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The coronavirus disease (COVID-19) pandemic has posed several challenges to the hematology community to re-organize the medical care of patients with hematologic malignancies. Whereas the oncology societies favored a more or less conservative approach which considered the possibility of delaying treatment administration on a case-by-case basis, the hematology community guidelines were less stringent and recommended adequate individualized regimens. As countries are de-escalating the lockdown and the medical community is unable to foresee the end of the current outbreak will and whether the pandemic would eventually come back as a seasonal infection, there is interest in screening of patients with hematology malignancies with COVID-19 instead of limiting access to curative treatments. The rapidly accumulating knowledge about COVID-19 allows a better understanding of the diagnostic tools that may be potentially used in screening. Herein, we briefly review the pathophysiology of COVID-19, the rationale of screening of patients with hematologic malignancies, tools for screening, and available guidelines., (© 2020 John Wiley & Sons Ltd.)

Opportunistic infections remain a major problem across a broad spectrum of immunocompromised haematological patient groups, with viruses, bacteria, fungi and protozoa all presenting significant challenges. Given the major difficulties in treating many of these infections with the currently available antimicrobial chemotherapeutic arsenal, and the rapid emergence of antimicrobial resistance amongst all of the microbial kingdoms, novel strategies that enable host control or elimination of infection are urgently required. Recently, major progress has been made in our understanding of host immunocompromise in the haematological patient. In addition, a wide range of novel immunomodulatory strategies for infectious diseases have been developed. Here we discuss the major and wide-ranging areas of progress that have been made for host-directed immunotherapies in the context of infectious diseases, with relevance to haematological immunocompromise., (© 2017 John Wiley & Sons Ltd.)

Study Objective: To determine the impact of primary prophylactic colony-stimulating factor (CSF) use on febrile neutropenia in a large patient population receiving contemporary chemotherapy regimens to treat breast cancer, colorectal cancer, or non-small cell lung cancer (NSCLC)., Design: Retrospective claims analysis., Data Sources: The Surveillance, Epidemiology, and End Results (SEER)-Puget Sound cancer registry and insurance claims records., Patients: A total of 2728 patients aged 25 years or older who received a diagnosis of breast cancer (998 patients), colorectal cancer (688 patients), or NSCLC (1042 patients) between January 1, 2002, and December 31, 2005, and received chemotherapy., Measurements and Main Results: Initial chemotherapy regimen, CSF use (filgrastim or pegfilgrastim), and febrile neutropenia events were evaluated after the first chemotherapy administration. Subsequently, febrile neutropenia rates in patients receiving primary prophylactic CSF were compared with febrile neutropenia rates in patients receiving CSF in settings other than primary prophylaxis or not at all. The impact of primary prophylactic CSF could not be assessed for patients with colorectal cancer or NSCLC because only 1 and 18 febrile neutropenia events, respectively, occurred in those receiving primary prophylactic CSF. Of the 998 patients with breast cancer, 72 (7.2%) experienced febrile neutropenia, 28 of whom received primary prophylactic CSF. In the patients with breast cancer, we observed that primary prophylactic CSF use was associated with reduced febrile neutropenia rates; however, the analysis may have been confounded by unmeasured factors associated with febrile neutropenia., Conclusion: The impact of primary prophylactic CSFs on febrile neutropenia rates could not be demonstrated. Given the substantive cost of CSFs to pharmacy budgets, there are numerous opportunities for pharmacists to optimize CSF use. Research studies are needed to evaluate if guideline-directed prescribing of primary prophylactic CSFs can improve clinical outcomes., (© 2012 Pharmacotherapy Publications, Inc.)

Myelosuppression, particularly febrile neutropenia (FN), are serious dose-limiting toxicities that occur frequently during the first cycle of chemotherapy. Identifying patients most at risk of developing FN might help physicians to target prophylactic treatment with colony-stimulating factor (CSF), in order to decrease the incidence, or duration, of myelosuppression and facilitate delivery of chemotherapy as planned. We present a risk model for FN occurrence in the first cycle of chemotherapy, based on a subgroup of 240 patients with non-Hodgkin lymphoma (NHL) enroled in our European prospective observational study. Eligible patients had an International Prognostic Index of 0-3, and were scheduled to receive a new myelosuppressive chemotherapy regimen with at least four cycles. Clinically relevant factors significantly associated with cycle 1 FN were older age, increasing planned cyclophosphamide dose, a history of previous chemotherapy, a history of recent infection, and low baseline albumin (<35 g/l). Prophylactic CSF use and higher weight were associated with a significant protective effect. The model had high sensitivity (81%) and specificity (80%). Our model, together with treatment guidelines, may rationalise the clinical decision of whether to support patients with CSF primary prophylaxis based on their risk factor profile. Further validation is required.

Chemotherapy-induced neutropenia is a major dose-limiting toxicity of systemic cancer chemotherapy that can lead to fever and infection, requiring prompt analysis and in-patient treatment with broad-spectrum antibiotics. Complicated neutropenia may lead to reduction and/or delay of systemic anti-cancer treatment, which may compromise outcome. Haematopoietic growth factors have the ability to augment haematopoietic cell cycling and are used to facilitate more dose-intense treatments and to decrease treatment-related complications. This review focuses on randomised trials that investigated the use of colony-stimulating factors (CSF) to prevent treatment-related febrile complications in haematological malignancies in (younger) adult patients. In general, these studies demonstrated that CSF reduced the duration of severe neutropenia but not always its febrile complications; therefore inconsistent results regarding clinically relevant reduction of hospitalisation, duration of therapeutic antibiotics, infection-related or disease-related mortality and economic effects were reported. Current developments in treatment of haematological malignancies will pose new challenges as a shift in infectious pathogens can be expected.

Study Objectives: Previous studies have used direct hospital costs to determine the threshold at which the cost of prophylactic use of colony-stimulating factor (CSF) is offset by savings from the lower risk of hospitalization for febrile neutropenia. By conducting a survey of patients in whom febrile neutropenia had developed during treatment with chemotherapy, we sought to reassess these costs by including estimates of indirect costs associated with febrile neutropenia as well as new categories of direct costs that were not previously available. Costs were included in an existing cost-minimization model, and their effect on the risk threshold at which the prophylactic use of CSF becomes cost saving was determined., Patients: A sample survey of 26 patients with ovarian cancer who were treated with chemotherapy and developed febrile neutropenia., Intervention: Analysis of data from patients' questionnaires containing survey items on indirect costs and additional direct costs associated with febrile neutropenia., Measurements and Main Results: Estimates of indirect costs and other direct costs from the questionnaires were included in an existing cost-minimization model, and risk thresholds were recalculated. Before modification, the model showed cost neutrality for prophylactic use of CSF when the risk of hospitalization for febrile neutropenia was approximately 23%. Including previously excluded direct costs and indirect costs ranging from 1000-5000 dollars attributable to severe neutropenia in the model lowered the risk threshold for hospitalization for febrile neutropenia at which the prophylactic use of CSF becomes cost neutral to between 22% and 18%., Conclusion: Including additional direct as well as indirect costs associated with chemotherapy-induced neutropenia permits a more realistic assessment of the possible effect of prophylactic use of CSF from a societal perspective. Despite the limited size of the survey, this study shows a cost-benefit rationale to support prophylactic use of CSF in a greater proportion of patients treated with chemotherapy.

Studies of primary prophylaxis of febrile neutropenia (FN) with recombinant human granulocyte colony-stimulating factor (rHu-G-CSF, filgrastim) administered to all patients starting their initial course of chemotherapy have demonstrated clinical effectiveness and an economic advantage in a wide range of settings. A recent meta-analysis confirmed the ability of filgrastim to reduce the risk of FN and documented infection in a variety of malignancies in both adults and children. The threshold risk for FN at which a cost saving is achieved by using filgrastim is inversely related to the daily cost of the drug and duration of hospitalization. Clinical practice guidelines for the use of filgrastim were developed based on these observations. Recent studies incorporating indirect institutional costs demonstrated that a cost saving can be achieved at substantially lower FN risk thresholds than previously estimated. Despite the demonstrated efficacy of filgrastim in primary prophylaxis, its value may be further increased by appropriately selecting patients and better understanding the importance of sustaining dose intensity in specific malignancies. Clinical prediction models capable of identifying individuals at high risk for neutropenic complications yield further reductions in FN risk thresholds and treatment costs in patients receiving cancer chemotherapy. These models also may be used to evaluate the cost-effectiveness or cost-efficiency of filgrastim. A clinical prediction model recently was presented and validated incorporating both baseline clinical characteristics as well as the results of the first cycle of chemotherapy in patients with early-stage breast cancer. A cost-effectiveness ratio of $34,297/year of life saved was estimated based on dose-response assumptions derived from a previously reported adjuvant breast cancer trial studying the impact of dose reduction on disease-free survival. The cost-effectiveness of filgrastim was evident over a wide range of clinical and cost assumptions. Clinical prediction models permit the rational and cost-effective identification of patients for filgrastim support. Existing clinical practice guidelines should be reevaluated in light of new information available on both the total costs associated with FN as well as the cost-effectiveness of these agents in patients receiving chemotherapy for sensitive and potentially curable malignancies.

Neutropenia is a common and often dose-limiting toxicity associated with chemotherapy One way to decrease the severity of this adverse event is to use colony-stimulating factors (CSFs) after chemotherapy. Colony-stimulating factors are relatively expensive agents, and most institutions limit their use. Unfortunately, it is difficult to predict which patients are likely to develop neutropenia. An improved ability to predict this situation might help institutions and clinicians determine which patients need CSFs as adjunctive therapy. The efficacy of CSFs and how they may affect patient outcomes are discussed. In addition, a primary literature review on the toxicity associated with chemotherapy regimens used for common cancers is summarized. Knowing the toxicity of individual regimens may help clinicians identify patients needing adjunctive therapy or less toxic regimens. Any action that helps reduce the occurrence, or severity, of neutropenia in patients receiving chemotherapy would be beneficial and enhance the patient's quality of life.

To determine the role of growth factors in nonchemotherapy drug-induced agranulocytosis, we reviewed 118 published reports of administration of colony-stimulating factors for the disorder. Main outcomes were total duration of neutropenia and mortality. The mean time to neutrophil recovery was 4.6 +/- 3.2 days and 7.7 +/- 5.1 days in patients with a granulocyte count at diagnosis of 0.1-0.5 x 10(3)/mm3 and less than 0.1 x 103/mm3, respectively. The mortality rate was 4.2%. Without therapy with growth factors, the mean time to neutrophil recovery after discontinuation of the offending agent was reported to be 10 +/- 8 days. The mortality rate was 16% in one study. We conclude that hematopoietic growth factors may shorten the duration of neutropenia and reduce mortality in patients with severe drug-induced agranulocytosis.

Recombinant human colony-stimulating factors (CSFs) have potential for wide use in the areas of oncology and infectious disease. Granulocyte CSF and granulocyte-macrophage CSF currently are approved for use in the treatment of neutropenia associated with standard-dose cancer chemotherapy and bone marrow transplantation, respectively. Other settings in which these agents have shown promise are dose-intensive chemotherapy, enhancement of progenitor cell support, primary and acquired neutropenias, myelodysplasia, aplastic anemia, and cytopenias associated with human immunodeficiency virus infection or myelosuppressive therapies for such infection or related conditions. Clinical findings in these areas are encouraging, and potential exists for additional applications of the CSFs.

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) generally are rapidly eliminated from the blood after intermittent intravenous infusion. Subcutaneous administration of these agents results in lower peak concentrations but is associated with prolonged systemic exposure. Elimination of the factors appears to occur by several mechanisms, including white blood cell receptor-mediated endocytosis, metabolism by proteases, and urinary excretion by glomerular filtration with subsequent reabsorption and catabolism. The pattern and route of elimination are affected by type of factor and dosage, degree of glycosylation, renal function, and number of white blood cell receptors for the particular CSF. Granulocyte CSF and GM-CSF are approved for use in patients with nonmyeloid malignancy who are receiving myelosuppressive chemotherapy, and those undergoing high-dose chemotherapy and bone marrow transplantation, respectively. In these indications, treatment generally is initiated no earlier than 24 hours after chemotherapy and continued beyond the expected chemotherapy-associated neutrophil count nadir. Limited information suggests that subcutaneous administration is more effective than intermittent intravenous infusion. The latter may require the addition of albumin to ensure stability. Storage and handling guidelines include preventing exposure to extreme temperatures and avoiding excessive agitation of the solution.

A 65-year-old woman with refractory anemia with excess of blasts received sequential courses of granulocyte-macrophage colony-stimulating factor therapy (GM-CSF) and low-dose cytosine arabinoside. Each course of GM-CSF induced a rapid and tremendous increase in leukocyte count as well as in spleen size, 111indium chloride scanning suggested a myeloid metaplasia of the spleen. This observation suggests that in some patients the granulopoietic response to the myeloid growth factor stimulation may be predominant in the spleen.

In an attempt to stimulate granulopoiesis, we administered recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) to 11 patients with lymphoproliferative disorders. Ten patients had neutropenia, six of whom had severe neutropenia (less than 500 neutrophils), including two with agranulocytosis. GM-CSF (60-250 micrograms/m2/day) was administered by continuous intravenous infusion daily for 14 days at 2-week intervals. Significant increases in white blood cell counts (1.3-to 11.7-fold) and neutrophils (1.7- to more than 29-fold) were seen in 10 of 11 patients, including one patient with agranulocytosis. Eosinophils (3.9- to greater than 65-fold) and monocytes (1.3- to 5-fold) increased as well. In contrast, no significant increases were seen in total lymphocytes or in different phenotypic subsets of lymphocytes during treatment. The overall proportion of myeloid and lymphoid elements in bone marrow remained stable. These results indicate that GM-CSF is effective in stimulating myelopoiesis in neutropenic states associated with lymphoproliferative disorders. Further studies will be necessary to determine whether the correction of neutropenia ultimately translates into clinical benefit.

Haemopoietic progenitor cell levels were determined in the blood and marrow of 37 patients with advanced malignancies undergoing a phase I/II clinical trial of 0.3-30 micrograms/kg/d recombinant human granulocyte-macrophage colony stimulating factor (rGM-CSF). After injection of rGM-CSF, the absolute number of circulating progenitor cells fell initially but after 4 d of infusion a dose-dependent increase was observed in progenitor cells of all lineages with a slight bias favouring granulocyte-macrophage progenitors. A mean 8.4-fold increase in GM-CFC and a 3.3-fold increase in BFU-E were observed at a dose level of 20 micrograms/kg/d of rGM-CSF. Patients with malignant lymphoma showed a greater response than other patients at the same dose level and the CFU-E rise correlated with the haematocrit. This study suggests that GM-CSF may be of value in elevating circulating progenitor cells for subsequent autografting.

We examined the rate and quantity of superoxide anion (O2-) generation by granulocytes harvested from the blood of patients before and after a 12-24 h constant intravenous infusion with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSFrh). Seven previously untreated patients with sarcomas who exhibited no bone marrow involvement by their disease were studied. Granulocytes were harvested from the peripheral blood of each patient before and after intravenous infusion with GM-CSFrh. The total quantity of O2- produced and the kinetics of its release were then determined following in vitro activation of the cells by the chemotactic peptide N-formyl methionyl-leucylphenylalanine (fMLP) or by phorbol myristate acetate (PMA). In all cases, the amount of O2- generated and the rate of its release were significantly increased after GM-CSFrh infusion. Our findings indicate that intravenous administration of GM-CSFrh to patients heightens the functional responsiveness of circulating granulocytes.