The lead investigator of the study from the Children's Oncology Group said the findings represent a new standard of care.
Children with a first relapse of B-cell acute lymphoblastic leukemia (B-ALL) avoided infections and were more likely to receive a bone marrow transplant if treated with the immunotherapy blinatumomab instead of standard chemotherapy, according to a study presented Tuesday at the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida.
Use of blinatumomab improved survival by 20%, and the drop in minimal residual disease (MRD) was so dramatic that an independent review panel stopped the phase 3 trial of children and young adults early, after it was clear that the drug’s benefits were enough to set a new standard of care. Investigators had planned to randomize 220 patients when the study began in January 2015, but randomization was halted in September 2019 at 208 patients.
Blinatunomab, marketed by Amgen as Blincyto, is approved for use in relapsed and refractory B-ALL, but this trial from the Children’s Oncology Group sought to confirm its benefits in pediatric patients who have still have MRD after a month of chemotherapy following a relapse. Trial participants were 1-30 years of age.
Patrick A. Brown, MD, of the Johns Hopkins Kimmel Cancer Center and the study’s lead author, explained that prognosis is poor for the 15% of patients of children and young adults with B-ALL who have a relapse within the first 3 years of diagnosis. Getting these patients to transplant offers the best chance for a cure. But this has required a 2-part chemotherapy protocol that threatens survival if infections or other complications arise during the process, which can take up to 4 months.
“This is a new standard of care,” said Robert Brodsky, MD, director of the Division of Hematology at Johns Hopkins, who moderated a press briefing on the ASH late-breaking session. Pediatric B-ALL patients can be challenging to treat, he said, because “when they relapse, it’s very hard to get them back into remission.” Yet, driving down MRD levels is essential for a bone marrow transplant to work. The results presented Tuesday show that blinatumomab greatly improves those odds, Brodsky said.
In this study, patients who had a relapse all received the standard 1-month chemotherapy reinduction. They were stratified by risk level, based on the timing of their relapse or a measurement of MRD. Brown explained that those with early relapse, or late relapse but elevated MRD levels, proceeded to the consolidation phase that leads to transplant; these patients were randomized 1:1 to receive either 2 blocks of chemotherapy or 2 cycles of blinatumomab.
After a median follow-up of 1.4 years, the results showed:
“Based on our study, it appears that blinatumomab is a much more effective bridge to transplant for this patient population, leading to a much larger portion of patients who are actually able to receive a bone marrow transplant,” Brown said in a statement. “We believe that is the reason for the striking improvement in survival among patients who received blinatumomab.”
A bispecific T cell engager, or BiTE, blinatumomab binds specifically to CD19, a protein on the surface of B cells, and CD3, a protein expressed on the surface of T cells, causing the T cells to kill leukemia cells. When it was approved, blinatumomab reached the market at a list price of $178,000 for 2 cycles, making it one of the most expensive cancer drugs on the market at the time. However, a July 2017 analysis in the Journal of Medical Economics found it to be cost-effective based on its survival and quality-of-life benefits.
Importance of Reducing Infection Risk
In response to a question from The American Journal of Managed Care®, Brown explained that studies show the burden of life-threatening infection from chemotherapy in B-ALL falls more heavily on the adolescent and young adult (AYA) population compared with older patients. “It’s likely that the impact of improvement in survival with immunotherapy in the relapse setting may be particularly important in the AYA population, since the burden of infection seems to be greatest in those patients,” he said.
Brown said during the press briefing that the survival benefits for blinatumomab were driven in part by the reduced infection risk, as there were 4 infection-related toxicity deaths among patients in the traditional chemotherapy group and none in the blinatumomab group. A comparison of adverse events (AEs) of grade 3 or higher for the final 2 blocks of chemotherapy in the control group and the 2 cycles of blinatumomab appears as follows:
In the blinatumomab group, notable AEs included cytokine release syndrome; in the first cycle, 22% overall and 1% grade 3 or higher; in the second cycle, 1% overall, 0% grade 3 or higher. For other neurotoxicities, the rate was 14% overall, with 2% grade 3 or higher in the first cycle; 11% overall and 2% grade or higher in the second cycle. Investigators reported that all AEs were fully resolved.
Brown said future research in this area of treating pediatric B-ALL includes combining blinatumomab and checkpoint inhibitors, using immunotherapy to replace or augment reinduction chemotherapy, and using chimeric antigen receptor (CAR) T-cells to replace or augment hematopoietic stem cell transplant.
Brown PA, Ji L, Xu X, et al. A randomized phase 3 trial of blinatumomab vs chemotherapy as post-reinduction therapy in high and intermediate risk (HR/IR) first relapse of B-acute lymphoblastic leukemia (B-ALL) in children and adolescents/young adults (AYAs) demonstrates superior efficacy and tolerability of blinatumomab: a report from Children’s Oncology Group Study AALL1331. Presented at the 61st American Society of Hematology Annual Meeting and Exposition, Orlando, Florida; December 7-10, 2019; Abstract LBA-1.