Therapy-related core binding factor Acute Myeloid Leukemia – a Study of the french acute leukemia intergroup

Abstract

Abstract Introduction Therapy-related CBF-AMLs represent approximately 10% of all CBF-AMLs and are associated with poorer outcomes, partly due to the associated solid tumor. Existing studies are small, and more data—especially NGS and cytogenetics—are needed to better define their characteristics and prognosis. Methods We analyzed data from a retrospective multicenter study (NCT05070208) and the prospective CBF-2006 trial (NCT00428558, Jourdan et al. 2014) from the French AML intergroup, including CBF-AML patients diagnosed between 2007–2020. Cases with prior chemo- or radiotherapy were classified as therapy-related (t-AML). Baseline characteristics were compared in the overall cohort. Outcomes were assessed in a sub-population of fit patients (≤80 years, cancer in remission, intensive chemotherapy). Centralized NGS was performed using 40- and 68-gene panels (36 genes in common), and MRD was assessed by RT-qPCR for RUNX1::RUNX1T1 and CBFB::MYH11. Results Among 749 CBF-AML patients included between 2007 and 2021, 78 had t-AML. t-AML patients were older (median age: 59 vs. 45 years, p<0.001), more likely to be female (68% vs. 44%, p<0.001), and had lower white blood cell counts (WBC) at diagnosis (median: 6 vs. 15 G/L, p<0.001). was the most common prior neoplasm (42%). Median interval from chemo/radiotherapy to t-AML onset was 38 months (IQR [interquartile range]: 25–69). Neoplasms were in complete remission after chemotherapy (74%) and/or radiotherapy (49%) at CBF-AML diagnosis in 83% pts and remained in sustained remission in 78% after a median follow up of 1.8 years. The distribution of RUNX1::RUNX1T1 and CBFB::MYH11 subtypes was similar between therapy-related and de novo cases (44% and 43% for RUNX1::RUNX1T1, p>0.9). Cytogenetically, X chromosome deletions were more frequent in t-AML (16% vs. 8%, p=0.016). t-AMLs showed fewer on NGS (63% vs. 75%, p = 0.019), and fewer FLT3 mutations (10% vs. 24%, p = 0.03). No other difference was observed in the mutational landscape of t-AML, including KIT and TP53 alterations. In the selected population of patients without active cancer at AML diagnosis and treated with intensive chemotherapy (n=693, including 57 t-AML), induction regimens were mainly based on 7+3 ( in t-AML vs 72% in non-t-AML, p=0.07) and consolidation courses on intermediate/high dose cytarabine courses (93% in t-AML vs 90% in non-t-AML, p=0.64). Gemtuzumab-ozogamycin was added to Cx in 9% of t-AML (vs. 10% of non-t-AML, p=1.0). Allogeneic transplant in first complete remission was performed in 9% of t-AML and 5% of non-t-AML (p=0.21). Therapy-related AML patients had a CR/CRp rate of 95%, not different from de novo patients (95%, p=0.74). MRD after one cycle of induction was not different in t-AML in bone marrow (median: 0.20% [IQR: 0.04-0.82%] vs. 0.17% [IQR: 0.03-0.49%], p=0.50) nor in peripheral blood (median: 0.02% [IQR: 0.002-0.14%] vs. 0.03% [IQR: 0.001-0.19%], p=0.85). With a median follow-up of 5.3 years (IQR :3.9-6.8), the 3-year cumulative incidence (CI) of relapse was 41% (95%CI [confidence interval]:27%-54%) in t-AML patients and 38% (95%CI:34%-42%) in non-t-AML patients (csHR=1.07 [95%CI:0.69-1.68], p=0.76). No difference was also observed for non-relapse mortality (NRM) (3-year CI-NRM: 2% [95%CI:0%-9%] for t-AML vs. 3% [95%CI:2%-5%] for non-t-AML, csHR=0.87 [95%CI:0.21-3.66], p=0.85). Overall survival (OS) was lower in t-AML in univariable analysis (3-year OS: 62% [95%CI:50%-77%] in t-AML vs 79% [95%CI:75%-82%] in non-t-AML, p=0.03). Nevertheless, this was not confirmed in multivariable analysis (HR=1.36, 95%CI:0.84-2.18, p=0.21 for t-AML) when accounting for age (per 10 years of age HR=1.27, 95%CI:1.14-1.42, p<0.001), WBC count (log10 scale HR=1.25, 95%CI:0.94-1.65, p=0.12), and CBF subtype (HR=1.19, 95%CI:0.87-1.62, p=0.29 for RUNX1::RUNX1T1). In patients who experienced relapse (n=249 including 21 t-AML), OS after relapse was dismal in t-AML (16% [95%CI:6%-45%] vs 56% [95%CI:50%-64%], p<0.0001). Conclusion This study shows that therapy-related CBF-AML patients are older, have lower WBC at diagnosis, and present with similar molecular profiles compared to de novo cases. Among a homogenous cohort of patients without active cancer and treated with intensive chemotherapy, there were no differences in CR/CRp rates, relapse incidence, or non-relapse mortality. Unlike previous studies, overall survival was not significantly different after multivariable adjustment for age, WBC count, and CBF subtype.