Tri-partied analyses define clinical outcomes and molecular features of patients (pts) with acute promyelocytic leukemia (APL)

Abstract Introduction APL is molecularly characterized by t(15;17)/PML::RARA gene fusion as a disease-initiating event and by recurrent gene mutations (mut). Although a highly aggressive disease, its treatment was revolutionized with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), making APL a curable malignancy. While pt-associated factors [age, socioeconomic status (SES), race/ethnicity, genetic ancestry] and disease-associated features (disease risk, prognostic molecular features) impact outcomes in hematologic diseases, no large-scale analyses have assessed the aforementioned factors in the ATRA/ATO era to identify unmet needs and potentially improve outcomes of APL pts. Methods For nationwide population analyses, we used Flatiron Health real-world database to identify 770 adults diagnosed with APL in 2014-2024 and 2 sets of cancer registries in the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 829 pts in 1995-2019. To assess survival in the setting of clinical trials, we analyzed 249 pts treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols with inclusion of ATRA. For Alliance pts, a neighborhood social deprivation index (SDI) was assigned based on pt-reported residence zip code and classified as low (1-25, n=33) or high deprivation (26-100, n=95). Molecular features were analyzed in 224 Flatiron pts who were tested for ≥1 gene with available targeted sequencing data (n=26 genes). To account for potentially unrecognized molecular features of Black pts, we performed integrated genomic profiling (paired tumor/normal whole-exome and transcriptome sequencing) on 23 Black APL pts treated on Alliance protocols. Results In Flatiron database, 14.7% of pts presented with high-risk APL based on defined disease risk stratification [high-risk, white blood cell count (WBC) ≥10x109/L; low-risk, WBC <10 x109/L]. No difference in disease risk was observed by race. Black pts were diagnosed at a younger age (median: Black, 46 years (y) vs White, 54 y; p=0.0013) and there were more White pts diagnosed at age ≥65 y (White 30.1% vs Black 16.3%; p=0.0487). There was no difference in OS by race, ethnicity, SES or disease risk. Negative OS predictors were age ≥65 y at diagnosis [median OS: ≥65 y, 3201 days (d) vs <65 y, NR; p=0.0001) and male sex (median OS: male, 3699 d vs female, NR; p=0.0479). OS of pts receiving ATRA+ATO (3699 d) or intensive chemotherapy+ATRA/ATO (NR) was longer than OS of pts treated with ATRA+other agents (1483 d, p=0.0339). Using SEER data, there was no difference in OS based on self-reported race between Black and White pts before or after 2012. This also held true in race-specific considerations of median household income, Yost index and urban/rural status. As in more recent Flatiron data, the only strong predictor of OS was older age (3y OS rates, 1995-2012: <40y, 79%, 40-59y, 71%, and ≥60y, 44%; 2012-2019: <40y, 92%, 40-59y, 80%, and ≥60y, 56%). OS of Black and White pts did not differ significantly within age groups. We also found no significant difference in OS of Black versus White APL pts treated in the setting of clinical trials. Older age represented a strong negative survival predictor (p<0.001). Pts with SDI >25 (n=95) had a worse OS than pts with SDI <25 (n=33, p=0.03). A comparison of OS of pts treated on clinical trials with OS of pts in population-based analyses found a longer OS for trial pts (3y rates: 84% vs 64%, p<0.001). Molecularly, most prevalent in Flatiron database were mut in FLT3 (FLT3-ITD 40.4%, FLT3 24.5%, FLT3-TKD 17.5%) followed by ETV6 (10.7%), NRAS (7.7%) and TET2 (6.4%). Paired tumor/normal whole exome sequencing of 23 Black pts confirmed FLT3-ITD and/or FLT3-TKD as most frequent mut in 65% of pts. Notably, FLT3-wildtype pts harbored clonal mutations in CALR, MYC and SLIT pathway genes, which hitherto have not been reported in APL. Conclusions We assessed defining features impacting OS of APL pts in the era of ATRA/ATO. In contrast to most cancer types, including AML, we found no survival disparity with respect to race/ethnicity, SES, and disease risk in pts with APL. Older age at diagnosis was a negative OS predictor. A higher frequency of early-onset APL occurred in Black pts. Molecularly, our data reveal the existence of ancestry-associated differences in driver mutations that may represent proliferative signals in addition to the PML::RARA-driven differentiation arrest.