For many years, standard of care first-line treatment of chronic lymphocytic leukemia (CLL) has been the FCR (fludarabine, cyclophosphamide, rituximab) regimen, which was pioneered for CLL at MD Anderson Cancer Center in large phase II trials and generated impressive results. The efficacy of the regimen was validated by the German CLL study group in phase III trials. Three separate research groups demonstrated the long-term efficacy of the regimen, publishing data sets showing a majority of patients remaining in first complete remission beyond five years. Yet, many practitioners who have used the regimen have discovered its drawbacks. It is both myelosuppressive and immunosuppressive, significantly so. I have quite a bit of experience with the regimen and have witnessed patients becoming transfusion dependent for as long as a year after FCR, and who never recovered normal blood counts. The risk for opportunistic infections is substantial and can persist for several years after treatment. Finally, there is a small but real risk (approximately 5%) of developing myelodysplastic syndromes/acute myeloid leukemia. Given the drawbacks of this highly efficacious therapy, the CLL community has been anxious to develop new frontline strategies.
A bold U.S. intergroup trial has put FCR to the test and identified a worthy replacement in the form of ibrutnib-rituximab. Dr. Tait D. Shanafelt and colleagues conducted a randomized phase III clinical trial comparing FCR against ibrutinib-rituximab in 529 patients with previously untreated CLL. Patients needed to meet International Working Group Criteria for therapy and needed to be 70 years or younger to be eligible. Patients with 17p deletion were not eligible. The FCR regimen was administered at the usual dose and was scheduled for six cycles. Ibrutinib was administered at a dose of 420 mg daily, given until disease progression, while rituximab was administered for six months. Ibrutinib-rituximab was more efficacious. With a median follow-up of 33 months, the three-year progression-free survival was 89 percent for ibrutinib-rituximab versus 73 percent for FCR. Somewhat surprisingly, there was also a statistically significant overall survival (OS) advantage for ibrutinib-rituximab. Of note, FCR performed similarly to ibrutinib-rituximab in the patients with mutated IgVH genes. Toxicities for FCR were typical for that regimen. The ibrutinib-rituximab regimen was reasonably well tolerated with low levels of grade 3 to 4 toxicity.
One might conclude that this trial signals the death knell for FCR given the OS advantage for ibrutinib-rituximab. Before planning FCR’s memorial service, a few considerations merit further thought. First, the overall number of death events was quite low (4 vs. 10). Hazard ratios can be very large with low numbers of events, and it is quite possible the OS signal will diminish with time. Second, this trial allowed participation of patients as old as 70 years, which is pushing the envelope for safe administration of FCR. It would be nice to see the data analyzed by age. Third, in IgVH-mutated CLL, FCR performed similarly to ibrutinib-rituximab for efficacy. Finally, ibrutinib is an expensive, chronic therapy, while FCR is finite.
Based on these considerations, FCR can continue to be an option for select CLL patients, meaning those with mutated IgVH genes and younger than 65 years. For patients meeting those criteria, it is a complicated discussion. One must walk them through the pros and cons of finite immunochemotherapy versus indefinite targeted therapy. In my experience, some patients opt for FCR while others strongly preferred ibrutinib. While the discussions are long and complex, at least we have options, which is always a good problem.
Conflict of Interests
Dr. Kahl indicated no relevant conflicts of interest.
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