Disorders of Blood Cell Production in Clinical Oncology

Summary of Key Points

Anemia is very common in patients with cancer and is multifactorial.
The anemia of persons with chronic disease is associated with decreased absorption of oral iron and decreased ability to access storage iron pools.
Iron-restricted erythropoiesis may limit the efficacy of erythropoietic agents for the treatment of anemia in these patients and can be overcome with parenteral iron.
Treatment of anemia in patients with cancer reduces transfusions and symptoms of anemia.
Erythropoietic agent therapy is associated with an increased risk of venous thromboembolism.
Neutropenia in patients with cancer is usually due to treatment.
Myeloid growth factors can be used to reduce infection risk in patients for whom the risk is significant, and use of these growth factors is preferable to delaying or reducing the dose of chemotherapy when prolonging life is the intent.
New agents for the stimulation of platelet production are in clinical development.
Biosimilar preparations for commonly used hematopoietic growth factors will be appearing on the US market. It will be important for oncologists to participate responsibly in postmarketing surveillance programs.

Hematopoiesis, defined as production and maintenance of adequate marrow production of red blood cells (RBCs), white blood cells, and platelets, is tightly regulated through maintenance of a steady state of cellular production and destruction of cells. Hematopoiesis occurs in two different physiologic spaces within the human body: the extravascular and peripheral compartments. The extravascular or central compartment is defined as any organ not confined within the vascular circulation. The extravascular compartment for hematopoiesis is primarily considered the bone marrow, where hematopoietic stem cells live in a constant state of flux, balancing latency and production in response to various external stimuli. Maturation of cells from their progenitor state typically occurs once progenitor cells have been released from the extravascular space into the circulatory vasculature of the intravascular space.

The bone marrow is able to produce and release into circulation approximately 6 billion cells per kilogram of body weight per day. Hematopoietic stem and progenitor cells (HPSCs) repopulate these bone marrow elements. Quiescent when homeostasis has been maintained, HPSCs are stimulated in response to various stressors to proliferate to meet the demands of physiologic insults. Once the hematopoietic demands have been met, homeostasis is restored and HSPCs exit the cell cycle to return to a quiescent state. The production, differentiation, and release of each type of cell into circulation is highly regulated through cytokine and hormone signaling pathways.

Cancer-associated hematologic abnormalities represent a major contributor to morbidity and mortality, quality of life, and outcomes. The pathophysiology of these abnormalities in cancer is multifactorial. Malignancy itself creates an inflammatory state. In addition, given the nonselective nature of most traditional antineoplastic agents, myelotoxic or myelosuppressive effects aimed at killing or inhibiting tumor cells also affect normal hematopoietic cells and can cause cytopenias across cell lineages. Chemotherapy-induced myelosuppression can be mediated through multiple mechanisms; the most common shared mechanism is through direct DNA effects that can inhibit cell cycle progression at various phases or cause direct DNA damage. These can result in apoptosis or impaired growth and proliferation of progenitor cells. Radiation therapy can also cause direct bone marrow apoptosis and bone marrow failure.

Neutropenia is generally the major dose-limiting side effect of cytotoxic chemotherapy. Therefore antineoplastic agents are typically administered in defined time intervals, or cycles, that can occur over the span of weeks. Depending on the cycle length and specific agents, the hematopoietic response to chemotherapy is typically predictable, with an expected decline in cell counts followed by a subsequent rise back to baseline levels. Chemotherapy-related myelotoxicity is typically dose dependent, so the route and frequency of delivery (e.g., intravenous versus oral or twice versus once weekly) are also considerations in designing dosage schemas because these can affect drug distribution, peak drug concentrations, and consequently the degree of myelosuppressive toxicity.

Management of these hematologic abnormalities remains one of the most difficult clinical challenges in the care of cancer patients. Chemotherapy-induced cytopenias increase treatment-related morbidity and mortality, through infection, bleeding, or impaired quality of life. Unfortunately, the combination regimens that produce the greatest survival benefit are also often the most highly myelosuppressive. Because of potential associated complications, neutropenia, thrombocytopenia, and anemia are the primary causes of unplanned delays or dose reductions in chemotherapy. The changes in dosage levels and interval frequency of administration that reduce relative dose intensity (RDI) may result in suboptimal levels that potentially compromise therapeutic efficacy. Over time, repeated exposure to cytotoxic agents can also injure bone marrow function beyond recovery, resulting in a chronic hypoplastic state with permanently decreased cell counts, which further limits therapy options. When possible, chemotherapy regimens should be administered with the goal of avoiding unplanned delays or dose reductions so that RDI can be maintained. Cancer-related myelosuppression therefore represents a major clinical challenge in balancing optimal treatment dosage and schedules against their potential hematologic complications. Pathophysiology and management of these hematologic dilemmas related to nonmyeloid cancers with a specific focus on chemotherapy-related effects are discussed here.

Anemia

Pathophysiology

In normal healthy adults, the bone marrow produces 2 million erythrocytes per second. To maintain adequate red cell mass, production of RBCs requires balanced loss or destruction of RBCs in circulation. An RBC lifespan is about 120 days with a resultant loss of approximately 1% of total RBCs on a daily basis. To replace this, erythropoiesis requires generation of more than 10 ¹⁰ new cells per hour. Production of RBCs requires the necessary cellular components to facilitate continued DNA synthesis, proliferation, and hemoglobin production. Folate is necessary for conversion of 2′-deoxyuridine 5′-triphosphate (dUTP) to 2′-deoxythymidine-5′-triphosphate (dTTP) in DNA synthesis. Vitamin B ₁₂ acts as a cofactor for folate release. Hemoglobin production requires iron for synthesis of heme groups.

When RBC loss exceeds RBC production, anemia results. Three mechanisms lead to anemia: decreased RBC production (hypoproliferation), increased RBC destruction, or blood loss. In cancer patients, various competing pathophysiologic processes result in a complex presentation of these mechanisms. Hypoproliferation of red cells can be directly caused by bone marrow replacement of tumor cells. Commonly found in cancer patients, poor nutritional status and malabsorption can lead to depletion of nutrients necessary for generating the building blocks required for erythropoiesis: DNA, amino acids, and hemoglobin. Red cell production is additionally dependent on levels of erythropoietin (EPO), a key hormone whose signaling network is frequently altered in malignancy.

Red cell mass is dynamically regulated by the endogenous cytokine EPO and its receptor (EPOR), found on bone marrow erythroid progenitors. In adults 90% of plasma EPO is produced by the interstitial kidneys, with the remainder produced by the liver and other sites, such as the spleen, liver, and testis. EPO stimulates cell cycling of quiescent erythroid progenitors into terminal maturation and survival of later progenitors. Because EPO is normally produced below capacity, about 20% of bone marrow erythroid cells are undergoing apoptosis at any moment to maintain control of erythropoietic balance.

The optimal hematocrit is determined by tissue oxygen demand and subsequent EPO response. In conditions of severe anemia, normal EPO levels (<5 to 25 U/L) can increase up to 1000-fold to meet oxygen requirements. Hypoxic conditions (<26 mm Hg O ₂ ) stimulate production and release of EPO into circulation from the kidney. Adaptation to hypoxia is regulated through complex erythropoiesis signaling pathways. The most important of these include the hypoxia-inducible factor (HIF) family, which transcriptionally regulates multiple genes involved in survival, proliferation, and differentiation of RBCs. Hypoxia induces de novo synthesis of EPO through increased transcription of EPO mRNA in addition to its stabilization.

In patients with malignancy, regulation of EPO is altered. Malignancy itself can cause suppression of erythropoiesis by promoting proinflammatory cytokines (e.g., interleukin-1 [IL-1], tumor necrosis factor–α [TNF-α], interferon-γ [IFN-γ]) that inhibit EPO production, dubbed anemia of chronic disease (AoCD). In patients with AoCD and in the elderly, EPO levels are inappropriately low, and erythroid progenitor responsiveness to EPO is additionally dampened.

Chemotherapy-Induced Anemia

Myelosuppressive treatment with chemotherapy and radiation further compounds the challenges in management of cancer-related anemia. In the European Cancer Anaemia Survey (ECAS), of the 14,520 cancer patients at study enrollment, nearly one in three (31.7%) patients who had not yet received treatment were anemic at presentation. The incidence of anemia in patients who received chemotherapy was 62.7%, with the greatest risk factor for development of anemia related to duration of chemotherapy. The prevalence of anemia was 50.5% in patients receiving chemotherapy compared with those receiving chemoradiotherapy (43.5%) or radiation alone (28.7%). Sixty-seven percent of patients developed anemia during the course of the study; 39.3% of the patients had documented hemoglobin levels below 10 g/dL.

Chemotherapy-induced suppression of erythropoiesis can occur through direct toxicity to DNA, subsequently impairing DNA replication. Certain agents, such as cisplatin, also directly suppress EPO production in the kidneys.

Hemolysis

Hemolysis is a much less common cause for anemia in cancer patients, but very important to recognize clinically. RBC destruction, or hemolysis, can occur intravascularly while the RBCs are actively circulating or, more commonly, extravascularly as the cells pass through the spleen or liver. Hemolysis typically occurs through cell membrane rupture. In the case of microangiopathic hemolytic anemias (MAHAs), RBC cell membranes are prone to rupture through mechanical shear stress through a non–immune-mediated process. When MAHAs are accompanied by thrombocytopenia, these are characterized as a group of disorders called thrombotic microangiopathies (TMAs). In patients with solid tumors, MAHAs and TMAs can be associated with cancer or induced by chemotherapy.

In cancer-associated MAHAs, circulating erythrocytes pass through small vessels with microvascular metastasis that cause obstructions and consequently fragmentation of RBCs. Tumor-associated endothelial injury promotes development of thrombi, which consume platelets to cause the thrombocytopenia found in TMAs. Cancers of the stomach, lung, breast, and prostate are the solid tumors most commonly associated with TMA. The difficulty with the presentation of cancer-associated TMAs is that they are virtually clinically indistinguishable from thrombotic thrombocytopenic purpura (TTP) and complement-mediated hemolytic uremic syndrome (HUS), for which treatments are vastly different and costly. TTP is caused by severely reduced levels of ADAMTS13 (defined as <10%), and treatment entails emergent plasma exchange and carries procedural and infection risk. HUS is mediated by uncontrolled complement activation and is treated with the C5 complement inhibitor eculizumab or plasma exchange. In contrast, because cancer-associated TMAs are not caused by deficient ADAMTS13 levels nor complement, they are typically poorly responsive to plasma exchange or eculizumab, and treatment requires chemotherapy initiation directed at the malignancy. Although initiation of treatment of TTP or HUS likely cannot be delayed awaiting confirmatory diagnostic tests (e.g., ADAMTS13, complement-associated autoantibodies), a poor response to treatment should trigger a search for an alternative diagnosis, such as an occult malignancy.

Certain chemotherapeutic agents also have well-documented associations with induction of MAHA and TMA. Mitomycin, gemcitabine, vascular endothelial growth factor (VEGF) inhibitors (e.g., bevacizumab, sunitinib), and platinum agents such as oxaliplatin have all been associated with both TMA and isolated MAHA. Antineoplastic agents are thought to mediate MAHA through direct cytotoxic injury to endothelial surfaces in a dose-dependent fashion or by drug-induced antibody development. Toxicity-associated TMAs typically have a more slowly progressive clinical course, such as an associated gradually worsening renal function. Immune-mediated drug-induced TMAs are typically acute and are associated with reexposure to drug.

Iron Metabolism

Iron is necessary for synthesis of the oxygen-carrying heme groups in hemoglobin and consequently RBC production. Regulatory mechanisms to alter plasma levels of iron are interconnected through signaling networks affecting iron storage, release of iron from iron stores, and iron exchange across cellular membranes into circulation.

Free iron in the blood is bound to transferrin, whereas intracellular iron is bound to ferritin. Hepcidin is the primary regulator of circulating iron levels. Produced mainly by hepatocytes, macrophages, and adipocytes, hepcidin prevents efflux of intracellular iron into circulation by inducing endocytic degradation of the iron transmembrane transporter ferroportin. Proinflammatory cytokines present in malignancy also increase hepcidin levels, thus reducing serum iron levels through increased sequestration in the reticuloendothelial system and decreased iron absorption. The decreased iron availability limits hemoglobin production for erythropoiesis and results in a “functional” iron deficiency.

Blood Loss

Blood loss is a common complication of malignancy that can result from bleeding necrotic tumor tissue, tumor-associated leaky microvasculature, direct vascular invasion by tumor, and comorbid conditions such as gastritis and peptic ulcer disease. Identification of the source of bleeding should be attempted because correction of anemia through transfusion or iron will be transient as bleeding continues. Acute and chronic blood loss can manifest with different clinical symptoms and laboratory findings and have different management algorithms. Acute blood loss requires urgent intervention. Symptoms suggestive of sudden intravascular volume depletion and hemodynamic instability, such as tachycardia, hypotension, or syncope, point to an acute bleeding source that needs to be identified in order to stem blood loss. With bleeding in the acute setting, hemoglobin levels, hematocrit, and the results of iron studies may be spuriously normal or near normal because volume redistribution has yet to occur between the bleeding event and blood draw. In the setting of acute bleeding, rapid correction of anemia to hemodynamic stability with blood transfusions and aggressive fluid hydration is warranted, followed by rapid diagnostic studies.

In contrast, chronic blood loss tends to allow time for volume redistribution and physiologic compensation. Vital signs may be unremarkable without evidence of tachycardia or hypotension. Hemoglobin and hematocrit will gradually decline, and iron studies would more likely reflect low iron stores, which is discussed later.

Identifying the source of bleeding in both acute and chronic settings should be initially guided by focal symptoms. Most commonly, absolute iron deficiency is suggestive of gastrointestinal blood loss that can be evaluated by esophagogastroduodenoscopy or colonoscopy. In other cases the source of bleeding is not readily evident, such as bleeding from tumor tissue, vascular tumor invasion, or retroperitoneal bleeding. In these cases, additional diagnostic procedures (e.g., bronchoscopy for lung tumor) or imaging is required to identify the source of bleeding.

Management of Anemia

Hemoglobin levels in anemia have been defined by the World Health Organization (WHO) as levels below 12.0 g/dL in women and below 13.0 g /dL in men. Found in 30% to 90% of patients, anemia in cancer profoundly affects patient management, survival outcomes, and quality of life. Anemia in these patients is associated with indices of poor functional status and cognition, which may be more profound in the elderly.

Decreased oxygen-carrying capacity from the decreased red cell mass leads to the clinical symptoms of fatigue, dyspnea with or without exertion, generalized weakness, decreased endurance, and dizziness. Patients may also have evidence of cardiovascular compromise with the potential for myocardial infarction or stroke from insufficient oxygen availability, manifesting with clinical signs of chest pain, tachycardia, hypotension, or neurologic changes (e.g., focal weakness, speech or visual changes, sensory changes). Correction of anemia requires consideration of various clinical parameters counterbalanced against the risks of each approach.

The cause of anemia in cancer patients is often multifactorial from chemotherapy, AoCD, iron deficiency, or blood loss. Commonly present in cancer patients who often have poor appetite and intake, nutritional deficiencies also may also lead to anemia, given the lack of the necessary components necessary for effective erythropoiesis. In this circumstance, laboratory evaluation for nutritional deficiencies, such as low vitamin B ₁₂ or folate levels, can be identified and replaced with oral supplementation. If a chemotherapy-induced MAHA or TMA is identified, the offending drug should be stopped.

After blood loss and hemolysis have been ruled out and nutritional deficiencies have been corrected, the management of anemia primary falls into three categories: RBC transfusion, erythropoiesis-stimulating agents (ESAs), or iron supplementation. These modalities of anemia management are discussed in the following sections.

Red Blood Cell Transfusion

RBC transfusions provide rapid correction and improvement in anemia-related symptoms, such as fatigue and dyspnea, but the effects are transient. In patients with hemoglobin levels less than 8 g/dL, transfusion immediately improves anemia-related symptoms, but interesting to note, symptomatic benefit decreases over the next 2 weeks even if hemoglobin levels are maintained.

Assessment of clinical symptoms and timing of marrow suppressive chemotherapy are considerations in determining acuity of correction needed. Per National Comprehensive Cancer Network (NCCN) guidelines, asymptomatic patients with chronic stable anemia should undergo transfusion once hemoglobin is below 7 g/dL. At higher levels of hemoglobin, for patients with signs or symptoms related to anemia, such as tachycardia, hypotension, dyspnea, fatigue, or chest pain, blood transfusions until symptom resolution occurs are recommended unless a significant relative or absolute contraindication exists (e.g., significant risk of volume overload in the setting of end-stage renal disease). Acute and active bleeding are also indications for transfusion, in addition to attempts at identifying the source of bleeding. In the setting of hemorrhage, blood should be transfused until evidence of hemodynamic stability has been demonstrated.

Risks of blood transfusion

Transfusions are associated with a low (0.5% to 3%) risk of adverse events, but with significant consequences, so appropriateness should be weighed according to clinical context. These consequences include risk of transmission of viral infections (e.g., human immunodeficiency virus [HIV] infection, hepatitis B, hepatitis C) and bacterial contamination of blood products. In addition, RBC transfusions have been associated with an increased risk of venous (odds ratio [OR], 1.60; 95% confidence interval [CI], 1.53 to 1.67]) and arterial (OR, 1.53; 95% CI, 1.46 to 1.61) thromboembolism and in-hospital mortality (OR, 1.34; 95% CI, 1.29 to 1.38). Other risks include immune-mediated adverse events, such as alloimmunization with hemolytic reactions or anaphylaxis and transfusion-related acute lung injury (TRALI). Acute hemolytic reactions are typically related to ABO blood type incompatibility as a result of laboratory error. However, repeated transfusions may contribute to the development of RBC antibodies with potential for delayed hemolytic transfusion reactions. The introduction of additional red cell volume can lead to transfusion-associated circulatory overload (TACO). In cancer patients, in whom comorbid conditions such as cardiovascular disease and poor renal function are common, blood transfusion may increase the risk of volume overload. Careful evaluation of the clinical scenario, including symptoms, laboratory values, and comorbid conditions, should be considered in determining whether blood transfusion is appropriate and can be safely administered.

Erythropoiesis-Stimulating Agents

The development of recombinant human EPO agents (ESAs) in the 1990s allowed minimization of blood transfusion and avoidance of potential transfusion-related complications. Recombinant human analogues, such epoetin alfa and the longer-acting glycosylated analogue darbepoetin alfa, have been studied in the treatment of cancer-related anemias as exogenous replacements for EPO. In an initial randomized double-blind trial, the use of ESAs compared with placebo was shown to decrease the need for or minimize the number of blood transfusions ( P = .0057) and to improve quality-of-life measures, such as energy level and activities of daily living ( P < .1).

However, the use of ESAs is not without risk. Although ESAs corrected cancer-associated anemia, there is controversy surrounding potential adverse outcomes with ESA use in cancer patients. In particular, there has been concern about the impact of ESAs on progression-free survival (PFS) and overall survival (OS). In a study by Henke and colleagues, head and neck cancer patients treated with epoetin beta had decreased locoregional control with radiotherapy, although this was subsequently disputed by a randomized phase III study by Hoskin and colleagues that showed no difference with epoetin beta treatment. A meta-analysis of randomized controlled trials in cancer patients showed that ESAs were associated with increased mortality and decreased OS. A subsequent Cochrane review showed that although blood transfusion requirements were significantly reduced, ESAs resulted in significantly increased risk of thromboembolic events. In a randomized controlled trial in breast cancer patients, although administration of epoetin alfa did not decrease relapse-free survival or OS, thrombotic events were increased. In locally advanced cervical cancers, ESA administration was associated with poorer response to radiation therapy. Target hemoglobin levels above 14 g/dL were also associated increased cardiovascular events owing to presumed increased blood viscosity. The poorer outcomes of these patients led to the suggestion that ESAs may decrease tumor control, although this is still under debate. These findings suggest that although ESAs improve symptoms of anemia and possibly quality of life, they may have worsened overall outcomes. Accordingly, ESAs should be cautiously administered with consideration based on clinical characteristics and goals of care for each patient with careful discussion regarding risks and the patient's preferences. Combining ESA treatment with iron infusion is considered in certain circumstances discussed later. ESAs should not be used in the curative setting but can be considered in patients receiving palliative treatment, such as in a US Food and Drug Administration (FDA)–mandated Risk Evaluation and Mitigation Strategy (REMS) program. The NCCN guidelines, which are updated regularly, are recommended for review in guiding decision making.

Erythropoiesis-Stimulating Agent Biosimilars

Epoetin alfa and its glycosylated analogue darbepoetin alfa are the major stimulating agents (SAs) used in the management of anemia in the cancer chemotherapy patient. Given the cost of the originator product and subsequent patent expiration, efforts to produce biologically similar products to epoetin alfa in order to expand access and reduce health care costs are ongoing.

Originator products are manufactured through proprietary processes. Both origination and biosimilar products are complex biologic agents manufactured through independently developed methods. This may include production through a biologic system, such as a cell line, that may differ in its production or manufacturing process from the original reference product. Because of the differing methods of production, an inherent potential for structural or functional variation in the biosimilar compared with the originator product may result. These changes may include posttranslational modifications of the proteins, such as through glycosylation, which may alter functional activity of the drug. Biosimilars are consequently not identical to the originator product. This is in contrast to a generic drug, which is synthesized in a laboratory and identical both structurally and chemically to the original drug.

Signed into law by President Obama in 2010, the Biologics Price Competition and Innovation Act (BPCI) provided a mechanism for biosimilars to undergo an abbreviated licensure pathway for development compared with the originator “reference” products if “interchangeability” in safety and efficacy could be demonstrated. The major challenge for obtaining regulatory approval of epoetin biosimilars is meeting standards of equivalent efficacy, safety, and quality compared with the original agents. Standards for these measures are highly variable depending on the country. Several epoetin biosimilars have been developed and have shown product quality similar to that of the reference products. Two epoetin biosimilars (epoetin alfa HEXAL, epoetin zeta) have been approved in Europe. The first biosimilar ESA was approved in the United States in 2018 (epoietin alfa-epbx).

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