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S. Kayser et al.
plete remission was associated with higher 5-year relapse-free and overall survival as compared to consoli- dation chemotherapy: 45% (95%CI: 35-59%) and 53% (95%CI: 42-66%) versus 7% (95%CI: 3-19%) and 23% (95%CI: 13-38%), respectively. For patients undergoing allo-HCT, there was no difference in overall survival rates at five years according to whether it was performed in first [53% (95%CI: 42-66%)], or second [58% (95%CI: 31-100%); n=10] complete remission or with active disease/relapse [54% (95%CI: 34-84%); n=18] (P=0.67). Neither FLT3-ITD nor additional chromosomal abnormalities impacted survival. In conclu- sion, outcomes of t(6;9)(p22;q34) AML are poor with chemotherapy, and can be substantially improved with allo-HCT.
Introduction
Acute myeloid leukemia (AML) with t(6;9)(p22;q34) has been listed as a distinct entity in the World Health Organization classification since 2008 and accounts for a small group (1-2%) of AML patients.1,2 The translocation t(6;9), first described in AML in 1976,3 results in formation of the DEK-NUP214 chimeric fusion gene, where DEK at 6p223 is fused to NUP214 (formerly known as CAN), located at 9q34.4 This fusion gene acts as an aberrant tran- scription factor and alters nuclear transport by binding sol- uble transport factors.5 In addition, DEK-NUP214 has been reported to enhance protein synthesis in myeloid cells.6,7 In a murine model, DEK-NUP214 induced leukemia when transduced to long-term repopulating stem cells.8
Acute myeloid leukemia with t(6;9) occurs in children and adults, as reported in a retrospective cohort analysis of 69 patients (31 children and 38 adults) with a median age of 23 years, most of whom presented with de novo AML.2 Of note, 42-69% of pediatric and 73-90% of adult AML patients with t(6;9) are described to harbor a concomitant internal tandem duplication of the FLT3 gene (FLT3- ITD),2,9-13 while secondary cytogenetic abnormalities are observed in 12-19% of pediatric and adult patients.2,13
Clinically, t(6;9) AML has been associated with a poor prognosis in children and adults,2,12-15 with reported 5-year overall survival (OS) rates of 28% and 9%, respectively.2 With this, adult patients with this translocation are catego- rized into the adverse risk group according to the National Comprehensive Cancer Network guidelines.16 Allogeneic hematopoietic cell transplantation (allo-HCT) may improve survival if performed during first complete remis- sion (CR1).2,17 However, the results were hampered by the small number of patients. Even results derived from a large registry data base were inconclusive on this issue due to missing data on allo-HCT.15 Additionally, results on AML patients with t(6;9)(p22;q34) are rarely reported, although these patients were included in a recent large randomized trial.18 Thus, international multicenter cohort studies are the only opportunity to better describe characteristics and evaluate outcome according to treatment strategies.
The objectives of our study were to characterize a large cohort of AML patients with t(6;9)(p22;q34) in an interna- tional, multicenter cohort and to evaluate outcomes according to treatment.
Methods
Patients and treatment
Information on 178 patients with AML and t(6;9)(p22;q34) diagnosed between 1989 and 2016 was collected from fourteen
study groups/institutions in the US and Europe. Participating cen- ters were chosen upon network relationships of the first and last author. Detailed case report forms (including information on baseline characteristics, chemotherapy, allo-HCT, response, and survival) were collected from all participating centers. Inclusion criteria were adult patients with t(6;9)(p22;q34), eligible for inten- sive therapy (ECOG 0-2), including (but not limited to) allo-HCT. All patients who fulfilled these criteria were included by the par- ticipating groups/institutions, respectively. Diagnosis of AML was based on French-American-British Cooperative Group crite- ria19 and, after 2003, on revised International Working Group cri- teria.20 Chromosome banding was performed using standard techniques, and karyotypes were described according to the International System for Human Cytogenetic Nomenclature.21 FLT3 mutation screening for internal tandem duplications (ITD) and point mutations within the tyrosine kinase domain (TKD) was carried out at each institution per local practice.10,22 Data col- lection and analysis were approved by the Institutional Review Boards of the participating centers.
Treatment
One-hundred and seventy-six of the 178 patients (99%) received intensive induction treatment either within clinical trials (n=116) or according to local institutional standards (n=62). Treatment protocols included the Study Alliance Leukemia (SAL) AML9623 and AML200324 trials, the United Kingdom AML10,15 AML11,25 AML12,15 AML14,25 AML15,15 AML1626 and AML1727 protocols, as well as the ALFA 9801,28 980229 and 070230 trials. Induction therapy according to local standard most frequently consisted of the 7+3 regimen of anthracycline plus cytarabine (n=53). Two patients (1%) received either azacitidine or decitabine as induction therapy and both went on to allo-HCT. Response was assessed according to International Working Group recommendations.20 All studies were approved by the institutional review boards of the participating centers. All patients provided written informed consent for participation in one of the treatment trials or for therapy according to local stan- dards.
Statistical analysis
Survival end points including OS, relapse-free survival (RFS), cumulative incidence of relapse (CIR), and cumulative incidence of death in CR (CID) were defined according to the revised rec- ommendations of the International Working Group.20 Comparisons of patients' characteristics were performed with the Kruskal-Wallis rank sum test for continuous variables and Fisher’s exact test for categorical variables. The median follow-up time was computed using the reverse Kaplan-Meier estimate.31 The Kaplan-Meier method was used to estimate the distribution of RFS and OS.32 Confidence interval (CI) estimation for survival curves was based on the cumulative hazard function using Greenwood’s formula for variance estimation. Log rank tests were employed to compare survival curves between groups. A Cox proportional hazards regression model was used to identify
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haematologica | 2020; 105(1)