Is International Prognostic Scoring System (IPSS) still standard in predicting prognosis in patients with myelodysplastic syndrome? External validation of the WHO Classification‐Based Prognostic Scoring System (WPSS) and comparison with IPSS

Background: This study was undertaken to evaluate the prognostic value of the WHO Classification‐Based Prognostic Scoring System (WPSS) and to compare it with that of the International Prognostic Scoring System (IPSS). Patients and methods: 149 patients de novo diagnosed as having myelodysplastic syndrome between December 1994 and February 2007, were evaluated retrospectively. Results: WPSS presented an excellent method for risk‐stratifying patients into five subgroups, with different risks of death and leukaemic evolution. On univariate analysis, three components of WPSS – cytogenetic risk, WHO category and transfusion dependency – had good correlations with overall survival (OS) and time to leukaemic evolution (TTL). However, one component of IPSS – number of peripheral cytopenias – did not correlate with OS or TTL. WPSS could distinguish the truly low‐risk patients (very low) who had an excellent long‐term survival with rare leukaemic evolution, while IPSS could not. These patients should be managed with clinical observation and delayed treatment strategies. Furthermore, on multivariate analysis for OS, WPSS was found to be an independent prognostic factor for survival along with age [P = 0.04; hazard ratio (HR) = 1.71; 95% confidence interval (CI) 1.02–2.85] and lactate dehydrogenase (LDH) (P = 0.002; HR = 2.47; 95% CI 1.41–4.31). On the other hand, the prognostic significance of IPSS was not confirmed. Conclusion: These results suggest that the WPSS might be a more powerful predictor of prognosis than IPSS and that independent validation of several other, larger data sets should be necessary.     

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.     

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.     

Iron‐chelating therapy with deferasirox in transfusion‐dependent,higher risk myelodysplastic syndromes: a retrospective,multicentre study

Iron chelation is controversial in higher risk myelodysplastic syndromes (HR‐MDS), outside the allogeneic transplant setting. We conducted a retrospective, multicentre study in 51 patients with transfusion‐dependent, intermediate‐to‐very high risk MDS, according to the revised international prognostic scoring system, treated with the oral iron chelating agent deferasirox (DFX). Thirty‐six patients (71%) received azacitidine concomitantly. DFX was given at a median dose of 1000 mg/day (range 375–2500 mg) for a median of 11 months (range 0·4–75). Eight patients (16%) showed grade 2–3 toxicities (renal or gastrointestinal), 4 of whom (8%) required drug interruption. Median ferritin levels decreased from 1709 μg/l at baseline to 1100 μg/l after 12 months of treatment (P = 0·02). Seventeen patients showed abnormal transaminase levels at baseline, which improved or normalized under DFX treatment in eight cases. One patient showed a remarkable haematological improvement. At a median follow up of 35·3 months, median overall survival was 37·5 months. The results of this first survey of DFX in HR‐MDS are comparable, in terms of safety and efficacy, with those observed in lower‐risk MDS. Though larger, prospective studies are required to demonstrate real clinical benefits, our data suggest that DFX is feasible and might be considered in a selected cohort of HR‐MDS patients.     

Impact of socioeconomic status on disease phenotype,genomic landscape and outcomes in myelodysplastic syndromes

Genetic and epigenetic alterations contribute to the biological and clinical characteristics of myelodysplastic syndromes (MDS), but a role for socioeconomic environment remains unclear. Here, socioeconomic status (SES) for 283 MDS patients was estimated using the Scottish Index of Multiple Deprivation tool. Indices were assigned to quintile categorical indicators ranked from SES1 (lowest) to SES5 (highest). Clinicopathological features and outcomes between SES quintiles containing 15%, 20%, 19%, 30% and 16% of patients were compared. Prognostic scores identified lower‐risk MDS in 82% of patients, with higher‐risk disease in 18%. SES quintiles did not associate with age, gender, cytogenetics, International Prognostic scores or, in sub‐analysis (n = 95), driver mutations. The odds ratio of a diagnosis of refractory anaemia was greater than other MDS sub‐types in SES5 (OR 1·9, P = 0·024). Most patients (91%) exclusively received supportive care. SES did not associate with leukaemic transformation or cause of death. Cox regression models confirmed male gender (P < 0·05), disease‐risk (P < 0·0001) and age (P < 0·01) as independent predictors of leukaemia‐free survival, with leukaemic transformation an additional determinant of overall survival (P = 0·07). Thus, if access to healthcare is equitable, SES does not determine disease biology or survival in MDS patients receiving supportive treatment; additional studies are required to determine whether outcomes following disease‐modifying therapies are influenced by SES.     

Bone marrow blasts level predicts prognosis in patients with refractory cytopenia with multilineage dysplasia

Objectives: Current prognostic models for myelodysplastic syndrome (MDS) do not consider the prognostic value of a bone marrow blast level that is <5%. Exploring the prognostic value of the International Prognostic Scoring System (IPSS) and a marrow blast level that is <5% may lead to better risk‐adapted therapeutic strategies. Methods: According to the World Health Organization classification, most of our patients (65.5%) fell into the new category ‘refractory cytopenia with multilineage dysplasia’ (RCMD). We evaluated the prognostic value of the IPSS in 435 adult patients with de novo MDS and in the 285 of them that had RCMD in a Chinese population. We also analyzed the prognostic value of bone marrow blast levels in patients with RCMD and in different IPSS risk groups. Results: We found a significant difference in survival times between RCMD patients with a marrow blast level of 3.5% or higher vs. those with a blast level of <3.5%, with median survival times of 23.7 and 40.8 months, respectively. In addition, application of a marrow blast level cutoff of 3.5% in patients with RCMD could identify patients with a lower IPSS risk but with a potentially worse prognosis. Multivariate analysis showed marrow blast level (using 3.5% as the cutoff) to be an independent factor that impacted survival times of patients with RCMD. Furthermore, we also found that IPSS had strong prognostic value in Chinese RCMD population. Conclusion: In patients with RCMD, a higher percentage of marrow blasts was associated with a worse prognosis.     

Overall survival in lower IPSS risk MDS by receipt of iron chelation therapy,adjusting for patient‐related factors and measuring from time of first red blood cell transfusion dependence: an MDS‐CAN analysis

Analyses suggest iron overload in red blood cell (RBC) transfusion‐dependent (TD) patients with myleodysplastic syndrome (MDS) portends inferior overall survival (OS) that is attenuated by iron chelation therapy (ICT) but may be biassed by unbalanced patient‐related factors. The Canadian MDS Registry prospectively measures frailty, comorbidity and disability. We analysed OS by receipt of ICT, adjusting for these patient‐related factors. TD International Prognostic Scoring System (IPSS) low and intermediate‐1 risk MDS, at RBC TD, were included. Predictive factors for OS were determined. A matched pair analysis considering age, revised IPSS, TD severity, time from MDS diagnosis to TD, and receipt of disease‐modifying agents was conducted. Of 239 patients, 83 received ICT; frailty, comorbidity and disability did not differ from non‐ICT patients. Median OS from TD was superior in ICT patients (5·2 vs. 2·1 years; P < 0·0001). By multivariate analysis, not receiving ICT independently predicted inferior OS, (hazard ratio for death 2·0, P = 0·03). In matched pair analysis, OS remained superior for ICT patients (P = 0·02). In this prospective, non‐randomized analysis, receiving ICT was associated with superior OS in lower IPSS risk MDS, adjusting for age, frailty, comorbidity, disability, revised IPSS, TD severity, time to TD and receiving disease‐modifying agents. This provides additional evidence that ICT may confer clinical benefit.     

Patient‐related factors independently impact overall survival in patients with myelodysplastic syndromes: an MDS‐CAN prospective study

Little is known about the effects of frailty, disability and physical functioning on the clinical outcomes for myelodysplastic syndromes (MDS). We investigated the predictive value of these factors on overall survival (OS) in 445 consecutive patients with MDS and chronic monomyelocytic leukaemia (CMML) enrolled in a multi‐centre prospective national registry. Frailty, comorbidity, instrumental activities of daily living, disability, quality of life, fatigue and physical performance measures were evaluated at baseline and were added as covariates to conventional MDS‐related factors as predictors of OS in Cox proportional hazards models. The median age was 73 years, and 79% had revised International Prognostic Scoring System (IPSS‐R) risk scores of intermediate or lower. Frailty correlated only modestly with comorbidity. OS was significantly shorter for patients with higher frailty and comorbidity scores, any disability, impaired grip strength and timed chair stand tests. By multivariate analysis, the age‐adjusted IPSS‐R, frailty (Hazard ratio 2·7 (95% confidence interval [CI] 1·7–4·2), P < 0·0001) and Charlson comorbidity score (Hazard ratio 1·8 (95% CI 1·1–2·8), P = 0·01) were independently prognostic of OS. Incorporation of frailty and comorbidity scores improved risk stratification of the IPSS‐R by 30% and 5%, respectively. These data demonstrate for the first time, the importance of considering frailty in prognostic models and a potential target for therapeutic intervention in optimizing clinical outcomes in older MDS patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02537990.     

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.     

Telomere length is an independent prognostic marker in MDS but not in de novo AML

Telomere dysfunction is implicated in the generation of large‐scale genomic rearrangements that drive progression to malignancy. In this study we used high‐resolution single telomere length analysis (STELA) to examine the potential role of telomere dysfunction in 80 myelodysplastic syndrome (MDS) and 95 de novo acute myeloid leukaemia (AML) patients. Despite the MDS cohort being older, they had significantly longer telomeres than the AML cohort (P < 0·0001) where telomere length was also significantly shorter in younger AML patients (age <60 years) (P = 0·02) and in FLT3 internal tandem duplication‐mutated AML patients (P = 0·03). Using a previously determined telomere length threshold for telomere dysfunction (3·81 kb) did not provide prognostic resolution in AML [Hazard ratio (HR) = 0·68, P = 0·2]. In contrast, the same length threshold was highly prognostic for overall survival in the MDS cohort (HR = 5·0, P < 0·0001). Furthermore, this telomere length threshold was an independent parameter in multivariate analysis when adjusted for age, gender, cytogenetic risk group, number of cytopenias and International Prognostic Scoring System (IPSS) score (HR = 2·27, P < 0·0001). Therefore, telomere length should be assessed in a larger prospective study to confirm its prognostic role in MDS with a view to integrating this variable into a revised IPSS.     

Identification of a risk dependent microRNA expression signature in myelodysplastic syndromes

The myelodysplastic syndromes (MDS) display both haematological and biological heterogeneity with variable leukaemia potential. MicroRNAs play an important role in tumour suppression and the regulation of self-renewal and differentiation of haematopoietic progenitors. Using a microarray platform, we evaluated microRNA expression from 44 patients with MDS and 17 normal controls. We identified a thirteen microRNA signature with statistically significant differential expression between normal and MDS specimens (P < 0·01), including down-regulation of members of the leukaemia-associated MIRLET7 family. A unique signature consisting of 10 microRNAs was closely associated with International Prognostic Scoring System (IPSS) risk category permitting discrimination between lower (Low/Intermediate-1) and higher risk (Intermediate-2/High) disease (P < 0·01). Selective overexpression of MIR181 family members was detected in higher risk MDS, indicating pathogenetic overlap with acute myeloid leukaemia. Survival analysis of an independent cohort of 22 IPSS lower risk MDS patients revealed a median survival of 3·5 years in patients with high expression of MIR181 family compared to 9·3 years in patients with low MIR181 expression (P = 0·002). Our pilot study suggested that analysis of microRNA expression profile offers diagnostic utility, and provide pathogenetic and prognostic discrimination in MDS.     

High flow cytometric scores identify adverse prognostic subgroups within the revised international prognostic scoring system for myelodysplastic syndromes

The estimation of survival of myelodysplastic syndromes (MDS) and risk of progression into acute myeloid leukaemia is challenging due to the heterogeneous clinical course. The most widely used prognostic scoring system (International Prognostic Scoring System [IPSS]) was recently revised (IPSS‐R). The aim of this study was to investigate the prognostic relevance of flow cytometry (FC) in the context of the IPSS‐R. Bone marrow aspirates were analysed by FC in 159 patients with MDS. A flow score was calculated by applying the flow cytometric scoring system (FCSS). Patients were assigned to IPSS and IPSS‐R risk groups. The FCSS correlated with the World Health Organization classification, IPSS and IPSS‐R risk groups. Mild flow cytometric abnormalities were associated with significantly better overall survival (OS) and lower risk of disease evolution. The presence of aberrant myeloid progenitors was associated with transfusion dependency and disease progression. Most importantly, the FCSS identified prognostic subgroups within the IPSS‐R cytogenetic good risk and low risk group. Flow cytometric analysis in patients with MDS provides additional prognostic information and is complementary to the IPSS‐R. The addition of a flow cytometric score next to the clinical parameters within the IPSS‐R is a further refinement of prognostication of patients with MDS.     

Mean corpuscular volume predicts prognosis in MDS patients with abnormal karyotypes

The prognostic value of karyotype in patients with myelodysplastic syndrome (MDS) is generally appreciated. However, the factors that are predictive of prognosis of patients with abnormal karyotypes are not known. In this study, we evaluated the prognostic value of International Prognostic Scoring System (IPSS) and World Health Organization classification-based prognostic scoring system (WPSS) in 164 adult MDS patients with abnormal karyotypes. We also analyzed the prognostic relevance of mean corpuscular volume (MCV) in these patients. We found that both IPSS and WPSS had strong prognostic value in patients with abnormal karyotypes (P < 0.001, P < 0.001). Furthermore, we observed the significant differences in the survival of patients with abnormal karyotypes based on MCV stratification: The median survival of patients with macrocytosis was 31.0 months, significantly longer than the 16.5-month median survival time of patients with MCVs of less than 100 fl (P = 0.001). Multivariate analysis revealed that lower level of hemoglobin (P = 0.012, HR = 6.83), higher level of marrow blasts (P < 0.001, HR = 1.93), complex karyotype (P = 0.001, HR = 3.32), and MCV of less than 100 fl (P = 0.026, HR = 1.75) were independent risk factors that affected the survival of patients with abnormal karyotypes.     

Elevated fetal haemoglobin is a predictor of better outcome in MDS/AML patients receiving 5‐aza‐2′‐deoxycytidine (Decitabine)

Although azanucleoside DNA‐hypomethylating agents (HMAs) are routinely used for the treatment of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), very few outcome predictors have been established. Expression of the β‐like globin gene locus is tightly regulated by DNA methylation, is HMA‐sensitive in vitro, and fetal haemoglobin (HbF) expression is under study as a potential biomarker for response of MDS patients to azacitidine. We determined HbF expression in 16 MDS and 36 AML patients receiving decitabine (DAC). Pre‐treatment HbF was already elevated (>1·0% of total haemoglobin) in 7/16 and 12/36 patients, and HbF was induced by DAC in 81%/54% of MDS/AML patients, respectively. Elevated pre‐treatment HbF was associated with longer median overall survival (OS): 26·6 vs. 8·6 months for MDS (hazard ratio [HR] 8·56, 95% confidence interval [CI] 1·74–42·49, P = 0·008, with similarly longer progression‐free and AML‐free survival), and 10·0 vs. 2·9 months OS for AML (HR 3·01, 95% CI 1·26–7·22, P = 0·014). In a multivariate analysis, the prognostic value of HbF was retained. Time‐dependent Cox models revealed that the prognostic value of treatment‐induced HbF induction was inferior to that of pre‐treatment HbF. In conclusion, we provide first evidence for in vivo HbF induction by DAC in MDS/AML, and demonstrate prognostic value of elevated pre‐treatment HbF, warranting prospective, randomized studies.     

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.     

Efficacy and safety of darbepoetin alpha in patients with myelodysplastic syndromes: a systematic review and meta‐analysis

We conducted a systematic review and meta‐analysis to estimate the efficacy of darbepoetin alpha (DA) for treatment of myelodysplastic syndrome (MDS)‐related anaemia. Eligible studies were prospective, interventional, and reported World Health Organization, French‐American‐British, or International Prognostic Scoring System (IPSS) criteria. Outcomes included erythroid response rate (primary); haemoglobin response; change in haemoglobin, transfusion status, and quality‐of‐life (QoL); and safety. Ten studies (N = 647) were analysed. Erythroid response rate range was 38–72%; median response duration range was 12–51+ months. Patients with erythropoietin (EPO) <100 iu/l had 35% [95% confidence interval (CI): 22–48%; P < 0·001) better response than patients with EPO >100 iu/l. Erythropoesis‐stimulating agent (ESA)‐naïve patients had 17% (95% CI: 3–32%; P = 0·022) greater response rate than those previously treated with ESA. Nonetheless, previously treated patients had response rates of 25–75%. Higher baseline haemoglobin levels, higher dose, transfusion‐independence and low‐risk IPSS status were reported by several studies to be associated with better response. QoL, transfusion rates and haemoglobin levels improved with treatment. Hypertension, thromboembolism and progression to acute myeloid leukaemia were reported in 2%, 1% and 1% of patients, respectively. This meta‐analysis suggests that DA treatment can be useful for improving erythroid response in MDS patients with anaemia, even among patients previously treated with ESA.     

Prognosis of myelodysplasic patients: non-parametric multiple regression analysis of populations stratified by mean corpuscular volume and marrow myeloblast number

Myelodysplastic (MDS) patients at diagnosis (n = 162) were analysed by the International Prognostic Scoring System (IPSS). The two intermediate groups were not significantly different. The IPSS was of limited value in predicting survival of MDS patients after preliminary separation into subgroups with < 5%, or >/= 5%, myeloblasts. Cox's proportional hazards analysis of these subgroups enabled discrimination of highly significant prognostic groups. In both subgroups, longer survival was associated with macrocytosis. Mean corpuscular volume (MCV) and marrow myeloblast number were used to define four groups with prognostic significance similar to the IPSS. A low-risk group was described by macrocytosis associated with < 5% myeloblasts and high risk was related to blast counts >/= 5% and MCV < 100 fl. Further analysis defined factors identifying very high-risk patients and those with benign disease, together with many intermediate survival patterns. Results were consistent in two time-separated patient groups.     

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.     

TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis

This study aimed to determine the incidence/prognostic impact of TP53 mutation in 318 myelodysplastic syndrome (MDS) patients, and to correlate the changes to cytogenetics, single nucleotide polymorphism array karyotyping and clinical outcome. The median age was 65 years (17–89 years) and median follow‐up was 45 months [95% confidence interval (CI) 27–62 months]. TP53 mutations occurred in 30 (9·4%) patients, exclusively in isolated del5q (19%) and complex karyotype (CK) with ‐5/5q‐(72%), correlated with International Prognostic Scoring System intermediate‐2/high, TP53 protein expression, higher blast count and leukaemic progression. Patients with mutant TP53 had a paucity of mutations in other genes implicated in myeloid malignancies. Median overall survival of patients with TP53 mutation was shorter than wild‐type (9 versus 66 months, P < 0·001) and it retained significance in multivariable model (Hazard Ratio 3·8, 95%CI 2·3–6·3,P < 0·001). None of the sequentially analysed samples showed a disappearance of the mutant clone or emergence of new clones, suggesting an early occurrence of TP53 mutations. A reduction in mutant clone correlated with response to 5‐azacitidine, however clones increased in non‐responders and persisted at relapse. The adverse impact of TP53 persists after adjustment for cytogenetic risk and is of practical importance in evaluating prognosis. The relatively common occurrence of these mutations in two different prognostic spectrums of MDS, i.e. isolated 5q‐ and CK with ‐5/5q‐, possibly implies two different mechanistic roles for TP53 protein.     

Azacitidine improves outcome in higher‐risk MDS patients with chromosome 7 abnormalities: a retrospective comparison of GESMD and GFM registries

Treatment with azacitidine (AZA) has been suggested to be of benefit for higher‐risk myelodysplastic syndrome (HR‐MDS) patients with chromosome 7 abnormalities (Abn 7). This retrospective study of 235 HR‐MDS patients with Abn 7 treated with AZA (n = 115) versus best supportive care (BSC; n = 120), assessed AZA treatment as a time‐varying variable in multivariable analysis. A Cox Regression model with time‐interaction terms of overall survival (OS) at different time points confirmed that, while chromosome 7 cytogenetic categories (complex karyotype [CK] versus non‐CK) and International Prognostic Scoring System risk (high versus intermediate‐2) retained poor prognosis over time, AZA treatment had a favourable impact on OS during the first 3 years of treatment compared to BSC (Hazard ratio [HR] 0·5 P < 0·001 at 1 year, 0·7 P = 0·019 at 2 years; 0·73 P = 0·029 at 3 years). This benefit was present in all chromosome 7 categories, but tended to be greater in patients with CK (risk reduction of 82%, 68% and 53% at 1, 3 and 6 months in CK patients; 79% at 1 month in non‐CK patients, P < 0·05 for all). AZA also significantly improved progression‐free survival (P < 0·01). This study confirms a time‐dependent benefit of AZA on outcome in patients with HR‐MDS and cytogenetic abnormalities involving chromosome 7, especially for those with CK.