RAS and TP53, Not NOTCH1, Can Predict Survival in Adults with Acute T-Cell Lymphoblastic Leukemia Treated with Hypercvad

Context: Adult T-cell lymphoblastic leukemia (T-ALL) is a rare heterogeneous group of acute leukemias which accounts for about one third of all Philadelphia negative ALLs. Risk stratification of T-ALL is based predominantly on measurable residual disease (MRD) at the end of induction therapy. Recently, an oncogenetic classifier (NOTCH1/FBXW7/RAS/PTEN) was shown to distinguish low and high risk groups in adult T-ALL patients enrolled in GRAALL-2003 and -2005 trials (J Clin Oncol. 2013). However, it is not known if this oncogenetic classifier can stratify adult T-ALL patients treated with a different regimen (hyperCVAD).

Design: We searched our institutional database to identify adult T-ALL patients with available mutational analysis. Clinically validated next-generation sequencing gene panel assays were performed in all patients. We retrieved clinicopathologic, cytogenetic and mutational data from medical records. Overall survival (OS), defined from the time of diagnosis to death from any cause, and event-free (EFS) survival, defined as the time from diagnosis to first outcome event (induction failure, induction death, death during remission, second malignant neoplasm, or relapse), were calculated.

Results: We identified 28 T-ALL patients with available mutational analyses at the time of diagnosis. All patients received hyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with or without nelarabine for the first induction chemotherapy. The study cohort included 23 men and 5 women with a median age of 37 years at diagnosis (range: 18 - 75). The median blast percentage was 79% (range: 6 - 96) and 56.5% (range: 0 - 91) in bone marrow (BM) and peripheral blood (PB), respectively. Conventional cytogenetic analysis was available for 26 patients. These included 11 cases with normal karyotype, 8 patients with simple karyotypic abnormality (less than 3 abnormalities), and 7 patients with complex karyotype (at least 3 abnormalities). Twenty-seven (96%) patients achieved complete remission. With a median follow-up of 16.1 months (range: 0.6 - 46), 21 (71%) patients were alive and the 3-year overall survival rate was 60%. The five most commonly mutated genes were NOTCH1, NRAS, DNMT3A, KRAS and TP53 in 17 (61%), 7 (25%), 6(21%), 4 (14%) and 3 (11%) patients, respectively. Mutations in FBXW7 and PTEN were not detected. TP53 and K/NRAS mutations were mutually exclusive. The oncogenetic classifier (NOTCH1/FBXW7/RAS/PTEN) and NOTCH1 mutation did not show significant risk stratification (p>0.05, figure - 1) in overall (OS) or event-free (EFS) survival. However, patients with K/NRAS or TP53 mutation had a worse outcome compared to patients without mutations in respective genes. DNMT3A mutation did not show a significant difference in outcome (p>0.05). Designating high-risk when patients had mutations in RAS or TP53 and low-risk when mutations are not detected in those genes, patients with high-risk disease had a significant worse outcome (p=0.01, figure 2).

Conclusion: Our data suggest that the oncogenetic classifier (NOTCH1/FBXW7/RAS/PTEN) might not be applicable to adult T-ALL patients treated with hyperCVAD. Instead, RAS/TP53 mutation status showed significant risk stratification.

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