Some patients with relapsed diffuse large B-cell lymphoma (DLBCL) may markedly benefit from treatment with Farydak (panobinostat), an oral drug that targets histone-modifying enzymes, according to the results of a Phase 2 clinical trial conducted in Canada.
The study, “Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma,” published in Blood, showed that Farydak led to 14.5 months of remission, on average, in patients who responded, and for some to an extended remission of longer than three years. The treatment was particularly effective in DLBCL patients with mutations in the MEF2B gene.
“DLBCL is one of the more common forms of lymphoma and is highly aggressive,” Sarit Assouline, an associate professor of medicine and oncology at McGill University, oncologist at the Segal Cancer Centre at the Jewish General Hospital and clinician-scientist at the Lady Davis Institute, said in a press release. “Following relapse, there are no effective standards of treatment and life expectancy averages six months. Our challenge is to identify new biomarkers and target specific mutations in order to improve the prognosis.
“While many clinical trials simply report on how patients respond to a therapy, we devised this study to reveal the mechanisms on which the therapy works in order to understand which patients would benefit,” Assouline, the trial’s chief investigator, added.
As many as 40 percent of patients with DLBCL do not respond effectively to standard chemoimmunotherapy or combinations of existing treatments and an autologous stem cell transplant. Since most DLBCL tumors contain mutations in genes associated with histone-modifying enzymes, drugs known as histone deacetylase inhibitors may be a way of improving their outcomes.
Histones are a family of proteins that associate with DNA and help condense it; certain modifications in histones may influence a variety of cellular processes, as they determine whether a particular gene to which the modified histones are associated is active or repressed.
This Phase 2 study (NCT01238692) enrolled 40 patients with relapsed or refractory DLBCL, who were randomly assigned to receive either Farydak (30 mg three times a week), or Farydak in combination with Rituxan (rituximab). Results revealed that 28 percent of patients had a positive response to treatment, which lasted an average of 14.5 months. Rituxan did not appear to increase the overall response rate, the researchers said.
Extensive genomic analysis showed that those patients most likely to respond to treatment had a mutation in the MEF2B gene, which is found in approximately 11 percent of DLBCL patients. Some who best responded to the therapy remained in remission after ending its use.
The researchers also measured the levels of circulating tumor DNA (ctDNA) in patient’s plasma samples — a measure associated with tumor burden — and showed that increased levels of ctDNA at day 15 after initiation of therapy strongly correlated with a failure to respond. This suggests that measuring ctDNA in blood samples may be a useful way of predicting early responses to treatment.
“We have entered the era of molecular subtyping of DLBCL and evaluating the role of precision medicine through integration of patient-specific molecular characteristics and treatment selection,” Dr. Mark Roschewski of the National Cancer Institute, wrote in an accompanying editorial. “As we pivot from conventional ‘one-size-fits-all’ paradigms to treatment approaches that consider individual molecular variability, precision molecular monitoring becomes an important translational component.”
Farydak was approved by the U.S. Food and Drug Administration in 2015 to treat multiple myeloma patients who received at least two prior therapies, including bortezomib and an immunomodulatory agent. It is taken in combination with bortezomib, a type of chemotherapy, and dexamethasone, an anti-inflammatory.