Findings Support Venetoclax Plus HMAs for Patients With AML Ineligible for Intensive Chemo

Daniel Pollyea, MD, MS

Among older patients with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy, preliminary findings demonstrated that more than 70% achieved complete responses (CRs) to venetoclax (Venclexta) in combination with hypomethylating agents (HMAs).

CR rates (including patients with incomplete hematologic recovery [CRi]) were similar whether venetoclax was paired with azacitidine or decitabine. A majority of patients had response durations of 12 months or longer with the combination therapy, as reported at the 2018 American Society of Hematology Annual Meeting in San Diego.¹

“Venetoclax plus hypomethylating agents was well tolerated in previously untreated older patients with AML who were ineligible for intensive chemotherapy,” said Daniel Pollyea, MD. “Deep and durable responses were observed in a majority of patients.”

In general, baseline genetic mutations and cytogenetic risk did not affect response to the combination therapy, added Pollyea, a clinical director of Leukemia Services and an associate professor of medicine at the University of Colorado School of Medicine in Aurora.

In another preliminary clinical evaluation, venetoclax plus low-dose cytarabine led to complete responses in more than half of a mixed group of older patients with AML, including a 71% response rate in patients with previously untreated disease.²

AML primarily affects older adults (median age, 68 at diagnosis), many of whom have limited treatment options and are ineligible for or refractory to intensive induction chemotherapy, Pollyea noted in the introduction to his presentation. BCL-2, the target of venetoclax, has antiapoptotic effects and is overexpressed in AML and AML stem cells. Preliminary data from a phase Ib clinical trial showed promising clinical activity with venetoclax/HMA treatment among older patients with untreated AML.³

These results support the recent FDA accelerated approval for venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine for newly diagnosed AML in patients 75 or older, or younger patients with comorbidities that preclude use of intensive therapy.

Stephen A. Strickland, Jr., MD

Pollyea reported findings from a phase Ib dose escalation/expansion study evaluating venetoclax 400 to 1200 mg in combination with either azacitidine or decitabine in older patients with untreated AML. His report focused on patients treated with 400 mg of venetoclax, which trial investigators identified as the recommended phase II dose.⁴

The analysis included 115 patients, 84 who received azacitidine as the HMA component and 31 who received decitabine. Eligibility criteria included a minimum age of 60, and the median age was 75 for the azacitidine subgroup and 72 for the decitabine group.

Overall, 31 of the 115 patients had <30% bone marrow blasts at baseline, 43 had 31% to <50%, and 41 had &ge;50%. Mutational analyses identifiedTP53in 27 patients,IDH1/2in 25,FLT3in 14, andNPM1in 17. Cytogenetic risk was intermediate in 66 patients and poor in 48. A total of 30 patients had secondary AML.

The primary outcome was response rate, limited to those patients who attained a CR/CRi. The results showed a 71% response rate for patients who received azacitidine with venetoclax (27% with CRi) and 74% in the decitabine group (19% with CRi).

Total response (irrespective of the HMA agent used) did not differ substantially by cytogenetic risk category, AML type (de novo or secondary), or baseline mutation status.

The median time to CR was 1.2 months (range, 0.7-5.5) in the azacitidine group and 1.9 months (range, 0.9-4.6) in the decitabine group. Pollyea noted that the time to response was lower than typically seen in older patients with AML treated with other therapies. As a result, patients treated with venetoclax-containing regimens probably should have earlier response assessments.

The venetoclax/azacitidine group had a median response duration of 21.2 months (95% CI, 14.4-30.2) and a 12-month event-free rate of 69% (95% CI, 52%-80%) after achieving a CR/CRi. The decitabine group had a median response duration of 15.0 months (95% CI, 5.0-22.5) and a 12-month event-free rate of 57% (95% CI, 32%-76%).

Analysis of all 115 patients yielded a median overall survival (OS) of 16.9 and 16.2 months with azacitidine and decitabine, respectively, and the 12-month event-free survival (EFS) was 57% and 61%.

When survival and EFS were analyzed by response status, CR was associated with a median OS of 40.3 months in the azacitidine group and a 12-month EFS of 72%, declining to 4.5 months and 19% for patients who did not attain a CR. In the decitabine group, median survival was 18.2 months and the 12-month EFS was 74% for responders and 4.8 months and 28% for all other patients.

Data analysis for the phase I/II venetoclax/low-dose cytarabine trial included 82 patients who had a median age of 74. Almost half (n = 40) had secondary AML, 24 had prior exposure to an HMA, and 41 patients had received a CYP3A inhibitor, said Stephen A. Strickland, Jr., MD, clinical director of acute leukemia at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.

The venetoclax dose was escalated from 50 to 400 mg over 5 days, and starting on day 6, patients received 600 mg. Patients received cytarabine 20 mg/m²on days 1 to 10. With that regimen, 1 patient developed laboratory tumor lysis syndrome (TLS), but no patient had clinical TLS, said Strickland.

The response rate (CR, including patients with CRi) was 54%. More variation by baseline characteristics was observed as compared with the data reported by Pollyea. Patients with intermediate cytogenetics had a 63% response rate, compared with 42% in the high-risk group. Prior HMA exposure was associated with a response rate of 33%, increasing to 62% with no HMA treatment history. Patients with de novo AML had a response rate of 71% versus 35% for patients with secondary AML.

The median time to first response was 1.4 months (range, 0.8-14.9), and the median time to best response was 2.8 months (range, 0.8-22.4).

The median OS was 10.1 months (95% CI, 5.7-14.2), which included a 6% mortality rate during the first 30 days. The 12-month OS rate was 100% in patients who had a CR, 73% for patients with CRi, and 5% for all other patients. The median OS had yet to be reached for patients with CR and hematologic recovery, was 18.4 months for all patients with CR, and 3.5 months for all others.

The most common treatment-emergent adverse events (TRAEs, all grades) were nausea (70%), diarrhea (49%) hypokalemia (48%), fatigue (43%), febrile neutropenia (43%), and thrombocytopenia (38%). Grade 3/4 TRAEs included febrile neutropenia (42%), thrombocytopenia (38%), decreased white blood cells (34%), neutropenia (27%), and anemia (27%). The most frequent serious adverse events were anemia (31%), febrile neutropenia (27%), pneumonia (10%), and sepsis (7%).

&ldquo;Venetoclax plus low-dose cytarabine demonstrated a tolerable safety profile,&rdquo; said Pollyea. &ldquo;The response rate was 54% in a group of patients who were ineligible for intensive chemotherapy, including 71% and a median overall survival of 16.9 months in patients with de novo AML.

&ldquo;The high rates of remission and low rates of early mortality make venetoclax plus low-dose cytarabine an attractive option in these patients.

References:

1. Pollyea DA, Pratz K, Jonas BA, et al. Venetoclax in combination with hypomethylating agents induces rapid, deep, and durable responses in patients with AML ineligible for intensive therapy. Presented at: 60th Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA. Abstract 285.
2. Wei A, Strickland SA, Hou JZ, et al. Venetoclax with low-dose cytarabine induces rapid, deep, and durable responses in previously untreated older adults with AML ineligible for intensive chemotherapy. Presented at: 60th Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA. Abstract 284.
3. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study.Lancet Oncol.2018;19(2):216-228. doi: 10.1016/S1470-2045(18)30010-X.
4. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia [published online October 25, 2018].Blood.doi: 10.1182/blood-2018-08-868752.