By Basem M. William, MD, MRCP(UK), FACP
Patients with diffuse large B-cell lymphoma (DLBCL), who progressed on upfront chemotherapy, have a dismal survival of 6.3 months based on the results of the international SCHOLAR-1 study, as noted by Georg Lenz, MD, of the University Hospital Muenster, who introduced the sixth and final Plenary abstract.
Impressive responses are possible with CD19 chimeric antigen receptor T cells (CAR-T) in patients with relapsed/refractory (R/R) DLBCL. Unfortunately, however, at least half of such patients relapse after CAR-T, with no good treatment options. Representing an international team of investigators , Stephen Schuster, MD, of University of Pennsylvania, reported the results of an open-la- bel, multicenter, phase I/Ib, dose-escalation/expansion study of mosunetuzumab, a bispecific antibody engaging CD3 (on the surface of T cells) to CD20 (on the surface of B cells), in 270 patients with R/R B-cell non-Hodgkin lymphoma (B-NHL). Patients were treated with step-up dosing on days 1, 8, and 15 of cycle 1 (C1), and then a fixed dose on day 1 of each subsequent 21-day cycle (for 8 cycles initially; if patients experienced a complete remission [CR], treatment was discontinued, and if they experienced partial remission [PR] or stable disease [SD], treatment continued to a maximum of 17 cycles). Most patients treated had aggressive NHL (aNHL; n=180), mainly DLBCL (n=117), followed by indolent NHL (iNHL; n=85), mainly follicular lymphoma (FL; n=82). The median number of prior systemic therapies was three (range, 1-14). Among patients evaluated for efficacy across all dose levels, overall response rates (ORRs) and CR rates were 62.7 percent and 43.3 percent, respectively, in patients with iNHL, and 37 percent and 19.4 percent, respectively, in patients with aNHL.
The development of a cytokine storm related to T-cell expansion and activation was recognized with early experience, with bispecific T-cell-engaging molecules and CD19 CAR-T and other immune effector cells (IEC) leading to the development of cytokine-release syndrome (CRS) and neurotoxicity (IEC-associated neurotoxicity syndrome; ICANS). CRS was observed in 28.9 percent of patients, with most occurring during C1, largely grade 1/2 (27.8%). Neurological adverse events (NAEs) were reported in 43.7 percent of patients, and 40 percent were grade 1/2. Common NAEs were headache (15.6%), insomnia (9.3%), and dizziness (9.3%). ICANS-like events occurred in only 1.1 percent of patients and were also grade 1/2. No correlation between mosunetuzumab exposure and CRS/NAEs was observed, and treatment discontinuation due to AEs in general was rare. Of particular interest, 30 patients treated on this trial have had prior CAR-T therapy (17 with DLBCL, 8 with transformed FL, and 5 with FL); of those 30, 18 were evaluable for efficacy. ORR and CR rates were 28.9 percent and 22.2 percent, respectively. Expansion of previously administered CAR-Ts after mosunetuzumab administration was detected by quantitative polymerase chain reaction. CRS was seen in 26.7 percent of CAR-T pretreated patients (mostly grade 1/2), and NAEs in 43.3 percent (mostly grade 1/2) with no ICANS-like events observed. Dr. Schuster also reported on four patients who sustained a CR on mosunetuzumab, subsequently progressed after treatment was discontinued, and were re-treated again with mosunetuzumab with ORR and CR rates of 75 and 25 percent respectively.
I have witnessed how novel therapies have rewritten history of disease for chronic myeloid leukemia and myeloma since I began my career as house-officer in hematology on the other side of the Atlantic, 20 years ago. This is an exciting time for B-cell lymphomas, and we are starting to see the dawn of a new era where most patients now experience long-term remissions and possibly a cure.
Dr. William indicated no relevant conflicts of interest.