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.
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.
Division of Hematology, Mayo Clinic, Rochester, Minnesota.
Clive S
CS
Zent
Ronald P
RP
Taylor
Margaret A
MA
Lindorfer
Paul V
PV
Beum
Betsy
B
LaPlant
Wenting
W
Wu
Timothy G
TG
Call
Deborah A
DA
Bowen
Michael J
MJ
Conte
Lori A
LA
Frederick
Brian K
BK
Link
Sue E
SE
Blackwell
Suresh
S
Veeramani
Nisar A
NA
Baig
David S
DS
Viswanatha
George J
GJ
Weiner
Thomas E
TE
Witzig
D000368:Aged; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects; D018951:Antigens, CD20 / Q000096:biosynthesis* / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000276:immunology; D015649:Pentostatin / Q000008:administration & dosage / Q000009:adverse effects; D012008:Recurrence; D012074:Remission Induction; D000069283:Rituximab
D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D015649:Pentostatin; D000074323:Alemtuzumab; D000069283:Rituximab