Secondary AML After a History of Myelodysplastic Syndrome Is An Independent Adverse Prognostic Factor for Achievement of Complete Remission, Relapse-Free and Overall Survival. An Analysis of 2,819 Adult Patients with Newly Diagnosed AML Enrolled On Seven AMLSG Treatment Trials.

AML patients with a prior history of a myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN) (in the following referred to as secondary AML [s-AML]) in the new WHO classification are listed in the category “AML with myelodysplasia-related changes”. Patients with s-AML are considered to have an inferior outcome compared with de novo AML. Even after accounting for clinical and cytogenetic risk factors, s-AML is believed to remain an important predictor of poor outcome although mechanisms for this effect remain elusive. The minimal time period between diagnosis of MDS and occurrence of s-AML has been defined differently, 3 months by Cheson et al. (J Clin Oncol 1990) versus 6 months according to the WHO 2001 classification.

To study the clinical impact of s-AML in a large cohort of patients with newly diagnosed AML, in the context of clinical characteristics as well as cytogenetics and mutational status of the NPM1, CEBPA and FLT3 genes.

The study included 3,139 adult patients (median age, 53.5 years; range, 16-85 years) with newly diagnosed AML entered on 7 protocols of the German-Austrian AML Study Group (AMLSG) between 1993 and 2008. In all protocols intensive induction and consolidation therapy was used. Information on type of AML, karyotype and molecular marker status of NPM1 and FLT3 (internal tandem duplication [ITD]) was available in 2,858 of 3,139 (91%) and 2,126 of 3,139 (68%) patients, respectively. Since this report focuses on the comparison of s-AML versus de novo AML, patients with therapy-related AML (t-AML) and those lacking information on type of AML were excluded (n=200, n=120, respectively).

151 of the 2,819 patients (5.4%) were classified as s-AML, 122 with at least a 6-month (s-AML-6), and 29 with a 3- to 6-month (s-AML-3) time period of a preceding MDS or MDS/MPN. Compared with patients with de novo AML, those with s-AML-6 and s-AML-3 were significantly older (62 and 58 years vs 53 years; p<0.0001), and they had significantly lower median white blood counts (WBC) (6.9 and 4.6 vs 12.5 ×10⁹/L; p=0.005), lower percentage of bone marrow blast (50 and 52 vs 75%; p<0.0001) and of peripheral blast counts (22 and 20 vs 55%; p=0.004). Compared to patients with de novo AML, those with s-AML-6 or s-AML-3 showed more frequently MDS-related cytogenetic changes (as defined by WHO 2008) (22% and 31% vs 16%, p=0.02), whereas the frequency of cytogenetically normal AML was equally distributed (48% and 52% vs 49%). However, the distribution of molecularly defined subgroups in cytogenetically normal AML was significantly different (p<0.0001) with a lower frequency of the subgroups CEBPA^mut, NPM1^mut/FLT3-ITD^neg and FLT3-ITD^pos in s-AML-6 and s-AML-3 and a higher frequency of the triple-negative genotype (75% and 45% vs 28%). In univariable analyses for the clinical endpoints achievement of complete remission (CR), relapse-free (RFS) and overall survival (OS), s-AML-6 and s-AML-3 showed a significant inferior outcome (p<0.0001, equivalent for all endpoints). Therefore s-AML-6 and s-AML-3 were combined as s-AML for further multivariable analyses. In multivariable analyses, s-AML was consistently an independent adverse prognostic factor for the endpoints achievement of CR (OR, 0.48, p=0.0001), RFS (HR, 1.38, p=0.0005) and OS (HR, 1.27, p=0.02). In cytogenetic subgroup analyses, s-AML was an unfavorable factor for OS particularly in patients with cytogenetically normal karyotype AML (p=0.01) and in patients with the molecularly defined genotype NPM1^neg, FLT3-ITD^neg as well as CEBPA^neg (p=0.04). In as treated analysis, younger adult patients (age <61 years) with s-AML had a beneficial effect from allogeneic hematopoietic stem cell transplantation (HSCT) on OS (p=0.008).

In this large cohort of adult patients with newly diagnosed AML, s-AML showed consistent features irrespective of duration of prior history of MDS (>6 months versus 3 to 6 months) and was an adverse prognostic factor for achievement of CR, RFS and OS. Younger adult patients with s-AML appear to benefit from allogeneic HSCT.

No relevant conflicts of interest to declare.