Specific research needs include comparative studies of novel treatment combinations like ibrutinib plus venetoclax, which has shown singular promise in clinical trials, and further investigation of emerging immunotherapies like bi-specific T-cell engagers (BiTEs), said review author Mubarak Al-Mansour, MD.
The review article, published online in Clinical Lymphoma, Myeloma & Leukemia, includes a proposed treatment algorithm based on the latest data.
“Since the introduction of [Bruton’s tyrosine kinase] inhibitors, the treatment algorithm and response of R/RMCL patients have dramatically changed. Nevertheless, Bruton's tyrosine kinase resistance is common, which necessitated further investigations to develop novel agents with a more durable response,” explained Dr. Al-Mansour a medical oncologist at Princess Noorah Oncology Center, Jeddah, Saudi Arabia.
Modest clinical activity and tolerability observed with novel agents that targeted B-cell receptor signaling led to investigation of combination strategies in preclinical and early clinical settings, in order to assess whether more durable response rates could be achieved than with single-agent therapy, he said.
“[Of] these combinations, ibrutinib plus venetoclax had the highest response rates in the setting of clinical trials, even in high-risk patients,” Dr. Al-Mansour noted.
Other promising therapies include chimeric antigen receptor (CAR) T-cell therapies (CAR-T) and BiTEs, which “appear to be powerful agents in the therapeutic arsenals of R/RMCL, especially among heavily pretreated patients,” he said, adding, however, that “further investigations are still warranted to assess the clinical activity of CAR-T or BiTEs therapies in combination with other agents.”
Comparative studies also will be needed to assess the relative advantages of various treatment approaches, he said.
These investigations are important given the generally short duration of remission among patients with MCL, which now accounts for between 2% and 6% of all non-Hodgkin lymphoma cases, an incidence that has risen steadily over the past few decades, Dr. Al-Mansour pointed out.
Although many patients achieve an adequate response in the upfront treatment setting, with overall response rates ranging from 60% to 97%, remission is generally short-lived, and the rapid relapses that occur pose a challenge. Additionally, most patients are elderly and have a poor prognosis: Reported progression-free survival in older patients ranges from 2 to 3 years and median overall survival ranges from 28.8 to 52 months, compared with 62 and 139 months, respectively, in young, fit patients, he said.
Furthermore, there is no consensus on the best treatment options in the relapsed/refractory setting, and international guidelines vary widely, he added.
For the current review, Dr. Al-Mansour conducted an online bibliographic search for relevant clinical trial data and meeting abstracts published through the end of March 2022. The data addressed treatment pathways, resistance mechanisms, various approved and investigational agents and treatments used alone or in combination regimens, and stem cell transplant (SCT).
Based on the evidence, Dr. Al-Mansour proposed the following “general algorithm” for the management of R/RMCL:
“Fit patients should be categorized according to their time until disease progression into early (< 24 months) and late (> 24 months) groups. In patients with early progression of the disease, Bruton's tyrosine kinase inhibitors should be offered. Other alternatives should be offered in case of relapse or failure, including CAR-T, [allogeneic-SCT (allo-SCT)], or enrollment in a clinical trial.”
For patients with late disease progression, the algorithm calls for offering Bruton's tyrosine kinase inhibitors, rituximab-bendamustine–based chemotherapy, or rituximab-lenalidomide.
“Other alternatives should be offered in case of relapse or failure, including CAR-T, allo-SCT, or enrollment in a clinical trial. Unfit patients can be offered Bruton's tyrosine kinase inhibitors, considering CAR-T or enrollment in a clinical trial in case of failure.”
Dr. Al-Mansour also noted COVID-19 pandemic–related caveats for the management of R/RMCL.
“Recent epidemiological figures demonstrated that cancer patients are at excessive risk of severe COVID-19. In the case of hematological malignancies, patients are usually on immunosuppressants, which further increase the risk of severe disease and death,” he wrote.
For this reason, and because current treatments consist mainly of targeted agents, which “exert negative effects on patients’ humoral and cell-mediated immunity,” the timing and schedules of treatment regimens should be determined with consideration of COVID-19–related risks, he advised.