Adding venetoclax to fludarabine, cytarabine, granulocyte-colony stimulating factor, and idarubucin (FLAG-IDA) translated into high response rates across subgroups of patients with acute myeloid leukemia (AML), according to results of a phase Ib/II study presented at the virtual 62nd ASH Annual Meeting and Exposition.
"In relapsed/refractory AML patients, a remarkable 67% of patients achieved a composite complete response, including 69% who ultimately achieved a [measurable residual disease] negative complete response," said lead author and presenter Curtis Lachowiez, MD, of University of Texas MD Anderson Cancer Center.
The study included adults with treatment-naive, newly diagnosed, or relapsed/refractory AML. In the phase Ib, dose-escalation portion of the study, 16 patients with relapsed/refractory disease were enrolled. The phase II dose-expansion portion included two arms: 29 patients with newly diagnosed AML in arm A and 23 patients with relapsed/refractory disease in arm B.
Dr. Lachowiez noted that because five of six patients initially enrolled in phase Ib developed bacteremia or sepsis, the protocol was amended to include a reduced dose of cytarabine (from 2 g/m2 to 1.5 gm/m2) in the phase II portion and the duration of venetoclax was shortened (from days 1-21 to days 1-14).
The median number of treatment cycles was two. The most common reason for study discontinuation was transition to transplant (56%), including 69% of newly diagnosed patients and 46% of relapsed/refractory patients. The median time to best response was approximately one month across all patient cohorts.
At the time of data presentation, the median duration of response at the phase II dosing level had not yet been reached in in either group.
Median time to count recovery was longer in cycle two compared with cycle one across the three cohorts. "As myelosuppression is common following a second cycle of FLAG-IDA therapy, this finding with FLAG-IDA plus venetoclax was not entirely unanticipated," Dr. Lachowiez said.
Grade 3/4 adverse events occurring in at least two patients included febrile neutropenia (50%), bacteremia (35%), and pneumonia (28%). Febrile neutropenia and pneumonia were evenly distributed between newly diagnosed and relapsed/refractory patients, but bacteremia was significantly more common in the relapsed/refractory group. The researchers attributed this to the increased number of phase Ib patients that developed bacteremia prior to dose adjustment.
The overall response rate was 82%, with 76% of patients achieving a composite complete response (CR), which includes complete response with incomplete hematologic recovery. Composite CR occurred in 90% of patients with newly diagnosed disease and 67% of patients with relapsed/refractory disease.
The median event-free (EFS) and overall survival (OS) in newly diagnosed patients has not been reached, and the rate of one-year OS was 94%. In the phase Ib portion relapsed/refractory patients had a median EFS of six months and a median OS of nine months.
At the optimized phase II dose, relapsed/refractory patients had a median EFS of 11 months, while OS had not been reached. The one-year OS rate in this patient subgroup was 68%.
When asked what venetoclax is adding to the FLAG-IDA regimen, Dr. Lachowiez responded that it may be increasing the depth of responses. "We know that, particularly going into allogeneic transplant, the depth of remission is important as far as post-transplant outcomes," he said. "In relapsed/refractory disease, achieving a durable remission after relapse is very difficult … and by adding venetoclax, we are seeing more remissions so that we can bridge these patients to transplant."
Measurable residual disease negativity was achieved in 83% of patients (96% of newly diagnosed and 69% of relapsed/refractory patients). Among relapsed/refractory patients, 46% were able to proceed to transplant, with a one-year OS rate of 87% and a one-year post-transplant survival rate of 78%.
Patients with TP53 mutations continued to have poor outcomes despite treatment with this combination, Dr. Lachowiez said. Four of the 10 patients with TP53 mutations at diagnosis did not respond. The composite CR for the TP53-mutant subset was 60%; however, four patients (67%) ultimately relapsed. Survival in TP53-mutated patients was significantly inferior to that of wild-type patients.
The authors concluded that FLAG-IDA plus venetoclax was associated with an "expected and acceptable safety profile and impressive efficacy in both newly diagnosed and relapsed/refractory AML patients." However, the study's findings are limited by the small patient population and lack of a comparator arm.
Study authors report no relevant conflicts of interest.
Lachowiez C, Konopleva M, Kadia TM, et al. Interim analysis of the phase 1b/2 study of the BCL-2 inhibitor venetoclax in combination with standard intensive AML induction/consolidation therapy with FLAG-IDA in patients with newly diagnosed or relapsed/refractory AML. Abstract #332. Presented at the 2020 American Society of Hematology Annual Meeting, December 6, 2020.