APPROACH TO THE DIAGNOSIS AND TREATMENT OF ACUTE MYELOID LEUKEMIA (AML) Hematology Rounds Thurs July 23, 2009 Carolyn Owen

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1 APPROACH TO THE DIAGNOSIS AND TREATMENT OF ACUTE MYELOID LEUKEMIA (AML) Hematology Rounds Thurs July 23, 2009 Carolyn Owen

2 Outline Diagnosis Prognosis Treatment AML Elderly AML APL Future directions

3 AML definition Clonal hematopoietic stem cell disorder characterised by an uncontrolled proliferation of myeloblasts Pre LSC Myeloblasts HSC LSC Acquisition of mutations

4 Normal hematopoiesis

5 DIAGNOSIS

6 AML: Signs and symptoms Symptoms usually related to cytopenias and not to leukemic blasts Anemia (dyspnea, fatigue) Neutropenia (fever, infection) Thrombocytopenia (bleeding, bruising) Rarely symptoms/signs due to leucostasis: Pulmonary infiltrates Renal failure Headaches, seizures, reduced LOC Priapism

7 Signs and symptoms (cont d) Leukemic infiltration of tissues Gingival or skin infiltration Myeloid (granulocytic) sarcoma Organomegaly

8 Diagnostic Tests Bone marrow aspirate/biopsy Flow cytometry Cytogenetics Molecular studies

9 Diagnosis 20% blasts on bone marrow aspirate/biopsy Any blast count in the setting of specific cytogenetic abnormalities New WHO classification AML with recurrent cytogenetic abnormalities 2. AML with MDS-related changes 3. Therapy-related myeloid neoplasms 4. AML not otherwise specified (NOS) 5. Myeloid sarcoma 6. Myeloid proliferations related to Down Syndrome 7. Blastic plasmacytoid dendritic cell neoplasm

10 AML with recurrent genetic abnormalities t(8;21) inv(16) t(15;17) t(9;11) t(6;9) inv(3) t(1;22) megakaryoblastic

11 AML NOS (ie old FAB) FAB subtype Name Approximate % of adult AML M0 AML, minimally differentiated <5 M1 AML without maturation M2 AML with maturation M3 Acute promyelocytic leukaemia (APML) 5-10 M4 M4eo M5a M5b Acute myelomonocytic leukaemia (AMML) AMML with eosinophilia Acute monoblastic leukaemia Acute monocytic leukaemia M6 Acute erythroid leukaemia <5 M7 Acute megakaryoblastic leukaemia <5

12 Morphology M1 M3

13 Flow/immuno markers Blast marker: CD34, CD117 Myeloid markers: CD33, CD38, CD13, CD15 Monocytic markers: CD14, CD64, CD11b/c Immuno: MPO (M2-M5), NSE (M4-M5), PAS (M6)

14 PROGNOSIS

15 Prognostic features Age (>60) WBC (>50 or 100) Cytogenetics Performance status Previous therapy / previous MDS Failure of 1 st induction

16 Cytogenetics

17 Outcome in AML based on cytogenetics 65% 40% 20%

18 Cytogenetics Risk Group Medical Research Council (UK) South West Oncology Group (USA) Favourable Intermediate Adverse t(15;17) inv(16), t(16;16) t(8;21) *alone or in conjunction with other abnormalities Normal karyotype del(7q) del(9q) abnormal 11q23 all other structural/numerical abnormalities complex ( 5 abnormalities) -5-7 del(5q) abnormal 3q *alone or in conjunction with other intermediate or adverse risk abnormalities t(15;17) inv(16), t(16;16) t(8;21) del(9q) Normal karyotype _Y del(5q) -7q t(9;11) +11 del(11q) abnormal 12p +13 del(20q) +21 complex ( 3 abnormalities) inv(3) or t(3;3) t(6;9) t(6;11) alone or with 1 other abnormality t(11;19)q23;p13.1 Grimwade et al Blood 1998 Byrd et al Blood 2002

19 Molecular genetics t(15;17) : PML-RARa t(8;21) :RUNX1-RUNX1T1 (AML-ETO) inv(16) or t(16;16) : CBFB-MYH11

20 Limitations of conventional cytogenetics 40-50% of patients are classified as cytogenetically normal (CN) prognosis variable within CN group new molecular markers for risk stratification: gene mutations altered gene expression

21 Molecular genetics in AML Favourable NPM1 CEBPA Adverse FLT3 C-KIT MLL-PTD RUNX1 WT1 BAALC, ERG, MN1

22 Molecular genetics in AML Schlenk et al NEJM 2008; 358: 1909

23 NPM1mut/FLT3wt as a favourable prognostic group Schlenk et al NEJM 2008; 358: 1909 Any treatment Allo HSCT

24 Relapse post HSCT in CR1 for FLT3 ITD Auto Auto All o FLT3 ITD still bad even with HSCT Gale, R. E. et al. Blood 2005;106:3658-

25 TREATMENT

26 Pre-treatment tests/procedures Coagulation tests Viral studies Lumbar puncture (if neuro sx or M4/M5 or WBC>100) Cardiac function assessment Central venous access HLA typing

27 Treatment Goal = achieve complete remission Limit TRM = prophylaxis against infections (anti-fungals + anti-virals) Allopurinol Transfusion support Platelets if < 10 or < 20 with fever RBCs for symptoms (usually threshold <80) G-CSF for severe neutropenic sepsis

28 Complete remission Morphological leukemia-free state (<5% blasts in D28 bone marrow) Recovery of normal bone marrow function (ANC 1.0, plts 100) Cytogenetic / molecular remission optimal

29 Principles of therapy Induction chemotherapy Consolidation: Chemo (2-4 cycles) Allogeneic stem cell transplantation Maintenance: Only for Acute Promyelocytic Leukemia (M3)

30 Induction chemotherapy Long term survival noted in patients with AML receiving ARA-C (cytarabine) + Daunorubicin Survival (5year): : 1.8% : 9.8% : 11.8% Keating et al JAMA 1982;248: 2481

31 Induction Chemotherapy: Is more better? Priesler et al (Blood 69: 1441, 1987) Phase III study of 7 & 3 vs. 10 & 3 vs. 7 & TG. No differences in response rate or survival. Bishop et al (Blood 75: 27, 1990) Phase III study of 7 & 3 vs. 7 & 3 + etoposide (75 mg/m 2 /day x 7 days). Improved remission duration but no effect on response rate or OS. Subset analysis suggested improved OS in pts < 55 (9 months vs. 17 months, p=0.03). Farag et al (JCO 23: 482, 2005) Comparison of 7 & 3 vs. 7 & 3 + etoposide across CALGB studies in AML pts < 60 with normal cytogenetics. CR rate improved with 3 drugs (82% vs. 73%, p=0.04). OS unchanged.

32 Induction Chemotherapy: Does the choice of anthracycline matter? Rowe et al (Blood 103: 479, 2004) 7 & 3 (daunorubicin vs. idarubicin vs. mitoxantrone) in older patients with newlydiagnosed AML. No differences in CR rates. AML Collaborative Group Meta-analysis of 5 studies comparing idarubicin vs. daunorubicin. Idarubicin had an improved CR rate (62% vs. 53%) and OS at 5 years (13% vs. 9%). criticised regarding whether equivalent doses of the 2 drugs were administered in all trials.

33 Calgary AML induction 2009 Standard dose ARA-C + anthracycline (daunorubicin or idarubicin) 7+3 Assess for remission at D28-30 Likelihood of achieving a CR estimated at ~70% Salvage chemo for failed induction (~50% chance of CR) FLAG-IDA, Cyclophosphamide/Etoposide

34 CSF prophylaxis: to use or not to use? Phase 3 study of G-CSF in AML induction and consolidation No difference in DFS or OS. G-CSF-treated patients: Achieved neutrophil recovery 5 days earlier Shorter duration of fever (7 vs. 8.5 days) Shorter duration of parenteral abx use (15 vs days) Shorter duration of hospitalization (20 vs. 25 days) Less frequent use of anti-fungal tx (34 vs 43%) Heil et al. Leukemia 2006; 20:404

35 Consolidation 1978 pilot study/1982 randomised Ara-c + DNR (+ thioguanine) CR 65-70% (50% for >60) 0% chance of 4yr survival if no further treatment 24% LFS at 4 years in group getting consolidation Buchner et al JCO 1985; 3: 1583

36 High Dose Cytarabine (HiDAC) A randomized investigation of high-dose versus standard-dose cytarabine with DNR in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Randomised (induction) to standard (200mg/m2 x7d) vs HiDAC (2g/m2 q12h x12doses) Patients in CR randomised to 2x (7+3) consolidation vs 1x HiDAC + DNR More toxicity than benefit for induction patients who survived induction with HiDAC, got CR and further therapy had lower relapse rates Weick et al Blood 1996; 88:2841

37 HiDAC in consolidation Patients in remission (after 2 cycles of induction) randomised to HiDAC (3g/m2 x 12 doses) + DNR vs standard dose (100mg/m2 x7days) +DNR More toxicity but less relapses and trend to better OS in the HiDAC group Fopp et al Ann Oncol 1997; 8:251

38 HiDAC benefit by cytogenetic group Comparison of outcomes following HiDAC consolidation CBF leukemias 5year OS: 78% 3g/m2 57% 400mg/m2 16% 100mg/m2 Bloomfield et al Cancer Res 1998; 58: 4173

39 How many cycles of consolidation are needed? Are 4 HiDACs better than 3? Comparison of patients treated on different CALGB studies (complicated analysis) Patients < 60 with normal cytogenetics 4 cycle group included patients getting 400mg/m2 or 3g/m2 in same group (3 cycle comparison got 3g/m2) 28% vs. 41% 4-year DFS (favouring 4 cycles). No difference in OS Farag et al. JCO 23: 482, 2005

40 Consolidation in Calgary Chemo = high dose ARA-C (HiDAC) Side effects of HiDAC Rash Conjunctivitis Cerebellar dysfunction

41 Chemo vs allo SCT for consolidation CBF AML: OS better with HiDAC than SCT (?c-kit mutation importance) Byrd JCO 1999/Byrd JCO 2004 NPM1c+/FLT3wt evidence of 60% OS survival with chemo alone (same as for CBF) Schlenk NEJM All high risk patients with donor should be referred for allo SCT

42 To transplant or not transplant?

43 Elderly AML (>65 years) CR rate 40-50% with standard induction With high risk cytogenetics, CR rate <30% Mortality due to treatment much higher in older patients Median survival with chemo = 7-9 mo Median survival with supportive care (including hydrea) = 3-4 mo

44 TREATMENT ELDERLY MRC AML 16 trial intensive: Ara-c/DNR vs DNR/clofarabine +/- Myelotarg Non-intensive : low-dose ara-c (LDAC) + Myelotarg vs clofarabine vs LDAC + arsenic Anti-CD33 (Myelotarg) So far, no evidence of survival benefit to consolidation chemo in the elderly No benefit of farnesyl transferase inhibitors

45 APL M3 M3v

46 ACUTE PROMYELOCYTIC LEUKEMIA (APL) Blasts have typical immunophenotype (CD34 -/dim, HLA DR-/dim, CD117- /dim, CD13+ Typical morphology (granules, Auer rods) microgranular variant FISH for t(15;17)

47 APL - Management Exclude/correct coagulopathy Treat emergently Prophylaxis (dexamethasone 10mg iv bid) against Retinoic Acid Syndrome for high risk patients (WBC>10, elderly)

48 APL Treatment ATRA + High dose anthracycline (dauno 60mg/m2, Idarubicin 12mg/m2 x 5days) +/- Cytarabine.. Used in high risk (WBC>10, age>60) at least once in consolidation 90-95% CR Sanz Blood 2000; 96:1247

49 APL Treatment (cont d) ATO (arsenic) at relapse or in those unfit for high dose anthracycline QTc prolongation Studies of up-front ATRA/ATO ongoing

50 Future directions/studies Gemtuzumab ozogamycin (Myelotarg) : anti-cd33 linked to calicheamicin (NCIC ALC2) FLT3 inhibitors (NCIC ALC3) HDAC inhibitors Other targeted therapies?

51 Future directions/studies (cont d) Improved risk stratification: Gene expression profiling MicroRNA profiling Minimal residual disease monitoring