scholarly journals Evaluation of the Main Regulators of Systemic Iron Homeostasis in Pyruvate Kinase Deficiency

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1993-1993
Author(s):  
Anna Zaninoni ◽  
Roberta Russo ◽  
Roberta Marra ◽  
Elisa Fermo ◽  
Immacolata Andolfo ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Pyruvate Kinase ◽  
Hemolytic Anemia ◽  
Iron Homeostasis ◽  
Advisory Board ◽  
Ineffective Erythropoiesis ◽  
Advisory Committees ◽  
Pyruvate Kinase Deficiency ◽  
Rbc Membrane

Abstract Iron loading anemias are characterized by ineffective erythropoiesis and iron overload. This group of anemias includes thalassemia syndromes, congenital dyserythropoietic anemias (CDA), and some forms of congenital hemolytic anemias. Among them pyruvate kinase deficiency (PKD) has been shown to develop iron overload also in absence of transfusions suggesting dyserythropoietic features. Moreover, severe forms can be misdiagnosed as CDA due to bone marrow abnormalities and ineffective erythropoiesis further supporting this evidences. The hormone erythroferrone (hERFE) is produced by erythroblasts in response to erythropoietin (EPO), and acts by suppressing hepcidin, thereby increasing iron absorption and mobilisation for erythropoiesis demand. The ERFE-hepcidin axis seems to play a crucial role in the pathogenesis of these disorders; an increased erythroferrone release by immature erythroid cells results in hepcidin suppression and secondary iron overload that could finally results in ineffective erythropoiesis and anemia. To investigate the pathophysiological basis of iron overload in PKD, we analysed the levels of hERFE, EPO, hepcidin, and soluble transferrin receptor (sTFR) in a large group of 41 PKD patients equally distributed by gender, age and severity. The results were analysed in comparison with two groups of patients affected by hemolytic anemia with overt dyserythropoiesis (42 patients with CDA type II) and with congenital hemolytic anemia due to RBC membrane defects (51 patients with hereditary spherocytosis [HS]), respectively. Demographic, hematologic, and biochemical features of the three groups of patients are reported in the table. Among the PKD patients, 18/41 were <18 yrs, median Hb level at the time of the study was 9.05g/dL (range 5.5-14.5), 12 underwent splenectomy, 28 ever received at least three transfusions their life, 14 of them transfusion dependent (>6 tx/yrs). Mean ferritin levels at the time of the study were 546 ng/ml (range 59-4990), 15/41 patients requiring chelation therapy for iron overload developed also in absence of transfusions. As expected, CDAII patients showed decreased hepcidin levels (3.74 ng/mL; n.v. 17.25, P<0.001) associated with increased erythropoietin (62.7 IU/L, n.v. 6.5, P=0.01) and hERFE (24.8 ng/mL, n.v. 1, P<0.0001). On the contrary, HS showed increased hepcidin, with less marked increased of ERFE (9.9 ng/mL, P=0.02) and EPO (36.4IU/L, P=0.005). In PKD patients we observed decreased hepcidin levels (7.15 ng/mL, P=0.03)), increased hERFE (18ng/mL, P<0.0001) and EPO (75.6 IU/L, P=0.009). Instead, sTFR was equally increased in the three groups of patients (Figure). Interestingly, by comparing the three groups of patients, PKD showed dyserythropoietic features as evidenced by the observation of intermediate values between HS and CDAII of hepcidin (P=0.007 PKD v CDAII and P=0.0002 PKD vs HS), hEFRE, and sTFR. This study provides the first analysis of the main regulators of systemic iron homeostasis in PK deficiency compared either with the model of a structural RBC defect (HS) or with the typical model of dyserythropoietic anemia with ineffective erythropoiesis, such as CDAII. These data provide evidence of the dyserythropoietic features of PK deficiency, underlining the need of accurate diagnosis and paving the way of novel therapeutic approaches in PK deficiency. Zaninoni A. and Russo R. equally contributed to the study Figure 1 Figure 1. Disclosures Fattizzo: Kira: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Momenta: Honoraria, Speakers Bureau; Annexon: Consultancy; Apellis: Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Barcellini: Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria. Iolascon: Bluebird Bio: Other: Advisory Board; Celgene: Other: Advisory Board. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Mitapivat Improves Ineffective Erythropoiesis and Reduces Iron Overload in Patients with Pyruvate Kinase Deficiency

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2005-2005
Author(s):  
Eduard J. Van Beers ◽  
Hanny Al-Samkari ◽  
Rachael F. Grace ◽  
Wilma Barcellini ◽  
Andreas Glenthoej ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Pyruvate Kinase ◽  
Research Funding ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Controlled Study ◽  
Publicly Traded ◽  
Ineffective Erythropoiesis ◽  
Advisory Committees

Abstract Background: Pyruvate kinase (PK) deficiency is a rare hereditary disease resulting in chronic hemolytic anemia, which is associated with serious complications, including iron overload, regardless of transfusion status. Ineffective erythropoiesis is linked to iron overload in patients (pts) with hemolytic anemias. Mitapivat is a first-in-class, oral, allosteric activator of the red blood cell PK enzyme (PKR) that has demonstrated improvement in hemoglobin (Hb), hemolysis, and transfusion burden in pts with PK deficiency. This analysis assessed the effect of mitapivat on markers of erythropoiesis and iron overload in pts with PK deficiency enrolled in 2 phase 3 studies, ACTIVATE (NCT03548220) and ACTIVATE-T (NCT03559699), and the long-term extension (LTE) study (NCT03853798). Methods: In ACTIVATE (double-blind, placebo-controlled study), 80 pts (age ≥ 18 years [yrs]) with a confirmed diagnosis of PK deficiency who were not regularly transfused (≤ 4 transfusion episodes in the prior yr; none in the prior 3 months) were randomized to receive mitapivat or placebo. In ACTIVATE-T (open-label, single-arm study), 27 pts (age ≥ 18 yrs) with a confirmed diagnosis of PK deficiency who were regularly transfused (≥ 6 transfusion episodes in the prior yr) were treated with mitapivat. Pts who completed either trial (24 weeks [wks] [ACTIVATE], 40 wks [ACTIVATE-T]) were eligible to continue in the LTE. Erythropoiesis markers included erythropoietin (EPO), erythroferrone, reticulocytes, and soluble transferrin receptor (sTfR). Markers of iron overload included hepcidin, iron, transferrin saturation (TSAT), ferritin, and liver iron concentration (LIC) by magnetic resonance imaging (MRI). In the LTE all pts received mitapivat. Pts from ACTIVATE were categorized into either the mitapivat-to-mitapivat arm (M/M) or the placebo-to-mitapivat arm (P/M). The ACTIVATE-T/LTE analysis includes pts who achieved transfusion-free status in ACTIVATE-T. The ACTIVATE/LTE analysis assessed change in markers from baseline (BL) over time in both study arms. Results: Eighty pts were included in the ACTIVATE/LTE analysis (M/M = 40; P/M = 40). Pts in both arms had abnormal BL erythropoiesis markers consistent with underlying ineffective erythropoiesis, and BL abnormal markers of iron overload. In the M/M arm, mean (SD) EPO, erythroferrone, reticulocytes, and sTfR decreased from BL to Wk 24 of mitapivat treatment by -32.9 IU/L (62.47), -9834.9 ng/L (13081.15), -202.0 10 9/L (246.97), and -56.0 nmol/L (82.57), respectively, while they remained stable or increased in the P/M arm on placebo (Figure). Twenty-four wks after starting mitapivat in the LTE (Wk 48 post BL), pts in the P/M arm had comparable beneficial decreases in mean (SD) EPO, erythroferrone, reticulocytes, and sTfR of -11.6 IU/L (30.74), -9246.1 ng/L (8314.17), -283.7 10 9/L (374.27), and -38.7 nmol/L (48.37), respectively. Improvements in hepcidin, iron, TSAT, and LIC were also observed with mitapivat treatment; ferritin remained stable (Table). Mean (SD) hepcidin increased in the M/M arm at Wk 24 and in the P/M arm 24 wks after starting mitapivat (Wk 48 post BL). At Wk 24, mean (SD) iron and TSAT, and median (Q1, Q3) LIC decreased in the M/M arm, while they increased on placebo. In the P/M arm, iron, TSAT, and LIC decreased 24 wks after starting mitapivat (Wk 48 post BL). Transfusion-free responders from ACTIVATE-T (n = 6) also experienced improvements in markers of erythropoiesis and iron overload in the LTE. Conclusions: In addition to improving Hb, hemolysis, and transfusion burden, data from ACTIVATE, ACTIVATE-T, and the LTE study indicate that activation of PKR with mitapivat improves markers of ineffective erythropoiesis and iron homeostasis in PK deficiency, thereby decreasing iron overload in these pts. Mitapivat has the potential to become the first approved therapy in PK deficiency with beneficial effect on iron overload. Figure 1 Figure 1. Disclosures Van Beers: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; RR Mechatronics: Research Funding; Pfizer: Research Funding. Al-Samkari: Amgen: Research Funding; Argenx: Consultancy; Rigel: Consultancy; Novartis: Consultancy; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. Grace: Agios: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Principia: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Barcellini: Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria; Novartis: Honoraria; Agios: Honoraria, Research Funding. Glenthoej: Bluebird Bio: 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; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Research Funding; Novo Nordisk: Honoraria. Judge: Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Kosinski: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Xu: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Beynon: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. McGee: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Porter: La Jolla Pharmaceuticals: Honoraria; Protagonism: Honoraria; Agios: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kuo: Celgene: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Bluebird Bio: Consultancy; Apellis: Consultancy.

scholarly journals PIEZO1 Mutation May Determine Early Onset of Clinical Manifestation of Anemia of Myelodysplastic Syndromes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1528-1528
Author(s):  
Enrico Attardi ◽  
Immacolata Andolfo ◽  
Lucia Tiberi ◽  
Roberta Russo ◽  
Daniela Formicola ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Missense Variant ◽  
Advisory Board ◽  
Pathogenic Role ◽  
Advisory Committees ◽  
High Coverage ◽  
Rbc Membrane ◽  
Membrane Defects ◽  
Mode Of Inheritance

Abstract BACKGROUND: Anemia is the most frequent cytopenia in myelodysplastic syndromes (MDS), neoplastic diseases characterized by ineffective hematopoiesis and bone marrow dysplasia. MDS usually affect elderly individuals (median age in Italy 74 years), and quite rarely concern younger patients. It is of increasing interest to verify whether "young", not therapy-related MDS patients carry germline (GM) predisposition, in order to optimize therapeutic and transplant choices. The best approach is to perform Whole Exome Sequencing (WES) instead of targeted next-generation sequencing (t-NGS) panel in cases in which MDS patients have no syndromic signs or any indicative sign of predisposing alterations. AIM: We considered a cohort of 21 consecutive MDS cases with age at diagnosis < 60 years and anemia, referred to our MDS Unit for a second opinion. METHODS: After bone marrow (BM) re-evaluation and morphological confirmation of dysplasia compatible with MDS, we screened the 21 MDS patients by WES on BM-DNA or peripheral blood DNA (PB-DNA). For DNA sequencing, DNA libraries were sequenced using the NextSeq 550 Illumina System. Variant calling was carried out using GATK caller. T-NGS myeloid panel was in some cases applied to confirm somatic nature of mutations. Samples of 5/21 MDS patients and their relatives were further analyzed after WES by applying high-coverage t-NGS 86-gene custom panel for hereditary anemias on PB-DNA. WES of DNA extracted from saliva (S-DNA) samples was performed to provide a GM confirmation. In order to confirm pathogenic role in red blood cell (RBC) membrane defects of identified variants, we also performed the ektacytometry analysis that evaluates the erythrocyte deformability and the hydration status by subjecting them to an increasing osmotic gradient with constant shear stress. RESULTS: Five of 21 MDS cases (23.8%) with symptomatic anemia (3 MDS-MLD, 1 MDS-SLD, 1 MDS with isolated del5q) were identified as carriers of variants suspected responsible of RBC membrane defects in both BM/PB-DNA and S-DNA samples, where no other germline myeloid predisposing alterations were demonstrated. MDS-associated somatic variants were present in 4/5 patients (KRAS, TET2, CBL, SRSF2, U2AF1, IDH2, with VAF >25 %). High coverage t-NGS analysis confirmed the presence of a heterozygous rare missense variant in PIEZO1 in probands 1 and 5; a heterozygous rare missense variant in PIEZO1 and ANK1 in proband 2; a heterozygous rare missense variant in PIEZO1 and SPTA1 in proband 3; a complex mode of inheritance in proband 4 with causative variants in G6PD, KCCN4, SPTB, and ABCB6 genes. PIEZO1 or KCNN4 gene variants result in erythrocyte dehydration and determine dehydrated hereditary stomatocytosis (DHS). Ektacytometry analysis showed a significant difference in the osmolarity curve of these patients, confirming the pathogenic role of the variants identified. Among these MDS suspected cases, only proband 4 was diagnostically re-categorized because of lack of acquired recurrent somatic mutations and presence of multiple alterations in erythroid genes causing dysplasia of erythroid precursors, masquerading as MDS. None of the patients presented a history of unexplained anemia before the onset of MDS, consistent with what shown for DHS1 patients with well-compensated hemolysis. Inheritance pattern of the identified variants according the study of the families confirmed the segregation of the pathogenic variants. CONCLUSION: Onset of de novo MDS in unusually young age should always prompt investigation of predisposing conditions. We suggest here that co-existence of inherited RBC membrane defects with MDS may determine earlier clinical manifestation of the clonal disease. Hereditary anemias, in particular xerocytosis, may mimic MDS morphology. In our study, among the 5 "young" MDS with concomitant inherited RBC membrane defect, one case did not finally confirm MDS diagnosis by karyotype or NGS myeloid mutation analysis. This case fulfilled the diagnostic criteria for combined hereditary hemolytic anemia: DHS2, G6PD deficiency, spherocytosis, familial pseudohyperkalemia 2, with multi-locus mode of inheritance that justifies the clinical condition (splenomegaly, hemolytic crisis, ascites). Addition of genetic testing for hereditary anemias beside assessment of germline predisposing variants may allow a more precise diagnosis in controversial cases of "young" MDS. Disclosures Sanna: Janssen: Consultancy; Abbvie: Consultancy; Astra Zeneca: Consultancy. Iolascon: Celgene: Other: Advisory Board; Bluebird Bio: Other: Advisory Board. Santini: Menarini: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Nrf2 Plays a Key Role in Iron-Overload Cardiomyopathy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3068-3068
Author(s):  
Enrica Federti ◽  
Francesca Vinchi ◽  
Iana Iatcenko ◽  
Alessandra Ghigo ◽  
Alessandro Mattè ◽  
...  
Keyword(s):  
Iron Overload ◽  
Research Funding ◽  
Iron Homeostasis ◽  
Advisory Board ◽  
Beta Thalassemia ◽  
Mrna Levels ◽  
Collagen Deposition ◽  
Advisory Committees ◽  
Iron Overload Cardiomyopathy

Abstract Cardiomyopathy due to iron-overload is a severe complication of patients undergoing chronic transfusion regimen such as β-thalassemia and myelodysplastic syndromes. Previous studies have shown the key role of Nrf2, a redox-related transcriptional factor, in both β-thalassemia erythropoiesis and iron homeostasis (Matte A et al. ARS 2018, 2019; Lim PJ et al Nat Metab, 2019). Here, we compared Nrf2 knockout male mice (Nrf2 -/-) and C57BL-6J as wild-type (WT) controls, with a focus on cardiac function. Nrf2 -/- mice were characterized by a mild chronic hemolytic anemia associated with ineffective erythropoiesis, similar to what observed in murineβ-thalassemia (Toya SCM et al., Blood, 2019). Aging Nrf2 -/- mice developed systolic and diastolic dysfunction, associated with increased cardiac oxidative stress, degradation of the calcium-dependent SERCA2A transporter and activation of metalloproteinase MMP9, involved in both SERCA2A degradation and heart remodeling. In Nrf2 -/- mice, we observed increased plasma NTBI, heart iron deposition and elevated expression of cardiac ferroportin when compared to WT animals. Moreover, cardiac Hamp mRNA levels were down-regulated in aging Nrf2 -/- mice when compared to WT mice. This pattern was consistent with progressive cardiac iron overload in absence of Nrf2. Interestingly, activation of TGF-b receptor and PDGF-B-related pathway as well as increased collagen deposition were observed in hearts from 12 months old Nrf2 -/- mice. Taken together our data suggest an aging-associated development of iron-overload cardiomyopathy in mice genetically lacking Nrf2. To evaluate the role of Nrf2 in iron overload cardiomyopathy, Nrf2 -/- and WT mice were exposed to dietary iron supplementation (2.5% w/w carbonyl iron for 28 days). Nrf2 -/- mice developed cardiac hypertrophy which was accompanied by a worsening in collagen deposition and persistent activation of PDGF-B pathway. This was associated with inflammatory vasculopathy. The biologic importance of Nrf2 is supported by the cardiac activation of Nrf2, degradation of SERC2A and activation of TGF-b receptor and PDGF-B pathway in a mouse model of beta thalassemia intermedia, the Hbb3th/+ mice. Collectively our data support the crucial role of Nrf2 in the protection of cardiomyocytes against iron cytotoxicity which significantly develops in aging as well as in β-thalassemia. Disclosures Vinchi: Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Vifor Pharma: Research Funding; PharmaNutra: Research Funding; Novartis: Research Funding. Ghigo: Kither Biotech: Other: Board member and Co-Founder. Iolascon: Bluebird Bio: Other: Advisory Board; Celgene: Other: Advisory Board.

scholarly journals Effects of AG-348, a Pyruvate Kinase Activator, on Anemia and Hemolysis in Patients with Pyruvate Kinase Deficiency: Data from the DRIVE PK Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 402-402 ◽  
Author(s):  
Rachael F Grace ◽  
Christian Rose ◽  
D Mark Layton ◽  
Hassan M Yaish ◽  
Wilma Barcellini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Missense Mutation ◽  
Pyruvate Kinase ◽  
Blood Cells ◽  
Advisory Board ◽  
Board Meeting ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Dose Reductions

Abstract BACKGROUND Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by deficiency of the glycolytic enzyme red cell PK (PK-R). AG-348 is an orally available, small molecule, allosteric activator of PK-R that activates wild-type and a range of mutated PK-R enzymes in vitro, and increases PK-R activity and restores adenosine triphosphate (ATP) levels in red blood cells from patients with PK deficiency ex vivo. AIMS To describe data from the ongoing DRIVE PK study (NCT02476916), an open-label, dose-ranging trial of AG-348 in transfusion-independent adults with PK deficiency. Early data from this study have been reported (Grace et al. EHA 2016, S466). METHODS After providing informed consent, patients are randomized to AG-348 50 mg or 300 mg orally twice daily (BID) for 6 months. Transfusion independence is defined as no more than 3 units of red blood cells transfused in the 12 months preceding first dose and no transfusions in the 4 months preceding first dose. Patients are followed weekly for Weeks 1-3, then every 3 weeks until Week 12, and then monthly until Week 24. Sex hormone levels and iron status are evaluated at Baseline, Week 12 and End of Study. RESULTS As of the data cutoff date of June 20, 2016, 25 patients have been enrolled and treated for ≥3 weeks. Adverse events (AEs) were mild to moderate. The most frequent AEs were nausea (n=11/25), headache, and insomnia (each n=8/25). One serious AE (Grade 2 osteoporosis) has been reported. Grade 3 AEs were hypertension (n=1), hypertriglyceridemia (n=1), insomnia (n=2), and anemia (n=1). One patient was discontinued from treatment because anemia worsened. There were no Grade 4 AEs and no deaths. Three patients had dose reductions because of headache, nausea, or insomnia. Serum levels of sex steroids were measured at baseline, 12 and 24 weeks; increases in free and total testosterone, and decreases in estradiol and estrone, indicate aromatase inhibition by AG-348, consistent with previously reported results. In 25 patients with ≥3 weeks on treatment, 13 patients (52%) showed a hemoglobin (Hgb) increase >1.0 g/dL (range: 1.2-4.9 g/dL; median: 3.40 g/dL). Three patients had dose reductions because of Hgb values exceeding the protocol-mandated maximum. Hgb responses were typically observed within 2 weeks of treatment and were stable with continued treatment. Two patients had dose increases because of insufficient response to 50 mg. Maximal change in Hgb from baseline according to genotype is shown in Figure 1. Of the 25 enrolled patients with ≥3 weeks on treatment, 6 (24%) had two non-missense mutations and none of these had an Hgb response >1.0 g/dL. Of the 19 patients with at least one missense mutation, 13 (68%) had an Hgb increase exceeding 1.0 g/dL. CONCLUSION AG-348 is a novel, first-in-class, PK-R activator in clinical testing as a disease-altering therapy to improve anemia in patients with PK deficiency. The ongoing DRIVE PK study has now enrolled over 25 patients, and data from additional patients will be available at the time of presentation. Daily dosing with AG-348 is well tolerated and has demonstrated clinically relevant durable increases in Hgb in the majority of the patients with at least 1 missense mutation. Out of the 19 patients with at least one missense mutation, 13 had an Hgb increase of >1.0 g/dL. These data highlight the potential of AG-348 as the first disease-altering treatment for patients with PK deficiency. Figure 1 Maximum hemoglobin (Hgb) increase by genotype Figure 1. Maximum hemoglobin (Hgb) increase by genotype Disclosures Grace: Agios Pharmaceuticals: Other: Scientific Advisor, Research Funding. Rose:Novartis: Honoraria; Celgene: Honoraria; Genzyme: Honoraria. Layton:Novartis: Other: Advisory board meeting; Alexion: Other: Advisory board meeting; GSK: Other: Advisory board meeting; Agios: Speakers Bureau. Yaish:Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare: Consultancy; Octapharma: Consultancy. Barcellini:Agios: Consultancy. Kuo:Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apotex: Other: Unrestricted education grant; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Silver:Agios Pharmaceuticals, Inc.: Consultancy. Merica:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Kung:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Cohen:Agios Pharmaceuticals, Inc.: Consultancy. Yang:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hixon:Agios Pharmaceuticals, Inc.: Equity Ownership, Other: Employment (former); KSQ Therapeutics: Employment, Equity Ownership. Kosinski:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Silverman:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Dang:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yuan:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Barbier:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Glader:Agios Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase 2a Study Evaluating the Safety and Pharmacokinetics (PK) of Luspatercept in Pediatric Patients with Transfusion-Dependent β-Thalassemia (TDT)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4161-4161
Author(s):  
Vip Viprakasit ◽  
Thomas D. Coates ◽  
Khaled M. Musallam ◽  
Julie Vienne Buerki ◽  
Meera Patturajan ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Study Design ◽  
Research Funding ◽  
Safety Data ◽  
Age Group ◽  
Ineffective Erythropoiesis ◽  
Advisory Committees ◽  
Expansion Cohort ◽  
Rbc Transfusion

Abstract Background: β-thalassemia is an inherited hemoglobinopathy caused by mutations in the gene encoding the β-globin chain of hemoglobin (Hb), resulting in ineffective erythropoiesis, impaired red blood cell (RBC) maturation, and anemia. Patients (pts) with severe disease require regular, lifelong RBC transfusions and iron chelation therapy (ICT) shortly after diagnosis in early childhood. There is an unmet need for safe and effective treatments for pediatric pts to address the underlying pathophysiology of β-thalassemia and reduce the burden of chronic RBC transfusions early to prevent secondary iron overload and associated morbidity. Luspatercept is a first-in-class erythroid maturation agent approved in the USA and EU for the treatment of anemia in adult pts with β-thalassemia who require regular RBC transfusions. In previous studies, treatment with luspatercept resulted in clinically significant reductions in RBC transfusion burden in adults with TDT (phase 3 BELIEVE; Cappellini MD, et al. N Engl J Med 2020;382:1219-1231) and increased Hb levels in adults with non-TDT (phase 2 BEYOND study; Taher AT, et al. HemaSphere 2021;5[Suppl 2];Abstract S101). This phase 2a study (NCT04143724, EudraCT 2019-000208-13) will evaluate the safety and PK of luspatercept in pediatric pts with β-thalassemia who require regular RBC transfusions. The results will determine a recommended dose (RD) for each age group. Study Design and Methods: Eligible pts will be 6 to < 18 years of age; diagnosed with β-thalassemia, Hb E/β-thalassemia, or α-thalassemia/β-thalassemia; require ≥ 4 RBC units in the 24 weeks prior to enrollment (with no transfusion-free period ≥ 42 days and with a regular history of transfusions for ≥ 2 years); and have Karnofsky (≥ 16 years of age) or Lansky (< 16 years of age) performance status score ≥ 50 at baseline. Exclusion criteria include: a Hb S/β-thalassemia or α-thalassemia diagnosis, chronic anticoagulant therapy ≤ 28 days prior to enrollment, erythropoiesis-stimulating agent or hydroxyurea use ≤ 24 weeks prior to enrollment, ICT initiation ≤ 8 weeks prior to enrollment, use of any investigational drug ≤ 28 days prior to enrollment, or have undergone or are scheduled for transplant or gene therapy. A total of 54 pts will be enrolled in a staggered study design by age, beginning with a 12-week screening/run-in period. During Part A, pts 12 to < 18 years of age will receive luspatercept at 0.75 mg/kg (n = 6; Cohort 1) or 1.0 mg/kg (n = 6; Cohort 2) subcutaneously (s.c.) once every 21 days for ≤ 4 cycles (Figure A). The RD will be determined for each age group strata at the time of enrollment using descriptive statistics or frequency tabulations between and in aggregate across age-group arms. An expansion cohort (n = 30 pts 12 to < 18 years of age; Cohort 3) will then receive luspatercept for at least 1 year at the RD based on tolerability and safety data from Cohorts 1 and 2; if the RD is 1 mg/kg, titration up to 1.25 mg/kg is allowed in the expansion cohort based on erythroid response during the previous 2 dose cycles. Part B will be initiated following completion of Part A and review of overall safety data with the Data Monitoring Committee, Scientific Steering Committee, and health authorities. Pts 6 to < 12 years of age will be treated with luspatercept at 1.0 mg/kg (n = 6; Cohort 4) or 1.25 mg/kg (n = 6; Cohort 5) s.c. once every 21 days for ≤ 4 cycles (Figure B). Any pt who benefits from treatment can continue to receive luspatercept for ≤ 5 years from first dose and will be monitored for 5 years from first dose or 3 years from last dose, whichever occurs later. Pts may receive best supportive care, including RBC transfusions, ICT, antibiotics, antifungal or antiviral therapy, and/or nutritional support, as needed. The primary objectives are to determine the RD of luspatercept that is safe and tolerable and the PK of luspatercept in pediatric pts with TDT. Key secondary objectives include evaluating mean change in RBC transfusion burden, change in Hb levels, mean change in daily dose of ICT, mean change in serum ferritin, and the immunogenicity and safety of luspatercept in pediatric pts. Safety endpoints include evaluating the type, frequency, seriousness, and severity of adverse events and their relationship to luspatercept treatment. Exploratory endpoints include evaluating exposure-response, health-related quality of life, biomarkers/markers of iron overload and ineffective erythropoiesis, and SARS-CoV-2 serology. Figure 1 Figure 1. Disclosures Viprakasit: Bristol Myers Squibb: Research Funding. Coates: Celgene: Consultancy, Honoraria, Research Funding; Forma Pharma: Consultancy; Sangamo: Consultancy; UpToDate: Patents & Royalties; Vifor Pharma: Consultancy; Apo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chiesi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Musallam: Celgene, Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Agios Pharmaceuticals: Consultancy; CRISPR Therapeutics: Consultancy; Vifor Pharma: Consultancy. Vienne Buerki: Bristol Myers Squibb: Current Employment. Patturajan: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Holot: Bristol Myers Squibb: Current Employment. Aydinok: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Resonance Health: Research Funding; CRISPR Therapeutics: Consultancy; SLN Therapeutics: Consultancy; Imara: Research Funding; Protagonist: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ionis Pharmaceuticals: Research Funding; La Jolla: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Selecting ß-Thalassemia Patients for Gene Therapy: A Decision-Making Algorithm

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 972-972 ◽  
Author(s):  
Donatella Baronciani ◽  
Maddalena Casale ◽  
Lucia De Franceschi ◽  
Giovanna Graziadei ◽  
Filomena Longo ◽  
...  
Keyword(s):  
Decision Making ◽  
Gene Therapy ◽  
Risk Stratification ◽  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Exclusion Criteria ◽  
Advisory Committees ◽  
Clinical Issues

Introduction and Aim Till today, the only curative and most widely used therapy for β-thalassemia (β-TDT) is allogeneic HSCT: the European Society for Bone Marrow Transplantation Hemoglobinopathy Registry reported over 90% overall survival in under-14 patients transplanted from an HLA identical family donor. However, with the new therapeutic scenario opened up by Gene Therapy (GT), it has become essential to identify and prioritize patient profiles for which GT could be applied. The "Pesaro Patients Risk Classification" showed the importance of risk stratification in order to achieve the best results. The Italian Scientific Society for Thalassemias and Hemoglobinopathies (SITE) closely involved in the cure and overall approach to these pathologies, decided to carry out this project of analysis and assessment to establish the possible inclusion and exclusion criteria for access to GT of patients with β-TDT and to collect the outcomes. The aim of this study is to identify which patients with β-TDT could benefit from GT, based on evidence and consensus. Methods The decision-making algorithm was developed within the scientific activity of SITE, which defined the feasibility of the project and selected the multidisciplinary panel of experts in hemoglobinopaties for the elaboration of clinical issues. Published literature (Medline, PubMed, Embase, Cochrane Library) was searched in order to get solid evidences regarding best candidates to allogeneic SCT, who should not therefore undergo GT. Evaluation of literature and scientific evidences were reported and discussed through call conferences and mails communications. The final review has been performed by a pool of external reviewers who evaluated the clinical relevance, the applicability, the legibility of the document and the consistency between the recommendations and the summaries of the tests produced to test the algorithm. This step is in progress. The final version of the document will be made available on the web site of SITE (www.site-italia.org). The outcomes of the procedures will be collected in the electronic clinic database used by the Centers (i.e Webthal©) to perform a risk stratification. Results and Conclusions The patient selection procedure must be performed by the joint evaluation of the Center of the "Hemoglobinopathies Italian Network" together with the qualified treatment Center for HCS transplantation. The document is proposed as a dynamic and up-datable tool. It is structured such as to allow two levels of consultation: an interactive flow chart (Figure) presenting the different clinical issues discussed with conclusive practical indications linked to chapters providing detailed information on each aspect of the subject. Applying the appropriate cautionary considerations, patients are considered non-eligible in the case of: exclusion criteria indicated by the Regulatory Authorities (i.e. EMA/CHMP/166977/2019);Severe iron overload and/or organ damage (i.e. pulmonary hypertension). Manageable iron overload is a condition of re-evaluation. Caution is mandatory in the evaluation of patients with complications or comorbidities. The access to GT needs to be re-evaluated on the basis of scientific and regulatory updates. Figure Disclosures Longo: Blue Bird Bio: Consultancy. Pinto:Novartis: Consultancy; Bluebird Bio.: Consultancy. Angelucci:Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees; Vifor Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; CRISPR Therapeutics: 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. Piga:Acceleron Pharma: Research Funding; Novartis: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding. Forni:Roche, Erithropoiesis Stimulation: Research Funding; Celgene, Erithropoiesis Stimulation: Research Funding; Novartis, Iron chelation: Research Funding; BlueBirdBio: Consultancy.

scholarly journals Tfr2 Genetic Deletion Makes Transfusion-Independent a Murine Model of Transfusion-Dependent β-Thalassemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 575-575
Author(s):  
Simona Maria Di Modica ◽  
Violante Olivari ◽  
Emanuele Tanzi ◽  
Mariateresa Pettinato ◽  
Maria Rosa Lidonnici ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Gene Dosage ◽  
Genetic Defect ◽  
Severe Form ◽  
Blood Transfusions ◽  
Wild Type ◽  
Ineffective Erythropoiesis ◽  
Advisory Committees ◽  
Over Time

Abstract β-thalassemia is an autosomal recessive disorder due to mutations in the β-globin gene, that leads to defective production of hemoglobin (Hb) and red blood cells (RBC). The main features of the disease are anemia, ineffective erythropoiesis and iron overload. Patients affected by the most severe form of β-thalassemia are transfusion-dependent (TDT) and require lifelong blood transfusions and iron chelation, symptomatic treatments that affect the quality of life. The only curative option, unfortunately limited by the insufficient number of HLA-matched donors, is allogenic bone marrow (BM) transplantation. Other recently approved treatments (i.e. Luspatercept and gene therapy) are only partially effective and/or suitable for selected patients. Thus, the identification of novel therapeutic approaches is a clinical need. Transferrin receptor 2 (TFR2) contributes to the transcriptional activation of hepcidin, the master regulator of iron homeostasis, in the liver and is a brake of Erythropoietin signaling in erythroid cells, thus balancing RBC production and iron availability. We have recently proved that BM Tfr2 deletion enhances erythropoiesis in wild-type mice (Nai et al., Blood 2015) and ameliorates anemia in non-TDT mice models, both alone (Artuso et al., Blood 2018) and in combination with iron-restricting agents (Casu, Pettinato et al., Blood 2020). Here we aim at investigating whether Tfr2 targeting might be beneficial also for TDT. To this purpose we generated TDT mice (Hbb th1/th2; Casu et al., Haematologica 2020) with heterozygous (Tfr2 BMhetero/Hbb th1/th2) and homozygous (Tfr2 BMKO/Hbb th1/th2) BM Tfr2 deletion by transplantation of Hbb th1/th2, Tfr2-hetero/Hbb th1/th2 and Tfr2-ko/Hbb th1/th2 fetal liver cells (FLT) from day E14.5 embryos into lethally irradiated wild-type mice. BM Tfr2 deficient mice have increased RBC count and Hb levels and decreased percentage of reticulocytes with a gene dosage effect 8 weeks after FLT, before the onset of transfusion-dependance. At this time-point, complete BM Tfr2 deletion ameliorates ineffective erythropoiesis, decreasing the percentage of polychromatic erythroblasts and increasing orthochromatic erythroblasts and mature RBCs both in the BM and in the spleen. The improved anemia was also accompanied by a partial correction of two debilitating TDT complications, iron overload and cardiomegaly. The beneficial effect of Tfr2 deletion was maintained over time. Indeed, Hbb th1/th2 mice became transfusion-dependent 14 weeks after FLT, when Hb levels drop below 5.5 g/dL, requiring transfusions of an average 108.75±56.87μL of blood/animal/week. On the contrary, animals with both heterozygous and homozygous BM Tfr2 deletion are still non-transfusion-dependent at 20 weeks, maintaining Hb levels above 7 and 9 g/dL respectively. Overall, our results prove that, despite the persistence of the genetic defect, hematopoietic Tfr2 deletion ameliorates anemia, ineffective erythropoiesis and secondary complications also in the most severe form of β-thalassemia. This improvement is associated to a substantial increase in transfusion-free survival of both Tfr2 BMhetero/Hbb th1/th2 and Tfr2 BMKO/Hbb th1/th2 mice, which are transfusion-independent 6 weeks after the time of blood transfusion requirement in Hbb th1/th2 animals. The difference of blood transfusions needs will be evaluated over time for at least 10 additional weeks. Our findings demonstrate that TFR2 targeting represents a new promising therapeutic opportunity for the management of β-thalassemia, worth to be tested both as a monotherapy and in association with available treatments. Disclosures Rivella: Incyte: Consultancy; MeiraGTx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Theraputics: Consultancy; Keros Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Disc Medicine: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ionis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy.

scholarly journals Survey of 275 Patients and Caregivers Affected By Pyruvate Kinase Deficiency: Impact of Communication with Hematologists on Mental Health and Quality of Life

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1948-1948
Author(s):  
Rachael F. Grace ◽  
Wilma Barcellini
Keyword(s):  
Quality Of Life ◽  
Disease Management ◽  
Board Of Directors ◽  
Pyruvate Kinase ◽  
Research Funding ◽  
Adult Patients ◽  
Advisory Committees ◽  
Pyruvate Kinase Deficiency ◽  
Adult Caregivers

Abstract Background. Pyruvate Kinase deficiency (PKD) is a rare congenital hemolytic anemia which affects approximately three people per million individuals worldwide. With no disease-modifying treatments currently available, management tends to focus on supportive symptom control such as blood transfusions. PKD has a profound, wide-ranging impact on quality of life (QoL). Patient advocacy and patient-reported outcomes research has been limited. The PKD Advocacy Advisory Council (AAC), a group of patients, caregivers, patient advocates and physicians, was formed in 2020, by Agios Pharmaceuticals, to improve both timely diagnosis and access to education, support and care for individuals with PKD. Objective. The AAC initiated a survey to explore communication between patients/ caregivers affected by PKD and their hematologists to inform future best practices and improve outcomes. Methods. A web-based, quantitative and qualitative survey was conducted amongst adult patients with PKD, and adult caregivers, with respondents from 11 countries including France, Germany, Italy, Spain, the UK and US. Question types included closed-ended, multiple choice, Likert scale and binary choice plus free text. The survey was carried out according to British Healthcare Business Intelligence Association Legal and Ethical Guidelines, as well as guidelines established by the UK's Market Research Society. Participants were recruited via online panels and via AAC member channels, including PKD Facebook groups. Results : The survey was completed by 200 adult patients with PKD and 75 adult caregivers (n=275). Twenty percent of patients were >50 years of age, 64% were ages 31-50 years and 17% were 18-30 years of age. Half of the patients had been diagnosed for >10 years. Although 82% of patients reported that their hematologist manages PK deficiency "well", the survey revealed gaps in hematologists' understanding. Only 56% of respondents stated their hematologist is able to answer disease management questions and only 44% say their hematologist searches for and finds solutions to optimize disease management. Less than half of respondents, 44%, reported that their hematologists demonstrate a deep knowledge of PKD. The survey revealed an unmet need regarding emotional and psychosocial support with 25% of respondents reporting feeling neither positive nor negative, or somewhat negative, after hematologist interactions and 29% reporting at least one negative emotion following interactions. After meeting with their hematologist, 21% of respondents report feeling worried, 17% anxious, and 17% depressed. Communication with the hematologist was reported to be negative most often among patients who receive 0 transfusions per year. Within this group, only 62% report that their hematologist manages their condition well compared to 82% overall (p=0.003). Only 51% state that their hematologist understands the impact of PK deficiency on their QoL (compared to 83% amongst respondents receiving one or more transfusions per year, p<0.001). Of those who are not transfused, only 44% state their hematologist takes their perspective and experiences into consideration for their disease management plan (compared to 75% amongst respondents receiving one or more transfusions per year, p<0.001). Conclusions PKD is a lifelong chronic disease that significantly impacts QoL of patients and families. The results of this largest ever survey of patients and caregivers with PKD point to a need to adapt clinical approaches to improve outcomes. Hematologists should seek to improve their understanding of the disease and its burden, particularly in non-transfused patients. Care should attend to emotional and psychosocial health aspects. Clinicians should consult with other medical specialists, including hematologists who specialize in PKD, to ensure complications are managed effectively. More research is needed to build on the survey insights, drive further awareness and understanding of the needs of those living with PKD among hematologists, and inform approaches to improve outcomes. The authors would like to acknowledge and thank members of the AAC that made this work possible. Figure 1 Figure 1. Disclosures Grace: Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Agios: Research Funding; Principia: Membership on an entity's Board of Directors or advisory committees. Barcellini: Novartis: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees.

IRON OVERLOAD IN CONGENITAL ERYTHROCYTE PYRUVATE KINASE DEFICIENCY

1980 ◽  
Vol 1 (11) ◽  
pp. 531-532 ◽  
Author(s):  
H. H. Salem ◽  
M. B. Van Der Weyden ◽  
B. G. Firkin
Keyword(s):  
Iron Overload ◽  
Pyruvate Kinase ◽  
Pyruvate Kinase Deficiency
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