Prognosis of AML with Unfavourable Cytogenetics Treated with Intensive Double Induction Chemotherapy: An Analysis of 342 Patients from the German AMLCG-2000 Study.
Authors: Metzeler Klaus H. , Buske Christian , Braess Jan , Spiekermann Karsten , Feuring-Buske Michaela , Bohlander Stefan K. , Unterhalt Michael , Sauerland Maria-Cristina , Berdel Wolfgang E. , Wörmann Bernhard , Heinecke Achim , Büchner Thomas , Hiddemann Wolfgang 
Published: October 2019

Abstract
Background: The prognosis of patients with acute myeloid leukemia (AML) has improved in recent years, partly due to the use of intensive double induction chemotherapy. Patients with adverse cytogenetic risk factors, especially those with a complex aberrant karyotype, however, still have a grave prognosis. Previous results from the German AMLCG study group have shown that younger patients with a complex karyotype may profit from double induction therapy containing one course of high dose AraC. It is unclear whether further intensification of induction chemotherapy may prolong survival.
Methods: We investigated the outcomes of patients with unfavourable cytogenetics treated with either high-dose AraC and mitoxantrone (HAM) followed by thioguanine, conventional-dose AraC and daunorubicin (TAD) or with two courses of HAM in the prospectively randomized AMLCG-2000 trial. We included patients with unbalanced chromosomal aberrations (−5, −7, del(5q) or del(7q), or abnormalities involving 3q) and patients with a complex aberrant karyotype.
Results: A total of 392 patients with unfavourable cytogenetics were analysed. Of those, 261 had de novo AML, 51 had secondary AML following a myelodysplastic syndrome (sAML) and 30 had therapy-related AML (tAML). The rate of complete remissions (CR) was significantly higher in patients with de novo AML compared with secondary or therapy-related AML (39 % vs. 20% vs. 23%, P=0.01). The overall survival (OS), however, was significantly shortened only in patients with tAML but not in those with sAML (median OS, 43 d (tAML) vs. 248 d (sAML) vs. 213 d (de novo AML), P=0.027). 233 patients had a complex aberrant karyotype. Although their CR rate was similar to patients with other unfavourable cytogenetics, OS was significantly worse (median, 169 vs. 327 days, P<0.001). Among patients with a complex karyotype, those with 5 or more cytogenetic abnormalities had a significantly shorter event-free survival (EFS) than those with only 3 or 4 aberrations, but OS was similar. 171 patients were randomly assigned to HAM-HAM induction therapy and 171 received TAD-HA. Both groups were well matched with respect to baseline characteristics. The CR rate was 32% in both arms, and there were no significant differences in EFS or OS. When the impact of the induction regimen was analyzed for younger patients (≤ 60 years) with a complex karyotype (N=90), HAM-HAM induced a CR rate of 48%, compared to 34% with TAD-HAM (n.s.) and significantly prolonged the EFS (median, 85 vs. 61 days; P=0.037). So far, this advantage in the EFS did not translate into an improved OS.
Conclusion: Among patients with AML and unfavourable cytognetics, subgroups with different risks for relapse and death can be identified. Therapy-related AML with adverse cytogenetic features had a particularly bad prognosis in this trial. For the total cohort, double induction with HAM-HAM does not result in significantly improved outcomes. However, younger patients with a complex karyotype may profit from treatment with two courses of high-dose AraC.