WHO Classification-based Prognostic Scoring System Research Articles

Application of Newly Developed IPSS-M and Comparison of Different Prognostic Systems in Patients with Myelodysplastic Syndrome

Introduction: A risk-adapted treatment strategy is of crucial importance in patients with myelodysplastic syndromes (MDS). With the rapid development of high through-put technology like next generation sequence (NGS), multiple mutations have been revealed as significant factors in MDS. However, previous risk prognostic scoring systems such as the International Prognostic Scoring System (IPSS), the revised IPSS (IPSS-R), and the World Health Organization-classification-based Prognostic Scoring System (WPSS) did not integrate molecular abnormalities. The newly published IPSS-Molecular (IPSS-M) model, which combining genomic profiling with hematologic and cytogenetic parameters in the IPSS-R system (including bone marrow blasts, platelets and hemoglobin), was recently developed to evaluate the associations with leukemia-free survival (LFS), leukemic transformation, and overall survival (OS). This model is considered to be a valuable tool for clinical decision-making. However, it has not yet been widely validated in the clinic. This study is to further validate the prognostic power of IPSS-M based on the real-world data, and to compare the prognostic value of different scoring systems in patients with MDS. Methods：A population of 255 adult MDS was considered. The IPSS-M Web calculator (https://mds-risk-model.com) was used to calculator a tailored IPSS-M score of each patient, and the risk category was therefore divided correspondingly. We then compared the IPSS-M prognostic power to that of IPSS, IPSS-R, and WPSS. The receiver operating characteristic curve (ROC) was used to evaluate the efficiency of the prognostic models. The Spearman's rank correlation rho was used to evaluate the relevance of different tools. Kaplan-Meier (K-M) survival curve with Log-Rank analysis was performed in the study. Results: Median follow-up was 33.2 (95%CI: 27.8-41.1, reverse K-M) months for the whole cohort. Median OS was 28.3 (21.3-35, K-M) months. We mapped at least one oncogenic gene alteration in 75% of patients with MDS, and found that TET2 (23%), ASXL1 (19%), TP53 (15%), DNMT3A (10%), U2AF1 (9%), SF3B1(9%), EZH2 (9%), RUNX1 (5%), WT1 (5%) and SETBP1(5%) are the top 10 genes with the highest mutation frequency (Fig. 1a). Similar with the other three prognostic systems, IPSS-M risk classification was statistically significant for OS (P<0.0001 for IPSS-M, P=0.00061 for IPSS, P<0.0001 for IPSS-R and WPSS) and LFS (P<0.0001 for IPSS-M, IPSS, IPSS-R and WPSS) (Fig 1b). However, no prognostic tool predicted the probability of achieving an objective response. Among the four risk stratification tools, WPSS was more superior in sensitivity and accuracy for OS, while IPSS-M was more superior for LFS (Fig. 1c). The Spearman's rho of IPSS-M with IPSS, IPSS-R and WPSS was 0.646, 0.786 and 0.729, respectively. This indicated that IPSS-M was more correlated with IPSS-R. The mapping C-index between IPSS-R and IPSS-M categories resulted in improved discrimination across the OS and LFS but not leukemic transformation (Fig. 2a). Additionally, it is also resulted in the re-stratification of 45% of MDS patients (114/255) (Fig. 2b). Of these, 85 (33%) were upstaged and 29 (11%) were down-staged. Among re-stratified patients, 19 of 80 (24%) had one mutated gene in IPSS-M, whereas 23 of 80 (29%) had two or more (Fig. 2c). Thus, patient re-stratification was not a single gene effect, but the cumulative contribution of the prognostic mutations for each patient. To further explore the effect of hypomethylation agents (HMAs) or best supportive care (BSC) on different groups, we analyzed the K-M survival curves of higher-risk (HR) and lower-risk (LR) groups stratified by IPSS-M and IPSS-R (Fig. 2d). The results showed that compared with BSC, HMAs did not improve OS and LFS either in HR or LR groups. In patients treated with HMAs, IPSS-M was more superior in both sensitivity and applicability than IPSS-R in OS, with the C-index value of 0.611 vs. 0.582. Conclusions: Overall all prognostic scoring systems well represent the prognostic risk of MDS patients. A highly significant correlation was found between the IPSS-M and IPSS-R risk classifications. IPSS-M provides relevant information for the implementation of risk-adapted strategies in MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Retrospective Validation Study Comparing the IPSS-M and IPSS-R Risk Stratification Scores in Primary and Secondary Myelodysplastic Syndrome (MDS)

Introduction: Myelodysplastic syndrome (MDS) is a stem cell disorder characterized by bone marrow stem cell dysfunction, cytopenia(s), and increased risk of acute myeloid leukemia (AML) transformation. Treatment of MDS varies based on a patient's estimated risk of transformation to AML and the presence of molecular and cytogenetic changes known to confer poor clinical outcomes. Significant effort over the last few decades has been undertaken to develop prognostic models to risk stratify patients, resulting in the international prognostic scoring system (IPSS), revised version (IPSS-R), and WHO classification-based prognostic scoring system (WPSS). Recently, the molecular international prognostic scoring system (IPSS-M) was proposed to consider clinical indices, laboratory and pathology parameters, cytogenetics, and mutational data in the progression of MDS. Currently, this model has only been validated within a Japanese database, wherein 42% of patients were re-stratified by IPSS-M in comparison to IPSS-R. To date, these results have yet to be validated in a cohort of patients in the U.S. Methods: We conducted a single-center retrospective validation cohort study of adults with a known diagnosis of MDS referred to Oregon Health & Science University from 2019 through 2021. The study was approved by the Institutional Review Board prior to initiation (OHSU IRB number- STUDY00023980). Patients were identified using relevant diagnostic codes for MDS and those who were <18 years of age, did not have a biopsy-confirmed diagnosis of MDS, did not have next-generation sequencing performed on diagnostic tissue, or were lost to follow-up shortly after diagnosis were excluded. Patients with treatment-related MDS were included. The primary outcomes, measured from MDS diagnosis and determined through May 2022, were overall survival (OS) and leukemia-free survival (LFS). Predictors of interest were IPSS-R, age-adjusted IPSS-R, WPSS, and IPSS-M, each with categories of "very low", "low", "intermediate" (called "moderate" for IPSS-M), "high", and "very high" risk. OS and LFS in specific prognostic risk categories/groups were estimated by the Kaplan-Meier method and compared using the log-rank test. Median follow-up was estimated by the reverse Kaplan-Meier method. Cox regression models of OS and LFS were fit to estimate the relative risk of AML transformation or death with hazard ratios (HRs) and the prognostic accuracy with concordance indices (C-index). Results: One hundred and forty-nine patients, diagnosed between 2011 and 2021, met inclusion criteria and were analyzed: 136 diagnosed with primary MDS and 13 with secondary/treatment-related MDS (Table 1). After IPSS-M re-stratification, 32% of patients were up-staged (with 24 moving into the "very high" group) and 12% down-staged (with 3 patients exiting the "very high" group) from their IPSS-R risk category. Median follow-up time was 2.8 years and 54 patients died (36%) during the study period. Among the 32 patients (21%) whose disease transformed to AML, median time from MDS diagnosis to transformation was 7 months. When considering death as a competing risk, estimated cumulative incidence of AML transformation was 14% at 1 year and 19% at 3 years post-diagnosis. IPSS-R groups were significantly segregated by LFS (log-rank p=6.3e-05; "very high" vs. "low" HR=4.08, p=3.3e-04; Figure 1, Table 1) and by OS (log-rank p=4.9e-06; "very high" vs. "low" HR=5.38, p=1.0e-04; Fig 1, Table 1). IPSS-M was also highly significantly associated with LFS (log-rank p=1.2e-07; "very high" vs. "low" HR=5.64, p=4.4e-06; Fig 1, Table 1) and OS (log-rank p=4.6e-08; "very high" vs. "low" HR=7.30, p=6.1e-06; Fig 1, Table 1). IPSS-M had better discrimination than IPSS-R for LFS (C-index 0.72 [95% CI: 0.67 - 0.78] vs. 0.68 [95% CI: 0.62 - 0.75]) and for OS (C-index 0.74 [95% CI: 0.68 - 0.81] vs. 0.70 [95% CI: 0.63 - 0.78]). This discrimination advantage was also observed for LFS (0.73 vs. 0.70) and OS (0.76 vs. 0.73) when taking into account a patient's transfusion dependence at MDS diagnosis. Discussion & Conclusion: This single-center study is the first U.S. cohort validation of the IPSS-M, finding that this mutation-incorporating prognostic index has greater discriminative potential than IPSS-R in predicting AML transformation and any-cause mortality. Further multicenter prospective studies are needed to confirm the utility of the IPSS-M model. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Past, present and future in low-risk myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) is a heterogeneous group of disorders characterized by increased risk of acute myeloid leukemia transformation and cytopenia. The prognosis of MDS patients can be evaluated with various scoring systems, the most commonly used are IPSS (International Prognostic Scoring System), revised-IPSS, and WPSS (WHO classification-based prognostic scoring system). MDS treatment is decided according to the risk classification. The goal of treatment in low-risk MDS is to improve cytopenia, reduce transfusion needs, improve quality of life, prolong overall survival, and maybe reduce the risk of progression to leukemia. In the near future, combining both genomics-based, ex vivo functional based and molecular stratification analysis will lead the way to a personalized and targeted approach.

Model Heterogeneity in Predicting Outcomes of Patients with Myelodysplastic Syndromes (MDS)

BackgroundThe outcome of MDS patients (pts) is heterogeneous, with some pts living for years, while others die within a few months of diagnosis. Several prognostic models have been developed to risk stratify pts with MDS including: the International Prognostic Scoring System (IPSS), Revised IPSS (IPSS-R), World Health Organization classification-based Prognostic Scoring System (WPSS), and MD Anderson Prognostic Scoring System (MDPSS). When applying these models to clinical practice, considerable heterogeneity in their prediction of outcomes is observed. Understanding such heterogeneity can impact disease expectations and treatment recommendations, as these can differ considerably based on the model used.MethodsClinical data from pts who were diagnosed with MDS according to 2008 WHO criteria and treated at our institution between 1/2000 and 1/2017 were analyzed. All prognostic models were calculated at the time of MDS diagnosis. Overall survival (OS) was calculated from the time of diagnosis to time of last follow up or death. Descriptive statistics were used to study the changes in risk categories across models.ResultsOf 687 pts included in the final analysis, the median age at diagnosis was 68 (11-99) years with a male (63%) predominance. Cytogenetic analysis per IPSS-R: very good 19 (3%), good 441(64%), intermediate (INT) 117 (17%), poor 47 (7%), and very poor 63 (9%). Risk categories by IPSS included: 204 (30%) with low risk, 319 (46%) intermediate-1 (INT-1), 124 (18%) intermediate-2 (INT-2), and 40 (6%) high risk. Risk categories by IPSS-R included: 114 pts (17%) with very low risk, 264 (38%) low, 128 (19%) intermediate, 118 (17%) high, and 63 (9%) very high.Significant heterogeneity was observed when comparing all models to IPSS-R risk categories. Among 378 pts with lower-risk disease (Very Low / Low) per IPSS-R, 3 pts (1%) were re-classified INT-2 per IPSS, 73 (19%) as INT and 28 (7%) as high/very high per WPSS, and 11 (29%) as higher-risk per MDAPSS, Table 1. Among 128 pts with intermediate risk by IPSS-R, 102 (20%) were reclassified as lower-risk per IPSS, 44 (34%) as lower-risk and 47 (37%) as higher-risk per WPSS, and 65 (50%) as lower-risk per MDAPSS, Table 1. Among 181 pts with high/very high-risk by IPSS-R, 44 (25%) were reclassified as lower-risk by IPSS, 54 (30%) per WPSS, and 58 (32%) per MDAPSS, Table1. Among 523 pts with lower-risk (low / INT-1) by IPSS, 102 (20%) were reclassified as INT risk and 46 (9%) as higher-risk per IPSS-R, 113 (22%) as INT and 62 (12%) as higher-risk per WPSS, and 186 (36%) as higher risk per MDAPSS, Table 2. Among 164 pts with higher-risk (INT-2/High) per IPSS, 26 (16%) were reclassified as INT per IPSS-R, 24 (15%) per WPSS, and 53 (32%) per MDAPSS, Table 2.The predicted OS per IPSS-R was overestimated when compared to the actual OS (evaluable in 429 pts) for pts in lower-risk categories. The difference between the median predicted IPSS-R OS and median actual OS was 70.6 months (m) for very low risk, 54 m for low, 9.5 m for INT, 6.7 m for high, and -2.4 m for very high risk (pts lived longer than their predicted OS). The IPSS, on the other hand, underestimated the OS, as the difference between the median predicted OS and median actual OS was -23.3 m for low risk, -16.5 m for INT1, -11.8 m for INT2, and -11.1 m for high risk.ConclusionsSignificant intra-patient (difference of outcome in the same pt based on the model used) and intra-group (difference in outcome among pts who have similar risk category by a given model) variability is observed when applying commonly used models in MDS. More importantly, IPSS-R overestimate OS for lower-risk disease and IPSS underestimate OS across all risk categories. This heterogeneity can impact survival expectations, treatment strategies, and clinical trial eligibility criteria based on the model used. A personalized prediction model that can precisely forecast the actual outcome of a pt is needed. [Display omitted] DisclosuresGerds:Incyte: Consultancy; CTI BioPharma: Consultancy. Advani:Pfizer: Consultancy; Takeda/ Millenium: Research Funding. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fees; Apellis Pharmaceuticals: Consultancy; Ra Pharma: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees.

Comparison of the Three Scoring Systems— Ipss、Wpss、and IPSS-R in Predicting the Prognosis of MDS in Chinese

Objective There are many kinds of prognostic scoring systems of myelodysplastic syndrome (MDS) which are all risk-based stratification systems with their own dominance. IPSS、WPSS and IPSS-R are the most commonly used systems in clinical work in CHINA. So we do this research to explore the significance among this three systems in predicting the prognosis of MDS and to guide the clinical accurate prognosis stratification for personal treatment.Methods The clinical data of 74 patients with diagnosed MDS according to NCCN from 2014 to 2017 in Wuhan Union Hospital were retrospectively reviewed, the prognosis was evaluated according to international prostate symptom score (IPSS), World Health Organization classification-based prognostic scoring system (WPSS) and revised international prognostic scoring system (IPSS-R). Then we compare the fatality rate of different stratifications in each system from the 0th month to the 60th month and contrast the 2-year fatality rate of each stratification.Results The difference of median survival time between different groups of prognostic scoring system was statistically significant . The survival curve of WPSS had more intersections between each group, IPSS-R prognosis had less intersections. For low risk group, prognostic evaluation of IPSS and WPSS were poor, IPSS-R was the best way to predict the prognosis(Figure1/2/3 & Table 1).At the same time, we find that TP53 gene do strongly relate with complex karyotype at an odds of 83.3% which all have an OS less then 1 year; and the gene of ASXL1 correlates with a longer OS.Conclusions All the three scoring systems can well predict the prognosis of patients with diagnosed MDS, and IPSS-R has more advantages. Integrated using 3 scoring system and taking the condition of gene mutations in clinical work is more favorable for clinical prognosis evaluation of MDS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cytogenetic characteristics of 665 patients with myelodysplastic syndrome in China: A single‑center report

The karyotype is highly important for diagnosis and prognosis in myelodysplastic syndrome (MDS). The objective of the present study was to investigate the cytogenetic characteristics of patients with MDS in China. The karyotypes of 665 Chinese patients with MDS were analyzed, and it was identified that 298 cases (298/665, 44.8%) had abnormal karyotypes. Among the 298 patients with abnormal karyotypes, the 75 patients with trisomy 8 (+8) constituted the most common subset (75/298, 25.2%). The incidence of abnormal karyotypes was significantly higher in patients who were ≥51 years old compared with those <51 years old, (54.8 vs. 34.7%, respectively; P<0.05). Based on World Health Organization (WHO) classification-based Prognostic Scoring System (WPSS) criteria, the incidence of poor-prognosis karyotypes was significantly higher (17.4 vs. 5.4%; P<0.05) in the older patient group, and based on the Revised International Prognostic Scoring System (IPSS-R) criteria, the incidence of poor-/very poor-prognosis karyotypes was also significantly higher (17.4 vs. 6.6%; P<0.05) in patients ≥51 years old compared with younger ones. Based on the WHO classification of MDS subtypes, the incidence of abnormal karyotypes in patients with high percentages of bone marrow (BM) blasts [excess blasts (EB)-I + EB-II, ≥5% blasts] was significantly higher than that in patients with low percentages of BM blasts (those with single lineage dysplasia + multilineage dysplasia, <5% blasts) (62.5 vs. 36.0%; P<0.05). The incidence of poor-prognosis karyotypes based on WPSS criteria was significantly higher in patients with high percentages of BM blasts than those with low percentages (22.0 vs. 6.9%, respectively; P<0.05), and the incidence of poor-/very poor-prognosis karyotypes based on IPSS-R criteria was also significantly higher (23.0 vs. 7.4%, respectively; P<0.05). These results demonstrate that +8 is the most common abnormal karyotype in Chinese patients with MDS. Age and the percentage of BM blasts are associated with the incidence of both abnormal karyotypes and karyotypes with poor prognosis. The results of cytogenetic abnormalities in this study will supplement the data on patients of MDS in China.

Prolonged response to recombinant human erythropoietin treatment in patients with myelodysplastic syndrome at a single referral centre in Brazil

OBJECTIVES:To evaluate the effects of epoetin (EPO) alfa treatment on overall survival, event-free survival and response duration in patients with myelodysplastic syndrome (MDS) who were treated at a haematological referral centre in northeastern Brazil.METHODS:This was a retrospective cohort study of 36 patients diagnosed with MDS and treated with EPO alfa at 30,000 to 60,000 IU per week. Clinical data were collected from medical records. The events assessed were non-response to treatment and progression to acute myeloid leukaemia (AML). Statistical analyses were performed using GraphPad Prism 7 and SPSS 24 software.RESULTS:The overall survival of patients who received EPO alfa treatment was 51.64%, with a median of 65 months of treatment, and the overall survival of this group was 100% during the first 24 months. We detected a 43.5-month median event-free survival, with a response rate of 80.5%. We observed responses from 25 to 175 months. Patients with transfusion dependence and those with a high-risk stratification, as determined by the International Prognostic Scoring System (IPSS), the Revised International Prognostic Scoring System (IPSS-R), the WHO classification-based Prognostic Scoring System (WPSS) and the WHO 2016, had a lower event-free survival than other patients.CONCLUSIONS:Despite the wide use of EPO alfa in the treatment of anaemia in patients with MDS, the median response duration is approximately only 24 months. Our data provide encouraging results concerning the benefits of using EPO alfa for the improvement of the quality of life, as patients treated with EPO showed higher overall survival, event-free survival rates and longer response durations than have been previously described in the literature.

Abnormal changes in the quantity and function of osteoblasts cultured in�vitro in patients with myelodysplastic syndrome

Changes in bone marrow niches can lead to the occurrence of myelodysplastic syndrome (MDS). As an important part of the bone marrow niche, osteoblasts serve a key role in the progression of MDS. The present study investigated the quantity and function of osteoblasts and, through in vitro assays, detected changes in signaling pathways and the association with progression in MDS patients. The ratios of osteoprogenitors (CD34+OCN+) and OCN+CD34−Lin− osteoblasts in MDS patients were significantly less than those of normal controls. The results of this study demonstrated that the quantity and activity of osteoblasts in MDS patients were lower than those in normal controls. Furthermore the activity of osteoblasts in patients correlated with the severity of MDS. The quantity of osteoblasts cultured in vitro from high-risk and very high-risk MDS patients (WHO Classification-Based Prognostic Scoring System score 3–6) was decreased. The levels of T-cell immunoglobulin and mucin domain-containing 3 (TIM3) and Jagged 1 were also increased in the osteoblasts in vitro. These results indicated that osteoblasts are abnormally altered in MDS patients, and that there are associations between abnormal changes of osteoblasts and the severity of MDS.

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 100000 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 ≤70years. 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.

Benefits of hypomethylating therapy in IPSS lower-risk myelodysplastic syndrome patients: A retrospective multicenter case series study

We retrospectively analyzed the results of hypomethylating therapy in 586 patients (azacitidine in 423 and decitabine in 163) with International Prognostic Scoring System (IPSS) lower-risk myelodysplastic syndrome (MDS). The patients were reclassified with newer scoring systems (revised IPSS [R-IPSS], revised WHO classification-based Prognostic Scoring System [R-WPSS], and Lower Risk Prognostic Scoring System [LR-PSS]), and 21.8–38.4% of patients had high or very high risk features by the newer scoring systems. Median overall survival (OS) was 27.3 months and newer scoring systems well stratified the patients in terms of OS (R-IPSS, P=0.001; R-WPSS, P<0.001; LR-PSS, P<0.001). Hematologic improvement (HI) was observed in 279 patients (47.6%). OS differed by the achievement of HI (39.4% vs. 36.2%, P=0.067). The differences were significant only in patients of intermediate or high risk group by LR-PSS (P=0.034) or R-IPSS (P=0.018). In summary, IPSS lower-risk MDS included a broad range of prognosis, and hypomethylating therapy induced HI in approximately half of the patients. Achievement of HI was associated with longer survival, especially in patients with intermediate or high risk features by newer scoring systems. Hypomethylating therapy seems to have potential benefits in IPSS lower-risk MDS.

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.

Incorporation of Molecular Data into the Current Prognostic Models in Treated Patients with Myelodysplastic Syndromes: Which Model Is the Best

▪BackgroundSeveral prognostic models have been developed to risk stratify patients (pts) with MDS including: the International Prognostic Scoring System (IPSS), Revised IPSS (IPSS-R), World Health Organization classification-based Prognostic Scoring System (WPSS), and MD Anderson Prognostic Scoring System (MDPSS). All except for the MDPSS were developed in treatment-naive pts and, if validated in treated pts, were done so primarily in those receiving one line of therapy. Incorporation of molecular data into the IPSS-R improves its predictive power, and adding molecular data to the IPSS can upstage or downstage some pts. In this study, we compared the prognostic utility of each prognostic model, after adding molecular data, in treated MDS pts.MethodClinical and mutational data from MDS pts diagnosed between 1/2000-1/2013 were analyzed. A panel of 60 gene mutations that were described as commonly mutated in myeloid malignancies was included. Patients who underwent hematopoietic cell transplant (HCT) were censored at the time of transplant. Univariable and multivariable analyses on the training cohort were performed by applying Cox proportional hazards regression analyses that included age, model score, and molecular mutations with an outcome of overall survival (OS). All molecular models were then applied to the validation cohort. The fit of the proposed models to the data was assessed by using Akaike's information criterion (AIC, lower values imply better fit) and concordance (c-) index.ResultsA total of 610 pts were included and divided into two cohorts, training (404 pts), and validation (206 pts). Median age of the training cohort was 67 years (range, 19-88); 83 pts (20%) had MDS/MPN including chronic myelomonocytic leukemia (CMML). Pts received a median of 2 lines of therapies (range, 0-7) and 15% of pts underwent HCT. First line therapies included: supportive care (22%), growth factors (22%), azacitidine +/- combinations (30%), decitabine +/- combinations (6%), lenalidomide (5%), induction chemotherapy (3%), immunosuppressive therapy (3%), and other therapies /clinical trials (9%). The median OS in the training and validation cohorts per scoring system (SS), i.e. IPSS, WPSS, MDPSS, and IPSS-R, is summarized in Table 1. The most common mutations in the training cohort were: TET2 (19%), ASXL1 (16%), SF3B1 (13%), DNMT3A (9%), STAG2 (9%), RUNX1 (8%), and U2AF1 (7%). In univariate analyses, mutations in EZH2 (HR1.8, p = .02), TP53 (HR2.3, p < .001), RUNX1 (HR 1.5, p = .05), and NPM1 (HR1.49, p = .001) had a negative impact on OS while SF3B1 (HR .34, p < .001) mutations were associated with favorable outcome. In multivariate analyses that included SS, mutations (from the list above), and age (except for the MDPSS, which already includes age), the following independent prognostic factors for OS were identified: age, EZH2, SF3B1, TP53, and each SS. Based on the fitted coefficients of each prognostic factor, a molecular version of each model including IPSSm, WPSSm, MDPSSm, and IPSS-Rm was proposed with median OS in the training and validation cohorts as summarized in Table 1. The addition of molecular data improved (reduced) the AIC and (raised) the C-index for the IPSS (2332.6, .69 vs. 2365.8, .64), WPSS (2322.3, .68 vs. 2356.2, .65), MDPSS (2308.4, .71 vs. 2323.4, .69), and IPSS-R (2305.2, .70 vs. 2330.5, .66), respectively. Further, the addition of molecular data to the IPSS upstaged 37% of pts from lower- to higher-risk disease and downstaged 5% of intermediate-1 to low risk disease. In the WPSS, it upstaged 21% of pts and downstaged 24%; in the MDPSS it upstaged 19% and dowstaged 22% of pts from intermediate-1 to low risk; and in the IPSS-R it upstaged 26% to higher-risk disease and 59% of pts with intermediate risk to a higher risk category.ConclusionsThe addition of molecular data to established MDS prognostic models can improve their predictive power, even in treated MDS patients. More importantly, adding molecular information can upstage or downstage pts into different risk categories. This study highlights the importance of incorporating molecular data into clinical prognostic systems. [Display omitted] DisclosuresMukherjee:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding.

RBC-Transfusion Dependency Improves the Prognostic Value of the Revised-IPSS in MDS Patients: Analysis of South Australian and Dusseldorf MDS Registries

▪RBC-transfusion dependency (RBC-TD) is an independent prognostic factor for poor survival 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) includedthree haemoglobincut-offs, which were thought to substitute for RBC-TD. Thus, none 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, in addition to that offered by haemoglobin levels at diagnosis. South Australian MDS registry (SA-MDS registry) data were used to derive a prognostic index while Dusseldorf registry (Germany) data was used as a validation cohort.Inclusion criteria for this study were: primary MDS not treated with disease-modifying therapy, bone marrow blasts ≤30% and peripheral blasts ≤20%. RBC TD was defined as at least one unit of packed red cells transfused every eight weeks for four months (mos), according to WPSS classification. In this study IPSS-R was calculated at the time of diagnosis and the RBC-TD was continuously reassessed after diagnosis.In South Australian Registry, the prevalence of RBC-TD at diagnosis was 61/295 (20.7%), while the incidence of RBC-TD during follow-up was 64/234 (27.4%; Table I). The poor prognosis associated with RBC-TD was demonstrated in a series of landmark analyses. The median overall survival (OS) of RBC-TD patients was significantly inferior to RBC transfusion independent (RBC-TI) patients at 6mos (18 vs. 64 months; n=255; p < 0.0001), 12mos (24 vs. 71 months; n=231; p < 0.0001) and 24mos (40 vs. 87 months; p < 0.0001; n=173; Fig 1A-C). Subgroup analysis of IPSS-R Low and Intermediate risk groups also showed inferior OS in RBC-TD compared to RBC-TI within each risk category. The adverse prognosis of RBC-TD was substantiated in multivariate analysis using a Cox-proportional regression model. We tested 46 models and in each of the three models with least Akaike Information Criterion (AIC) or minimum AIC difference RBC-TD wasan independent adverse prognostic marker in addition to age, sex, and IPSS-R variables(Wald test; P<0.0001). In the best-fitting model, the IPSS-R variables were used as continuous variables (except IPSS-R cytogenetic risk groups).This Cox-proportional regression model (Table 2) was used to derive a prognostic index using cut-off points determined by Cox’s method and was validated in the Dusseldorf cohort.Dusseldorf validation cohort: This cohort consisted of 106 patients (160 start-stop intervals) with a median follow-up of 5.66 years. Cox proportional hazard regression of OS on the prognostic index resulted in a slope coefficient of 0.663 in the validation cohort. This difference in slope could be due to differences between the datasets: e.g. the validation cohort comprised younger patients, more patients with RBC-TD at diagnosis and fewer cases with favourable cytogenetic risk (Table 1).The validation cohort was divided into four prognostic groups using cut-offs determined by Cox’s method (derivation dataset). Cox-proportional hazard regression of OS showed significant OS difference between the four prognostic groups (p<0.001) and significantly higher risk of death in groups 3 (p=0.032) and 4 (p=0.007) relative to group 1 (Table 1).Conclusion: Multivariate analysis by Cox proportional hazards regression and serial landmark analysisof dataset clearly demonstrates that development of RBC-TD at any time during the disease course is associated with poor OS, independent of IPSS-R. This was confirmed in the Dusseldorf validation cohort. This is the first report demonstrating that inclusion of RBC-TD can refine the IPSS-R. Furthermore, despite inclusion of three haemoglobin cut-off values in the IPSS-R model, the onset of RBC-TD during follow-up provides additional prognostic value and could be included in future prognostic scoring systems and in treatment decision algorithms for MDS patients. [Display omitted] [Display omitted] [Display omitted] DisclosuresRoss:Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria.

Comparison of Myelodysplastic Syndrome Prognostic Scoring Systems.

Objective:Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease. Patients are at risk of developing cytopenias or progression to acute myeloid leukemia. Different classifications and prognostic scoring systems have been developed. The aim of this study was to compare the different prognostic scoring systems.Materials and Methods:One hundred and one patients who were diagnosed with primary MDS in 2003-2011 in a tertiary care university hospital’s hematology department were included in the study.Results:As the International Prognostic Scoring System (IPSS), World Health Organization Classification-Based Prognostic Scoring System (WPSS), MD Anderson Prognostic Scoring System (MPSS), and revised IPSS (IPSS-R) risk categories increased, leukemia-free survival and overall survival decreased (p<0.001). When the IPSS, WPSS, MPSS, and IPSS-R prognostic systems were compared by Cox regression analysis, the WPSS was the best in predicting leukemia-free survival (p<0.001), and the WPSS (p<0.001) and IPSS-R (p=0.037) were better in predicting overall survival.Conclusion:All 4 prognostic systems were successful in predicting overall survival and leukemia-free survival (p<0.001). The WPSS was found to be the best predictor for leukemia-free survival, while the WPSS and IPSS-R were found to be the best predictors for overall survival.

A Novel Model to Predict Outcome of Patients with Myelodysplastic Syndromes (MDS) at the Time of Hypomethylating Agent Failure

Background:Several validated prognostic models exist for patients (pts) with myelodysplastic syndromes (MDS), including the International Prognostic Scoring System (IPSS), the Revised IPSS (IPSS-R), the World Health Organization (WHO) classification-based Prognostic Scoring System (WPSS), and the MD Anderson Prognostic Scoring System (MDAPSS). All were developed in pts with newly diagnosed MDS, and their prognostic value in subsequent stages of disease, such as at the time of hypomethylating agents failure (HMAs, azacitidine (AZA) and decitabine (DAC), has not been established. Despite this, the IPSS and IPSS-R is often used to determine clinical trial eligibility for pts who fail HMA and has been used by the FDA for drug labeling in this setting. Here in we developed a new prognostic model that predicts outcome post HMAs failure (HMAF).MethodsIncluded patients were diagnosed with higher-risk MDS (per 2008 WHO criteria, higher-risk defined as IPSS Intermediate-2/High) with clinical and pathologic data entered into the MDS Clinical Research Consortium database. The IPSS, IPSS-R, WPSS and MDAPSS were calculated at the time of diagnosis and HMAF. HMAF was defined as no response to AZA or DAC following >4 cycles, loss of response, or progression to acute myeloid leukemia (AML) at any time after starting therapy. Responses were defined per International Working Group criteria (IWG 2006). Overall survival (OS) was calculated from the time of diagnosis to time of death or last follow up when the models were applied at diagnosis and from HMAF date to time of death or last follows up when the models were applied at the time of HMAF. Cox proportional hazard analysis within the multivariable model-building with fractional polynomials (MFP) approach, which automatically select from all factors at the time of HMAF, was used to build the new model. Akaike information criterion (AIC) was used to compare fits from Cox proportional hazards models.ResultsOf 450 higher-risk MDS pts who failed HMAs, 311 (69.1%) were treated with AZA and 139 (30.9%) with DAC. The median age at diagnosis was 70 years (range: 35-91). Best responses (BR) to HMA were: 96 (21.3%) with complete remission, 40 (8.9%) partial remission, 46 (10.2%) hematologic improvement, 180 (40.0%) stable disease, and 88 (19.6%) with progressive disease. The median number of cycles received during treatment was 6 (range, 2-51). With a median follow up of 17.4 months (IQ range, 16.1, 18.7), the median OS from diagnosis for the entire group was 18.5 months (IQ range, 17.2, 19.8). Median OS from diagnosis was similar for patients treated with AZA compared to DAC (18.0 months vs. 20.3 months, p = .36). The median OS after HMAF was 7.3 months (IQ range, 6.3, 8.4). Survival plots for each prognostic scoring system at diagnosis and HMAF are shown in Figure 1. Comparing the predictive power of these scoring systems at the time of HMAF, the AICc for each model was: MDASS (3541.1); IPSS-R (3562.0), IPSS (3570.0), and WPSS with AICc of (3572.2) (lower AICc indicates better fit of the model). Given the lower predictive power of the current prognostic models at the time of HMAF, we developed a new prognostic model specific for this patient population. Our MFP modeling approach selected 6 factors that have significant association with OS at the time of HMAF in the final Cox multivariate model (Table 1). The new model identified two risk groups: Low: score < 2.25, median OS 11.0 months (95% CI 8.8-13.6) and a high risk group with score of > 2.25 and median OS 4.5 months (95% CI 3.9-5.3). Using the internal model validation assessment, the estimated AICc for the new model was 3520.4 (lowest AICc). When the new model was applied at time of diagnosis, the AICc decreased to 3515.1, a much smaller decrease compared to the existing prognostic systems built at diagnosis: MDASS (3515.7), IPSS-R (3528.2), WPSS (3537.5) and IPSS (3537.7).ConclusionCurrently available MDS prognostic scoring systems should be used cautiously in pts at the time of HMAF and, given their inconsistent reliability, should be avoided for clinical trial eligibility or drug labeling. A new prognostic model was developed specific for this patient population. [Display omitted] [Display omitted] DisclosuresKomrokji:Celgene: Consultancy, Research Funding; Incite: Consultancy; Novartis: Speakers Bureau; GSK: Research Funding. Steensma:Celgene: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Onconova: Consultancy. Padron:Novartis: Speakers Bureau; Incyte: Research Funding. List:Celgene Corporation: Honoraria, Research Funding. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

The Clinical and Biological Studies of Myelodysplastic Syndrome

Objective:To analyse systematically the clinical and biological characteristics of 2080 myelodysplastic syndrome patients in our laboratory from 1984 to 2013 and to reveal the unique features of MDS patient in our area.Methods:1. Conventional cytogenetics were performed to investigated the cytogenetics changes in 2080 MDS patients. All patients were classified according to the FAB criterion, in which, 1493 cases were reclassified according to the WHO (2008) criterion; and 550 patients' outcomes were evaluated according to the International Prognostic Scoring System, WHO classification-based Prognostic Scoring System (WPSS) and the revised International Prognostic Scoring System (IPSS-R).2. We analysed the clinical, cytogenetic characteristics and survival of 2080 MDS patients by statistical methods.Results:1. According to the FAB criterion: 1040 (50.0%) patients with RA, 135 (6.5%) patients with RARS, 691 (33.2%) patients with RAEB, 145 (7.0%) patients with RAEB-t, and 69 (3.3%) patients with CMML. The median age was 51 years old (range, 5-93 years old). The ratio of male and female was 1.54. 40.3%(839/2080) patients had clonal chromosome abnormalities, in which 277 (13.3%) patients with complexed karyotype. The rate of karyotype abnormalities was higher in RAEB than that in other subtypes. Survival analysis show that the subgroup with RA had a longer median survival duration than the subgroup with RAS, RAEB, RAEB-t, their median survival duration was 50 months, 32 months, 13months and 16 months, respectively.2. According to the WHO (2008) criterion: 220 patients (14.7%) with RA/RN/RT/RCUD, 75 patients (5.0%) with RARS, 385 patient (25.8%) with RCMD, 14 patient (0.9%) with 5q- syndrome, 282 patients (18.9%) with RAEB-1, 306 patients (20.5%) with RAEB-2, 211 patients (14.1%) with MDS-U. The ratio of male and female was 1.51 (898/595) and the median age was 54 years old (range, 6-93 years old). In all patients, the median hemoglobin level was 70g/L (11~167 g/L), the median platelet count was 51.5×109/L (2~1045 ×109/L) and the median WBC count was 2.65×109/L (0.11~52×109/L). The rate of clonal chromosome abnormalities was 42.1% (628/1493), in which 216 (14.5%) patients with complexed karyotype. There was statistically significant difference in the rate of chromosomal abnormalities among different subtypes (P<0.01). RA/RN/RT/RCUD had a longer median survival duration than other subgroups, in order of MDS-U, RCMD, RARS, RAEB-1 and RAEB-2.3. Among 2080 patients, 839 patients with clonal chromosome abnormalities. chromosome aberration types mainly uneven anomalies, the most common trisomies or monomer. The most common abnormity was +8. Other aberrations in frequent order was -7/del(7q), del(20q), del(5q), and so on.4. Stastistics for survival, 550 patients' outcomes were evaluated according to the IPSS, WPSS and IPSS-R. The results show the IPSS, WPSS and IPSS-R score were significantly affected OS (P<0.001). When comparing the prognostic value of the IPSS, WPSS, and IPSS-R, using the Cox regression model, a significantly higher predictive power for OS became evident for the IPSS-R, compared with the IPSS and WPSS.Conclusion:1. In our study, the MDS patients showed the unique clinical and biological features. We found that the characteristics of cytogenetics has significant differences from western MDS patients. The most common abnormity was +8. Other aberrations in frequent order was -7/del(7q), del(20q), del(5q), and so on.2. IPSS-R is a powerful tool in MDS survival analysis. DisclosuresNo relevant conflicts of interest to declare.

WPSS is a strong prognostic indicator for clinical outcome of allogeneic transplant for myelodysplastic syndrome in Southeast Asian patients.

To better understand the predictive factors and improve clinical outcome of allogeneic transplant for patients with myelodysplastic syndrome (MDS), we retrospectively analyzed the post-transplant outcome of 60 Southeast Asian patients with MDS. Multivariate analysis showed that WHO classification-based Prognostic Scoring System (WPSS) significantly affect overall survival (OS), progression-free survival (PFS), cumulative incidence of relapse (CIR), and cumulative incidence of non-relapse mortality (CINRM). Stratified by WPSS into very low/low, intermediate, high, and very high-risk categories, 3-year OS was 100, 61, 37, and 18% (p = 0.02); PFS was 100, 55, 32, and 18% (p = 0.014); CIR was 12, 24, 38, and 59% (p = 0.024); CINRM was 0, 6, 12, and 26% (p = 0.037), respectively. WHO classification, Revised International Prognostic Scoring System (IPSS-R), IPSS-R-defined cytogenetic risk groups, donor gender, and acute and chronic graft vs host disease (GVHD) also influenced different aspects of transplant outcome. We found that WPSS is a powerful predictor of post-transplant outcome. WPSS provides an important model not only for prognostication but also for exploration of further post-transplant measures such as immunological maneuvers or novel therapy to improve the poor outcome of high-risk patients.

Improved Prognostic Assessment Of Patients With MDS By IPSS-R and MDS-CI

PurposeMyelodysplastic syndrome (MDS) is a broad spectrum of bone marrow failure syndromes characterized by diversity concerning clinical behavior, influence on patient's outcome and risk for leukemic evolution. For more accurate prognostic assessment, the International Prognostic Scoring System (IPSS) has been recently revised. The purpose of this single-center study was to validate the r-IPSS and to compare this model with the MD Anderson Risk Model Score (MDAS), the IPSS and the (revised) WHO classification-based Prognostic Scoring System (WPSS(-R)). Furthermore, the predictive value of the MDS-Specific Co-morbidity Index (MDS-CI) as several other prognostic factors were analyzed. MethodsData were retrospectively collected from 222 MDS patients diagnosed at the VUmc between January 2000 and 2013. Selection was based on informative cytogenetics and the availability of peripheral blood and bone marrow counts. The MDAS, (r-)IPSS, (r-)WPSS and MDS-CI were applied and the impact of individual prognostic factors on patients' outcome was investigated. Kaplan-Meier method was used for estimating survival and the value of prognostic models was determined by Cox's multivariate regression method. ResultsOf our study population, 25 (11%), 83 (38%), 51 (23%), 37 (17%) and 25 (11%) patients were classified according to the IPSS-R as very low, low, intermediate, high and very high risk with, respectively, median overall survival (OS) of 129 (95%CI 96-161), 89 (95%CI 73-105), 43 (95%CI 30-57-61), 31 (95%CI 20-42) and 19 (95%CI 7-31) months (P < 0.000). Compared to the MDAS, IPSS, WPSS(-R) and MDAS, the IPSS-R had a higher predictive power for OS. The MDS-CI was of significant predictive value additional to IPSS-R (P < 0.003). Low risk MDS-CI patients who underwent stem cell transplantation (SCT) had a significantly higher mean overall survival (OS), respectively 104 versus 43 months (P < 0.038). However, mean OS of intermediate and high risk MDS patients who received SCT was not better. ConclusionOur data confirm the predictive value of the IPSS-R and show the additional value of the MDS-CI. Combined application of these models refines the prognostic assessment and identifies co-morbidity among MDS patients, which may assist and influence clinical decision making. Disclosures:No relevant conflicts of interest to declare.

The Evaluation of iron overload through hepcidin level and its related factors in myelodysplastic syndromes

We chose hepcidin and its related factors as evaluating indicators to determine the degrees of iron overload in myelodysplastic syndromes (MDS) patients. A total of 73 patients and 28 healthy volunteers were enrolled in this study. We performed enzyme-linked immunosorbent assay to measure both bone marrow and peripheral blood serum hepcidin. Real-time quantitative polymerase chain reaction was used to determine the gene expression of growth differentiation factor 15 and twisted gastrulation 1. Serum ferritin (SF), C-reactive protein (CRP), and erythropoietin were measured by routine standard laboratory assays. CD4+ and CD19+ lymphocytes and Th polarization were detected by flow cytometry. Twenty-four MDS patients were measured their cardiac and liver iron deposition levels through magnetic resonance imaging (MRI) T2* examination. No significant difference was found between the bone marrow hepcidin levels and peripheral blood hepcidin levels (P = 0.134). Stratified according to different World Health Organization subtypes, refractory anemia with ringed sideroblasts patients had the lowest hepcidin levels (105.40 ± 5.13 ng/ml), while refractory anemia with excess blasts-1 had the highest levels (335.71 ± 25.16 ng/ml). Stratified according to International Prognostic Scoring System and WHO Classification-based Prognostic Scoring System, there was a significant difference of hepcidin levels between low-risk group and high-risk group in two systems, respectively (P = 0.033 and 0.009). The hepcidin levels of CD4+ high-expression group were demonstrated higher than the normal expression groups (P = 0.02), but the CD19+ high-expression group did not show the same result (P = 0.206). Meanwhile, patients with a Th1 polarization trend had a high level of hepcidin versus normal group (P < 0.001). Liver iron concentration (LIC) measured by MRI T2* had a closer correlation (r = 0.582, P < 0.001) to hepcidin than serum ferritin, by stepwise regression. C-reactive protein and LIC seemed to be the key determinants of hepcidin, by multivariate regression. Inflammation plays an important role in the regulation of hepcidin expression. T-lymphocyte activation and Th polarization trend might participate in the regulatory mechanism partly. The capability of organ iron load assessment of MRI T2* seems better than that of SF. It seems that hepcidin with CRP and LIC measured by MRI T2* are potential indicators of iron overload in MDS patients.

Research advances in value of flow cytometric immunophenotyping in diagnosis and prognostic evaluation of myelodysplastic syndrome

Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by dysplasia in one or more linages of cells and increased risk of development of acute myeloid leukemia (AML). Along with the deeply understanding of myelodysplastic syndrome, the diagnosis standards of this disease experienced a leap in essence: from a single standard of morphological test in FAB to multiple detecting means in WHO standard of 2008, flow cytometry has been proposed as an adjunctive diagnostic test in the 2007 Vienna standards and the 2008 WHO standards. Recently, A heterogeneous spectrum of immunophenotypic abnormalities have been reported in MDS, and some of which are of great significance to the diagnosis, classification, prognosis assessment, and treatment of the disease. In the year of 2003, a flow cytometric scoring system (FCSS) was built to evaluate the prognosis of MDS patients, which was able to qualify the phenotypic aberrancies in the myelomonocytic, erythroid, and megakaryocytic lineage. It filled the gap of the international prognostic scoring system (IPSS) and the WHO classification-based prognostic scoring system (WPSS), and was of great value to the clinical diagnosis and treatment of MDS. In this article, the value of MDS immunophenotyping in diagnosis and prognosis evaluation of MDS is reviewed in term of MDS immunophenotypic abnormalities and flow cytometric scoring system.