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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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.
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).
Ferric carboxymaltose (FCM) infusions (n= 122).
Placebo (n= 122).
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.
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
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.
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
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.
Pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials of darbepoetin alfa in the treatment of patients with chemotherapy-induced anemia
Ludwig H, Crawford J, Osterborg A, Vansteenkiste J, Henry DH, Fleishman A, Bridges K, Glaspy JA
Journal of Clinical Oncology. 2009;27((17):):2838-47.
PURPOSE Although numerous clinical trials have demonstrated the efficacy and tolerability of erythropoiesis-stimulating agents (ESAs) in patients with chemotherapy-induced anemia (CIA), results of some recent trials and one meta-analysis have suggested that ESAs may negatively impact survival and/or disease control in patients with cancer. METHODS To assess the benefits and risks of ESAs in CIA, we conducted a pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials in 2,122 patients with CIA receiving darbepoetin alfa (DA; n = 1,200) or placebo (n = 912). RESULTS DA did not increase mortality (hazard ratio = 0.97; 95% CI, 0.85 to 1.1) and had no effect on progression-free survival (hazard ratio = 0.93; 95% CI, 0.84 to 1.04) and disease progression (hazard ratio = 0.92; 95% CI, 0.82 to 1.03), but, as expected, increased the risk for thromboembolic events (hazard ratio = 1.57; 95% CI, 1.10 to 2.26). Overall and progression-free survival were not affected by baseline hemoglobin and seemed better in patients who achieved hemoglobin more than 12 or more than 13 g/dL. Transfusions and rates of hemoglobin increase (> 1 g/dL in 14 days; > 2 g/dL in 28 days) owing to transfusions were associated with an increased risk for death and disease progression in both treatment groups; in the absence of transfusions, rates of hemoglobin increase did not appear to increase the risk for adverse outcomes. Compared with placebo, DA significantly reduced the risk of receiving one or more transfusion. CONCLUSION There seemed to be no association between DA and risk of death or disease progression in this meta-analysis of individual patient data from DA studies conducted in CIA, the approved indication for ESAs in oncology.
Health-related quality of life (HRQoL) in patients (pts) with chronic immune thrombocytopenic purpura (ITP): results from two placebo-controlled phase 3 studies of AMG 531
George JN, Lyons R, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Mathias SD, Gao S, et al
Blood. 2007;110((11):): Abstract No. 1314.
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.
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.
Is thromboembolism in cancer patients treated with erythropoietic stimulating agents related to thrombocytosis and iron restricted erythropoiesis?
Henry DH, Dahl N, Auerbach M
Blood. 2007;110((11):): Abstract No. 1625.
Final results of a randomized study comparing two dosing regimens of epoetin alfa in patients with chemotherapy-induced anemia: 80,000 U every two weeks vs 40,000 U weekly
Henry DH, Kamin M, Wilhelm F, Williams D, Xie J, Woodman RC
Journal of Clinical Oncology. 2006;24((18_suppl)):8624.
8624 Background: Epoetin alfa is typically administered weekly (QW) for the treatment of chemotherapy (CT)-induced anemia. Less frequent dosing can be more convenient for patients (pts) and healthcare providers. This is the first study to examine extended interval initial dosing with epoetin alfa 80,000 U every two weeks (Q2W) vs the standard 40,000 U QW regimen. METHODS This randomized, open-label, 13-week study enrolled pts with non-myeloid malignancies with baseline (BL) hemoglobin (Hb) < 11 g/dL and CT planned for > 12 weeks. Pts were assigned (1:1) to receive epoetin alfa 40,000 U QW or 80,000 U Q2W subcutaneously. Drug was held for Hb > 13 g/dL and dose was reduced for Hb > 12 g/dL or rate of rise > 1 g/dL in any 2-week period. For inadequate Hb response, 80,000 U Q2W pts were switched to 40,000 U QW and 40,000 U QW patients were increased to 60,000 U QW. The primary analysis was a comparison of the mean Hb change from BL to end of study (EOS). RESULTS 298 pts received > 1 dose of drug (153 Q2W, 145 QW). BL characteristics were comparable between groups: 66% female, overall mean age 62 yrs, and BL Hb 10.0 g/dL. Most common tumor types were breast (25%), NSCLC (15%) and colorectal (14%). Efficacy was analyzed in 295 pts (151 Q2W, 144 QW) who had > 1 post-BL Hb value. The mean Hb change from BL to EOS for Q2W was 1.27 +/- 1.48 g/dL compared to 1.28 +/- 1.60 g/dL for QW [difference 0, 1-sided 95% CI -0.25,-]. In the per protocol population, the difference in mean Hb change was similar. Mean Hb values over time were also similar between groups. Kaplan-Meier estimates of post-28 day transfusion rates were 11.2% in Q2W vs. 12.0% in QW. Fewer Q2W pts compared to QW pts required dose holds (21% vs 42%) or dose reductions (41% vs 59%). 13% of Q2W pts were switched to QW dosing and 37% of QW pts required a dose increase. The incidences of clinically relevant TVEs and deaths were similar in the Q2W vs QW groups (7.8% vs 7.6% and 6.5% vs 6.2%, respectively). CONCLUSIONS Pts treated with epoetin alfa 80,000 U Q2W demonstrated similar Hb increases, transfusion rates, and safety outcomes compared to pts treated with 40,000 U QW. Epoetin alfa 80,000 U every other week is an effective regimen that may provide a more convenient dosing option for pts with CT-induced anemia. [Table: see text].
Randomized, open-label comparison of epoetin alfa extended dosing (80 000 U Q2W) vs weekly dosing (40 000 U QW) in patients with chemotherapy-induced anemia
Henry DH, Gordan LN, Charu V, Wilhelm FE, Williams D, Xie J, Woodman RC
Current Medical Research and Opinion. 2006;22((7):):1403-13.
OBJECTIVE This randomized, open-label, multicenter study compared the efficacy and safety of epoetin alfa (EPO) 80 000 U every 2 weeks (Q2W) to the FDA-approved regimen of 40 000 U weekly (QW) in patients with chemotherapy-induced anemia. RESEARCH DESIGN AND METHODS A total of 310 patients with nonmyeloid malignancy and baseline hemoglobin (Hb) RESULTS Analysis of the primary endpoint revealed that the mean change in Hb from baseline to study end was comparable between the Q2W and QW groups in the per-protocol population (1. 6 g/dL vs 1. 8 g/dL, respectively; treatment difference, -0. 2 g/dL; one-sided 95% confidence interval [-0. 56, -]); similar results were observed in the mITT population. Among patients on study at Day 29, 9. 6% (13/135) and 11. 1% (14/126) of patients in the Q2W and QW groups, respectively, received a transfusion between Day 29 and the end of the study (p = 0. 709). Dose withholds (21% vs 42%, p < 0. 001) and dose reductions (41% vs 59%, p = 0. 003) were less common for Q2W than QW. Safety profiles were similar between groups; clinically relevant thrombotic vascular events occurred in 8% of patients in each group. The open-label dosing and the patient attrition rate did not appear to influence overall study results. CONCLUSIONS Extended dosing (80 000 U Q2W) and once-weekly dosing (40 000 U QW) of EPO provided comparable safety and efficacy for chemotherapy-induced anemia.
Clinical benefits and risks associated with epoetin and darbepoetin in patients with chemotherapy-induced anemia: a systematic review of the literature
Ross SD, Allen IE, Henry DH, Seaman C, Sercus B, Goodnough LT
Clinical Therapeutics. 2006;28((6):):801-831.
BACKGROUND Erythropoiesis-stimulating proteins (ESPs) are indicated for the treatment of chemotherapy-induced anemia (CIA). Evidence-based guidelines and systematic reviews of the management of CIA do not yet include all currently approved ESPs or all of the clinically relevant benefits and risks of ESPs. OBJECTIVES The aims of this work were to provide up-to-date assessments of the clinical efficacy and effectiveness (ie, transfusions and quality-of-life [QoL] benefits) and safety (ie, risk of venous thromboembolism [VTE] and all-cause or treatment-associated death) of epoetin-alfa, epoetin-beta, and darbepoetin-alfa for the treatment of CIA in cancer patients with hemoglobin<11 g/dL. We also considered the impact of differences in study design, patients, and treatments on the results. METHODS A systematic review of the literature was performed to identify and analyze English-language studies (controlled trials and prospective uncontrolled studies with >or=300 patients) published between 1980 and July 2005. The databases searched were MEDLINE and the Cochrane Library. Relevant abstracts from the last 2 annual meetings of the American Society of Clinical Oncology, American Society of Hematology, and European Society for Medical Oncology were also included. Studies were selected, using predefined eligibility criteria. Two reviewers had to agree on all included and excluded studies, and on all data extracted from each accepted study before they were entered into a relational database. Meta-analyses were performed to quantify benefit and risk outcomes. RESULTS In total, 40 studies including 21,378 patients were eligible for analysis. Each ESP was found to have efficacy relative to standard care or placebo. The odds ratio (OR) for transfusions in studies of epoetin versus controls was 0.44 (95% CI, 0.35-0.55) and of darbepoetin versus controls was 0.41 (95% CI, 0.31-0.55). Patients receiving ESPs experienced a significant improvement in QoL; the mean difference in Functional Assessment of Cancer Therapy-Fatigue score for ESPs versus controls was 0.23 (95% CI, 0.10-0.36; P=0.001). The frequency of VTE and death was not significantly different between ESPs and control (VTE OR, 1.41 [95% CI, 0.81-2.47]; all-cause mortality OR, 1.00 [95% CI, 0.69-1.44]). CONCLUSIONS This analysis of key clinical benefits and risks of epoetin and darbepoetin in the treatment of CIA found no clinically relevant differences between these drugs.