Bendamustine and Rituximab for the Treatment of Multiply Relapsed Hairy Cell Leukemia,

Hairy cell leukemia (HCL) is highly sensitive to purine analogs cladribine (CdA) and pentostatin (DCF), but patients who relapse have decreasing remission rates with each course and can eventually become purine analog-refractory. Bendamustine and rituximab (BR) have been reported as effective with acceptable toxicity in several B-cell malignancies, particularly B-cell lymphomas and chronic lymphocytic leukemia. The structure of bendamustine contains an alkylating group and also part of cladribine, suggesting it might be useful in HCL. In one case report, bendamustine achieved a transient partial response in a patient with relapsed/refractory HCL, but its activity in other patients with this disease is not reported. The combination of DCF and rituximab (DCFR) is reported to achieve high complete remission (CR) rates in HCL in retrospective series, but prospective phase II trials of this combination have not been reported.

To determine the activity of BR relative to DCFR in HCL, a randomized trial was undertaken in multiply relapsed HCL comparing the 2 regimens in which each arm could constitute a prospective phase II trial, with 2-way crossover for lack of response to or relapse from the originally assigned regimen. The primary endpoint is an overall response rate of 65% for each arm and the 2 arms will be compared with respect to response and other secondary endpoints including toxicity, response duration, and eradication of minimal residual disease (MRD). Patients received 6 cycles at 4-week intervals of rituximab 375 mg/m² days 1 and 15 with either pentostatin at 4 mg/m² days 1 and 15, or bendamustine days 1 and 2. To test the tolerability of bendamustine prior to randomizing 56 patients between the 2 arms, 12 non-randomized patients received BR using 70 (n=6) or 90 (n=6) mg/m²/dose of bendamustine. Doses of all agents could be delayed but not reduced.

A total of 20 patients are so far enrolled and the 12 patients receiving the 2 dose levels of BR are evaluable for response and toxicity. Patients had 1–6 (median 3) prior courses of purine analog and 8 (67%) had prior rituximab. All toxicity was reversible and only 1 patient at 90 mg/m² required >2-week delay due to prolonged neutropenia and thrombocytopenia. However, this delay was only between cycles 1 and 2 and not between subsequent cycles after responding to BR. Of the 36 cycles of BR administered to each group of 6 patients on the 2 dose levels of bendamustine, 90 vs 70 mg/m²/dose, common grade 3–4 toxicities included lymphopenia (28 vs 22%), leukopenia (19 vs 17%), and thrombocytopenia (14 vs 17%). Febrile neutropenia requiring hospitalization occurred just once in 3 patients at 90 vs 0 patients at 70 mg/m²/dose. Major response was achieved in 10 (83%) of 12 patients. CR was achieved in 3 (50%) of 6 patients at each dose level, while 2 (33%) at 70 and 3 (50%) at 90 mg/m² achieved clearance of MRD at all sites including bone marrow aspirate by flow cytometry. No patient in CR has relapsed after 8–14 (median 11) months of follow-up. Of 4 patients evaluable by clone-specific real-time PCR, previously reported sensitive to 1 HCL cell in 10⁶ normal, 3 patients at 90 mg/m²/dose were negative.

BR can achieve responses including CRs in multiply relapsed HCL, and its safety profile permits comparison of BR with DCFR using the more common dose level of bendamustine, 90 mg/m² days 1 and 2. Additional patients and follow-up will be required to access durability of response and long-term eradication of MRD, and to compare BR with DCFR (Supported in part by NCI, intramural research program, NIH, Genentech, Inc, and Cephalon, Inc).

Kreitman:Cephalon: Research Funding; Genentech: Research Funding. Off Label Use: Use of bendamustine and rituximab for HCL. Arons:Genentech: Research Funding.