associated with Barrett's esophagus If there is high grade dysplasia or Tis lesions: 60% risk of developing invasive cancer Consider endoscopic resection and/or ablation, or even esophagectomy Low grade dysplasia risk to become invasive is much lower Can do anti reflux therapy followed by EGD in 6-12 months Treatment: Localized/ Locally Advanced Resectable: Tis or T1a: Endoscopic Submucosal Dissection (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) Perioperative FLOT → Surgery ( ESOPEC Trial) Perioperative FLOT + durvalumab → Surgery ( Matternhorn trial) Definitive chemoRT: Those who decline surgery Preferred for cervical esophagus Consider IO if MSI-H/dMMR Any patient who receives neoadjuvant chemoRT with residual pathologic disease should receive adjuvant Nivolumab x1 year (Checkmate-577) Metastatic Disease/Locally Advanced Unresectable: If squamous cell carcinoma: First line: Chemoimmunotherapy is preferred independent of PD-L1 CPS: FOLFOX (or CAPEOX) + Nivolumab FOLFOX (or CAPEOX) + Pembrolizumab FOLFOX (or CAPEOX) + 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 (BRAF V600E mutated) Selpercatinib (RET positive) If Adenocarcinoma: HER2 positive: FOLFOX (or CAPEOX) + Trastuzumab +/- Pembro (based on PDL1 CPS) HER2 negative: If PDL1 CPS >1: FOLFOX (or CAPEOX) + Nivolumab FOLFOX (or CAPEOX) + Pembrolizumab FOLFOX (or CAPEOX) + tislelizumab If IO is contraindicated or PD-L1 CPS 0: 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 for HER2+ Docetaxel/ Paclitaxel Irinotecan +/- 5FU Dabrafenib/ Trametinib (BRAF V600E mutated) Selpercatinib (RET positive) Lonsurf (trifluridine/Tipiracil): 3rd line

Background: 10-15% of all leukemias Male/Female: 1.5 Median age of 65 years old Ionizing radiation is the only known causative factor (usually within 6 to 8 years of exposure) No known genetic factors determine susceptibility to CML Pathophysiology: >95% of CML patients have Philadelphia chromosome (Ph) in the marrow. Contains BCR-ABL1 fusion gene (translocation between BCR on chromosome 22 and ABL1 on chromosome 9)  BCR-ABL1 oncoprotein has tyrosine kinase activity. BCR-ABL1 is found in all cells of the myeloid lineage and B cells but not in T cells. At diagnosis, it is usually a mixed population of Ph-positive and negative cells in the bone marrow. With time, normal stem cells are replaced by BCR-ABL1 positive clones.  Genomic instability: Usually starts with chronic and relatively benign phase May evolves to a more aggressive phase with additional chromosomal abnormalities and 10-20% blasts Neutrophil function is preserved → Does not present with bacterial or fungal infections. Diagnosis: High leukocyte count with basophilia and a hypercellular marrow is pathognomonic of CML. Eosinophilia is also common. Chromosome analysis shows t(9;22) translocation. Leukocyte alkaline phosphatase is low in CML. It is important to distinguish CML presenting as acute leukemia from de novo (Ph-negative) acute leukemia because the treatment approaches are distinct. → pre-B ALL: TdT-positive, CD10+, CD19+, CD33±, CD34± → undifferentiated AML: peroxidase weak-positive, CD33+, CD34+, CD13± Chloromas often respond poorly to chemotherapy, the best treatment option is radiotherapy. Prognostic factors: Massive splenomegaly with B symptoms High basophil counts High peripheral blood blast percentage CML phases: Chronic phase (CP): >80% of patients Accelerated phase (AP): Peripheral blood myeloblast 15-30% Peripheral blood myeloblast + promyelocytes ≥ 30% Peripheral blood basophil >20% Plt count <100k unrelated to therapy Additional chromosome abnormalities in Ph+ cells Blastic phase (BP):   ≥ 30% blasts in blood or BM Extramedullary infiltration of leukemic cells Treatment: If WBC >80,000 → Tx: Hydroxyurea 0.5-2.5 g daily + Allopurinol 300 mg daily (until normal WBC) Once CML is confirmed and WBC count is controlled → Treatment with TKI  Treatment response: Hematologic response (HR): Complete HR: Normal WBC Cytogenetic response (CR): Minor CR: 35-85% Ph Major CR: 5-35% Ph Complete CR: 0% Ph Molecular response (MR): Major MR: <0.1% BCR-ABL1 Complete MR: undetectable BCR-ABL1 - Chronic Phase (CP): Standard first-line treatment for CP: Low risk CP : 1st generation TKI: Imatinib 400 mg daily 2nd generation TKI: Dasatinib 100 mg daily Nilotinib 300 mg BID 3rd generation TKI: Bosutinib 400 mg daily Intermediate and high risk CP:   Same dose Dasatinib, Nilotinib and Bosutinib (2nd and 3rd gen) If failure to first-line TKI: Alternative TKI is indicated. BCR-ABL1 kinase domain mutations (such as T315I) are highly resistant to imatinib, dasatinib and nilotinib (1st and 2nd gen). Treatment for T315I: ponatinib is preferred. Tx: first-line TKI → if resistant to first-line TKI (BCR-ABL1 >10% after 3 months of treatment) → Tx: alternative TKI + check BCR-ABL1 kinase domain mutation status → if resistant to treatment → Tx: another alternate TKI (including Ponatinib) based on mutation analysis result → if resistant to treatment → Tx: allo-HSCT If patient is not suitable for HSCT → Tx: Cytosine arabinoside (ARA-C) + IFN-α HSCT can be the first line of treatment for CP only if the patient is <30 years old with low probability of morbidity and mortality. - Accelerated Phase (AP): Treatment options: Dasatinib, Nilotinib, Ponatinib (2nd and 3rd gen) Omacetaxine mepesuccinate (If resistance to ≥ 2 TKIs) allo-HSCT ARA-C + IFN-α de-novo AP can be initially managed like CP with a single agent TKI (2nd or 3rd gen) followed by evaluation for allo-HSCT. Doses of TKIs used for treatment of AP are higher than CP. - Blastic Phase (BP): Tx: Imatinib + chemotherapy If resistant to treatment: Myeloid BP : Dasatinib or nilotinib + AML-based induction chemotherapy (anthracycline and ARA-C) Lymphoid BP : Dasatinib or nilotinib + ALL-based induction chemotherapy Lymphoid BP requires prophylactic CNS treatment to prevent meningeal leukemia. Tyrosine Kinase Inhibitors: Dasatinib: Dasatinib compared to Imatinib caused higher CR and MR rate and lower rate or progression to BP and AP but did not change overall survival. (DASISION) Crosses the blood–brain barrier/ effective for CNS disease. Patients with significant lung disease should avoid dasatinib.  Up to 30% of patients develop pleural effusions. May require dose reduction, diuretics or corticosteroids. Side effects: cytopenia, diarrhea, pleural effusion, heart failure, prolonged QT  Dasatinib 140 mg daily is better tolerated than divided doses of 70 mg twice daily. Nilotinib: Reduce the incidence of progression to BP. Avoid Nilotinib in significant atherosclerotic disease or diabetes. It can cause elevated liver enzymes, electrolyte abnormalities and pancreatitis. FDA black box warning: prolonged QT interval, arrhythmia and sudden cardiac death Check QT interval at baseline and one week after initiation of Nilotinib Ponatinib: Efficacious against T315I mutations (31% HR in such CML BP patients). Increase risk of arterial and venous thrombosis, pancreatitis, heart failure and TLS. Monitoring response to treatment: CBC q2 weeks until complete HR which should be confirmed on two subsequent occasions. BMBx q6 months until complete CR (0% Ph) which should be confirmed on two subsequent occasions, then BMBx q12 months. Quantitative PCR for BCR-ABL1 transcripts in the blood q3 months Reduction of BCR-ABL1 transcripts by 3 or more logs below the baseline is associated with good outcome.  After allo-HSCT, quantitative PCR should be monitored q3 months for 2 years and then q3-6 months. Failure of TKI treatment: No HR in 3 months No CR (Ph >95%) in 3 months Less than partial CR (Ph >35%) in 6 months BCR-ABL1 >10% in 6 months No complete CR (any Ph detected) in 12 months BCR-ABL1 >1% in 12 months Loss of previously achieved responses Development of TKI-resistant mutations If TKI fails → Check kinase domain mutation analysis Pregnancy: TKIs are contraindicated in pregnancy. Women on TKI should not breastfeed.  Female patients are advised to have optimal control of CML before conceiving and stop TKI at least 3 months before conception. Male patients can continue TKI during conception. Leukapheresis is performed if there is significant leukocytosis off treatment. Hydroxyurea and IFN-α have also been used in pregnancy without complications. Criteria for TKI discontinuation: Chronic Phase CML with no history of AP or BP On an approved TKI therapy for at least 3 years Stable molecular response (BCR-ABL1 ≤ 01%) for ≥2 years as documented on at least four tests, performed at least 3 months apart Access to a reliable quantitative PCR test with a sensitivity of detection BCR-ABL1 ≤ 0.0032%

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

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 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) FOLFCIS: Leucovorin ( Fol inic acid), 5- F luorouracil , Cis platin Anal SCC FOLFIRI: Leucovorin ( Fol inic acid), 5- F luorouracil , Iri notecan GI cancers FOLFIRINOX: Leucovorin ( Fol inic acid), 5- F luorouracil , Iri notecan, Ox aliplatin GI cancers FOLFOX: Leucovorin ( Fol inic acid), 5- F luorouracil , 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, 5- F l uorouracil , 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 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..!

Bone marrow failure: Disrupted hematopoietic stem and progenitor homeostasis → Inadequate WBC, RBC, Plt Pancytopenia differential diagnosis: Autoimmune: HLH, TTP, Lupus, Evan’s syndrome Malignancy: Leukemia, lymphoma, metastatic tumors (myelophthistic), myelofibrosis Infectious Metabolic/Toxins: B12/folate deficiency, excess zinc, storage diseases, alcoholism Bone marrow failure (least common cause) Acquired Bone Marrow Failure: Rapid onset, no family history, usually associated with preceding/inciting event Generally treated with immunosuppression Causes: Drug reaction Infectious Vitamin/Mineral deficiency Acquired aplastic anemia (AAA) Most commonly idiopathic (80%) Immune-mediated disorder in which cytotoxic T cells attack hematopoietic stem and progenitor cells → profound marrow hypocellularity (usually <30%) and reduction in all hematopoietic lineages. Absence of significant dysplasia and clonal markers in BM Associated with drug, hepatitis, EBV, HIV, parvovirus, pregnancy BM cellularity often <30% and frequently in the range of 5–10% Likely T cell mediated: Cytotoxic activity against marrow cells Cytokines that inhibit blood cell production Associated with development of clonal hematopoesis 13q deletion, PIGA mutations, HLA mutations, CHIP, MDS related mutations (Monosomy 7, complex cytogenetics, DNMT3A, ASXL1, TP53, RUNX1) “Severe” AAA: Bone marrow cellularity < 25% + two of the followings: ANC <500 Plt count <20K Retic count <60 Treated with matched sibling donor HSCT (if available) If unavailable: trial with immune suppression Equine ATG Prednisone Cyclosporine A Eltrombopag (up to 6 months) If unsuccessful: Haplo/unrelated HSCT Acquired pure red cell aplasia: Normocytic normochromic anemia Very low/zero retic count WBC and plt are normal Normal BM cellularity with few/no erythroid precursors Hypocellular MDS: Hypocellularity Dysplasia in ≥10% of cells in ≥1 lineage (possibly chromosome 5 or 7 abnormalities) Possible increased blasts Clonal cytogenetic/molecular abnormalities Higher risk of progression to AML, poorer prognosis Paroxysmal Nocturnal Hemoglobinuria (PNH): Acquired mutation in PIGA gene leads to loss of GPI anchored cell surface proteins RBCs lacking CD55/CD59 → complement activation and intravascular hemolysis/thrombosis Typically only develop symptoms or requirement treatment with clones >30% of blood cells AA may have small PNH populations ~1% HSCT is only cure More commonly treated with complement inhibitors Important: Needs meningococcal/pneumococcal vaccination before treatment with complement inhibitors Lifelong therapies, expensive Eculizumab: C5 inhibition, blocks intravascular hemolysis IV q1 week loading x4, followed by maintenance q2 week Ravulizumab: C5 inhibition, blocks intravascular hemolysis IV q2 week loading x2, followed by maintenance q8 week Pegcetacoplan: C3 inhibition, blocks intravascular and extravascular hemolysis SQ q2 weeks, patient administered Inherited Bone Marrow Failure: Slow onset, long history, family history of blood disorders Usually associated with other developmental abnormalities Stem cell transplant is the only cure Causes: Diamond-Blackfan Anemia Autosomal dominant (except GATA1 mutated) Ribosomal disorder (gene likely contains RB__, or GATA) Macrocytic anemia Long thumbs (Buzz word) , short stature, cardiac/renal abnormalities Associated with osteosarcoma, lower GI malignancies Usually responses to corticosteroids and chronic transfusions HSCT is potentially curative Fanconi Anemia Most common Diagnosed with chromosomal breakage testing Defective DNA repair Associated with >22 genes (mostly autosomal recessive) Buzzwords: short stature, cafe au lait spots, hypoplastic thumbs, microcephaly, hypogonadism/pituitary abnormalities, VACTERL abnormalities, cognitive delays Treatment: HSCT is only curative option Androgens (danazol, oxymetholone) Gene therapy Associated with leukemia, head and neck, skin, CNS and gyn malignancies GATA2 related bone marrow failure Haploinsufficiency (variable phenotype) Associated with transcription factor involved in early hematopoesis Most common cause of monosomy 7 in MDS in young patients SAMD9/SAMD9L syndromes Severe congenital neutropenia Due to misfolded neutrophil elastase (ELANE on 19q) Leads to death of neutrophil precursors (arrest at promyelocyte stage) Delayed cord separation ( Buzzword) , severe neutropenia (<200), recurrent infections High doses of GCSF can help (long term complications) Schwachman-Diamond Syndrome (SDS) Ribosome disorder (mutation in SBDS) Autosomal recessive  Pancreatic insufficiency, thoracic dystrophy, metaphyseal dysplasia High risk of MDS/AML HSCT with a reduced intensity regimen  Telomere Biopsy Syndromes (dyskeratosis congenita) TTAGGG repeats on telomeres, maintained by telomerase Defective telomerase activity leads to quick aging of cells/telomeres Test: Telomere length analysis Dyskeratotic nails/hair, rash/skin hypertrophy on hands/feet, pulmonary fibrosis, leukoplakia Highly associated with head and neck, skin and anorecal cancers Treatment: Androgens, HSCT WHIM syndrome W arts, H ypogammaglobulinemia, I mmunodeficiency, M yelokathexis Treatment: Plerixafor

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: Doce t axel + C arboplatin + Trastuzumab ( H erceptin) + P ertuzumab 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

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: If resectable: Surgery  If metastatic/not resectable: systemic therapy Ivosidenib (If IDH1 mutation) Pazopanib Dasatinib Pembrolizumab (if TMB >10 or MSI-H) If recurrence: reexcision If mesenchymal chondrosarcoma: Treat like ewing sarcoma If dedifferentiated chondrosarcoma: Treat like osteosarcoma 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: M ethotrexate+ Doxorubicin ( A driamycin) + Cis p latin 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: V incristine, D oxorubicin, C yclophosphamide alternating with I fosfamide and E toposide VIDE: V incristine, I fosfamide, D oxorubicin, E toposide VAIA: V incristine, Dactinomycin ( A ctinomycin D), I fosfamide, Doxorubicin ( A ctinomycin) 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)

Introduction: Non-Hodgkin lymphoma 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" lymphomas: MYC and BCL2 and BCL6 rearrangements Burkit lymphoma (BL): Highly aggressive, germinal center origin Low-grade B-cell lymphomas (LGBL): Follicular lymphoma (FL): Indolent, arising from germinal center B cells Marginal zone lymphoma (MZL): Subtypes: 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) T-cell lymphomas (10-15%): (discussed in a separate post T-Cell Non-Hodgkin lymphoma ) 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 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 Baseline FDG-PET for staging and response assessment CNS risk assessment CNS International Prognostic Index (CNS- IPI) score is u sed to 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 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. 5 year overall survival rate 40-50% 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 to 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 +/- ISRT R-CHOP: R ituximab, C yclophosphamide, H ydroxydaunorubicin (Doxorubicin), Vincristine ( O ncovin), P rednisone 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 Considered for frail or elderly patients Pola-R-CHP Pola tuzumab vedotin, R ituximab, C yclophosphamide, H ydroxydaunorubicin (Doxorubicin), P rednisone Need to be on PJP and Herpesvirus prophylaxis while on polatuzumab Relapsed/refractory disease: If transplant-eligible AND relapse occurred >12 months after initial R-CHOP : Platinum-based salvage therapy →  auto-HSCT R-DHAP: R ituximab, D examethasone,  H igh-dose cytarabine ( A ra-C), Cis p latin R-GDP: R ituximab, G emcitabine, D examethasone, Cis p latin/Carboplatin RICE: R ituximab, I fosfamide, C arboplatin, E toposide 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 Pola tuzumab vedotin, B endamustine, R ituximab R-GemOx R ituximab, Gem citabine, Ox aliplatin CD20 x CD3 Bispecific antibodies: Epcoritamab Glofitamab Mosunetuzumab Glofitamab + GemOX Mosunetuzumab + Pola tuzumab 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 IT treatment Surveillance:  H&P q3-6 months for 5 years and then annually CT CAP with contrast q6 months for 2 years, then as indicated HGBL with MYC, BCL2/BCL6 rearrangements Background: Clinically 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) R-EPOCH: R ituximab, E toposide,  P rednisone, Vincristine ( O ncovin), C yclophosphamide, H ydroxydaunorubicin (Doxorubicin) 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, 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 (dose adjusted R-EPOCH) R-CODOX-M/IVAC + Intrathecal CNS prophylaxis 2-4 cycles alternating R-CODOX-M and R-IVAC R-CODOX-M: R ituximab, C yclophosphamide, Vincristine ( O ncovin) , Dox orubicin, High-dose M ethotrexate R-IVAC: R ituximab, I fosfamide, Etoposide ( V P-16), high-dose A ra-C ( C ytarabine) No need for maintenance therapy Low grade B-Cell NHL Follicular Lymphoma (FL) Background: Low grade B-Cell Lymphoma 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 → overexpression of the BCL2 protein in B cells → blocks the normal apoptotic program Positive BCL2 helps to distinguish FL from Burkitt lymphoma and other germinal center lymphomas Typically presents with multistation LAP, BM involvement, and splenomegaly Staging: Limited stage: Stage I: Single LN region Single group of adjacent nodes Single extranodal lesion without nodal involvement Stage II contiguous: ≥2 nodal groups on the same side of the diaphragm limited contiguous extranodal extension Advanced stage: Stage II non-contiguous: "bulky" mass (size cutoff typically ≥7.5 cm, though some studies use 10 cm). 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 GELF criteria: Set of clinical parameters used to assess tumor burden in FL and guide the decision to initiate therapy vs observation: Any nodal/extranodal tumor mass ≥ 7 cm ≥3 nodes involvement, each ≥3 cm B symptoms Splenomegaly Compression syndrome Pleural effusion/ascites Leukemic phase (>5000 malignant cells) Cytopenias (WBC <1000 and/or platelets <100k) First Line Treatment: R-CHOP or Obi-CHOP R-CVP or Obi-CVP BR: B endamustine, R ituximab Bendamustine, Obinutuzumab R-Squared ( R²): R ituximab + Lenalidomide ( R evlimid) 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: Epcoritimab (bispecific ab targeting CD20 and CD3) Mosunetuzumab (bispecific ab targeting CD20 and CD3) Axi-cel Tisa-cel Liso-cel Tazemetostat 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 NHL with median survival often >10 years but risk of transformation to aggressive lymphoma exists Divided into three main subtypes: Extranodal (EMZL) or Mucosa-Associated Lymphoid Tissue ( MALT) lymphoma Most common, typically involving the stomach, but can affect other mucosal sites (lung, ocular adnexa, skin, salivary glands Nodal (NMZL) Most patients with NMZL present with advanced-stage but non-bulky disease. Splenic (SMZL) MZL often arises in the context of chronic immune stimulation from infections or autoimmune diseases: Gastric MALT- H. Pylori Infection SMZL - Hepatitis C infection Small Bowel- Campylobacter jejuni Thyroid- Hashimoto’s disease Parotid- Sjogren’s syndrome Ocular- 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. Treatment: EMZL /MALT lymphoma: For gastric MALT, H. pylori eradication is first-line if infection is present. For localized non-gastric EMZL, involved-site radiotherapy (ISRT) is preferred. Systemic therapy (rituximab ± chemotherapy) is reserved for advanced, multifocal, or symptomatic disease. NMZL: Treatment is similar to follicular lymphoma: Observation for low burden disease Rituximab-based regimens for symptomatic or high burden disease. SMZL: 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: Stage II Bulky noncontiguous , Stage III, and Stage IV are categorized as: Classical TP53 Wild Type Classical TP53 Mutated Indolent Characterized by t(11;14) translocation → cyclin D1 overexpression (essential for diagnosis) Typically presents with LAP, splenomegaly, BM and GI involvement. The disease course ranges from indolent (especially in leukemic non-nodal MCL) to aggressive, with most patients requiring 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 or cytarabine-containing regimens) → auto-HSCT + Rituximab maintenance ( NORDIC regimen) Older or transplant-ineligible patients: Less intensive regimens (BR, R-CHOP, VR-CAP) + Rituximab maintenance VR-CAP: Bortezomib ( V elcade) , R ituximab, C yclophosphamide, Doxorubicin ( A driamycin), P rednisone Relapsed/refractory disease: Covalent BTK inhibitors (zanubrutinib, acalabrutinib) R-squared Bortezomib ( V elcade) R-DHAP Clinical trials CAR T-cell therapy Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) Discussed in a separate post " Chronic Lymphocytic Leukemia (CLL) " Lymphoplasmocytic Lymphoma (L PL) 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% of WM/LPL 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

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 → c omplement 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: V acuolization in marrow cells E 1 ubiquitin activating enzyme (encoded by UBA1 gene) X -linked A utoinflammatory  S omatic 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 Hemolyt ic 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

Anthracyclines: Myelosuppression (esp neutropenia ) Nausea, vomiting Total alopecia Mucositis Red-colored urine Cardiomyopathy (mostly with Doxorubicin, risk increases with cumulative dose) Secondary malignancies (AML, MDS) Topoisomerase I inhibitors: Irinotecan: Severe diarrhea , nausea, vomiting Neutropenia Top otecan: Myelosuppression Less GI toxicity Interstitial lung disease (rare but serious) Topoisomerase II inhibitors:  Doxorubicin: Discussed in Anthracyclines section Etoposide: Myelosuppression (esp neutropenia and thrombocytopenia) Nausea, vomiting Secondary leukemias (with long-term use) Hypersensitivity reactions (anaphylaxis, rash, urticaria) Embryo-fetal toxicity, Infertility Alkylating agents: Myelosuppression (neutropenia, anemia, thrombocytopenia) Nausea and vomiting Mucositis Alopecia Gonadal dysfunction (infertility, premature menopause, ovarian/testicular failure) Hemorrhagic cystitis (esp with cyclophosphamide and ifosfamide) Secondary malignancies (leukemia and myelodysplasia) Organ-specific toxicities (cardiac, renal and hepatic toxicities) Pulmonary fibrosis (with Busulfan, Melphalan and Carmustine) Taxens: Peripheral neuropathy (esp Paclitaxel) Hypersensitivity reactions (esp Paclitaxel) Myelosuppression (severe neutropenia in Docetaxel) Fluid retention (esp Docetaxel) Organ-specific toxicities Erythropoiesis Stimulating Agents (ESA): Allergic reactions Hypertension Seizures Thrombosis Decreased overall survival in cancer patients Neutralizing antibodies can lead to pure red cell aplasia Granulocyte Colony-Stimulating Factor (G-CSF): Allergic reactions Bone pain (treat with NSAID and/or antihistamines) ARDS Splenic Rupture Sickle Cell Crises Sweet syndrome, cutaneous vasculitis MDS/AML (0.4% absolute risk) Granulocyte-macrophage colony-stimulating factor (GM-CSF): Allergic reaction Edema/ capillary leak syndrome Pleural/pericardial effusion Supraventricular tachycardia Thrombomimetics (TPO): Headache, Arthralgia/myalgia, GI symptoms, thromboembolism (venous and arterial) + Eltrombopag (Promacta): Menorrhagia Hepatic toxicity (rare) Avatrombopag (Doptelet): Fever Headache Peripheral edema Romiplostim (Nplate): Bone marrow reticulin ( myelofibrosis ) Increase in blasts (in patients with MDS) IN PROGRESS..!

Background: Second most common acute leukemia in adults 75% of cases are B-cell lineage, 25% are T-cell lineage Work up: CBC BMBx: Cytogenetics, Molecular analyses Important to identify if presence of philadelphia chromosome or philadelphia-like chromosome Philadelphia-like chromosome: Lacks the BCR-ABL1 gene Associated with poor prognosis Consider use of TKIs and early transplantation Risk assessment: Favorable risk: Hyperdiploidy ETV6-RUNX1 Poor risk: Hypodiploidy (<44 chromosomes) TP53 mutation KMT2A rearranged (t[4;11]) IgH rearranged HLF rearranged ZNF384 rearranged MEF2D rearranged MYC rearranged PAX5alt t(9;22) with IKZF1 plus and/or antecedent CML Complex karyotype (5 or more chromosomal abnormalities) BCR-ABL1-like (JAK-STAT, ABL class, other etc) Intrachromosomal amplification of chromosome 21 Alterations of IKZF1 Induction Treatment: All patients need CNS prophylaxis Ph+ B-ALL : TKI + chemo TKI + steroid (frail patient) TKI + blinatumomab  Blinatumomab: Bispecific CD19-directed CD3 T-cell engager If CR after induction : check MRD status: MRD+ Blinatumomab +/- TKI Inotuzumab +/- TKI Inotuzumab increases risk of veno-occlusive disease/liver toxicity in transplant patients TKI TKI + chemo alloHSCT followed by TKI MRD- Blinatumomab + TKI TKI TKI + chemo alloHSCT (appropriate candidate) If no CR: Treat as relapsed/refractory disease Ph- B-ALL : Adolescent/Young Adult (AYA):  Pediatric regimen or multi-agent chemo Adult <65 and no significant comorbidities:  Multi-agent chemo Adult >65 or with significant comorbidities: Multi-agent chemo Inotuzumab Palliative corticosteroid If CR after induction: check MRD status: MRD+ Blinatumomab → allo-HSCT Inotuzumab → allo-HSCT MRD- Blinatumomab +/- alternating with chemo Consider alloHSCT if high risk features If no CR : Treat as relapsed/refractory disease T-ALL: Typically present with leukocytosis, mediastinal, CNS involvement  Adolescent/Young Adult (AYA):  Pediatric regimen or multi-agent chemo Adult <65 and no significant comorbidities:  Multi-agent chemo Adult >65 or with significant comorbidities: Multi-agent chemo Palliative corticosteroid If CR after induction : check MRD status: MRD+ (or high risk features) AlloHSCT Continue multi-agent chemo (POMP maintenance) MRD- Continue multi-agent chemo (POMP maintenance) Consider allo-HSCT If no CR : Treat as relapsed/refractory disease Relapsed/Refractory treatment: Ph+ B-ALL ABL domain testing TKI +/- chemo TKI +/- steroid Blinatumomab +/- TKI Inotuzumab +/- TKI CAR-T Ph- B-ALL Blinatumomab Inotuzumab Revumenib (if KMT2A rearranged) Multiagent chemo CAR-T T- ALL Nelarabine Revumenib (if KMT2A rearranged) Multiagent chemo Should then consider alloHSCT for all patients CAR-Ts include: Tisa-Cel < 26 years of age with refractory disease or 2 or more relapses Brexa-Cel Obeca-Cel