High Dose Cytarabine Salvage Regimen Combined with Bortezomib Is Feasible and Highly Effective in Relapsed Mantle Cell Lymphoma.

Introduction: Mantle cell lymphoma (MCL) is a subtype of malignant lymphoma with an especially poor prognosis. However, molecular targeted therapy may alter the natural history of disease. Bortezomib (BZ) is a potent, selective and reversible inhibitor of the 26S proteasome thereby interfering with intracellular protein homeostasis. Various clinical phase II trials revealed significant efficacy of BZ monotherapy in relapsed MCL with approximately 40% response rate, but rare CR and short duration of response. Based on our preclinical data demonstrating synergy of BZ and cytarabine (Ara-C) we performed a pilot study to explore the clinical impact of such combined approach.

Treatment: 2 g/m² Ara-C was applied on day 2 and 3 (1 g/m² in patients with impaired hematopoiesis or age >60 years) combined with BZ 1.5 mg/m² iv bolus (day 1 and 4). In addition, dexamethasone 40 mg was given over a 4 day period. R was added to the outlined regimen in 6 patients (375 mg/m²). Treatment was repeated in 3 week intervals for a total of 4 cycles with staging procedures performed after 2 and 4 cycles.

Results: After informed consent 8 patients with relapsed or refractory advanced stage MCL were treated accordingly to the outlined protocol. Median age was 65 years (54–76), 5 patients were male. Median number of prior systemic therapies was 4 (2–7). All patients had previously been treated with CHOP and at least one rituximab (R)-containing regimen, 2 patients previously failed BZ monotherapy, and none of them was considered eligible for myeloablative treatment. Currently data from 7 patients are available for analysis of toxicity and response. At time of analysis, a total of 22 cycles has been applied with a median follow-up of 214 days (119–366). As expected, hematologic toxicity CTC grade III/IV occurred in all 7 patients, but only one case of neutropenic fever (grade 3) and no major bleeding were observed. Ara-C dose was reduced in 5 patients. Two patients developed new onset or worsening of preexisting polyneuropathy. Dose of BZ had to be reduced in 1 patient and stopped after cycle 2 in another patient with preexisting polyneuropathy. Of note, 2 patients developed herpes zoster (grade 2). In 3 patients treatment was stopped after cycle 2 due to insufficient response (progressive disease, stable disease and minimal response, respectively). In the 4 patients completing 4 cycles 1 CR and 3 PR were archieved.

Conclusion: Salvage therapy with high-dose Ara-C combined with BZ in relapsed or refractory MCL was associated with considerable but manageable hematotoxicity and only few infectious complications. The high efficacy in heavily pretreated patients justifies a comparative trial of the European MCL Network evaluating a high-dose cytarabine containing regimen +/− BZ.