Prognostic Impact Of Monosomal Karyotype Research Articles

Monosomal karyotype as an adverse risk factor for inferior survivals in children with acute myeloid leukemia

BackgroundAlthough monosomal karyotype (MK) has been recognized as an adverse risk factor in adult acute myeloid leukemia (AML), its impact on pediatric AML outcomes remains unclear. MethodsClinical characteristics, cytogenetic and molecular profiling, and prognostic impact of MK were analyzed in a cohort of 284 children with AML in a Chinese population. ResultsMK was present in 14 (4.5%) cases of the study cohort. MK-AML showed low prevalence of TP53 mutant and 17p13 aberrations. Children with MK-AML had shorter overall survival (OS) and event-free survival (EFS) compared to those with intermediate-risk features (OS: 26 ± 9.7% vs. 2 ± 1.5%, p < 0.001; EFS: 20 ± 7.4% vs. 1 ± 0.3%, p < 0.001) as well as adverse risk (OS: 15 ± 1.4% vs. 2 ± 1.5%, p = 0.012; EFS: 12 ± 1.6%, p = 0.014). Multivariate analysis demonstrated MK as an independent adverse risk factor for reduced survival (OS: HR 2.09, 95% CI 1.12–3.88, p = 0.02; EFS: HR 5.24, 95% CI 1.55–17.54, p = 0.08). ConclusionsThe results show MK as an independent adverse risk factor for inferior survivals.

The Prognostic Value of Monosomal Karyotype (MK) in High-Risk Patients with Myelodysplastic Syndromes Treated with 5-Azacitidine

INTRODUCTIONCytogenetic abnormalities constitute an important prognostic factor in myelodysplastic syndromes (MDS). Recently, a new cytogenetic group termed monosomal karyotype (MK), defined by the presence ≥ 2 autosomal monosomies or one autosomal monosomy plus at least one structural abnormality in the same clone, has been introduced and was associated with worse outcome in patients with acute myeloid leukemia (AML). 5-Azacitidine (AZA) is a front-line treatment for high-risk patients (intermediate-2 or high IPSS risk) with MDS and AML who are ineligible for intensive chemotherapy. The prognostic impact of MK+ in AZA-treated patients remains unclear. In this study, we investigated the incidence and prognostic impact of MK in MDS patients treated with AZA. METHODSThis retrospective study of the Hellenic MDS Study Group included 405 intermediate-2 or high risk MDS patients treated with AZA. Extensive biostatistical analysis performed in this study included Kaplan-Meier survival analysis and Cox regression. The level of statistical significance was set at a probability value of less than 0.050 (P <0.050). RESULTSThe median age of patients was 74 years (range: 33 - 89). Baseline patient characteristics are presented in Table 1. MK was identified in 66 out of 405 (16.3%) patients, most of whom had complex karyotype. The overall response rate in the entire cohort was 46.2% (CR: 17.2%, PR: 11.2%, and HI: 17.8%). Stable disease (SD) was achieved by 24.8% of patients, while 29.0% had progression of disease (PD) or treatment failure. ORR was not different between MK+ and MK- patients (46.6% vs 46.2%). During a follow-up time period of 18.0 months, the duration of response was 1 - 41 months (median: 11) in the entire cohort, 9.5 months (range: 3 - 28) in MK+ patients and 11 months (range: 1 - 41) in MK- patients. The estimated median time to transformation to AML for MK+ patients was 17 months (95% confidence interval [CI] = 12.4-21.6) vs. 23 months (95% CI = 18.8-27.2) for MK- patients (P=0.025) (Figure 1a). Multivariate Cox regression analysis revealed that performance status (hazard ration [HR]=2.0, 95% CI = 1.5-2.8, P <0.001), IPSS-R (HR=1.5, 95% CI = 1.2 - 1.9, P <0.001) and MK (HR=1.8, 95% CI = 1.2-2.7, P=0.002) were independently associated with overall survival (OS). The estimated median OS for MK+ patients was 12 months [95% CI = 7.8-16.2] vs. 18 months; [95% CI = 15.3-20.7] for MK- patients (P <0.001) (Figure 1b). In a subgroup consisting of high and very-high risk patients according to IPSS-R, MK- patients showed better OS rates that MK+ patients (estimated median OS: 17 months; 95% CI = 14.1-19.9 vs. 12 months, 95% CI = 6.6 - 17.4, P=0.002) (Figure 1c). CONCLUSIONSMK is associated with reduced OS in patients with intermediate-2 or high risk MDS treated with AZA. In MDS with high or very high IPSS-R risk score, MK can further distinguish patients with poorer outcome. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The prognostic value of monosomal karyotype (MK) in higher‐risk patients with myelodysplastic syndromes treated with 5‐Azacitidine: A retrospective analysis of the Hellenic (Greek) Myelodysplastic syndromes Study Group

In this study, we investigated the incidence and prognostic impact of monosomal karyotype (MK) in 405 higher-risk Myelodysplastic Syndromes (MDS) patients treated with 5-AZA. The MK was present in 66 out of 405 (16.3%) patients, most of whom had complex karyotype (CK). MK was strongly associated with CK and the cytogenetic risk defined according to IPSS-R, as well as with high-risk disease, according to IPSS (P = .029), IPSS-R (P < .001), and WPSS (P < .001) classification systems. The overall response rate (ORR) was not different between MK+ and MK- patients (46.6% vs. 46.2%). At 28 months median follow-up, the median duration of response was 11 months in the entire cohort, 9.5 months in MK+ patients and 11 months in MK-patients (P = .024). The estimated median time to transformation to acute myeloid leukemia for MK+ patients was 17 months vs. 23 months for MK- patients (P = .025). The estimated median OS for MK+ patients was 12 months vs. 18 months for MK- patients (P < .001). Multivariate Cox regression analysis revealed that performance status (P < .001), IPSS-R (P < .001), and MK (P = .002) were independently associated with overall survival (OS). In a subgroup consisting of high and very-high risk patients according to IPSS-R, MK- patients showed better OS rates compared to MK+ patients (estimated median OS: 17 months vs. 12 months, P = .002). In conclusion, we found that MK is associated with reduced OS in patients with higher-risk MDS treated with 5-AZA. Furthermore, we showed that in MDS with high or very-high IPSS-R risk score, MK can further distinguish patients with worse outcome.

Allogeneic Hematopoietic Cell Transplantation May Alleviate the Negative Prognostic Impact of Monosomal and Complex Karyotypes on Patients with Acute Myeloid Leukemia

Monosomal karyotype (MK) and complex karyotype (CK) are well known to be associated with a very poor clinical outcome in patients with acute myeloid leukemia (AML). However, whether or not the prognostic impact of MK and CK remains relevant for patients who have undergone allogeneic hematopoietic cell transplantation (allo-HCT) is still unclear. We retrospectively analyzed the status of MK and CK, as well as other clinical laboratory features, in 148 allo-HCT AML patients at our institution and correlated with their event-free survival (EFS) and overall survival (OS) after transplantation. MK and CK were identified in 14 (9%) and 19 (13%) cases, respectively. On univariate analysis, only age (≥60 years) and WBC count (≥15 × 109/L) were significant adverse predictors for EFS (P < .001 and P = .017, respectively) and OS (P = .002 and P = .021, respectively). MK, CK, and other relevant parameters analyzed did not affect the clinical outcome. Multivariable analysis confirmed that both older age and high WBC count were independent prognostic factors for a shorter OS (P = .001 and P = .003, respectively) and a shorter EFS (P < .001 and P = .001, respectively). Our results indicate that neither MK nor CK are high-risk factors in AML patients undergoing allo-HCT.

Evaluation of revised IPSS cytogenetic risk stratification and prognostic impact of monosomal karyotype in 783 patients with primary myelodysplastic syndromes

Cytogenetic classification by the revised international prognostic scoring system (IPSS-R) and the prognostic value of monosomal karyotype (MK) were assessed in 783 patients with primary myelodysplastic syndromes (MDS). At 22 months median follow-up, 562 (72%) deaths were recorded. Percentages of patients with IPSS-R "very good," "good," "intermediate," "poor," and "very poor" cytogenetic categories was 5, 63, 18, 4, and 10%, respectively. The corresponding median survivals were 21, 40, 24, 18, and 6.5 months and the inter-group differences (good vs. very good/intermediate/poor vs. very poor; P < 0.01) or similarities (very good vs. intermediate vs. poor; P = 0.79) were not significantly modified in multivariable analysis. Results were similar when analysis was restricted to 602 patients managed by supportive care. MK adversely affected survival in both poor and very poor karyotype groups (P < 0.01). In conclusion, we were unable to confirm the prognostic superiority of IPSS-R-very good karyotype or prognostically distinguish between very good, intermediate and poor karyotypes. Furthermore, we show additional prognostic information from MK in poor/very poor karyotype.

Monosomal Karyotypes among 1147 Chinese Patients with Acute Myeloid Leukemia: Prevalence, Features and Prognostic Impact

A monosomal karyotype (MK), defined as ≥2 autosomal monosomies or a single monosomy in the presence of additional structural abnormalities, was recently identified as an independent prognostic factor conveying an extremely poor prognosis in patients with acute myeloid leukemia (AML). In the present study, after excluding patients with t(15;17), t(8;21), inv(16) and normal karyotypes, 324 AML patients with cytogenetic abnormalities were the main subject of analysis. The incidences of MK were 13% in patients aged 15 to 60 years and 18% in those between 15 and 88 years old. MK was much more prevalent among elderly patients (p<0.001) and was significantly associated with the presence of -7, -5, del(5q), abn12p, abn17p, -18 or 18q-, -20 or 20q- and CK (for all p<0.001 except for abn12p p=0.009), and +8 or +8q was less frequent in MK+ AML(p=0.007). No correlation was noted between monosomal karyotype and FAB subtype (p>0.05); MK remained significantly associated with worse overall survival among patients with complex karyotype (p=0.032); A single autosomal monosomy contributed an additional negative effect in OS of patients with structural cytogenetic abnormalities (P=0.008). This report presents the prevalence, feature and prognostic impact of MK among a large series of Chinese AML patients from a single center for the first time.

Evaluation of IPSS-Revised (IPSS-R) Cytogenetic Risk Stratification and Prognostic Impact of Monosomal Karyotype in 1,014 Patients with Myelodysplastic Syndromes (MDS)

AbstractAbstract 423 Background:Cytogenetic abnormalities at diagnosis are seen in 20–70% of patients with myelodysplastic syndromes (MDS). The International Prognostic Scoring System -revised (IPSS-R) classifies these cytogenetic abnormalities into five prognostic groups: very good (del(11q), ΠY with overall survival (OS) of 61 months); good (normal, del(20q), del(5q), del(12p) with OS 49 months); intermediate (+8,7q-, i(17q),+19,+21 with OS 26 months); poor (der(3)q21/q26, −7, complex with 3 abnormalities with OS 16 months); and very poor (complex with >3 abnormalities with OS of 6 months) (Schanz J, JCO 2012, Greenberg P, Blood 2012). Monosomal karyotype (MK) is defined as the presence of two or more autosomal monosomies or a single monosomy associated with a structural abnormality. We have previously shown that MK identifies a prognostically worse subgroup of MDS patients with a complex karyotype (Patnaik M, Leukemia 2010). Objectives:i.To validate the IPSS-R cytogenetic risk groups in an independent cohort of patients with MDS.ii.Evaluate the prognostic impact of MK to refine the current IPSS-R cytogenetic risk classification. Methods:The Mayo Clinic database for MDS was used to identify patients in whom bone marrow histologic and cytogenetic information was obtained at the time of diagnosis. WHO criteria were used for MDS diagnosis and leukemic transformation. Results:i) Patient characteristics: A total of 1,014 patients met the above-stipulated criteria. Median age of the cohort was 71 years (range: 18–98 years) with 684 (67%) males. 819 patients (81%) had primary MDS with 195 cases (19%) of therapy-related MDS. 759 patients (75%) are dead at a median follow-up of 18 months (range: 0–223 months) with leukemic transformation documented in 125 cases (12%). IPSS-R risk distribution was as follows: very low (n=149, 15%), good (n=261, 26%), intermediate (n=221, 22%), high (n=131, 13%), and very high (n=252, 25%).ii) IPSS-R karyotype (Entire cohort; n=1,014): The five cytogenetic groups by IPSS-R were as follows: very good (n=43, 4%), good (n=577, 57%), intermediate (n=187, 18%), poor (n=83, 8%), and very poor (n=124, 12%). We evaluated the prognostic impact of the above groups by Kaplan Meier and Cox proportional hazards analysis. OS for the five cytogenetic groups was as follows: good (36 months), very good (28 months), intermediate (20 months), poor (13 months), and very poor (6 months) (Figure 1). OS of patients with very good karyotype was significantly better than patients with very poor and poor karyotype (p<0.0001, RR 3.2 and p=0.04, RR 1.6 respectively) but similar to patients with intermediate and good karyotype (p=0.22 and 0.28 respectively).iii) IPSS-R karyotype (Primary MDS; n=819): Cytogenetic risk groups by IPSS-R were as follows: very good (n=38, 5%), good (n=512, 63%), intermediate (n=153, 19%), poor (n=46, 6%), and very poor (n=70, 9%). OS of the five groups was as follows: good (39 months), very good (23 months), intermediate (21.5 months), poor (14.5 months), and very poor (6.5 months). OS of patients with very good karyotype was significantly better than patients with very poor karyotype (p=0.0002, RR 2.5) but similar to patients with poor, intermediate and good karyotype (p=0.23, 0.26 and 0.18 respectively).iv) Monosomal karyotype: MK was identified in 153 (15%) cases of which 4 cases were intermediate, 42 poor, and 107 very poor by IPSS-R. OS of patients with MK was similar to those with very poor karyotype (6 months). In addition, OS of patients with very poor without MK was akin to patients with poor without MK (p=0.21). Furthermore, among primary MDS we identified 83 (8%) cases of MK of which 4 were intermediate, 21 were poor, and 58 very poor by IPSS-R. We confirmed that OS of patients with MK was similar to patients with very poor karyotype (6.5 months). Moreover, survival of patients with very poor without MK was similar to patients with poor without MK (p=0.51). Conclusions:In this independent analysis of 1,014 patients with MDS, IPSS-R cytogenetic risk characterization failed to discriminate between very good, good and intermediate prognostic groups. In addition, patients with very poor without MK have a similar prognosis to patients with poor without MK and should be included in the poor category whereas the presence of MK should warrant inclusion into the very poor risk category. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Prognostic implication of monosomal karyotype in patients with acute myeloid leukemia who received allogeneic hematopoietic cell transplantation.

6564 Background: Monosomal karyotype (MK), defined as at least two autosomal monosomies or one single autosomal monosomy with one or more structural cytogenetic abnormalities, has been associated with worse outcomes in acute myeloid leukemia (AML). We evaluated the prognostic impact of MK on outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) in AML. Methods: We retrospectively analyzed 169 adult patients with AML, who received allo-HCT in the first complete remission (CR) between 2000 and 2009. All patients had cytogenetic results at the diagnosis of AML. Patients were classified as having good, intermediate, or poor risk cytogenetics according to the NCCN guideline, and MK status was also determined. Results: MK was observed in 12 patients (7.1%); of whom, 11 patients also had complex karyotype (CK). Compared to patients without MK, those with MK had significantly lower overall survival (OS) (62.2% vs. 0%) and event free survival (EFS) (58.9% vs. 0%), and higher relapse probability (RP) (22.9% vs. 66.7%) at 5 years (all, p&lt;0.001). 22 patients with CK also showed inferior outcomes, but CK with MK was associated with more inferior outcomes than CK without MK. Multivariate analysis showed that MK had a significantly adverse impact on OS (hazard ratio [HR], 5.192; p&lt;0.001), EFS (HR, 4.531; p&lt;0.001), and RP (HR, 6.558; p&lt;0.001) after allo-HCT (Table). Conclusions: MK is a major prognostic factor predicting extremely worse outcomes in AML patients who underwent allo-HCT in the first CR. [Table: see text]

Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies

We aimed to determine the prognostic impact of monosomal karyotype (MK) in acute myeloid leukemia (AML) in the context of the current World Health Organization (WHO) classification and to evaluate the outcome of MK(+) patients after allogeneic HSCT. Of 1058 patients with abnormal cytogenetics, 319 (30%) were MK MK(+). MK(+) patients were significantly older (P = .0001), had lower white blood counts (P = .0006), and lower percentages of BM blasts (P = .0004); MK was associated with the presence of -5/5q-, -7, 7q-, abnl(12p), abnl(17p), -18/18q-, -20/20q-, inv(3)/t(3;3), complex karyotype (CK), and myelodysplasia (MDS)-related cytogenetic abnormalities (P < .0001, each); and NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and tyrosine kinase domain mutations (P = .02) were less frequent in MK(+). Response to induction therapy and overall survival in MK(+) patients were dismal with a complete remission rate of 32.5% and a 4-year survival of 9%. MK retained its prognostic impact in AML with CK, AML with MDS-related cytogenetic abnormalities, and in a revised definition (MK-R) excluding cases with recurrent genetic abnormalities according to WHO classification and those with derivative chromosomes not leading to true monosomies. In younger patients, allogeneic HSCT from matched related and unrelated donors resulted in a limited improvement of overall survival.

Prognosis of acute myeloid leukemia harboring monosomal karyotype in patients treated with or without allogeneic hematopoietic cell transplantation after achieving complete remission

To evaluate the prognostic impact of monosomal karyotype on post-remission outcome in acute myeloid leukemia, we retrospectively analyzed 2,099 patients who had achieved complete remission. Monosomal karyotype was noted in 73 patients (4%). Of these, the probability of overall survival from first complete remission was 14% at four years, which was significantly lower than that reported in patients without monosomal karyotype, primarily due to a high relapse rate (86%). Monosomal karyotype remained significantly associated with worse overall survival among patients with unfavorable cytogenetics or complex karyotype, and even in patients who underwent allogeneic hematopoietic cell transplantation during first complete remission. These findings confirm that monosomal karyotype has a significantly adverse effect on post-remission outcome in patients with acute myeloid leukemia treated with and without allogeneic hematopoietic cell transplantation in first complete remission, emphasizing the need for the development of alternative therapies for this patient population.

Prognostic Impact of Monosomal Karyotype in Patients with Myelodysplastic Syndrome and Abnormal Karyotype. A Report From the Spanish Group of MDS (GESMD)

Abstract 1724Cytogenetic 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.

Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience

AbstractMonosomal karyotype (MK), defined as 2 or more monosomies, or a single monosomy in the presence of structural abnormalities, has recently been reported as identifying a distinct subset of acute myeloid leukemia (AML) patients with an extremely poor prognosis. In an effort to confirm this observation, we analyzed the prognostic impact of MK in 1344 AML patients between the ages of 16 and 88 years treated on Southwest Oncology Group protocols. MK was found in 176 (13%) patients. The proportion of patients with MK increased with age, being present in 4% of patients age 30 or younger, but in 20% of those over age 60. Ninety-eight percent of MK cases were within the unfavorable cytogenetic risk category and comprised 40% of this group. The complete remission rate in patients with unfavorable cytogenetics without MK was 34% versus 18% with MK (P < .01). The 4-year overall survival of patients with unfavorable cytogenetics but without MK was 13% in contrast to a 4-year survival of only 3% with MK (P < .01). Thus, MK defines a sizeable subset of patients with unfavorable cytogenetics who have a particularly poor prognosis.