Clinical Outcomes in Pediatric Mixed Phenotype Acute Leukemia (MPAL) Differ Depending on Disease Classification Criteria; A Multi-Center Cohort Study

INTRODUCTION: Mixed phenotype acute leukemia (MPAL) is a category of acute leukemia established in the World Health Organization (WHO) 2001 classification, significantly modified in WHO2008, and again refined in the most recent WHO2016 update. The current WHO2016 iteration conceptualizes MPAL as a stem cell disorder whereby most cases will manifest heterogeneity of lineage-specific antigen expression by multi-parameter flow cytometry. The WHO2016 definition also urges caution for cases otherwise consistent with B-cell acute lymphoblastic leukemia (B-ALL) that express myeloperoxidase (MPO) as the sole representation of myeloid lineage. These cases met the WHO2008 definition but may not meet the newer WHO2016 criteria. There is limited data on the clinical impact of these recent changes in the WHO classification for MPAL.

METHODS: Six institutions identified cases diagnosed as MPAL between 2008 and 2016 according to WHO criteria. The diagnostic flow cytometry was then reanalyzed by two independent hematopathologists blinded to clinical outcomes. The cases were evaluated as to whether they met criteria for WHO2008 MPAL and/or WHO2016 MPAL. Cases of WHO2008 MPAL were further subdivided into those that otherwise met criteria for B-ALL (including non-lineage specific expression of ±CD13, ±CD15, ±CD33) but qualified as MPAL due to MPO expression (MPO+MPAL) and all remaining cases of MPAL that demonstrated additional myeloid lineage specificity as described by the WHO criteria (MLS+MPAL). Data for a distinct cohort of pediatric B-ALL without significant MPO expression diagnosed during the same study period was submitted from one participating site to serve as a reference cohort (n=258). Endpoints of interest to evaluate clinical outcomes according to the WHO classification were event-free and overall survival (EFS, OS). All statistical tests were two-sided with significance set at p<0.05.

RESULTS: The cohort consisted of 112 cases submitted for central review; 94/112 met the strict criteria for WHO2008 MPAL. Of these, 21/94 cases also had sufficiently comprehensive testing performed at diagnosis to meet criteria for WHO2016 MPAL. Five-year EFS and OS for patients identified as WHO2016 MPAL (63±11% and 69±11%) was significantly worse than the remainder meeting only the WHO2008 criteria (69±7% and 87±5%, p=0.024 and p<0.001, respectively). Patterns of failure occurred earlier for the WHO2016 MPAL subset (Figure 1). For those diagnosed with WHO2008 MPAL, 67/94 (71%) cases were found to be MPO+MPAL, and the remaining 27 were consistent with MLS+MPAL. Favorable prognostic features (age<10 years, WBC <50 K/uL, favorable cytogenetics) were significantly less prevalent at diagnosis in MLS+MPAL and MPO+MPAL versus B-ALL. Five-year EFS and OS for patients with MPO+MPAL (68±7% and 87±5%) or MLS+MPAL (68±9% and 72±9%) were significantly worse when compared to B-ALL overall (84±3% and 93±2%, Wilcoxon p<0.001 for EFS and OS) (Figure 2). However, on multivariable analysis inclusive of prognostic features, OS differed significantly from B-ALL for MLS+MPAL but not for MPO+MPAL (p=0.016 and p=0.629, respectively). There was no association between percentage of MPO+ blasts and EFS or OS.

CONCLUSIONS: Reported survival rates for MPAL continue to vary with changes to the WHO classification. The subset fulfilling WHO2016 criteria demonstrated significantly worse EFS and OS than the WHO2008 cohort; WHO2016-defined MPAL may better represent the concept of MPAL as a stem cell disorder. Applying WHO2016 versus WHO2008 criteria to diagnostic flow cytometry in this retrospective cohort resulted in fewer patients classified as MPAL. As a retrospective study, the antigen combinations necessary to fulfill newer WHO2016 criteria for blast heterogeneity were not tested in many cases; however, it remains likely that the updated WHO2016 criteria will reduce apparent disease prevalence. While cases of WHO2008 MPAL otherwise meeting criteria for B-ALL apart from MPO expression were less likely to have favorable prognostic features at diagnosis, survival on multivariable analysis was similar to B-ALL; it remains unclear how best to categorize this group of MPO+ acute leukemia. Better understanding of the biology of MPAL is therefore essential to appropriately classify these rare leukemias and to develop optimal therapy.

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