Acute leukemia as a secondary malignancy in children and adolescents: Current findings and issues

Abstract

Secondary acute leukemia is a devastating complication in children and adolescents who have been treated for cancer. Secondary acute lymphoblastic leukemia (s-ALL) was rarely reported previously but can be distinguished today from recurrent primary ALL by comparison of immunoglobulin and T-cell receptor rearrangement. Secondary acute myeloid leukemia (s-AML) is much more common, and some cases actually may be second primary cancers. Treatment-related and host-related characteristics and their interactions have been identified as risk factors for s-AML. The most widely recognized treatment-related risk factors are alkylating agents and topoisomerase II inhibitors (epipodophyllotoxins and anthracyclines). The magnitude of the risk associated with these factors depends on several variables, including the administration schedule, concomitant medications, and host factors. A high cumulative dose of alkylating agents is well known to predispose to s-AML. The prevalence of alkylator-associated s-AML has diminished among pediatric oncology patients with the reduction of cumulative alkylator dose and limited use of the more leukemogenic alkylators. The best-documented topoisomerase II inhibitor-associated s-AML is s-AML associated with epipodophyllotoxins. The risk of s-AML in these cases is influenced by the schedule of drug administration and by interaction with other antineoplastic agents but is not consistently found to be related to cumulative dose. The unpredictable risk of s-AML after epipodophyllotoxin therapy may discourage the use of these agents, even in patients at a high risk of disease recurrence, although the benefit of recurrence prevention may outweigh the risk of s-AML. Studies in survivors of adult cancers suggest that, contrary to previous beliefs, the outcome of s-AML is not necessarily worse than that of de novo AML when adjusted for cytogenetic features. More studies are needed to confirm this finding in the pediatric patient population.

Secondary hematopoietic malignancies in survivors of childhood cancer

“…Another study by Hijiya et al 17 comparing outcomes of ALL, AML, and secondary AML using SEER data showed significantly lower 5-year survival (23.7%; P < .001) for children with secondary AML compared with those with de novo AML (53.2%). Twenty-four patients with secondary AML in a Children's Cancer Group study (CCG 2891) had lower remission induction rates, survival, and event-free survival than patients with de novo AML.…”

NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase

“…Another problem concerning use of a DNA-PK inhibitor is the occurrence of a second, therapy-related malignancy, such as leukemia or myelodysplastic syndrome, especially in combination with Top2 inhibitors, alkylating agents, and irradiation. 50,51 In the literature, Top2␣ is more abundantly expressed in cancer cells and regulates the cell cycle. 41,52 Inhibition of Top2␣ is responsible for cytotoxic effects on cancer cells, whereas inhibition of Top2␤ might influence the development of a second malignancy.…”

Adolescent and Young Adult Oncology, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology

“…58 Higher cumulative doses of cisplatin, ifosfamide, or epipodophyllotoxins are associated with hearing loss, renal dysfunction, and secondary AML, respectively. [59][60][61][62] See also the section on "Late Effects in AYA Cancer Survivors" in the complete version of these guidelines (available at NCCN.org).…”