RÉSUMÉ
Cure rates for patients with acute lymphoblastic leukemia (ALL) have improved markedly in recent decades, in part due to risk stratification incorporating leukemia genomics, response to treatment, and clinical features to be able to determine at diagnosis which patients are more likely to relapse or have refractory disease. While risk stratification is well-developed for patients with B lineage ALL (B-ALL), it remains challenging for those with T lineage ALL (T-ALL). Prognostic factors validated across clinical trials and real-world data in T-ALL include age, central nervous system (CNS) involvement, and minimal residual disease (MRD) response. Immunophenotype, including early T-cell precursor (ETP) ALL is widely used to classify T-ALL, but is not consistently associated with outcome in multivariable risk models. Historically, few genetic alterations have been consistently associated with outcome, but recent comprehensive, large-scale genomic profiling has identified multiple genetic subtypes and alterations associated with outcome independent of MRD. This review highlights ongoing efforts to identify reliable prognostic biomarkers and underscores the potential of genomics-based classification to guide future T-ALL treatment strategies.
RÉSUMÉ
Patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) have poor outcomes compared with newly diagnosed, treatment-naïve patients. The phase 2, open-label DELPHINUS study evaluated daratumumab (16 mg/kg intravenously) plus backbone chemotherapy in children with relapsed/refractory B-cell ALL (n=7) after ≥2 relapses and children and young adults with T-cell ALL (children, n=24; young adults, n=5) or LL (n=10) after first relapse. The primary endpoint was complete response (CR) in the B-cell ALL (end of Cycle 2) and T-cell ALL (end of Cycle 1) cohorts, after which patients could proceed off study to allogeneic hematopoietic stem cell transplant (HSCT). Seven patients with advanced B-cell ALL received daratumumab with no CRs achieved; this cohort was closed due to futility. For the childhood T-cell ALL, young adult T-cell ALL, and T-cell LL cohorts, the CR (end of Cycle 1) rates were 41.7%, 60.0%, and 30.0%, respectively; overall response rates (any time point) were 83.3% (CR+CR with incomplete count recovery [CRi]), 80.0% (CR+CRi), and 50.0% (CR+partial response); minimal residual disease-negativity (<0.01%) rates were 45.8%, 20.0%, and 50.0%; observed 24-month event-free survival rates were 36.1%, 20.0%, and 20.0%; observed 24-month overall survival rates were 41.3%, 25.0%, and 20.0%; and allogeneic HSCT rates were 75.0%, 60.0%, and 30.0%. No new safety concerns with daratumumab were observed. In conclusion, daratumumab was safely combined with backbone chemotherapy in children and young adults with T-cell ALL/LL and contributed to successful bridging to HSCT. This trial was registered at www.ClinicalTrials.gov as NCT03384654.
RÉSUMÉ
Early T-precursor acute lymphoblastic leukemia (ETP-ALL) is a unique subtype of immature T-ALL that was initially associated with a dramatically inferior prognosis as compared to non-ETP T-ALL (Not-ETP) when it was first described in 2009. Analyses of larger patient cohorts treated with more contemporary regimens, however, have shown minimal survival differences between ETP and Not-ETP. In this manuscript we utilize representative cases to explore therapeutic advances and address common clinical questions regarding management of children, adolescents, and young adults with ETP-ALL. We describe our recommended treatment approach for a child or adolescent with newly diagnosed ETP-ALL, with an emphasis on the prognostic significance of induction failure and detectable minimal residual disease and the role for hematopoietic stem cell transplant in first remission. We discuss the interplay between the ETP immunophenotype and genomic markers of immaturity in T-ALL. Finally, we review novel therapeutic approaches that should be considered when managing relapsed or refractory ETP-ALL.