Treatment outcomes for children, adolescents, and young adults with leukemia have improved dramatically over the last few decades, with a 5-year relative survival rate of 85.3%, according to the National Cancer Institute.
In pediatric acute myeloid leukemia (AML), rates of prolonged event-free survival now approach 70%, up from less than 50% around 1990. However, relapse is seen in about 20-40% of youngsters with AML, and in this group, the long-term survival story remains grim. Up to 70% do not survive highly toxic curative-intent regimens 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,” according to 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 using chemotherapy and stem cell transplantation.”
In their systematic literature review, the experts identified 12 cohort studies of relapsed AML carried out between 1980 and 2014 in a total of 1,928 patients younger than age 20; only one randomized clinical trial was reported. The average 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 risk-stratified treatment were lacking.
“There is no standard treatment for relapsed AML in children,” concluded Gertjan J.L. Kaspers, MD, PhD, of Emma Children’s Hospital, Amsterdam University Medical Center, in the Netherlands, and co-authors.
The most frequently reported statistically significant prognostic factor was duration of CR1, the review showed. Children treated with chemotherapy only in CR1 tended to have a better outcome after relapse than children receiving allo-SCT in CR1. However, allo-SCT appeared to be a more effective consolidation therapy than chemotherapy in children achieving CR2 after relapse.
Outcomes varied for CR2, with mean 2-year and 10-year overall survival rates of 64% and 31%, respectively, the review showed. Treatment regimens varied over time and even within the same study. “Future controlled clinical trials on pediatric relapsed AML will hopefully lead to more effective treatment, without undue side-effects,” the authors wrote.
“Interestingly, outcomes seem to continue to improve without the use of novel agents yet,” Kaspers told MedPage Today. “Therefore, better supportive care and probably improved allo-SCT must explain most of it. A worrying fact is that doing clinical trials has become more and more complex and time-consuming, making it less appealing for investigators to initiate studies.”
New drug therapies that can be combined with conventional chemotherapy provide opportunities to improve clinical outcomes. The emergence of novel 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 subgroups of patients, hold promise for improving outcomes, said Kaspers. New treatment modalities, including CAR T-cell therapy, also look promising.
Rigorous follow-up well into adulthood is of utmost importance for all survivors of pediatric relapsed AML, since new side effects and late effects can accompany new therapies, Kaspers emphasized in an earlier report.
Novel ways of using existing agents may also prove useful, he said. “After all, most if not all of the progress made in the treatment of pediatric AML over the past decades was achieved with the same old drugs.”
The current review findings are consistent with his 15-year experience treating children with relapsed AML, commented 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 not been major improvements over the time period reviewed.”
Randomized clinical trials are needed with international collaboration to adequately power them, Brown pointed out. “It will be equally important for these trials to incorporate novel molecularly targeted and immunotherapy approaches to capitalize on 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 ages 3 to 22 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 discrete subsets 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 heavily relapsed and refractory acute myeloid leukaemia suggests that this combination should be tested in newly diagnosed pediatric patients with high-risk acute myeloid leukemia.”
The investigators found that the recommended phase II dose of venetoclax was 360 mg/m2 (maximum 600 mg) combined with cytarabine (1,000 mg/m2 per dose for eight doses), with or without idarubicin (12 mg/m2 as a single dose). Out of 20 evaluable patients treated at the recommended phase II dose, 14 (70%) showed complete responses with or without complete hematological recovery after one cycle of therapy. Notably, ten patients (71%) were negative for minimum residual disease.
A total of 22 patients (66%) developed grade 3-4 febrile neutropenia, and bloodstream and invasive fungal infections were seen in six patients (16%) each. There was one treatment-related death due to colitis and sepsis.
Despite the greater prior therapy burden 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 using CPX-351 (Vyxeos). The data suggest that complete responses might be more frequent when venetoclax is combined with high-dose chemotherapy rather than with intermediate-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 investigators said. In addition, patients with exclusively BCL-XL-dependent samples had poor responses to therapy and one patient converted from BCL-2 dependence to BCL-XL dependence after one cycle of therapy.
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 relationships with industry.
Source: MedicalNewsToday.com
