Treatment-related myelodysplastic syndrome (t-MDS)/acute myeloid leukemia (AML) in children with cancer: A single-center experience

Abstract

Treatment-related myelodysplastic syndrome (t-MDS)/acute myeloid leukemia (AML) is a devastating early or late complication of treatment for childhood cancer related with a significant morbidity and mortality. We retrospectively studied survivors of childhood cancer. Overall, 287 patients were recorded in the databases and we identified three (1.04%) with t-MDS. The primary cancer diagnoses were Langerhans cell histiocytosis (one patient) and acute lymphoblastic leukemia (ALL; two patients). The mean age of patients was 12.1 years. All patients had received systemic antifungal treatment for invasive pulmonary aspergillosis successfully treated with voriconazole and liposomal amphotericin B before diagnosis of t-MDS. Two patients (66%) remain alive after a median follow-up period of 3.5 years.

Introduction

Treatment-related myelodysplastic syndrome (t-MDS)/acute myeloid leukemia (AML) (ICD-10: C94.6/C.92) is a devastating early or late complication of treatment for childhood cancer related with significant morbidity and mortality. Although relapse of primary cancer still remains the main cause of death in survivors of childhood cancer, t-MDS/AML represents a rare complication related with poor prognosis.

Hodgkin disease, non-Hodgkin lymphoma, Ewing sarcoma, and acute lymphoblastic leukemia (ALL) represent the most frequently underlying diseases. The major factors related to t-MDS are exposure to alkylating agents, stem cell transplantation, topoisomerase II inhibitors, and radiotherapy. ¹ According to the 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia no changes have been registered for t-MDS/AML in childhood. ²

The incidence of pediatric t-MDS is in the range of 1–6% in different studies.^3,4 Therefore, the aim of our study was to estimate the incidence of t-MDS/AML and describe the clinical characteristics and outcomes of patients with t-MDS/AML admitted in our department.

Case presentation

We searched databases of the Department of Pediatrics (hematogical malignancies, solid tumors) at the AHEPA Hospital for patients registered during 2000–2015. For each patient, we registered clinical and pathological characteristics (initial diagnosis, age, sex, treatment, latency period, age at the time of diagnosis of the t-MDS/AML). Overall, 287 patients were recorded in the databases and we identified three (1.04%) with t-MDS. The primary cancer diagnoses were Langerhans cell histiocytosis (ICD-10: 96.6) (one patient) and acute lymphoblastic leukemia (ICD-10: C.91) (ALL; two patients). The mean age of patients was 12.1 years. Conventional cytogenetic analysis performed on bone marrow aspirates demonstrated pathological findings in 2–3 patients (monosomy of chromosome 7 in the third patient; [add(15)(q26)] in the second patient). The first patient developed t-MDS after chemotherapy with antimetabolites and cytarabine due to relapse of the primary underlying disease (Langerhans cell histiocytosis) followed by progression to ALL. The second patient with ALL developed t-MDS during induction treatment with cytarabine and the third patient during consolidation treatment for ALL (after induction chemotherapy/radiotherapy). The second patient underwent spontaneous remission without intensive chemotherapy three months after discontinuation of combined antifungal treatment with voriconazole and liposomal amphotericin B for invasive pulmonary aspergillosis while the third patient developed AML. All patients had received systemic antifungal treatment for invasive pulmonary aspergillosis successfully treated with voriconazole and liposomal amphotericin B before diagnosis of t-MDS. Two patients received chemotherapy after progression to AML and ALL according to BFM AML 2004 and ALLIC BFM 2009 protocols while the third continued consolidation treatment for ALL according to ALLIC BFM 2009 protocol. Two patients (66%) remain alive after a median follow-up period of 3.5 years.

Discussion

In our retrospective analysis, the proportion of children diagnosed with t-MDS/AML among those admitted for malignancy was 1.04% and is similar to that reported in larger studies in literature.^1,3,4 In the larger pediatric study reported in literature performed at MD Anderson Cancer Centre during a 32-year period, the incidence of t-MDS/AML was 0.85% in concordance with our findings. ³

Although the etiology of t-MDS/AML remains still unknown, our patients have all possible predisposing factors such as intensive prior chemotherapy/radiotherapy treatment and genetic susceptibility. Additionally, we found that all our patients developed invasive pulmonary aspergillosis and underwent antifungal treatment with voriconazole combined or not with liposomal amphotericin B. These antifungal agents have a different and distinct mechanism of action by inhibition of the biosynthesis of ergosterol and by binding to the sterol component of a cell membrane, leading to cell death, respectively. Neither of the antifungals has a known direct or indirect effect on bone marrow but according to our data a certain question arises: Could the prolonged use of antifungals for invasive fungal infections cause damage to bone marrow cell precursors, thus predisposing them to arrest of growth or to malignant change? In our opinion more studies are needed to proof or not a possible correlation of systemic antifungal agents use with the development of t-MDS/AML in childhood.