For a study, researchers sought to determine if ibrutinib combined with fludarabine, cyclophosphamide, and rituximab (iFCR) is safe and effective for use as an initial therapy for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL).

In the cohort, between January 2019 and March 2021, iFCR was administered to 34 CLL patients between the ages of 18 and 65. Ibrutinib was administered orally (420 mg/day) continuously starting on day 0, followed by intravenous administration of rituximab (375 mg/m2 on cycle 1’s day 0 and 500 mg/m2 on cycle 2-6’s day 0), fludarabine (25 mg/m2, days 1-3), and cyclophosphamide (250 mg/m, days 1-3), per 28-day cycles. In the initial step, 3 cycles of iFCR were administered to each patient. A mid-term effectiveness assessment was performed using the 2018 iwCLL criteria, and flow cytometry was used to identify the minimum residual disease (MRD). Low MRD (LMRD) was defined as 1 to <100 CLL cells per 10,000 leukocytes, whereas high MRD (HMRD) was defined as ≥100 CLL cells per 10,000 leukocytes. Patients who obtained a complete response (CR) or a bone marrow (BM) undetectable MRD (uMRD) level (<10-4) were then given 3 cycles of ibrutinib plus rituximab (IR) or the 4th cycle of induction-free complete response (iFCR), followed by 2 cycles of IR, before switching to ibrutinib maintenance. Depending on their desire to accept therapy and tolerance for toxicity, additional patients might have chosen to receive a total of 6 cycles of iFCR or to follow the same protocol as the patients above.

The median follow-up at the data cut-off (May 1st, 2022) was 31 months (range 12-38 months). The best overall response rate (ORR) was generally 100%, with 21 of 34 patients (61.8%, 95% CI 0.454-0.781) achieving CR/ CRi and BM uMRD at their best response and 25 of 34 patients (73.5%, 95% CI 0.587-0.884) achieving CR/ CRi or BM uMRD. CR/CRi and BM uMRD were attained in 8 of 13 patients (61.5%, 95% CI 0.351-0.880) with mutant IGHV and 13 of 21 patients (61.9%, 95% CI 0.411-0.827) with unmutated IGHV. Those with unmutated IGHV had a significantly lower percentage of CR/CRi (66.7% vs. 84.6%), PB uMRD (71.4% vs. 84.6%), and BM uMRD (66.7% vs. 84.6%) than patients with mutant IGHV. Additional research revealed that 5 of the 6 patients who had TP53 mutations and/or deletions did not attain CR or BM uMRD. They all had an unmutated IGHV status. When responses between those with IGHV mutations and those without mutations without TP53 aberration were evaluated, it was discovered that there was no difference in the percentage of patients who achieved CR/CRi, PB MRD, or BM MRD. Directly leading to IR for the subsequent 3 cycles might preserve or deepen the effectiveness in patients who received 3–4 cycles or 6 cycles of iFCR at each assessment time point and for the majority of CLL patients who achieved early phase CR and/or BM uMRD. However, even 6 cycles of iFCR were unable to produce deeper remission for the patients who had achieved PR and BM HMRD (4/8 patients with TP53 mutation) at the post-3 cycles response evaluation. During follow-up, there was just one progression event (the Richter transformation), and the 2-year PFS and 2-year OS rates were 96.9% and 100%, respectively. According to the safety analysis, the majority of the toxic effects experienced during the iFCR phase were hematological, with neutropenia (any grade, 19/34 [55.9%]; grade 3 or 4, 16/34 [47.1%]), thrombocytopenia (any grade, 18/34 [52.9%]; grade 3 or 4, 10/34 [29.4%]), anemia (any grade, 16/34 [47.1%]; grade 3 or 4, 4/34 [11.8%]) and febrile neutropenia (grade 3 or 4, 6/34 [17.6%]). Ibrutinib-related toxicities were found to include 2 cardiovascular adverse events (1 grade 3 atrial fibrillation, 1 grade 2 hypertension, and 2 grade 2 hematuria) during maintenance. Notably, patients who had 3–4 cycles of iFCR experienced significantly lower rates of hematological adverse events (AEs), such as anemia, febrile neutropenia, and thrombocytopenia, in cycles 5, 6, and during ibrutinib maintenance compared to those who got 6 cycles of iFCR.

For CLL/SLL patients with fair physical conditions, iFCR as an initial therapy had a good response rate and a high percentage of undetectable MRD. The tolerability was controlled generally. Patients lacking TP53 aberration and either mutant or unmutated IGHV status had roughly similar response rates. In this cohort, 3–4 rounds of iFCR could be sufficient to establish long-lasting remission and lessen the toxicity of chemotherapy.