Novel Oncogenetic Classifier Identifies Low- and High-Risk Patients With Adult T-Cell Acute Lymphoblastic Leukemia
The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported significantly better outcome in T-cell acute lymphoblastic leukemia (ALL) harboring NOTCH1 or FBXW7 (N/F) mutations, although relapse was still observed in one-third of patients with N/F-mutated T-cell ALL. In a study reported in the Journal of Clinical Oncology, Amélie Trinquand, MD, of University Paris Descartes, and colleagues in GRAALL examined the prognostic interaction of N/F mutations and N/K-RAS and PTEN abnormalities in adult T-cell ALL. They found that N/F mutation in the absence of RAS/PTEN abnormalities identifies a large low-risk subgroup of patients.
The study involved 212 adult patients with T-cell ALL included in the randomized phase II GRAALL-2003 and phase III GRAALL-2005 trials with available diagnostic DNA or cDNA. Samples were assessed for N/F mutations, N/K-RAS mutations, and PTEN mutations and deletions.
Associations With Outcome
N/F mutations were found in 143 patients (67%) of 212 patients. Event-free survival (P < .001) and overall survival (P < .001) were significantly prolonged in patients with N/F mutations compared with nonmutated T-cell ALL. K-RAS, N-RAS, and PTEN mutations/deletions were found in 3 (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. RAS and PTEN abnormalities, which were virtually mutually exclusive, were associated with poorer cumulative incidence of relapse (P = .003 and P = .028), relapse-free survival (P = .004 and P = .027), and overall survival (P = .033 and P = .025). When patients with RAS or PTEN abnormalities were grouped together, they had significantly poorer relapse-free survival (P < .001) and overall survival (P = .003).
On multivariate analysis, the favorable prognostic significance of N/F mutation was maintained and showed a significant interaction with RAS/PTEN abnormalities, indicating that the benefit was limited to patients without these abnormalities. For cumulative incidence of relapse, relapse-free survival, and overall survival, outcomes were significantly better in the absence of RAS/PTEN abnormalities (P < .001 for all) but not in the presence of these abnormalities (P = .65, P = .78, and P = .43).
NF-RAS/PTEN Classification Scheme
A novel T-cell ALL oncogenetic classifier was proposed that defined low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients, 51%) and all other patients (49%, including 13% with N/F and RAS/PTEN mutations) as high-risk patients. On multivariate analysis adjusting for age and white blood cell count, the oncogenetic classifier remained the only significant prognostic covariate for event-free survival (hazard ratio [HR] = 3.2, P < .001) and overall survival (HR = 3.2, P < .001).
The investigators concluded, “These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-cell ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.”
In addition, they noted that “the absence of N/F or presence of RAS/PTEN alterations identifies the 50% of patients who are most likely to benefit from alternative therapies that target either the PI3K/PTEN/Akt/mTOR or the Ras/Raf/MEK/ERK pathways.”
The study was supported by a grant from the Association Laurette Fugain, the Comité Départemental de la Ligue Contre le Cancer, and the Institut National du Cancer.
Vahid Asnafi, MD, of Hôpital Necker-Enfants Malades, Paris, is the corresponding author for the Journal of Clinical Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
