Non-erythropoiesis stimulating agent, non-iron therapies for the management of anemia: A scoping review.

Abstract

Anemia contributes substantially to the global burden of disease, affecting approximately one third of the population.1 Anemia is associated with an array of poor outcomes, and—when coupled with other comorbidities—increased mortality.2-13 Chronic disease and inflammation retard normal pathways of iron metabolism, leading to iron sequestration and suppression of marrow function.14 Inflammation induces pro-inflammatory cytokines and mediators which upregulate the iron transport regulatory protein, hepcidin.14, 15 Hepcidin expression downregulates the iron transport protein ferroportin and thus limits iron egress from cells, leading to restricted uptake and reticuloendothelial sequestration of iron.14, 15 While iron deficiency remains the leading cause of anemia worldwide, amongst hospitalized patients the anemia of chronic disease is a common cause of anemia.14 Both iron deficiency and inflammation contribute to anemia in the peri-operative population, with anemia conferring a heightened risk of complications, readmission, and mortality.3, 5, 10, 16-18 Given the burden of anemia amongst hospitalized and surgical patients, there has been considerable research interest in the treatment of anemia as a modifiable risk factor to reduce peri-operative complications. Trials of intravenous iron and erythropoietin (EPO) as part of surgical Patient Blood Management programs have had mixed results.19-24 Furthermore, both iron supplementation and EPO are associated with economic costs and adverse effects which may limit their clinical utility.25, 26 Increased understanding of the pathophysiology of anemia and inflammation have yielded new therapeutic targets, some of which have translated to promising novel drug treatments in pre-clinical and early clinical trials.27-34 Prominent amongst this group are the prolyl hydroxylase inhibitors, a class of agents which stabilize the transcription factor for EPO induction. These agents have demonstrated efficacy in treating anemia in patients with chronic kidney disease.29, 31-34 The etiology of anemia in surgical patients is complex, involving both inflammation and blood loss; hence, the efficacy of these novel therapies in these patients remains unclear.16 Thus, we sought to review the existing clinical literature exploring novel therapeutics for anemia and describe: (1) the mechanism of action for non-erythropoiesis stimulating agent (ESA), non-iron therapies to increase hemoglobin concentration (Hb); (2) the evidence for efficacy and stage of development in peri-operative populations; and (3) if there was sufficient preliminary evidence and equipoise to justify a clinical trial in surgical patients using patient-centered outcome measures. As these agents are relatively new, there are no current systematic reviews of novel anti-anemia agents in a non-renal population. Therefore, to see where these agents may have been used, we undertook a scoping review.35 In contrast with a systematic review, a scoping review seeks to examine the landscape of existing literature, including gaps and directions for future research. This is valuable for novel therapies where there are often different agents and products, with different indications and populations, meaning data are too heterogeneous for a formalized systematic review. Once completed, a scoping review may act as a precursor for future systematic review if the scoping review shows this to be feasible. This scoping review was conducted in accordance with the methodological principles described by Arksey and O'Malley,35 and reported in keeping with the Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols Extension for Scoping Review guideline (PRISMA-ScR) (Appendix S1).36 A protocol was registered with Open Science Framework was published previously.37 A search strategy was developed following a preliminary literature search with input from information specialists at the University of Western Australia (Appendix S2). Novel agents were defined as those which were first introduced after 2010, and accordingly studies were restricted to those published after 1st January of that year. All studies which investigated the treatment of anemia using a non-ESA, or non-iron based therapy were reviewed. Given the scoping review method, we sought to include a broad and heterogeneous range of drugs and thus did not restrict the search to specified groups of agents. Studies were eligible for inclusion if they examined persons ≥18 years of age with anemia defined as Hb <13.0 g/dL regardless of sex. This definition of anemia was chosen to ensure breadth in capturing all relevant literature. Excluded studies included patients with anemia resulting from marrow failure, leukemia, lymphoma, or multiple myeloma. Sideroblastic anemias and those resulting from hemoglobinopathies, such as sickle cell anemia or thalassemia were also excluded, as were anemias resulting from hemolytic conditions or infections. This approach of excluding disease entities—rather than restricting to a single disease—reflects that anemia is a heterogeneous condition, that studies may not report a specific anemia subtype and is in keeping with the scoping review method. The use of novel agents used to treat the anemia of chronic kidney disease has been reported elsewhere,33 and thus studies specifically investigating renal anemia were excluded. Case studies or case reports, and studies with non-human participants were also excluded. All other study designs were eligible and there was no language restriction. Multiple databases were searched (MEDLINE, Scopus, and EMBASE). To add further rigor, reference lists of included articles were manually screened, and eligible papers were included. Finally, conference abstracts and the gray literature were searched. Prospective registration of clinical trials was also searched using the Australian New Zealand Clinical Trials Registry, European Union Clinical Trial Register, and the International Clinical Trials Registry Platform. Following execution of the search, two researchers (AD and PD) independently screened titles and abstracts for initial eligibility using review management software (Covidence, Melbourne, Australia). Where there was discrepancy, a third researcher (CD) adjudicated. This process was blinded so that the third party was unaware of how the initial researchers had decided. Eligibility was determined using an agreed upon set of inclusion criteria. Following screening, the applicable studies underwent full text review to further determine their eligibility (AD and PD, with discrepancies resolved by CD). All researchers involved in this process acted independently. Where full text articles were not available, authors were contacted. Data were independently charted by two authors (AD and PD), with any discrepancies settled by adjudication by CD or LFM. Data were charted using a predetermined form (Appendix S3), which had been piloted by members of the research team. Where data were unable to be obtained from the primary manuscript of included studies, appendices were searched, and authors were contacted for further information. The primary endpoint was Hb (g/dL) at the conclusion of follow-up. Data were sought for a number of parameters including: participant characteristics including sample size, age, sex, diagnosis and comorbidities, and treatment history; baseline hematological parameters, iron status and inflammatory parameters (Hb, ferritin, transferrin, transferrin saturation, hepcidin, C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], IL-6 and tumor necrosis factor alpha [TNF-α]); study method and design, including setting and length of follow-up, study intervention including comparator, duration of treatment, route of intervention, frequency and dose of intervention. Secondary endpoints included: resolution of anemia, ferritin concentration, transferrin, transferrin saturation, hepcidin, CRP, adverse effects, health related quality of life, mortality, length of hospital stay, and disease specific outcomes. Given that the scoping review method seeks to assess the state of existing literature broadly to shape future areas for research, no formal assessment of methodological quality was performed. The search was executed on 28th August 2021 and yielded 5719 unique results, of which 48 were considered potentially relevant following initial screening and eight were included after full-text review (Figure 1). The eight studies described different populations (Table 1). Four studies included a total of 1895 patients with rheumatoid arthritis.38-41 Three studies included 212 patients with cancer.42-44 One study reported on 9986 patients with a history of myocardial infarction that included 1303 patients with Hb <12.0 g/dL at baseline.45 No studies specifically included patients undergoing surgery. RCT N = 132 Analysis of two RCTs N = 55 Combined groups 0.1 mg/kg 0.3 mg/kg + 15 mg 0.5 mg/kg + 30 mg Placebo: RCT N = 124 RCT N = 33 Part A (every 3 weeks) LY2787106 Part B: Weekly dosing for 8 weeks Part A: Part B: RCT N = 1303 Pooled canakinumab: 300 mg canakinumab 150 mg canakinumab 50 mg canakinumab Placebo RCT N = 129 Post hoc analyses of four RCTs N = 1164 RCT N = 151 Significant reduction in mean hepcidin concentration in sirukumab patients compared to placebo 24% American College Rheumatology 50 response, not related to anemia The therapeutic interventions assessed included inhibitors of IL-6, JAK, activin receptors, IL-1β, and hepcidin (Table 1 and Figure 2). Four studies explored IL-6 inhibition although several different agents were explored.38, 39, 41, 43 JAK inhibition via filgotinib was assessed in one study of 448 patients with rheumatoid arthritis.41 LY2787106, a monoclonal anti-hepcidin antibody, was investigated in a study of 33 patients with solid malignancies.44 IL-1β inhibition via canakinumab was explored in a study of 9986 (1303 anemic at baseline) patients with inflammation following myocardial infarction.45 A further study investigated sotatercept, an activin receptor inhibitor, for anemia in cancer patients; however, this was stopped early due to poor recruitment.42 Patient demographics of age and sex were not consistently reported. All included studies assessed changes in Hb but with heterogeneity, as some studies reported resolution of anemia and others provided specific Hb values (Table 1). Overall, most reported improvement in anemia,38-43, 45 with the exception of one study reporting on LY2787106 (monoclonal anti-hepcidin antibody), which found no significant difference between baseline and end of treatment hemoglobin values (mean change at 4 weeks −0.05 g/dL; 60% CI −0.069, p = .31).44 Trials of IL-6 inhibitors demonstrated improvements in Hb associated with treatment. Of the two trials investigating sirukumab (anti IL-6) therapy, both reported significant increases in Hb with similar findings for tocilizumab (anti IL-6) therapy. ALD581, also an inhibitor of IL-6 demonstrated efficacy in patients with cancer, with an increase in Hb from 1.15 to 1.34 g/dL (SD 0.16, p < .001). JAK inhibition via filgotinib was associated with normalization of Hb amongst patients with mild anemia at baseline. Activin inhibition through sotatercept also demonstrated improvements in Hb amongst patients undergoing chemotherapy. Pooled analysis of canakinumab (anti- IL-1β) therapy for anemic patients demonstrated a mean improvement in Hb of 0.939 g/dL (95% SD 1.385, p = .001) at 12 months. Hepcidin was reported in three studies including two studies reporting on patients with rheumatoid arthritis and one study of patients with cancer. Patients with rheumatoid arthritis undergoing tocilizumab therapy demonstrated rapid and early decreases in serum hepcidin compared with placebo controls, which was sustained for the 12 weeks of follow-up.40 This was associated with a fall in ferritin levels at 4 weeks, sustained for the duration of the study.38 In another study, IL-6 inhibition induced similar reductions in hepcidin and increased transferrin compared with placebo amongst patients with rheumatoid arthritis over 16 weeks.39 In patients with cancer, LY287106 (anti-hepcidin) therapy was associated with transient increases in hepcidin, lasting less than 1 week. However, this was mediated by drug-related receptor neutralization and increases in hepcidin release due to concurrent oral iron administration.44 Two studies reported changes in inflammatory markers. In a study of 132 rheumatoid arthritis patients, tocilizumab therapy was associated with reduced CRP and ESR within 1 week of commencement.38 LY2787106 therapy was not associated with consistent changes in inflammatory markers of IL-6, CRP, and TNF-α.44 Four studies reported safety outcomes. Amongst patients treated with sotatercept, 22% experienced likely treatment related adverse effects, and 16% of all patients who received sotatercept discontinued treatment due to adverse effects.42 One of 93 (1%) patients undergoing treatment with ALD518 (anti IL-6) experienced a potentially treatment related adverse event (rectal hemorrhage), however, of the 124 patients included in the study, five withdrew due to adverse events; it is unclear if these patients received placebo or ALD518.43 Of patients treated with LY2787106 (anti-hepcidin), 12% experienced adverse effects including neutropenia, prolonged QT interval, and systolic heart failure, with one of 33 patients (3%) withdrawing due to serious treatment related adverse effects.44 Patients treated with canakinumab demonstrated increased risk of mild thrombocytopenia and neutropaenia.45 Toedter et al. explored the impact of sirukumab on rheumatoid arthritis disease activity, as measured by the American College of Rheumatology (ACR) 50 scale.40 This demonstrated a 24% improvement in disease activity, however, failed to demonstrate a relationship between Hb normalization and clinical response. Health related quality of life, mortality, and length of hospital stay were not reported in any studies. In this review, we explored novel therapeutic strategies for the treatment of anemia. This included therapies that affected pathways of iron metabolism either via an anti-inflammatory mechanism or direct inhibition of the iron regulatory protein, hepcidin. Overall, most studies reported a beneficial impact on Hb. Several agents were identified (Table 1 and Figure 2), with over half the included studies investigating IL-6 inhibition. Most studies examined patient populations of those with rheumatoid arthritis or those with malignancy, with one study investigating myocardial infarction patients with ongoing inflammation. Saliently, we found no studies exploring management of perioperative anemia with novel agents (Table 2). Most novel agents were effective in treating anemia of inflammation, although there was substantial heterogeneity in the populations studied and the reporting of outcomes. This hindered the ability to draw direct comparison between agents, or between studies comparing the same agents. The most compelling evidence existed for the use of canakinumab (anti IL-1), supported by a large sample size and robust method.45 Canakinumab therapy resulted in an increase in Hb of 0.939 g/dL (95% SD 1.385, p = .001) at 12 months compared to placebo amongst post-myocardial infarction patients with baseline anemia, and a reduction in anemia incidence by 16%.45 Of the agents studied, the vast majority sought to ameliorate the anemia of inflammation through targeting underlying pro-inflammatory pathways, with only one agent studied (LY2787106) directly inhibiting hepcidin itself.44 Agents targeting inflammation appeared broadly effective in managing anemia; however, many of the studies included in this review were small and potentially underpowered. This was most prominent in trials of anemia in cancer patients, in which loss to follow-up due to patient attrition or death, and slow recruitment limited sample sizes. The study by Raftopoulous et al.,46 investigating the activin inhibitor sotatercept in patients with breast cancer or advanced solid malignancies was stopped early due to poor recruitment, and the study by Vadhan-Raj et al.,44 comprised only 33 patients. Although most studies had high quality methodological designs, there was substantial heterogeneity in the reporting of outcomes. These factors, taken together, limit the strength of conclusions which can be drawn surrounding novel therapies and highlight the need for further high-quality studies. Despite best practice guidance supporting the need to effectively manage peri-operative anemia,22 we did not identify any studies specifically exploring the utility of novel agents in this group. Existing therapies including iron supplementation and the EPO have not been found to be effective in improving patient centred outcomes in patients with peri-operative anemia.47 As peri-operative anemia is multifactorial, it is likely that inflammation-induced functional iron deficiency is a significant factor that may account for the lack of efficacy seen with intravenous iron therapy.16, 48 An acceptable agent in the peri-operative context would (1) need to target the underlying pathological mechanisms relevant to peri-operative anemia; (2) act over a short period; and (3) have few adverse effects. This review highlights that there are several mechanisms which could be targeted in peri-operative anemia, some of which may have appropriate safety profiles. However, none have been specifically applied in this context. The populations studied differ from peri-operative patients, and the drivers of inflammatory anemia in them may differ. Amongst cancer patients included within the studies, the myelosuppressive effects of chemotherapy are an integral cause of anemia. Thus, the generalizability of these studies to the peri-operative context is limited, and it remains unclear whether the agents included in this review translate into the surgical setting. Furthermore, many of the agents included may not be appropriate peri-operatively due to lengthy treatment durations (>12 weeks) and immunosuppressive properties. This highlights the need for further exploration of agents specifically targeted for peri-operative use. Few of the studies included within this review reported on clinical outcomes. As such, it remains unclear the extent to which observed changes in Hb translate to clinically significant outcomes. Future studies including patient-specific outcomes, such as morbidity, mortality, quality of life scores, functional status, and duration of hospitalization are needed. A prominent recent development in the treatment of anemia is the advent of prolyl hydroxylase inhibitors. These agents have been assessed through early phase studies in patients with chronic kidney disease associated anemia.31, 33, 34, 49, 50 Small molecular inhibition of prolyl hydroxylase enzymes upregulates hypoxia inducible factor (HIF)-1α, with wide ranging gene induction including EPO, vascular endothelial growth factor, inducible nitric oxide synthase and the enzymes of glycolysis and gluconeogenesis (Figure 2).31 Prolyl hydroxylase inhibitors have several advantages, including oral administration, making them favorable options compared with conventional ESAs.50 A 2021 systematic review of 30 studies (n = 13,146) exploring prolyl hydroxylase inhibitors for the anemia of chronic kidney disease found significant improvements in Hb amongst patients treated with these agents compared to placebo.29 Similar findings have been captured in various studies of individual prolyl hydroxylase inhibitors in chronic kidney disease, with findings of non-inferiority compared to standard treatments.32, 51, 52 Duration of treatment differed between studies, with durations as short as 2 weeks.53 Nonetheless, the risk-to-benefit profile of prolyl hydroxylase inhibitors remains an area of ongoing research. Theoretical concerns exist about potentially negative off-target effects, with HIF activation implicated in malignancies, pulmonary hypertension, liver disease, polycythemia, and renal disease progression.54 These concerns are predicated on observations made in patients with HIF mutations and have yet to be confirmed in clinical trials. Pre-clinical studies have described several beneficial off-target effects, including management of ischemic reperfusion injury.30, 55-58 A notable finding from our review was the paucity of studies utilizing these agents in populations other than chronic kidney disease. Given the benefits and effectiveness of these agents in renal patients, further study of these agents in non-renal settings is warranted. A strength of the scoping review method is that it seeks to capture the breadth of literature and thus can be used to guide future research efforts by highlighting gaps and identifying promising novel targets. To date, there has been no previous scoping review investigating novel anti-anemic agents, meaning this review adds to our overall understanding of current literature. A limitation of the scoping approach is that heterogeneity prevents direct comparison between studies or synthesis of results. This review highlights several promising domains for future research. In conclusion, anemia accounts for a substantial burden of global disease, and is associated with both morbidity and mortality in a range of contexts, most saliently the peri-operative setting. However, existing therapies for anemia are limited to iron supplementation and ESAs; these therapies do little to address the mechanisms of the anemia of inflammation and have limited efficacy in peri-operative anemia, particularly in the improvement of patient-centred postoperative outcomes. Furthermore, concerns about the cardiovascular, cerebrovascular, and thromboembolic events associated with the use of ESAs, further hinder their clinical use.25 Thus, the optimal treatment of peri-operative anemia continues to elude researchers, spurring interest in the use of novel treatments. This review highlights the paucity of literature exploring the use of novel anti-anemic treatments for peri-operative patients and the need both to explore the applications of existing novel agents and in the development of new agents specifically applicable to perioperative patients. We thank the information specialists at the University of Western Australia for assistance in the design and execution of the search strategy. Open access publishing facilitated by The University of Western Australia, as part of the Wiley - The University of Western Australia agreement via the Council of Australian University Librarians. TR reports grants, personal fees, and non-financial support from Pharmocosmos Therapeutics; grants, personal fees, and non-financial support from Vifor Pharma Pty; grants and personal fees from Pfizer Pty (Australia); and personal fees from BioAge Labs, outside the submitted work. TR is a director of The Iron Clinic, London, UK. Lachlan F. Miles reports grants from Vifor Pharma Pty Ltd as part of a matched funding agreement with the Victorian Department of Health outside the submitted work. PMD, ATD, and CD have disclosed no conflicts of interest. Appendix S1: Prisma checklist. Appendix S2: Search strategies. Appendix S3: Extraction form for included studies. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.