Orlando, FL—The combination of the BCL2 inhibitor venetoclax (Venclexta) and intensive chemotherapy has demonstrated notable results in fit patients with newly diagnosed or relapsed or refractory acute myeloid leukemia (AML), according to results from a phase 1b/2 single-center clinical trial presented at ASH 2019.
The median overall survival (OS) was 9.4 months and the median relapse-free survival was 13.4 months in the relapsed or refractory cohort after a median follow-up of 5.2 months. In the newly diagnosed cohort, the median OS and relapse-free survival were 100%, after a median follow-up of 5.5 months.
“Venetoclax in combination with standard intensive AML induction or consolidation therapy with FLAG-IDA showed activity in high-risk AML, especially in prior patients with allogeneic stem-cell transplantation and MLL rearrangements,” said Iman Abou Dalle, MD, Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX. “However, longer follow-up is necessary to establish long-term survival benefit.”
As Dr Abou Dalle explained, venetoclax is a potent and selective small-molecule inhibitor of BCL2 that has demonstrated activity against AML and is currently used in combination with hypomethylating agents or with low-dose cytarabine in patients with newly diagnosed AML who are not eligible for intensive chemotherapy.
Venetoclax’s ability to reduce the apoptotic threshold makes it an ideal agent to combine with a cytotoxic agent that induces apoptosis, said Dr Abou Dalle. In addition, the FLAG-IDA regimen is known to be a highly effective intensive chemotherapy in the front-line and in the relapsed setting of AML.
For this phase 1b/2 study, Dr Abou Dalle and colleagues evaluated the safety and overall efficacy of the venetoclax combination by assessing the overall response rate (ORR), duration of response, OS, and relapse-free survival. Fit, adult patients who were diagnosed with AML or with high-risk myelodysplastic syndrome and had good performance status and adequate organ function were eligible for participation.
The study consisted of 2 parts—(1) a phase 1 dose-escalation cohort that included only patients with relapsed or refractory disease, and (2) a phase 2 dose-expansion cohort that enrolled treatment-naïve patients as well as patients with relapsed or refractory disease.
The phase 2 section included 24 patients—14 in the newly diagnosed cohort and 10 patients in the relapsed or refractory cohort—up to data cutoff. The median age of patients was 48 years and the median number of previous therapies was 2.
The ORR was 75% among patients with relapsed or refractory disease who received treatment in the phase 1b section and 70% in patients treated in the phase 2 section, said Dr Abou Dalle. Minimal residual disease (MRD)-negativity was achieved by 56% and 50% of patients, respectively. The ORR in newly diagnosed patients who received treatment in the phase 2 section was 93%, with 85% of the patients testing negative for MRD.
“The modified FLAG-IDA schedule with a reduction of cytarabine dose to 1.5 g/m2 and venetoclax duration to 14 days with induction and 7 days with consolidations appeared optimal, with no prolonged myelosuppression and no early mortality,” said Dr Abou Dalle, adding that the majority of the patients achieved response after the first cycle.
Of the 26 patients with relapsed or refractory disease, 19 had responded to treatment and 10 had allogeneic stem-cell transplant (ASCT).
Newly Diagnosed AML
In the patients with newly diagnosed AML, 14 patients received treatment. In all, 13 patients had a response to treatment with the combination, 6 patients had undergone ASCT, and no relapses or deaths were reported, said Dr Abou Dalle. Dr Abou Dalle said that 6 patients are still ongoing in the study.
Furthermore, in the 10 patients who previously had ASCT, the ORR was 60%, and 5 of these patients then underwent a second transplant. In addition, all 5 patients with MLL rearrangement had subsequent ASCT and responded to treatment with this combination.
Of those 5 patients with MLL rearrangements, 4 are still alive after a median of 8 months.
The phase 2 portions of newly diagnosed and of relapsed or refractory cohorts are still ongoing, Dr Abou Dalle concluded.
In a previous report of the CAVEAT study, the front-line combination of venetoclax with chemotherapy was shown to be safe and effective. In this phase 2 study, grade 3 or 4 adverse events were primarily infections, which occurred in 32% of patients, and the incidence of gram-negative bacteremia was 18%.
Among the 26 patients with relapsed or refractory disease, 3 relapses occurred, and 3 patients died while in complete remission—all from severe infections. At data cutoff, 3 patients were still active in the study.