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Intravenous Iron Supplementation for the Treatment of Chemotherapy-Induced Anemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Buchrits S, Itzhaki O, Avni T, Raanani P, Gafter-Gvili A
Journal of clinical medicine. 2022;11(14)
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Abstract
BACKGROUND The pathophysiology of cancer-related anemia is multifactorial, including that of chemotherapy-induced anemia (CIA). The guidelines are not consistent in their approach to the use of intravenous (IV) iron in patients with cancer as part of the clinical practice. MATERIALS AND METHODS All randomized controlled trials that compared IV iron with either no iron or iron taken orally for the treatment of CIA were included. We excluded trials if erythropoiesis-stimulating agents (ESAs) were used. The primary outcome was the percentage of patients requiring a red blood cell (RBC) transfusion during the study period. The secondary outcomes included the hematopoietic response (an increase in the Hb level by more than 1 g/dL or an increase above 11 g/dL), the iron parameters and adverse events. For the dichotomous data, risk ratios (RRs) with 95% confidence intervals (Cis) were estimated and pooled. For the continuous data, the mean differences were calculated. A fixed effect model was used, except in the event of significant heterogeneity between the trials (p < 0.10; I(2) > 40%), in which we used a random effects model. RESULTS A total of 8 trials published between January 1990 and July 2021 that randomized 1015 patients fulfilled the inclusion criteria. Of these, 553 patients were randomized to IV iron and were compared with 271 patients randomized to oral iron and 191 to no iron. IV iron decreased the percentage of patients requiring a blood transfusion compared with oral iron (RR 0.72; 95% CI 0.55-0.95) with a number needed to treat of 20 (95% CI 11-100). IV iron increased the hematopoietic response (RR 1.23; 95% CI 1.01-1.5). There was no difference with respect to the risk of adverse events (RR 0.97; 95% CI 0.88-1.07; 8 trials) or severe adverse events (RR 1.09; 95% CI 0.76-1.57; 8 trials). CONCLUSIONS IV iron resulted in a decrease in the need for RBC transfusions, with no difference in adverse events in patients with CIA. IV iron for the treatment of CIA should be considered in clinical practice.
PICO Summary
Population
People with chemotherapy induced anaemia enrolled in randomised controlled trials (RCTs), and identified by systematic review (n= 1,015, 8 RCTs).
Intervention
Intravenous [IV] iron (n= 553).
Comparison
Oral iron (n= 271), or no iron (n= 191).
Outcome
IV iron decreased the percentage of patients requiring a blood transfusion compared with oral iron (Risk ratio [RR] 0.72; 95% confidence interval [CI] 0.55-0.95) with a number needed to treat of 20 (95% CI 11-100). IV iron increased the hematopoietic response (RR 1.23; 95% CI 1.01-1.5). There was no difference with respect to the risk of adverse events (RR 0.97; 95% CI 0.88-1.07; 8 trials) or severe adverse events (RR 1.09; 95% CI 0.76-1.57; 8 trials).
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Low-dose fludarabine with or without darbepoetin alfa in patients with chronic lymphocytic leukemia and comorbidity: primary results of the CLL9 trial of the German CLL Study Group
Goede V, Busch R, Bahlo J, Chataline V, Kremers S, Muller L, Reschke D, Schlag R, Schmidt B, Vehling-Kaiser U, et al
Leukemia & Lymphoma. 2016;57((3)):596-603.
Abstract
This study was planned as a phase 3 trial to investigate low-dose fludarabine with or without darbepoetin alfa in older patients with previously untreated or treated chronic lymphocytic leukemia (CLL) and comorbidity. Due to slow recruitment, the study was terminated prematurely after accrual of 97 patients who, on average, were 74 years old and had a cumulative illness rating scale (CIRS) total score of 5. We report toxicity and efficacy of the study treatment. Grade 3-5 neutropenia and infection were observed in 25% and 10% of patients, respectively. Response was seen in 73% (5% complete remissions). Median event-free and overall survival was 12.2 and 44.8 months, respectively. No differences in outcome were found for patients treated with versus without darbepoetin alfa. In subjects with progressive/recurrent CLL during or after study treatment, overall survival was similar for patients receiving chemotherapy versus chemoimmunotherapy as salvage treatment.
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Erythropoietin therapy after allogeneic hematopoietic cell transplantation: a prospective, randomized trial
Jaspers A, Baron F, Willems E, Seidel L, Hafraoui K, Vanstraelen G, Bonnet C, Beguin Y
Blood. 2014;124((1):):33-41.
Abstract
We conducted a prospective randomized trial to assess hemoglobin (Hb) response to recombinant human erythropoietin (rhEPO) therapy after hematopoietic cell transplantation (HCT). Patients (N = 131) were randomized (1:1) between no treatment (control arm) or erythropoietin at 500 U/kg per week (EPO arm). Patients were also stratified into 3 cohorts: patients undergoing myeloablative HCT with rhEPO to start on day (D)28, patients given nonmyeloablative HCT (NMHCT) with rhEPO to start on D28, and patients also given NMHCT but with rhEPO to start on D0. The proportion of complete correctors (ie, Hb >13 g/dL) before D126 posttransplant was 8.1% in the control arm (median not reached) and 63.1% in the EPO arm (median, 90 days) (P < .001). Hb levels were higher and transfusion requirements decreased (P < .001) in the EPO arm, but not during the first month in the nonmyeloablative cohort starting rhEPO on D0. There was no difference in rates of thromboembolic events or other complications between the 2 arms. This is the first randomized trial to demonstrate that rhEPO therapy hastens erythroid recovery and decreases transfusion requirements when started one month after allogeneic HCT. There was no benefit to start rhEPO earlier after NMHCT. 2014 by The American Society of Hematology.
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Darbepoetin-alfa and intravenous iron administration after autologous hematopoietic stem cell transplantation: A prospective multicenter randomized trial
Beguin Y, Maertens J, De Prijck B, Schots R, Seidel L, Bonnet C, Hafraoui K, Willems E, Vanstraelen G, Servais S, et al
American Journal of Hematology. 2013;88((12):):990-6.
Abstract
We conducted a randomized study analyzing the impact of darbepoetin alfa (DA) administration with or without intravenous (i.v.) iron on erythroid recovery after autologous hematopoietic cell transplantation (HCT). Patients were randomized between no DA (Arm 1), DA 300 mug every 2 weeks starting on Day 28 after HCT (Arm 2), or DA plus i.v. iron 200 mg on Days 28, 42, and 56 (Arm 3). The proportion achieving complete hemoglobin (Hb) response within 18 weeks (primary end point) was 21% in Arm 1 (n=24), 79% in Arm 2 (n=25), and 100% in Arm 3 (n=23; P<0.0001). Erythropoietic response was shown to be significantly higher in Arm 3 (n=46) than in Arm 2 (n=50; P=0.008), resulting in lower DA use, reduced drug costs, and improved quality of life scores, but the effect on transfusions was not significant. In multivariate analysis, DA administration (P<0.0001), i.v. iron administration (P=0.0010), high baseline Hb (P<0.0001), and low baseline creatinine (P=0.0458) were independently associated with faster achievement of complete Hb response. In conclusion, DA is highly effective to ensure full erythroid reconstitution after autologous HCT when started on Day 28 post-transplant. I.v. iron sucrose further improves erythroid recovery. Am. J. Hematol. 88:990-996, 2013. 2013 Wiley Periodicals, Inc. Copyright 2013 Wiley Periodicals, Inc.
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Transfusion risk in cancer patients with chemotherapy-induced anemia when initiating darbepoetin alfa therapy at a baseline hemoglobin level of <9 g/dL versus 9 to <10 g/dL versus >= 10 g/dL: an exploratory analysis of a phase 3 trial
Canon JL, Vansteenkiste J, Hedenus M, Gascon P, Bokemeyer C, Ludwig H, Vermorken J, Legg J, Pujol B, Bridges K
Medical Oncology. 2012;29((3):):2291-9.
Abstract
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.
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Epoetin alpha decreases the number of erythrocyte transfusions in patients with acute lymphoblastic leukemia, lymphoblastic lymphoma, and Burkitt leukemia/lymphoma: results of a randomized clinical trial
Cabanillas ME, Kantarjian H, Thomas DA, Mattiuzzi GN, Rytting ME, Bruera E, Xiao L, Bekele BN, Foudray MC, Cortes JE
Cancer. 2012;118((3):):848-55.
Abstract
BACKGROUND Anemia is an expected consequence of intensive chemotherapy regimens administered to patients with acute leukemia. This study was designed to determine whether epoetin alpha would decrease the number of transfusion events and units of packed erythrocytes (PRBCs) transfused, and the secondary objective was to study the effects of epoetin alpha on quality of life (QOL) and complete remission (CR) rates. METHODS Patients with acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL), or Burkitt lymphoma (BL) who were receiving frontline myelosuppressive chemotherapy were randomized to receive epoetin alpha or no epoetin during the first 6 cycles of their planned chemotherapy. QOL was assessed by using the Edmonton Symptom Assessment Scale (ESAS) and the Functional Assessment of Cancer Therapy (FACT)-Anemia questionnaires. RESULTS Fifty-five patients were randomized to receive epoetin alpha, and 54 patients received no epoetin. Transfusion data were available for 79 of 81 evaluable patients (98%) who completed the treatment/observation period. The trial was stopped early because of poor accrual before the target of 123 evaluable patients was met. A mean of 10.6 units of PRBCs over 5 months were administered to those who received epoetin alpha compared with 13 units for those who did not receive epoetin (P = .04). There was no significant difference in QOL as assessed by the FACT-Anemia or ESAS instruments. The CR rate and the 3-year CR duration were not affected adversely by use of epoetin alpha. CONCLUSIONS Epoetin alpha decreased the number of PRBC transfusions and did not appear to have a negative impact on remission duration. No difference in QOL was observed. Copyright 2011 American Cancer Society.
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Risk of venous thromboembolism with the erythropoiesis-stimulating agents (ESAs) for the treatment of cancer-associated anemia: a meta-analysis of randomized control trials
Zhan P, Wang Q, Qian Q, Yu LK
Chinese Clinical Oncology. 2012;1((2):):19.
Abstract
BACKGROUND In anemic patients receiving myelosuppressive chemotherapy, erythropoiesis-stimulating agents (ESAs) raise hemoglobin levels and reduce transfusion requirements, but ESA-related safety concerns exist. To evaluate the overall risk of venous thromboembolism (VTE) associated with the use of ESAs, a systematic review and meta-analysis of published randomized controlled trials (RCT) was performed. METHODS The databases of PubMed and Web of Science were searched from January 1966 until December 2012 and abstracts presented at American Society of Clinical Oncology conferences held between January 2000 and December 2012 were searched to identify relevant clinical trials. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated. RESULTS Data from a total of 11,632 patients with cancer in 50 RCTs were identified and included for meta-analysis. Among those patients receiving ESAs, the summary incidences of all-grade VTE were 7.62%. Patients with cancer who received ESAs had increased VTE risks (482 events among 6,238 patients treated with ESA vs. 269 events among 5,394 control patients; RR=1.75; 95% CI, 1.49-2.05). The highest risk of VET was found in patients with ovarian and cervical cancer for 2.45 (1.12-5.33). CONCLUSIONS The use of ESAs was significantly associated with an increased risk of developing VTE in cancer patients receiving this drug. The risks of VTE may vary with various tumor types.
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Survival effect of darbepoetin alfa in patients with diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy: The LNH03-6B study
Delarue R, Haioun C, Coiffier B, Fornecker L, Fournier M, Mounier N, Molina TJ, Bologna S, Fruchart C, Picard S, et al
Journal of Clinical Oncology. 2011;29((15_suppl)):9048.
Abstract
9048 Background: Use of erythropoiesis-stimulating agents (ESAs) in chemotherapy-induced anemia is a major issue. Based on recent studies, FDA has modified labeling for ESAs to include a black box warning that limited prescription to pts receiving chemotherapy for non-curative intent. The GELA has conducted a randomized phase III study to evaluate survival impact of Darbepoetin alfa (DA) in pts with DLBCL treated by chemotherapy. We report results of the second interim analysis, with a median follow-up of 44 months Methods: Pts aged from 60 to 80y with DLBCL and aaIPI>1 were eligible and randomized between two chemotherapy regimens (R-CHOP14 or R-CHOP21) for 8 cycles and between an investigational arm with DA given to maintain Hb level between 13 and 15 g/dL and a conventional arm with usual management of anemia, including transfusion and ESA. Objective was to evaluate efficacy of DA as measured by PFS, EFS, DFS and OS, and to analyze toxicity Results: 602 pts were included, 600 were evaluable; 238 in DA arm and 362 in conventional arm, difference being a consequence of transient stop of randomization asked by French Authorities in 2005. Median age was 70 years. Pts characteristics were similar in both arms. Median baseline Hb level was 12.3 g/dL. During treatment, median Hb level was 11.6 g/dL in DA arm and 10.8 g/dL in conventional arm. Response rate was similar in both arms. Three-year PFS was 66% in DA arm compared to 58% in conventional arm (HR 0.77; CI95%: 0.59-0.99; p=0.04). This difference was also significant for DFS (HR 0.65; CI95%: 0.45-0.92; p=0.02). Despite a trend, OS was not statistically significantly longer in DA arm (HR 0.81; CI95%: 0.60-1.09; p=0.16). In conventional arm, 40% of pts received ESA. Despite no difference in Hb level, PFS was better when comparing pts who receive ESAs with those who did not (HR: 0.73; CI95%: 0.57-0.94; p=0.01). Rate of thrombotic events was higher in DA arm (13%) than in conventional arm (6%). Number of serious adverse events and treatment-related deaths were similar in both arms. CONCLUSIONS Prophylactic use of DA was associated with better PFS. This is the first evidence of positive survival impact of DA in pts receiving chemotherapy for malignancy.
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Epoetin alfa in patients with advanced-stage Hodgkin's lymphoma: results of the randomized placebo-controlled GHSG HD15EPO trial
Engert A, Josting A, Haverkamp H, Villalobos M, Lohri A, Sökler M, Zijlstra J, Sturm I, Topp MS, Rank A, et al
Journal of Thrombosis and Haemostasis. 2010;28((13):):2239-45.
Abstract
PURPOSE To determine whether epoetin alfa reduces anemia-related fatigue, improves other aspects of health-related patient-recorded outcomes (PROs), reduces the number of RBC transfusions, and has an impact on freedom from treatment failure (FFTF) and overall survival (OS) in patients with advanced-stage Hodgkin's lymphoma (HL). PATIENTS AND METHODS The prospectively randomized HD15EPO study performed by the German Hodgkin Study Group investigated epoetin alfa administered at doses of 40,000 U weekly during and after chemotherapy (six to eight cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP]) in a double-blind, placebo-controlled setting. The study accrued 1,379 patients, of whom 1,328 were assessable for safety, 1,303 were assessable for clinical outcome, and 930 were assessable for PROs. RESULTS PROs were not different in patients receiving placebo or epoetin alfa, both after the end of chemotherapy and 6 months thereafter. There was no difference between patients treated with epoetin alfa or placebo with respect to FFTF and OS. There were also no differences in the numbers of deaths, progressions, relapses, and thromboembolic events. The median number of RBC transfusions was reduced from four per patient in the placebo group to two per patient in the epoetin alfa group (P < . 001), with 27. 4% of patients needing no RBC transfusion in the placebo group compared with 36. 7% of patients in the epoetin alfa group (P < . 001). CONCLUSION Epoetin alfa administered at 40,000 U weekly parallel to BEACOPP chemotherapy was safe in patients with advanced-stage HL and reduced the number of RBC transfusions but had no impact on fatigue and other PRO domains.
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10.
Phase II trial comparing darbepoetin alfa every 3-week versus weekly epoetin alfa for the treatment of chemotherapy-induced anemia
Hassan MA, Sleem MM
Journal of Clinical Oncology. 2009;27((15_suppl)):e20724.
Abstract
e20724 Background: Anemia is common in patients receiving chemotherapy and may adversely affect health-related quality of life. Erthyrpiotic factors darbepoetin alfa (DA) and epoetin alfa (EA) are currently approved for the treatment of anemia in patients with nonmyeloid malignancies who receive chemotherapy. METHODS Forty patients with a diagnosis of nonmyeloid malignancy with 8 weeks of planned chemotherapy, age 18 years, and anemia (hemoglobin 10 g/dL). 20 patients received DA 500 mug every three weeks (Q3W) and the others 20 patients received EA 40,000 units every week (QW) for up to 18 weeks. Treatment was hold at week 6 for nonresponse, which was defined as failure to achieve a hemoglobin increment of at least 2 g/dL above the baseline measurement. Efficacy was assessed by the incidence of RBC transfusion. RESULTS Forty patients with a diagnosis of nonmyeloid malignancy, the median age was 49 years and 52 years for DA and EA groups respectively, The majority of patients had solid tumors: Common cancer types for (DA - EA) groups were gastrointestinal (8 -5), breast (3-6), lung (3-3), soft tissue sarcoma (2-1), genitourinary (2-1), non-Hodgkin's lymphoma (1-1), multiple myeloma (1-1), Hodgkin's lymphoma (0-1), and metastatic with unknown primary in (1-0) respectively . 75% 0f the patients in both group achieved the target hemoglobin level. Transfusion incidence from week 6 to the end of the treatment phase (the primary end point) was required in 5 patients (25%) in both groups. The side effects reported in this study were thromboembolic in two patients in both groups 10%. Nausea, diarrhea and neutropnia were 25%, 15% and 10% for DA group respectively compare to 20%, 10%, and 15% in AE group respectively. CONCLUSIONS This study demonstrates comparable efficacy and safety of DA 500 mug every three weeks (Q3W) and EA40, 000 units every week (QW). No significant financial relationships to disclose.
