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Ibrutinib or FCR for First-Line CLL: Why Not Both?

Impressively high response rates were demonstrated with frontline ibrutinib (Imbruvica) plus chemoimmunotherapy followed by maintenance ibrutinib in young fit patients with chronic lymphocytic leukemia (CLL), a single-arm phase II trial indicated.

Two months after completing the combined portion of the treatment approach, ibrutinib plus FCR — fludarabine, cyclophosphamide, and rituximab (Rituxan) — 33% of patients achieved a complete response (CR) or CR with incomplete count recovery and undetectable minimal residual disease (MRD), which compared favorably to the historical rate of 20% with FCR alone (P=0.0035), reported Matthew Davids, MD, of Dana-Farber Cancer Institute in Boston, and colleagues.

And patients continued to achieve this level of response during the maintenance phase of the study. At a median follow-up of 16.5 months, 44% achieved a CR with undetectable MRD in bone marrow, as described in the Lancet Haematology.

Furthermore, 84% attained the best response of undetectable MRD in bone marrow, which to the best of the researchers’ knowledge represents “the highest ever published for any regimen” in a CLL population with both high- and low-risk markers.

“This time-limited treatment approach could increase the potential for FCR to functionally cure patients with mutated IGHV and, importantly, might for the first time extend this potential to patients with unmutated IGHV,” they wrote.

A similar proportion of patients in the IGHV mutated (42%) and unmutated (39%) groups achieved a CR or CR with incomplete count recovery plus undetectable MRD.

“Although a randomized phase III trial comparing ibrutinib plus FCR with chemotherapy-free approaches would be needed to definitively determine the optimum initial regimen for this population, our results represent an initial step towards establishing a new standard of care with curative potential for a broad population of younger fit patients with chronic lymphocytic leukemia,” Davids’ team concluded.

Commenting on the findings in an accompanying editorial, Clemens-Martin Wendtner, MD, of Ludwig-Maximilian University in Munich, pointed out that the approach taken by the investigators is appealing as it uses the most effective chemoimmunotherapy available and combined it with a targeted drug, thus producing high and durable remissions in high-risk patients with unmutated IGHV.

“The time-limited treatment approach of ibrutinib plus FCR could represent an attractive option for young fit patients,” Wendtner said, but cautioned that the current follow-up precludes definitive assessment of long-term activity and toxicity, and how many patients will eventually relapse following the 2-year maintenance phase remains unclear.

This approach would join a crowded field of highly effective first-line options, many of which are now chemotherapy-free. For example, ibrutinib monotherapy in older patients topped bendamustine (Bendeka) plus rituximab, while ibrutinib plus rituximab was shown to be superior to FCR in many young patients. The latest FDA-approved regimen is the BCL2 inhibitor venetoclax (Venclexta) in combination with the anti-CD20 agent obinutuzumab (Gazyva).

And the combination of ibrutinib plus venetoclax, which is not approved, led to high rates of CR or CR with incomplete count recovery (88%) and undetectable MRD in bone marrow (61%) in previously untreated CLL patients.

“With the evolution in medicine favoring chemotherapy-free drug combinations with a targeted approach and a limited exposure time, chemotherapy-based treatments including ibrutinib plus FCR might now have limited life expectancy,” Wendtner wrote. “Hopefully, in the future, we can reclassify chronic lymphocytic leukemia to a more chronic disease with an acceptable quality of life for patients.”

From October 2014 to April 2018, the current study enrolled 85 patients who were 65 years or younger (median 55) with previously untreated CLL. Patients first received daily single-agent ibrutinib at a dose of 420 mg for 1 week, followed by six cycles of FCR with daily ibrutinib. Patients who had at least a partial response within 2 months of completing the ibrutinib-FCR portion remained on ibrutinib maintenance for up to 2 years. At the time of data analysis, the median number of maintenance ibrutinib cycles was 11 and more than half of patients remained on maintenance ibrutinib after the study had been completed.

An overall response was achieved in all but one patient and responses were durable, with only one patient experiencing disease progression at study end, the investigators reported. One death was deemed possibly related to ibrutinib. Median progression-free survival had not been reached at the time of analysis and overall survival at both 1 and 2 years was 100%.

Response rates grew over time. For example, 35% of patients achieved a CR or CR with incomplete count recovery 2 months after they had received the last cycle of ibrutinib plus FCR, which increased to 66% after ibrutinib maintenance. Median time to achieving a CR was 8.3 months.

The most common grade 3/4 hematologic adverse events (AEs) were thrombocytopenia (32%), neutropenia (35%), and anemia (11%). For non-hematological AEs, the most common grade 3/4 AEs were hyperglycemia (7%), elevated liver enzymes (5%), and lung infection (5%). A small group of patients (6%) discontinued FCR before completing all six cycles for non-hematologic AEs.

Davids declared relationships with AbbVie, Acerta Pharma, Adaptive Biotechnologies, AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech/Roche, Gilead Sciences, Janssen, MEI Pharma, Merck Sharp & Dohme, Pharmacyclics, Surface Oncology, Syros Pharmaceuticals, TG Therapeutics, and Verastem. Some co-authors reported relationships with industry.

Wendtner declared financial relationships with AbbVie, AstraZeneca, Celgene, Gilead, Hoffmann-La Roche, Janssen-Cilag, Novartis, and MorphoSys.