Background: Cladribine-based regimens combined with venetoclax (VEN) have shown promising efficacy in newly diagnosed (ND) acute myeloid leukemia (AML), both in intensive and low-intensity settings. However, data on outcomes and patterns of relapse following allogeneic stem cell transplantation (allo-SCT), remain limited.

Methods: This is a retrospective study of pts with ND AML who received either intensive chemotherapy (IC) or low-intensity therapy (LIT) using cladribine-based regimens combined with VEN, followed by allo-SCT in first remission. We aimed to analyze survival outcomes and patterns of relapse after SCT.

Results: A total of 303 pts with ND AML were treated with cladribine-based therapy, among whom 140 (46%) underwent allo-SCT in first remission. Of these, 77 (55%) received LIT consisting of cladribine, low dose cytarabine and VEN alternating with azacitidine and VEN (Clad + LDAC + VEN), and 63 (45%) received IC with cladribine, high-dose cytarabine, idarubicin, and VEN (CLIA + VEN). The median age for the entire cohort was 62 years (range, 19-78), 67 years (range, 52-78) for those treated with LIT and 48 years (range, 19-63) for those treated with IC. Secondary AML and therapy-related AML were present in 23 (16%) and 17 (12%) pts, respectively. The most common mutations were DNMT3A (26%), NPM1 (18%), TET2 (15%), SFSR2 (14%). According to the European LeukemiaNet (ELN) 2022 classification system, 24 pts (17%) were classified as favorable-risk, 43 pts (31%) intermediate-risk, and 73 pts (52%) adverse-risk.

Pts received a median of 2 cycles of therapy (range, 1–18) prior to allo-SCT, regardless of treatment intensity. The median time from AML diagnosis to allo-SCT was 4.4 months (range, 1–30). MRD negativity by flow cytometry, assessed as the best response prior to allo-SCT, was achieved in 104 pts (78%), including 61/74 pts (82%) in the LIT group and 43/60 pts (72%) in the IC group. All but one of the 125 pts with available MRD assessment at day +30 post-allo-SCT were MRD-negative. Maintenance therapy following allo-SCT was given to 45 of 139 pts (32%) with available post-transplant data, including 25 (18%) in the LIT group and 20 (14%) in the IC group. The most commonly used maintenance regimens were: azacitidine combined with VEN (19 pts), hypomethylating agent monotherapy (15 pts), and FLT3 inhibitors (8 pts).

With a median follow-up of 38 months, the median relapse-free survival (RFS) and overall survival (OS) were not reached. The 3-year RFS and OS for the entire cohort were 77% and 78%, respectively. The day +100 mortality was 5.1%, and the 1-year mortality was 17.2%. For pts with s-AML and t-AML (n=39), the 3-year RFS and OS were both 75%. In the LIT group, 3-year RFS and OS were 72% and 74%, compared to 85% and 84% in the IC group. Among patients treated with LIT, 3-year RFS rates were 92% for favorable-risk, 86% for intermediate-risk, and 62% for adverse-risk groups, and the corresponding OS rates were 92%, 86%, and 66%. In the IC group, 3-year RFS was 100%, 77%, and 87%, and OS was 100%, 74%, and 86% for favorable-, intermediate-, and adverse-risk groups, respectively.

The 3-year cumulative incidence of relapse (CIR) for LIT-treated pts was 0% for favorable and intermediate-risk and 14% for adverse-risk, while the non-relapse mortality (NRM) was 8%, 14%, and 25%, respectively. In the IC group, the 3-year CIR was 0%, 12%, and 9%, and the NRM was 0%, 11%, and 4% for favorable-, intermediate-, and adverse-risk pts, respectively.

Among the 12 pts (8.5%) who relapsed, the median time to relapse following allo-SCT was 5.7 months (range, 2.1–55.9); 0 (0%), 3 (25%), and 9 (75%) had baseline ELN 2022 favorable, adverse, and intermediate risk. Of the 10 relapsed pts with pre-SCT MRD data available, 4 (40%) were MRD-positive. Four pts presented with extramedullary disease (EMD) at relapse, including three with isolated EMD involvement. Of the 7 pts who underwent comprehensive cyto-molecular testing at relapse, 5 showed evidence of clonal evolution. Ten pts (83%) died following relapse, with a median OS of 6.7 months from the time of relapse.

Conclusion: Cladribine-based regimens combined with VEN followed by allo-SCT result in high rates of durable remission and survival in ND AML, including in older pts treated with LIT. Outcomes were favorable across all ELN 2022 risk groups, although pts with adverse-risk disease had higher relapse rates and NRM, particularly in the LIT group.

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2025
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