A novel therapy first used at Sarah Cannon Research Institute is changing the prognosis for relapsed blood cancer patients. In late July, the U.S. Food and Drug Administration approved Zydelig® (idelalisib) for patients with relapsed chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma.
While the drug is new to pharmacies, patients and physicians at Sarah Cannon have used idelalisib since participating in its phase 1 clinical trial more than six years ago. Tennessee Oncology’s Ian Flinn, MD, PhD, leads the hematologic malignancies research program at SCRI and said idelalisib was a breakthrough and effective therapy from the onset.
“Sarah Cannon was the first to treat patients with idelalisib, and we started seeing immediate activity which is pretty unusual,” Flinn said. “This early activity generated a lot of enthusiasm, and it started causing groundswell. People in the field said it was different than what we’ve seen before, and it got to be known very quickly within the field.”
The Idelalisib DifferenceTraditional chemo agents work through cytotoxic chemotherapy, attacking the entire cell. Idelalisib is a targeted molecule, attacking one small pathway in the cancer cell and preventing off-target toxicity and side effects, including metabolism and glucose problems common with much broader agents. Another caveat of traditional chemo is the need for healthy bone marrow function. With idelalisib, patients can have bone marrow deficiencies and still receive treatment.
Flinn said the primary concern during initial trials was the risk of resistance caused by targeting those narrow, redundant pathways in cancer cells. Six years later, idelalisib’s high remission rates are defusing those fears.
“I’m excited about getting away from traditional chemo altogether and using a more targeted approach that can help patients avoid so many terrible side effects that often accompany chemotherapy,” Flinn said.Side Effects & Effectiveness
Idelalisib is a daily, oral medication that is taken continuously, yet boasts surprisingly mild side effects compared to the nausea, vomiting and hair loss associated with traditional chemo. Flinn said some patients reported a rash or diarrhea after a year, while others noticed a slight change in liver enzymes.
The drug label warning includes fatal and serious toxicities including liver toxicity, diarrhea and colon inflammation, lung inflammation and intestinal perforation that can occur in idelalisib-treated patients. Common lab abnormalities include decreased levels of white blood cells, high levels of triglycerides in the blood, high blood sugar and elevated levels of liver enzymes.
Studies show tremendous improvement among patients who’ve been on the drug four years with decreased risk of progression or death from treatment, said Flinn. According to the FDA, idelalisib’s safety and effectiveness to treat relapsed CLL were established in a clinical trial of 220 participants who were randomly assigned to receive idelalisib and the IV chemo drug rituximab, or placebo and rituximab. The trial was stopped for efficacy following the first pre-specified interim analysis point, which showed participants treated with idelalisib and rituximab had the possibility of living at least 10.7 months without their disease progressing compared to about 5.5 months for participants treated with placebo and rituximab. Results from a second interim analysis continued to show a statistically significant improvement for the combination of idelalisib and rituximab.
“Although people on the control arm were allowed to cross over, we still saw improved survival,” Flinn said. “Idelalisib has the potential to change how patients with certain blood cancers receive treatment, and their outcomes can be greatly improved. It’s been an honor to watch our clinical trial participants thrive on the drug. This is why we do what we do … to improve the lives of those with cancer.” In a Class of Its OwnWhile idelalisib is known as a B Cell Receptor Pathway Drug, Flinn said the medication more specifically is a P13K Delta Inhibitor since it blocks pathways by interfering with the cell’s street map of survival signals. And while pan-P13K Inhibitors are already used in the treatment of solid tumors, idelalisib represents the first successful delta inhibitor for leukemia and lymphoma patients.
“This is a tremendous paradigm shift for people who have relapsed lymphoma,” Flinn said. “In the future, our goal is to give idelalisib on the frontline so patients don’t have to suffer side effects of traditional chemotherapy.”
For now, Flinn said the drug is most effective in patients who have received prior treatment that was not effective. However, studies are underway to test the drug in patients with no prior therapy, although using idelalisib up front poses another host of questions:“How long are rates of remission? How well does it work in comparison to other treatments? Do you bring your best drug up front, and do you use it alone or in combination with something else?” Flinn asked. “We’re just starting trials to research this. When someone comes in, I tell them we’ll have this in a few years, but right now we’re only recommending it for relapse patients and not as frontline therapy.”
While idelalisib is considered a win in the fight against blood cancers, Flinn and fellow researchers are already working on second and third generation molecules with hopes to create formulas with a broader spectrum of activity. Flinn is particularly hopeful about a drug that targets delta and gamma isoforms and promises less liver toxicity.
“We’re working with other molecules in the same class to advance therapies to the next level,” Flinn said. “This medication and others coming along mean major differences for patients and are very different from how we treated lymphoma in the past. It’s really a major step as we develop more targeted treatment options for patients.”
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