Chemoimmunotherapy for relapsed/refractory and progressive 17p13-deleted chronic lymphocytic leukemia (CLL) combining pentostatin, alemtuzumab, and low-dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells.

Abstract

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab-containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short-duration regimen combining pentostatin, alemtuzumab, and low-dose high-frequency rituximab designed to decrease the risk of treatment-associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13-) (n = 3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy, with only five (13%) patients having treatment-limiting toxicity and no treatment-related deaths. Twenty-two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression-free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B-cell lymphoma (n = 6). Correlative studies showed that low-dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low-dose high-frequency rituximab is a tolerable and effective therapy for CLL and that low-dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression.

• Authors: Clive S Zent, Ronald P Taylor, Margaret A Lindorfer, Paul V Beum, Betsy LaPlant, Wenting Wu, Timothy G Call, Deborah A Bowen, Michael J Conte, Lori A Frederick, Brian K Link, Sue E Blackwell, Suresh Veeramani, Nisar A Baig, David S Viswanatha, George J Weiner, Thomas E Witzig
• Journal: American journal of hematology (Am J Hematol) Vol. 89 Issue 7 Pg. 757-65 (Jul 2014) ISSN: 1096-8652 [Electronic] United States
• PMID: 24723493 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antibodies, Monoclonal, Murine-Derived
• Antigens, CD20
• Pentostatin
• Alemtuzumab
• Rituximab

Topics

• Aged
• Alemtuzumab
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects)
• Antibodies, Monoclonal, Murine-Derived (administration & dosage, adverse effects)
• Antigens, CD20 (biosynthesis, immunology)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Chromosome Deletion
• Chromosomes, Human, Pair 17
• Disease-Free Survival
• Female
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy, genetics, immunology)
• Male
• Middle Aged
• Neoplastic Cells, Circulating (immunology)
• Pentostatin (administration & dosage, adverse effects)
• Recurrence
• Remission Induction
• Rituximab