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Outcome of adult t(6;9) AML
therapy.49 Therefore, the HiDAC approach might be beneficial in patients with t(6;9) and should be addressed further.
In addition, anthracycline dose intensification during induction therapy with daunorubicin at 90 mg/m2 has been shown to have a beneficial impact,27 not only in patients with core-binding factor leukemia,50 but also in patients with FLT3-ITD.27,51 Although our analysis includ- ed patients from the AML17 trial (n=22), which studied high-dose daunorubicin, no meaningful analysis could be made due to the low number of patients.
In our analysis, we found that allo-HCT resulted in an excellent RFS and OS, which is in line with the data of Ishiyama et al.17 In a matched-pair analysis of de novo AML using data from the Japanese allo-HCT data registry, they compared outcome of 57 patients with t(6;9) to that of 171 patients with normal karyotype.17 All patients received an allo-HCT between 1996 and 2007, either in CR1 or CR2 (n=116), or with active disease (n=112). In patients with t(6;9), the 5-year OS (45% vs. 40%), disease-free survival (42% vs. 33%), CIR (42 vs. 45%), and non-relapse mortal- ity (16 vs. 22%) did not differ from those observed in AML with normal karyotype.17 Nevertheless, the results were hampered by a lack of molecular profile in the group of AML with normal karyotype, as well as lack of data on FLT3-ITD mutational status in AML with t(6;9). Our data are particularly impressive when compared to the dismal survival of patients with t(6;9) disease treated with chemotherapy alone. Thus, allo-HCT seems to ameliorate outcome in patients with t(6;9), with outcomes compara- ble to those of patients with intermediate-risk cytogenet- ics.52 As expected, CIR was significantly reduced in our cohort after allo-HCT performed in CR1 as compared to intensive consolidation chemotherapy.
Since supportive care might have impacted outcome, we have included the decade of treatment in multivariable analysis. However, this had no impact on overall survival. In addition, neither type of conditioning nor donor type had any impact on outcome. Outcome after allo-HCT was also favorable if performed in CR2, or even with active disease. Overall, this suggests the existence of a specific and very strong graft-versus-leukemia effect in this molec- ular context. Of note, recently presented data by Beya et al. on behalf of the EBMT demonstrated similar efficacy of allo-HCT in AML with t(6;9) transplanted in CR2 or active (relapsed/refractory) disease.42 Although this partly sup- ports the finding from our cohort, we would like to emphasize that retrospectively collected data have serious limitations since the factors for allocating patients to allo- HCT, such as co-morbidities, individual assessment of the treating physician, choice of conditioning, and availability of a donor, remain unknown, and this needs to be taken into account when evaluating the value of allo-HCT in our series.
Despite the large number of patients with FLT3-ITD, only thirteen patients were treated with TKI, either front- line with lestaurtinib (n=6) in combination with intensive induction chemotherapy,40 or after relapse either with sin- gle-agent gilteritinib41 or sorafenib (n=6), or with lestaur- tinib in combination with intensive chemotherapy (n=1). Interestingly, all six patients who received front-line lestaurtinib + chemotherapy achieved a CR, whereas TKI treatment ± chemotherapy in relapsed patients showed limited efficacy, with only two patients achieving CR2. Currently, midostaurin is the only approved TKI in de novo
Figure 4. Overall survival after allogeneic hematopoietic cell transplantation according to remission status.
AML with FLT3 mutations, based on the positive results from the large, international randomized phase III trial.18 The combination of midostaurin with intensive chemotherapy significantly improved OS in younger adults with FLT3-mutated AML, as compared to the place- bo arm. In that study, patients receiving an allo-HCT in CR1 had a better outcome if they were treated with midostaurin during induction therapy, suggesting that the optimal treatment strategy in FLT3-mutated AML would be to move on to allo-HCT early in CR1.18 Unfortunately, no data were presented either in the manuscript or in the supplement for the small subgroup of patients character- ized by t(6;9).18 Thus, the impact of adding TKI to induc- tion chemotherapy in t(6;9) AML is currently unknown.
Conclusions
Our cohort of AML patients with t(6;9)(p22;q34) showed a high CR rate after intensive induction therapy, suggesting that these patients should be candidates for intensive induction therapy whenever possible. Despite the initial high chemo-sensitivity of the disease, treatment with consolidation chemotherapy alone resulted in dismal survival outcomes. Thus, based on our encouraging results with allo-HCT, this should be standard of care whenever possible for these patients.
Funding
SK gratefully acknowledges to be supported by the Olympia- Morata fellowship program from the Medical Faculty of the Heidelberg University as well as financial support by Deutsche Forschungsgemeinschaft within the funding program Open Access Publishing, by the Baden-Württemberg Ministry of Science, Research and the Arts and by Ruprecht-Karls- Universität Heidelberg. MJL is supported by a grant from the NCI (NCI Leukemia SPORE P50 CA100632). RBW is a Leukemia & Lymphoma Society Scholar in Clinical Research. ZR, JM, PZ and TS were supported by the Ministry of the Czech Republic, grant No. 15-25809A. Data from the AML10, AML11, AML12, AML14, AML15, AML16, and AML17 tri- als were supplied by Cardiff University HCTU on behalf of the NCRI AMLWG.
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