Combination of Lenalidomide and R-DHAP for Treatment of Relapsed and Refractory Aggressive B-NHL

Background: Primary treatment results of aggressive B-NHL improved substantially after introduction of chemoimmunotherapy. However, current salvage treatment of primary progressive and relapsed disease is often disappointing with remission rates of < 50%. Lenalidomide (L) has been shown to exert single drug activity in this situation. We therefore investigated the combination of L and a standard salvage regimen (R-DHAP: rituximab, dexamethasone, cytarabine, cisplatinum/carboplatinum) in a phase I/II dose escalation study.

Patients and Methods: Younger patients (18 to 70 yrs) with primary progressive or relapsed aggressive B-NHL were included into the study. R-DHAP at standard doses was combined with L. Three 21-day-cycles of L at four dose levels (DL) were planned (DL1: 5 mg, day 1 - 7, cycles 2 and 3; DL2: 5 mg, day 1 - 7, cycles 1 to 3; DL3: 15 mg, day 1 - 7, cycles 1 to 3; DL4: 15 mg days - 6 to 7.. All patients were to receive IV heparin for prophylaxis of thromboembolic events. Mobilization of hematopoietic stem cells was attempted after cycle 2 in patients scheduled for autologous stem cell transplantation. Primary endpoint point was the maximum tolerated dose (MTD) of L in combination with R-DHAP. Death due to any cause, prolonged leuko- and thrombopenia (> 28 days) as well as any organ toxicity grade 4 with exception of infection were considered dose-limiting. Escalation to the next DL occurred after complete analysis of > 18 treatment cycles failed to show prohibitive toxicities.

Results:From 11/2010 to 10/ 2011 33 patients were included (28 pts DLBCL, 2 DLBCL / Burkitt-like, 1 DLBCL / FL grade III, 2 FL grade III). Median age was 52.9 years (range: 24 - 70). Seventy-seven cycles combining L with R-DHAP were given. Ten patients did not receive all 3 cycles of therapy due to progressive disease (6 pts), hematological toxicity (3 pts) and withdrawal of informed consent (1 pt). Ten patients experienced a severe adverse event (SAE): two cases of renal failure, two cases of arterial embolism of the lung, two cases of prolonged thrombocytopenia, and four infections .. At dose levels 1 to 3 no dose limiting toxicity occurred. With 17 treatment cycles at DL 4 two patients experienced prolonged cytopenia and two other patients failed to mobilize stem cells. Therefore, treatment at DL 4 was stopped and 7 additional patients were treated at DL 3: no further dose-limiting toxicities were observed. Seventeen of 31 evaluable pts (55%) achieved a remission (12 CR/CRu, 5 PR). At time of this analysis, 19 pts (58%) are alive at a median observation time of one year.

Conclusion: The combination of L with R-DHAP was feasible and safe up to DL 3 (15 mg of L, days 1 – 7 of max. 3 treatment courses). In contrast, administration of L during the time of recovering hematopoiesis (DL 4) resulted in prolonged thrombocytopenia and failures to mobilize stem cells. The combination of L at DL 3 and R-DHAP at the MTD gave promising results and will be evaluated in the phase II part of this study (DSHNHL-R6).