Ibrutinib Plus Fludarabine, Cyclophosphamide, and Rituximab As the Treatment for Chronic Lymphocytic Leukemia/ Small Lymphocytic Leukemia: A Single-Center Real World Study
Authors: Zhu Huayuan , Shen Hui , Yang Yilian , Ding Chong-Yang , Sha Yeqin , Mi Hongling , Qiu Jingyan , Chen Ruize , Wu Yujie , Qiao Chun , Wang Li , Fan Lei , Xu Wei , Li Jianyong 
Published: November 2020

Purpose: To evaluate the safety and efficacy of ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) as the treatment for chronic lymphocytic leukemia (CLL)/ small lymphocytic leukemia (SLL) patients, we conducted time-limited, minimal residual disease (MRD)-driven real world study in The First Affiliated Hospital of Nanjing Medical University
Methods: We enrolled patients aged 18 to 65 years old with CLL/SLL who required treatment. Oral Ibrutinib was given continuously (420 mg/day) from day 0, and patients were administered intravenously rituximab (375mg/m2 in day 0 of cycle 1; 500mg/m2 in day 0 of cycle 2-3), fludarabine (25mg/m2, days 1-3) and cyclophosphamide (250mg/m2, days 1-3), every 28-day cycles. All the patients received 3 cycles of iFCR in the first stage. Interim analysis was done according to the 2018 iwCLL criteria and MRD was detected by flow cytometry. Patients who achieved complete response (CR) or partial response (PR) with low MRD level (L-MRD, 10-4-10-2) or undetectable MRD (uMRD) level (&lt;10-4) in peripheral blood (PB) were given 3 times of rituximab or the 4th cycle of iFCR, and then turned to ibrutinib maintenance. Patients who achieved PR with high MRD level (&gt;10-2) in PB or bone marrow (BM), or with diameter of residual lymph node larger than 3cm were administered another 3 cycles of iFCR (6 in all) and followed by ibrutinib maintenance. The primary endpoint was the proportion of patients who achieved uMRD in the PB after 3 cycles of iFCR. The secondary endpoint was overall response rate (ORR), complete response rate (CR) and the number of adverse events (AE).
Results: Between May 2019 and June 2020, 29 CLL/SLL patients were enrolled in this cohort with 27 CLL and 2 SLL. 26 of patients were the previously untreated and 3 of patients were relapse or treated before. The median age of patients was 53 years old. Unmutated IGHV was detected in 14 (50.0%) of 29 patients, 4 patients had del(17p) and/or TP53 mutation (13.8%), 7 patients had del(11q) (24.1%), 7 had NOTCH1 mutation (24.1%) and 7 had MYD88 mutation (24.1%). 8 patients (30.8%) were classified as low-risk group according to CLL-IPI, with 9 in intermediate-risk group (34.6%), 5 in high-risk group (19.2%) and 4 in very-high risk group (15.4%). At data cutoff (1st July, 2020), the median follow-up and treatment time was seven months (1-13 months) with 23 patients had completed at least two cycles of iFCR. At interim analysis, the ORR was 100% with 8 patients achieved CR (34.8%), 3 achieved CRi (13.0%) and 12 achieved PR (52.2%). 57.1% (12/21) achieved uMRD in both PB and BM, among which 6 of them (28.6%) achieved CR/CRi and 6 achieved PR (28.6%). All four patients with TP53 abnormalities achieved PR and two of them (50.0%) achieved uMRD in both PB and BM. One of 6 patients with del(11q) achieved CR (16.7%) and five achieved PR (83.3%), with 2 achieved uMRD in both PB and BM (33.3%). Among 13 assessable patients with unmutated IGHV, four of them achieved CR (30.8%) and nine achieved PR (69.2%), with 5 achieved uMRD in both PB and BM (38.5%). 18 patients had turned to ibrutinib maintenance with 12 of them finished 4th cycle of iFCR or 3 additional cycles of rituximab and could be assessed further. 10 of the patients achieved CR/CRi (83.3%) and 2 achieved PR (16.7%), with 8 achieved uMRD in both PB and BM (66.7%). The most common hematological toxicity events were neutropenia and thrombocytopenia and the non-hematological toxicity events were nausea and vomiting. The occurrence rate of grade 3 to 4 neutropenia and agranulocytic fever were 51.9% (15/29) and 17.2% (5/29) respectively. The most common ibrutinib-related AE were purpura, rash and diarrhea. The occurrence rate of AE induced discontinued ibrutinib more than 7 days, discontinued ibrutinib fewer than 7 days and ibrutinib decrement were 20.7%(6/29), 17.2%(5/29) and 20.7%(6/29) respectively.
Conclusion: MRD-driven Ibrutinib plus FCR could achieve high response rate with uMRD in yonger fit patients with CLL/SLL, with manageable toxicity. Ibrutinib plus FCR could be one of the most promising choice as a time-limited regimen in the new drug era.

Disclosures
No relevant conflicts of interest to declare.