Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001

Abstract

Background/objectives: While outcomes for pediatric T-cell acute lymphoblastic leukemia (T-ALL) are favorable, there are few widely accepted prognostic factors, limiting the ability to risk stratify therapy.

Design/methods: Dana-Farber Cancer Institute (DFCI) Protocols 05-001 and 11-001 enrolled pediatric patients with newly diagnosed B- or T-ALL from 2005 to 2011 and from 2012 to 2015, respectively. Protocol therapy was nearly identical for patients with T-ALL (N = 123), who were all initially assigned to the high-risk arm. End-induction minimal residual disease (MRD) was assessed by reverse transcription polymerase chain reaction (RT-PCR) or next-generation sequencing (NGS), but was not used to modify postinduction therapy. Early T-cell precursor (ETP) status was determined by flow cytometry. Cases with sufficient diagnostic DNA were retrospectively evaluated by targeted NGS of known genetic drivers of T-ALL, including Notch, PI3K, and Ras pathway genes.

Results: The 5-year event-free survival (EFS) and overall survival (OS) for patients with T-ALL was 81% (95% CI, 73-87%) and 90% (95% CI, 83-94%), respectively. ETP phenotype was associated with failure to achieve complete remission, but not with inferior OS. Low end-induction MRD (<10^-4 ) was associated with superior disease-free survival (DFS). Pathogenic mutations of the PI3K pathway were mutually exclusive of ETP phenotype and were associated with inferior 5-year DFS and OS.

Conclusions: Together, our findings demonstrate that ETP phenotype, end-induction MRD, and PI3K pathway mutation status are prognostically relevant in pediatric T-ALL and should be considered for risk classification in future trials. DFCI Protocols 05-001 and 11-001 are registered at www.clinicaltrials.gov as NCT00165087 and NCT01574274, respectively.

Keywords: ALL; T-ALL; clinical trials; minimal residual disease; molecular diagnosis and therapy; pediatric oncology.

FIGURE 1

DFCI 05-001 and 11-001 patient enrollment and risk group stratification for patients with T-ALL All patients with T-ALL were enrolled to the initial HR arm and received a multiagent induction regimen. Final risk stratification was performed post-induction chemotherapy for patients who achieved CR. Three patients with T-ALL were upstaged to the final VHR arm (one participant on the basis of a KMT2A-rearrangement and two participants with ETP-ALL). Details of protocol therapy are provided in Supplementary Information Table S1. CR, complete remission; HR, high risk; VHR, very high risk; Ph, Philadelphia chromosome.

FIGURE 2

Outcomes for patients with T-ALL treated on DFCI 05-001 and 11-001. (A) Kaplan-Meier analysis of overall (OS) and event-free (EFS) survival for all 123 patients with T-ALL treated on DFCI 05-001 and 11-001. (B) End-induction minimal residual disease (MRD) results for T-ALL participants treated on DFCI Protocols 05-001 and 11-001. Kaplan-Meier analysis of (C) disease-free survival (DFS) and (D) OS for patients with low (<10⁻⁴) and high (≥10⁻⁴) MRD; and (E) EFS and (F) OS for ETP vs. non-ETP ALL. A two-sided log rank (Mantel-Cox) test was used to test for differences in survival between groups in panels B-F. ■ denotes MRD assessment by RT-PCR; ▲ denotes MRD assessment by NGS of Ig and TCR rearrangements. MRD, Minimal residual disease.

FIGURE 3

Mutational landscape and clinical outcomes of patients with T-ALL on DFCI 05-001 and 11-001. Summary of pathogenic mutations identified within Notch, PI3K, and Ras signaling pathways that are known to drive T-ALL and clinical outcome in patients treated on DFCI 05-001 and 11-001. ETP, Early T-cell Precursor; MRD, Minimal residual disease.