When used together, two drugs that treat the most common leukemia in adults significantly increase survival and lower the risk that the disease will worsen, according to a new study.
The interim analysis of a clinical trial for chronic lymphocytic leukemia, published Wednesday in the New England Journal of Medicine, found that the drugs – ibrutinib and rituximab – fared better than a combination chemoimmunotherapy that’s known to be effective against the cancer.
Researchers found that the “risk of progression or death was 65% lower and the risk of death was 83% lower with ibrutinib-rituximab than with chemoimmunotherapy.” After three years of follow-up, progression-free survival was 89.4% among those receiving ibrutinib-rituximab, versus 72.9% for those on chemoimmunotherapy. Overall survival at three years was 98.8% vs. 91.5%, respectively.
Study author Dr. Tait Shanafelt, professor of medicine at Stanford University School of Medicine, said the study’s data safety monitoring committee requested that the results be “shared immediately with the world because they were so dramatic, and they were immediately practice-changing.”
“For that to happen so early on against what traditionally was a very effective treatment – just one that had high side effects – I think was a surprise.”
Still, the chemoimmunotherapy, a combination of three drugs including rituximab, “led to a higher frequency of complete response” and showed less residual cancer, the study says.
“That historical approach actually is a very effective treatment,” Shanafelt said. “It’s just that it’s also very toxic and that many patients with CLL are unable to tolerate it because it’s so intense.”
Because chemotherapy affects healthy cells in addition to cancerous ones, people taking those drugs can experience a range of symptoms including hair loss, fatigue, changes in appetite, and nausea and vomiting.
The segment of patients who experienced a serious adverse event was similar in both groups – but the types of events differed.
Chemo drugs, as well as leukemia itself, carry the risk of serious infections because of how they suppress the immune system, Shanafelt explained. Meanwhile, ibrutinib was linked in the study to cardiovascular side effects including high blood pressure and an irregular heart rhythm.
Ibrutinib-rituximab, he said, has “a more favorable overall side effect profile.”
What is CLL?
Chronic lymphocytic leukemia, or CLL, is typically a slow-growing cancer in which immature white blood cells multiply in the bone marrow and spread throughout the body.
Many people don’t even have symptoms when they’re diagnosed, as it can be caught during routine or unrelated blood tests. But as the cancer crowds out the bone marrow, replacing healthy cells, patients may develop anemia, be more susceptible to infections, and bruise or bleed easily.
According to the American Cancer Society, CLL rarely affects people under 40; the average age of diagnosis is around 70. The organization estimates that there will be 20,720 new cases of CLL and nearly 4,000 deaths from it in 2019.
Both ibrutinib and rituximab are approved by the US Food and Drug Administration to treat CLL, which can be treated a number of other ways, including with radiation. Rituximab, which was also one of three drugs in the chemoimmunotherapy treatment, targets a receptor found among immune cells like those in CLL.
Ibrutinib, which comes in pill form, has sometimes been used in CLL patients whose cancer develops a high-risk genetic mutation that makes it less responsive to treatment. However, the new study didn’t include them and, in doing so, showed benefits for a broader set of CLL patients.
“We already know in that group that the traditional approaches aren’t as effective. So, if we include those [patients in the study], it’s easier for the ibrutinib to win,” Shanafelt explained.
But there’s a ‘catch’
“When there’s an impact on overall survival, it’s always notable,” said Dr. Nelson Chao, chief of the Division of Hematologic Malignancies and Cellular Therapy at the Duke University School of Medicine. He is not involved in the research.
The catch, Chao said, is that chemoimmunotherapy begins and ends; ibrutinib must be taken indefinitely or until a patient relapses.
“There’s clearly a survival advantage … but we don’t really know what the impact is going to be to keep people on ibrutinib,” Chao said. Not to mention how to extrapolate the effects of the drug on people over 70, the maximum age at which the study enrolled patients.
“This raises this question of what the overall toxicity for the patient is going to be long-term” – and the financial impact of a drug known to be expensive, he said.
Shanafelt wonders about the same obstacles: “Is this economically feasible and available to everybody who needs it, both in the US and around the world?”
Another potential downside of an indefinite treatment, according to the research: It’s possible for drug resistance to emerge if cancer cells accumulate mutations that make ibrutinib less effective. Shanafelt said that such mutations have been identified among patients taking the drug, albeit rarely.
Chao said doctors aren’t putting all their eggs in one basket with ibrutinib. There are other drugs that, like ibrutinib, target cell signaling pathways and don’t kill cells in the same way as chemo.
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For that reason, doctors are looking forward to trials that might pit these drugs head-to-head or in combination. Not only might researchers find a best-yet cocktail, but Shanafelt hopes there’s a solution ahead that’s chemotherapy-free and doesn’t require patients to be on ibrutinib indefinitely.
“If we could get to a combination with ibrutinib that we could perhaps use for a briefer period of time and get even deeper control but eliminate that need for chronic therapy,” he said, “maybe we would decrease the likelihood of selecting those genetic abnormalities that breed resistance.”