Low International Prognostic Scoring System Research Articles

Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes

Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study. The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent. Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03–6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent. Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.

Programmed necroptosis is upregulated in low-grade myelodysplastic syndromes and may play a role in the pathogenesis

Myelodysplastic syndrome (MDS) is characterized by persistent cytopenias and evidence of morphologic dysplasia in the bone marrow (BM). Excessive hematopoietic programmed cell death (PCD) and inflammation have been observed in the bone marrow of patients with MDS, and are thought to play a significant role in the pathogenesis of the disease. Necroptosis is a major pathway of PCD that incites inflammation; however, the role of necroptosis in human MDS has not been extensively investigated. To assess PCD status in newly diagnosed MDS, we performed immunofluorescence staining with computational image analysis of formalin-fixed, paraffin-embedded BM core biopsies using cleaved caspase-3 (apoptosis marker) and necroptosis markers (receptor-interacting serine/threonine-protein kinase 1 [RIPK1], phospho-mixed lineage kinase domain-like protein [pMLKL]). Patients with MDS, but not controls without MDS or patients with de novo acute myeloid leukemia, had significantly increased expression of RIPK1 and pMLKL but not cleaved caspase-3, which was most evident in morphologically low-grade MDS (<5% BM blasts) and in MDS with low International Prognostic Scoring System risk score. RIPK1 expression highly correlated with the distribution of CD71+ erythroid precursors but not with CD34+ blast cells. We found that necroptosis is upregulated in early/low-grade MDS relative to control participants, warranting further study to define the role of necroptosis in the pathogenesis of MDS and as a potential biomarker for the diagnosis of low-grade MDS.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.

Iron Overload in Lower International Prognostic Scoring System Risk Myelodysplastic Syndromes Patients Receiving Red Blood Cell Transfusions: Relation to Infection and Possible Benefit of Iron Chelation Therapy

Background: Analyses in lower risk myelodysplastic syndromes (MDS) suggest inferior survival in patients (pts) with transfusional iron overload (IOL). Some studies suggest an increased incidence of infections and infection related mortality in transfused MDS pts. Reducing IOL with iron chelation therapy (ICT) appears to give clinical benefit. The literature suggests that IOL can predispose to bacterial, fungal and viral infections, as organisms use iron for metabolism and cell division, and IOL can adversely affect neutrophil function. There are no clinical studies examining infection risk in MDS pts with IOL in the non-stem cell transplant (SCT) setting, and whether this risk can be attenuated with ICT.Methods: We performed a retrospective analysis of pts with a bone marrow biopsy confirmed diagnosis of lower International Prognostic Scoring System (IPSS) risk MDS receiving red blood cell (RBC) transfusions. Pts were identified from the clinical database and charts reviewed. Clinical data extracted included baseline characteristics, serum ferritin level (SF), treatment, and infectious episodes requiring antibiotics, antifungal or antiviral medications. Statistical analyses were performed using SPSS for Windows, version 24.Results: Of 182 transfused MDS pts, 138 were lower IPSS risk. 44 pts were excluded for: not transfused as lower risk, n=19; higher IPSS risk, or received hypomethylating agent or SCT, n=13; and inadequate information, n=12. The median (range) age at first RBC transfusion was 72.5 (31-93) years and 78 (57%) pts were male. 59 pts received ICT: deferasirox (DFX), n=45 (76.3%); deferoxamine (DFO), n=13 (22.0%); and deferiprone, n=1 (1.7%); and 79 did not receive ICT. Median (range) time from 1st RBC transfusion to ICT was 22.5 (1.4-209) months and duration of ICT 13 (1-75) months. Clinical factors differing between ICT and non-ICT pts, respectively, were (median [range]): age at 1st RBC transfusion, 67 (31-88) and 75 (43-93) years; number of RBC units (U) transfused while lower risk, 76 (10-675) and 24 (2-200); number of RBCU/4 weeks, 2.2 (0.5-9.1) and 2.0 (0.1-5.4); SF 914 (49-15608) and 266 (12-5009) ng/mL; and other treatments received, 18 (30.5%) and 5 (6.3%); p</=0.04 for all. Factors not differing between groups were: gender; French American British or World Health Organization MDS diagnosis; marrow blast count; IPSS or IPSSR cytogenetic risk; IPSS or IPSSR risk; neutrophil count at first RBC transfusion or at first infection; and causes of death, p=NS for all. Infections included: bacterial, n=88; viral; fungal; and mycobacterial; n=2 each. In ICT and non-ICT pts, respectively, infections while lower IPSS risk were (number [%]): pts, 23 (40.0%) and 22 (27.8%); episodes (median [range]), 2 (1-6) and 2 (1-5); hospitalizations, 16 (27.1%) and 8 (10.1%); and infectious deaths, 0 (0%) and 1 (1.3%), p=NS for all. In ICT pts, infections occurred pre-ICT in 9 (15.3%); on DFX, n=10 (22.2%), and on DFO, n=4 (30.8%), p<0.0001. Median overall survival (OS) from 1st RBC transfusion while lower IPSS risk was not reached at 105, and 50.1 months for ICT and non-ICT pts, respectively, p=0.01. ICT remained significant for OS in a multivariate analysis (MVA) including: ICT; IPSS cytogenetic risk; and hospitalization for infection; (all p</=0.06 in univariate analysis), p=0.003, hazard ratio (HR) 0.3, 95% confidence intervals (CI) 0.2-0.7, and lost significance when number of RBCU received (p<0.0001) was added to the MVA. However, OS was significantly superior for ICT pts receiving >20 and >50 RBCU (p=0.02, and <0.0001, respectively). Median time to first infection (TTI) was 27 and 7.8 months for ICT and non-ICT pts, respectively, p<0.0001 (Figure 1). ICT remained significant for TTI in an MVA including: age; IPSS cytogenetic risk; marrow blast count; and number of RBCU received (p=0.03, HR 0.3, 95% CI 0.09-0.9). For TTI, marrow blast count was also significant in the MVA (p=0.04). TTI remained significantly longer for ICT pts with blast count <5% (p=0.004).Conclusions: In this retrospective, non-controlled analysis, for lower IPSS risk MDS patients receiving RBC transfusions, receiving iron chelation therapy was associated with superior overall survival. Though number and type of infections were similar between groups and despite similar neutrophil counts, time to first infection was significantly longer in ICT patients. These results should be confirmed in larger, prospective analyses. [Display omitted] DisclosuresLeitch:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exjade: Speakers Bureau; Abbvie: Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

The impact of transfusion burden and comorbidities on the prognosis of patients with myelodysplastic syndromes

PurposeEarly comorbidity detection has been reported to be associated with treatment-related outcomes in several diseases. Two main goals of the present study were to investigate both the impact of comorbidities and transfusion frequencies on the survival and quality of life of patients with myelodysplastic syndromes (MDS). MethodsOne hundred and four MDS patients with a median International Prognostic Scoring System (IPSS) score of 0.5 (range: 0–3) were included in the study. Almost half of the patients had more than one comorbidity. ResultsMedian short form health surveys (SF)-36 mental and physical scores were 42.1 (range: 20.6–66.1) and 38.7 (range: 18–59.7), respectively. Mean scores of the Eastern Cooperative Oncology Group (ECOG) performance scales at diagnosis and during recruitment were 1.0 (1.4 ± 1.0) and 2.0 (1.8 ± 1.1), respectively. The mean Charlson Comorbidity Index (CCI) score was 1.0 (1.4 ± 1.5). In the model that was constructed using variables with a p value < 0.100 in the univariate analysis, factors that predicted death were refractory anemia with excess blasts (RAEB) and ECOG scores at recruitment. When ECOG was removed from the model, RAEB and CCI at diagnosis moved to the forefront as mortality predictors. ConclusionThis study demonstrated that both CCI and ECOG performance status had an impact on survival in MDS patients who had low IPSS scores. ECOG stood out as a better and more practical predictor of survival than CCI, especially after considering its (ECOG) ease of use.

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.

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.

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.

Prognosis of Patients with Waldenström Macroglobulinemia: A Simplified Model

Prognosis of Patients with Waldenström Macroglobulinemia: A Simplified Model

80 - Phase 1 safety outcomes of mesenchymal stromal stem cell therapy in pateints with low and intermediate-1 ipss risk myelodysplastic syndrome

Myelodysplastic syndrome (MDS) is a haematological disorder of bone marrow failure which presents with low blood counts. The incidence is increasing in developed countries due to population aging. The prognosis for patients with MDS is defined by risk classification systems such as the International Prognostic Scoring System (IPSS). In patients with low or intermediate-1 (lower) risk IPSS MDS, standard care is supportive. Another treatment is immunotherapy. Allogeneic MSC infusion represents a novel immunotherapy in MDS with tolerable side effect profile. We designed a phase 1 study to assess the safety of MSC infusion in a population of lower risk MDS patients.

Iron overload in lower international prognostic scoring system risk patients with myelodysplastic syndrome receiving red blood cell transfusions: Relation to infections and possible benefit of iron chelation therapy

BackgroundAn increased incidence of infections and infectious mortality has been reported in myelodysplastic syndromes (MDS) patients receiving red blood cell (RBC) transfusions. MethodsWe examined incidence of infections requiring antibiotics, antifungal or antiviral medications in transfused lower International Prognostic Scoring System (IPSS) risk MDS patients and whether this differed with iron chelation therapy (ICT). Results138 transfused MDS patients were lower IPSS risk. 59 received ICT; median duration was 13 months. There was no significant difference between groups in neutrophil count at first RBC transfusion or first infection. Infections included: bacterial, n = 88; viral; fungal; and mycobacterial; n = 2 each. In ICT and non-ICT patients, respectively, infections were (number [%]): patients, 23 (40.0%) and 22 (27.8%); episodes (median [range]), 2 (1–6) and 2 (1–5); hospitalizations, 16 (27.1%) and 8 (10.1%); and deaths, 0 (0%) and 1 (1.3%), p = NS for all. Median overall survival (OS) from first RBC transfusion was superior in ICT patients, p = 0.01, and remained significant in a multivariate analysis (MVA), p = 0.003. Median time to first infection (TTI) was 27 and 7.8 months, respectively, p < 0.0001, and ICT remained significant for TTI in an MVA, p = 0.02, hazard ratio 0.3. For ICT patients with blast count <5%, TTI was significantly superior (p = 0.004). ConclusionsIn this retrospective analysis, for lower IPSS risk MDS patients receiving RBC transfusions, though number and type of infections were similar between groups and despite similar neutrophil counts, time to first infection was significantly longer in ICT patients (p < 0.0001). These results should be confirmed in larger, prospective analyses.

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

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

Impact of Driver Mutations in Patients with Lower-Risk Myelodysplastic Syndromes Classified By the MD Anderson Lower-Risk Prognostic Scoring System

▪INTRODUCTION: Patients with lower-risk myelodysplastic syndromes (MDS) as defined by the International Prognostic Scoring System (IPSS) are generally considered to have favorable prognosis. The MD Anderson Lower-risk Prognostic Scoring system (MDA LR-PSS) is a validated prognostic model that defines a subset of patients with shorter than expected survival. Presence of EZH2mutations has been reported to independently impact survival of these patients. Further evaluation and validation of the addition of mutation data to this prognostic model is needed.METHODS: We conducted whole exome sequencing of 74 previously untreated patients with Low or Int-1 IPSS. Exome capture hybrid was performed using Agilent SureSelect All Exon V4. Sequencing was performed with Illumina HiSeq 2000 and aligned to the hg19 human genome reference. Common virtual normal in house pool was used for somatic variant calling. Generalized linear models were used to study association of overall response (OR), complete response (CR) and risk factors. Response was defined following 2006 IWG criteria. The Kaplan-Meier produce limit method was used to estimate the median overall survival (OS) and leukemia-free survival (LFS).RESULTS: Patient characteristics are summarized in Table 1. Seventeen (23%) patients had CMML and 57 (77%) had MDS. Seventy (95%) patients had evaluable cytogenetics. A total of 46 (66%) patients had normal karyotype with 4 (6%) patients having complex karyotype. Twenty-three (31%) patients were classified as Low risk by IPSS and 51 (69%) as Int-1. Twelve (16%) patients were classified as Category 1 by the MDA LR-PSS, 38 (51%) as Category 2 and 24 (32%) as Category 3. A total of 148 driver mutations in 27 genes were detected. Median number of driver mutations per patient was 2 (range 0-5). Mutations in TET2, SRSF2, ASXL1, SF3B1 and ZRSR2 were the most frequently detected mutations present in >10% cases. Frequency of identified mutations is shown in Figure 1A. The median follow up was 26.5 months (range 3-102 months). Median OS was 43.2months (95% CI 35.04-50.46). Survival by MDA LR-PSS category is shown in Figure 1B. A total of 6 patients had transformation to acute myeloid leukemia with a median time to transformation of 22.4 months (95% CI 0.00-45.28). By univariate analysis, mutations in BCOR (HR 5.49, 9% CI 1.24-24.29, p=0.011), RUNX1 (HR 2.8, 95% CI 1.11-7.09, p=0.023) and STAG2 (HR 3.32, 95% CI 1.12-9.82, p=0.022) predicted for shorter OS. When analyzing for LFS, mutations in EZH2 (HR 18.61, 95% CI 2.99-115.92, p<0.001) and U2AF1 (HR 5.08, 95% CI 0.92-28.06, p=0.038) predicted for shorter LFS. By multivariate analysis combining the identified driver mutations with prognostic relevance and the MDA LR-PSS category, presence of MDA LR-PSS Category 3 (HR 5.98, 95%CI 1.28-28, p=0.023), RUNX1 mutation (HR 4.18, 95%CI 1.36-12.81, p=0.012) and STAG2 mutation (HR 3.7, 95%CI 1.02-13.47, p=0.047) retained there prognostic significance. Based on these results we designed a new model with scoring being based on HR for each given variable: MDA LR-PSS Category 3 2 points, RUNX1mut 1 point and STAG2mut 1 point. Patients were classified into three categories: Low, High or Very high with significantly different survival outcomes (Figure 1C). Based on this new model, patients with Category 2 MDA LR-PSS with either STAG2 or RUNX1 mutations had similar outcomes to those with Category 3 and no mutations (p=0.747). Patients with either Category 1 or Category 2 by MDA LR-PSS without STAG2 or RUNX1 mutations had similar OS (p=0.306) and represented the population with most favorable outcomes (p<0.001). Finally, patients with Category 3 with STAG2 or RUNX1 mutations had the worse outcomes in terms of survival (p<0.001).CONCLUSION: Similar to previous studies, our data suggests integration of mutation data into the MDA LR-PSS can improve our ability to predict outcomes of patients with lower-risk MDS. Mutations in STAG2 and RUNX1 can help identify a subset of patients with worse than expected outcomes as predicted by the MDA LR-PSS. [Display omitted] [Display omitted] DisclosuresJabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Daver:Otsuka: Consultancy, Honoraria; Kiromic: Research Funding; Ariad: Research Funding; BMS: Research Funding; Sunesis: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Kantarjian:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

Real-life use of erythropoiesis-stimulating agents in myelodysplastic syndromes: a “Gruppo Romano Mielodisplasie (GROM)” multicenter study

The Gruppo Romano Mielodisplasie (GROM) conducted a retrospective study in 543 patients with myelodysplastic syndromes (MDS) to evaluate the safety and efficacy of erythropoiesis-stimulating agents (ESAs) in "real-life" clinical practice. The 40.000-UI/week erythropoietin (EPO)-alpha and 30.000-UI/week EPO-beta starting dose were defined "standard," and 80,000UI/week EPO-alpha and 60.000UI/week EPO-beta were defined "high." Response was defined according to International Working Group (IWG) 2006 criteria. At ESA's start, median age was 74.2years (interquartile range (IR) 67.8-79.5) and median hemoglobin was 8.9g/dl (IR 8.2-9.6). Median time from diagnosis to ESAs start was 3.8months (IR 0.8-13.2). ESA starting dose was "standard" in 361 patients (66.5%) and "high" in 182 patients (33.5%). Erythroid response was observed in 82/185 (44.3%) transfusion dependent (TD) patients as compared with 226/329 (68.6%) transfusion independent (TI) ones (p < 0.001). At multivariate analysis, in TD patients, only endogenous EPO levels <50mU/l were significant (p = 0.046), whereas in TI patients, high-dose ESAs (p < 0.001), abnormal creatinine levels (0.009), and endogenous EPO levels <50mU/l (p = 0.014) were predictors of response. Responders showed a higher 5-year overall survival (OS) (57.8 vs. 32.2%, p < 0.001) and leukemia-free survival (76.0 vs. 49.8%, p < 0.001). At multivariable analysis for OS, response to ESA, low International Prognostic Scoring System (IPSS), no transfusion need, and female sex showed an independent favorable prognostic role. Our results confirm that treatment with ESAs is effective in a real-life MDS setting, particularly at high dose and in TI patients. Prospective studies are needed to define the optimal starting dose.

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).

Treatment of Patients With Myelodysplastic Syndrome With Lenalidomide in Clinical Routine in Austria.

Lenalidomide has demonstrated remarkable efficacy for therapy of lower-risk myelodysplastic syndromes (MDS) associated with 5q(-). The present evaluation aimed to describe the characteristics and outcomes of low-risk MDS patients treated with lenalidomide in Austria. For this retrospective, multicenter, observational analysis of MDS patients who received lenalidomide, data were collected at various hospitals in Austria over a period of 3 years. MDS classification, previous and current MDS therapies, and outcome and safety of lenalidomide were evaluated. Forty-six percent of the patients (n= 23) had a 5q(-) syndrome, while 12% (n= 6) exhibited 5q(-) plus additional aberrations or isolated 5q(-) but≥ 5% blasts in the bone marrow (10%, n= 5). The remaining 32% of patients (n= 16) had MDS with other World Health Organization classifications. Seventy percent belonged to lower International Prognostic Scoring System risk classes. Sixteen centers participated, involving a total of 50 patients. Most frequently used lenalidomide doses were 10 mg and 5 mg on days 1 to 21 of a 28-day cycle. Seventy-five percent of the patients received 11 months of treatment, with a median therapy period of 3.5 months; median follow-up was 3.9 months (range, 0-26 months). Response rate, defined as transfusion independence during the 2 months after lenalidomide therapy, was 64%. Median overall survival was not reached. Lenalidomide was well tolerated and is an effective and well-tolerated option for therapy of patients with 5q(-) syndrome but also lower-risk MDS patients with other World Health Organization classifications in clinical practice.

Non-hematologic predictors of mortality improve the prognostic value of the international prognostic scoring system for MDS in older adults.

The International Prognostic Scoring System (IPSS) is commonly used to predict survival and assign treatment for the myelodysplastic syndromes (MDS). We explored whether self-reported and readily available non-hematologic predictors of survival add independent prognostic information to the IPSS. Retrospective cohort study of consecutive MDS patients ≥age 65 who presented to Dana-Farber Cancer Institute between 2006 and 2011 and completed a baseline quality of life questionnaire. Questions corresponding to functional status and symptoms and extracted clinical-pathologic data from medical records. Kaplan-Meier and Cox proportional hazards models were used to estimate survival. One hundred fourteen patients consented and were available for analysis. Median age was 73 years, and the majority of patients were White, were male, and had a Charlson comorbidity score of <2. Few patients (24%) had an IPSS score consistent with lower-risk disease and the majority received chemotherapy. In addition to IPSS score and history of prior chemotherapy or radiation, significant univariate predictors of survival included low serum albumin, Charlson score, performance status, ability to take a long walk, and interference of physical symptoms in family life. The multivariate model that best predicted mortality included low serum albumin (HR=2.3; 95% CI: 1.06-5.14), therapy-related MDS (HR=2.1; 95% CI: 1.16-4.24), IPSS score (HR=1.7; 95% CI: 1.14-2.49), and ease taking a long walk (HR=0.44; 95% CI: 0.23-0.90). In this study of older adults with MDS, we found that low serum albumin and physical function added important prognostic information to the IPSS score. Self-reported physical function was more predictive than physician-assigned performance status.

Decision Analysis of Allogeneic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome Stratified According to the Revised International Prognostic Scoring System (IPSS-R)

Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms that range from indolent conditions to forms very close to acute leukemia (AML). The International Prognostic Scoring System (IPSS) is the benchmark for clinical decision-making. Recently, the International Working Group for Prognosis in MDS (IWG-PM) defined 5 new cytogenetic risk groups on a large cohort of patients representing the basis for the revised IPSS (IPSS-R) together with refined categories for marrow blasts and cytopenias (Blood. 2012;120:2454-65). IPSS-R categorization enables more accurate definition of the prognosis of MDS patients, in particular those in low or intermediate-1 IPSS risk groups. Despite recent progress, the only curative treatment for MDS remains allogeneic stem cell transplantation (allo-SCT), which however involves a non-negligible risk of mortality/morbidity. Allo-SCT is not considered in patients with very low IPSS-R risk, whose median survival is 9 years. Conversely, eligible patients with high or very high IPSS-R risk, whose survival is 1–2 years, should be offered immediate transplantation. Uncertainty exists about the optimal timing of allo-SCT in the low and intermediate IPSS-R risk groups, and to address this issue we performed an ad hoc decision analysis. We analyzed two cohorts of MDS patients (age 18-70 years): i) 477 patients diagnosed with MDS at the Policlinico S. Matteo, Pavia, Italy between 2000–2010, who mostly received best supportive care; ii) 488 patients who received allo-SCT in the same period reported to the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) registry. We adopted a continuous time multi-state Markov approach to model the natural history of the disease. Each IPSS-R risk group is represented by a state, and transition is allowed to the next state (to AML from very high risk) or to death. A transition intensity (i.e., instantaneous risk of moving to another state) is then estimated for each possible transition. Allo-SCT is modeled as a time-dependent covariate with 3 levels: i) no allo-SCT; ii) transplantation done no more than 3 months before; iii) transplantation done more than 3 months before. The effect of allo-SCT on survival was estimated by hazard ratios (HR) with respect to the no allo-SCT level. We examined two different policies: policy A) perform allo-SCT after t months since entering the low IPSS-R risk state or immediately in case of disease progression before the planned delay time t; policy B) perform allo-SCT after t months since entering the intermediate IPSS-R risk state or immediately in case of disease progression before the planned delay time t. For each policy, the expected survival of patients with different age at diagnosis was calculated. According to the model, a patient with a low IPSS-R risk is expected to spend 2.13 years in this risk group, and 2.39 years in the intermediate one. The cumulative incidence of progression from low to a higher IPSS-R risk was 27% at 3 years, while that of progression from intermediate to a higher risk was 39% at 3 years. Overall, expected survival times from diagnosis were higher under policy B vs policy A. Expected survival times were up to three years greater under policy B with respect to policy A for younger patients. When the waiting time before transplantation was progressively increased from 0 to 60 months, there was an increase in expected survival under policy A (in younger patients this increases by about two further years if transplant is delayed until 60 months in low IPSS-R risk state). Conversely, under policy B, delaying transplant further reduces expected survival, by up to about three years with a delay of 60 months after entering intermediate risk state or further progression to high risk state. In summary, this study suggests that a delayed transplantation strategy is advisable for patients with early disease, i.e. very low and low IPSS-R risk, whereas no further delay is advised for patients belonging to intermediate or higher risk categories. When indicated, setting the timing of intervention immediately after disease progression makes such a strategy easy to implement in the clinical practice. These results provide clinicians with a base of evidence to maximize the effectiveness of allo-SCT in MDS patients. DisclosuresNo relevant conflicts of interest to declare.

Next-Generation Sequencing Of ASXL1, TP53, RUNX1, EZH2, and ETV6 Identifies a Significant Proportion Of Lower-Risk Myelodysplastic Syndromes With Poor Prognostic Indicators

IntroductionManagement of patients with myelodysplastic syndrome (MDS) is dependent in part on risk stratification by the International Prognostic Scoring System (IPSS). Patients with lower-risk disease as defined by low and intermediate-1 IPSS are predicted to have a relatively indolent clinical course and are usually offered less aggressive therapies, including transfusions, growth factors, or observation without treatment. In contrast, patients with higher-risk disease as defined by intermediate-2 and high IPSS are predicted to have a relatively aggressive clinical course and are usually treated with disease-modifying hypomethylating agents or considered for stem cell transplantation. However, despite IPSS risk stratification a subset of patients with lower-risk MDS will have more aggressive disease with shorter overall survival and increased risk of transformation to acute myeloid leukemia. Somatic mutations are common in MDS, but are not currently included in either the IPSS or revised IPSS (IPSS-R). Recent literature (Bejar et al. N Engl J Med 2011;364:2496-2506) revealed that mutations in ASXL1, TP53, RUNX1, EZH2, and ETV6 are indicators of poor overall survival in patients with MDS independent of IPSS and other established risk factors, and that mutations in one or more of these 5 genes essentially up-scores the IPSS to the next highest risk group. The aim of this study is to evaluate the frequency of mutations in these 5 genes using a clinically validated and sensitive next-generation sequencing (NGS) assay, and to determine the percentage of lower-risk MDS patients with a worse than expected prognosis who may potentially benefit from earlier treatment with disease-modifying therapy. MethodsDNA sequences of key exons in ASXL1, TP53, RUNX1, EZH2, and ETV6 were determined from the bone marrow aspirates of 200 MDS patients (29% low, 52% intermediate-1, 18% intermediate-2, and 1% high IPSS) using a clinically validated and sensitive (5% limit of detection) NGS assay on the Illumina MiSeq platform. Mutations were compared between duplicate samples and annotated using software that queried databases containing known somatic mutations and germline variants. ResultsSomatic mutations in one or more of the 5 genes were detected in 50.5% of MDS patients in this study. Mutations in ASXL1 were the most frequent (29.5%), followed by mutations in TP53 (15.5%), RUNX1 (9.5%), EZH2 (7%), and ETV6 (7%). While mutant allele percentage varied among the genes, 64% of MDS patients with ETV6 mutations had <20% mutant allele, followed by 37% for ASXL1, 29% for TP53, 21% for RUNX1, and 7% for EZH2. Mutations were detected in 45% (46/102) of MDS patients with normal cytogenetics and 60% (37/92) with abnormal cytogenetics. When stratifying by IPSS, 46% of MDS patients with lower-risk disease had a mutation, compared with 72% with higher-risk disease. When stratifying by IPSS-R, 41% of MDS patients with lower-risk disease (very low and low) had a mutation, compared with 77.5% with higher-risk disease (high and very high). ConclusionsSomatic mutations in ASXL1, TP53, RUNX1, EZH2, and ETV6 have previously been shown to be indicators of poor overall survival in patients with MDS independent of IPSS and other established risk factors. Using a clinically validated and sensitive NGS assay, 50.5% of MDS patients in this study were shown to have a mutation in one or more of the 5 genes. This percentage is higher than previously reported by Bejar et al (31.2%), and is likely explained by the higher sensitivity of NGS (5% limit of detection) as compared to Sanger sequencing (typically 20% limit of detection), which was utilized in the aforementioned study for ASXL1, EZH2, and ETV6. Mutations in one or more of the 5 genes were detected in 46% of MDS patients with lower-risk disease defined by IPSS, and a similar 41% with lower-risk disease defined by IPSS-R. Mutational profiling using NGS can thus help identify a significant proportion of lower-risk MDS patients with a worse than expected prognosis who may potentially benefit from earlier treatment with disease-modifying therapy. Disclosures:No relevant conflicts of interest to declare.

Increased plasma thrombopoietin levels in patients with myelodysplastic syndrome: a reliable marker for a benign subset of bone marrow failure

Although myelodysplastic syndromes are heterogeneous disorders comprising a benign subset of bone marrow failure similar to aplastic anemia, no laboratory test has been established to distinguish it from bone marrow failures that can evolve into acute myeloid leukemia. Plasma thrombopoietin levels were measured in 120 patients who had myelodysplastic syndrome with thrombocytopenia (< 100 × 10(9)/L) to determine any correlation to markers associated with immune pathophysiology and outcome. Thrombopoietin levels were consistently low for patients with refractory anemia with excess of blasts, while patients with other myelodysplatic syndrome subsets had more variable results. Patients with thrombopoietin levels of 320 pg/mL and over had increased glycosylphosphatidylinositol-anchored protein-deficient blood cells (49.1% vs. 0%), were more likely to have a low International Prognostic Scoring System (IPSS) score (≤1.0, 100% vs. 65.5%), a higher response rate to immunosuppressive therapy (84.2% vs. 14.3%), and a better 5-year progression-free survival rate (94.1% vs. 63.6% for refractory cytopenia with unilineage dysplasia; 100.0% vs. 44.4% for refractory cytopenia with multilineage dysplasia). In conclusion, increased plasma thrombopoietin levels were associated with a favorable prognosis of bone marrow failure and could, therefore, represent a reliable marker for a benign subset of myelodysplastic syndrome.