Abstract
The malignant Hodgkin and Reed-Sternberg (RS) cells of Hodgkin lymphoma (HL) reside among an overwhelming number of benign stromal cells. The majority of the cells in this microenvironment are T and B lymphocytes. Both B and T cells have been reported to express growth and survival factors that may support HRS cells survival. Specifically, we and others reported that B cells in HL lesions express CD30 ligand and CD40 ligand that are known to activate NF-kB and provide survival and resistance signals to HRS cells. To determine the contribution of benign B-cells to the survival of RS cells in vivo, we have recently conducted a pilot study using rituximab alone in patients with relapsed classical HL. Depleting benign B cells from HL lesions produced an overall response rate was 23% in heavily pretreated patients (response rate was 50% when patients with no extranodal site involvement). We therefore hypothesized that depleting benign B cells from HL lesions by rituximab may deprive HRS cells from critical growth and survival factors which may synergizes with chemotherapy. To test this hypothesis, we evaluated the safety and efficacy of the novel combination of rituximab and gemcitabine chemotherapy in patients with relapsed/refractory classical HL. Rituximab was given at 375 mg/m2 weekly for 6 weeks to rapidly deplete B lymphocytes, while gemcitabine was given at a 1 gm/m2 on day 1 and 8 of a 21-day cycle. The first dose of rituximab was given concurrently with the first dose of gemcitabine. Patients were eligible if they had biopsy-confirmed relapsed/refractory classical HL irrespective of CD20 expression on HRS cells, bidimensionally measurable disease that is confined to lymph nodes, adequate bone marrow reserve (ANC > 1,000/uL, Platelet > 100,000/uL) and adequate cardiac and renal functions. Patients with prior autologous stem cell transplantation were eligible. Patients were excluded if they had extranodal disease, HIV infection, or were pregnant women. To date 29 patients are enrolled, of whom 26 are evaluable for treatment response. Median age 32 years (range 19–73), 11 were females and 15 males. The median number of prior treatment regimens was 4 (Range 1–6), and 17 (65%) were refractory to their last regimen. Fourteen patients (54%) received prior stem cell transplantation. Twenty-one patients (81%) were previously treated with platinum-based therapy. Treatment was reasonably well tolerated with the most frequent toxicity being thrombocytopenia and neutropenia. Thirteen patients (50%) responded to therapy irrespective of CD20 expression by HRS cells. Our results compare favorably with the reported single agnet activity of gemcitabine in less heavily pretreated patients. This encouraging results warrants evaluating this novel therapeutic concept in less heavily pretreated patients, perhaps in a randomized phase II design to shed more light on the potential contribution of rituximab to gemcitabine.
