The impact of myelosuppression on quality of life of patients treated with chemotherapy

Despite the emergence of targeted drugs and recent advances in immunotherapy, chemotherapy remains a cornerstone of treatment for many people with cancer [1]. Unfortunately, the side effects of chemotherapy can have a negative impact on quality of life (QoL) [1,2].

Chemotherapies target not only cancer cells, but also healthy cells that divide quickly, including hair cells and cells in the digestive system, which can result in hair loss (alopecia), nausea, vomiting and diarrhea. Chemotherapy can also kill blood-forming cells known as hematopoietic stem and progenitor cells (HSPCs) found in the bone marrow [3]. HSPCs give rise to normal blood cells, including white blood cells (WBCs), red blood cells (RBCs) and platelets. Destruction of HSPCs, known as myelosuppression, can reduce the numbers of one, two or all of these blood cell types, resulting in neutropenia (decreased neutrophils, which are a type of WBC), anemia (decreased RBCs), thrombocytopenia (decreased platelets) and/or pancytopenia (decrease in all three types). The presentation of myelosuppression and how often it occurs depends on the individual person, the chemotherapy that is used and when it is administered [3,4].

The symptoms of chemotherapy-induced myelosuppression can have a negative impact on patients' QoL [1,2]. In Box 1, we present insights from our patient author, Katerina Gmitter, in which she describes the numerous side effects of chemotherapy treatment for triple-negative breast cancer, how they impacted her life, and the need for medical professionals to proactively discuss the side effects of chemotherapy with each patient.

Chemotherapy-induced myelosuppression is often managed with dose delays or reductions, but these can affect the efficacy of treatment and negatively impact patient outcomes [5,6]. Prophylactic (preventive) drugs for neutropenia are available in the form of granulocyte colony-stimulating factors (G-CSF), and reactive/therapeutic treatments include G-CSF for neutropenia, and erythropoiesis-stimulating agents (ESAs) and blood transfusions for anemia and thrombocytopenia [7–11]. Although these supportive care interventions have been shown to improve symptoms and QoL for patients receiving myelosuppressive therapy [12–14], some symptoms may not be completely alleviated. Furthermore, these treatments, specifically G-CSF, can cause bone pain and other side effects that negatively impact QoL, and ESAs carry a boxed warning [15,16].

In 2021, the US FDA approved trilaciclib to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to an etoposide/platinum- or topotecan-containing regimen for extensive-stage small-cell lung cancer (ES-SCLC) [17]. Trilaciclib is administered intravenously to patients up to 4 h before the start of each chemotherapy treatment and works by temporarily stopping HSPCs from dividing, thus protecting them from the toxic effects of chemotherapy (myeloprotection) [17–19]. After chemotherapy treatment, when the effects of trilaciclib have worn off, HSPCs can continue to divide and develop into blood cells [18,19]. This proactive mechanism is different to other supportive care therapies, which are administered to treat myelosuppression after the damage to HSPCs has already occurred [9].

In clinical studies, administering trilaciclib before chemotherapy resulted in reductions in the duration and occurrence of severe (grade 4) neutropenia, the rate of chemotherapy-induced anemia and thrombocytopenia, and the need for supportive care interventions [20–24]. The protective effects of trilaciclib on blood cells were reflected in improved patient experiences, as assessed using patient-reported outcome (PRO) measures such as the Functional Assessment of Cancer Therapy-Lung (FACT-L) and FACT-Anemia (FACT-An) questionnaires, which are designed to assess health-related QoL (HRQoL). Compared with patients receiving placebo, patients receiving trilaciclib reported significant improvements in several aspects of HRQoL [23].

Several investigational agents are currently in clinical development for the management of chemotherapy-induced myelosuppression, including plinabulin, roxadustat, romiplostim, avatrombopag, eltrombopag and hetrombopag. Details of these agents are summarized in Table 1.

The aims of this review are to describe the burden of chemotherapy-induced myelosuppression on patients, and detail the strengths and limitations of current and future management strategies, with a focus on how they may improve patient QoL.

Chemotherapy-induced neutropenia

Neutropenia occurs when the number of neutrophils in the blood, or absolute neutrophil count (ANC), drops below normal levels (i.e., lower than 2000 cells per mm³ of blood), with severity classified according to the ANC measurement. When a person's neutrophil count falls below 1000 cells per mm³ of blood and is accompanied by a fever, this is defined as febrile neutropenia (FN) (Table 2) [40].

Risk factors for the development of neutropenia or FN include treatment with myelosuppressive chemotherapies; advanced-stage cancer; cancers that directly affect the bone marrow, such as leukemia, lymphoma and multiple myeloma; radiation therapy targeted at areas of the body that produce bone marrow; older age (≥70 years) and comorbidities (other conditions) that impair the immune system, such as HIV or hepatitis infections [50].

Severe neutropenia and FN often result in hospitalization and are associated with an increased risk of sepsis and death. Hospitalized patients with lung cancer experience higher rates of FN-related mortality compared with hospitalized patients with other solid tumors. Patients with lung cancer who develop FN tend to be older, are more likely to have multiple comorbidities, and have a greater incidence of pneumonia, each of which are independent risk factors for mortality, as are sepsis, infection and intensive care unit stay [51]. In addition to the risk of death, neutropenia-related hospitalizations present a major time and financial burden to patients and their caregivers, affecting their normal daily activities, and incurring costs due to travel expenses and lost work time [43].

Lower ANC is associated with worse HRQoL [2,43,52]. In a survey of 301 patients with chemotherapy-induced myelosuppression, including 59% with neutropenia, patient-reported symptoms such as fatigue and worry about the risk of infection affected their ability to be physically active, complete work or continue meaningful relationships with friends and family [1,53]. Furthermore, in a separate study of 872 patients with advanced non-small-cell lung cancer (NSCLC), patients who developed severe neutropenia reported significantly increased fatigue and nausea/vomiting, significantly worse physical, social and cognitive functioning, and increased arm and shoulder pain compared with those without severe neutropenia [54].

In addition to generalized QoL measures such as the FACT-General (FACT-G) questionnaire for measuring physical, social, emotional and functional wellbeing, several neutropenia-specific tools have been developed, which may provide a better understanding of QoL in patients with chemotherapy-induced neutropenia. The most notable is FACT-Neutropenia (FACT-N), a 19-item questionnaire used in addition to the FACT-G, which focuses on neutropenia-specific issues such as malaise, worry and flu-like symptoms [55,56].

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Hematopoietic Growth Factors (Version 1.2024) recommend the prophylactic use of G-CSF (filgrastim, pegfilgrastim or biosimilars) for the management of chemotherapy-induced neutropenia, as well as the therapeutic use of G-CSF in patients who have already developed FN [35]. For patients with ES-SCLC, NCCN Guidelines^® include trilaciclib as a prophylactic option to decrease the incidence of chemotherapy-induced myelosuppression when administered before platinum/etoposide ± immune checkpoint inhibitor-containing regimens or a topotecan-containing regimen [35].

G-CSF is a type of medication often used to stimulate the production of WBCs, including neutrophils, which are important in fighting infection [57]. For prophylactic management with G-CSF, a patient's risk for developing FN is assessed on the basis of type and stage of cancer, chemotherapy regimen, patient risk factors and whether the treatment is curative or palliative. If a patient has a high risk of FN (>20%), prophylactic use of G-CSF after the first chemotherapy cycle is recommended. For patients with an intermediate FN risk (10–20%), prophylactic G-CSF use is considered on the basis of risk factors such as older age, prior chemotherapy or radiation therapy, persistent neutropenia and bone marrow involvement by the tumor [7,8]. The risk of FN in the first chemotherapy cycle is reported to be greater in patients who receive pegfilgrastim on the same day as chemotherapy than in those who receive it 1–4 days post chemotherapy [41] and, in the US, G-CSF is typically given during separate visits to those for myelosuppressive chemotherapy [42].

Therapeutic use of filgrastim (or filgrastim biosimilars) is recommended for patients already presenting with FN who have previously received these treatments in a preventive manner; however, the therapeutic use of G-CSF is not recommended in those who have previously received long-acting G-CSF (pegfilgrastim or pegfilgrastim biosimilars). For patients with FN who have not received any prophylactic G-CSF, assessment of risk factors associated with infection-related complications or poor clinical outcomes is recommended [7,8].

Although data are scarce on the impact of G-CSF use on QoL, patients who receive G-CSF prophylaxis are likely to have better HRQoL owing to: their ability to maintain their relative dose of chemotherapy; a reduced need for antibiotic treatment; a reduced likelihood of hospitalization or death due to FN; and a reduced impact on aspects of daily life and work [15,58,59].

However, there are also side effects associated with G-CSF that can negatively affect patients' QoL. The most common side effect of G-CSF is bone pain, which occurs mainly because the medication stimulates the production of neutrophils, causing pain or discomfort in the bones [15,60]. The severity of bone pain can vary from person to person and may be most notable in the bones of the spine, pelvis and legs [61]. In addition, bone pain may be accompanied by other symptoms, such as fatigue, fever or muscle aches [15,57,61]. Bone pain was reported by our patient author as a severe side effect of treatment with pegfilgrastim (Box 1). In most cases, bone pain can be managed by other medications [15,60]. However, patients should report any persistent or severe pain to a healthcare provider [62]. In addition to interfering with daily activities, bone pain can lead to dose delays or discontinuation of treatment [15], which can have a negative impact on patients and their friends and family. Pegfilgrastim is approved for next-day use, and, unless the on-body injector is used, additional appointments further complicate the lives of the patient and caregiver.

In addition to current US FDA approvals for G-CSF and trilaciclib, other agents that may impact myelosuppression are under development. In September 2022, the US FDA-approved eflapegfilgrastim-xnst, a long-acting G-CSF with a novel formulation to decrease the incidence of infection, as manifested by FN, in adult patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with clinically significant incidence of FN [63,64].

Plinabulin is an investigational small molecule in development for the management of chemotherapy-induced neutropenia (Table 1). In addition to showing efficacy in phase III trials, plinabulin was associated with significantly less patient-reported bone pain compared with pegfilgrastim (difference, -0.67; 95% CI, -1.17 to -0.16; p = 0.01), as well as resulting in fewer chemotherapy dose delays of >7 days (3.8 vs 5.7%) and discontinuations (13.5 vs 26.4%), and a better immunosuppressive profile (neutrophil-to-lymphocyte ratio of >5 at day 8, 3.8 vs 46.0%; p < 0.001) [25,27]. Additionally, plinabulin was shown to improve QoL in a phase III study in patients with advanced NSCLC treated with docetaxel, in which QoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Cancer Core 30-item (QLQ-C30) and Lung Cancer 13-item (QLQ-LC13) measures. Outcomes were comparable between plinabulin and placebo during the first ten chemotherapy cycles; however, after the first ten cycles, patients who received plinabulin had more favorable cumulative EORTC QLQ-C30 and QLQ-LC13 scores, and significant improvements in symptoms, including mouth sores, dysphagia and coughing [28].

ALRN-6924 (sulanemadlin) is an investigational molecule that increases the activity of the p53 tumor suppressor protein. The role of p53 is to stop cells from dividing too fast and becoming cancerous. p53 is present in healthy cells, such as HSPCs in the bone marrow. Treatment with ALRN-6924 stops HSPCs from dividing, potentially protecting them from the toxic effects of chemotherapy [65,66]. However, in a phase Ib study (NCT05622058), patients receiving ALRN-6924 plus chemotherapy for the treatment of p53-mutated breast cancer experienced grade 4 neutropenia and alopecia. The study failed to meet its primary and secondary end points of duration and incidence of severe neutropenia in cycle 1 and incidence of chemotherapy-induced alopecia, respectively, and the study was terminated [67]. Moreover, further development of ALRN-6924 was stopped, including the termination of clinical trials in p53-mutated ES-SCLC and NSCLC [67].

G-CSF stimulates stem cell growth and neutrophil production after the bone marrow has received chemotherapy, raising concerns about a risk of longer-term damage, including conditions such as myelodysplasia and leukemia, which are known risks of chemotherapy [68]. By contrast, trilaciclib has been shown to proactively protect the bone marrow from chemotherapy-induced damage, resulting in longer-term protection of HSPCs [19]. Pooled data from the three clinical studies evaluating trilaciclib in patients with ES-SCLC showed that administering trilaciclib before chemotherapy significantly reduced the duration and occurrence of severe neutropenia compared with placebo, regardless of whether patients had received G-CSF [24]. Although the frequency of FN was low across the studies, there was a threefold decrease in its occurrence among patients who received trilaciclib. This translated into improvements in patients' QoL, with patients who received trilaciclib reporting significant improvements in physical and functional wellbeing, and in the symptoms and impact of fatigue [23].

Overall, therefore, by expanding upon existing treatment options, the inclusion of trilaciclib in treatment guidelines and the development of the investigational agent plinabulin are important advances in supportive care for chemotherapy-induced neutropenia. Further studies of these agents in other settings are eagerly awaited.

Chemotherapy-induced anemia

The circulatory system is responsible for distributing oxygen throughout the body. This is achieved by RBCs, which contain the oxygen-binding molecule hemoglobin. A normal level of hemoglobin is 12–16 g per 100 ml (g/dl) of blood for women and 14–18 g/dl for men, and anemia is defined by a reduction in the amount of hemoglobin in the blood below the lower limit of normal (Table 2) [40,44].

A drop in hemoglobin count may be caused by a reduced ability of the body to make new RBCs (e.g., because of nutritional deficiencies), loss of RBCs through bleeding, or destruction of RBCs. People with cancer have a greater risk of anemia compared with healthy individuals, even before starting cytotoxic chemotherapy, and having advanced-stage cancer or nutritional deficiencies associated with cancer (such as iron, folate or B12 deficiencies) are risk factors for developing this condition [69].

Chemotherapy-induced anemia is a common side effect of platinum-based chemotherapy treatments such as cisplatin, carboplatin or oxaliplatin. The production of RBCs in the bone marrow (erythropoiesis) is usually stimulated by a chemical called erythropoietin, which is produced in the kidneys. Platinum-based drugs can damage the erythropoietin-producing cells in the kidneys and directly suppress HSPCs in the bone marrow, resulting in reduced RBC production. Among patients with solid tumors, chemotherapy-induced anemia is particularly common in patients with lung cancer, as they are often treated with platinum-based chemotherapy, tend to be older and frequently have pulmonary or cardiovascular comorbidities that can make anemia symptoms worse [44,70].

Symptoms of chemotherapy-induced anemia include lethargy and poor concentration, shortness of breath (dyspnea), heart palpitations or murmurs, vertigo and loss of appetite. However, the most common symptom (in 60–90% of patients) is fatigue, which can have major adverse effects on patients' QoL [44,45], as reflected in the experiences of our patient author (Box 1). When patients with cancer are asked to rank which side effects of chemotherapy have the greatest impact on their lives, fatigue is often reported as being the most debilitating across all cancer types [45,71,72]. Participants of the 2010 LIVESTRONG Survey, which included 3129 cancer survivors, reported ‘energy and rest’ as being the most common physical concern and causing the most functional impairment. However, less than 20% of respondents who reported having concerns with energy indicated that they had received care to address this concern [72]. Another survey, of 152 patients with various solid tumors, found that patients with anemia reported significantly worse physical, social and role functioning, and experienced more fatigue, sickness and vomiting and loss of appetite compared with patients without anemia. In addition, low hemoglobin levels were associated with worse global QoL and fatigue, and higher depression scores [73].

The impact of anemia and fatigue on patients can be assessed using PRO measures such as the FACT-An or Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaires [74]. FACIT-F includes the 27-item FACT-G and a 13-item questionnaire designed to assess the effects of fatigue in patients with cancer. FACT-An includes the 40-item FACIT-F plus an additional seven items related to anemia [48]. Several studies have shown that increases in patients' hemoglobin levels correlate with improvements in FACT-G, FACIT-F and FACT-An scores, reflecting improved QoL [14,75–77]. In an analysis of five clinical studies of patients with cancer who had anemia, patients whose hemoglobin levels had increased reported significantly greater improvements in FACIT-F subscale scores, which translated into greater energy and activity levels and improved self-perception of overall health [76]. Similarly, results from a phase IV study of patients with solid tumors who had received treatment for chemotherapy-induced anemia (NCT01444456; eAQUA) showed that an increase in hemoglobin levels by >1 g/dl was associated with improved QoL, as measured by changes in FACT-F scores [14]. More recently, a study of 133 chemotherapy-treated patients with cancer found that hemoglobin levels correlated with self-reported QoL scores for fatigue, physical and functional wellbeing and performance status [13].

Current NCCN Guidelines^® recommend using RBC transfusions, ESAs or iron supplementation for the management of chemotherapy-induced anemia. In addition, trilaciclib is a prophylactic option to decrease the incidence of anemia and RBC transfusions when administered before platinum/etoposide with or without immune checkpoint inhibitor-containing regimens or a topotecan-containing regimen for ES-SCLC [35]. In contrast to European guidelines, the choice of treatment is not based on a certain hemoglobin threshold, and RBC transfusions are reserved mainly for high-risk and/or symptomatic patients. ESAs are recommended on the basis of patient preference, with the goals of gradual symptom improvement and avoidance of transfusion, whereas iron supplementation is recommended for absolute or functional iron deficiency [9,35].

RBC transfusions can result in an immediate increase in hemoglobin levels, providing rapid relief from the symptoms of chemotherapy-induced anemia [9]. However, transfusions carry the risk of transfusion-related reactions, volume overload or iron overload, and have the added burden of time spent in the clinic and the associated travel [9,46]. Results from a study of 103 patients with cancer found that the average chair time for patients receiving RBC transfusions was 4 h, and the average time spent traveling to and from the clinic was approximately 1 h. In addition to chair and travel time, RBC transfusions were associated with indirect financial costs to patients, such as lost wages, food costs, childcare expenditures, hotel accommodation and transportation or parking costs [46]. Furthermore, the hemoglobin threshold level at which RBC transfusions are considered has become lower over time (<7.0–8.0 g/dl compared with a historic threshold of <9.0–10.0 g/dl), which negatively impacts the QoL of patients who are receiving myelosuppressive chemotherapy agents for cancer treatment.

In a systematic review of studies measuring HRQoL in patients with chemotherapy-induced anemia, 34 of 35 studies reported significant improvements in patient QoL following ESA treatment, as assessed by FACT-F, FACT-An, Linear Analog Scale Assessment, and QLQ-C30, compared with patients who did not receive ESAs [78]. Among 114 patients treated with the ESA epoetin beta during cancer treatment, increased hemoglobin levels were associated with improved HRQoL, measured using visual analogue scale scores for fatigue [79]. Furthermore, in a study of 223 patients receiving myelotoxic chemotherapy for breast cancer, patients who received epoetin alfa had greater improvements in hemoglobin levels and significant improvements in FACT-An anemia and fatigue subscales compared with those who received best standard care [80]. In a separate study of 269 patients with chemotherapy-related anemia, early treatment of mild anemia with epoetin alfa significantly improved hemoglobin levels, QoL and productivity compared with delaying treatment until hemoglobin level decreased to <9.0 g/dl [81]. Finally, treatment with darbepoetin alfa has been associated with an improvement in symptom burden as measured by the MD Anderson Symptom Inventory [82].

ESA therapy reduces the need for transfusions and can relieve symptoms; however, unlike RBC transfusions, it can take several weeks for ESA therapy to stimulate an increase in hemoglobin levels. There are additional risks associated with ESAs, which can make physicians reluctant to use them, including an increased risk of thromboembolic events, hypertension and potential increased mortality and tumor progression [9,10]. In 2007, the US FDA approved a boxed warning for ESA products and, in 2010, introduced the Risk Evaluation and Mitigation Strategy (REMS) implementation for ESA use. This required medical professionals to be REMS-certified to be able to use ESAs and required patients to complete a consent form describing the benefits and risks of ESAs. The REMS program was discontinued in 2017, as it was no longer considered necessary for ensuring that the benefits of ESA therapy outweigh the risks in patients with cancer [83]. However, the US FDA label carries a boxed warning stating that, in patients with cancer, ESAs should be used only for the treatment of chemotherapy-induced anemia, be discontinued upon completion of the chemotherapy course, and not be used when treatment is curative in intent [16]. Prescription of ESAs fell significantly in the USA when safety concerns were first reported, and there is evidence to show a further reduction in ESA use after changes in reimbursement were brought into effect in 2008 [84]. However, there is also evidence that the implementation of the REMS program had little effect on ESA administration [83,85].

Both RBC transfusions and ESAs are administered after anemia is already apparent, whereas trilaciclib can provide prophylactic protection from chemotherapy-induced anemia. In a pooled phase III analysis, administering trilaciclib prior to chemotherapy significantly reduced the occurrence of grade 3 or 4 anemia, the use of ESAs, and the need for RBC transfusions on or after week 5 of study treatment [23,24]. The frequency of RBC transfusions was approximately halved with the administration of trilaciclib, which may translate into reduced patient burden in terms of the additional time and costs associated with transfusion visits. Additionally, patients receiving trilaciclib reported significant improvements in symptoms associated with anemia, as assessed by FACT-An [23].

Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor that was investigated for the treatment of chronic kidney disease-related anemia in patients not on dialysis (Table 1). Results from a phase III trial in this patient population showed that administering roxadustat significantly increased hemoglobin levels compared with placebo, although there were no differences in PROs between the two treatment groups [29]. Roxadustat has also been shown to increase hemoglobin levels in patients with non-myeloid cancers and chemotherapy-induced anemia, regardless of the tumor type and chemotherapy regimen. In this study, fewer patients required an RBC transfusion on or after week 5 when starting on 2.5 mg/kg compared with a lower 2.0 mg/kg dose [31].

Chemotherapy-induced thrombocytopenia

Platelets, also known as thrombocytes, are a type of blood cell that help the blood to clot (thrombosis). Thrombocytopenia is defined by a lower-than-normal number of platelets per mm³ of blood (Table 2). The incidence of thrombocytopenia varies according to the type of chemotherapy, being more common in patients receiving highly myelosuppressive treatments such as gemcitabine- and platinum-based chemotherapies [39,86]. Chemotherapy drugs can cause thrombocytopenia in different ways, with some reducing platelet production through effects on HSPCs and others increasing the rate of platelet destruction [39,87].

There is a shortage of literature describing the impact of chemotherapy-related thrombocytopenia on patients' QoL. However, having a low platelet count can potentially cause serious problems for patients with cancer, as it increases the risk of bleeding. At platelet counts lower than 10,000 per microliter (μl) of blood, the risk of spontaneous bleeding is increased, and surgical procedures are often complicated by bleeding at platelet counts <50,000/μl. Even at platelet counts <100,000/μl, chemotherapy and radiation therapy should be administered carefully to avoid making the thrombocytopenia worse and increasing the bleeding risk [87]. In addition to bleeding, other symptoms of a low platelet count include bruising, small purple or red dots under the skin (called petechiae), severe headaches and blood in the urine, vomit or bowel movements [47]. Having a diagnosis of thrombocytopenia has been reported to worsen patients' feelings of anxiety and fear beyond those associated with the cancer diagnosis [39,87]. Moreover, the costs of care related to chemotherapy-induced thrombocytopenia can be substantial [86], creating an additional burden on patients, caregivers and healthcare systems.

PROs used to measure the impact of thrombocytopenia on patients' QoL include the FACT-Thrombocytopenia 18-item version (FACT-Th18), which is composed of the FACT-G and an 18-item thrombocytopenia subscale that includes questions relating to bleeding, bruising, activity and concerns about bleeding or dose reductions/delays. Two shorter versions with reduced thrombocytopenia subscales are also available in the form of the FACT-Th11 (11 items) and FACT-Th6 (6 items) [48,88].

Chemotherapy-induced thrombocytopenia is commonly managed with treatment delays or dose reductions, which aim to allow bone marrow recovery [49]. Changes to planned treatment can cause inconvenience and/or additional worry to patients, as reflected in the FACT-Th questionnaires [48]. Platelet transfusions are an effective and rapid treatment for severe thrombocytopenia and are recommended in AABB (Association for the Advancement of Blood & Biotherapies; formerly, the American Association of Blood Banks) guidelines to reduce the risk of spontaneous bleeding in patients with therapy-induced thrombocytopenia [49,89]. However, platelet transfusions offer only a temporary improvement in platelet counts [34]. Additionally, transfusions may be ineffective in some patients and/or cause febrile or allergic reactions. Platelet transfusions are also associated with a risk of infection due to bacterial contamination [49,90].

Although not FDA-approved for chemotherapy-induced thrombocytopenia, NCCN Guidelines^® for Hematopoietic Growth Factors also recommend romiplostim, or enrollment in a clinical trial of another thrombopoietin receptor agonist such as avatrombopag, eltrombopag or hetrombopag, as alternative options to maintain the dose schedule and intensity of chemotherapy if the benefit is expected to outweigh the risks [35,39]. Romiplostim is an Fc-peptide fusion protein that binds to and activates the thrombopoietin receptor, stimulating increased platelet production (Table 1). It is FDA approved and widely used to treat immune thrombocytopenia [32,33]. Additionally, romiplostim has shown efficacy in improving platelet counts among patients with solid tumors and chemotherapy-induced myelosuppression in a phase II randomized trial, as well as several retrospective studies and case series [32,34]. In the phase II study, which included patients who had platelet counts of <100,000/μl for at least 4 weeks, treatment with romiplostim for 2 weeks (n = 52) resulted in a mean platelet count of 141,000/μl compared with 57,000/μl after 3 weeks in the untreated observation group (n = 8) [32]. In one retrospective study that included 153 patients with solid tumors, romiplostim allowed 79% of patients to avoid further chemotherapy dose reductions/treatment delays and 89% avoided platelet transfusions [34]. It should be noted, however, that thrombopoietin receptor agonists are associated with an increased risk of venous thromboembolism and should be used with caution in patients with cancer [34]. To our knowledge, the impact of romiplostim on QoL has not been investigated in patients with chemotherapy-induced thrombocytopenia, although patients with chronic immune thrombocytopenia have reported better HRQoL following romiplostim therapy in phase III trials, including improvements in measures of symptoms, fear and activity [91].

Conclusion

Not only can myelosuppressive side effects affect the ability to deliver planned chemotherapy treatment, potentially adversely affecting clinical outcomes, but they can also have a substantial negative impact on patients' HRQoL. Despite the availability of G-CSF, ESAs and transfusions, chemotherapy-induced myelosuppression is associated with a significant QoL burden on patients and their caregivers, with symptoms resulting in impairment of normal daily functioning and worries over infection or bleeding risk. Traditional supportive care measures are also often used reactively, after symptoms have already emerged, and are each associated with certain risks and limitations that can further exacerbate the QoL burden.

Administering trilaciclib prior to chemotherapy has been shown to result in clinically meaningful reductions in myelosuppression and its symptoms, as well as fewer hospitalizations and a reduced need for supportive care interventions. These effects translate into improvements in HRQoL measures related to the protected cell lineages, including fatigue and physical and functional wellbeing [23]. Several pipeline drugs such as plinabulin and roxadustat have also shown encouraging results in clinical trials and have the potential to improve QoL for patients on chemotherapy, both by improving blood counts to directly alleviate symptoms, and indirectly by reducing the need for G-CSF, ESAs, or transfusions.

Future perspective

Following on from the approval of trilaciclib in patients with ES-SCLC in 2021, the myeloprotective benefit of trilaciclib is being investigated in clinical trials in other cancer types, including advanced bladder cancer and breast cancer. Additionally, it is likely that several pipeline agents, some of which are already recognized by the FDA as having potential utility for managing chemotherapy-induced myelosuppression, will also be commercially available for the prevention/treatment of one or more cytopenias. The availability of more treatment options in the future will likely expand our current supportive care of G-CSF, ESAs, trilaciclib and transfusions, to include new indications and options, ultimately improving outcomes for our patients.