International Prognostic Scoring System Risk Research Articles

High PRAME expression is associated with poor survival and early disease progression in myelodysplastic syndromes with a low bone marrow blast percentage

We investigated the clinical implications of preferentially expressed antigen in melanoma (PRAME) expression in bone marrow cells of 116 patients with myelodysplastic syndromes (MDS). Quantitative RT-PCR was carried out to examine the PRAME expression level. High PRAME expression was observed in MDS patients classified into higher revised International Prognostic Scoring System (IPSS-R) risk categories (Very high and High) with a high bone marrow blast percentage (5% or higher). Kaplan-Meier analysis demonstrated that high PRAME expression is significantly associated with a poorer overall survival (OS) in MDS patients with a low bone marrow blast percentage (less than 5%) (log-rank test p = .0014) and those classified into lower IPSS-R risk categories (Very Low, Low, and Intermediate) (log-rank test, p = .0035). In contrast, there was no significant association between PRAME expression and OS in MDS patients with a high bone marrow blast percentage or those classified into higher IPSS-R risk categories. In addition, high PRAME expression was associated with early disease progression in MDS patients with a low bone marrow blast percentage. This study suggested PRAME expression to be a prognostic factor in MDS.

The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes.

Two oral hypomethylating agents, oral azacitidine (CC-486) and decitabine/cedazuridine (ASTX727), have recently entered the clinical domain. CC-486 has been shown to improve overall survival as maintenance therapy for older patients with acute myeloid leukemia in complete remission, whereas the combination of decitabine with cedazuridine, a cytidine deaminase inhibitor, is indicated for the treatment of adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia with intermediate-1, or higher, International Prognostic Scoring System risk. This article briefly summarizes the clinical development of both drugs, the pivotal studies that led to their approval and some of the issues faced in extending the use of these drugs to other indications.

Randomized Phase 2 Trial of Pevonedistat Plus Azacitidine Versus Azacitidine in Higher-Risk Myelodysplastic Syndromes/Chronic Myelomonocytic Leukemia or Low-Blast Acute Myeloid Leukemia: Exploratory Analysis of Patient-Reported Outcomes

Randomized Phase 2 Trial of Pevonedistat Plus Azacitidine Versus Azacitidine in Higher-Risk Myelodysplastic Syndromes/Chronic Myelomonocytic Leukemia or Low-Blast Acute Myeloid Leukemia: Exploratory Analysis of Patient-Reported Outcomes

Long-Term Outcome of Low-Dose Hypomethylating Agents in Lower-Risk Myelodysplastic Syndromes: A Randomized Phase 2 Study

Long-Term Outcome of Low-Dose Hypomethylating Agents in Lower-Risk Myelodysplastic Syndromes: A Randomized Phase 2 Study

Association between Transfusion Status (TS) and Clinical and Economic Outcomes in Patients with Myelodysplastic Syndromes (MDS) from the Physicians' Perspective

Introduction: Studies have shown that transfusion-dependent (TD) patients with MDS have worse overall survival (OS) than transfusion-independent (TI) patients. However, few studies have examined physicians' perspectives on the relationship between transfusion dependence and OS and other clinical and economic outcomes in MDS. The current study investigated physicians' understanding of the impact of transfusion status (TS) on clinical and economic outcomes in 5 European countries. Methods: Interviews were conducted with physicians (3 each in France, Germany, Italy, Spain, and the UK) to pre-test and revise the study questionnaire, a 40-minute web-based physician survey via the M3 Global Research physician panel, for relevance and understanding. The revised questionnaire was translated to allow physicians to complete the survey in their native language. To participate in the survey, physicians had to be specialized in oncology/hematology, have been in practice for 2-35 years, spend ≥ 75% of their time in direct patient care, and have managed ≥ 15 patients with MDS in the past 3 months. The survey asked physicians for their perspectives on the impact of TS on risk of death, acute myeloid leukemia (AML) progression, chance of leukemia-free state (LFS), significant bleeding events, number of infection events, hospitalizations, and ER visits, based on their own clinical experience, beliefs, and knowledge of the literature. In the instructions accompanying the survey, physicians were provided with a definition of transfusion dependence (≥ 1 unit(s) every 8 weeks), transfusion burden (TB; high burden: ≥ 4 units every 4 weeks), and MDS International Prognostic Scoring System (IPSS) and revised IPSS (IPSS-R) risk levels to ensure consistency across all physicians. All results were reported descriptively, with frequency counts and percentages for categorical/ordinal data and mean (standard error [SE]) for continuous data. Results: Overall, 244 hematologist/oncologists, 124 hematologists, and 10 oncologists completed the survey in France, Germany, Italy, Spain, and the UK (n = 75 [approx.] in each country). On average, physicians were in practice for 14.70 years (SE 0.32), 41.3% were between the age of 45 and 54 years, and 64.3% were male. Physicians had seen an average of 54.5 patients (SE 2.26) with MDS in the past 3 months. The average risk of death among TI patients versus TD patients was 35.27% (SE 1.06) lower in the lower-risk MDS population and 37.61% (SE 0.87) lower among patients of all risk levels. The average risk of death among patients with low versus high TB was 42.65% (SE 0.95) lower among lower-risk TD patients and 41.89% (SE 0.75) lower among all-risk TD patients. The average risk of death for TD patients who became TI after treatment was 40.64% (SE 0.79) lower than for those who remained TD after treatment, across all risk levels (Figure). Similar results were found for AML progression and chance of LFS with TD patients having worse outcomes. The mean number of infection events per person per year (PPPY) was reported to be 3.96 (SE 0.82) for lower-risk TI patients and 5.15 (SE 0.91) for lower-risk TD patients, and the mean number of significant bleeding events PPPY reported was 2.88 (SE 0.85) for lower-risk TI patients and 3.46 (SE 0.81) for lower-risk TD patients. The mean number of all-cause hospitalizations PPPY reported was 3.62 (SE 0.76) among TI patients and 6.35 (SE 0.89) among TD patients. Physicians also reported TI patients having 3.28 (SE 0.84) ER visits PPPY and TD patients having 5.61 (SE 0.84) ER visits PPPY. These findings were numerically similar across all 5 countries. Conclusions: Overall, physicians reported a greater risk of death, AML progression, and leukemic death, more infections and significant bleeding events, and increased hospitalization and ER visits for patients with MDS who are TD versus TI, based on their clinical experience and knowledge of the literature. The results were similar across patients with different risk levels and across the countries in question. New treatment options for patients with MDS to reduce or eliminate TB are warranted. Disclosures Kulasekararaj: Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gupta:Kantar: Current Employment; Bristol Myers Squibb: Consultancy, Research Funding. Constantino:Kantar: Current Employment. Grisolano:Kantar: Current Employment; Bristol Myers Squibb: Consultancy. Tang:Bristol Myers Squibb: Current Employment; Asclepius Analytics: Current Employment. Jones:Bristol Myers Squibb: Current Employment. Tang:BMS: Current Employment, Current equity holder in publicly-traded company.

No clear survival benefit of azacitidine for lower-risk myelodysplastic syndromes: A retrospective study of Nagasaki.

The efficacy of azacitidine (AZA) on survival of lower risk (LR) ‐ myelodysplastic syndromes (MDS) is controversial. To address this issue, we retrospectively evaluated the long‐term survival benefit of AZA for patients with LR‐MDS defined by International Prognostic Scoring System (IPSS). Using data from 489 patients with LR‐MDS in Nagasaki, hematologic responses according to International Working Group 2006 and overall survival (OS) were compared among patients that received best supportive care (BSC), immunosuppressive therapy (IST), erythropoiesis‐stimulating agents (ESA), and AZA. Patients treated with AZA showed complete remission (CR) rate at 11.3%, marrow CR at 1.9%, and any hematologic improvement at 34.0%, with transfusion independence (TI) of red blood cells in 27.3% of patients. and platelet in 20% of patients, respectively. Median OS for patients received IST, ESA, BSC, and AZA (not reached, 91 months, 58 months, and 29 months, respectively) differed significantly (P < .001). Infection‐related severe adverse events were observed in more than 20% of patients treated with AZA. Multivariate analysis showed age, sex, IPSS score at diagnosis, and transfusion dependence were significant for OS, but AZA treatment was not, which maintained even response to AZA, and IPSS risk status at AZA administration was added as factors. We could not find significant survival benefit of AZA treatment for LR‐MDS patients.

Effect of enhancer of zeste homolog 2 mutations on the prognosis of patients with myelodysplastic syndrome: A meta-analysis.

Background:Gene mutations with important prognostic roles have been identified in patients with myelodysplastic syndrome (MDS). Overall, it is not yet fully clear whether enhancer of zeste homolog 2 (EZH2) is affected and contributes to the disease in MDS patients. Thus, we performed a meta-analysis to investigate the effects of EZH2 mutations on the prognosis of patients with MDS.Methods:We searched English-language databases (PubMed, Embase, and Cochrane Library) for studies published on the effects of EZH2 mutations in MDS patients. The study had to include at least 1 of the following indices as therapeutic evaluation data: overall survival (OS), transformation time to leukemia, and International Prognostic Scoring System risk. Revman, version 5.2 software was used for all statistical processing. We calculated the risk ratio and the 95% confidence interval (CI) of continuous variables, and determined the hazard ratio and 95% CI of time-to-event data.Results:We included 5 studies with a total enrolment of 994 patients. There was a significant adverse effect on OS in the EZH2-mutation group compared to the unmutated group (hazard ratio = 2.47, 95% CI: 1.37–4.47, P < .00001), while the heterogeneity was relatively high (I2 = 68%). There was no significant correlation between EZH2 mutations and IPSS risk (low/int-1 vs int-2/high) (odds ratio: 0.69, 95% CI: 0.14–3.39, P = .65), with significant heterogeneity (I2 = 78%). The analysis did not show significant publication bias in the studies.Conclusion:This meta-analysis indicated an adverse effect of EZH2 mutations with regard to OS in patients with MDS. However, larger cohort trials are still needed to better understand the prognostic impacts of EZH2 mutations on MDS patients.

RAS/CBL mutations predict resistance to JAK inhibitors in myelofibrosis and are associated with poor prognostic features

AbstractThe dysregulation of the JAK/STAT pathway drives the pathogenesis of myelofibrosis (MF). Recently, several JAK inhibitors (JAKis) have been developed for treating MF. Select mutations (MTs) have been associated with impaired outcomes and are currently incorporated in molecularly annotated prognostic models. Mutations of RAS/MAPK pathway genes are frequently reported in cancer and at low frequencies in MF. In this study, we investigated the phenotypic, prognostic, and therapeutic implications of NRASMTs, KRASMTs, and CBLMTs (RAS/CBLMTs) in 464 consecutive MF patients. A total of 59 (12.7%) patients had RAS/CBLMTs: NRASMTs, n = 25 (5.4%); KRASMTs, n = 13 (2.8%); and CBLMTs, n = 26 (5.6%). Patients with RAS/CBLMTs were more likely to present with high-risk clinical and molecular features. RAS/CBLMTs were associated with inferior overall survival compared with patients without MTs and retained significance in a multivariate model, including the Mutation-Enhanced International Prognostic Score System (MIPSS70) risk factors and cytogenetics; however, inclusion of RAS/CBLMTs in molecularly annotated prognostic models did not improve the predictive power of the latter. The 5-year cumulative incidence of leukemic transformation was notably higher in the RAS/CBLMT cohort. Among 61 patients treated with JAKis and observed for a median time of 30 months, the rate of symptoms and spleen response at 6 months was significantly lower in the RAS/CBLMT cohort. Logistic regression analysis disclosed a significant inverse correlation between RAS/CBLMTs and the probability of achieving a symptom or spleen response that was retained in multivariate analysis. In summary, our study showed that RAS/CBLMTs are associated with adverse phenotypic features and survival outcomes and, more important, may predict reduced response to JAKis.

Phase II study of pevonedistat (P) + azacitidine (A) versus A in patients (pts) with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (LB AML) (NCT02610777).

7506 Background: P, the first and only small-molecule inhibitor of the NEDD8-activating enzyme, disrupts proteasomal degradation of select proteins and has shown promising clinical activity and good tolerability in combination with A in AML. Methods: 120 pts with higher-risk (Revised International Prognostic Scoring System risk &gt; 3) MDS/CMML or LB AML naïve to hypomethylating agents were randomized 1:1 to receive P 20 mg/m2 intravenously (IV) on days (d) 1, 3, 5 + A 75 mg/m2 (IV/subcutaneously) on d 1–5, 8, 9 (n = 58), or A alone (n = 62), in 28-d cycles until unacceptable toxicity, relapse, transformation to AML, or progression. The primary endpoint was overall survival (OS), although the study was underpowered for OS. Results: Baseline characteristics were generally balanced between arms. Pts received a median of 13.0 vs 8.5 cycles of P+A vs A. Median OS in the intent-to-treat (ITT) population with P+A vs A (n = 120) was 21.8 vs 19.0 mos (hazard ratio [HR] 0.80; 95% CI 0.51–1.26; P = .334; median follow-up 21.4 vs 19.0 mos). Subanalyses showed median OS with P+A vs A in higher-risk MDS (n = 67) of 23.9 vs 19.1 mos (HR 0.70; 95% CI 0.39–1.27; P = .240) and in LB AML (n = 36) of 23.6 vs 16.0 mos; HR 0.49; 95% CI 0.22–1.11; P = .081). Event-free survival (EFS – time from randomization to death/transformation to AML) with P+A vs A trended longer in the ITT population (median 21.0 vs 16.6 mos; HR 0.65; 95% CI 0.41–1.02; P = .060) and was significantly longer in higher-risk MDS (median 20.2 vs 14.8 mos; HR 0.54; 95% CI 0.29–1.00; P = .045). In response-evaluable pts, overall response rate was 71% (n = 39/55; 46% complete remission [CR] + CR with incomplete blood count recovery [CRi], 5% partial response [PR], 20% hematologic improvement [HI]) with P+A vs 60% (n = 32/53; 38% CR+CRi, 8% PR, 15% HI) with A. In higher-risk MDS, CR rate was 52% vs 27% ( P = .050) with P+A vs A. Median A dose intensity was 97% vs 98% with P+A vs A. Rates of grade ≥3 adverse events were 90% vs 87% with P+A vs A; the most common were 31% vs 27% neutropenia, 26% vs 29% febrile neutropenia, 19% vs 27% anemia, and 19% vs 23% thrombocytopenia. On-study deaths occurred in 9% of P+A pts and 16% of A pts. Conclusions: P+A had a comparable safety profile to A alone, did not increase myelosuppression, and maintained A dose intensity. Although not statistically significant, P+A increased OS, EFS, and response rates vs A, particularly in pts with higher-risk MDS. Further evaluation of P+A vs A is ongoing in a randomized phase. Clinical trial information: NCT02610777 .

Real-world disease burden for patients (pts) with myelofibrosis (MF) treated with ruxolitinib (RUX).

e19539 Background: MF is an aggressive myeloid neoplasm and until recently RUX was the only treatment available. Real-world, long-term outcomes in pts with MF have not been described. Methods: Providers from multiple community oncology clinics in the USA reviewed the charts of consecutive pts with MF (primary or post-polycythemia vera/essential thombocythemia MF) who received RUX at any time from Jan 1, 2015 to Dec 31, 2017; data were collected Nov 15–26, 2019. Pt characteristics, treatment patterns, and outcomes (symptoms, blood counts, disease transformation) were retrospectively abstracted into an electronic case report form (eCRF) at each visit during the first 6 months, at any RUX dose modification; and at 12, 24, and 36 months post-RUX initiation. Pt characteristics, treatment patterns, rationale for dose modification, and treatment duration are described for pts during the first 6 months of therapy. Results: eCRFs were completed for 104 pts with MF treated with RUX. 42 pts received a RUX dose modification and 62 did not. Median follow-up from RUX initiation was 23.5 months. In the first 6 months of therapy, 40.4% of pts had a RUX dose modification (76.2% dose reduced; 23.8% dose increased). The most common reason (70%) for dose increase was titration to therapeutic dose. The most common reason (75%) for dose reduction was hemoglobin 8–10 g/dL or platelet count 50–75 × 109. The starting dose of RUX was higher for no RUX dose modification pts (mean total daily dose 34.9 mg vs 27.0 mg, P &lt; 0.01). RUX dose-modified pts were older vs pts with no RUX dose modification ( P = 0.01); International Prognostic Scoring System (IPSS) risk score ( P = 0.89) and the proportion of pts with primary MF ( P = 0.06) were similar (Table). Overall, 64.4% of RUX treated pts discontinued therapy (RUX dose-modified 78.6%; no RUX dose modification 54.8%, P = 0.01). Median duration of RUX treatment was 11.0 months (RUX dose modified 10.6 months; no RUX dose modification 12.2 months; log rank P = 0.12). Conclusions: In this real-world study, 64.4% of pts discontinued RUX during follow-up. Higher rates of discontinuation and shorter time to discontinuation were noted for pts with a dose modification during the first 6 months of therapy. Given the short duration of therapy observed in this study as compared with published clinical trials, additional MF treatments are needed that offer pt benefit. [Table: see text]

Increased incidence of infection in patients with myelofibrosis and transfusion-associated iron overload in the clinical setting.

Transfusion-associated iron overload may lead to increased risk of infection, but its role in myelofibrosis (MF) has been scarcely explored. We evaluated 106 consecutive patients with primary or secondary MF. Up to 38% of patients were transfusion-dependent (TD) with a median of 14 RBC units received. Median observation time was 36months (range 3-203). Forty-five percent of patients experienced one or more infectious episodes for a total of 69 infectious events, 13 (19%) of which were severe. The 60-month cumulative incidence of infection was 64.1 ± 6.5%. TD patients showed a higher incidence of infection (HR = 2.13, p = 0.019). Transfusion burden was markedly greater in TD patients with infectious complication (median 24 RBC units vs 15 RBC units; p = 0.012). The 60-month overall survival was 40 ± 5.9%. Lower International Prognostic Scoring System (IPSS) risk (p < 0.0001) and ruxolitinib (p = 0.027) were significantly correlated with higher survival. This real-world study showed increased infections in patients with higher transfusion burden. It may therefore be interesting to further investigate the role of iron chelation in improving infection-free survival in MF patients.

Assessment of B-lymphocyte and T-lymphocyte function in patients with myelodysplastic syndromes

Background An activated immune system has been observed in patients with myelodysplastic syndrome (MDS), but its exact contribution to disease development and control has not been fully clarified. The successful use of immunosuppressive therapies, the potentially curative role of allogeneic stem cell transplant, and the more recent data showing improved peripheral cytopenias and elimination of certain common cytogenetic abnormalities with immunomodulatory agents highlight the role immune dysregulation in the development of MDS. Aim The aim of this study is to assess B-cell and T-cell function in patients with MDS and correlate them to the risk status of MDS. Patients and methods The study included 30 adult Egyptian patients diagnosed with MDS based on blood picture, bone marrow (BM) examination, and cytogenetic studies. Patients were classified according to International Prognostic Scoring System risk scoring system. Immune system assessment was done by performing antinuclear antibodies, direct Coombs test, serum protein electrophoresis, and CD4/CD8 ratio in peripheral blood. Results We have found an association between inverted CD4/CD8 ratio and higher risk strata, presence of neutropenia, and transfusion dependence. Regarding humoral immune system involvement, a positive Coombs test was related significantly to younger age and higher BM blasts count. Marked polyclonal gammopathy as well was found to be associated with higher BM blasts count and presence of cytogenetic abnormalities. Conclusion Immune dysregulation, in the form of inverted CD4/CD8 ratio, positive antinuclear antibodies, positive Coombs test, and polyclonal gammopathy, is well documented in MDS. It is probably related to younger age, higher International Prognostic Scoring System risk, higher BM blasts count, and the presence of cytogenetic abnormalities.

Serum ferritin and ECOG performance status predict the response and improve the prognostic value of IPSS or IPSS-R in patients with high-risk myelodysplastic syndromes and oligoblastic acute myeloid leukemia treated with 5-azacytidine: a retrospective analysis of the Hellenic national registry of myelodysplastic and hypoplastic syndromes.

Background:5-azacytidine (5-AZA) improves survival of patients with higher-risk myelodysplastic syndromes (MDSs) and oligoblastic acute myeloid leukemia (AML); however, predictive factors for response and outcome have not been consistently studied.Methods:This study of the Hellenic MDS Study Group included 687 consecutive patients with higher-risk MDS and oligoblastic AML treated with 5-AZA.Results:The International Prognostic Scoring System (IPSS) revised version (IPSS-R), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 or 1 versus ⩾2) and baseline serum ferritin (SF) levels > 520 ng/ml were shown to independently predict response to 5-AZA. In the survival analysis, the IPSS and IPSS-R risk classification systems along with the ECOG PS and SF levels > 520 ng/ml proved to be independent prognosticators for overall survival (OS), as well as for leukemia-free survival (LFS). Next, we built new multivariate models for OS and LFS, incorporating only ECOG PS and SF levels besides IPSS or IPSS-R risk classification systems. Thereby, the new modified IPSS and IPSS-R risk classification systems (H-PSS, H-PSS-R) could each discriminate a low, an intermediate and a high-risk patient group regarding OS and LFS. The H-PSS and H-PSS-R proved to be better predictors of OS than their previous counterparts as well as the French prognostic score, while the most powerful OS predictor was the new, H-PSS-R system.Conclusions:ECOG PS and SF levels > 520 ng/ml independently predict response to 5-AZA, OS and LFS. Their incorporation in the IPSS and IPSS-R scores enhances these scores’ predictive power in 5-AZA-treated higher-risk MDS and oligoblastic AML patients.

Combining gene variants with clinical characteristics improves outcome prediction in Chinese patients with myelodysplastic syndromes

Genetic variants have been identified in the majority of myelodysplastic syndromes (MDS) patients and have considerably influenced the diagnosis, classification, risk stratification and treatment of MDS. To explore the prognostic significance of genomic variants and build a new prognostic scoring model, we performed next-generation sequencing of 51 known genes in 499 Chinese patients with MDS. Ultimately, the TP53, GATA2, DNMT3A, age and the revised International Prognostic Scoring System (IPSS-R) risk stratification were included in a new Cox model and divided into three prognostic categories, and had a better prediction of overall survival. The C-index of the new prognostic scoring model (0.772) was clearly better than IPSS-R risk stratification (0.717), which was validated in 163 cases. Moreover, the new model was also suitable for the prediction of OS for patients undergoing allogeneic hematopoietic stem cell transplantation. The inclusion of genomic variants and age into the IPSS-R could improve prognostic algorithms for MDS patients.

A Phase 1b Study of Glasdegib in Combination with Azacitidine in Patients with Untreated Higher-Risk Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia

A Phase 1b Study of Glasdegib in Combination with Azacitidine in Patients with Untreated Higher-Risk Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia

A Systematic Literature Review on the Burden of Illness in Lower-Risk Transfusion-Dependent Myelodysplastic Syndromes

Introduction: Anemia occurs in 80-90% of patients with myelodysplastic syndromes (MDS), nearly half of whom are red blood cell (RBC) transfusion dependent (TD) at diagnosis. The presence of anemia, transfusion dependency, and the resulting complications exacerbate the burden of MDS. Patients with lower-risk MDS have longer overall survival (OS) than patients with higher-risk MDS; however, TD status and higher transfusion load significantly reduce OS. Treatment of lower-risk TD MDS aims to achieve RBC transfusion independence (TI), hematologic improvements and alterations in erythroid response according to IWG 2006 criteria, and improved health-related quality of life (HRQoL). To evaluate these points, we performed a systematic literature review (SLR) to assess the burden experienced by adult patients with RBC TD anemia in lower-risk MDS. Methods: Embase®, MEDLINE®, and the Cochrane Library were systematically searched from inception to March 2019 to identify observational studies reporting on the HRQoL, clinical, and epidemiological burden as well as treatment patterns for adult patients with lower-risk MDS who were RBC TD. Conference proceedings from the last 2 years were searched to identify recent data not yet published as a full text article. Only English language articles and conference abstracts were included. References were screened at the title/abstract and full-text levels by 2 independent reviewers, with methodology following Cochrane guidelines. Results: Database searches yielded 1,175 records. After removing duplicates, 837 abstracts were reviewed, with 152 publications progressing to full-text review. Ten studies met the eligibility criteria. Two additional records were identified from hand searching (Figure). Many studies reported on mixed MDS patient populations, where only a subset were lower-risk and TD, limiting the amount of data available. Nine studies were from the USA or EU5 (France Germany, Italy, Spain, United Kingdom) as well as 1 international study encompassing Europe, the USA, and Australia. The majority of studies defined risk status using the International Prognostic Scoring System (IPSS) risk score, with only 1 study reporting both IPSS and Revised-IPSS (IPSS-R) score. Where reported, patients were mostly older (mean age &gt; 70 years). Burden data were sparse, with few outcomes reported across multiple studies (Table). One study from Italy (mean age 72 years) reporting EuroQoL 5-dimension Visual Analogue Scale data indicated that patients with TD MDS had worse scores (53.0) compared with patients aged 65-74 years in the general Italian population (67.8). Clinical data indicated a variable OS rate across studies conducted in Spain and France, as well as in the 1 international study, with a 2-year OS rate of 73.2% and 4-year OS rates ranging from 27.6% to 73%. The data consistently reported that patients with TD MDS had shorter OS than patients with TI MDS. Differences in timepoints for assessment, types of treatments, and RBC transfusion load increased the variation in OS data. TI was defined as a transfusion-free period of ≥ 56 days, or 8 weeks, in most studies. Median time to reach TI (when reported) ranged from 32-97 weeks, although the prolonged length of time it took to reach TI and the proportion of patients achieving TI indicated an extensive time on treatment. Similar conclusions were drawn in 3 studies that compared OS in patients who became TI with those who remained TD. Epidemiology data were limited to mortality data, and no data were available on morbidity, incidence, or prevalence of disease. Mortality data provided an incomplete picture; deaths were reported as overall mortality or non-leukemic deaths, obscuring mortality rates specifically associated with lower-risk TD MDS. Treatment patterns were reported in 3 studies; erythropoiesis-stimulating agents and hypomethylating agents were the most common treatments reported. Conclusions: Data on the burden of illness in patients with lower-risk MDS with TD anemia were limited and reported inconsistently across studies. Despite this heterogeneity, HRQoL outcomes had a trend toward worse scores in patients with TD MDS than in the general population. OS rate at 2 and 4 years indicated worse prognosis in patients with TD MDS compared with the general population. To better understand the burden of illness, further robust observational studies are needed to close the evidence gaps in this population. Disclosures Deshpande: Evidera: Employment; Celgene Corporation: Consultancy. Turner:Evidera: Employment; Celgene Corporation: Consultancy. Byrnes:Evidera: Employment. Pelligra:Celgene Corporation: Research Funding; Evidera: Employment. Rines-MacEachern:Evidera: Employment. Chitnis:Celgene Corporation: Consultancy; Evidera: Employment. Kulasekararaj:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Achilleon: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akari Therapeutics: Consultancy. Tang:Celgene Corporation: Employment, Equity Ownership. Morison:Celgene Corporation: Employment. Oliva:Apellis: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Speakers Bureau.

Validation of Low Risk Prognostic Scoring System (LR-PSS) in Patients with Lower Risk IPSS-R Myelodysplastic Syndrome. Results from a Single Center

Background: Myelodysplastic syndrome (MDS) therapeutic decisions have been traditionally based on the International Prognostic Scoring System (IPSS) (Greenberg et al, Blood 1997) and IPSS-R (Greenberg et al, Blood 2012). Recently, next-generation sequencing genetics has been incorporated into management of MDS, however its use is limited in routine clinical practice. Current prognostic models do not allow the identification of patients with low risk disease (low or intermediate-1 IPSS) and poor prognosis, who could benefit from an early intervention. Garcia-Manero et al (Leukemia 2008) described a specific prognostic scoring system for this subgroup of patients (LR-PSS) based on age ≥60 years, hemoglobin &lt;10g/dl, platelet count &lt;50k/uL or 50-200k/uL, bone marrow blasts ≥4% and unfavorable cytogenetics (non-del(5q), non-diploid). This LR-PSS score system enables the stratification of low risk MDS patients into 3 different risk categories; interestingly, the third category identifies a subgroup of patients with a median overall survival (OS) similar to that of patients classified as intermediate-2 and high risk IPSS. Besides, the IPSS-R described by Greenberg et al (Blood 2012) has demonstrated a strong prognostic value for OS and LFS as compared to the IPSS when applied to different independent series of MDS patients. The prognostic impact of the LR-PSS has not been analyzed in MDS patients with very low-, low- and intermediate IPSS-R scores. Aim: To analyze the prognostic value of Low Risk Prognostic Scoring System(LR-PSS) in a population of lower risk MDS patients (very low, low and intermediate IPSS-R) analyzing as endpoints overall survival (OS) and leukemia free survival (LFS). Methods: A total of 890 consecutive patients with MDS (01/1992-7/2018) diagnosed at the Catalan Institute of Oncology in Barcelona were included in the study. 539 (60%) had available cytogenetics and therefore, IPSS-R could be assessed. 474 (88%) patients were classified as very low, low and intermediate IPSS-R and were included in the study. Results: 178 (37.6%) patients were classified as very low, 219 (46.2%) low and 77 (16.2%) intermediated IPSS-R risk MDS. Median age at diagnosis was 73 years (range 32-101). 332 (70%) were male. According to the 2008 WHO classification, 2.5% CRDU, 7.4% RA, 42.2% RCMD, 13.7% RAEB‐1, 3.6% RAEB‐2, 26.4% CMML and 4.2% MDS‐U with isolated 5q deletion. At diagnosis, median hemoglobin, platelet and bone marrow blast were 11.6 g/dL (5.5-17.1), 157 x109/L (1-1492) and 2 % (0-17), respectively. 84 (17.7%) patients had unfavorable LR-PSS cytogenetics at diagnosis. Median follow up time for survivors was 5.4 years (range 0.25-23.8). At the time of last follow up, 58.4 % (277) had died and 71 (15%) had progressed to acute myeloid leukemia. When the LR-PSS was applied to the very low, low and intermediate IPSS-R subgroups, three well-differentiated prognostic categories could be identified: 103 patients (21.7%) category 1 (scores 0-2); 330 (69.6%) patients category 2 (scores 3-4) and 41 (8.7%) patients category 3 (scores 5-7) with significant different OS and LFS. Median OS for categories 1, 2 and were 7.1 years (95% CI 4.9-9.2), 5.7 years (95% CI 4.7-6.7) and 2.8 years (95% CI 2.1-3.6), p&lt;0.001 (Figure 1), respectively. Rate of progression to acute myeloid leukemia was 10% (10/99), 15% (48/323) and 27% (11/411) for categories 1, 2 and 3, respectively. Summary/Conclusion: When applied to a low risk (very low, low and intermediate) IPSS-R cohort of MDS population, LR-PSS identifies a subgroup of patients with a significantly worse prognosis who could benefit from an early treatment intervention. Disclosures Sureda: Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead: Consultancy; Roche: Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau.

Overexpression of WT1 and PRAME predicts poor outcomes of patients with myelodysplastic syndromes with thrombocytopenia

AbstractThrombocytopenia is associated with life-threatening bleeding and is common in myelodysplastic syndromes (MDS). Robust molecular prognostic biomarkers need to be developed to improve clinical decision making for patients with MDS with thrombocytopenia. Wilms tumor 1 (WT1) and preferentially expressed antigen in melanoma (PRAME) are promising immunogenic antigen candidates for immunotherapy, and their clinical effects on patients with MDS with thrombocytopenia are still not well understood. We performed a multicenter observational study of adult patients with MDS with thrombocytopenia from 7 different tertiary medical centers in China. We examined bone marrow samples collected at diagnosis for WT1 and PRAME transcript levels and then analyzed their prognostic effect for patients with MDS with thrombocytopenia. In total, we enrolled 1110 patients diagnosed with MDS with thrombocytopenia. Overexpression of WT1 and PRAME was associated with elevated blast percentage, worse cytogenetics, and higher Revised International Prognostic Scoring System (IPSS-R) risk. Further, both WT1 and PRAME overexpression were independent poor prognostic factors for acute myeloid leukemia evolution, overall survival, and progression-free survival. Together, the 2 genes overexpression identified a population of patients with MDS with substantially worse survival. On the basis of WT1 and PRAME transcript levels, patients with MDS with IPSS-R low risk were classified into 2 significantly divergent prognostic risk groups: a low-favorable group and a low-adverse group. The low-adverse group had survival similar to that of patients in the intermediate-risk group. Our study demonstrates that the evaluation of WT1/PRAME transcript analysis may improve the prognostication precision and better risk-stratify the patients.

PS1513 ESTIMATING LIFE‐YEAR LOSS OF PRIMARY MYELOFIBROSIS IN EUROPE

Background:Primary myelofibrosis (PMF) is a myeloid neoplasm impacting patient survival and quality of life. Although JAK2 inhibitors were recently approved for the treatment of patients with PMF, there is still a lack of strong evidence supporting a survival benefit in this patient population.1 Existing published survival data focus on describing duration of survival, however as there is no general population comparator for this outcome, interpretations are often subjective.Aims:This study aimed to quantify the real‐world mortality caused by PMF in comparison with the general population in Germany, France, Italy, Spain, and the UK (EU5).Methods:A simulation model was developed in Microsoft Excel, using parameters sourced from a large‐scale European‐based real‐world retrospective MF study by the International Working Group for Myeloproliferative Neoplasm Research and Treatment.2 Baseline demographics predictive of survival, including age, sex, and International Prognostic Scoring System (IPSS) risk level, were simulated using the patient characteristics statistics published by Cervantes et al. in 2012.2 The survival of patients with PMF was simulated using the exponential survival function. To examine the rate of mortality, the exponential distribution parameter (modeled as a function of age, sex, and IPSS risk level) was estimated using published median survival times and derived hazard ratios. Patient characteristics and survival statistics from the simulation sample were verified with the published data.2 Real‐world life‐year loss was calculated as the difference between simulated survival time and the population‐level life expectancy specific to the patient's age, sex, and country.Results:A total of 5,000 patients were simulated (Table), with 1,000 from each EU5 country. The simulated sample generated similar patient characteristics statistics and median survival years as found by Cervantes et al.2 The additional mean life‐year loss of PMF was estimated at 9.6 years (median 10.7 years; 5 and 95 percentile [−18.7, 33.4]), with a 45% relative survival loss, compared with the general population. Overall, 81% of patients with PMF were estimated to experience life‐year loss. More pronounced life‐year loss was found to be associated with being male (mean 11.3 years; 57% relative survival loss; 86% with life‐year loss), age &lt;65 years (mean 14.3 years; 48% relative survival loss; 84% with life‐year loss), and IPSS Intermediate‐2 to High risk classification (mean 15.4 years; 73% relative survival loss; 95% with life‐year loss). The results were consistent among the EU5 countries modeled.Summary/Conclusion:PMF patients experience significant real‐world life‐year loss when compared with the general population in Europe.image

Favorable Outcomes With Tumor Burden Reduction Following Administration of Hypomethylating Agents Before Allogeneic Hematopoietic Cell Transplantation in Patients With Higher Risk Myelodysplastic Syndrome

IntroductionThe clinical significance of tumor burden reduction following administration of hypomethylating agents (HMAs) for transplant-eligible patients with higher risk myelodysplastic syndrome (MDS) was evaluated. Patients and MethodsData of 79 transplant-eligible patients (< 65 years) diagnosed with higher-risk MDS between July 2002 and March 2013 were retrospectively analyzed. Among 79 patients, 30 (38%) underwent allogeneic hematopoietic cell transplantation (HCT group), and 49 (62%) were treated with HMA alone (non-HCT group). ResultsThe median follow-up duration was 732 days (range, 28-1952 days), and the 3-year overall survival (OS) rate of all patients was 30.6%. In the HCT group, early HCT showed a better 3-year OS rate than late HCT (67.1% vs. 25.7%; P = .035). In multivariate analysis, time/performance of allogenic transplant (no HCT vs. early HCT, hazard ratio, 0.18; 95% confidence interval, 0.04-0.81; P = .026) and follow-up higher risk International Prognostic Scoring System (hazard ratio, 6.22; 95% confidence interval, 2.09-18.51; P = .001) were significantly correlated with OS. ConclusionTo predict the clinical outcomes of patients with higher risk MDS, the optimal time for tumor burden evaluation is prior to follow-up rather than at the time of initial diagnosis. Patients with lower International Prognostic Scoring System risk groups after HMA treatment or early HCT had favorable OS.