Acute Myeloid Leukemia

Pimjai Niparuck

Division of Hematology, Department of Medicine

Ramathibodi Hospital, Mahidol University

Outline

• Molecular biology

• Chemotherapy and Hypomethylating agent

• Novel Therapy

Treatment

Treatment for elderly patients with AML

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, MD1, Hagop M. Kantarjian, MD1, Guillermo Garcia-Manero, MD1, Gautam Borthakur, MD1, Tapan Kadia, MD1, Xuelin Huang, PhD2*, Naval Daver, MD1, Courtney D. DiNardo,

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, MD1, Hagop M. Kantarjian, MD1, Guillermo Garcia-Manero, MD1, Gautam Borthakur, MD1, Tapan Kadia, MD1, Xuelin Huang, PhD2*, Naval Daver, MD1, Courtney D. DiNardo,

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 2008-001290-15)

• 117 patients were randomly 1:1

1. observation (control group )

2. azacitidine maintenance (aza group), 50 mg/m2 (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 109/L had a significant better OS in favor of aza maintenance treatment (logrank; p=0.01).

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 2008-001290-15)

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/m2 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.

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

Novel Therapy

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

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

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

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

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, 66-87 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/m2/day SQ was given on days 1-10 of each cycle

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

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-of-

the-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.

Frontline Cytarabine, Idarubicin, Nivolumab for AML: Phase II Study Design

Pts 18-60 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

Induction

Ravandi F, et al. ASH 2017. Abstract 815. ClinicalTrials.gov. NCT02464657.

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

Consolidation Maintenance

*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.

Slide credit: clinicaloptions.com

Allogeneic SCT for eligible pts at any time during or after consolidation

• Primary endpoint: MTD of nivolumab (phase I)

• Secondary endpoint: EFS (phase I/II)

Characteristic IA + Nivolumab

(N = 35)

Median age, yrs (range) 54 (26-65)

Male, % 43

Median WBC x 109/L (range) 5 (0.4-46.1)

Median creatinine, mg/dL (range) 0.8 (0.51-1.31)

Median bilirubin, mg/dL (range) 0.7 (0.2-2.5)

Median BM blasts, % (range) 42 (15-96)

AML/MDS, %

De novo AML

Secondary AML

Therapy-related AML

High-risk MDS (≥ 10% blasts)

74

11

9

6

Previous therapy for MDS, %

None

Hypomethylating agents

89

11

Characteristic, % IA + Nivolumab (N =

35)

Cytogenetics

Diploid

Other

intermediate

-7/7q-/-

5/complex

23

23

40

ELN

Favorable

Intermediate

Adverse

14

46

40

Mutations

FLT3-ITD

FLT3-0835

NPM1

TP53

IDH1

IDH2

DNMT3A

KRAS/NRAS

9

9

17

23

6

23

17

14 Ravandi F, et al. ASH 2017. Abstract 815.

Frontline Cytarabine, Idarubicin, Nivolumab for AML: Phase II Study Design

0 3 6 9 12

15

18

Ravandi F, et al. ASH 2017. Abstract 815.

OS Event-Free Survival

Relapse-Free

Survival

Median OS: 15.8 mos (range: 0.5-21.1) N = 35; 12 died

Median EFS: 8.3 mos (range: 0.5-18.0) N = 35; 17 events

Median RFS: 17.3 mos (range: 0.6-17.3) N = 26 (CR/CRi/CRp); 9 relapses

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Frontline Cytarabine, Idarubicin, Nivolumab for AML: Phase II Study Design