Initial Results of a Multicenter, Phase II Study of Ibrutinib Plus FCR (iFCR) As Frontline Therapy for Younger CLL Patients

Introduction

The oral BTK inhibitor ibrutinib was recently approved for frontline CLL therapy based on RESONATE-2, which included only patients (pts) age ≥65 (Burger et al., 2016). In the absence of comparative data, FCR remains a standard initial therapy for younger CLL pts, particularly in light of recent data suggesting that mutated IGHV predicts long disease free survival after FCR (Thompson et al., 2016, Fischer et al., 2016). However, pts with higher risk CLL such as del(17p) and unmutated IGHVhave less durable responses. Moreover, only about 20% of CLL pts will achieve complete response (CR) with bone marrow minimal residual disease negativity (BM MRD-neg) with frontline FCR (Boettcher et al., 2012). Given the favorable toxicity profile and substantial efficacy of ibrutinib across CLL risk types, we developed an investigator-initiated, multicenter phase II study of ibrutinib plus FCR (iFCR) as frontline treatment for young, fit CLL pts (NCT02251548).

Methods

The primary objective is to determine the rate of CR with BM MRD-neg in younger CLL pts treated upfront with iFCR. Secondary endpoints include response rate, PFS, and safety/tolerability. Ibrutinib 420 mg daily monotherapy is started 7 days prior to FCR, which is given at standard doses together with ibrutinib for up to 6 cycles. Responders continue on ibrutinib maintenance until progression or unacceptable toxicity. Growth factor support and antimicrobial prophylaxis are mandatory. Eligibility criteria include: age ≤ 65, requiring initial treatment by IW-CLL criteria, ECOG PS ≤1, and adequate organ function. CTCAE v4 and IW-CLL criteria are used to evaluate toxicity and efficacy, with response evaluations after 3 cycles, 2 mos. after final FCR (primary endpoint evaluation), and q6 mos. thereafter. MRD is assessed by 4-color flow cytometry (10^-4sensitivity).

Results

As of August 1, 2016, the study reached full accrual at 35 pts. The median age at enrollment was 55 yrs (range 38-65). 9/33 tested (27%) had del(11q) and 4/33 tested (12%) had del(17p). 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%).

We initially enrolled 10 pts in a safety lead-in cohort and did not see any unexpected toxicities. In the entire cohort of 35 pts, hematologic toxicity included grade (gr) 4 neutropenia in 1 pt (3%), as well as gr 3 neutropenia (15%), thrombocytopenia (18%), and anemia (6%). All grade non-hematologic toxicities occurring in >15% of pts 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 pts. SAEs included gr 4 febrile neutropenia, gr 3 atrial fibrillation, gr 3 transaminitis, gr 3 pneumonia, and gr 3 appendicitis in 1 pt each. 9% of pts experienced ≥gr 3 infection. A median of 6 cycles of FCR were given (range 3-6). One pt had ibrutinib dose reduction (pt with febrile neutropenia), and 18% of pts had at least 1 dose reduction of chemotherapy.

Twenty-eight pts have undergone primary endpoint re-staging after completing the iFCR combination and 26 pts have been tested for BM MRD. In these 26 pts, the rate of CR with BM MRD-neg is 39% (10/26). In the 28 pts with re-staging, the ORR is 100%, including 39% (11/28) with CR or CRi. 17/28 (61%) pts had a PR, and all 17 PR pts have residual lymph nodes ≤ 2.5 cm in long axis by CT imaging. BM was MRD-neg in 23/26 tested (89%), including 13/17 (76%) of pts in PR. With a median follow-up of 12.1 months (range 0.1-21.1), all pts are alive, and 33 of the 35 pts remain on treatment. One pt who completed 6 cycles of iFCR and achieved CR with BM MRD-neg declined ibrutinib maintenance and remains in MRD-neg CR at 10 months off therapy, and one pt with del(17p) achieved MRD-pos PR and elected to pursue allogeneic stem cell transplant.

Conclusions

iFCR induces deep responses in previously untreated young CLL pts, with 39% of evaluable pts achieving CR with BM-MRD-neg and 89% achieving BM MRD-neg, significantly higher than the 20% rate seen historically with FCR alone. Low rates of hematologic and infectious toxicities were observed, possibly due to mandatory use of growth factor support and antimicrobial prophylaxis. 76% of PR pts have achieved BM MRD-neg, and all of these pts have small residual lymph nodes. Pts continue on ibrutinib maintenance and will be monitored for conversion to CR with BM MRD-neg. over time.