By Gene Emery
NEW YORK (Reuters Health) - 1/5/2019
The treatment - where a patient's disease-fighting T-cells are removed, then genetically engineered to attack telltale proteins on tumor cells before being re-infused into the body - also produced a gamut of serious but manageable hematologic side effects.
The researchers, led by Dr. James Kochenderfer of the National Cancer Institute in Bethesda, Maryland, characterized the safety profile of the treatment as "favorable."
Updated findings from the so-called bb2121 phase 1 study, financed by Bluebird Bio and Celgene, appear in the May 2 New England Journal of Medicine.
"We're not sure how many, if any, will be cured with this therapy," Dr. Kochenderfer told Reuters Health by phone. "The longest we have is three years and he had almost no toxicity at all. That's the ideal outcome. But we can't really say at this point that anyone is cured. We can say half the people didn't have progression for 11.8 months which is a long time. And remember these are patients who have been through a lot of prior therapy."
All the volunteers in the test had relapsed after receiving between three and 23 other treatments; the median number was seven. All but one had received an autologous stem-cell transplant.
The therapy "is inconvenient because the patient has to be in the hospital for 14 days" and may fall ill with fever, fatigue and other side effects, said Dr. Kochenderfer, who is with the NCI's Experimental Transplantation and Immunology Branch.
"This CAR therapy was significantly less toxic than other CAR trials I've participated in. Most all toxicities go away in a couple of weeks. But then the payoff is - and this is very different in other myeloma treatments - they don't get any other therapy until the myeloma progresses. They get several months, on average, of a treatment-free interval, which they greatly appreciate."
"It's a great step forward for some pretty sick patients," said Dr. Edward Ball, director of the Blood and Marrow Transplant Program at University of California San Diego Health, who was not involved in the study but is testing a different CAR T-cell treatment.
He said "the significance is you're taking patients who have had a median of seven lines of therapy and by the time I'm getting to therapy number six I have a very low expectation of success because the cells are resistant. These patients had a pretty good response rate. The durability is good in some, but not all. But this, in a nutshell, is what we see in oncology."
The new report focuses more on the side effects than the efficacy of the bb2121 therapy, assessing adverse outcomes up until 6.2 months after the last infusion date. The list of problems ranked grade 3 or higher were neutropenia (seen in 85%), leukopenia (seen in 58%) and anemia and thrombocytopenia (both with rates of 45%). Grade 3 or 4 lymphopenia appeared in 18%.
Neurologic problems - a category that included bradyphrenia, brain edema, confusional state, dizziness, hallucination, insomnia, lethargy, memory impairment, neurotoxicity, nystagmus, somnolence, or tremor - appeared in 42% of patients, but in nearly every volunteer the problem was grade 1 or 2.
Only one of the 33 did not have an adverse event that was grade 3 or higher.
Drs. Ball and Kochenderfer said it is possible to re-administer the CAR therapy to rejuvenate the response. Some of the patients in the new study have been given a second dose.
"The other thing is, there could be another target," said Dr. Ball. "This targets BCMA (the B-cell maturation antigen). There might be other targets that might add additional activity."
In addition, "when it gets approved, we might be using it earlier in a patient's course, and that might make a big difference," Dr. Ball told Reuters Health by phone.
The first two CAR-T therapies, developed by Novartis and Gilead Sciences, were approved for blood cancers in 2017.
Bluebird and Celgene are already experimenting with an updated cell therapy, bb21217, which is designed to improve the persistence of the altered cells.
N Engl J Med 2019.