Clinical Characteristics and Outcomes of Mixed Phenotype Acute Leukemia (MPAL): A Large Multi-Center Retrospective Study
Authors: Cohen-Nowak Adam Julian , Coltoff Alexander , Patel Anand Ashwin , Atallah Ehab L. , El Kettani Mobachir , Wang John , Symes Emily , Venkataraman Girish , Siddon Alexa , Giever Emily , Shallis Rory M. , Altman Jessica Kaplan , Bell-Burdett Kirsten , Badar Talha , Aqil Barina , Abaza Yasmin 
Published: December 2024

Introduction:
MPAL is a rare and heterogenous subtype of acute leukemia characterized by a single blast population with phenotypic expression of both myeloid and lymphoid lineages (biphenotypic) or multiple co-existing lineages of blasts that satisfy criteria for both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). MPAL presents both a diagnostic and therapeutic challenge given its rarity and resistance to traditional therapies. Data suggest ALL-directed or hybrid therapies are most effective at inducing durable remissions as a bridge to allogeneic stem cell transplantation (Allo-SCT; Lazzarotto 2023, Rasekh 2021); however, many are single-institution with limited sample sizes.
Methods:
A retrospective analysis at 7 US academic centers was performed. Adult patients (pts) with a confirmed diagnosis of MPAL between 2003-2023 were included. Comparisons of categorical and continuous variables utilized the Fisher exact test and Wilcoxon rank-sum or Kruskal-Wallis test as appropriate. Time-to-event outcomes were calculated using the Kaplan-Meier method and compared using log-rank test.
Results:
A total of 79 pts with MPAL were included in this study. Median age at diagnosis was 61 years (range, 18-89); 52% were ≥ 60 years. Majority of pts were male (60%), non-Hispanic white (64%), and had an ECOG ≤ 1 (83%). Of the 50 pts with baseline CSF analysis, 5 (10%) had CNS disease. Phenotypically, the predominant blast population was biphenotypic in 68%, myeloid in 17%, and lymphoid in 15% of cases. KMT2A-rearrangement and BCR::ABL1 translocation constituted 4% and 14% of cases, respectively, and 30% of pts had complex cytogenetics. Most common mutations at baseline included RUNX1 (33%), DNMT3A (30%), FLT3-ITD (26%), TET2 (19%), WT1 (19%), NRAS (18%), TP53 (17%), and ASXL1 (14%) mutations.
Of the 79 pts, 61 (77%) received intensive chemotherapy (IC), 12 (15%) received HMA-based regimens, 4 (5%) received other non-intensive regimens, and 2 (3%) transitioned to hospice prior to therapy. Among those receiving IC, 37 (61%) received ALL-directed therapies, 16 (26%) AML-directed, and 8 (13%) received hybrid regimens which included FLAG-VIPR (6/8), 7+3+vincristine (1/8), and cladrabine/low-dose cytarabine/vincristine/dexamethasone (1/8). Therapies were phenotype-discordant in 4/61 pts receiving IC; 3 myeloblast-predominant MPAL pts received ALL-directed therapy and one lymphoid-predominant pt received AML-directed therapy. Among 54 pts with predominant biphenotypic blasts, 52% received ALL-directed regimens. Of the 11 pts with BCR::ABL1 translocation, 8 (73%) received dasatinib, 2 (18%) ponatinib, and 1 (9%) received both. Only 30% of pts with FLT3-ITD mutated MPAL (5/17) received a FLT3 inhibitor.
Overall, 56% of pts achieved complete remission (CR) or CR with incomplete count recovery (CRi), with a median duration of response of 16.7 months (IQR: 8.1-46.1). The rates of CR/CRi were 39%, 56%, and 75% for myeloid, biphenotypic, and lymphoid MPAL, respectively. All pts with CNS disease (5/5) cleared after induction. Thirty-seven percent of pts proceeded with Allo-SCT in first remission (23% of myeloid pts, 58% lymphoid, 35% biphenotypic). Thirty-two percent of responders (CR/CRi; 14/44) relapsed with a median time to relapse of 9.4 months (range, 0.5-42).
Median overall survival (OS) for the entire cohort was 51 months (95% CI: 15-89). The 2-year OS rate was higher in pts with lymphoid-predominant phenotype (83%) compared to biphenotypic (55%) or myeloid-predominant phenotype (38%; p=0.16). Median OS was significantly longer in transplant versus non-SCT recipients (121 vs 14 months) with a 1-year OS rate of 97% vs. 59% (p&lt;0.0001), respectively. Among pts who achieved CR/CRi, median OS significantly longer in transplant versus non-SCT recipients (121 vs 55 months, p=0.031), with a 2-year OS rate of 91% vs 75%.
Conclusions
In this large multi-center study, there were differences in survival based on predominant blast phenotype, with improved OS in lymphoid-predominant MPAL. Although most pts with biphenotypic-predominant MPAL received ALL-directed regimens, OS was worse in this subtype compared to lymphoid-predominant MPAL. There was significantly improved OS among Allo-SCT recipients underscoring the importance of Allo-SCT in this subtype of acute leukemia. Additional studies are needed to understand this rare and heterogenous disease.