Long-Term Continuing Second Complete Remission (CCR2) despite Allogeneic Stem Cell Transplantation in CR1: Results from the International Randomised Phase III Study Pediatric Relapsed AML 2001/01
Authors: Kaspers G.J.L. , Zimmermann M. , Reinhardt D. , Gibson B. , Tamminga R. , Armendariz H. , Dworzak M. , Ha S. , Hovi L. , Maschan A. , Baruchel A. , Bertrand Y. , Razzouk B. , Rizzari C. , Smisek P. , Smith O. , Stark B. , Creutzig U. 
Published: April 2020

Abstract
Relapse remains the commonest adverse event in newly diagnosed AML patients, and the reported long-term survival after relapse in pediatric AML is 20–30%. Allogeneic stem cell transplantation (allo-SCT) in CR1 is employed by several groups with the aim of reducing the relapse rate. There is a widely held view that patients with AML who relapse after an allo-SCT in CR1 have no or minimal chances of long-term survival. However, such a cohort has never been described in the literature. Therefore, the outcome of children with AML who received an allo-SCT in CR1 and who subsequently relapsed and were enrolled in study Relapsed AML 2001/01 is described. This is a prospective, randomised study for relapsed AML, excluding AML M3 and those &gt;18 years of age at initial diagnosis comparing FLAG with Daunoxome-FLAG. FLAG is given for 2 consecutive courses: fludarabine 30 mg/m2/day × 5 days, cytarabine 2 g/m2/day × 5 days, G-CSF 200 μg/m2/dose × 6 days, starting day −1. Liposomal daunorubicin (DaunoXome®, DNX; a new anthracycline with potentially less cardiotoxicity) at 60 mg/m2/day on days 1, 3 and 5 is added or not in a 1:1 randomised fashion to the first course of FLAG. After two courses, patients are eligible for allo-SCT, sometimes bridged by high-or low-intensity consolidation chemotherapy. Efficacy data for both arms are still blinded as the study remains open until the end of 2008. Thirteen groups worldwide are enrolling patients. More than 500 patients were registered by April 2008, but this analysis relates to 329 fully evaluable patients diagnosed before July 2007, who are known to have or have not received an allo-SCT in CR1. Reasons for allo-SCT in CR1 differ between groups, but in general it is reserved for higher-risk patients and predominantly those with a matched-sibling donor. As part of relapsed treatment, 214 patients underwent allo-SCT to consolidate second line therapy, and for 11 patients this was their second allo-transplant. Twenty-two (7%) of these 329 patients had undergone allo-SCT in CR1, 12 boys and 10 girls, the majority being between 1 and 10 years of age. Three out of these 22 patients had a favorable karyotype, i.e. inv(16) or t(8;21). The majority of these patients (17/22, 77%) had a late relapse (occurring at least one year from initial diagnosis) compared to 47% of relapsed AML patients who had not received an allo-SCT in CR1 (p=0.01). There was no significant difference in chemotherapy related morbidity or mortality between those children who had received an allo-SCT in CR1 and those who had not, including cardiotoxicity. The percentage of so-called poor early responders (more than 20% bone marrow blasts on day “28” sampled shortly before the 2nd reinduction course) was 24% versus 23% (n.s.) and the CR2 rate 45% versus 65% (p=0.09) in the yes and no allo-SCT in CR1 patients, respectively. Within late relapsed AML only, the rate of poor early responders was 23% versus 15% (n.s.) and the CR2 rate 50% versus 77% (p=0.03) in the yes and no allo-SCT in CR1 patients, respectively. Finally, 4-year probability of survival from relapsed AML was 27% (95%-C.I. 8–47%) in the “yes allo-SCT in CR1” subgroup compared to 33% (27–39%) in the remaining patients (n.s.). Limiting this analysis to late relapsed AML patients, it was 29% (6–53%) versus 45% (36–54), respectively (n.s.). Five of the 6 patients who survived after allo-SCT in CR1 (median follow up 2 years) received a second allo-SCT. In conclusion, the small number of trial patients who relapsed early and who had received an allo-SCT in CR1 suggests that clinicians may have been reluctant to enter these patients into trial. In general, patients with an early relapse of AML treated in this study have a reasonable chance of cure (Kaspers et al., ASH 2007 and 2008), but the very small number of such patients who had an allo-SCT in CR1 preclude any firm conclusions for that subgroup. Patients with a late relapse who have received an allo-SCT in CR1 appear to have a somewhat (but statistically not significant) inferior outcome compared to patients who were not transplanted in CR1. The probability of survival at 4 years from relapse of nearly 30% warrants the use of second line therapy in patients with a late relapse despite allo-SCT in CR1.