Mixed phenotype acute leukemia: Clinical characteristics and real-world outcomes

Abstract Introduction MPAL is a rare, heterogeneous leukemia defined by myeloid and lymphoid marker co-expression. The 2022 WHO classifies subtypes as B/My, T/My, or those with BCR::ABL1 or KMT2A-r. MPAL lacks standardized treatment and has poor outcomes; its prognostic and therapeutic alignment with ALL subtypes remains unclear. Aim To characterize clinical features and treatment outcomes of MPAL patients(pts) treated with intensive chemotherapy. Methods We conducted a retrospective single-center study of adults (≥18 y) diagnosed with MPAL (2003–2023), classified per WHO 2022. Induction regimens were categorized as ALL-like (PMH-DFCI or HyperCVAD), AML-like (anthracycline + cytarabine), or FLAG-IDA; BCR::ABL1+ pts received TKIs. OS was measured from diagnosis to death or last follow-up; CIR from CR to relapse or death. Standard statistical methods were used. Each MPAL subtype was compared to its phenotypically similar ALL counterpart using 1:2 propensity score matchings, balanced for age (<60 vs. ≥60 years), gender, presence or absence of extramedullary disease (EM), and white blood cell count at diagnosis (<30 vs. ≥30 ×10⁹/L). Subgroup analyses included comparisons of B/My MPAL vs. B-ALL, T/My MPAL vs. T-ALL, and BCR::ABL1+ MPAL vs. Philadelphia chromosome-positive (Ph+) ALL Results Among 841 ALL pts treated with intensive chemotherapy, 64 cases were re-reviewed by two hematopathologists due to suspicion of MPAL. 41 pts (5%) met MPAL criteria per WHO 2022. Median age at diagnosis was 51 years (IQR 40–62); 29% were aged ≥60 years, and 59% were male. The most common MPAL subtype was B/My: 19 (46%), followed by T/My: 10 (24%), BCR::ABL1mut: 7 (17%), KMT2Ar: 3 (7%), and other rare subtypes: 2 (5%). Among 36 pts with evaluable cytogenetics, 11 (27%) had complex karyotype. EM disease was present in 10 pts (24%). Induction regimens included ALL-like protocols in 26 pts (63%), FLAG-IDA in 13 (32%), and AML-like in 2 (5%). Intrathecal chemotherapy was administered in 35 pts (85%) Thirty-three pts (80.5%) achieved CR after first induction: 21/26 (81%) with ALL-like protocols, 11/13 (85%) with FLAG-IDA, and 1/2 (50%) with AML-like regimens (p=0.503). Of the 8 pts (19.5%) who failed to achieve CR, 7 received reinduction therapy: 1 (12.5%) with an ALL-like regimen, 3 (37.5%) with AML-like, 1 (12.5%) with FLAG-IDA, and 2 (25%) with venetoclax-based regimens. Of these, 6 (85.7%) achieved CR after reinduction. Fourteen of 39 responders (36%) relapsed, with a median time to relapse of 10 (2–46) m. Immunophenotypic data at relapse were available for 8 pts (57%): 1 relapsed with the same phenotype; 2 shifted to B-ALL (both initially B/My and treated with ALL-like regimens at diagnosis); 1 to T-ALL (initially B/ T/My also treated with an ALL-like regimen); and 4 to AML (2 initially B/My, 2 T/My all treated with FLAG-IDA at diagnosis). Median follow-up was 75mo(IQR 41–88). OS was 80% (95% CI, 64–90) at 1 y and 54% (37–68) at 5 y. CIR was 10% (2–53) at 1 y and 24% (3–67) at 5 y. In the PSM analysis, MPAL had numerically inferior OS: 1 y OS was 78% (61–88) vs. 86% (82–88), and 5 y OS 54% (37–68) vs. 65% (61–68) (HR 1.52, 1–2.4; p=0.0659). CIR was significantly higher in MPAL at 1 y (24% [12–43] vs. 12% [10–15]) and 5 y (46% [29–67] vs. 33% [29–37]; HR 2.3, 1.5–3.7; p=0.0003). By subtype, B/My MPAL (n=19) had outcomes comparable to B-ALL (n=38): 1 y OS 90% (64–97) vs. 82% (65–92), 5 y OS 74% (45–88) vs. 57% (37–73) (HR 0.71, 0.3–1.7; p=0.4507). CIR was also comparable at 1 y: 27% (11–56) vs. 24% (13–42) (HR 0.61, 0.3–1.5; p=0.2645). T/My MPAL (n=10) showed a tendency toward lower OS vs. T-ALL (n=20): 1 y OS 68% (29–88) vs. 73% (46–88), 5 y OS 28% (4–59) vs. 56% (31–75) (HR 1.74, 0.6–5; p=0.2996); 1 y CIR was comparable (21% vs. 27%). BCR::ABL1+ MPAL (n=7) and Ph+ ALL (n=14) had similar survival: 1 y OS 86% vs. 93%, 5 y OS 57% vs. 71% (HR 1.43, 0.32–6.40; p=0.6408), with identical 1 y CIR (14%; HR 0.99, 0.2–4.0; p=0.9913). In PSM censoring for allo-HSCT, outcomes remained consistent except for T/My MPAL, which had significantly inferior OS vs. T-ALL (1 y OS 30% [4–62] vs. 67% [41–82]; HR 4.22, 1.3–14; p=0.0105), with no survivors beyond 5 y. Conclusion MPAL showed a trend toward worse OS and higher CIR vs. lineage-defined ALL, with significantly inferior OS in the T/My subtype post-transplant censoring. These findings underscore its high-risk nature and the need for collaborative studies to refine subtype-specific, risk-adapted treatment strategies for MPAL.

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