Compared with standard chemotherapy, blinatumomab as consolidation prior to hematopoietic cell transplantation (HCT) is associated with fewer severe toxicities, higher response rates, and longer survival in children and young adults with high-risk relapse of B-cell acute lymphocytic leukemia (B-ALL), according to a results from a phase III trial presented at the 2019 ASH Annual Meeting.
"The current standard treatment for children and young adults with relapsed B-ALL is re-induction chemotherapy in an attempt to induce a second remission, followed by bone marrow transplant," lead investigator Patrick A. Brown, MD, from Johns Hopkins University in Baltimore, told ASH Clinical News. In the Children's Oncology Group Study AALL1331, researchers sought to determine if substituting the bispecific antibody blinatumomab for intensive consolidation chemotherapy could improve survival in patients with a first relapse of B-ALL. Dr. Brown shared findings from an analysis of patients who had high- or intermediate-risk relapse.
"High-risk" referred to early relapse, within 3 years of diagnosis if the relapse occurred in the bone marrow or within 18 months of diagnosis if the relapse occurred outside of the bone marrow. "Intermediate-risk" referred to later relapse but with detectable minimal residual disease (MRD) after the first month of re-induction chemotherapy.
A total of 208 patients (median age = 9 years; age range = 1-29 years) were enrolled and randomized to one of 2 arms:
- arm A: 2 intensive consolidation chemotherapy blocks (dexamethasone, mitoxantrone, methotrexate, PEG-asparaginase, vincristine; n=103)
- arm B: Two 4-week blocks of blinatumomab, with each block followed by 1 week of rest (n=105)
Patients in both arms were scheduled to proceed to HCT after consolidation.
After a median follow-up of 1.4 years, the 2-year disease-free survival (DFS; primary endpoint) rate was significantly higher in the blinatumomab arm: 59.3% vs. 41.0% (p=0.05). The rate of 2-year overall survival (OS), a secondary endpoint, also was higher with blinatumomab versus standard chemotherapy: 79.4% versus 59.2% (p=0.005).
Dr. Brown offered three reasons for the substantial DFS and OS improvement with blinatumomab. "First, the toxicities the patients experienced in the blinatumomab arm were far less than what patients experienced in the chemotherapy arm," he said.
Rates of grade â‰¥3 AEs in block 2/3 of arm A and blocks 1/2 in arm B were similar:
- febrile neutropenia: 44%/46% vs. 4%/0%
- infections: 41%/61% vs. 10%/11%
- sepsis: 14%/21% vs. 1%/2%
- mucositis: 25%/7% vs. 0/1% (p<0.001 for all comparisons except for p=0.16 for mucositis)
Selected blinatumomab-related AEs in cycle 1 and 2 of arm B included:
- cytokine release syndrome (CRS): 22% and 1%, respectively
- seizure: 4% and 0%
- other neurotoxicity (cognitive disturbance, tremor, ataxia, dysarthria): 14% and 11%
During the study, all AEs associated with blinatumomab fully resolved. In arm A, though, 4 patients in arm A experienced a fatal AE (all infection-related), compared with none in arm B (p=0.05).
"Second, blinatumomab was much more effective in clearing any residual disease that the patient had at the end of re-induction chemotherapy before transplant," Dr. Brown continued. Of patients who had detectable MRD after re-induction chemotherapy, more patients in arm B achieved undetectable MRD levels (<0.01%): 79% vs. 21% (p<0.0001).
The lower toxicity and improved disease clearance "translated into the third point, which is that, in the experimental arm, a much higher portion of patients actually made it to bone marrow transplant [73% vs. 45%; p<0.001], which we believe is the one standard curative therapy for this group of patients," he reported.
While Dr. Brown said that the results of this analysis establish blinatumomab as a new standard of care for consolidation therapy in patients ages 1-30 with high-risk relapse, the study does not yet change practice for patients with lower-risk relapse or for patients outside the tested age range. "Further studies are needed to determine whether blinatumomab is better than chemotherapy for lower-risk patients with late relapse that are MRD negative," he told ASH Clinical News.
Study authors reported relationships with Amgen, the manufacturer of blinatumomab.
Brown PA, Ji L, Xu X, et al. A randomized phase 3 trial of blinatumomab vs. chemotherapy as postreinduction 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. Abstract #LBA-1. Presented at the 2019 ASH Annual Meeting, December 10, 2019; Orlando, FL.