It’s been five years since weakness and fatigue brought your patient, then seventy years old, to see his doctor. A routine blood test revealed an abnormally elevated white blood cell count. Doctors quickly diagnosed him with chronic lymphocytic leukemia. Soon afterward, he was started on his first of three treatment regimens that took him from rituximab to cyclophosphamide to fludarabine. But the leukemia had progressed. And while the drugs hadn’t suppressed his disease, they had wreaked havoc on his body. Now, he was ill and frail with platelets so low and kidney function so impaired that further chemotherapy simply wouldn’t make sense.
“Isn’t there anything else we can try?” he asks.
The answer now might be a cautious yes. Two studies in this week’s issue of NEJM describe promising results about a new oral drug called idelalisib. In one study, researchers show that idelalisib might help patients with CLL who aren’t candidates for further chemotherapy – like your patient – live longer. The other trial, published by a different team, demonstrates that the same drug might offer a benefit without a hefty side-effect profile for patients with non-Hodgkin’s lymphoma whose disease has progressed despite traditional therapies.
The results are driven by basic science studies into how signaling in B cells, the cells that go awry in both these disease, works. In the lab, scientists have learned that a specific set of cell signals becomes inappropriately hyperactive in malignancies like chronic lymphocytic leukemia. But attempts to inhibit individual pathways are often thwarted by side effects and resistance. Idelalisib represents an advance, because the drug targets a very specific pathway – the delta isoform of the phosphoinositide 3-kinase (PI3K) signal transduction pathway – and does so elegantly, without devastating adverse events.
Taken together, the two studies are striking. In one, Richard Furman and colleagues randomly assigned 220 patients with relapsed CLL to receive rituximab plus either idelalisib or placebo. These were all patients whose co-morbidities rendered them ineligible for further standard chemotherapy. The study was stopped early because the patients receiving idelalisib clearly did so much better. Those taking the study drug were less likely to see progression in their disease and more likely to be alive 12 months later.
In the other study, Ajay Gopal and his team looked at whether idelalisib could benefit a group of patients with “indolent” non-Hodgkin’s lymphoma. This term refers to slow-growing but largely incurable lymphomas that had either not responded, or had come back after a course of treatment, and could lead to death. In this study, patients were not randomly assigned to the drug, or to placebo. Instead, 125 patients were given the drug – and monitored. What the researchers found was that the study drug was just as good as, and maybe better than, the other current treatment options. Importantly, toxicity of the drug was described as “acceptable,” with most common adverse events being diarrhea and elevation in liver function tests.
While the precise target population and long-term effects of this drug remain to be seen, its success in these two studies serves as an example of how science can move from bench to bedside, write biologists and cancer researchers David Fruman and Lewis Cantley in an accompanying editorial: “The emerging success of idelalisib illustrates the clinical translation of basic research studies of signaling pathways in malignant B cells into clinical advances in treatment of patients with B-cell malignancies.”