A phase I/II study examining pentostatin, chlorambucil, and theophylline in patients with relapsed chronic lymphocytic leukemia and non-Hodgkin's lymphoma

Jamie K. Waselenko, Amy Reese, Kathy Park, Margaret Lucas, Amy Goodrich, Carl R. Willis, Louis F. Diehl, Michael R. Grever, John C. Byrd, Ian W. Flinn

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)301-307
Number of pages7
JournalAnnals of Hematology
Volume85
Issue number5
DOIs
StatePublished - May 2006

Fingerprint

Pentostatin
Chlorambucil
B-Cell Chronic Lymphocytic Leukemia
Theophylline
Non-Hodgkin's Lymphoma
Follicular Lymphoma
Maximum Tolerated Dose
Reaction Time
Histology
Survival

Keywords

  • Chlorambucil
  • Chronic lymphocytic leukemia
  • Follicular lymphoma
  • Non-Hodgkin's lymphoma
  • Pentostatin
  • Theophylline

ASJC Scopus subject areas

  • Hematology

Cite this

A phase I/II study examining pentostatin, chlorambucil, and theophylline in patients with relapsed chronic lymphocytic leukemia and non-Hodgkin's lymphoma. / Waselenko, Jamie K.; Reese, Amy; Park, Kathy; Lucas, Margaret; Goodrich, Amy; Willis, Carl R.; Diehl, Louis F.; Grever, Michael R.; Byrd, John C.; Flinn, Ian W.

In: Annals of Hematology, Vol. 85, No. 5, 05.2006, p. 301-307.

Research output: Contribution to journalArticle

Waselenko, Jamie K. ; Reese, Amy ; Park, Kathy ; Lucas, Margaret ; Goodrich, Amy ; Willis, Carl R. ; Diehl, Louis F. ; Grever, Michael R. ; Byrd, John C. ; Flinn, Ian W. / A phase I/II study examining pentostatin, chlorambucil, and theophylline in patients with relapsed chronic lymphocytic leukemia and non-Hodgkin's lymphoma. In: Annals of Hematology. 2006 ; Vol. 85, No. 5. pp. 301-307.
@article{59d7fadb84aa4dfe83feebba062aee06,
title = "A phase I/II study examining pentostatin, chlorambucil, and theophylline in patients with relapsed chronic lymphocytic leukemia and non-Hodgkin's lymphoma",
abstract = "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/na{\"i}ve 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.",
keywords = "Chlorambucil, Chronic lymphocytic leukemia, Follicular lymphoma, Non-Hodgkin's lymphoma, Pentostatin, Theophylline",
author = "Waselenko, {Jamie K.} and Amy Reese and Kathy Park and Margaret Lucas and Amy Goodrich and Willis, {Carl R.} and Diehl, {Louis F.} and Grever, {Michael R.} and Byrd, {John C.} and Flinn, {Ian W.}",
year = "2006",
month = "5",
doi = "10.1007/s00277-005-0025-9",
language = "English (US)",
volume = "85",
pages = "301--307",
journal = "Annals of Hematology",
issn = "0939-5555",
publisher = "Springer Verlag",
number = "5",

}

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.

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

UR - http://www.scopus.com/inward/record.url?scp=33646681429&partnerID=8YFLogxK

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

VL - 85

SP - 301

EP - 307

JO - Annals of Hematology

JF - Annals of Hematology

SN - 0939-5555

IS - 5

ER -