Page 90 - 2019_06-Haematologica-web

F. Baron et al.
Having an HLA-identical related donor improved overall survival from complete remission in patients with a monosomal karyotype
A total of 92 MK+ patients achieved a CR/CRi on study. Among them, 35 patients had and 55 did not have an HLA-identical related donor (information was missing for 2 patients). Among those with an HLA related donor, 25 patients (71%) received an allogeneic HSCT, including 20 (57%) who were transplanted in first CR/CRi (Figure 1). In addition, 23 patients (including 22 without an HLA- matched related donor) underwent autologous HSCT in first CR/CRi.. The median time between CR/CRi and HSCT in first CR/CRi was 91 days for patients who received an autologous transplant (range, 42-167), 76 days for patients who received an allogeneic HSCT (range, 46- 171), 91 days for patients without a donor (range: 42.0 - 171.0) and 71 days for patients with a donor (range, 46.0 - 148.0). OS from CR/CRi was longer in patients with a donor than in those without, such that the 5-year OS rates following CR/CRi were 24.1% (95% CI: 11.4-39.3%) and 3.8% (95% CI: 0.7-11.5%), respectively (HR=0.59, 95% CI: 0.37-0.95) (Figure 3A).
Given the clinical importance of the observations described just above, we performed several sensitivity analyses to assess the impact of allogeneic HSCT on out- comes among MK+ patients. The exclusion of patients with a CRi had little impact on the estimated hazard ratio (HR=0.60, 95% CI: 0.37-0.98). The advantage of having an HLA-identical related donor remained present (HR=0.61, 95% CI: 0.38-0.99) after adjusting for patient’s age (< or ≥ 45 years old).
Furthermore, the size of the estimated treatment effect confirmed the benefit of allogeneic HSCT when the post- transplant survival of patients who received an allogeneic graft was compared to that of patients who received an autologous graft (HR=0.54, 95% CI: 0.26-1.12) (Figure 3B). Second, in a Cox model including allogeneic HSCT (mod- eled as a time-varying covariate) and age, and stratified by protocol, allogeneic HSCT was associated with a longer survival from CR/CRi (HR=0.61, 95% CI: 0.36-1.02).
Discussion
As demonstrated in this study, several other studies have established that the presence of a MK is associated with a particularly poor outcome in younger AML patients.8,15-17 However, the number of studies regarding the best remission-induction regimens for MK+ AML patients as well as the impact of allogeneic HSCT on the outcomes of such patients have been the focus of only a few studies.16,18 In order to investigate these important issues, we used the data concerning the MK+ patients included in the EORTC/GIMEMA AML-10 and AML-12 phase III multicenter trials. Several observations were made.
First, our study confirms the poor prognosis associated with MK+ in younger AML patients. Specifically, MK+ was associated with a lower probability of achieving a CR/CRi, a shorter OS and a shorter OS from CR/CRi, whether taking other prognostic factors into account or not. This is in concordance with prior observations that the CR/CRi rate for adult MK+ patients ranged from 14- 43% and the OS rate from 9-18%.8,15-17
In addition, we investigated whether the type of anthra-
cycline given during remission induction affected the out- comes of MK+ patients among patients included in the AML-10 trial. Unfortunately, none of the assessed anthra- cyclines was associated with better outcomes among MK+ patients. These findings are consistent with the results of prior phase III trials showing that increasing the dose of daunorubicin was beneficial mainly in patients with favor- able or intermediate-risk cytogenetics.19,20
In the first analysis of the AML-12 trial, we observed that induction with high-dose cytarabine increased the proportion of patients achieving a CR/CRi and prolonged OS in patients younger than 46 years of age.1 This benefit was also observed in patients with adverse cytogenetic abnormalities and/or FLT3-internal tandem duplication (ITD) mutations, as well as in those with secondary AML. Here we found no evidence of a benefit of high-dose cytarabine in the subgroup of patients with a MK. There was even a suggestion of a lower incidence of CR/CRi in MK+ patients randomized to the high-dose cytarabine arm. This finding could be explained by previous studies showing that up to 80% of MK+ patients have a mutation in the TP53 gene.21 Patients with TP53 mutation in their tumor cells are resistant to high-dose cytarabine, as has been demonstrated in patients with mantle cell lym- phoma.22 Unfortunately, the TP53 gene mutation was not evaluated in the present study.
Finally, we investigated whether patients with a donor had an OS benefit in comparison to those without a donor. As previously demonstrated by us and by other groups of investigators, among MK– AML patients with intermediate or unfavorable karyotype, the presence of a
Table 2. Association between monosomal karyotype and Medical Research Council adverse-risk group and achievement of complete remission with or without hematologic recovery after induction.
Covariate
Cytogenetic group NotAdvMK- AdvMK-
MK+
OR of no CR/CRi 95% CI
Unadjusted analysis^
1
1.80 1.33 - 2.42 3.09 2.26 - 4.22
Multivariate analysis*
P value <0.001
<0.001
0.028
<0.001
0.001
Cytogenetic group
NotAdvMK-
AdvMK- 1.91 MK+ 3.34
Age (years)
15-25 1 26-45 1.35 46-60 1.61
WHO Performance Status at baseline 01
1 1.07 2-4 1.83
WBC at diagnosis (x109/L)
<25 1 ≥25and<100 1.21 ≥ 100 1.79
1
1.41 - 2.59 2.42 - 4.59
0.92 - 1.99
1.10 - 2.36
0.85 - 1.34 1.35 - 2.48
0.96-1.52
1.31 - 2.46
OR: odds ratio; 95% CI: 95% confidence interval; NotAdvMK–: not adverse cytogenetic
excluding a monosomal karyotype; AdvMK–: adverse cytogenetic excluding a mono-
+
somal karyotype; MK : monosomal karyotype;WHO:World Health Organization;WBC:
white blood cell count.^Obtained with a logistic regression model including protocol (AML-10 vs. AML-12) and cytogenetic group. *Obtained with a logistic regression model including protocol and all covariates presented in the Table.
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haematologica | 2019; 104(6)