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T-Lymphoblastic Leukemia (T-ALL) Shows Excellent Outcome, Lack of Significance of the Early Thymic Precursor (ETP) Immunophenotype, and Validation of the Prognostic Value of End-Induction Minimal Residual Disease (MRD) in Children’s Oncology Group (COG) Study AALL0434

Brent L. Wood, Stuart S. Winter, Kimberly P. Dunsmore, Meenakshi Devidas, Si Chen, Barbara Asselin, Natia Esiashvili, Mignon L. Loh, Naomi J. Winick, William L. Carroll, Elizabeth A. Raetz and Stephen P. Hunger

Abstract

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Background: Although outcomes for children and young adults with T-ALL continue to improve, relapse on therapy continues to be a major cause of treatment failure. COG AALL0434 is a phase III study for patients with T-ALL that used a standard 4-drug induction followed by response-based risk stratification at Day 29 with Intermediate and High-risk patients randomized to receive or not receive six 5-day courses of nelarabine during consolidation, delayed intensification and maintenance. All patients are also randomized to receive either Capizzi or high-dose methotrexate during interim maintenance and all patients except those who were Low-risk received cranial irradiation (1200 cGY for CNS1 or 2 and 1800 cGy for CNS3). Risk stratification incorporates MRD detection by flow cytometry at Day 29 using the following cutoffs: Low-risk < 0.1%, Intermediate-risk < 1%, and High-risk > 1%. Recently, the immunophenotype has been associated with a particularly poor outcome in T-ALL, a finding that requires confirmation in a large prospective trial using contemporary therapy.

Methods: 1144 children with T-ALL enrolled on COG AALL0434 between January 22, 2007 and June 30, 2014 were categorized at the time of study enrollment as ETP (n=130; 11.3%), Near-ETP (ETP but with elevated CD5; n=195; 17%) or Not-ETP (n=819; 71.6%) by flow cytometry. MRD was assessed by 8-9 color flow cytometry at Day 8 in peripheral blood (PB) and Day 29 in bone marrow (BM). Flow cytometry to characterize ETP status and MRD was performed in a single central laboratory. Event-free survival (EFS) and Overall survival (OS) were estimated by Kaplan-Maier curve analysis.

Results: Despite significantly higher (P<0.0001) rates of induction failure (>25% blasts by morphology at end induction) for ETP (7.8%) and Near-ETP (6.7%) than Not-ETP (1.1%), all 3 immunophenotypic groups showed excellent 5-year EFS and OS that were not statistically different: ETP (87.0%; 93.0%), Near-ETP (84.4%; 91.6%), and Not-ETP (86.9%; 92.0%). In all 3 groups, most events occurred within 12 months from diagnosis and plateaued after 2 years, although events generally occurred earlier for ETP and Near-ETP than Not-ETP. There were no relapses in ETP patients later than 12 months post diagnosis. Initial white blood cell count (WBC) greater than 200,000/microliter was seen in 9.6% of ETP and 30% of Not-ETP/Near-ETP (P<0.0001) and was associated with inferior EFS and OS for Near-ETP (EFS p=0.0003) and Not-ETP (EFS p=0.012), but not ETP. Day 29 MRD > 0.01% was associated with inferior EFS (76.3% vs. 89.0%; p=0.0001) and OS (86.6% vs. 93.8%; p=0.0008) for the total cohort and was detected in 81.4%, 64.8%, and 30.5% of ETP, Near-ETP and Not-ETP patients, respectively. Interestingly, there was no difference in EFS or OS for Day 29 MRD <0.01% vs. 0.01%-1.0%, suggesting significance largely for MRD > 1.0%. Day 29 MRD >0.01% was also associated with inferior EFS (76.6% vs. 90.8%; p=0.0001) and OS (84.3% vs. 94.0%; p=0.0064) in Not-ETP and inferior EFS (80.2% vs. 94.0%; p=0.0073) in Near-ETP, but no difference was seen for EFS or OS in ETP. Day 8 PB MRD > 0.01% was associated with inferior EFS (80.3% vs. 92.0%; p=0.017) but not OS and lost significance in the subset having Day 29 MRD < 0.01%, suggesting Day 8 does not add prognostic information to Day 29 MRD.

Conclusions: AALL0434 is the largest study of T-ALL ever conducted and shows excellent outcomes for T-ALL. In particular, ETP is found to have an outcome identical to non-ETP patients. WBC count > 200,000/microliter is associated with inferior outcome in non-ETP T-ALL. BM MRD > 1% at Day 29 is able to identify a subset of non-ETP T-ALL patients having inferior outcomes. PB Day 8 MRD does not provide unique prognostic information.

Disclosures No relevant conflicts of interest to declare.

  • * Asterisk with author names denotes non-ASH members.

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