The Pentostatin, Cyclophosphamide, and Rituximab Regimen (PCR) Is Highly Active and Well Tolerated Regardless of Patient Age, Creatinine Clearance, and Performance Status: Analysis of a Multi-Center Phase II Trial.

Background: CLL is a disease of the elderly and at least half of the patients requiring therapy are over age 70. While chemoimmunotherapy (CIT) has dramatically improved response rates in patients with CLL, some CIT regimens are not well tolerated by elderly patients. The MD Anderson group has reported that the fludarabine, cyclophosphamide, rituximab (FCR) regimen is not well tolerated in individuals ≥age 70 (Ferrajoli Leuk Lymph 46:S86). The German CLL Study Group has postulated that physiologic health is more important than chronologic age and have conducted a trial of FCR that permits enrollment of patients ≥age 70 provided they have a creatinine clearance (CrCl) ≥70 and good performance status (PS). While this approach expands the number of individuals who can receive CIT, it still excludes large percentages of CLL patients in need of treatment. Here, we examine how age, CrCl, and PS relate to the efficacy and tolerability of the pentostatin, cyclophosphamide, and rituximab (PCR) regimen. Methods: We treated 64 previously untreated CLL patients meeting NCI 96 criteria for treatment with pentostatin (2mg/m2), cyclophosphamide (600 mg/m2) and rituximab (375mg/m2) (Kay ASH 2006). All medications were administered on day 1 of every 3 week cycle with the intent of administering 6 cycles. We measured ECOG PS at study entry and used age, weight, and baseline creatinine to calculate the CrCl of all patients at study entry using the Cockroft-Gault equation. Results: Eighteen of 64 patients (28%) were ≥age 70. Although individuals ≥age 70 were more likely to have a dose delay of >1 week at some point during the trial (7% vs. 28%; p=0.03), there was no difference in the average number of cycles administered, the number of patients requiring dose reductions, or the number of patients with grade 3/4 hematologic toxicity, infectious complications, or other non-hematologic toxicity. No difference in OR (93% vs 83%; p=0.34) or CR (41% vs. 39%; p=0.86) was observed between patients <age 70 compared to those ≥70. We next evaluated whether CrCl related to the efficacy and tolerability of PCR. 25 patients (39%) had a CrCl<70, including 15 (23%) with a CrCl<60 and 5 (8%) with CrCl<50. Although individuals with CrCl<70 were more likely to have a dose reduction (5% vs. 24%; p=0.05), there was no difference in the average number of cycles administered, the number of patients requiring a dose delay, or the number of patients with grade 3/4 hematologic toxicity, infectious complications, or other non-hematologic toxicity. No difference in OR (89% vs 92%; p=1.0) or CR (45% vs. 36%; p=0.60) was observed between patients with CrCl≥70 and those with CrCl<70. We next evaluated how PS related to the efficacy and tolerability. 34 patients (53%) were PS 0 and 30 (47%) were PS≥1. This analysis suggested PCR was well tolerated among those with PS≥1. Again no difference in the OR or CR was observed between patients with PS 0 and those with PS≥1. Conclusions: In this phase II clinical trial, the PCR regimen was well tolerated by patients ≥age70, those with higher PS, and the 25 individuals with CrCl≤70 (range 34–67). The efficacy of PCR was also not significantly affected by age, renal function, or performance status. These findings suggest the PCR regimen may be superior to the FCR regimen for elderly patients and those with decreased renal function.