The study showed that failure-free survival at 3 years was 72% with chemotherapy alone, 86% with ibrutinib alone, and 88% with ibrutinib plus ASCT. However, the ibrutinib plus ASCT group seemed to have much more toxicity, comorbidities, and other complications from the transplant. The OS data are not mature yet, but looking at the available data, ibrutinib alone might be more beneficial to our patients— not only in terms of efficacy, but also in tolerability and response, with less toxicity over time.
To put things in perspective, we did not have good salvage therapies a decade ago. At the time ASCT was incorporated, it was a good option that allowed numerous patients to achieve a deep response with durable remission duration. Before ibrutinib was approved, the overall response rate for the best salvage therapies was not as encouraging as the initial therapy and, with each relapse, the duration of response shortened. When ibrutinib came along, the overall response rate improved significantly. But again, these patients had relapsed/refractory disease. Researchers have been investigating what would happen if we used such a drug in earlier lines of therapy. Can we get better outcomes? Can we get patients in remission longer, similar to what we have seen with ASCT, but without the ASCT?
There has never been a single modern trial that has demonstrated that transplant improves survival. Transplantation can improve progression-free survival, but not OS. For a disease for which we do not have a cure, if we can keep patients in remission with a good salvage therapy and give them a better quality of life, without subjecting them to an ASCT, then I might choose that. New targeted agents and novel therapies are in clinical development all the time, so the future is bright for patients with this diagnosis. Given the novel salvage therapies in the pipeline, we may be able to no longer recommend ASCT upfront for most patients soon.
Can you share more about the potential benefits of using salvage therapies over ASCT, and particularly any promising newer agents in the salvage therapy setting?
Dr. Barrientos: Recently we had the FDA approval of pirtobrutinib —a noncovalently bound BTK inhibitor—for patients with relapsed/refractory MCL in whom at least 2 lines of systemic therapy had failed, including another BTK inhibitor. In the trial that led to the accelerated approval, pirtobrutinib-treated patients showed an overall response rate of 50% in those who received the drug at 200 mg daily (n = 120); most of the responses were partial responses. The efficacy of other novel drugs are being studied in patients with MCL. For example, ROR1 (receptor tyrosine kinase–like orphan receptor 1) inhibitors and BTK degraders are currently in clinical trials. Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has been approved for the treatment of adult patients with relapsed or refractory MCL, and this may be an option for some patients.
Multiple novel agents might be able to salvage our patients without subjecting them to an upfront transplant. My hope is to get away from using the intense chemotherapy regimens that might cause myelosuppression, infection risk, or other toxicities, and try to stay with the novel agents. We need to do better for our patients.