The Children’s Oncology Group (COG) Phase 3 AALL1331 trial, led by Dr. Patrick Brown of Johns Hopkins University, established the bispecific T-cell engager blinatumomab as a new standard of care for pediatric patients with a first relapse of intermediate- or high-risk B-cell ALL.
Lia Gore, MD, professor of pediatrics in hematology-oncology and bone marrow transplantation and co-director of the Developmental Therapeutics Program at the University of Colorado Cancer Center, spoke with Nucleus about what’s next for blinatumomab in pediatric ALL and whether the agent has a future in the frontline setting.
Dr. Gore was a co-investigator on the AALL1331 trial and led the preceding open-label Phase 1–2 trial, AALL1121, which was the first to demonstrate the antileukemic activity of single-agent blinatumomab in children with relapsed or refractory B-ALL. In a recent review article on moving immunotherapy into the frontline in ALL, on which she was the senior author, she wrote: “Blinatumomab is an excellent candidate for pediatric investigational studies in B-lineage ALL because it is the first readily available agent introduced as monotherapy that has had substantial capacity to induce MRD remissions.”
Blinatumomab received accelerated FDA approval in March 2018 for use in adults and children with B-ALL who are in their first or second remission and have detectable MRD at or above 0.1%. In the United States this was the first approval of a drug for childhood ALL in 12 years and the first regulatory approval of an immune-based therapy for pediatric ALL.
The most significant factor limiting the introduction of blinatumomab into the frontline setting, Dr. Gore said, is the “spectacular” success of chemotherapy in curing pediatric ALL. Cure rates for some children with low- or standard-risk disease approach 99%, setting an extremely high bar for establishing the superiority of any novel therapy. The long-term cost of cure can be high, however, with patients vulnerable to cardiac, orthopedic, endocrine, neurodevelopmental, and other late adverse effects.
“If we cure their cancer, but they need a kidney or heart transplant or a knee or hip replacement in their teens or young adulthood, that’s a significant medical cost, both to the individual patient and to society,” she said. “As the number of long-term survivors of childhood cancer grows, the burden of therapy becomes an increasing issue.”
In AALL1331, at a planned interim analysis after a median of 1.4 years of follow-up, patients treated with blinatumomab fared significantly better than controls on disease-free survival (59% vs 41%), overall survival (79% vs 59%), and ability to proceed to transplant (73% vs 45%). Among the patients who had detectable MRD at the completion of induction chemotherapy, 79% of those randomized to blinatumomab achieved undetectable MRD after one treatment cycle, compared with 21% of controls who received a second block of chemotherapy. Compared with patients in the blinatumomab arm, control patients who received chemotherapy alone experienced significantly more fevers, infections, sepsis, and mucositis; four patients in the control group died from infections. In the blinatumomab arm, the most common adverse event was cytokine release syndrome (22%); no patients died due to therapy-related toxicity.
Although these results strongly suggest that blinatumomab – as well as, perhaps, other bispecific T-cell engagers – could significantly reduce the burden of therapy in pediatric ALL, a cautious approach is required, said Dr. Gore. “Over time, numerous studies have tried to reduce therapy in pediatric ALL, but many of those trials resulted in more patients relapsing. Yes, our goal is to reduce toxicity, but not at the cost of reducing efficacy.”
Where blinatumomab may have substantial impact is in the treatment of certain groups of difficult-to-treat pediatric patients, she said. For example, children with Down syndrome have an elevated risk both for developing childhood leukemias and for experiencing high rates of toxicity from certain classes of chemotherapy agents.
“We know that we can give blinatumomab to children with Down syndrome without that risk of enhanced toxicity,” she said. “Blinatumomab does not affect the same cellular repair pathways as the chemotherapy agents that they have trouble with. So that is a really important advance for this vulnerable population. We also know that we can use blinatumomab safely in infants, another group that is challenging to treat and who cannot tolerate certain chemotherapy drugs.”
COG investigators are planning to follow up AALL1331 with a Phase III trial that will evaluate the augmentation of chemotherapy with either blinatumomab alone or blinatumomab in combination with a PD-1 checkpoint inhibitor in patients with relapsed B-ALL. This trial is expected to launch in Fall 2020.
“This new trial will test taking the next step in trying to remove chemotherapy from the treatment regimen for relapsed ALL,” said Dr. Gore.
Is it possible that in the foreseeable future chemotherapy can be eliminated from the treatment arsenal for pediatric ALL? “That is certainly a future we would all like to see,” she said. “I suspect it will be a while before we get there – but as we move cautiously toward that goal, agents like blinatumomab can help us do better at reducing toxicities and maximizing survivors’ quality of life.”
Citations for linked articles
[AALL1331 trial] Brown PA, Ji L, Devidas M, 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. Blood. 2019;134(S2):LBA-1. https://doi.org/10.1182/blood-2019-132435
[Phase 1–2 trial, AALL1121] von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol. 2016;34(36):4381-4389. doi:10.1200/JCO.2016.67.3301
[review article] Winters A, Gore L. Moving immunotherapy into the front line in ALL. Hematology Am Soc Hematol Educ Program. 2019;2019(1):209-217. doi:10.1182/hematology.2019000017
[accelerated FDA approval] U.S. Food and Drug Administration. FDA granted accelerated approval to blinatumomab (Blincyto, Amgen Inc.) for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia. 2018 March 29. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-granted-accelerated-approval-blinatumomab-blincyto-amgen-inc-treatment-adult-and-pediatric