SAN DIEGO – Patients with mantle cell lymphoma in their first remission who test negative for minimal residual disease (MRD) may be able to safely skip standard autologous hematopoietic stem cell transplant, according to an interim analysis of the ECOG-ACRIN Phase III EA4151 clinical trial presented at the American Society of Hematology's annual meeting.
The trial showed that stem cell transplant didn't benefit patients who were in remission following induction therapy and who had undetectable MRD as measured by Adaptive Biotechnologies' ClonoSeq MRD assay. Although there is not a singular standard-of-care treatment pathway in this disease setting, Timothy Fenske, a hematologist at the Medical College of Wisconsin, said at a press briefing at the meeting that it's common practice for MCL patients who are under 70 years of age but otherwise in good health to undergo hematopoietic stem cell transplant in their first remission. Although it is not currently standard practice to use MRD to inform that decision, Fenske said more than 70 percent of patients will test negative for MRD at that point.
"[The results] could be practice-changing," Fenske said about the EA4151 trial. "If there is an albeit small subgroup that may still benefit from transplant that we can identify through MRD testing, it may be important to identify those patients and at the same time spare the majority."
In the trial, which ECOG-ACRIN is conducting with contributions from SWOG through the US National Clinical Trials Network and Blood and Bone Marrow Transplant Clinical Trials Network, researchers are comparing the overall survival of mantle cell lymphoma patients in first complete remission who receive a stem cell transplant plus Genentech and Biogen's monoclonal antibody Rituxan (rituximab) to those who receive Rituxan alone. Following induction therapy, patients undergo PET/CT imaging and bone marrow biopsy and have a peripheral blood sample tested on the ClonoSeq MRD assay. Investigators are also tracking progression-free survival as a secondary endpoint.
The investigators randomized 516 MRD-negative patients to either Rituxan plus stem cell transplant or Rituxan alone but conducted a separate analysis of patients who were treated as assigned because about 25 percent of patients in this group that were randomized to stem cell transplant declined the transplant. Among 375 patients treated as assigned, the three-year overall survival rate for patients with undetectable MRD treated with Rituxan and stem cell transplant was 86.2 percent versus 84.8 percent for those on Rituxan alone. The three-year progression-free survival rates for each patient group treated as assigned were 81.5 percent and 80.4 percent, respectively.
Among MRD-positive patients who received a stem cell transplant with Rituxan, the three-year overall survival rate was 81.9 percent, and 76.9 percent lived three years without signs of disease progression. Among patients whose MRD results were indeterminate or ambiguous, the three-year overall survival and progression-free survival rates were 85.1 percent and 73.4 percent, respectively. The researchers did not find it necessary to conduct a separate analysis for treated as assigned patients for the MRD-positive groups.
Fenske said the study marks a significant advance for the field due to the high rate of toxicities from autologous stem cell transplant. "Somewhere in the range of 1 percent to 2 percent of patients actually die from complications from the transplant," he said. "And other patients will experience significant toxicities and effects on their quality of life. If we can spare patients going through all of that, it will be a big step forward."
Fenske noted that EA4151 is the second study to suggest that stem cell transplantation can be safely omitted in most mantle cell lymphoma patients in their first remission. In the TRIANGLE trial, researchers found that autologous stem cell transplant may not add benefit to induction regimens comprising high-dose cytarabine, Rituxan, and BTK inhibitors. "Identifying the many [MRD]-positive patients may be important, since it does appear that those patients may still benefit from transplants," Fenske said. "In my practice, I would do this testing so that we can differentiate those two populations."
Fenske cautioned that assays that are less sensitive than ClonoSeq MRD, such as fluorescence in situ hybridization or PCR-based assays, may not be reliable for determining which patients can avoid a stem cell transplant. "Part of the underlying concept of the study was that if we have more effective induction and maintenance regimens now, that patients are getting into deeper remission with induction and perhaps those are the patients that may not benefit from high-dose therapy," he said. "I would be reluctant to extrapolate these results to scenarios where you have less sensitive testing."
MRD testing is also coming into use in other hematologic malignancies. "We are starting to incorporate it in acute myeloid leukemia," Mikkael Sekeres, a hematologist at the University of Miami Miller School of Medicine who was not involved in the EA4151 study, said during the briefing. "We do chase down the MRD status of patients with NPM1 mutations, and we're increasingly seeing other mutations validated."
In April, the US Food and Drug Administration's Oncologic Drugs Advisory Committee supported the use of MRD as a surrogate endpoint in multiple myeloma clinical trials.
Laurie Sehn, a clinical professor at the University of British Columbia, who was also not involved with the study, noted in the briefing that MRD can also be prognostic in lymphoma and lymphoid malignancies and can help doctors differentiate between patients likely to have better outcomes versus less favorable outcomes. "[The EA4151 study] presented today in mantle cell lymphoma is really where the field should be going and is a proof of concept that MRD can be a very valuable tool to allow us to direct tailored approaches to patients and certainly allow us to spare toxicity [associated] with some of our approaches."