A Phase II Study of Gemcitabine, Rituximab, and Oxaliplatin In Combination for Relapsed/Refractory Non-Hodgkin's Lymphomas

Non-Hodgkin's Lymphomas (NHL) are heterogeneous group hematologic malignancies. Although diffuse large B-cell lymphoma can be treated effectively with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) there is a relatively high relapse rate requiring alternative chemotherapy regimen. The optimal salvage regimen is not known. Intensive multi-agent chemotherapy in combination with rituximab yield often responses up to 50 to 60% in relapsed/refractory NHL. In this study we sought to evaluate the efficacy of gemcitabine, rituximab and oxaliplatin in combination as a useful salvage regimen in patients with relapsed or refractory NHL.

This trial was designed as a prospective, open and uncontrolled phase II study. From May 2004 to December 2009, 59 patients with relapsed or refractory NHL from Auxilio Mutuo Cancer Center, (San Juan, PR) and H. Lee Moffitt Cancer Center & Research Institute (Tampa, FL) was enrolled in this study examining the efficacy of GROC on a 2 week schedule. On day 1, patients with CD20 positive NHL received rituximab at 375mg/m² followed by gemcitabine (1000 mg/m² to 1750mg/m²) and oxaliplatin (100mg/m²) on day 2 along with growth factor support on a day 14 of each cycle. Patients with CD20 negative malignancies (i.e. peripheral T-cell lymphoma) received only day 2 of therapy along with growth factor support. Primary endpoint was response rate. Secondary endpoints were toxicity evaluation, progression free and overall survival. Patients were followed for toxicity, response, progression free survival (PFS) and overall survival (OS). Patients were allowed to come off study for hematopoietic stem cell transplant (HSCT) consolidation after a minimum of six cycles of therapy.

57 evaluable patients represented typical heterogeneity noted in NHL in North America. Most of the patients were male 63% (36 patients) with ages ranging from 24 to 88 (median 62) years old with 31% patients age 60 or greater. Histologies included large B-cell (79%), follicular (7%), lymphoblastic (1.8%), Burkitt's (1.8%), primary mediastinal large B-cell (3.5%), and peripheral T-cell lymphoma (7%). Twenty-one patients (37%) demonstrated extranodal disease at one or more sites at presentation indicating a more aggressive lymphoma. Median IPI (International Prognostic Index) score was 3 though most patients presented with advanced stage (III or IV). Most patients had received first line therapy utilizing an anthracycline based regimen such as CHOP, 89% (51 patients) and 65% (37 patients) percent having received prior rituximab therapy. Other utilized regimens included CHOP modifications, methotrexate plus cytarabine, bleomycin plus ESHAP (etoposide, solumedrol, cytarabine and cisplatin), and CHOP plus melatonin in at most one patient per therapy. The majority of patients after first line induction therapy were complete responders.

In intent-to-treat analysis of responses a majority of the patients experienced either a CR (including unconfirmed, 14 of 57) or PR (19 of 57) demonstrating an overall response rate approaching 58%. Stable disease was observed in 10.5% (6) patients. Disease progression occurred in 29.8% (17) patients. Progression free survival ranged from zero to 67 with a median of 4 months. Overall survival measured from 1 to 38 months with a median of 7 months, follow-up of this population continues. At last follow-up 37% of (21 of 57) were alive.

Toxicity profile of this regimen was similar to other salvage therapies used in this patient population with an increased incidence of grade 3/4 thrombocytopenia (9%) and neutropenic infections (3.5%). Several patients, 8, were able to proceed with adequate hematopoietic stem cell collection post GROC therapy for autologous HSCT. No grade 3 and 4 non-hematologic toxicities were observed.

Our results demonstrate that in patients with advanced stage, relapsed or refractory non-Hodgkin's lymphomas, GROC is a useful salvage regimen with acceptable toxicities and comparable efficacy to similar salvage regimens. GROC can also be used as a bridge to auto-HSCT.

Off Label Use: Bendamustine in the treatment of multiple myeloma. Sokol:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cabanillas:Bayer Pharmaceuticals: Research Funding; Genentech: Research Funding.