Associate Professor of Internal Medicine
Director of Lymphoid Malignancies Program
Harold C. Simmons Comprehensive Cancer Center
University of Texas Southwestern Medical Center
Farrukh Awan, MD, MS, has disclosed that he has received consulting fees from AbbVie, AstraZeneca, Blueprint, Celgene, Dava Oncology, Genentech, Gilead Sciences, Janssen, Karyopharm, Kite Pharma, MEI Pharma, Pharmacyclics, and Sunesis
This is an exciting time for those of us who treat patients with relapsed mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL), as new treatment options and approaches continue to emerge and provide opportunities for improved outcomes. In this commentary, I discuss my current standard of care for these lymphomas in this evolving therapeutic context.
In the relapsed MCL setting, there are a few considerations that I use to guide my treatment selection: How old are the patients and what are their comorbidities? How fit are they? Are they a candidate for more aggressive therapy? Are they eligible for autologous stem cell transplantation (ASCT)? Patients who have not yet received ASCT typically are treated with initial chemotherapy and achieved a temporary remission, after which their disease progressed. In these cases, I typically give patients who are eligible for transplant additional chemotherapy followed by consolidation with ASCT. In those patients who have had ASCT and relapsed, I consider their comorbid conditions, age, access to other therapeutic options, availability for clinic visits, and concomitant medications before I choose a more definitive treatment regimen. Of importance, this is a shared decision with the patient.
Among the treatments currently available for these patients are BTK inhibitors. Inhibiting BTK in the B-cell signaling cascade stops cell proliferation and induces apoptosis, and oral BTK-targeted agents have proven efficacious for various B-cell malignancies. Ibrutinib was the first BTK inhibitor approved by the FDA to treat some of these indolent hematologic diseases and has given patients who have failed previous therapies, as well as those who are less fit and cannot tolerate chemotherapy or ASCT, a unique opportunity to receive therapy that may improve their outcomes.
Currently, 3 BTK inhibitors are approved by the FDA for relapsed MCL—ibrutinib, acalabrutinib, and zanubrutinib—and all are very effective and generally well tolerated. Ibrutinib is well tolerated for most patients, although the newer BTK inhibitors might be better tolerated for some patients. Bleeding is the main adverse event of concern with all 3 BTK inhibitors and appears to be a class effect. For that reason, for a patient receiving anticoagulation or antiplatelet agents, I would likely recommend an alternate approach such as chemotherapy or alternative targeted agents like venetoclax rather than a BTK inhibitor. Also, if a patient has extensive cardiovascular issues, I would be less inclined to use ibrutinib and instead might recommend acalabrutinib or zanubrutinib, which may be better tolerated by these patients. Currently, no head‑to‑head clinical trial results are available to determine if one BTK inhibitor is more effective or less toxic than any other, although multiple such trials are ongoing, comparing zanubrutinib to ibrutinib in Waldenström macroglobulinemia and in chronic lymphocytic leukemia (CLL) (the ALPINE trial) and acalabrutinib to ibrutinib in CLL. I look forward to the results of these trials to help guide management of patients with BTK inhibitors.
Additional BTK inhibitor adverse events to consider include arthralgia, myalgia, and diarrhea, which appear to be more common with ibrutinib in patients with MCL. These slight differences in the ibrutinib adverse event profiles in these different disease settings may be due to the higher dose used for patients with MCL compared with CLL (560 mg vs 420 mg, respectively). At this time, there is not a clear advantage of any one BTK inhibitor regarding toxicities. In my practice, if a patient who is receiving ibrutinib experiences a BTK inhibitor–associated toxicity, I would initially employ a dose reduction strategy depending on the adverse event before I switch to a different BTK inhibitor due to ibrutinib intolerance. If a patient were at a high risk of ibrutinib-related toxicity, I would recommend one of the other BTK inhibitors. Of importance, if a patient relapsed on a BTK inhibitor, switching to a different BTK inhibitor is not appropriate because the mechanism of resistance appears similar with all 3.
Historically, patients with MZL have fairly indolent disease; they progress slowly and usually don’t require treatment for years. When they do require treatment, we typically choose either rituximab monotherapy or chemoimmunotherapy based on the disease burden. Those patients with MZL who do progress after initial rituximab or chemoimmunotherapy are candidates for BTK inhibitors. Similar to MCL, my personal preference in MZL is to use a therapy with the best tolerability, discussing with the patient their treatment options: chemotherapy vs nonchemotherapy, time‑limited vs continuous therapy, and which BTK inhibitor would be best for them considering their comorbid conditions.
Of note, stem cell transplant is also an option in MZL, although few patients receive one. Typically, patients with more-aggressive MZL tend to have disease that has already transformed into an aggressive large‑cell lymphoma, for which there are different treatment paradigms. This is important to determine for any patient with MZL who is being considered for BTK inhibitor therapy.
In both MCL and MZL, it is important that patients are seen by a lymphoma specialist and that they have the option to enroll on clinical trials evaluating new therapeutic strategies such as combining BTK inhibitors with chemoimmunotherapy or other targeted agents with a goal of improving the depth and duration of response. For example, recently we have seen promising activity with combinations of ibrutinib and obinutuzumab with or without venetoclax in patients with both relapsed/refractory and newly diagnosed MCL. In the future, similar combination regimens may provide an opportunity to discontinue therapy in patients with MCL who achieve deep remissions with no measurable residual disease in contrast with the current paradigm of continuous treatment with BTK inhibitors.
What issues have you faced when treating patients with MCL/MZL? I encourage you to answer the polling question and join the conversation in the discussion box below.
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