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1. Header Subhead Acute and Chronic Myeloid Leukemia Patrick Brown, MD

2. Classification of Myeloid Neoplasms • WHO, 4th edition, 2008 (2016 revision)

3. Epidemiology • Know the incidence of ALL, AML and CML, and the peak age at which each of these occur

4. Epidemiology CML

5. Epidemiology CML

6. Epidemiology • Know the concordance rate of ALL and AML in identical twins

7. Monozygotic twins • Index case < 1 yo • Very high (close to 100%) concordance with short latency (weeks) • Prenatal preleukemic event (MLL-r, e.g), intrauterine transfer • MLL-r promotes rapid development of cooperating “hits” • Index case 1-6 yo • ~10-20% concordance (most clonal), longer latency • Prenatal preleukemic event (TEL-AML1, AML1-ETO, e.g), intrauterine transfer • Compared to MLL-r, relatively low risk of cooperating “hits” • Index case > 6 yo • Minimal increased risk • No prenatal preleukemic event

8. Leukemogenesis • Know which constitutional and genetic conditions predispose to the development of leukemia

9. Major Leukemia Predispositions • Marrow failure syndromes – MDS, AML • JMML-related conditions (NF1, Noonan) • Down syndrome – ALL, TMD/AMKL • Others • Ataxia-telangiectasia (ALL, NHL) – ATM mutations; defective DNA repair, immunodeficiency • Bloom syndrome (broad) – BLM mutations; short stature, sun rash, sister chromatid exchanges • Li-Fraumeni syndrome (broad) – TP53 mutations

10. Marrow Failure and MDS/AML • Pancytopenia

11. Marrow Failure and MDS/AML • Anemia

12. Marrow Failure and MDS/AML • Neutropenia

13. Marrow Failure and MDS/AML • Thrombocytopenia

14. Classification • Know the FAB (old) and WHO (new) classifications of AML • Know the characteristic clinical presentations of AML, and associate these with specific AML subtypes • DIC/bleeding • Hyperleukocytosis • CNS leukemia • Leukemia cutis • Chloromas

15. AML Subtype Comment s M0 AML without differentiation Diff icult to distinguish from ALL; diagnosis requires expression of surface markers s uch as CD13, CD33 and CD117 (c - kit ) in the absence of lymphoid differentiation M1 AML with minimal differentiation Myeloperoxidase detectable by special stains/flow cytom etry M2 AML with differentiation Auer rods; common t(8;21) - > AML1 - ETO fusion, good prognosis , chloromas a M3 Acute promyelocytic leukemia Auer rods; DIC/bleeding;; t(15;17) - > PML - RAR fusion, good (APL) , hypergranular type prognosis with ATRA therapy M3 v APL, microgranular variant Cytoplasm of promyelocytes demonstrates a fine granularity, and nuclei are often folded. Same clinical, cytogenetic and therapeutic implications as FAB M3. M4 Acute myelomonocytic leukemia Mixture of myeloblasts (at le ast 20%) and monocytic blasts; often (AMML) with peripheral monocytosis M4Eo AMML with eosinophilia AMML with >5% abnormal eosinophil precursors in marrow (with basophilic granules) , common inv(16), good prognosis M5 Acute monocytic leukemia >80% of bone marrow non - erythroid cells are monocytic; M5a: for both M4 monoblastic; M5b: monocytic (more differentiated); and M5 : i nfant age, MLL 11q23 rearrangements, CNS involvement, chloromas, gingival hyperplasia M6 Acute erythroblastic leukemia Rare in children M7 Ac ute megakaryoblastic leukemia Seen mostly in children with Down syndrome (good prognosis if < 2 years old ; GATA1 mutations ) or mosaicism for trisomy 21; rare in normal children (poor prognosis , t(1;22) - > OTT - MAL fusion, often infants ); myelofibrosis commo n FAB: morph/phenotype; 30% blasts , leukemia cutis

16. WHO: clinical/molecular; 20% blasts • Is the AML due to prior XRT/chemo? • If yes: Dx is Therapy-related AML (t-AML) • Is the AML in a child with Down syndrome? • If yes: Dx is DS-related AML • Is major (“Big 4”) recurring abnormality present? • If yes: Dx is AML w/ t(8;21); inv(16); t(15;17); MLL-r (a few others) • NOTE: No minimum blast % needed • Is there dysplasia, prior MDS and/or MDS-related mutation (-7, del(5q), etc.)? • If yes, Dx is AML with MDS-related changes • If no to all: Dx is AML, NOS - use FAB to subclassify

17. t-AML • Know the characteristic chromosomal abnormalities and clinical characteristics in secondary acute myeloid leukemia resulting from topoisomerase II inhibitors and from alkylators, respectively

18. t-AML • Alkylating agents and radiation • Long latency (5-7 years) from exposure, common preceding MDS • Cytogenetics: -7, del(7q), -5, del(5q); complex cytogenetics • Topoisomerase II inhibitors (etoposide > anthracyclines) • Short latency (1-2 years) from exposure, rare preceding MDS • Cytogenetics: 11q23 rearrangements most common, but t(8;21), t(15;17), t(9;22) and inv(16) can also occur • Regardless of age at presentation or etiology, t-MDS/t-AML tends to be more refractory to therapy than de novo MDS or AML

19. Recurring Cytogenetic Lesions • Correlate clinical characteristics with chromosomal abnormalities in acute myeloid leukemia • Understand the significance of rearrangements of the ATRA receptor gene in M3 acute myeloid leukemia • Recognize specific clinical syndromes associated with t(8;21), inv(16), t(9;11), t(15;17), and monosomy 7 or 7q- in acute myeloid leukemia • Know the molecular abnormalities with which specific and recurring chromosomal abnormalities are associated in acute nonlymphoblastic leukemia

20. “The Big 4”

21. t(15;17) and ATRA • Understand the significance of rearrangements of the ATRA receptor gene in M3 AML Adapted from: Shen, et al. Frontiers in Bioscience 2004; 9:2666

22. Clinical aspects of APL • High risk of life-threatening bleeds (~10% mortality) due to DIC/fibrinolysis + low plts • Basics: close monitoring of PT, aPTT, fibrinogen, D-dimer, plts with liberal use of products: plts, cryo, FFP • Start ATRA immediately with suspected APL: rapidly improves coag parameters and reduces bleeding risk • Other interventions controversial (heparin, amicar, rVIIa, …) • Differentiation syndrome • Fever, edema, pulm infiltrates, hypoxia, resp distress, hypotension, renal/hepatic dysfunction, effusions, rash • Risk correlates with high WBC; can occur in absence of ATRA • Rx: Prompt recognition and use of dexamethasone, hold ATRA until resolving • Arsenic Trioxide • Increasingly incorporated into consolidation for APL in effort to reduce cumulative anthracycline exposure - recent data suggests that “low risk” APL (<10k WBC) is curable with ATRA and Arsenic only!

23. MDS vs. AML • Know the relationship between myelodysplastic syndromes and acute myeloid leukemia • In children (unlike adults), the vast majority of AML cases are “de novo” (i.e., not preceded by MDS) • MDS in children commonly arises in setting of underlying constitutional disorder (DS, marrow failure syndrome, etc.) • MDS in children has similar implications as in adults • Eventual progression to AML is the general rule; pace of progression is variable • Generally requires HSCT for cure • Questionable role for pre-HSCT chemotherapy

24. Hyperleukocytosis • Recognize the potential complications of hyperleukocytosis in acute myeloid leukemia • Plan the management of hyperleukocytosis in acute myeloid leukemia

25. Hyperleukocytosis • Risk factors: Elevated WBC (>100K); AML>ALL • Etiology: Sludging of viscous blood in brain, lungs, kidneys, other organs • Features: • Management • Treat leukemia ASAP • Exchange transfusion or leukopheresis if symptomatic

26. Immunophenotype • Know the immunophenotypic differences between acute lymphoid and acute myeloid leukemia • Know how to identify lymphoid/myeloid mixed lineage acute lymphoblastic leukemia and biphenotypic leukemia (by immunophenotyping)

27. Immunophenotype • Pan-myeloid: 13, 33, MPO (except M7) • Monocytic: 11b, 14 • Erythroid: Glycophorin A (235a) • Megakaryocytic: 41a, 42, 61, absent MPO • APL: auto-fluorescence, bright 33, HLA-DR neg, 34 neg • t(8;21): often CD19+ Campana et al. JIM 2000: 59-75

28. Acute Leukemia of Ambiguous Lineage • Acute Undifferentiated Leukemia (AUL) • Express no lineage-specific markers • Mixed Phenotype Acute Leukemia (MPAL) • Distinct populations of blasts of different lineages; and/or single population of blasts co-expressing antigens of multiple lineages • Often MLL-rearranged • T/myeloid, B/myeloid most common

29. Prognostic Factors & Risk Stratification • Know prognosis of various sub-types of acute myeloid leukemia • Know the prognostic significance of the non-random cytogenetic abnormalities in acute myeloid leukemia • Know the prognostic importance of Down syndrome in acute nonlymphoblastic leukemia Risk Stratification is the prospective use of prognostic factors to assign patients to specific treatments. Only a subset of prognostic factors are used in risk stratification

30. Prognostic Factors not used • Host characteristics • Age and sex: not independent on most recent studies • Race: non-whites - inferior survival • BMI: under- or over-weight - inferior survival • Pharmacogenomics • Disease characteristics • High WBC – no longer used, except in APL (> 10K is high risk – use anthracycline immediately) • FAB – supplanted by cyto/molecular

31. Recent Risk Stratification • Favorable • Down syndrome-related (esp. if < 4 y.o.) • APL with t(15;17) or variant • Cytogenetics: inv(16), t(8;21) • Molecular: NPM1, CEBPA • Unfavorable • t-AML, MDS-related AML • Cytogenetics: -7, 5q-, abn(3q) • Molecular: FLT3/ITD (high allelic ratio) • Primary induction failure (>5% blasts after course 2) • Intermediate: everything else Separate protocols

32. Update: incorporation of MRD • Intermediate Risk • Sub-classified into favorable or unfavorable according to end-course 1 flow cytometric MRD • centralized laboratory, using +/- threshold of 0.1% • Grouped with “traditional” favorable/unfavorable groups Adapted from: Loken, et al. Blood. 120(8): 1581

33. Current Risk Stratification • Favorable (Low Risk, LR) • Down syndrome-related (esp. if < 4 y.o.) • APL with t(15;17) or variant • Cytogenetics: inv(16), t(8;21) • Molecular: NPM1, CEBPA • Intermediate with end course 1 MRD negative • Unfavorable (High Risk, HR) • t-AML, MDS-related AML • Cytogenetics: -7, 5q-, abn(3q) • Molecular: FLT3/ITD (high allelic ratio) • Primary induction failure (>5% blasts after course 2) • Intermediate with end course 1 MRD positive Separate protocols

34. Therapy • Know which drug combinations are most effective in the treatment of acute myeloid leukemia • Know that high-dose cytarabine is effective in the treatment of acute myeloid leukemia • Know the role of CNS prophylaxis in the treatment of acute myeloid leukemia • Know the evidence against the use of extended maintenance therapy for AML • Know the indications for allogeneic HSCT in AML • Know the various components of prophylactic and acute supportive care for children with acute myeloid leukemia receiving treatment

35. Current Standard Therapy Remission induction 2 courses of intense chemotherapy (Ara-C, Doxo, Etoposide); high risk of invasive infection; CR rate ~ 75-80% Current protocol “switches” 2nd induction course to mitoxantrone/ HD Ara-C for HR patients Post-remission consolidation BMT All HR with best donor (matched sib preferred, MUD/UCB/haplo donors acceptable) No LR (even with matched sib) Additional chemo “intensification” courses (2) HR w/o any donor, and all LR Usually HD Ara-C combined with drugs not used in induction (mitoxantrone, L-asp, e.g.)

36. Current Standard Therapy CNS Prophylaxis Much less intense than in ALL due to low rates of CNS relapse with standard therapy For CNS+ at diagnosis, weekly or bi-weekly IT Ara-C until CSF clears, then once per course; no cranial XRT Maintenance Unlike ALL, there is no role for extended maintenance (a survival benefit has never been demonstrated)

37. Current Standard Therapy Supportive care Admission during periods of neutropenia recommended, due to significant risk of life-threatening infections Most infections are episodes of bacteremia and sepsis Strep. Viridans Gram negative enterics (E. coli, Klebsiella, Pseudomonas, etc.) Aggressive empiric treatment with broad spectrum antibiotics to cover these organisms is standard Bacterial prophylaxis is controversial and not considered standard due to concerns re: antibiotic resistance Fungal and pneumocystis prophylaxis are commonly used G-CSF and other growth factors are not commonly used due to concerns re: promoting leukemia cell growth/survival

38. Late Effects in AML • Recognize the late complications of therapy for AML • After chemotherapy only • Anthracyclines: cumulative exposure ~ 450 mg/m2 doxorubicin equivalents – cardiotoxicity • Etoposide: t-MDS/AML • High dose Ara-C: neurotoxicity • After HSCT • Above, plus HSCT-related risks

39. Radiation in AML • Know the indications for radiotherapy in AML • Generally limited to emergent treatment of life-threatening complications of chloromas (e.g., spinal cord compression) • TBI is not a typical component of HSCT prep regimens for AML • Cranial XRT is generally not required to control CNS disease in AML

40. CML: Biology • Know the clinical, laboratory, and prognostic features of CML • Recognize priapism as a presenting feature of chronic myeloid leukemia (?) • Recognize the hematologic changes associated with a blast crisis in chronic myeloid leukemia • Know that a blast crisis in chronic myeloid leukemia can involve other cell lines • Know the association of BCR-ABL1 oncogene with chronic myeloid leukemia • Know the clinical, laboratory and molecular characteristics that differentiate Ph+ chronic myeloid leukemia from Ph+ acute lymphocytic leukemia

41. CML: Definition • Myeloproliferative neoplasm (MPN) • Origin: abnormal pluripotent HSC • Ph+; t(9;22)(q34;q11.2); BCR-ABL1 • Triphasic natural history: • Chronic Phase (CP) • Accelerated Phase (AP) • Blast Crisis (BC)

42. CML: Clinical Features • Most pts diagnosed in Chronic Phase (CP) • 20-40% asx, dx’d due to abnl CBC (incidental findings of leukocytosis with left shift, +/- anemia, +/- thrombocytosis, basophilia, +/- eosinophilia) • Sx: abd pain, dysphagia, inc abd girth (all from splenomegaly), fatigue, wt loss, night sweats, bleeding, (rarely) leukostasis/priapism(?) • Natural history: progression (widely variable latency) • Accelerated phase (AP): decreased response to treatment, clonal evolution, inc blasts (<20%), inc basophilia • Blast crisis (BC): acute leukemia (2/3 AML, 1/3 ALL) Distinguishing CML-CP or CML-AP from Ph+ ALL is simple due to obvious differences in CBC and PB smear; CML presenting with lymphoid BC vs. Ph+ ALL is a more challenging distinction – molecular studies and remission testing are crucial.

43. CML: Diagnosis • Demonstration of p210 BCR-ABL1 fusion (PCR) in blood in proper clinical context is likely sufficient • Marrow typically included to definitively rule out accelerated phase and improve karyotyping Adapted from: Faderl, et al. Blood 1998; 91: 3995

44. CML: Molecular Biology Adapted from: Rosenbloom, et al. Annals of Int Med 2010; 152(3): 163

45. CML: Treatment • Know the principles of using targeted therapy (such as imatinib) in patients with chronic myeloid leukemia • Plan the treatment of a blast crisis in a patient with chronic myeloid leukemia • Know the indications for and timing of HSCT in a patient with chronic myeloid leukemia • Know the therapeutic options for a patient who has a recurrence of chronic myeloid leukemia after HSCT

46. CML: Impact of Tyrosine Kinase Inhibitors • Pre-TKI Era • The only curative long term curative therapy is allogeneic stem cell transplant, so essentially all children receive HSCT with best available donor • Hydroxyurea and interferon used to control disease prior to SCT • Post-TKI Era • Begin TKI, continue indefinitely • Consider HSCT in chronic phase only for patients with HLA-matched family donor (even then controversial) • For recurrent or refractory chronic phase, try higher dose TKI and/or new TKI first (guided by mutation analysis), then HSCT for treatment failure • For accelerated phase or blast crisis, attempt to induce remission with chemotherapy (AML or ALL, depending on blast phenotype) + TKI, and then take to HSCT

47. CML: Treatment of CML-CP • ABL tyrosine kinase inhibitors (TKI) • Imatinib • Kids: 340 mg/m2 qd (600 mg max) • Adol/adult: 400 mg qd (may increase to 600 mg and 800 mg as needed for response) • Dasatinib (100 mg qd) • Nilotinib (400 mg bid) • *Ponatinib (45 mg qd) – active against T315I mutant • HSCT – controversial • HSCT remains the only proven cure for CML – TKI’s achieve sustained disease control, but recurrence likely upon discontinuation • Major prognostic factor for HSCT: disease phase (CP>AP>BC) • CML is very sensitive to graft vs. leukemia (GVL) effect – relapses post-HSCT can be effectively treated with donor lymphocyte infusions (DLI), especially if no GVH with first HSCT • When HSCT is used, TKI “maintenance” may be considered post-engraftment in effort to prevent relapse More rapid and sustained cytogenetic/molecular responses

48. CML: Response • There are three principal strategies to assess response • Hematologic response (HR; determined with PB and exam) • Complete (CHR): normal counts, no HSM • Cytogenetic response (CyR; determined with BCR-ABL FISH on BMA) • Complete (CCyR): no Ph+ • Partial (PCyR): major <= 35%; minor 36-95% • Molecular response (MR; determined with BCR-ABL qPCR on PB) • Complete (CMR): PCR neg • Major (MMR): BCR-ABL:ABL ratio <0.1% (international scale), or 3 log reduction in copy# • Most recent guidelines • BMA for response not needed if validated qPCR testing available • Every 3 month testing until MMR, then every 3-6 months

49. CML: Response

50. CML: Response • Response to TKI treatment is the most important prognostic factor in CML • Patients with a rapid and sustained response to TKI have an excellent outcome • TKI resistance • Primary – treatment failure or suboptimal response with TKI • Secondary - loss of response (rising qPCR, recurrence of FISH+, development of CML-AP, etc.) • Both types are most commonly caused by acquired mutations in ATP-binding pocket of ABL – T315I mutations have been most problematic, since they are also resistant to 2nd and 3rd line TKI’s – recently approved ponatinib has T315I activity • TKI-resistant patients generally require HSCT for cure