PF374 IBRUTINIB PLUS FLUDARABINE, CYCLOPHOSPHAMIDE, AND RITUXIMAB (IFCR) AS INITIAL THERAPY FOR YOUNGER PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: A SINGLE‐ARM, MULTICENTER, PHASE 2 TRIAL
Authors: Davids M.S. , Brander D.M. , Kim H.T. , Tyekucheva S. , Bsat J. , Savell A. , Hellman J.M. , Bazemore J. , Francoeur K. , Alencar A. , Shune L. , Omaira M. , Jacobson C.A. , Armand P. , Ng S. , Crombie J. , LaCasce A.S. , Arnason J. , Hochberg E.P. , Takvorian R.W. , Abramson J.S. , Fisher D.C. , Brown J.R. 
Published: June 2019

Background:Fludarabine, cyclophosphamide, rituximab (FCR) can provide prolonged disease free survival for young, fit chronic lymphocytic leukemia (CLL) patients with mutated IGHV; however, patients with unmutated IGHV rarely have durable response. The oral Bruton Tyrosine Kinase inhibitor, ibrutinib, is highly effective for patients irrespective of IGHV mutation status, but requires continuous therapy. We hypothesized that a time‐limited regimen of ibrutinib plus FCR (iFCR) would have curative potential for a broad population of young, fit CLL patients.Aims:The primary objective was to determine the rate of complete remission (CR) with undetectable bone marrow minimal residual disease (BM‐uMRD) two months after completing iFCR combination therapy. Secondary objectives were to assess clinical response rates, progression‐free and overall survival, rates of best response and BM‐uMRD, safety/tolerability, ibrutinib pharmacokinetics (PK), and association of established CLL prognostic factors with clinical response.Methods:We performed a multicenter, open‐label, non‐randomized, phase 2 investigator sponsored trial of iFCR, and enrolled CLL patients age ≤65 years without restriction by IGHV mutation status, all of whom met iwCLL criteria for initial treatment. Ibrutinib 420 mg daily was given for 7 days, followed by combination ibrutinib with FCR for up to 6 cycles. Responders continued on ibrutinib maintenance, and patients with BM‐uMRD after 2 years of maintenance discontinued therapy. Response was assessed by 2008 iwCLL criteria, and toxicity was assessed by CTCAE v4.03 and iwCLL criteria. This trial is registered with ClinicalTrials.gov (NCT02251548).Results:Between October, 2014, and April, 2018, 85 patients were enrolled at 9 US sites. The median age was 55 years (range 38–65). IGHV was unmutated in 46/79 patients (58.2%). Deletion of 17p and TP53 mutation were present in 4/83 (4.8%) and 3/81 (3.7%) patients, respectively; 2 of these patients had both. The median number of FCR cycles completed was 6 (range 1–6). The median AUC of ibrutinib in combination with FCR was 337.2 (IQR 198.6–553.9), and the median Cmax was 97.3 (IQR 65.1–168.8). These PK parameters are similar to ibrutinib monotherapy in prior studies, and did not appear to be altered by FCR. The rate of CR‐BM‐uMRD 2 months post‐FCR was 33% (28/85 patients, 95% CI: 0.25–1.0)), with a best rate at any point on trial that increased to 41% (35/85), and a best rate of CR/CRi irrespective of MRD status of 66%. The best rate of BM‐uMRD irrespective of IW‐CLL response status was 84% (71/85), and did not differ by IGHV mutation status (Figure 1). With a median follow‐up of 16.5 months (range 3.1–48.9), one patient progressed and one died due to a presumed cardiac event. The most common treatment‐emergent grade 3/4 adverse events were hematologic, including neutropenia 35%, thrombocytopenia 32%, and anemia 11%. Eight patients (9%) experienced grade ≥3 febrile neutropenia. No cases of Richter's Syndrome have been observed.Summary/Conclusion:The rate of BM‐uMRD induced by iFCR is, to our knowledge, the highest ever reported for a regimen treating a population of CLL patients unrestricted by prognostic marker status. The safety profile of iFCR was generally favorable, with typical toxicities of ibrutinib and FCR observed, and no additional toxicities discernable with the combination. These data establish iFCR as a highly effective novel‐agent‐containing time‐limited combination for initial therapy for young, fit CLL patients.image