Therapy for children and adults with mixed phenotype acute leukemia: a systematic review and meta-analysis

Abstract

The rarity of mixed-phenotype acute leukemia (MPAL) has resulted in diffuse literature consisting of small case series, thus precluding a consensus treatment approach. We conducted a meta-analysis and systematic review to investigate the association of treatment type (acute lymphoblastic leukemia [ALL], acute myeloid leukemia [AML], or "hybrid" regimens), disease response, and survival. We searched seven databases from inception through June 2017 without age or language restriction. Included studies reported sufficient treatment detail for de novo MPAL classified according to the well-established European Group for Immunological Characterization of Acute Leukemias (EGIL) or World Health Organization (WHO2008) criteria. Meta-analyses and multivariable analyses of a patient-level compiled case series were performed for the endpoints of complete remission (CR) and overall survival (OS). We identified 97 reports from 33 countries meeting criteria, resulting in 1,499 unique patients with data, of whom 1,351 had sufficient detail for quantitative analysis of the study endpoints. Using either definition of MPAL, meta-analyses revealed that AML induction was less likely to achieve a CR as compared to ALL regimens, (WHO2008 odds ratio [OR] = 0.33, 95% confidence interval [95% CI] 0.18-0.58; EGIL, OR = 0.18, 95% CI 0.08-0.40). Multivariable analysis of the patient-level data supported poorer efficacy for AML induction (versus ALL: OR = 0.45 95% CI 0.27-0.77). Meta-analyses similarly found better OS for those beginning with ALL versus AML therapy (WHO2008 OR = 0.45, 95% CI 0.26-0.77; EGIL, OR = 0.43, 95% CI 0.24-0.78), but multivariable analysis of patient-level data showed only those starting with hybrid therapy fared worse (hazard ratio [HR] = 2.11, 95% CI 1.30-3.43). MPAL definition did not impact trends within each endpoint and were similarly predictive of outcome. Using either definition of MPAL, ALL-therapy is associated with higher initial remission rates for MPAL and is at least equivalent to more intensive AML therapy for long-term survival. Prospective trials are needed to establish a uniform approach to this heterogeneous disease.

Mixed‐phenotype acute leukemia: A cohort and consensus research strategy from the Children’s Oncology Group Acute Leukemia of Ambiguous Lineage Task Force

“…Mixed‐phenotype acute leukemia (MPAL) is uncommon and composes 1% to 5% of newly diagnosed acute leukemias . MPAL exhibits a complex phenotype with concurrent representation of multiple leukemia lineages either as distinct populations of cells or as a single population expressing different features .…”

“…Past reports on MPAL suggest that contemporary ALL treatment regimens may be sufficient to cure many, if not most, pediatric patients with MPAL . However, the majority of these case series have lacked central review and, despite age‐associated differences in survival, included only aggregate pediatric and adult data . The most robust pediatric‐only MPAL data stem from the 2012 International Berlin‐Frankfurt‐Munster Study of Leukemias of Ambiguous Lineage (iBFM AMBI2012 study) .…”

“…However, many of the analyses included MPAL diagnosed according to either the World Health Organization (WHO) classification system or the European Group for Immunological Characterization of Acute Leukemias (EGIL) classification system. Within AMBI2012 and other cohorts, the varying classifications for MPAL and even updated versions of the same classification demarcate different populations and influence survival estimates . To best understand treatment effects within a uniformly defined MPAL population, we, therefore, assembled a cohort strictly defined only by the most recent WHO classification (World Health Organization 2016 [WHO2016]) …”

Peripheral blood flow cytometry for the diagnosis of pediatric acute leukemia: Highly reliable with rare exceptions

“…By conventional cytogenetics, the majority of the blasts demonstrated clear‐cut WHO‐defined myelodysplasia‐related cytogenetic changes: del(5q) and a complex karyotype. Following treatment with an ALL‐directed protocol, which a mounting body of evidence continues to support for MPAL, the patient relapsed as a pure AML bearing the same cytogenetic changes seen at presentation (Figure M–O). The persistence and expansion of this aggressive clone with ALL‐directed therapy would favor that, in this case at least, MPO expression was indeed reflective of the myeloid component of a true MPAL.…”

Treatment of CD19‐positive mixed phenotype acute leukemia with blinatumomab

“…Based on the current literature, treating patients with newly diagnosed MPAL with an acute lymphoblastic leukemia (ALL) regimen, rather than an acute myeloid leukemia (AML) regimen, has better efficacy in inducing complete remission (CR), albeit with only~20% 5-year overall survival (OS). 3 Moreover, the prognosis of refractory or relapsed (R/R) MPAL is grim, with a median survival of <3-6 months. 4 Blinatumomab, a bispecific CD19-directed CD3 T-Cell engager antibody, is approved by the United States Food and Drug Adminis- Here, we report two patients with CD19 + MPAL (B/myeloid) who were successfully treated with blinatumomab.…”