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.12 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 2017), 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 13% 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 can be 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%.