Clinical, cytogenetic and molecular characteriszation of Mecom- rearranged pediatric de novo Acute Myeloid Leukemia (AML): A retrospective cohort study of the international-berlin-frankfurt-Münster (I-BFM) AML-study group

Abstract Introduction: MECOM-rearranged (r) acute myeloid leukemia (AML) is a distinct WHO-defined genetic subtype and includes cases with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) or 3q26.2 fusions with alternative partners. These rearrangements occur in <2% of adult AML cases and are even rarer and poorly characterized in pediatric AML. MECOM-r AML is associated with chemotherapy resistance and poor clinical outcomes. Management of children with this high-risk leukemia subtype remains insufficiently defined. This study thus aimed to characterize the clinical, cytogenetic, and molecular features of pediatric MECOM-r AML and to explore potential prognostic markers and therapeutic approaches. Methods: We conducted a retrospective international cohort study of pediatric and adolescent/young adult patients (0–21 years) newly diagnosed with MECOM-r AML between 1998 and 2022. Eligible cases harbored inv(3)/t(3;3) or alternative 3q26 rearrangements. Data were collected via 18 national and cooperative pediatric AML study groups. Patients with acute promyelocytic leukemia or myeloid leukemia of Down syndrome were excluded. Karyotypes were centrally reviewed. Descriptive statistics, Kaplan-Meier survival analysis, and multivariate logistic regression were used to assess clinical features and predictors of response and survival. Due to missing data, some analyses were limited to evaluable cases (EC). Results: Of 69 submitted cases, 10 were deemed ineligible as MECOM rearrangement was unconfirmed. Amongst the 59 patient study cohort, median age was 14.3 years (range 0.9–20.8) with equal sex distribution. Median diagnostic bone marrow blast percentage was 65% (range 6–95), although 12% (6/47 ECs) had <20% blasts and may have been classified as myelodysplastic syndrome (MDS) in prior years. Dysmegakaryopoiesis was observed in 61% (16/26 EC). Inv(3)was identified in54% (32/59 ECs), while others harbored rare fusions, most commonly from t(3;12)(q26;q22). Monosomy 7 was detected in 80% (45/56 EC) and FLT3-ITD in 26% (12/46 EC) with similar frequencies across subtypes. Six of 39 patients (15%) presented with diabetes insipidus at diagnosis, four with abnormal hypophyseal imaging. Nearly all patients (55/56 EC) received multi-agent AML chemotherapy. After two induction cycles, 68% of patients with response data (n=38) showed resistant disease. Overall, complete remission (CR) rates were low but similar between inv(3) and non-inv(3) cases (47% vs. 50%). In a multivariate logistic regression, monosomy 7 was significantly associated with resistant disease (OR 6.21, 95% CI 1.08–44.75, p=0.048), while inv(3) showed a non-significant trend toward poorer response (OR 2.60, 95% CI 0.54–14.95, p=0.25). Hematopoietic stem cell transplantation (HSCT) in first CR or without morphologic CR was performed in 67% (35/52) patients; 37% (13/35) survived (7 transplanted in CR, 3 in non-CR, 3 unknown), while 63% (22/35) died post-HSCT (13 due to relapse; toxicity 5; unknown cause 4). Of the 17 patients without primary HSCT, two survived, but both required HSCT subsequent to relapse. Only 29% (15/52 EC) of patients achieved long-term remission with 38% 5-year overall survival (OS). Kaplan-Meier analysis showed no significant survival difference between inv(3)and other MECOM-r subtypes (p=0.20). Cox regression analysis of the subset of 26 patients with evaluable data showed a non-significant increase in hazard of death for inv(3)(HR 2.04, 95% CI 0.72–5.77, p=0.18). Conclusion: This is the largest international cohort of pediatric MECOM-r AML to date and underscores the poor prognosis of this high-risk leukemia subtype also in children. Co-occurring monosomy 7 was a significant independent predictor of chemotherapy resistance. Our data prove that also pediatric MECOM-r AML shares features with MDS, including prominent dysplasia and monosomy 7. As updated in the WHO 2022 classification, blast count is no longer a defining criterion when specific genetic alterations are present. However, since MDS diagnosis was not an inclusion criterion, patients with <20% blasts were likely underrepresented, limiting insight into the full clinical spectrum of MECOM-driven myeloid malignancies. While HSCT remains the only chance for durable remission, OS of patients with MECOM-r AML remains poor. Ongoing molecular and functional analyses are needed to identify cooperating mutations and cellular vulnerabilities potentially amenable to new and more effective therapeutic approaches.