Ibrutinib-containing Combination Induced High Rate of Bone Marrow MRD Negativity, 100% ORR in IGHV-Mutated CLL

Nitin Jain, MD

Patients with IGHV-mutated chronic lymphocytic leukemia (CLL) had high rates of minimal residual disease-negative (MRD—) status in bone marrow following first-line treatment with a combination of ibrutinib (Imbruvica), fludarabine, cyclophosphamide, and obinutuzumab (GA101; iFCG).

Lead author Nitin Jain, MD, assistant professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, 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,” he told Targeted Oncology in an interview. “All 9 patients who reached the 1-year time point achieved marrow negativity and have discontinued ibrutinib per the study design.”

Jain and his team 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).

Eligible patients had treatment-naïve CLL or small lymphocytic leukemia (SLL) meeting International Workshop on Chronic Lymphocytic Leukemia guidelines. Patients had IGHV-mutated disease but no del(17p) or TP53 mutation. They were also assessed for adequate organ function before enrollment.

For Course 1, patients received obinutuzumab 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15. Patients received fludarabine 25 mg/m² and cyclophosphamide 250 mg/m² on days 2, 3, and 4. Once-daily 420 mg ibrutinib was administered 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 continuous once-daily 420 mg ibrutinib. Granulocyte-colony stimulating factor (G-CSF) was permitted but not required.

Patients were evaluated for response via blood, bone marrow, and CT after completing 3 cycles of iFCG. Those 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.

MRD— patients who achieved CR or CRi 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%.

Twenty-nine patients have initiated treatment with a goal to eventually enroll a total of 45. 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).

Median age was 60 years (range, 25-71), and 24 patients (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, including SF3B1, NOTCH1, BIRC3, and ATM. The most common was MYD88, in 3 patients (11%).

ORR is 100% among patients who completed 3 cycles of iFCG. Twenty 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 said.

Ten patients (42%) had CR/CRi, including MRD— status, after 3 cycles of treatment. Fourteen patients (24%) had a partial response; of these, 10 patients (71%) were MRD–.

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 who developed infections, 4 had neutropenic fever, and 1 each had pneumocystis pneumonia, mycobacterium avium complex pulmonary infection, acute cholecystitis, and herpes zoster.

More than half of patients (57%) required a dose reduction of FC and 18% of patients required a dose reduction of ibrutinib because of AEs. 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 Oncol 35, 2017 (suppl; abstr 7522).