New Treatment Combination Poses Potential Way to Combat Chemo-Resistant DLBCL

Each year, roughly 20,000 Americans are diagnosed with diffuse large B-cell lymphoma (DLBCL), an aggressive cancer of abnormal B-cells. Most people with DLBCL are cured with the standard chemotherapy regimen rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), but 30-40 percent of cases are resistant to chemotherapy for reasons that may be related to the way that genes are regulated within the cancer cells.

Prior WCM laboratory research demonstrated that certain genes within chemotherapy-resistant DLBCL cells are often inappropriately turned off and that long-term exposure to low doses of oral hypomethylating agent azacitidine (also known as CC-486) can turn those genes back on, thereby re-sensitizing the cells to chemotherapy.

Lymphoma Program chief Dr. Peter Martin, Dr. Leandro Cerchietti, Dr. John P. Leonard, Dr. Maria Revuelta and Dr. ldefonso Ismael Rodriguez-Rivera, and colleagues from around the country, set out to test a novel therapeutic alternative for these chemo-resistant cases with a phase I, open-label, multicenter trial of oral azacitidine plus R-CHOP in people with high-risk, previously untreated DLBCL, grade 3B follicular lymphoma (FL), or transformed lymphoma. The trial was conducted in collaboration with Alliance Foundation Trials (AFT), a research organization that develops cancer clinical trials with pharmaceutical companies, scientific investigators and the Alliance for Clinical Trials in Oncology (ACTO) institutional member network.

Patients in the trial received CC-486 for seven days prior to R-CHOP initiation, then for 14 days prior to each of five following R-CHOP cycles. The research team found that the combination of CC-486 plus R-CHOP was safe and well tolerated, and that it produced a higher-than-anticipated complete response (CR) rate, or disappearance of signs of cancer, exceeding 85 percent. Dr. Cerchietti’s lab also identified key changes in genes and gene expression consistent with the anticipated CC-486 effect. Dr. Martin presented the team’s findings at the American Society of Hematology Annual Meeting and Exposition on December 9, 2017, in Atlanta, GA.

Weill Cornell Medicine

“We are at an exciting moment in time: CC-486 is emerging simultaneously with a peak in collaborative efforts between scientists, physicians and patients,” said Dr. Martin. “We are working day and night to move this concept forward, including the possible opening of randomized trials.”

Two Modes of DLBCL Relapse

Yanwen JiangBy Yanwen Jiang PhD 

Despite improvements in care for patients with diffuse large B-cell lymphoma (DLBCL), roughly one-third of patients do not respond to initial therapy or relapse within the first 2-3 years after treatment. Unfortunately, our current understanding of the molecular mechanisms of relapse is extremely poor.

During the recent 2013 American Society of Hematology meeting, we reported for the first time that there exist at least two distinct scenarios of DLBCL relapse.  In the first scenario, the tumor cells at diagnosis are almost genetically identical to tumor cells at relapse. Both tumors harbor the same set of mutations with the relapsed tumor possessing a few additional mutations, suggesting that the relapsed tumor evolved continuously from the tumor present at diagnosis. We termed this scenario “linear” mode.  In the second scenario, the tumors at diagnosis and relapse carry different mutations, suggesting that an early divergent event occurred and that the tumors developed in parallel.  Therefore, we named this scenario the “divergent” mode.  Moreover, we observed that tumors with higher genetic heterogeneity at diagnosis were more likely to relapse through the divergent mode. This may provide a foundation for evaluation of different treatment strategies for different relapse modes.

Currently, we are expanding our study to investigate the role of epigenetics, particularly DNA methylation, in DLBCL relapse.  For more research information on DLBCL, and relapsed DLBCL, please visit our websites at the Elemento Lab and the Melnick lab.

%d bloggers like this: