This article is more than 5 years old. Information may no longer be current.
Higher, split doses may reduce toxicity of CTL019 in adult ALL
Click Here to Manage Email Alerts
CHICAGO — Higher and split doses of treatment with anti-CD19 chimeric antigen receptor T cells may improve efficacy and safety for adults with acute lymphoblastic leukemia, according to study results presented at the ASCO Annual Meeting.
Children with relapsed or refractory CD19–positive ALL have demonstrated 90% response rates with genetically modified T cells that express an anti-CD19 chimeric antigen receptor (CTL019, Novartis). For these patients, cytokine release syndrome is the most common adverse event, but it is usually managed with anti-cytokine therapy.
“We have seen tremendous response rates but it has become apparent that this treatment has significant treatment-related side effects, the most significant of which is cytokine release syndrome,” Noelle V. Frey, MD, assistant professor of medicine at Hospital of University of Pennsylvania, told HemOnc Today. “This research sought to start a conversation about maintaining high response rates while also improving tolerability especially cytokine release syndrome.”
Frey and colleagues presented data on the efficacy of CTL019 and the incidence of cytokine release syndrome in 27 adults (median age, 44 years; range, 21-72) with ALL treated on two trials. Five patients had primary refractory disease, nine had received prior blinatumomab (Blincyto, Amgen) and nine previously underwent allogeneic stem cell transplantation.
The patients were treated in one of four dosing cohorts. Participants received lymphodepletion followed by CTL019 as a one-time infusion or fractionated infusions over 3 days (day 1, 10%; day 2, 30%; day 3, 60%). CTL019–planned dosage varied (5 x 107–5 x 108) with cytokine release syndrome toxicity modifications.
Nine patients received CTL019 at a dose of 5 x 107 — six of whom received this dose over one infusion and three who had fractionated dosing. Three (33%) of these patients achieved complete response. Six of these patients experienced grade 3 to grade 4 cytokine release syndrome managed with tocilizumab (Actemra, Genentech/Roche).
Six patients received CTL019 in a one-time 5 x 108 dose. Three of these patients achieve complete response. The other three patients died as a result of treatment-related adverse events all of whom had both cytokine release syndrome, which was refractory to tocilizumab and corticosteroids, and sepsis.
The other 15 patients received 5 x 108 fractionated dosing. If these patients experienced early cytokine release syndrome, researchers held subsequent CTL019 infusions and allowed for intra-patient modification. Patients who experienced grade 3 cytokine release syndrome received anti-cytokine treatment.
Nine of these patients experienced manageable grade 3 to grade 4 cytokine release syndrome. The overall response rate in this cohort was 86%.
“By administering the large dose in a fractionated way, physicians were able to prolong or delay treatment for patients who experienced toxicity,” Frey said. “However, administering multiple infusions of the high dosage is a significant logistical challenge — further research is necessary to determine if split-dosing is the best way to mitigate cytokine release syndrome.” – by Nick Andrews
References:
Frey F, et al. Abstract 7002. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclos ure: Frey reports a consultant/advisory role with Amgen and research funding from Novartis. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
Back to Top
Eytan M. Stein, MD
We know that chimeric antigen receptor (CAR) T cells are very effective in relapsed and refractory acute lymphoblastic leukemia. Yet, we also know that the toxicity of the drugs can be significant. These patients can get very sick very quickly due to cytokine release syndrome and neurotoxicity. The fact that Noelle V. Frey, MD, and colleagues were able to show that attenuating and splitting the doses of the CAR T-cell therapy led to a decrease in grade 5 toxicity is really significant, because we did not know beforehand whether the split dosing would lessen the efficacy of these agents. These findings paint a path forward so that we can give these agents with manageable toxicity, understanding that the drugs remain somewhat toxic. Patients need close monitoring and an experienced team of doctors who can manage these effects.These drugs are very effective. I hope that when the appropriate clinical trials are completed, the FDA will consider providing accelerated approval for these agents. Having said that, it will be difficult to administer these agents in a community hospital or even academic centers that do not have the experience, because there is a bit of learning curve in using these drugs. You must have a team of doctors and ICU–level care.
Another abstract presented during the same oral abstract session by Jae Hong Park, MD, and colleagues used a differently constructed CAR T-cell therapy that targets the CD19 receptor to evaluate whether CAR T cells are more effective in — as well as the appropriate dosing for — patients who have minimal residual disease compared with patients who have overt disease. Park and colleagues showed that the minimal residual disease population and patients with morphologic disease can overcome their disease with the CAR T cells.
These researchers also had very interesting data on the need for allogeneic transplant after CAR T cells, an area of research that really needs to be explored. We do not know if patients need to have a bone marrow transplant after they have gone into remission from CAR T cells. If they do not, that could potentially save the patient from many more doctors’ visits, as well as save the health care system a tremendous expense.
Reference:
Park JH, et al. Abstract 7003.Click Here to Manage Email Alerts