Roxanne Nelson, RN, BSN
November 08, 2022
A novel approach in which two products were co-administered achieved a 99% complete response rate in children with relapsed or treatment-resistant B-cell acute lymphoblastic leukemia (B-ALL).
In this trial, the largest study to date of a CAR T-cell therapy for such patients, the researchers co-administered two CAR T-cell therapies, one targeting CD19 and the other targeting CD22.
The results showed that 192 of 194 patients (99%) achieved a complete remission.
The combined overall 12-month event-free survival was 73.5%.
The study was published online on November 8 in the Journal of Clinical Oncology.
These results are better than what has been reported for CAR T cells that are already on the market. These products, which target CD19, have achieved complete remission in 85.5% of cases and a 12-month event-free survival of 52.4% in children with B-ALL.
“We do believe [this approach] will become standard of care,” said study author Ching-Hon Pui, MD, of the Departments of Oncology, Pathology, and Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, Tennessee.
He noted that this work builds on the huge success that has already been achieved in this field with CAR T-cell products directed at CD19. The first of these products to reach the market was tisagenlecleucel-T (Novartis).
“To put this study in context, the first child who received CAR T-cell therapy for B-ALL after multiple relapses has recently celebrated her 10-year cancer-free survival milestone, and we hope that our finding will result in many more such milestones,” he said.
These new results are very impressive, said Stephen P. Hunger, MD, an expert commenting for the American Society of Clinical Oncology, which highlighted the research in a press release. “They were also able to treat almost 200 patients in a relatively short time.”
Hunger pointed out that dual administration and targeting is not a new idea and is one of the strategies that is currently under investigation. But it is too early to consider this to be the standard of care, he said. “We want to see it replicated in other centers and to see longer follow-up,” said Hunger, who is Distinguished Chair in Pediatrics and director of the Center for Childhood Cancer Research at Children’s Hospital of Philadelphia, Pennsylvania. “We can establish this as a first step down the road, and we will see if others will achieve similar results.”
Strategy of Dual Targeting
Despite the success CAR T-cell therapy in childhood leukemia, the currently available products have limitations, Pui and colleagues note.
About half of patients treated with CD19 CAR T cells experience relapse within 1 year, owing either to loss of CAR T-cell persistence or to loss of CD19 antigen because of splice variants, acquired genetic mutations, or lineage switch.
With further treatment with CAR T cells directed against CD22, 70% to 80% of patients who failed CD19 CAR-T will achieve into complete remission. However, most will experience relapse.
Recent efforts in the field have turned to exploring the safety and feasibility of CAR T cells that target both CD19 and CD22. The results were not superior to those of the CD19 CAR T-cell therapy given alone, although sequential treatment has yielded promising response rates, the authors note.
They hypothesized that co-administration of CD19- and CD22-targeted CAR T cells would improve efficacy, as it could forestall the development of drug resistance.
Achieved 99% Remission
Pui and colleagues conducted a phase 2 trial that included 225 evaluable patients aged 20 years or younger who were being treated at five urban hospitals in and near Shanghai, China. Of this group, 194 had refractory disease or hematologic relapse, and 31 patients had isolated extramedullary relapse.
A safety run-in stage to determine the recommended dose was initially conducted. An interim analysis of the first 30 patients who were treated (27 at the recommended dose) showed that the approach was safe and effective. Additional patients were then enrolled.
The 192 patients (of 194) who achieved complete remission attained negative minimal residual disease status.
At a median follow-up of 11 months, 43 patients experienced relapse (24 with CD191/CD221 relapse, 16 with CD19– /CD221, one CD19– /CD22– , and two unknown), for a cumulative risk of 22.2%.
Transplant and Relapse Options
In an interview, Pui noted that various treatment options were available for the children who experienced relapse. “For patients who were in good clinical condition, we will treat them with molecular therapeutics, allogeneic CAR T cells from donor, or even repeated humanized CD19 and/or CD22 CAR T cells with or without CD20 CAR T cells in an attempt to induce a remission for allogeneic transplantation,” he said.
The site-specific 12-month event-free survival rate in the trial was 69.2% for patients who did not receive a transplant, 95% for those children who had an isolated relapse to the testicles, and 68.6% for those who had an isolated central nervous system (CNS) relapse.
After censoring 78 patients for consolidative transplantation, the 12-month overall survival was 87.7%.
Consolidative transplantation was performed in 24 of the 37 patients with KMT2A-rearranged or ZNF384-rearranged ALL and in 54 patients because of parental request. The reason for this was that patients with these two genetic subtypes of leukemia (KMT2A-rearranged and ZNF384-rearranged), under the pressure of phenotype-specific treatment (such as CAR T cells or blinatumomab), are at risk of lineage switch and development of secondary acute myeloid leukemia, explained Pui. “That is an even more resistant form of leukemia, and up to 5% to 10% of the patients have been reported to develop this complication.
“We performed consolidation transplantation in these patients to avoid the risk of lineage switch but would accept the parental request not to perform allogeneic transplant after they were clearly informed of the risk,” he told Medscape Medical News.
He also suggested that this approach of co-administration of two types of CAR T cells would be especially suitable for “patients with extramedullary involvement, because most of them will be spared of local irradiation so that they can preserve their neurocognitive function and fertility and avoid radiation-induced second cancer, such as brain tumor,” he said.
Lower Toxicity
With regard to toxicity, the majority of patients (n = 98, 88%) developed cytokine release syndrome, which was grade ≥3 in 64 (28.4%) patients and fatal in one. Neurotoxicity occurred in 47 (20.9%) patients, was of grade ≥3 in nine (4.0%) patients, and was fatal in two patients who received 12 x 106 and 5.6 x 106 CAR T cells/kg.
In addition, grade 3 or 4 seizure developed in 14.2% of the patients; it was more common in those who had presented with isolated or combined CNS leukemia. Grade 3 or 4 hypotension occurred in 40.9% of the patients. About three quarters of the patients were treated with tocilizumab (n = 67, 74.2%), and 79 (35.1%) were treated with corticosteroids.
“In general, CD19 and CD22 CAR T cells were less toxic than CD19 CAR T cells, the historical controls, in our experience,” said Pui. “There were three fatal complications, a rate not excessive considering a large number of patients were treated.”
Future Studies Needed
The researchers note that in this trial, the CD22 CAR T cells did not expand as robustly or persist as long as did the CD19 CAR T cells, and they hope that future studies will elucidate whether enhancing CD22 CAR T-cell persistence and activity would further improve outcomes.
The study was supported in part by the National Natural Science Foundation of China, the Shanghai Collaborative Innovation Center for Translational Medicine, the Research Programs of Shanghai Science, the Technology Commission Foundation, the US National Cancer Institute, the VIVA China Children’s Cancer Foundation, and the American Lebanese Syrian Associated Charities.
J Clin Oncol. Published online November 8, 2022.
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