Ibrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (iFCG) for First-Line Treatment of IGHV-Mutated CLL and without Del(17p)/Mutated TP53
Authors: Jain Nitin , Thompson Philip A. , Burger Jan A. , Ferrajoli Alessandra , Takahashi Koichi , Estrov Zeev E. , Borthakur Gautam M. , Bose Prithviraj , Kadia Tapan M. , Pemmaraju Naveen , Sasaki Koji , Garg Naveen , Wang Xuemei , Kanagal-Shamanna Rashmi , Patel Keyur , Jorgensen Jeffrey L. , Wang Sa A , Lopez Wanda , Ayala Ana , Plunkett William , Gandhi Varsha , Kantarjian Hagop M. , O'Brien Susan , Keating Michael J , Wierda William G. 
Published: February 2020

BACKGROUND
Combined fludarabine, cyclophosphamide, and rituximab (FCR) was the preferred regimen for young fit patients (pts) with CLL. The CLL10 trial established FCR as the preferred first-line chemoimmunotherapy (CIT). Recently, the E1912 trial compared first-line FCR vs. ibrutinib + rituximab for young fit pts with CLL. The ibrutinib arm showed an improved PFS and OS vs. the FCR arm; however, there was no difference in PFS for mutated IGHV (M-IGHV) group. With the FCR studies, it is already known that the long-term benefit is seen in pts with M-IGHV. In the MD Anderson Cancer Center (MDACC) FCR trial, long-term follow up demonstrated that the PFS at 10 yrs was approximately 55% for M-IGHV pts with a plateau after 8 yrs, suggesting that these pts may be cured of their CLL. Hence, CIT remains an appropriate first-line option for pts with M-IGHV with fixed duration treatment and expectation for long treatment-free interval.
We hypothesized that 1) achieving higher U-MRD would improve PFS and OS and 2) reducing the amount of chemotherapy might lower the risk of t-MDS/AML. We thus developed a CIT regimen called iFCG which consists of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA101) for young fit CLL patients with mutated IGHV and without del(17p)/mutated TP53. To decrease chemotherapy exposure, we administered only 3 cycles of chemotherapy in the iFCG regimen.
METHODS
We designed a phase II study for previously untreated pts with CLL with M-IGHV and absence of del(17p)/mutated TP53 (NCT02629809). All pts had a 2008 IWCLL indication for treatment. Pts received ibrutinib, fludarabine, cyclophosphamide, obinutuzumab for the first 3 cycles. Pts who achieved CR/CRi with bone marrow (BM) undetectable minimal residual disease (U-MRD) after the first 3 cycles received 9 additional cycles of ibrutinib with 3 additional cycles of obinutuzumab; all other pts received 9 additional cycles of ibrutinib and obinutuzumab. Pts with U-MRD (CR/CRi or PR) at 12 cycles stop all therapy, including ibrutinib. Responses were assessed by 2008 IWCLL criteria with BM and CT scans every 3 cycles during the first yr. BM MRD was assessed by flow cytometry (sensitivity 10-4). Post-cycle 12, pts have MRD assessed in blood every 6 months. In pts with available BM samples, MRD was also assessed by an NGS assay (sensitivity up to 10-6).
RESULTS
45 pts were treated. Pretreatment characteristics are in Table 1. The median follow-up is 30.2 months. After 3 cycles of iFCG, 39% achieved CR/CRi and 89% achieved BM U-MRD. Responses improved with continued therapy with ibrutinib and obinutuzumab (Figure 1); 73% achieved CR/CRi and 100% achieved BM U-MRD after cycle 12. 41/45 pts completed all planned 12 cycles (4 pts came off study, details below).
Per trial design, all 41 pts completing 12 cycles of treatment discontinued ibrutinib since all achieved U-MRD. PFS and OS are shown in Figure 2. No pt had MRD recurrence, CLL progression or Richter transformation, with a median follow-up of 18.7 months (range, 0.2-28.8) post discontinuing ibrutinib.
In pts with available BM samples, we also assessed MRD by NGS assay. After 3 cycles of iFCG, 68% (n=28) achieved U-MRD at 10-5 sensitivity and 50% (n=22) achieved U-MRD at 10-6 sensitivity. After cycle 6, the corresponding numbers were 83% (n=30) and 58% (n=24), respectively. After cycle 12, the corresponding numbers were 91% (n=22) and 63% (n=16), respectively.
Reasons for study discontinuation included 1) death due to CHF (see below), 2) pulmonary MAC infection, 3) infusion reaction to obinutuzumab, and 4) pt decision. One pt died; 26-yr-old man who developed CHF in cycle 9 (receiving ibrutinib and obinutuzumab). He had no known cardiac comorbidities; he started a weight loss supplement (sympathomimetic agent) few days prior to symptom onset. The pt died from worsening heart failure. One pt developed t-MDS.
Grade 3-4 neutropenia and thrombocytopenia occurred in 58% and 40% pts, respectively. Neutropenic fever occurred in 6 pts (culture negative 4 pts, PJP pneumonia 1 pt, staphylococcus skin infection 1 pt). Additional infectious complications without neutropenia leading to hospitalization included pneumonia (culture negative) (n=2), cellulitis (n=1), pulmonary MAC infection (n=1), fever (n=1), acute cholecystitis (n=1), and colitis (n=1).
CONCLUSIONS
The iFCG regimen with only 3 cycles of chemotherapy is an effective time-limited regimen for young pts with M-IGHV and without del(17p)/ mutated TP53.

Disclosures
Jain: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Thompson:Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Pfizer: Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Research Funding. Burger:Pharmacyclics, an AbbVie company: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria; BeiGene: Research Funding; Gilead Sciences: Research Funding; Aptose Biosciences, Inc: Research Funding; AstraZeneca: Honoraria. Takahashi:Symbio Pharmaceuticals: Consultancy. Borthakur:AstraZeneca: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Strategia Therapeutics: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Cyclacel: Research Funding; Tetralogic Pharmaceuticals: Research Funding; NKarta: Consultancy; Cantargia AB: Research Funding; Arvinas: Research Funding; PTC Therapeutics: Consultancy; Oncoceutics, Inc.: Research Funding; BMS: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly and Co.: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Polaris: Research Funding. Bose:Pfizer: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding; Constellation: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; NS Pharma: Research Funding; Astellas: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pemmaraju:mustangbio: Consultancy, Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Garg:Garglet LLC: Other: Owner; Enlitic inc.: Other: Advisor. Plunkett:Cyclacel Ltd: Research Funding. Kantarjian:Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Immunogen: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria. Wierda:Xencor: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; KITE pharma: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding.

OffLabel Disclosure:
Combination of ibrutinib with chemotherapy is not FDA approved