WHO-based Prognostic Scoring System Research Articles

The Use of Immunosuppressive Therapy (IST) in Patients with the Myelodysplastic Syndromes (MDS): Clinical Outcomes and Their Predictors in a Large International Patient Cohort

The Use of Immunosuppressive Therapy (IST) in Patients with the Myelodysplastic Syndromes (MDS): Clinical Outcomes and Their Predictors in a Large International Patient Cohort

Influence of Acute Myeloid Leukemia Progression on the Prognosis of 831 Patients With Myelodysplastic Syndromes From the Argentine Database.

A large group of patients with myelodysplastic syndromes (MDS) will die of causes intrinsic to bone marrow failure. One third of patients will develop acute myeloid leukemia (AML), which is associated with an extremely poor outcome and a short survival. Our objectives were to analyze the prognostic variables and scoring systems in the attempt to determine the influence of progression on the overall survival of MDS patients. We performed a retrospective analysis of 831 MDS patients, including those from the Argentine Registry. Of the 831 MDS patients, 158 (19.0%) experienced transformation, with a median overall survival of 17.9 months from diagnosis and 3.5 months after progression. The survival of patients with adverse karyotypes or greater risk, according to the International Prognostic Scoring System-revised (IPSS-R) or World Health Organization-based Prognostic Scoring System (WPSS) was not affected when stratified by patients with and without evolution to AML (P > .05). In contrast, the survival of lower risk patients was significantly reduced for those patients with progression to AML (P<.001) and those younger (P= .024) than those who died of non-AML-related causes. The intermediate-risk patients were heterogeneously distributed; however, an upgrade from a lower IPSS-R to a higher WPSS-hemoglobin risk category was associated with a worse outcome, not affected by progression (P= .420), with a median event-free survival of 16 months. The use of the IPSS-R and WPSS systems simultaneously might help in identifying those patients who require more aggressive treatment. Nevertheless, more efforts are needed to improve the identification of those lower risk patients whose survival is significantly reduced by progression to AML.

Prognostic value of self-reported fatigue on overall survival in patients with myelodysplastic syndromes: a multicentre, prospective, observational, cohort study

The clinical presentation of myelodysplastic syndromes is highly variable and so accurate prediction of outcomes in these patients is crucial. We aimed to assess whether self-reported fatigue severity predicts overall survival beyond gold-standard prognostic indices in patients with higher-risk myelodysplastic syndromes. We did a multicentre, prospective, observational, cohort study of patients from 37 centres in Europe, USA, and east Asia. Adults (≥18 years) with myelodysplastic syndromes were consecutively enrolled within 6 months of diagnosis with an intermediate-2-risk or high-risk score according to the International Prognostic Scoring System (IPSS). Patients were enrolled irrespective of older age, comorbidities, performance status, and progression from a lower IPSS risk score category. All patients had to complete a quality of life assessment at baseline. With use of univariate and then multivariate Cox proportional hazards regression analysis, we constructed a multivariate model of how prognostic variables, including IPSS and fatigue score from the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire-core 30, predicted overall survival. The primary endpoint was overall survival by baseline self-reported fatigue scale ratings. This study was registered with ClinicalTrials.gov, number NCT00809575. Between Nov 10, 2008, and Aug 13, 2012, we enrolled 280 patients with a median age of 71 years (IQR 64-77). The median follow-up was 15 months (IQR 8-27), and the last patient was assessed Feb 16, 2015. The median overall survival from diagnosis was 17 months (95% CI 15-19). In univariate analysis, the baseline factors that were significantly associated with reduced overall survival were increasing age, transfusion dependency (defined as having received at least one red blood cell transfusion every 8 weeks over a period of 4 months), Eastern Cooperative Oncology Group (ECOG) performance status of two or more, increased white blood cell count, high-risk IPSS score, and higher self-reported fatigue severity. In multivariate analysis, baseline factors independently associated with reduced overall survival were high-risk IPSS score (hazard ratio [HR] 2·525, 95% CI 1·357-4·697; p=0·0035) and a higher score for fatigue (1·110, 1·040-1·170, for every ten points of fatigue deterioration; p=0·0007). In further multivariate models for survival, including either the WHO-based prognostic scoring system or the revised version of the IPSS classification, fatigue remained a statistically significant independent prognostic factor with a HR of 1·120 (1·050-1·180, p=0.0003) and a HR of 1·130 (1·060-1·190, p=0·0002), respectively. In patients with newly diagnosed higher-risk myelodysplastic syndromes, self-reported fatigue severity provides prognostic information for survival independent from gold-standard risk classifications. Our findings suggest that fatigue assessment should be included in routine diagnostic investigation for these patients and considered as a standard baseline stratification factor in future randomised controlled trials. Associazione Italiana contro le Leucemie, Linfomi e Mieloma (AIL).

Use of newer prognostic indices for patients with myelodysplastic syndromes in the low and intermediate-1 risk categories: a population-based study

We aimed to compare the ability of recently developed prognostic indices for myelodysplastic syndromes to identify patients with poor prognoses within the lower-risk (low and intermediate-1) categories defined by the International Prognosis Scoring System (IPSS). We included patients with de-novo myelodysplastic syndromes diagnosed between Nov 29, 1972, and Dec 15, 2011, who had low or intermediate-1 IPSS scores and were in the Spanish Registry of Myelodysplastic Syndromes. We reclassified these patients with the new prognostic indices (revised IPSS [IPSS-R], revised WHO-based Prognostic Scoring System [WPSS-R], Lower Risk Scoring System [LRSS], and the Grupo Español de Síndromes Mielodisplásicos [Spanish Group of Myelodysplastic Syndromes; GESMD]) and calculated the overall survival of the different risk groups within each prognostic index to identify the groups of patients with overall poor prognoses (defined as an expected overall survival <30 months). We calculated overall survival with the Kaplan-Meier method. We identified 2373 patients. None of the prognostic indices could be used to identify a population with poor prognoses (median overall survival <30 months) for the patients with low IPSS scores (1290 individuals). In the group with intermediate-1 scores (1083 individuals), between 17% and 47% of patients were identified as having poor prognoses with the new prognostic indices. The LRSS had the best model fit with the lowest value in the Akaike information criteria test, whereas the IPSS-R identified the largest proportion of patients with poor prognoses (47%). Patients with intermediate-1 scores who were classified as having poor prognoses by one or more prognostic index (646 [60%] individuals) had worse median overall survival (33·1 months, 95% CI 28·4-37·9) than did patients who were classified as having low risk by all prognostic indices (63·7 months, 49·5-78·0], HR 1·9, 95% CI 1·6-2·3, p<0·0001) INTERPRETATION: Recently proposed prognostic indices for myelodysplastic syndromes can be used to improve identification of patients with poor prognoses in the group of patients with intermediate-1 IPSS scores, who could potentially benefit from a high-risk treatment approach. None.

Initial Clinical Findings From a Population-Based Study of Adult Myelodysplastic Syndrome: Discordance Between World Health Organization (WHO) Classifications

Abstract 1733 Introduction:Much remains to be elucidated regarding the etiology of myelodysplastic syndrome (MDS) and why some cases progress to acute myeloid leukemia. Further, there are few data on how accurate case classification is within state cancer registries and the impact of the 2008 WHO MDS classification modifications on clinical practice. We are conducting a large population-based prospective study of MDS to investigate risk factors for initial disease as well as disease progression. Our study includes comprehensive central review of all cases. Initial findings are reported here. Methods:We began evaluation and follow-up of all newly diagnosed MDS cases in Minnesota between the ages of 20 and 85 years from April 1, 2010 onward. Our process includes rapid case identification by the Minnesota Cancer Surveillance System (MCSS), contact of individual patients after primary physician approval, and, for interested patients, participation in an extensive questionnaire with medical history review and optional saliva sample for DNA. In concert, all cases pass through central medical review including: 1) independent pathology report +/− slide review by two hematopathologists to confirm diagnosis and subclassification; 2) independent cytogenetic review by a cytogeneticist; and 3) medical chart review by an oncologist to identify pertinent clinical history and prospectively calculate the International Prognostic Scoring System (IPSS) and WHO-based prognostic scoring system (WPSS) scores. Annual follow-up is planned to monitor for disease progression and outcome. In cases of unknown cytogenetics, IPSS calculations are not completed. In cases of unknown cytogenetics or diagnosis of MDS-U, not currently stratified in the WPSS, WPSS calculations are not completed. Results:We describe the first 67 patients enrolled on this study that have completed central review. The majority of patients were male (n=44) and the median age of the cohort at diagnosis was 71 (range 41–85). Table 1Table 1:Patient DemographicsVariableTotal (n = 67)Age:41-601161-701571-8541IPSS Risk Category: #Low17Intermediate-121Intermediate-223High5WPSS: *Very Low15Low5Intermediate9High30Very High5Concordance assessment of initial WHO diagnosis determined by MCSS and WHO diagnosis after central review found a total of 21 discordant diagnoses (31.3%). The discordant cases included: 10 cases initially diagnosed as MDS-U that central review further delineated into RA (1), RT(1), RARS (1), RCMD (3), RAEB (2), and therapy related MDS (2); 1 case originally classified as RA to MDS-U; 6 cases transitioned from RAEB to t-MDS (5) and RCMD (1); and 4 cases initially described as RCMD changed to MDS del 5q (1), RAEB (2), t-MDS (1). Table 2#IPSS not calculable in 1 case due to missing cytogenetics*WPSS not calculable in 3 cases due to MDS-U (2) and no cytogenetics (1)Table 2:Comparison of WHO ClassificationWHO Classification per MCSSWHO Classification after Central ReviewRefractory Anemia (RA)22Refractory Thrombocytopenia (RT)1Refractory Anemia with Ringed Sideroblasts (RARS)1011Refractory Cytopenias with multilineage dysplasia (RCMD)1414Refractory Anemia with Excess Blasts (RAEB):–RAEB-1299–RAEB-218MDS with deletion 5q12MDS-Unclassifiable (MDS-U)112Therapy related MDS (t-MDS)8 Conclusion:Ours is the first large prospective population-based study of MDS that includes central pathology, cytogenetic, and clinical review of newly diagnosed patients with prospective calculation of IPSS and WPSS and plans for long term follow-up. This study is expected to enroll approximately 700 MDS cases over a five year period. While early in investigation, our initial review highlights the variability in distinct WHO diagnosis between initial cancer registry (i.e., MCSS) designation and designation after thorough central review of all appropriate diagnostic components. Our data suggest the robustness of the WHO RA, RARS, and RCMD classifications, the possible over-utilization of MDS-U classification, and highlight the under-representation of therapy-related MDS identification with registry designation. The impact of discordant diagnoses between MCSS and central review on therapeutic strategies is uncertain, but warrants continued evaluation and underscores the importance of complete central review in evaluation of MDS cases. Supported by NIH R01 CA142714. Disclosures:No relevant conflicts of interest to declare.

Prognostic Performance of the Cytogenetic Risk Classification Defined by the German-Austrian Myelodysplastic Syndromes (MDS) Study Group and Its Contribution to the International Prognostic Scoring System (IPSS) and the World Health Organization-Based Prognostic Scoring System (WPSS)

AbstractAbstract 4005 Background and objective:the cytogenetic risk classification defined by the 1997 IPSS remains the most widely used to assess the prognostic impact of karyotype in the MDS. Recently, the German-Austrian MDS Study Group (Haase, Ann Hematol 2008; 87:515) has proposed a new, more comprehensive cytogenetic risk classification. Our aim was to assess the prognostic performance of the Haase's cytogenetic classification, as compared to that defined by the IPSS, and what would be its contribution to the IPSS and WPSS. Methods: MDS patients seen at our center after 1986 were eligible for inclusion if they had a cytogenetic study performed at diagnosis that could be scored according to both the IPSS and the Haase's criteria. The prognostic performance was assessed by the Harrell's concordance index and the R2 explained variation (the closer both statistics to 1 the better the prognostic performance). Results: 327 out of 494 patients seen after 1986 met the eligibility criteria. Median age was 73 (range: 16–97) years and 55% were women. The 2001 WHO categories were refractory anemia (RA, 6%), RA with ringed sideroblasts (RARS, 2%), refractory cytopenia with multilineage dysplasia (RCMD, 54%), RCMD with ringed sideroblasts (RCMD-RS, 11%), RA with excess of blasts (RAEB-1, 11%; RAEB-2, 14%), and del(5q) (2%). According to the IPSS cytogenetic classification, 232 (71%) patients were in the low risk group, 46 (14%) in the intermediate, and 49 (15%) in the high risk group. According to Haase's criteria, 239 (73%) patients were in the good prognosis group, 26 (8%) in the int-1, 25 (8%) in the int-2, and 37 (11%) in the poor prognosis group. Agreement between both karyotype-based risk classifications was high (Kendall's tau=0.92; Kruskal's gamma=0.99). At the study closing date, median survival for the whole series was 4.1 years, 160 (49%) patients had died and 27 (8%) were lost to follow-up. Median survival (95% CI) in years according to the IPSS cytogenetic classification was 5.2 (4.2-6.4) for the low risk group, 3.8 (1.7-5.0) for the intermediate, and 0.9 (0.7-1.1) for the high risk group. Median survival (95% CI) in years according to Haase's criteria was 5.2 (4.1-6.4) for the good prognosis group, 3.9 (1.6-not reached) for the int-1, 3.1 (0.9-3.8) for the int-2, and 0.8 (0.6-1.9) for the poor prognosis group. There was no statistically significant difference in survival between the int-1 and Int-2 groups. Grouping the Int-1 and Int-2 into a single intermediate risk category yielded a median survival of 3.5 (1.7-4.4) years, which was significantly different from that of good and poor risk groups (p=0.014 and p=0.0001, respectively). The figure shows the concordance and R2 statistics for both cytogenetic classifications as well as those of the IPSS and the WPSS had they been based on the Haase's score, as compared to the standard ones. For this latter analysis, the Haase's int-1 and int-2 categories were grouped together. Conclusion: The new cytogenetic risk classification was comparable to that defined by the IPSS with regard to prognostic performance and did not improve the discriminatory power of the IPSS or the WPSS. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Prognostic Factors of Long-Term Outcomes In Low- or Int-1-Risk MDS with del5q Treated with Lenalidomide (LEN): Results From a Randomized Phase 3 Trial (MDS-004)

AbstractAbstract 4027▪ Background:Transfusion dependence is a significant negative predictor of overall survival (OS) and risk of AML-progression in MDS (Malcovati L, et al. JCO 2007;25:3503-10). LEN 5 mg and 10 mg induced significant RBC-transfusion independence (TI) versus placebo (PBO) in a randomized, phase 3, multicenter, double-blind (DB) study (MDS-004) in RBC transfusion-dependent patients (pts) with Low- or Int-1-risk MDS with del5q (Fenaux P, et al. Blood 2009;114:Abstract 944). The aim of this analysis is to identify prognostic factors for AML-free survival and OS during LEN treatment in the MDS-004 study after prolonged follow-up (pts enrolled between July 8, 2005 and July 26, 2007; last pt visit June 14, 2010; final data cutoff July 9, 2010). Methods:LEN-naïve pts with RBC transfusion-dependent Low- or Int-1-risk del5q MDS were randomized to receive LEN 5 mg on days 1–28 or LEN 10 mg on days 1–21, both of every 28-day cycle, or PBO. First response was assessed at 16 wks. Responders continued DB treatment for up to 52 wks, until erythroid relapse or disease progression. Pts who completed 52 wks of therapy could enter an open label (OL) extension phase at their current LEN dose. PBO and LEN 5 mg recipients who did not respond by wk 16 or who had erythroid relapse could receive LEN 5 or 10 mg, respectively, in the OL phase. This analysis included data through completion of the OL phase for pts randomized to LEN 5 and 10 mg combined in the DB phase; pts randomized to PBO were excluded as all except 11 pts crossed-over to LEN 5 mg. LEN 5 and 10 mg dose groups were comparable, allowing data for the two groups to be combined. A Cox proportional hazard model was used to evaluate effect of potential baseline risk factors, with RBC-TI ≥ 26 wks and cytogenetic response (CyR) as time-dependent covariates on AML-free survival and OS. The full model with all covariates and the final model, based on backward model selection method, are presented. Results:All 138 pts randomized to LEN who received ≥ 1 dose were included: median age 68 y (range 36–86); 74% of pts were female; 66% had an isolated del5q abnormality and 28% had ≥ 1 additional abnormality; and 43% of pts had WHO-based Prognostic Scoring System (WPSS) low/int risk, 32% high/very high, and 25% missing data. At baseline, median time since diagnosis was 2.7 y (range 0.2–29.2) and median RBC transfusion requirement was 6 units/8 wks (range 1–25). Duration of LEN was 12.9 mo (range 0.3–36.7); 54 of 62 responders entered the OL phase. Median follow-up for the cohort was 36 mo (range 0.4–59.4). Overall, 31 (22%) pts progressed to AML (median time to AML progression 4.01 y; 95% confidence interval [CI] 3.17–4.03) and 66 (48%) died (median OS 3.68 y; 95% CI 2.93–not estimable). The cumulative 3-year AML-progression rate was 34.8% and the 3-year OS rate was 56.0%. Multivariate results are presented in the Table. Achieving RBC-TI ≥ 26 wks was associated with a 45% and 51% reduction in the risk of AML progression (P=0.022) and death (P=0.008), respectively. Lower baseline ferritin level and younger age were associated with a reduced risk of AML-progression and death. Conclusion:Achievement of RBC-TI with LEN was associated with a significantly reduced risk of AML progression and death. Other predictors for longer AML-free survival and OS were lower baseline ferritin levels and younger age. Disclosures:Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; J&J: Honoraria; Merck: Honoraria; Cephalon: Honoraria; Novartis: Honoraria. Giagounidis:Celgene: Consultancy, Honoraria. Beyne-Rauzy:Amgen: Consultancy; Celgene: Consultancy, Research Funding; Roche: Research Funding; Novartis: Consultancy. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mittelman:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Sanz:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Backstrom:Celgene: Employment, Equity Ownership. Fu:Celgene: Employment, Equity Ownership. Hellström-Lindberg:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Validation of a Flow Cytometric Scoring System for the Prognostication of the Myelodysplastic Syndromes: a Retrospective Cohort Study

AbstractAbstract 4012The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders, characterized by cytopenia(s), dysplasia and a propensity to evolve into acute myeloid leukemia. The International Prognostic Scoring System (IPSS) and WHO-based prognostic scoring system provide prognostic information. However, even if patients are allocated in the same risk category their clinical course remains heterogeneous. Recent developments in the treatment of MDS require refinement of prognostication and identification of patients who might benefit from treatment with potentially disease modifying agents such as lenalidomide or azacitidine. Flow cytometry (FC) is emerging as a valuable technique for the diagnosis and prognosis of MDS. Recently, we demonstrated that flow cytometric analysis of BM in low and int-1 risk MDS is instrumental to identify clinically relevant subgroups. (Westers et al, Blood 2010) Previously, it was reported that a flow cytometric scoring system (FCSS) is predictive for worse outcome in MDS. (Wells et al, Blood 2003, van de Loosdrecht et al, Blood 2008) The FCSS is a scoring system that allows for a numerical display of immunophenotypic aberrancies in the (im)mature myelo-monocytic lineage. Scores are generated by enumerating abnormalities; a high score reflects a high number of aberrancies. The current study aimed to validate the FCSS for identification of prognostic subgroups in MDS. We analyzed aberrancies in (im)mature myelo-monocytic cells by FC in BM of 102 MDS patients, including 48 MDS patients from the previous cohort. The diagnoses according to WHO 2001 classification were RA(RS) n=19, RCMD(RS) n=54, RAEB-1 n=11, RAEB-2 n=13, MDS-U n=5 and also age-matched healthy volunteers (n=39) were included. The median age of MDS patients was 66 and of healthy volunteers 57. The FCSS in RA(RS) (median=3, range 1–6) patients was significantly higher compared with healthy controls (median=1, range 0–2, p<0.001). In contrast to our previous results the FCSS for RA(RS) and RCMD(RS) patients did not differ. This is a remarkable finding, since by morphology RA(RS) patients have unilineage dysplasia, in contrast to flow cytometric findings, where 84% (16/19) of the RA(RS) patients had two or more aberrancies in the (im)mature myelomonocytic compartment. The FCSS was higher in RAEB-1 (median=6, range 2–7) and RAEB-2 (median=6, range 4–8) compared with RCMD(RS) (median=3, range 0–6, p=0.02 and p<0.0001, respectively). Overall, the FCSS correlated significantly with WHO 2001 classification (p<0.0001). The FCSS showed a significant correlation with IPSS categories low, int-1, int-2 and high (p<0.0001). Remarkably, the FCSS was not correlated with cytogenetic risk categories low, intermediate and poor. The new German-Austrian Cytogenetic Prognostic Scoring System for MDS was also not correlated with the FCSS. This indicates that the FCSS and cytogenetics might provide separate prognostic information in MDS. Neutrophil granularity corresponding with side scatter by FC was significantly decreased in MDS patients compared with healthy volunteers (p<0.0001). In the RA(RS) and RCMD(RS) category, 40% (29/73) of patients expressed an aberrant marker such as CD5, CD7 and/or CD56 on myeloid progenitors. Transfusion data was available of 51 patients. Interestingly, the majority of MDS patients who were transfusion dependent or progressive, had aberrant expression of CD5, CD7 and/or CD56 on myeloid progenitors compared with MDS patients without aberrant marker expression (64% (16/25) vs 31% (8/26), respectively p=0.04). When the cumulative amount of all aberrancies in the (im)mature myelo-moncytic cells were taken into account, transfusion dependent patients had significantly more aberrancies than transfusion independent MDS patients, (median 6.5 vs 4, respectively, p=0.006). In conclusion, we here confirmed our previous findings in a larger cohort. The majority of RA(RS) patients already has multilineage dysplasia as detected by FC, which might be of prognostic relevance. Although the FCSS correlates with current prognostic systems, a striking heterogeneity remains within prognostic subgroups. Therefore, the FCSS and detection of aberrant myeloid progenitors can provide refined prognostication by identification of patients at risk for transfusion dependency and adverse clinical outcome, independent of current classification systems. Disclosures:Ossenkoppele:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van de Loosdrecht:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Host immunity affects survival in myelodysplastic syndromes: Independent prognostic value of the absolute lymphocyte count

The prognostic significance of the peripheral blood absolute lymphocyte count (ALC) has been carefully examined in lymphoid malignancies, but the importance of the baseline ALC in chronic myeloid neoplasms is less clear. In a recent analysis of myelodysplastic syndromes (MDS) associated with deletion of chromosome 5q, we observed that an ALC < 1.2x 10(9) cells/L at diagnosis is independently associated with poorer survival. Clinicopathological data from 503 patients with non-del(5q) MDS evaluated at Mayo Clinic between 1996 and 2007 were reviewed to determine the prognostic impact of ALC at diagnosis in non-del(5q) MDS. Patients with MDS and an ALC at diagnosis > or =1.2x 10(9) (N = 248) experienced a superior overall survival (OS) compared with patients with an ALC < 1.2x 10(9)/L (N = 255, median OS of 26.6 months versus 18.5 months, P < 0.001, respectively). ALC at diagnosis was an independent predictor for OS when compared with the International Prognostic Scoring System and the WHO-based Prognostic Scoring System. This study suggests that ALC at diagnosis is a prognostic factor for OS in MDS, and argues in favor of further studies to assess the role of host immunity in MDS clinical outcomes.

Independent Validation of the MD Anderson Cancer Center Risk Model for Myelodysplastic Syndromes (MDS), and Comparison to the International Prognostic Scoring System (IPSS) and the World Health Organization-Based Prognostic Scoring System (WPSS).

Abstract 3814Poster Board III-750 IntroductionThe 1997 IPSS remains the most widely used prognostic scoring system for patients with MDS, and it has important strengths, but several other prognostic systems have been proposed recently to overcome some of the well-recognized IPSS limitations. These systems include a new risk model for patients with MDS and CMML – including previously treated patients and those with secondary (treatment-related) MDS – proposed by Kantarjian and colleagues at the MD Anderson Cancer Center (MDACC) (Cancer 2008; 113:1351), as well as the WPSS, proposed by Malcovati and colleagues in Europe (J Clin Oncol 2007; 25:3503) To date, the MDACC risk model has not been validated in a large external independent cohort or directly compared to the WPSS. We assessed the performance of the MDACC model compared to the WPSS and the IPSS in a 12-year Mayo Clinic MDS/CMML cohort. Patients and MethodsWe reviewed the medical records of 1,503 adult patients (pts; 984 males; median age 71 years, range 17-98) with MDS (n=1,249) or CMML (n=254) evaluated at Mayo Clinic between January 1996 and December 2007. Pediatric pts (age ≤16 and pts with ≥30% marrow blasts were excluded. IPSS and WPSS scores were calculated, and data collected for MDACC risk model assignment (age, performance score, platelet count, hemoglogbin, marrow blast proportion, white blood cell count, karyotype, and transfusion history). Data were analyzed using Kaplan-Meier survival analysis and Cox proportional hazards regression models. ResultsThe overall median survival was 17.8 months (mos) – 13.7 mos for CMML, 19.1 mos for WHO-defined MDS, and 9.6 mos for RAEB-t – similar to the 14.1 mos observed in the test cohort used to derive the MDACC risk model. Follow-up was complete until death in 1,122 (74.7%) pts. Pts excluded from the cohort stratified using IPSS included 122 patients with CMML and leukocytosis (>12 × 109/L), and 176 pts with secondary MDS/CMML (there were 12 pts with secondary CMML with leukocytosis) – total excluded, 286 pts. Patients excluded from the WPSS cohort included 27 pts with RAEB-t, 254 pts with CMML, and 148 pts with secondary MDS – total excluded, 429 pts. Survival by IPSS risk group was 38.9 mos for Low (n=413), 17.9 mos for Int-1 (n=541), 9.6 mos for Int-2 (n=206), and 6.6 mos for High (n=57). Survival by WPSS risk group was 39.0 months for Very Low (n=352), 26.6 months for Low (n=276), 15.9 months for Intermediate (n=185), 11.2 mos for High (n=221), and 4.9 months for Very High (n=40). Survival by MDACC risk group was 45.6 mos for Low (n=426), 20.0 mos for Int-1 (n=552), 12.3 mos for Int-2 (n=325), and 4.9 mos for High (n=200). When the MDACC risk model was used to classify only the 1,074 pts with conditions for which the WPSS has been validated, survival was 51.4 mos for Low (n=336), 21.2 mos for Int-1 (n=411), 13.3 mos for Int-2 (n=213), and 4.6 mos for High (n=114) (p<0.001 for all comparisons). In a multivariable proportional hazards model, all of the MDACC risk model components except WBC>20 × 109/L retained independent prognostic significance. ConclusionsAll 3 systems stratify patients accurately, but the MDACC risk model best identifies the lowest-risk patients, and also classifies the broadest group of patients (i.e., primary and secondary MDS, and primary and secondary CMML with or without leukocytosis). The revised IPSS that is currently in development should include the patient factors accounted for by the MDACC risk model, with the possible exception of leukocytosis. Disclosures:No relevant conflicts of interest to declare.

Retrospective Survey of Iron Overload Prevalence & Chelation Practices in Transfusion-Dependent Myelodysplastic Syndromes in a West Kent District General Hospital, SE England.

Abstract 4857 BackgroundThe incidence of myelodysplastic syndromes is about 9 -10 / 250000 population. Iron overload is increasingly recognised as a factor contributing to increased morbidity & mortality in transfusion-dependent myelodysplastic syndromes. Transfusion dependency, a variable in WHO based Prognostic Scoring System ( WPSS), is associated with reduced overall survival. However iron chelation uptake remains poor. Lack of robust data on prevalence of iron overload & absence of randomised controlled trials showing efficacy of iron chelation in improving overall survival & patient outcome complicates clinical management as well as resource planning to provide for iron chelation therapy. MethodsThis retrospective survey was conducted to assess the red cell transfusion dependency, iron overload prevalence, iron chelation practices in a District General Hospital based in West Kent, SE England covering a population of 250000.The data was collected from clinical, laboratory & blood bank records. ResultsBetween Jan – Dec 2008, of 129 patients transfused ; MDS 27 ( M 12/ F 15), age range 57 -89 years, FAB subtypes :RA( n= 1) RARS( 3 )RCMD (4 )RAEB-1( 2)MDS transformed to AML (3)MPD/MDS ( 4 )NOS ( 5 ) Secondary MDS (4) Del 5q (1); IPSS score : 0 (n= 16), 0.5 ( 5), 1 ( 1), 1.5 ( 1 ), 2 ( 1), 2.5 ( 1) 3.5 ( 2);WHO score : 0 ( n= 13), 1 ( 3), 2 ( 1), 3 ( 1 ), 9 deaths in this cohort. Red cell transfusions/patient range was 2 – 66 units( median 12 ), baseline ferritin 4.4 – 2406.9 ug/l( median 969.7), last ferritin 30.8 – 5580.6 ug/l( median 969.7).Based on eligibility criteria for iron chelation being ferritin > 1000 ug/l & expected survival > 1 year, 12 patients were eligible of which 4 (33%)were on therapy ( n= 3 on Desferrioxamine ( SC ( 1), intermittent IV ( 2) ), 1 on Deferasirox ( previous intolerance to Desferrioxamine). Of 12 eligible, 3 had renal impairment ( eGFR < 60 ml/min). Of 4 chelated patients, age range was 66 – 87, last Ferritin 1007.2 – 5580.6 ug//l, IPSS 0 – 0.5, red cell transfusions/patient 29 – 66 units, FAB subtypes : RA( 1)RARS (2) Secondary MDS (1).There were 9 deaths ( n= 1 on chelation) in this cohort with age range 62 -89 years IPSS 0 – 3.5, FAB subtypes at diagnosis :RARS( 1)RCMD( 2 ) MDS transformed to AML ( 2 ) MPD/MDS (1) NOS ( 1)Secondary MDS (1) Del 5q ( 1); last ferritin 574.1 – 3719.3 ug/l. Contributing causes of deaths other than MDS included : Neutropenic sepsis ( 1) IHD/ CCF (2) Carcinoma prostate (1) Transformed AML (4) Pneumonia (1) COPD (1) NHL (1). ConclusionThe survey confirms poor iron chelation uptake. This could be due to varied reasons such as patient or physician preferences, clinical awareness & availability of resources. Adequate resource planning is needed to improve iron chelation practices along with tools to aid clinical decision making process such as a computerised prompt to consider iron chelation based on IPSS, predicted survival, red cell transfusion dependency & ferritin level. A longitudinal prospective survey will also help clarify the cost effectiveness of this intervention as well as provide useful quality of life, patient outcome & overall survival data. DisclosuresNo relevant conflicts of interest to declare.

Analysis of WHO-based Prognostic Scoring System (WPSS) of myelody-splastic syndrome and its comparison with international prognostic scoring system (IPSS) in 100 Chinese patients

The aims of this study were to assess the prognostic significance of WHO-based Prognostic Scoring System (WPSS) in myelodysplastic syndrome (MDS) from a single center institute and to compare WPSS with the international prognostic scoring system (IPSS). A total of 100 cases with de novo MDS were reviewed and their karyotypes were detected. All of them were followed up and classified according to IPSS and WPSS risk groups. SPSS 13.0 software was applied to deal with all the data. The statistical methods included Kaplan — Meier, Log-rank test and cox regression. Multivariate cox regression analysis indicated that WHO Classification (P=0.0190), karyotype abnormalities categorized according to IPSS (P=0.0159) and red blood cell (RBC) transfusion (P=0.0009) were the three most important independent factors for predicting overall survival (OS) of MDS. WPSS and IPSS both had great capacity in predicting the OS of MDS at the time of diagnosis (P<0.0001). In time-dependent analysis, WPSS can predict the OS accurately in the following three years after diagnosis (P<0.0001), while IPSS failed to predict the OS 24 months after diagnosis (P=0.1094). Our single center results proved that WPSS is a dynamic prognostic system which can predict the OS of MDS patients at any time during the course of their disease. This time-dependent prognostic scoring system may replace the IPSS in the near future.

Independent Validation of the 2008 World Health Organization (WHO) Reclassification of Myelodysplastic Syndromes (MDS) Associated with Ring Sideroblasts

Background: The 2001 WHO classification of myeloid neoplasms distinguished 2 forms of MDS associated with >=15% ring sideroblasts and <5% marrow blasts: refractory cytopenia with multilineage dysplasia and with ring sideroblasts (RCMD-RS) vs. refractory anemia with ring siderblasts (RARS, erythroid-restricted dysplasia). However, the real prognostic value of separating RCMD-RS from RCMD with <15% ring sideroblasts and from RARS is uncertain, and the WHO has proposed merging RCMD-RS and RCMD in the 2008 classification revision. Furthermore, the WHO-based Prognostic Scoring System (WPSS), proposed by Malcovati and colleagues in 2005 as a dynamic system that overcomes some of the limitations of the 1997 International Prognostic Scoring System (IPSS), has undergone limited independent external validation to date and its applicability to sideroblastic MDS in particular is unclear. We assessed the validity of the 2008 WHO reclassification and the WPSS for MDS cases associated with >=15% ring sideroblasts and a normal blast proportion.Methods: We reviewed WPSS and IPSS component parameters at diagnosis and the clinical outcomes of 465 patients (68% males, median age 72) evaluated at our institution over a 13-year period: 140 with RARS, 114 with RCMD-RS, and 211 with RCMD. Patients were assigned a WPSS score and risk category (very low-risk group=0 points; low=1; intermediate=2, high=3 or 4) by summing 3 subscores: 2001 WHO classification (0 for RARS, 1 point for RCMD or RCMD-RS), IPSS cytogenetic risk group (0=good, 1=indeterminate, 2=poor), and red cell transfusion dependence (0=no, 1=yes). Survival was assessed by Kaplan-Meier estimates, and prognostic factors examined by proportional hazards analysis.Results: The median time until death or last followup was 26 months, and 70% of patients were known to have died. The median survival by WHO MDS subtype was 75 months for RARS, 25 months for RCMD-RS, and 26 months for RCMD (Log-Rank p<0.0001 for RARS vs. either RCMD-RS or RCMD; p=0.60 for RCMD vs. RCMD-RS ). Both the WPSS and IPSS predicted overall survival in patients with ring sideroblasts. Median survival for the patients grouped by WPSS risk category was 89 months for very low risk (n=95), 41 for low risk (n=198), 31 for intermediate risk (n=82), and 11 for high risk (n=91) (p<0.0001, except for low risk vs. intermediate risk, p=0.31). (Very high risk WPSS scores cannot be achieved without excess marrow blasts, and such patients were excluded from this analysis.) Median survival by IPSS was 73 months for low-risk, 33 months for intermediate-1, and 8 months for intermediate 2 (p<0.0001). The IPSS' predictive power was unchanged if patients with secondary MDS were included or excluded (the IPSS was based on a review of 816 patients with apparently de novo MDS).Conclusions: These data support the WHO's proposal to merge RCMD and RCMD-RS, and suggest that the adverse prognostic significance of multilineage dysplasia renders the presence of ring sideroblasts unimportant. The WPSS is a valid prognostic tool in patients with MDS associated with ring sideroblasts, but in this subgroup both the WPSS and IPSS stratify patients into 3 risk groups, and the WPSS does not offer additional value over the IPSS. [Display omitted]

Quantitative Dynamics of Flow Cytometric Aberrancies during Treatment with Erythropoietin/G-CSF Are Predictive for Responses in LOW/INT-I Risk Myelodysplastic Syndromes.

Flow cytometry (FCM) in myelodysplastic syndromes (MDS) is recognized as a useful tool in identifying aberrancies in expression of differentiation antigens on immature and mature bone marrow cells of erythroid and myelomonocytic lineages. FCM in MDS correlates significantly to morphology according to WHO and the WHO-based Prognostic Scoring System (WPSS). Moreover, certain aberrancies in pure RA+/−RS patients, i.e. CD7 on myeloid blasts, seemed to predict transfusion dependency and disease progression independent of classical prognostic parameters such as WHO, cytogenetics and IPSS (Van de Loosdrecht et al., Blood 2008, 111). Flow cytometric aberrancies in bone marrow of 29 patients with low or int-I risk MDS were analyzed at diagnosis and after approximately 1 year of treatment with a standardized regimen of Epo (NeoRecormon®) and G-CSF (median: 12 months (range: 4–24) in order to evaluate the value of FCM in disease monitoring. Patients were classified as RA+/−RS (n=11), RCMD+/−RS (n=15), 1 hypoplastic MDS, 1 MDS-U and 1 MDS/MPD. Progression was defined as an increase in WHO subgroup to at least RAEB-1 within 18 months after diagnosis of MDS. Before treatment, median number of aberrancies in the myelomonocytic lineage, as assessed by FCM, was 4 in RA+/−RS (range 1–8) and 5 in RCMD+/−RS (range 3–10); other MDS subgroups were too small. In age-matched normal bone marrow samples the median number of aberrancies was 1 (range 0–3, n=18). Aberrant expression of CD5, CD7 or CD56 was observed on myeloid blasts at diagnosis in 13 out of 18 patients that were transfusion-dependent or suffered from progressive disease during follow-up (4 RA+/−RS, 7 RCMD+/−RS, 1 MDS-U and 1MDS/MPD). Interestingly, expression of these markers was only detected in 1 out of 11 patients that were not or low transfusion dependent. This particular RCMD-RS patient had short response duration. The number of blast aberrancies correlated significantly to transfusion dependency and disease progression (r=0.459, p=0.012). Nine patients showed hematological improvement upon Epo/G-CSF treatment. In most of these patients (4/6 RA+/−RS and 2/3 RCMD+/−RS) the number of flow cytometric aberrancies decreased (median 4 at diagnosis to 2.5 at follow-up in all responders). This decrease was caused by a diminished number of monocytic aberrancies (p=0.028); a stable blast aberrancy was seen in only one patient. In 15 patients with stable disease, no significant changes in the number of flow cytometric aberrancies could be detected (median 5 and 5, at diagnosis and follow-up, respectively); whereas in 4 of the 5 patients with progressive disease during Epo/G-CSF (2/2 RA+/−RS, 1/2 RCMD+/−RS and 1 MDS/MPD) the number of aberrancies increased (median 7 and 9, at diagnosis and follow-up, respectively). This increase was mainly caused by changes in the number of aberrancies in blast and granulocyte subpopulations. The response to therapy seems to depend on the number of blast aberrancies (r=0.351, p=0.062). From these data we hypothesize that FCM can be used as an objective sensitive disease monitoring parameter in low/int-I risk MDS. Furthermore, in a subset of these patients treatment with Epo/G-CSF might have altered disease progression reflected by normalization or stabilization of aberrancies on myelomonocytic cells. This underscores observations that Epo/G-CSF improves overall survival and/or leukemia free survival. Prospective studies are being conducted to validate flow cytometric analysis in the diagnosis, prognostication and disease monitoring of low/int-I risk MDS during Epo/G-CSF and lenalidomide. To conclude, FCM can contribute to the management of low/int-I risk MDS patients as changes in the number of flow cytometric aberrancies reflect response to treatment.

Independent Impact of Iron Overload and Transfusion Dependency on Survival and Leukemic Evolution in Patients with Myelodysplastic Syndrome

Transfusion dependency seems to have a major prognostic impact in patients with myelodysplastic syndrome (MDS) (Malcovati L et al. J Clin Oncol 2007; 25:3503). Preliminary data also suggest that the development of iron overload could influence outcome (Malcovati L et al. J Clin Oncol 2005; 23:7594 and Garcia-Manero G et al. Leukemia 2008; 22:538), but small numbers have precluded a meaningful analysis of the prognostic value of this characteristic. The main aim of this study was to evaluate the independent prognostic value of transfusion dependency (as defined in WHO-based Prognostic Scoring System [WPSS]) and iron overload (defined as serum ferritin level >1,000 ng/mL) in a large series of 2,994 patients (median age, 74 yr) with de novo MDS according to FAB criteria (2,107 MDS according to WHO criteria). Complete transfusional history was available in 2,241 patients (835 transfusion dependent [TD] at diagnosis, 526 TD during follow-up, and 880 non-TD) and serum ferritin levels in 1,634. Karyotyping was successfully performed in 2,074 patients, who could then be classified by the International Prognostic Scoring System (IPSS) as low (861 patients), intermediate-1 (748), intermediate-2 (311), and high-risk (154). The numbers of patients in the five risk categories defined by the WPSS (available for 1,228 patients) were 257 (21%) in very low, 385 (31%) in low, 217 (18%) in intermediate, 271 (22%) in high, and 98 (8%) in very high, closely similar to those reported in the original WPSS series. Actuarial curves of overall survival (OS) and risk of evolution to acute myeloblastic leukemia (AML) were built by Kaplan-Meier method and differences between curves compared with log-rank tests. Multivariate analyses of OS and risk of evolution to AML were performed by Cox proportional hazards regression method, with development of transfusion dependency and iron overload entered as time-dependent covariates. Other variables included in the prognostic factor analyses were age, gender, hemoglobin level, absolute WBC, PMN, and platelet counts, proportion of blasts in blood and marrow, percentage of dysplastic features in the three different hematopoietic cell lines, cytogenetics according to IPSS cytogenetic risk subgroups, FAB and WHO classifications, ferritin, beta-2 microglobulin, erythropoietin, and LDH levels at diagnosis, and IPSS and WPSS risk categories. All the previous variables showed a statistically significant relationship with OS and/or AML risk on univariante analyses. Median OS for TD patients at diagnosis, TD patients during evolution, and non-TD patients was 19, 60, and 96 months, respectively (P<.0001). Multivariate analyses in a set of 902 cases with complete data confirmed that development of iron overload (1st variable selected to enter the model; hazard ratio [HR], 52.4; P<.0001) and transfusion dependency (2nd to enter; HR, 8.8; P<.0001) were strongly associated with OS and added significant independent prognostic information to that afforded by the IPSS and WPSS scores or by other characteristics with universally recognized prognostic value. Further, multivariate analyses of AML transformation risk showed that iron overload (1st to enter; HR, 6.6; P<.0001) and transfusion dependency (2nd to enter; HR, 3.5; P=.003) had also independent impact on that endpoint. These results demonstrate for the first time the independent prognostic value of development of iron overload on OS and AML risk in MDS, confirm the impact of transfusion dependency on those outcomes, and support that the inclusion of both variables in a new prognostic scoring system would add clinically relevant information. They also suggest that avoiding or reducing iron overload by an appropriate chelation therapy could improve OS and reduce the risk of AML transformation in MDS patients.