Background:MECOM-rearranged (MECOM-r) AML is a rare AML subtype that is characterized by the disease-defining inv(3)(q21q26.2), t(3;3)(q21;q26.2), and other rare alterations involving 3q26.2. MECOM-r AML is an adverse-risk genetic abnormality associated with dismal outcomes in pts treated with intensive cytotoxic chemotherapy (IC). However, there are limited data on clinical outcomes in pts with MECOM-r treated with frontline low-intensity treatment regimens such as venetoclax and hypomethylating agents (VEN/HMA) or hypomethylating agent monotherapy (HMA). We set out to assess clinical outcomes in patients with MECOM-r AML treated with frontline HMA combinations in the largest analysis to date in this rare AML subtype.

Methods: We retrospectively analyzed clinical and molecular characteristics of 93 newly diagnosed adult AML pts with MECOM rearrangements (based on 2022 WHO/ICC criteria) as part of the Myeloid Malignancy Association on Rapid Research Outcomes Working Group (MARROW) Consortium, treated at 10 major US Cancer Centers, who underwent central data review and analyses. In addition, we leveraged the Flatiron Health electronic health record-derived and de-identified database allowing us to assess characteristics and survival outcomes for pts treated at large Cancer Centers as well as real-world data. We collected treatment data and assessed rates of composite complete remission (CRc: CR + CRi + CRh), disease-free survival (DFS), and overall survival (OS).

Results: A total of 224 patients with MECOM-r AML were included (MARROW: n=93; Flatiron: n=131). Clinical and molecular characteristics, treatment types, and survival outcomes did not differ between the 2 patient cohorts. 92% were treated for their AML, while 8% received only supportive care. The median age at diagnosis was 69 years (y; range, 19-91). One hundred sixty-five pts (75%) were ≥65 y, 48% were female, 78% of pts had ECOG Performance Status 0-1. Molecularly, pts frequently harbored RAS pathway mutations (31% total; KRAS, 20%; NRAS, 13%; PTPN11, 24% [not available for Flatiron pts]), TP53 (19%) and RUNX1 (18%) mutations, as well as mutations in spliceosome genes (51% total; SF3B1, 13%; SRSF2, 7%; U2AF1, 13%; [not available for Flatiron pts]). As frontline treatment, 45% received IC (7+3, CPX-351), 30% VEN/HMA, and 25% received HMA monotherapy; 24% of pts underwent allogeneic stem cell transplant (alloSCT).

Overall, 38% (86) of pts achieved a CRc (IC, 54%; VEN/HMA, 32%, HMA, 14%, p= <0.001), of whom 52% eventually relapsed (IC, 56%; VEN/HMA, 36%; HMA, 67%). In multivariable logistic regression analysis for CRc, younger age was the only prognostic factor. DFS was poor for all treatment regimens, with 3-y DFS rates of 18% for IC (median: 9 months; mo), 0% for VEN/HMA (median: 7 mo), and 0% for HMA (median 4 mo). Multivariable Cox regression analysis for DFS demonstrated that both pts without chromosome 7 abnormalities (HR 2.70, p=0.01) and those without AML-MR defining gene mutations (HR 2.41, p=0.02) had longer DFS than pts with these alterations.

3-y OS was longest for pts treated with IC (14%, median 14 mo), compared to VEN/HMA (0%, median 8 mo) and HMA (3%, median 6 mo). In the multivariable analysis, factors associated with worse OS included presence of chromosome 7 abnormalities (HR 1.75, p=0.03), NRAS mutations (HR 2.16, p=0.02), those not undergoing alloSCT (HR 0.19, p<0.001), and treatment with VEN/HMA or HMA (HR 0.58, p=0.04). However, even for pts undergoing alloSCT, the 3-y OS rate was only 26% (Median Overall 23 mo, pts treated with HMA+Ven and HMA: 16 mo, and those treated with IC: 26 mo).

Conclusion: This real-world analysis encompasses the largest reported dataset of MECOM-r AML pts with molecular and outcome data receiving modern therapy. VEN/HMA and HMA did not provide OS benefit, and the addition of VEN was not superior to HMA alone, suggesting that pts may be spared additional toxicities with monotherapy. While multivariable analyses suggested better outcomes for pts without chromosome 7 abnormalities or NRAS mutations, and those who underwent alloSCT, OS was still dismal across all age groups, molecular subgroups, and treatment types. Pts treated with IC and consolidative alloSCT were the only survivors >3 y after diagnosis. The investigation of alternative therapies is thus urgently needed in MECOM-r AML and represents one of the highest unmet needs in AML.

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2025
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