Obinutuzumab plus gemcitabine, dexamethasone and cisplatin (O-GDP) as salvage chemotherapy prior to autologous stem cell transplant in aggressive B cell lymphoma

Background: The LY.1 2 randomized phase 3 clinical trial defined gemcitabine, dexamethasone and cisplatin (GDP) as an effective outpatient salvage chemotherapy regimen in relapsed/refractory (R/R) patients with aggressive lymphomas who are candidates for autologous stem cell transplant (ASCT) (Crump et al. JCO 2014). When the anti-CD20 antibody rituximab (R) was added to GDP, the ORR was 45.6% by Ct imaging and 51.9% of patients were able to receive ASCT. Obinutuzumab (O) is a type 2 CD20 antibody that has demonstrated superiority to R in some studies in indolent lymphomas and is active in R-refractory follicular lymphoma. Improvements in the outcome of salvage therapy have tested alternative CD20 antibodies (Van Imhoff, JCO 201 7), to date without success. We report a single centre, single arm clinical trial of O-GDP to assess safety and efficacy in R/R aggressive B cell lymphoma. Methods: Transplant eligible patients with DLBCL and transformed indolent lymphoma were treated with O-GDP for two cycles, followed by response assessment by CT. Non-progressors received a third cycle of O-GDP for stem cell mobilization and a PET/CT scan was obtained after stem cell collection. Responders then proceeded to ASCt per investigator decision. O was given at 1000 mg weekly during the first cycle of GDP and then on day 1 of cycles 2 and 3. Responses were determined by Lugano criteria using investigator assessment. The primary outcome was ORR by Ct imaging after 2 cycles. The pre-specified statistical analysis stated that the trial will be declared positive if the ORR was >60%, negative if the ORR was <40% and indeterminate if in-between. Secondary outcomes included PEt CR rate after 3 cycles of O-GDP and the rate of proceeding to ASCT. Exploratory outcomes included measurements of circulating tumor (ct) DNA during protocol therapy, and analysis of individual mutations. Results: The trial has completed its planned accrual of 30 patients. Median age was 59.5 (range 30-70), with 40% female, 70% with DLBCL NOS and 30% with transformed indolent lymphoma (all but one patient having transformed follicular lymphoma). IPI at study entry was 0-1 (20% of patients), 2(30%) or 3+ (50%). Grade 3 or 4 toxicity was observed in 87% of patients. This was mainly myelosuppression with grade 4 neutropenia (47%) and thrombocytopenia (37%). Other grade 4 adverse events were sepsis (2 patients), febrile neutropenia (1 patient) and hypokalemia (1 patient). No grade 5 events were attributed to study treatment. One additional case of myelodysplastic syndrome caused treatment discontinuation. Events necessitating dose reductions (33% of patients), dose delays (23%) and dose holds (23%) occurred in a total of 57% of patients. At the time of submission, data are evaluable for the primary endpoint in 28 patients. The ORR (CR + PR) by Ct imaging after 2 cycles of study therapy was 60.7% (95% CI 40.6-78.5) Overall, 65.5% of patients (95%CI = 45.7%-82.1%) proceeded to ASCT. In addition, 15 patients are evaluable by PET/CT after 3 cycles of O-GDP, with 47% attaining a complete metabolic response (Deauville 1-3), 40% a partial metabolic response and 1 3% with no metabolic response by Lugano criteria. Plasma ctDNA measurements were taken at baseline, after 1 cycle of O-GDP, and at the time of PET/CT. CtDNA quantities will be compared to imaging assessments. Conclusions: O-GDP is an outpatient salvage regimen that enables ASCt in patients with R/R DLBCL. Compared to R-GDP there is a greater frequency of grade 3-4 toxicity (O-GDP 87%, R-GDP previously reported at 47%), although the difference is mainly due to cytopenias and c managed by dose adjustments to the GDP regimen. Further data analysis is required to determine if the trial will meet the primary endpoint of an ORR > 60%. The overall rate of proceeding to ASCt with O-GDP salvage in this trial was 65.5% compared to that previously reported for R-GDP at 51.9%.