New Approaches to Treating Challenging Subtypes of ALL in AYA Patients.

PURPOSE OF REVIEW: The treatment of acute lymphoblastic leukemia (ALL) in adolescent and young adult (AYA) patients has markedly improved with the adoption of pediatric-inspired protocols. However, there remain several subtypes of ALL that represent significant therapeutic challenges. Here, we review the current evidence guiding treatment of Philadelphia chromosome-positive (Ph+), Philadelphia chromosome-like (Ph-L), and early T-precursor (ETP) ALL in the AYA population. RECENT FINDINGS: Clinical trials in Ph + ALL have demonstrated the superior efficacy of second- and third-generation tyrosine kinase inhibitors (TKIs) to induce and maintain remission. Current efforts now focus on determining the durability of these remissions and which patients will benefit from transplant. For Ph-like and ETP ALL, recent studies are investigating the addition of novel agents to standard treatment. The treatment of Ph + ALL has significantly improved with the addition of potent TKIs. However, the treatment of Ph-like and ETP ALL remains a challenge. At this time, the judicious use of allogenic transplant is the only current approach to modify this increased risk.

Inotuzumab: from preclinical development to success in B-cell acute lymphoblastic leukemia.

Inotuzumab ozogamicin (InO) is a recently US Food and Drug Administration-approved antibody-drug conjugate for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). InO consists of a CD22-targeting immunoglobulin G4 humanized monoclonal antibody conjugated to calicheamicin. Although initially developed for the treatment of non-Hodgkin lymphoma (NHL) because of activity in preclinical models and high response rates in indolent lymphomas, a phase 3 trial was negative and further development focused on CD22+ ALL. Although results in NHL were disappointing, parallel testing in early-phase trials of CD22+ ALL demonstrated feasibility and efficacy. Subsequently, the randomized phase 3 Study Of Inotuzumab Ozogamicin Versus Investigator's Choice Of Chemotherapy In Patients With Relapsed Or Refractory Acute Lymphoblastic Leukemia trial showed that InO was superior to standard of care regimens with a significantly improved complete remission (CR) rate in patients with relapsed/refractory disease (80.7% vs 29.4%, P < .001). Patients achieving CR with InO also had a significantly higher rate of undetectable minimal residual disease compared with chemotherapy (78.4% vs 28.1%, P < .001). InO-specific side effects, including veno-occlusive disease, have been an ongoing area of concern, and consensus guidelines for minimizing toxicities are now available. Ongoing trials are investigating the combination of InO with other agents in the relapse setting and the addition of InO to frontline therapy. This review details the preclinical and clinical development of InO, focusing on how best to use it and future directions for further development.