Dexrazoxane-Associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease

Purpose Pediatric Oncology Group (POG) studies 9426 and 9425 evaluated dexrazoxane (DRZ) as a cardiopulmonary protectant during treatment for Hodgkin's disease (HD). We evaluated incidence and risk factors of acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and second malignant neoplasms (SMNs). Patients and Methods Treatment for low- and high-risk HD with doxorubicin, bleomycin, vincristine, and etoposide (ABVE) or dose-intensified ABVE with prednisone and cyclophosphamide (ABVE-PC), respectively, was followed by low- dose radiation. The number of chemotherapy cycles was determined by rapidity of the initial response. Patients were assigned randomly to receive DRZ (n = 239) or no DRZ ( n = 239) concomitantly with chemotherapy to evaluate its potential to decrease adverse cardiopulmonary outcomes. Results Ten patients developed SMN. Six of eight patients developed AML/MDS, and both solid tumors ( osteosarcoma and papillary thyroid carcinoma) occurred in recipients of DRZ. Eight patients with SMN were first events. With median 58 months' follow-up, 4-year cumulative incidence rate (CIR) for AML/MDS was 2.55% +/- 1.0% with DRZ versus 0.85% +/- 0.6% in the non-DRZ group ( P =.160). For any SMN, the CIR for DRZ was 3.43% +/- 1.2% versus CIR for non-DRZ of 0.85% +/- 0.6% ( P =.060). Among patients receiving DRZ, the standardized incidence rate ( SIR) for AML/MDS was 613.6 compared with 202.4 for those not receiving DRZ ( P =.0990). The SIR for all SMN was 41.86 with DRZ versus 10.08 without DRZ ( P =.0231). Conclusion DRZ is a topoisomerase II inhibitor with a mechanism distinct from etoposide and doxorubicin. Adding DRZ to ABVE and ABVE-PC may have increased the incidence of SMN and AML/MDS.