Flavopiridol, Fludarabine, and Rituximab in Mantle Cell Lymphoma and Indolent B-Cell Lymphoproliferative Disorders

Flavopiridol downmodulates antiapoptotic proteins associated with resistance to fludarabine and rituximab and is effective against p53-mutated chronic lymphocytic leukemia (CLL). We conducted a phase I study of flavopiridol, fludarabine, and rituximab (FFR) in patients with mantle-cell lymphoma (MCL...

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Published in:	Journal of clinical oncology Vol. 28; no. 3; pp. 418 - 423
Main Authors:	LIN, Thomas S, BLUM, Kristie A, SCHAAF, Larry J, GREVER, Michael R, BYRD, John C, BETH FISCHER, Diane, MITCHELL, Sarah M, RUPPERT, Amy S, PORCU, Pierluigi, KRAUT, Eric H, BAIOCCHI, Robert A, MORAN, Mollie E, JOHNSON, Amy J
Format:	Journal Article
Language:	English
Published:	Alexandria, VA American Society of Clinical Oncology 20-01-2010
Subjects:	Adult Aged Aged, 80 and over Antibodies, Monoclonal - administration & dosage Antibodies, Monoclonal, Murine-Derived Antineoplastic Agents - therapeutic use Antineoplastic Combined Chemotherapy Protocols - therapeutic use B-Lymphocytes Biological and medical sciences Female Flavonoids - administration & dosage Hematologic and hematopoietic diseases Humans Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Lymphoma, B-Cell - drug therapy Lymphoma, Mantle-Cell - drug therapy Lymphoproliferative Disorders - drug therapy Male Medical sciences Middle Aged Original Reports Piperidines - administration & dosage Rituximab Tumors Vidarabine - administration & dosage Vidarabine - analogs & derivatives Antineoplastic agent Purine nucleotide Purine derivatives Rituximab B cell neoplasm Malignant hemopathy B-Lymphocyte Nucleotide analog Monoclonal antibody Non Hodgkin lymphoma Flavonoid Cyclin dependent kinase inhibitor Polyphenol Cancerology Flavopiridol Fludarabine Treatment Antimetabolic Immunotherapy Lymphoproliferative syndrome Mantle cell lymphoma Phenols Fluorine Organic compounds Cancer
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Summary:	Flavopiridol downmodulates antiapoptotic proteins associated with resistance to fludarabine and rituximab and is effective against p53-mutated chronic lymphocytic leukemia (CLL). We conducted a phase I study of flavopiridol, fludarabine, and rituximab (FFR) in patients with mantle-cell lymphoma (MCL), indolent B-cell non-Hodgkin's lymphomas (B-NHL), and CLL to determine the activity of FFR. Therapy included fludarabine 25 mg/m(2) intravenously (IV) days 1 to 5 and rituximab 375 mg/m(2) day 1 every 28 days for 6 cycles. We administered flavopiridol 50 mg/m(2) by 1-hour IV bolus (IVB) day 1 (n = 15); day 1 to 2 (n = 6); 20 mg/m(2) 30-minute IVB + 20 mg/m(2) 4-hour IV infusion (n = 3); or 30 mg/m(2) + 30 mg/m(2) (n = 14). Thirty-eight patients (median age, 62 years) with MCL (n = 10); indolent B-NHL including follicular (n = 9), marginal zone (n = 4), lymphoplasmacytic (n = 1), or small lymphocytic lymphoma (n = 3); and CLL (n = 11), were enrolled. Twenty-two patients were previously untreated; 16 had received one to two prior therapies. Two patients in cohort 2 developed grade 3 dose-limiting toxicity (seizures, renal insufficiency). The median number of treatment cycles was 4, with cytopenias (n = 10) and fatigue (n = 3) the most common reasons for early discontinuation. Overall response rate was 82% (complete response, 50%; unconfirmed complete response, 5%; partial response, 26%), including 80% of patients with MCL (median age, 68; seven complete responses, one partial response). Median progression-free survival (PFS) was 25.6 months. Median PFS of patients with nonblastoid variant MCL (n = 8) was 35.9 months. FFR was active in MCL, indolent B-NHL, and CLL and should be studied for older patients with MCL who are not candidates for aggressive chemotherapy.
ISSN:	0732-183X 1527-7755
DOI:	10.1200/JCO.2009.24.1570