By Gene Emery
(Reuters Health) - 31/7/2019
Among patients with untreated chronic lymphocytic leukemia (CLL) who lack a key mutation, therapy with a combination of ibrutinib and rituximab produces longer survival and progression-free survival than standard chemoimmunotherapy, according to the official findings of a phase 3 study published online July 31 in The New England Journal of Medicine.
"Although we had previous studies showing that ibrutinib was an effective treatment, it had never been compared to our most effective therapy for CLL," chief author Dr. Tait Shanafelt, a professor of medicine at Stanford University, told Reuters Health in a telephone interview.
The interim findings were so dramatic, "it was felt those results had to be immediately reported so they're immediately practice-changing," he said.
Among all volunteers, overall three-year survival rates were 98.8% among the 354 who got the combination versus 91.5% for the 175 who received standard treatment with a combination of fludarabine, cyclophosphamide, and rituximab (FCR) (P<0.001).
Progression-free survival rates were 89.4% and 72.9% respectively (P<0.001).
But the real difference was seen among the 281 patients without an immunoglobulin heavy-chain variable region (IGHV) mutation. For them, progression-free survival at three years was dramatically higher with ibrutinib and rituximab: 90.7% with the combination versus 62.5% with standard therapy.
When the research team looked at patients with the mutation, the rates were comparable: 87.7% with ibrutinib and rituximab and 88.0% with conventional treatment.
Pharmacyclics LLC, a subsidiary of AbbVie, which sells ibrutinib under the brand name Imbruvica, paid for the study, along with the U.S. National Cancer Institute.
CLL strikes nearly 21,000 Americans each year and kills about 4,500, according to the American Cancer Society. It is the most prevalent form of leukemia in adults.
The U.S. Food and Drug Administration and the European Medicines Agency approved ibrutinib for CLL in 2016.
The new study, known as E1912, only included adults younger than 71. Those with a chromosome 17p13 deletion were excluded. Results were initially announced in December at the annual meeting of the American Society of Hematology in San Diego.
The rates of serious side effect were comparable in the two groups, but infectious complications higher than grade 2 were half as likely with the ibrutinib-rituximab combination, seen in 10.5%, compared with 20.3% with conventional care.
Rates of grade 3 or 4 neutropenia were 25.6% in the ibrutinib group and 44.9% with standard therapy.
However, atrial fibrillation was twice as common with ibrutinib, at a rate of 7.4%. "It's not a common complication, but it's an important one," said Dr. Shanafelt.
One problem with the conventional FCR regimen is that its side effects can be substantial, including severe myelosuppression. "That gold standard is a very effective treatment but it's just so intense many of our older patients can't tolerate it," he said.
The ibrutinib treatment is easier for patients because it's pill-based and doesn't require three days of intravenous therapy per month for six cycles. On the other hand, ibrutinib has to be taken indefinitely, and it's costly.
While the average wholesale price for six cycles of FCR is about $61,000, a one-year supply of ibrutinib at average wholesale is about $118,000, Dr. Shanafelt said.
Even if Medicare or other health insurance is covering part of the expense, "the out-of-pocket cost is still a barrier for many patients," he said.
Researchers are investigating whether adding AbbVie's venetoclax will allow doctors to limit the duration of treatment, Dr. Shanafelt said.
N Engl J Med 2019.