Frontline immunotherapeutic combination strategies in adult B-cell acute lymphoblastic leukemia: reducing chemotherapy intensity and toxicity and harnessing efficacy

Using immunotherapeutic agents like inotuzumab ozogamicin (InO), blinatumomab, or chimeric antigen receptor T (CAR T)-cell therapy in frontline adult B-cell acute lymphoblastic leukemia (B-ALL) therapy is promising. These agents are mostly well tolerated and have different toxicity profiles than conventional chemotherapy, enabling their combination with chemotherapy. Additionally, they have often been shown to overcome the traditional adverse ALL risk features. Recently blinatumomab was approved as part of consolidation therapy in MRD negative B-ALL; however, a significant proportion of patients had progressed or relapsed before reaching the timepoint of blinatumomab administration. Including InO/blinatumomab from induction onwards could induce earlier and deeper remissions. Modifications of dosing and administration schedules, as with the fractionated InO schedule with low-intensity chemotherapy, and subcutaneous blinatumomab, appear to reduce the toxicity and improve the anti-ALL efficacy. CAR T-cell therapies like brexucabtagene autoleucel as a consolidation approach have shown positive outcomes. The feasibility of using CAR T-cells to reduce the need for long-drawn maintenance and the need for allogeneic hematopoietic stem cell transplantation (HSCT) are questions of ongoing clinical trials. Newer generation CAR T-cell products like obecabtagene autoleucel appear as effective and safer. Better disease monitoring through next generation sequencing based measurable residual disease analysis could identify patients where treatment intensification including HSCT, or deintensification, is suitable.