Original Article

Annals of Hematology

, Volume 85, Issue 5, pp 301-307

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

  • Carl R. WillisAffiliated withNashville Oncology AssociatesHematology/Oncology Department, Walter Reed Army Medical Center
  • , Amy GoodrichAffiliated withDivision of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • , Kathy ParkAffiliated withHematology/Oncology Department, Walter Reed Army Medical Center
  • , Jamie K. WaselenkoAffiliated withHematology/Oncology Department, Walter Reed Army Medical CenterSarah Cannon Research Institute Email author 
  • , Margaret LucasAffiliated withDivision of Hematology–Oncology, Ohio State University
  • , Amy ReeseAffiliated withHematology/Oncology Department, Walter Reed Army Medical Center
  • , Louis F. DiehlAffiliated withDivision of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsHematology/Oncology Associates, Duke University
  • , Michael R. GreverAffiliated withDivision of Hematology–Oncology, Ohio State University
  • , John C. ByrdAffiliated withDivision of Hematology–Oncology, Ohio State University
    • , Ian W. FlinnAffiliated withDivision of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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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.

Keywords

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