Examining Overtreatment in Mantle Cell Lymphoma

While some high-risk patients with mantle cell lymphoma may benefit from aggressive initial therapy, a recent study found that this may not be necessary for others who could benefit from more targeted therapies.
BY Jessica Skarzynski
PUBLISHED January 29, 2019
First-line treatment for mantle cell lymphoma varies by patient age and other factors, but often includes intensive induction chemoimmunotherapy followed by a process called autologous hematopoietic cell transplantation (AHCT) consolidation.

However, according to a recent study published in the Journal of Clinical Oncology, now that newer therapies like Rituxan (rituximab) are available, treatment involving AHCT consolidation may not be as effective – or necessary – in some patients.

CURE spoke with the lead author of the study, Stefan K. Barta, M.D., MS, of the University of Pennsylvania, about these findings and what they could mean for patients with mantle cell lymphoma.

CURE: What prompted this research?

Barta: Outcomes for patients with mantle cell lymphoma are very heterogeneous. Some patients have an indolent course, whereas other patients have a very aggressive course. Furthermore, upfront treatment for patients with mantle cell lymphoma in the US is currently not standardized. In most centers in the United States, younger, fit patients get treated with aggressive induction therapy followed by consolidation with an autologous stem cell transplant.

However, this approach is mainly based on older data, and has not been examined recently. In the era of new biological and more active therapies, stem cell transplant may no longer be necessary; we likely “overtreat” some patients, who may not benefit from such an aggressive upfront approach.

Can you define what “the Rituxan era” means as it pertains to this study?

The data supporting the use of autologous stem cell transplant stems from an era before routine use of (Rituxan) in the treatment for mantle cell lymphoma. (Rituxan) was first approved in the US in 1997 for the treatment of relapsed or refractory indolent B-cell lymphoma; therefore, we evaluated patients treated between 2000 to 2015 to make sure that the enrolled patients would have had the opportunity to be treated with (Rituxan) during their disease course.

Can you explain the process of AHCT consolidation and what it means for patients?

ACHT consolidation is a process where blood stem cells are removed from a patient's circulation and then stored in a freezer prior to the patient receiving high doses of chemotherapy followed by reinfusion of the patient's own blood stem cells, that had been stored in the freezer and were not exposed to the high doses of chemotherapy. This allows safer administration of high doses of chemotherapy that otherwise would result in prolonged bone marrow suppression.

Therefore, another (and maybe more appropriate) term for AHCT is high-dose chemotherapy with stem cell rescue. This process can result in significant toxicities, both long and short-term, including second cancers.

Consolidation means consolidating a treatment response to initial (or induction) therapy to prolong remission and hopefully improve survival.

Can you explain the differences you found in progression-free survival compared with overall survival when performing different analyses?

When we perform multivariate analysis, we try to control for confounders and differences in characteristics between patients who received a transplant and patients who did not, which may have influenced the decision to perform a transplant or not.

Propensity score weighting attempts to do the same (i.e. reduce the effects of confounding in observational studies) but is a more elaborate and sophisticated method. It creates a balancing score to create a synthetic sample in which the distribution of measured baseline covariates is independent of treatment assignment (i.e. transplant or not).

This method eliminates a greater proportion of the systematic differences in baseline characteristics and allows for a more reliable estimation of a treatment effect. This explains the slightly different results. In the propensity score weighting analysis, we still found a progression free survival benefit, but the overall survival benefit was no longer significant.

Why do you think these differences exist, resulting in a conclusion that AHCT is not associated with improved overall survival?

We think the reason for the slightly different results between the multivariate analysis and the propensity score weighting analysis are explained by a reduced selection bias in the propensity score weighting that led to the decision to perform an AHCT or not, as AHCT was not a “random event.”

In general, we believe that while some high-risk patients may benefit from aggressive initial therapy, this may not be necessary for everybody with (mantle cell lymphoma), and many patients can potentially be salvaged with modern biological and more targeted therapies.

What next steps will be taken as a result of this research?

The next important step will be to identify which patients do not benefit from AHCT. Genetic studies and measurement of minimal residual disease after induction therapy may provide important prognostic information and direct therapy. These questions can best be answered in prospective clinical trials, such as the currently ongoing EA4151 clinical trial, in which patients with no evidence of minimal residual disease after induction therapy get randomized to receive consolidation with AHCT or not.
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