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

Abstract 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. Disclosures Sekeres: 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.

Download Full-text

Impact of Hypomethylating Agent Therapy in Myelodysplastic Syndromes with Chromosome 3 Abnormalities

Blood ◽

10.1182/blood.v126.23.1705.1705 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1705-1705

Author(s):

David Sallman ◽

Guillermo Garcia-Manero ◽

Elias Jabbour ◽

Mikkael A. Sekeres ◽

Amy E. DeZern ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Lower Risk ◽

Research Funding ◽

Chromosome 3 ◽

Advisory Committees ◽

Monosomy 3 ◽

Risk Patients

Abstract Background In myelodysplastic syndromes (MDS), abnormalities of chromosome 3 (i.e. inversion 3 (inv(3)), translocation 3q (t(3q)), or deletion 3q (del(3q)) represent a poor-risk karyotype in the Revised International Prognostic Scoring System (IPSS-R). In acute myeloid leukemia (AML) patients with 3q abnormalities, patients with inv(3)/t3;3 represented the most unfavorable group with a median overall survival (OS) of 10.3 months (Lugthart et al., 2010). We previously presented a single institution experience regarding outcomes of MDS patients with chromosome 3 abnormalities. Here, we sought to further define outcomes of chromosome 3 abnormalities in MDS and address the impact of hypomethylating agents (HMA) on outcome in multiple institutions. Patients and Methods Patients were identified through the MDS Clinical Research Consortium and were included if they had a WHO diagnosis of MDS, MDS/myeloproliferative neoplasm (MPN), therapy related MDS (t-MDS), or AML (20-30% myeloblasts) and had any karyotypic abnormality involving chromosome 3. Data analyzed included baseline demographics, disease characteristics, IPSS/IPSS-R scores, treatment and outcome. Responses to HMA therapy were evaluated using International Working Group (IWG) 2006 criteria. Kaplan-Meier estimates were used for overall survival. Results A total of 413 patients were identified with a median age at diagnosis of 67 years. WHO classification was as follows: 9% RA/RARS, 12% RCMD, 26% RAEB-1, 31% RAEB-2, 2% MDS/MPN, 7% MDS Unclassified, 13% AML; 34% had t-MDS. Overall, 97% of patients were higher risk by IPSS-R (i.e., intermediate to very high risk) with a median blast % in bone marrow of 8%. Distribution of cytogenetic abnormalities were inv(3) (10%), del(3q) (12%), t(3q) (18%), monosomy 3 (22%), 3p abnormalities (22%), and other chromosome 3 changes (17%). Median OS for the cohort was 12.0 months (95% C.I. 10.8 to 13.9 months) and 31% of patients without AML transformed to AML. IPSS-R was predictive of median OS across subgroups (P < 0.00001). The specific cytogenetic abnormality was predictive for survival (P < 0.00001) with median OS for t(3q) 19 months, inv(3) 13 months, del(3q) 13 months, 3p 10 months, monosomy 3 9 months, and other 3 abnormalities 11 months. There was no survival difference between patients with translocations of 3q21 versus 3q26 (median OS 18 months versus 18.6 months, P = 0.96). Patients with an isolated chromosome 3 abnormality had significantly improved OS (25.1 months versus 10.9 months (P < 0.00001). Complex karyotype (>/= 3 abnormalities) was observed in 74% of patients and was associated with decreased OS (11 months versus 21 months, P < 0.00001). Of patients who received HMA therapy (48%), the overall response rate was 46% (17% hematological improvement (HI), 7% PR, 20% CR, 2% marrow CR (CRm) with stable disease in 23%). Median OS with and without HMA was 15.5 months versus 8.4 months (p=0.038). In int-2/high risk patients by IPSS, HMA treated patient had a median OS of 14.0 months versus 7.6 months for patients not treated with HMAs (P = 0.005) with no benefit for HMAs in lower-risk patients (median OS 24.5 months with HMA versus 38.7 months without; P =0.41). Cox regression modeling with HMA therapy, IPSS and clinical site confirmed the HMA OS benefit in higher-risk patients (HR 0.69; 95% CI 0.53-0.89; P = 0.005), but showed decreased OS in lower-risk patients (HR 2.0; 95% CI 1.03-3.92; P = 0.04). Allogeneic transplantation was performed in 18% (n=75) of patients, with median OS of 18 months versus 10 months in non-transplanted patients (P < 0.00001). Conclusion In this large cohort of patients with MDS and oligoblastic AML associated with chromosome 3 abnormalities, survival was heterogeneous but overall poor, with isolated chromosome 3 abnormality and t(3q) patients having a more favorable OS than patients with other chromosome 3 anomalies. MDS patients with 3p changes have poor outcomes. Although some patients with chromosome 3 respond to HMA therapy, the overall survival remains poor and novel approaches are needed. Disclosures Sekeres: Amgen: Membership on an entity's Board of Directors or advisory committees; 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. Steensma:Amgen: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Onconova: Consultancy. Lancet:Boehringer-Ingelheim: Consultancy; Kalo-Bios: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy. List:Celgene Corporation: Honoraria, Research Funding. Komrokji:Incyte: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau.

Download Full-text

Mutation Profiles Identify Distinct Clusters of Lower Risk Myelodysplastic Syndromes with Unique Clinical and Biological Features and Clinical Endpoints

Blood ◽

10.1182/blood-2020-138549 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 29-29

Author(s):

Luca Malcovati ◽

Simon Crouch ◽

Aniek O. De Graaf ◽

Sarah Sandmann ◽

Magnus Tobiasson ◽

...

Keyword(s):

Risk Assessment ◽

Disease Progression ◽

Board Of Directors ◽

Clinical Features ◽

Myelodysplastic Syndromes ◽

Lower Risk ◽

Research Funding ◽

Information Criterion ◽

Advisory Committees ◽

The Right

Background. The severity of hematopoietic impairment and the kinetics of disease progression in lower risk myelodysplastic syndromes (LR-MDS) are extremely variable. Genomic profiling has the potential to inform the clinical management of these disorders, including improved classification, risk assessment and therapeutic choice. In the present study, based on a comprehensive mutation analysis in a large and clinically well-characterized cohort of LR-MDS patients, either recruited into the European MDS Registry or referred to European excellence centers involved in the MDS-RIGHT project, we adopted unsupervised hierarchical clustering analyses to identify relevant genetically defined disease subtypes within early stage MDS. Methods. The dataset comprised 856 cases identified as LR-MDS based on IPSS risk low or intermediate-1. Median age was 73 years (range 36-98); IPSS-R risk was very low in 30.1% of patients, low in 50.4%, intermediate in 19.5%. We investigated possible sub-structure amongst patients according to their mutational profiles, and correlated this sub-structure with relevant endpoints. For this analysis, unsupervised clustering was used, based on a mixture model of multivariate Bernoulli distributions. The optimal number of clusters was chosen using the Bayes Information Criterion (BIC), with secondary structure identified with the Akaike Information Criterion (AIC). Results. This analysis identified three distinct clusters within LR-MDS. Cluster 1 comprised exclusively patients with SF3B1 mutation, either isolated or associated with other mutations (SF3B1-mutant cluster) (37% of patients). Cluster 2 was characterized by excess mutations associated with higher risk disease (high-risk (HR) cluster) (27% of patients), including a significantly higher prevalence of ASXL1, IDH1/IDH2, SRSF2, RUNX1, CBL and EZH2 mutations (P<.001). This cluster also showed a significantly higher number of mutations per patient compared to other groups (P<.001), suggesting a subtending clonal progression resulting in the accumulation of sub-clonal mutations. Finally, cluster 3 was characterized by mutation profiles as observed in Clonal Hematopoiesis of Indeterminate Potential (CHIP) (CHIP-like cluster) (36% of patients), mainly including isolated DNMT3A, TET2 or ASXL1 mutations, pointing toward the contribution of extra-clonal factors to disease expressivity. In addition, this cluster showed enrichment in TP53 mutations, as recently reported in community-dwelling elderly individuals with unexplained anemia (Blood 2020;135:1161-70). The three recognized clusters showed distinct clinical features and outcome measures. Patients within HR cluster were significantly older (P=.008) and showed significant enrichment in WHO categories with multi-lineage dysplasia and excess blasts (P<.001) and IPSS-R intermediate risk scores (P<.001), as well as significantly lower platelet count (P=.001). Conversely, patients within the CHIP-like cluster showed significantly higher hemoglobin values compared with the other two clusters (P=.001). As expected, the SF3B1-mutant cluster was significantly enriched for MDS with ring sideroblasts (MDS-RS) and showed significantly lower hemoglobin values (P=.001) and increased values of serum ferritin and transferrin saturation compared to other clusters (P=.001 and P=.002, respectively). HR-cluster showed significantly lower overall survival (OS) compared to CHIP-like and SF3B1-mutant clusters (median 2.6 vs 6.8 or 6.4 years; P<.001), and higher risk of progression into higher-risk MDS or acute myeloid leukemia (AML) (median 4.2 vs 12.7 years or not reached; P<.001). No significant difference in either OS or risk of disease progression was noticed between SF3B1-mutant and CHIP-like clusters. However, a significantly shorter time-to-treatment with erythropoiesis stimulating agents was noticed in the SF3B1-mutant cluster (P=.007), suggesting a more rapid erythropoietic impairment that did not translate into a worse outcome. Conclusion. Mutation profiling identifies meaningful clusters of lower risk MDS with distinct molecular pathways, clinical features and endpoints. These results represent a robust basis to inform genetic ontogeny-based classification and individual risk assessment, as well as to inspire biology-driven clinical trials in lower risk MDS. Disclosures Symeonidis: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; WinMedica: Research Funding; Celgene: Honoraria, Research Funding; Astellas: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stauder:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Research Funding. Fenaux:Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Van Marrewijk:EUMDS and MDS-RIGHT (Providing the right care to the right patient with MyeloDysplastic Syndrome at the right time) project: Other: Project manager of the EUMDS Registry.

Download Full-text

Clinical Parameters in 391 Iron-Overloaded Patients with Lower-Risk MDS Enrolled in a Prospective, Non-Interventional Multicenter Registry.

Blood ◽

10.1182/blood.v114.22.4834.4834 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4834-4834

Author(s):

Guillermo Garcia-Manero ◽

Billie J. Marek ◽

Roger M. Lyons ◽

Noelia Martinez-Lopez ◽

Carole Paley ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Serum Ferritin ◽

Lower Risk ◽

Research Funding ◽

Chelation Therapy ◽

Iron Chelation ◽

Iron Chelation Therapy ◽

Advisory Committees ◽

The Impact

Abstract Abstract 4834 Introduction Despite recent improvements in therapies for patients with myelodysplastic syndromes (MDS), 60–80% will require continuing packed red cell blood (pRBC) transfusions for prolonged periods. Complications resulting from the iron burden may, therefore, become clinically significant for many patients during the course of their disease. Patients with lower-risk MDS have a greater chance of developing the long-term toxicity of iron overload because of their prolonged survival, and are more likely to benefit from effective iron chelation therapy. This report describes data from a registry designed to study the impact of iron overload and iron chelation therapy on organ function and survival in patients with lower-risk MDS. Methods This is an ongoing, prospective, non-interventional, multicenter 5-year registry in 107 US centers, enrolling 600 patients (aged ≥18 years) with lower-risk MDS (by WHO, FAB and/or IPSS criteria) and transfusional iron overload (defined as serum ferritin ≥1000 μg/L and/or having received ≤20 cumulative pRBC units and/or an ongoing transfusion requirement ≥6 units every 12 weeks). Follow-up will be performed at least every 6 months for a maximum of 60 months or until death. Recommended assessments include serum ferritin, creatinine, calculated creatinine clearance, echocardiograms, and endocrine and hematological status. Results As of May 31 2009, 391 patients have enrolled in the registry. Demographic data are available from 389 patients. Median age: 74.4 years (range 21–99); male: 218, female: 171; ethnicity: 331 Caucasian (85%), 25 African-American (6%), 24 Hispanic (6%), five Asian (1%), two Native American (0.5%), and two other (0.5%). The median time since diagnosis (n=385) was <3 years in 217 patients (56%); ≥3–<5 years in 72 (19%); ≥5–<7 years in 48 (12%); and ≥7 years in 48 (12%). The MDS classification of the patients by WHO, FAB and IPSS, as well as patients' serum ferritin and transfusion burden, are summarized in the table. The most frequent concomitant conditions classified by organ (n=384 patients) were: 205 (53%) patients with vascular, 160 (42%) endocrine, and 171 (45%) cardiac dysfunction. At registry entry, 249 patients were receiving erythropoietin; 61 granulocyte colony stimulating factor; seven hydroxyurea; 25 thalidomide (Thalomid); 147 5-azacytidine (Vidaza); 95 lenalidomide (Revlimid) and 90 decitabine (Dacogen). 137 of 391 (35%) patients were on iron chelation therapy at study entry: 34 (9%) received deferoxamine for mean and median treatment durations of 803 and 383 (range 1–4386) days, respectively, while 117 (30%) received deferasirox for mean and median durations of 488 and 396 (9–1269) days, respectively. Calculated creatinine clearance was normal (>80 mL/min) in 37 (9%) patients; mildly abnormal (51–80 mL/min) in 30 (8%); and moderately abnormal (30–50 mL/min) in nine (2%) patients. Conclusions These baseline data indicate the demographic distribution as well as the co-morbidities associated with lower-risk MDS patients. In spite of recent guidelines, fewer than 50% of iron-overloaded patients are receiving any iron chelation treatment, despite the presence of cardiac, vascular and endocrine concomitant conditions in 40-54% of patients. Recent retrospective data highlights the impact of chelation on mortality in lower-risk MDS patients. This ongoing registry will prospectively assess the impact of iron chelation on survival and organ function in iron-overloaded patients with lower-risk MDS. Disclosures Lyons: Novartis: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genzyme: Research Funding. Martinez-Lopez:Novartis Pharmaceuticals: Employment. Paley:Novartis Pharmaceuticals: Employment, Equity Ownership. Greenberg:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Gender Disparities in Myelodysplastic Syndromes: Phenotype, Genotype, and Outcomes

Blood ◽

10.1182/blood-2021-149894 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1984-1984

Author(s):

Sara Marie Tinsley-Vance ◽

Najla Al Ali ◽

Somedeb Ball ◽

Luis E. E. Aguirre ◽

Akriti G Jain ◽

...

Keyword(s):

Gender Differences ◽

Overall Survival ◽

Data Base ◽

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Lower Risk ◽

Research Funding ◽

Cancer Center ◽

Advisory Committees ◽

Men And Women

Abstract BACKGROUND: Over the past 25 years research has shifted from predominantly focused on men to research that includes both men and women. In addition, myelodysplastic syndromes (MDS) have only been included in the SEER registry since 2001 and are largely understudied. This has resulted in a knowledge gap in the difference in clinical phenotype, genotype, and outcomes between men and women diagnosed with MDS. The aim of this abstract is to identify those gender-based differences. METHODS: This was a retrospective study using a large MDS database at Moffitt Cancer Center. We compared baseline clinical and molecular characteristics and outcomes based on gender. Chi-square tests were used for comparing categorical variables and t-test for continuous variables. Kaplan-Meier method was used to compare survival. RESULTS: The Moffitt Cancer Center MDS data base includes 4413 patients among whom 2922 (66%) were men and 1658 (34%) were women. Table-1 summarizes baseline characteristics based on gender. Women were slightly younger (mean age at diagnosis 66.5 versus 69 years for men, p < 0.001). There were more Hispanic/black women than men (9% versus 5%, p =<0.001). Women had slightly lower hemoglobin (mean Hgb 9.4 versus 9.8 g/dl for men, p=0.032) and higher platelet count (mean platelets count 171 versus 136, p < 0.001). More women had del 5/monosomy abnormalities compared to men (p=<0.001), with 353 women (25%) affected. Therapy-related MDS also occurred more often in women (p=<0.001) 413 (25%). More women had isolated del5 q by WHO 2016. (6% vs 2%, p=<0.001). There was no difference in disease risk based on R-IPSS. There were gender differences in molecular profile. (Table-2). SRSF2 mutation, U2AF1 mutation, ZRSR2 mutation, ASXL1 mutation, and RUNX1 mutations were observed more frequently in men. ZRSR2 was expected. The median overall Survival (mOS) was longer for women in lower-risk MDS, but not in higher-risk MDS. (Figure- 1 and 2) The overall mOS was 37.5 months (mo) for females compared to 35 mo for males, p=0.002). The mOS for very/low R-IPSS was 81 and 62 mo, for intermediate risk R-IPSS 35 mo vs 33 mo, and for high/very high-risk R-IPSS 16.7 versus 17.4 mo respectively for females and males (p< 0.001). The rate of AML transformation was not different (32% and 34%, respectively for women and men, p =0.16). Women were more likely response to ATG/CSA than men (38% versus 19%, p= 0.04) There were no differences in response to erythroid stimulating agents, hypomethylating agents, lenalidomide treatment or rate of allogeneic hematopoietic stem cell transplant (AHSCT). CONCLUSION: This retrospective review of a large data base of MDS patients highlights important gender differences in clinical and molecular MDS disease features. We identified differences in rates of selected somatic mutations. Men had more splicing machinery mutations, ASXL-1, and RUNX-1 mutations. Women had better overall survival mainly in lower risk MDS and higher responses to immunosuppressive therapy. Acknowledgement of Funding: NINR Grant # 1K23NR018488-01A Figure 1 Figure 1. Disclosures Tinsley-Vance: Novartis: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Taiho: Consultancy; Fresenius Kabi: Consultancy; Abbvie: Honoraria; Astellas: Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Padron: Kura: Research Funding; Blueprint: Honoraria; Stemline: Honoraria; BMS: Research Funding; Taiho: Honoraria; Incyte: Research Funding. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet: Daiichi Sankyo: Consultancy; Agios: Consultancy; Astellas: Consultancy; AbbVie: Consultancy; ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy; BerGenBio: Consultancy; Celgene/BMS: Consultancy; Jazz: Consultancy. Kuykendall: BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Prelude: Research Funding; PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sallman: Syndax: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau. Komrokji: Geron: Consultancy; Acceleron: Consultancy; AbbVie: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Improved Survival with Iron Chelation Therapy for Lower IPSS Risk MDS Appears to Have a Stronger Association in Patients with a Non-RARS Diagnosis

Blood ◽

10.1182/blood.v118.21.1732.1732 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1732-1732

Author(s):

Heather A Leitch ◽

Christopher Chan ◽

Chantal S Leger ◽

Lynda M Foltz ◽

Khaled M Ramadan ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Chelation Therapy ◽

Ferritin Level ◽

Iron Chelation ◽

Iron Chelation Therapy ◽

Advisory Committees

Abstract Abstract 1732 Background: Several retrospective analyses suggest that transfusional iron overload portends inferior survival in lower risk MDS and that iron chelation therapy (ICT) is associated with improved survival in this group of patients. However an analysis of 126 patients with RARS from the Mayo Clinic showed no association between elevated ferritin level at diagnosis or transfusion burden on overall survival (OS). We performed a retrospective analysis of 268 MDS patients seen at our center to determine whether an association between transfusional iron overload or receiving iron chelation therapy (ICT) and survival differed between RARS and other lower risk MDS. Methods: Patients were identified from the clinical database of the hematology practice. Patients with a diagnosis (dx) of MDS confirmed by bone marrow biopsy (bmbx) were included. Clinical and laboratory data were collected by retrospective chart review. Survival analyses were performed using SPSS version 19. Results: 268 patients with a bmbx confirmed diagnosis of MDS by WHO or FAB criteria were identified. The following patients were excluded: uncertain IPSS score, n=35; intermediate-2 risk, n=33; high risk, n=16; RAEB-t, n=3; concomitant diagnosis of advanced stage non-Hodgkin lymphoma of uncertain type, n=1. The remaining 182 patients had the following characteristics: median age 69.5 (range 30–94) years and 109 (69.9%) were male. Specific MDS dx were: RA, n=27; RARS, n=53; RCMD, n=34; RAEB, n=15; MDS-U, n=22; hypocellular MDS, n=6; 5Q- syndrome, n=6; CMML, n=21. IPSS scores for all patients were: intermediate-1, n=101; low, n=74; uncertain (but IPSS score not >1.0), n=7. The marrow blast count was 6–9 x109/L in 4 patients and <5 x109/L in all others. Specific MDS treatment (rx) was: supportive care, n=82; erythropoiesis stimulating agents (ESA), n=22; immunosuppressive therapy (IST), n=10; lenalidomide, n=7; and chemotherapy, n=6. 137 patients received RBC transfusions and 38 received ICT: deferasirox (DFX), n=19; deferoxamine (DFO), n=9; DFO followed by DFX, n=9; and DFX followed by DFO, n=1. The median duration of ICT was 10.5 (range 0.5–64) months. Clinical features significantly associated with OS in univariate analyses of all 182 patients included: specific MDS dx; IPSS score; total number of red blood cell (RBC) units transfused over the course of follow-up; receiving ICT; specific MDS rx received; requirement for hospitalization; experiencing at least one episode of infection; and AML transformation (P</=0.01 for all); serum ferritin level >1000ng/mL was not significant in this analysis (P=not significant [NS]). In a multivariate analysis (MVA), the following factors remained significant for OS: specific MDS dx; IPSS score; receiving ICT; specific MDS rx; and AML transformation (P</=0.01 for all). In an MVA stratified for RARS, significant were: specific MDS dx (P<0.0001); IPSS score (P=0.005); specific MDS rx (P=0.038) and receiving ICT (P=0.039). At a median follow-up of 28 (0.1–245.9) months, 121 patients were alive (non-RARS, n=83 [64.3%]; RARS, n=38 [71.6%]) and the projected median OS for all patient was 99 months. The projected median OS for non-RARS patients without ICT and with ICT was 44 months and not reached (NR), respectively, and for RARS without and with ICT was 99 and 134.4 months (P<0.0001). The 5 year OS in these four groups was 39.2% and 91.7% (P=0.04); and 72.4% and 76.3%, respectively (P=NS). However, when RARS ICT patients were compared to only RBC transfusion dependent RARS patients not receiving ICT, the median OS was 73.8 vs 134.4 months, respectively, and 5 year OS was 59.9% and 76.3%, respectively (P=0.025). Conclusions: These results suggest an association between receiving iron chelation therapy and survival in lower IPSS risk MDS, in keeping with prior analyses. However, the association between ICT and OS in non-RARS MDS appeared to be stronger than in RARS, in keeping with data from Mayo suggesting transfusional iron overload may not have a major association with outcome in RARS. The median follow-up in the current study was just over 2 years, and median duration of ICT only 10.5 months; longer follow-up may be needed in RARS to determine whether ICT is potentially beneficial in this subgroup of patients with a relatively long expected survival. As with all retrospective analyses, these results must be considered hypothesis generating, and prospective trials are needed for firm conclusions to be drawn. Disclosures: Leitch: Novartis Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Iron chelation agents for the treatment of transfusional iron overload in MDS. Vickars:Novartis Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Iron Chelation and Ferritin below 500 Mcg/L in Transfusion Dependent Thalassemia: Beyond the Limits of Clinical Trials

Blood ◽

10.1182/blood-2019-130237 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3542-3542 ◽

Cited By ~ 1

Author(s):

Natalia Scaramellini ◽

Carola Arighi ◽

Alessia Marcon ◽

Dario Consonni ◽

Elena Cassinerio ◽

...

Keyword(s):

Clinical Practice ◽

Liver Function ◽

Iron Overload ◽

Board Of Directors ◽

Chelation Therapy ◽

Iron Chelation ◽

Published Data ◽

Iron Chelation Therapy ◽

Iron Intake ◽

Advisory Committees

Introduction The current therapeutic management of transfusion dependent thalassemia (TDT) is based on regular blood transfusion and iron chelation therapy. Transfusion iron overload remains one of the major causes of morbidity and mortality in these patients because of the accumulation in heart, liver and endocrine glands. Three iron chelators are available in clinical practice: deferoxamine (DFO), deferiprone(DFP) and deferasirox (DFX). Guidelines clearly recommend when to start iron chelation, while discontinuation criteria are not well defined. Authorised product information state that we should consider interrupting DFX if serum ferritin (SF) falls consistently below 500mcg/L. This cut off was arbitrarily determined and there are no studies evaluating the effects of chelators in presence of SF below 500 mcg/L. In our clinical practice at Rare Diseases center of Fondazione IRCCS Ca' Granda Policlinico in Milan we do not completely interrupt iron chelation in TDT patients for SF levels below 500 mcg/L. Aims and methods Aim of our study was to evaluate the appearance of adverse events due to the assumption of iron chelation therapy in those TDT patients who had SF below 500 mcg/L. In this study we retrospectively evaluated renal and liver function from 2008 throughout December 2018 in TDT patients on DFX who presented SF below 500 mcg/L for 24 consecutive months. DFX dose are all expressed with the new tablets formulation dose. We evaluated SF, iron intake, LIC and MIC, renal and hepatic function. .A total of 5076 observations were collected, with 99.5 average per patient. We evaluated the relationships among variables with correlation models with random intercept Results One hundred ninety-two TDT patients are regularly followed at our center. They receive regular transfusion treatment and iron chelation therapy to prevent secondary iron overload. 51 out of 192 patients (32 F, 19 M, aged 44 ± 7 years) treated with DFX presented mean SF below 500 mcg/L for at least 24 consecutive months. Hematological and iron status parameters are described in Table 1. We found a strong correlation between SF and LIC (p<0.001) and for SF<500 mcg/L no hepatic iron overload was observed. Conversely we did not found a correlation between SF and MIC. For SF values below 500 mcg/L there was a minimal increase in creatinine levels, however the mean creatinine values remained within the normal range.Moreover, creatinine variation between two consecutive evaluation was below 0.3 mg/dl, cut off for acute kidney injury. Similar results were observed for liver function. Although a minimal increase of mean ALT value was observed for SF below 500 mcg/L, it remained within the normal range. None of our patient showed ALT level indicative of liver damage (ALT> 10 x upper limit of normal) We evaluated the relation between SF and DFX dose. Mean DFX dose decreases according to SF reduction. However, for SF value < 240 mcg/L, DFX dose remained stable at an average of 14 mg/kg per day. Conclusion According to our preliminary data, administration of DFX in TDT patients in presence of SF below 500 mcg/L is safe. Creatinine and ALT fluctuations, that usually remain within the range of normality, are mild, and transient and do not require specific treatment. Consistently with previously published data by Cohen et al, we show that a mean dosage of DFX of 14 mg/Kg die of film-coated tablet (20 mg/Kg of dispersable formulation) are necessary to balance an iron intake of 0.3 mg/kg die in absence of iron overload. Based on these results we suggest that in TDT patients with a continuous iron intake, iron chelation should be continued even when ferritin is below 500mcg/L. Monitoring of liver and kidney function tests are recommended in patient's follow up, as well as tailoring iron chelation. Disclosures Cappellini: Vifor Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Genzyme/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Motta:Sanofi-Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Safety and Effectiveness of Apixaban, LMWH, and Warfarin Among Venous Thromboembolism Patients with Active Cancer: A Retrospective Analysis Using Four US Claims Databases

Blood ◽

10.1182/blood-2019-121769 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 326-326 ◽

Cited By ~ 1

Author(s):

Alexander T Cohen ◽

Allison Keshishian ◽

Theodore Lee ◽

Gail Wygant ◽

Lisa Rosenblatt ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Lower Risk ◽

Select Committee ◽

Advisory Committees ◽

Recurrent Vte ◽

High Risk Cancer ◽

Similar Risk ◽

Active Cancer

BACKGROUND: Venous thromboembolism (VTE) is the second leading cause of death in cancer patients. The treatment of cancer-associated VTE carries a significantly greater risk of major bleeding (MB) and recurrent VTE compared to that in non-cancer patients. CHEST Guidelines suggest the use of low molecular weight heparin (LMWH) over a vitamin K antagonist (VKA) in patients diagnosed with VTE and cancer. The last decade has seen an emergence of non-VKA anticoagulants (NOACs) for the treatment of VTE. Despite completed and ongoing clinical trials, there is a lack of real-world evidence comparing the effectiveness and safety of LWMH with VKAs and NOACs among VTE patients with active cancer. Therefore, this study evaluates the risk of MB, clinically relevant non-MB (CRNMB), and recurrent VTE (fatal or non-fatal) among VTE patients with active cancer prescribed apixaban, LMWH, or warfarin in routine clinical practice. METHODS: Four US commercial insurance claims databases were used to identify VTE patients with active cancer (defined as cancer diagnosis or cancer treatment [chemotherapy, radiation and cancer-related surgery] within 6 months before or 30 days after VTE diagnosis) who initiated apixaban, LMWH, or warfarin within 30-days following the first VTE event (01SEP2014-31MAR2018). Patients who used LMWH as bridging therapy for warfarin (≤14 days before or after warfarin initiation) were classified as warfarin users. Patients were followed to the earliest of: health plan disenrollment, death, index therapy discontinuation, switch to another anticoagulant, study end, or a maximum of 6 months. Additional analysis using all available follow-up was also conducted. Stabilized inverse probability treatment weighting (IPTW) was used to balance treatment cohorts. Cox proportional hazard models were used to evaluate the risk of MB, CRNMB, and recurrent VTE. RESULTS: After applying all eligibility criteria, 3,393 apixaban, 6,108 LMWH, and 4,585 warfarin patients were identified with mean ages of 65, 64, and 64 years, respectively. After IPTW, all patient characteristics were balanced. The mean follow-up was 105, 88, and 113 days for apixaban, LMWH, and warfarin, respectively. Among the weighted VTE cancer population, 51% of the patients had metastatic cancer and 77% of patients received cancer treatment. Further, 15% of patients had very high-risk cancer (brain, stomach, or pancreas), and 40% patients had high-risk cancer (lung, lymphoma, gynecologic, bladder, testicular, renal cell carcinoma). Apixaban patients had a lower risk of MB, CRNM bleeding, and recurrent VTE compared to LMWH. Apixaban patients also had a lower risk of recurrent VTE and a similar risk of MB and CRNM bleeding compared to warfarin. Warfarin patients had a similar risk of MB, CRNM bleeding, and recurrent VTE compared to LMWH (Figure). When the entire available follow-up period (mean follow-up was 137, 106, and 166 days for apixaban, LMWH, and warfarin, respectively) was used, the trends were similar to the 6-month analysis for apixaban vs. LMWH and warfarin vs. LMWH. However, apixaban patients were associated with a lower risk of both MB and recurrent VTE compared to warfarin patients. CONCLUSION: VTE patients with active cancer initiating apixaban had significantly lower risk of MB, CRNM bleeding, and recurrent VTE compared to LMWH patients. Apixaban patients also had a lower risk of recurrent VTE compared to warfarin patients. These results may be helpful for clinicians in evaluating different anticoagulation treatments for VTE patients with active cancer. Further studies are needed to evaluate these outcomes between different anticoagulation treatment options. Figure Disclosures Cohen: Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Temasek Capital: Consultancy; ACI Clinical: Consultancy; Navigant: Consultancy; McKinsey: Consultancy; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy; Aspen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boston Scientific: Consultancy; Boehringer-Ingelheim: Consultancy, Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; GLG: Consultancy; Guidepoint Global: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy; Medscape: Consultancy, Speakers Bureau. Keshishian:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Bristol-Myers Squibb Company and Pfizer Inc.. Lee:Pfizer Inc.: Employment, Equity Ownership. Wygant:Bristol-Myers Squibb Company: Employment. Rosenblatt:Bristol-Myers Squibb: Other: Stock Owner ; Bristol-Myers Squibb Company: Employment. Hlavacek:Pfizer Inc.: Employment. Mardekian:Pfizer Inc.: Employment. Wiederkehr:Pfizer Inc.: Employment. Sah:STATinMED Research: Other: I am a paid employee of STATinMED Research which is a paid consultant to Bristol-Myers Squibb Company and Pfizer Inc.. Luo:Pfizer Inc.: Employment.

Download Full-text

To Treat or Not to Treat? Understanding Treatment Patterns in Patients with Lower-Risk Myelofibrosis at the Time of Enrollment in the MOST Study

Blood ◽

10.1182/blood-2020-134958 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 49-51

Author(s):

Rami S. Komrokji ◽

Brady L. Stein ◽

Robyn M. Scherber ◽

Patricia Kalafut ◽

Haobo Ren ◽

...

Keyword(s):

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Symptom Burden ◽

Risk Groups ◽

Treatment Patterns ◽

Low Risk ◽

Publicly Traded ◽

Advisory Committees ◽

Therapy Initiation

Background: Myelofibrosis (MF) is a chronic Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) characterized by extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly, constitutional symptoms, and diminished quality of life. Treatment decisions may involve a variety of factors including prognosis and symptomatology. Data regarding real-world disease and demographic factors that contribute to therapy initiation and choice in pts with lower risk MF are limited. This analysis of data from the ongoing Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST; NCT02953704) assessed whether these factors differ for lower risk pts who were treated vs untreated at enrollment. Methods: MOST is a longitudinal, noninterventional, prospective, observational study in pts with MF or essential thrombocythemia enrolled at clinical practices within the US. Pts included in the analysis (≥18 y), had low risk MF by the Dynamic International Prognostic Scoring System (DIPSS; Blood. 2010;115:1703), or intermediate-1 (INT-1) risk by age >65 y alone. Pt data were entered into an electronic case report form during usual-care visits over a planned 36-month observation period. Pt-reported symptom burden was assessed using the MPN-Symptom Assessment Form (MPN-SAF); Total Symptom Score (TSS) was calculated (0 [absent] to 100 [worst imaginable]; J Clin Oncol. 2012;30:4098). Data were analyzed with basic descriptive and inferential statistics. Results: Of 233 pts with MF enrolled at 124 sites between 11/29/2016 and 03/29/2019, 205 were included in this analysis; 28 were excluded for being INT-1 risk for reasons other than age. Of the 205 pts, 85 (41.5%) were low- and 120 (58.5%) were INT-1 risk; 56.5% (48/85) and 59.2% (71/120), respectively, were being treated at enrollment. Pt characteristics are listed in Table 1A. Fewer low- vs INT-1 risk pts were JAK2 V617F or MPL positive, and more were CALR positive. The proportion of pts with palpable splenomegaly was similar for treated low- and INT-1 risk pts. In low risk pts, the proportion of pts with palpable splenomegaly was higher in untreated vs treated pts; whereas, in INT-1 risk pts, the opposite was observed (ie, lower proportion in untreated vs treated pts). Blood counts were generally similar across cohorts, except median leukocytes were lower for low risk treated pts and platelet counts were elevated in low- vs INT-1 risk pts. The proportion of pts with comorbidities was similar across cohorts, except for fewer cardiovascular comorbidities in low- vs INT-1 risk pts. Mean TSS was lower in low- vs INT-1 risk pts, but the proportion of pts with TSS ≥20 was greater in treated vs untreated pts in both low- and INT-1 risk groups. Fatigue was the most severe pt-reported symptom in all cohorts. Differences in mean TSS and individual symptom scores between risk groups were not significant (P > 0.05), except itching was worse among INT-1 risk pts (P=0.03). Physician-reported signs and symptoms were generally more frequent for untreated vs treated pts, irrespective of risk (all P > 0.05). Most low risk (69.4%) and INT-1 risk pts (61.2%) who were currently untreated at enrollment had not received any prior MF-directed treatment (Table 1B); the most common prior treatment among currently untreated pts was hydroxyurea (HU) in both risk groups. Of currently treated pts, HU was the most common MF-directed monotherapy at enrollment in low-risk pts, and ruxolitinib was most common in INT-1 risk pts. No low risk pts and few INT-1 risk pts were currently receiving >1 MF-directed therapy at enrollment. Conclusion: These real-world data from pts with MF enrolled in MOST show that a substantial proportion of both low- and INT-1 risk pts who had received treatment before enrollment were not being treated at the time of enrollment. Although watch-and-wait is a therapeutic option, the finding that many of these lower risk pts had in fact received prior therapies suggests an unmet need for effective and tolerable second-line treatment options. Treated pts had greater pt-reported symptom burden vs untreated pts, which suggests that high symptom burden may contribute to the decision for treatment. Prospective studies are needed to evaluate symptom burden change with therapy initiation. In this regard, future analyses of data from MOST are planned to assess the longitudinal evolution of the clinical characteristics, treatment patterns, and management of pts with MF. Disclosures Komrokji: Geron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Acceleron: Honoraria. Stein:Incyte: Research Funding; Kartos: Other: educational content presented; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmaessentia: Membership on an entity's Board of Directors or advisory committees. Scherber:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Kalafut:Incyte: Current Employment, Current equity holder in publicly-traded company. Ren:Incyte: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; CTI Biopharma Corp: Research Funding; NS Pharma: Research Funding; ItalPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding.

Download Full-text

A Phase I/II, Open-Label, Dose-Escalation Trial of Once-Daily Oral Chelator Deferasirox to Treat Iron Overload in HFE-Related Hereditary Hemochromatosis: Final Results of the Core Study.

Blood ◽

10.1182/blood.v114.22.1514.1514 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1514-1514 ◽

Cited By ~ 1

Author(s):

Pradyumna D. Phatak ◽

Pierre Brissot ◽

Herbert Bonkovsky ◽

Mark Wurster ◽

Lawrie Powell ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Dose Escalation ◽

Safety Profile ◽

Research Funding ◽

Hereditary Hemochromatosis ◽

Advisory Committees ◽

The Core ◽

Upper Limit ◽

Dose Dependent

Abstract Abstract 1514 Poster Board I-537 Background and aims Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by progressive iron overload through increased intestinal absorption. Phlebotomy treatment is the standard of care, but compliance is variable and some patients are poor candidates due to underlying medical disorders and/or poor venous access. An oral iron chelator such as deferasirox (Exjade®) may provide an alternative treatment option for HH patients. Methods This is an inter-patient dose-escalation study of deferasirox (5, 10, 15 and 20 mg/kg) administered daily for 24 weeks to C282Y HFE homozygous HH patients with a pre-treatment serum ferritin (SF) value of 300–2000 ng/mL, transferrin saturation ≥45% and no known history of cirrhosis. A 6-month extension of this trial has recently been completed. The primary endpoint is the incidence and severity of adverse events (AEs). Secondary endpoints include change in SF, time to SF normalization (<100 ng/mL), longitudinal course of SF, and pharmacokinetics of deferasirox. Results 49 patients were enrolled and 48 patients were treated (33 men, 16 women; mean age 50.6 years; mean of 3.1 years since HH diagnosis) with deferasirox 5 (n=11), 10 (n=15) or 15 mg/kg/day (n=23) for at least 24 weeks. 37 (75.5%) patients completed the study (10 [90.9%], 11 [73.3%]; 16 [69.6%] patients in the 5, 10 and 15 mg/kg/day groups, respectively. The most common reasons for discontinuation were AEs in 3 (20.0%) patients and 4 (17.4%) patients in the 10 and 15 mg/kg/day groups, respectively. Bayesian analysis and medical review were performed between dose escalations. Meaningful reductions in SF were observed across the first three dose groups (median decrease -31.1%, -52.8% and -55.4% in the 3 groups respectively), and escalation to 20 mg/kg/day was not undertaken. Time course of the SF decline was dose-dependent (Figure). AEs in the core were dose dependent and consistent with the known safety profile of deferasirox. The most common drug-related AEs (≥10% in all patients) reported were diarrhea in 1 (9%), 4 (27%) and 9 (39%) patients, nausea in 0 (0%), 2 (13%) and 4 (17%) patients and abdominal pain in 0 (0%), 2 (13%), 3 (13%) patients in the 5, 10 and 15 mg/kg/day groups, respectively. One patient had ALT >5X upper limit of normal, and 11 patients had serum creatinine ≥33% over baseline and upper limit of normal on two consecutive occasions. All resolved with dose cessation or modification. Conclusions The results from the CORE trial suggest that deferasirox doses of 5, 10 and 15 mg/kg/day are effective at reducing iron burden in HH patients. Based on the safety profile, only the 5 and 10 mg/kg/day doses are being considered for further study in this population. The results of the 24 week extension phase will be available at the time of the meeting. Larger studies are required to define the appropriate treatment regimen in HH. Disclosures Phatak: Novartis: Honoraria, Speakers Bureau. Brissot:Novartis: Honoraria, Research Funding. Bonkovsky:Boehringer-Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Clinuvel: Consultancy; Lundbeck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Merck: Research Funding; Roche: Research Funding; Vertex: Research Funding. Niederau:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Adams:Novartis: Honoraria. Griffel:Novartis: Employment, Equity Ownership. Lynch:Novartis Pharmaceuticals: Employment. Schoenborn-Kellenberger:Novartis Pharma AG: Employment.

Download Full-text

The Tolerability of Combination Therapy with Thalidomide and 5-Azacitidine in Patients with Advanced Myelodysplastic Syndromes (MDS).

Blood ◽

10.1182/blood.v114.22.1749.1749 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1749-1749 ◽

Cited By ~ 1

Author(s):

Melita K Kenealy ◽

John F Seymour ◽

Cowan Linda ◽

Alvin Milner ◽

Pratyush Giri ◽

...

Keyword(s):

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Standard Dose ◽

Performance Status ◽

Single Agent ◽

Median Number ◽

Respiratory Disorder ◽

Advisory Committees ◽

Impaired Performance

Abstract Abstract 1749 Poster Board I-775 Introduction Both thalidomide (Thal) and 5-azacitidine (Vidaza; AZA) have single-agent activity in patients (pts) with myelodysplastic syndromes (MDS), but there is limited experience with the combination. The addition of Thal to AZA may improve efficacy, but tolerability of the combination may be limited by side-effects. Patients and Methods This analysis included all evaluable pts on the Ph I/II Australasian Leukaemia and Lymphoma group (ALLG) MDS3 study of Thal and AZA. Pts were eligible if they had any FAB subtype of MDS; those with RA and RARS also required clinically significant cytopenias. Pts were excluded if they had previously received Thal or its derivatives or any demethylating agent. All pts were treated with Thal 50mg/d for the first 28d increasing to 100mg/d for a max of 12 Mo treatment and AZA 75mg/m2/d x7d every 28d until progression or prohibitive toxicity. The protocol specified dose delays or reductions for treatment-related toxicities. Results A total of 80 pts have been enrolled, with 41 treated between 7/08 – 7/09 currently evaluable. Median age is 68.5y (42-81) with 66% male. FAB MDS category was RA 15%, RARS 10%, RAEB 46%, RAEB-t 10% and CMML 17% with IPSS low 12%, intermed-1 37%, intermed-2 34% and high 12%. Median baseline Hb 88g/L (71-127), ANC 1.91×10 9/L (0.06-87.65) and platelets 75 ×10 9/L (10-399). Median time post diagnosis was 9 Mo. Seventeen pts (41%) remain on treatment with AZA alone (n=3) or both agents (n=14) with a median follow-up of 208d (60-297d). For those still on Thal and AZA median exposure to Thal is 209d (60-297d), with a median 7 cycles of AZA (2-9). For those 27 ceased Thal median exposure was 49d (17-220d) and of 24 ceasing AZA, median number cycles was 2 (1-8). Of 27 pts ceasing one (n=3) or both (n=24) agents; 7 withdrew consent, 3 at investigator decision, 4 for toxicity, 6 progressive disease, 1 lack of efficacy, 2 death (1 respiratory failure in setting of PD and WCC>300, 1 sepsis) and 4 unknown. There were 3 additional deaths within 28d of ceasing study therapy (all with PD); 2 due to sepsis and 1 intracranial haemorrhage. No pt experienced peripheral neuropathy Gr3 or worse. During cycle 1 of the first 40 consecutive patients on treatment, there were 18 episodes of Gr3+ non-haematologic toxicity in 13 patients; this was more likely in those with ECOG 2 (67% v 26%, p=0.053), age>65y (39% v 19%, p=0.175) and baseline ANC'0.5 (75% v 21%, p=0.008). Most of these events were infection related (a recognised risk of underlying MDS and of AZA alone); others occurred on only one occasion each (syncope, postop hemorrhage, respiratory disorder, renal failure, abdominal pain, pain, thrombosis and hypokalemia). Conclusions The combination of Thal 50-100mg/d and standard dose AZA is feasible without unexpected toxicity. Infections are common in the first cycle, particularly in pts with baseline neutropenia or impaired performance status. An updated toxicity analysis will be presented. Disclosures Kenealy: Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Seymour:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mills:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Szer:Celgene Pty Ltd: Honoraria, Speakers Bureau.

Download Full-text