Measuring Response to Novel Therapies in ALL

Response to treatment for patients with acute lymphoblastic leukemia (ALL) is rapid and deep if minimal residual disease (MRD) negativity (less than .001% leukemic cells) is achieved after 28 days. In general, those who achieve this milestone experience better overall outcomes. Although there may be problems measuring MRD, as a concept it is important, states Dan Douer, MD. With the broad efficacy seen with novel therapies, MRD is now being used to truly determine which therapies are the most effective.

Chimeric antigen receptor (CAR) modified T-cell therapies are manufactured through the leukapheresis of T cells, which are then genetically engineered to have a gene inserted that can recognize the CD19 epitope on leukemia cells. Preliminary data have shown complete remission (CR) rates of around 90% for patients with ALL treated with CAR T-cell therapies. Additionally, nearly all of these CRs are MRD-negative by flow cytometry.

When studied in chronic lymphocytic leukemia, researchers found that the modified T-cells eventually disappeared, says Douer. As a result, several questions remain with regard to the durability of the response as well as more technical concerns regarding the timing associated with injection of the modified cells into the patient.

Cytokine release syndrome is a common adverse event experienced by patients treated with CAR-modified T cells, which is related to tumor burden, says Douer. For this event, greater occurrences ensue with higher tumor burden. Neurotoxicity can also occur, which may present as seizures, but typically presents as alterations in mental status.

Another novel agent, inotuzumab ozogamicin, is comprised of a monoclonal antibody that targets CD22 linked to a cytotoxic agent. The monoclonal antibody, inotuzumab, binds to CD22 on leukemia cells, is internalized, and blocks DNA by delivering the toxic therapy ozogamicin specifically to leukemia cells.

Early phase data have shown a CR rate of 40% to 60%, notes Douer. Additionally, phase III findings presented at the 2015 EHA Congress showed a CR or CR with incomplete platelet recovery rate of 81% with inotuzumab ozogamicin in relapsed or refractory ALL. A majority of these CRs were MRD-negative (<0.01% cells by central flow cytometry).