Flavopiridol, fludarabine, and rituximab in mantle cell lymphoma and indolent B-cell lymphoproliferative disorders.

Abstract

PURPOSE:

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.

PATIENTS AND METHODS:

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).

RESULTS:

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.

CONCLUSION:

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.

• Authors: Thomas S Lin, Kristie A Blum, Diane Beth Fischer, Sarah M Mitchell, Amy S Ruppert, Pierluigi Porcu, Eric H Kraut, Robert A Baiocchi, Mollie E Moran, Amy J Johnson, Larry J Schaaf, Michael R Grever, John C Byrd
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 28 Issue 3 Pg. 418-23 (Jan 20 2010) ISSN: 1527-7755 [Electronic] United States
• PMID: 20008633 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Antineoplastic Agents
• Flavonoids
• Piperidines
• alvocidib
• Rituximab
• Vidarabine
• fludarabine

Topics

• 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
• Female
• Flavonoids (administration & dosage)
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy)
• Lymphoma, B-Cell (drug therapy)
• Lymphoma, Mantle-Cell (drug therapy)
• Lymphoproliferative Disorders (drug therapy)
• Male
• Middle Aged
• Piperidines (administration & dosage)
• Rituximab
• Vidarabine (administration & dosage, analogs & derivatives)