Treatment With iFRC and Ibrutinib Maintenance Led to Durable PFS in Patients With CLL

In patients with previously untreated chronic lymphocytic leukemia (CLL), treatment with ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) followed by 2 years of ibrutinib maintenance (I-M) resulted in sustained rates of undetectable minimal residual disease (uMRD) in the peripheral blood (PB) and strong progression-free survival (PFS), according to the results of a study published in Blood Advances.

Durable disease control has remained a particularly difficult obstacle for patients with CLL, and a previous study has indicated that standard-of-care treatment with venetoclax plus obinutuzumab (VO) provided high rates of uMRD.

Chronic lymphocytic leukemia | Image Credit: © jarun011 - stock.adobe.com

However, the study also showed that patients with unmutated immunoglobulin heavy-chain variable gene (U-IGHV) lost uMRD twice as fast as those with mutated IGHV (M-IGHV), along with significantly shorter PFS, the investigators wrote. This realization compelled the investigators to search for treatment alternatives that can overcome the poor prognostic impact of U-IGHV in patients with CLL.

FCR has remained a relevant treatment approach, in addition to ibrutinib, which could provide a blueprint for providing long-lasting, treatment-free remission. The investigators sought to determine the curative potential of this combination and whether it could provide sustained remission for patients with CLL, regardless of their IGHV status.

The primary end points of the study were the patients with bone marrow uMRD <10^–4 (BM–uMRD4) who had a complete response to the treatment, in addition to the rate of sustained BM-uMRD after 2 years of I-M in patients who achieved BM-uMRD4 after iFCR, the investigators wrote. Clinical responses to treatment and PFS were among the secondary outcomes.

Eighty-five patients were included in the study and treated with iFRC. Ibrutinib administration was stopped for 1 patient, whereas the remaining 84 patients were given at least 3 cycles of iFRC; most of the patients (61 patients; 71.8%) completed the planned 6 iFRC cycles, the investigators determined.

The 5-year PFS was 94% (95% CI, 89%-100%), and 5-year overall survival (OS) was 99% (95% CI, 96%-100%). The investigators found no statistically significant difference in PFS based on the patient’s IGHV status or the duration of I-M beyond 2 years.

Restricting the data to 49 patients with clinical response and BM-MRD data after iFCR and 2-year I-M, treatment with I-M doubled the CR rate over time (34.7% [17/49] at 2 months after iFRC to 79.6% [39/49] after 2-year I-M). Forty-four of the 49 patients (89.8%) had BM-uMRD4 at 2 months after iFRC, with this remaining durable after 2 years.

Overall, iFRC followed by 2 years of I-M led to durable responses in young, fit patients with previously untreated CLL with favorable genetic risk profiles, the investigators found. Despite some dose reduction in 22% of the patients, the treatment was deliverable overall, with most patients receiving 6 full cycles of FCR and a low rate of ibrutinib discontinuation.

Although the investigators noted that fewer than 6 cycles of chemoimmunotherapy may be as effective as 6 cycles, their data argue against the association between cumulative doses of chemoimmunotherapy and treatment-related myeloid neoplasm (tMN). This indicates that the number of cycles added to ibrutinib treatment may not be important in determining the cause of tMN in patients.

The investigators concluded by noting that treatment with iFRC represents a promising strategy in this cohort of young patients with CLL, and that the treatment possibilities should be further explored in larger, comparative studies.

Reference

Ahn IE, Brander DM, Ren Y, et al. Five-year follow-up of a phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL. Blood Adv. 2024;8(4):832-841. doi:10.1182/bloodadvances.2023011574