Nelarabine Is Active in Pediatric T/Myeloid Mixed Phenotype Acute Leukemia
Authors: Summers Ryan J , Mumme Hope L , Khanna Anjali , Bhasin Manoj , Miller Tamara P. , Raikar Sunil S 
Published: December 2024

Background: Mixed phenotype acute leukemia (MPAL) is a rare form of leukemia that expresses features from both the lymphoid and myeloid lineages. Treatment approaches have been historically variable, but recent data support starting with acute lymphoblastic leukemia (ALL)-directed therapy. Nelarabine is a nucleoside analogue with efficacy in T-cell ALL (T-ALL) as demonstrated in the Children's Oncology Group trial AALL0434. However, the use of nelarabine-containing regimens in T/myeloid (T/My) MPAL has not been studied.
Methods: This retrospective review included children with T/My MPAL treated at Children's Healthcare of Atlanta between 2010-2022. The clinical features of those who were treated with and without a nelarabine-containing regimen were manually abstracted and are reported descriptively and compared using Fisher's exact or unpaired t tests with a significance level of 0.05. Patients received nelarabine as part of a multi-agent chemotherapy backbone as per AALL0434. Event-free survival (EFS) and overall survival (OS) was determined using the Kaplan-Meier method. Events were defined as relapse or death. Furthermore, an in silico analysis of drug sensitivity was performed using single-cell RNA sequencing data obtained from diagnostic bone marrow samples of patients with B/myeloid (B/My) (n=4) and T/My MPAL (n=3). The in silico drug screening platform was created utilizing the genomic profiles of drug sensitivity from 41 different leukemia/lymphoma cell lines and included 479 different agents.
Results: We identified 11 patients (5-17 years of age at diagnosis) with T/My MPAL treated at our center during the study period; 1 was excluded due to therapy abandonment after induction. Of the 10 patients analyzed, 5 were treated without nelarabine and 5 were treated with a regimen containing nelarabine; 7/10 (70%) had an early T-precursor (ETP)/myeloid immunophenotype. All patients received a 4-drug ALL-directed induction. There were no differences in race, ethnicity, CNS status, presenting WBC count, or end-induction minimal residual disease (EOI MRD) between patients who did and did not receive nelarabine. Median EOI MRD was 0% (range 0-13.8%). Patients treated without nelarabine were significantly more likely to undergo hematopoietic stem cell transplant (HSCT) (80% vs 0%; p=0.0476) and to receive myeloid-directed therapy after induction (80% vs 0%; p=0.0476). The switch to myeloid therapy followed by HSCT was based on provider choice in 2 cases and EOI MRD positivity in 2 cases. Patients treated with nelarabine had superior but not significantly different EFS (75% vs 40%; p=0.1877) and OS (75% vs 40%; p=0.1877). There was 1 death due to relapse and 2 deaths after stem cell transplant in the no nelarabine group and 1 death in remission due to infection (during maintenance therapy) in the nelarabine group. Our in silico analysis of drug sensitivity demonstrated that malignant blasts in T/My MPAL samples were predicted to be more sensitive than resistant to nelarabine, ranking 36 of 479 agents tested (top 8%ile) as compared to B/My MPAL (271/479, 57%ile).
Conclusions: Nelarabine is considered standard of care in pediatric T-ALL in the United States but has not been studied in T/myeloid MPAL. Here, for the first time, we report the clinical outcomes in T/My MPAL patients treated with a nelarabine-containing regimen. Furthermore, our in silico drug sensitivity analysis predicts malignant blasts are more sensitive to nelarabine in T/My MPAL compared to B/My MPAL. Larger studies should be performed to validate these findings, but our data support the use of nelarabine in pediatric patients with T/My MPAL.