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

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) FLOT: F luorouracil (5-FU), L eucovorin (Folinic acid) , O xaliplatin, Doce t axel Esophageal and EGJ cancers Gastric cancers FOLFCIS: Leucovorin ( Fol inic acid), F luorouracil (5-FU) , Cis platin Anal SCC FOLFIRI: Leucovorin ( Fol inic acid), F luorouracil (5-FU) , Iri notecan GI cancers FOLFIRINOX: Leucovorin ( Fol inic acid), F luorouracil (5-FU) , Iri notecan, Ox aliplatin GI cancers FOLFOX: Leucovorin ( Fol inic acid), F luorouracil (5-FU) , Ox aliplatin GI cancers FRC: F ludarabine + R ituximab + C yclophosphamide CLL GDP: G emcitabine, D examethasone, Cis p latin/Carboplatin DLBCL GELAD: G emcitabine, E toposide, Pegaspargase ( a form of L - a sparaginase ), D examethasone Extranodal NK/T-cell lymphoma (ENKTL) GVD: G emcitabine, V inorelbine, Liposomal D oxorubicin Hodgkin lymphoma ICE I fosfamide, C arboplatin, E toposide Hodgkin lymphoma DLBCL MAP: M ethotrexate, Doxorubicin ( A driamycin), Cis p latin Osteosarcoma Urothelial (bladder) carcinoma NALIRIFOX: Na no L iposomal Iri notecan, F l uorouracil (5-FU) , Ox aliplatin Pancreatic adenocarcinoma P-GEMOX: P egaspargase, Gem citabine, Ox aliplatin Extranodal NK/T-cell lymphoma (ENKTL) Pola-BR: Pola tuzumab vedotin, B endamustine, R ituximab DLBCL Pola-R-CHP: Pola tuzumab vedotin, R ituximab, C yclophosphamide, H ydroxydaunorubicin (Doxorubicin), P rednisone DLBCL POMP: Mercapto p urine, Vincristine ( O ncovin), M ethotrexate, P rednisone ALL R-CHOP: R ituximab, C yclophosphamide, H ydroxydaunorubicin (Doxorubicin), Vincristine ( O ncovin), P rednisone DLBCL R-CODOX-M/IVAC: R ituximab, C yclophosphamide, Vincristine ( O ncovin) , Dox orubicin, High-dose M ethotrexate/ I fosfamide, Etoposide ( V P-16), high-dose A ra-C ( C ytarabine) Burkitt lymphoma R-DHAP (Rituximab + DHAP): R ituximab, D examethasone,  H igh-dose cytarabine ( A ra-C), Cis p latin DLBCL Mantle Cell Lymphoma R-EPOCH (R-CHOP + Etoposide): R ituximab, E toposide, P rednisone, Vincristine ( O ncovin), C yclophosphamide, H ydroxydaunorubicin (Doxorubicin) DLBCL R-GDP (Rituximab + GDP): R ituximab, G emcitabine, D examethasone, Cis p latin/Carboplatin DLBCL R-GemOx: R ituximab, Gem citabine, Ox aliplatin DLBCL RICE (Rituximab + ICE): R ituximab, I fosfamide,  C arboplatin,  E toposide DLBCL SMILE: S teroid (Dexa), M ethotrexate, I fosfamide, L -asparaginase, E toposide Extranodal NK/T-cell lymphoma (ENKTL) TAC: Doce t axel, Doxorubicin ( A driamycin), C yclophosphamide Breast cancer TCHP: Doce t axel, C arboplatin, Trastuzumab ( H erceptin), P ertuzumab Breast cancer TIP: Pacli t axel, I fosfamide, Cis p latin Testicular cancer Cervical cancer Transitional cell carcinoma /Urothelial cancer TPF: Doce t axel, Cis p latin, 5- F luorouracil SCC of head and neck cancers VAIA: V incristine, Dactinomycin ( A ctinomycin D), I fosfamide, Doxorubicin ( A ctinomycin) Ewing sarcoma Rhabdomyosarcoma VDC/IE: V incristine, D oxorubicin (Adriamycin), C yclophosphamide alternating with I fosfamide and E toposide Ewing sarcoma VeIP: V inblastine , E toposide,  I fosfamide, Cis p latin Testicular cancer VIDE: V incristine, I fosfamide, D oxorubicin, E toposide Ewing sarcoma VR-CAP: Bortezomib ( V elcade) , R ituximab, C yclophosphamide, Doxorubicin ( A driamycin), P rednisone Mantle Cell lymphoma IN PROGRESS..!

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

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

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

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

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

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

Chemotherapy Anthracyclines: 💉 Intercalate into DNA, inhibit topoisomerase II, generate free radicals → DNA damage → cell death Doxo rubicin (Adriamycin) Dauno rubicin Epi rubicin Ida rubicin (Idamycin) Topoisomerase inhibitors: 💉 Interfere with DNA unwinding and replication → cell death Topoisomerase I inhibitors: Irin otecan Top otecan Topoisomerase II inhibitors:  Doxorubicin (Adriamycin) (Anthracycline and Tomoisomerase II inh) Etoposide Alkylating agents: DNA cross-linking → inhibits replication → cell death Cyclophosphamide 💊   💉 Ifosfamide   💉 Busulfan 💉 Melphalan 💊 💉 Benda mustine 💉 Car mustine   💉 Lo mustine 💊 Temozolomide (Temodar) 💊 Pro carbazine 💊 Da carbazine   💉 Microtubule-targeting agents :   💉 Disrupt mitotic spindle formation → mitotic arrest → cell death Taxanes:  Pacli taxel (Taxol) Doce taxel Cabazi taxel Vinca alkaloids: Vin cri stine (Oncovin) Vin bla stine Platinum compounds:   💉 DNA cross-linking → inhibits replication → cell death Cis platin Carbo platin Oxali platin Antimetabolites:   Hypomethylating agents (DNA hypomethylation →  reactivation of tumor suppressor gene): Acacitidine   -SubQ Decitabine   💉 Decitabine/cedazuridine  (Inqovi) 💊 Antifolates: Methotrexate  💊   💉 Peme trexed  (Alimta) 💉 Ralti trexed   💉 Purine analogues: 6-mercaptopurine  💊 6-thioguanine  💊 Fludarabine   💉 Cladribine  💉 Pyrimidine analogues: Cytarabine 💉 5-fluorouracil (5-FU) 💉 Gem citabine (Gemzar) 💉 Cape citabine (Xeloda)   💊 Floxuridine  💉 Immunotherapy PDL-1 inhibitors:   💉 Atezolizumab Durvalumab (Imfinzi) Avelumab PD-1 inhibitors:   💉 Pembrolizumab (Keytruda) Nivolumab (Opdivo) Tislelizumab Cemip limab Dostar limab Retifan limab Toripa limab CTLA-4 inhibitors:   💉 Ipi limumab Treme limumab Bispecific T-cell engager (BiTE):   💉 Binds two targets simultaneously (CD3 on T cells and Tumor-associated antigen on cancer cells) → directs T cells to the tumor → T-cell mediated cytotoxicity Blinatumomab Teclistamab Immunomodulatory imide drugs (IMiDs): 💊 Len alidomide Th alidomide Pom alidomide Targeted Therapy BRAF inhibitors: 💊 Vemu rafenib Dab rafenib Enco rafenib So rafenib MEK inhibitors: 💊 (Often combined with BRAF inhibitors) Tra metinib Cobi metinib mTOR inhibitors: Si rolimus 💊 Eve rolimus 💊 Temsi rolimus   💉 VEGF inhibitors:   💉 Block VEGF signaling → inhibit tumor angiogenesis → reduce tumor growth Bevacizumab (Avastin) Ramucirumab Aflibercept Small molecule VEGFR (multi-kinase) inhibitors:   💊 Sunitinib Sorafenib (VEGFR and BRAF inhibitor) Pazopanib Axitinib Cabozantinib Lenvatinib KRAS inhibitors:   💊 Soto rasib Adag rasib BCR-ABL inhibitors:   💊 Imatinib Dasatinib Nilotinib Ponatinib EGFR inhibitors:   💊 Erlotinib Gefitinib Osimertinib (Tagrisso) NTRK inhibitors: 💊 Laro trectinib En trectinib Repo trectinib BTK inhibitors: 💊 Ibrutinib Zanu brutinib Pirtobrutinib Remibrutinib ROS1 inhibitors: 💊 Entrectinib (NTRK and ROS1 inh) Repotrectinib (NTRK and ROS1 inh) Crizotinib (ALK and ROS1 inh) Lorlatinib (ALK and ROS1 inh) ALK inhibitors:   💊 Crizotinib Lorlatinib Alectinib Brigatinib RET inhibitors: 💊 Selpercatinib Pralsetinib JAK-2 inhibitors: 💊 Ruxolitinib Fedratinib Pacritinib Momelotinib HER-2 inhibitors: Tyrosine kinase inhibitor:   💊 Lapatinib Neratinib Monoclonal antibody:   💉 Trastuzumab (Herceptin) Pertuzumab (Perjeta) Margetuximab Antibody-drug conjugates:   💉 Ado-trastuzumab emtansine Trastuzumab deruxtecan (Enhertu) Proteasome inhibitors: Borte zomib  (Velcade) 💉 Carfil zomib   💉 Ixa zomib   💊 Phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors: 💊 Idela lisib Umbralisib Zandelisib Linperlisib Leniolisib CD20 inhibitors: 💉 Rituximab Ublituximab Obinutuzumab Ofatumumab Ocrelizumab

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

Early detection: Individualized informed decision-making for prostate cancer screening (DRE and PSA) Discuss risks and benefits: Age 45–75 at average risk Age 40–75 at high risk (Black/African American, family history, germline mutations) Definitive diagnosis: Requires prostate biopsy, Gleason grading, and TNM staging. Clinical Pearls: Think of Prostate Cancer treatment on a "spectrum": Localized Disease → Biochemical recurrence (BCR) → Non-metastatic castrate resistant prostate cancer (NMCRPC) or Metastatic Castrate Sensitive Prostate Cancer (MCSPC) → Metastatic Castrate Resistant Prostate Cancer (MCRPC) PSA after radical prostatectomy (RP) should be undetectable. Post-radiation PSA should not, monitor for the nadir to determine BCR.  BCR is defined as: After RP: PSA ≥ 0.2 after RP or 2 rising PSA’s from nadir after RP (should be 0 after RP) After RT: : PSA increase by ≥2 above nadir PSA after radiation (Phoenix Criteria) Consider PSA doubling time of ~ 6-10 months. Androgen Deprivation therapy (ADT):  LHRH agonist (goserelin, leuprolide, triptorelin) Causes initial testosterone surge (typically start bicalutamide before Lupron to prevent tumor flare) GnRH antagonists (degarelix, relugolix) Consider relugolix if patient has cardiovascular comorbidities Side effects: “manopause” with night sweats, hot flashes, weight gain, sexual dysfunction, mood changes, cardiovascular side effects, DVT, hypertension, osteoporosis. Monitor DEXA scans q2 years Neoadjucant Hormonal Therapy (NHT): Abiraterone + Prednisone If taken without prednisone, can cause HTN and hypokalemia due to hyperaldosteronism Side effects: hepatotoxicity, HTN, hypokalemia and fluid retention (from mineralocorticoid excess), hyperglycemia (due to prednisone), cardiovascular adverse events, adrenal insufficiency Need to monitor LFT Enzalutamide Can cause falls and lower seizure threshold Darolutamide Apalutamide Localized prostate cancer: Risk stratification based on NCCN guideline: Very low risk T1c + Grade Group 1 + PSA <10 + Fewer than 3 prostate biopsy fragments/cores positive, ≤50% cancer in each fragment/core + PSA density <0.15 Low risk T1–T2a + Grade Group 1 + PSA <10 Intermediate risk No high- or very-high-risk features + one or more intermediate risk factors: T2b–T2c Grade Group 2 or 3 PSA 10–20 Favorable intermediate: intermediate risk factors and Grade Group 1-2 and <50% biopsy cores positive Unfavorable intermediate: 2-3 intermediate risk factors and/or Grade Group 3 and/or ≥ 50% biopsy cores positive High risk T3a OR Grade Group 4 or Grade Group 5 OR PSA > 20 Very high risk T3b–T4 OR Primary Gleason pattern 5 OR 4 cores with Grade Group 4-5 Treatment: If undergoing radical prostatectomy: Check if any adverse features are present on final pathology. Positive margins Seminal vesicle involvement Extracapsular extension Detectable PSA If any adverse feature is seen can either monitor or EBRT +/- ADT Expect PSA to become undetectable after radial prostatectomy. Very low risk localized prostate cancer: Active surveillance (in patients with >10 years anticipated survival) Observation (in patients with <10 years anticipated survival) Low risk localized prostate cancer: Active surveillance RT Radical prostatectomy Observation (in patients with <10 years anticipated survival) Intermediate risk localized prostate cancer: Favorable: Active surveillance RT Radical prostatectomy + PLND (in patients with >10 years survival) Unfavorable: Baseline bone and soft tissue imaging Radical prostatectomy + PLND (in patients with >10 years survival) RT + 4-6 months ADT (5-10 years survival) Observation (5-10 years survival) High Risk/Very High Risk localized prostate cancer: Baseline bone and soft tissue imaging needed >5 years survival or symptomatic: RT + ADT x2 years + Abiraterone/Prednisone (if very-high risk) x2 years Radical prostatectomy + PLND <5 years survival and asymptomatic: Observation ADT EBRT Node positive, M0: >5 years survival or symptomatic: EBRT + ADT + Abiraterone (preferred) < 5 years survival and asymptomatic: Observation or ADT Biochemical Recurrence: Obtain imaging to rule out local recurrence or distant metastasis: If negative: Salvage RT + ADT x2 years If positive for pelvic recurrence: RT + ADT + Abiraterone/Prednisone x2 years If distant metastasis: treat as M1 disease Non-metastatic castrate resistant prostate cancer (nmCRPC): Definition of castrate resistance: elevated PSA despite testosterone <50 ADT + Neoadjuvant Hormonal Therapy (Apalutamide, Enzalutamide, Darolutamide) Metastatic prostate cancer: Treatment: Metastatic castrate sensitive prostate cancer (mCSPC): mCSPC low volume: ADT + NHT (Abiraterone, Enzalutamide, Apalutamide) Consider addition of SABR ( Stereotactic Ablative Body Radiotherapy ) mCSPC high volume: presence of visceral mets or 4+ bony mets with at least 1 beyond vertebra or pelvis (CHAARTED) Docetaxel + ADT + Abiraterone (PEACE-1) Docetaxel + ADT + Darolutamide (ARASENS) If poor PS (not able to tolerate triplet therapy) can use ADT + NHT Metastatic castrate resistance prostate cancer (mCRPC): Cabazitaxel if progressed on Docetaxel (TROPIC) Olaparib (if BRCA positive) Rucaparib (if BRCA positive) PARP inhibitor + NHT Olaparib + Abiraterone Talazoparib + Enzalutamide Pembrolizumab (If MSI-high/MMRd) Radium-223 (Xofigo, for bone only disease) Lutetium-PSMA  (if fails Docetaxel)  Radioligand delivers beta-particle radiation to PSMA-expressing cells (VISION) Approved for patients with symptomatic bone metastases but no signs of visceral disease Causes bone marrow toxicity Sipuleucel-T recommended if: Asymptomatic/minimally symptomatic No liver metastases Life expectancy > 6 months ECOG 0-1 Clinical Pearls If patient has rapid progression of disease discordant from PSA, consider neuroendocrine differentiation Treat with with cisplatin/etoposide Bisphosphonate decreases skeletal related events in patients with castration-resistant prostate cancer and bone mets No clear benefit to using bisphosphonate in patients with castration sensitive disease as it has not shown to reduce skeletal related events Germline testing may be considered in patients with: Intermediate risk prostate cancer with intraductal/cribriform histology History of prostate cancer + history of pancreatic, colon, gastric, melanoma, urothelial, GBM, bile duct, small intestinal cancer High risk/very high risk/node positive/metastatic prostate cancer

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

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

Background: Second most common acute leukemia in adults 75% of cases are B-cell lineage, 25% are T-cell lineage Diagnosis requires ≥20% bone marrow lymphoblasts Work up: CBC with diff, CMP, LFT DIC panel TLS panel Hepatitis B/C and HIV serologies BMBx: Cytogenetics, Molecular analyses To identify if philadelphia chromosome/ philadelphia-like chromosome is present Philadelphia-like chromosome: Lacks the BCR-ABL1 gene Associated with poor prognosis Consider use of TKIs and early transplantation Peripheral blood smear: May be substituted for BMBx if there is significant circulating disease (≥1000 lymphoblasts), especially when BMBx is not feasible Risk assessment: Favorable risk: High hyperdiploidy (51–65 chromosomes) Especially with simultaneous trisomies of chromosomes 4, 10, and 17 ETV6-RUNX1 fusion Poor risk: Hypodiploidy (cells with <44 chromosomes) TP53 mutation KMT2A (MLL) rearrangements, especially t(4;11) IgH rearrangement HLF rearrangement ZNF384 rearrangement MEF2D rearrangement MYC rearrangement PAX5-altered Complex karyotype (5 or more chromosomal abnormalities) Philadelphia-like chromosome (JAK-STAT, ABL class) Intrachromosomal amplification of chromosome 21 IKZF1 alterations Treatment: ALL therapy is divided into: Induction: Initial phase of multiagent chemo to rapidly reduce tumor burden by eradicating leukemic blasts from the BM and achieving CR. Consolidation: Post-induction phase of multiagent chemo to eliminate residual leukemic cells and further reduce the risk of relapse. Maintenance All patients need CNS prophylaxis Intrathecal chemo ± systemic high-dose MTX or cytarabine Philadelphia chromosome positive B-cell ALL: TKI + chemo (e.g. HyperCVAD) TKI + blinatumomab  Blinatumomab: Bispecific T-cell engager (CD19 × CD3) TKI + steroid or vincristine/dexamethasone If elderly or frail patient If CR after induction : check MRD status: MRD+ Blinatumomab +/- TKI Inotuzumab ozogamicin +/- TKI I notuzumab ozogamicin: Anti-CD22 ADC I ncreases risk of veno-occlusive disease/liver toxicity TKI TKI + chemo allo-HSCT followed by TKI MRD- Blinatumomab + TKI TKI TKI + chemo allo-HSCT If no CR: Treat as relapsed/refractory disease: ABL domain testing TKI +/- chemo TKI +/- steroid Blinatumomab +/- TKI Inotuzumab ozogamicin +/- TKI CAR-T cell therapy Philadelphia chromosome negative B-cell A L L: Adolescent/Young Adult (AYA):  Pediatric-inspired protocols: CALGB 10403: Daunorubicin, pegaspargase, prednisone, vincristine DFCI Protocol 00-01: Doxorubicin, high-dose methotrexate, pegaspargase, prednisone, vincristine Adult <65 and no significant comorbidities:  Multi-agent chemo: ECOG 1910: Cyclophosphamide, cytarabine, daunorubicin, dexamethasone, mercaptopurine, pegaspargase, vincristine + rituximab for CD20+ disease and CD20 expression ≥20% HyperCVAD: Hyper fractionated C yclophosphamide, V incristine, Doxorubicin ( A driamycin), D examethasone Alternating with high-dose methotrexate and cytarabine + rituximab for CD20+ disease and CD20 expression ≥20% Adult >65 or with significant comorbidities: Multi-agent chemo (less intense chemo: e.g. POMP) POMP: P rednisone, Vincristine ( O ncovin), M ethotrexate, 6-Mercapto p urine Palliative steroid Inotuzumab ozogamicin If CR after induction: check MRD status: MRD+ Blinatumomab → allo-HSCT Inotuzumab ozogamicin → allo-HSCT MRD- Blinatumomab +/- alternating with chemo allo-HSCT if high risk features If no CR : Treat as relapsed/refractory disease: Blinatumomab Inotuzumab ozogamicin Revumenib (if KMT2A rearranged) Multiagent chemo CAR-T cell therapy T-cell ALL: Typically present with leukocytosis, mediastinal, CNS involvement  Adolescent/Young Adult (AYA) and Adult <65 and no significant comorbidities: Pediatric-inspired protocols: CALGB 10403 DFCI Protocol 00-01 Adult >65 or with significant comorbidities: Multi-agent chemo (less intense chemo: e.g. POMP) Palliative steroid If CR after induction : check MRD status: MRD+ (or high risk features) Allo-HSCT Continue multi-agent chemo (POMP maintenance) MRD- Continue multi-agent chemo (POMP maintenance) Consider allo-HSCT If no CR : Treat as relapsed/refractory disease: Nelarabine → allo-HSCT Revumenib (if KMT2A rearranged) → allo-HSCT Multiagent chemo → allo-HSCT

Diffuse large B-cell lymphoma (DLBCL) Anti-CD19 CAR-T cell: Preferred for relapsed/refractory DLBCL if relapsed <1 year. Tisagenlecleucel (tisa-cel) Axicabtagene ciloleucel (axi-cel) Lisocabtagene maraleucel (liso-cel) Brexucabtagene autoleucel (brexu-cel) Anti-CD19 mAb: Tafasitamab Anti-CD20 mAb: Rituximab Obinutuzumab Anti-CD79b ADC ( Antibody-Drug Conjugate) : Polatuzumab vedotin Used in Pola-R-CHP regimen Anti-CD19 ADC: Loncastuximab Tesirine CD20 x CD3 Bispecific Ab: Engineered antibody that simultaneously binds to CD20 on B cells and CD3 on T cells → redirecting T cells to recognize and kill malignant B cells Epcoritimab Glofitamab Mosunetuzumab XPO1 inhibitor (nuclear exporter protein): Selinexor   Follicular Lymphoma/ Nodal Marginal Zone Lymphoma Anti-CD19 CAR-T cell: Tisagenlecleucel (tisa-cel) Axicabtagene ciloleucel (axi-cel) Anti-CD20 mAb: Obinutuzumab Rituximab CD20 x CD3 Bispecific Ab: Epcoritimab Mosunetuzumab EZH2 inhibitor: Tazametostat For relapsed/refractory FL who have received at least two prior systemic therapies, regardless of EZH2 mutation status (better response in EZH2 mutated, but still derived benefit in wild type) PI3K inhibitor: Copanlisib   Hodgkin Lymphoma Anti-CD30 ADC: Brentuximab Vedotin Used in BV-AVD regimen PD-1 inhibitor: Nivolumab Pembrolizumab   Multiple Myeloma (MM) Anti-CD38 mAb: Daratumumab Isatuximab BCL-2 inhibitor: Venetoclax B-cell maturation antigen (BCMA) CAR T-cell: Idecabtagene vicleucel (ide-cel) Ciltacabtagene autoleucel (cilta-cel) BCMA x CD3 Bispecific Ab: Engineered T-cell engaging antibody that binds CD3 on T cells and BCMA on MM cells. Teclistamab Elranatamab GPRC5D x CD3 Bispecific Ab: Engineered T-cell engaging antibody that binds CD3 on T cells and GPRC5D on MM cells. Talquetamab SLAMF7 mAb: Elotuzumab   Acute Lymphoblastic Leukemia (ALL) Anti-CD19 mAb: Blinatumomab Anti-CD22 ADC: Inotuzumab ozogamicin   Acute Myeloid Leukemia (AML) Anti-CD33 ADC: Gemtuzumab ozogamicin BCL-2 inhibitor: Venetoclax FLT3 inhibitor: Midostaurin Quizartinib Gilteritinib Hedgehog pathway inhibitor: Glasdegib IDH inhibitor: IDH1 inhibitor: Ivosidenib Olutasidenib IDH2 inhibitor: Enasidenib Sezary Syndrome Anti-CCR4 mAb: Mogamulizumab Anti-CD30 ADC: Brentuximab Vedotin Histone deacetylase ( HDAC) inhibitor: Romidepsin Vorinostat

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

Types: Papillary Thyroid Carcinoma Medullary Thyroid Carcinoma Follicular Thyroid Carcinoma Hurthle Cell Carcinoma Anaplastic Thyroid Carcinoma Suspicious features of thyroid nodules on US: Irregular margins Microcalcifications Taller than wide shape Rim calcifications with small extrusive soft tissue component Extrathyroidal extension Central vascularity Treatment: Treatment typically entails surgery (lobectomy vs. thyroidectomy) Indications for thyroidectomy : History of prior radiation exposure (Category 2B) Extrathyroidal extension Poorly differentiated and differentiated high-grade carcinoma Lateral cervical LN metastases or gross central neck LN metastases Tumor >4 cm Bilateral nodularity Known distant metastases Post thyroidectomy Post-operative thyroglobulin should be negative. If positive, concerning for residual disease.  Obtain Radioactive Iodine (RAI) uptake scan if has any high risk features: Largest primary tumor >2 cm in size Detectable anti-Tg antibodies High-risk subtypes (poorly differentiated, tall cell, columnar cell, hobnail variants, diffuse sclerosing, and insular) Lymphatic invasion Cervical LN metastases Macroscopic multifocality (one focus > 1 cm) Postoperative unstimulated thyroglobulin 1 - 10 ng/mL Microscopic positive margins Can defer RAI if all criteria met: Papillary thyroid cancer Small primary tumor (≤ 2 cm) Intrathyroidal Unifocal or multifocal (all foci ≤ 1 cm) No detectable Tg antibodies Postoperative unstimulated thyroglobulin <1 ng/mL or stimulated Tg <2ng/mL Negative postoperative ultrasound, if done RAI is not indicated in the treatment of Medullary thyroid cancers. Levothyroxine To maintain low TSH levels in the treatment of patients with papillary, follicular, or Hurthle cell carcinoma Papillary Thyroid Cancer Highly curable Localized disease is treated with surgery as above In patients who undergo thyroid lobectomy + isthmusectomy and are found to have any of the following features, should undergo a complete thyroidectomy: Tumor >4 cm Gross positive resection margins Confirmed nodal metastasis Vascular invasion Confirmed contralateral disease Gross extra-thyroidal extension Metastatic Disease Responds well to RAI if it takes up radioiodine on scans- can be curative Can use lenvatinib or sorafenib if no other actionable mutations If NTRK gene fusion: Larotrectinib Entrectinib If BRAF mutation: Dabrafenib Trametinib If RET fusion positive: Pralsetinib Selpercatinib Can consider cabozantinib if progressed following prior VEGFR-targeted therapy Medullary Thyroid Cancer Arise from parafollicular C cells of the thyroid Workup: Screening for germline RET proto-oncogene mutations CEA level Calcitonin level Screen for pheochromocytoma Contrast-enhanced CT of Neck/Chest and Liver MRI (or 3-phase CT of liver) or Ga-68 DOTATATE PET-CT scan if there is a high concern of distant metastases.  Systemic imaging is considered for patients who have a high burden of disease, calcitonin level >500 pg/mL, or elevated CEA levels.   Treatment: ≥ 1 cm in diameter OR bilateral thyroid disease: Total thyroidectomy with bilateral central neck dissection . <1 cm in diameter AND unilateral thyroid disease: Total thyroidectomy with consideration of a bilateral central neck dissection. Post-operative levothyroxine to normalize the TSH. RAI is not indicated Calcitonin can be used to monitor for disease recurrence If slightly rising: continue to monitor CEA and calcitonin levels In patients with stable or slowly progressive indolent disease, can be closely monitored and not be started immediately on kinase inhibitor If calcitonin level rises to ≥ 150 pg/mL: CT with contrast of the neck, liver, and chest and possibly a bone scan Metastatic Disease: Treatment includes kinase inhibitors use: Vandetanib Cabozantinib Selpercatinib (if RET mutated) Anaplastic Thyroid Cancer Very aggressive- worst prognosis of all types of thyroid cancer All patients classified as having Stage IV disease Originate from the follicular cells of the thyroid Often invade the surrounding tissues including the trachea, esophagus and larynx They do not have any uptake of iodine nor do they synthesize thyroglobulin.  RAI therapy is ineffective as treatment Should be genomically profiled to see if the tumor harbors a BRAF V600E mutation, RET fusion, or NTRK gene fusion is present Treatment:  Locoregional disease: Consider total thyroidectomy with therapeutic LN dissection.  Can consider adjuvant EBRT/IMRT with radiosensitizing chemotherapy. Locally advanced/unresectable: EBRT/IMRT + chemotherapy (weekly Carboplatin/Taxol).  Reconsider surgery after neoadjuvant therapy depending on the response. Can consider targeted neoadjuvant therapy for patients with borderline resectable disease. Metastatic:  Consider surgery or RT for local palliative control Same: If NTRK gene fusion: Larotrectinib Entrectinib If BRAF mutation: Dabrafenib Trametinib If RET fusion positive: Pralsetinib Selpercatinib

Risk factors: History of cryptorchidism (undescended testis) Family history of testicular cancer Personal history of testicular cancer Initial work up: Testicular ultrasound Tumor markers: AFP, hCG, LDH Do not biopsy testis. Radical inguinal orchiectomy (through inguinal incision, not scrotum) Brain MRI recommended if: Neurologic symptoms Post-orchiectomy beta-hCG > 5000 Extensive lung metastases Non-pulmonary visceral metastases AFP >10000 (non-seminoma) Predominant choriocarcinoma component (non-seminoma) isochromosome 12p is a hallmark cytogenetic abnormality in testicular germ cell tumors It is a somatic genetic abnormality/ Not considered a hereditary predisposition factor Types: Seminoma: More likely to present with localized disease, indolent growth, less likely to be metastatic beyond RP nodes Non seminoma: Embryonal Carcinoma, Choriocarcinoma, Yolk Sac Tumor (endodermal sinus tumor), Teratoma Tumor Markers: AFP: NOT produced by seminomas (if high, assume non-seminoma) Half life ~7 days May be elevated due to liver disease/toxicity.  Generally ignore if <20-25 ng/mL B-HCG: Can be made by any germ cell tumor.  Half life ~3 days.  Can have false positives from hyperthyroidism, marijuana consumption or in hypogonadism from pituitary HCG production (can test this by administering testosterone. if coming down, then not from cancer). LDH: Very non-specific. used for staging purposes, but not very important in response to treatment or relapse. Risk Stratificatio n: Risk Status Nonseminoma Seminoma Good Risk Testicular or retroperitoneal primary tumor + No nonpulmonary visceral metastases + Post-orchiectomy markers (all): AFP <1000, hCG <5,000, LDH < 1.5 ×ULN Any primary site + No nonpulmonary visceral metastases + Normal AFP, any hCG, any LDH Intermediate Risk Testicular or retroperitoneal primary tumor + No nonpulmonary visceral metastases + Post-orchiectomy markers (any): AFP 1,000–10,000, hCG 5,000–50,000, LDH 1.5–10 ×ULN Any primary site + Nonpulmonary visceral metastases + Normal AFP, any hCG, any LDH Poor Risk Mediastinal primary tumor OR Nonpulmonary visceral metastases OR Post-orchiectomy markers (any): AFP >10,000, hCG >50,000, LDH >10 ×ULN No patients classified as poor prognosis Seminoma Testicular Cancer AFP is normal in seminomas. Treatment: Stage IA, IB (limited to testes): Radical inguinal orchiectomy followed by:   Surveillance - preferred approach Adjuvant Carboplatin (AUC/Area Under Curve 7) x1-2 cycles Adjuvant radiation to retroperitoneum (consider risk of secondary cancers in younger patients) Consider adjuvant treatment if “high risk” features for recurrence, specifically rete testis invasion or tumor size > 4cm. Monitor tumor markers to ensure downtrended Stage IS (limited to testis but have persistent elevation of tumor markers after orchiectomy) Tumor marker elevation after orchiectomy generally indicates presence of metastatic disease despite radiographic evidence of disease, thus treat like stage III (see below) Treat as good/intermediate risk based of how high tumor markers are CAP CT with contrast Stage IIA Seminoma (spread to RP nodes, <3cm) RT to para-aortic and ipsilateral LNs BEP x 3, or EP x 4 BEP: B leomycin + E toposide + Cis p latin Nerve sparing RPLND Stage IIB Seminoma (spread to RP nodes, >3 cm) BEP x3, or EP x 4 Stage IV: Treatment is same for seminomas and nonseminomas Chemo regimen based on risk stratification (Table above): Good risk: BEP x3 cycles, or EP x4 cycles Intermediate/Poor risk: BEP x4 cycles, or VIP x4 cycles (if contraindication to Bleomycin) Residual Masses >3 cm: PET CT and resect if FDG avid If residual mass is present after completion of treatment: perform PET/CT and likely surgery (if FDG avid). The mass may be teratoma vs fibrosis/necrosis. About 10-15% of resected residual masses harbor viable germ cell tumor Late relapse (> 2 years after completion of chemo) Consider surgery if resectable Consider VeIP or TIP x 4 Consider high dose chemotherapy Non-Seminoma Testicular Cancer Stage I: Radical inguinal orchiectomy followed by:   Surveillance (preferred) BEP x 1 RPLND RT is NOT an option for non-seminoma. Consider adjuvant treatment if “high risk” features for recurrence, specifically lymphovascular invasion, predominant embryonal carcinoma >50%, histology, Invasion of spermatic cord or scrotum Monitor tumor markers to ensure downtrended Stage II: RPLND → if malignant nodes, consider adjuvant EP x2 BEP x3 or EP x4 Stage IV: Treatment is same for seminomas and nonseminomas Chemo based on risk stratification (Table above): Good risk: BEP x3 cycles, or EP x4 cycles Intermediate/Poor risk: BEP x4 cycles, or VIP x4 cycles (if contraindication to Bleomycin) Later Line therapies: TIP: Pacli t axel, I fosfamide, Cis p latin VeIP: V inblastine , E toposide, I fosfamide, Cis p latin High-Dose chemo: Carboplatin/Etoposide x2 cycles Paclitaxel/Ifosfamide/Carboplatin/Etoposide x3 cycles Pembrolizumab (MSI-high, dMMR, TMB high) HSCT Residual Masses >3 cm: Resect RPLND: all NSGCT residual masses MUST be resected. Clinical Pearls Check tumor markers immediately prior to initiation of treatment for risk stratification. It is unlikely to be a seminoma if AFP is elevated, regardless of what pathology says. Beta-hCG can be mildly elevated in hypogonadism, hyperthyroidism, marijuana use. Avoid bleomycin in patients with underlying lung disease, elderly, reduced GFR If bleomycin toxicity develops: complete course with EP or change to VIP Bleomycin does not cause neutropenia. Typically G-CSF is not needed and would treat through myelosuppression Testicular cancer is associated with cryptorchidism

Cutaneous Melanoma The BRAF V600 mutation is a frequent somatic/acquired driver mutation in cutaneous melanoma. Cyclin-dependent kinase inhibitor 2A (CDKN2A) is the most frequently mutated high-risk gene associated with familial cutaneous melanoma. Staging: Any N+ disease is Stage IIIA and up Memorize staging: Stage Thickness Ulceration T1a < 0.8 mm No T1b < 0.8 mm Yes T1b 0.8–1 mm with or without T2a 1–2 mm No T2b 1–2 mm Yes T3a 2–4 mm No T3b 2–4 mm Yes T4a > 4 mm No T4b > 4 mm Yes Stage T N M Stage 0 Tis N0 M0 Stage IA T1a N0 M0 Stage IB T1b, T2a N0 M0 Stage IIA T2b, T3a N0 M0 Stage IIB T3b, T4a N0 M0 Stage IIC T4b N0 M0 Stage III Any T, Tis ≥N1 M0 Stage IV Any T Any N M1 Localized Melanoma:  Surgical Margins are based on the Breslow thickness: Thickness: Surgical margin: In situ 0.5-1 cm ≤ 1 mm 1 cm > 1 mm - 2 mm 1-2 cm >2 mm 2 cm Adjuvant radiation : Consider for desmoplastic melanoma with risk factors for local recurrence: Location on the head and neck Extensive neurotropism Pure desmoplastic melanoma subtype Close margins where re-resection in not feasible, or locally recurrent disease Extracapsular extension of melanoma in clinically (macroscopic) involved lymph node ≥1 involved parotid node ≥ 2 involved cervical or axillary nodes ≥ 3 involved inguinofemoral nodes ≥3 cm cervical or axillary node ≥ 4 cm inguinofemoral node Routine imaging: NOT recommended for stage IA-IIA melanoma with no evidence of disease (only if concerning sign/symptom). Routine SLN biopsy : NOT recommended for patients with Stage IA (T1a N0 M0) Consider SLN biopsy for Stage IB (T1b/T2a N0 M0) If clinically negative node but SLN+ → complete LN dissection + ultrasounds q3 months For in-transit metastasis (Stage III): If resectable: Resection followed by adjuvant therapy If unresectable: Systemic therapy Local treatment options (TVEC, IL2, imiquimod, RT) Adjuvant therapies: For stage IIB/C : Adjuvant Nivolumab (Checkmate-76K) Adjuvant Pembro x1 year (Keynote-716) For stage IIIA: Better outcomes than Stage IIB/C, consider against adjuvant therapies (great prognosis) For stage IIIB/C/D: Adjuvant Nivolumab x1 year (Checkmate-238) Adjuvant Pembro x1 year (Keynote-054: d id not include stage IIIA with SNL+ and <1 mm tumor burden) Perioperative pembro (3 doses prior and 15 doses after) for stage IIIB-IVC (SWOG 1801) Adjuvant Dabrafenib/Trametinib if actionable BRAF mutation: only BRAF/MEK combination approved (COMBI-AD) Metastatic Melanoma: First line treatment Ipilimumab + Nivolumab Checkmate-067 (Nivo 1 + ipi 3) - combo more side effects Checkmate-511: flip dosing (Nivo 3 + Ipi 1) - improved AE’s Nivolumab/relatlimab-rmbw (Opdualag)- preferred in metastatic disease Nivolumab Pembrolizumab  If BRAF V600E or V600K:  Still use IO in 1L setting DREAMSeq Trial: Ipi + Nivo followed by Dabrafenib+Trametinib (BRAF/MEK inhibitor) after PD showed OS benefit in patients with BRAF V600E (compared to the opposite) BRAF/MEK inhibitor provides a rapid response rate compared to immune-based therapy. However, responses can sometimes be short-lived. Consider using first in patients with visceral crisis who have BRAF V600E/V600K mutation Associated with increased risk of hemorrhage, cardiomyopathy, and ocular toxicities Treatment options with BRAF/MEK inhibitors: Dabrafenib/Trametinib Best CNS penetration- Associated with fevers Cobimetinib/Vemurafenib Vemurafenib causes more SCC and rash/photosensitivity Encorafenib/Binimetinib If progression with above options: Consider tumor-infiltrating lymphocyte therapy (TILs) with Lifileucel If oligometastatic disease: Can do resection followed by “peri-adjuvant” therapy Uveal Melanoma Associated with BAP1 (familial uveal melanoma) or GNAQ/GNA11 mutation They like to metastasize to liver (Buzz word) Treatments for advanced disease: Pembrolizumab Nivolumab Ipi/Nivo Tebentafusp (ImmTAC) T cell receptor targeting gp100  MHC-A/class 1 molecule Preferred over immunotherapy in patients with HLA-A*01:01-positive disease Ipilimumab Chemotherapy Trametinib HEPZATO KIT (melphalan for injection/hepatic delivery system) Acral/Mucosal Melanoma Acral melanoma: Distinct type of melanoma found on palms of hands or feet Mucosal Melanoma: Markers are S-100 and HMB-45 and Melan-A If KIT mutation is present: Can treat with imatinib, dasatinib, nilotinib, ripretinib Basal Cell Carcinoma (BCC) Associated with abnormalities in the sonic hedgehog pathway Rarely Metastasizes  Local Disease: Low risk disease : Location in trunk/extremity <2cm in size Well defined borders Primary disease No sites of prior RT No immunosuppression Nodular and superficial subtypes No perineurial invasion High risk disease : Poorly defined borders Larger than 2cm on trunk/extremities Any lesions located on head, neck, hands, feet, anogenital area Recurrent disease Site of prior RT With perineural invasion Aggressive growth pattern Treatment: If low-risk disease: Resection If high-risk disease: Mohs, standard excision with wider margins, radiation (avoid in patients with predisposition to develop neoplasm), systemic therapy Metastatic/Locally Advanced: First line: Sonidegib For patients with recurrence following surgery or radiation therapy For patients who are not candidate for surgery or radiation therapy Not approved for metastatic disease Vismodegib For metastatic disease (SHH pathway) Subsequent lines: Cemiplimab upon progression Squamous Cell Carcinoma (SCC) Risk factors:  Sun exposure, advanced age, sensitivity to UV radiation, immunosuppression use. Local disease: Treatment: Surgical resection Consider neoadjuvant cemiplimab if: Locally advanced disease/surgery would be too morbid Very rapid growth Positive lymphovascular invasion) For high-risk localized disease ( same criteria as BCC ): Consider adjuvant radiation, standard excision with wider margins, Mohs, PDEMA Metastatic disease: First line: Cemiplimab Pembrolizumab Second line: Carboplatin/paclitaxel/cetuximab (also consider if contraindication to immunotherapy) Merkel Cell Carcinoma Background: Cutaneous neuroendocrine cancers Highly aggressive Associated with polyomavirus CK20 is highly positive marker Local disease: Surgery with SLNB +/- radiation in high risk patients (HIV, CLL, Head and Neck Primary site, +LVI, >1cm) Metastatic disease: First line: Pembrolizumab (Keynote-017) Avelumab (JAVELIN Merkel 200) Nivolumab Ipi + Nivo Retifanlimab Subsequent lines: platinum/etoposide, topoitecan, cyclophosphamide, doxorubicin, and vincristine, TVEC, Ipi/nivo, pazopanib, somatostatin analogues (if positive) Kaposi Sarcoma Typically associated with HIV Limited disease: If asymptomatic: Consider observation or treating HIV If symptomatic: Consider local therapies, RT, or systemic therapies Advanced disease: In patients with untreated HIV → start HAART In patients with treated HIV: First line: Doxil (preferred), Paclitaxel Subsequent lines: Nivolumab, Pembro, Pomalidomide, Abraxane (if paclitaxel intolerant), Bortezomib, Etoposide, Gemcitabine, Imatinib, Ipi/Nivo, Lenalidomide, Sirolimus (for transplant associated KS), Thalidomide (for patients with IRIS), Vinorelbine

Background: Genetic Risks: Li-Fraumeni syndrome (p53) NF1 (malignant peripheral nerve sheath tumors) Familial Rb Gardeners/FAP (APC) Desmoid tumors Most are sporadic tumors Risk factors: Prior radiation is the #1 risk factor (esp within 10-30 years) HIV or HHV-8 (Kaposi Sarcoma) Chronic Lymphedema (Angiosarcoma) Most common types: Gastrointestinal stromal tumor (GIST) Characterized by c-KIT or PDGFRA mutations Liposarcoma Well-differentiated/Dedifferentiated liposarcoma MDM2 and CDK4 are highly sensitive and specific Myxoid round cell liposarcoma Associated with t(12;16) translocation involving DDIT3 Leiomyosarcoma Synovial sarcoma Associated with SYT-SSX Undifferentiated pleomorphic sarcoma malignant peripheral nerve sheath tumor (MPNST) Diagnosis : Needle or excisional biopsy Staging: Require MRI if in extremity or trunk TNM Staging: T is variable based on the tumor location CT chest: Tumors tend to metastasize to lungs SCARE ( higher propensity for lymphatic/LN metastasis ): S ynovial sarcoma C lear cell sarcoma A ngio sarcoma R habdomyo sarcoma E pithelioid  sarcoma Treatment: Localized disease: Surgery Consider pre-op vs post-op radiation Post-op: larger volume of radiation, less wound healing complication Benefit of chemotherapy is not very clear with soft tissue sarcoma Consider use of adjuvant pembrolizumab in high grade/stage III sarcomas Local recurrence: Re-excision +/- radiation is the preferred treatment Systemic therapy is controversial Consider for high-grade, rapidly growing, or multifocal recurrences Metastatic disease: Resection for oligometastatic disease (potentially curative)  Systemic Therapy: Doxorubicin AIM: Doxorubicin ( A driamycine), I fosfamide, M esna Doubles response rates, but no change in OS AD: Doxorubicin ( A driamycine), D acarbazine Used in leiomyosarcoma Doxorubicin + Trabectidin Gemicitabine +/- Docetaxel Trabectidin Liposarcoma and leiomyosarcoma Associated with muscle injury Eribulin liposarcoma Paclitaxel Angiosarcoma and kaposi sarcoma Pazopanib Soft tissue sarcoma but not liposarcoma Pembrolizumab (if TMB >10) Palbociclib Well/de-diff liposarcomas Imatinib Dermatofibrosaroma pertuburans  Nabsirolimus Pecoma Tazametostat Epithelioid sarcoma Benign but locally aggressive tumors Synovial giant cell tumor: High recurrence rate Treatment: Surgery Medication: Paxidartinib (liver toxicity) Vimsultinib (ORR 40%, no serious liver injury) Desmoid tumor: Associated with FAP/Gardner syndrome Treatment: Observation is preferred approach Can be asymptomatic or spontaneously regress Surgery Ablation: Cryo or Radiofrequency ablation (RFA) Nirogasestat  Ovarian toxicity (early menopause) Other TKIs such as sorafenib (off label) Kaposi Sarcoma: Associated with HIV and HHV8 Treatment: HAART: if associated with HIV Pomalidomide If failure of HAART therapy HIV negative patients Paclitaxel Doxorubicin Local excision or radiation