Ibrutinib Plus Fludarabine, Cyclophosphamide, and Rituximab Followed by Ibrutinib Maintenance Continues to Demonstrate Deep, Durable Responses for Patients With Previously Untreated CLL

5-Year Follow-up of a Phase 2 Study

Ibrutinib plus fludarabine, cyclophosphamide, and rituximab followed by 2 years of ibrutinib maintenance led to durably deep responses in patients with previously untreated chronic lymphocytic leukemia (CLL) regardless of immunoglobulin heavy-chain variable region gene status, according to 5-year follow-up data.

Investigators presented updated data from this phase 2 study with a median follow-up of 63 months. Of the 85 patients who were enrolled, including 5 (6%) patients with deletion 17p or TP53 mutation, 91% of participants completed the ibrutinib plus fludarabine, cyclophosphamide, and rituximab regimen and 2-year ibrutinib maintenance. The first primary end point was the rate of bone marrow-undetectable minimal residual disease (BM-uMRD4) with complete response (CR), including CR with or without count recovery after ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR). The secondary primary end point was the rate of sustained BM-uMRD after 2-years of ibrutinib maintenance among patients who achieved BM-uMRD4 after iFCR.

Patients received ibrutinib 420 mg orally daily during a 7-day lead-in period, followed by the addition of up to 6 cycles of fludarabine, cyclophosphamide, and rituximab administered with the continuous daily doses of ibrutinib. Fludarabine, cyclophosphamide, and rituximab was administered intravenously in 28-day cycles using fludarabine 25 mg/m² on days 1 to 3 of each cycle, cyclophosphamide 250 mg/m² on days 1 to 3 of each cycle, and rituximab 375 mg/m² on day 1 of cycle 1 then 500 mg/m² on day 1 of cycles 2 to 6. 

Additionally, patients in complete or partial response (PR) after at least 3 cycles of iFCR continued ibrutinib 420 mg orally daily for up to 2 years as maintenance therapy. For participants in the original cohort, the continuation of ibrutinib beyond 2 years of maintenance was allowed regardless of the BM-MRD status. Within the expansion cohort, the amended protocol required patients with BM-uMRD4 to terminate ibrutinib after 2 years. Retreatment with ibrutinib was allowed when patients developed detectable MRD or clinical progression, which was determined at the discretion of the patient and study investigators.

Results demonstrated 5-year progression-free survival (PFS) and overall survival data (OS) were 94% (95% confidence interval [CI], 89% to 100%) and 99% (95% CI, 96% to 100%), respectively. Furthermore, no difference in PFS was observed by immunoglobulin heavy-chain variable region gene status or duration of ibrutinib maintenance. High rates of peripheral blood (PB) uMRD4 were maintained (72% at the end of iFCR, 66% at the end of 2-year ibrutinib maintenance, and 44% at 4.5 years from treatment initiation). 

Investigators recorded that 13 patients developed MRD conversion without clinical progression, mostly (77%) after stopping ibrutinib. No patients had Bruton tyrosine kinase (BTK) mutations, while 1 patient had PLCG2 mutation. Additionally, 6 of these patients underwent ibrutinib retreatment per study protocol, where the median time on ibrutinib retreatment was 34 months. 

The safety profile took the following adverse events into consideration: The most common hematologic toxicity was thrombocytopenia (84.7%, 31.8%, grade ≥3 [G ≥ 3]), followed by neutropenia (67.1%; 40% G ≥ 3). Febrile neutropenia occurred in 11.8% (10 patients; all G ≥ 3). These high rates of cytopenias lead to fludarabine, cyclophosphamide, and rituximab dose reduction in 22% of the patients. The most common non-hematologic toxicity was nausea (74.1%; 1.2% G ≥ 3), followed by hyperglycemia (69.4%; 8.2% G ≥ 3) and fatigue (65.9%; 0% G ≥ 3). It was further noted that the cumulative incidence of atrial fibrillation was 8%. Second malignancy or non-malignant hematologic disease occurred in 13% of patients, which was mostly non-melanoma skin cancer.

Inhye Ahn, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachussetus, and colleagues concluded, “Overall, iFCR with 2-year I-M achieved durably deep responses in patients with diverse CLL genetic markers. Re-emergent clones lacked BTK mutation and retained sensitivity to ibrutinib upon retreatment.” 

“The treatment was largely deliverable, with the majority of patients receiving 6 cycles of [fludarabine, cyclophosphamide, and rituximab] and a low rate of ibrutinib discontinuation owing to toxicity during 2-year maintenance (8%),” they added, despite the reported higher levels of cytopenias. 

Source:

Ahn I, Brander D, 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