Improved Outcome for Patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) with Poor Risk Cytogenetics – Result from An Analysis on 172 Patients Receiving FLAMSA-RIC Conditioning for Allogeneic Stem Cell Transplantatioin (SCT).
Authors: Pfeiffer Tim , Schleuning Michael , Eder Matthias , Krejci Marta , Kolbe Karin , Scheid Christof , Arnold Renate , Gerbitz Armin , Bunjes Donald , Holler Ernst , Bug Gesine , Christopeit Maximillian , Greinix Hildegard , Stelljes Matthias , Bethge Wolfgang A. , Oruzio Daniel V , Dammann Elke , Rothmayer Margret , Meyer Ralf , Mayer Jiri , Schwerdtfeger Rainer , Ganser Arnold , Kolb Hans-Jochem , Schmid Christoph 
Published: April 2020

Abstract
To improve the results of allogeneic SCT for high-risk AML and MDS, the FLAMSA-RIC conditioning regimen for allogeneic SCT combines cytoreductive chemotherapy (fludarabine, HD AraC, amsacrine), followed three days later by reduced intensity conditioning (4Gy TBI/EDX). Since in particular patients with an unfavorable karyotype seemed to benefit from this approach (Schmid et al., JCO, 2005), we analysed the outcome of 172 patients with poor risk cytogenetics according to NCCN criteria, who had been allografted following FLAMSA-RIC conditioning in 11 European centres between 1999 and 2008. Median time from diagnosis to transplantation was 5 months. Donors were matched siblings, matched unrelated, or mismatched unrelated donors in 34%, 47%, and 19%. Patients suffered from progressive MDS (10%), de novo AML (47.5%), or secondary AML (43.5%). SCT was performed upfront, after primary induction failure, in CR1 and in relapsed disease in 17%, 33%, 22% and 28% of patients, respectively. Median patient age was 53 (18–71) years. 95 patients (56%) had a complex aberrant karyotype, 55 and 65 had abnormalities of chromosome 5 (−5/5q-) and 7 (−7/7q-), respectively. After a median follow up of 20 months, overall survival (OS) at 2 and 4 years was 46.4% and 40.5%, the respective leukemia-free survival was 37.7% and 32.0%. Causes of death were leukemia in 30%, and non-relapse mortality in 21%. Encouraging results were observed in patients with chromosome 7 aberrations or with a complex karyotype leukemia (4y OS=49.3% and 40.3%). In contrast, results were inferior in patients with chromosome 5 aberrations (4y OS=30%), mainly due to an increased rate of leukemia-associated death (p=.008). Patiens with MDS, who received allogeneic SCT as first line treatment, achieved a 4y OS of 80% despite unfavorable cytogenetics. Unlike, patients with secondary AML after MDS had an inferior outcome (4y OS=28%, p=.018). In a Cox regression model, a stage of remission at transplantation, a 8/8 or 10/10 matched family or unrelated donor, and lack of monosomy 5 or deletion 5q were associated with superior OS (p=.025, .05, and .05). In conclusion, allogeneic SCT following the FLAMSA-RIC regimen is a highly effective treatment for MDS and AML with unfavorable karyotype, comparing favourably with published data. In MDS, SCT should be performed before transformation into sAML. Long term remission is achieved in a substantial percentage of patients with complex karyotype disease and aberrations of chromosome 7. Aberrations of chromosome 5 may require alternative or additive strategies.