Clofarabine (CLO) Has Single Agent Activity in Relapsed and Refractory Non-Hodgkin Lymphoma (NHL) Including Rituximab (R)-Refractory Patients (pts).

CLO is a second generation nucleoside analogue with known activity in acute leukemia and myelodysplasia. As there is no standard therapy for refractory and transplant-ineligible relapsed NHL, and given the activity that purine analogues have in lymphoid malignancies, we sought to investigate the activity of CLO in this pt population regardless of histology.

Eligible pts had measurable disease by CT and/or PET, ECOG performance status ≤ 2, and adequate renal, cardiac, liver, and bone marrow function (unless cytopenias were disease-related). CLO was given in the outpatient setting intravenously over 1-hour days 1-5 every 28 days for 6 cycles maximum. All pts received anti-viral and anti-pneumocystis jiroveci prophylaxis. First, we initiated a phase I portion using a standard 3×3 study design. CLO was given at 4 mg/m² in cohort 1 with subsequent cohorts to be escalated by 2 mg/m² each. Once the maximum tolerated dose (MTD) was determined, the phase II portion of this study was initiated at the MTD. All pts were followed until disease progression.

Thirty-three pts (18 females, 15 males) have been enrolled (7 in the phase I portion and 26 in the phase II), of which 29 are evaluable for response and/or toxicity (2 just started therapy, 1 taken off due to persistent cytopenias, and 1 withdrew consent). Median age was 69 years (range 27-88), median number of prior therapies was 3 (range 1-8), with 21% failing prior stem cell transplantation and 74% being R-refractory. Median time from original diagnosis to first CLO treatment was 36 months (range 6-216). Histologies included 12 diffuse large cell, 5 follicular, 5 small lymphocytic, 4 anaplastic large T-cell, and 1 each for Richter, mantle cell, marginal zone, peripheral T-cell, transformed, non-specific T-cell, and mixed histology. Median number of CLO cycles was 4 (range 1-6). Thrombocytopenia was the dose-limiting toxicity at 6 mg/m² in 2/6 pts. The MTD recommended for phase II was 4 mg/m². With a median follow up of 8 months (range 1-33), 7 pts (24%) showed complete response (CR) and 8 (27%) had partial response (PR) for an overall response rate of 51%. Four pts (13%) demonstrated stable disease and 10 (34%) showed progression. Median duration of response was 7 months (range 2-33+) with 6 pts continuing in remission including a patient who is undergoing stem cell transplantation. Median time to progression (TTP) was 3.5 months with median overall survival of 8 months. sEVEN pts (24%) remain progression-free. Of patients who were followed for more than 12 months, 60% were alive at 1-year. Five of the CR pts were of low-grade histology while only 2 had large cell lymphoma. All pts required growth factor support. Toxicity was mainly hematologic with 63% experiencing grade 3/4 thrombocytopenia, 60% grade 3/4 neutropenia, and 39% grade3/4 anemia, and 63%. Grade 3 and/or 4 non-hematologic toxicity included 2 (6%) with tumor lysis syndrome, 2 (6%) infectious episodes (pneumonia and bilateral cellulitis), 2 (6%) renal insufficiency, 2 (6%) fatigue, 1 (3%) seizure activity, 1 (3%) pleural effusion, and 1 hypokalemia (3%). No treatment-related mortality.

CLO is active in heavily pre-treated B-cell NHL including R-refractory pts. Activity appears more pronounced in low-grade histology. The drug is well-tolerated and can be administered as an outpatient. Reversible myelosuppression is the major toxicity. Future studies in front-line in combination with R are warranted.

Nabhan:Bayer: Honoraria, Research Funding, Speakers Bureau; Genzyme: Research Funding; Genentech: Honoraria, Speakers Bureau. Venugopal:Genzyme: Honoraria, Research Funding; Genentech: Honoraria, Research Funding, Speakers Bureau.