International Prognostic Scoring System Int-2 Research Articles

Danazol Treatment for Thrombocytopenia in Myelodysplastic Syndromes: Can an "Old-fashioned" Drug be Effective?

Danazol Treatment for Thrombocytopenia in Myelodysplastic Syndromes: Can an "Old-fashioned" Drug be Effective?

Clinical Outcomes of Decitabine Treatment for Patients with Lower-Risk Myelodysplastic Syndrome By the International Prognostic Scoring System

IntroductionDecitabine has shown clinical benefits in patients with International Prognostic Scoring System (IPSS) intermediate (INT)-2 or high risk myelodysplastic syndrome (MDS), but the benefits have not been well defined in patients with lower-risk disease group (IPSS low or INT-1). Recently, it was proposed that the prognosis for patients with lower-risk disease is heterogeneous, with a substantial fraction of these patients having poor survival. Therefore, we classified IPSS lower-risk MDS patients using the Lower-Risk Prognostic Scoring System (LR-PSS) and then identified clinical outcomes after decitabine treatment in each subgroup.MethodsTwo observational studies (DIVA [NCT01041846] and DRAMA [NCT01400633]) on the effectiveness of decitabine treatment in patients with IPSS INT-1, 2, or high risk MDS were previously conducted. This analysis included patients with IPSS INT-1 risk disease from these two studies, and the patients were classified into one of the LR-PSS categories (category 1, 2, or 3) classifying patients by clinical variables such as cytogenetic, age, hemoglobin, platelet levels, and bone marrow blast percentage, so that patients with higher scores would be classified into higher risk categories. Patients in each LR-PSS category were divided by response or non-response to decitabine treatment. Overall response rate (ORR) included complete response (CR), partial response, marrow CR with or without hematologic improvement (HI), and stable disease with HI by the modified IWG 2006 response criteria. The overall survival (OS) in each subgroup was calculated and we analyzed differences in survival by response in each category group.ResultsA total of 130 patients were included in this analysis: 12 patients (9.2%) in LR-PSS category 1, 65 (50.0%) in category 2, and 53 (40.8%) in category 3. Patients in LR-PSS category 3 were older, predominantly male, and had more comorbidities. Overall refractory cytopenia with multilineage dysplasia (RCMD) was the most common WHO subtype (53/130, 40.8%), but there was a trend toward more patients with refractory anemia with excess of blasts (RAEB-1) in LR-PSS category 3. Transfusion dependency at baseline was more common in LR-PSS category 3. ORR was observed in 74 patients (56.9%) after decitabine treatment: there was no significant difference in ORR between the LR-PSS groups (category 1, 58.3%; category 2, 56.9%; and category 3, 56.6%, P = 0.9940). Unlike patients in category 1 or 2, those in category 3 showed a significant difference in OS between responders and non-responders (P = 0.0015). A higher platelet count at baseline (≥50 x 109/L) was a favorable predictor of ORR (odds ratio, 2.24; 95% confidence interval [CI], 1.03 to 4.84) and a patient with lower percentage of bone marrow blasts at baseline (<4%) showed significantly lower ORR (odds ratio, 0.26; 95% CI, 0.12 to 0.56). The presence of comorbidities was the only variable significantly associated with OS in Cox proportional hazards regression model (hazard ratio, 0.35; 95% CI, 0.129 to 0.922).ConclusionsDecitabine treatment was effective in patients with lower-risk disease and showed a survival benefit in patients with lower-risk MDS classified as LR-PSS category 3 who responded to treatment. DisclosuresNo relevant conflicts of interest to declare.

Impact of Transfusion Dependency on Health-Related Quality of Life Outcomes in Newly Diagnosed Patients with Myelodysplastic Syndromes (MDS). Analysis on 669 Patients By Disease Risk

Background:There is some evidence indicating that transfusion dependency negatively impact health-related quality of life HRQOL of patients with myelodysplastic syndromes (MDS). However, there is paucity of evidence-based on this relationship across all different disease risk-group categories.Aims:The primary objective of this study is to examine whether transfusion dependency has a different impact on HRQOL outcomes (ie. functional wellbeing and symptom burden) by disease risk according to the International Prognostic Scoring System (IPSS).Methods:Analysis is based on 669 newly diagnosed MDS patients enrolled in ongoing international prospective observational study. Patients with any IPSS risk score category were consecutively enrolled in 37 centers from nine countries. Patients were invited to participate during one of the first consultations, after confirmed diagnosis of MDS. Multidimensional HRQOL and fatigue outcomes were assessed at baseline (i.e., before treatment) with the well validated European Organization for Research and treatment of Cancer (EORTC) QLQ-C30 and the Functional Assessment of Chronic Illness Therapy (FACIT)Fatigue questionnaires. Patients were classified as transfusion dependent (TD) or transfusion independent (TI) using the following definition of “transfusion dependency”: having received at least one red blood cell transfusion every 8 weeks over a period of 4 months (Malcovati L, et al, J Clin Oncol . 2007; 25: 3503-10). We used proportions, means and medians to describe data, by risk and transfusion-dependence groups. Possible statistically significant differences between groups were assessed by Fisher and Wilcoxon-Mann-Whitney tests according to the type of variable. We also investigated possible clinically meaningful differences according to previously published guidelines.Results:Median age of the entire cohort (N=669) was of 77 years (range 18-96 years) and there were 418 men (62%) and 251 (38%) women. Of the entire cohort, 364 (54%) were classified as IPSS intermediate-2 or high-risk (higher risk disease: HRD) and 305 (46% as IPSS low or intermediate-1 (lower risk disease: LRD). There were: 44(14%) and 261(86%) patients respectively classified TD and TI in the LRD group, while in the HRD group there were 78(21%) and 286 (79%) patients respectively classified as TD and TI. Within LRD and HRD groups, there were no statistically significant differences in age, gender, comorbidity and education level between TD and TI patients. In addition, there were no statistically significant imbalances in the distribution of IPSS risk categories, respectively low and int-1 in LRD patients and int-2 and high-risk in HRD patients, between TD and TI groups. Within LRD, median hemoglobin (Hb) level was 10.2 g/dl and 8.9 g/dl for TI and TD patients and within HRD, median Hb level was 9.5 g/dl and 8.2 g/dl for TI and TD patients respectively. HRQOL profile of TD patients was generally worse than that of TI patients in both LRD and HRD. However, statistically and clinically meaningful differences in key symptoms of fatigue (P=.001, mean difference of 11.1) and pain (P=.002, mean difference of 8.4) were only noted between TD and TI patients within the HRD group. The trend of a fatigue was also confirmed by the FACIT Fatigue scale. Details on mean differences in selected HRQOL scales by disease risk groups (LRD versus HRD) are provided in Figure 1.Conclusion:This study suggests that impact of transfusion dependency on HRQOL can be different depending on disease risk at diagnosis with some major impact in fatigue and pain for HRD patients. This data might help physicians to provide more targeted interventions. [Display omitted] DisclosuresEfficace:Incyte: Consultancy; Seattle Genetics: Consultancy; TEVA: Consultancy, Research Funding; Lundbeck: Research Funding; Amgen: Consultancy, Research Funding. Gaidano:AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Breccia:TEVA: Speakers Bureau. Platzbecker:Acceleron: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

A Retrospective Real-World Study of the Current Treatment Pathways for Myelofibrosis in the UK (The REALISM UK Study)

Introduction Current treatment options for myelofibrosis (MF) are diverse; apart from rare patients who are eligible for allogeneic transplantation, active treatments are focused on controlling MF-related symptoms and are not disease modifying. Patients who are initially asymptomatic and those at low risk for progression are usually observed without active treatment (watch and wait) until the appearance of symptoms or progression. There are limited real-world data on the management of patients with MF in the United Kingdom (UK). The REALISM UK study documented the early management pathways for patients with MF in routine clinical practice. Method REALISM UK was a multi-centre, retrospective, non-interventional study in 15 UK secondary care centres. Eligible patients were those aged ≥18 years at diagnosis of MF, with diagnosis &gt;6 months and ≤5 years prior to data collection and with ≥1 follow-up visit. Data on patient demographics, clinical characteristics, MF management strategies and outcomes were collected from patients' medical records; the observation period was from the date of MF diagnosis until data collection. The primary endpoint was the time from diagnosis to active treatment. Watch and wait strategies included supportive therapies (blood transfusions, erythropoiesis-stimulating agents, and steroids). Results A total of 200 patients were recruited (63% [n=126/200] with primary MF (PMF); 37% [n=74/200] with secondary MF). The median age at MF diagnosis was 69.7 years (interquartile range [IQR] 63.5-75.7) and 71% (n=141/200) had a JAK2 mutation. At diagnosis, 52% (n=104/200) of patients had International Prognostic Scoring System (IPSS) categories of intermediate-2 (Int-2) or high. Common documented features of disease at diagnosis included an enlarged spleen (47%, n=94/200), anaemia (44%, n=88/200), and constitutional symptoms (e.g. night sweats, unexplained fever, or weight loss [30%, n=60/200]). The median (IQR) time to first active treatment was 46 days (range 0-350) in the total population; patients with higher risk disease were prescribed active treatment sooner: IPSS low, 136.5 days (range 0-625; n=26); IPSS Int-1, 90 days (range 0-494; n=70); IPSS Int-2, 0 days (range 0-252; n=65); IPSS high: 0 days (0-216; n=39). The choice of first management strategy by IPSS at diagnosis is shown in Table 1. During the study period, watch and wait was the first management strategy for 54% (n=107/200) of patients, with the median (IQR) time from diagnosis to active treatment in this group being 322 (130-610) days. Constitutional symptoms were recorded in 20% (n=21/107) of patients for whom watch and wait was the first management strategy. Active treatment was started at diagnosis for 47% (n=93/200) of patients, with the most commonly used medications being hydroxycarbamide (22.5% [n=45/200]) and ruxolitinib (17.5% [n=35/200]). The median (IQR) treatment duration during the study observation window was 346 days (range 121-768) for hydroxycarbamide and 375 days (range 172-691) for ruxolitinib. In total, 5.5% (n=11/200) of patients were recorded as having undergone allogenic stem cell transplantation during the observation period. Conclusion Clinicians in the UK apply a broad range of management strategies for the treatment of patients with MF. Many patients were observed without active treatment following diagnosis, despite having symptomatic disease. The most common active treatments as first management strategies were hydroxycarbamide and ruxolitinib. Disclosures Mead: Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; Bristol Myers-Squibb: Consultancy. Somervaille:Novartis: Consultancy, Honoraria. Butt:Novartis: Consultancy, Honoraria, Speakers Bureau. Whiteway:Novartis: Consultancy, Honoraria, Speakers Bureau. Kirkpatrick:Novartis: Consultancy, Honoraria. Roughley:Novartis: Consultancy, Honoraria. Ewing:Novartis: Honoraria, Other: Meeting attendance sponsorship ; Bristol Myers-Squibb: Other: Meeting attendance sponsorship . Garg:Novartis: Consultancy, Honoraria. Harrison:Promedior: Honoraria; Shire: Speakers Bureau; Sierra Oncology: Honoraria; Celgene: Honoraria, Speakers Bureau; Roche: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Incyte: Speakers Bureau; Gilead: Speakers Bureau; CTI: Speakers Bureau; AOP: Honoraria; Janssen: Speakers Bureau. Bains:Novartis: Employment. Chiu:Novartis: Employment. Hickey:OPEN VIE: Employment.

Clinical Outcomes of Decitabine Treatment for Patients With Lower-Risk Myelodysplastic Syndrome on the Basis of the International Prognostic Scoring System

IntroductionDecitabine has shown clinical benefits in patients with intermediate (INT)-2 or high-risk myelodysplastic syndrome (MDS), determined according to the International Prognostic Scoring System (IPSS), but the benefits have not been well demonstrated in patients with lower-risk (IPSS low or INT-1) disease. Recently, it was proposed that the prognosis for patients with IPSS lower-risk disease is heterogeneous, with a substantial proportion of these patients having poor survival. Patients and MethodsThis study included patients with IPSS lower-risk MDS from the DRAMA (An Observational Study for Dacogen Long-Term Treatment in Patients With Myelodysplastic Syndrome; NCT01400633) and DIVA (A Study for Dacogen Treatment in Patients With Myelodysplastic Syndrome; NCT01041846) studies, which were prospective observational studies on the efficacy and safety of decitabine treatment in patients with MDS. Using the Lower-Risk Prognostic Scoring System [LR-PSS], we classified IPSS lower-risk MDS. Patients in each LR-PSS category were divided according to overall response (OR) to decitabine treatment, and survival outcomes were compared. ResultsOne hundred sixteen patients were enrolled: LR-PSS category 1 (n = 12; 10.3%), category 2 (n = 56; 48.3%), and category 3 (n = 48; 41.4%). Survival outcomes differed among the 3 categories (P = .046). The overall survival according to OR showed a significant difference in total patients (P = .008) and category 3 patients (P = .003). We analyzed predictive factors for OR, but no variable was found to significantly affect OR. ConclusionDecitabine treatment showed a survival benefit in the higher-risk group of IPSS lower-risk MDS patients who responded to treatment, and classification using the LR-PSS category was helpful for this subgroup, indicating that decitabine treatment might alter the natural course of disease in these patients.

Factors Associated with Early Therapy Initiation in Patients (pts) with Myelodysplastic Syndromes (MDS) in the Connect® MDS/AML Disease Registry

Factors Associated with Early Therapy Initiation in Patients (pts) with Myelodysplastic Syndromes (MDS) in the Connect® MDS/AML Disease Registry

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.

Serum LDH Is Useful to Predict Prognosis for Intermediate-Risk Myelodysplastic Syndrome

International prognostic scoring system (IPSS) has been employed for prognosis assessment of myelodysplastic syndrome (MDS). However, clinical course of IPSS-intermediate-1 (Int1) MDS is heterogeneous. Despite the introduction of Revised-IPSS (IPSS-R), clinical course and prognosis of intermediate-risk MDS patients are still controversial. Identification of the patients with poor prognosis among intermediate-risk MDS would be helpful for making treatment decision.We retrospectively analyzed 139 patients (47 females and 92 males) who were diagnosed with MDS based on diagnostic bone marrow (BM) examination performed at our hospital. Median age at BM examination was 68 (18-88) years old. Patients were categorized as IPSS low (31), Int1 (74), Int2 (29) and high (5) (Figure 1). Based on IPSS-R, IPSS-Int1 MDS patients were subsequently divided into two groups: IPSS-RHigh (IPSS-R score ≥3.5; intermediate (28), high (7) and very high (2)) and IPSS-RLow (IPSS-R score ≤3; very low (1), low (36)). Median overall survival (OS) was significantly different (p = 0.006) between IPSS-RHigh (1154 days) and IPSS-RLow (not reached). AML-free survival was significantly longer in IPSS-RLow group (p=0.018).To extract poorer-prognostic population from IPSS-RHigh patients, we analyzed serumlactate dehydrogenase (LDH) level, which is often elevated in patients with hematologic malignancies. Serum LDH data at the initial diagnosis was available for 36 out of 37 IPSSInt1/IPSS-RHigh MDS patients.Patients with LDH ≥320 [U/L] (LDHHigh, n = 8) showed significantly shorter OS, compared with patients with LDH <320 [U/L] (n = 28) (median OS 347 and 1339 days, respectively; p=0.03). Between IPSSInt1/IPSS-RHigh/ LDHHigh (n=8) and IPSS-Int2 (n=29) groups, there was no significant difference regarding OS (p=0.41) (Figure 2) and AML-free survival (p=0.34). Median OS was 347 and 522 days; two-year cumulative incidence of AML was 0.42 and 0.25, respectively.Recent studies using next-generation sequencing revealed genomic profiling of MDS. To understand the mutational pattern of IPSS-Int1 MDS, targeted deep sequencing using next generation sequencer, Ion Proton (Life Technologies), was performed for 26 IPSS-Int1 MDS patients with available genomic DNA samples, following written informed consent. We examined mutations in 11 commonly-mutated genes, TET2, SF3B1, ASXL1, SRSF2, DNMT3A, RUNX1, U2AF1, ZRSR2, STAG2, TP53 and EZH2. In total, 12 gene mutations were observed; the average number of mutations per patient was 0.46. SF3B1 mutation was most frequent (n=6), followed by TP53, DNMT3A, EZH2 and RUNX1 mutations. A total of 6 SF3B1 mutations including K700E (n=4), K666T (n=1) and R625C (n=1) were detected in 5 patients; one patient harbored two different SF3B1 mutations (K700E and K666T). WHO criteria for 5 patients with SF3B1 mutation included 4 RCUD (refractory cytopenia of unilineage dysplasia) and 1 RCMD (refractory cytopenia with multilineage dysplasia). None of the patients with SF3B1 mutation died or progressed into AML during the observation, while AML progression rate was 24% among the patients without SF3B1 mutation.Although IPSS Int1 has been regarded as low-risk category, our results confirmed its heterogeneity. Sub-classification of IPSS-Int1 MDS patients using IPSS-R revealed that IPSS-RHigh patients showed shorter OS and AML-free survival compared with IPSS-RLow patients, however the prognosis among IPSSInt1/IPSS-RHigh patients was still heterogeneous. From IPSSInt1/IPSS-RHigh patients, serum LDH level successfully extracted higher-risk patients, whose prognosis was no better than that of IPSS-Int2 MDS patients.Mutational status has not been considered either in IPSS or in IPSS-R. Our result suggests that SF3B1 mutation indicates better prognosis without blast increase or AML progression. On the other hand, none of 26 IPSS-Int1 MDS patients harbored TET2 mutation, the most frequently mutated gene among MDS patients. TET2 mutation have been shown to often present with higher BM blasts percentage. In our analysis, only 4 out of 26 subjects presented BM blasts above 5%, which might explain the absence of TET2 mutation.Combination of IPSS-R and serum LDH is beneficial to extract patients with poorer prognosis from IPSS-Int1 MDS patients. In the near future, gene mutation profiles including SF3B1 can be a useful marker for risk stratification among heterogeneous IPSS-Int1 MDS patients. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Long-Term Outcome of Myelodysplastic Syndromes (MDS) Patients Treated with Erythropoiesis Stimulating Agents (ESAs)

Background: The majority of MDS patients (pts) have anemia and are treated initially with ESAs. Particularly for lower-risk MDS pts (International Prognostic Scoring System (IPSS) Low and Int-1), once ESAs are no longer effective, treatment options are limited to drugs commonly used for higher-risk MDS, such as hypomethylating agents, or off-label use of immunomodulatory drugs. As a result, most pts receive only transfusion support post-ESA, representing a pt group with an unmet medical need frequently targeted for drug development, for whom long-term outcome is unknown.Methods: We studied pts diagnosed with lower-risk MDS from 1997-2014 at MDS CRC institutions and treated with ESAs (epoetin alpha (epo) or darbepoetin (darb)). The best response to treatment was categorized per International Working Group 2006 response criteria (hematological improvement (HI), complete response (CR), or partial response (PR)). The primary endpoint was overall survival (OS) at the time of ESA failure, defined as cessation of treatment due to relapse or refractoriness; a secondary endpoint was time to AML transformation or death, from time of response (for responders) or failure (for nonresponders) determination. Descriptive statistics were used for baseline characteristics. The Kaplan Meier method was used to estimate OS and a log rank analysis was used to compare response categories. Cox regression analysis was performed for multivariable analysis.Results: Of 206 patients included in analyses, median age was 71.6 years (range: 25.3-88.1), 36% were female, 5% were African-American, and 11% had t-MDS. WHO categories included RA (14%), RARS (16%), RCMD (42%), MDS-u (6%), del (5q) (4%), RAEB-1 (9%), RAEB-2 (2%), RARS-T (2%), MDS/MPN-u (3%), and CMML-1 (2%), with pts classified as IPSS Low (39%), Int-1 (61%), or IPSS-R Very Low (16%), Low (55%), Intermediate (26%), and High (4%). IPSS cytogenetic risk groups were Good (72%), Intermediate (22%), and Poor (6%). Baseline median hemoglobin was 9.4 g/dl (range: 5.5-14.2), serum epo level was 97.2 (range: 14.2-3899.0), and 11% were transfusion-dependent. Treatment included darb (59%) and epo (41%) at median doses of 300 mcg (range: 100-500) and 40,000 units (range: 5,000-80,000), respectively. Pts remained on therapy for a median of 30.4 weeks (range: 0.0-447.7) and had a median follow-up of 28.4 months (95% confidence interval (CI): 24.5, 45.4). First treatments following ESA failure included azacitidine (41.7%), decitabine (10.2%), lenalidomide (16.6%), experimental drugs (3.1%), other growth factors (13.6%), ATG and/or other immunosuppressants (8%), chemotherapy (0.1%) , transplant (0.1%) and others (6.6%). The overall response rate (ORR) to ESAs was 18.8%, with 0% achieving CR; 0.1% PR; and 18.7% HI. Responses for epo were 17.3% and for darb were 19.8% (p=.67 for difference). For both ESAs, 81.2% of patients had disease refractory to treatment: 69.4% with stable disease and 12% with progressive disease with no significant differences between epo and darb by responder status. Median response duration for epo and darb were 21.9 weeks (range: 3.0 - 447.7) and 39.1 weeks (range: 0.0 - 350.7) respectively (p=0.045). Median survival from the date of diagnosis was 28.4 months (95% CI: 24.5, 45.4), and from ESA failure was 23.9 months (95% CI: 19.9, 33.0): 21.6 months (95% CI: 15.6, 39.2) for epo and 28.8 months (95% CI: 21.2, 39.7) for darb (p=0.99) (Figure). Median time to AML transformation or death was 17.4 Months (95% CI: 14.1, 22.9): 25.4 months for responders and 16.8 months for non-responders (p=.069). For patients who received ESAs for a minimum of 4 months (39% of pts for epo and 61% for darb), ORR was 16.5%, and median survival from ESA failure was 23.0 months (95% CI: 14.7, 33.0): 22.3 months (95% CI: 13.1, NA) for epo and 24.7 months (95% CI: 14.3, 39.7) for darb (p=0.87).Conclusion: In this large, but uncontrolled cohort, response rates were similar for lower-risk MDS patients treated with epo and darb, though duration was longer for darb. There was a trend for improved outcomes in patients who responded to ESAs. Lower-risk MDS patients treated with ESAs have an OS of less than 2 years from the time of failure, and can thus be considered a high-risk MDS group for whom subsequent therapies are not standardized, representing an unmet medical need. [Display omitted] DisclosuresSekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Komrokji:Incyte: Consultancy, Honoraria, Research Funding; Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Speakers Bureau.

Myelodysplastic syndromes

Myelodysplastic syndrome (MDS) encompasses a heterogeneous group of diseases originating in hematopoietic stem cells and is characterized by inefficient hematopoiesis and dysplastic changes in the bone marrow. In peripheral blood patients show anemia (mostly macrocytic), frequently accompanied by neutropenia and thrombocytopenia. Thus, clinically the patients suffer from fatigue (anemia), increased bleeding (thrombocytopenia) and infectious complications (neutropenia). Approximately one quarter of MDS patients develop acute myeloid leukemia (AML) in the course of the disease, which is characterized by a 20 % or more increase of blasts in the bone marrow. The estimated overall survival as well as the risk for AML transformation can be calculated with the international prognostic scoring system (IPSS) as well as the revised IPSS score (IPSS-R). Novel sequencing methods (e.g. next generation sequencing) allow the detection of recurrent gene mutations in MDS patients. Genes of the splicing machinery as well as genes involved in epigenetic regulation (e.g. ASXL1 and TET2) are most frequently mutated in MDS. Therapy is selected based on the patient risk profile (IPSS). Allogeneic stem cell transplantation is a curative approach for high risk patients (i.e. IPSS int-2 and higher) with a good performance status and a biological age below 70 years. Otherwise, high risk patients are treated with demethylating agents (e.g. decitabine and azacitidine). Low risk patients (IPSS low and int-1) mainly receive supportive therapy including iron chelation. An exceptional position is presented by MDS with an isolated 5q deletion as it can be treated with lenalidomide with good success. Enrolling patients in clinical trials is strongly recommended to improve the prospects of this disease.

Comparison of Risk Models for Patients with Lower Risk Myelodysplastic Syndromes

Accurate prognostication is essential for patients with myelodysplastic syndromes (MDS) to facilitate optimal patient management. Several systems for predicting the outcome of patients with MDS are commonly used in clinics, including the International Prognostic Scoring System (IPSS), revised IPSS, and a low risk MDS model developed by The University of Texas MD Anderson Cancer Center (MDA). We designed this study to evaluate and compare these three models in lower risk MDS patients in order to accurately identify patients with a poor prognosis who may need early therapeutic intervention.A total of 733 adult patients, median age 69 years (range, 24-91), who were diagnosed as lower risk MDS (IPSS low or intermediate-1) with complete cytogenetic evaluations at MDA were included in this study. Both IPSS and revised IPSS systems stratified the study cohort into groups with significantly different overall survival (OS) (P<0.001 in both). The MDA model further stratified patients into significantly different OS groups (P<0.001), and further stratified the revised IPSS low group (N=248, P<0.001) by OS, but not the very low or intermediate (INT) groups.Because both IPSS models are heavily weighted toward cytogenetic features, but over half of MDS patients present with normal (diploid) cytogenetics, we compared the effectiveness of these models in risk stratification among diploid MDS patients. Without the effects of cytogenetics, all 3 models still stratified OS significantly (P<0.001 for all). Revised IPSS further stratified IPSS low (N=171, P<0.001) and INT-1 (N=184, P=0.005) into significant different OS groups. The MDA model further stratified IPSS low (P=0.041) and INT-1 (p<0.001) into significant different OS groups. Multivariate analyses showed that age, bone marrow blast count, and hemoglobin and platelet levels were independent factors for survival in all MDS patients and in diploid MDS patients, whereas absolute neutrophil count was not significant for either group.Molecular markers hold promise for further risk stratification in diploid MDS patients. We assessed the prognostic significance of common gene mutations, such as NPM1, FLT3, DNMT3A, NRAS and KIT. We also identified a signature of plasma microRNAs of which expression levels can predict survival of diploid MDS patients more accurately than all three models.In summary, the revised IPSS system has improved the stratification of patients in the IPSS low and INT-1 categories. The MDA model improves the OS stratification in IPSS low and INT-1 groups, as well as the revised IPSS low group. All three systems effectively predict survivals in diploid MDS patients. Development of novel molecular markers will enable further risk stratification of MDS patients, especially in the diploid MDS group. [Display omitted] [Display omitted] DisclosuresKantarjian:ARIAD, Pfizer, Amgen: Research Funding. Cooper:InCellerate: Equity Ownership; Sangamo: Patents & Royalties; Targazyme: Consultancy; GE Healthcare: Consultancy; Ferring Pharmaceuticals: Consultancy; Fate Therapeutics: Consultancy; Janssen Pharma: Consultancy; BMS: Consultancy; Miltenyi: Honoraria.

Salvage induction chemotherapy after azacitdine treatment failure in patients who received azacitidine as a bridge to allogeneic stem cell transplantation

Salvage induction chemotherapy after azacitdine treatment failure in patients who received azacitidine as a bridge to allogeneic stem cell transplantation

A Phase II Clinical Trial Of Lenalidomide and Prednisone In Low and Intermediate-1 IPSS Risk, Non-Del (5q) MDS Patients

IntroductionAnemia remains the most common management challenge for patients (pts) with lower risk MDS (Low and int-1 International prognostic Scoring System (IPSS) groups). Lenalidomide (LEN) is the treatment of choice for lower risk MDS pts with chromosome 5 deletion (del5q) where 67% of pts on MDS-003 study became red blood cell transfusion independence (RBC-TI). The MDS-002 study reported 26% RBC TI rate in non-del5q MDS pts. Strategies to optimize LEN responses in non-del5q include identifying predictive biomarkers or combination strategies to potentiate erythropoietin receptor signaling.Dexamethasone increases the proliferation of immature erythroid progenitors and in vitro increases erythroid progenitor sensitivity to LEN by enhancing erythropoietin (EPO)-transcriptional response and colony forming capacity (BL Ebert, un-published data).We hypothesize that combination treatment with LEN and prednisone will yield a higher erythroid response rate in patients with non-del (5q) lower risk MDS compared to the historical clinical trial experience with LEN monotherapy (MT). MethodsThe study was an investigator initiated two- step phase II design. In the first step 25 eligible patients were to be registered. If fewer than 4 of these 25 achieved erythroid hematological response (HI-E), then the study will be terminated early with the conclusion that the regimen does not warrant further investigation. Key eligibility criteria included confirmed MDS diagnosis, low or int-1 IPSS, RBC transfusion-dependent anemia defined as having received ≥4 transfusions of RBCs for Hgb ≤ 9.0 g/dl within 56 days or symptomatic anemia (Hgb ≤ 9.0 g/dl), erythroid stimulating agents failure or endogenous serum epo > 500 mU/ml., absolute neutrophil count (ANC) ≥ 500 /mm≥, platelet count ≥ 50,000 /mm≥, and creatinine Clearance ≥ 30 mL/min. The planned dose of LEN for subjects with a baseline CrCl >60ml/min was 10 mg/day. Prednisone dose was 30 mg po daily cycle 1 tapered by 10 mg after each cycle to 5 mg po every other day for responders beyond cycle 6. The primary objective was best response (HI-E) by IWG 2006 criteria within 24 weeks. ResultsTwenty five pts were enrolled. Baseline characteristics are summarized in table-1. The HI-E rate was 20% (5/25), and 22% (5/23) of evaluable patients. All responders became RBC TI (5 out of 23). The median time to response was 57 days. The median duration of response was 80 days (95% CI 69-91). Three out of 5 responders did not have hypomethylating agent (HMA) while 14 out of 20 non-responders received prior HMA. No patient transformed to acute myeloid leukemia. At a median follow up of 25 months the median OS was not reached (2 deaths).The most common adverse events deemed related to study drug (>10% of pts) included, neutropenia 54%, thrombocytopenia 40%, anemia 32%, diarrhea 27%, myalgia 20%, edema 24%, rash 20%, infection 12%, fever 12%, and fatigue 12%. Grade III/IV events included anemia (n=8), neutropenia (n=4), thrombocytopenia (n=3), and Cerebrovascular event (n=1). The most common causes for study discontinuation were no response (10 pts), loss of response (4pts), infection (4pts) and rash (4pts).Table 1n=25Agemedian72GenderMale17 (68%)RaceWhite23 (92%)ECOG PS08 (32%)116 (64%)21 (4%)RBC TDYes23 (92%)WHORA3 (12%)RARS6 (24%)RCMD13 (52%)RAEB-I2 (8%)MDS-U1 (4%)IPSSLow15 (60%)Int-110 (40%)Revised IPSSVery low1 (4%)Low19 (76%)intermediate5 (20%)LR-MDPSS15 (20%)214 (56%)34 (16%)Prior TherapyAzacitidine16 (64%)Decitabine3 (12%)ESA19 (76%) ConclusionCombination treatment with LEN and prednisone did not yield a higher erythroid response rate in patients with non-del (5q) lower risk MDS compared to the historical LEN MT. HI-E rates are less in pts who received HMA compared to MDS-002 study. Toxicity profile was similar to LEN (MT). Disclosures:Komrokji:Celgene: Research Funding, Speakers Bureau. Off Label Use: use of lenalidomide in non del 5q. Lancet:Celgene: Research Funding. List:Celgene: Research Funding.

Comparing The Prognostic Value Of Risk Stratifying Models For Patients With Lower-Risk Myelodysplastic Syndromes (MDS): Is One Model Better? A Report on The Behalf of The MDS Clinical Research Consortium

BackgroundMDS are a spectrum of diseases commonly divided clinically into lower- and higher-risk subtypes to reflect underlying disease biology and to guide treatment. The International Prognostic Scoring System (IPSS), the most widely used tool for risk stratification is limited in its ability to identify poor prognosis lower-risk patients (pts). A prognostic scoring system specifically for lower-risk MDS pts (LR-PSS) was developed (Garcia-Manero Leukemia 2008) based on unfavorable (non-del(5q), non–diploid) cytogenetic, hemoglobin (hgb) <10g/dl, platelet count (plt) <50 k/uL or 50-200k/uL, bone marrow blast %≥4, and age ≥60 years. The newly revised IPSS (IPSS-R) also addressed some IPSS limitations. We examined the prognostic utility of IPSS, LR-PSS and the IPSS-R in a large cohort of lower-risk MDS pts, including those with secondary (s) MDS and chronic myelomonocytic leukemia (CMML) – both excluded from IPSS and IPSS-R - within the MDS Clinical Research Consortium. MethodsMDS pts with IPSS Score <1.5 were identified at Moffitt Cancer Center (MCC) or Cleveland Clinic (CC) from 2002-2012 and included if adequate data for analyses were available. Overall Survival (OS) was calculated from diagnosis. The Kaplan–Meier method was used to estimate median OS. Univariable analyses were performed using the log-rank test and adjusted for multiple comparisons; multivariable analyses used a Cox proportional hazards model. Harrell's c index and the Akaike information criteria (AIC) were used to assess the discriminatory power of the models and relative goodness of fit, respectively. ResultsThe analysis included 1196 MDS patients with IPSS scores <1.5. Comparing MCC (n=668) to CC (n=528), baseline characteristics were similar except plt <50k/uL: 16% vs. 22% (p=0.01); ANC <1.5 k/uL: 40% vs. 28% (p<0.0001); blasts <4%: 78% vs. 72% (p=0.02); sMDS: 11% vs. 6% (p=0.0024); and CMML: 2% vs. 10% (p<0.001 for WHO subgroup). R-IPSS cytogenetic groups were very good/ good/ int/ poor/ and very poor in 2/74/16/6/3 % at MCC and 2/63/19/7/10 % at CCF (p < 0.001). The median OS was 47 months (95% C.I. 44 - 52) and median follow-up of patients still alive was 62 months (range 2-326). LR-PSS and IPSS-R classifications for MCC and CCF Pts and OS are summarized in Table 1 and Figure 1. In univariable analyses, The IPSS, LR-PSS, and IPSS-R were all predictive of OS (p<0.0001 for all). Multivariable analyses confirmed the overall predictive abilities of the 3 prognostic tools adjusted for Hgb, plt, and age (p <0.0001). Compared to the IPSS-R, the LR-PSS had the higher (better) Harrell's c value (.66 vs. .60) and lower (better) AIC (5600 vs. 5605), and both were superior to the IPSS (.46 and 5609, respectively). [Display omitted] [Display omitted] The LR-PSS upstaged 302 pts (25%) from IPSS low or Int-1 to LR-PSS Category 3, and downstaged 104 pts (8.6%) from Int-1 to Category 1. The IPSS-R upstaged 449 pts (37%) from IPSS low or Int-1 to IPSS-R Categories ≥Intermediate, and downstaged 18 pts (1.5% ) from Int-1 to Very Low. ConclusionsThe LR-PSS and IPSS-R are superior tools for distinguishing outcome among pts previously thought to have lower-risk disease by the IPSS, including those with sMDS and CMML. Upstaged pts may benefit from earlier interventions with disease-modifying therapies, and should be considered in trials targeting higher-risk MDS pts. The LR-PSS appears to provide slightly better prognostic information. Disclosures:No relevant conflicts of interest to declare.

Validation Of The Revised International Prognostic Scoring System (IPSS-R) In 1000 Newly Diagnosed MDS Patients With Low- and Intermediate-1 Risk MDS In The European Leukemianet MDS (EUMDS) Registry

BackgroundThe EUMDS registry was initiated to provide an overview of the real-world demographics, diagnostics and disease-management of MDS. The first patient was registered in December 2007 and today 16 countries and 131 centers are participating. In 1997 the International Prognostic Scoring System (IPSS) was developed to predict clinical outcomes for patients with MDS and is still the most widely used prognostic scoring system. Recently, the IPSS has been revised (IPSS-R). ObjectiveTo validate the prognostic discrimination of the IPSS and IPSS-R in the first 1000 newly diagnosed lower risk MDS patients. ResultsThe median age of the population at diagnosis was 75 years (range 19-95). WHO 2001 classification was RCMD (35%), RARS (18%), RA (18%), RAEB-1 (12%), RCMD-RS (7%), 5q- syndrome (6%), MDS-U (3%) and RAEB-2 (0.4%). Within the first two years of follow-up 57% of the patients received MDS specific treatment: 48% received erythropoiesis stimulating agents (ESA), 11% granulocyte colony-stimulating factor (G-CSF), 51% received at least one red blood cell transfusion and 8% iron chelation therapy.IPSS risk score was Low in 49%, Intermediate-1 in 45% (0.5=32%, 1=13%) and unknown in 6% (no cytogenetic analysis) of the patients. IPSS-R risk score was Very Low in 25%, Low in 44%, Intermediate in 16%, High/Very high in 4% of the patients, and 10% unknown (Figure 1; Table 1). 77% of IPSS karyotypes were Good, 15% Intermediate, 1% Poor and unknown in 6%. 7% of the IPSS-R cytogenetic groups were Very good, 72% Good, 11% Intermediate, 1% were each Poor or Very poor and 8% unknown. [Display omitted] Overall survival (OS) and disease progression (DP) (high risk MDS/Leukaemia) were both evaluated. Median follow-up time was 2.1 years (range 0 - 4.9 years). The mortality rate in patients with IPSS Low was 23% and 38% among those with an Intermediate IPSS (HR 2.09, 95%CI: 1.64-2.66; Figure 2A). The mortality rate in patients according to the IPSS-R was Very Low (21%; HR 0.77, 95%CI: 0.55-1.07), Low (26%; HR 1), Intermediate (51%; HR 2.53, 95%CI: 1.90-3.38) and High/Very high (65%; HR 4.47, 95%CI: 2.94-6.78) (Figure 2B). [Display omitted] The prognostic discrimination of the scoring systems was assessed using the Akaike Information Criterion (AIC) from univariate proportional hazards models; the lower the AIC value the more informative the prognostic scoring system. The AIC of the IPSS and IPSS-R models were 3198.77 and 3154.48, respectively for OS and 1323.16 and 1274.19, respectively for DP (Table 1). A similar assessment of the components of the IPSS and IPSS-R scores revealed comparable fits to both OS and DP, regardless of which component was considered (Table 2).Table 2Prognostic impact of componentsOverall SurvivalDisease ProgressionAICAICIPSS:Blasts3212.451320.92Cytopenias3202.071339.59Cytogenetics3228.151351.85IPSS-R:Blasts3213.221309.27Hb3196.521343.63ANC3226.801347.98Platelets3210.031326.13Cytogenetics3220.581345.29 ConclusionIPSS and IPSS-R both predict OS and DP very well. IPSS-R was slightly superior in evaluating the clinical outcome, but it identified a subgroup (4.5% of all patients) of High and Very High-risk patients with a very poor prognosis, and another subgroup of good prognosis patients (IPSS-R Very Low) within the IPSS INT-1 cohort (13.6% of IPSS INT-1). Both scoring systems appear to be more strongly associated with predicting the risk of developing DP than OS. This observation may be due to the average high age at diagnosis of MDS reflecting the effect of competing causes of death associated with high age. Disclosures:Guerci-Bresler:Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria; Amgen: Honoraria.

Validation of the Lower Risk MD Anderson Prognostic Scoring System for Patients with Myelodysplastic Syndromes

AbstractAbstract ▪3826▪This icon denotes a clinically relevant abstract Background:The International Prognostic Scoring System (IPSS) is the most widely used clinical tool for risk stratification and tailoring treatment in myelodysplastic syndromes (MDS). Outcome of patients stratified as lower risk MDS by IPSS is variable, with a subset of patients experiencing inferior than expected outcomes. Identifying patients with higher risk disease behavior is indispensible for proper implantation of disease altering therapy. The Lower Risk MD Anderson Risk Model (LR-MDAS) is a recently proposed model provides prognostic refinement to identify such patients (Garcia-Manero et al, Leukemia 2008). To validate this model, we tested the new risk model in large external single institution cohort of patients. Methods:Data were collected retrospectively from the Moffitt Cancer Center (MCC) MDS database and chart review. The primary objective was to validate the new risk model when applied at time of initial presentation to MCC. The LR-MDAS was calculated as published using the sum of points generated from unfavorable (non-del(5q), non–diploid) cytogenetics, hemoglobin (hgb) <10g/dl, platelet count (plt) <50 k/uL or 50–200k/uL, bone marrow blast % >= 4, and age>= 60 years. Patients were divided into 3 prognostic categories. All analyses were conducted using SPSS version 15.0. (SPSS Inc, Chicago, IL). The Kaplan–Meier method was used to estimate median overall survival. Log rank test was used to compare Kaplan–Meier survival estimates between the groups. Cox regression was used for multivariable analysis. Results:Between January 2001 and December 2009, 479 patients with low or int-1 risk IPSS were captured by MCC MDS database. The median age was 69 years, MDS subtypes were coded as Refractory anemia (RA) 113 (24%), refractory anemia with ring sideroblasts (RARS) 73 (15%), MDS with del(5q) 19 (4%), refractory cytopenia with multi-lineage dysplasia (RCMD) 109 (23%), refractory anemia with excess blasts (RAEB) 147 (31%), and MDS-unclassified (U) 18 (4%). IPSS risk groups were low risk in 145 (30%), and intermediate-1 (int-1) 334 (70%). Only 31 patients (7%) had a poor risk karyotype by IPSS. Red blood cell transfusion dependence was documented in 42% (n=202), 22% had elevated serum ferritin ≥ 1000 ng/ml, and 45% (n=217) received azanucleoside treatment.Based on the LR-MDAS, 52 patients (11%) were category 1, 188 (39%) category 2, 232 (48%) category 3, and 7 (2%) were unknown. The median OS from time of referral to MCC for all patients was 32 months (95% CI 27–37 mo), Age, IPSS risk group, serum ferritin, and RBC transfusion dependence were all significant prognostic factors in univariate analysis. The median OS for the corresponding categories was, 1 - not reached (NR), 2– 50 mo (95%CI 33–68 mo), and 3 – 22 mo (95%CI 16–27 mo), from time of MCC referral, respectively. (Figure-1) (P < 0.005).Among 142 patients classified as low risk by IPSS, 25 patients (18%) were category 1 LR-MDAS, 81 (57%) category 2, and 36 (25%) category 3 with corresponding median OS of, NR, 62 month, and 35 month respectively (p=0.002). Among 330 patients risk stratified as int-1 IPSS group, 27 patients where category 1 LR-MDAS, 107 category 2, and 196 category 3 where median OS was NR, 28 months and 20 months, respectively. (p< 0.001) (Figure-2).When we applied IPSS risk stratification among each category of LR-MDAS to assess if IPSS can further refine prognosis within LR-MDAS categories, only in patients classified as Category 2 LR-MDAS the median OS was different among low and int-1 risk IPSS (62 month versus 28 month). (p <0.005).The rate of AML transformation according to LR-MDAS was 4%, 12%, and 20% for category 1,2, and 3, respectively. (p<0.02). In Cox regression analysis higher risk LR-MDAS predicted inferior OS (Hazard ratio (HR) 1.8 (95%CI 1.4–2.3) (p <0.005) independent of IPSS risk group (HR 2 95%CI 1.4–2.8) (p <0.005). Conclusion:Our data validates the prognostic value of the proposed LR-MDAS risk model, demonstrating predictive power for overall survival and AML transformation among low/int-1 risk IPSS. The LR-MDAS is complementary to the IPSS, offering further discrimination to identifying those patients with aggressive disease behavior that merit disease altering therapy. The utility of the model as treatment decision tool should be studied prospectively. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Efficacy and Safety of Eltrombopag for the Treatment of Thrombocytopenia of Low and Intermediate-1 IPSS Risk Myelodysplastic Syndromes: Interim Analysis of a Prospective, Randomized, Single-Blind, Placebo-Controlled Trial (EQoL-MDS)

AbstractAbstract 923 Introduction:The increased risk of bleeding in myelodysplastic syndromes (MDS) is due to low platelet (PLT) counts and abnormalities of PLT morphology and function. Severe thrombocytopenia occurs in about 10% of low and Int-1 International Prognostic Scoring System (IPSS) risk MDS patients in whom PLT transfusions are indicated mainly in the presence of bleeding. Short therapeutic effect and the development of refractoriness to PLT transfusions motivate research in novel treatments. Eltrombopag is an oral, non peptide, non-competitive agonist of the thrombopoetin-receptor (TPOR) which interacts selectively with the TPOR transmembrane domain to initiate TPO signaling. Eltrombopag is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura. Its potential in increasing PLT count in lower risk MDS has not been evaluated. Study Design and Methods:We present preliminary results of a Phase II, multicentre, prospective, placebo-controlled, single blind study to evaluate the safety and efficacy of eltrombopag in low and intermediate-1 risk adult MDS patients with PLT count <30 Gi/L. Patients are included if: ECOG performance status < 4; ineligible for or relapsed or refractory to other treatments; and naive to TPO-R agonists. Secondary endpoints include differences in: changes in quality of life (QoL) scores by EORTC QLQ-C30 and QOL-E v. 3 questionnaires, frequency of PLT transfusions, incidence and severity of bleeding, and overall and leukemia-free survival. Eltrombopag or placebo (2:1 ratio) is administered to 69 patients at a 50 mg daily initial dose with 50 mg increases every 2 weeks to a target PLT count of 100 Gi/L. Dose interruptions or reductions are required for PLT >200 Gi/L or adverse events. PLT response is defined as Response (R) if: 1) baseline > 20 Gi/L: absence of bleeding and absolute increase in PLT ≥ 30 Gi/L/mm3; 2) baseline < 20 Gi/L: PLT <20 Gi/L and increase by at least 100%, not due to PLT transfusion; and Complete Response (CR) if PLT count ≥ 100 Gi/L and absence of bleeding. Bone marrow (BM) aspirate smears, cytogenetics and peripheral blood (PB) smears are performed throughout the study and blinded centralized morphology review is performed. Results:Seventeen patients (10 on active drug – Arm A) of mean age 64, SD 12, years are randomized and 2 are in screening at the time of the present report. Baseline mean PLT count was 14, SD 8, Gi/L. Three cases had significant bleeding (2 in Arm A, and 1 in Arm B) and 2 patients in each arm required PLT transfusions during screening. After a mean follow up of 6 months, 5 cases on the eltrombopag arm have obtained a CR (1 at day 8, 3 at day 15 with 50 mg dosing, and 1 at day 54 with 100 mg dosing) and one case is in R at 8 weeks follow-up; amongst non-responders, two have reached a 300 mg dose, the remaining are ongoing at a 100 and 150 mg dose, respectively. In Arm B, there was one case with an unstable R. In Arm A, PLT count increased by mean 68 SD 76 Gi/L (p=0.010) after 4 weeks and 114 SD 110 Gi/L (p=0.021) after 8 weeks, versus no significant change in Arm B. Furthermore, after 2 months, no bleeding occurred in Arm A (N=9) versus 3 cases with bleeding in Arm B (N=6). In fact, no PLT transfusions were required in Arm A, while 3 patients were transfused at 2 months in Arm B. At baseline, patients presented poor QoL scores. Overall, of the 9 patients in arm A reaching a 3-month follow-up, there were significant improvements in functional QoL, from baseline median score 33 (IQR 22–67) to 78 (IQR 31–92, p=0.047) and treatment-related scores from median 51 (IQR 35–66) to 74 (IQR 35–82, p=0.029). Grade III-IV adverse events (worsening of pre-existing arthritis; acute febrile enteritis) occurred in only 2 patients in Arm A, all unrelated to eltrombopag. Progressions have not been observed in Arm A, versus 1 progression in Arm B. No deaths have occurred at the time of the present analysis. Conclusions:Preliminary results suggest safety of eltrombopag in terms of drug-related adverse events and disease progression in MDS patients with low and Intermediate-1 risk IPSS and thrombocytopenia. In such patients, eltrombopag treatment is effective in raising PLT counts and in reducing the risk of bleeding and is associated with significant improvements in QoL. Disclosures:Off Label Use: Eltrombopag is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) .

Prognostic Impact of Mutations in a Large Series of Patients with Myelofibrosis

AbstractAbstract ▪431▪This icon denotes a clinically relevant abstract Background.Primary myelofibrosis (PMF) has the worst prognosis among myeloproliferative neoplasms with median overall survival (OS) of 4.6y in the International Prognostic Scoring System (IPSS) series (Cervantes F, Blood 2009;113:2895) and 6.5y in patients (pts) seen more recently (Cervantes F, JCO, 2012 in press). OS is predicted by the four risk categories of IPSS, dynamic-IPSS and IPSS-plus system, and these scores are used for therapeutic choices particularly allogeneic stem cell transplantation. Nevertheless, pts heterogeneity still remains within these categories, necessitating improved risk stratification. A number of molecular abnormalities have been reported in PMF pts, but their prognostic relevance is incompletely understood, particularly with regard to transformation to leukemia (AL). The aim of this work was to analyze the prognostic impact of known mutations detected close to diagnosis in an international series of 429 pts. Patients and methods.PMF diagnosis had to satisfy the 2008 WHO criteria. Mutations in JAK2V617F, MPLW515, EZH2, ASXL1, TET2, IDH1/2, DNMT3A, CBL, SRSF2 were genotyped in whole blood or granulocytes using allele specific RTQ-PCR, HRM and direct sequencing; all mutations were confirmed at least twice. Missense, nonsense and frameshift mutations were considered; in case of novel mutations, SNPs were excluded by database searching and when feasible by germline DNA genotyping. The prognostic value of the molecular variables with regard to overall survival (OS) was analyzed by Cox regression and adjusted for the IPSS category. The association of molecular features with the risk of progression to AL was investigated in the framework of competing risks by the Fine & Gray regression method. Replicability of the prognostic models for both OS and progression to AL was assessed by replication in 1000 bootstrap samples randomly taken from the original series. Results.Patient median age was 60y. Median follow-up was 3.7y (95% CI, 0.02–27.9), death occurred in 157 pts (32%). Frequency of pts with constitutional symptoms was 28%, splenomegaly 74%, anemia 27%, leukocytosis 8%, >1% blasts 16%, thrombocytopenia 12%. Abnormal karyotype was found in 24% (of 229 evaluated). IPSS risk category: low-risk 35%, Int-1 30%, Int-2 21%, High-risk 14%. Frequency of mutations was: JAK2V617F 59.8% with 49% of pts having <25% allele burden; MPLW515 14%; EZH2 5%; ASXL1 21.3%; TET2 9.5%; IDH1-2 2.4%; DNMT3A 5.6%; CBL 4.3%; SRSF2 8.4%. Survival Model.Median survival was 9.7y (CI, 7.9–12.2), 22y in low-risk, 10y Int-1, 6.2y Int-2, 2.5y high-risk (P<0.0001). We found a strong association between IPSS risk categories and ASXL1 and SRSF2 mutated cases that clustered in the high-risk category (41.5% and 25.4%, respectively, P<0.001). ASXL1 mutations were associated with leukocytosis, blasts and constitutional symptoms; mutations in SRSF2 with older age, leukocytosis and symptoms. No other relevant associations between IPSS and molecular parameters was found. In the final prognostic model, only mutations in ASXL1 (Hazard ratio, HR:2.02; P<0.001) were found to add to IPSS (HR: 2.40; P<0.001) with regards to OS independently of the association of ASXL1 mutations and high-risk category. Within the Int-2/high-risk category, ASXL1 mutations were associated with significantly shorter survival (median survival 2.6 years months for mutated versus 5.8 years for unmutated; P=0.0004). According to bootstrap analysis, ASXL1 mutations were selected as significant predictor for OS in 74.6% of the samples.Leukemia Model. AL occurred in 75 pts (15.2%) after of a median of 3.8y (95%, 0.04–26.5) from diagnosis. Mutations in ASXL1 and IDH1/2 were the only molecular variables associated with higher risk of AL with a SHR of 2.33 (P<0.001) and 3.63 (P=0.008), respectively. Bootstrap validation approach resulted in ASXL1 and IDH1/2 mutations being significant predictors for AL in 60% and 54% of the samples, respectively. Conclusions.In this comprehensive series of mutations profiled in PMF pts, mutations in ASXL1 emerged as a powerful prognostic variable for survival refining prognosis in the Int-2/high risk IPSS categories. ASXL1 and IDH1/2 mutations predicted for death due to AL. Therefore, genotyping for ASXL1 and IDH1-2 mutations at diagnosis may help to tailor therapy for pts with IPSS Int-2/high risk PMF. Disclosures:No relevant conflicts of interest to declare.

Comparison of IPSS and IPSS-R Scoring in a Population Based Myelodysplastic Syndromes (MDS) Study

AbstractAbstract 3841 Introduction:The International Prognostic Scoring System (IPSS) has recently been revised (IPSS-R) to capture more inclusive cytogenetic characterization, more stringent blast description, and more detailed cytopenia assignments. To validate the IPSS-R in a prospective cohort of patients, we compared IPSS and IPSS-R categorization within a group of newly diagnosed MDS patients in a prospective population-based epidemiologic study in Minnesota. Methods:We identified all newly diagnosed MDS cases in Minnesota between the ages of 20 and 85 years from April 1, 2010 to April 2012. Our process includes rapid case identification by the Minnesota Cancer Surveillance System (MCSS), patient contact and enrollment, central medical review including: 1) independent review by two hematopathologists to confirm diagnosis and WHO subclassification; 2) independent cytogeneticist's review for classification as defined by IPSS and IPSS-R; and 3) medical chart review with prospective calculation of IPSS, IPSS-R, and WPSS by a an oncologist. Results:Classification of the 128 patients by IPSS versus IPSS-R is shown (Table)IPSS-R dxTotalVery LowLowIntermediateHighVery HighIPSS dxLow161910036INT-1410138035INT-2008172550High000077Total2029222532128Kendall's Tau = 0.77In this comparative classification, IPSS-R scoring refined the MDS prognostic risk groups. Low IPSS remained low risk in the IPSS-R spanning the Very Low and Low groups, while all high risk IPSS remained in the Very High risk group in the IPSS-R. However, those in the INT-1 and INT-2 IPSS categories were inconsistently reclassified in the IPSS-R. INT-1 IPSS spanned from Very Low to High and INT-2 IPSS spanned from Intermediate to Very High in the IPSS-R. While reclassification of this prospective cohort resembles results in the IPSS-R reports, ongoing follow-up will be needed to determine if the survival and AML progression measures are reproducible. Conclusion:Until molecular data are available to refine future prognostic scoring systems, the IPSS-R enhances our prognostic risk stratification abilities and is applicable to the general MDS population. As treatment decisions are based on this initial prognostic risk assessment, the more diverse differentiation of risk within the IPSS-R will directly refine prognosis and impact decisions on therapy. Disclosures:Miller:Celgene: Membership on an entity's Board of Directors or advisory committees; Coronado Bioscience: Membership on an entity's Board of Directors or advisory committees.

Validating the Lower-Risk MD Anderson Prognostic Scoring System (LR-PSS) and the Revised International Prognostic Scoring System (IPSS-R) for Patients with Myelodysplastic Syndromes

Abstract 1720 Background:The myelodysplastic syndromes are commonly divided into lower- and higher-risk subtypes depending on blast percentage and International Prognostic Scoring System (IPSS) score (0–1.0, low or Int-1, median overall survival (OS) 3.5–5.7 years). Because the IPSS is limited in its ability to identify poor prognosis lower-risk patients (pts), a prognostic scoring system specifically for lower-risk MDS pts (LR-PSS) was developed (Garcia-Manero Leukemia 2008) at MD Anderson (MDA), based on unfavorable (non-del(5q), non–diploid) cytogenetics, hemoglobin (hgb) <10g/dl, platelet count (plt) <50 k/uL or 50–200k/uL, bone marrow blast %≥4, and age ≥60 years. The IPSS-R (Greenberg Leuk Res 2011) improves upon the IPSS using novel cytogenetics classifications (Schanz EHA 2010) and a neutrophil cut-off of 800 k/uL. We validated the LR-PSS and the IPSS-R in a separate cohort of lower-risk MDS patients seen at Cleveland Clinic (CC) or at MDA not included in LR-PSS development. Methods:Of 1293 MDS patients identified at CC or MDA from 1991–2010, 664 had lower-risk disease and adequate data for analyses. OS was calculated from first date seen at either institution. The Kaplan–Meier method was used to estimate median OS. Univariable analyses were performed using the log-rank test; multivariable analyses used a Cox proportional hazards model stratified by treatment center. Harrell’s c index and the Akaike information criteria (AIC) were used to assess the discriminatory power of the models and relative goodness of fit, respectively. Results:Comparing CC to MDA, baseline values were similar except median age: 70 vs. 67 years (p=.02); time since diagnosis: 2.7 vs. 1.1 months (p<.0001); hgb <10: 51% vs. 43% (p=.05); plt <50k/uL: 30 vs. 24% (p=.06); ANC <1.5 k/uL: 27% vs. 36% (p=.01); blasts <4%: 75% vs. 65% (p=.003); WHO classification RA/RARS/RCMD/CMML: 11/15/26/12% vs. 16/9/45/0% (p<.0001). Cytogenetics were diploid: 61% vs. 66%; del(5q): 9% vs. 2%; del(20q): 3% vs. 5%; -Y: 4% vs. 2%, respectively (p=.5). Median OS was 36.8 months (95% C.I. 33–45) and median follow-up of patients still alive was 13.9 months (range 0.01–155). LR-PSS and IPSS-R classifications for CC and MDA Pts and OS are in Table 1 and Figure 1. In univariable analyses, The IPSS, LR-PSS, and IPSS-R were all predictive of OS (p=.002, <.0001, and <.0001, respectively). Multivariable analyses confirmed the overall predictive abilities of the prognostic tools and of Hgb, plt, age, and IPSS/IPSS-R cytogenetics (all p≤.03). Compared to the IPSS-R, the LR-PSS had the higher (better) Harrell’s c value (.64 vs.63) and lower (better) AIC (2518 vs. 2525). The LR-PSS upstaged 156 pts (25%) from IPSS low or Int-1 to LR-PSS Category 3, and downstaged 47 pts (12%) from Int-1 to Category 1. The IPSS-R upstaged 164 pts (27%) from IPSS low or Int-1 to IPSS-R Categories ≥Intermediate, and downstaged 5 pts (1%) from Int-1 to Very Good.Table 1:LR-PSS and IPSS-R Survival EstimatesLR-PSS Category:CC n = 292(%)MDA n = 372(%)Median Survival in Months, MDA 2008 (%)Median Survival in Months, CC + MDA (%)152 (21)79 (21)80.3 (21)91.4 (21)2139 (57)190 (51)26.6 (48)35.6 (53)353 (22)103 (28)14.2 (31)22.0 (25)IPSS-R Category:Median Survival in Months, IPSS-RVery Good48 (20)64 (17)81.691.4 (18)Good135 (56)202 (55)51.635.9 (55)Intermediate47 (19)79 (21)27.627.8 (27)*High11 (5)20 (5)18Very High2 (1)5 (1)10.8*(Combined Intermediate + Good + Very Good) [Display omitted] Conclusions:The LR-PSS and IPSS-R are valid tools for distinguishing among pts previously thought to have lower-risk disease by the IPSS, and identifying those who have better and worse survival. This latter group of pts may benefit from earlier interventions with disease-modifying therapies, and should be considered in trials targeting higher-risk MDS pts. The LR-PSS appears to provide slightly better prognostic information. Disclosures:Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau. Maciejewski:Celgene: Membership on an entity's Board of Directors or advisory committees.