Early Treatment Intensification in High Risk (HR)-AML Patients Using Allogeneic Hematopoietic Stem Cell Transplantion in a Randomized Multicenter Setting.
Authors: Illmer Thomas , Schaich Markus A. , Thiede Christian , Platzbecker Uwe , Hannes Wandt , Anthony Ho D. , Eckhard Thiel , Norbert Schmitz , Hermann Einsele , Andreas Neubauer , Reinhard Andresen , Walter Aulitzky , Matthias Haehnel , Hubert Serve , Wolfgang Berdel , Martin Bornhaeuser , Gerhard Ehninger 
Published: October 2019

Abstract
There are several biological markers that are now known to confer HR in AML patients as there are cytogenetic high risk aberrations, FLT3 length mutations with a high allelic ratio (AR) and the initial response to therapy as defined by more than 10% blasts in the “day 15” bone marrow blast count (d15). For most of those patients categorized as having HR-AML allogeneic transplantation comprises the only option of cure. Recently we reported (Platzbecker et al., Leukemia 2006) on a highly active transplantation strategy using reduced intensity conditioning that allowed for an upfront allogeneic transplantation in HR-AML patients as part of the induction treatment. In 2003 we started a multicenter randomized trial which investigates both the feasibility and efficacy of allogeneic stem cell transplantation as upfront intensification therapy in HR-AML patients. Here we report the feasibility of the approach. The study is being conducted in a classical 2×2 design with intensified treatment arms B and D that scheduled allogeneic transplantation in HR patients as part of the induction therapy (IT) during marrow aplasia achieved by DA (daunorubicin 60 mg/m2 - day 3–5; cytarabine 100 mg/m2 - day1–7). Intensified risk adapted therapy was compared to a “conventional” treatment strategy (arm A and C) which allows for allogeneic transplantation only in patients achieving remission after two induction courses (DA) with a complex aberrant karyotype or in patients with aberrant chromosome 7 and 5. We identified 109 patients with HR in the intensified treatment groups (B/D) where HR was defined by cytogenetic criteria (n=73); FLT3-AR (n=14) and d15 blast count (n=21). At the same time a fast search strategy was conducted and revealed donor availability (related or unrelated) in 92 patients (84.4%). Consequently, 46 out of 109 HR-AML patients assigned to the intensified treatment strategy (B/D) received allogeneic transplantation within the protocol (42.2%). In contrast, 8 out of 102 HR patients in the none-intensified treatment arms (A/C) were treated with allogeneic transplantation within the protocol (7.8%). Whereas 19 of 109 patients (17%) with an intensified treatment strategy (B/D) were transplanted after achieving remission, 27 of the 109 patients (25%) were treated with allogeneic transplantation during marrow aplasia after IT1 (n=9) or IT2 (n=18) respectively. Available donors were predominantly family donors for patients receiving transplant after IT1 (6/9) but were more often unrelated donors after IT2 (12/18). Allogeneic transplantation was performed in (B/D) HR-AML patients with a median time from diagnosis of the disease to transplantation of 54 days (range 29–204). In conclusion, early allogeneic transplantation is possible in 40–50% of HR-AML patients during the induction phase of therapy in a randomized AML trial. An early upfront transplantation strategy in aplasia is logistically challenging. However, the presented data show that given a fast search strategy at the time point of diagnosis about 25% of patient can be transplanted during the aplasia of induction therapy.