The oral Bruton’s tyrosine kinase inhibitor ibrutinib was recently approved for frontline chronic lymphocytic leukemia (CLL) therapy based on RESONATE-2, which included only patients aged ≥65 years.1 In the absence of comparative data, fludarabine/ cyclophosphamide/ rituximab (FCR) remains a standard initial therapy for younger CLL patients, particularly in light of recent data suggesting that mutated IGHV predicts long disease-free survival after FCR.2,3 However, patients with higher-risk CLL, such as del17p and unmutated IGHV, have less durable responses. Moreover, only approximately 20% of CLL patients will achieve complete response (CR) with bone marrow minimal residual disease negativity (BM MRD-neg) with frontline FCR.4 Given the favorable toxicity profile and substantial efficacy of ibrutinib across CLL risk types, Davids and colleagues reported on an investigator-initiated, multicenter phase 2 study of ibrutinib plus FCR (iFCR) as frontline treatment for young, fit CLL patients.
The primary objective of the study was to determine the rate of CR with BM MRD-neg in younger CLL patients treated first-line with iFCR. Secondary end points included response rate, progression-free survival, and safety/tolerability. Ibrutinib 420 mg daily monotherapy was started 7 days prior to FCR, which is given at standard doses together with ibrutinib for up to 6 cycles. Responders continued on ibrutinib maintenance until progression or unacceptable toxicity. A total of 35 patients were enrolled; 9/33 that were tested (27%) had del11q and 4/33 tested (12%) had del17p. Unmutated IGHV was present in 20/31 tested (65%), ZAP-70 was positive in 21/32 tested (66%), TP53 mutation was present in 2/31 tested (6%), and NOTCH1 mutation was present in 2/21 tested (10%).
In the cohort of 35 patients, hematologic toxicity included grade (gr) 4 neutropenia in 1 (3%), as well as gr 3 neutropenia (15%), thrombocytopenia (18%), and anemia (6%). All grade nonhematologic toxicities occurring in >15% of patients included nausea (68%), bruising (35%), fatigue (29%), and rash (21%) (all gr 1/2) and diarrhea (21%) (all gr 1). The only bleeding events were gr 1 epistaxis in 2 patients. Serious adverse events included gr 4 febrile neutropenia, gr 3 atrial fibrillation, gr 3 transaminitis, gr 3 pneumonia, and gr 3 appendicitis in 1 patient each. A total of 9% of patients experienced ≥gr 3 infection. A total of 30 patients were evaluable for the primary clinical end point and tested for BM MRD-neg after completing the iFCR combination. In these patients, the rate of CR with BM MRD-neg is 43% (13/30). The overall response rate is 100%, including 47% (14/30) with CR or CRi. A total of 16/30 (53%) patients had a partial response (PR), with residual lymph nodes ≤2.5 cm by CT imaging. The best BM MRD-neg rate was 84%, including 12/18 (67%) patients in PR. All 4 patients with del17p and TP53 mutation achieved PR, but were MRD-positive. With a median follow-up of 12.1 months, all patients are alive, and 33 of the 35 remain on treatment.
The authors conclude that iFCR induces deep responses in previously untreated young CLL patients, with 43% of evaluable patients achieving CR with BM MRD-neg and 84% achieving BM MRD-neg, significantly higher than the 20% rate seen historically with FCR alone. Low rates of hematologic and infectious toxicities were observed, comparable to that seen with ibrutinib and FCR individually.
Davids MS, et al. ASH 2016. Abstract 3243.
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