Q: How does having an extended response to initial treatment for MCL inform decisions about subsequent lines of therapy?

Patients with MCL who relapse after long remissions generally have a more favorable tumor biology than those who relapse after brief remissions. Nearly any therapy you select, whether it be chemotherapy, radiation therapy, Bruton tyrosine kinase (BTK) inhibitor therapy, immunomodulatory therapy, or proteasome inhibitor therapy, will work better in those who have had long remissions than in those who have had brief remissions. For patients with late relapse of MCL, you have the same options that are available to those who relapse after shorter remissions, plus some additional options as well. For most patients who have had short remissions following cytotoxic chemotherapy, you may be reluctant to offer another round of chemotherapy because it did not work well the first time it was administered. However, for a patient who has had 7 years of remission following cytotoxic chemotherapy, for example, you might return to that option because it worked well the first time. You might also consider molecularly targeted therapies such as BTK inhibitors, lenalidomide, bortezomib, or investigational protocols with small molecules, all of which are attractive options for MCL relapse. The impact of mutations acquired during initial treatment on the response to subsequent treatments has not been well studied in MCL. There are not many available therapies for MCL that are specifically mutation-based agents—unlike for solid tumors, where mutation sequencing panels help to identify specific mutations that support certain therapeutic options. In those with relapsed MCL who are being treated with acalabrutinib, you can expect a response rate of approximately 80% in unselected patients. In accordance with the current knowledge base, it does not appear to be necessary to perform mutation testing before administering a drug that is going to work 8 out of 10 times.

It is critical to assess the myeloid reserve in a patient with late relapse of MCL. Patients may have low myeloid reserve in association with advanced age or the myelotoxicity of previous treatments. In those with low myeloid reserve, you do not want to revisit combination chemotherapy, if possible, even if the tumor protein p53 gene, TP53, mutation and 17p deletion are absent, as this approach could lead to irreversible myelotoxicity, particularly in older patients. I do think that acalabrutinib is an excellent drug; we have used it at our institution and have had good outcomes. And the same applies to ibrutinib. Perhaps the challenge lies in trying to find agents that may couple with these small molecules. We have also seen favorable results in investigational protocols with bendamustine-bortezomib administered with or without rituximab in patients with late relapse of MCL. Lenalidomide is a drug that seems to arrest proliferation by blocking the cyclin dependent kinase inhibitor 1A, CDKN1A. If one does not want to consider the use of cytotoxic chemotherapy or BTK inhibitors, lenalidomide can be well tolerated for extended periods of time when administered at lower doses.

For most lymphomas, a longer first response generally suggests a higher probability of achieving a second response and, oftentimes, a more durable second response at that. In a patient with MCL who experienced a longer remission, a suitable treatment approach may involve a BTK inhibitor with or without rituximab, depending on whether the patient received rituximab maintenance following chemotherapy or stem cell transplant. There are individuals with MCL who may not be good candidates for BTK inhibitor therapy due to their age or comorbidities. In these cases, investigational protocols may be considered, with options that include lenalidomide combinations and, certainly, bortezomib, rituximab with or without bendamustine, and venetoclax combinations. I might be less likely to retest these patients for TP53 mutation or 17p deletion. Although these markers should certainly be examined in those with early relapse of MCL, I would not say that it is absolutely necessary in all patients; however, it might be very helpful when choosing your therapeutic options.