Press release
Thursday June 20, 2024
Combination therapy developed by NIH researchers demonstrates the power of precision medicine.
Researchers at the National Institutes of Health (NIH) have developed a chemotherapy-free treatment regimen that achieves complete remission in some people with aggressive B-cell lymphoma that has come back or no longer responds to standard treatments. The five-drug combination targets multiple molecular pathways that diffuse large B-cell lymphoma (DLBCL) tumors use to survive.
In a clinical trial conducted at the National Cancer Institute of the NIH, researchers tested the combination of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (called ViPOR) in 50 patients with DLBCL, the most common type of lymphoma. more frequent. The treatment significantly shrank tumors in 26 of 48 (54%) evaluable patients, and 18 (38%) of these patients’ tumors disappeared completely, known as a complete response. At two years, 36% of all patients were alive and 34% were disease free. These benefits were seen primarily in people with two specific subtypes of DLBCL.
The results were published on June 20, 2024 in the New England Journal of Medicine.
“Many of these patients who stopped responding to standard treatments would otherwise have died within a year, and now we have a good proportion who have been alive for two years, and some for four years,” Christopher said. J. Melani, MD, of the NCI Cancer Research Center, who co-led the study. “It’s rewarding to see these long-term remissions and potential cures in patients.”
Previous studies have identified various genetic pathways involved in the development and survival of different molecular subtypes of DLBCL, such as activated B cell-like (ABC) DLBCL and germline B-cell-like DLBCL (GCB). Targeted drugs have been shown to block some of these pathways, but individual drugs have rarely produced durable responses in patients because tumors may be resistant due to other survival pathways. Dr. Melani and colleagues hypothesized that combining targeted drugs that block multiple survival pathways would lead to more durable responses.
Based on laboratory studies in which they analyzed which targeted drugs could best be combined to kill DLBCL cells synergistically, the researchers designed the five-drug regimen to test in drug trials. man. To allow the targeted drugs to work synergistically in patients, researchers administered the drugs simultaneously in two-week cycles. To limit the accumulation of side effects, they scheduled a one-week break between each cycle.
DLBCL is one of the most genetically heterogeneous forms of cancer and, therefore, we do not yet have the ability to identify exactly which combination of drugs would be most effective for a given patient,” said Dr. Melani . “By putting five drugs together, we think there will be a combination of drugs – either two, three or more drugs – that will be particularly effective against this patient’s tumor.”
In the phase 1b/2 trial, 50 people with DLBCL who had relapsed or stopped responding to treatment received six cycles of the ViPOR regimen. Responses to ViPOR varied by DLBCL subtype, with complete responses concentrated in two subtypes, including 8 of 13 (62%) people with non-GCB DLBCL and 8 of 15 (53%) people. presenting with a form of GCB DLBCL known as high-grade “double hit” B-cell lymphoma.
At two years, people with non-GCB DLBCL and double-hit GCB DLBCL had higher rates of progression-free survival and overall survival than others in the study. Non-GCB DLBCL and double-hit GCB DLBCL are highly dependent on survival mechanisms targeted by ViPOR. So it makes sense that they responded particularly well to the combination therapy. ViPOR also helped 6 in 20 (30%) patients whose lymphomas had not responded or returned after CAR T cell therapy – the current standard of care for people with relapsed DLBCL – achieve lasting remission .
Side effects of the five-drug regimen were generally mild to moderate compared with standard treatments and improved during treatment breaks. Only five patients had to stop treatment prematurely for various reasons, including side effects. Given these relatively mild to moderate side effects, additional drugs could potentially be added to ViPOR to improve its effectiveness, the researchers said. The team is also studying the ViPOR diet in people with other types of lymphomas resistant to previous treatments.
Researchers have developed a larger Phase 2 study, which will be conducted at multiple centers, to confirm the activity of ViPOR in people with non-GCB DLBCL and double-impact DLBCL GCB.. Further work is needed to develop therapies for GCB DLBCL subtypes that do not respond as well to ViPOR.
NCI Cancer Research Center investigators Wyndham H. Wilson, MD, Ph.D., Mark Roschewski, MD, and Louis M. Staudt, MD, Ph.D., co-led the study with Dr. Melani. Investigators from the NIH’s National Center for Advancing Translational Sciences and other institutions contributed to the study.
About the National Cancer Institute (NCI): The NCI leads the National Cancer Program and NIH efforts to significantly reduce the prevalence of cancer and improve the lives of people with cancer. NCI supports a wide range of cancer research and education extramural through grants and contracts. The NCI Intramural Research Program conducts innovative, transdisciplinary basic, translational, clinical, and epidemiologic research into the causes of cancer, avenues for prevention, risk prediction, early detection, and treatment, including research in NIH Clinical Center, the largest research hospital in the world. Learn more about the intramural research being done at the NCI Cancer Research Center. For more information about cancer, please visit the NCI website at cancer.gov or call the NCI Contact Center at 1-800-4-CANCER (1-800-422-6237).
About the National Institutes of Health (NIH):
The NIH, the nation’s medical research agency, is comprised of 27 institutes and centers and is part of the U.S. Department of Health and Human Services. The NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research, and studies the causes, treatments, and cures for common and rare diseases. For more information about the NIH and its programs, visit www.nih.gov.
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