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Efficacy and Safety of Ferric Carboxymaltose Infusion in Reducing Anemia in Patients Receiving Chemotherapy for Nonmyeloid Malignancies: a Randomized, Placebo-Controlled Study (IRON CLAD)
Makharadze T, Boccia R, Krupa A, Blackman N, Henry DH, Gilreath JA
American journal of hematology. 2021
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Abstract
PURPOSE Erythropoiesis-stimulating agents (ESA) are effective for chemotherapy-induced anemia (CIA) but associated with serious adverse events. Safer alternatives would be beneficial in this population. The efficacy and safety of ferric carboxymaltose (FCM) as monotherapy for CIA was evaluated. METHODS This Phase 3, 18-week, double-blind, placebo-controlled study randomized adults with ≥4 weeks of chemotherapy remaining for treatment of nonmyeloid malignancies with CIA to FCM (two 15 mg/kg infusions 7 days apart; maximum dose, 750 mg single/1500 mg total) or placebo. The primary efficacy endpoint was percentage of patients with decreases in hemoglobin (Hb) ≥0.5 g/dL from weeks 3 to 18; the key secondary efficacy endpoint was change in Hb from baseline to week 18. Inclusion criteria included: (Hb) 8-11 g/dL, ferritin 100-800 ng/mL, and transferrin saturation (TSAT) ≤35%. RESULTS In 244 patients (n=122, both groups), the percent who maintained Hb within 0.5 g/dL of baseline from weeks 3 to 18 was significantly higher with FCM versus placebo (50.8% vs 35.3%; P=0.01). Mean change in Hb from baseline to week 18 was similar between FCM and placebo (1.04 vs 0.87 g/dL) but significantly greater with FCM with baseline Hb ≤9.9 g/dL (1.08 vs 0.42 g/dL; P=0.01). The percent with ≥1 g/dL increase from baseline was significantly higher with FCM versus placebo (71% vs 54%; P=0.01), occurring in a median 43 versus 85 days (P=0.001). Common adverse events in the FCM arm included neutropenia (17%), hypophosphatemia (16%), and fatigue (15%). CONCLUSION FCM monotherapy effectively maintained Hb and was well tolerated in CIA. This article is protected by copyright. All rights reserved.
PICO Summary
Population
Patients receiving chemotherapy for non-myeloid malignancies with chemotherapy-induced anaemia (CIA), enrolled in the IRON-CLAD study conducted at 58 sites in the United States, Bulgaria, Georgia, Hungary, and Poland (n= 244).
Intervention
Ferric carboxymaltose (FCM) infusions (n= 122).
Comparison
Placebo (n= 122).
Outcome
The percentage of patients who maintained Hb within 0.5 g/dL of baseline from weeks 3 to 18 was significantly higher with FCM versus placebo (50.8% vs. 35.3%). Mean change in Hb from baseline to week 18 was similar between FCM and placebo (1.04 vs. 0.87 g/dL) but significantly greater with FCM with baseline Hb <= 9.9 g/dL (1.08 vs. 0.42 g/dL). The percent with >= 1 g/dL increase from baseline was significantly higher with FCM versus placebo (71% vs. 54%), occurring in a median 43 versus 85 days. Common adverse events in the FCM arm included neutropenia (17%), hypophosphatemia (16%), and fatigue (15%). FCM monotherapy effectively maintained Hb and was well tolerated in CIA.
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Roxadustat for the Treatment of Anemia in Patients with Lower-Risk Myelodysplastic Syndrome: Open-label, Dose-selection, Lead-in Stage of a Phase 3 Study
Henry DH, Glaspy J, Harrup R, Mittelman M, Zhou A, Carraway HE, Bradley C, Saha G, Modelska K, Bartels P, et al
American journal of hematology. 2021
Abstract
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 open-label (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 any 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. This article is protected by copyright. All rights reserved.
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A Randomized, Double-Blind, Placebo-Controlled, Phase III Noninferiority Study of the Long-Term Safety and Efficacy of Darbepoetin alfa for Chemotherapy-Induced Anemia in Patients With Advanced Non-Small Cell Lung Cancer
Gascon P, Nagarkar R, Smakal M, Syrigos KN, Barrios CH, Sanchez JC, Zhang L, Henry DH, Gordon D, Hirsh V, et al
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2019
Abstract
INTRODUCTION This study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with non-small cell lung cancer (NSCLC) treated to a 12.0-g/dL hemoglobin (Hb) ceiling. METHODS Adults with stage IV NSCLC expected to receive ≥2 cycles of myelosuppressive chemotherapy and Hb≤11.0 g/dL were randomized 2:1 to blinded 500 mug darbepoetin alfa or placebo Q3W. The primary endpoint was OS; a stratified Cox proportional hazards model was used to evaluate noninferiority (upper confidence limit for hazard ratio [HR] <1.15). Secondary endpoints were PFS and incidence of transfusions or Hb≤8.0 g/dL from week 5 to end of the efficacy treatment period (EOETP). RESULTS The primary analysis set included 2516 patients: 1680 randomized to darbepoetin alfa; 836 to placebo. The study was stopped early per independent Data Monitoring Committee recommendation after the primary endpoint was met with no new safety concerns. Darbepoetin alfa was noninferior to placebo for OS (stratified HR=0.92; 95%CI, 0.831.01) and PFS (stratified HR=0.95; 95%CI, 0.871.04). Darbepoetin alfa was superior to placebo for transfusion or Hb ≤8.0 g/dL from week 5 to EOETP (stratified OR=0.70; 95%CI, 0.570.86; P<.001). Objective tumor response was similar between the arms (darbepoetin alfa, 36.4%; placebo, 32.6%). Incidence of serious adverse events (AEs) was 31.1% in both arms. No unexpected AEs were observed. CONCLUSIONS Darbepoetin alfa dosed to a 12.0-g/dL Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb≤8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.
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Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy
Henry DH, Dahl NV, Auerbach M, Tchekmedyian S, Laufman LR
The Oncologist. 2007;12((2):):231-42.
Abstract
PURPOSE To evaluate the safety and efficacy of intravenous (IV) sodium ferric gluconate complex (FG), oral ferrous sulfate, or no iron to increase hemoglobin (Hb) in anemic cancer patients receiving chemotherapy and epoetin alfa. PATIENTS AND METHODS In this open-label, multicenter trial, 187 patients with chemotherapy-related anemia (Hb <11 g/dl; serum ferritin > or =100 ng/ml or transferrin saturation > or =15%) scheduled to receive chemotherapy and epoetin alfa (40,000 U subcutaneously weekly) were randomized to 8 weeks of 125 mg of IV FG weekly, 325 mg of oral ferrous sulfate three times daily, or no iron. The primary outcome was a change in Hb from baseline to endpoint, first whole-blood or red blood cell transfusion, or study withdrawal. RESULTS One hundred twenty-nine patients were evaluable for efficacy (FG, n = 41; oral iron, n = 44; no iron, n = 44). Mean increase in Hb was 2. 4 g/dl (95% confidence interval [CI], 2. 1-2. 7) for FG (p = . 0092 vs. oral iron; p = . 0044 vs. no iron), 1. 6 g/dl (95% CI, 1. 1-2. 1) for oral iron (p =. 7695 vs. no iron), and 1. 5 g/dl (95% CI, 1. 1-1. 9) for no iron. Hb response (increase > or =2 g/dl) was 73% for FG (p = . 0099 vs. oral iron; p = . 0029 vs. no iron), 46% for oral iron (p = . 6687 vs. no iron), and 41% for no iron. FG was well tolerated. CONCLUSION For cancer patients with chemotherapy-related anemia receiving epoetin alfa, FG produces a significantly greater increase in Hb and Hb response compared with oral iron or no iron, supporting more aggressive treatment with IV iron supplementation for these patients.
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Recombinant human erythropoietin for patients with AIDS treated with zidovudine
Fischl M, Galpin JE, Levine JD, Groopman JE, Henry DH, Kennedy P, Miles S, Robbins W, Starrett B, Zalusky R,, et al
New England Journal of Medicine. 1990;322((21):):1488-93.
Abstract
Bone marrow suppression and anemia are frequent side effects of treatment of the acquired immunodeficiency syndrome (AIDS) with zidovudine (formerly azidothymidine [AZT]). We conducted a randomized, double-blind, placebo-controlled clinical trial of recombinant human erythropoietin (100 U per kilogram of body weight thrice weekly by intravenous bolus) in 63 patients with AIDS treated with zidovudine (29 in the erythropoietin group and 34 in the placebo group). Reductions in the number of units of red cells transfused and the number of patients given transfusions per month became apparent in the second and third months of the trial. The reductions were observed in patients with endogenous erythropoietin levels less than or equal to 500 IU per liter at base line, but not in patients whose levels were greater than 500 IU per liter at the beginning of the study. Although the hematocrit and hemoglobin level were not used as the primary criteria of efficacy because the patients received transfusions when their physicians decided that they needed them, a significantly higher rate of increase in the hematocrit was observed in the patients treated with recombinant human erythropoietin whose levels of endogenous erythropoietin were less than or equal to 500 IU per liter (0.00353 points per week) than in the patients given placebo (0.00116 points per week). This effect was not seen in patients with higher levels of endogenous erythropoietin. Serious side effects did not occur more often in the group treated with erythropoietin than in the placebo group. We conclude that recombinant human erythropoietin may be useful in patients with AIDS treated with zidovudine, although the indicators for its use remain to be clarified.