Characteristics and Outcome of Therapy-Related MDS Developing after Primary Cancer in Children.

Abstract

Treatment-related myelodysplastic syndrome (tMDS) is a serious complication of therapy of childhood cancer. Here we report on 59 patients (pts) (35 males, 24 females) with tMDS enrolled in the prospective study EWOG-MDS 98. Prior malignancy was ALL in 21 pts, AML in 5, lymphoma in 6, CNS tumors in 12, and other solid tumors in 15. Median age at diagnosis of tMDS was 11.2 yrs (range 1.2 – 23.2), and median time between first malignancy and tMDS 3.3 yrs (range 0.5 – 11.1). Disease was classified as refractory cytopenia in 15 pts, RAEB in 30 and RAEB-T in 14. Of the 47 pts with cytogenetic analysis at diagnosis, 77% had an abnormal karyotype, including 38% that were complex. Monosomy 7 with or without other abnormalities was detected in 38%. Progression of disease was noted in 26 of 52 evaluable pts at a median time of 2.5 mo (range 0.3 – 16) from diagnosis; the cumulative incidence of progression being 74%. After a median follow-up time of 20 mo (range 3–69) 28 pts are alive with an estimated 5-year overall survival of 32% (95% CI 20 – 51). No child survived beyond 15 mo from diagnosis without receiving allogeneic hematopoietic stem cell transplantation (HSCT). HSCT was performed in 45 pts. Source of stem cells was bone marrow in 24 pts, peripheral blood in 20 and cord blood in 1. The donor was an HLA-identical relative (MFD) in 18 cases, while 26 pts were transplanted from an HLA-matched or 1-antigen/allele disparate unrelated donor (UD) and 1 pt from a 2-antigen disparate parent. Preparative regimen included busulfan 16 mg/kg, cyclophosphamide 120 mg/kg and melphalan 140 mg/m2 in 32 pts. Prophylaxis of GVHD generally consisted of cyclosporine-A for MFD, combined with methotrexate and ALG for UD. Two patients had graft failure. The cumulative incidence of grade II–IV acute GVHD and chronic GVHD were 32% (95% CI 28 – 37) and 24% (95% CI 19 – 28), respectively. Twelve pts suffered transplant-related mortality (TRM), the cumulative incidence of TRM in pts transplanted from a MFD or UD being 12% and 39%, respectively (P=0.058). Prior therapy with platinum compounds was an independent predictor of an increased risk of TRM. Fifteen pts relapsed at a median time of 9 mo (range 2 – 29) after HSCT, the 5-year cumulative incidence of relapse being 44% (95% CI 21 – 66). A WBC > 4 G/L at diagnosis predicted a higher risk of relapse. Twenty-one of the 45 pts transplanted are alive and 19 are disease-free. The estimated 5-year EFS after HSCT was 27% (95% CI 15 – 47). Prior therapy with platinum compounds, a WBC > 4 G/L at diagnosis, and a female donor predicted inferior EFS, while HSCT from an UD versus MFD resulted in similar outcome (5-year EFS, 21% and 39%, respectively). AML-type therapy prior to HSCT did not improve survival. Innovative stragegies for improving the outcome of these patients are warranted.