TY - JOUR
T1 - A phase I/II study examining pentostatin, chlorambucil, and theophylline in patients with relapsed chronic lymphocytic leukemia and non-Hodgkin's lymphoma
AU - Waselenko, Jamie K.
AU - Reese, Amy
AU - Park, Kathy
AU - Lucas, Margaret
AU - Goodrich, Amy
AU - Willis, Carl R.
AU - Diehl, Louis F.
AU - Grever, Michael R.
AU - Byrd, John C.
AU - Flinn, Ian W.
N1 - Funding Information:
Acknowledgements We are indebted to the patients who participated in this study and to the excellent nursing staff in both the Walter Reed Army Medical Center and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins who made this trial possible. We would also like to thank Dr. Candis Morrison for her assistance in enrolling patients, Charlotte Shinn for her assistance in the laboratory, and Drs. Edward Gorak and Jennifer Crook for their thoughtful review of our manuscript. This work was supported, in part, by a research grant from Supergen, Inc.
PY - 2006/5
Y1 - 2006/5
N2 - In an attempt to exploit bcl-2 overexpression and aberrant p53 function, two frequently encountered aberrations that predict marked treatment resistance and worse prognosis in patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), we combined theophylline, pentostatin, and chlorambucil at two dose levels (cohort I: 30 mg/m2; cohort II: 20 mg/m2) on a 21-day cycle for up to six courses. We employed a phase I/II design to determine feasibility, define the maximum tolerated dose (MTD), and explore the impact of biologic modulation on response and time to progression (TTP) in 20 patients with relapsed or refractory CLL and NHL. Eight patients were enrolled in cohort I. They demonstrated a response rate (RR) of 28% and a 16.5-month TTP after receiving a median of two cycles. A 50% RR was observed in this cohort when patients with adverse histologies were excluded. Because of myelotoxicity, this dose level defined the MTD, and de-escalation occurred. All 12 patients in cohort II received 20 mg/m2 chlorambucil. A 50% RR and an 18-month TTP were observed after a median of 5.5 cycles. An RR of 47% and a complete remission (CR) of 5% were observed for the entire group, although responses and TTP varied greatly by histology. Significant activity was observed in patients with B-cell CLL and follicular lymphoma (FL). RR and TTP for fludarabine-sensitive/naïve and fludarabine-refractory (FR) B-cell CLL patients were 66 vs 25% and 20 vs 8.5 months, respectively. Both FL patients responded (one with partial remission and one with CR), with a 22.5-monthly median TTP. For responding patients, median TTP and overall survival (OS) was 21 and 69 months, respectively, compared to a median TTP of 2 months and an OS of 13.5 months for nonresponders. The combination of pentostatin, chlorambucil, and theophylline is the active regimen in patients with FL and B-cell CLL.
AB - In an attempt to exploit bcl-2 overexpression and aberrant p53 function, two frequently encountered aberrations that predict marked treatment resistance and worse prognosis in patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), we combined theophylline, pentostatin, and chlorambucil at two dose levels (cohort I: 30 mg/m2; cohort II: 20 mg/m2) on a 21-day cycle for up to six courses. We employed a phase I/II design to determine feasibility, define the maximum tolerated dose (MTD), and explore the impact of biologic modulation on response and time to progression (TTP) in 20 patients with relapsed or refractory CLL and NHL. Eight patients were enrolled in cohort I. They demonstrated a response rate (RR) of 28% and a 16.5-month TTP after receiving a median of two cycles. A 50% RR was observed in this cohort when patients with adverse histologies were excluded. Because of myelotoxicity, this dose level defined the MTD, and de-escalation occurred. All 12 patients in cohort II received 20 mg/m2 chlorambucil. A 50% RR and an 18-month TTP were observed after a median of 5.5 cycles. An RR of 47% and a complete remission (CR) of 5% were observed for the entire group, although responses and TTP varied greatly by histology. Significant activity was observed in patients with B-cell CLL and follicular lymphoma (FL). RR and TTP for fludarabine-sensitive/naïve and fludarabine-refractory (FR) B-cell CLL patients were 66 vs 25% and 20 vs 8.5 months, respectively. Both FL patients responded (one with partial remission and one with CR), with a 22.5-monthly median TTP. For responding patients, median TTP and overall survival (OS) was 21 and 69 months, respectively, compared to a median TTP of 2 months and an OS of 13.5 months for nonresponders. The combination of pentostatin, chlorambucil, and theophylline is the active regimen in patients with FL and B-cell CLL.
KW - Chlorambucil
KW - Chronic lymphocytic leukemia
KW - Follicular lymphoma
KW - Non-Hodgkin's lymphoma
KW - Pentostatin
KW - Theophylline
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UR - http://www.scopus.com/inward/citedby.url?scp=33646681429&partnerID=8YFLogxK
U2 - 10.1007/s00277-005-0025-9
DO - 10.1007/s00277-005-0025-9
M3 - Article
C2 - 16518606
AN - SCOPUS:33646681429
SN - 0939-5555
VL - 85
SP - 301
EP - 307
JO - Annals of hematology
JF - Annals of hematology
IS - 5
ER -