Myeloid and monocytic dyspoiesis as determined by flow cytometric scoring in myelodysplastic syndrome correlates with the IPSS and with outcome after hematopoietic stem cell transplantation

Marrow cells of myeloid lineage from 115 patients with myelodysplastic syndrome (MDS) were characterized by multidimensional flow cytometry and compared with findings in 104 patients with various disorders and 25 healthy donors. Based on phenotypic and scatter characteristics, a flow cytometric scoring system (FCSS) was developed that allowed for a simple numerical display of results. The flow cytometric scores were categorized as normal/mild (0-1), moderate (2-3), or severe (> or = 4). Most flow cytometric abnormalities were significantly (P <.05) more frequent in patients with MDS than in the control cohort. Flow cytometric scores in MDS patients were then retrospectively compared with marrow blast counts assessed by morphology, cytogenetics, hematologic parameters, and International Prognostic Scoring System (IPSS) risk categorization. The flow cytometric scores correlated inversely with leukocyte and absolute neutrophil counts (P <.01) and correlated directly with IPSS scores (P <.01) and with IPSS cytogenetic risk categories (P <.01). In 111 MDS patients who underwent allogeneic hematopoietic stem cell transplantation, flow scores correlated with posttransplantation outcome. The probabilities of posttransplantation relapse were 3%, 15%, and 33% for patients with mild, moderate, and severe FCSS scores, respectively (P <.01), and overall survival was 74%, 40%, and 36%, respectively, for the 3 groups (P <.01). In multivariate analyses, there was a significant contribution of the flow score independent of the IPSS in predicting survival and relapse (P <.01, P =.02, and P =.03, respectively). These data suggest that FCSS is useful in assessing marrows for diagnosis of MDS and in determining the prognostic outcome in patients with this disorder.     

Validation of a flow cytometric scoring system as a prognostic indicator for posttransplantation outcome in patients with myelodysplastic syndrome

A total of 152 patients with myelodysplastic syndrome (MDS) receiving a first stem cell transplant had marrow cells prospectively analyzed to calculate the flow cytometric scoring system (FCSS) score. The FCSS scores were retrospectively compared with patient outcomes in both univariate and multivariate models. The cumulative incidence of posttransplantation relapse at 3 years was 15%, 10%, and 36% for patients with mild, moderate, and severe FCSS scores, respectively, with the hazard for relapse of 2.8 (P = .02) for severe scores in comparison to patients with mild or normal FCSS scores. In multivariate analyses, the FCSS score was associated with relapse even after accounting for International Prognostic Scoring System (IPSS) score or for marrow myeloblast percentage. Among patients with intermediate-1 risk by IPSS, severe FCSS scores were associated with an increased hazard of relapse (3.8; P = .02) compared with patients with normal/mild/moderate FCSS scores. Among patients with less than 5% marrow myeloblasts, myeloblast dyspoiesis was associated with an increased hazard of relapse (3.7; P = .02). This analysis confirmed that FCSS scores are predictive of posttransplantation outcomes in patients with MDS even after adjusting for risk factors such as marrow myeloblast percentage and IPSS score.     

Validation of the revised international prognostic scoring system (IPSS‐R) in patients with lower‐risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry

Baseline characteristics, disease‐management and outcome of 1000 lower‐risk myelodysplastic syndrome (MDS) patients within the European LeukaemiaNet MDS (EUMDS) Registry are described in conjunction with the validation of the revised International Prognostic Scoring System (IPSS‐R). The EUMDS registry confirmed established prognostic factors, such as age, gender and World Health Organization 2001 classification. Low quality of life (EQ‐5D visual analogue scale score) was significantly associated with reduced survival. A high co‐morbidity index predicted poor outcome in univariate analyses. The IPSS‐R identified a large group of 247 patients with Low (43%) and Very low (23%) risk score within the IPSS intermediate‐1 patients. The IPSS‐R also identified 32 High or Very high risk patients within the IPSS intermediate‐1 patients. IPSS‐R was superior to the IPSS for predicting both disease progression and survival. Seventy percent of patients received MDS‐specific treatment or supportive care, including red blood cell transfusions (51%), haematopoietic growth factors (58%) and iron chelation therapy (8%), within 2 years of diagnosis; while 30% of the patients only required active monitoring. The IPSS‐R proved its utility as a more refined risk stratification tool for the identification of patients with a very good or poor prognosis and in this lower‐risk MDS population.     

Does mutational burden add to other prognostic factors in MDS?

Myelodysplastic syndromes (MDS) are clonal bone marrow disorders characterized by complex genomic abnormalities that define disease phenotype, prognosis, and progression. The overall outcomes of MDS patients are very heterogeneous and can be measured in months in some patients and years in others. Several scoring systems have been developed in MDS, with the International Prognostic Scoring System (IPSS) and its revised version (IPSS-R) the most widely accepted risk stratification tools in clinical practice and trial eligibility. Recently, somatic mutations have been shown to impact overall survival and the risk of progression to acute myeloid leukemia. Attempts to add this information to current models or develop newer models are underway, but the optimal approach remains controversial. Newer methods to develop a personalized prediction model that provides outcomes specific for a patient were developed and could change the prognostic paradigm for MDS patients in the near future.     

Dynamic assessment of RBC‐transfusion dependency improves the prognostic value of the revised‐IPSS in MDS patients

RBC‐transfusion dependency (RBC‐TD) is an independent prognostic factor for poor overall survival (OS) in the WHO classification‐based prognostic scoring system (WPSS) for MDS patients. However, WPSS did not include cytopenia, whereas revised International Prognostic Scoring System (IPSS‐R) did not include RBC‐TD. Thus, neither of these prognostic scoring systems incorporates both cytopenia and RBC‐TD. We aimed to test whether RBC‐TD adds prognostic value to the IPSS‐R. We analyzed MDS patients not treated with disease‐modifying therapy, and enrolled in SA‐MDS Registry (derivation cohort; n = 295) and Dusseldorf registry (Germany; validation cohort; n = 113) using time‐dependent Cox proportional regression and serial landmark analyses. In the derivation cohort, RBC‐TD patients had inferior OS compared to RBC transfusion‐independent (RBC‐TI) patients (P < 0.0001) at 6‐ (18 vs. 64 months), 12‐ (24 vs. 71 months), and 24‐months (40 vs. 87 months). In a Cox proportional regression analysis, RBC‐TD was an independent adverse prognostic marker in addition to age, sex, and IPSS‐R variables (P < 0.0001). A prognostic index (PI) was derived using these Cox‐proportional regression model variables. In the validation cohort, this PI classified patients into four prognostic groups with significantly different OS (P < 0.001) as in the derivation cohort. In conclusion, multivariate analysis by Cox proportional hazards regression and serial landmark analyses clearly demonstrates that development of RBC‐TD at any time during the course of MDS is associated with poor OS, independent of IPSS‐R. This study demonstrates that dynamic assessment of RBC‐TD provides additional prognostic value to IPSS‐R and should be included in treatment decision algorithms for MDS patients.     

IPSS‐R in 555 Taiwanese patients with primary MDS: Integration of monosomal karyotype can better risk‐stratify the patients

The revised International Prognostic Scoring System (IPSS‐R) was recently developed to better assess the clinical outcome of adult patients with myelodysplastic syndrome (MDS). In this study, we aimed to investigate the prognostic impact of this new risk model on 555 MDS patients in Taiwan. Generally, the IPSS‐R could discriminate MDS patients regarding risk of leukemia evolution and overall survival in our cohort and it further refined prognostic stratification in all IPSS risk categories. However, we could not find the inter‐group difference between IPSS‐R very low and low risk subgroups in both leukemia‐free survival (LFS) and overall survival (OS). IPSS‐R couldn't distinguish the prognosis between very good and good and between good and intermediate risk cytogenetic categories in OS, and between very good and good and between intermediate and poor cytogenetic‐risk categories in LFS, either. On the other hand, incorporation of monosomal karyotype (MK) into IPSS‐R could further stratify MDS patients with higher‐risk IPSS‐R (intermediate, high and very high risk) into four groups, rather than three groups, with different OS (P < 0.001). Intriguingly, patients receiving allogeneic hematopoietic stem cell transplantation had longer survival than those without in the IPSS‐R high and very high, but not other risk groups. Similarly, patients treated with hypomethylating agents had better survival than those not in the IPSS‐R very high risk group. In conclusion, IPSS‐R can risk‐stratify MDS patients in Taiwan but with some limitations, especially in very low risk category, and MK has additional prognostic value in discriminating MDS patients with higher‐risk IPSS‐R. Am. J. Hematol. 89:E142–E149, 2014. © 2014 Wiley Periodicals, Inc.     

Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population‐based setting: a report from the Swedish MDS register

The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population‐based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population‐based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS‐R) and the World Health Organization (WHO) Classification‐based Prognostic Scoring System (WPSS). We also present population‐based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy‐related MDS (t‐MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2·9 per 100 000 inhabitants. IPSS‐R had a significantly better prognostic power than IPSS (P < 0·001). There was a trend for better prognostic power of IPSS‐R compared to WPSS (P = 0·05) and for WPSS compared to IPSS (P = 0·07). IPSS‐R was superior to both IPSS and WPSS for patients aged ≤70 years. Patients with t‐MDS had a worse outcome compared to de novo MDS (d‐MDS), however, the validity of the prognostic scoring systems was comparable for d‐MDS and t‐MDS. In conclusion, population‐based studies are important to validate prognostic scores in a ‘real‐world’ setting. In our nationwide cohort, the IPSS‐R showed the best predictive power.     

Hypoalbuminemia is an independent prognostic factor for overall survival in myelodysplastic syndromes

We hypothesized that hypoalbuminemia is an independent prognostic factor in patients with myelodysplastic syndromes (MDS). We analyzed records of 767 patients treated at Moffitt Cancer Center between January 2001 and December 2009 to evaluate the relationship between serum albumin (SA) at the time of presentation and overall survival (OS). Patients (median age of 69 years) were stratified into three groups based on SA concentration (≤3.5, 3.6–4.0, and >4.0 g/dL). Two‐thirds of the patients had low or intermediate‐1 International Prognostic Scoring System (IPSS)‐based risk for MDS. Median OS by SA concentration of ≤3.5, 3.6–4.0, and >4.0 g/dL was 11, 23, and 34 months, respectively (P < 0.005), whereas rate of acute myeloid leukemia progression was highest in patients with low SA (≤3.5 g/dL). The SA level offered prognostic discrimination for outcomes within the lower and higher IPSS risk groups, as well as with the MD Anderson risk model. In multivariable analysis, SA was a significant independent co‐variate for OS after adjustment for IPSS, age, serum ferritin, and transfusion dependence (hazard ratio = 0.8; 95% CI 0.6–0.9; P = 0.004). Our findings indicate that hypoalbuminemia is an independent prognostic biomarker that may serve as a surrogate representative of disease biology or comorbidities in patients with MDS. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.     

Enumerating bone marrow blasts from nonerythroid cellularity improves outcome prediction in myelodysplastic syndromes and permits a better definition of the intermediate risk category of the Revised International Prognostic Scoring System (IPSS‐R)

The Revised International Prognostic Scoring System (IPSS‐R) has been recognized as the score with the best outcome prediction capability in MDS, but this brought new concerns about the accurate prognostication of patients classified into the intermediate risk category. The correct enumeration of blasts is essential in prognostication of MDS. Recent data evidenced that considering blasts from nonerythroid cellularity (NECs) improves outcome prediction in the context of IPSS and WHO classification. We assessed the percentage of blasts from total nucleated cells (TNCs) and NECs in 3924 MDS patients from the GESMD, 498 of whom were MDS with erythroid predominance (MDS‐E). We assessed if calculating IPSS‐R by enumerating blasts from NECs improves prognostication of MDS. Twenty‐four percent of patients classified into the intermediate category were reclassified into higher‐risk categories and showed shorter overall survival (OS) and time to AML evolution than those who remained into the intermediate one. Likewise, a better distribution of patients was observed, since lower‐risk patients showed longer survivals than previously whereas higher‐risk ones maintained the outcome expected in this poor prognostic group (median OS < 20 months). Furthermore, our approach was particularly useful for detecting patients at risk of dying with AML. Regarding MDS‐E, 51% patients classified into the intermediate category were reclassified into higher‐risk ones and showed shorter OS and time to AML. In this subgroup of MDS, IPSS‐R was capable of splitting our series in five groups with significant differences in OS only when blasts were assessed from NECs. In conclusion, our easy‐applicable approach improves prognostic assessment of MDS patients.     

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.     

Identification of distinct prognostic subgroups in low- and intermediate-1-risk myelodysplastic syndromes by flow cytometry

The World Health Organization (WHO) classification contributes to refined classification and prognostication of myelodysplastic syndromes (MDSs). Flow cytometry might add significantly to diagnostic and prognostic criteria. Our analysis of bone marrow samples from 50 patients with MDS showed aberrant expression of differentiation antigens in the myelomonocytic lineage. This also accounted for refractory anemia (RA) with or without ringed sideroblasts (RS), indicating multilineage dysplasia. In 38% of patients, CD34(+) myeloid blasts expressed CD5, CD7, or CD56. Flow cytometry data were translated into a numerical MDS flow-score. Flow-scores increased significantly from RA with or without RS, refractory cytopenia with multilineage dysplasia (RCMD) with or without RS up to refractory anemia with excess of blasts-1 (RAEB-1) and RAEB-2. No significant differences were observed between WHO cytogenetic subgroups. Flow-scores were highly heterogeneous within International Prognostic Scoring System (IPSS) subgroups. Patients in progression to advanced MDS or acute myeloid leukemia had a significantly higher flow-score compared with non-transfusion-dependent patients. In 60% of patients with transfusion dependency or progressive disease, myeloid blasts expressed CD7 or CD56, in contrast to only 9% of non-transfusion-dependent patients. Moreover, all patients with pure RA with or without RS with aberrant myeloid blasts showed an adverse clinical course. In conclusion, flow cytometry in MDS identified aberrancies in the myelomonocytic lineage not otherwise determined by cytomorphology. In addition, flow cytometry identified patients at risk for transfusion dependency and/or progressive disease independent of known risk groups, which might have impact on treatment decisions and the prognostic scoring system in the near future.     

Monosomal karyotype improves IPSS‐R stratification in MDS and AML patients treated with Azacitidine

IPSS‐R classifies cytogenetic abnormalities into five prognostic groups for survival. Monosomal karyotype (MK) is not a subgroup of IPSS‐R. Additional prognostic information from MK in poor and very poor karyotype has been recently shown. The aim of our study was to determine the prognostic value of IPSS‐R and MK for response and survival in AZA‐treated high‐risk MDS and AML with 20–30% of blasts patients. The study population included 154 patients who were classified according to IPSS‐R. IPSS‐R was not predictive of response (intermediate, 64%; poor, 44%; very poor, 56%; P = 0.28) or survival (intermediate, 25 months; poor, 12 months; very poor, 11 months; P = 0.14). Twenty‐one patients (15%) presented with MK and had a median OS of 9 months. Patients with a very high IPSS‐R score without MK had a median OS of 15 months, while patients with a high IPSS‐R score without MK had a median OS of 13 months (P = 0.18). We reclassified patients into the following three groups to include MK status: very high (MK only; OS median: 9 months), high (very high IPSS‐R without MK and high IPSS‐R without MK; OS median: 14 months) and intermediate (OS median: 25 months). As in recent publication including MK prognostic, we confirmed that this classification was predictive for survival in AZA treated patients (P = 0.008). IPSS‐R failed to discriminate between the prognostic subgroups. Stratification with MK has value in the prognosis of our cohort of AZA‐treated patients. Am. J. Hematol. 88:780–783, 2013. © 2013 Wiley Periodicals, Inc.     

The hematopoietic stem cell transplantation comorbidity index is of prognostic relevance for patients with myelodysplastic syndrome

We studied the impact of comorbidities on survival and evaluated the prognostic utility of comorbidity scores in MDS patients, who received best supportive care and were assessable according to the Charlson Comorbidity Index (CCI) and the Hematopoietic Stem Cell Transplantation Comorbidity Index (HCTCI): 171 patients were identified in the Duesseldorf MDS Registry. The HCTCI captured more comorbidities. Both scoring systems had prognostic relevance, but the HCTCI more clearly distinguished between low-, intermediate- and high-risk patients. Median survival times of the different risk groups according to the HCTCI were 68, 34 and 25 months, respectively. The HCTCI showed prognostic impact in the IPSS intermediate- and high-risk group. On multivariate regression analysis, only the HCTCI remained a prognostic factor independent of IPSS. Considering their prognostic impact, comorbidities of MDS patients should receive appropriate attention in clinical trials as well as day-to-day clinical decision making.     

Myelodysplastic syndromes: 2015 Update on diagnosis,risk‐stratification and management

Disease overview : The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy. Diagnosis : Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry, or molecular genetics is complementary but not diagnostic. Risk‐stratification : Prognosis of patients with MDS can be calculated using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow, and cytogenetic characteristics. The most commonly used system still is probably the International Prognostic Scoring System (IPSS). IPSS is being replaced by the new revised score IPSS‐R. Risk‐adapted therapy : Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts, and more recently cytogenetic and mutational profiles. Goals of therapy are different in lower risk patients than in higher risk. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML, as well as to improve survival. In higher risk, the goal is to prolong survival. Current available therapies include growth factor support, lenalidomide, hypomethylating agents, intensive chemotherapy, and allogeneic stem cell transplantation. The use of lenalidomide has significant clinical activity in patients with lower risk disease, anemia, and a chromosome 5 alteration. 5‐Azacitidine and decitabine have activity in higher risk MDS. 5‐Azacitidine has been shown to improve survival in higher risk MDS. A number of new molecular lesions have been described in MDS that may serve as new therapeutic targets or aid in the selection of currently available agents. Additional supportive care measures may include the use of prophylactic antibiotics and iron chelation. Management of progressive or refractory disease : At the present time there are no approved interventions for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options include participation in a clinical trial or cytarabine based therapy and stem cell transplantation. Am. J. Hematol. 90:832–841, 2015. © 2015 Wiley Periodicals, Inc.     

Myelodysplastic syndromes: 2014 update on diagnosis,risk‐stratification,and management

Disease overview : The myelodysplastic (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older male and in individuals with prior exposure to cytotoxic therapy. Diagnosis : Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry or molecular genetics is complementary but not diagnostic. Risk‐stratification : Prognosis of patients with MDS can be calculated using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow and cytogenetic characteristics. The most commonly used system is the International Prognostic Scoring System (IPSS). IPSS is likely to be replaced by a new revised score (IPSS‐R) and by the incorporation of new molecular markers recently described. Risk‐adapted therapy : Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts and more recently cytogenetic profile. Goals of therapy are different in lower risk patients than in higher risk. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML, as well as to improve survival. In higher risk, the goal is to prolong survival. Current available therapies include growth factor support, lenalidomide, hypomethylating agents, intensive chemotherapy, and allogeneic stem cell transplantation. The use of lenalidomide has significant clinical activity in patients with lower risk disease, anemia, and a chromosome 5 alteration. 5‐Azacitidine and decitabine have activity in higher risk MDS. 5‐Azacitidine has been shown to improve survival in higher risk MDS. A number of new molecular lesions have been described in MDS that may serve as new therapeutic targets or aid in the selection of currently available agents. Additional supportive care measures may include the use of prophylactic antibiotics and iron chelation. Management of progressive or refractory disease : There are no approved interventions for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options include cytarabine based therapy, transplantation and participation on a clinical trial. Am. J. Hematol. 89:98–108, 2014. © 2013 Wiley Periodicals, Inc.     

Survival analysis and AML development in patients with de novo myelodysplastic syndromes: comparison of six different prognostic scoring systems

A number of prognostic scoring systems for patients with myelodysplastic syndromes (MDS) have been introduced in the past. In the present study, survival and AML evolution were analyzed retrospectively in a total of 180 patients with de novo MDS (observation period: 1989-1999; median age: 71; range 27-93; f/m ratio: 1/1.2). Diagnoses were established according to FAB criteria (RARS, n=37; RA, n=53; RAEB, n=50; RAEB-t, n=19; CMML, n=21). Six different multiparameter scoring systems (the Mufti, Aul, Sanz, Morel, and Toyama scores, and the international prognostic scoring system [IPSS]) were applied. The Aul, Sanz, and Mufti scores were applied to all 180 patients, Morel and Toyama scores to 109 patients, and the IPSS to 102. As assessed by multivariate analysis, the percentage of bm-blasts, hemoglobin, platelet count, neutrophil count, LDH, and karyotype were found to be independent single variables for survival, and bm-blasts, neutrophil count, platelet count, and karyotype for AML evolution. All prognostic scoring systems applied appeared to be highly predictive for survival and AML development (P<0.001). The highest predictive values were found for the Aul, Sanz, and Toyama scores for overall survival, and the IPSS, Toyama, and Morel scores for AML-free survival. In summary, our data show that scoring systems are useful for predicting overall and AML-free survival in patients with MDS. Karyotype-based multiparameter systems appear to be particularly effective in defining MDS patients who are at high risk of transforming to leukemia.     

The impact of intensive antileukaemic treatment strategies on prognosis of myelodysplastic syndrome patients aged less than 61 years according to International Prognostic Scoring System risk groups

The present study applied the International Prognostic Scoring System (IPSS) to 306 consecutive myelodysplastic syndrome (MDS) patients diagnosed between August 1977 and September 2000 at the University Medical Centre Nijmegen. The aim was to investigate whether the IPSS could be used as a prognostic tool in MDS patients aged less than 61 years who were treated with acute myeloid leukaemia (AML)-like chemotherapy with or without transplantation, and whether the scoring system discriminated between the subgroups of patients who benefit from intensive treatment strategies. The patients were retrospectively assigned to the IPSS risk categories and compared with the IPSS workshop patients. Eighty-three of 159 patients aged < 61 years, classified as intermediate 1, intermediate 2 and high risk according to the IPSS, received intensive treatment consisting of chemotherapy only (n = 30), chemotherapy followed by either autologous stem cell transplantation (n = 7) or allogeneic stem cell transplantation (n = 46). After intensive treatment, the median survival was 2.6 years for the intermediate 1 risk group (n = 33), 3.4 years for the intermediate 2 risk group (n = 27) and 0.9 years for the high-risk group (n = 23). We conclude that the IPSS is an improved scoring system for patients receiving supportive care. Nevertheless, the scoring system does not seem to be the best method for predicting outcome after intensive antileukaemic treatment. In particular, intermediate 2 risk patients may benefit from intensive treatment.     

Multidimensional assessment of patient condition and mutational analysis in peripheral blood,as tools to improve outcome prediction in myelodysplastic syndromes: A prospective study of the Spanish MDS group

The International Prognostic Scoring System and its revised form (IPSS‐R) are the most widely used indices for prognostic assessment of patients with myelodysplastic syndromes (MDS), but can only partially account for the observed variation in patient outcomes. This study aimed to evaluate the relative contribution of patient condition and mutational status in peripheral blood when added to the IPSS‐R, for estimating overall survival and the risk of leukemic transformation in patients with MDS. A prospective cohort (2006–2015) of 200 consecutive patients with MDS were included in the study series and categorized according to the IPSS‐R. Patients were further stratified according to patient condition (assessed using the multidimensional Lee index for older adults) and genetic mutations (peripheral blood samples screened using next‐generation sequencing). The change in likelihood‐ratio was tested in Cox models after adding individual covariates. The addition of the Lee index to the IPSS‐R significantly improved prediction of overall survival [hazard ratio (HR) 3.02, 95% confidence interval (CI) 1.96–4.66, P < 0.001), and mutational analysis significantly improved prediction of leukemic evolution (HR 2.64, 1.56–4.46, P < 0.001). Non‐leukemic death was strongly linked to patient condition (HR 2.71, 1.72–4.25, P < 0.001), but not to IPSS‐R score (P = 0.35) or mutational status (P = 0.75). Adjustment for exposure to disease‐modifying therapy, evaluated as a time‐dependent covariate, had no effect on the proposed model's predictive ability. In conclusion, patient condition, assessed by the multidimensional Lee index and patient mutational status can improve the prediction of clinical outcomes of patients with MDS already stratified by IPSS‐R.     

Cross-validation of prognostic scores in myelodysplastic syndromes on 386 patients from a single institution confirms importance of cytogenetics

In myelodysplastic syndromes (MDS) different prognostic risk analysis systems based on clinical and morphological data are used for predicting survival. Data on diagnostic and prognostic relevance of karyotype aberrations have prompted the development of scores including cytogenetics. The aim of this study was to assess and compare the explanatory power of different scoring systems and to assess the additional explanatory power of cytogenetics by evaluating the clinical and laboratory data of MDS patients from a single institution. Data of 386 MDS patients was available, with cytogenetic analysis at time of diagnosis in 256. Clinical/morphological scores: Bournemouth, modified Bournemouth and Düsseldorf; and scores including cytogenetics: Lausanne-Bournemouth, Lille and the International Prognostic Scoring System (IPSS), were calculated and their predictive power was compared for both overall survival and preleukaemic duration. Each of the scores had significant correlation on both endpoints. Calculating the prognostic value of different cytogenetic aberrations we found that differentiating between evidence for no aberration, single aberrations excluding chromosomes 7 and 8, aberrations on chromosomes 5, 7 or 8 and complex aberrations was important. These data were incorporated in a 'prognostic index cytogenetics' (pi score). Cytogenetic scores significantly improved the prognostic value of the best clinical/morphological score in regard to both overall survival and preleukaemic duration. In conclusion, our data further stress the importance of cytogenetics for predicting prognosis in MDS.     

Comparing the prognostic value of risk stratifying models for patients with lower‐risk myelodysplastic syndromes: Is one model better?

Some patients classified as having lower‐risk (LR)‐disease by the International Prognostic Scoring System (IPSS) fare more poorly than predicted. We examined the prognostic utility of IPSS, the MD Anderson LR‐Prognostic System (LR‐PSS), and the revised IPSS (IPSS‐R) in a large cohort of patients classified as having IPSS LR‐MDS in the MDS Clinical Research Consortium database. Actual overall survival (OS) was assessed in patients with IPSS LR‐MDS (i.e. low and intermediate‐1) using Kaplan–Meier methods. Harrell's c index (HCI) and Akaike information criteria (AIC) were used to compare the models. Median OS of 1,140 eligible patients was 47 months (95% CI, 44–52). Median follow‐up was 62 months. HCI values indicating the discriminatory power of the models (higher is better) were better for LR‐PSS (0.74, 95% CI, 0.70–0.78) than IPSS‐R (0.64, 95% CI, 0.60–0.67) and IPSS (0.64, 95% CI, 0.60–0.68). Similarly, AIC values indicating the goodness of the fit were better for LR‐PSS than IPSS‐R and IPSS (8,110, 8,147, and 8,150, respectively, lower is better). LR‐PSS assigned 25.1% and 37.4% of patients with IPSS LR‐MDS into LR‐PSS Category 3 and IPSS‐R Categories ≥Intermediate, respectively. Of 291 patients (25.5%) who survived ≤24 months from diagnosis, only 37.1% and 45% were classified as LR‐PSS category 3 and IPSS‐R categories ≥Intermediate, respectively (P = 0.06). While both LR‐PSS and IPSS‐R distinguish groups with varied survival outcome among patients with IPSS LR‐MDS, both tools fail to identify a significant subset with poor OS. Future studies should assess whether patients identified as at increased risk will benefit from earlier interventions with disease‐modifying therapies. Am. J. Hematol. 90:1036–1040, 2015. © 2015 Wiley Periodicals, Inc.