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Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and primarily affects the elderly. Treatment of CLL has evolved significantly in recent years. There is currently no standard of care for patients with CLL older than 70 years or patients with co-morbidities and an impaired physical condition (“Slow go”). These patients may be offered a mild chemotherapy regimen: chlorambucil or dose-reduced fludarabine or bendamustine. Dose-modified combination regimens such as Fludarabine, Cyclophosphamide, Rituximab (FCR)-Lite seem to deliver the FCR therapy with a lower toxicity, but this combination still has to be tested on a large scale, in less fit patients. Similarly, the use of pentostatin, cyclophospamide, rituximab (PCR) was investigated to achieve a reduced toxicity, with promising results, both in pretreated CLL patients than in frontline.

Starting in December 2010, we selected elderly patients with “slow-go” CLL to evaluate efficacy and safety of PCR regimen in this subset.

To date, we observed 16 cases of “slow-go” elderly CLL, most were high risk patients. They were treated with PCR regimen consisting of pentostatin (P:2mg/m²), cyclophospamide (C:600 mg/m²) and rituximab (R:375 mg/m²) on day 1 (21-day cycles). Dose 1 of R was given on day 8 (Cycle 1) and was increased to 500 mg/m², from cycle 2. The dose of pentostatin was increased to 4 mg/m2, from cycle 3, in the absence of grade III-IV hematologic toxicity. This PCR regimen was given on a 21-day, 6-cycle schedule. Support from granulocyte colony-stimulating growth factor was provided, as required. Patients received prophylaxis with cotrimoxazole and lamivudine (as required).

13 patients (82%) were treated in frontline and 3 patients (18%) at relapse. The median age was 73 years and 88% were 70 years older. 69% (RAI stages 3-4) and 100% (Binet B-C).  Cytogenetics showed Trisomy 12 (31%) and 13q14 deletion (19%). No other cytogenetic abnormalities were detected. IgVH status resulted “unmutated” in 81% of cases. All patients had comorbidities and 87% had a Creatinìne Clearance (CrCl)<70 ml/min. The overall response rate (ORR) on the whole population was 88%, complete response (CR):25%, partial response  (PR):63%. The ORR in frontline was 85%, CR(31%), PR(54%). All patients completed the planned six courses of PCR, without dose reductions or delayed. Toxicities were: grade III-IV neutropenia (18%) and anemia (6%); grade II thrombocytopenia (18%), grade II nausea (31%), grade II constipation (6%), grade II hypertransaminasemia (6%). We didn’t observe severe or prolonged infections or other toxicities. There were no significant differences in the number of cycles administered, need for dose reductions, grade 3-4 toxicities in patients with CrCl<70 ml/min. At a median follow-up of 29 months (range: 6-44), the median progression free survival (mPFS) was 17.6 months (range: 3-42), 75% of patients are alive, 3 patients (25%) died for cardiovascular disease, respectively after 6, 12 and 12 months and 1 patient for severe pneumonia after 3 months from the end of therapy.

Therapeutic strategies for “slow-go” patients with CLL are still lacking, especially for elderly patients. In previous studies, PCR regimen demonstrated activity, both in frontline and at relapse. Moreover, PCR seems feasible and safe because loaded from toxicities less than FCR regimen. In our experience, PCR was well tolerated in elderly and “slow-go” CLL, also in patients with CrCl<70 ml/min. Then, PCR may be a treatment option in this subset of patients.