Using immunotherapy and novel trial designs to optimise front-line therapy in adult acute lymphoblastic leukaemia: breaking with the traditions of the past

Multidrug chemotherapy has historically been the cornerstone of therapy for both children and adults with acute lymphocytic leukaemia. However, in the past decade, several novel immunotherapies have proven to be highly effective in the treatment of acute lymphocytic leukaemia, including the anti-CD22 antibody–drug conjugate inotuzumab ozogamicin, the CD3 × CD19 bispecific antibody blinatumomab, and two CD19-directed chimeric antigen receptor T-cell products. These agents are all approved in the USA as monotherapy for relapsed or refractory B-cell acute lymphocytic leukaemia. However, their use as single agents in the salvage setting might not be taking full advantage of their anti-leukaemia potential, because our ability to cure a patient is likely to be greatest when the most effective therapies are safety integrated into front-line treatment regimens. Several ongoing studies have yielded encouraging data with routine incorporation of inotuzumab ozogamicin or blinatumomab, or both, in patients with newly diagnosed acute lymphocytic leukaemia, and these approaches are emerging as new standards of care. In Philadelphia chromosome-positive acute lymphocytic leukaemia, chemotherapy-free regimens combining blinatumomab and a BCR-ABL1 tyrosine kinase inhibitor are changing acute lymphocytic leukaemia therapy, highlighting the potential for these novel agents to reduce—or perhaps eliminate—the need for chemotherapy in some subtypes. In this Viewpoint, we review promising data from ongoing clinical trials of novel immunotherapy-based combinations that are being explored in patients with newly diagnosed acute lymphocytic leukaemia. We also discuss the challenges of randomised studies in the rapidly evolving therapeutic landscape and argue for the ability of well designed, non-randomised studies to more rapidly advance the standard of care in acute lymphocytic leukaemia.