Clinical Impact of Additional Cytogenetic Aberrations, cKIT and RAS Mutations, and Treatment Elements in Pediatric t(8;21)-AML: Results From an International Retrospective Study by the International Berlin-Frankfurt-Münster Study Group

Abstract

Purpose This retrospective cohort study aimed to determine the predictive relevance of clinical characteristics, additional cytogenetic aberrations, and cKIT and RAS mutations, as well as to evaluate whether specific treatment elements were associated with outcomes in pediatric t(8;21)-positive patients with acute myeloid leukemia (AML). Patients and Methods Karyotypes of 916 pediatric patients with t(8;21)-AML were reviewed for the presence of additional cytogenetic aberrations, and 228 samples were screened for presence of cKIT and RAS mutations. Multivariable regression models were used to assess the relevance of anthracyclines, cytarabine, and etoposide during induction and overall treatment. End points were the probability of achieving complete remission, cumulative incidence of relapse (CIR), probability of event-free survival, and probability of overall survival. Results Of 838 patients included in final analyses, 92% achieved complete remission. The 5-year overall survival, event-free survival, and CIR were 74%, 58%, and 26%, respectively. cKIT mutations and RAS mutations were not significantly associated with outcome. Patients with deletions of chromosome arm 9q [del(9q); n = 104] had a lower probability of complete remission (P = .01). Gain of chromosome 4 (+4; n = 21) was associated with inferior CIR and survival (P < .01). Anthracycline doses greater than 150 mg/m2 and etoposide doses greater than 500 mg/m2 in the first induction course and high-dose cytarabine 3 g/m2 during induction were associated with better outcomes on various end points. Cumulative doses of cytarabine greater than 30 g/m2 and etoposide greater than 1,500 mg/m2 were associated with lower CIR rates and better probability of event-free survival. Conclusion Pediatric patients with t(8;21)-AML and additional del(9q) or additional +4 might not be considered at good risk. Patients with t(8;21)-AML likely benefit from protocols that have high doses of anthracyclines, etoposide, and cytarabine during induction, as well as from protocols comprising cumulative high doses of cytarabine and etoposide.

Decreased relapsed rate and treatment‐related mortality contribute to improved outcomes for pediatric acute myeloid leukemia in successive clinical trials

“…(Figure 5) Studies conducted by the Medical Research Council and the Berlin-Frankfurt-Münster Study Group (BFM) have also shown that children with AML and t(8;21) benefit from higher intensity therapy, based on either higher dose anthracycline or high dose cytarabine. 8-10 In contrast, increasing the intensity of therapy failed to decrease the risk of relapsed or refractory disease for high-risk patients on our AML02 protocol, emphasizing the futility of this approach for this subgroups of patients. Therefore, addition of novel agents, possibly with decreased intensity of conventional AML chemotherapy, may be appropriate for high-risk AML.…”

Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia. A NOPHO‐DBH‐AML study

“…In compliance with previous studies (Breems et al, 2008;Haferlach et al, 2012;Kayser et al, 2012), patients presenting either normal karyotype or CBF aberrations, including inv(16)/t(16;16) and t(8;21), were not included in the survival analysis, as the favourable prognostic influence of the latter independent from additional chromosomal abnormalities [e.g. sex chromosome loss (Klein et al, 2015) or del7q (Hasle, 2014)] will skew the differences in survival, and thus overestimate the adverse influence of MK on prognosis.Refractory disease was defined as no remission (blasts ≥5%) after two induction courses. Relapse was defined as ≥5% blasts in blood or bone marrow blasts or development of extramedullary disease.…”

Results of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia with t(8;21)(q22;q22)/RUNX1-RUNX1T1 and Additional Cytogenetic Abnormalities

“…Она встречается приблизительно у 7-8 % взрослых больных ОМЛ и у 12-14 % детей [1][2][3]. Согласно по-следней международной классификации ВОЗ 2008 г., этот вариант ОМЛ относится к категории лейкозов c повто-ряющимися генетическими аномалиями и относительно благоприятным прогнозом.…”

“…К настоящему времени к прогностически неблагоприятным факторам относятся наличие дополнительных хромосомных нарушений, прежде всего делеции del(9)(q22), трисомии некоторых хромосом, а также сложные нарушения кариотипа [2,3,[10][11][12][13][14]. Что же касается молекулярных маркеров, то про-гностически неблагоприятными являются мутации генов ASXL, BAALC, c-KIT, FLT3 [3,13].…”