P360: measurable/minimal residual disease (mrd) status is the most relevant indicator of clinical outcome in mixed phenotypic acute leukemias (mpal)

Background: Mixed phenotypic acute leukemia (MPAL) is a rare disease with poor clinical outcomes. Due to its rarity, a specific risk-adapted therapeutic protocol is not available. Minimal residual disease (MRD) has been proven as a powerful predictor of therapeutic response and higher risk in acute lymphoblastic and myeloid leukemia. However, systematic studies evaluating the clinical value of MRD status and MRD time-points in MPAL are extremely rare. There is no data on the clinical implication of MRD in adult MPAL patients. We present the largest single-centre study on the significance of MRD assessment in MPAL. Aims: Evaluating the clinical relevance of MRD monitoring in MPAL Methods: The study included MPAL patients diagnosed according to WHO2016 criteria from Jan-2015 to June-2022. Cytogenetics was performed using karyotyping and FISH. Molecular studies were performed using targeted next-generation sequencing (NGS). Flow Cytometric MRD (FC-MRD) was estimated at post-induction (PIMRD, day 33) in all patients and post-consolidation (PCMRD, day 78) in PIMRD positive patients. Any detectable value was taken as MRD-positive. Results: We included 120 MPAL patients with median age 15.5-years (range:0.9-66 years; children n=60, <1-18 years and adult n=60, >18-66 years) and M:F-1.8:1. These included 48/120 (40%) B/Myeloid, 15/120 (12.5%) B/T, 56/120 (46.7%) T/Myeloid, & 1/120 (0.8%) B/T/Myeloid subtypes. Pediatric patients were treated with MCP841 & among adult patients, 49 received BFM90 (with tyrosine-kinase inhibitors in BCR::ABL1 positive) & remaining 11 received 3 + 7HIDAC therapy. There was no association between age, sex and immunophenotypic subset with event-free-survival (EFS) and overall-survival (OS). Cytogenetic studies were available in 111 patients and molecular studies in 73 patients. These included BCR::ABL1 (20/111, 18%), KMT2A-rearrangement (5/111, 4.5%), Monosomy7/del7q (10/111, 9%), del5q (4/111, 3.6%), tri/tetrasomies (10/111, 9%), NUP98::NSD1 (2/111, 1.8%), CBFA2T3-GLIS2 (2/111, 1.8%), CEBPA-mutation (9/111, 8.1%), FLT3-ITD(5/111, 4.5%), RAS-mutations (8/111, 7.2%), TP53-mutation (1/111, 0.9%), and other abnormalities (6/111, 5.4%). Among them, Monosomy7/del7q was found to be associated with shorter EFS with Hazard Ratio (HR)-2.23 (median EFS 18.8 versus 72.2 months; p=0.02) and shorter OS with HR-2.6 (median OS 8.8 versus 28.6 months; p=0.02). PI-MRD was positive in 86/120(71.7%) patients with median 1.7% (range:0.0008-58.5%). Among 86 PIMRD positive, PCMRD was available in 70 and was positive in 40/70 (57.1%) patients with median 0.27% (range:0.0005-30.2%). Positive PIMRD was strongly associated with shorter EFS with HR-3.12 (median EFS 21.4 months vs. not reached; p=0.0004) and shorter OS with HR-3.5 (median OS 26.5 months versus not reached; p=0.002) (Figure-1). Positive PCMRD was also strongly associated with shorter EFS (HR-2.4; median EFS 16.5 vs. 39.1 months; p=0.006) and shorter OS (HR-3.7; median OS 26.6 months vs. not reached; p=0.005). Multivariate analysis using the Cox hazard model (n=120) showed that PI-MRD was the most significant and independent high-risk factor for shorter EFS (HR-3.4; p=0.0009) and OS (HR-4.1; p=0.003). Conclusion: Our data showed that the positive status of PIMRD and PCMRD strongly predicts high-risk MPAL patients with short event-free and overall survival. It is independent of age, sex, cytogenetics aberrancies & therapeutic protocol. Thus, PIMRD status was the most relevant Indicator of clinical outcome in MPAL.Keywords: MRD, Minimal residual disease (MRD), Mixed lineage leukemia