New Drug Combinations for a Type of Non-Hodgkin Lymphoma

A study found why some patients with mantle cell lymphoma develop resistance to the drug ibrutinib. The finding that could help researchers identify new treatment options.

Mantle cell lymphoma is a rare type of non-Hodgkin lymphoma. It is frequently diagnosed in adults older than 60 years of age, and at a later stage when the disease has spread to multiple lymph nodes, spleen, liver, bone marrow, and other organs.

According to the federal SEER database, more than 70,000 cases of non-Hodgkin lymphoma are diagnosed in the U.S. each year. Mantle cell lymphoma patients represent about 6 percent of these new cases, accounting for about 4,200 new cases each year.

Most patients with mantle cell lymphoma are treated with chemotherapy in combination with the monoclonal antibody rituximab.

Ibrutinib (Imbruvica) is a cancer drug approved by the FDA in November 2013 for mantle cell lymphoma. In a phase II clinical trial, ibrutinib showed promising results in patients with mantle cell lymphoma. However, most patients eventually relapsed, because their lymphoma stopped responding to the drug, a process known as acquired drug resistance.

A team of researchers at Weill Cornell Medical College conducted studies to understand why patients with mantle cell lymphoma treated with ibrutinib develop acquired resistance. They published their findings in Cancer Discovery, a journal of the American Association for Cancer Research (AACR).

In their study, the researchers analyzed tumor samples from a mantle cell lymphoma patient who responded to ibrutinib but eventually developed resistance to the drug. They compared data from the patient’s tumor samples with samples taken from healthy tissues of the same patient, and found a mutation in the tumor sample that seemed to have appeared when the patient stopped responding to ibrutinib.

Next, the researchers analyzed another patient’s tumor that developed resistance to ibrutinib, and found the same mutation in this patient’s tumor as well. However, this mutation was not present in tumors from patients who did not respond to ibrutinib right from the beginning of the treatment.

The researchers conducted further studies and found that cancer cells that never responded to ibrutinib and didn’t have the mutation became sensitive to the drug once they were treated with palbociclib, an investigational cancer drug.

Treating ibrutinib-resistant mantle cell lymphoma cells that had the mutation with palbociclib caused them to respond to some other investigational drugs that target a molecule called PI3K.

“This study not only suggests new approaches for treating mantle cell lymphoma but also has implications for treatment of other B-cell lymphomas, such as CLL, and a diverse group of non-Hodgkin lymphomas,” said Lewis C. Cantley, PhD, who directs the Sandra and Edward Meyer Cancer Center at Weill Cornell.

Based on the findings, the researchers have initiated a clinical trial (NCT02159755) to test a combination of ibrutinib and palbociclib in patients who were previously treated for mantle cell lymphoma, but not with the study drugs.