Phase I/II Study for the Effectivity of Rituximab, Gemcitabin and Oxaliplatin in Relapsed Indolent Lymphoma – An Interim Report.

Indolent lymphoma and mantle cell lymphoma have typically a history of multiple relapses. Especially elderly patients who are not fit enough for intensive treatments may receive various chemotherapies in the course of their disease. Therefore, new cytostatic drugs are needed which are not cross resistant to the common combinations. The aim of the study is to establish a chemotherapy regimen which is non cross resistant to alkylating agents, anthracyclines and purin antimetabolites. Gemcitabine and Oxaliplatin have activity in several lymphoma entities. Different side effects and in vitro synergy make the combination even more attractive.

Eligible were patients with age above 18 and relapsed or refractory indolent lymphoma or mantle cell lymphoma, measurable tumour lesion, ECOG performance status 0-2. Patients were excluded if they had a secondary high grade lymphoma or were eligible for high dose therapy. Leukocyte count ≥1.5/nl and platelets ≥100/nl were required unless bone marrow infiltration accounted for blood counts. Study entry required adequate renal (creatinine < 2.0 mg/dl) and hepatic function (≥ 3.0x the upper limit of laboratory normal for AST and ALT and ≥2.0 mg/dl for total bilirubin).

Patients achieved 2 cycles of R-GO (Rituximab 375 mg/m² at day 0, Gemcitabine 1,000 mg/m² and Oxaliplatin at day 1 and 15 [in phase 1 Oxaliplatin was escalated from a dose of 70 mg/m² in steps of 10 mg/m², in phase 2 the maximal tolerable dose (MTD) of phase 1 was used] every 28 days for a maximum of 4 cycles.

In phase 1 dose limiting toxicity (DLT) was defined as granulocytes < 0.5/nl or platelets < 25/nl, bleeding due to thrombocytopenia, any non haematological toxicity ≥ WHO grade 3 with exception of alopecia and emesis, granulocytes < 1.5/nl or platelets < 100/nl at day 29 of cycle 1, persistency of any toxicity ≥ WHO grade 2 until day 29 of cycle 1.

Response and progression were based on International Working Group Response Criteria for NHL. The primary end point was the MTD of Oxaliplatin in the phase 1 part and the overall remission rate (ORR) in the phase 2 part of the study.

The study enrolled 54 patients at 22 sites until June 2009. The median age was 69 years (range 31 – 82). 26 patients were male and 28 female. The median number of prior therapies was 2 (range 1 to 10).

Phase 1: 14 patients were treated in the phase 1 part of the study. 7 out of 14 received Gemcitabine and Oxaliplatin only before a protocol amendment added Rituximab to the combination. 6 patients were treated with Oxaliplatin 70 mg/m² (dose level 1) and 8 patients were treated with Oxaliplatin 80 mg/m² (dose level 2). At dose level 2 occurred 3 DLT (peripheral neurotoxicity 1, neutropenia 1, thrombocytopenia 1). Therefore, the MTD for Oxaliplatin was 70 mg/m² in phase 2.

11 patients (dose level 1: 4 without Rituximab, dose level 2: 1 without Rituximab, 6 with Rituximab) were evaluable for response. There were 8 PR, 2 SD and 1 PRO.

Phase 2: 40 patients were enrolled and 27 patients had response data after 1 - 4 cycles (median number of cycles: 4). 2 had to be excluded due to false histology. Objective responses were observed in 21 patients (0 CR/19 PR/2 MR), 3 had stable disease and only one patient had progressive disease. Median follow up time was 16 months. Median time to treatment failure was 8 months, median overall survival was about 31 months.

28 patients were evaluable for toxicity. WHO grade 3-4 toxicity was mainly haematological. (11 patients had WHO grade 3-4 thrombocytopenia, 11 leukopenia, 12 neutropenia, 7 anaemia). Non-haematogical toxicity grade 4: 1 patient with constipation, grade 3: 2 infection, 1 fever, 1 nausea and emesis, 1 mucositis, 1 liver toxicity, 1 peripheral neuropathy.

The combination of Gemcitabine and Oxaliplatin with Rituximab showed encouraging activity in a heavily pretreated, elderly patient population with indolent lymphoma and mantle cell lymphoma. Toxicity was acceptable and mainly haematological. Phase 2 of the trial is ongoing.

Hoffmann:Sanofi: Research Funding; Roche: Research Funding; Lilly: Research Funding. Off Label Use: Gemcitabine and Oxaliplatin are not approved for treatment in lymphoma. Dreyling:Lilly: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Dührsen:Roche: Honoraria, Research Funding. Unterhalt:Roche: travel support.