Genomics improves risk stratification of adults with T-cell acute lymphoblastic leukemia enrolled in measurable residual disease-oriented trials

Abstract

Genetic information has been crucial to understand the pathogenesis of T-cell acute lymphoblastic leukemia (T-ALL) at diagnosis and at relapse, but still nowadays has a limited value in a clinical context. Few genetic markers are associated with the outcome of T-ALL patients, independently of measurable residual disease (MRD) status after therapy. In addition, the prognostic relevance of genetic features may be modulated by the specific treatment used. We analyzed the genetic profile of 145 T-ALL patients by targeted deep sequencing. Genomic information was integrated with the clinicalbiological and survival data of a subset of 116 adult patients enrolled in two consecutive MRD-oriented trials of the Spanish PETHEMA (Programa Español de Tratamientos en Hematología) group. Genetic analysis revealed a mutational profile defined by DNMT3A/ N/KRAS/ MSH2/ U2AF1 gene mutations that identified refractory/resistant patients. Mutations in the DMNT3A gene were also found in the non-leukemic cell fraction of patients with T-ALL, revealing a possible mutational-driven clonal hematopoiesis event to prime T-ALL in elderly. The prognostic impact of this adverse genetic profile was independent of MRD status on day +35 of induction therapy. The combined worse-outcome genetic signature and MRD on day +35 allowed risk stratification of T-ALL into standard or high-risk groups with significantly different 5- year overall survival (OS) of 52% (95% confidence interval: 37-67) and 17% (95% confidence interval: 1-33), respectively. These results confirm the relevance of the tumor genetic profile in predicting patient outcome in adult T-ALL and highlight the need for novel gene-targeted chemotherapeutic schedules to improve the OS of poor-prognosis T-ALL patients.

Figure 1.

Genetic profile of T-cell acute lymphoblastic patients at diagnosis. (A) Frequency of variants per patient in the cohort (n=145). (B) Frequency of patients showing recurrently mutated genes (cut-off of ≥5 mutations/gene). (C) Pairwise associations observed between the recurrently mutated genes and the biological characteristics of the disease at presentation. Positive and negative correlations are depicted as magenta and green circles, respectively. Circle diameters indicate the degree of significance. Y: years; ETP-ALL: early T-cell precursor acute lymphoblastic leukemia; NDI: not determined immunophenotype; abn: abnormalities; CK: complex karyotype; NE: non-evaluable karyotype.

Figure 2.

Scheme of the genetic profile of each T-cell acute lymphoblastic patient, its response and evolution during treatment. Only genes recurrently mutated in ≥5 patients are shown. Each mutation is indicated by a square: brown squares correspond to genes contained in the worse-outcome genetics (WOG) signature; dark green squares correspond to mutations in the FBXW7 gene (good-outcome genetics [GOG] signature) and pink squares correspond to other mutated genes. Treatment response and patient evolution data are shown at the bottom. Induction + 14d indicates the percentage of blast cells in bone marrow 14 days after starting induction therapy; induction + 35d corresponds to measurable residual disease (MRD) values at the end of the first induction blocks (induction 1); induction-2 indicates patients that received or not an Induction-2 treatment block. Consolidation corresponds to MRD values at the end of consolidation chemo-block. Post-consolidation indicates treatment choice (allogeneic stem cell transplantation or chemotherapy) based on MRD values at the end of the consolidation treatment. On the right, the percentage of cases mutated in the different genes are indicated. NA: not available.

Figure 3.

Prognostic stratification of adult T-cell acute lymphoblastic patients according to overall survival defined by the presence of worse-outcome genetic mutations and measurable residual disease status 35 days after starting therapy. (A) Overall survival (OS) according to measurable residual disease (MRD) levels at 4 years (y) showed rates of (95% confidence interval [CI]: 35-63) in patients with MRDlow (<0.1%) and 8% (95% CI: 0-23) for those with MRDhigh (.0.1%). (B) OS according to worse-outcome genetics (WOG) mutational status at 5 y showed rates of 13% (95% CI: 0-26) in the WOG-mutated patients (WOG+) and 45% (95% CI: 32-58) in non-mutated patients (WOG-). (C) OS according to WOG mutational status and MRD values (d+35) at 5 y was 52% (95% CI: 37-67) for patients with MRDlow (<0.1%) and WOG- (standard-risk-patients), compared with 17% (95% CI: 1-33) for high-risk patients including MRDhigh plus WOG-, MRDlow plus WOG+ and MRDhigh plus WOG+.