Navigating Anemia in Solid and Hematologic Malignancies: A Comprehensive Review of Classical and Emerging Therapies

Abstract

Anemia frequently complicates cancer care, leading to reduced quality of life and poorer overall prognosis. Even mild-to-moderate anemia in cancer patients has been associated with worse outcomes, including increased fatigue, physical decline, and decreased tolerance to cancer therapies. Importantly, studies have demonstrated that correcting anemia and improving hemoglobin levels can significantly alleviate fatigue, enhance emotional well-being, and improve overall quality of life. An improved understanding of the underlying mechanisms of cancer-related anemia has led to the development of a range of therapeutic strategies, from traditional supportive measures to innovative targeted therapies. In the following manuscript, we provide an in-depth review of these approaches, beginning with established treatments and progressing to newer investigational therapies and specialized strategies for patients with solid tumors and hematologic malignancies. This framework aims to guide clinicians in selecting and tailoring anemia management to improve outcomes and quality of life for patients across cancer types.

1 |. Introduction

Anemia is defined as a hemoglobin below 12 g/dL for women and 13 g/dL for men by the World Health Organization (WHO) [1]. These diagnostic criteria for anemia remain the same for individuals with cancer [2]. Anemia is a frequent complication of both cancer and cancer-directed treatment [3, 4]. The mechanisms for malignancy-associated anemia include malignancy-associated bleeding, bone marrow infiltration, functional iron deficiency from chronic inflammation, kidney or liver dysfunction, immune-mediated hemolysis, and nutritional deficiencies from poor oral intake [3–6]. Cancer treatment can also result in anemia through chemotherapy-related myelosuppression and radiation-induced hematologic toxicity [3, 7–8]. Malignancy-associated anemia affects 20%–60% of cancer patients and 60%–90% of patients undergoing chemotherapy [3, 4, 9]. Notably, longer chemotherapy courses are associated with a higher incidence of anemia [10].

While red blood cell transfusions remain an essential tool for rapidly correcting severe anemia and are often employed in more chronic hematologic malignancies like myelodysplasia, their use is associated with significant limitations and risks. Transfusion-related complications include acute and delayed reactions, transfusion-associated circulatory overload (TACO), transfusion-related acute lung injury (TRALI), iron overload with associated organ dysfunction, alloimmunization, and infection [11, 12]. Additionally, frequent transfusions are resource-intensive, costly, and can negatively impact patients’ quality of life by requiring recurrent healthcare visits [13].

Consequently, current management strategies for treatment of cancer-associated anemia emphasize reducing transfusion dependence whenever possible.

Given the high prevalence and multifactorial nature of anemia in cancer, an individualized and comprehensive approach to its management is essential. In this review, we summarize both established and emerging treatment options for anemia across different malignancy types. We begin by discussing classical treatments for anemia, including intravenous iron and erythropoiesis-stimulating agents (ESAs). We will also review anemia management in hematologic malignancies with disease modifying therapies, including luspatercept, imetelstat, lenalidomide, thalidomide, and androgens. We finish with a discussion of modalities undergoing investigation for the treatment of anemia in patients with both solid tumor and hematologic malignancies, including prolyl-hydroxylase inhibitors and hepcidin antagonists (Figure 1, Table 1).

FIGURE 1 |.

Therapeutic targets and mechanisms of action in cancer-related anemia. Schematic representation of pharmacological interventions targeting erythropoiesis in the bone marrow microenvironment. EPO, Erythropoietin; ESA, Erythropoiesis-stimulating agent; EPOR, Erythropoietin receptor; HIF, Hypoxia-inducible factor; SMAD2/3, Suppressor of Mothers Against Decapentaplegic 2 and 3. Created with BioRender.com.

TABLE 1 |.

Overview of treatment options for cancer-related anemia stratified by oncologic context, including drug mechanisms of action, FDA regulatory status, and NCCN recommendation status.

Drug class	Representative agents	Mechanism	Oncology context			FDA regulatory status	NCCN recommended
			Malignancy type	Exclusion criteria	Inclusion criteria
Section 1: Classical Therapies
B- Vitamins	Folate, B12	Essential vitamins required for DNA synthesis and erythropoiesis	All	Adequate levels of B12 and folate	Inadequate levels of B12 and folate	Yes	Yes
IV Iron	Iron dextran, Iron sucrose, Ferric gluconate, Ferumoxytol, Ferric carboxymaltose, Ferric derisomaltose	Provides supplemental iron for erythropoiesis	Solid Tumor Malignancies	Iron overload	IV iron alone for absolute iron deficiency (ferritin < 30 ng/mL and Tsat < 20%), and consideration of IV iron ± ESA for functional iron deficiency (ferritin < 500 ng/mL and Tsat < 50%)	Yes	Yes
Blood transfusion	Packed red blood cells	Replacement of blood	All	Per AABB guidelines	Per AABB guidelines; generally, transfuse for Hgb < 8 in patients with cardiac comorbidities, and Hgb < 7 in other patients	Yes	Yes
ESAs	Darbepoetin alfa, epoetin alfa, and biosimilars	Stimulates erythropoietin receptors to increase erythropoiesis	Solid tumor, lymphoproliferative malignancies	Major thrombotic risk factors, uncontrolled hypertension, curative intent of cancer therapy, uncorrected nutritional deficiency (B12, folate, iron), hemolysis	Hgb < 10g/dL, mild to moderate symptoms, the clinical stability to permit a 2–4 week period for Hgb response	Yes	Yes
			MDS		Hgb < 10g/dL, lower-risk MDS, insufficient EPO ≤ 500 IU/L	Yes	Yes
			MF		Hgb < 10g/dL, Insufficient EPO ≤ 500 IU/L, Hgb < 10g/dL	No	Yes
			Multiple Myeloma		Hgb < 10g/dL, mild to moderate symptoms, the clinical stability to permit a 2–4week period for Hgb response	No	Yes
Section 2: Disease-Specific Therapies, Approved and Investigational
Erythroid maturation agents	Luspatercept	Ligand trap that inhibits TGF-/β signaling leading to increased effective erythropoiesis	MDS	Contraindicated in pregnancy; caution in setting of poorly controlled HTN	May consider first-line for anemia in transfusion-dependent lower-risk MDS, including ESA-naïve patients; also approved for anemia in low to intermediate risk MDS with ring sideroblasts	Yes	Yes
	Sotatercept		Solid tumor malignancies	Use outside of clinical trial	Investigational: Metastatic breast cancer undergoing myelosuppressive chemotherapy regimen and solid tumors and advanced/metastatic disease who were undergoing non-curative treatment with platinum-based chemotherapy	No	No
Telomerase inhibitor	Imetelstat	Prevents telomere binding, leading to apoptosis of malignant hematopoietic cells	MDS	ESA-eligible or ESA-naïve, pregnancy	Transfusion-dependent, low- to intermediate-1 risk MDS and ESA ineligible or failed	Yes	Yes
			MF	Use outside of clinical trial	Investigational: myelofibrosis with intermediate- or high-risk disease, relapsed/refractory to JAK inhibitors	No	No
Immunomodulatory drugs	Lenalidomide	Targets a component of the cullin-ring E3 ubiquitin ligase complex to promote erythropoiesis	MDS	Platelet count < 50 k, pregnancy; caution with major thrombotic risk factors	First-line for transfusion-dependent, low or intermediate-1-risk MDS associated with del (5q)	Yes	Yes
	Thalidomide		Multiple Myeloma	Pregnancy; caution with major thrombotic risk factors	As part of combination regimen involving multiple other agents	Yes	Yes, in combination with other drugs
			MF		Investigational: Used in combination (e.g., with prednisone and danazol)	No	No
Androgens	Danazol	Promotes erythroid progenitor cell proliferation	MF	Markedly impaired hepatic, renal or cardiac function; prostate and other androgen-sensitive cancers; porphyria; history of thrombosis or thromboembolic disease	Anemia with ongoing symptomatic splenomegaly, constitutional symptoms	No	Yes
			MDS		Investigational/off-label: low-risk MDS and high-risk MDS in low-resource settings	No	No
Section 3: Investigational therapies
HIF-PHIs	Roxadustat	Increases gene expression for effective erythropoiesis and iron metabolism	Solid Tumor malignancy	Use outside of clinical trial	Investigational: Palliative chemotherapy related anemia with Hgb < 10	No	No
	Daprodustat		MDS	Use outside of clinical trial	Investigational: MDS patients with chronic kidney disease (CKD) stage ≥ 3	No	No
Hepcidin Inhibitors	LY2787106	Decreases hepcidin and increases iron availability for erythropoiesis	Myeloid and solid tumor malignancies	Use outside of clinical trial	Investigational: Diagnosis of cancer and anemia, and a baseline serum hepcidin level of ≥ 5 ng/mL	No	No
	DISC-0974	Hemojuvelin monoclonal antibody that binds to hemojuvelin to suppress hepcidin expression	MF	Use outside of clinical trial	Investigational: intermediate to high-risk primary MF (RALLY-MF)	No	No

Abbreviations: AABB, Association for the Advancement of Blood and Biotherapies; ESA, Erythropoiesis stimulating agent; Hgb, hemoglobin; HIF-PHIs, Hypoxia-Inducible Factor Prolyl Hydroxylase inhibitors; MDS, Myelodysplastic syndrome; MF, Myelofibrosis; NCCN, National Comprehensive Cancer Network.

2 |. Intravenous Iron

Iron deficiency anemia in patients with solid tumors is often multifactorial, with chronic blood loss, nutritional deficiency, inflammation, and adverse effects of chemotherapy all contributing. Studies have demonstrated that both absolute and functional iron deficiency are prevalent in this population, emphasizing the need for targeted iron supplementation strategies [14]. Absolute iron deficiency refers to an inadequate availability of iron for erythropoiesis in the setting of insufficient iron stores. Absolute iron deficiency does not have a universally accepted definition, but it is commonly characterized by a serum ferritin concentration below 30 ng/mL, although some clinicians use thresholds as high as 50 ng/mL [15, 16]. Functional iron deficiency refers to an inadequate availability of iron for erythropoiesis despite sufficient or elevated iron stores. Chronic inflammation from cancer results in cytokine-mediated upregulation of hepcidin (Figure 2), which blocks iron absorption from enterocytes in the gut and sequesters iron in macrophages in liver cells. This results in decreased availability of iron for red blood cell production, creating a functional iron deficiency [17, 18]. Functional iron deficiency is typically defined by a serum ferritin greater than 100 ng/mL in combination with a transferrin saturation (TSAT) below 20%, indicating impaired iron mobilization. Cancer patients with functional iron deficiency with high ferritin levels have been shown to benefit from intravenous (IV) iron in small studies, although routine use is not standardized. For example, an observational study noted an improvement in hemoglobin with iron therapy in patients with a ferritin > 500 ng/mL and TSAT < 20% [17].

FIGURE 2 |.

Overview of the Hepcidin-Ferroportin Axis and mechanisms leading to cancer-related anemia. Therapeutic targets shown in green text include androgens and the monoclonal antibodies DISC-0974 (targeting hemojuvelin) and LY2787106 (targeting hepcidin). Fe, Iron. Created with BioRender.com.

Oral iron is often inadequate in the setting of malignancy due to gastrointestinal side effects, poor enteral absorption, and anorexia. In contrast, IV iron therapy has proven to be an effective strategy for managing iron deficiency in patients with solid tumors, significantly improving hemoglobin levels while reducing the need for red blood cell transfusions, ultimately enhancing patient quality of life [14, 19]. Moreover, several clinical trials demonstrated that the combination of IV iron with ESAs potentiates the hematologic response while allowing for lower ESA doses, which may help mitigate associated risks [20]. The safety profile of IV iron is favorable, with most adverse events being mild and manageable through prudent infusion protocols and monitoring [20].

Collectively, these findings support the integration of IV iron into the therapeutic regimen for managing anemia in patients with solid tumors, with the goal of improving symptoms and clinical outcomes, and reducing the burden of transfusion therapy [21]. Currently, the NCCN guidelines recommend iron for the treatment of iron deficiency anemia, defined as ferritin < 30 ng/mL and Tsat < 20%. The NCCN guidelines also recommend concomitant use of iron and ESAs in patients with a ferritin of up to 500 ng/mL, if the Tsat is < 50%. For patients with ferritin levels between 500 and 800 ng/mL and Tsat < 50%, iron stores are considered sufficient, although iron supplementation can still be considered in select patients [11, 17, 22].

3 |. Erythropoiesis-Stimulating Agents

Erythropoiesis-stimulating agents (ESAs) are considered first-line therapy for anemia associated with both solid tumors and hematologic malignancies, after excluding hemolysis and other correctable causes such as vitamin B12, folate, or iron deficiency [11]. The ESAs include darbepoetin alfa, epoetin alfa, and biosimilars (Figure 3). ESAs are used to reduce transfusion burden and associated complications, such as alloantibody formation, transfusion-related reactions, and iron overload. Chronic red blood cell transfusions also impose significant financial and human resource strain, which can be mitigated by ESAs [13, 23].

FIGURE 3 |.

Schematic illustration of pathways regulating erythropoietin (EPO) production and erythropoiesis. AR, androgen receptor; EPO, erythropoietin; HIF, hypoxia-inducible factor; HIF-1α, hypoxia-inducible factor-1 alpha; HIF-1β, hypoxia-inducible factor-1 beta; HIF-PHI, hypoxia-inducible factor prolyl hydroxylase inhibitor; VHL, von Hippel–Lindau protein. Created with BioRender.com.

ESA use must be carefully weighed against possible safety concerns, including the risk of tumor progression, increased mortality, thromboembolism, hypertension, and cardiovascular events. Eight randomized trials using ESAs to target a hemoglobin > 12 g/dL in a variety of malignancies, including non-small cell lung, breast, head and neck, non-myeloid, and lymphoid cancers demonstrated that while ESAs are effective in treating chemotherapy-associated anemia, they may be associated with decreased overall survival and/or increased risk of tumor recurrence or progression [11]. In a meta-analysis of 60 randomized controlled trials (RCTs), ESAs were associated with a 1.5-fold increase in venous-thromboembolic risk [24, 25]. A Cochrane review that included 91 trials evaluating ESAs in patients with malignancy concluded that while ESAs reduce the need for red blood cell transfusions, they increase the risk of thromboembolic events and mortality [26]. There was insufficient evidence to support ESA effect on tumor response [26]. Notably, a systematic review completed by the Agency for Healthcare Research and Quality including 5 RCTs demonstrated reduced mortality and fewer thromboembolic events when targeting a hemoglobin goal of < 9–11 g/dL [11, 27].

3.1 |. Solid Tumors

For patients with solid tumors and chemotherapy-induced anemia, ESAs are indicated for those meeting all the following criteria based on ASCO and ASH practice guidelines: hemoglobin levels < 10 g/dL, mild to moderate symptoms, no major thrombotic risk factors or uncontrolled hypertension, and the clinical stability to permit a 2 to 4-week period for erythropoietic response before a measurable rise in hemoglobin is expected [11, 20]. Additionally, the absence of other correctable causes of anemia, such as nutritional deficiency or hemolysis, is required. ESAs are typically reserved for patients receiving palliative (non-curative) treatment. ESA use with curative intent treatment remains controversial due to concerns about disease progression. Therefore, both the ASCO and ASH guidelines recommend against their use in this setting [20]. The ASCO and ASH guidelines also recommend against ESAs for anemia unrelated to chemotherapy in patients with solid tumors [20]. Consideration of ESA use requires a tailored approach with careful patient selection and detailed patient counseling regarding the risks and benefits, particularly concerning disease progression and thromboembolic complications.

The off-label use of ESAs in patients with solid tumors not undergoing chemotherapy has decreased over the last decade given the evidence demonstrating potential harm without a clear benefit [20]. Exceptions to this include patients with chronic kidney disease (CKD) and those who cannot receive transfusions. Given the increased risks of thromboembolism and tumor progression, strict adherence to treatment guidelines and careful patient monitoring are essential for safe and effective ESA use, with recommendation to decrease ESA dose once hemoglobin achieves a sufficient level to avoid transfusion [11, 20]. It is also recommended to discontinue ESA treatment if no significant hemoglobin response is observed within 6–8 weeks [20]. All ESA formulations are considered equivalent in terms of efficacy, although dosing protocols vary significantly [20].

3.2 |. Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) is a clinically heterogeneous group of disorders characterized by clonal hematopoiesis and morphologic dysplasia of the myeloid lineage leading to ineffective hematopoiesis and cytopenias, with 90% of patients presenting with anemia at diagnosis [28]. Treatment options for low risk MDS have historically been limited, with therapy focused on improving anemia [13, 23]. ESAs are first-line treatment for transfusion-dependent anemia and an endogenous erythropoietin (EPO) level < 500 IU/L [13].

Prospective clinical trials have demonstrated that ESA treatment can offer substantial benefits by augmenting erythroid response and decreasing transfusion burden [29, 30]. A phase III RCT in patients with low risk MDS demonstrated a decrease in transfusion incidence by ~23% with an erythroid response in ~15% of patients on darbepoetin compared with 0% in placebo. The median duration of response was 15–18 months with some patients deriving a sustained, years-long response [30]. In another phase III placebo controlled RCT in patients with low/intermediate risk MDS and hemoglobin < 10 g/dL, epoetin-α demonstrated a significantly increased erythroid response (defined using IWG-2006 criteria) in 45.9% in the treatment group compared with 4.4% with placebo [29].

3.3 |. Myelofibrosis

Anemia is a significant cause of morbidity in myelofibrosis (MF), affecting 35%–54% of patients at diagnosis and up to 80% as the disease progresses [31–33]. Currently, there is a paucity of RCT data and most studies informing care are observational. There is also no clear consensus on which patients with MF are most likely to benefit from ESA treatment. Response rates to ESA in MF are variable depending on patient and disease factors, with 23%–60% of patients responding to treatment. Factors found to predict better response include female sex, smaller spleen size, low red blood cell transfusion requirements (≤ 1–2 units per month), leukocyte count ≥ 10 × 10⁹/L (p = 0.033), serum ferritin < 200 ng/mL and significantly lower endogenous serum erythropoietin (EPO) and β2-microglobulin [31, 32, 34–36]. In clinical practice, ESAs are an appropriate treatment option for patients with anemia and inadequate endogenous EPO levels, typically defined as less than 500 IU/L [37]. There is some limited data showing an increased risk of acute leukemic transformation with ESA use. In a retrospective cohort study of 311 patients with primary MF, treatment with either ESA was associated with a hazards ratio of 3.1 [35]. Prospective studies are required to validate these limited data, as history of administration of an ESA could be a surrogate for more aggressive disease.

3.4 |. Lymphoproliferative Disorders

ESAs have been shown to reduce transfusion requirements in patients undergoing myelosuppressive chemotherapy for lymphoproliferative disorders, including lymphoma, and chronic and acute lymphocytic leukemia, without clear effects on disease progression or mortality as demonstrated by a large meta-analysis [38]. ESAs were also shown to be effective and safe in patients with diffuse large B-cell lymphoma and anemia after at least 3 cycles of treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone based on a phase II clinical trial [39].

3.5 |. Multiple Myeloma

Anemia is prevalent in approximately 75% of multiple myeloma (MM) patients at diagnosis [40]. For patients with persistent symptomatic anemia, ESAs are initiated after excluding other causes of anemia. Clinical guidelines from ASH and ASCO recommend administering the lowest possible dose of ESAs that allows avoidance of transfusions, with treatment cessation after 6–8 weeks if no response is achieved [20]. In a sub-analysis of the phase III Vista trial, ESAs did not adversely impact long-term outcomes in patients with newly diagnosed multiple myeloma receiving either bortezomib/melphalan/prednisone or melphalan/prednisone. Rather, a higher transfusion burden was linked to reduced overall survival in this study [41].

3.6 |. Myeloid Leukemia

ESAs are generally deferred in patients with myeloid leukemias, as they have been shown in preclinical studies to inhibit chemotherapy-induced cell death and promote a senescence-like state in myeloid leukemia cells, potentiating tumor cell survival [42].

4 |. Luspatercept

Luspatercept (luspatercept-aamt; Reblozyl) is a recombinant fusion protein that enhances late-stage erythropoiesis. It functions as a ligand trap for select members of the transforming growth factor-β (TGF-β) superfamily, which normally suppress erythroid maturation. By binding these ligands, luspatercept attenuates downstream SMAD2/3 signaling, thereby promoting differentiation and maturation of late-stage erythroid precursors and increasing hemoglobin production. Notably, SMAD2–SMAD3 signaling pathways have been shown to be upregulated in patients with MDS and thalassemia at baseline [43, 44].

Luspatercept’s approval, at present, is limited primarily to adult patients with transfusion-dependent lower-risk MDS and certain thalassemias. Initially indicated for the management of anemia in beta-thalassemia, luspatercept was approved by the FDA in 2020 in very low to intermediate-risk MDS with ring sideroblasts patients with anemia that did not respond to ESA and required greater than two red blood cell transfusions over 8 weeks. The approval was based on data from the phase III MEDALIST trial, which showed higher rates of red blood cell transfusion independence for greater than or equal to 8 weeks with Luspatercept compared with placebo [45]. Notably, patients in the MEDALIST trial were also shown to have improved clinical response to treatment and fewer adverse events compared with other therapies previously studied for ESA-refractory anemia in MDS—namely, lenalidomide [45].

The FDA subsequently expanded this indication in 2023 to very low to intermediate-risk, transfusion-dependent, ESA-naïve, adult MDS patients, supported by the results of the phase III COMMANDS trial that demonstrated luspatercept as superior to epoetin alfa in achieving a primary endpoint of at least 12 weeks of transfusion independence with a concurrent increase in hemoglobin [46]. The use of luspatercept in low-risk MDS is currently confined to those patients requiring regular red blood cell transfusions. The ELEMENT-MDS trial, a recently initiated phase III trial, will seek to compare transfusion-independent patients receiving either luspatercept or epoetin alfa, potentially resulting in wider prescribing capabilities in patients with MDS going forward [47].

Luspatercept is generally well-tolerated, with a favorable safety profile. Clinical evidence has pointed to patients most often experiencing low-grade and manageable side effects, including fatigue, nausea, diarrhea, and malaise. More serious adverse effects include neutropenia, infection, and hypertension, though the incidences are not significantly increased from patients receiving ESA therapy. Additionally, treatment with luspatercept has not been shown to cause an increased risk of progression to high-risk MDS/AML as compared to control groups [48].

Luspatercept is also being actively investigated within MF-related anemia. A recent phase II clinical trial showed promising results, achieving its primary endpoint of anemia improvement across all subgroups with the highest response rate achieved in the subgroup of patients receiving luspatercept and concomitant disease-modifying therapy with a Janus kinase inhibitor (JAKi). No new safety signals were identified in this study [49]. Use of luspatercept in MF remains investigational.

5 |. Imetelstat

Imetelstat inhibits telomerase, an enzyme that is upregulated in 85%–90% of malignancies, by targeting the RNA template region and preventing telomere binding in a dose-dependent manner, leading to tumor cell apoptosis [23]. Imetelstat is thought to improve anemia through anticlonal effects, with clonal reductions demonstrated on cytogenetic analysis [23]. Imetelstat has been investigated across a spectrum of hematologic malignancies through a series of clinical trials designed to evaluate its disease-modifying potential, with promising results in MDS and MF.

The IMerge Phase 2/3 trial established the efficacy of imetelstat in lower-risk MDS refractory to ESAs, demonstrating durable transfusion independence in ~40% of patients compared with 15% of placebo, forming the basis for its regulatory approval: it gained FDA approval in June 2024 for treatment of anemia in low to intermediate-1 risk MDS patients who have transfusion-dependent anemia and are either ineligible for or are not responding to ESAs [50]. The IMpress investigator-initiated Phase 2 trial is currently underway, evaluating imetelstat in high-risk MDS and acute myeloid leukemia (AML) refractory to hypomethylating agents [51].

In myelofibrosis (MF), the IMbark Phase 2 single-blind study in patients relapsed or refractory to JAKi therapy showed improvements in anemia, marrow fibrosis, spleen volume, symptom burden, and overall survival [23, 52], supporting the ongoing IMpact-MF Phase 3 trial, which is comparing imetelstat to best available therapy with overall survival as the primary endpoint, with interim analysis expected in early 2026 [53]. Adverse treatment effects seen in IMbark included nausea, diarrhea, and reversible cytopenias. The IMproveMF Phase 1b/2 trial is also underway, exploring the combination of imetelstat with ruxolitinib in JAKi-naïve MF to assess safety and synergistic efficacy [54, 55].

Overall, Imetelstat is an FDA-approved agent for lower risk MDS refractory to ESAs. It remains in clinical trials for JAKi relapsed or refractory MF, but perhaps soon will be a standard treatment pending results of IMpact-MF.

6 |. Lenalidomide and Thalidomide

The exact mechanism by which lenalidomide and thalidomide treat anemia is incompletely understood. Lenalidomide and thalidomide are thought to modulate immune pathways, reduce inflammation, and inhibit angiogenesis by targeting a component of the cullin-ring E3 ubiquitin ligase complex [56].

In patients with low or intermediate-1 risk MDS associated with del(5q) with transfusion-dependent anemia, lenalidomide has been shown to reduce transfusion dependence, decrease the risk of progression to AML, and improve overall survival, forming the grounds for its FDA approval in this setting [57]. There is no survival benefit or decreased risk of AML progression in patients without the 5q deletion, though a minority of patients without 5q deletion had transient transfusion-independence [58, 59]. Lenalidomide treatment is associated with neutropenia, thrombocytopenia, and increased risk of thromboembolic events [56, 58]. Lenalidomide is also used off label for treatment of anemia in MF, though the inability to tolerate treatment is high largely due to hematologic toxicity, and anemia response rates are relatively low between 22% and 32%. Combination with prednisone has been shown to improve tolerance [60–62]. In clinical practice, the use of lenalidomide with prednisone in anemia in MF can be considered after ESA and androgen in patients not on disease-modifying treatment with JAKi.

The FDA has approved Thalidomide for the treatment of multiple myeloma, though it is less commonly used in the U.S. due to more effective, better tolerated treatments. Thalidomide has demonstrated little benefit in improving anemia in several phase II clinical trials in those with MDS and lymphomas, with poor side effect profile [63, 64]. Side effects associated with high dose thalidomide include worsening of anemia, increase in platelets and/or white blood cells, fatigue, constipation, and neuropathy [37]. One study, which pooled data from five phase II clinical trials, found that only 34% of participants were able to tolerate thalidomide monotherapy for the full planned six-month course [65]. A new area of investigation is combination therapy of thalidomide and other agents in primary MF. One retrospective cohort study found that patients with primary MF treated with thalidomide, prednisone, and danazol had the highest rates of improvement in anemia (71%), with mild adverse side effects [66]; confirmation of these results will require clinical trial. The use of thalidomide for anemia secondary to MDS and MF remains investigational and not the standard of care.

7 |. Androgens

Androgens are postulated to treat anemia through multiple mechanisms, including immunomodulation, upregulation of telomerase, downregulation of hepcidin, and stimulation of hematopoiesis through increasing EPO and enhancing EPO downstream signaling (Figure 2, Figure 3) [67]. Androgens, especially Danazol, have been used off-label to treat anemia in MF patients and refractory anemia in low-risk MDS patients, though significant gaps persist in the evidence regarding their efficacy. They are also a treatment option in intermediate and high-risk MDS in low-resource settings where alternatives are not fiscally feasible [68].

In MF, observational studies support Danazol as effective in treating anemia in 30%–60% of patients [69]. However, a recent phase III double-blind RCT (MOMENTUM) did show superiority of the myelofibrosis disease-modifying therapy JAKi momelotinib in improving anemia for MF patients relative to Danazol [70]. In clinical practice, Danazol is an acceptable option for MF patients with anemia and adequate endogenous EPO levels, when disease-modifying therapy with JAKi is not being considered, or as an adjunct to other agents [61, 69]. The most common toxicity includes a moderate elevation in liver enzymes, and patients should be routinely monitored with liver function tests and liver ultrasound. When considering starting Danazol, it is important to screen for prostate cancer, as this is a contraindication.

In MDS, a systematic review by Garcia-Horton et al. identified 13 studies (11 observational, 2 RCTs) encompassing a total of 366 patients treated with androgens, with most studies utilizing Danazol [71]. This systematic review was limited by small study sample sizes, varying definitions for treatment response, skew toward higher risk disease, and inconsistent inclusion criteria. Notably, only one study included International Prognostic Scoring System (IPSS) scoring for MDS risk stratification, as many of the studies occurred before IPSS scoring was available in 1997 [68, 71–72]. Overall, the results were mixed, with response rates ranging from 5% to 75%. The most consistent favorable outcome across studies was improvement in platelet count. Importantly, some studies reported a potential increased risk for leukemic transformation [68, 73]. Further evaluation of androgens in low-risk MDS in the age of IPSS scoring is needed for a conclusive evaluation of Danazol’s treatment effect.

8 |. Emerging Therapies

There are many experimental therapies for anemia in patients with solid tumor malignancy that target pathways involved in erythropoiesis, including hepcidin antagonists and inhibitors of the hypoxia-inducible factor prolyl hydroxylase and the transforming growth factor TGF-β signaling pathway. The following section will discuss the mechanisms of action, clinical trial data, associated adverse effects, and approval status of these treatments.

8.1 |. Hepcidin Inhibitors

Chronic inflammation, such as that associated with cancer, induces hepatic overproduction of hepcidin, a key regulator of iron homeostasis, resulting in impaired iron availability and anemia. Hepcidin binds to ferroportin, the transmembrane protein that transports iron, leading to internalization and eventual degradation of the hepcidin-ferroportin complex thereby reducing iron availability for erythropoiesis (Figure 2) [74]. Hepcidin inhibition has been a target for drug development in the treatment of anemia [74, 75]. LY2787106, a hepcidin monoclonal antibody, has been studied in clinical trials for the treatment of cancer-induced anemia [74]. A multicenter phase I trial evaluated LY2787106 in anemic cancer patients with solid tumors and non-myeloid hematologic malignancies, including a large proportion of multiple myeloma patients. The study found that the drug was well tolerated, with only 4/33 patients experiencing treatment-related adverse events that were primarily grade 1 or 2 [74]. The study observed a transient increase in serum iron levels in those receiving LY2787106, with levels returning to baseline by day 8 [74]. No significant changes were observed in ferritin levels, hemoglobin values, or reticulocyte counts. The clinical trial validated the mechanism, and demonstrated the drug’s safety; however, the lack of sustained improvement in iron, ferritin, and hemoglobin was less encouraging for clinical efficacy.

DISC-0974 is a monoclonal antibody that binds to hemojuvelin, a protein involved in the signaling pathway that leads to increased hepcidin expression. Targeted inhibition of hemojuvelin is hypothesized to improve anemia of chronic disease by increasing iron availability for erythropoiesis. A Phase-I double-blind, placebo-controlled study evaluated the efficacy and safety of DISC-0974 in healthy participants, with 32 receiving treatment and 10 receiving placebo. DISC-0974 resulted in a decrease in mean hepcidin, with up to a 75% reduction compared with baseline. The decrease in hepcidin correlated with an increase in serum iron and hemoglobin levels. The drug was found to have a favorable safety profile with only four participants experiencing mild and transient adverse effects (resolved within 24 h), such as dizziness and peripheral swelling. No serious adverse effects were seen. Notable limitations of the study include the small sample size and no statistical analysis conducted on results [76]. DISC-0974 is currently undergoing early phase clinical trials in patients with myelofibrosis (RALLY-MF) [77]. The initial data from the phase Ib trial demonstrated acceptable tolerability and safety, sustained hepcidin reduction with increased iron, and hematologic response in both transfusion dependent and independent patients [77].

8.2 |. Transforming Growth Factor-β Pathway Inhibitors

The transforming growth factor-β (TGF-β) signaling pathway regulates erythropoiesis and is often altered in hematologic disorders. Mechanistically, TGF-β binding initiates an intracellular signal cascade that activates SMAD2/SMAD3; SMAD2/3 inhibit erythroid maturation, resulting in anemia. Thus, several drugs targeting downregulation of this pathway are being investigated for treatment of anemia. Sotatercept, a ligand trap that inhibits TGF-β signaling, has been studied in patients with solid tumor malignancies [75, 78–79]. A phase 2 double-blinded placebo-controlled RCT in metastatic breast cancer patients treated with either Sotatercept or placebo found that a higher proportion of patients in the Sotatercept group achieved a mean hemoglobin increase of > 1 g/dL compared with the placebo group, with a possible dose-dependent response. The researchers also conducted a non-blinded phase 2a study in patients with metastatic solid tumor malignancies receiving platinum-based chemotherapy randomized to receive Sotatercept or placebo, which demonstrated the same improvement in anemia. However, in both studies the exact hemoglobin increase was not reported, and both were terminated early due to slow patient enrollment [75, 80].

8.3 |. Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors

Hypoxia-inducible factor (HIF) is a transcription factor that plays an essential role in the response to hypoxia by increasing erythropoietin gene transcription and iron metabolism gene expression (Figure 3). HIF is immediately degraded by proline hydroxylation under normoxic conditions. For this reason, hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) have been studied in the treatment of anemia of chronic kidney disease and are being actively investigated as an adjunct in the treatment of chemotherapy-related anemia [81–84]. However, safety concerns persist in this setting [85, 83].

Roxadustat, a HIF-PHI, is approved for treatment of anemia in patients with renal disease in the European Union, Japan, and China, though it is not FDA approved in the United States due to concerns regarding cardiovascular side effects [83]. It is also being investigated for use in patients with solid and hematologic malignancies. In a US phase II single-arm study of 92 patients with non-myeloid malignancies currently on myelosuppressive palliative chemotherapy, treatment with Roxadustat demonstrated a mean hemoglobin increase of 2.4–2.5 g/dL. This increase was present in all cancer types and chemotherapy regimens. While these findings suggest promise for anemia management in patients with solid and hematologic malignancies, there was a potential safety signal for thromboembolic events, with 7.6% of patients developing deep vein thrombosis or pulmonary embolism that investigators attributed to the study drug and 25% of all patients experiencing a deep vein thrombosis or pulmonary embolism (note analysis was limited by lack of a control group) [81]. A multi-center, two-arm non-inferiority phase III trial was conducted in China comparing Roxadustat and recombinant human EPO-α in the treatment of anemia in patients with non-myeloid malignancies on palliative chemotherapy, demonstrating non-inferiority of Roxadustat with similar improvements in Hgb and number of adverse events between the two drugs [84]. Overall, both studies were limited by small sample size and short follow-up time. Additional long-term studies are necessary to evaluate Roxadustat’s clinical effect in the treatment of anemia in malignancy.

A second HIF-PHI, Daprodustat, is currently approved for the treatment of anemia secondary to CKD in patients on dialysis based on the results of the phase III ASCEND-D trial (NCT02879305) [86]. Analysis in anemia of malignancy is limited. In a small study (n = 17) analyzing the effects of Daprodustat on hematologic insufficiency in CKD patients with myelodysplastic syndrome (all IPSS-R risk groups represented), the HIF-inhibitor was found to significantly increase hemoglobin concentrations in 8 of the 17 study participants without leading to any adverse progression in underlying MDS [82]. Notably, the study found that the greatest clinical indicator of “hematologic improvement” was a TSAT < 45%, whereas pre-treatment EPO levels, ferritin levels, and IPSS-R classes were not predictive of treatment response [82].

Mechanistically, there are concerns with the routine use of HIF-prolyl hydroxylase inhibitors (HIF-PHIs) for cancer-associated anemia, especially in the curative-intent setting. Pharmacologic stabilization of HIF-α can activate pathways of angiogenesis, metabolic reprogramming, epithelial-mesenchymal transition (EMT), immune evasion (e.g., PD-L1 upregulation), and therapy resistance, which are broadly associated with worse outcomes across solid and hematologic malignancies [83, 85]. Regulatory labeling reflects this caution. For example, the US prescribing information for daprodustat states that increased HIF-1 may be associated with unfavorable effects on cancer growth and use is not recommended in patients with active malignancy. Clinical experience in chemotherapy-induced anemia remains limited, with expert commentary highlighting unresolved tumor-biology safety questions and urging a cautionary approach. Although HIF-PHIs are effective for CKD-related anemia, there is currently limited data supporting their use in oncology care.

9 |. Conclusions

Anemia remains a major complication in cancer and its treatment, impacting up to 90% of patients receiving chemotherapy and leading to reduced quality of life, impaired treatment tolerance, and diminished clinical outcomes. Current management of anemia in patients with solid tumor malignancies relies on chemotherapy adjustment, transfusions, ESAs, and IV iron. While IV iron and ESAs can improve hemoglobin levels initially, many patients do not achieve durable benefit, underscoring the need for alternatives. The novel agents luspatercept and imetelstat show promise in myelodysplastic syndrome. There are also emerging therapies such as HIF prolyl hydroxylase inhibitors, hepcidin antagonists, and TGF-β inhibitors, under investigation for the broader treatment of anemia in cancer. Older agents, including thalidomide, lenalidomide, and androgens, remain options in select settings; however, they are limited by tolerability. Overall, anemia management in cancer is evolving rapidly, with ongoing clinical trials exploring new agents, combinations, and sequencing strategies. Future directions include optimizing therapy sequencing, identifying predictive biomarkers, and defining long-term safety and efficacy data with randomized trials.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.