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Outcome of adult t(6;9) AML
prognostic variables for OS.33 The following variables were included in the Cox models: age at diagnosis, gender, logarithm of white blood cells, platelet count, FLT3-ITD mutational status, and detection of additional cytogenetic abnormalities. The effect of allo-HCT on OS as a time-dependent intervening event was tested by using the Mantel-Byar method34 for univariable and Andersen-Gill model for multivariable analyses.35 The method of Simon and Makuch was used to estimate survival distributions with respect to time-dependent interventions.36
The individuals at risk were initially all represented in the chemotherapy group. If patients received an allo-HCT, they were censored at this time point in the chemotherapy group and fur- ther followed up within the allo-HCT group.
Cumulative incidence of relapse and CID and their standard errors were computed according to the method described by Gray37 and included only patients attaining CR. Missing data were replaced by 50 imputations using multivariate imputations by chained equations applying predictive mean matching.38 Backward selection applying a stopping rule based on P-values was used in multivariable regression models to exclude redun- dant or unnecessary variables. All statistical analyses were per- formed with the R statistical software environment, version 3.3.1, using the R packages prodlim, version 1.5.7, and survival, version 2.39-5.39
Results
Study cohort
Overall demographic and clinical data were collected from 178 patients (MRC, n=75; SAL, n=27; Fred Hutchinson Cancer Research Center, Seattle, n=12; ALFA, n=12; Dana-Faber Cancer Institute and Massachusetts General Hospital, Boston, n=12; Johns Hopkins University, Baltimore, n=8; Charité-University Medical Center Berlin, n=7; University of Maryland Greenebaum Comprehensive Cancer Center, n=6; Memorial Sloan Kettering Cancer Center, New York, n=6; Perelman School of Medicine at the University of Pennsylvania, n=4; Mayo Clinic Rochester, n=4; Czech Leukemia Centers, n=4; University Hospital Bonn, n=1) diagnosed with t(6;9)(p22;q34) AML between 1989 and 2016. Baseline characteristics are summarized in Table 1; median age was 46 years (range: 16-76) and 82 patients (46%) were female. Type of AML was de novo in 157 (88%), therapy-related in 4 (2%), and secondary after previous myelodysplastic syn- drome (MDS)/myeloproliferative neoplasm in 12 (7%) patients. In addition, five (3%) patients with MDS treated intensively according to AML protocols were included in this analysis. Median white blood cell (WBC) count was 16.6x109/L (range: 0.5-274) and was significantly higher in patients with, compared to without, FLT3-ITD (P=0.02).
Cytogenetic and molecular analyses
The balanced translocation t(6;9)(p22;q34) was the sole abnormality in 140 (79%) patients, while additional cyto- genetic abnormalities were present in 38 (21%). Of note, trisomy 13 was present in ten patients, either as a sole additional abnormality (n=1), in combination with tri- somy 8 (n=2) or with another balanced translocation (n=2), or within a complex karyotype characterized by gains only (n=5). FLT3-ITD molecular testing was avail- able in 127 (71%) patients and 79 (62%) had FLT3-ITD. FLT3-TKD mutational status was available in 76 (43%) and 4 (5%) were mutated (Table 1).
Response to induction therapy
Data on response to induction therapy were available in all patients. Early death (ED) occurred in two (1%) patients. Overall, CR was achieved in 144 patients (81%). Thirty-five patients with initial induction failure received a salvage therapy [high-dose cytarabine (HiDAC-)-based, n=23; other intensive, n=3; not intensive, n=4; unknown, n=5)] and 23 of them achieved a CR (66%), including 14 after HiDAC. The CR rate in patients with FLT3-ITD was 81% (64 of 79 patients) as compared to 77% (37 of 48 patients) in patients without FLT3-ITD (P=0.65). No prog- nostic factors for CR achievement were identified within the available baseline characteristics. Two of five patients with MDS achieved a CR according to AML criteria. In six patients with FLT3-ITD treated on the AML15 (n=2) or AML17 (n=4) trials, lestaurtinib40 was added to induction therapy and all patients achieved a CR.
Further therapy including intensive consolidation and allogeneic hematopoietic stem cell transplantation
Fifty-five (38%) of 144 patients in CR1 received inten- sive consolidation chemotherapy without transplantation, whereas 89 (62%) proceeded to allo-HCT. The majority of the patients (n=52 of 89, 58%) who went on to allo-HCT received a consolidation therapy prior to transplant.
Relapses occurred in 47 (85%) patients after consolida- tion chemotherapy and in 28 (31%) after allo-HCT in CR1. Relapsed patients without allo-HCT died after in median 5.4 months (range: 1-31.6 months). Twenty-one patients who relapsed after allo-HCT died.
Three patients died after consolidation chemotherapy and seventeen in CR after allo-HCT in CR1, mainly due to graft-versus-host disease (GvHD; n=5) or infections (n=4).
Tyrosine kinase inhibitors (TKI) were given after relapse in seven patients with FLT3-ITD, either as single agents (n=6) or in combination with chemotherapy (n=1) (post allo-HCT, n=4; post chemotherapy, n=3). A CR2 was achieved in one patient after treatment with gilteritinib41 and a second patient achieved CR2 with incomplete hematologic recovery (CRi) after treatment with lestaur- tinib in combination with mitoxantrone/etoposide/cytara- bine. The first patient died in CR one month after initiation of gilteritinib due to a perforated intestine and sepsis. The second patient relapsed six months after achieving CR2 and received donor lymphocytes, but died six months later due to progressive disease. Another patient was salvaged with quizartinib and achieved a par- tial remission (9% blast cells in bone marrow). The patient then went on to allo-HCT, but died one month later due to GvHD. Treatment with either gilteritinib or sorafenib was not successful in the other four patients.
Allogeneic hematopoietic stem cell transplantation in second complete remission
Among patients not proceeding to allo-HCT in CR1, ten patients were transplanted in CR2. Of those, six have died at a median of 16.5 months after allo-HCT. Causes of death in CR were infection (n=2), graft failure (n=1), multi-organ failure (n=1), and unknown (n=1). One patient relapsed and died due to AML.
Allogeneic hematopoietic stem cell transplantation with residual disease
In 34 patients not achieving a CR after intensive induc- tion therapy, 15 (44%) proceeded to allo-HCT with active
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