The Fate of Chronic Lymphocytic Leukemia Patients After Failure of Fludarabine, Cyclophosphamide, and Rituximab Regimen

The clinical course of patients with chronic lymphocytic leukemia (CLL) is remarkably heterogeneous. All CLL patients who require therapy are destined to relapse. The prognosis and management of these relapsed patients differs based on the nature of the first-line therapy and the quality and duration of remission to that therapy, as well as biological prognostic factors. Currently, the first treatment option for younger and fit CLL patients is FCR (fludarabine, cyclophosphamide, rituximab) chemoimmunotherapy. Although it regards a very potent treatment option, patients inevitably relapse after the treatment and even approximately 7% of the patients, during initial FCR regimen treatment would fit the standard definition of refractory CLL. So far, little is known about the efficacy of subsequent therapy of patients who relapsed after FCR or were refractory to FCR. Therefore, the goal of this study was to analyze the fate of these patients in the context of routine hematological practice.

We retrospectively analyzed the data of 119 patients (85 males; 34 females) consecutively entered into the databases of three large tertiary Czech hematological centers. All patients were indicated to receive FCR regimen in standard doses (F: 25mg/m²i.v. day 1–3; C: 250mg/m²i.v. day 1–3; R: 375mg/m²i.v.day 0 cycle 1, and 500mg/m²day 1 of all subsequent cycles).

The median age was 57 years (range, 31–75) at the time of the CLL diagnosis, and 60 years (range, 32–78) at the start of FCR therapy. The median follow-up was 42 months (range, 3–114). Our cohort of patients consisted of two groups of patients which received the FCR regimen as first-line therapy (Group 1; n=63) and patients receiving FCR in second or subsequent line of treatment (Group 2; n=56). With respect to the basic parameters (age, clinical stage, FISH cytogenetics, molecular genetics), the statistics of these groups did not differ significantly. In Group 1, the overall response rate (ORR) was 84%, in Group 2, 78% (p=ns) after FCR. Complete remission (CR) rate was 53% in Group 1, and 38% in Group 2 (p=0.04). The median progression-free survival (PFS) was 18.6 months for Group 1 and 14.7 months for Group 2 (p=ns). With subsequent therapy (repeated FCR, alemtuzumab, R-CHOP, rituximab plus high-dose corticosteroids) for relapsed disease after FCR, ORR was 59% in Group 1 (33% CR) and 44% in Group 2 (21% CR) (p=ns). PFS after subsequent therapy after FCR was 13.3 months (Group 1) and 5.9 months (Group 2) (p=0.01). The median OS was insignificantly shorter in Group 2 (44.5 months in Group 2 vs. not reached in Group 1; p=ns). After FCR therapy, there was no statistically significant change in cytogenetic findings, however, new occurrence of 17p deletion was observed in 5 patients. Prior to FCR therapy and during relapse after FCR, the p53 function was analyzed in 37 patients. After FCR, the new mutation of p53 was newly found in 6 patients (16%). These patients received a higher cumulative dose of FCR than the patients who did not develop the mutation (F 591 mg vs. 334 mg; C 5072 mg vs. 3375mg; R 3700mg vs. 2000 mg) (p=ns).

Subsequent treatment for patients who relapse after FCR or are FCR refractory is very heterogeneous. Regardless of the type of therapy selected, the prognosis of these patients is poor. In addition, new p53 mutations/deletions occur after FCR.

No relevant conflicts of interest to declare.