Long-Term Results of a Low-Dose Cytarabine-Based Regimen for the Treatment of Acute Megakaryoblastic Leukemia and Myelodysplastic Syndrome in Children with Down Syndrome.
Authors: Hitzler Johann , Al-Ahmari Ali , Shah Niketa , Sung Lillian , Zipursky Alvin 
Published: April 2020

Abstract
Children with Down syndrome (DS) have an estimated 500-fold increased risk of acute megakaryoblastic leukemia (DS-AMKL), which is frequently preceded by a myelodysplastic syndrome. The leukemic blasts of DS-AMKL uniquely harbor somatic mutations of the hematopoietic transcription factor gene GATA1 and are highly sensitive to cytotoxic agents such as cytarabine in vitro. While DS-AMKL shows a favorable overall response to chemotherapy, highly dose-intensive chemotherapy regimens developed for the general pediatric population may result in excessive treatment-related mortality in children with DS. Thus, a low dose chemotherapy approach has been developed, in which low dose cytarabine (10 mg/m2/dose) is administered subcutaneously to out-patients over a prolonged period of time. We report the outcomes of 18 children with DS and AMKL (or MDS) treated with a low dose cytarabine-based regimen and 16 patients treated with standard dose chemotherapy at The Hospital for Sick Children and collaborating centers between 1990 and 2003 according to case-specific decisions taken by parents and treating physicians. The clinical features of patients in both groups were not significantly different. In the low dose group, 15 of 18 patients (83.3 %) achieved a complete remission. Of three patients with refractory leukemia, one achieved a long term remission after subsequent treatment with standard therapy and two died of disease progression (one patient after receiving no further intervention). Twelve of the 15 responders remain in continuous remission (median duration 93 months; range 4 to156 months). All five deaths (27%) in the low dose group were due to refractory or relapsed disease; in three cases no second chemotherapy regimen was used. Among three patients who did receive a second chemotherapy regimen (one with relapse, two with refractory disease), a long term remission was achieved in one. In the standard dose group, 15 of 16 patients (93.7%) achieved a complete remission lasting for a median duration of 57 months (range 5 to 152 months). One patient, who showed no response, was subsequently treated with intensive AML chemotherapy (UKMRCAML 10) and remains in remission. Three of the 15 responding patients relapsed: one patient received a stem cell transplant from a sibling donor and died 9 months later in remission from pulmonary hypertension; two patients were refractory to further therapy and died. In a intention-to-treat analysis, the event-free and overall survival were not significantly different in the low dose and standard dose group (EFS 66.7 and 75.0%, p=0.5; OS 76.5% and 80.4 %, p=0.6, respectively). In the entire cohort age, gender and cytogenetic abnormalities in addition to constitutional trisomy 21 were not associated with significant differences in survival. Within treatment groups patients 2 years and older at diagnosis had a lower EFS and OS after standard dose therapy. Both patients with monosomy 7 in the low dose group died compared to a EFS of 66.7% of 3 patients with monosomy 7 in the standard dose group. In both treatment groups, cytogenetic abnormalities other than monosomy 7 had no significant impact on outcome. Based on the largest experience reported to date on the use of low-dose cytarabine for the treatment of AMKL in children with DS, we conclude that this therapeutic option merits prospective evaluation.