The combination regimen of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab achieved a high rate of minimal residual disease-negative status in bone marrow as a first-line treatment in patients with <em>IGHV</em>-mutated chronic lymphocytic leukemia
Nitin Jain, MD
The combination regimen of ibrutinib (Imbruvica), fludarabine, cyclophosphamide, and obinutuzumab (GA101; iFCG) achieved a high rate of minimal residual disease-negative (MRD) status in bone marrow as a first-line treatment in patients withIGHV-mutated chronic lymphocytic leukemia (CLL), according to initial results of a phase II trial presented at the 2017 ASCO Annual Meeting.
“By adding ibrutinib and obinutuzumab to the standard fludarabine, cyclophosphamide, and obinutuzumab [FCR] regimen, we cut down the number of chemotherapy cycles from 6 to 3 and are seeing much higher marrow negativity rates than expected with standard treatment,” lead author Nitin Jain, MD, assistant professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, toldTargeted Oncologyin an interview. “All 9 patients who reached the 1-year time point achieved marrow negativity and have discontinued ibrutinib per the study design.”
The investigators hypothesized that improving MRD rates would also improve progression-free survival (PFS) and overall survival (OS). They also hypothesized that reducing chemotherapy exposure may lower the risk of patients developing therapy-related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (AML).
For trial eligibility, patients were required to have previously untreated CLL or small lymphocytic leukemia (SLL) meeting International Workshop on Chronic Lymphocytic Leukemia guidelines. Patients hadIGHV-mutated disease but no del(17p) orTP53mutation. They were also assessed for adequate organ function before enrollment.
The iFCG treatment schema for Course 1 was as follows: patients received obinutuzumab 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15. They received fludarabine 25 mg/m2on days 2, 3, and 4. Cyclophosamide (250 mg/m2) was also given on days 2, 3, and 4. Patients received 420 mg of ibrutinib once daily continuously.
In courses 2 and 3, patients received 1000 mg of obinutuzumab on day 1. Fludarabine (25 mg/m2) and cyclophosphamide (250 mg/m2) were both given on days 1, 2, and 3. Patients received 420 mg of ibrutinib once daily continuously. Throughout, granulocyte-colony stimulating factor (G-CSF) was permitted but not required.
According to the study design, patients were evaluated for response via blood, bone marrow, and CT after completing 3 cycles of iFCG. Patients who had a complete response (CR) or CR with incomplete blood count recovery (CRi) and achieved MRD status then received 3 cycles of ibrutinib plus obinutuzumab (iG). Patients who had a partial response (PR) or were MRD-positive (MRD+) also received iG for 3 cycles. PR was defined as the presence of lymph nodes >1.5 cm on CT.
CR, CRi, and MRD patients then received ibrutinib alone for 6 cycles. PR and MRD+ patients received iG for 6 additional cycles. After 12 cycles, ibrutinib was discontinued in MRD– patients. Patients who were MRD+ continued receiving ibrutinib until progression.
The primary endpoint was CR/CRi and MRD status after 3 cycles of iFCG. The null hypothesis was 26% and the target response was 45%.
The enrollment target was 45 patients; 29 patients have initiated treatment to date. Of these, 24 patients have completed 3 cycles of iFCG and 4 have begun their cycles. One patient received 1 dose of obinutuzumab (100 mg) and 1 dose of ibrutinib before going off the study due to adverse events (AEs).
The patients’ median age was 60 years (range, 25-71). Twenty-four (83%) were male. Fluorescence in situ hybridization (FISH) testing revealed del(13q) in 20 patients (69%), while 6 patients (21%) had trisomy 12. FISH testing was negative in 3 patients (10%). Cytogenetic testing on 24 patients revealed that 14 patients (58%) had diploid, 6 (25%) had del13 and 4 (17%) had trisomy 12. A variety of mutations were present in 28 tested patients, includingSF3B1, NOTCH1, BIRC3, andATM. The most common wasMYD88, in 3 patients (11%).
Among patients who completed 3 cycles of iFCG, 24 patients achieved a response, amounting to an ORR of 100%, and 20 patients (83%) achieved MRD status. “This 83% bone marrow negativity compares to the 26% we would have expected on the standard treatment of FCR,” Jain noted.
After 3 cycles, 10 patients (42%) had a CR/CRi, including MRD status. Fourteen patients (24%) had a partial response; of these, 10 patients (71%) were MRD–.
Toxicities were not insignificant. Neutropenia was the most common AE, with 9 patients (31%) with grade 3 and 12 patients (41%) with grade 4. Thrombocytopenia was also common, with 12 patients (41%) with grade 3 and 1 patient (3%) with grade 4.
Among patients with infections, 4 had neutropenic fever, and 1 each had pneumocystis pneumonia, mycobacterium avium complex pulmonary infection, acute cholecystitis, and herpes zoster.
AEs led to 57% of patients requiring a dose reduction of FC and 18% of patients requiring a dose reduction of ibrutinib. Just over one-third of patients (35%) required a treatment delay of 2 or more weeks due to AEs.
Jain N, Thompson PA, Burger JA, et al. Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA101) (iFCG) for previously untreated patients with chronic lymphocytic leukemia (CLL) with mutated IGHV and non-del (17p).J Clin Oncol35, 2017 (suppl; abstr 7522).