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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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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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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.
Abstract
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.
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Efficacy and safety analysis of epoetin alfa in patients with small-cell lung cancer: a randomized, double-blind, placebo-controlled trial
Grote T, Yeilding AL, Castillo R, Butler D, Fishkin E, Henry DH, DeLeo M, Fink K, Sullivan DJ
Journal of Clinical Oncology. 2005;23((36):):9377-86.
Abstract
PURPOSE This randomized, double-blind, placebo-controlled trial (N93-004) evaluated the effects of epoetin alfa on tumor response to chemotherapy and survival in patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS Adult patients with hemoglobin < or = 14. 5 g/dL starting chemotherapy received epoetin alfa 150 U/kg or placebo subcutaneously 3 times weekly until 3 weeks after completion of chemotherapy. Survival was assessed for 3 years. The primary end point was the proportion of patients with complete or partial response after three chemotherapy cycles. RESULTS The trial was terminated prematurely after 224 of a projected 400 patients were accrued. Baseline characteristics were similar between groups. Epoetin alfa and placebo patients (n = 109 and n = 115, respectively) had mean baseline hemoglobin of 12. 8 g/dL and 13. 0 g/dL, respectively. Overall tumor response was similar between the epoetin alfa and placebo groups after three chemotherapy cycles (72% and 67%, respectively; 95% CI of difference, -6% to 18%) and after completion of chemotherapy (60% and 56%, respectively; 95% CI of difference, -9% to 17%). Epoetin alfa and placebo groups had similar median overall survival (10. 5 and 10. 4 months, respectively) and overall mortality (91. 7% and 87. 8%, respectively; hazard ratio, 1. 172; 95% CI, 0. 887 to 1. 549; P = . 264). Hemoglobin was maintained in the prechemotherapy range in epoetin alfa patients, but decreased substantially in placebo patients. Fewer epoetin alfa patients than placebo patients required transfusion. CONCLUSION These results suggest that in newly diagnosed patients with SCLC epoetin alfa does not affect tumor response to chemotherapy or survival. However, the early trial closure makes these conclusions preliminary.
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Randomized, open-label study of epoetin alfa 40,000 U once weekly versus 80,000 U every two weeks in anemic patients with cancer receiving chemotherapy
Henry DH, Xie J, Woodman RC
Blood. 2005;106((11):): Abstract No. 3772.
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Intravenous ferric gluconate (FG) for increasing response to epoetin (EPO) in patients with anemia of cancer chemotherapy results of a multicenter, randomized trial
Henry DH, Dahl NV, Auerbach M, Tchekmedyian S, Laufman LR
Blood. 2004;104((11, Pt 2):):10b.. Abstract No. 3696.
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Benefits of epoetin alfa therapy in anemic cancer patients receiving chemotherapy
Henry DH, Abels RI
Journal of Clinical Oncology. 1995;13((9):):2473-4.
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Recombinant human erythropoietin in the treatment of cancer and chemotherapy-induced anemia: results of double-blind and open-label follow-up studies
Henry DH, Abels RI
Seminars in Oncology. 1994;21((2 Suppl 3):):21-8.
Abstract
Anemia associated with advanced cancer is common. Contributing factors include the anemia of chronic disease, chemotherapy, radiation therapy, and bone marrow invasion with tumor. Based on the observation that endogenous erythropoietin (EPO) levels in anemic patients with cancer are inadequate for the degree of anemia, three randomized double-blind, placebo-controlled trials of recombinant human erythropoietin (rHuEPO) treatment in anemic patients with cancer were performed in patients (1) not receiving concomitant chemotherapy (NO CTX), (2) receiving myelosuppressive chemotherapy that did not include cisplatin (CTX-NO PLAT), and (3) receiving myelosuppressive cisplatin-containing chemotherapy (CTX-PLAT). In the NO CTX trial, patients were treated with rHuEPO 100 U/kg or placebo subcutaneously (SQ) three times per week for up to 8 weeks. In the CTX trials, patients were treated with rHuEPO 150 U/kg or placebo SQ three times per week for 12 weeks. Four hundred thirteen patients were enrolled (124, NO CTX; 157, CTX-NO PLAT; and 132, CTX-PLAT). In all three trials, patients receiving rHuEPO had a significantly (P < .004) greater increase in hematocrit (HCT) than placebo-treated patients. In the two CTX trials combined, rHuEPO-treated patients also had a significantly (P < or = .009) lower transfusion requirement than placebo-treated patients after the first month of therapy. Quality of life improved significantly (P < .05) in responding (> or = 6%-point HCT increase without transfusion) rHuEPO-treated patients compared with placebo-treated patients. Overall, no adverse events occurred more frequently in rHuEPO-treated patients compared with placebo-treated patients. Following completion of the double-blind phase, patients received rHuEPO on an open-label basis as needed for correction of anemia with the dose titrated to a maximum of 900 U/kg/wk. During total rHuEPO exposure (either started at the beginning of double-blind therapy for patients initially randomized to rHuEPO or at the beginning of open-label therapy for patients initially randomized to placebo; 363 treated/347 evaluable for efficacy), 40.0%, 56.1%, and 58.3% of the NO-CTX, CTX-NO PLAT, and CTX-PLAT patients, respectively, responded to rHuEPO therapy with an increase of HCT > or = 6% unrelated to transfusion.(ABSTRACT TRUNCATED AT 400 WORDS)
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Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy
Case DC Jr, Bukowski RM, Carey RW, Fishkin EH, Henry DH, Jacobson RJ, Jones SE, Keller AM, Kugler JW, Nichols CR,, et al
Journal of the National Cancer Institute. 1993;85((10):):801-6.
Abstract
BACKGROUND Patients with advanced cancer frequently experience clinically significant anemia, which is often exacerbated by myelosuppressive chemotherapy. Consistent with the anemia of chronic disease, studies have documented serum erythropoietin levels that are inappropriately low for the degree of anemia in cancer patients. Myelosuppressive chemotherapy impairs erythropoiesis, which may not fully recover between treatment cycles. Recombinant human erythropoietin (rHuEPO) has been used safely and effectively to treat anemia in AIDS patients receiving zidovudine (AZT) and in patients with chronic renal failure. PURPOSE This study was designed to evaluate the clinical role of rHuEPO in reducing symptomatic anemia in patients with advanced cancer who were receiving myelosuppressive chemotherapy (excluding cisplatin). METHODS We studied 153 anemic cancer patients receiving cyclic combination chemotherapy in a prospective multicenter, double-blind, placebo-controlled trial. The patients were randomly assigned to receive either rHuEPO (150 U/kg) or placebo subcutaneously three times a week for a maximum of 12 weeks or until the hematocrit level increased to 38%-40%. If the hematocrit reached this target level before 12 weeks, the rHuEPO dose could be reduced to maintain the hematocrit at that level for the duration of the study. Response to rHuEPO therapy was assessed by measuring changes in hematocrit level, transfusion requirements, and quality of life. Quality-of-life assessment was based on patients' responses to questionnaires before and after the courses of therapy. RESULTS The increase in hematocrit in the rHuEPO-treated group compared with hematocrit in the placebo-treated group was statistically significant (P = .0001) as measured by percentage point of change from baseline to final evaluation, by an increase in hematocrit level of six percentage points or more unrelated to transfusion, and by a rise in hematocrit level to 38% or more unrelated to transfusion. There was a trend toward the reduction in mean units of blood transfused per patient during months 2 and 3 of therapy combined in rHuEPO-treated patients compared with placebo-treated patients (0.91 U versus 1.65 U; P = .056). In addition, rHuEPO-treated patients experienced a statistically significant improvement in energy level and ability to perform daily activities (P < or = .05). The two treatment groups showed no statistically significant differences in toxic effects except for increased incidence of diaphoresis (P < .05) and diarrhea (P = .05) in the rHuEPO-treated group. CONCLUSIONS We conclude that rHuEPO is safe and effective for reversing anemia related to advanced cancer or to chemotherapy for cancer.