Study design 1

Study M14-358 was a non-randomized, open-label trial (NCT02203773) that evaluated the efficacy and safety of VENCLEXTA (venetoclax tablets) in combination with azacitidine (VEN+AZA; N=84) or decitabine (VEN+DEC; N=31) in patients with newly diagnosed acute myeloid leukemia (AML).

Of those patients, 67 who received AZA combination and 13 who received DEC combination were 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria:

  • Baseline ECOG performance status of 2-3
  • Severe cardiac or pulmonary comorbidity
  • Moderate hepatic impairment
  • CLcr <45 mL/min, or
  • Other comorbidity

Dosing:

  • Patients received VENCLEXTA 400 mg orally once daily following completion of the ramp-up dosing schedule in combination with azacitidine (75 mg/m2 either intravenously or subcutaneously on Days 1-7 of each 28-day cycle beginning on Cycle 1, Day 1) or decitabine (20 mg/m2 was administered intravenously on Days 1-5 of each 28-day cycle beginning on Cycle 1, Day 1)
  • During the ramp-up phase, patients received TLS prophylaxis and were hospitalized for monitoring
  • Treatment was continued until disease progression or unacceptable toxicity

Baseline characteristics 1

The median age of patients treated with VEN+DEC was 75 years (range: 68-86 years). ECOG performance status at baseline was 0-1 for 92% of patients and 2 for 7.7% of patients.

Of the 13 patients in the VEN+DEC arm, those who had mutations identified were as follows:

  • 31% with TP53
  • 23% with FLT3
  • 15% with NPM1
  • No patients with IDH1 or IDH2

Intermediate or poor cytogenetic risk was present in 38% and 62% of patients, respectively.

First-line efficacy and fast remissions with VEN+DEC 1

  • Complete remission (CR) was 54% (n=7); 95% CI: (25, 81)
  • Complete remission with partial hematologic recovery (CRh) was 7.7% (n=1); 95% CI: (0.2, 36)
  • Median duration of response of CR was 12.7 months; 95% CI: (1.4, -)
  • Median time to first response (CR or CRh) was 1.9 months (range: 0.8-4.2 months)

Descriptive prespecified exploratory analysis of CR+CRh rates in different mutational
and cytogenetic risk subgroups 6

CR+CRh rates were:

  • 33% (n=1/3; 95% CI: [0.8, 91]) for FLT3
  • 100% (n=2/2; 95% CI: [16, 100]) for NPM1
  • 75% (n=3/4; 95% CI: [19, 99]) for TP53
  • 60% (n=3/5; 95% CI: [15, 95]) for the intermediate cytogenetic risk group, and
  • 63% (n=5/8; 95% CI: [25, 92]) for the poor cytogenetic risk group

CR rates were:

  • 50% (n=2/4; 95% CI: [7, 93]) for TP53, and
  • 50% (n=4/8; 95% CI: [16, 84]) for the poor cytogenetic risk group

CR rates for FLT3, NPM1, and the intermediate cytogenetic risk group were the same as rates seen for CR+CRh. No patients had an IDH1/2 mutation.

4 patients had insufficient sample for analysis. Patients could have expressed one or more, or none of the identified mutations. The subgroup analyses were not powered or tested to demonstrate a statistically significant difference in outcomes for any subgroup examined.

CR was defined as absolute neutrophil count (ANC) >1,000/microliter, platelets >100,000/microliter, red blood cell transfusion independence, and bone marrow with <5% blasts. Absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. 1

CRh was defined as <5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter). 1

VEN=VENCLEXTA; ECOG=Eastern Cooperative Oncology Group; CLcr=creatinine clearance; TLS=tumor lysis syndrome; TP53=tumor protein 53; FLT=fms-like tyrosine kinase; NPM=nucleophosmin; IDH=isocitrate dehydrogenase; CI=confidence interval.

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