Superior Survival with Intensive Chemotherapy, Compared to Hypomethylating Agent + Venetoclax, in Patients with Intermediate/Adverse Risk Acute Myeloid Leukemia Unable to Proceed to Transplant

Background: Intensive chemotherapy (IC) with cytarabine and an anthracycline (7+3) is considered standard of care for fit patients with newly diagnosed acute myeloid leukemia (AML). The combination of hypomethylating agents (HMAs) and venetoclax (VEN) is the standard for older/frail patients and is being investigated in younger patients. Regardless of upfront regimen, patients with non-favorable AML may benefit from proceeding to allogeneic stem cell transplantation (allo-sct) in first remission. Due to various barriers, many patients with non-favorable risk AML are unable to proceed to transplant. Optimal treatment regimen in this subset is largely unknown. Here we report our experience of IC vs. HMA/VEN in patients with intermediate and adverse-risk AML, unable to proceed to allo-sct.

Methods: We conducted a matched retrospective study to compare outcomes of adult patients (age 18-75y) with newly diagnosed intermediate and adverse-risk AML treated with either HMA/VEN or IC at our site from January 2016 to December 2023. Patients treated with HMA/VEN were matched in a 1:1 ratio to patients receiving IC following a hierarchal algorithm based on age, ELN 2022 risk stratification, and year of diagnosis. Treatment with HMA consisted of azacitidine 75mg/m² for 7 days or decitabine 20mg/m² for 5 days. VEN was administered at an effective dose of 400mg daily for 21-28 days per cycle (adjusted for concomitant azole). Idarubicin 12mg/m² was used in patients ≤65y and daunorubicin 45mg/m² in patients >65y. Midostaurin was added for FLT3-mutated AML.

Results: There were 158 patients included in the analysis (HMA/VEN=79, IC=79). The baseline characteristics were well balanced except for an overrepresentation of black patients in the HMA/VEN group (28% vs. 19%, p=0.02). The median age of the HMA/VEN and IC groups was 66y (39-72y) and 66y (39-73y), respectively with 75% of patients >60y of age in both groups. By ELN 2022, majority of the patients had adverse-risk disease in both groups (HMA/VEN = 88%, IC=84%). In the HMA/VEN group, 21 patients (27%) received azacitidine and 58 (73%) received decitabine. At diagnosis, the median comorbidity index (HCT-CI) for the HMA/VEN and IC group was 4 (0-6) and 3 (0-5), respectively (p=0.09). Main reasons for administering HMA/VEN were age (31%), disease biology (22%) and cardiac comorbidities (16%).

The overall response rate (CR/CRi/MLFS) after the first cycle was 45% in the HMA/VEN group and 67% in the IC group (p=<0.01). The best overall response rate was 61% (median 2 cycles) in the HMA/VEN group and 71% (median 1 cycle) in the IC group (p=0.01). The CR rate was 40% (best response) in the HMA/VEN group and 61% in the IC group (p<0.01). The 30-day mortality was 14% in the HMA/VEN group and 12% in the IC group (0.06).

Subsequent therapy in the HMA/VEN group consisted of IC in 6 patients, targeted therapy in 3 patients and clinical trial in 3 patients. In the IC group, 16 patients received HMA/VEN, 3 patients received targeted therapy and 2 were enrolled in clinical trial subsequently. More patients in the IC group (n=30, 38%), compared to the HMA/VEN group (n=8, 10%), proceeded to allo-sct (p=0.01).

The median overall survival (mOS) for the HMA/VEN group was 6m, compared to 21m for the IC group (p<0.001). In patients that proceeded to allo-sct, the mOS for the HMA/VEN group was not reached and was 98m for the IC group (p=0.8). In patients that were unable to proceed to allo-SCT, the mOS for the HMA/VEN group was 4m, compared to 7.5m for the IC group (p=0.006).

A sub analysis was conducted to evaluate the outcomes of responders to therapy. In patients that responded to first-line therapy but were unable to proceed to allo-sct, the mOS for the HMA/VEN group was 11m, compared to 18m for the IC group (p=0.05). There was no significant difference in those who proceeded to transplant.

Conclusion: In patients with intermediate and adverse-risk AML, responses were higher with IC compared to HMA/VEN induction. For patients unable to proceed to allo-sct, treatment with IC was associated with improved survival. This survival benefit favoring IC was maintained in a subset analysis of responders only as well. Survival was similar in patients proceeding to transplant, regardless of upfront regimen. Given the retrospective nature of this analysis, randomized trials are needed to validate the difference in outcomes observed between these two regimens in intermediate and adverse-risk AML.