Abbreviated Regimen with 4 Cycles of Fludarabine, Cyclophosphamide and Rituximab (FCR) in Physically Fit Patients with Chronic Lymphocytic Leukemia Who Achieve Early Complete Remission with Undetectable Minimal Residual Disease: Safety and Efficacy Follow-up Results of a Single Center Experience

Introduction: Chemoimmunotherapy with 6 cycles of fludarabine, cyclophosphamide and rituximab (FCR) is considered standard therapy for physically fit patients with chronic lymphocytic leukemia (CLL). Due to treatment toxicity, some patients are unable to undergo standard 6 cycles of FCR. We evaluated safety and efficacy of abbreviating FCR treatment to 4 cycles in a cohort of 35 untreated physically fit CLL patients who achieved CR with negative minimal residual disease (MRD).

Patients and methods:  Within 150 physically fit CLL patients treated with FCR on 1^st line at our Center, from April 2003 to  November 2014, a subgroup of  35 patients interrupted treatment after achieving negative MRD at the end of the 4^th cycle. Median age at start of treatment was  62.8  years (34-81). Binet A/B: 24pts and C: 11. CD38 expression was positive (>7% off cells) in 57.1% and negative in 9% of the pts. A bone marrow biopsy was performed at start of treatment and 1 month post 4^th cycle. Response was assessed in peripheral blood (PB) or bone marrow (BM). Negative MRD was defined as < 10^-4.  We used NCI criteria for response modified for the evaluation of MRD by flow cytometry. Progression was defined according to the NCI recommendations. Overall survival (OS) was defined as the time of initiation of therapy until death or last follow-up and progression free survival (PFS) as the time to progression. Data analysis included frequency and contingency tables, survival curves were plotted by the Kaplan Meier method. Treatment schedule: Fludarabine 25 mg/m2 IV day 1-3, cyclophosphamide 250 mg/m2 IV day 1-3, rituximab 375 mg/m2 IV day 3 cycle 1 and day 1 cycles 2-4, in all cycles every 28 days.

Results: All 35 patients had negative MRD in PB after one month post 4^th cycle. In addition, 28 had bone marrow evaluation showing CR with negative MRD in all of them.  No splenomegaly nor hepatomegaly, enlarged lymphadenopathies nor lymphocytosis was observed in all the patients with negative MRD. After a median follow-up of 57 months (7 -141),  median PFS was  65.8 months, not being yet reached the median of OS. PFS and OS at 72 months was  46% and 68% respectively.  A total of 10 pts ( 3.5%) died: 7 on progressive disease, 3 on secondary neoplasms. Patients who progressed before 24 months had a median of survival of 22 months; median not reached on the group who progressed after 24 months (p=0.0001). Neutropenia grade 3-4 and infectious events were observed in 25.7% and 9.1% during all cycles respectively. Grade 3-4 neutropenia showed to increase over time (Cycle 1: 24%, Cycle 4: 39%). There was no treatment related death.

Conclusion: With a long median follow-up, abbreviating treatment  to 4 courses of FCR in patients who obtained negative MRD   showed durable remissions  with high PFS and OS at 72 months, minimizing treatment related toxicity.  Sixty five percent of the patients who progressed after 24 months are still alive. Large randomized trials will be necessary to confirm our data.