Double Induction Containing Two Courses Versus One Course of High- Dose AraC/ Mitoxantrone (HAM) and Autologous Stem Cell Transplantation Versus Prolonged Maintenance for Acute Myeloid Leukemia (AML).
Authors: Buchner Thomas , Berdel Wolfgang E. , Schoch Claudia , Haferlach Torsten , Serve Hubert L. , Kienast Joachim , Schnittger Susanne , Kern Wolfgang , Tchinda Joelle , Reichle Albrecht , Staib Peter , Ludwig Wolf-Dieter , Aul Carlo , Sauerland Maria-Cristina , Heinecke Achim , Woermann Bernhard , Hiddemann Wolfgang 
Published: April 2020

Abstract
Intensification by high-dose araC in post-remission (NEJM331:896,1994) or induction (Blood87:1710,1996; Blood88:2841,1996) therapy, and autologous stem cell transplantation (Lancet351:700,1998) are efforts to improve the cure rate in AML. Starting in 1999 the German AMLCG randomized the patients to receive double induction (Blood93:4116,1999) by TAD- HAM (TAD, standard dose thioguanine/araC/daunorubicin; HAM, high-dose araC 3 (age &lt;60y) or 1 (age 60+y) g/m2 x 6 with mitoxantrone) versus HAM-HAM. The 2nd course was initiated on day 21 in all patients of &lt;60 years and in those older patients with residual b.m. blasts. By the same up-front randomization patients &lt;60 years were assigned to post-remission BuCy myeloablative chemotherapy and autologous stem cell transplantation, or to prolonged maintenance by monthly reduced TAD courses (JCO21:4496,2003), whereas all patients of 60+ years went on to maintenance. Each of the two initial randomizations was balanced for the other, and was also balanced for age, de-novo versus secondary AML/high-risk MDS, cytogenetic groups (favorable, intermediate, unfavorable), LDH, and WBC. A total of 1770 patients entered the trial with 840 patients of &lt;60 years and 930 patients of 60+ years, 1324 patients with de-novo AML, 295 patients with AML after MDS, 97 patients with tAML, 54 patients with high-risk MDS. The outcome in the younger and older patients was 70% and 53% CR, 42% and 19% overall survival at 3 years, 40% and 19% relapse-free survival, and 47% and 23% ongoing remissions. The calculated dosage of araC delivered for remission induction differed by factor 2 within each age group. There was, however, no difference in the CR rate, overall survival, relapse-free survival, or remission duration between the two randomized induction arms in any age group. Furthermore, there was no such difference in any risk group defined by de-novo or other AML, favorable or intermediate or unfavorable karyotype, WBC, LDH, and day 16 residual b.m. blasts. Similarly, the randomization to autologous transplantation versus maintenance failed to produce different outcome in any prognostic subgroup. These findings were even true after adjustment for allogeneic stem cell transplantations which were performed with priority in patients having matched family donors. In conclusion, on the basis of age adapted TAD-HAM double induction and prolonged maintenance the cytotoxic potential may have been exhausted and may not be further escalated in any prognostic group of AML. Only novel targeted chemotherapy and optimized conditioning allogeneic stem cell transplantation is expected to contribute additional curative potential to current management for AML.