In patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) receiving second-line therapy with a Bruton tyrosine kinase inhibitor (BTKi), outcomes were largely driven by time to progression of disease (POD), and to a lesser extent by the Ki67 index or MCL International Prognostic Index (MIPI) at diagnosis. This is according to a study published in Blood Advances.
In current practice, covalent BTKi monotherapy is the most common second-line strategy for R/R MCL, explained lead author Diego Villa, MD, MPH, of the British Columbia Cancer Centre for Lymphoid Cancer and University of British Columbia in Vancouver, Canada. “BTKis have been a major advance in the management of MCL, but patients will develop progressive disease and require additional therapy to control their disease. Managing patients with progressive disease on a BTKi can be challenging, as their disease can often quickly progress,” Dr. Villa said.
“We propose a simple clinical tool to identify patients starting second-line BTKis who are unlikely to experience long-term disease control and who should be considered for other therapies together with second-line BTKis or as consolidation while their disease remains under relative control,” Dr. Villa said.
In this international, multicenter, retrospective, observational study, the researchers aimed to evaluate the factors predicting outcomes in patients with R/R MCL initiating single-agent BTKis after firstline treatment with any rituximab-containing chemotherapy regimen. They created multivariable models assessing the link between time to POD and clinical and pathologic factors and converted these models into nomograms and prognostic indexes predicting outcomes. A total of 360 patients were included, with 160 in the main cohort (median age = 67 years; 73% male) and 200 in the validation cohort (median age = 71 years; 70% male). The primary endpoint was second progression-free survival (PFS2), which was defined as the time from initiation of second-line BTKis until disease progression or death from any cause. The secondary endpoint was second overall survival (OS2), which was defined as the time from initiation of second-line BTKis until death from any cause.
Time to POD, Ki67 of 30% or greater, and MIPI were the three statistically significant variables included in the final models. In the main cohort, with a median follow-up after second-line BTKi in living patients of 1.5 years, the median PFS2 was 0.45 years (95% CI 0.3-0.6) in patients with early POD (within 24 months of firstline therapy) and 2.3 years (95% CI 1.7-2.8; p<0.001) in patients with late POD (after 24 months of firstline therapy). The respective median OS2s were 0.9 years (95% CI 0.5-1.3) and 5.5 years (95% CI 3.5-7.5; p<0.001) in patients with early and late POD. The nomograms and prognostic indexes were used to develop calculators to estimate PFS2 and OS2. The second-line BTKi MIPI calculator identified three groups with distinct two-year PFS2, including high, intermediate, and low risk, at 14%, 50%, and 64%, respectively.
“The first takeaway is that not all patients with R/R MCL do well on second-line BTKi. The second takeaway is that we can easily identify most of these patients with simple clinical features: time to POD after firstline therapy, Ki67, and MIPI. We have incorporated these into the second-line BTKi MIPI. An important study finding is that disease refractory to firstline therapy (POD6) alone does not identify all [patients with high-risk disease],” Dr. Villa said. “The third takeaway is that when clinicians identify high-risk [MCL], they should be proactive and have a strategy that at a minimum includes close surveillance, and more importantly that lines up other treatments such as CAR T-cell therapy or other novel agents, as these will likely become necessary sooner rather than later.”
Blastoid or pleomorphic morphology was not statistically significant in the models, which was likely explained by its strong correlation with Ki67. Meanwhile, TP53 mutations, MIPI at relapse, and biopsy findings at relapse could not be included in the models due to missing data. A model incorporating clinical and biologic factors at first relapse rather than at diagnosis may better estimate outcomes from the point of second-line BTKi initiation, but these variables were not included in the models because of factors influencing the decision to biopsy at first relapse.
“Our results are immediately applicable to the current management algorithm of MCL, which generally involves firstline rituximab-containing chemotherapy and subsequent second-line covalent BTKi monotherapy. Also, all of the centers participating in this large international collaboration identified consecutive patients in a systematic fashion, which we hope will reassure readers about the external validity of our findings,” Dr. Villa said.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Villa D, Jiang A, Visco C, et al. Time to progression of disease and outcomes with second-line BTK inhibitors in relapsed/refractory mantle cell lymphoma. Blood Adv. 2023;7(16):4576-4585.
