A Multicenter, Phase 2 Study of Ibrutinib plus FCR as Frontline Therapy for Younger Patients with CLL

Conference Correspondent - ASH 2017 - CLL

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.


  1. Jain P, et al. Br J Haematol. 2017 Nov 21. doi: 10.1111/bjh.15018. Epub ahead of print.
  2. Davids MS, et al. ASH 2017. Abstract 496.
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