iFCG Regimen Induces High Rate of Bone Marrow MRD Negativity in IGHV-Mutated CLL

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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.

&ldquo;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,&rdquo; 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. &ldquo;All 9 patients who reached the 1-year time point achieved marrow negativity and have discontinued ibrutinib per the study design.&rdquo;

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&ndash; 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&rsquo; 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. &ldquo;This 83% bone marrow negativity compares to the 26% we would have expected on the standard treatment of FCR,&rdquo; 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&ndash;.

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.

Reference:

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).

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