麻豆传媒

Maintenance therapy with rituximab yielded better survival outcomes for older patients with minimal residual disease (MRD) negativity after induction therapy for mantle cell lymphoma (MCL), results from the European Mantle Cell Lymphoma Elderly trial showed.

Compared with interferon-alpha maintenance, rituximab maintenance prolonged both progression-free survival (PFS; HR 0.38, 95% CI 0.21-0.63) and overall survival (OS; HR 0.37, 95% CI 0.20-0.68) in MRD-negative patients in clinical remission at the end of induction, reported Christiane Pott, MD, PhD, of Christian-Albrechts University in Kiel, Germany, and colleagues.

This was particularly evident in patients initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine (Oncovin), prednisone (R-CHOP), with significant improvements in PFS (HR 0.23, 95% CI 0.10-0.52) and OS (HR 0.19, 95% CI 0.07-0.52), according to findings published in the .

"With the introduction of immunochemotherapy, high-dose treatment followed by autologous stem-cell transplantation, high-dose cytarabine-containing induction, and rituximab maintenance ... the clinical course of advanced-stage MCL has substantially improved during the past two decades," the authors wrote.

"Our results confirm the importance of rituximab maintenance in patients with MCL and conclusively show that treatment de-escalation by omitting rituximab maintenance in MRD-negative patients cannot be recommended," they concluded.

Induction with rituximab, fludarabine, cyclophosphamide (R-FC) achieved more frequent and faster MRD clearance versus R-CHOP, but in this group the benefit of rituximab maintenance "appeared less prominent than after R-CHOP," the authors noted. Overall, the median duration of maintenance therapy was 10 months with interferon-alpha, as compared with 2.2 years with rituximab.

In MRD-positive patients, outcomes still appeared to favor rituximab maintenance but to a lesser degree, both in the overall population (PFS HR 0.51, 95% CI 0.26-1.03; OS HR 0.80, 95% CI 0.34-1.84) and in the R-CHOP induction group (PFS HR 0.59, 95% CI 0.28-1.27; OS HR 0.91, 95% CI 0.36-2.30).

Furthermore, MRD positivity in post-induction clinical remission was associated with a short median time to clinical progression of approximately 1 to 1.7 years.

"More effective consolidation strategies should be explored in MRD-positive patients to improve their long-term prognosis," Pott and colleagues wrote.

Commenting on the study, Henry C. Fung, MD, of Fox Chase Cancer Center in Philadelphia, said the European recommendations generally align with U.S. practice. "We do recommend post-induction maintenance for all patients, and MRD negativity is not used to guide treatment," he told 麻豆传媒.

He added, however, that R-CHOP and R-FC are less often used for MCL in the U.S., where the most common regimen is a combination of bendamustine and rituximab, based on results from the .

In addition, recent data from the which combined the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) with the bendamustine-rituximab regimen, showed superior PFS over bendamustine-rituximab followed by rituximab.

Fung noted that no prospective trial has been performed to evaluate if patients treated with either bendamustine-rituximab or bendamustine-rituximab plus a BTK inhibitor will benefit from rituximab maintenance, "and certainly no MRD data are available."

"In the era of bendamustine-rituximab with or without a BTK inhibitor, the role of rituximab maintenance in mantle cell lymphoma remains to be determined," said Fung.

Offering another U.S. perspective on the European trial, Christine Ryan, MD, of the Dana-Farber Cancer Institute in Boston, noted that continuous treatment carries ongoing toxicity risk, and there is considerable interest in time-limited and/or shorter treatment durations.

While patients who are MRD-negative may be thought to be those who can safely discontinue treatment, the current study interestingly demonstrates that these patients in deep clinical response may in fact benefit from further therapy, she told 麻豆传媒. "Such a result may reflect that those patients with treatment-sensitive disease benefit most from continued treatment."

Several questions remain regarding the best approach to treatment de-escalation, Ryan added. "Treatment decisions by clinical and MRD status may be best addressed by randomized phase III studies in both MRD-negative and MRD-positive patients."

To that end, the multicenter study in transplant-eligible patients is expected to generate important results in this area. The study randomizes patients in MRD-negative complete remission at end of induction to either consolidative autologous stem cell transplant (SCT) followed by maintenance rituximab or maintenance rituximab alone.

"This study will provide important insights into the relative efficacy and toxicity of auto-SCT in MRD-negative younger patients in first remission," Ryan said. "Randomized studies have not addressed the question of how best to approach patients who are MRD-positive with treatment continuation or de-escalation, for example, and this is an important area that requires further investigation."

For , Pott and colleagues initially randomly assigned 560 previously untreated patients with Ann Arbor stage II-IV MCL to rituximab versus interferon-alpha maintenance after response to R-FC versus R-CHOP from January 2004 to October 2010.

MRD monitoring was performed by real-time quantitative polymerase chain reaction (qPCR). A qPCR assay with a median sensitivity of 1 × 10^-5 could be generated in 80% of 288 patients.

These 288 patients had a generally more favorable risk profile than patients not screened, and those with a clonal marker more often had stage IV and bone marrow involvement, as well as higher lactate dehydrogenase levels.

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