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

• Published in: Clinical lymphoma, myeloma and leukemia myeloma and leukemia, 2010-06, Vol.10 (3), p.E27-E27
• Main Authors: Dunleavy, Kieron, Shapiro, Geoff, Disinski, Megan, Chirieac, Lucian, Pittaluga, Stefania, Jaffe, Elaine S, Janik, John E, Wiestner, Adrian, Wilson, Wyndham H
• Format: Article
• Language: English
• Subjects: Hematology, Oncology and Palliative Medicine
• ISSN: 2152-2650; 2152-2669
• DOI: 10.3816/CLML.2010.n.037

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/m2 ) followed by a 4-hour continuous infusion (mg/m2 ), 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 reversi