Early Allogenic Transplantation Improves Overall Survival (OS) and Event Free Survival (EFS) Independently of the Applied Chemotherapy in AML Patients with Unfavourable Cytogenetic Karyotype.
Authors: Becker Cornelia , Krahl Rainer , Al Ali Haifa , Heyn Simone , Poenisch Wolfram , Cross Michael , Lange Thoralf , Gerhardt Anke , Schulze Antje , Haehling Detlev , Schulze Manfred , Freund Mathias , Kettner Erika , Doelken Gottfried , Assmann Michael , Wolf Hans-Heinrich , Zschuppe Ernst , Peter Norma , Franke Astrid , Wedding Ullrich , Uharek Lutz , Kreibich Ute , Grobe Norbert , Ittel Thomas , Florschuetz Axel , Opitz Bernhard , Senftleben Kristiane , Schirmer Veronika , Fenchel Klaus , Fiedler Friedrich , Huhn Renate , Zojer Niklas , Helbig Werner , Niederwieser Dietger 
Published: October 2019

Abstract
AML patients with unfavourable cytogenetics generally have a poor outcome. Over the last decade a number of strategies to improving survival have been assessed by the East German Study Group (OSHO). Here, we analyse the results of three protocols (AML 93, AML 96 and AML 2002) for effects on outcome in younger patients (<60 years) with unfavourable cytogenetics.
Methods: Unfavourable cytogenetics, defined as abn 3q26, -5/5q-, -7/7q-, abn 11q23 or a multiaberrant clone were present in 20 (12,3%), 76 (20,5%) and 60 (26,3%) patients from the AML 93/96/2002 respectively. In the AML 93 protocol, therapy consisted of double induction (Idarubicin and standard dose AraC 3+7), followed by consolidation (Mitoxantron, Etoposide) and re-induction (Idarubicine + high dose AraC). In both AML 96 and AML 2002, a single course of induction therapy (intermediate dose AraC and Idarubicine 3+7) was repeated as the first consolidation for all patients achieving CR. In AML 96, patients in PR after the first induction received intermediate dose AraC and Mitoxantrone as a 2nd induction therapy. In AML 2002, both non-responders and those achieving PR were randomized between the same induction therapy or a more intensive regime (Mitoxantrone, Fludarabin and intermediate dose AraC).
Results: Of all patients with unfavourable cytogenetics (n=156), 40%, 50%, and 65% achieved CR in the AML 93, 96 and 2002 studies respectively, with no statistically significant difference between the CR rates in the three studies (p=0,19). OS and EFS were analyzed both with and without censoring HCT. OS and EFS in patients censored at the time of transplant was not different between the three AML studies although intensity of chemotherapy differed widely (standard, intermediate and high dose AraC). The same analysis performed without censoring allogenic HCT revealed OS at 3 years of 10% for the AML 93, 14% for the AML 96 and 34% for the AML 2002 study (log rank p < 10 −2). EFS at 3 years was 9%, 10% and 32% in the AML 93, 96 and 2002 respectively (log rank p < 0,10−3). In AML 96, 32% of the patients with unfavourable karyotype underwent HCT, 40 % of these in CR1. In AML 2002, 60% of such patients were transplanted and 75% of them were in CR1. The interval from diagnosis to HCT decreased from median 204 (range 142–329) days in the AML 96 to median 125 (range 47–321) days in the AML 2002 (p=0,001). This decrease was associated with fewer cycles of chemotherapy prior to transplant: Patients in the AML 96 protocol received a median of 3 courses (range 2–4) and those in AML 2002 a median of 2 courses (p= 0,002).
Conclusion: We conclude that intensity of induction and consolidation chemotherapy is not crucial for CR rate, OS or EFS in patients with unfavourable karyotype,. Improvement in OS and EFS was observed only using HCT as early as possible after CR1.