Phase I/II Dose-Escalation Study of Lenalidomide in Combination with R-GDP for Treatment of Transplant-Ineligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma Followed By Maintenance Lenalidomide

Introduction Patients with relapsed/ refractory (R/R) diffuse large B-cell lymphoma (DLBCL) whom are transplant-ineligible have limited treatment options. To address this specific treatment challenge, we undertook a clinical trial combining lenalidomide and rituximab (R2) with an established salvage regimen for DLBCL in gemcitabine, dexamethasone, cisplatin (GDP). Methods This was a single-center, open-label, phase I/II dose-escalation study of lenalidomide in combination with R-GDP for treatment of transplant-ineligible R/R DLBCL. The study was divided into a phase I dose-escalation study employing a '3+3' design followed by an expansion (phase II) portion with the recommended phase 2 dosing (RP2D), and a maintenance phase using 10 mg daily for 21 out of a 28-day cycle, for up to 1 year. The primary objective was to determine the maximum tolerated dose (MTD) of lenalidomide when combined with RGDP while secondary objectives was to analyze progression-free (PFS) and overall (OS) survival. Dose-escalation included 4 dose levels (DL) of 10 mg, 15 mg, 20 mg, 25 mg, starting at DL1. Lenalidomide was given for 6 cycles during induction therapy on days 1-21 every 28 days for a total of 6 cycles. The expansion phase used lenalidomide at the RP2D. Based on interim PET-CT assessment after cycle 2 (PET-2), patients in CR completed 2 more cycles of R2-GDP followed by two cycles of R2 and then stopped treatment without lenalidomide maintenance; patients with stable disease (SD) or partial remission (PR) completed 2 more cycles of R2-GDP and repeated PET-CT assessment after cycle 4 (PET-4). Based on PET-4, all responding patients (CR or PR) completed a further 2 cycles followed by maintenance with lenalidomide 10mg/day. Patients who failed to achieve at least PR at the point of PET-4 assessment were deemed treatment failure and stopped study treatment. Results The first patient was enrolled in February 2017. At data cut-off (July 20, 2020), 10 patients were enrolled into the dose-escalation study and a further 9 patients in the phase II part using lenalidomide at the RP2D of 15 mg/day (DL2). The MTD of lenalidomide of 15 mg/day was established after 2 of 3 patients at 20 mg/day (DL3) suffered neutropenic sepsis. The median age was 57.5 years (range, 40-76). Seven patients had primary refractory disease after R-CHOP while 13 had relapsed disease. Median time from first diagnosis to trial enrolment was 11.87 months. Median number of prior treatments were 2, including 4 patients who had previously undergone autologous transplant. After a median follow-up of 23.6 months in surviving patients, overall response rate was 68% (CR, N=7; PR, N=6). Median number of lenalidomide cycles completed in the induction phase was 4. Four patients completed less than 3 lenalidomide cycles due to progressive disease (PD). Nine patients died while on follow-up, 7 from PD and 2 infective deaths related to study treatment. The most common grade 3/4 treatment-emergent adverse events were neutropenia and thrombocytopenia with 4 and 11 patients experiencing at least one episode of grade 3 and 4 neutropenia and thrombocytopaenia, respectively. Out of these patients, 2 had neutropenic sepsis. Six patients went on to receive maintenance lenalidomide, completing a median of 5 cycles. Only one patient completed the planned 12 months of lenalidomide maintenance; 2 patients discontinued due to infective complications, one due to neutropenia, one due to patient's decision to stop without any adverse events documented, and one due to PD. For the entire cohort, median PFS and OS were 4.7 months and 26 months, respectively. Patients with primary refractory disease (N=7) had a median PFS of only 2 months. When these patients were excluded, the remaining (N=13) had a median PFS of 21 months. Conclusion In our cohort of transplant ineligible R/R DLBCL patients R2-GDP resulted in an ORR of 68%. Patients with primary refractory disease did not benefit from study treatment. However, for the remaining patients, the median PFS of 21 months compares favorably with other salvage regimens in this population. Lenalidomide at 15 mg/day may safely augment RGDP responses in chemotherapy-sensitive relapsed DLBCL. Disclosures No relevant conflicts of interest to declare.

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