Clinical Challenge: Pediatric Relapsed AML

According to the National Cancer Institute, treatment outcomes for children, adolescents and young adults with leukemia have improved dramatically in recent decades, with a relative 5-year survival rate of 85.3%.

In pediatric acute myeloid leukemia (AML), long-term event-free survival rates are now approaching 70%, up from less than 50% around 1990. However, relapse is seen in approximately 20-40% of young people with AML, and in this group, the long-term survival story remains grim. Up to 70% survive non-toxic treatments with curative intent, such as intensive chemotherapy and allogeneic stem cell transplantation (allo-SCT).

“There is a clear and compelling rationale for developing therapies that specifically target the molecular abnormalities that cause leukemia,” said Patrick A. Brown, MD, professor of oncology and pediatrics at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School. of Medicine, in Baltimore, and colleagues, writing in Expert Review of Hematology. “Such therapies hold the promise of being more effective and less toxic than the standard approaches involving chemotherapy and stem cell transplantation.”

In their systematic literature search, the experts identified 12 cohort studies of relapsed AML conducted between 1980 and 2014 in a total of 1,928 patients under the age of 20; only one randomized clinical trial was reported. The mean median follow-up was 4.6 years and the duration of first remission (CR1) was 10.9 months. Although the researchers found that allo-SCT was routinely used in second complete remission (CR2), there was no consensus on optimal chemotherapy and the timing of allo-SCT, and well-defined prognostic factors on which to base a risk-stratified treatment. .

“There is no standard treatment for recurrent AML in children,” concluded Gertjan JL Kaspers, MD, PhD, of Emma Children’s Hospital, Amsterdam University Medical Center, in the Netherlands, and co-authors.

The most reported statistically significant prognostic factor was the duration of CR1, the review found. Children treated with chemotherapy alone in CR1 tended to have a better outcome after relapse than children who received allo-SCT in CR1. However, allo-SCT was found to be a more effective consolidation therapy than chemotherapy in children who achieved CR2 after relapse.

Outcomes varied for CR2, with mean 2-year and 10-year survival rates of 64% and 31%, respectively, the review found. The treatment regimens varied over time and even within the same study. “Future controlled clinical trials in pediatric relapsed AML will hopefully lead to more effective treatment, without unnecessary side effects,” the authors wrote.

“Interestingly, the results seem to continue to improve without the use of new agents,” Kaspers told MedPage Today. “Therefore, better supportive care and probably improved allo-SCT should explain the most. A worrying fact is that doing clinical trials has become increasingly complex and time-consuming, making it less attractive for researchers to start trials.”

New drug therapies that can be combined with conventional chemotherapy offer opportunities to improve clinical outcomes. The emergence of new agents, from the broadly applicable, such as the BCL-2 inhibitor, venetoclax (Venclexta), to the use of targeted agents such as FMS-like tyrosine kinase 3 (FLT3) inhibitors in small subsets of patients, shows promise improving results, Kaspers said. New treatment modalities, including CAR T-cell therapy, also look promising.

Rigorous follow-up well into adulthood is paramount for all survivors of pediatric relapsed AML, as new side effects and late effects may accompany new therapies, Kaspers emphasized in a previous report.

New ways of using existing agents could also be helpful, he said. “After all, most if not all of the advances made in the treatment of pediatric AML over the past few decades have been achieved with the same old drugs.”

The review’s current findings are consistent with his 15-year experience treating children with relapsed AML, noted Brown, who is also director of the pediatric leukemia program at the Sidney Kimmel Comprehensive Cancer Center. “Only a minority of these children survive, and there have been no major improvements over the period assessed.”

Randomized clinical trials are needed with international collaboration to give them enough power, Brown emphasized. “It will be equally important for these trials to incorporate new molecularly targeted and immunotherapy approaches to take advantage of the rapidly expanding understanding of AML biology,” he told MedPage Today.

Recently, a phase I dose-escalation study of venetoclax in combination with conventional intensive chemotherapy in patients aged 3 to 22 years with relapsed or refractory AML offered new hope, at least for some patients.

The addition of venetoclax was well tolerated and there was an overall response rate of 80%, said Jeffrey E. Rubnitz, MD, PhD, director of the Leukemia/Lymphoma Division at St. Jude Children’s Research Hospital in Memphis, and colleagues in The Lancet. oncology. However, poor responses were observed in separate subgroups of patients, including 100% of study participants with FLT3 activation; this occurs in 20-25% of patients with AML.

“To our knowledge, this is the first study of venetoclax in children and young adults with relapsed acute myeloid leukemia,” the researchers wrote. “The safety and activity of venetoclax plus chemotherapy in pediatric patients with highly relapsed and refractory acute myeloid leukemia suggests that this combination should be tested in newly diagnosed pediatric patients with high-risk acute myeloid leukemia.”

The researchers found that the recommended Phase II dose of venetoclax was 360 mg/m2 (up to 600 mg) in combination with cytarabine (1,000 mg/m2 per dose for eight doses), with or without idarubicin (12 mg/m2 as a single dose). ). Of the 20 evaluable patients treated with the recommended Phase II dose, 14 (70%) showed complete response with or without complete haematological recovery after one cycle of therapy. Notably, ten patients (71%) were negative for minimal residual disease.

A total of 22 patients (66%) developed grade 3-4 febrile neutropenia and six patients (16%) each had bloodstream and invasive fungal infections. There was one treatment-related death from colitis and sepsis.

Despite the greater burden of prior therapy in this pediatric study population, the overall response rate was similar to that reported in the AML 2001/01 study after two cycles of intensive therapy with fludarabine (Fludara), cytarabine, and granulocyte colony stimulating factor with or without liposomal daunorubicin, the authors pointed out.

The results also compared favorably with those reported in AAML1421 after one cycle of therapy with CPX-351 (Vyxeos). The data suggest that complete reactions may be more common when venetoclax is combined with high-dose chemotherapy rather than medium-dose cytarabine, Rubnitz and colleagues said.

The study also showed that there was no response in all five patients with FLT3 activation. “Combining venetoclax with FLT3 inhibitors is an attractive therapeutic approach for these patients,” the researchers said. In addition, patients with exclusively BCL-XL dependent samples showed poor response to therapy and one patient transitioned from BCL-2 dependence to BCL-XL dependence after one cycle of therapy.

Kristin Jenkins has been a regular contributor to MedPage Today since 2015 and is a columnist for Reading Room.

disclosures

Kaspers reported having no potential conflicts of interest.

Brown reported relationships with Novartis, Amgen, Kite, Kura Oncology and Takeda; the venetoclax study was funded by the National Institutes of Health, the American Lebanese Syrian Associated Charities, AbbVie, and Gateway for Cancer Research.

Rubnitz reported relationships with AbbVie and Gateway, and co-authors also disclosed industry relationships.

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