HemOnc Today's PharmAnalysis

HemOnc Today's PharmAnalysis

Issue: April 2020
Disclosures: Rubinstein reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures
April 09, 2020
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CAR T-Cell Therapy May be Safe for Leukemia Subset with Neurologic Comorbidities

Issue: April 2020
Disclosures: Rubinstein reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures
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Neurotoxicity is one of the major treatment-related toxicities associated with chimeric antigen receptor T-cell therapy, and it can discourage or disqualify patients from receiving commercial CAR-T products or participating in clinical trials.

A case series published in Pediatric Blood & Cancer demonstrated that CAR T-cell therapy could be successfully given to three children with relapsed or refractory leukemia without any serious neurotoxicity events — despite all three children having some grade of existing neurologic comorbidity.

The study’s lead author, Jeremy D. Rubinstein, MD, PhD, a clinical fellow in hematology/oncology with the Cancer and Blood Diseases Institute at Cincinnati Children’s Hospital Medical Center, said that despite the sample’s small size, physicians should keep CAR T-cell therapy as an option for certain patients with leukemia who have had bridging chemotherapy.

Rubinstein spoke with Cell Therapy Next to discuss the results of his team’s research, its impact and plans for future investigation in this area.

Q: What was your group’s rationale for initiating this research?

Neurotoxicity is one of the primary therapy-related side effects that has been seen with CAR T-cell therapy. Accordingly, many clinical trials investigating CAR T-cell therapy have excluded patients with active central nervous system leukemia and/or serious neurologic comorbidities. Because the risk factors for neurotoxicity are not fully understood and recipients of CAR T-cell therapy for relapsed leukemia are often unfit for other forms of leukemia-directed therapy, we offered tisagenlecleucel (Kymriah, Novartis) to patients with neurologic comorbidities under certain circumstances.

Q: What are the key takeaways from this research?

Jeremy D. Rubinstein

The number of patients reported in this research is very small, at just three. However, the key takeaway is that if the patient has a leukemia that is amenable to bridging chemotherapy, and a patient with a CNS insult is allowed time to return to their neurologic baseline status, then CAR T-cell therapy seems to be a safe choice. We saw zero cases of immune effector cell-associated neurotoxicity syndrome (ICANS) in our series. Additionally, early and active collaboration with a consulting neurology team — particularly with a physician with a specific interest in this field — and prophylactic administration of anti-epileptic medications can be crucial for the safe use of these products.

Q: Should clinical trials and commercial CAR T-cell therapy for pediatric indications be expanded to include patients with neurologic comorbidities?

In certain circumstances, this could be beneficial to our understanding of neurotoxicity risk factors. The patients we reported on had CNS insults related to methotrexate toxicity, posterior reversible encephalopathy syndrome and HHV-6 encephalopathy. In all cases, they returned to their baseline status before CAR T-cell infusion. Including patients who have recovered from an acute insult in clinical trials could be a reasonable approach.

Q: Could the results of this study have any impact on clinical practice?

Again, this was a small case series, so I hesitate to apply too much weight to it. But I hope that other physicians would at least consider CAR T-cell therapy for patients such as those we described in our case series rather than taking that option off the table out of concern for increased neurotoxicity risk.

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Q: Do you have plans for further research in this area?

Our group is interested in seeing what we can learn about efficacy, persistence and toxicity in patients who received CAR T-cell therapy for extramedullary disease.

There has been great translational work done to date in this field, defining risk factors and increasing our understanding of the pathogenesis of neurotoxicity. However, there is clearly much we still do not understand about the topic, including how best to prevent and manage it. Recent work has demonstrated that interleukin (IL)-1, more so than IL-6, is important for ICANS development, and I look forward to seeing data on the use of an IL-1 receptor antagonist, anakinra (Kineret, Sobi), as a treatment. – by Drew Amorosi

Disclosures: Rubinstein reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.