Blinatumomab improves outcomes over chemotherapy as post-reinduction therapy for pediatric B-ALL
ORLANDO — Blinatumomab demonstrated superiority over chemotherapy as post-reinduction consolidation prior to hematopoietic stem cell transplantation among children and young adults with B-acute lymphoblastic leukemia in intermediate- or high-risk first relapse, according to results of the Children’s Oncology Group Study AALL1331 presented during the late-breaking abstract session of ASH Annual Meeting and Exposition.
Specifically, blinatumomab (Blincyto, Amgen) — a CD3-CD19 bispecific T-cell engager — appeared associated with fewer toxicities, higher rates of minimal residual disease (MRD) negativity, greater likelihood of patients proceeding to HSCT, and improved DFS and OS.
Due to a lack of adequate treatments, first relapse of B-ALL among children and adolescents and young adults (AYAs) often leads to subsequent relapse and death. This is especially true for patients in early relapse — which is designated as high-risk relapse and defined as marrow relapse within 36 months of diagnosis or isolated extramedullary relapse within 18 months of diagnosis — and those in late relapse, or intermediate-risk relapse, indicated by MRD of at least 0.1% at the end of re-induction chemotherapy.
“Cure rates for children, adolescents and young adults with ALL have improved dramatically over the years, but relapse still occurs in 15% of patients, and survival is poor after relapse, especially when relapse occurs early after diagnosis, or when the patient’s relapse has measurable residual disease after the first month of therapy,” Patrick A. Brown, MD, director of the pediatric leukemia program and associate professor of oncology at Johns Hopkins Medicine and Sidney Kimmel Comprehensive Cancer Center, said during a press conference. “Standard treatment approaches for these high-risk relapses include intensive chemotherapy for 3 to 4 months followed by a hematopoietic stem cell transplant.”
However, most patients are not able to proceed to transplant due to chemotherapy-related adverse events or lack of MRD-negative remission.
Because blinatumomab has demonstrated single-agent activity for children with relapsed/refractory B-ALL and adults with MRD-positive B-ALL, Brown and colleagues sought to evaluate whether substituting the agent for chemotherapy improved survival among patients aged 1 to 30 years with intermediate- or high-risk first relapse B-ALL.
After receiving reinduction chemotherapy (block 1), researchers randomly assigned 208 patients to receive two intensive chemotherapy blocks (n = 103; median age, 9 years; 52% male) or two 4-week blocks of blinatumomab (n = 105; median age, 9 years; 54% male), each followed by 1 week of rest. Patients in both arms then proceeded to HSCT.
“We planned to enroll and randomize 222 patients on this trial, but after 208 patients were enrolled and randomized, the trial was closed early when the independent data monitoring committee determined that the blinatumomab arm was superior,” Brown said.
DFS served as the study’s primary endpoint. Researchers also assessed adverse events, MRD response, OS and ability to proceed to HSCT.
Median follow-up was 1.4 years.
Researchers reported intent-to-treat 2-year DFS rates of 41% (± 6.2%) for the control group vs. 59.3% (± 5.4%) for the blinatumomab group (P = .05). Intent-to-treat 2-year OS rates were 59.2% (± 6%) for the control group and 79.4% (± 4.5%) for the blinatumomab group (P = .005).
“The improved survival with blinatumomab was likely related to three major factors,” Brown said. “The first was that patients treated with blinatumomab were much more likely to have their residual disease in their bone marrow cleared than the patients treated with chemotherapy. The second is that the rates of serious adverse events were much lower in the patients receiving blinatumomab than chemotherapy. The primary adverse events that were seen with chemotherapy included life-threatening or even fatal infections, and this was not seen with blinatumomab. Finally, patients treated with blinatumomab were far more likely to successfully proceed through therapy to receive a bone marrow transplant.”
Specifically, among patients with detectable MRD of at least 0.01% after reinduction chemotherapy, 21% assigned the control regimen and 79% assigned blinatumomab achieved undetectable MRD after the first block of their respective treatments (P < .0001).
In total, 45% of patients assigned chemotherapy and 73% of patients assigned blinatumomab proceeded to HSCT (P < .0001).
“Given the fact that transplant is the treatment most likely to cure patients with relapsed ALL, this third factor is particularly important,” Brown said.
More patients who received the chemotherapy regimen experienced grade or higher febrile neutropenia (block 2/block 3, 44%/46% vs. 4%/0%), infections (41%/61% vs. 10%/11%), sepsis (14%/21% vs. 1%/2%) and mucositis (25%/7% vs. 0%/1%; P < .001 for all except mucositis in block 3). Four patients in the control arm died of post-induction toxicities — all of which were infections — compared with no patients assigned blinatumomab (P = .05).
“The burden of infections was primarily seen within the chemotherapy arm. However, the first month of therapy before randomization also was associated with high rates of infection,” Brown said. “When we look at risk factors for which patients within the randomized treatment arm were most at risk for life-threatening or fatal infections, it was definitely skewed toward adolescents and young adults. That is something that has been seen in prior studies of ALL, as well. It’s likely that the impact of the improvement of survival with immunotherapy in the relapsed setting may be particularly important in that AYA population, because the burden of infections with chemotherapy seems to be greatest in those patients.”
Blinatumomab-related adverse events included cytokine release syndrome (block 2/block 3, 22%/1%), seizure (4%/0%) and other neurotoxicity (14%/11%). Researchers noted that all these adverse events fully resolved in patients.
“Based on these findings, blinatumomab constitutes a new standard of care in this setting,” Brown said. “We will be attempting to build on these results by optimizing immunotherapy in relapsed ALL with strategies such as combining blinatumomab with checkpoint inhibitors, attempting to use immunotherapy to replace or augment reinduction chemotherapy, and studying the ability of chimeric antigen receptor T cells to replace or augment transplant.” – by Alexandra Todak
Brown PA, et al. Abstract LBA-1. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Brown reports board of directors or advisory committee roles with Jazz Pharmaceuticals, Servier Laboratories and Novartis. Please see the abstract for all other authors’ relevant financial disclosures.