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Evaluation of the Efficacy and Safety of Oral Azacitidine plus Best Supportive care versus Placebo and Best Supportive care in subjects with red blood cell (RBC) transfusion-dependent anemia and thrombocytopenia due to International Prognostic Scoring System (IPSS) lower risk myelodysplastic syndromes (MDS).
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We used the CAG regimen (low-dose cytarabine [10 mg/m2 per 12 hours, days 1-14], aclarubicin [14 mg/m2 per day, days 1-4], and granulocyte colony-stimulating factor [200 micrograms/m2 per day, days 1-14]) for the treatment of patients with primary resistant acute myelogenous leukemia (AML) and previously untreated elderly patients with AML, secondary AML, and refractory anemia with excess blasts in transformation (RAEB-T) in addition to relapsed AML. Forty-three of 69 (62%) patients achieved complete remission (CR), including 29 of 35 (83%) patients with relapsed AML, 1 of 8 patients with primary resistant AML, 5 of 8 elderly patients with previously untreated AML, and 8 of 18 patients with previously untreated secondary AML or RAEB-T. Ten of 22 (45%) patients > or = 65 years old achieved CR. The patients who achieved CR received at least 1 course of modified CAG therapy as the first consolidation therapy, followed by various second consolidation and intensification therapies. The median disease-free survival and overall survival were 8 and 15 months, respectively, for relapsed AML; 11 and 8 months for the elderly patients; and 8 and 17 months for secondary AML and RAEB-T. Myelosuppression was mild to moderate, and other than fever, severe nonhematologic toxicity was rare. CAG as the induction therapy seems promising for the treatment of various categories of poor-prognosis AML.
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Introduction: MDS is associated with an erythroid maturation defect, characterized by ineffective erythropoiesis leading to anemia and RBC transfusion dependence. Treatment of anemia in lower-risk MDS remains an unmet medical need. Luspatercept is a first-in-class erythroid maturation agent which binds to select TGFβ superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis (Suragani RN, et al. Nat Med. 2014;20:408-14). Preliminary clinical studies have shown promising activity in MDS (Platzbecker U, et al. Lancet Oncol. 2017;10:1338-47). We report the results of a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of luspatercept in patients with anemia due to Revised International Prognostic Scoring System (IPSS-R)-defined Very low-, Low-, or Intermediate-risk MDS with RS who require RBC transfusions. ClinicalTrials.gov identifier: NCT02631070. Methods: Eligible patients were aged. 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS according to the WHO 2016 criteria; were refractory, intolerant, or ineligible to receive erythropoiesis-stimulating agents (ESAs); and required RBC transfusions. Patients were randomized 2:1 to receive either luspatercept, at a starting dose level of 1.0 mg/kg with titration up to 1.75 mg/kg, if needed, or placebo, subcutaneously every 3 weeks for. 24 weeks. The primary endpoint was RBC transfusion independence (RBC-TI) for. 8 weeks between week 1 and week 24. A key secondary endpoint was RBC-TI for. 12 weeks between week 1 and 24. Achievement of modified hematologic improvementerythroid (mHI-E) response using IWG 2006 criteria was also assessed. Results: A total of 229 patients were randomized and treated. Median age was 71 years (range 26-95), median time from diagnosis was 41.8 months (range 3-421), and 62.9% were male. Overall, patient baseline characteristics were balanced between the treatment groups. Patients received a median of 5 RBC units (range 1-20) transfused over 8 weeks during the 16 weeks prior to treatment (43.2% of patients had. 6 RBC units/8 weeks, 27.9% had. 4 to < 6 RBC units/8 weeks, and 28.8% had < 4 RBC units/8 weeks). At baseline, 138 (60.3%), 58 (25.3%), and 32 (14.0%) patients had serum erythropoietin levels < 200 IU/L, 200-500 IU/L, and > 500 IU/L, respectively. A total of 218 (95.2%) patients had previously received ESAs. Overall, 206 (90.0%) patients had an SF3B1 mutation. Of 153 patients receiving luspatercept, 58 (37.9%) achieved the primary endpoint of RBC-TI for. 8 weeks compared with 10 of 76 patients (13.2%) receiving placebo (odds ratio [OR] 5.1, P < 0.0001). Of those receiving luspatercept, 43 of 153 (28.1%) achieved the key secondary endpoint of RBC-TI for. 12 weeks (weeks 1-24) compared with 6 of 76 (7.9%) receiving placebo (OR 5.1, P = 0.0002). Patients receiving luspatercept were more likely to achieve an mHI-E response, defined as a reduction in transfusion of. 4 RBC units/8 weeks or a mean hemoglobin increase of. 1.5 g/dL/8 weeks in the absence of transfusions, compared with patients receiving placebo (52.9% vs 11.8% during weeks 1-24; P < 0.0001). The safety profile of luspatercept was consistent with that reported in the phase 2 PACE-MDS study (Platzbecker U, et al. Lancet Oncol. 2017;10:1338-47). Conclusions: Treatment with luspatercept resulted in a significantly reduced transfusion burden compared with placebo in patients with anemia due to IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS, who require RBC transfusions, and was generally well tolerated. P.F. and U.P. contributed equally to this abstract as lead co-authors. R.S.K. and A.F.L. contributed equally to this abstract as senior co-authors. As of May 8, 2018, cutoff date.
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Objectives: To determine the optimum starting dose of intravenous C.E.R.A. for maintenance treatment of anemia in pediatric patients with CKD on HD. Methods: This open-label multicenter study included a 2-week screening period, 16-week dose-titration period, 4-week evaluation period, and a 1- year optional safety extension. Patients aged 6-17 years on HD with stable chronic renal anemia were given C.E.R.A. at a starting dose determined by previous epoetin alfa/beta or darbepoetin dosing. The initial dose of C.E.R.A. was 4μg every 4 weeks for each weekly dose of 250IU epoetin alfa/beta or 1.1μg darbepoetin ('intermediate dose'). After an interim analysis of the first 16 patients showed that this starting dose did not maintain hemoglobin (Hb) in the target range (10-12g/dL), the starting dose was doubled to 4μg for each weekly dose of 125IU epoetin alfa/beta or 0.55μg darbepoetin ('high dose'). Results: 64 patients have been enrolled (16 intermediate/48 high dose), with 48 evaluable for efficacy (12 and 36, respectively). Most withdrawals were due to renal transplantation. In the intermediate and high dose groups respectively, the mean ages were 11 and 13 years, and 69%and 48% were male. In the high dose group, adjusted mean change in Hb between evaluation and baseline was -0.09g/dL (95%CI -0.45, 0.26). Results were consistent across age groups (6- 11, 12-17 years) and previous type of erythropoiesis-stimulating agent. Hb concentrations over time in response to adjusted doses of C.E.R.A. were stable. In the high dose group 29/36 patients (81%) maintained Hb within 10- 12g/dL, 27 (75%) maintained Hb within 1g/dL of baseline, and 25 (69%) fulfilled both criteria. Safety results were consistent with the known safety profile for C.E.R.A. in adults Conclusions: Pediatric patients on HD with stable anemia of CKD can be switched from maintenance treatment with epoetin alfa/beta or darbepoetin to C.E.R.A., using a defined conversion factor for the starting dose of C.E.R.A.
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This was a multi‐centric, open‐label, randomized, prospective, comparative, parallel‐group, active‐controlled, phase III clinical trial (in the Russian Federation). The purpose of this study was to evaluate non‐inferiority for efficacy and safety of Ferrum Lek® (iron (III) hydroxide polymaltosate), compared to MALTOFER®, in the treatment of patients with mild and moderate iron‐deficiency anaemia. Participants underwent screening for up to 7 days. Eligible participants were randomized in 1:1 ratio to two treatment arms. Subjects in Group 1 received 2 tablets per day (200 mg) of chewable tablets Ferrum Lek® during or immediately after meals; once daily. Subjects in Group 2 (reference product) received 2 tablets per day (200 mg) of chewable tablets Maltofer® during or immediately after meals; once daily. The subjects received the medicinal products daily for 12 weeks. After the last scheduled study site visit, a follow‐up visit (by phone) was scheduled 14 days after the completion of the active treatment period (day 98±2) to record any delayed adverse events.
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Darbepoetin alfa (DA) is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anemia (CIA). Safety concerns have prompted changes to the ESA-product information, which now recommends initiating ESAs at hemoglobin (Hb) levels < 10 g/dL (US) or ≤ 10 g/dL (EU). The present exploratory analysis of a DA trial examined how baseline-Hb levels at ESA initiation affect transfusion rates, Hb response, and safety outcomes in CIA patients. Data were retrospectively analyzed from a phase 3 trial of CIA patients randomised to 500 mcg DA every 3 weeks (Q3 W) or to 2.25 mcg/kg DA weekly (QW) for 15 weeks. In the current analysis, data were reanalyzed by baseline-Hb categories of <9 g/dL (n = 126), 9 to <10 g/dL (n = 225), and ≥ 10 g/dL (n = 354). The Q3 W and QW groups were combined. Transfusion rates were highest in the <9 g/dL baseline-Hb group in all time periods examined. The Kaplan-Meier percentage (95% CI) of patients achieving Hb ≥ 10 g/dL was 68% (59, 78) and 88% (82, 92) in the <9 g/dL and 9 to <10 g/dL baseline-Hb groups, respectively. With lower baseline-Hb, incidence of a ≥ 1 g/dL-Hb rise in 14 days progressively decreased. Incidence of venous thromboembolic events was similar in all baseline-Hb groups and similar between patients with or without a ≥ 1 g/dL-Hb rise in 14 days. Overall, transfusion risk increased and Hb response decreased at lower baseline-Hb levels in this exploratory analysis. When following ESA-product information to initiate ESAs at Hb ≤ 10 g/dL, the greatest benefit may be achieved when initiating close to 10 g/dL. Prospective studies are needed to further examine this hypothesis.