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Abstract: The Philadelphia (Ph) chromosome is one of the few genetic aberrations in which a casualty has been proven and, as such, represents a success in the history of medicine. This is also evident in the setting of Ph+ acute lymphoblastic leukemia (ALL), the most frequent genetic subgroup in adult ALL, whose incidence increases with age and whose prognosis, before the advent of tyrosine kinase inhibitors (TKIs), was particularly poor. The outcome and management of patients with Ph+ ALL have greatly improved since the incorporation of first-, second-, and third-generation TKIs in the therapeutic backbone and is further changing with the more recent introduction of immunotherapy. This allows for long-term survival rates currently ranging between 75% and 80%. The clinical scenario of adult Ph+ ALL has thus changed profoundly, and new challenges are emerging. In this article, illustrative clinical cases are used to discuss the current role of systemic chemotherapy and allogeneic stem cell transplant, the difficulty in treating central nervous system relapses and, more in general, relapses in the current therapeutic era, and the possibility of stopping TKIs. Finally, the challenges related to an optimal management of these patients are discussed.

Abstract: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a unique subtype of immature T-cell ALL that was initially associated with a dramatically inferior prognosis compared with non-ETP T-cell 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 use representative cases to explore therapeutic advances and address common clinical questions regarding the 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 of hematopoietic stem cell transplant in first remission. We discuss the interplay between the ETP immunophenotype and genomic markers of immaturity in T-cell ALL. Finally, we review novel therapeutic approaches that should be considered when managing relapsed or refractory ETP-ALL.

We evaluated the prognostic and therapeutic significance of measurable residual disease (MRD) during remission induction in pediatric acute lymphoblastic leukemia (ALL) patients. In the CCCG-ALL-2015 protocol, 7640 patients were categorized into low-, intermediate-, or high-risk groups based on clinical and genetic features. Final risk classification was determined by MRD assessed via flow cytometry on Days 19 and 46 of remission induction, with additional intensified chemotherapy for Day 19 MRD ≥1%. B-ALL patients with negative MRD (<0.01%) on Day 19 or Day 46 had significantly better 5-year event-free survival (EFS) than those with MRD 0.01-0.99%, who in turn had better EFS than patients with MRD ≥1%. Provisional low-risk patients with Day 19 MRD ≥1% but negative Day 46 MRD, reclassified as intermediate-risk, had comparable 5-year EFS to low-risk patients with Day 19 MRD 0.3-0.99% and negative Day 46 MRD (82.5% vs. 83.0%) and better EFS than provisional low-risk patients with MRD on both days (83.0% vs. 72.6%, P<0.001). Similarly, provisional intermediate-risk B-ALL patients with Day 19 MRD ≥1% but negative Day 46 MRD, who received additional therapy, had better 5-year EFS compared to those with Day 19 MRD between 0.3-0.99% (70.7% vs. 53.0%, P<0.001). Among low-risk patients with negative Day 46 MRD, those with negative Day 19 MRD had superior EFS compared to those with positive Day 19 MRD (91.7% vs. 86.1%, P<0.001). Optimal use of Day 19 MRD could improve individualized treatment and outcomes. Chinese Clinical Trial Registry (ChiCTR-IPR-14005706).