Extended Follow-Up of a Chemo-Immunotherapy Regimen FCR (Fludarabine, F; Cyclophosphamide, C; and Rituximab, R) as Initial Therapy for Chronic Lymphocytic Leukemia (CLL).
Authors: Keating Michael J. , O’Brien Susan , Albitar Maher , Lerner Susan , Wierda William , Kantarjian Hagop 
Published: October 2019

Abstract
Combination regimens are increasingly being used in CLL. The addition of R to F±C has increased the complete response (CR) rate in previously untreated patients (pts) with CLL. FCR was given to 300 previously untreated pts with CLL; 70.3% male, 33% Rai stage III-IV, with median value and ranges for age − 57 years (17–86), hemoglobin − 12.5G% (6.1–18.7), white cell count − 76 x 103/μl (2.1–620), platelets − 154 x 103/μl (8–406). 51% had splenomegaly. All pts fulfilled the NCIWG indications for therapy. 72% achieved CR, 10% nodular partial remission (NPR), and 12% PR. The pretreatment characteristic most strongly associated with CR was the beta-2-microglobulin level (P<.001) with significant differences between those with a value less than twice normal versus higher values. Advanced age (≥ 70 yrs), advanced stage, low hemoglobin (<11G%), low albumin (<3.6G%), and elevated BUN (>23mg%) were all significantly associated with a lower CR rate (P<.01). CD38 was not associated with CR. Mutation status, ZAP70, and FISH cytogenetics were not routinely measured. Median follow-up was 43 months (18–73). Several characteristics were associated with remission duration (R Dur). Multivariate analysis showed that (1) PCR for IgVH, (2) NCIWG response, and (3) flow responses were all independently associated with R Dur. PCR negativity for IgVH was most strongly correlated with R Dur. Seven of 79 PCR negative pts have relapsed at 31, 39, 43, 44, 62, 64, and 67 months.
Response Patients 4-Yr. R Dur Θ 4-Year Surv. Flow CR† PCR Neg.$ *P<.01;𝛉Projected;†Marrow CD5+CD19<1%;$PCR IgVH CR 217 83%* 84%* 165/208 (79%) 69/160 (43%) NPR 31 64% 84% 10/27 (37%) 7/19 (37%) PR 37 38% 50% 10/26 (38%) 3/13 (23%) Overall 300 77% (CR+PR) 83% 185/261 (71%) NA
There was no significant difference in survival between CR and NPR pts despite a significantly shorter R Dur (P<.01) for NPR pts. Survival was similar for progressive Rai 0-II and III-IV pts with projected four-year survival of >80%. The median survival for the 300 patients and various prognostic subgroups has not been reached. Second cancers occurred in 53 cases (20 with non-melanomatous skin cancers). Three cases of AML and 3 additional cases of myelodysplastic syndrome occurred. Autoimmune hemolytic anemia (AIHA) or red cell aplasia (RCA) occurred in 25 and 6 cases respectively. These complications remain a significant clinical problem in CLL. There was no significant difference in the IgA or IgM levels over time but a lower mean initial IgG (837±567mg%) versus 690±338mg% six months after FCR was completed (P<.005) was noted. 56/72 (78%) who failed or relapsed have been started on salvage therapy. The salvage response rate on retreatment with FCR+alemtuzumab was 9/17 (53%). More pts failing after initial CR or NPR claimed a second response (17/29, 59%) compared with the PR or refractory pts (3/20, 16%; P=.002).
Multivariate analysis of characteristics associated with CR rate and survival for FCR and preceding non-R protocols demonstrated a significant advantage for FCR (P<.001).
Conclusion
When compared with other completed chemotherapy protocols without R, FCR significantly improved CR rate, time-to-progression and treatment failure, and overall survival establishing FCR as the most successful protocol which we have conducted to date.