Blinatumomab was superior to standard chemotherapy in children, adolescents, and young adults at the first relapse of B-cell acute lymphoblastic leukemia (ALL) as post-reinduction consolidation therapy prior to hematopoietic stem cell transplant (HSCT), according to the results of a late-breaking study presented at the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition.1
Treatment with blinatumomab led to fewer and less severe toxicities, higher rates of minimal residual disease (MRD) response, and a greater likelihood of proceeding to transplant. Importantly, blinatumomab improved event-free survival and overall survival compared with standard chemotherapy.
“In children, adolescents, and young adults with B-cell ALL in first relapse—either early relapse or MRD-positive—blinatumomab is superior to standard chemotherapy as post-reinduction consolidation, and blinatumomab represents a new standard of care,” stated Patrick A. Brown, MD, of Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore.
Patrick A. Brown, MD
“From past experience, our understanding is that HSCT gives these children and young adults the best chance of cure. 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 proportion of patients who are actually able to receive HSCT. We believe that this is the reason for the striking improvement in survival among patients who received blinatumomab,” Dr. Brown stated.
“We are excited that these patients, whose survival has not substantially improved for decades, now have a new and better standard of care,” he added.
Blinatumomab is a CD3-CD19 bispecific T-cell engager that binds to CD19 on the surface of B cells and CD3 expressed on the surface of T cells. Blinatumomab is the first such agent to be approved by the U.S. Food and Drug Administration, and the indication is for patients with relapsed or refractory B-cell ALL.
This is the first trial to confirm the benefits of blinatumomab in pediatric patients who have MRD following an initial course of chemotherapy after relapse. These patients are typically unable to proceed to transplant and have a poor prognosis.
Although cure rates for children, adolescents, and young adults with B-cell ALL have improved dramatically over the past decades, about 15% will relapse. The prognosis for relapsed patients is poor, especially when relapse occurs within 3 years of diagnosis or when relapse is MRD-positive. Allogeneic stem cell transplant is considered the treatment of choice for this group of patients, but many cannot undergo transplantation due to adverse events from chemotherapy or an inability to achieve an MRD-negative second remission that is associated with optimal outcomes.
Methodology and Outcomes
Patients enrolled in the trial ranged in age from 1 to 30 years. All patients were treated with 1 month of induction chemotherapy. Patients who were identified as being at high or intermediate risk based on whether they had early relapse or later relapse with MRD-positive status were randomly assigned to two groups, receiving either 2 months of blinatumomab therapy or 2 additional months of standard chemotherapy (controls) followed by HSCT.
“Initially, the plan was to enroll 222 patients, but after 208 patients were enrolled, the study was closed early by the independent data-monitoring committee because the results in the blinatumomab arm were superior for the primary endpoint of disease-free survival [ie, survival without relapse or disease progression],” Dr. Brown stated.
At a median follow-up of 1.5 years, blinatumomab was associated with an 18% improvement in disease-free survival and a 20% improvement in overall survival compared with an additional 2 months of chemotherapy. The rate of disease-free survival was 59% in the blinatumomab group vs 41% in controls. Overall survival rates were 79% and 59%, respectively. Almost three-quarters (73%) of patients in the blinatumomab group were able to proceed to transplant, compared with 45% in the control group.
“We think the improvement in survival is likely related to three factors,” said Dr. Brown. First, patients treated with blinatumomab were more likely to be MRD-negative. Second, the rate of adverse events was lower with blinatumomab than with chemotherapy. Third, patients treated with blinatumomab were more likely to undergo HSCT.
“This last factor is possibly the most important in accounting for a survival difference,” Dr. Brown noted. “HSCT is the most likely treatment that can cure relapsed B-cell ALL,” he added.
Among patients with detectable MRD after the first month of chemotherapy, 79% of those in the blinatumomab group achieved undetectable MRD status compared to 21% treated with chemotherapy alone.
“In our trial, MRD clearance correlated with survival. This is not universally seen in other trials. It is controversial whether to use MRD as a surrogate for survival in clinical trials, so we decided to use disease-free survival from the time of randomization as the primary endpoint,” Dr. Brown explained in an interview.
Blinatumomab was associated with significantly fewer side effects compared with standard cytotoxic chemotherapy. Patients receiving chemotherapy had more fevers, infections, sepsis, and mucositis. Adverse events associated with blinatumomab in this trial included cytokine-release syndrome, seizures, and other neurologic effects, which fully resolved. There were four deaths in the chemotherapy group due to toxicity, and no deaths in the blinatumomab group.
“This is a practice-changing study,” Dr. Brown emphasized. “Blinatumomab has widespread access in the United States. It can be given off-the-shelf at every institution where these patients are treated.”
Future studies will look at strategies that build on these results, for example, by combining blinatumomab with a checkpoint inhibitor, using blinatumomab to replace or augment chemotherapy, and using the drug in combination with chimeric antigen receptor T-cell therapy to augment HSCT.
Robert A. Brodsky, MD
“Blinatumomab improves survival in B-cell ALL and is a new standard of care for high- and intermediate-risk children, adolescents, and young adult patients with B-cell ALL who are scheduled for bone marrow transplant. The big problem in B-cell ALL is that when patients relapse, it is difficult to get them into remission. This study shows that with blinatumomab, patients have a better chance of going on to transplantation, and transplantation is their best chance of a cure,” said ASH Secretary Robert A. Brodsky, MD, of Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore.
DISCLOSURE: The study was led by the Children’s Oncology Group, and blinatumomab was provided by Amgen. Dr. Brown has served in a consulting or advisory role for Novartis, Servier, and Jazz. Dr. Brodsky has served in a consulting or advisory role for Alexion and has received research funding from Achillion.
1. Brown PA, Ji L, Xu X, et al: A randomized phase III trial of blinatumomab vs chemotherapy as post-reinduction therapy in high and intermediate risk first relapse of B-acute lymphoblastic leukemia in children and adolescents/young adults demonstrates superior efficacy and tolerability of blinatumomab: A report from Children’s Oncology Group Study AALL1331. 2019 ASH Annual Meeting & Exposition. Abstract LBA-1. Presented December 10, 2019.
Howard J. Weinstein, MD
Commenting on the blinatumomab study, Howard J. Weinstein, MD, Chief of Pediatric Hematology-Oncology at Massachusetts General Hospital for Children and Harvard Medical School in Boston, said: “These are very promising results for children, adolescents, and young adults ...