There are few images as powerful as that of a child afflicted by acute leukemia. Vulnerable, and innocent, through no fault of their own, they must suddenly embark on a terrible and difficult journey. Unpredictable, random, and aggressive like an earthquake, leukemia threatens the future of our young. An unwelcomed invader, the disease transforms lives to a new reality that patients and families have no choice but to face, head-on.
Once universally fatal, B-cell acute lymphoblastic leukemia (B-ALL) can now be cured in most pediatric patients. Iterative improvements in treatment have consistently led to better outcomes through intensive, risk-adapted, dynamically adjusted combinations of chemotherapy and hematopoietic cell transplantation, until a seemingly impenetrable ceiling was reached. Until now.
The tipping point began with the success of immunotherapy. Monoclonal antibodies and chimeric antigen receptor T cells have revolutionized treatment in later lines, hinting that their use in earlier treatment lines could potentially break through the treatment barrier. Finally, as discussed at yesterday’s Plenary Scientific Session, the glass ceiling has shattered, and the journey to a cure for all children continues.
In the Children’s Oncology Group (COG) AALL1731 phase III clinical trial, patients with newly diagnosed, standard-risk B-ALL (aged 2-10 years) were randomized to receive standard therapy or two nonsequential cycles of blinatumomab plus chemotherapy. Children in the experimental arms achieved a three-year disease-free survival rate of 96%, compared to 87.9% in the control arms, leading to the early termination of randomization according to prespecified stopping criteria.
“With blinatumomab, all patients now have an outcome previously only seen in those of the most favorable risk group,” said lead study author Rachel E. Rau, MD. “The data leave little doubt.” Senior study author Mingon L. Loh, MD, PhD, agrees. “It already has changed our approach and has been incorporated into all of our ongoing clinical trials,” she said.
However, challenges remain, as 10 of 19 relapses observed in blinatumomab-treated patients involved the central nervous system. The drug was associated with cytokine release syndrome, neurological toxicity, and increased rates of infection. Additionally, the need for a continuous 28-day infusion is burdensome, particularly for patients living in remote locations, with quality-of-life analyses ongoing. As with all other medical innovations, the road towards widespread implementation is long. “If not every child who would benefit from blinatumomab has access to it, then what good have we done?” wondered Dr. Rau. As a global hematology community, we must advocate for and work toward access for all. For those of us working in health systems in low- and middle-income countries — where most patients with B-ALL live globally — it will be a difficult economic burden to bear. According to Dr. Loh, “balancing the use of this drug against the cost of taking care of patients who experience relapse outweighs its current cost.”
“The standard indications for blinatumomab keep piling on,” noted #ASH24 attendee Oscar González-Llano, MD, PhD, a senior pediatric hematologist at a university hospital in Monterrey, Mexico. “Meanwhile, investigators working in limited-resource settings are forced to study alternative strategies. Perhaps this is an opportunity to lower the intensity of chemotherapy or design shorter blinatumomab courses.”
Conducting the trial was a tremendous effort involving physicians, nurses, pharmacists, and administrators from more than 250 sites in the U.S. and Canada. There are many stories left to tell, such as that of Susan Conway, a research coordinator with decades of experience in the COG who came out of retirement to participate in this trial. She spent hours (including weekends and holidays) answering endless emails and calls to help investigators navigate the intricacies of the study. But the real heroes of the story are each child, parent, and caregiver who considered enrolling in AALL1731. Their journey is leaving an indelible mark on our field.
Since discovery of the efficacy of aminopterin in the 1940s by Sidney Farber, MD, the remarkable progress in science and clinical research in ALL continues — and is being witnessed by our generation. One of the greatest stories of triumph in modern medicine over a terrible disease carries on, with many chapters yet to be written, bringing us closer to the goal of curing every human diagnosed with leukemia around the world.
