Acute Myeloid Leukemia

Transcription

1 Acute Myeloid Leukemia Pimjai Niparuck Division of Hematology, Department of Medicine Ramathibodi Hospital, Mahidol University

2 Outline Molecular biology Chemotherapy and Hypomethylating agent Novel Therapy

3

4

5

6

7

8

9

10

11

12 Treatment

13

14

15

16

17

18

19

20

21

22

23 Treatment for elderly patients with AML

24

25

26

27

28 A Randomized Phase II Trial of 5-Day Versus 10-Day Schedules of Decitabine for Older Patients with Previously Untreated Acute Myeloid Leukemia Nicholas J Short, MD 1, Hagop M. Kantarjian, MD 1, Guillermo Garcia-Manero, MD 1, Gautam Borthakur, MD 1, Tapan Kadia, MD 1, Xuelin Huang, PhD 2*, Naval Daver, MD 1, Courtney D. DiNardo,

29 A Randomized Phase II Trial of 5-Day Versus 10-Day Schedules of Decitabine for Older Patients with Previously Untreated Acute Myeloid Leukemia Nicholas J Short, MD 1, Hagop M. Kantarjian, MD 1, Guillermo Garcia-Manero, MD 1, Gautam Borthakur, MD 1, Tapan Kadia, MD 1, Xuelin Huang, PhD 2*, Naval Daver, MD 1, Courtney D. DiNardo,

30

31 Randomized Maintenance Therapy with Azacitidine (Vidaza) in Older Patients ( 60 years of age) with Acute Myeloid Leukemia (AML) and Refractory Anemia with Excess of Blasts (RAEB, RAEB-t). Results of the HOVON97 Phase III Randomized Multicentre Study (EudraCT ) 117 patients were randomly 1:1 1. observation (control group ) 2. azacitidine maintenance (aza group), 50 mg/m 2 (5 days) q 4 weeks, until relapse for a maximum of 12 cycles 52 patients received at least 1 cycle of aza 44, 40, 34 and 32 patients received at least 3, 6, 9 and 12 cycles respectively The 12 months DFS = 39% (control group), 63% (aza group) Difference in OS between the two groups : not statistically significant in the cohort of patients in this pre-final analysis The 12 months OS (after censoring allo transplanted patients) = 64% (control group), 83% (aza group) Subgroup analysis (CR vs CRi at inclusion) revealed that patients with platelet count 100 x 10 9 /L had a significant better OS in favor of aza maintenance treatment (logrank; p=0.01).

32 Randomized Maintenance Therapy with Azacitidine (Vidaza) in Older Patients ( 60 years of age) with Acute Myeloid Leukemia (AML) and Refractory Anemia with Excess of Blasts (RAEB, RAEB-t). Results of the HOVON97 Phase III Randomized Multicentre Study (EudraCT )

33 Sequential Azacitidine (Aza) and Lenalidomide (Len) for Patients (Pts) with Relapsed and Refractory (R/R) Acute Myeloid Leukemia (AML): Clinical Results and Predictive Modeling Using Computational Analysis and Serial Genomics Adult pts with R/R AML or myelodysplastic syndromes (MDS) and preserved organ function with a WBC<10,000/μL (hydroxyurea permitted) were eligible. The tx consisted of aza 75 mg/m 2 d1-7, a bone marrow biopsy on cycle (C) 1 day 8, len 50 mg d8-28, and 2 weeks off tx, constituting a 42-day cycle.

34 Sequential Azacitidine (Aza) and Lenalidomide (Len) for Patients (Pts) with Relapsed and Refractory (R/R) Acute Myeloid Leukemia (AML): Clinical Results and Predictive Modeling Using Computational Analysis and Serial Genomics

35

36

37

38

39

40 Novel Therapy

41

42

43 Phase II SORAML Trial of Sorafenib versus Placebo in Addition to Standard Therapy for Younger Patients with Newly Diagnosed AML

44 Phase II SORAML Trial of Sorafenib versus Placebo in Addition to Standard Therapy for Younger Patients with Newly Diagnosed AML

45 Phase II SORAML Trial of Sorafenib versus Placebo in Addition to Standard Therapy for Younger Patients with Newly Diagnosed AML

46 Phase II SORAML Trial of Sorafenib versus Placebo in Addition to Standard Therapy for Younger Patients with Newly Diagnosed AML

47

48

49

50

51

52

53

54

55

56 Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with AMLUnfit for Intensive Chemotherapy: 1-Year Outcomes; Age>65 years Venetoclax (VEN) is a small molecule inhibitor of BCL-2 that achieved remission rates of >60% combined with low-dose cytarabine (LDAC) Total= 71 pts, median age, 74 years [range, years] cycle 1, VEN 50 mg/day PO and increased over a 5-day ramp-up to reach the designated cohort dose of 600 or 800 mg/day on day 6, which was continued through day 28 In subsequent cycles, the desingated dose of VEN 600 or 800 mg/day was administered on days 1-28 LDAC 20 mg/m 2 /day SQ was given on days 1-10 of each cycle

57 Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with AMLUnfit for Intensive Chemotherapy: 1-Year Outcomes; Age>65 years

58 Phase II Study: Frontline Cytarabine and Idarubicin + Nivolumab in Newly Diagnosed AML Integrating New Hematology Findings Into Practice: Independent Conference Coverage of ASH 2017,* December 9-12, Atlanta, Georgia *CCO is an independent medical education company that provides state-ofthe-art medical information to healthcare professionals through conference coverage and other educational programs. This activity is supported by educational grants from AbbVie; AstraZeneca; Celgene Corporation; Genentech; Janssen Biotech, Inc administered by Janssen Scientific Affairs, LLC; Jazz Pharmaceuticals; Novartis Pharmaceuticals Corporation; Pharmacyclics Inc; Seattle Genetics; and Takeda Oncology.

59 Frontline Cytarabine, Idarubicin, Nivolumab for AML: Phase II Study Design Allogeneic SCT for eligible pts at any time during or after consolidation Induction Consolidation Maintenance Pts yrs of age (or > 60 if very fit) with either AML by WHO criteria or high-risk MDS with 10% blast cells; ECOG PS 0-2; adequate cardiac, renal, hepatic function (N = 35) Cytarabine 1.5 g/m² IV D1-4* Idarubicin 12 mg /m² IV QD x 3 Nivolumab 3 mg/kg Q2W starting on D24 ± 2 days Cytarabine 0.75 g/m² IV QD x 3 Idarubicin 8 mg /m² IV QD x 3 5 cycles Nivolumab 3 mg/kg Q2W 1 yr *Cytarabine given over 24 hours; pts older than 60 yrs of age received 3 days instead of 4. First 3 pts treated at run-in phase with nivolumab 1 mg/kg with no drug-related toxicity. The remaining 32 pts treated as noted in schema. Primary endpoint: MTD of nivolumab (phase I) Secondary endpoint: EFS (phase I/II) Ravandi F, et al. ASH Abstract 815. ClinicalTrials.gov. NCT Slide credit: clinicaloptions.com

60 Frontline Cytarabine, Idarubicin, Nivolumab for AML: Phase II Study Design Characteristic IA + Nivolumab (N = 35) Median age, yrs (range) 54 (26-65) Male, % 43 Median WBC x 10 9 /L (range) Median creatinine, mg/dl (range) Median bilirubin, mg/dl (range) Median BM blasts, % (range) AML/MDS, % De novo AML Secondary AML Therapy-related AML High-risk MDS ( 10% blasts) Previous therapy for MDS, % None Hypomethylating agents Ravandi F, et al. ASH Abstract ( ) 0.8 ( ) 0.7 ( ) 42 (15-96) Characteristic, % Cytogenetics Diploid Other intermediate -7/7q-/- 5/complex ELN Favorable Intermediate Adverse Mutations FLT3-ITD FLT NPM1 TP53 IDH1 IDH2 DNMT3A KRAS/NRAS IA + Nivolumab (N = 35)

61 Probability of OS Frontline Cytarabine, Idarubicin, Nivolumab for AML: Phase II Study Design Probability of Event-Free Survival Probability of Relapse-Free Survival OS Event-Free Survival Relapse- Free Survival Median OS: 15.8 mos (range: ) N = 35; 12 died Mos Median EFS: 8.3 mos (range: ) N = 35; 17 events Mos Median RFS: 17.3 mos (range: ) N = 26 (CR/CRi/CRp); 9 relapses Mos Ravandi F, et al. ASH Abstract 815.