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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

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

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

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

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