A small pilot study could point the way to a new option for patients with B-cell acute lymphoblastic leukemia (B-ALL) who experience cytokine release syndrome (CRS) that cannot be cured with the standard therapy.
A new study suggests that ruxolitinib (Jakafi) may help mitigate steroid-refractory cytokine release syndrome (CRS) in children who receive chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphoblastic leukemia (B-ALL).
CAR T-cell therapy has been a promising advancement in a number of malignancies, including B-ALL, the most common type of cancer in children. However, the therapy has been associated with significant adverse effects, including CRS and immune effector cell–associated neurotoxicity syndrome (ICANS).
Investigators including corresponding author Xiaoming Feng, PhD, of the Chinese Academy of Medical Sciences and Peking Union Medical College, noted that the typical treatment for patients who suffer CRS or ICANS involves drugs like tocilizumab (Actemra) along with steroids. In cases of CRS grade 3 or higher, high-dose steroids are recommended, and high-dose methylprednisolone is recommended for refractory CRS. Unfortunately, those therapies do not always work, and their failure can pose a major barrier to patient survival.
“[L]ife-threatening consequences may occur if severe CRS cannot be controlled by current regimens,” the investigators said.
In hopes of providing another therapeutic avenue, Feng and colleagues turned to ruxolitinib, which is a Janus kinase 1 and 2 inhibitor. These kinases play a role in transmitting cytokine-induced signals and thus have become a target for a number of inflammatory diseases. The drug has already been approved for the treatment of steroid-refractory graft-vs-host disease, prompting hopes that it might be a meaningful intervention in other conditions, such as severe CRS.
The new study was a pilot study that involved just 14 patients, but the results were uniform.
Each patient in the study had received CD19 or CD22 CAR T-cell therapies, and 4 of those patients went on to develop grade 3 or higher CRS that could not be alleviated with high-dose steroids.
Each of those 4 patients was then administered oral ruxolitinib (5 mg twice daily). The results were rapid and convincing.
“CRS-related cytokines including IL-6, IL-10, sCD25, TNF‐γ, and SF quickly decreased in these four patients after ruxolitinib intervention, which implicates that ruxolitinib successfully stops these cytokines’ release,” the authors said.
In addition to the decrease in CRS symptoms, serum cytokines also decreased significantly.
At 30 days post CAR T-cell infusion, each patient had achieved complete remission, and the investigators were still able to detect CAR T expansion in vivo. No obvious adverse events were reported related to ruxolitinib.
There was, however, a caveat to the findings. Despite the positive in vivo results, in vitro assays suggested that ruxolitinib could dampen CAR T expansion and cytotoxicity.
“This discrepancy may be due to the presence of excretive systems or an intermediate cellular part in humans which await future clarification,” the authors said.
They added that their data also showed that ruxolitinib has a stronger impact on CAR T effector function than dexamethasone.
“Ruxolitinib mainly inhibits CAR T cell expansion and releasing of T cell cytotoxicity related cytokine (INF‐γ and Granzyme B) in vitro,” they said. “It would be interesting to measure INF‐γ and Granzyme B in patients with CAR T cell therapy in future study.”
In the meantime, the authors said physicians should carefully consider the timing and dosage of ruxolitinib in patients with steroid-refractory CRS in order to avoid dampening the anti-leukemia response.
Pan J, Deng B, Ling Z, et al. Ruxolitinib mitigates steroid-refractory CRS during CAR T therapy. J Cell Mol Med. Published online December 12, 2020. doi:10.1111/jcmm.16176