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  • 1. Overview of the Myeloid Malignancies Omar Abdel-Wahab, MD MSK Housestaff Lecture
  • 2. Myeloid Leukemias MPN MDS/MPN overlap MDS AML Lymphoid Leukemias Acute ALL Chronic CLL, HCL
  • 3. Overview of the myeloid malignancies • The most up-to-date classfication is the 2008 WHO CLASSIFICATION • The FAB Classification of AML (“M0” to “M7”), although still used is out-dated and does not take into new molecular understanding of AML.
  • 4. Overview of the myeloid malignancies MYELOPROLIFERATIVE NEOPLASMS MYELODYSPLASTIC SYNDROME ACUTE MYELOID LEUKEMIA ALL ARE CLONAL DISORDERS OF HEMATOPOIESIS •Increased mature-appearing Cells •Less fulminant clinical course than AML in many instances (chronic) •Variable risk of transformation To AML •Decreased circulating Peripheral blood cells •Abnormal differentiation of Blood cells in marrow •Less fulminant clinical course than AML in many instances (chronic) •Variable risk of transformation To AML •Decreased circulating mature Peripheral blood cells •Presence of immature cells In BM and/or periphery •Fulminant clinical course, Almost invariably lethal without Therapy.
  • 5. 2008 WHO classification of myeloid malignancies • Myeloproliferative neoplasms • Myeloid/lymphoid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 • Myelodysplastic/Myeloproliferative neoplasms • Myelodysplastic Syndrome (MDS) • Acute myeloid leukemia
  • 6. Acute myeloid leukemia • DIAGNOSIS: ANY ONE OF THESE 3 THINGS – > 20% blasts in the bone marrow OR peripheral blood OR – Cytogenetic alteration diagnostic of AML: t(15;17), t(8;21), inv(16), t(16;16) – Accumulation of blasts in an extramedullary site (choloroma, myeloid sarcoma, granulocytic sarcoma)
  • 7. Acute myeloid leukemia The best current guideline on how to diagnose, classify (based on 2008 WHO), And treat AML in adults.
  • 8. Types of AML • Former, out of date, classification: FAB CLASS M3 AML = ACUTE PROMYELOCYTIC LEUKEMIA (APL) A specific subtype of AML, genetically and clinically Distinct from any other myeloid malignancy. A medical emergency; VERY CURABLE!! Highest mortality is in initial Dx due to DIC. Except for M3AML the FAB Subtype of AML Does not inform prognosis or management!! Risk of death from DIC reduced massively with ATRA.
  • 9. CASE: • A 54-year-old man presents with gingival hypertrophy and bleeding. • At presentation his WBC is 39 000/L • the hemoglobin is 7.9 g/dL, and the platelet count is 6000/L.
  • 10. M3 AML Majority of patients: t(15;17) PML-RARa translocation Responsive to ATRA. -Check Smear and DIC labs (PT, PTT, Fibrinogen, D-dimer) whenever AML Is suspected -Start ATRA asap. Oral medication, Minimal side-effects in short-term Administration of a few days. Current standard of care: ATRA + Cytotoxic chemotherapy Arsenic Trioxide consolidation  ATRA maintenance Very high rate of cure
  • 11. M6 AML M6 AML -acute leukemia of eryrthroid Precursors -”Di Guglielmo” disease for Person who first described it
  • 12. M7 AML M7 AML -acute leukemia of Megakaryocyte lineage ~1-3% of adult AML cases -often accompanied by Fibrosis in BM -poor px histologic subtype -more common in children -Some important associations: 1/3 patients with M7 AML Have Down Syndrome Another 1/3 have a t(1;22)(p13;q13) translocation The last 1/3 have a novel Fusion not even published Yet.
  • 13. CASE CONT’D: • A 54-year-old man presents with gingival hypertrophy and bleeding. • At presentation his WBC is 39 000/L • the hemoglobin is 7.9 g/dL, and the platelet count is 6000/L. • SMEAR: 60% blasts. BMA/Bx confirms >20% blasts. Appear of monocytic lineage (M5)
  • 14. M4/M5 AML Classically associated with soft-tissue infiltration, especially infiltration of gums.
  • 15. CASE CONT’D: • A 54-year-old man presents with gingival hypertrophy and bleeding. • At presentation his WBC is 39 000/L • the hemoglobin is 7.9 g/dL, and the platelet count is 6000/L. • SMEAR: 60% blasts. BMA/Bx confirms >20% blasts. Appear of monocytic lineage (M5) • Flow confirms myeloid lineage AML, monocytic lineage • Cytogenetics and FISH reveal normal karyotype • Additional molecular analysis reveals presence of FLT3 ITD
  • 16. 2008 WHO CLASSIFICATION OF AML • AML with recurrent genetic abnormalities • AML with myelodysplasia-related changes • Therapy-related myeloid neoplasms (t-MDS or t-AML) • AML not otherwise specified • Myeloid sarcoma (granulocytic sarcoma, chloroma)
  • 17. 2008 WHO CLASSIFICATION OF AML • AML with recurrent genetic abnormalities – – – – – – – – – T(8;21) Inv(16) T(16;16) T(15;17) T(9;11) T(6;9) Inv(3) t(1;22) AML with mutated NPM1 or mutated CEBPA
  • 18. Genetic abnormalities in AML • Why do we care? – Risk stratification of patients (good, intermediate, adverse risk) – Clinical management of AML
  • 19. Pre-2012 Risk Stratification of AML CYTOGENETICS FAVORABLE MOLECULAR GENETICS Mutated CEBPA t(9;11) Mutated FLT3 ITD (+/NPM1 mutation) tri(8) ADVERSE Mutated NPM1 without FLT3-ITD Inv16 or t(16;16) INTERMEDIATE t(8;21)(q22;q22) No NPM1, CEBPA, FLT3ITD mutations Inv(3) t(6;9) t(v;11) -5 or del(5q); -7; abn(17p); >3 abnormalities Schlenk RF, et al. N Engl J Med 2008;358:190918.
  • 20. Current Risk Stratification of AML Our patient: NK, FLT3ITD mutant
  • 21. Management of AML: 2012 (1) Clinical trial if at all possible!! (2) No clinical trial: Induction chemotherapy: “7+3” chemotherapy Daunorubicin (3d) + Cytarabine (cont IV infusion x 7d) --If <60 give 90mg/m2 DNR dose, proven survival benefit Consolidation chemotherapy: 4-6 cycles of high-dose cytarabine Possible post-consolidation therapy: If intermediate risk or adverse risk  allogeneic transplant
  • 22. Management of AML: 2012 AML 16-60 years old
  • 23. Challenges in AML mgmt (1) Few established therapeutic options for induction (2) No established options for RELAPSED or REFRACTORY AML (3) Role of allogeneic transplant not totally clear (4) Few studies on consolidation chemotherapy (other agents, # of cycles needed) (5) Challenge in clinical trials of newer targeted agents
  • 24. CASE CONT’D: • A 54-year-old man presents with gingival hypertrophy and bleeding. • At presentation his WBC is 39 000/L • the hemoglobin is 7.9 g/dL, and the platelet count is 6000/L. • SMEAR: 60% blasts. BMA/Bx confirms >20% blasts. Appear of monocytic lineage (M5) • Flow confirms myeloid lineage AML, monocytic lineage • Cytogenetics and FISH reveal normal karyotype • Additional molecular analysis reveals presence of FLT3 ITD
  • 25. MSKCC AML CLINICAL TRIALS
  • 26. MSKCC AML CLINICAL TRIALS
  • 27. Overview of the myeloid malignancies MYELOPROLIFERATIVE NEOPLASMS MYELODYSPLASTIC SYNDROME ACUTE MYELOID LEUKEMIA ALL ARE CLONAL DISORDERS OF HEMATOPOIESIS •Increased mature-appearing Cells •Less fulminant clinical course than AML in many instances (chronic) •Variable risk of transformation To AML •Decreased circulating Peripheral blood cells •Abnormal differentiation of Blood cells in marrow •Less fulminant clinical course than AML in many instances (chronic) •Variable risk of transformation To AML •Decreased circulating mature Peripheral blood cells •Presence of immature cells In BM and/or periphery •Fulminant clinical course, Almost invariably lethal without Therapy.
  • 28. MPN’s • BCR-ABL (t9;22) + – CML • BCR-ABL negative – “Classic MPN’s” • PV • ET • Primary myelofibrosis – Chronic eosinophilic leukemia – Mastocytosis
  • 29. MPN’s
  • 30. Case #2: • A 68yo M presents for routine physical exam. Routine CBC reveals WBC of 25,000, Hb of 12 and Plt of 600,000. • Prior CBC 1 year prior was normal.
  • 31. Case #2: • A 68yo M presents for routine physical exam. Routine CBC reveals WBC of 25,000, Hb of 12 and Plt of 600,000. • Prior CBC 1 year prior was normal. W/U: -Differential -Iron studies (ferriting, Fe, TIBC) -Smear -BMA/Bx for review, FISH/cytogenetics, BCR-ABL translocation testing by qRTPCR, and JAK2V617F mutation (possibly also MPL Mutation)
  • 32. CML • Pre-TKI’s Chronic phase Accelerated phase Survival Blast phase 8+ years <1.5 years < 6 months High or normal High or low Decreased >20 - - <10% >10% >30% Basophils Platelets WBC count Blasts QUESTIONS NOW 1) Which TKI to start first? Imatinib, Dasatinib, Nilotinib 2) Can you ever stop the TKI? 3) Do the “T315I” drugs work?
  • 33. PV, ET, PMF JAK2V617F mutation -95% PV -50% ET -50% PMF JAK2 exon 12 mutations ~5% PV patients MPL mutations 10-15% JAK2VF negative ET/PMF patients
  • 34. PV, ET, PMF PV PMF ET A M L
  • 35. PV Median age @ Dx: 70yo Compared to age- and sex-matched controls total mortality is 1.2 higher in PV. 45% of deaths were due to cardiovascular disease. GRADE A Treatment Recommendation Aspirin 75 - 100 mg/day Grade B recommendation Phlebotomy to maintain the Hct to <0.45 Cytoreduction should be given to: -All patients with platelets > 1.5 million IFN or Hydroxyurea -leukocyte count > 15 x109/L
  • 36. ET It is unclear if ET shortens Life expectancy on average. Studies which found a shorter life expectancy: Fenaux et al: 73.5% survival 7 years after diagnosis Jensen et al: 76% survival at 5 years REACTIVE THROMBOCYTOSIS CAUSES: iron deficiency, splenectomy, surgery, infection, inflammation, connective tissue disease, metastatic cancer, and lymphoproliferative disorders
  • 37. Management of ET Grade A recommendation • Platelet lowering therapy should be given to; - all patients over 60 years of age - all patients with earlier thromboembolic complications -all patients with platelets >1.5million • Aspirin 75-100 mg daily to all ET patients except when platelets are >1500 x 109/L, in patients with bleeding symptoms or in patients with other contraindications to aspirin. • The goal of platelet lowering therapy should be platelets < 400 x 109/L (Grade B recommendation) Choice of cytoreductive therapy in ET: • Hydroxyurea is the best documented therapy in ET • However, due to the concern of possible increased risk of leukemia transformation with long-term use it is not recommended as 1st line therapy in younger patients • <60 years: 1st line interferon-α or anagrelide, 3rd line Hydroxyurea • >75 years: 1st line Hydroxyurea, 2nd line consider combination therapy (HU-Ana, HU-IFN),
  • 38. PMF
  • 39. PMF SPLENOMEGALY EARLY SATIETY FATIGUE CYTOPENIAS HIGH RISK OF AML TRANSFORMATION
  • 40. 2012 FDA-APPROVAL FOR JAK1/2 INHIBITOR Ruxolitinib for MF
  • 41. 2012 FDA-APPROVAL FOR JAK1/2 INHIBITOR Ruxolitinib for MF
  • 42. Questions now in MPN’s 1) Do JAK inhibitors change the natural history of PMF? 2) Should we use combination strategies of JAKi + something else? 3) Many newer JAK inhibitors coming are they better than ruxolitinib? (JAK2 specific, JAK1 specific, JAK2V617F specific) 4) What is the genetic abnormality present in the 50% of ET and PMF without JAK2 or MPL mutations? 5) Are JAK2 mutations really driving the disease?
  • 43. Myelodysplastic Syndrome MDS with low blast % can be very difficult to diagnose and the true incidence of MDS is likely not known. Definition: >10% of the cells >1 myeloid BM lineage (erythroid, granulocytic, megakaryocytic must show morphologic dysplasia. Also, in setting of persistent cytopenia, if the patient has one of the following cytogenetic Abnormalities, MDS may be diagnosed:
  • 44. Case #3 78y F presents with CC of slight increase in DOE over last few months. She has a h/o HTN and type II DM. Physical exam is unrevealing. CBC reveals Hb 8.2g/dL, WBC 1.8, and Plt 170,000.
  • 45. What is dysplasia? Some common morphologic features characteristic of MDS: -hypolobated neutrophils in peripheral blood -increased reticulocytes in peripheral blood -abnormal contours of erythroid precursors in bone marrow -micromegakaryocytes in bone marrow -increased RBC precursors with rings of iron around the nuclei (ringed sideroblasts) -Also MDS usually characterized by a hypercellular bone marrow (but not always)
  • 46. 2008 WHO CLASSIFICATION OF MDS Disease Blood findings BM findings Refractory cytopenia with unilineage dysplasia 1-2 cytopenias >10% of the cells in one myeloid lineage dysplasia; <5% blasts <15% RBC prec with ringed sideroblasts Refractory anemia with ringed sideroblasts (RARS) Anemia >15% ringed sideroblasts Erythroid dysplasia only <5% blasts Refractory cytopenia with multilineage dysplasia (RCMD) Cytopenias Dysplasia, <5% blasts Refractory anemia with excess blasts 1 (RAEB-1) Cytopenias 5-9% blasts Refractory anemia with excess blasts 2 (RAEB-2) Cytopenias 10-19% blasts MDS with isolated del 5q Anemia with normal to High plt count Isolated deletion 5q
  • 47. Assessing risk in MDS MDS CLASSIFICATION SCORING SYSTEM IPSS R-IPSS WHO PSS (takes into account WHO category of MDS) MDACC MDS Scoring System (takes into account peformance status) Newer systems incorporating molecular mutations coming….
  • 48. Assessing risk in MDS
  • 49. Treatment options for MDS 1) Supportive care: transfusions, ESA, GCSF, ESA + GCSF 2) Lenalidomide  especially for MDS with Isolated deletion 5q 3) Hypomethylating agents  Decitabine or 5-Azacitidine 4) If RAEB-1 or -2 in young patient, sometimes treated as if AML with induction Chemotherapy +/- allogeneic transplant
  • 50. MPN, MPN/MDS overlap, MDS TET2 ASXL1 SRSF2 JAK2 MPL BCR-ABL MPN PV ET CML PMF RARS-t EZH2 MDS/MPN MDS with fibrosis del5q MDS RA RARS--SF3B1
  • 51. MDS/MPN overlap syndromes Chronic myelomonocytic leukemia Atypical CML, BCR-ABL1 negative Juvenile myelomonocytic leukemia MDS/MPN-U RARS-t
  • 52. CMML
  • 53. CMML Monocytosis of >1 X 109/l + dyplasia (less than 20% of cells in bone marrow). CMML-1: <10% blasts in BM CMML-2: 10-19% blasts in BM RARS-t RA + Ringed Sideroblasts + Thrombocytosis Mixed MPN (JAK2 or MPL mutation) and MDS >15% ringed sideroblasts + Plt count >450K