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.”

Chemo-Free Follicular Lymphoma Treatment Regimen Shows Promise in Phase II Clinical Trial

CaptureThe combination of lenalidomide and rituximab may represent a reasonable alternative to chemotherapy for some people with previously untreated follicular lymphoma (FL), according to a study led by Dr. Peter Martin, chief of the Weill Cornell Medicine and NewYork-Presbyterian Hospital (WCM/NYP) Lymphoma Program.

Dr. Martin collaborated with the Lymphoma Program’s Drs. Jia Ruan and John Leonard, along with experts from academic medical centers across the country, to evaluate the non-chemotherapy drug combination in a phase II trial known as CALGB 50803, the results of which were recently published in the Annals of Oncology. The formalized collaboration was made possible by the Alliance for Clinical Trials in Oncology, a cooperative group sponsored by the National Cancer Institute (NCI).

Lenalidomide plus rituximab was administered over twelve 28-day cycles to 65 adults with previously untreated follicular lymphoma. Seventy-two percent of patients achieved a complete response. At five years, the overall survival rate was 100 percent, and 70 percent of patients remained free from disease progression. Rates are comparable with those typically produced by standard chemotherapy.

The study also demonstrated low rates of hematologic toxicity, such as neutropenia (low white blood cell count), lymphopenia (low lymphocyte levels) and thrombocytopenia (low platelet count), but low-grade side effects like fatigue, constipation, diarrhea and rash were commonly reported.

The results of the CALGB 50803 study do not definitively establish whether lenalidomide-rituximab is more or less toxic or more or less effective than a standard chemotherapy regimen; such insights will be clearer following completion of the randomized phase III RELEVANCE trial, which compares lenalidomide-rituximab to chemotherapy plus rituximab.

Optimal use of chemotherapy requires a careful balance of anti-tumor activity with tolerability. WCM/NYP is proud to be a leader in the discovery and development of therapies that are both active against cancer and well tolerated.

FDA Approves Copanlisib for Certain Types of Follicular Lymphoma

The United States Food and Drug Administration (FDA) recently granted accelerated approval to copanlisib for treatment of adults with relapsed follicular lymphoma (FL) who have received at least two prior lines of therapy. Copanlisib is a kinase inhibitor that works by blocking some of the enzymes responsible for cancer cell growth.

The FDA’s decision is based on favorable safety and efficacy results in over 100 patients around the world as part of the CHRONOS-1 clinical trial.

Instead of having to wait years to learn whether a drug actually extends survival for cancer patients, accelerated approval enables the FDA to more quickly approve drugs that fulfill an unmet clinical need for serious conditions. Scientists look to measure surrogate or intermediate clinical endpoints – like tumor shrinkage, for example – that indicate whether a drug is reasonably likely to predict clinical benefit.

As a condition of accelerated approval, a randomized control (comparison) trial will be required to verify the clinical benefit of copanlisib before it can move on to help relapsed follicular lymphoma patients whose treatment options are often limited.