Fludarabine Combination Therapy Response, Progression and Toxicity Profile in a Minority Predominant Population with Chronic Lymphocytic Leukemia from a Public Health Hospital
Authors: Ciobanu Bety , Sreenivasappa Shylendra B , Yim Barbara , Smiley Tracy , Angelova Victoria , Kovarik Paula , Ofori Samuel , Shah Mousami , Kouz Rafid , Telfer Margaret Clare , Catchatourian Rosalind 
Published: April 2020

Abstract
Background: Fludarabine based chemotherapy has been increasingly used in the treatment of chronic lymphocytic leukemia (CLL). We describe our experience with fludarabine combination chemotherapy (mainly FCR-fludarabine, cyclophosphamide, rituximab) in a minority predominant population with CLL.
Methods: 35 patients (pts) with progressive or advanced CLL treated with fludarabine based regimens at Cook County Hospital, Chicago, IL over an 8-year period were studied as a retrospective cohort for clinical response, remission duration and long-term survival. Clinical and survival data were analyzed via Student’s T test and Fisher’s exact test. Time to progression was analyzed with Kaplan-Meier life table analyses and Log Rank test.
Results: Twenty out of 35 pts (57.14%) received fludarabine combination therapy as initial treatment (19 FCR, 1 FC) and 15 pts (42.85%) at relapse (12 FCR, 3 FCR/alemtuzumab). Eight pts had previous exposure to fludarabine. Median time to treatment was 17 months. Fourteen pts (40%) were women, and 21 pts (60%) men. Median age at treatment was 58 years. African Americans were the predominant group with 23 pts (65.7%), Caucasian 8 (22.9%), Hispanics 3 (8.6%), and Asian 1 (2.9%) pts. According to Binet stage at diagnosis, 6 pts (17.1%) were stage A, 16 (45.7%) stage B, and 13 (37.1%) stage C. Performance status was 0 in 12 pts (34.3%), and 1 in 23 (65.7%). CD 38 was present in 9 pts (25.7%) and Zap-70 in 11 pts (31.4%). A WBC above 100,000/dL was seen in 16 pts (45.71%) and the median absolute lymphocyte count was 72,900/dL. Lymphocyte doubling time was less then 6 months in 18 pts (51.4%). Seven pts (20%) had prolymphocyte counts between 10–20%. Data for FISH studies was available in 28 pts (80%) and revealed del 11 in 5 pts, del 13 in 8 pts, del 17 in 1, trisomy 12 in 5 pts and 9 pts had normal cytogenetics with negative FISH results.
Majority of pts 19 (54.28%) received 6 cycles of chemotherapy. Complete clinical response (CR) was seen in 19 pts (54.3%), partial response (PR) in 11 (31.4%) for an overall response rate of 30 pts (85.7%). There were 3 (8.6%) nonresponders (NR) and 2 pts died (5.7%). Pts with CR were compared to NR and pts with PR. There was no statistically significant difference in response according to age, gender, ethnicity or stage at diagnosis. A borderline significant decrease in CR rate with increasing number of comorbidities (p=0.055) was observed. Previous exposure to fludarabine and number of prior therapies did not impact response significantly. Median duration of follow up was 44 months. Median time to tumor progression (TTP) was 16 months. TTP was analyzed with regards to age, gender, ethnicity, stage, number of comorbidities and no significant differences were found. Also no differences in CR rate or TTP according to flowcytometry (CD38, Zap-70) or genetic tests were found.
Neutropenia G3 and G4 was noted in 16 pts (45.71%) with neutropenic fever in 7 pts (20%), and infections in 6 pts (17.14%). Severe anemia and thrombocytopenia was seen in 13 pts (37.14%) and 6 pts (17.1%) respectively. Infusion reactions were observed in 8 pts (22.8%), mainly rigors/chills G1. Therapy was discontinued in 11 pts (31.4%) because of severe infection in 3, intractable cytopenias in 6, death and compliance with 1 patient each. Nineteen (54.2%) pts had delays in chemotherapy mainly due to cytopenias 10 pts, infection 3 pts, neutropenic fevers 2 pts, and Coombs positive hemolytic anemia 1 pt. Prophylactic antibiotic prophylaxis was given in 24 pts (68.75%) and all patients who developed neutropenia received support with growth factors.
Conclusions: Our complete clinical response rate to fludarabine combination therapy (FCR) was similar to that previously reported. No statistically significant differences in CR and TTP were found according to age, gender, ethnicity, stage, previous exposure to fludarabine, flowcytometric and genetic parameters were found. A borderline significant decrease in CR rate with increasing number of comorbidities (p=0.055) was observed. In our study there was a high incidence of neutropenia, neutropenic fever and infections that lead to treatment delays in 42.85% and discontinuity in 25.71% of pts despite prophylactic use of antibiotics. Our number of patients does not allow for more definitive conclusions and more studies are needed to address the efficacy and tolerability of fludarabine based regimens in CLL.