The addition of venetoclax to fludarabine, cytarabine, idarubicin and G-CSF resulted in high complete response rates and enables a high consolidative allogeneic transplantation rate in patients with newly diagnosed acute myeloid leukemia.
The addition of venetoclax (Venclexta) to fludarabine, cytarabine, idarubicin and G-CSF (FLAG-IDA) resulted in high complete response rates and enables a high consolidative allogeneic transplantation rate in patients with newly diagnosed acute myeloid leukemia (AML), according to data presented at the 2021 SOHO Annual Meeting.
Eighty-five percent of newly diagnosed AML patients experience complete remission (CR) after FLAG-IDA induction. However, anywhere between 30-40% will experience relapse. The addition of the BCL-2 inhibitor venetoclax may help to improve long-term outcomes in this patient population.
The results are based on the phase 2 portion of a phase 1b/2 study (NCT03214562) looking at this combination in patients with both newly diagnosed and relapsed/refractory AML. This analysis comes from the newly diagnosed cohort. The study overall has an estimated enrollment of 116 participants. Primary end points include overall response rate (ORR) up to 6 years, CR rate, hematologic response, duration of response (DoR), event-free survival (EFS), overall survival (OS), anti-tumor activity, pharmacodynamic markers, drug exposure levels, and overall incidents and severity of all adverse events (AEs). The secondary end point is morphologic leukemia-free state.
The newly diagnosed cohort included 38 patients. The median age was 44 years (range, 20-65). 35 patients were included in the analysis presented. The ORR was 94% with a CR rate of 69%. The median DoR was 18.4 months with no 30- or 60-day mortality. Molecular residual disease (MRD) negativity was seen in more than 90% of patients who achieved a CR.
Sixty-six percent of patients (n = 27) bridged to hematopoetic allogeneic stem cell transplantation (HSCT) at the time of analysis. At the median follow-up of 16 months (range, 15-23), median OS has yet to be reached in those who underwent HSCT. The median EFS had also not been reached by data cutoff. The 12-month EFS was 73% and the 24 month-EFS was 60%. The median OS at 12 months was 95% and the 24-month OS was 82%. At a median follow-up of 7.4 months, for patients who did not undergo HSCT, the 12-month EFS was 93%. The 24-month EFS was not available for this group. The 12- and 24-month OS was 100%.
For patients who underwent HSCT, the median OS was not reached compared to 24 months in those who did not undergo transplant. The median EFS was not reached for either group.
“Survival is quite favorable, regardless of whether or not patients transition to transplant, though it is worth noting that the follow up for patients not proceeding to transplant is short with a median follow up of only 7.4 months,” said lead study author and presenter Curtis Lachowiez, MD, a hematology and medical oncology fellow at the University of Texas MD Anderson Cancer Center.
TP53 mutations were associated with worse EFS and OS. The combination was effective across a variety of molecular subgroups, including NPM1, KMT2A, RUNX1, IDH2, and TP53. However, patients in these subgroups were at an increased risk of relapse. The emergence of a TP53 mutation was more common at relapse than other mutations.
“So, 67%, or 6 out of 9 patients that have relapsed, had p53 mutations. And it is worth noting 1 of the patients who has relapsed without a p53 mutation, harbored an inversion 3 mutation” Lachoweiz said.
Infectious AEs tended to be the most common associated with the regimen. AEs included febrile neutropenia (34%), pneumonia (28%), cellulitis (16%), and bacteremia (16%).
“We see that FLAG-IDA with venetoclax in newly diagnosed AML is associated with a high composite CR rate and de novo in secondary and therapy related AML and MRD negativity is attained in over 90% of patients who achieve the composite CR,” said Lachoweiz. “FLAG-IDA with venetoclax is associated with an acceptable safety profile with infectious complications being most common and resulted in a high rate of transition to allogeneic transplantation to date.”