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

Abstract

BACKGROUND:Optimal chemotherapy for treating mixed-phenotype acute leukemia (MPAL) and the role of hematopoietic stem cell transplantation (HSCT) remain uncertain. Major limitations in interpreting available data are MPAL's rarity and the use of definitions other than the currently widely accepted criteria: the World Health Organization 2016 (WHO2016) classification. METHODS: To assess the relative efficacy of chemotherapy types for treating pediatric MPAL, the Children's Oncology Group (COG) Acute Leukemia of Ambiguous Lineage Task Force assembled a retrospective cohort of centrally reviewed WHO2016 MPAL cases selected from banking studies for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Patients were not treated in COG trials; treatment and outcome data were captured separately. The findings were then integrated with the available, mixed literature to develop a prospective trial in pediatric MPAL. RESULTS: The central review confirmed that 54 of 70 cases fulfilled WHO2016 criteria for MPAL. ALL induction regimens achieved remission in 72% of the cases (28 of 39), whereas AML regimens achieved remission in 69% (9 of 13). The 5-year event-free survival (EFS) and overall survival (OS) rates for the entire cohort were 72% ± 8% and 77% ± 7%, respectively. EFS and OS were 75% ± 13% and 84% ± 11%, respectively, for those receiving ALL chemotherapy alone without HSCT (n = 21). CONCLUSIONS:The results of the COG MPAL cohort and a literature review suggest that ALL chemotherapy without HSCT may be the preferred initial therapy. A prospective trial within the COG is proposed to investigate this approach; AML chemotherapy and/or HSCT will be reserved for those with treatment failure as assessed by minimal residual disease. Embedded biology studies will provide further insight into MPAL genomics. Cancer 2020;126:593-601.

Mixed phenotype acute leukemia in a child associated with a NUP98‐NSD1 fusion and NRAS p.Gly61Arg mutation

“…However, all known MPAL treatment data that supports upfront ALL-based therapy is retrospective, and can be challenging to interpret given the changing definitions of this disease. 5,18,19 The current Children's Oncology Group (COG) study AALL1732 After relapse, tacrolimus was switched to sirolimus, in an attempt to target NRAS downstream by inhibiting mTOR. 17 mTOR inhibitors in combination with additional agents have been studied in AML and other advanced cancers.…”

“…However, all known MPAL treatment data that supports upfront ALL‐based therapy is retrospective, and can be challenging to interpret given the changing definitions of this disease. 5 , 18 , 19 The current Children's Oncology Group (COG) study AALL1732 (NCT03959085), is the very first clinical trial to enroll MPAL patients prospectively. This study is designed to treat all de novo MPAL patients with ALL‐directed therapy, but allows for patients with a poor treatment response to switch to AML chemotherapy followed by allogeneic HSCT.…”

Pediatric Mixed-Phenotype Acute Leukemia: What’s New?

“…Currently, MPAL are classified based on lineage-specific immunophenotypic markers determined by flow cytometry, immunohistochemistry, or cytochemistry and primary molecular alteration, and are considered by most co-operative groups to be high-risk leukemias [ 5 ]. The majority of MPAL present as B-lymphoid/myeloid (in about 2/3 cases), with a T-lymphoid/myeloid immunophenotype being the second most common presentation.…”

“…However, the true prevalence and survival can be difficult to determine given the various diagnostic criteria utilized, lack of a centralized review of cases, and treatment protocols that are based on results from retrospective studies. The Children’s Oncology Group Acute Leukemia of Ambiguous Lineage Task Force reported that routine institutional flow cytometry was insufficient for the diagnosis of MPAL in about 15% of children, which further highlights the diagnostic challenge faced by oncologists [ 5 ].…”

Mixed phenotype acute leukemia: Biological profile, clinical characteristic and treatment outcomes: Report of the population‐based study

“…The optimal therapy for this subtype of leukemia has not been established, especially in pediatric patients and the role of hematopoietic stem cell transplantation (HSCT) in first remission remains contentious 6 . Even though HSCT in first complete remission (CR‐1) for adult patients with MPAL is recommended, recent pediatric report by Orgel et al suggests no benefit for HSCT in CR1, particularly for those with favorable features 9 . Thus, the aim of this retrospective, population‐based study was to analyze biological and clinical features and treatment results in children diagnosed with MPAL in centers of Polish Pediatric Leukemia/Lymphoma Study Group between 2007 and 2018.…”