A Multi-Center, Open-Label Study To Evaluate the Safety and Efficacy of Pentostatin, Cytoxan, and Rituxan (PCR) in the Treatment of Previously Untreated or Treated, Stage III or IV, Low-Grade CLL.

Introduction: The decision to treat indolent CLL is often based on progressing bulky disease, worsening symptoms, and increasing hematologic derangement. When treatment is indicated, these lymphoproliferative disorders are very sensitive to combination chemotherapies. Combination therapy with pentostatin (P), purine analog, cyclophosphamide (C), alkylator, and rituximab (R), anti-CD20 monoclonal antibody, represents a promising new approach in the treatment of patients with low grade CLL. Most regimens have utilized fludarabine as the purine analog, but the myelosuppression and immunosuppression of these combinations and the disease of CLL frequently results in severe infections. We have previously reported our experience with pentostatin and rituximab in a cohort of 133 previously treated and untreated patients with Grade III/IV NHL or CLL (2005 Pan-Pacific Lymphoma Conference). Methods: Thirty-five patients have been enrolled in this study through the Pharmatech Research Network (64 sites). The expected accrual is 180 patients. Eligibility criteria allows previously treated and treatment naive patients diagnosed with low-grade stage III/IV CLL (modified Rai classification). Treatment consisted of intravenous infusions of P (4 mg/m 2 ), C (600 mg/m 2 ), and R (375 mg/m 2 ) on day 1 of a 21-day cycle for a total of 8 cycles. Clinical evaluation (including CT scan) was performed after even-numbered cycles. Patients were stratified by disease and by prior treatment status. Results: CLL patients (median age 63, range 35–84) have received 138 cycles (median 5.5) so far. ECOG status at enrollment was 0 (80%) and 1 (14%). Overal response rate (N=29 evaluable) was 65% (CR 14%, CRu 7%, PRu 3%, PR 41%). One grade 4 neutropenia has been documented in this cohort. Five deaths have been recorded. One death occurred within 30 days of receiving chemotherapy. This patient (81 YO) was hospitalized 4 days after cycle 1 and death was due to sepsis and multi-organ failure occurred 18 days later. Another death (76 YO) was reported 30 days after cycle 1 due to pneumonia/respiratory insufficinency. An 84 YO patient had treatment delayed after cycle 2, she died at home of an apparent MI. An 83 YO man was hospitalized 2 weeks after completing cycle 2. This patient was dehydrated as a result of gastroenteritis however he developed atrial flutter and died as a result of pulmonary edema. The last patient discontinued therapy after achieving CRu following 3 cycles. Three months later she died of sepsis and pneumonia. Conclusions: This immunochemotherapeutic regimen is active in Grade III/IV CLL and the incidence of significant toxities was low with deaths occurring in elderly patients. Future trials evaluating the use of R as maintenance therapy following this PCR regimen may also be warranted with an eye toward increasing the overall survival of patients with CLL. The use of combination therapy in elderly patients should be used with caution due to associated co-morbidities.