Background: Acute megakaryoblastic leukemia (AMKL, AML-M7) is a rare, biologically heterogeneous subset of Acute Myeloid Leukemia (AML) arising from megakaryoblasts, that portends a dismal prognosis. While AMKL in children with Down syndrome has relatively favorable prognosis, adults face significantly worse outcomes. Determinants of survival in adult AMKL remain poorly defined. Here, we report the clinco-genomic profile and treatment outcomes of patients with AMKL.

Methods: We retrospectively reviewed patients aged ≥ 18 yrs with AMKL treated at our institution between 2012 - 2024. Demographic, molecular, and cytogenetic data, as well as treatment and survival outcomes, were collected from medical records. Cytogenetic abnormalities were classified using the European Leukemia Network (ELN) 2022 guidelines, and mutational profiling was done using next-generation sequencing. Overall survival (OS) was analyzed using Kaplan-Meier method, and log-rank test was used for comparison between subgroups.

Results: 28 pts with AMKL were identified, of which 12 (42%) were newly diagnosed. The median age was 59 yrs (range 22 – 80) and 50% were male. At diagnosis, the median WBC was 3.2x109/L (0.1–33), hemoglobin 8.5 g/dl (5.7–11.7), platelet count 41 x109/L (6–394), LDH 757 U/L (202 – 21225) and bone marrow blast percentage 26% (1–84). Antecedent hematologic disorders (AHD) were noted in 14%; and 32% had prior non-hematologic malignancies. Bone marrow fibrosis was present in 50%. Cytogenetics revealed complex karyotype (53%), del(5q) (35%), del(17p) (28%), and del(7q) (14%); with 78% classified as adverse risk and only 3% being diploid. The most frequent mutations were TET2 (57%), TP53 (53%), and EZH2 (17%), ASXL1 (14%), KIT (14%), KMT2A (14%), FLT3 (14%), NRAS (10%), JAK 2(10%).

4 pts received intensive chemotherapy (IC) and 6 received low-intensity regimens (LIT) in the frontline (F/L) setting. In the salvage (R/R) setting, LIT was administered to 6 patients, while 3 received IC regimens. The overall response rate (CR/CRi/MLFS) was 60% and 30% in F/L and R/R, respectively. Complete remission (CR) rate was 30% and 20% in pts with F/L and R/R AML, respectively. In F/L pts, the ORR was 75% and 50% among pts treated with IC and LIT, respectively. In R/R pts, the ORR was 33% and 20% among pts treated with IC and LIT, respectively. 7 and 5 pts in the F/L and R/R settings were treated with venetoclax-based regimens, with ORR of 57% and 20%, respectively. Median OS from treatment initiation was 16 weeks for pts with AMKL in the F/L setting and 11 weeks in the R/R setting. Pts undergoing allogeneic hematopoietic stem cell transplant (allo-HSCT; n=1 in F/L, 7 in R/R) had significantly better OS (70 vs. 17 weeks, p =0.0016) compared to chemotherapy alone.

In univariate Cox regression analysis, receipt of allo-HSCT was significantly associated with improved overall survival (HR = 0.17; 95% CI, 0.06–0.53; p <0.01). Elevated LDH trended toward inferior survival (HR = 1.00; 95% CI, 1.00–1.00; p = 0.055), as did presence of AHD (HR = 2.92; 95% CI, 0.95–8.97; p = 0.06). Other variables, including age, sex, WBC count, F/L or salvage therapy intensity and venetoclax exposure in either setting were not significantly associated with survival. In multivariate Cox analysis including all variables, allo-HSCT was independently associated with improved survival (HR = 0.0043; 95% CI, 0.0001–0.18; p <0.01).

Conclusions: Adult AMKL is a rare subset of AML, associated with resistance to conventional therapies, low rates of remission, and poor outcomes. This study underscores the potential benefit of allo-HSCT in improving OS. Markers such as elevated LDH and AHD emerged as predictors of poor outcomes. Notably, a third of pts with AMKL had history of a prior malignancy. These findings help establish baseline expectations in this high-risk disease and emphasize the need for novel therapies and a better understanding of disease biology to improve survival.

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2025
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