NCCN Guidelines® Insights: Hematopoietic Growth Factors, Version 1.2022.

The NCCN Guidelines for Hematopoietic Growth Factors provide recommendations for the appropriate use of growth factors in the clinical management of febrile neutropenia (FN), chemotherapy-induced thrombocytopenia (CIT), and chemotherapy-induced anemia (CIA). Management and prevention of these sequelae are an integral part of supportive care for many patients undergoing cancer treatment. The purpose of these guidelines is to operationalize the evaluation, prevention, and treatment of FN, CIT, and CIA in adult patients with nonmyeloid malignancies and to enable the patient and clinician to assess management options for FN, CIT, and CIA in the context of an individual patient's condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for Hematopoietic Growth Factors, with particular emphasis on the incorporation of a newly developed section on CIT.

Stem cell-secreted factor therapy regenerates the ovarian niche and rescues follicles.

BACKGROUND: Ovarian senescence is a normal age-associated phenomenon, but increasingly younger women are affected by diminished ovarian reserves or premature ovarian insufficiency. There is an urgent need for developing therapies to improve ovarian function in these patients. In this context, previous studies suggest that stem cell-secreted factors could have regenerative properties in the ovaries. OBJECTIVE: This study aimed to test the ability of various human plasma sources, enriched in stem cell-secreted factors, and the mechanisms behind their regenerative properties, to repair ovarian damage and to promote follicular development. STUDY DESIGN: In the first phase, the effects of human plasma enriched in bone marrow stem cell soluble factors by granulocyte colony-stimulating factor mobilization, umbilical cord blood plasma, and their activated forms on ovarian niche, follicle development, and breeding performance were assessed in mouse models of chemotherapy-induced ovarian damage (n=7 per group). In addition, the proteomic profile of each plasma was analyzed to find putative proteins and mechanism involved in their regenerative properties in ovarian tissue. In the second phase, the most effective plasma treatment was validated in human ovarian cortex xenografted in immunodeficient mice (n=4 per group). RESULTS: Infusion of human plasma enriched bone marrow stem cell soluble factors by granulocyte colony-stimulating factor mobilization or of umbilical cord blood plasma-induced varying degrees of microvessel formation and cell proliferation and reduced apoptosis in ovarian tissue to rescue follicular development and fertility in mouse models of ovarian damage. Plasma activation enhanced these effects. Activated granulocyte colony-stimulating factor plasma was the most potent inducing ovarian rescue in both mice and human ovaries, and proteomic analysis indicated that its effects may be mediated by soluble factors related to cell cycle and apoptosis, gene expression, signal transduction, cell communication, response to stress, and DNA repair of double-strand breaks, the most common form of age-induced damage in oocytes. CONCLUSION: Our findings suggested that stem cell-secreted factors present in both granulocyte colony-stimulating factor-mobilized and umbilical cord blood plasma could be an effective treatment for increasing the reproductive outcomes in women with impaired ovarian function owing to several causes. The activated granulocyte colony-stimulating factor plasma, which is already enriched in both stem cell-secreted factors and platelet-enclosed growth factors, seems to be the most promising treatment because of its most potent restorative effects on the ovary together with the autologous source.

NCCN Guidelines Insights: Hematopoietic Growth Factors, Version 1.2020.

Management of febrile neutropenia (FN) is an integral part of supportive care for patients undergoing cancer treatment. The NCCN Guidelines for Hematopoietic Growth Factors provide suggestions for appropriate evaluation, risk determination, prophylaxis, and management of FN. These NCCN Guidelines are intended to guide clinicians in the appropriate use of growth factors for select patients undergoing treatment of nonmyeloid malignancies. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines regarding the incorporation of newly FDA-approved granulocyte-colony stimulating factor biosimilars for the prevention and treatment of FN.

Medication overuse in oncology: current trends and future implications for patients and society.

The high cost of cancer care worldwide is largely attributable to rising drugs prices. Despite their high costs and potential toxic effects, anticancer treatments could be subject to overuse, which is defined as the provision of medical services that are more likely to harm than to benefit a patient. We found 30 studies documenting medication overuse in cancer, which included 16 examples of supportive medication overuse and 17 examples of antineoplastic medication overuse in oncology. Few specific agents have been assessed, and no studies investigated overuse of the most toxic or expensive medications currently used in cancer treatment. Although financial, psychological, or physical harms of medication overuse in cancer could be substantial, there is little published evidence addressing these harms, so their magnitude is unclear. Further research is needed to better quantify medication overuse, understand its implications, and help protect patients and the health-care system from overuse.

Hematopoietic growth factors in lung cancer.

PURPOSE OF REVIEW: Most patients affected by lung cancer are treated with chemotherapy, and hence are at risk of myelosuppression. Hematopoietic growth factors have a relevant role in this setting, as they can improve quality of life, reduce the rate of chemotherapy-induced complications and allow the administration of full-dose chemotherapy. RECENT FINDINGS: Most data of hematologic growth factors in lung cancer come from dated publications or large trials involving different malignancies, thus limiting specific information for lung neoplasms. Nonetheless, most studies consistently identified myeloid growth factors as effective on specific end-points such as the duration and severity of neutropenia, or complications such as hospitalizations and febrile neutropenia; on the other hand, erythropoiesis-stimulating agents (ESAs) consistently improved anemia-specific end-points including hemoglobin values, transfusions rate and fatigue, although some specific safety issues characterized this drug class. The most recent international guidelines address these characteristics and include the main indications for hematologic growth factors in solid neoplasms, including lung cancer. SUMMARY: Myeloid growth factors and ESAs have a relevant role in selected patients undergoing chemotherapy for nonsmall cell lung cancer and small cell lung cancer. Notably, a comprehensive risk-benefit assessment is required in the specific case of ESAs.

Economic impact on US Medicare of a new diagnosis of myelodysplastic syndromes and the incremental costs associated with blood transfusion need.

BACKGROUND: Recent retrospective studies suggest myelodysplastic syndromes (MDSs) are more common than previously recognized and patients who develop transfusional dependence may be at risk for increased comorbid complications. STUDY DESIGN AND METHODS: A retrospective review was undertaken of Medicare claims focusing on costs associated with patients with a new claim listing ICD-9-CM Diagnosis Code 238.7 in first quarter of 2003. Patients were followed until 2005 to assess resource use and costs. RESULTS: A total of 512 patients aged 65 years or more with newly diagnosed MDS were identified. Forty percent had received red blood cell transfusions between 2003 and 2005. During the 3-year follow-up, transfused patients experienced increased prevalence of cardiac diseases, dyspnea, and infections. Cumulative 3-year mean Medicare costs for MDS patients were $49,156. Transfused patients had greater use of hospital inpatient and outpatient services and incurred significantly higher mean costs than nontransfused patients ($88,824 vs. $29,519, p < 0.001). After adjustment for baseline characteristics and clinical complications, transfusion was independently associated with a 48% increase in monthly costs in addition to the cost of transfusion administration. CONCLUSION: MDS places a significant economic burden on the US Medicare system. MDS patients requiring transfusions experience higher prevalence of new comorbid conditions and incur significantly higher Medicare costs than nontransfused patients during the initial 3 years after diagnosis.

Successful use of eculizumab in a pediatric patient treated for paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, debilitating life-threatening clonal hematopoietic stem cell disease. The clinical manifestations of PNH are usually seen in adulthood and are very rarely reported in children. Eculizumab, a humanized monoclonal antibody targeting and preventing cleavage of the terminal complement protein C5, has become the "gold standard" of treatment for hemolysis or significant disease-related complications in patients with PNH. Although eculizumab is not licensed for use in pediatrics, we report a young PNH patient with bone marrow failure and severe episodes of hemolytic anemia who was treated successfully with eculizumab for >18 months.

[Myelopoiesis and bone marrow function in elderly tumor patients]. / Myelopoese und Knochenmarkfunktion des alten Tumorpatienten.

According to a model described by Balducci, the human myelopoietic stem cell reserve shows a shift from the reproductive to the proliferative pool corresponding to higher immunological demands resulting from the breakdown of infection defences. Every "hematopoietic stress," i.e., sepsis and/or cytoreductive chemotherapy, leads to a reduction of myelopoietic stem cells in the elderly in contrast to an increase in younger individuals. These changes are relevant starting at the age of 70 years and show a reduced compensation capacity in the aged organism. In addition, the function of the effector cells, i.e., the granulocytes and especially their phagocytic capacity, as well as the balance between stimulating and inhibiting cytokines are compromised. A significant influence on leukopenia and febrile septicemia has been shown for several comorbidities, especially chronic inflammation. The prophylactic use of myelopoietic growth factors is, therefore, recommended for the elderly when there is an expected risk for hematotoxicity grade III or IV. However, prognostic tests to predict the individual risk of hematotoxicity and septicemia are lacking.

The hematopoietic growth factors in acute leukemia: a European perspective.

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are malignant clonal disorders of the blood system requiring intensive and long-term cytotoxic treatment. Current chemotherapy protocols not only target the malignant cell, but are also highly toxic to normal hematopoietic cells as well. Leukemia patients thus experience prolonged times of neutropenia, thrombocytopenia, and anemia, which increase the risk for secondary complications like infections and bleeding. Twenty years ago leukemia patients were considered the ideal candidates to benefit from accelerated recovery of cytopenias by treatment with recombinant cytokines. Moreover, based on in vitro data, it was hypothesized that myeloid growth factors may sensitize AML cells to cytotoxic agents. Numerous clinical trials have documented the biologic activity of granulocyte and granulocyte-macrophage growth factors to accelerate neutrophil recovery after chemotherapy. However, there is high-level evidence that these myeloid growth factors neither reduce the incidence of severe infections nor improve the outcome of AML patients. Evidence from ALL trials is mixed with some studies suggesting a reduction of severe infections by myeloid growth factors whereas others report no effect. Most studies of acute leukemia patients suggested that myeloid growth factors are safe to use, however, a negative impact on event-free survival was found in one trial and an increased risk for secondary AML was reported in pediatric ALL patients. Thrombopoietins have not led so far to a significant increase in platelet numbers in leukemia patients. Chemokine receptor antagonists are now being evaluated in clinical trials for synergistic effects with chemotherapy and will be discussed briefly. Cytokine development mirrors the great advances that have been achieved in the understanding of regulatory mechanisms in hematopoiesis. As this understanding grows, new drugs and new applications will emerge.

Management of aplastic anemia: the role of systematic reviews and meta-analyses.

Aplastic anemia is a rare bone marrow failure disorder. Allogeneic hematopoietic cell transplantation (alloHCT) and immunosuppressive therapy (IST) are the main therapeutic modalities currently used to treat patients with aplastic anemia. Systematic reviews and meta-analyses of randomized controlled trials (RCTs) are regarded as the highest level of evidence and as such aid practitioners in solving clinical questions. The objective of this review is to assess the base of evidence for the common practice and the current guidelines for the management of aplastic anemia. It focuses on data obtained from systematic reviews and meta-analyses of RCTs conducted in this field. Specifically, it focuses on four major therapeutic questions: the roles of alloHCT, IST, hematopoietic growth factors and supportive care.

Successful management of gelatinous transformation of the bone marrow in anorexia nervosa with hematopoietic growth factors.

Serous atrophy or gelatinous transformation of the bone marrow (GMT), often seen with severe nutritional deprivation in Anorexia Nervosa (AN), is characterized by hypocellularity and patchy or diffuse replacement of the bone marrow with hyaluronic acid-like mucopolysaccharide material. Treatment with nutritional support alone is often temporary due to the relapsing nature of AN. We present the case of a patient with pancytopenia due to GMT who had multiple prior hospitalizations for infections and blood transfusions. Nutritional support was inadequate in restoring her bone marrow function. She was successfully treated with hematopoietic growth factors and achieved a sustained hematopoietic recovery. In addition, use of growth factors resulted in a 91% reduction in the cost of health care delivered to this patient.

How to treat MDS without stem cell transplantation.

Although allogeneic hematopoietic cell transplantation (HCT) is the only proven curative treatment for myelodysplastic syndromes (MDS), it is only used to treat a minority of MDS patients. The majority of patients are too old or suffer from comorbidities rendering allogeneic HCT too risky. Alternative treatment strategies for patients with higher risk MDS try to alter the natural course of disease by preventing or delaying leukemic transformation. In patients with lower risk MDS, treatment is mainly focused on maintaining or improving the quality of life.

Hematopoietic growth factors in aplastic anemia patients treated with immunosuppressive therapy-systematic review and meta-analysis.

Immunosuppressive therapy is the treatment for aplastic anemia patients ineligible for transplantation. The role of hematopoietic growth factors as adjunct to treatment in these patients is unclear. We conducted a systematic review and meta-analysis of randomized controlled trials comparing treatment with immunosuppressive therapy and hematopoietic growth factors to immunosuppressive therapy alone in patients with aplastic anemia. Two reviewers appraised the quality of trials and extracted data. For each trial, results were expressed as relative risks with 95% confidence intervals (CI) for dichotomous data. The addition of hematopoietic growth factors yielded no difference in overall mortality at 100 days, one year and five years [relative risks 1.33 (95% CI 0.56-3.18), relative risks 0.90 (95% CI 0.50-1.63) and relative risks 0.89 (95% CI 0.55-1.46), respectively]. There was no difference in overall hematologic response and in the occurrence of infections. HGF significantly decreased the risk for relapse, relative risks 0.45 (95% CI 0.30-0.68, 3 trials). Hematopoietic growth factors were not associated with higher occurrence of myelodysplastic syndrome and acute myeloid leukemia or paroxysmal nocturnal hemoglobinuria. The addition of hematopoietic growth factors does not affect mortality, response rate or infections occurrence. Therefore, it should not be recommended routinely as an adjunct to the immunosuppressive therapy for patients with aplastic anemia.

Intermediate dose gemcitabine-cisplatin combination chemotherapy without treatment delay for cytopenia followed by autografting--a new standard of care in relapsed or refractory Hodgkin lymphoma?

Ten percent to 20% of patients with Hodgkin Lymphoma (HL) are refractory to first-line therapy or relapse. Existing salvage regimens have response rates of 60-85%, considerable toxicity and frequent treatment delay or dose reduction. We report a gemcitabine, cisplatin, and dexamethasone regimen (GemCis) with intensive growth factor and platelet support and no treatment delay. Seventeen patients with relapsed or refractory biopsy proven HL were treated. Toxicity, transfusion requirement, stem cell harvesting and engraftment data were collected. Response assessment was by computed tomography and positron emission tomography. Overall and complete response rates were high (94% and 65%, respectively). There were no episodes of febrile neutropenia, treatment delays or hospital admissions. All 15 patients intended for autograft were successfully harvested. All engrafted successfully with a median time for the entire group to neutrophil engraftment of 14 days. With a median follow-up of 22 months, the median survival has not yet been reached, and the estimated 2-year survival is 88%. GemCis is a well-tolerated outpatient regimen for relapsed/ refractory Hodgkin lymphoma which does not inhibit stem cell mobilisation, gives excellent response rates and compares favourably with previously published salvage regimens using these or other chemotherapy agents.

Are guidelines on use of colony-stimulating factors in solid cancers flawed?

In cancer care in Australia, we are very reliant on an array of expensive pharmaceuticals. Our use of these treatments is often based on multinational or foreign clinical studies. Oncologists are, to varying degrees, reliant on how the studies are interpreted by the writers of journal editorials, clinical guidelines and opinion pieces. Therefore it is important that these guidelines are balanced and evidence based. We have examined in detail one of the most influential and wide ranging clinical guidelines used in oncology, The American Society of Clinical Oncology (ASCO) 2006 Update of Recommendations for the use of White Blood Cell Factors: An Evidence-Based Clinical Practice Guideline. We have discussed in detail some of the controversial recommendations in this guideline and have exposed what we believe are some flaws in these recommendations. We would urge that we continue to be rigorous in our oversight of international research agendas and international clinical guidelines in the future.

Haematopoietic growth factors and their therapeutic use.

Haematopoietic growth factors constitute an important group of proteins that predominantly regulate the process of haematopoiesis. While some of these proteins have a very broad array of action on very early haematopoietic progenitors leading to multi-lineage increases in haematopoietic cell production and differentiation, others act in a restricted manner on specific committed terminally differentiated cell types. On the basis of their unique spectrum of activities, several factors are approved for clinical use in various indications while others are under investigation in the clinic either alone or as combination therapy. In this review, we have described factors which directly and in some cases indirectly influence haematopoiesis with particular focus on those factors which are either approved or show potential for clinical use. A brief description of the products that are currently available for clinical use is also provided. At present, several new products which include fusion proteins, peptide mimetics are either at the pre-clinical stage or in clinical development for various indications and these are also briefly described.

The potential of hematopoietic growth factors for treatment of Alzheimer's disease: a mini-review.

There are no effective interventions that significantly forestall or reverse neurodegeneration and cognitive decline in Alzheimer's disease. In the past decade, the generation of new neurons has been recognized to continue throughout adult life in the brain's neurogenic zones. A major challenge has been to find ways to harness the potential of the brain's own neural stem cells to repair or replace injured and dying neurons. The administration of hematopoietic growth factors or cytokines has been shown to promote brain repair by a number of mechanisms, including increased neurogenesis, anti-apoptosis and increased mobilization of bone marrow-derived microglia into brain. In this light, cytokine treatments may provide a new therapeutic approach for many brain disorders, including neurodegenerative diseases like Alzheimer's disease. In addition, neuronal hematopoietic growth factor receptors provide novel targets for the discovery of peptide-mimetic drugs that can forestall or reverse the pathological progression of Alzheimer's disease.

Common acute oncological emergencies: diagnosis, investigation and management.

In the UK an aging population is resulting in more people being diagnosed with cancer, and an increasing number of treatment options means that many patients live significantly longer with their disease. It is anticipated therefore that an increasing number of patients will present to primary and secondary care with acute complications of cancer, or the treatment thereof. Many doctors have limited experience in managing patients with cancer and acute oncological emergencies. This article reviews the diagnosis and management of four common oncological emergencies: febrile neutropenia, metastatic spinal cord compression, superior vena cava obstruction, and malignancy associated hypercalcaemia. It is vital to recognise these conditions, as failure to implement immediate and appropriate treatment may result in significant morbidity or death.

Alternatives to blood transfusion.

Blood transfusion therapy in the 21st century continues to present limitations regarding efficacy and risks. Blood management partners optimal blood transfusion therapy with anemia management that incorporates nonblood strategies and techniques. A planned approach to anemia prevention, identification, and treatment can reduce the need for blood transfusion and improve patient outcomes. The use of pharmaceutical agents and tools to minimize blood loss also leads to blood transfusion reduction. Nurses play an integral role in affecting the use of alternatives to blood transfusion. Through assessment, communication, and an understanding of blood management strategies, nurses are patients' front-line innovators in promoting best practices.

Have hematopoietic growth factors made an impact on the management of liver disease?

It is clear that the major indication for the use of hematopoietic growth factors in hepatology is to counteract the adverse effects of interferons (neutropenia and thrombocytopenia) and ribavirin (hemolytic anaemia) during the treatment of hepatitis C infection. This is important because the probability of SVR depends on proper adherence to therapy (at least 80% of the requisite dose maintained for at least 80% of the requisite duration) and proper adherence can only be achieved if the side effects are reduced to a minimum. Even though the studies have demonstrated beyond doubt that the use of hematopoietic growth factors does indeed reduce the incidence and severity of these adverse effects and helps the patients to complete the course of therapy, the data on improvement of SVR is still limited. There is only one study of darbepoetin and filgrastim showing the beneficial effect on SVR. Even among the hematological side effects, possibly the only significant effect which limits the use of optimal HCV therapy is the hemolytic anaemia induced by ribavirin. The other two main side effects, i.e. neutropenia and thrombocytopenia are not clinically problematic. The use of such growth factors would be particularly effective if patients who have advanced liver disease or cirrhosis are able to receive adequate anti-viral therapy as has been demonstrated in the study of eltrombopag among HCV cirrhotics. Apart from this, other indications of G-CSF or GM-CSF use are still in the experimental stage. So, as of now, apart from erythropoietic factors, the role played by other hematopoietic growth factors in hepatology is limited. But future research, especially in the areas of immunotherapy of liver cancers and stem cell therapy for endstage liver disease, is surely going to give these factors their due place in hepatology.