NEW YORK – Three courses of treatment with the novel combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) was well tolerated and associated with a high rate of minimal residual disease (MRD)–negative remission in the bone marrow of favorable-risk, treatment-naive patients with chronic lymphocytic leukemia, based on early results from an ongoing investigator-initiated phase II trial.
Of 29 patients, 24 had completed treatment and been followed for a median of 8.3 months. All 24 had an overall response rate (42% complete response/complete remission with incomplete blood count recovery and 58% partial response), and 83% of patients achieved MRD negativity (100% with complete response and 71% with partial response), Nitin Jain, MD, reported at the annual meeting of the International Workshop on Chronic Lymphocytic Leukemia.
Dr. Nitin Jain
All nine patients who reached the 12-month time point are off therapy and are being monitored, he said.
Patients with IGHV mutations generally have favorable long-term outcomes with 10-year progression-free survival rates greater than 60% after receiving standard first-line therapy with fludarabine, cyclophosphamide, and rituximab (FCR). However, ibrutinib is approved for patients with CLL, and obinutuzumab, a glycoengineered type II CD20 monoclonal antibody, was superior to rituximab in the CLL11 trial, Dr. Jain said.
Further, data from the HELIOS trial indicated that combining targeted therapies with chemoimmunotherapy is safe and effective.
iFCG was developed with the intent to limit fludarabine and cyclophosphamide to three courses, potentially reducing short- and long-term toxicity, while maintaining efficacy through the addition of ibrutinib and obinutuzumab, he explained.
Of note, higher pretreatment levels of beta-2 microglobulin were associated with a lower MRD-negativity rate after 3 cycles of iFCG, he said.
In six patients with beta-2 microglobulin of 4 mg/dL or greater, the rate was 50%, compared with 94% in 18 patients with beta-2 microglobulin less than 4 mg/dL.
The patients in the current analysis had a median age of 60 years and adequate organ function. All had IGHV mutation and did not have del(17p) or TP53 mutation. They received three courses of iFCG, including ibrutinib at 420 mg once daily continuously starting at day 1 of course 1 (C1D1); obinutuzumab at 100 mg C1D1, 900 mg C1D2, 1000 mg C1D8, 1000 mg C1D15, 1000 mg C2D1, and 1000 mg C3D1; fludarabine at 25 mg/m2 daily for 3 days each course; and cyclophosphamide at 250mg/m2 daily for 3 days each course.
Per study protocol, all patients receive ibrutinib with obinutuzumab for courses 4-6. Patients meeting the primary endpoint of complete response/complete remission with incomplete blood count recovery and bone marrow MRD negativity received ibrutinib monotherapy for courses 7-12. Those who did not achieve the primary endpoint received six more courses of ibrutinib and obinutuzumab. All patients who are MRD negative at 1 year stop all therapy, including ibrutinib, while those who are MRD positive at 1 year may continue ibrutinib monotherapy until disease progression.
The target bone marrow MRD-negative rate after 3 cycles of iFCG is 45%. The historic C3 bone marrow MRD-negative rate with standard FCR therapy in patients with IGHV mutation is 26%, Dr. Jain said, noting that the rate in the current analysis compared favorably with both.
The treatment thus far has been generally well tolerated. Toxicities included neutropenia (grade 3 and 4 occurring in 9 and 12 patients, respectively), thrombocytopenia (grade 3 and 4 occurring in 12 and 1 patients, respectively), ALT/AST (grade 3 and 4 occurring in 3 and 1 patients respectively), atrial fibrillation (grade 3 occurring in 1 patient), arthralgia (grade 3 occurring in 1 patient), and infusion-related reaction (grade 2 and 3 occurring in 9 patients and 1 patient, respectively).
Infections included herpes zoster, acute cholecystitis, pulmonary mycobacterium avium complex infection, and pneumocystis pneumonia, which occurred in 1 patient each, and neutropenic fever, which occurred in 4 patients.
“Notably, no patient has progressed or died in the study so far,” Dr. Jain said.
The trial continues to enroll patients, with plans for enrolling a total of 45.
Dr. Jain has received research support from and/or served on an advisory board for Pharmacyclics, Genentech, Abbvie, Prizer, Incyte, BMS, Infinity, ADC Therapeutics, Seattle Genetics, Celgene, Servier, Novartis Novimmune, and Adaptive Biotechnologies.