The combination of fludarabine, cyclophosphamide, and rituximab (FCR) provides prolonged disease-free survival for many patients with chronic lymphocytic leukemia (CLL) and mutated IGHV; however, patients with unmutated IGHV typically have less durable responses.1 Furthermore, complete response (CR) with bone marrow minimal residual disease negativity (BM MRD-neg) is only achieved in about 20% of patients. At ASH 2017, the authors reported on an ongoing investigator-initiated, multicenter phase 2 study of ibrutinib plus FCR (iFCR) as frontline treatment for young, fit patients with CLL.2
The results reported at ASH 2017 included 49 patients with treatment-naïve CLL who were aged ≤65 years, met International Working Group on CLL criteria for initial therapy, had adequate organ function, and had an Eastern Cooperative Oncology Group performance status ≤1. The primary end point for the study was the rate of CR with BM MRD-neg 2 months after iFCR. Secondary end points included response rates, progression-free survival, and safety/tolerability. Ibrutinib 420-mg-daily monotherapy was given for 7 days, followed by combination with FCR for up to 6 cycles. Responders continued on ibrutinib maintenance for at least 2 years. The patients included del(11q) in 12/47 tested (26%), del(17p) in 4/47 tested (9%), unmutated IGHV in 26/46 tested (57%), ZAP-70 positivity in 27/46 tested (59%), TP53 mutation without del(17p) in 3 patients (6%), and NOTCH1 mutation in 2/33 tested (6%).
In the 35 patients evaluable for toxicity, grade 3/4 hematologic toxicity included neutropenia in 29% (23% grade 3, 6% grade 4), thrombocytopenia in 26% (all grade 3), and anemia in 6% (all grade 3). All-grade nonhematologic toxicities occurring in >15% of patients included nausea, bruising, rash, fatigue, and diarrhea. Bleeding events included grade 1 epistaxis (n = 2), and grade 1 rectal bleeding and grade 2 menorrhagia (n = 1 each). Serious adverse events (all grade 3) included pneumonia (n = 2), febrile neutropenia, atrial fibrillation, transaminitis, pneumatosis intestinalis, anaplasmosis infection, and appendicitis (n = 1 each).
In the 35 patients evaluable for efficacy, the overall response rate was 100%, including 22 (63%) with CR/CR with incomplete blood count recovery, and 13 (37%) with partial response with residual lymph nodes ≤2.5 cm in long axis by computed tomography imaging. The rate of CR with BM MRD-neg 2 months post iFCR (primary end point) was 37% (13 of 35). After ibrutinib maintenance, this rate increased to 57% (20 of 35). With a median follow-up of 21 months, the rate of best BM MRD-neg is 83%, which is higher than any prior regimen for first-line therapy across CLL risk types.
The authors concluded that iFCR induced deep responses in a relatively high-risk group of previously untreated young patients with CLL. The low rates of hematologic and infectious toxicities may have been due to mandatory growth factor and antimicrobial prophylaxis.
- Jain P, et al. Br J Haematol. 2017 Nov 21. doi: 10.1111/bjh.15018. Epub ahead of print.
- Davids MS, et al. ASH 2017. Abstract 496.