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Prognostic Impact of Monosomal Karyotype in Patients with Myelodysplastic Syndrome and Abnormal Karyotype. A Report From the Spanish Group of MDS (GESMD)
Abstract
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Cytogenetic abnormalities (CA) are the most important prognostic factor in patients with myelodysplastic syndromes (MDS). Monosomal karyotype (MK) defined as the presence of at least two autosomal monosomies or one monosomy plus other structural CA, has been associated with poor prognosis in acute myeloid leukemia (AML) but its significance in MDS remains unclear. The aim of our study was to analyze the prognostic impact of MK in adult patients with MDS and CA.
Patients from Spanish Registry of MDS diagnosed with MDS by WHO 2008 criteria and with CA detected by conventional cytogenetics have been included in the study. Statistical analysis consisted of Kaplan-Meyer univariate analysis (UA) including all known variables associated with prognosis in MDS and a Cox-regression multivariate analysis (MA) in which we included only those variables with a P<0.1 in UA.
There were 1054 patients, 478 (45.3%) women. The median age was 71 (range 16–96) years. Median follow-up for survivors was 24.1 (range 0–210) months. There were 609 (57,8%) refractory anemia (RA) and 445 (42.8%) refractory anemia with excess of blasts (RAEB). The IPSS was low, intermediate-1, intermediate-2 and high in 18.3%, 39.3%, 25%, and 10.6%, respectively (6.7% were unclassifiables). Complex karyotype (CK) and MK was observed in 203 (19.3%) and 172 (16.3%) patients, respectively. Patients with MK showed worse prognostic characteristics than those without MK: More Intermediate-2 and high risk patients (50% vs. 20% and 30% vs. 6.7%; P<0.001); more frequent CK: (87.2% vs. 6%; P<0.001), higher median bone marrow (BM) blast count (7% vs. 3%; P<0.001) and lower hemoglobin (Hb) level (89 vs. 96 g/L; P<0.001).
Median OS for the whole group was 32.7 months. In the UA, the variables associated with lower OS were: Male sex, RAEB subtype (vs. RA), higher IPSS, CK, MK, older age, higher peripheral blood (PB) and bone marrow (BM) blast percentage and lower Hb, platelets and neutrophil count. In the MA the variables associated with lower OS were: Age>60 years (HR 1.7; P<0.001), CK (HR 2.19; P<0.001), higher BM blast (HR 1.07; P<0.001), Hb<100 g/L (HR 1.788; P<0.001) and platelet count <100×109/L (HR 1.62; p<0.001). MK did not reach statistical significance in the MA (HR 1.45; P=0.059).
In the group of patients with CK the UA showed that the presence of MK was associated with a trend to lower OS (Log rank 2.8, P=0.092) while the presence of ≥4 vs. 3 CA was associated with lower OS (Log rank 7.5; P=0.006). Other variables associated with lower OS in UA in this subset of patients were: RAEB (vs RA), presence of abnormalities of 5 and/or 7 chromosome, higher IPSS group, older age, higher BM blast percentage, and lower Hb and platelet count. In MA the variables associated with lower OS in patients with CK were: age>60 years (HR 1.734, P=0.008), RAEB vs. RA (HR 1.542, P=0.02) Hb <100 g/L (HR 2.1, P<0.001) platelets <100×109/L (HR1.886; P=001) and the presence of abnormalities of both 5 and 7 chromosomes (HR 2.058; P=0.001). The presence of MK did not reach statistical significance in the MA.
At last follow-up, 221(21%) patients had shown AML evolution at a median of 9 months (0–125 months) for a 1 and 4 years probability of AML evolution of 14.2% (95% CI 11.8–16.6) and 28.6% (95 CI: 24.8–32.4). The variables associated with higher risk of AML evolution in the UA were: RAEB, higher IPSS, CK, MK, higher PB and BM blast percentage and lower hemoglobin, platelet and neutrophil count. In multivariate analysis the only variables that retained statistical significance were BM blasts (HR 1.13; P<0.001) and CK (HR 3.2; P<0.001).
In conclusion, our study shows that the presence of MK is highly associated with CK and other high-risk features of MDS. In our population, the MK was not an independent risk factor for OS while the presence of CK was the main risk factor associated with poorer OS in MDS patients with abnormal karyotype.
Disclosures
No relevant conflicts of interest to declare.
... Although MK was highly associated with high-risk abnormal karyotypes and invariably demonstrated it as an adverse risk factor, the additional prognostic value of MK on conventional high-risk cytogenetic abnormalities is still controversial. A Spanish group recently reported that MK was not an independent risk factor for OS, while the presence of CK was the main risk factor associated with shorter OS in MDS patients with abnormal karyotype (15). ...
Objective: Monosomal karyotype (MK) is defined as the presence of two or more autosomal monosomies or a single monosomy associated with a structural abnormality. It was first described as a high-risk cytogenetic abnormality for acute myeloid leukemia and more recently in myelodysplastic syndromes (MDS). However, allotransplant outcome in MDS with MK has not been described. Patients and Methods: We retrospectively reviewed data of 79 patients with MDS who underwent allotransplant at the University of Iowa from 1990 to 2009. We recorded patients' cytogenetic data, clinical characteristics and evaluated outcome following allogeneic stem cell transplant stratified by cytogenetic classification. Results: Of 79 patients, 37 (47%) had unfavorable karyotypes (23 complex karyotype, 25 abnormal chromosome 7). Twenty-four patients (30%) had MK. Twenty-four patients (30%) relapsed and 59 (74.7%) died during study period. Patients with MK had higher 2-yr relapse incidence (RI) (51% vs. 29%; P = 0.01), lower 2-yr event-free survival (EFS) (8% vs. 40%; P = 0.02), and lower 2-yr overall survival (OS)(6% vs. 41%; P = 0.02) than patients without MK. We further analyzed the effect of MK in each unfavorable karyotype composite. Although the outcome was not statistically different, unfavorable karyotypes with patients with MK showed a trend toward higher 2-yr RI [hazard ratio (HR), 1.7; P = 0.34], lower 2-yr EFS (HR, 1.5; P = 0.29), and lower 2-yr OS (HR, 1.5; P = 0.28) compared to unfavorable karyotypes without MK. Conclusion: Cytogenetic abnormalities remain an important prognostic factor for allotransplant outcome of MDS. Our results suggested poor allotransplant outcomes with high RI and low OS in MDS with MK.
Clonal cytogenetic abnormalities are a major risk factor for relapse after hematopoietic cell transplantation (HCT) for myelodysplastic syndrome (MDS). We determined the impact of the recently established 5-group cytogenetic classification of MDS on outcome after HCT. Results were compared with the impact of the International Prognostic Scoring System (IPSS) 3 cytogenetic risk groups, and the additional effect of a monosomal karyotype was assessed. The study included data on 1007 patients, 1-75 years old (median 45 years), transplanted from related (n = 547) or unrelated (n = 460) donors. Various conditioning regimens were used, and marrow, peripheral blood, or cord blood served as stem cell source. Both IPSS and 5-group cytogenetic risk classifications were significantly associated with post-HCT relapse and mortality, but the 5-group classification discriminated more clearly among the lowest- and highest-risk patients. A monosomal karyotype tended to further increase the rates of relapse and mortality, even after considering the IPSS or 5-group classifications. In addition, the pathologic disease category correlated with both relapse and mortality. Mortality was also impacted by patient age, donor type, conditioning regimen, platelet count, and etiology of MDS. Although mortality declined significantly in recent years, novel strategies are needed to overcome the barrier of high-risk cytogenetics.
Monosomal karyotype (MK) is defined as the presence of two or more autosomal monosomies or a single monosomy associated with a structural abnormality. It was first described as a high-risk cytogenetic abnormality for acute myeloid leukemia and more recently in myelodysplastic syndromes (MDS). However, allotransplant outcome in MDS with MK has not been described.
We retrospectively reviewed data of 79 patients with MDS who underwent allotransplant at the University of Iowa from 1990 to 2009. We recorded patients' cytogenetic data, clinical characteristics and evaluated outcome following allogeneic stem cell transplant stratified by cytogenetic classification.
Of 79 patients, 37 (47%) had unfavorable karyotypes (23 complex karyotype, 25 abnormal chromosome 7). Twenty-four patients (30%) had MK. Twenty-four patients (30%) relapsed and 59 (74.7%) died during study period. Patients with MK had higher 2-yr relapse incidence (RI) (51% vs. 29%; P = 0.01), lower 2-yr event-free survival (EFS) (8% vs. 40%; P = 0.02), and lower 2-yr overall survival (OS)(6% vs. 41%; P = 0.02) than patients without MK. We further analyzed the effect of MK in each unfavorable karyotype composite. Although the outcome was not statistically different, unfavorable karyotypes with patients with MK showed a trend toward higher 2-yr RI [hazard ratio (HR), 1.7; P = 0.34], lower 2-yr EFS (HR, 1.5; P = 0.29), and lower 2-yr OS (HR, 1.5; P = 0.28) compared to unfavorable karyotypes without MK.
Cytogenetic abnormalities remain an important prognostic factor for allotransplant outcome of MDS. Our results suggested poor allotransplant outcomes with high RI and low OS in MDS with MK.
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