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

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

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

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

Major components of hemostasis: Primary hemostasis (platelet plug) Defects lead to mucosal bleeding (petechiae, purpura, epistaxis) Secondary hemostasis (blood clot) Defects lead to larger bleeds related to surgery/trauma (joint bleeds, muscle bleeds) Coagulation Cascade: Intrinsic pathway Initiated by Factor XII → activates prekallikrein to kallikrein and high-molecular-weight kininogen → activation of factor XI and IX and VIII Extrinsic pathway Initiated by tissue factor → activate factor 7 Common pathway Factor X, V, II and I (symmetrical roman numerals) Vitamin K dependent factors: Factor II, VII, IX, X, protein C and S Inhibited by warfarin All produced in liver Natural anticoagulants: Antithrombin Protein C and Protein S Tissue factor pathway inhibitor (TFPI) Individual factor clinical pearls: Factor XIII deficiency: Does not affect INR and PTT Factor XII deficiency: May affect PTT in vitro but no clinical bleeding, does not require treatment Factor XI deficiency: Mild to no bleeding- May present late in life Factor VIII, IX deficiency: Hemophilia A & B May require recombinant/activated factor VIII, IX or downstream product Factor VII deficiency: Rare autosomal recessive Affects PT/INR, not PTT Treated with recombinant factor VIIa q6-8h or FFP If both INR and PTT affected: think something in the common pathway X, V, II, I, or fibrinogen Acquired factor X deficiency is associated with AL amyloidosis If acquired inhibitor present: Most likely would require some type of immune suppression such as corticosteroids, IVIG, Rituximab, cyclosporine, PLEX, etc.  Fibrinolysis & clot degradation: Plasminogen activators Convert plasminogen to plasmin, which degrades fibrin clots Mechanism of action of tPA (tissue plasminogen activator) Antithrombotic/Anticoagulants Vitamin K antagonist Warfarin: Competitively inhibits vitamin K oxide reductase Prevents carboxylation of Gla residues on their amino terminus Hepatic clearance Main indications: anticoagulation for mechanical heart valves Antiphospholipid syndrome (APLS) Administration requires close monitoring of INR Rare side effect is warfarin skin necrosis Due to hypercoagulable state within 24 hours of warfarin treatment Due to shorter half life of protein C which leads to thrombotic state Deficiency of protein C and S, Factor V Leiden, antithrombin III, hyperhomocysteinemia, and antiphospholipid antibodies are common risk factors Reversible with: Hold medication If INR < 10, no bleeding Vitamin K If INR > 10, no bleeding FFP is technically an option PCC (preferred in emergent situations) Antithrombin activation Heparin Hepatic clearance Reversible with protamine sulfate Lovenox More specific to target factor Xa activity Renal clearance Reversible with protamine sulfate Fondaparinux More specific to target factor Xa activity  Renal clearance NOT reversible with protamine sulfate Factor Xa inhibitor Apixaban, Edoxaban, Betrixaban Antidote: Andexanet Alpha Direct Thrombin inhibitors Argatroban Hepatic clearance Non-peptide  Parenteral  Bivalirudin Renal clearance Peptide (20 aa) Parenteral  Dabigatran (Pradaxa) Oral  Renal clearance Antidote: Idarucizumab  Antiplatelets COX inhibitor Aspirin Irreversible platelet inhibitor Acetylates cyclooxygenase 1 & 2 Commonly used in cardiac/stent patients P2Y12 Antagonists (ADP receptor) Ticlopidine, clopidogrel, prasugrel, ticagrelor Commonly used in cardiac/stent patients GPIIB/IIIa antagonists Has indication in ACS with PCI but not widely used Can cause rapid thrombocytopenia (drug/platelet complex leads to ab formation) Abciximab Half life 14 days Eptifibatide  Cyclic heptapeptide Very short half life <1 hour Tirofiban Protease activated receptor 1 (PAR1) Vorapaxar Irreversible  Used to reduce thrombotic cardiovascular events in MI and PAD (secondary prevention) Cleared in feces and renally Von Willebrand Disease (VWD) Von Willebrand Factor: Found in endothelial surface Binds with GP1b on platelets Subtypes of vWD: Type 1 and Type 3: Quantitative disorders Function proportional to level of enzyme/protein present Type 1C: Associated with increased clearance/shorter half life of vWF Type 2: Functional disorder/ Function is disproportion to level of enzyme/protein present Type 2A: Reduction/absence of high-molecular-weight vWF multimers → decreased platelet-dependent vWF activity Heyde syndrome: Aortic stenosis + intestinal angiodysplasia + Type 2A vWD Type 2B: Gain-of-function mutation in vWF → increases its affinity for platelets → enhanced platelet binding and clearance → thrombocytopenia The only one wit h elevated Ristocetin-Induced Platelet Aggregation (RIPA) Autosomal dominant Never give ddAVP Type 2M: Decreased vWF interactions with platelets/collagen but with a preserved multimer pattern Type 2N: Reduced binding of vWF to factor VIII → low factor VIII levels Like hemophilia (may have a female patient to delineate from hemophilia) The presence of a female patient with a hemophilia-like bleeding phenotype should prompt consideration of vWD rather than hemophilia. FVIII:C vWF:Ag vWF: RCoF RIPA Type 1 (most common) ↓ ↓ ↓ ↓ or normal Type 2A ↓ ↓ ↓↓ ↓↓ Type 2B ↓ ↓ ↓↓ ↑ Type 2N (recessive) ↓↓ normal normal normal Type 3 (rare, recessive) ↓↓↓ ↓↓↓ ↓↓↓ ↓↓↓ Treatment: Depends on type of vWD Desmopressin (ddAVP) Transiently increases vWF and FVIII in plasma Used in: Type 1 and Type 2A (minor procedures) Administered nasally or IV Ideally can perform a challenge to document response (pre, 1hr, 4 hr levels) Hyponatremia can occur (from SIADH) Development of tachyphylaxis after a few doses Intermediate-purity factor concentrates Humate-P Alphanate Wilate Recombinant vWF Does NOT contain factor 8, therefore not for acute bleed in Type 3 Indications: Moderate/severe Type 1 for major procedures Type 2A for major procedures Type 2B for most procedures Antifibrinolytics Tranexamic acid Aminocaproic acid Pregnancy: Normally one can expect physiologic increase in vWF during pregnancy that exceeds 50IU/dL Should be above 50IU/dL for epidural to be placed or surgery/delivery (and for 3-5 days after delivery) vWF levels also decline over 2-3 weeks postpartum Acquired von Willebrand disease: Associated with certain lymphoproliferative disorders, plasma cell dyscrasias, neoplasms, severe thrombosis, hypothyroidism, ECMO/LVAD Treatment: Desmopressin, factor VIII/vWF concentrates, IVIG, plasmapheresis, plateletpheresis, corticosteroids, rituximab, other types of immunosuppression Hemophilia X-linked recessive Deficiency of factor VIII (type A) and factor IX (type B) Levels correlate with bleeding severity Severe: <1% Spontaneous bleeding, risk of intracranial bleeding, risk of developing inhibitors Moderate: 1-5% Fewer spontaneous bleeds, but can become severe once bleed starts Mild: 5-50% Bleeding with certain procedures (surgery/trauma), catastrophic bleeding is rare Lead to larger bleeds related to surgery/trauma (joint bleeds, muscle bleeds), intracranial Can lead to compartment syndrome Long term sequelae: Hemophilic arthropathy Decreased joint space Bony erosion Treatment: Factor therapy Raise levels to normal for severe bleeds or treat minor bleeds Goal: above 50% Factor VIII 1 unit/kg body weight raises factor level 2% Example: 50 U/kg raises level to 100%, followed by maintenance 25 U/kg in 12 hours Factor IX 1 unit/kg body weight raises factor level 1% Ex: 100 U/Kg raises level to 100%, followed by maintenance 50 U/Kg Use Aminocaproic acid (Amicar) or TXA for mucosal/oral cavity bleeding Consider DDAVP for mild hemophilia A Emicizumab: (factor 8 mimetic) approved for prophylaxis of bleeding in congenital hemophilia A Associated with thrombotic complications when used with FEIBA Gene therapy is also an option for hemophilia A and B Bypassing agents are useful in factor deficiencies, particularly with inhibitors Be suspicious of an inhibitor if bleeding does not resolve with factor replacement Hypercoagulability Who needs a work up? DVT/PE with intermediate risk of recurrence Unprovoked VTE in unusual locations Cerebral vein/sinus, retinal vein/artery, splanchnic veins, renal veins, gonadal vein, skin Arterial thrombus (if unexplained) Timing of testing should be at least 1 month after being off of anticoagulation Do not test during acute clot as it can skew test results/difficult to interpret Thrombophilias: Antiphospholipid syndrome Needs history of thrombosis and/or pregnancy morbidity Labs tested need to be down 2 times > 12 weeks apart Anti-cardiolipin (IgG/IgM) Anti-beta2-glycoprotein (IgG/IgM) Lupus anticoagulant Strongest independent factor Can be falsely positive if drawn while on anticoagulation Treatment: Warfarin Antithrombin deficiency Protein C & S deficiency Homozygous Factor V Leiden (most common) Homozygous Prothrombin gene mutation (factor II) Heterozygous for both F5L and prothrombin gene Hemolytic diseases

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: did 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

Qualitative: Defects in membrane glycoproteins Bernard-Soulier Syndrome (GPIb/IX/V) Glanzmann Thrombasthenia (GPIIB/IIIa) Collagen Defects (GPVI and GPIa/IIa) Defect in platelet granules Storage Pool Deficiency Gray Platelet Syndrome Quebec Platelet Disorder Hermanksy Pudlak syndrome Defects in platelet secretion and signaling Defects in platelet coagulant activity Defects of transcription factors RUNX1 Defects of cytoskeletal/structural proteins Wiskott-Aldrich Syndrome B1-Tubulin Deficiency Kindlin Defect Acquired (iatrogenic) Medications Uremia Cardiopulmonary Bypass Quantitative: Thrombocytosis Essential Thrombocythemia (ET) Thrombocytopenia Decreased bone marrow production Sequestration Hemodilution Increased consumption Increased clearance Alloimmune Pseudothrombocytopenia Platelet Function Tests: Arachidonic acid: Tests the thromboxane pathway Epinephrine: Tests receptor binding leading to ADP release Ristocetin: Tests for the functional vWF receptor/GP1b/IX complex Thrombin: Tests full platelet aggregation independent of both the ADP and prostaglandin pathway Aggregation studies: Primary wave/aggregation: Initial and reversible clumping of platelets stimulated by exogenous agonists like ADP/epinephrine/collagen Secondary wave/aggregation: subsequent often irreversible aggregation caused by the release of internal platelet agonists, such as ADP/ epinephrine Defects in membrane glycoproteins: Bernard-Soulier Syndrome (GPIb/IX/V: receptor for vWF): Autosomal recessive Platelets are unable to bind to vWF on endothelial surface → no platelet adhesion to the vessel walls Platelets increased in size Prolonged bleeding time No aggregation in response to ristocetin  Normal response (with primary and secondary wave) to ADP/epinephrine/collagen Treatment for acute bleeding: platelet transfusion Glanzmann Thrombasthenia (GPIIB/IIIa): Autosomal recessive Heterozygotes without bleeding Platelets are unable to bind with fibrinogen and aggregate with other platelets Impaired clot retraction Normal platelet appearance Normal aggregation with ristocetin No primary or secondary wave with ADP/epinephrine/collagen Treatment: platelet transfusion If refractory to platelet transfusion: use recombinant factor VIIa (NovoSeven) Collagen Defects (GPVI and GPIa/IIa) Defects in platelet granules Storage Pool Deficiency Deficiency of dense or alpha granules Normal aggregation  with ristocetin No secondary wave  with ADP/epinephrine/collagen Robust aggregation to primary ADP but much less with secondary ADP Gray Platelet Syndrome Deficiency of alpha granules VWF, factor V, multimerin, fibrinogen, fibronectin, thrombospondin Gray appearance of platelets on PBS No significant abnormality in aggregation studies Mutations in NBEAL2 (responsible for vesicle trafficking) Predisposed to myelofibrosis and elevated Vit B12 Quebec Platelet Disorder Autosomal dominant Normal to reduced platelet counts Decreased alpha granule proteins due to abnormal proteolysis due to increased urokinase plasminogen activator (PLAU) Platelet transfusion does not provide benefit. Hermanksy Pudlak syndrome Autosomal recessive Defect in dense granules Presents with mild bleeding diathesis (avoid anticoagulants), oculocutaneous albinism, and pulmonary fibrosis Defects in platelet secretion and signaling Defects in receptors and signaling Abnormalities in arachidonic acid pathways and TXA synthesis Normal aggregation with ristocetin Reduced secondary wave with ADP/epinephrine Defects in platelet coagulant activity Defects of transcription factors RUNX1: familial platelet defect  Autosomal dominant Impaired megakaryopoiesis Predisposed to AML Defects of cytoskeletal/structural proteins Wiskott-Aldrich Syndrome X-linked Deficiency of dense granules Immunodeficiency, eczema, and thrombocytopenia B1-Tubulin Deficiency Kindlin Defects Acquired (iatrogenic) Medications Uremia Leads to platelet dysfunction through increased nitric oxide production Treated with hemodialysis and DDAVP Cardiopulmonary Bypass Platelets being exposed to different surfaces/substances can activate them and lose their function Should recover in a few days after surgery Thrombocytosis Reactive Essential Thrombocythemia (ET): Associated with increased risk of thrombosis Very high levels of platelets can be associated with acquired vWD → bleeding Small percentage will progress to post-ET myelofibrosis or leukemic transformation Risk criteria: Very low risk:   age <60 + no JAK2 mutation + no history of thrombosis Low risk : age <60 + JAK2 mutation + no history of thrombosis Treatment: Aspirin Intermediate risk:   age >60 + no JAK2 mutation + no history of thrombosis Treatment: Aspirin +/- Hydroxyurea High risk: (age >60 + JAK2 mutation) or (History of thrombosis) Treatment: Aspirin + Hydroxyurea Consider addition of anticoagulation if history of DVT/PE Thrombocytopenia Platelet type bleeding involves skin or mucous membranes Petechiae, ecchymoses, epistaxis, menorrhagia, GI hemorrhage Usually when platelet count less than 20,000 Decreased bone marrow production Congenital disorders: MYH9 thrombocytopenias (May-Hegglin anomaly) Large platelets, thrombocytopenia, nephropathy, deafness Mediterranean macrothrombocytopenia RUNX1 mutation Paris-Trousseau thrombocytopenia DiGeorge Syndrome Congenital amegakaryocytic thrombocytopenia MPL mutation which encodes TPO receptor Wiskott-Aldrich Syndrome GATA-1 mutation Bernard-Soulier Syndrome Acquired disorders: Leukemias, lymphoma, myeloma Aplastic anemia Fanconi anemia Medications Hemodilution Pregnancy: Blood volume increased by up to 30% Sequestration Hypersplenism Kasabach-Merritt syndrome Linked to giant cavernous hemangioma- when hemangioma grows rapidly, trapping platelets causes thrombocytopenia (platelet sequestration) Also associated with DIC (plt consumption) Increased consumption DIC Treat underlying cause: Pancreatitis, trauma/shock, infection, hepatic necrosis Sepsis Cardiovascular disease (ECMO, artificial heart valves) Vasculitis SLE Wegener's disease (Granulomatosis with polyangiitis) Thrombotic microangiopathy Thrombotic thrombocytopenic purpura (TTP) Hemolytic Uremic Syndrome (HUS) Typically patient has diarrhea (from E.coli strains produce Shiga toxin) and renal failure Shiga toxin PCR in stool helps diagnosis Triad of MAHA, thrombocytopenia, AKI Treat infection, plasmapheresis, supportive care 25% mortality without PLEX 50% of patients with permanent renal failure on HD aHUS Complement mediated, leads to renal failure Diagnosis of exclusion Rule out HUS and TTP Treat with anti-C5 therapy (eculizumab, ravulizumab) Pregnancy complications Pre-eclampsia HELLP syndrome Medications Gemcitabine, ticlopidine, clopidogrel, zosyn, sulfa drugs, vancomycin Heparin induced thrombocytopenia (HIT) Vaccine induced thrombocytopenia (VITT) Similar mechanism to HIT without heparin Treat with: DOAC (could also use bivalirudin, argatroban, fondaparinux), IVIG, Steroids, PLEX can be considered Increased clearance Immune thrombocytopenia purpura (ITP) Alloimmune Neonatal alloimmune thrombocytopenia (NAIT) Fetal platelet antigen leads to material antibodies that transfer the placenta and induce thrombocytopenia in fetus Post-transfusion purpura Parous females form high titer anti-HPA-1a (anti Gp2b3a) alloantibodies that destroy autologous platelets Passive alloimmune thrombocytopenia Transfused platelets contain Ab against recipient platelets Transplantation associated alloimmune thrombocytopenia Patient is refractory to platelet transfusion due to residual host lymphocytes Platelet transfusion refractoriness Alloimmunization due to heavy transfusion history Pseudothrombocytopenia EDTA in the collecting blood tubes can cause platelet clumping Repeat the lab but collect the blood sample in a heparin or citrated tube Conditions with giant platelets: Bernard-Soulier Syndrome (GPIb/IX/V) Gray platelet syndrome ITP May-Hegglin anomaly Montreal platelet syndrome (Type IIb vWD) Heparin Induced Thrombocytopenia (HIT) Heparin binds to platelets and releases PF4 eventually causes heparin-PF4 complexes. Heparin-dependent Ab attaches to complex which activates platelets. Usually cause 50% drop in platelet count between 3-30 days after heparin exposure Median plt count is 60K Not associated with plt count <10K Spontaneous HIT: No prior heparin exposure Happens after orthopedic surgeries (usually knee replacement surgery) Also associated with monoclonal gammopathies Should know 4T score: Degree of thrombocytopenia Timing of thrombocytopenia Presence of thromboses Any other cause of thrombocytopenia? Lab tests: Serotonin release assay, Heparin-PF4 antibody Management: Stop heparin and start anticoagulant with direct thrombin inhibitor Bivalirudin is preferred in abnormal hepatic function Argatroban is preferred in abnormal renal function Transition to warfarin, fondaparinux, or DOAC at discharge Plt count should increase to >150K before transitioning to warfarin (bridging). Also, there should be at least 5 days of overlap between direct thrombin inhibitor and warfarin before the former medication is discontinued. Target INR is 2-3. Fondaparinux is contraindicated if CrCl<30 Duration of AC dependent on if clot present If present: 3-6 months If NOT present: unknown (4 weeks usually offered) Platelet transfusion is associated with higher odds of arterial thrombosis and mortality in patients with HIT and TTP. Immune Thrombocytopenia Purpura (ITP) Ab bind to platelet surface (GP2b3a or GP1ba) → splenic/hepatic clearance Peak incidence in childhood (2-10 years) and adult Causes sudden onset bruising and petechiae and sometimes mucosal bleeding Sometimes preceded by viral illness or immunization/vaccination, also associated with H.pylori infection Smear shows normal RBCs but no platelets Could also see giant platelets Bone marrow biopsy should show megakaryocytes Treat only if plt <20K and/or major bleeding and/or preoperative management Treatment : Acute setting: Dexamethasone vs. prednisone IVIG Secondary Treatment (long term):  Rituximab TPO agonists (Eltrombopag) Splenectomy Tertiary Treatment: Cyclophosphamide, azathioprine, prednisone, anti-D antigen therapy (WinRho), danazol. Vyvgart  Fostamitinib (spleen tyrosine kinase, Syk inhibitor) Splenectomy (if unresponsive to steroids and IVIG) Pregnancy : Treatment is the same as in non-pregnant patients. Steroids are preferred in the first trimester but IVIG is recommended if the patient is close to delivery (IVIG acts more quickly) Thrombotic Thrombocytopenic Purpura ( TTP) Mechanism: Lack of ADAMTS13 (normally cleaves vWF multimers) usually due to inhibitor → vWF multimers persist → adhesion/aggregation of platelets → Shearing/clotting Classic pentad: Microangiopathic hemolytic anemia (Jaundice, purpura) Thrombocytopenia Renal insufficiency Neurologic abnormalities Fever Treatment : Initially treated with PLEX + prednisone If refractory: PLEX (daily) + prednisone + Rituximab ± Caplacizumab Some medications can cause TTP-HUS in rare cases: Quetiapine Oxaliplatine Gemcitabine Bactrim Quinine Congenital TTP is called Upshaw-Schulman syndrome Autosomal recessive Can give regular plasma infusion or recombinant ADAMTS13 since disease is characterized by lack of ADAMTS13 protein

Background: Diagnosis is based on morphological evidence of dysplasia in BMBx Additional studies: karyotyping, flow cytometry, molecular genetics Pearl: Regardless of blast percentage, if a characteristic AML cytogenetic abnormality is seen on BMBx, then should treat as AML. Can be associated with previous drug exposures Example: alkylating chemotherapy or topoisomerase inhibitors Associated with del 5, del 7, or complex chromosomal abnormalities Risk Stratification: Based on the IPSS-R or IPSS-M (newer scoring system includes gene mutations) Classified as Low, Intermediate, High Risk Favorable risk: Cytogenetics: t(8;21), t(15;17), and inv(16) Confer a favorable prognosis regardless of blast percentage Gene mutations: NPM1 (without FLT3-ITD), in-frame bZIP CEBPA Poor risk Cytogenetics: Monosomy 7, inv(3), del(3q), del(7q), complex (2-3 abnormalities) Gene mutations : ASXL1, EZH2, SRSF2, U2AF1, ZRSR2, RUNX1, TP53, IDH2, STAG2, NRAS, ETV6, GATA2, BCOR, FLT3, WT1, NPM1 Very Poor Cytogenetics: Complex (>3 abnormalities) Treatment: Low/Intermediate Risk MDS (IPSS-R 1-4) Erythropoiesis-Stimulating Agents (ESA): Consider first line treatment for symptomatic anemia if serum EPO <500 Goal: Hb 10-12 Hypomethylating Agents (HMA): Acacitidine Decitabine Oral decitabine/cedazuridine Lenalidomide: Treatment of choice for Deletion 5q Luspatercept: “Ringed Sideroblasts” or “MDS-SF3B1” There is now an expanded indication to include in first-line setting regardless of ringed sideroblast status Imetelstat Newer telomerase inhibitor Immunosuppressive Therapy (cyclosporine/ATG) For hypoplastic MDS Ivosidenib/olutasidenib IDH1 mutated Supportive Care Transfusion and Iron Chelation Therapy High Risk MDS (IPSS 5 or more): Hypomethylating Agents (HMA): Acacitidine Decitabine Oral decitabine/cedazuridine AlloSCT: Potentially curative for appropriate population Intensive chemotherapy Chronic Myelomonocytic Leukemia (CMML) Subtype of MDS, not CML! CMML-1 : <10% bone marrow blasts/equivalents CMML-2: <20% bone marrow blasts/equivalents Associated with absolute monocyte >500 PDGFR rearranged associated with eosinophilia Sensitive to imatinib MDS with increased blasts  IB1: 5-9% blasts, no auer rods IB2: 10-19% blasts, auer rods Treat as high risk MDS, consider alloSCT MDS/MPN overlap Atypical CML Associated with SETBP1, CSF3R, ETNK1 mutations Idiopathic Cytopenia of Undetermined Significance (ICUS) Persistent unexplained cytopenia(s) that remain unexplained despite an appropriate evaluation including BMBx. Without evidence of clonality (no somatic mutations or clonal cytogenetic abnormalities) and no morphologic dysplasia. ICUS is a heterogeneous entity; some cases resolve spontaneously, while others may progress to myeloid neoplasms, but the overall risk is lower than CCUS or CHIP. Typically observed Clonal Hematopoiesis of Indeterminate Potential (CHIP) Presence of clonal mutations in leukemia-associated genes, but without cytopenia or morphologic dysplasia ( does not yet meet criteria for diagnosis of a hematologic neoplasm). Common in older adults and confers a low but definite risk of progression to hematologic malignancy (1% per year) and increased risk of cardiovascular disease and all-cause mortality. Typically observed Clonal Cytopenia of Undetermined Significance (CCUS) Persistent cytopenia(s) with evidence of clonality but without morphologic dysplasia or diagnostic criteria for MDS. Higher risk of progression to MDS or AML compared to ICUS or CHIP, especially with high-risk mutations (spliceosome genes, RUNX1, JAK2) or multiple mutations. CCUS is considered a direct precursor to myeloid neoplasms. Typically observed/supportive care Condition Cytopenia Clonality Dysplasia ICUS Yes No No CHIP No Yes No CCUS Yes Yes No MDS   Yes Yes Yes

Non-Small Cell Lung Cancer (NSCLC) T1  T2: 3 cm T3: 5 cm T4: 7 cm N1: Hilar nodes N2: Ipsilateral N3: Contralateral or supraclavicular Stage I:  N0 Stage Ia: T1  (<3 cm, No NGS) Stage Ib: T2a (3-4 cm):              Alectinib if ALK mutated              Osimertinib if EGFR exon 19 deletion or L858R Stage II:  >N1 If unresectable:              Radiation If resectable: Alectinib if ALK mutated Osimertinib if EGFR exon 19 deletion or L858R Chemotherapy: Platinum/Taxol x4 Platinum/Pemetrexed x4 Immunotherapy: (No adjuvant IO if EGFR+) Pembrolizumab x1 year (regardless of PD-L1) Atezolizumab x1 year if PD-L1 1% or higher Stage III: If resectable: same as stage II If unresectable:          Definitive concurrent chemo-RT followed by consolidation Durvalumab x1 year            If EGFR+ after definitive chemo-RT: Adjuvant Osimertinib 80 mg PO once daily Neoadjuvant Therapies for Resectable NSCLC: Nivo + Chemo x3 cycles → surgery → option chemotherapy Nivo + Chemo x3 cycles → surgery → Nivo (if R0) x6 months Pembro + Chemo           → surgery → Pembro Durvalumab + Chemo     → surgery → Durvalumab Stage IV: NGS, Check for driver mutations and PD-L1  Chemo + IO: if no driver mutations/ large burden of disease and need for quick robust response Carboplatin + Pemetrexed + Pembro Carboplatin + Taxol + Pembro Pembrolizumab: if PD-L1 >50% Second Line agents: Docetaxel + Ramucirumab, Pemetrexed, Gemcitabine, Abraxane, Vinorelbine EGFR Exon 21 L858R or Exon del 19  Osimertinib monotherapy Osimertinib + Chemotherapy Amivantamab + Lazertinib EGFR Exon 20 mutation Amivantamab ALK fusion Alectinib, Brigatinib, Crizontinib, Lorlatinib RET fusion Selpercatinib ROS1 fusion  Repotrectinib, Entrectinib, Crizontinib, Lorlatinib KRAS G12C Sotorasib and Adagrasib for 2L MET Exon 14 Skipping Mutation Capmatinib, Crizotinib, Tepotinib BRAF V600E Dabrafenib/Trametinib HER2 Fam-trastuzumab deruxtecan (Enhertu) NTRK Repotrectinib Larotrectinib Entrectinib NRG1 Zenocutuzumab Small Cell Lung Cancer (SCLC) Limited stage-SCLC: T1-2 only: Surgery →  adjuvant chemo (Cisplatin and etoposide) > T2:         ChemoRT Consider:  ChemoRT → consolidation Durvalumab  Consider PCI in LS-SCLC Extended stage-SCLC: No radiation or surgery MRI brain: If brain mets: WBRT + steroids Chemo (carboplatin/cisplatin + etoposide x4 cycles) + IO (Atezolizumab or Durvalumab) Relapsed SCLC If relapse >6 months: re-challenge with Carboplatin + etoposide If relapse < 6 months: Lurbinectedin and Topotecan Talratamab (bispecific Ab) May present with SVC Syndrome IR consult to get tissue and Rad-Onc for chemoRT Mesothelioma Types: Epithelioid Mesothelioma (better prognosis) Non-Epithelioid Mesothelioma (Sarcomatoid or Biphasic) For 1L:  Ipilimumab + Nivo  (prefered for sarcomatoid) Cisplatin + Pemetrexed Cisplatin + Pemetrexed + bevacizumab For 2L:  If immunotherapy used in first line: use chemo If chemo used in first line: use ipi/nivo

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

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

CBC & differential See "How to interpret a CBC with differential" lecture for a detailed discussion. Retic Reticulocytes are immature red blood cells that spend ~3 days maturing in the bone marrow, followed by 1–2 days in the peripheral blood before becoming mature RBCs. Retic count is a real-time indicator of bone marrow erythropoietic activity. Corrected reticulocyte count = % Retic × (Patient's Hct / Normal Hct) Reticulocyte production index (RPI) = Corrected retic count / Maturation factor You do not need to calculate RPI yourself! Use Mdcalc.com. Interpretation: RPI >2 : Appropriate BM response to anemia (hemolysis, acute blood loss) RPI ≤2 : Inadequate erythropoiesis (iron deficiency, BM suppression, chronic disease) Peripheral Blood Smear (PBS) *** SchistoSite will feature a separate lecture on peripheral blood smear (PBS) interpretation with a more detailed discussion and representative pathology images. Marked increase of mature-appearing lymphocytes: Consider CLL (particularly in older adults; correlate with flow cytometry) Other cause: Reactive lymphocytosis in viral infections EBV, CMV, acute HIV infection Granulocytes at all stages of maturation + basophilia + eosinophilia Consider CML (confirm with BCR-ABL1 testing) >20% blasts in blood or BM: Acute leukemia: Predominantly lymphoblasts → Consider ALL Predominantly myeloblasts → Consider AML Smudge cells → Suggest CLL Auer rods → Suggest AML, particularly acute promyelocytic leukemia (APL) Hematologic emergency until APL is excluded. Hairy cells → Hairy cell leukemia Sézary cells → Sézary syndrome Hypersegmented neutrophils → Vitamin B12/folate deficiency Consider vitamin B12 deficiency before folate replacement. Schistocytes → Evaluate urgently for thrombotic microangiopathy (TTP/HUS, DIC), and mechanical valve Spherocytes → Autoimmune hemolytic anemia or hereditary spherocytosis. Platelet clumping → Exclude pseudothrombocytopenia before initiating a thrombocytopenia workup Repeat the lab but collect the blood sample in a heparin or citrated tube (EDTA in the collecting tubes can cause platelet clumping) Rouleax formation → Consider plasma cell disorders Target cells → Consider liver disease and thalassemia Mixing study When PT and/or aPTT is prolonged, mixing study can help to differentiate between factor deficiency or presence of an inhibitor. Technique: Mix patient plasma 1:1 with normal pooled plasma (NPP) NPP supplies ~50% of every factor and ~50% activity (sufficient to normalize the PT and aPTT) Immediately repeat the prolonged lab test (PT and/or aPTT) on the mixture. Interpretation: If the factor is deficient: Mixing study corrects PT and aPTT. If an inhibitor presents: Inhibitor neutralizes the added normal factor in NPP as well as the patient's factor, so the clotting time stays long. Iron Studies Serum iron: Circulating iron bound to transferrin (the transport protein) Falsely elevates by recent oral iron or iron-containing food Iron saturation (TSAT): The percentage of transferrin occupied by iron Reflects circulating bioavailable iron Ferritin (storage iron): Iron deficiency is essentially the only cause of a low ferritin (high specificity). Ferritin ≤30 has ~98% specificity and ~92% sensitivity for absent BM iron stores. Ferritin is an acute-phase reactant and rises with inflammation, infection, liver disease, and malignancy, so a "normal" value never excludes deficiency in those settings. Diagnostic criteria for iron deficiency anemia: Ferritin ≤30 in general population Ferritin <100 AND Iron sat (TSAT) <20% in inflammatory states, elderly and heart failure DIC Laboratory tests There is no single diagnostic lab test for DIC. Characteristic lab changes in DIC: Low/ progressive downward trend platelet Sensitive but nonspecific Prolonged PT/aPTT: Reflects consumption/depletion of clotting factors Normal values do not exclude DIC (serial testing matters) Elevated fibrin-related marker (D-dimer): Highest diagnostic efficiency of the individual assays. Low fibrinogen: Insensitive because fibrinogen is an acute-phase reactant and can stay "normal" despite active consumption. Hypofibrinogenemia appears only in severe DIC. Schistocytes: Add prognostic information but are not part of the formal ISTH score. ISTH score: Only use if an underlying disorder known to cause DIC (e.g., sepsis, malignancy, or trauma) is present. You can use Mdcalc.com A score ≥5 is compatible with overt DIC IN PROGRESS...

Background: Highest incidence: East Asia (Japan, Korea, China) Increased in Eastern Europe & South America Male predominance (~2:1) Major Risk Factors: Chronic H. pylori infection (strongest risk factor) Chronic atrophic gastritis / intestinal metaplasia Smoking High salt/smoked foods, low fruits/vegetables Pernicious anemia Partial gastrectomy (long-term) CDH1 mutation → hereditary diffuse gastric cancer Histologic types: Intestinal: Gland-forming Associated with: H. pylori, environmental Diffuse: Poorly cohesive, signet ring cells Associated with: CDH1 mutation may cause linitis plastica (leather bottle stomach) Metastatic signs: Virchow node (left supraclavicular) Sister Mary Joseph nodule (umbilical) Krukenberg tumor (ovarian metastasis) Ascites Diagnosis: EGD with biopsy Pathology testing: HER2, MSI/MMR status, PD-L1 (CPS score) Staging: CAP CT scan Endoscopic ultrasound (EUS) → T & N staging Diagnostic laparoscopy if >T1b to rule out peritoneal disease (can be missed on imaging) T staging: Tis: High grade dysplasia/ intraepithelial tumor without invasion T1: invasion is limited to mucosa (T1a) and submucosa (T1b) T2: invades muscularis propria T3: invades subserosa T4: invades serosa (viceral peritoneum) or adjacent structures >15 lymph nodes should be examined for accurate staging D Dissection Categories: D0 dissection: Incomplete lymphadenectomy (≤15 LNs are resected) D1 dissection: Removal of perigastric nodes (N1) only D2 dissection: Removal of perigastric nodes (N1) and second-tier (N2) nodes (left gastric, common hepatic, celiac, splenic arteries) Treatment: Localized Early Stage Gastric Cancer: Surgical approach: Tis or T1a: Endoscopic Mucosal Resection (EMR) or Surgery ≥T1b or any N+: Gastrectomy with LN dissection Adjuvant therapy depends on: Pathology: pT1: Observation pT2: Observation Adjuvant therapy (if high risk features or D0 dissection) ≥pT3 or any N+: Adjuvant therapy Extend of LN dissection If 5 Checkmate-649 FOLFOX (or CAPEOX) + Pembrolizumab: if PDL-1 CPS > 1 FOLFOX (or CAPEOX) + Tislelizumab: if PDL-1 CPS >1 FOLFOX (or CAPEOX) + Zolbetuximab: if CLDN18.2 positive FOLFOX or XELOX 5 FU + Cisplatin If MSI-H or dMMR (independent of PDL1 status): FOLFOX + IO Can use Pembrolizumab, Dostarlimab, Ipi/nivo If HER2 positive (more commonly in intestinal subtypes) FOLFOX (or CAPEOX) + trastuzumab +/- pembro (if PDL1 positive) Keynote-811 5FU + Cisplatin + trastuzumab +/- pembro (if PDL1 positive) Subsequent Lines: Ramucirumab Ramucirumab + Paclitaxel (RAINBOW) Paclitaxel Docetaxel Irinotecan Enhertu (Fam-trastuzumab deruxtecan) if HER-2 positive (DESTINY-Gastric-01) Pembrolizumab if TMB-high tumors (≥10 mut/Mb) Later-Line therapy: Lonsurf (Trifluridine/Tipiracil) for 3rd line or later (TAGS) Hereditary syndromes associated with gastric cancer: Familial Adenomatous Polyposis (FAP) Caused by germline APC mutation Autosomal dominant Associated with: Gastric polyps and duodenal adenomas/cancer Upper endoscopy surveillance recommended starting age 20–25 Colorectal cancer Penetrance approaches 100% if colectomy is not performed Colonoscopy begins in teenage years Papillary thyroid cancer Annual thyroid US is recommended Desmoid tumors Hereditary Diffuse Gastric Cancer Associated with CDH1 mutation Autosomal dominant Prophylactic total gastrectomy is recommended in many patients If gastrectomy is deferred: EGD with extensive biopsy protocol q 6-12 months

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

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

Background: Most common mesenchymal tumors of GI tract Risk assessment uses: Tumor size Mitotic rate Anatomic location Tumor rupture Significantly increases recurrence risk. Gastric GIST generally have better prognosis than non-gastric GIST. For example, a >10 cm gastric tumor with >5 mitoses/50 HPF has 34% metastasis risk, while the same parameters in small bowel GIST carry 71-90% risk. Work up: Histology + IHC: Confirm GIST with positive KIT and/or DOG1 immunostaining. Imaging: CAP CT scan MRI as needed for liver/rectal lesions Mutational testing: Essential to guide systemic therapy Common mutations: KIT mutation (~80%) KIT exon 11 mutations: Best response to imatinib 400 mg daily KIT exon 9 mutations: Better PFS with imatinib 400 mg BID PDGFRA mutations (~5-10%) Resistant to imatinib; use avapritinib as first-line Wild-type: Test for alternative drivers (BRAF, NF1, NTRK, FGFR fusions) via NGS Treatment: Localized resectable disease: Surgery Segmental resection with negative margins Extended resections rarely needed Preserve pseudocapsule (avoid tumor rupture) Lymphadenectomy usually unnecessary Neoadjuvant therapy: Indicated for tumors requiring high-morbidity surgery: Rectal Esophagogastric junction Duodenum Requiring multivisceral resection Preferred medications: Imatinib for KIT and PDGFRA mutations (except PDGFRA D842V) Avapritinib for PDGFRA D842V mutation (resistant to imatinib) Sunitinib for imatinib progression/intolerance Larotrectinib/entrectinib (NTRK inhibitors) if NTRK fusion present Adjuvant therapy: If moderate-high risk disease with imatinib-sensitive mutations: Adjuvant Imatinib for 3-6 years Surveillance: CT/MRI every 3-6 months for 5 years, then annually. Individualized approach after 10 years. Metastatic/unresectable disease: Life-long systemic therapy is recommended for TKI-sensitive GIST. Treatment options: 1st line: Imatinib for KIT/PDGFRA-mutation Avapritinib for PDGFRA D842V mutation 2nd line: Sunitinib if imatinib fails For limited/focal progression on imatinib, consider dose escalation or local therapy (resection, ablation, radiation) while continuing imatinib. 3rd line: Regorafenib 4th line: Ripretinib Surveillance: CAP CT scan every 3–6 months during stable disease MRI every 3–6 months if: Liver-dominant disease Rectal GIST Patients with contrast allergy Assessing tumor density and necrosis FDG-PET/CT to assess TKI efficacy after 2-4 weeks if rapid assessment is necessary Increase in tumor size with decreased density is consistent with drug efficacy (myxoid degeneration), not progression.

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

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

Vitamin K antagonist (VKA): Warfarin Mechanism: Inhibit hepatic synthesis of vitamin K–dependent clotting factors (II, VII, IX, X) Decreases proteins C and S Eliminated by hepatic metabolism Requires close INR monitoring INR interpretation may be challenging in significant hepatic dysfunction because liver disease can elevate the baseline INR Consider if other agents are contraindicated Direct oral anticoagulants (DOAC): Classes: Direct thrombin (IIa) inhibitors Dabigatran Direct factor Xa inhibitors Apixaban, Rivaroxaban, Edoxaban Mixed hepatic/renal clearance Renal clearance: Dabigatran (80%) > Edoxaban (50%) > Rivaroxaban (35%) > Apixaban (27%) Require dose adjustment or avoidance in significant renal dysfunction (CrCl <30 mL/min) Avoided in moderate-to-severe hepatic dysfunction (Child-Pugh B/C or significant LFT elevation) Associated with a higher risk of GI bleeding in patients with GI malignancy Indirect inhibitors: Classes: Unfractionated Heparin (UFH) Potentiates antithrombin → Inhibits both thrombin and factor Xa Primarily reticuloendothelial/hepatic clearance (10% renal) Preferred in: Severe renal dysfunction Rapid reversal is needed Low-Molecular-Weight Heparins (LMWH) Dalteparin, Enoxaparin Potentiates antithrombin → Predominantly inhibits factor Xa (less inhibition of thrombin) Preferred in: GI malignancy If DOACs are contraindicated Mostly renal clearance Requires dose adjustment and possible anti-Xa monitoring in renal dysfunction Synthetic pentasaccharide Fondaparinux Potentiating antithrombin → Inhibit factor Xa Almost entirely renal clearance IN PROGRESS...

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