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Cytogenetics, treatment variances may affect outcomes in pediatric t(8;21)-positive AML
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Pediatric patients with t(8;21)-positive acute myeloid leukemia and other cytogenetic aberrations or mutations may experience poorer outcomes, according to the results of an international retrospective study.
This patient population may benefit from treatment protocols with high doses of anthracyclines, etoposide and cytarabine, researchers wrote.
Kim Klein, MD, of the department of pediatric oncology at VU University Medical Center in Amsterdam, and colleagues from the International Berlin-Frankfurt-Münster Study Group assessed the relevance of clinical characteristics, cytogenetic aberrations, and cKIT and RAS mutations in pediatric patients with t(8;21)-positive AML. They also evaluated whether treatment elements corresponded with outcomes in these patients.
Klein and colleagues reviewed karyotypes from 916 pediatric patients diagnosed with t(8;21)-AML between 1988 and 2010 for the presence of additional cytogenetic aberrations. They screened 228 samples for cKIT and RAS mutations.
They used multivariable regression models to assess the relevance of different treatment platforms — such as anthracyclines, cytarabine and etoposide — during induction and overall treatment.
Study endpoints included the probability of achieving complete remission, cumulative incidence of relapse, and the probability of EFS and OS.
The final analysis included data from 838 patients. Of these, 767 (92%) achieved complete remission, and 452 (59%) remained in first complete remission until the end of follow-up.
The median overall time from diagnosis to achievement of complete remission was 38 days (interquartile range, 32-56).
At 5 years, researchers reported OS of 74%, EFS of 58% and cumulative incidence of relapse of 26%.
Of the 228 patients who died during the study period, 121 died during relapse. Eleven patients died during induction and 30 patients died as a result of refractory disease; 66 patients died while in complete remission.
The most common causes of death included progressive disease (n = 89), infection (n = 70), transplantation-related death (n = 21) and other toxicities (n = 9).
The presence of cKIT and RAS mutations did not appear associated with disease outcome. However, patients with deletions of the chromosome arm 9q (n = 104) had a lower probability of complete remission (P = .01).
Further, patients with gains of chromosome 4 (n = 21) experienced worse outcomes with regard to cumulative incidence of relapse and OS (P < .01 for both).
Treatment doses appeared associated with various outcomes. Anthracycline receipt in doses greater than 150 mg/m2 during first induction appeared associated with superior complete remission (P = .039), EFS (P = .033) and OS (P = .031). High-dose cytarabine (3 mg/m2) during induction appeared associated with better complete remission (P = .015) and higher EFS (P = .034).
Etoposide doses greater than 500 mg/m2 during induction appeared associated with longer EFS (P = .009) and OS (P = .022).
The use of a cumulative cytarabine dose greater than 30 mg/m2 appeared associated with a lower cumulative incidence of relapse (P = .029) and improved EFS (P = .007). Further, cumulative etoposide doses greater than 1,500 mg/m2 corresponded with lower cumulative incidence of relapse (P = .02) and improved EFS (P = .012).
The researchers acknowledged the uncertainty of treatment receipt as a study limitation.
“Multicenter, randomized trials are required to validate our results, establish combination therapy, define doses with acceptable toxicity and identify the impact of different treatment aspects among cytogenetic subgroups,” Klein and colleagues wrote. “Nevertheless, this is, to our knowledge, the largest pediatric t(8;21)-AML cohort evaluated for clinical, cytogenetic and treatment-related prognostic factors. Therefore, it provides valuable information about risk stratification for this AML subgroup.”
In an accompanying editorial, Emi H. Caywood, MD, and E. Anders Kolb, MD, both of the division of pediatric hematology and oncology at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., questioned whether effective clinical trials could be conducted in this pediatric population.
“Enrollment onto future studies will suffer in proportion to the bias of an expected benefit from treatment with a targeted therapy,” Caywood and Kolb wrote. “The design of clinical trials to evaluate novel therapy is further compounded by the discordant regulatory requirements between North America and Europe. … Given the high mortality rates of children with AML, international collaboration is urgently needed to address these challenges and to more rapidly identify improved therapies that both limit morbidity and improve survival. Although it is reassuring that intensification of conventional therapies has yielded benefit, we have seen in the past 10 years stagnancy or only small, incremental improvements in survival rates and high incidences of life-altering toxicities.” – by Cameron Kelsall
Disclosure: Klein reports no relevant financial disclosures. Other researchers report honoraria and travel expenses from and consultant roles with Boehringer Ingelheim, Celgene, Eusapharma, Galen Pharmaceuticals, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Medac, Pfizer and Takeda. Caywood and Kolb report no relevant financial disclosures.
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