Efficacy and Safety of Frontline Therapy with "FCR" Regimen for Chronic Lymphocytic Leukemia Outside Clinical Trials: Israeli CLL Study Group Experience
Authors: Herishanu Yair , Goldschmidt Neta , Bairey Osnat , Ruchlemer Rosa , Fineman Riva , Rahimi-Levene Naomi , Shvidel Lev , Tadmor Tamar , Aviv Ariel , Braester Andrei , Joffe Erel , Polliack Aaron 
Published: October 2019

Abstract
The combination of fludarabine, cyclophosphamide and rituximab (FCR) is still currently regarded as the standard regimen for treatment of physically fit patients with chronic lymphocytic leukemia (CLL). This therapy can be associated with significant toxicity, and patient adherence to the protocol may often be difficult outside of clinical trials.
This retrospective study aimed to evaluate the efficacy and safety of FCR therapy in the real life setting, with particular focus on the influence of dose reduction on treatment outcome. A total of 132 CLL patients (≤70 years of age) treated with FCR as frontline therapy from 10 medical centers, were reviewed. The majority of patients were males (73.5%, n=97) and younger than 60 years (78%, n=103). Eleven patients had Binet stage A (8.3%), 72 (54.5%) were stage B and 49 (37.1%) had Binet stage C. Results of FISH analysis were available for 99 patients, with high risk cytogenetics of del(11q) in 21 patients (21.2%) and del(17p) in 9 cases (9.1%). The majority (56.5%, n=74) received rituximab at a dose of 500mg/m2 and the rest 375mg/m2. Almost half of the patients (49.2%, n=65) were given a reduced dose of chemotherapy (<90% of the indicated dosage), while 23% (n=30) received 2/3 or less. Primary chemotherapy dose reduction was most commonly in accordance with the treating physician's judgment, while secondary dose modifications and less chemotherapy cycles were initiated mainly because of hematological toxicity. Most patients had a clinical complete response (69.8%, n=90) while only 10 (7.8%) failed to respond. Partial or non- responders were more commonly associated with lower pretreatment hemoglobin levels and platelet counts, Binet stage C, and presence of del(17p) and had also received lower doses of chemotherapy (p=0.024). The rituximab dose administered was not associated with differences in response rates (p=0.7). Reducing the dose of chemotherapy (≤2/3) was associated with an increase in risk of disease progression (HR 4.1, 95% CI 2.3-7.0, p<0.0001), resulting in a decrease in median progression free survival (PFS) from 46.9 months (for those receiving the full dose), to 15.8 months for patients given a reduced dose. In a multivariate analysis of PFS only a reduced dose of chemotherapy (≤2/3) and del(17) retained statistical significance, p=0.004 and p<0.0001, respectively. The median overall survival for the entire cohort was 99.5 months (95% CI 78.5-120.5). Del(17p) and failure to respond to treatment were independently associated with a worse overall survival (HR=9.2, 95% CI 2.0-41.8, p=0.004 and HR=15.1, 95% CI 3.2-72.0, p-0.001, respectively). The most commonly recorded severe adverse events included, at least one episode of infection or neutropenia in 25.8% and 24.2% of patients, respectively. Treatment related DAT+ autoimmune hemolysis occurred in 6.0% of the cases, late-onset neutropenia in 8.1%, Richter's transformation in 3% and therapy related MDS/AML in 2.3% of patients.
In conclusion, it is apparent that outside of clinical trials treating physicians tend more readily to reduce doses of chemotherapy. Reduced doses of fludarabine and cyclophosphamide but not of rituximab, is significantly associated with a shorter PFS.

Disclosures
No relevant conflicts of interest to declare.