Gemtuzumab Ozogamicin in Children and Adolescents With De Novo Acute Myeloid Leukemia Improves Event-Free Survival by Reducing Relapse Risk: Results From the Randomized Phase III Children's Oncology Group Trial AAML0531

Abstract

A B S T R A C T PurposeTo improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification. Patients and MethodsChildren, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children's Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m 2 /dose) administered once in induction course 1 and once in intensification course 2 (two of three). ResultsThere were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P ϭ .04) but not OS (3 years: 69.4% v 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P ϭ .39). Although remission was not improved (88% v 85%; P ϭ .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P ϭ .006). Despite an increased postremission toxic mortality (3 years: 6.6% v 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P ϭ .09), disease-free survival was better among GO recipients (3 years: 60.6% v 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P ϭ .07). ConclusionGO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML. J Clin Oncol 32:3021-3032. © 2014 by American Society of Clinical Oncology INTRODUCTIONAcute myeloid leukemia (AML) is among the most difficult to treat of the childhood cancers because of its disease heterogeneity, high relapse, and toxic mortality.1,2 Therapeutic advances have included chemotherapy intensification and adding allogeneic stem-cell transplantation (SCT). Children's Oncology Group (COG) legacy AML trials evaluated time-intensive induction and observed improvement in event-free survival rates (EFS) from 27% to 42%. 3,4 Matched family-donor (MFD) transplantation improved disease-free survival rates (DFS) by between 8% and 10% and postremission overall survival (OS) by between 5% and 13% in two previous phase III trials. 4,5 However, treatmentrelated mortality (TRM) increased substantially with therapy intensification. Supportive care improvements reduced TRM (from 19% to 12%). 4 However, it is increasingly evident that the limits of treatment intensification have been reached, 4,6,7 necessitating alternative approaches. JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R TVOLUME 3021The cell-surface antigen, CD33, is present in more than 80% of patients with AML but is absent from pluripotent hematopoietic stem cells and is a well established immunoconjugate target. 8,9 Early studies ...

Dose-related efficacy and toxicity of gemtuzumab ozogamicin in pediatric acute myeloid leukemia

“…This study could not be included since separate data in children were lacking. However, this study emphasizes the benefit of GO [38].…”

“…Four studies reported on the incidence of neutropenia [4,26,30,38]. Median incidence of neutropenia was 98% with a range from 40% to 100%.…”

Acute myeloid leukemia in children. Prospects for the optimization of treatment (review)

“…Улучшение 3-летней бессобытийной выживаемости [26] у больных ОМЛ сопровождалось повышением смертности взрослых, а не детей, что послужило основанием для снятия препарата с продаж в США в 2010 г. У детей экспе-риментальная терапия была продолжена и отчеты по исследованиям дают шанс на возрождение препарата в комбинированной терапии ОМЛ [27,28]. Ведутся исследования с использованием анти-СD33 в виде биспецифических антител (анти-СD33 и СD3).…”

The role of targeted therapy in the management of patients with AML

“…A children's oncology group study in newly diagnosed children with AML showed improved remission and event-free survival rates from the addition of a single GO dose of 3 mg/m 2 to standard intensive chemotherapy. 64 However, this effect was entirely counterbalanced by increased treatment toxicity, leading to no improvement in OS. In contrast, the French ALFA-0701 study conducted in older adults showed more promising results.…”