Equally important to efficacy for our patients is tolerability, and ibrutinib has been well tolerated in clinical studies. In RESONATE-2, the most common toxicities were diarrhea, fatigue, nausea, and cough. The rate of discontinuation due to toxicities was 9%. Serious toxicities included atrial fibrillation and bleeding. Atrial fibrillation often can be managed without permanent discontinuation of ibrutinib. Hemorrhage has usually been associated with the use of anticoagulants, so they should be administered with care in patients taking ibrutinib. Notably, no studies with longer follow-up have shown evidence of cumulative toxicity, with the exception of hypertension. Hypertension rates do increase over time, which will likely be an issue in patients who remain on these drugs for long periods. Attention will need to be paid to long-term cardiac complications that may arise.
Additionally, toxicities that are grade 1 or grade 2, such as joint pain, may be well tolerated for short periods of time, but difficult for patients to tolerate for years. While ibrutinib appears to be well tolerated over time in clinical trials, analyses of real-world patients showed toxicity to be the main reason for drug discontinuation, especially in the frontline setting. Since these real-world data are in contrast with the low discontinuation rates due to toxicity seen in trials, it will be important to see if these rates change as ibrutinib becomes even more commonly prescribed in the community setting.
Even with the limited currently available data, it appears that targeted therapy is superior to chemotherapy in terms of efficacy and safety for the vast majority of patients. However, the cost of an indefinitely dosed drug remains an issue. Careful studies of cost-effectiveness will need to be performed to determine whether the safety and efficacy of targeted therapies outweigh the cost, even if dosed indefinitely. In addition, combination studies of targeted therapies with or without antibody therapies may be an alternative strategy to potentially discontinue therapy and reduce drug costs. For example, ibrutinib in combination with venetoclax[14,15] and ibrutinib in combination with venetoclax and obinutuzumab have both recently been shown to induce high response rates and complete response rates, with eradication of minimal residual disease; trials of discontinuation are ongoing. If these targeted therapy combinations can lead to durable remissions in the absence of continuous therapy, the financial burden should be dramatically reduced.
With the promising current data on targeted therapies alone and in US Food and Drug Administration–approved combinations with antibodies, as well as ongoing studies with targeted combinations, the future for CLL is bright. Except for rare cases such as lymphodepletion for CAR T cells or preparative regimens for stem cell transplantation, I do not see a role for chemotherapy in the future of CLL. Elimination of chemotherapy from our combination regimens should be a shared goal among researchers that will move us a step closer to more patient-friendly and scientifically driven therapies for CLL.
Financial Disclosure: Dr. Woyach has received research funding from AbbVie, Karyopharm Therapeutics, and MorphoSys.
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