In this phase 2 study of anemia therapy in patients with end-stage renal disease on maintenance hemodialysis therapy, roxadustat was well tolerated and effectively maintained Hb levels.

Background We evaluated the efficacy and safety of roxadustat vs. epoetin alfa for the treatment of chronic kidney disease (CKD) related anemia in patients new to dialysis. Methods This was a phase 3, open-label, epoetin alfa-controlled trial. Eligible adults were on hemodialysis/peritoneal dialysis for ≥2 weeks and ≤4 months before randomization and had mean hemoglobin ≤10.0 g/dL. Primary endpoints were mean hemoglobin (g/dL) change from baseline averaged over weeks 28–52 regardless of rescue therapy (non-inferiority criterion: lower limit of 95% CI for treatment difference > −0.75) and percentage of patients achieving a hemoglobin response between weeks 1–24 censored for rescue therapy (non-inferiority margin for between-group difference: −15%). Adverse events were monitored. Results The intention-to-treat population included patients randomized to roxadustat (n = 522) or epoetin alfa (n = 521). Mean (SD) hemoglobin changes from baseline averaged over weeks 28–52 were 2.57 (1.27) and 2.36 (1.21) in the roxadustat and epoetin alfa groups. Roxadustat was non-inferior (least-squares mean difference: 0.18 [95% CI: 0.08, 0.29]) to epoetin alfa. Percentages of patients with a hemoglobin response were 88.2% and 84.4% in the roxadustat and epoetin alfa groups. Roxadustat was non-inferior to epoetin alfa (treatment-group difference: 3.5% [95% CI: −0.7%, 7.7%]). Adverse event rates were comparable between treatment groups. Conclusions Roxadustat was efficacious for correcting and maintaining hemoglobin levels compared to epoetin alfa. Roxadustat had an acceptable safety profile.

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Anemia is the predominant cytopenia in myelodysplastic syndromes (MDS) and treatment options are limited. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia of chronic kidney disease in the UK, EU, China, Japan, South Korea, and Chile. MATTERHORN is a phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of roxadustat in anemia of lower risk-MDS. Eligible patients had baseline serum erythropoietin ≤ 400 mIU/mL, and a low packed RBC transfusion burden. In this openlabel (OL), dose-selection, lead-in phase, enrolled patients were assigned to 1 of 3 roxadustat starting doses (n = 8 each): 1.5, 2.0, and 2.5 mg/kg. The primary efficacy endpoint of the OL phase was the proportion of patients with transfusion independence (TI) for ≥ 8 consecutive weeks in the first 28 treatment weeks. A secondary efficacy endpoint was the proportion of patients with a ≥ 50% reduction in RBC transfusions over an 8-week period compared with baseline. Adverse events were monitored. Patients were followed for 52 weeks. Of the 24 treated patients, TI was achieved in 9 patients (37.5%) at 28 and 52 weeks; 7 of these patients were receiving 2.5 mg/kg dose when TI was achieved. A ≥ 50% reduction in RBC transfusions was achieved in 54.2% and 58.3% of patients at 28 and 52 weeks, respectively. Oral roxadustat dosed thrice weekly was well tolerated. There were no fatalities or progression to acute myeloid leukemia. Based on these outcomes, 2.5 mg/kg was the chosen starting roxadustat dose for the ongoing double-blind study phase. | INTRODUCTIONMyelodysplastic syndromes (MDS) affect about 60 000 Americans, with an annual incidence of 4.5 per 100 000 people. [1][2][3] About 77% of patients diagnosed with MDS have a disease that is classified as lower risk (LR-MDS) at diagnosis, as defined by the revised International Prognostic Scoring System (IPSS-R) score of ≤ 3.5. [4][5][6] More than 90% of patients diagnosed with MDS have anemia at the time of their diagnosis, and over 60% of patients with MDS experience severe anemia at later stages of their disease. 7,8 Currently, there are limited anemia treatments with variable response rates approved for patients with LR-MDS in the US and EU for small subsets of LR-MDS patients. Epoetin alfa is approved in Europe for patients with LR-MDS with symptomatic anemia (hemoglobin < 10 g/dL). It was also granted orphan drug designation in the US for the study of adult patients with MDS. Red blood cell Clinical trial registration: NCT03263091.

Background: Roxadustat (FG-4592) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that promotes coordinated erythropoiesis through HIF-mediated transcription. Transient, intermittent HIF activation by roxadustat mimics a physiological response that increases endogenous erythropoietin (EPO) production to near physiologic range and stimulates EPO receptor synthesis. In addition, roxadustat promotes iron metabolism by reducing serum hepcidin to allow absorption of iron from the gut and mobilize iron from cellular storage making more iron available for erythropoiesis. Roxadustat corrected and maintained hemoglobin (Hb) in chronic kidney disease patients in multiple Phase 3 trials irrespective of underlying inflammation. In these studies, roxadustat-treated patients required less IV iron to correct and maintain Hb compared to erythropoiesis-stimulating agent (ESA)-treated patients. MDS is characterized by symptomatic anemia and many patients require RBC transfusion and/or ESA treatment. As response to ESAs varies across sub-populations with limited durability, there is an unmet need for treatment of anemia in LR-MDS. This is the first study to evaluate the effect of roxadustat in treating anemia in primary MDS patients. Methods: This is a two-part study; an open-label (OL), dose-finding segment (N=24) followed by a randomized double-blind (DB) placebo-controlled segment (N=156, 3:2 ratio of roxadustat to placebo). The primary goal of the OL segment is to identify the starting roxadustat dose-level for the DB segment. A total 24 patients in the OL segment have been enrolled in three sequential cohorts with 8 patients in each starting dose cohort (1.5, 2.0, or 2.5 mg/kg). RBC transfusion has been allowed per institutional criteria. Eligible patients were very low, low or intermediate risk primary MDS patients based on the International Prognostic Scoring System Revised classification with &lt;5% bone marrow blasts; had baseline Hb &lt; 10.0 g/dL; were &gt;18 years old; and had LTB defined as receiving 1-4 RBC units per 8 week period. Patients were ineligible if they used an ESA within 8 weeks of the study start; had endogenous EPO levels &gt;400 mIU/mL, or had a del(5q) cytogenetic abnormality. Roxadustat was administered TIW with doses titrated every 8 weeks per a dosing algorithm based on Hb response and transfusion need. Data from the OL segment were evaluated to identify the starting dose for the DB segment (currently enrolling). The primary endpoint is transfusion independence (TI) for ≥56 consecutive days during the first 28 weeks of treatment. The proportion of patients who achieve ≥50% reduction in RBC transfusion over any 8 weeks compared to baseline (8 weeks prior to Day 1) and proportion of patients who achieve TI for ≥20 consecutive weeks are evaluated. Safety and tolerability are assessed by adverse event reporting, percentage of patients progressing to acute myeloid leukemia (AML), and clinical laboratory values. Results: Twenty-four transfusion dependent, LR-MDS patients were enrolled in the OL segment of this global Phase 3 trial. Nine patients (38%) achieved TI for at least 56 consecutive days within the first 28 weeks.Three of 9 patients started at 1.5 mg/kg dose, 1 patient started at 2.0 mg/kg dose and 5 patients started at 2.5 mg/kg dose. At the time of achieving TI, 7 of 9 patients (78%) were on 2.5 mg/kg dose, 1 patient (11%) was on 2.0 mg/kg dose (started with 1.5 mg/kg dose) and one patient (11%) was on 1.5 mg/kg dose. Four patients remained TI for &gt;20 weeks (one at 1.5 mg/kg dose level and three at 2.5 mg/Kg dose-level). One additional patient achieved TI after the initial 28-week dosing period at a dose-level of 3.5 mg/kg (starting dose 2.0 mg/kg). A total of 14 patients (58%) achieved a ≥50% reduction in RBC units in any 8-week period compared to baseline (range of 2-4 RBC units in 8 weeks before dosing); 12 of these patients were at ≥ 2.5 mg/kg dose level when achieving a 50% reduction in transfusion without need for IV iron. The overall safety profile observed is consistent with the patient population under study. Six patients reported 8 treatment-emergent SAEs with none being fatal. No patient has progressed to AML. Full results from the OL segment of the study will be presented. Conclusion: Based on the observed response (TI and transfusion reduction) and safety profile in LR-MDS patients, 2.5 mg/kg was selected as the starting dose for the ongoing 156-patient DB portion of the trial. Disclosures Harrup: Cooperative Trial Group for NeuroOncolog: Other: Collaborative Clinical Trials Group; Cancer Council of Tasmania: Membership on an entity's Board of Directors or advisory committees. Mittelman:Novartis: Honoraria, Research Funding, Speakers Bureau. Bradley:FibroGen Inc.: Employment, Equity Ownership. Saha:FibroGen Inc.: Employment, Equity Ownership. Bartels:FibroGen Inc.: Employment, Equity Ownership. Robert:FibroGen Inc.: Employment, Equity Ownership. Yu:FibroGen Inc.: Employment, Equity Ownership.

Background: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. In Phase 3 trials, roxadustat increased hemoglobin (Hb) levels and reduced the number of red blood cell (RBC) transfusions vs placebo in patients with anemia of non-dialysis-dependent chronic kidney disease (CKD). In anemia of dialysis-dependent CKD, roxadustat achieved greater mean Hb increase vs epoetin alfa, and reduced IV iron use and RBC transfusions (Coyne, et al. Poster SA-0228 American Society of Nephrology (ASN) 2019; Charytan, et al. Poster SA-0227 ASN 2019) Low-risk myelodysplastic syndrome (LR-MDS), characterized by symptomatic anemia, is treated with RBC transfusion, erythropoiesis-stimulation agents (ESAs), or luspatercept. Suboptimal response and response durability across MDS subpopulations demonstrates an unmet medical need in LR-MDS. We report a 52-week update of the open-label (OL) phase of a study of roxadustat in anemia in primary MDS patients that determined the starting dose of the ongoing double-blind study phase (NCT03263091). Methods: The OL phase (N=24) used 3 sequential dose cohorts (1.5, 2.0, and 2.5 mg/kg) thrice weekly (TIW). Eligible patients had very low- to intermediate-risk primary MDS patients per International Prognostic Scoring System-Revised classification, with &lt; 5% bone marrow blasts; baseline Hb &lt; 10.0 g/dL; had low transfusion burden, defined as receiving 1-4 RBC units within 8 weeks before randomization; endogenous EPO levels ≤ 400 mIU/mL; and no 5q(del) cytogenetic abnormality. Red blood cell transfusion was allowed per institutional criteria. Roxadustat doses were titrated every 8 weeks based on Hb response and RBC transfusions. The primary endpoint was transfusion independence (TI) for ≥ 56 consecutive days during the first 28 treatment weeks; follow-up was at 52 weeks. Secondary endpoints included TI ≥ 56 consecutive days anytime during the study, proportion of patients who achieved ≥ 50% reduction in number of RBC transfusion over any 8 weeks vs baseline (BL), cumulative number of patient-exposure-week of TI, cumulative number of pRBC packs transfused, proportion of patients who achieved TI for &gt; 20 weeks. Safety was assessed via adverse events monitoring and patients (%) who progressed to acute myeloid leukemia (AML). Patients with and without ring sideroblasts (RS+/RS-) and BL EPO ≤ 200 mIU/ml and &gt; 200 mIU/ml were assessed for the primary endpoint. Results: In the OL phase, 24 transfusion-dependent LR-MDS patients were enrolled in 3 starting dose cohorts (Table). Nine patients (38%) achieved TI for ≥ 56 consecutive days within the first 28 and 52 weeks, 3 in cohort 1 (1.5 mg/kg), 1 in cohort 2 (2.0 mg/kg), and 5 in cohort 3 (2.5 mg/kg). When TI was achieved, 78% were receiving 2.5 mg/kg dose, 11% were receiving 2.0 mg/kg dose (started with 1.5 mg/kg) and 11% were receiving 1.5 mg/kg. Four patients (16.7%) remained TI for &gt; 20 weeks (1 at 1.5 mg/kg dose level and 3 at 2.5 mg/kg dose-level) at 52 weeks. The 50% reduction in number of transfusion compared with BL occurred in 13 patients (54.2%) at 28 weeks and 14 (58.3%) at 52 weeks. In patients with TI duration ≥ 56 days (n = 9), the mean (SD) TI duration was 182.9 (153.66) days. In patients with TI duration ≥ 140 days (n = 4), the mean (SD) TI duration was 324.5 (121.22) days. Subgroups met the primary endpoint at week 28 (23.1% and 54.5% MDS-RS+ and -RS-, respectively, and 38.9% and 33.3% BL EPO ≤ 200 mIU/ml and &gt; 200 mIU/ml, respectively); all subgroups maintained TI response to week 52. The overall safety profile was consistent with this patient population. Eight patients reported 8 treatment-emergent serious AEs; none were fatal. No patient progressed to AML. Conclusion: In this 52-week update, roxadustat 2.5 mg/kg TIW was effective in LR-MDS patients, based on observed response (TI and transfusion reduction), safety profile, and durable 52-week response. The ongoing, 156-patient, double-blind study phase uses a 2.5 mg/kg starting dose. Preliminary data in OL subgroups RS-/RS + and BL EPO ≤ 200 mIU/ml and &gt;200 mIU/ml suggest roxadustat may be effective in these subgroups. These data await confirmation in the ongoing double-blind, placebo-controlled study. Table 1 Disclosures Carraway: Abbvie: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC); Takeda: Other: Independent Advisory Committe (IRC); Stemline: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; BMS: Consultancy, Other: Research support, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Bradley:FibroGen, Inc.: Current Employment. Saha:FibroGen, Inc.: Current Employment. Bartels:FibroGen, Inc.: Current Employment. Leong:FibroGen Inc.: Current Employment, Current equity holder in private company. Yu:FibroGen, Inc.: Current Employment.

Background: Bone marrow aspiration is assessed for cytology and trephine biopsy provides overall cellularity, detection of focal lesion and infiltration. Bone marrow study plays a crucial role in identifying cause of aplastic anaemia in clinical practice. This study was carried out to see the etiological and clinical spectrum of pancytopenia based on bone marrow examination. Materials and Methods: This descriptive study was conducted in the Department of Medicine, Dhaka medical college Hospital, Dhaka, Bangladesh over a 2-year period (August 2016 to July 2018). A total 80 cases of pancytopenia were included in the study. Patients were diagnosed by hemoglobin less than 10 gm/ dL, total leukocyte count less than 4000/Cumm and platelet count less than 150000/cumm. Results: Maximum number of cases were seen in age group of 16-30 years (31.25%) and male to female ratio is 1.1:1. The commonest presenting complaint was fever in 40% (32/80) of the cases. Pallor was present in all the patients, Splenomegaly was seen in 20% (16/80) and hepatomegaly in 12.5% of the cases (10/80). Petechial hemorrhages were present in 5% (4/80). The commonest cause of pancytopenia was megaloblastic anemia (35%) and followed by aplastic anemia (32.5%). Conclusion: Pancytopenia is a common clinical problem encountered in clinical practice and the major differential diagnostic considerations of pancytopenia are aplastic anemia, megaloblastic anemia and hematological malignancies. J MEDICINE JUL 2019; 20 (2) : 68-71

Aim: This study aimed to evaluate the incidence of extra-axial cerebellopontine angle tumours and to characterize extra-axial cerebellopontine angle tumours. . All patients with clinical suspicion of CP angle tumours subjected 1.5 T MR imaging system. Total 30 patients were evaluated during this period.Results: Extra-axial CPA tumours accounts for 7-10% of brain tumours. Most common extraaxial CPA tumour is schwannoma (60%), followed by meningioma (27%), epidermoid (7%), arachnoid cysts (7%). 51-60 years is the most common age group involved. Schwannomas are common extra-axial CPA tumours which are enhancing round masses most commonly arise from the vestibular nerve and associated with enlargement of the internal auditory canal. Meningiomas are the second most common extra-axial CP angle tumours which oval or hemispheric lesions with a broad attachment to tentorium or petrous dura matter.Conclusion: MRI is the most sensitive noninvasive modality to characterize extra-axial CPA tumours. MRI identifies the location and extension of the lesions based on their characteristic signal and enhancement pattern on contrast.