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S. Kayser et al.
Figure 2. Simon Makuch plot evaluating the impact of allogeneic hematopoietic cell transplantation (allo-HCT) assessed as a time-dependent co-variable in comparison with chemotherapy consolidation on overall survival.
Discussion
The focus of our study was to characterize adult AML patients with t(6;9) in an international cohort study and compare outcomes according to treatment strategies, with a specific focus on the impact of FLT3 mutations as well as the impact of allo-HCT as compared to conventional chemotherapy on survival.
We studied 178 patients (AML, n=173; MDS, n=5), all harboring the balanced translocation t(6;9)(p22;q34). A concomitant FLT3-ITD has been described in 42-69% of pediatric and 62-90% of adult AML patients with t(6;9),2,9- 13,42 but these reports were hampered by the availability of mutational status in only a subset of patients2,9,42 and/or analysis of a low patient number.9-12 In our large cohort, with available mutational status in 71% of patients, a con- comitant FLT3-ITD was detected in 62% and was signifi- cantly associated with higher WBC at diagnosis, which adds to previously published data.2,9-13,42 Preliminary data suggest that FLT3-ITD promotes leukemia induction by DEK-NUP214 in a murine model.43 However, a synergistic effect to explain the high coincidence of the two muta- tions has yet to be demonstrated. In contrast, FLT3-TKD mutations were uncommon in our cohort and were slight- ly less frequent than those reported in AML with normal cytogenetics.44 In addition, secondary cytogenetic abnor- malities were present in 21% of our patients, most com- monly including trisomy 13, and/or trisomy 8, or a com- plex karyotype. To date, there are still conflicting data regarding the impact of FLT3-ITD on outcome in AML patients with t(6;9).13,14,45 While results of a meta-analysis in 50 adult patients indicated an association between FLT3-ITD mutations and an inferior outcome in t(6;9) AML,45 others were inconclusive due to the low number of patients without FLT3-ITD,2 or did not find a significant adverse impact in pediatric AML patients,13,14 which may be due to an already very dismal prognosis.14 In our large cohort, neither a concurrent FLT3-ITD nor the presence of additional cytogenetic abnormalities had an impact on the achievement of CR or OS, which adds to the recent eval-
Figure 3. Kaplan Meier plot illustrating the influence of allogeneic hematopoi- etic cell transplantation (allo-HCT) performed in first complete remission on relapse-free survival.
Table 3. Multivariable Andersen-Gill model on overall survival. HR (95%-CI) P
FLT3-ITD*
Log10(WBC)*
Platelets (10x109/L difference)
Female gender
Age (10 years difference)
Type of AML#
Additional abnormalities
Decade**
Transplant status
1.35 (0.80-2.27) 0.26
1.69 (1.14-2.51) 0.009
1.00 (0.95-1.04) 0.92
1.43 (0.96-2.13) 0.08
1.22 (1.05-1.42) 0.01
0.83 (0.44-1.56) 0.55
1.09 (0.67-1.77) 0.74
0.81 (0.58-1.13) 0.22
0.55 (0.33-0.90) 0.02
AML: acute myeloid leukemia; CI: confidence interval; HR: hazard ratio; ITD: internal tandem duplication; OS: overall survival; WBC: white blood cell count. *Sensitivity analysis revealed no significant interaction between transplant status and FLT3-ITD (P=0.44) or WBC (P=0.12) **Decade, 1989-1999, 2000-2009, 2010-2016. #Type of AML denotes: de novo versus therapy-related/secondary after previous myelodysplastic syn- drome/myeloproliferative neoplasm.
uation by the European Society for Blood and Marrow Transplantation (EBMT).42
Previous publications in adult AML patients with t(6;9) reported a fairly low CR rate of 33-58% in adult patients.2,46 In contrast to these reports, we observed a high CR rate of 81%. The favorable CR rate in our cohort after intensive chemotherapy was in part due to a high response rate of 66% after intensive salvage chemothera- py in patients with failure after standard induction thera- py. Intensive combination chemotherapy that incorpo- rates higher doses of cytarabine is frequently used in patients with relapsed/refractory AML, but no specific sal- vage regimen has emerged as standard. While CR/CRi rates with intensive combination chemotherapy were overall below 40% and nearly similar in refractory (36%) and relapsed AML (36.8%),47,48 the observed CR rate of 66% in our cohort points to a high sensitivity towards higher doses of cytarabine in patients with initial induc- tion failure. Particularly patients with adverse-risk cytoge- netics or FLT3-ITD were shown to benefit from HiDAC
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