Transfusion-dependent Myelodysplastic Syndromes Patients Research Articles

New therapy options for myelodysplastic syndrome—all for all or targeted?

SummaryThe OeGHO-Frühjahrstagung 2024 took place in Vienna. Thereby one session was dedicated specifically to the field of myelodysplastic syndrome (MDS). Just a few days before the meeting, the European Medicines Agency approved luspatercept for transfusion-dependent low-risk MDS patients in the first line. It was therefore more current than ever to discuss the future significance of this therapy for our patients in the low-risk field. In addition, there are other new substances in the pipeline; some of which already have mature phase III data (e.g., imetelstat), which have already led to the approval by the US Food and Drug Administration.

Combination Therapy with Luspatercept and the Ferroportin Inhibitor Vamifeport Is Superior to Either Drug Alone in Improving Anemia and Reducing Myeloid Skewing in MDS

Background: Patients with myelodysplastic syndromes (MDS) are prone to develop iron overload as a consequence of ineffective erythropoiesis and chronic transfusion therapy. Although iron overload is a common feature in MDS, it has remained unclear whether and how iron excess is detrimental for MDS pathophysiology. Recently, we have shown that iron restriction by the oral ferroportin (FPN) inhibitor vamifeport improves anemia and reduces myeloid skewing, being of benefit for MDS as single treatment. Luspatercept is a recombinant fusion protein acting as TGF-β superfamily ligands trap which has recently gained FDA approval for the treatment of anemia in transfusion-dependent low-risk MDS patients. Luspatercept promotes erythropoietin (EPO)-independent maturation of late-stage erythroid cells, resulting in increased hemoglobin and red blood cells (RBCs) count. However, this drug - due to a lack of improvement in myeloid skewing and AML evolution - is considered a non-disease-modifying therapy. Aims: In this study we investigated the effect of a combined therapy using luspatercept and the FPN inhibitor vamifeport in a preclinical MDS mouse model, with the hypothesis that both drugs could have additive effects with further benefit for the disease. Methods: To this end, we administered the FPN inhibitor vamifeport in NUP98-HOXD13 MDS mice for 3 months (0.5 mg/ml into drinking water), combined with luspatercept for the last 2 months (5 mg/kg twice a week, subcutaneous injection), starting at 3 months of age. Mice receiving the combined treatment were compared to those untreated or receiving single treatments. Results: At steady-state MDS mice develop anemia, neutropenia and lymphopenia, together with an iron overload phenotype, hallmarked by inappropriately low hepcidin levels, elevated serum iron and transferrin saturation, non-transferrin-bound iron (NTBI) formation and tissue iron deposition. Vamifeport administration in MDS mice reduced serum iron and NTBI formation and prevented tissue iron loading, either as a single or combined treatment with luspatercept. Luspatercept and vamifeport, as single-agent treatment, ameliorated anemia and the maturation of bone marrow and splenic RBCs in MDS mice. The combined therapy further improved anemia compared to the treatments with either drugs alone, as suggested by the higher hemoglobin levels, hematocrit and RBC count, and the decreased number of early erythroid precursors, sign of more effective erythropoiesis. Importantly, vamifeport, but not luspatercept, significantly altered myeloid skewing in MDS, revealing a major role of the iron status in myeloid expansion. Myeloid bias, monitored as percentage of CD11b + Gr1 + myeloid cells in the bone marrow was attenuated by iron restriction in vamifeport-treated MDS mice compared to control and luspatercept-treated MDS animals. The combined treatment merkedly reduced myeloid skewing in MDS mice, similarly to the single vamifeport treatment. Furthermore, the number of immature cKit + myeloid blasts in the peripheral blood of MDS animals were decreased by vamifeport alone and in combination with luspatercept, but not by luspatercept alone. Finally, splenomegaly was reduced in MDS mice treated with vamifeport alone or in combination with luspatercept, confirming that iron restriction improves ineffective erythropoiesis and limits myeloid skewing. Overall, the combination therapy with vamifeport and luspatercept showed superior effects in improving anemia and myeloid bias as compared to single treatments. Conclusion: In conclusion, our results show that iron restriction by vamifeport enhances the erythroid maturation action of luspatercept, likely by improving iron utilization in erythroid cells and ameliorating their survival. Furthermore, vamifeport improves the myeloid skewing in the MDS model, suggesting disease-modifying activity as single agent as well as combined therapy with luspatercept. Together, these data prove that combo therapies aimed at restricting iron and boosting erythroid maturation may offer additive beneficial effects in MDS and provide pre-clinical evidence for combining iron restriction and TFG-β superfamily ligand-trap approaches as more effective therapeutic strategies for the treatment of MDS.

Impact of iron overload on poor graft function after allo-HSCT in a patient with transfusion-dependent low-risk MDS: A case report and literature review.

Poor graft function (PGF) occurs in 5% to 27% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with high life-threatening complications. The etiology of PGF is complex and multifactorial, and iron overload (IOL) is considered as a predictive factor. A 45-years-old woman who was diagnosed as low-risk myelodysplastic syndrome in 2012 has been transfusion dependent and developed severe IOL. Due to transfusion dependency and also ineffective erythropoiesis, this patient was diagnosed as IOL and developed PGF after allo-HSCT. Deferasirox (20mg/kg/d) was administered regularly after allo-HSCT for 2 years. Hematopoiesis was gradually recovered during iron chelation therapy treatment after allo-HSCT and PGF was reverted. IOL, as a prognostic factor for PGF, is a common problem in Transfusion dependent myelodysplastic syndrome patients undergoing HSCT. IOL issues should be considered at the time of diagnosis and throughout the treatment course for patients who are potential candidates for HSCT.

Lessons from the European and Israel National MDS Registry

On behalf of the Israeli MDS working group and EUMDS Registry/ XIII Eurasian Hematology Oncology Congress (EHOC) 2022. The myelodysplastic syndromes (MDS) are a group of clonal stem cell diseases with cytopenias and a tendency to transform to leukemia. Despite the progress, there is still lack of real world data about the disease. In 2008, top European experts launched the EUMDS Registry. In this project, including 19 countries and 150 sites, epidemiological, clinical and lab data on newly diagnosed MDS patients, are collected and analyzed. As of today, 3300 patients have been recruited. In 2012, the Israel MDS group joined the project. We have contributed data on 360 patients, # 4 in the contributors. This project led to more than 100 abstracts in international meetings and 40 publications in first line journals. We will mention some of these studies. de Swart et al. summarized data on the first 1000 patients, validated the IPSS-R prognostic classification, showing its superiority on IPSS (de Swart L. BJH 2015). Another study, focusing on Quality of life (QoL) of LR-MDS patients revealed that these patients suffer from depression, anxiety, pain, discomfort and mobility difficulties, compared to controls (Stauder R, Leukemia 2018) The effects of Erythroid Stimulating Agents (ESAs,) was evaluated: Garelius et al. showed that ESA administration delays RBC transfusion dependency (Garelius HK. J Intern Med 2017). Since in most countries ESA is given to transfusion-dependent MDS patients, it might change the paradigm. Recently, we demonstrated that ESA treatment, is associated with improved outcomes and overall survival (Garelius HK. EHA 2022; submitted). Since prognostic factors are often determined at disease presentation, it was important to develop dynamic parameters. We showed that a rapid decline > 25% in the platelet count within 6 months is an adverse prognostic marker (Itzykson R. Bl Adv 2018) A study focusing on the mutational status was presented at ASH 2021 showing that LR-MDS patients can be grouped into 3 clusters, with a correlation to the clinical status (Malcovati L. ASH 2021) The Israeli group, independently and as a part of the EUMDS, was involved in several projects. Oster et al. suggested a non-invasive calculator to assess the probability of or excluding MDS diagnosis, based on patient characteristics, avoiding BM examination (Oster HS. Bl Adv 2021). We also investigated the correlation between Hb level and QoL. This correlation was found to be partial, and the decrease in QoL was not linear. This suggests that other factors other than Hb might play a role in determining QoL (Haring Y. ASH 2021). We recently presented data on lymphoid aggregates in BM biopsies, suggesting a possible association with poor prognosis (Book-Rabinowitz. Int MDS Symposium, Toronto 2021; submitted). In summary , the EUMDS registry is a platform of a scientific project, and an example of international collaboration. Such projects, especially in relatively uncommon diseases, allow collection of enough data to allow meaningful conclusions that might change paradigm and improve patient care. We call all participants of this meeting to join us and improve the quality of this wonderful important project.

Assessment By MRI T2*of Iron Accumulation and Removal in Transfusion Dependent MDS Patients

Introduction: Transfusion dependency in Myelodysplastic syndrome (MDS) patients is associated with shortened over-all survival and leukemia-free survival; however, it is not clear whether this detrimental effect is mediated by transfusional iron overload itself or whether the need for RBC transfusion is a surrogate marker of disease severity. Additionally, despite the negative effects of anemia and transfusion dependence on disease outcomes and patient quality of life, the clinical impact of iron overload in MDS remains controversial. Overall, the most common non-leukemic cause of death in MDS is heart failure. Recent T2* cardiac MRI (CMR) studies have shown that cardiac iron accumulation in MDS patients is variable and infrequent. T2* CMR is noninvasive, robust and the best available modality for assessing iron organ quantification. The current study assessed iron overload in transfusion dependent MDS patients using ferritin levels combined with myocardial and liver iron quantification using T2* CMR. The study monitored iron accumulation dynamics while on iron chelation therapy. Methods: We collected retrospectively clinical data in 18 RBC transfusion dependent MDS patients that had a CMR in our institution; some of the patients have serial scans. All scans were obtained using a 1.5 T scanner (Signa HDx ver 15 GE). Scans interpretation was performed using a dedicated workstation (Medis Medical imaging version 7.6, the Netherlands) for left ventricular ejection fraction measurement and T2* investigation as previously described. T2* values were recorded in milliseconds and converted to mg/gr dry tissue of myocardial liver and pancreatic tissue. Results: Ten of 18 patients were chelated. During the study period 4 patients have died from pneumonia, brain tumor, complications of Allo BMT and transformation to AML. Demographic data and prognostic score of MDS are shown in table 1. Before the first CMR, patients were treated with median of 48 PC (14-145) with median ferritin levels 1691.3ng/ml (269.4-3730ng/ml). In Table 2 we show iron accumulation in the first CMR. Iron accumulation in the heart was seen in 2 patients. The results are shown as severity of accumulation and not absolute numbers, as normal and abnormal range is different in the different organs. Seven patients had yearly serial CMR done, 6 of them were treated with iron chelation. We found iron accumulation in the heart in 4 of them. In table 3 we show example of a patient that was treated with chelation. Another patient, that had decrease ejection fraction with only moderate accumulation in the heart in CMR, improved her heart function with chelation. During the study period all patients continue to be transfusion dependent except 1 patient that became transfusion independent. She was transfused with 182 PC with maximal ferritin of 6926ng/ml. She was chelated with deferiprone and then with desferal. She is now transfusion independent for a year. Conclusion: Blood transfusion dependency in MDS patients, leads to high ferritin levels and evidences in CMR of iron accumulation in parenchymal orangs including the heart. During the study 4 patients had evidence of iron accumulation in the heart with 2 of them with severe accumulation that improved with iron chelation. Liver and pancreas accumulation was seen in 12 and 8 patients accordingly. Prospective studies documenting the correlation between chelation therapy and improvement in organ damage and survival are needed. Disclosures No relevant conflicts of interest to declare.

Differing Perceptions between Myelodysplastic Syndrome (MDS) Patients and Providers Regarding Blood Transfusions

Background: According to claims-based studies, a minority of MDS patients receive disease-modifying therapy. Unfortunately, these studies are limited by design in describing the shared decision-making process between MDS patients and their physicians in choosing supportive care, such as blood transfusions. Therefore, we surveyed and interviewed transfusion-dependent (TD) MDS patients and MDS physicians about the choice and use of supportive care, blood transfusions, and chemotherapy. Methods: Nearly 300 TD-MDS patients and MDS physicians were surveyed or interviewed under an IRB exempt protocol (WIRB). Semi-structured interviews of 15 patients and 10 providers were conducted between July and December of 2018 to inform survey development. Patients and providers within the AAMDSIF database were then invited via email and social media to participate in anonymous surveys. Survey respondents were entered into a lottery to receive a $50 gift card. Each interviewed patient was offered a $25 gift card and each provider interviewee was offered a $50 gift card. Survey 1 queried MDS patients who self-reported they had been TD, defined as 2 or more blood transfusions within a 2-month timespan, at some time since 2014. Between September 2018 and February 2019, 157 TD-MDS patients responded. Primary variables of interest included patient age, sex, use of disease-modifying therapies, use of chelating agents, and frequency of blood transfusions. Survey 2 queried providers who regularly manage TD-MDS patients (n=109). Nominal and ordinal variables were tested for possible association by the Goodman-Kruskal tau statistic. Results: Demographics and baseline disease characteristics of TD-MDS patients are shown in Table 1. In brief, the patient cohort had a median age of 69 years (range, 36-83), male 51%, and a greater proportion of low and low-intermediate IPSS risk. Nearly half of patients were unaware of their IPSS risk group. The majority (57%) of patients were TD within the past 2 months of answering the survey. Two-thirds of patients received care from an MDS specialist. MDS providers practiced in academic medical centers (61%), community hematology/oncology specialty practices (17%), community urban hospitals (10%), community suburban hospitals (5%), and rural community hospitals (4%), with some providers practicing in multiple locations. On a monthly basis, the majority (85%) of providers cared for up to 10 patients with TD-MDS. The highest ranked patient concerns about blood transfusions were transfusion reaction and iron overload. Concern for the more common risk of bacterial infection ranked 5th and was least often selected as the most important concern to patients. Approximately half of patients reported use of an iron chelating agent. On qualitative interview, most patients did not recall a discussion with their physician regarding the risks of blood transfusions, despite providers reporting they regularly educate patients and ask for informed consent. Further, although 98% of patients visited their MDS care provider at least quarterly, 48% stated they had not discussed alternatives to blood transfusion with their provider. Many patients held the sentiment there was "no choice to be made" in receiving blood transfusions. While providers said blood transfusions as primary management of MDS was rare, they reported they would recommend transfusions as stand-alone therapy in settings of patient preference for supportive therapy only, failure of ESAs, patient desire for transfusion-only therapy, and older patient age. Most patients (65%) ranked their quality of life positively, with 6% ranking excellent. The majority (58%) of patients drove themselves to their transfusion clinic, and 54% of patients traveled greater than 10 miles to these visits. Older age significantly associated with higher transfusion frequency (G-Test = 31.318, χ2 df = 18, p-value = 0.02644), but not with use of disease-modifying therapy. The presence of comorbidities was not associated with either transfusion frequency or active therapy. No significant association was found between patient income and either transfusion frequency, BMT, or administration of HMAs. Conclusions: MDS patients and physicians hold differing perceptions about the choice to receive and risks of receiving blood transfusions. Appraisal and optimization of the informed consent process between TD-MDS patients and physicians are needed. Disclosures No relevant conflicts of interest to declare.

Non-Requirement to Blood Transfusion in a Patient With Myelodysplastic Syndrome Following the Oral Administration of β-D-Mannuronic Acid: A Case Report

Myelodysplastic Syndromes (MDSs) is a heterogeneous group of hematologic neoplasms that causes cytopenia and dysplasia in one or more major bone marrow cell lines. The patients with this syndrome develop clinical complications associated with progressive bone marrow destruction leading to an increased risk for acute myelogenous leukemia. In the treatment of this syndrome, repeated infusion of Red Blood Cells (RBCs) may lead to iron overload, which is associated with a reduction in the survival rate of patients. In this paper, we report a case with MDS whose risk of dependence on blood transfusion was interstitial and received 4 units of packed RBCs once every 4 weeks. He had enrolled in our current clinical trial of β-D-mannuronic acid (M2000) in Iranian MDS patients. This 68-year-old man was treated with M2000, 500-mg capsule every 12 hours for 3 months. After 3 months of treatment, he experienced a non-requirement to blood transfusion following a hemoglobin increase of more than 2.5 g/dL in his blood sample. Moreover, the patient’s life quality was improved. This case report showed that M2000 drug might be an effective treatment for transfusiondependent MDS patients (Clinical trial identifier; IRCT20130622013739N11).

Treatment Patterns and Adherence Among Patients with Myelodysplastic Syndromes Receiving Deferasirox As Iron Chelation Therapy: A Real World Medicare Database Study

Background: Patients with myelodysplastic syndrome (MDS) may present with anemia and become red blood cell (RBC) transfusion dependent (TD), which increases the risk of iron overload (IO). Iron chelation therapy (ICT) treats IO and has been shown to be associated with improved survival and quality of life among TD MDS patients. Deferasirox (DFX) is an oral ICT used to reduce IO in TD MDS patients. This study aims to assess real-world treatment patterns and adherence among MDS patients on Medicare receiving DFX as ICT.Methods: This was a retrospective cohort study using 100% Medicare claims data from 2006-2013. Patients were diagnosed with MDS, identified using ICD-9 codes (238.72-238.76), and entered the study cohort when they met a minimum transfusion threshold of either: 10 consecutive weeks with at least 1 unit of RBC transfusion, or 20 total units of RBC transfusions. Treatment patterns, including discontinuation and treatment changes, were assessed among patients who received DFX as initial ICT and who had ≥180 days of follow-up. Discontinuation was defined as a minimum 45-day treatment gap. Adherence was defined as a medication possession ratio (MPR) ≥ 0.8. Treatment discontinuation, overall survival, acute myeloid leukemia (AML)-free survival, and cardiac event-free survival were compared between adherent and non-adherent patients using Kaplan Meier (KM) survival analysis, as well as Cox regressions controlling for time-dependent ICT use and baseline characteristics. Survivals were estimated as time from cohort entry to the event.Results: Among 6,796 MDS patients who met the minimum transfusion threshold, 591 (8.7%) received ICT. Median weeks of ICT was 15.14 (range=2.29 - 201.43 weeks). 583 (98.6%) initiated with DFX, and 374 DFX patients had a follow-up period of ≥180 days. Of these 374 patients, 213 (57.0%) discontinued DFX treatment within 180 days of initiation. Among the remaining 161 patients, one switched to deferoxamine (DFO), none augmented treatment with DFO, and 160 continued on DFX. The KM-estimated 3-month and 1-year DFX discontinuation rates were 36.5% and 77.4%, respectively, and the average time to discontinuation was 84.4 [Standard Deviation [SD]=48.6] days. Overall, the average 6-month MPR was 0.69 (SD=0.30), and 49.1% of patients were adherent (MPR≥0.8). Adherent patients had similar baseline characteristics compared with non-adherent patients, except that a lower proportion had renal disease (24.2% vs. 38.3%, P<0.01). Patients adherent to DFX had a lower risk of therapy discontinuation (Hazard Ratio=0.07, 95% Confidence Interval, 0.05-0.11) compared with non-adherent patients. Additionally, adherent patients had significantly longer cardiac event-free survival compared with non-adherent patients (1-year rate for cardiac-event/death: 66.1% vs. 76.1%, respectively, P<0.01). There were no statistically significant differences in overall survival and AML-free survival between adherent and non-adherent cohorts. Overall and AML-free survival were longer in the adherent cohort, however this did not reach statistical significance.Conclusions: DFX was the most commonly used ICT among eligible MDS patients. The majority of patients discontinued DFX within 1 year. Adherence to DFX was associated with statistically significant improved cardiac-event free survival. Further analysis on the long-term impact of the duration of chelation is warranted. DisclosuresFu:Novartis Pharmaceuticals Corporation: Consultancy. Hao:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Coe:Novartis Pharmaceuticals Corporation: Employment. Qiu:Novartis Pharmaceutical Corp: Employment, Equity Ownership. Li:Novartis Pharmaceuticals Corporation: Consultancy. Hanna:Novartis Pharmaceuticals Corporation: Consultancy. Tang:Novartis Pharmaceuticals Corporation: Consultancy. Elliott:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Paley:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership.

Early Treatment Initiation in Myelodysplastic Syndromes (MDS) Produces Higher Rate of and Earlier Transfusion Independence

Early Treatment Initiation in Myelodysplastic Syndromes (MDS) Produces Higher Rate of and Earlier Transfusion Independence

Preliminary Results from a Phase 1/2 Study of DSP-7888, a Novel WT1 Peptide-Based Vaccine, in Patients with Myelodysplastic Syndrome (MDS)

▪Background: Hypomethylating agents (HMA), including azacitidine (AZA) are currently the first-line treatment option for higher-risk myelodysplastic syndrome (MDS). However, the prognosis of patients after AZA failure is poor with a median overall survival of 5.6 months from the treatment failure (J Clin Onclol 2011;29:3322-7 Prébet T et al.), and currently there are no approved therapeutic options for such patients. Suzuki et al. reported that WT4869, one of the HLA-A*24;02-restricted synthetic peptide vaccine derived from Wilms’ tumor 1 (WT1) protein, demonstrated the sign of prolongation of overall survival (OS) with a median OS of 13.0 months in AZA failure higher-risk population, in the phase 1/2 study with MDS patients (Blood 126:2868, 2015;Suzuki et al.). DSP-7888 is a novel WT1-based peptide vaccine which induces the CTLs that recognize WT1 antigens in HLA-A*02:01/06 and HLA-A*24:02 restricted manner, and also includes a WT1-derived helper peptide applicable for various subtypes of HLA-DRB1. DSP-7888 is currently being investigated in a phase 1/2 study to evaluate the safety and efficacy in HLA-A*24:02+ and/or HLA-A*02:01/:06+ MDS patients, with some exploratory biomarker analyses.Methods: The objectives of this study were to assess the tolerability of DSP-7888 treatment in MDS patients in the phase 1 portion and to evaluate preliminary clinical activity of DSP-7888 in higher-risk MDS patients after AZA failure in the study. In phase 1 portion, higher-risk or transfusion-dependent lower-risk MDS patients including the AZA failure population were enrolled, and DSP-7888 was administered at doses of 3.5 to 10.5 mg/body by intradermal injections every two to four weeks in dose-escalation cohorts according to the 3 + 3 design until discontinuation criteria were met. Overall survival was evaluated for primarily clinical activity and hematological response and time to AML were also examined. Delayed type hypersensitivity (DTH), WT1-specific CTL induction and expression of WT1 mRNA in peripheral blood and bone marrow cells were also evaluated as exploratory biomarkers. The clinical data in phase 1 portion as of May 25th 2016 was presented in this report.Results: In phase 1 portion, enrollment of patients and dose-limiting toxicities (DLTs) evaluation were completed. Twelve patients including 7 higher- and 5 lower-risk patients were enrolled in 3.5 and 10.5 mg/body cohorts of 6 patients each, and safety profiles were evaluated. DLTs were not observed in either cohorts and the most common adverse drug reaction (ADR) was injection site reaction (ISR). ISR in 6 patients worsened to grade 3 with continuous treatment of DSP-7888 (2 patients at 3.5 mg/body, and 4 patients at 10.5 mg/body). Five serious ADR including 3 ISR, 1 pyrexia and 1 myocarditis were reported and dose-dependent toxicity was not observed except for ISR. All 12 patients were analyzed for preliminary clinical activity. Eight patients remained in stable disease (SD) with 2 hematological improvements (HI), and disease control rate (SD + any HI) was 66.6 %. Seven high risk AZA failure patients were enrolled, and the current survival time in this population is 7.3-10.8 months. Though preliminary, CTL induction was observed in 6 patients, and a trend of higher CTL induction was observed in patients with grade 3 ISR. DTH response was observed in 10 patients.Conclusions: In the phase 1 portion, DSP-7888 was well-tolerated in MDS patients although ISR was observed in all patients. CTL induction was detected with clinically observed reactions that may suggest preliminary signs of clinical activity. Further evaluation is needed to confirm the clinical potential of DSP-7888, and phase 2 portion is currently ongoing to evaluate the efficacy of DSP-7888 in higher-risk MDS patients after AZA failure. DisclosuresUsuki:Nippon Shinyaku: Honoraria; MSD: Honoraria; Kyouwa-Kirin: Honoraria; Novartis: Honoraria; Bristol-Myer-Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; SymBio Pharmaceuticals: Research Funding. Matsumura:Bristol-Myers Squibb Company: Honoraria; Novartis Pharma K.K: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria; Pfizer Japan Inc.: Honoraria. Ueda:Alexion Pharmaceuticals Inc.: Membership on an entity’s Board of Directors or advisory committees. Origuchi:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Tagashira:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Naoi:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Naoe:Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Pfizer Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Amgen Astellas BioPharma K.K.: Honoraria; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; CMIC Co., Ltd.: Research Funding; Celgene K.K.: Honoraria, Research Funding; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding. Heike:Sumitomo Dainippon Pharma: Consultancy; Chugai Pharma: Consultancy; Otsuka Pharma: Consultancy. Miyazaki:Kyowa Kirin: Honoraria; Nihonshinyaku: Honoraria; Celgene Japan: Honoraria; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria.

Rationale for Therapy Discontinuation in Patients with Lower-Risk Transfusion-Dependent Myelodysplastic Syndromes (MDS)

Introduction: Approximately 50% of patients with MDS are anemic at initial diagnosis, with many becoming transfusion dependent (TD), necessitating the introduction of therapy with a goal of achieving transfusion independence (TI). In addition to transfusions, treatments to improve hemoglobin levels have historically been limited to erythropoiesis-stimulating agents (ESAs), whereas patients with more advanced disease may require treatment with a hypomethylating agent (HMA) (azacitidine [AZA] or decitabine [DAC]) or lenalidomide (LEN). As there is no predetermined treatment course, these therapies are continued until unacceptable toxicity, lack/loss of response, or disease progression. We examined treatment patterns, clinical outcome(s) of patients with MDS, and the physician's report of reason for treatment discontinuation (previously shown to vary from patients' perspectives) in patients who became TD at or after MDS diagnosis (Gerds et al. Blood 2014;124:abstract 2642).Methods:Data were derived from disease-specific physician surveys and patient charts, which provided information on demographic, treatment, and outcome data on lower-risk TD MDS patients. Patient inclusion criteria were: age ≥ 18 years, diagnosis of Low/Intermediate-risk MDS (International Prognostic Scoring System defined) 2-6 years prior to study entry, and becoming TD at least once during the minimum follow-up of 24 months. TD was defined as having received ≥ 2 transfusions within 8 weeks during the follow-up period. Patients who progressed to higher-risk disease or acute myeloid leukemia prior to becoming TD, had an additional malignancy, or were in an MDS clinical trial were excluded. Demographics, disease history, treatment history, TI, and reasons for treatment discontinuation were collected and reported descriptively.Results: A total of 239 physicians provided information on 1,221 lower-risk TD MDS patients. The median age of patients was 65 years (range 27-95 years), 56.3% were male, and median time since diagnosis was 3.2 years (range 2-6 years). Along with packed red blood cell transfusions, 354 patients (29%) were prescribed LEN [of whom 12.7% had del(5q)], 348 patients (28.5%) were prescribed ESAs, and 32 patients (2.6%) were prescribed HMAs. During the follow-up period, 31.3% of ESA patients discontinued therapy (at a median of 12 months; range 3-47 months), 32% of HMA patients discontinued therapy (at a median of 10 months; range 3-52 months), and 26% of LEN patients discontinued therapy (at a median of 13 months; range 2-30 months). In the LEN-treated group, only 9.8% of patients who discontinued therapy had del(5q). The main reason cited for treatment discontinuation across therapy groups reported by physicians was "patients completing the scheduled course of treatment" (28.2%), which occurred in 32.6%, 20.2%, and 22.6% of the LEN, ESA, and HMA groups, respectively. Other reported reasons for discontinuation included "insufficient initial response" (20.0%), "patients no longer responding to therapy" (19.0%), "disease progression" (18.0%), "death" (13.3%), and "worsening hemoglobin levels" (12.8%). Across therapy groups, "patient preference to stop therapy" was reported less frequently (9.7%), occurring in 7.6%, 8.3%, and 12.9% of the LEN, ESA, and HMA groups, respectively.Conclusions:Over 30% of TD lower-risk MDS patients receiving LEN, ESAs, AZA, or DAC discontinued therapy. Per physician reports, the most frequent reason for discontinuation of therapy was completion of scheduled treatment course, which is in stark contrast to recommendations in consensus guidelines, as MDS is a chronic disease in which treatment should be continued ad infinitum. The significant number of patients who stop therapy for alternative reasons suggests opportunities for further investigation. Education on the expected duration of therapy is essential to help support physicians and inform patients about optimal treatment decisions in the care of all MDS patients. DisclosuresGupta:Kantar Health: Employment; Celgene Corporation: Consultancy, Research Funding. Binder:Celgene Corporation: Employment, Equity Ownership. Carraway:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Hawthorne:Kantar Health: Employment; Celgene Corporation: Consultancy, Research Funding. King-Concialdi:Kantar Health: Employment; Celgene Corporation: Consultancy, Research Funding. McGuire:Celgene Corporation: Employment, Equity Ownership.

Elevated Labile Plasma Iron Levels (LPI) and Increased Oxidative Stress Are Associated with Red Blood Cell Transfusions in Patients with Lower-Risk Myelodysplastic Syndromes (MDS) Subtitle: from the European Leukemianet MDS Registry

Background: The EUMDS registry, collecting prospective observational data on lower-risk MDS (LR-MDS) patients from 142 centers in 17 countries, is performing a study on the hypothesized negative impact of red blood cell transfusions (RBCT) on outcome in LR-MDS. The aim of this study istoevaluate in transfusion dependent (TD) patients temporal changes in iron metabolism and presence of potentially toxic forms of iron, measured as labile plasma iron (LPI) and their impact on oxidative stress, using malondialdehyde (MDA), and their impact on survival.Methods: We analyzed serum samples from 100 LR-MDS patients at 6-month intervals fortransferrin saturation (TSAT), non-transferrin bound iron (NTBI) and LPI.Cox proportional hazards regression models and Kaplan-Meier (KM) survival curves were used in time-to-event analyses to assess the impact of LPI, NTBI and TSAT by transfusion status. All variables were treated as time-varying covariates in the model by assessing the levels of the parameters: LPI, NTBI (<LLOD vs elevated), TSAT (<80% vs ≥80%) and transfusion status (TD vs transfusion independent (TI)) at each visit.We also explored in 56 patients the temporal prevalence of oxidative stress and its relation with toxic iron species by means of the MDA assay in paired samples with at least 1-year interval.Results: Themedian age was 73 years.IPSS-R risk groups of this cohort of LR-MDS, defined as IPSS low & intermediate-1 risk, were: very low 32%, low 41%, intermediate 8%, high 3% and unknown 16%. Patients were subdivided in ring sideroblastic MDS (RS-MDS) (34%) and non-RS-MDS (64%). Both groups were subdivided in TD and TI patients.Elevated LPI in combination with high TSAT (>80%) occurred almost exclusively in patients with TI RS-MDS and in all TD MDS patients.Time-dependent, multivariate analysis (MVA), adjusting for age and IPSS-R risk group, of elevated LPIconcentrations for overall survival (OS) resulted in a Hazard Ratio (HR) of 2.3 with 95%CI (0.9-5.8). Elevated NTBI was associated with HR of 0.7 and 95%CI: 0.3-1.8 and TSAT >80% with HR of 0.9 and 95%CI: 0.3-2.6.MVA of OS by LPI and transfusion status as time varying variable showed a significant impact of elevated LPI in the TD group only(HR=4.0, 95%CI: 1.02-15.9) (p = 0.05).MDA concentrations were measured in 28 patients with RS-MDS and 28 non-RS-MDS patients. 21 and 29 patients were TD at time of 1st and 2nd MDA measurement respectively. The overall median MDA concentrations in the 1st sample were elevated compared to controls: 0.9 (0.3 - 4.1) (range controls: 0.16 to 0.64 mM) and remained elevated in the 2nd sample. Median MDA increased from 0.8 to 0.9 mM in the MDS-RS group (p = 0.008 paired one-sided T-test). Significantly higher MDA concentrations were observed in TD patients at time of the 2nd measurement: a median MDA level of 0.7 mM (0.3 - 3.6) in TI and 1.3 (0.3 - 6.8) in TD patients resp. (p = 0.01). MDA levels did not increase in time in TI MDS, but showed a trend to higher MDA in 9 patients who became TD between 2 MDA measurements (p=0.11) and in the 21 patients TD before the 1st measurement (p = 0.12). Median MDA did not change in time in the majority of patients with LPI levels below the detection line (<LLOD). The correlation between elevated LPI and MDA concentrations was weak (r = 0.047, P = 0.82). Paired analysis of the 16 patients with LPI < LLOD at time of 1st measurement and elevated LPI at time of 2ndmeasurement showed a slight increase (p = 0.10) of the median MDA levels from 1.1 to 1.2mM/l. The impact on OS of lowest 50% of MDA levels at each measurement and the highest 50% of MDA levels, adjusted for MDS-RS status, TD and LPI>LLOD vs <LLOD was not evident with an unadjusted HR of 1.3 (0.6 - 3.1) and an adjusted HR of 0.6 (0.2 - 1.5).Interpretation:Iron toxicity and increased oxidative stress occurred in all types of TD MDS patients and in TI RS-MDS patients. This study illustrates LPIas a clinically relevant assay for identification of the toxic fraction of iron overload and its negative impact on overall survival. In contrast, high TSAT (>80%) and elevated NTBI concentrations did not predict survival.Oxidative stress, using MDA as a measurement of lipid peroxidation, is increased in the majority of lower-risk MDS patients, usually early after diagnosis. The highest MDA levels are measured in patients receiving RBCT, but the LPI and MDA were not correlated, which can be explained by the slower clearance of MDA after RBCT compared to the more rapid clearance of LPI. [Display omitted] [Display omitted] DisclosuresSymeonidis:Takeda: Consultancy, Honoraria; Amgen: Honoraria; Roche: Honoraria; Genesis: Honoraria. Smith:Jansen Cilag: Research Funding; Novartis: Research Funding; Amgen: Research Funding; Celgene: Research Funding. de Witte:Incyte: Consultancy; Celgene: Consultancy; Novartis: Honoraria, Research Funding.

Iron Chelation Is Associated with Improved Survival Adjusting for Disease and Patient Related Characteristics in Low/Int-1 Risk MDS at the Time of First Transfusion Dependence: A MDS-CAN Study

Iron Chelation Is Associated with Improved Survival Adjusting for Disease and Patient Related Characteristics in Low/Int-1 Risk MDS at the Time of First Transfusion Dependence: A MDS-CAN Study

Characteristic Macrocytic Anemia, Ineffective Erythropoiesis, and Iron Overload in 5q-Mice and Effect of Exogenous Transferrin

Low/intermediate risk myelodysplastic syndromes (MDS) is associated with relatively longer survival and high transfusion requirements, resulting in secondary iron overload. Iron overload is an independent variable associated with poor prognosis, impacting survival, and iron chelation therapy is associated with prolonged survival in transfusion-dependent MDS patients. We have previously shown that exogenous transferrin (Tf) results in more circulating red blood cells (RBCs), increased hemoglobin (Hb), reversal of splenomegaly, and improvement in ineffective erythropoiesis in β-thalassemic mice (Li Nat Med 2010) and recently demonstrate that erythroferrone (ERFE), a newly described physiologic erythroid regulator of hepcidin, is normalized in Tf-treated β-thalassemic mice (Chen, manuscript in review). We postulate that ineffective erythropoiesis in β-thalassemia shares many characteristics with that of low risk MDS, such as defective erythroid differentiation, anemia, splenomegaly, and systemic iron overload, suggesting that similar effects of exogenous Tf may be relevant also in MDS. Partial deletion of chromosome 5, 5q-syndrome, is the most common cytogenetic abnormality in low/intermediate risk MDS. We characterize a mouse model of 5q-syndrome, Cd74+/lox Nid67+/lox, Lmo2Cre+ mice (5q-mice) (Barlow Nat Med 2010). Our findings reveal that 5q-mice exhibit macrocytic anemia (Hb 6 vs. 12 g/dL, P<0.0001; MCV 61 vs. 48 fL, P<0.0001), splenomegaly (0.007 vs. 0.003 spleen/body weight, P<0.0001), extramedullary hematopoiesis in the liver (Fig 1A), expanded erythropoiesis in spleen (Fig 1B), and a lower percentage of erythroid precursors in the bone marrow (Fig 1C) despite increased serum erythropoietin (79 vs. 0.4 pg/L, P=0.04). Furthermore, 5q-mice exhibit evidence of iron overload relative to WT mice with increased Tf saturation (70 vs. 39%, P=0.004) and liver iron stores (1.0 vs. 0.3 mg iron/g liver weight, P=0.001). Although no difference in liver hepcidin expression or serum hepcidin concentration is evident (Fig 2A and 2B), bone marrow ERFE expression is increased (14-fold, P=0.002) and a trend toward decreased hepcidin:liver iron is observed in 5q- relative to WT mice (Fig 2C). We hypothesize that the effect of exogenous Tf applies to 5q- as β-thalassemic mice in light of similarities in disease characteristics. Using bone marrow transplantation to generate a cohort of 5q- mice with similar disease severity, 8x10^6 cells from 2 month old 5q- mice were transplanted into a cohort of sub-lethally irradiated 8 week old WT mice. Transplanted mice were allowed to recover and started Tf injections IP (10mg/day or equal volume PBS (200 uL) 2 weeks post-transplant. After completing 20 days of injection, mice were sacrificed and all erythroid- and iron-related parameters analyzed. Tf-treated 5q- mice exhibit statistically increased RBC count (10 vs. 8 x10^6 cells/uL, P<0.0001) and lower MCV (41 vs. 53 fL, P<0.0001) and MCH (12 vs. 16 pg, P<0.0001) compared to PBS injected 5q- mice. Results demonstrate an increase in reticulocyte count (676 vs. 477 x 10^9 cells/L, P=0.003) and platelet count (549 vs. 364 x 10^3 cells/ul, P=0.02) in the circulation and an increase in orthochromatophilic erythroblasts (19.3 vs. 16.1%, P=0.04) and reticulocytes (32.8 vs. 26.6%, P=0.04) in the bone marrow, without changes in Erfe expression. Although TfR1 mRNA expression is unchanged, membrane TfR1 MFI is increased in late stage erythroid precursors in both bone marrow (11 vs. 7 x 10^3 MFI, P=0.01) and spleen (16 vs. 12 x 10^3 MFI, P<0.05) from Tf-treated relative to PBS injected 5q-mice. Interestingly, intracellular ROS is increased in late stage splenic erythroid precursors from Tf-treated relative to PBS injected 5q-mice. Although increased ROS levels result in cellular damage, emerging evidence suggests that ROS is required for normal hematopoiesis, such that high ROS states are associated with differentiating HSCs. Taken together, our data demonstrates erythropoiesis- and iron-related characteristics of 5q- mice consistent with human disease. Although these preliminary experiments using exogenous Tf reveal no increase in Hb, improved ineffective erythropoiesis, or reversal of iron overload, our data suggests that TfR1 and ROS are intimately involved in the effect of exogenous Tf in erythropoiesis. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Elevated Basal Autophagy in SF3B1 Mutated Myelodysplastic Syndromes: Relationship with Survival Outcomes and Therapeutic Implications

About 60-80% of patients with myelodysplastic syndromes (MDS) manifest with anemia. Red blood cell (RBC) transfusions are the most commonly used therapy to alleviate anemia in patients that are ineligible for other curative approaches. Transfusion-dependent patients frequently develop iron overload, which correlates with infections, mortality, leukemia, and organopathy. At the subcellular level, long-term iron exposure produces iron-catalyzed hydroxyl radicals that induce oxidative damage to mitochondria and disrupt bioenergetic homeostasis. The use of iron-chelating drugs to counter transfusion-related iron overload remains controversial due to the significant side effects that these agents cause. New therapies that effectively address iron overload in transfusion-dependent MDS patients are clearly needed. Mitochondrial dysfunction frequently occurs during MDS cell maturation and leads to abnormal iron distribution. However, the mechanistic basis of this biological phenomenon has not been rigorously studied. We previously linked the presence of Splicing factor 3b subunit 1 (SF3B1) mutations, which are frequent in patients with refractory anemia with ring sideroblasts (RARS), with abnormalities in mitochondrial iron. Transmission electron microscopy and flow cytometry showed that mitochondria of SF3B1 mutant RARS patients have higher iron content than those of wild type (WT) RARS patients and expressed an increased mRNA level of the iron transporter, Mitoferrin 1. Despite these prevalent mitochondrial abnormalities and transfusional dependence, SF3B1 mutant lower-risk MDS patients experienced significantly longer median survival compared to SF3B1 WT lower-risk MDS patients (34 mos vs. 13 mos; P = .002; N=16 vs. 101). Autophagy is an evolutionarily conserved lysosomal mechanism of protein degradation that plays a critical role in the elimination of damaged mitochondria and other organelles. We hypothesized that autophagic clearance of defective mitochondria may contribute to the superior survival of SF3B1 mutant patients suffering from transfusion-mediated iron overload. We conducted RNA sequencing analyses on a group of fresh bone marrow (BM) cells of SF3B1 mutant and WT RARS patients and healthy donors (n = 11) to investigate the basal autophagy status in this distinct patient population. In addition to confirming increased levels of mitochondrial transporters such as Mitoferrin 1 and 2 (FC = 2.0), we detected a striking increase in multiple genes involved in the proximal and distal regulation of autophagy in cells of SF3B1 mutant RARS compared to WT RARS patients. Genes controlling the early stages of autophagy including the protein kinases ULK1 (FC = 2.0) and ULK3 (FC = 3.9; P=.05), ATG complexes ATG2A/B (FC = 1.9), ATG9A (FC = 5.5; P=.05), ATG18 (FC = 4.8; P=.02) and the cysteine proteases ATG4A/C (FC = 2.0) were all elevated in SF3B1 mutant RARS vs. SF3B1 WT RARS patients. Key components of the late stages of the autophagic degradation cascade, including multiple members of the cathepsin family of lysosomal proteases [CTSL1: FC = 20.9; CTSD: FC = 5.8 (P=.06); CTSB: FC = 2.1; CTSE: FC = 5.9 (P=.01); CTSD: FC = 1.8], were also significantly increased. qRT-PCR confirmed higher expression levels in the BM cells of RARS patients carrying sole SF3B1 mutations compared to cells of SF3B1 WT RARS patients. The link between SF3B1, mitochondrial iron, and elevated autophagy was specific as evidenced by the unmutated status and lack of significant mRNA changes in any other splicing factor genes including PRPF8. Our data demonstrate that autophagy may play an important, previously unreported role in SF3B1 mutant RARS. Based on our findings, we hypothesize that SF3B1 mutant RARS cells stimulate autophagy to eliminate damaged mitochondria and alleviate iron overload and that further stimulation of autophagy will diminish the pathogenic effects of chronic transfusions. We are currently investigating the therapeutic benefit and pharmacodynamics of autophagy-modulating drugs (temsirolimus, metformin, arsenic trioxide) in in vitro (primary cells) and in vivo (SF3B1 haploinsufficient mice) models of MDS to facilitate the design of an investigator-initiated clinical trial that will test autophagy modulation as a new precision strategy for the treatment of transfusion-dependent patients with low-risk MDS carrying SF3B1 mutations. DisclosuresSekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Carew:Boehringer Ingelheim: Research Funding.

Quality of End-of-Life Care for the Myelodysplastic Syndromes: Findings from a Large National Database

Background: End-of-life (EOL) care has been shown to be more intensive for blood cancers compared to solid tumors (e.g. Hui, Cancer, 2014); however, data are sparse regarding predictors of intensive care unit (ICU) use in the last 30 days of life and hospice enrollment among patients with specific hematologic malignancies. Moreover, little is known about EOL care specifically for the myelodysplastic syndromes (MDS), which are distinguished among the blood cancers by their relative indolence in many patients and high rate of transfusion dependence.Methods: We conducted a retrospective analysis using the Surveillance Epidemiology and End Results (SEER)-Medicare database. Patients ≥ 65 years of age who had a primary diagnosis of MDS between 2006 and 2011, lived for at least 30 days after their diagnosis, and died prior to December 31, 2012 were eligible for inclusion. Outcomes were two well-established quality measures for EOL care in oncology (Earle, JCO, 2003; Keating, Cancer, 2010): ICU admission within the last 30 days of life (an indicator of poor quality), and enrollment in hospice for any length of time (an indicator of good quality). After determining their overall prevalence, we fit multivariable logistic regression models to investigate sociodemographic and clinical associations (see table) with each outcome.Results: A total of 6,955 MDS patients were eligible. Overall, 28% were admitted to the ICU in the last month of life, and 49% had enrolled in hospice. In multivariable analyses, transfusion-dependent patients were more likely to be admitted to the ICU and less likely to enroll in hospice (both p<0.001). There was no significant association with marital status or time from diagnosis to death for either outcome. Patients who died in later years had a higher prevalence of ICU admissions (p=0.05) and were more likely to enroll in hospice (p<0.001). Additional multivariable associations are shown below.*Adjusted for all variables listed as well as marital status and time from diagnosis to deathConclusions: Only about half of the MDS patients in our cohort were enrolled in hospice; however, the odds of enrollment increased over time. Interestingly, the odds of ICU admission within the last 30 days of life also increased over time, a trend that has been seen in solid tumors (e.g. Wright, JCO, 2014). As bone marrow failure in MDS can lead to reversible sepsis and the need for temporary blood pressure support, it is difficult to determine if this trend truly represents a worsening in quality of EOL care. Finally, our finding that transfusion-dependent MDS patients were less likely to receive hospice suggests that one reason for suboptimal enrollment is that the current hospice model-which largely disallows transfusions-is not meeting the specific palliative needs of this population. [Display omitted] DisclosuresGore:Celgene: Consultancy, Honoraria, Research Funding. Davidoff:Celgene: Consultancy, Research Funding. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy.

A Phase 1/2 Study of WT1 Peptide Cancer Vaccine WT4869 in Patients with Myelodysplastic Syndromes (MDS)

A Phase 1/2 Study of WT1 Peptide Cancer Vaccine WT4869 in Patients with Myelodysplastic Syndromes (MDS)

Variations in erythropoiesis-stimulating agent administration in transfusion-dependent myelodysplastic syndromes impact response

IntroductionErythropoiesis-stimulating agents (ESAs) reduce red blood cell (RBC) transfusions in approximately 40% of patients with myelodysplastic syndrome (MDS) in clinical trials. We studied the association of timing of ESA initiation, agent (epoetin alfa, darbepoetin) and number of weeks of ESA use with response in MDS patients in routine practice. MethodsPatients diagnosed with MDS from 2001 to 2005 were identified in the Surveillance Epidemiology and End Results-Medicare linked database. The study cohort consisted of patients with new-onset transfusion dependence (TD). All patients received an ESA at least once during the study period, which began the week that criteria for TD were met and continued until transfusion independence (TI). Kaplan–Meier statistics and Cox Proportional Hazard models were used to assess relationships between time to ESA initiation, agent and number of weeks of ESA use and TI attainment. ResultsOf 610 TD patients treated with ESAs, 210 (34.4%) achieved TI. Median time from ESA initiation to TI was 13 weeks. Shorter time from TD to ESA initiation and use of darbepoetin were associated with higher probability of achieving TI. The probability of achieving TI decreased beyond 8 weeks of treatment, and was very low beyond 16 weeks (8–15 weeks: HR=0.64, 16–31 weeks: HR=0.25, 32+ weeks HR=0.10). ConclusionsIn this observational, population-based study, variations in ESA administration impacted response in transfusion-dependent MDS patients, with higher response rates with early administration and use of darbepoetin, and low response likelihood in non-responders beyond 16 weeks of therapy.

Prophylactic Rh and Kell Antigen Matching Significantly Decreases Rates of Alloimmunization in Transfusion Dependent MDS Patients

Background: 40-80 % of patients with myelodysplastic syndrome (MDS) become transfusion dependent during their disease course and are at risk for the development of alloimmunization. Red blood cell (RBC) alloantibodies can make finding compatible blood for transfusion more difficult, expensive and time consuming. Allommunization rates of approximately 30-47% have been reported in patients with sickle cell disease and the transfusion of RBCs prophylactically matched for Rh antigens E and C, and K antigens reduced the rate of alloimmunization from 3% to 0.5% per unit (Vichinsky et al, 2001). In 2007, our hospital instituted a policy of transfusing prophylactic Rh and K matched blood to MDS patients. The objectives of this study were to compare the rates of alloimmunization in MDS patients who received prophylactic Rh and K matched blood compared to those that did not and identify potential risk factors for alloimmunization. Methods: 193 Transfusion dependent MDS patients were identified out of 387 patients registered and prospectively followed in a local MDS registry. Transfusion dependence was defined as the receipt of at least 1 unit of PRBC every 8 weeks for a minimum of 16 weeks. Records of transfusions received up to May 1, 2014 were collected from blood bank databases of the hospitals at which patients were transfused. Patients were classified according to whether phenotyping had been performed, the location of transfusions (transfused only at our institution, transfused only at an outside institution or transfused at both sites) and whether prophylactic Rh (E, C antigens) and K matched blood was transfused. Data were descriptively analyzed and we conducted univariate and multivariate logistic regression using p< 0.05 as statistically significant to identify risk factors for alloimmunization.Results: 176 MDS patients with complete transfusion records are included, 73 transfused at Sunnybrook, 92 transfused in community hospitals and 11 at both. The median age was 72 yrs (range 22-89), 60% were male, and 8%, 43% and 27% had very low, low and intermediate risk R-IPSS scores respectively. Median follow up was 2.9 years (IQR 1.6-5) 3.49 SD). Blood groups O, A, B, AB and O were 45%, 38%, 15% and 2% respectively, while 85% were RhD+. The median time from diagnosis until first transfusion was 4 months (IQR: 0.2-14), with 51 patients having received at least 1 transfusion prior to diagnosis at a median time of 0.9 months. 4.5% had a pre-existing allo-antibody at time of MDS diagnosis. With a median follow up from diagnosis of 3 years (IQR:1.6-5)), the median number of RBC units transfused was 38 (IQR: 15-98)) and 36 (20%) patients developed new alloantibodies (median 2 (IQR (1-2.5) alloantibodies). The median number of RBC units until first allo antibody was 13.5 units (range 0-121) and 1.25 years from diagnosis (95% CI:0.4-2.1). The majority of the alloantibodies were in the Rh (n=28) and K (n=14) groups (80%) and co-existed 27% of the time. More patients transfused at our hospital received prophylactic Rh K matched blood sometimes or always (60% versus 26%) and rates of allo-immunization were decreased by 65% (absolute rate of alloimmunization 10% versus 29%). By multivariate analysis analysis, number of rbc transfused (p<.0001), receiving prophylactic phenotype matched blood (p=.0008) and location of transfusions (Sunnybrook versus elsewhere (p=.03)) were independent risk factors for alloimmunization.Conclusions: 20-30% of RBC transfusion dependent MDS patients will become allo-immunized to clinically significant blood group antigens, the majority being Rh and K antigens. The practice of phenotyping at baseline and prophylactically transfusing Rh and Kell matched blood decreases rates of alloimmunization up to 65% and should be strongly considered for routine transfusion practice in centres that treat MDS.Table 1All Patients (n=176)Sunnybrook (n=73)Community(n=92)Ever phenotyped45%64%28%Phenotyped before 1st transfusion20%38%8%Developed allo-antibodies20%10%29%Received prophylactic Rh K matched blood(developed alloantibodies)NeverSometimesAlways58% (16%)24% (42%)18% (6%)40% (3%)23% (23%)37% (7%)74% (22%)22% (60%)4% (0%) [Display omitted] DisclosuresWells:Celgene: Honoraria, Other, Research Funding; Novartis: Honoraria, Research Funding; Alexion: Honoraria, Research Funding. Buckstein:Celgene: Research Funding.

A Phase I/II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)

Background:Rigosertib is a small molecule anti-cancer agent targeting PI3/polo-like kinase pathways that promotes G2/M arrest and has effects on the B-Raf and Ras pathways. It is currently being tested as a single agent with the intravenous (IV) formulation in patients (pts) who have relapsed or are refractory to hypomethylating agents (HMAs) as well as with the oral formulation in lower-risk, red-cell transfusion-dependent MDS patients. Azacitidine (AZA) is first-line therapy for pts with higher-risk MDS. In vitro, the combination of rigosertib with AZA acts synergistically to inhibit growth and induce apoptosis of leukemic cells (Skidan et al 2006). This effect appears to be sequence dependent, requiring exposure to rigosertib first, followed by AZA. These nonclinical results provided the rationale to combine the 2 agents in a phase I/II study in pts with MDS and AML.Methods: Pts with MDS and non-proliferative AML, who were previously untreated or had failed or progressed on an HMA were included in the phase I component of the study. Oral rigosertib was administered twice daily from day 1 through day 21 of a 28-d cycle. AZA 75 mg/m2/d was administered for 7 days starting on day 8 of the 28-d cycle. Pts were entered in 3 escalating-dose cohorts of rigosertib in a classic 3+3 design: [1] 140 mg twice daily; [2] 280 mg twice daily; [3] 560 mg qAM and 280 mg qPM. A CBC was performed weekly and a bone marrow (BM) aspirate and/or biopsy was performed at baseline and every 4-8 weeks afterwards.Results: Eighteen pts have been treated with the combination of oral rigosertib and AZA. Pts had diagnoses of intermediate-1 MDS (3), intermediate-2 MDS (6), high-risk MDS (2), CMML (1), and AML (6); median age was 70.5 years; 61% of pts were male. Pts have received 1-10+ cycles of treatment with the total number of cycles administered thus far being 58. Cytogenetic profiles by IPSS were good (8 pts), poor (8 pts), and intermediate (2 pts). 11of 18 patients were transfusion dependent at baseline [RBC (11), platelet (6)]. One patient became RBC transfusion independent after 3 cycles of treatment. 5 additional patients have had a reduction in their RBC and platelet transfusion requirements. 56% of patients received prior treatment with HMAs: AZA (6 pts), decitabine (4 pts). The most frequent adverse events (AEs) in Cycle 1 included constipation, diarrhea, nausea, fatigue, hypotension, and pneumonia. The AEs did not differ significantly among the 3 cohorts. Elevation in creatinine in 1 pt in cohort 1 was a possibly related grade 3 dose-limiting toxicity that required subsequent expansion of the cohort. Drug-related dysuria/cystitis was not reported in this pt population. Responses according to IWG 2006 criteria were observed in the BM and peripheral blood: Complete Response (CR) (1 pt), Cri (CR with incomplete blood count recovery) (4 pts), stable disease (2), hematologic improvement-erythroid (1). Six pts received fewer than 4 cycles of treatment and are too early to evaluate. Six pts came off study for the following reasons: progression of disease (1), pt request (1), death from pneumonia (2), received stem cell transplant (1), persistent fungal pneumonia (1). Two evaluable pts have responded to the combination after progression or failure on HMA alone.Conclusions: The combination oforalrigosertib at 560/280 mg BID (recommended phase II dose) and standard-dose AZA can be safely administered and appears to be well tolerated in repetitive cycles in pts with MDS and non-proliferative AML. The AE profile does not differ significantly from that of AZA alone. Data from the Phase I component of this study suggest activity in patients with MDS after HMA failure. Additional data are required to evaluate this observation. The Phase II segment of this study is underway to further assess the response of the combination.TablePatient IDDiagnosisPrior HMA% Blasts in BM at Baseline% Blasts in BM after TreatmentIWG Response1MDSNo21CRi2AMLNo400CRi3AMLNo22N/ANE4MDSAzacitidine00NE5AMLNo59N/ANE6MDSNo21<5CRi7MDSNo21CR8MDSNo2.52SD9AMLDecitabine25N/ANE10MDSDecitabine123CRi11CMMLAzacitidine23SD12MDSAzacitidine41HI-E13AMLAzacitidine4740TE14AMLDecitabine77TE15MDSNo95TE16AMLNo256TE17AMLNo1519TE18AMLAzacitidine6445TEIWG = International Working Group CR = Complete Response CRi = Complete Response with incomplete blood count recovery NE = Not Evaluable SD = Stable Disease HI-E = Hematologic Improvement - Erythroid TE = Too Early DisclosuresWilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Demakos:Onconova: Consultancy. Azarnia:Onconova Therapeutics, Inc: Employment. Silverman:Onconova: with Icahn School of Medicine at Mount Sinai Patents & Royalties.