A Phase I/II Study of a Hybrid Schedule of Flavopiridol in Relapsed/Refractory Mantle Cell Lymphoma and Diffuse Large B-Cell Lymphoma

Abstract

Abstract Background Continuous infusion and bolus schedules of flavopiridol in mantle cell lymphoma (MCL) have yielded disappointing results. However, a pharmacologically derived hybrid schedule of administration is effective in refractory, genetically high-risk chronic lymphocytic leukemia (CLL), though life-threatening tumor lysis syndrome (TLS) may occur in patients with very high lymphocyte counts. Because flavopiridol decreases cyclin D1 and Mcl-1 and induces apoptosis in MCL cells, is significantly toxic for cell lines derived from the activated B-cell–like type of diffuse large B-cell lymphoma (DLBCL; OCI-Ly3), and downregulates NF-κB, we investigated the hybrid schedule in MCL and DLBCL. Patients and Methods Flavopiridol was administered as a 30-minute bolus (mg/m 2 ) followed by a 4-hour continuous infusion (mg/m 2 ), weekly for 4 doses every 6 weeks. Separate escalation rules applied to cycle 1 week 1 (C1W1) and all other weeks of treatment. Dose levels on C1W1 were DL1: 25/25 (4 patients), DL2: 30/30 (10 patients), and DL3: 30/50 (6 patients). Dose escalation on subsequent weeks was not possible due to toxicity, and all patients received 30/50. All patients received TLS prophylaxis. Paired biopsy samples obtained before and after the first dose were analyzed for CDK targets. Results Patient (n = 20) characteristics: median age, 59 years (range, 24-80 years); male, 15 (75%); median prior regimens, 2 (range, 1-6). Ten patients had MCL, and 10 had DLBCL. Responses included partial response (PR) in 2 patients (1 MCL; 1 DLBCL; 10%), stable disease (SD) in 5 patients (25%), and progressive disease (PD) in 13 patients (65%). Dose-limiting toxicities (DLTs) included TLS and severe vomiting/diarrhea in 2 patients at DL3. The maximum tolerated dose (MTD) and phase II dose have not yet been defined. Other toxicities were grade 4 absolute neutrophil count (ANC; 10 patients) requiring prophylactic granulocyte colony-stimulating factor (G-CSF), TLS (1 patient), and bowel perforation (1 patient). Decreased Rb staining at the S807/811 phospho-site was noted in 8 of 9 paired samples analyzed (range, 20%-75%; P = .027) and at the S780 site in 7 of 8 paired samples (range, 38%-91%; P = .00016), suggestive of G1 CDK inhibition. In 1 sample in which p53 was detected, there was an increase post-treatment, suggestive of CDK9 inhibition. Conclusion The hybrid schedule of flavopiridol has modest activity in relapsed MCL and DLBCL. TLS occurred infrequently and was reversible. DLTs were TLS and gastrointestinal toxicity. Accrual continues. Analysis of cell cycle and transcriptional CDK targets is ongoing.