Abeloff's Clinical Oncology, 4th Edition
Part II – Problems Common to Cancer and its Therapy
Section B – Hematologic Problems
Chapter 45 – Disorders of Blood Cell Production in Clinical Oncology
Chapter 45 – Disorders of Blood Cell Production in Clinical Oncology
SUMMARY OF KEY POINTS
Disorders of blood cell production, usually manifest as anemia, leucopenia, or thrombocytopenia, are both very common and enormously important in the clinical practice of oncology. Under ordinary conditions in the healthy adult, blood cell production is extraordinarily prolific, with daily outputs in the range of 2×1011 erythrocytes, 5×1010 neutrophils, and 2.5×1011 platelets, as well as substantial numbers of lymphocytes, macrophages, antigen-processing cells, eosinophils, and basophils. With more than 5 million blood cells produced every second under ordinary conditions, the mitotic yield of normal bone marrow is greater than that of almost any malignancy, where the production of a similar number of new cells would result in a daily increase of tumor cell burden of more than 0.25 kg per day. It is not surprising therefore that among the most common unintended consequences of cancer treatments with antimitotic mechanisms of action are clinically important degrees of anemia, neutropenia, or thrombocytopenia.
The rate of blood cell production is both tightly regulated and highly variable. Under conditions of either increased destruction of cells, such as bleeding, hemolysis, or immune destruction of platelets, or demand for increased numbers of cells, such as infection, production rates of appropriate cells increase several fold. The regulation of this dynamic system is complex but for practical purposes can be conceived of as involving an interaction between a pool of pluripotent hematopoietic stem cells, capable of both infinite self-renewal and differentiation into mature blood cells and regulatory factors, including both a well-characterized set of glycoprotein hematopoietic growth factors and a less well-understood group of inhibitory factors. Cancer and its treatment are very often associated with profound perturbations in this system controlling blood cell production. Understanding this biology is key to rational intervention and optimal care of the oncology patient.
DISORDERS OF RED CELLS
Anemia is common in cancer patients   and is often multifactorial, with frequent contributors including: bleeding, general malnu-trition, iron, folate or vitamin B12 deficiency, hemolysis, myelosuppressive chemotherapy, radiation to marrow-bearing bones, and the anemia of chronic illness. In addition to these factors, for B-cell malignancies and solid tumors extensively involving the marrow, disruption of the normal interactions of hematopoietic progenitor cells and endothelial and connective tissue stromal cells in the marrow microenvironment may play an important role. For patients with secretory multiple myeloma, renal insufficiency is a frequent and often unrecognized factor in the anemia. Finally, for patients with myelodysplasia and myeloid malignancies, the hematopoietic stem cells themselves are reduced in number and/or dysfunctional.
It has been recognized for some time that, in patients with chronic inflammatory illnesses including cancer, a diminished endogenous erythropoietin (EPO) response to anemia is frequently observed.More recently, it has been shown that inflammation is frequently associated with increased production of the iron-regulatory peptide, hepcidin, by the liver.     Hepcidin binds to and inactivates the iron transporter, ferroportin, impairing both absorption of dietary iron and access to storage iron pools.   These discoveries strongly suggest that iron-restricted erythropoiesis may occur despite the presence of what are believed to be adequate iron stores and be more common in patients with cancer than has been previously suspected. Our current understanding of the biology of anemia in cancer patients is shown in Figure 45-1 .
Figure 45-1 The pathophysiology of the anemia frequently observed in cancer patients. Type I acute-phase cytokines decrease the endogenous EPO response to anemia and suppress the effects of EPO on the marrow. Type II acute-phase cytokines induce hepcidin production in the liver, which decreases iron availability to erythropoiesis through decreased gastrointestinal absorption and accessibility of storage iron in reticuloendothelial cells. Other common factors include marrow suppression through disruption of the normal microenvironment, the myelosuppressive effects of chemotherapy, and nutritional deficiencies other than iron. Renal insufficiency is particularly common in patients with multiple myeloma and patients treated with cisplatin chemotherapy. eEPO, endogenous erythropoietin; IFN-γ, interferon γ IL1-β, interleukin-1β IL-6, interleukin-6; TNF-α, tumor necrosis factor a.
It is surprising how frequently the anemia observed in cancer patients is due, at least in part, to reversible factors, such as iron loss through bleeding or previously unsuspected vitamin B12 deficiency. In one recent study, 5% of cancer chemotherapy patients being considered for inclusion in an erythropoiesis-stimulating protein (ESP) clinical trial were found on screening evaluation to have serum vitamin B12concentrations below normal. Historically, the only available treatments for the remaining patients with cancer and anemia were red cell transfusions and successful treatment of the underlying malignancy. Because of the well-known risks associated with transfusions and the need to conserve a limited blood supply, specific anemia treatment was limited to those patients with profound degrees of anemia (hemoglobin [Hb] levels 8 g/dL or lower) or severe cardiovascular symptoms, such as chest pain or dypsnea at rest.
The key regulator of red cell production is the glycoprotein hormone EPO. The cloning, development and introduction into clinical use of recombinant human EPO represented a watershed in anemia management. Two preparations of recombinant ESPs are currently available in the United States, epoetin alfa and the hyperglycosylated recombinant EPO, darbepoetin alfa, which has a longer half-life. In randomized, placebo-controlled trials, both epoetin alfa      and darbepoetin alfa   have been shown to reduce red cell transfusion rates in patients with cancer receiving chemotherapy, and both agents are approved by the U.S. Food and Drug Administration (FDA) for this indication.
It had long been known that even mild and moderate degrees of anemia can impair function and limit productivity in otherwise healthy adults. When ESPs became available and were applied to the treatment of patients with renal failure, it was shown that quality of life and productivity improved when Hb levels increased and that this relationship continued to hold even at Hb levels well above the traditional transfusion threshold.     Comparisons of data gathered during ESP treatment of anemic dialysis patients to those from anemic cancer patients suggested that the impacts of anemia and the benefits of treatment in terms of improved quality of life and energy level were quite similar in the two settings. Analyses of the relationship between Hb level and energy, activity, and overall quality of life observed in large, uncontrolled series of cancer patients during treatment for anemia with epoetin alfa suggested that larger incremental increases in these patient-reported outcomes were observed with Hb increases from 11 to 12 g/dL than with any other 1-g increase. Two large surveys had demonstrated that fatigue is common and often the dominant symptom in cancer patients in the United States, limiting function and quality of life.   When analysis of data from randomized trials confirmed that ESP therapy for anemia is associated with improvements in fatigue in cancer patients,                  a second goal of ESP therapy beyond transfusion prevention emerged: maintenance of functionality and relief of fatigue. Although no ESP is currently approved by the FDA for relief of fatigue in anemic cancer patients, in clinical practice these agents are used with both goals in mind.
Both ESPs are currently used for the treatment of anemia in patients with cancer receiving chemotherapy, and randomized trials to date have failed to demonstrate that either agent is superior in terms of transfusion prevention or fatigue reduction when used at starting doses of epoetin alfa of 40,000U/week and darbepoetin alfa of 200 mg every 2 weeks.   Recently, it has been shown that darbepoetin alfa is effective for the treatment of chemotherapy-associated anemia when given every 3 weeks at doses of either 300 mg or 500 mg; every-3-week dosing on the same day as chemotherapy seems to be as effective as asynchronous dosing. Studies using initial weekly dosing followed by every-3-weekly epoetin alfa at a dose of 120,000U have demonstrated that it is also feasible to administer this agent every 3 weeks for at least a portion of the treatment period; trials exploring less frequent dosing of this agent throughout the treatment period are in progress. There is little evidence that higher doses of either ESP results in improved outcomes for cancer patients, and although it is common practice to increase doses in hyporesponsive patients, this practice has never been studied and its benefit, if any, is unknown.
It is important to bear in mind that weeks are usually required before ESP therapy increases Hb levels, and there is still a role for red cell transfusion for acute intervention in severe anemia and ominous symptoms such as chest pain and dypsnea at rest. The relatively slow onset of ESP effects has important implications for the optimal utilization of ESPs in the management of chemotherapy-induced anemia. Theoretically, when intervention with an ESP is withheld until the Hb level is less than 10 g/dL, some responsive patients will require transfusions for acute management of severe anemia before they respond to treatment. Several trials have now prospectively addressed the issue of early versus late intervention, and taken in aggregate the results strongly suggest that later intervention is associated with a substantial increase in transfusion risk. Moreover, later intervention will probably result in more fatigue for cancer patients. Both of the recently developed guidelines by the National Comprehensive Cancer Network and the European Organization for Research and Treatment of Cancer (EORTC) support the initiation of treatment when Hb levels fall to 11 g/dL, especially when symptoms such as fatigue are manifest and continued chemotherapy is contemplated.
Once ESP treatment is initiated, it should be continued, with doses adjusted to maintain a Hb level of approximately 12 g/dL. The safety of targeting higher Hb levels has not been demonstrated (see later discussion). This titrated treatment should be continued until the chemotherapy is completed and Hb levels remain in the target range without ESP support.
Problems of Iron
When therapy with recombinant EPO is given to patients with the anemia of renal failure, an increase in platelet count is observed in some patients. Although this was initially believed to reflect an effect of EPO on megakaryocyte growth and development, it has been shown to be due to inadequacy of iron supply to the marrow. When patients are treated with ESPs, evidence of iron-restricted erythropoiesis can develop, even in the presence of apparently adequate body iron stores. This phenomenon, thought to be due to an inability to mobilize storage iron rapidly enough to support the accelerated erythropoiesis associated with ESP treatment, has been termed functional iron deficiency to distinguish it from the more familiar absolute iron deficiency reflective of diminished total body iron stores. The limited quantity of oral iron that can be absorbed on a daily basis, coupled with the poor gastrointestinal tolerance of and consequently patient compliance with oral iron makes parenteral iron an attractive option for reversing functional or absolute iron deficiency during ESP therapy. For patients receiving ESPs for the anemia of chronic renal failure, treatment with parenteral iron has become a frequent adjunct that appears to enhance response and/or decrease the ESP dose required. Although earlier preparations of iron dextran were associated with infrequent but potentially life-threatening anaphylactic reactions, the newer low-molecular-weight dextran preparations and the iron salts ferric gluconate and ferric sucrate are relatively safe.    A summary of the available parenteral iron preparations and practical aspects of their administration is contained in Table 45-1 .
Table 45-1 -- Summary of Available Parenteral Iron Preparations
Anaphylactic reactions have been reported, and an intravenous test dose of 0.5 mL infused over ≥30 sec is recommended before the first dose. Intravenous doses containing ≤100 mg elemental iron (2 mL) can be given at a rate of ≤50 mg (1 mL) per minute as frequently as daily. Infusion of the total dose (TDI) calculated as
Similar to low-molecular-weight dextran, although reported rates of adverse drug reaction are greater   and the use of this preparation with ESP therapy in cancer patients cannot be supported.
Ferric gluconate complex
A test dose is not required. TDI is not feasible because of a high frequency of adverse events when doses of >10 mL (125 mg iron) are given in a single session. Doses of up to 125 mg can be diluted in 100 mL of normal saline and infused intravenously over 1 hour, or the solution can be pushed undiluted at a rate of 1 mL (12.5 mg) per minute.
A test dose is not required. TDI is not feasible, although doses of up to 400 mg can be administered by slow infusion over 3 hours. Doses of 100–200 mg can be given by slow intravenous push over 5 min. Alternatively, 100 mg can be diluted in 100 mL of normal saline and infused intravenously over 15 min or more.
ESP, erythropoiesis-stimulating protein.
Auerbach M, Witt D, Toler W, et al: Clinical use of the total dose intravenous infusion of iron dextran. J Lab Clin Med 1988;111:566–570; and Auerbach M, Winchester J, Wahab A, et al: A randomized trial of three iron dextran infusion methods for anemia in EPO-treated dialysis patients. Am J Kidney Dis 1998;31:81–86.
Auerbach M, Chaudhry M, Goldman H, Ballard H: Value of methylprednisolone in prevention of the arthralgia-myalgia syndrome associated with the total dose infusion of iron dextran: a double blind randomized trial. J Lab Clin Med 1998;131:257–260.
As noted previously, chronic illness such as cancer is associated with diminished absorption of oral iron and decreased accessibility of body iron stores (see Fig. 45-1 ) When patients with this anemia of chronic illness receive ESP therapy, it would be expected that the increased iron demand of the erythron would frequently result in functional iron deficiency. It is therefore surprising how few studies are available addressing the potential of parenteral iron to improve the response to ESPs in anemic cancer patients. In one randomized trial, iron dextran, given either as a weekly fixed dose containing 100 mg of elemental iron or as a single total dose infusion, was associated with a significantly better response to epoetin alfa than that observed with either oral iron or no iron support. Similar results have been reported in trials using ferric gluconate and darbepoetin alfa. These data strongly suggest that parenteral iron will play a substantially greater role in the future in the management of anemia in cancer patients.  
The most formidable challenge to rational iron support during ESP treatment of the cancer patient is the reliable detection of iron-restricted erythropoiesis in this patient population. The anemia of chronic illness is associated with reductions in serum iron and iron-binding capacity and with increases in serum ferritin levels, rendering transferrin saturation and ferritin determinations less reliable indicators of adequate iron delivery to the marrow or of body iron stores. Serum levels of soluble transferrin receptors are normal in patients with the anemia of chronic disease and increased in patients with iron deficiency anemia and therefore might be useful in distinguishing the two conditions; however, this laboratory parameter is not yet widely available. Moreover, soluble transferrin receptor levels are increased by ESP treatment and fluctuate during the chemotherapy cycle, making their future usefulness for monitoring iron supply to the marrow in anemic cancer chemotherapy patients during ESP therapy less promising. Similar limitations may apply to the use of the transferrin receptor-to-ferritin ratio.    Two parameters that can be reliably determined using flow cytometric techniques available in some hemogram autoanalyzers include the percentage of hypochromic red cells    and the reticulocyte hemoglobin content.       The relationship of these parameters to iron delivery to the marrow is not affected by the inflammatory milieu of chronic illness, ESP therapy, or chemotherapy, and both have been shown to be useful in guiding iron therapy in patients with renal failure receiving ESP therapy. When the proportion of red cells with a Hb concentration of less than 28 g/dL exceeds 5%, it can be concluded that there has been significant iron restriction of erythropoiesis over the preceding 2 weeks. Although the usefulness of the test is limited in the presence of macrocytosis, when the reticulocyte Hb content is less than 29pg, iron-restricted erythropoiesis has occurred during the preceding 2 days. Until these two tests are more widely available and validated for monitoring iron supply during ESP therapy for chemotherapy-associated anemia, it is prudent to consider parenteral iron therapy whenever the transferrin saturation is less than 25% to 30% or when the response to ESP therapy is inadequate. If the percentage of hypochromic red cells or reticulocyte Hb content is available, these values can be integrated into the evaluation. An algorithm for the management of anemia during cancer chemotherapy is shown in Figure 45-2 .
Figure 45-2 An approach to the treatment of anemia in cancer patients. CHr, reticulocyte hemoglobin content; ESP, erythropoiesis-stimulating protein; Fe, serum iron; %HYPO, percentage of hypochromic red blood cells; TDI, total dose infusion; TIBC, total iron-binding capacity; TSAT, transferrin saturation (Fe/TIBC).
Safety of Erythropoiesis-Stimulating Proteins in Oncology
Erythropoietic agents are generally well tolerated, although there are three issues regarding their safety that merit consideration on the part of the oncologist. First, shortly after the introduction of a new formulation of epoetin alfa in Europe and Canada, an increase in pure red cell aplasia was noted in chronic renal failure patients receiving ESP therapy. This complication was found to be caused by autoantibodies to EPO apparently developed in response to a subtle alteration in tertiary structure of the recombinant molecule and cross-reactive with endogenous EPO. With changes in the storage and handling of recombinant EPO, the incidence of red cell aplasia has diminished, and it did not occur in patients with cancer receiving ESP therapy, possibly as a result of either the short duration of treatment in this setting or the immunosuppressive effects of chemotherapy. However, this episode has implications for the development of generic EPO preparations and serves to emphasize the importance of correct and careful storage and handling of these agents.
Recent metaanalysis of randomized, placebo-controlled trials of ESPs administered to patients with cancer during chemotherapy has demonstrated an increase in the incidence of thrombotic events in patients receiving these agents.   The overall relative risk of thrombosis associated with ESPs is 1.5 to 1.9, but it appears that, rather than the incremental risk being spread evenly over all patient groups, it is greater in patients with gynecologic malignancies and those receiving combined radiotherapy and chemotherapy treatment regimens.   The mechanism by which ESP therapy affects thrombosis risk is unknown; significant correlations of thrombotic events with Hb level, rate of Hb rise, or ESP dose have not been observed with sufficient consistency to permit a conclusion that the increased risk is due, in whole or in part, to altered blood rheology. The increase in diastolic blood pressure that can occur with the initiation of ESP treatment suggests the possibility of a direct effect on vasculature, and there is some biochemical evidence of endothelial cell and platelet activation during ESP treatment in humans. There is in vitro evidence that ESPs may synergize with endogenous thrombopoietin in inducing platelet activation and that platelets may be activated through interaction with young red blood cells. Further studies are needed, both to elucidate the mechanism(s) of ESP-induced thrombosis and to establish rational approaches to prediction and prevention.
Recently, in two randomized trials of recombinant EPO used to prevent, rather than to treat, anemia in patients with breast cancer receiving chemotherapy or with head and neck cancer undergoing radiation therapy, an increase in the rate of tumor progression has been observed in the EPO-treated patients. Although there were methodologic issues in both trials, the results must be taken seriously until additional, better powered tumor progression and survival studies currently underway are completed and the final results are available. Meta-analyses of randomized, controlled trials of ESP treatment during cancer chemotherapy have not shown an increase in tumor progression or a decrease in overall survival in anemic patients treated with ESPs.     For the present, there is no evidence of decreased survival or enhanced tumor progression when anemic cancer patients receive ESPs. Until there is a much better understanding of the safety of erythropoietic agents used to prevent anemia or to normalize Hb levels in these patients, these practices cannot be condoned and a target Hb level of 12 g/dL is prudent in clinical practice.
It is important to bear in mind that anemia is associated with cellular hypoxia, especially in tumor cells,        and that tumor cell hypoxia has been associated with both enhanced mutation rates and selection of more apoptosis-resistant or invasive phenotypes                   and with resistance to both radiation        and chemotherapy.    Anemia is an independent negative prognostic factor across a wide range of malignancies; although this is an association rather than a demonstrated cause-and-effect relationship, the observation does serve to underscore the potential importance of rational anemia management to optimal cancer care and outcomes. One critical issue that remains to be addressed is the “optimal” Hb level for cancer patients. The vasculature of solid tumors is more tortuous and disorganized than that in normal tissues; just as tumor cell oxygenation drops off more rapidly as Hb levels fall below 12 g/dL,    there is some evidence that oxygenation may decline again as Hb levels rise above 13 g/dL, because of the altered rheology of blood in tumor vessels.     If tumor cell hypoxia is an important driver of tumor progression and resistance to treatment, it may be deleterious to patients to allow Hb levels to fall below 11 to 12 g/dL or to increase them to levels much greater than 13 g/dL. This hypothesis will be very difficult to test in clinical trials, but the answer is obviously essential to rational oncology care aimed at optimizing outcomes.
Several recent publications have reported on the detection of EPO receptor (EPO-R) protein in human cancer cells.     These studies have used immunohistochemistry with polyclonal rabbit antisera. Recent work has demonstrated that these antisera reagents also bind tumor-associated proteins other than EPO-R and are therefore not specific. The issue of the potential of ESPs to directly induce proliferation or apoptosis resistance in human cancers is obviously a very important one and merits more attention in future work rigorously addressing both the specificity of techniques used in EPO-R detection and the functionality of any true EPO-R found. Thus far, in vitro work with human cancer cell lines and in vivo studies using human tumor xenografts have not consistently demonstrated any effect of ESPs on cancer cell proliferation or tumor progression.  
Paraneoplastic polycythemia is an uncommon syndrome observed in a variety of human cancers including renal cell carcinoma,   hepatocellular cancers,    Wilms’ tumor  and, rarely, other malignancies.     The mechanism is usually ectopic production of EPO,      although increased EPO levels are not always observed and other mechanisms, such as ectopic renin secretion, have been suggested. In renal cell carcinomas, in which inactivating mutations of the von Hippel-Lindau gene are common, accumulation of hypoxia-inducible factor, the transcription factor driving EPO gene expression, occurs, causing polycythemia. In most cases of paraneoplastic polycythemia, Hb levels are only modestly elevated, presumably as a result of compensatory decreases in EPO production by the normal kidney. Rarely, polycythemia can be severe, with hematocrit levels exceeding 50% and/or the development of symptoms such as fatigue, headache, visual blurring, and dyspnea. In these cases, it is prudent to rule out other causes of polycythemia, including hypoxemia and coexisting myeloproliferative disorders, before treating the patient with phlebotomy or surgical removal of tumor.
DISORDERS OF WHITE CELLS
By far the most common cause of neutropenia in oncology practice is the relatively straightforward myelosuppressive effects of cytotoxic chemotherapy and radiation treatment. Because of their relatively short life spans, neutrophil counts are particularly sensitive to the effects of recently administered chemotherapy, and nadirs of these counts are frequently observed 7 to 10 days following the administration of chemotherapy. Less commonly, antibodies to neutrophils, bone marrow infiltration with disruption of normal marrow stromal function, and splenic sequestration can play a role. Neutropenia is a critically important problem in oncology practice for two reasons. First, neutropenia is the major factor driving the risk of life-threatening infections, one of the most serious and costly toxicities of cancer treatment. Second, neutropenia frequently results in substantial reductions in the delivered dose intensity of chemotherapy, causing even patients with curable malignancies to receive less than the planned, optimal antitumor treatment. For both reasons, good neutropenia management is essential in oncology care.
Although there are several glycoproteins with effects on neutrophil precursor cells including interleukin-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage colony-stimulating factor, granulocyte colony-stimulating factor (G-CSF) seems to be the primary regulator of basal and emergency neutrophil production      as well as mature neutrophil function.     GM-CSF plays a critical role in pulmonary homeostasis,     and a defect in this function seems to be involved in the pathogenesis of pulmonary alveolar proteinosis.    There are also negative regulatory factors of neutrophil production that are less well understood, including neutrophil elastase and the src family kinases. Neutropenia can also result from decreased neutrophil survival associated with immune destruction, sequestration, consumption at sites of infection, and the effects of inflammatory cytokines such as tumor necrosis factor.
PREVENTION OF INFECTION.
There are two effective strategies for the prevention of infection during myelosuppressive chemotherapy: the administration of myeloid growth factors and prophylactic antibiotics. Prophylactic antibiotics have the advantage of being less costly and the disadvantage of selection of resistant bacteria. There are three myeloid growth factor preparations currently in use in clinical practice in the United States: recombinant G-CSF (filgrastim), pegylated recombinant G-CSF (pegfilgrastim), and recombinant GM-CSF (sargramostim). In randomized, controlled clinical trials in patients receiving myelosuppressive chemotherapy for nonmyeloid malignancy, filgrastim, administered as a daily subcutaneous injection at doses of 5 μg/kg, commencing the day following chemotherapy and continued until resolution of the white blood cell nadir (usually 10–12 days of treatment), has been consistently associated with a reduction in the duration of neutropenia and in the incidence of febrile neutropenia across all cycles of chemotherapy.     The results with sargramostim, usually administered at a daily subcutaneous dose of 250 μg/kg, have been less consistent, with some trials suggesting reduction in febrile neutropenia across all planned cycles,   others not demonstrating an impact on febrile neutropenia,    and some demonstrating an effect on febrile neutropenia only during the first chemotherapy cycle.   There are some studies suggesting that the myeloid growth factor can be started later during the chemotherapy cycle or given on less than a daily basis to conserve resources.  However, in the best-powered randomized trial that has been carried out addressing the issue of late initiation of myeloid growth factor treatment, initiating filgrastim treatment once neutropenia was established was not effective in reducing infection risk. There are data suggesting that a daily G-CSF dose of 2 μg/kg may be as effective as 5 μg/kg in shortening the duration of neutropenia following standard dose chemotherapy.
Pegfilgrastim has a longer half life than filgrastim, particularly following the administration of chemotherapy. Because pegfilgrastim is cleared by neutrophils and their precursors, its half-life is prolonged by chemotherapy, and in this setting the drug is “self-regulating” with levels persisting through the postchemotherapy nadir and until the neutrophil count begins to recover. In randomized, placebo-controlled trials in patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy, pegfilgrastim given as a once-per-cycle subcutaneous dose on the day following the completion of chemotherapy was at least as effective as daily filgrastim in shortening the duration of neutropenia and reducing the incidence of febrile neutropenia.    In these comparative trials, pegfilgrastim was not associated with more toxicity, and specifically bone pain was not reported more frequently with pegfilgrastim. In a randomized, placebo-controlled trial involving patients with metastatic breast cancer, pegfilgrastim was associated with a reduction in the risk of febrile neutropenia. In prior studies of myeloid growth factors, the incidence of febrile neutropenia in the control group had been relatively high, at approximately 40% or greater, and myeloid growth factor treatment was associated with a 50% reduction in this risk. In the placebo-controlled trial of pegfilgrastim, the incidence of febrile neutropenia in the control group was approximately 20%, and pegfilgrastim treatment was associated with a 95% reduction in risk. This demonstration of efficacy of myeloid growth factor therapy at lower risks of febrile neutropenia has resulted in a change in practice guidelines, acknowledging the potential of myeloid growth factors to reduce lower risks of infection.   The issue of the cost effectiveness of myeloid growth factors used to prevent febrile neutropenia remains controversial.      Largely because of its increased convenience for patients, pegfilgrastim has become the most frequently used myeloid growth factor for the reduction of infection risk during chemotherapy. The increasing popularity of every-2-week chemotherapy regimens for the treatment of early breast cancer and lymphoma made it necessary to document the safety and efficacy of pegfilgrastim with every-2-week chemotherapy. Pegfilgrastim seems to be both safe and effective when used in this setting. When chemotherapy and myeloid growth factors are administered on the same day, it is possible that myeloid progenitors will be recruited into the cell cycle while cytotoxic chemotherapy is still in their environment, with myeloid growth factors having the paradoxic effect of increasing myelosuppression. Because it would be more convenient for patients, there has been an interest in exploring the administration of pegfilgrastim and chemotherapy on the same day. At the time of this writing, the preliminary results of studies of synchronous pegfilgrastim and chemotherapy are conflicting, and the safety and efficacy of this approach has not been documented. In practice, it remains prudent to administer pegfilgrastim the day following the completion of chemotherapy.
In approaching the decision to administer myeloid growth factors during chemotherapy, it is appropriate for the clinician to assess the patient's risk factors for infection, including the chemotherapy regimen being used, the patient's functional status and comorbidities, age, and the presence of open wounds.   If the risk of serious infection with the planned chemotherapy is unacceptably high, it is appropriate to use a myeloid growth factor. If the chemotherapy is being given every 2 weeks or less frequently, pegfilgrastim at a fixed dose of 6 mg administered on the day following the completion of chemotherapy is appropriate management.
Myeloid growth factor therapy is associated with both an increase in neutrophil numbers and enhanced function of mature neutrophils. In animal models of sepsis, the addition of G-CSF to antibiotic treatment results in improved outcomes as compared with antibiotics alone. It is therefore logical to investigate the combination of antibiotics and myeloid growth factors for the prevention of infection in chemotherapy patients at particularly high risk for infection. In one large randomized trial, the addition of filgrastim to prophylactic antibiotics (ciprofloxacin and roxithromycin) for patients receiving cancer chemotherapy was associated with a reduction in infection risk as compared with antibiotics alone, although the authors raise questions regarding the cost-effectiveness of filgrastim in this setting. The clinician has two options in the managing a cancer chemotherapy patient at risk of infection: prophylactic antibiotics and myeloid growth factors. For patients in whom the risk of infection remains unacceptably high despite prophylactic antibiotics, the addition of myeloid growth factor therapy will further reduce risk.
TREATMENT OF ESTABLISHED NEUTROPENIA OR NEUTROPENIC INFECTION.
As noted previously, the initiation of myeloid growth factors treatment late in the chemotherapy cycle, after neutropenia has already occurred, may shorten the duration of neutropenia but is not associated with a meaningful reduction in infection risk. There have been several randomized trials of myeloid growth factors for the treatment of chemotherapy patients with established febrile neutropenia who have not been receiving prophylactic myeloid growth factor.       Taken in aggregate, these studies document that treatment with either filgrastim or sargramostim probably shortens the duration of severe neutropenia, but for the typical patient with uncomplicated febrile neutropenia this hematologic effect does not translate into significant clinical benefit in terms of reduction in the duration of hospitalization or parenteral antibiotic use. For the exceptional patient who is quite ill and in whom a modest reduction in the duration of neutropenia may be expected to be of benefit, the initiation of myeloid growth factor treatment is prudent. For these patients, either filgrastim at a dose of 5 to 10 μg/kg per day or sargramostim, 250 to 500 μg/m2 per day is a reasonable treatment approach.
USE OF MYELOID GROWTH FACTORS TO MAINTAIN CHEMOTHERAPY DOSE INTENSITY.
When chemotherapy is being given with the intention to cure or significantly prolong life, substantial dose reductions may compromise those therapeutic goals. Studies of charts from community oncology practices suggest that the administered dose intensity of both adjuvant breast cancer chemotherapy and lymphoma treatment are frequently substantially lower than the published and planned regimen, suggesting that chemotherapy dose reductions and delays are common, even when cure is the therapeutic goal. In these and other studies, myeloid growth factor treatment use was highly variable between practitioners, and these agents were usually not used to maintain dose intensity. Myeloid growth factors can be used to enhance the delivered dose intensity and support the administration of full chemotherapy doses on time in these settings.     In clinical practice, when there is good evidence that a given chemotherapy regimen administered in full, planned doses given on time produces an improvement in cure rate or survival, it is prudent to use myeloid growth factors rather than dose delays or reductions to manage bone marrow tolerance and infection risk.
Leukocytosis occurs in oncology practice as a result of myeloid growth factor treatment, as a result of marrow involvement with tumor with a leukoerythroblastic pattern in the peripheral blood smear, or, rarely, as a paraneoplastic syndrome. In patients with squamous cell carcinomas, a paraneoplastic leukocytosis with hypercalcemia with or without cachexia and thrombocytosis can occur       The pathophysiology of this syndrome seems to be production of parathyroid hormone-like peptides coupled with G-CSF.     Isolated production of G-CSF can occur in any tumor and produce a neutrophilic leukocytosis   ; in fact, this factor was initially discovered and isolated from the conditioned medium of a human bladder cancer cell line. In general, paraneoplastic leukocytosis does not require specific therapy; knowledge of its existence is primarily important in aiding the clinician in differential diagnosis.
DISORDERS OF PLATELETS
The primary regulator of the platelet count in humans is thrombopoietin,   a glycoprotein that is produced primarily in the liver and cleared primarily by platelets and their precursors. Thrombopoietin induces growth and development of megakaryocytes; levels fluctuate with changes in platelet count due to variations in clearance. Interleukin-11 induces a modest increase in platelet counts but is not required for thrombopoiesis     ; its primary constitutive role seems to be the maintenance of female fertility.   Thrombocytopenia that is encountered in oncology practice may be due to the effects of chemotherapy, particularly with agents such as bortezomib, gemcitabine, or ifosfamide, or after multiple cycles of treatment, liver disease with decreased thrombopoietin levels, immune destruction, particularly in patients with lymphoid malignancies or infection with the human immunodeficiency virus, and sequestration. Occasionally, patients with underlying collagen vascular diseases present with thrombocytopenia due to autoantibodies directed against the thrombopoietin receptor.  
The mainstay of management has been the use of platelet transfusion to treat severe thrombocytopenia and/or bleeding patients, and treatment of the underlying cause. Recombinant interleukin-11, oprelvekin, has been shown to accelerate platelet recovery following chemotherapy and to reduce platelet transfusion burden in transfusion-dependent chemotherapy patients.     Oprelvekin is approved by the FDA for this indication. However, toxicities of this agent are substantial and include: fluid shifts, cardiac arrhythmias, optic neuropathy, and the potential for anaphylaxis; these toxicities have limited the usefulness of this drug in oncology practice. Oprelvekin is administered at a dose of 50 μg/kg per day, as a daily subcutaneous injection, commencing the day following chemotherapy and continuing until the nadir has past and the platelet count has returned to 50,000 cells/μL; the drug should be stopped 2 days before the next chemotherapy dose is given. For patients with significant renal impairment, the daily dose is reduced to 25 μg/kg/day.
The cloning of human thrombopoietin was met with hope that this would represent a safer platelet growth factor for clinical practice. Both a full-length clone (rTPO) and a truncated, pegylated preparation, megakaryocyte growth and differentiation factor (MGDF)    were introduced into clinical trials. Therapy with either rTPO     or MGDF     was associated with an increase in platelet counts and a reduction in the duration of postchemotherapy thrombocytopenia, without fluid shifts or arrhythmias. Unfortunately, some patients treated with MGDF developed antibodies to thrombopoietin, resulting in sustained thrombocytopenia, and the development of this molecule was discontinued in the United States. For reasons that are less clear, the development of rTPO has not been completed and therefore neither agent is available for prescription in this country. However, the potential of a thrombopoietin receptor agonist to provide oncologists with a rational, safe, and effective platelet growth factor was demonstrated.
Recently, two promising thrombopoietin receptor agonists have been introduced into clinical trials. AMG 531 is a peptibody that has no sequence homology with human thrombopoietin.    Eltrombopag is an orally bioavailable member of a new class of small molecule thrombopoietin receptor agonists. Neither agent would be expected to induce antibodies to thrombopoietin, and the initial results with both drugs suggest that they will be both safe and effective in increasing platelet counts.
It has been shown that immune thrombocytopenic purpura is associated with a relative thrombopoietin deficiency,         presumably because of increased clearance of this factor by the expanded platelet precursor pool.   It would therefore be expected that therapy with a thrombopoietin receptor agonist would increase platelet counts in immune thrombocytopenic purpura, and treatment with MGDF has been shown to do so. Both AMG 531 and eltrombopag have shown promising results in the treatment of immune thrombocytopenic purpura.   They are also being developed for the treatment of thrombocytopenia associated with liver disease, chemotherapy, and myelodysplasia. An approach to the thrombocytopenic patient in oncology practice is shown inFigure 45-3 .
Figure 45-3 An approach to the evaluation and treatment of thrombocytopenia in the cancer patient. B12, vitamin B12; CBC, complete blood count; ITP, idiopathic thrombocytopenic purpura; MDS, myelodysplastic syndrome.
When thrombocytosis is encountered in oncology practice, it is most often due to functional or absolute iron deficiency, infection or inflammation, or hyposplenism. As noted previously, thrombocytosis can occur in conjunction with leukocytosis and hypercalcemia, as a paraneoplastic syndrome, usually occurring in patients with a squamous cell malignancy. Rarely, it can occur as an isolated paraneoplastic syndrome, or as a coexisting myeloproliferative disorder such as essential thrombocytosis or polycythemia vera. In most instances the thrombocytosis does not require specific intervention. Platelet counts exceeding 800 to 1,000 cells/mL warrant a workup for a myeloproliferative syndrome, and if one is present, consideration should be given to antiplatelet therapy.
ACQUIRED MARROW FAILURE STATES
This syndrome is quite common in oncology practice, and usually presents as a clinically significant cytopenia. The reader is referred to Chapter 105 for a complete discussion of this topic. It is important to consider in the differential diagnosis of anemia, thrombocytopenia, or leukopenia, especially in patients who are elderly or have been treated in the past with cytotoxic chemotherapy. For the anemia that occurs in these patients, both recombinant EPO           and darbepoetin alfa     have been shown to increase Hb levels or reduce transfusion requirements in 30% to 60% of patients with low or intermediate-1 stage disease. There is some evidence that coadministration of a myeloid growth factor may enhance the erythropoietic response,         although the cost-effectiveness of this approach has been questioned. It is reasonable to treat a patient with either transfusion-dependent or symptomatic anemia, who has an IPSS low or intermediate-1 stage MDS with and ESP alone or an ESP with a myeloid growth factor, and to continue this therapy if it is effective in improving clinical status and not associated with increasing thrombocytopenia or the percentage of circulating blasts.
In early clinical trials, myeloid growth factors were shown to increase the neutrophil counts       and improve neutrophil function   in neutropenic patients with MDS. Myeloid growth factors have also been used to support myelosuppressive therapy for MDS.   There is not sufficient data available to support the long-term administration of myeloid growth factors to patients with MDS, except to support the treatment of anemia. Short-term administration of myeloid growth factors to support myelosuppressive therapy or to transiently increase neutrophil counts during an infection is reasonable.
A persistent vexing problem in these patients is transfusion-dependent thrombocytopenia, and it is hoped that one of the new thrombopoietin receptor agonists will be useful and become established in this setting.
Acute Nonlymphocytic Leukemia
Patients with acute nonlymphocytic leukemia (AML) develop prolonged and profound cytopenias during induction and consolidation chemotherapy. The reader is referred to Chapter 105 for a complete discussion of this topic. The mainstay of blood cell support in this setting has been and remains transfusion of red cells and platelets. There was initial concern regarding the safety of administering hematopoietic growth factors in this setting, because of the logical concern that they may stimulate or protect the malignant clone of cells.
The initial studies of a myeloid growth factor in this setting suggested that the treatment was safe and may have promise in shortening the duration of neutropenia, the main driver of morbidity during AML treatment. Subsequent studies shown that treatment with a myeloid growth factor during induction and consolidation treatment does not compromise remission rates and shortens the duration of neutropenia, with some benefit to patients, particularly those from vulnerable populations such as the elderly.    Attempts to utilize myeloid growth factors to recruit AML cells into cycle and enhance their sensitivity to chemotherapy have met with mixed results.   
CONGENITAL MARROW FAILURE STATES
Congenital and Cyclic Neutropenia
The congenital neutropenias are the only congenital marrow disorders for which specific treatment of the cytopenia other than transfusion has established benefit. These are rare disorders, usually diagnosed in childhood, but occasionally mild cases of cyclic neutropenia are identified in young adults. The administration of filgrastim to these patients has been shown to lead to sustained improvements in neutrophil counts and infection risk in some patients with congenital neutropenia and most patients with cyclic neutropenias.    Patients with severe congenital neutropenia frequently require relatively high doses of filgrastim, and long-term treatment could be a financial burden. Fortunately, filgrastim for these patients can currently be obtained through the Chronic Neutropenia Registry (http://depts.washington.edu/registry/). For the subset of these patients with severe congenital neutropenia, with the prolonged survival that filgrastim has supported has come the development of acute leukemia in some patients. Current data suggest that these leukemias are occurring in a clone that is unresponsive to G-CSF, suggesting that they are not caused by the filgrastim treatment but instead are occurring with a higher frequency because of the prolonged survival of patients at risk for evolution to leukemia.     
CELLULAR TREATMENT OF CYTOPENIAS
Until the development of hematopoietic growth factors, the mainstay of treatment for anemia and thrombocytopenia was transfusion, and this was reserved for severe cases. Transfusions are still the preferred treatment for patients in need of a rapid increase in these blood counts. The risks of transfusion include infections (hepatitis viruses, human immunodeficiency virus, malaria, and prion-mediated illness), nonhemolytic allergic reactions, and transfusion-associated graft versus host disease. For red cell transfusions, added risks include acute and delayed hemolytic transfusion reactions and iron overload. For platelets, repeated transfusions can be associated with allo-immunization, limiting the life span and clinical benefit of future platelet transfusions. Limiting the side effects of these transfusions is an important part of oncology practice; key strategies include: (1) Transfuse only when medically necessary (Hb<8 g/dL or severe anemia symptoms, platelets <20,000 cells/mL, or bleeding). (2) Discontinue all chemotherapy that is not associated with a benefit that more than offsets the risk of transfusions. (3) Limit the numbers of blood donors to whom the patient is exposed (use of single-donor platelets for instance). (4) Use white cell filters whenever possible. (5) Use irradiated blood products, especially when transfusing patients who have received bone marrow transplants or transfusing blood from related donors.
When granulocyte transfusions were initially attempted before the development of myeloid growth factors, they were unsuccessful, as a result of the relatively low dose of granulocytes that could be harvested and to the transmission of cytomegalovirus infection to compromised recipients. More recent trials of granulocyte transfusions harvested from filgrastim-treated donors have yielded promising results,   although in the postmarrow transplant setting human lymphocyte antigen incompatibility may limit the benefit. It is reasonable to consider granulocyte transfusions, if the institution has the capability, in the acute management of neutropenic patients who have infection that is not responding to antibiotics and who are not expected to recover granulopoiesis in the near future.
Therapy with myeloid growth factors is associated with the mobilization of progenitor cells into the peripheral blood progenitor cells which can be harvested by leukapheresis. As compared with traditional bone marrow, autologous peripheral blood progenitor cells used to support high-dose chemotherapy are associated with more rapid engraftment.       Use of peripheral blood progenitor cells has made it possible to modify the dose of progenitor cells given and aided attempts to manipulate the graft.     Engraftment following these transplants is sufficiently rapid that the benefit of additional myeloid growth factor given during this recovery phase is relatively small, though safe and probably cost-effective.    The use of peripheral blood progenitor cells as an alternative to marrow is feasible in the allogeneic transplant setting as well.             Finally, myeloid growth factors can be used to mobilize and harvest dendritic cell precursors for cancer vaccine applications.
- Erslev AJ: In: Williams WJ, Beutler E, Erslev AJ, Luchtman MA, ed. Production of Erythrocytes, New York: McGraw-Hill; 1983:365-375.
- Price TH, Chatta GS, Dale DC: Effect of recombinant granulocyte colony-stimulating factor on neutrophil kinetics in normal young and elderly humans. Blood1996; 88:335-340.
- Ballem PJ, Belzberg A, Devine DV, et al: Kinetic studies of the mechanism of thrombocytopenia in patients with human immunodeficiency virus infection. N Engl J Med1992; 327(25):1779-1784.
- Krause DS: Regulation of hematopoietic stem cell fate. Oncogene2002; 21:3262-3269.
- Groopman JE, Itri LM: Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst1999; 91:1616-1634.
- Ludwig H, Van Belle S, Barrett-Lee P, et al: The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer2004; 40:2293-2306.
- Miller CB, Jones RJ, Piantadosi S, et al: Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med1990; 322:1689-1692.
- Nicolas G, Chauvet C, Viatte L, et al: The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest2002; 110:1037-1044.
- Ganz T: Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood2003; 102:783-788.
- Andrews NC: Anemia of inflammation: the cytokine-hepcidin link. J Clin Invest2004; 113:1251-1253.
- Nemeth E, Valore EV, Territo M, et al: Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood2003; 101:2461-2463.
- Nemeth E, Tuttle MS, Powelson J, et al: Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science2004; 306:2090-2093.
- Fleming RE, Bacon BR: Orchestration of iron homeostasis. N Engl J Med2005; 352:1741-1744.
- Henry D, Dahl N, Auerbach D, et al: Intravenous ferric gluconate (FG) for increasing response to epoetin (EPO) in patients with anemia of cancer chemotherapy—results of a multicenter, randomized trial [abstract 3696]. Blood2004;104.
- Egrie JC, Browne JK: Development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer2001; 1:3-10.
- Case DC, Bukowski RM, Carey RW, et al: Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy. J Natl Cancer Inst1993; 85:801-806.
- Henry DH, Abels RI: Recombinant human erythropoietin in the treatment of cancer and chemotherapy-induced anemia: results of double-blind and open-label follow-up studies. Semin Oncol1994; 21(Suppl 3):21-28.
- Wilkinson PM, Antonopoulos M, Lahousen M, et al: Epoetin alfa in platinum-treated ovarian cancer patients: results of a multinational, multicentre, randomised trial. Br J Cancer2006; 94:947-954.
- Razzouk BI, Hord JD, Hockenberry M, et al: Double-blind, placebo-controlled study of quality of life, hematologic end points, and safety of weekly epoetin alfa in children with cancer receiving myelosuppressive chemotherapy. J Clin Oncol2006; 24:3583-3589.
- Littlewood TJ, Bajetta E, Nortier JW, et al: Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol2001; 19:2865-2874.
- Vansteenkiste J, Pirker R, Massuti B, et al: Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst2002; 94:1211-1220.
- Hedenus M, Adriansson M, San Miguel J, et al: Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol2003; 122:394-403.
- Basta SS, Soekirman , Karyadi D, Scrimshaw NS: Iron deficiency anemia and the productivity of adult males in Indonesia. Am J Clin Nutr1979; 32:916-925.
- Evans RW, Rader B, Manninen DL: The quality of life of hemodialysis recipients treated with recombinant human erythropoietin. Cooperative Multicenter EPO Clinical Trial Group. JAMA1990; 263:825-830.
- Levin NW, Lazarus JM, Nissenson AR: National Cooperative rHu Erythropoietin Study in patients with chronic renal failure—an interim report. The National Cooperative rHu Erythropoietin Study Group. Am J Kidney Dis1993; 22(Suppl 1):3-12.
- Parsons DS, Harris DC: A review of quality of life in chronic renal failure. Pharmacoeconomics1997; 12(Pt 1):140-160.
- Nissenson AR: Optimal hematocrit in patients on dialysis therapy. Am J Kidney Dis1998; 32(Suppl 4):S142-S146.
- Ross SD, Fahrbach K, Frame D, et al: The effect of anemia treatment on selected health-related quality-of-life domains: a systematic review. Clin Ther2003; 25:1786-1805.
- Crawford J, Cella D, Cleeland CS, et al: Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer2002; 95:888-895.
- Vogelzang NJ, Breitbart W, Cella D, et al: Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. The Fatigue Coalition. Semin Hematol1997; 34(Suppl 2):4-12.
- Curt GA, Breitbart W, Cella D, et al: Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition. Oncologist2000; 5:353-360.
- Leitgeb C, Pecherstorfer M, Fritz E, Ludwig H: Quality of life in chronic anemia of cancer during treatment with recombinant human erythropoietin. Cancer1994; 73:2535-2542.
- Ludwig H, Sundal E, Pecherstorfer M, et al: Recombinant human erythropoietin for the correction of cancer associated anemia with and without concomitant cytotoxic chemotherapy. Cancer1995; 76:2319-2329.
- Pawlicki M, Jassem J, Bosze P, et al: A multicenter study of recombinant human erythropoietin (epoetin alpha) in the management of anemia in cancer patients receiving chemotherapy. Anticancer Drugs1997; 8:949-957.
- Glaspy J, Bukowski R, Steinberg D, et al: Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol1997; 15:1218-1234.
- Glimelius B, Linne T, Hoffman K, et al: Epoetin beta in the treatment of anemia in patients with advanced gastrointestinal cancer. J Clin Oncol1998; 16:434-440.
- Cella D, Bron D: The effect of Epoetin alfa on quality of life in anemic cancer patients. Cancer Pract1999; 7:177-182.
- Quirt I, Robeson C, Lau CY, et al: Epoetin alfa therapy increases hemoglobin levels and improves quality of life in patients with cancer-related anemia who are not receiving chemotherapy and patients with anemia who are receiving chemotherapy. J Clin Oncol2001; 19:4126-4134.
- Cella D: The effects of anemia and anemia treatment on the quality of life of people with cancer. Oncology2002; 16(Suppl 10):125-132.
- Daneryd P: Epoetin alfa for protection of metabolic and exercise capacity in cancer patients. Semin Oncol2002; 29(Suppl 8):69-74.
- Osterborg A, Brandberg Y, Molostova V, et al: Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies. J Clin Oncol2002; 20:2486-2494.
- Cella D, Dobrez D, Glaspy J: Control of cancer-related anemia with erythropoietic agents: a review of evidence for improved quality of life and clinical outcomes. Ann Oncol2003; 14:511-519.
- Cella D, Zagari MJ, Vandoros C, et al: Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population. J Clin Oncol2003; 21:366-373.
- Cella D, Kallich J, McDermott A, Xu X: The longitudinal relationship of hemoglobin, fatigue and quality of life in anemic cancer patients: results from five randomized clinical trials. Ann Oncol2004; 15:979-986.
- Jones M, Schenkel B, Just J, Fallowfield L: Epoetin alfa improves quality of life in patients with cancer: results of metaanalysis. Cancer2004; 101:1720-1732.
- Chang J, Couture F, Young S, et al: Weekly epoetin alfa maintains hemoglobin, improves quality of life, and reduces transfusion in breast cancer patients receiving chemotherapy. J Clin Oncol2005; 23:2597-2605.
- Witzig TE, Silberstein PT, Loprinzi CL, et al: Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol2005; 23:2606-2617.
- Glaspy J, Vadhan-Raj S, Patel R, et al: Randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia: the 20030125 Study Group Trial. J Clin Oncol2006; 24:2290-2297.
- Boccia R, Malik IA, Raja V, et al: Darbepoetin alfa administered every three weeks is effective for the treatment of chemotherapy-induced anemia. Oncologist2006; 11:409-417.
- Canon JL, Vansteenkiste J, Bodoky G, et al: Randomized, double-blind, active-controlled trial of every-3-week darbepoetin alfa for the treatment of chemotherapy-induced anemia. J Natl Cancer Inst2006; 98:273-284.
- Glaspy J, Henry D, Patel R, et al: Effects of chemotherapy on endogenous erythropoietin levels and the pharmacokinetics and erythropoietic response of darbepoetin alfa: a randomised clinical trial of synchronous versus asynchronous dosing of darbepoetin alfa. Eur J Cancer2005; 41:1140-1149.
- Steensma DP, Molina R, Sloan JA, et al: Phase III study of two different dosing schedules of erythropoietin in anemic patients with cancer. J Clin Oncol2006; 24:1079-1089.
- Lyman GH, Glaspy J: Are there clinical benefits with early erythropoietic intervention for chemotherapy-induced anemia? A systematic review. Cancer2006; 106:223-233.
- National Comprehensive Cancer Network : Clinical Practice Guidelines in Oncology. Available at <http://www.nccn.org/professionals/physician_gls/f_guidelines.asp?button=I+Agree#care>2006
- Bokemeyer C, Aapro MS, Courdi A, et al: EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer2004; 40:2201-2216.
- Loo M, Beguin Y: The effect of recombinant human erythropoietin on platelet counts is strongly modulated by the adequacy of iron supply. Blood1999; 93:3286-3293.
- Glaspy J, Cavill I: Role of iron in optimizing responses of anemic cancer patients to erythropoietin. Oncology1999; 13:461-473.
- Eschbach JW: Iron requirements in erythropoietin therapy. Best Pract Res Clin Haematol2005; 18:347-361.
- Sheashaa H, El-Husseini A, Sabry A, et al: Parenteral iron therapy in treatment of anemia in end-stage renal disease patients: a comparative study between iron saccharate and gluconate. Nephron Clin Pract2005; 99:c97-c101.
- Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J: On the relative safety of parenteral iron formulations. Nephrol Dial Transplant2004; 19:1571-1575.
- Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J: Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant2006; 21:378-382.
- Auerbach M, Ballard H, Trout JR, et al: Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. J Clin Oncol2004; 22:1301-1307.
- Henry DH: The role of intravenous iron in cancer-related anemia. Oncology2006; 20(Suppl 6):21-24.
- Ludwig H: Iron metabolism and iron supplementation in anemia of cancer. Semin Hematol2006; 43(Suppl 6):S13-S17.
- Weiss G, Goodnough LT: Anemia of chronic disease. N Engl J Med2005; 352:1011-1023.
- Ferguson BJ, Skikne BS, Simpson KM, et al: Serum transferrin receptor distinguishes the anemia of chronic disease from iron deficiency anemia. J Lab Clin Med1992; 119:385-390.
- Cook JD, Flowers CH, Skikne BS: The quantitative assessment of body iron. Blood2003; 101:3359-3364.
- Thomas C, Thomas L: Biochemical markers and hematologic indices in the diagnosis of functional iron deficiency. Clin Chem2002; 48:1066-1076.
- Thomas C, Thomas L: Anemia of chronic disease: pathophysiology and laboratory diagnosis. Lab Hematol2005; 11:14-23.
- Macdougall IC, Cavill I, Hulme B, et al: Detection of functional iron deficiency during erythropoietin treatment: a new approach. BMJ1992; 304:225-226.
- Tessitore N, Solero GP, Lippi G, et al: The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin. Nephrol Dial Transplant2001; 16:1416-1423.
- Richardson D, Bartlett C, Jolly H, Will EJ: Intravenous iron for CAPD populations: proactive or reactive strategies?. Nephrol Dial Transplant2001; 16:115-119.
- Brugnara C, Laufer MR, Friedman AJ, et al: Reticulocyte hemoglobin content (CHr): early indicator of iron deficiency and response to therapy [letter]. Blood1994; 83:3100-3101.
- Fishbane S, Galgano C, Langley RC, et al: Reticulocyte hemoglobin content in the evaluation of iron status of hemodialysis patients. Kidney Int1997; 52:217-222.
- Cullen P, Soffker J, Hopfl M, et al: Hypochromic red cells and reticulocyte haemoglobin content as markers of iron-deficient erythropoiesis in patients undergoing chronic haemodialysis. Nephrol Dial Transplant1999; 14:659-665.
- Mast AE, Blinder MA, Lu Q, et al: Clinical utility of the reticulocyte hemoglobin content in the diagnosis of iron deficiency. Blood2002; 99:1489-1491.
- Tsuchiya K, Okano H, Teramura M, et al: Content of reticulocyte hemoglobin is a reliable tool for determining iron deficiency in dialysis patients. Clin Nephrol2003; 59:115-123.
- Casadevall N, Nataf J, Viron B, et al: Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med2002; 346:469-475.
- Bennett CL, Luminari S, Nissenson AR, et al: Pure red-cell aplasia and epoetin therapy. N Engl J Med2004; 351:1403-1408.
- Bohlius J, Langensiepen S, Schwarzer G, et al: Erythropoietin for patients with malignant disease. Cochrane Database Syst Rev2004;3.
- Bohlius J, Wilson J, Seidenfeld J, et al: Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev2006;3.
- Wun T, Law L, Harvey D, et al: Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin. Cancer2003; 98:1514-1520.
- Lavey RS, Liu PY, Greer BE, et al: Recombinant human erythropoietin as an adjunct to radiation therapy and cisplatin for stage IIB-IVA carcinoma of the cervix: a Southwest Oncology Group study. Gynecol Oncol2004; 95:145-151.
- Stohlawetz PJ, Dzirlo L, Hergovich N, et al: Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood2000; 95:2983-2989.
- Wun T, Paglieroni T, Hammond WP, et al: Thrombopoietin is synergistic with other hematopoietic growth factors and physiologic platelet agonists for platelet activation in vitro. Am J Hematol1997; 54:225-232.
- Valles J, Santos MT, Aznar J, et al: Platelet-erythrocyte interactions enhance a(IIb)b(3)-integrin receptor activation and P-selectin expression during platelet recruitment: down-regulation by aspirin ex vivo. Blood2002; 99:3978-3984.
- Leyland-Jones B, Semiglazov V, Pawlicki M, et al: Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol2005; 23:5960-5972.
- Henke M, Laszig R, Rube C, et al: Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet2003; 362:1255-1260.
- Bohlius J, Langensiepen S, Schwarzer G, et al: Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive metaanalysis. J Natl Cancer Inst2005; 97:489-498.
- Bohlius J, Wilson J, Seidenfeld J, et al: Recombinant human erythropoietins and cancer patients: updated metaanalysis of 57 studies including 9353 patients. J Natl Cancer Inst2006; 98:708-714.
- Hedenus M, Vansteenkiste J, Kotasek D, et al: Darbepoetin alfa for the treatment of chemotherapy-induced anemia: disease progression and survival analysis from four randomized, double-blind, placebo-controlled trials. J Clin Oncol2005; 23:6941-6948.
- Aapro M, Coiffier B, Dunst J, et al: Effect of treatment with epoetin beta on short-term tumour progression and survival in anaemic patients with cancer: a metaanalysis. Br J Cancer2006; 95:1467-1473.
- Glaspy JA: Cancer patient survival and erythropoiesis. J Natl Compr Cancer Netw2005; 3:799-807.
- Stone HB, Brown JM, Phillips TL, Sutherland RM: Oxygen in human tumors: correlations between methods of measurement and response to therapy. Summary of a workshop held November 19–20, 1992, at the National Cancer Institute, Bethesda, Maryland. Radiat Res1993; 136:422-434.
- Kelleher DK, Mattheinsen U, Thews O, Vaupel P: Blood flow, oxygenation, and bioenergetic status of tumors after erythropoietin treatment in normal and anemic rats. Cancer Res1996; 56:4728-4734.
- Fyles AW, Milosevic M, Pintilie M, Hill RP: Cervix cancer oxygenation measured following external radiation therapy. Int J Radiat Oncol Biol Phys1998; 42:751-753.
- Hockel M, Vaupel P: Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst2001; 93:266-276.
- Vaupel P, Thews O, Mayer A, et al: Oxygenation status of gynecologic tumors: what is the optimal hemoglobin level?. Strahlenther Onkol2002; 178:727-731.
- Vaupel P, Mayer A, Briest S, Hockel M: Oxygenation gain factor: a novel parameter characterizing the association between hemoglobin level and the oxygenation status of breast cancers. Cancer Res2003; 63:7634-7637.
- Vaupel P, Mayer A, Briest S, Hockel M: Hypoxia in breast cancer: role of blood flow, oxygen diffusion distances, and anemia in the development of oxygen depletion. Adv Exp Med Biol2005; 566:333-342.
- Graeber TG, Osmanian C, Jacks T, et al: Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours [see comments]. Nature1996; 379:88-91.
- Semenza GL: Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol2000; 35:71-103.
- Krishnamachary B, Berg-Dixon S, Kelly B, et al: Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res2003; 63:1138-1143.
- Semenza GL: Involvement of hypoxia-inducible factor 1 in human cancer. Intern Med2002; 41:79-83.
- Stoeltzing O, McCarty MF, Wey JS, et al: Role of hypoxia-inducible factor 1a in gastric cancer cell growth, angiogenesis, and vessel maturation. J Natl Cancer Inst2004; 96:946-956.
- Bos R, Zhong H, Hanrahan CF, et al: Levels of hypoxia-inducible factor-1a during breast carcinogenesis. J Natl Cancer Inst2001; 93:309-314.
- Buchler P, Reber HA, Buchler M, et al: Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer. Pancreas2003; 26:56-64.
- Vaupel P, Mayer A, Hockel M: Tumor hypoxia and malignant progression. Methods Enzymol2004; 381:335-354.
- Zhong H, De Marzo AM, Laughner E, et al: Overexpression of hypoxia-inducible factor 1a in common human cancers and their metastases. Cancer Res1999; 59:5830-5835.
- Biroccio A, Candiloro A, Mottolese M, et al: Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line. FASEB J2000; 14:652-660.
- Dachs GU, Tozer GM: Hypoxia modulated gene expression: angiogenesis, metastasis and therapeutic exploitation. Eur J Cancer2000; 36(Spec No):1649-1660.
- Semenza GL: HIF-1: using two hands to flip the angiogenic switch. Cancer Metastasis Rev2000; 19:59-65.
- Giatromanolaki A, Harris AL: Tumour hypoxia, hypoxia signaling pathways and hypoxia inducible factor expression in human cancer. Anticancer Res2001; 21:4317-4324.
- Oikawa M, Abe M, Kurosawa H, et al: Hypoxia induces transcription factor ETS-1 via the activity of hypoxia-inducible factor-1. Biochem Biophys Res Commun2001; 289:39-43.
- Pilch H, Schlenger K, Steiner E, et al: Hypoxia-stimulated expression of angiogenic growth factors in cervical cancer cells and cervical cancer-derived fibroblasts. Int J Gynecol Cancer2001; 11:137-142.
- Harris AL: Hypoxia—a key regulatory factor in tumour growth. Nature Rev Cancer2002; 2:38-47.
- Rofstad EK, Halsor EF: Hypoxia-associated spontaneous pulmonary metastasis in human melanoma xenografts: involvement of microvascular hot spots induced in hypoxic foci by interleukin 8. Br J Cancer2002; 86:301-308.
- Brizel DM, Sibley GS, Prosnitz LR, et al: Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys1997; 38:285-289.
- Fyles AW, Milosevic M, Wong R, et al: Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol1998; 48:149-156.
- Brizel DM, Dodge RK, Clough RW, Dewhirst MW: Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol1999; 53:113-117.
- Dunst J, Kuhnt T, Strauss HG, et al: Anemia in cervical cancers: impact on survival, patterns of relapse, and association with hypoxia and angiogenesis. Int J Radiat Oncol Biol Phys2003; 56:778-787.
- Semenza GL: Intratumoral hypoxia, radiation resistance, and HIF-1. Cancer Cell2004; 5:405-406.
- Thews O, Koenig R, Kelleher DK, et al: Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia. Br J Cancer1998; 78:752-756.
- Thews O, Kelleher DK, Vaupel P: Erythropoietin restores the anemia-induced reduction in cyclophosphamide cytotoxicity in rat tumors. Cancer Res2001; 61:1358-1361.
- Teicher BA, Holden SA, al-Achi A, Herman TS: Classification of antineoplastic treatments by their differential toxicity toward putative oxygenated and hypoxic tumor subpopulations in vivo in the FSaIIC murine fibrosarcoma. Cancer Res1990; 50:3339-3344.
- Van Belle SJ, Cocquyt V: Impact of haemoglobin levels on the outcome of cancers treated with chemotherapy. Crit Rev Oncol Hematol2003; 47:1-11.
- Caro JJ, Salas M, Ward A, Goss G: Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer2001; 91:2214-2221.
- Kallinowski F, Zander R, Hoeckel M, Vaupel P: Tumor tissue oxygenation as evaluated by computerized-pO2-histography. Int J Radiat Oncol Biol Phys1990; 19:953-961.
- Vaupel P, Briest S, Hockel M: Hypoxia in breast cancer: pathogenesis, characterization and biological/therapeutic implications. Wien Med Wochenschr2002; 152:334-342.
- Vaupel P, Mayer A, Hockel M: Impact of hemoglobin levels on tumor oxygenation: the higher, the better?. Strahlenther Onkol2006; 182:63-71.
- Acs G, Acs P, Beckwith SM, et al: Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res2001; 61:3561-3565.
- Arcasoy MO, Amin K, Karayal AF, et al: Functional significance of erythropoietin receptor expression in breast cancer. Lab Invest2002; 82:911-918.
- Acs G, Zhang PJ, Rebbeck TR, et al: Immunohistochemical expression of erythropoietin and erythropoietin receptor in breast carcinoma. Cancer2002; 95:969-981.
- Henke M, Mattern D, Pepe M, et al: Do erythropoietin receptors on cancer cells explain unexpected clinical findings?. J Clin Oncol2006; 24:4708-4713.
- Elliott S, Busse L, Bass MB, et al: Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood2006; 107:1892-1895.
- Hardee ME, Kirkpatrick JP, Shan S, et al: Human recombinant erythropoietin (rEpo) has no effect on tumour growth or angiogenesis. Br J Cancer2005; 93:1350-1355.
- Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D: Correction of anaemia through the use of darbepoetin alfa improves chemotherapeutic outcome in a murine model of Lewis lung carcinoma. Br J Cancer2005; 93:224-232.
- Tagnon HJ: Paraneoplastic syndromes. I. Endocrine paraneoplasia. Eur J Cancer Clin Oncol1981; 17:969-985.
- Alimonti A, Di Cosimo S, Maccallini V, et al: A man with a deltoid swelling and paraneoplastic erythrocytosis: case report. Anticancer Res2003; 23:5181-5184.
- Wiesener MS, Seyfarth M, Warnecke C, et al: Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma. Blood2002; 99:3562-3565.
- Kassianides C, Kew MC: The clinical manifestations and natural history of hepatocellular carcinoma. Gastroenterol Clin North Am1987; 16:553-562.
- Ndububa DA, Ojo OS, Adetiloye VA, et al: The incidence and characteristics of some paraneoplastic syndromes of hepatocellular carcinoma in Nigerian patients. Eur J Gastroenterol Hepatol1999; 11:1401-1404.
- Luo JC, Hwang SJ, Wu JC, et al: Clinical characteristics and prognosis of hepatocellular carcinoma patients with paraneoplastic syndromes. Hepatogastroenterology2002; 49:1315-1319.
- Dreicer R, Donovan J, Benda JA, et al: Paraneoplastic erythrocytosis in a young adult with an erythropoietin-producing Wilms' tumor. Am J Med1992; 93:229-230.
- Souid AK, Dubansky AS, Richman P, Sadowitz PD: Polycythemia: a review article and case report of erythrocytosis secondary to Wilms' tumor. Pediatr Hematol Oncol1993; 10:215-221.
- Kaito K, Otsubo H, Usui N, Kobayashi M: Secondary polycythemia as a paraneoplastic syndrome of testicular seminoma. Ann Hematol2004; 83:55-57.
- Al-Tourah AJ, Tsang PW, Skinnider BF, Hoskins PJ: Paraneoplastic erythropoietin-induced polycythemia associated with small lymphocytic lymphoma. J Clin Oncol2006; 24:2388-2389.
- Samyn I, Fontaine C, Van Tussenbroek F, et al: Paraneoplastic syndromes in cancer: case 1. Polycythemia as a result of ectopic erythropoietin production in metastatic pancreatic carcinoid tumor. J Clin Oncol2004; 22:2240-2242.
- Stephen MR, Lindop GB: A renin secreting ovarian steroid cell tumour associated with secondary polycythaemia. J Clin Pathol1998; 51:75-77.
- Thorling EB: Paraneoplastic erythrocytosis and inappropriate erythropoietin production. A review. Scand J Haematol Suppl1972; 17:1-166.
- Hammond D, Winnick S: Paraneoplastic erythrocytosis and ectopic erythropoietins. Ann N Y Acad Sci1974; 230:219-227.
- Shiramizu M, Katsuoka Y, Grodberg J, et al: Constitutive secretion of erythropoietin by human renal adenocarcinoma cells in vivo and in vitro. Exp Cell Res1994; 215:249-256.
- Kuderer NM, Dale DC, Crawford J, et al: Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer2006; 106:2258-2266.
- Lieschke GJ, Burgess AW: Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (1). N Engl J Med1992; 32:28-35.
- Lieschke GJ, Burgess AW: Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (2). N Engl J Med1992; 327:99-106.
- Kaushansky K: Lineage-specific hematopoietic growth factors. N Engl J Med2006; 354:2034-2045.
- Basu S, Hodgson G, Zhang HH, et al: “Emergency” granulopoiesis in G-CSF-deficient mice in response to Candida albicans infection. Blood2000; 95:3725-3733.
- Gessler P, Kirchmann N, Kientsch-Engel R, et al: Serum concentrations of granulocyte colony-stimulating factor in healthy term and preterm neonates and in those with various diseases including bacterial infections. Blood1993; 82:3177-3182.
- Peters WP, Stuart A, Affronti ML, et al: Neutrophil migration is defective during recombinant human granulocyte-macrophage colony-stimulating factor infusion after autologous bone marrow transplantation in humans. Blood1988; 72:1310-1315.
- Yong KL: Granulocyte colony-stimulating factor (G-CSF) increases neutrophil migration across vascular endothelium independent of an effect on adhesion: comparison with granulocyte-macrophage colony-stimulating factor (GM-CSF). Br J Haematol1996; 94:40-47.
- Peters WP, Rosner G, Ross M, et al: Comparative effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) on priming peripheral blood progenitor cells for use with autologous bone marrow after high-dose chemotherapy. Blood1993; 81:1709-1719.
- Yong KL, Rowles PM, Patterson KG, Linch DC: Granulocyte-macrophage colony-stimulating factor induces neutrophil adhesion to pulmonary vascular endothelium in vivo: role of b2-integrins. Blood1992; 80:1565-1575.
- Stanley E, Lieschke GJ, Grail D, et al: Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci USA1994; 91:5592-5596.
- Dranoff G, Crawford AD, Sadelain M, et al: Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science1994; 264:713-716.
- Seymour JF, Begley CG, Dirksen U, et al: Attenuated hematopoietic response to granulocyte-macrophage colony-stimulating factor in patients with acquired pulmonary alveolar proteinosis. Blood1998; 92:2657-2667.
- Trapnell BC, Whitsett JA, Nakata K: Pulmonary alveolar proteinosis. N Engl J Med2003; 349:2527-2539.
- Uchida K, Nakata K, Trapnell BC, et al: High-affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis. Blood2004; 103:1089-1098.
- El Ouriaghli F, Fujiwara H, Melenhorst JJ, et al: Neutrophil elastase enzymatically antagonizes the in vitro action of G-CSF: implications for the regulation of granulopoiesis. Blood2003; 101:1752-1758.
- Mermel CH, McLemore ML, Liu F, et al: Src family kinases are important negative regulators of G-CSF-dependent granulopoiesis. Blood2006; 108:2562-2568.
- Matsuyama W, Yamamoto M, Higashimoto I, et al: TNF-related apoptosis-inducing ligand is involved in neutropenia of systemic lupus erythematosus. Blood2004; 104:184-191.
- Crawford J, Ozer H, Stoller R, et al: Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med1991; 325:164-170.
- Trillet-Lenoir V, Green J, Manegold C, et al: Recombinant granulocyte colony stimulating factor reduces the infectious complications of cytotoxic chemotherapy!. Eur J Cancer1993; 29A:319-324.
- Welte K, Reiter A, Mempel K, et al: A randomized phase-III study of the efficacy of granulocyte colony-stimulating factor in children with high-risk acute lymphoblastic leukemia. Berlin-Frankfurt-Munster Study Group. Blood1996; 87:3143-3150.
- Geissler K, Koller E, Hubmann E, et al: Granulocyte colony-stimulating factor as an adjunct to induction chemotherapy for adult acute lymphoblastic leukemia—a randomized phase-III study. Blood1997; 90:590-596.
- Janik JE, Miller LL, Korn EL, et al: A prospective randomized phase II trial of GM-CSF priming to prevent topotecan-induced neutropenia in chemotherapy-naive patients with malignant melanoma or renal cell carcinoma. Blood2001; 97:1942-1946.
- Burdach SE, Muschenich M, Josephs W, et al: Granulocyte-macrophage-colony stimulating factor for prevention of neutropenia and infections in children and adolescents with solid tumors. Results of a prospective randomized study. Cancer1995; 76:510-516.
- Jones SE, Schottstaedt MW, Duncan LA, et al: Randomized double-blind prospective trial to evaluate the effects of sargramostim versus placebo in a moderate-dose fluorouracil, doxorubicin, and cyclophosphamide adjuvant chemotherapy program for stage II and III breast cancer. J Clin Oncol1996; 14:2976-2983.
- Steward WP, von Pawel J, Gatzemeier U, et al: Effects of granulocyte-macrophage colony-stimulating factor and dose intensification of V-ICE chemotherapy in small-cell lung cancer: a prospective randomized study of 300 patients. J Clin Oncol1998; 16:642-650.
- Wexler LH, Weaver-McClure L, Steinberg SM, et al: Randomized trial of recombinant human granulocyte-macrophage colony-stimulating factor in pediatric patients receiving intensive myelosuppressive chemotherapy. J Clin Oncol1996; 14:901-910.
- Hamm J, Schiller JH, Cuffie C, et al: Dose-ranging study of recombinant human granulocyte-macrophage colony-stimulating factor in small-cell lung carcinoma. J Clin Oncol1994; 12:2667-2676.
- Bajorin DF, Nichols CR, Schmoll HJ, et al: Recombinant human granulocyte-macrophage colony-stimulating factor as an adjunct to conventional-dose ifosfamide-based chemotherapy for patients with advanced or relapsed germ cell tumors: a randomized trial. J Clin Oncol1995; 13:79-86.
- Papaldo P, Lopez M, Marolla P, et al: Impact of five prophylactic filgrastim schedules on hematologic toxicity in early breast cancer patients treated with epirubicin and cyclophosphamide. J Clin Oncol2005; 23:6908-6918.
- Rahiala J, Perkkio M, Riikonen P: Prospective and randomized comparison of early versus delayed prophylactic administration of granulocyte colony-stimulating factor (filgrastim) in children with cancer. Med Pediatr Oncol1999; 32:326-330.
- Hartmann LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia. N Engl J Med1997; 336:1776-1780.
- Toner GC, Shapiro JD, Laidlaw CR, et al: Low-dose versus standard-dose lenograstim prophylaxis after chemotherapy: a randomized, crossover comparison. J Clin Oncol1998; 16:3874-3879.
- Johnston E, Crawford J, Blackwell S, et al: Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy. J Clin Oncol2000; 18:2522-2528.
- Holmes FA, O'Shaughnessy JA, Vukelja S, et al: Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol2002; 20:727-731.
- Green MD, Koelbl H, Baselga J, et al: A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol2003; 14:29-35.
- Vose JM, Crump M, Lazarus H, et al: Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma. J Clin Oncol2003; 21:514-519.
- Vogel CL, Wojtukiewicz MZ, Carroll RR, et al: First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol2005; 23:1178-1184.
- Smith TJ, Khatcheressian J, Lyman GH, et al: 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol2006; 24:3187-3205.
- Crawford J, Althaus B, Armitage J, et al: Myeloid growth factors clinical practice guidelines in oncology. J Natl Compr Cancer Netw2005; 3:540-555.
- Vose JM, Armitage JO: Clinical applications of hematopoietic growth factors [see comments]. J Clin Oncol1995; 13:1023-1035.
- Silber JH, Fridman M, Shpilsky A, et al: Modeling the cost-effectiveness of granulocyte colony-stimulating factor use in early-stage breast cancer. J Clin Oncol1998; 16:2435-2444.
- Nichols CR, Fox EP, Roth BJ, et al: Incidence of neutropenic fever in patients treated with standard-dose combination chemotherapy for small-cell lung cancer and the cost impact of treatment with granulocyte colony-stimulating factor. J Clin Oncol1994; 12:1245-1250.
- Lyman GH, Kuderer NM, Balducci L: Economic impact of granulopoiesis stimulating agents on the management of febrile neutropenia. Curr Opin Oncol1998; 10:291-296.
- Lyman GH, Kuderer NM, Balducci L: Cost-benefit analysis of granulocyte colony-stimulating factor in the management of elderly cancer patients. Curr Opin Hematol2002; 9:207-214.
- Burstein HJ, Parker LM, Keshaviah A, et al: Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol2005; 23:8340-8347.
- Meropol NJ, Miller LL, Korn EL, et al: Severe myelosuppression resulting from concurrent administration of granulocyte colony-stimulating factor and cytotoxic chemotherapy. J Natl Cancer Inst1992; 84:1201-1203.
- Wolff D, Culakova E, Poniewierski MS, et al: Predictors of chemotherapy-induced neutropenia and its complications: results from a prospective nationwide registry. J Support Oncol2005; 3(Suppl 4):24-25.
- Lyman GH, Morrison VA, Dale DC, et al: Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin's lymphoma receiving CHOP chemotherapy. Leuk Lymphoma2003; 44:2069-2076.
- Glaspy JA, Baldwin GC, Robertson PA, et al: Therapy for neutropenia in hairy cell leukemia with recombinant human granulocyte colony-stimulating factor. Ann Intern Med1988; 109:789-795.
- Smith WS, Sumnicht GE, Sharpe RW, et al: Granulocyte colony-stimulating factor versus placebo in addition to penicillin G in a randomized blinded study of gram-negative pneumonia sepsis: analysis of survival and multisystem organ failure. Blood1995; 86:1301-1309.
- Timmer-Bonte JN, de Boo TM, Smit HJ, et al: Prevention of chemotherapy-induced febrile neutropenia by prophylactic antibiotics plus or minus granulocyte colony-stimulating factor in small-cell lung cancer: a Dutch Randomized Phase III Study. J Clin Oncol2005; 23:7974-7984.
- Timmer-Bonte JN, Adang EM, Smit HJ, et al: Cost-effectiveness of adding granulocyte colony-stimulating factor to primary prophylaxis with antibiotics in small-cell lung cancer. J Clin Oncol2006; 24:2991-2997.
- Tjan-Heijnen VC, Postmus PE, Ardizzoni A, et al: Reduction of chemotherapy-induced febrile leucopenia by prophylactic use of ciprofloxacin and roxithromycin in small-cell lung cancer patients: an EORTC double-blind placebo-controlled phase III study. Ann Oncol2001; 12:1359-1368.
- Maher DW, Lieschke GJ, Green M, et al: Filgrastim in patients with chemotherapy-induced febrile neutropenia. A double-blind, placebo-controlled trial. Ann Intern Med1994; 121:492-501.
- Mitchell PL, Morland B, Stevens MC, et al: Granulocyte colony-stimulating factor in established febrile neutropenia: a randomized study of pediatric patients. J Clin Oncol1997; 15:1163-1170.
- Ravaud A, Chevreau C, Cany L, et al: Granulocyte-macrophage colony-stimulating factor in patients with neutropenic fever is potent after low-risk but not after high-risk neutropenic chemotherapy regimens: results of a randomized phase III trial. J Clin Oncol1998; 16:2930-2936.
- Vellenga E, Uyl-de Groot CA, de Wit R, et al: Randomized placebo-controlled trial of granulocyte-macrophage colony-stimulating factor in patients with chemotherapy-related febrile neutropenia. J Clin Oncol1996; 14:619-627.
- Arnberg H, Letocha H, Nou F, et al: GM-CSF in chemotherapy-induced febrile neutropenia—a double-blind randomized study. Anticancer Res1998; 18:1255-1260.
- Mayordomo JI, Rivera F, Diaz-Puente MT, et al: Improving treatment of chemotherapy-induced neutropenic fever by administration of colony-stimulating factors. J Natl Cancer Inst1995; 87:803-808.
- Lyman GH, Dale DC, Crawford J: Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: a nationwide study of community practices. J Clin Oncol2003; 21:4524-4531.
- Lyman GH, Dale DC, Friedberg J, et al: Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin's lymphoma: a nationwide study. J Clin Oncol2004; 22:4302-4311.
- Du XL, Lairson DR, Begley CE, Fang S: Temporal and geographic variation in the use of hematopoietic growth factors in older women receiving breast cancer chemotherapy: findings from a large population-based cohort. J Clin Oncol2005; 23:8620-8628.
- Paccagnella A, Favaretto A, Riccardi A, et al: Granulocyte-macrophage colony-stimulating factor increases dose intensity of chemotherapy in small cell lung cancer. Relationship between clinical results, peripheral blood cell modifications, and bone marrow kinetics. Cancer1993; 72:697-706.
- Woll PJ, Hodgetts J, Lomax L, et al: Can cytotoxic dose-intensity be increased by using granulocyte colony-stimulating factor? A randomized controlled trial of lenograstim in small-cell lung cancer. J Clin Oncol1995; 13:652-659.
- Seidman AD, Scher HI, Gabrilove JL, et al: Dose-intensification of MVAC with recombinant granulocyte colony-stimulating factor as initial therapy in advanced urothelial cancer. J Clin Oncol1993; 11:408-414.
- Font A, Moyano AJ, Puerto JM, et al: Increasing dose intensity of cisplatin-etoposide in advanced nonsmall cell lung carcinoma: a phase III randomized trial of the Spanish Lung Cancer Group. Cancer1999; 85:855-863.
- Yoneda T, Aufdemorte TB, Nishimura R, et al: Occurrence of hypercalcemia and leukocytosis with cachexia in a human squamous cell carcinoma of the maxilla in athymic nude mice: a novel experimental model of three concomitant paraneoplastic syndromes. J Clin Oncol1991; 9:468-477.
- Kato N, Yasukawa K, Onozuka T, Kimura K: Paraneoplastic syndromes of leukocytosis, thrombocytosis, and hypercalcemia associated with squamous cell carcinoma. J Dermatol1999; 26:352-358.
- Tanaka R, Okada M, Kajimura N, et al: Triple paraneoplastic syndrome of hypercalcemia, leukocytosis and cachexia in two human tumor xenografts in nude mice. Jpn J Clin Oncol1996; 26:88-94.
- Hiraki A, Ueoka H, Takata I, et al: Hypercalcemia-leukocytosis syndrome associated with lung cancer. Lung Cancer2004; 43:301-307.
- Er O, Coskun HS, Altinbas M, et al: Rapidly relapsing squamous cell carcinoma of the renal pelvis associated with paraneoplastic syndromes of leukocytosis, thrombocytosis and hypercalcemia. Urol Int2001; 67:175-177.
- Yoneda T, Nishimura R, Kato I, et al: Frequency of the hypercalcemia-leukocytosis syndrome in oral malignancies. Cancer1991; 68:617-622.
- Sato K, Fujii Y, Kakiuchi T, et al: Paraneoplastic syndrome of hypercalcemia and leukocytosis caused by squamous carcinoma cells (T3M-1) producing parathyroid hormone-related protein, interleukin 1a, and granulocyte colony-stimulating factor. Cancer Res1989; 49:4740-4746.
- Sohda T, Shiga H, Nakane H, et al: Cholangiocellular carcinoma that produced both granulocyte-colony-stimulating factor and parathyroid hormone-related protein. Int J Clin Oncol2006; 11:246-249.
- Hayashi T, Mizuki A, Yamaguchi T, et al: Primary adenosquamous carcinoma of the liver which produces granulocyte-colony-stimulating factor and parathyroid hormone related protein: association with leukocytosis and hypercalcemia. Intern Med2001; 40:631-634.
- Hirasawa K, Kitamura T, Oka T, Matsushita H: Bladder tumor producing granulocyte colony-stimulating factor and parathyroid hormone related protein. J Urol2002; 167:2130.
- Satoh H, Abe Y, Katoh Y, et al: Bladder carcinoma producing granulocyte colony-stimulating factor: a case report. J Urol1993; 149:843-845.
- Nakamura A, Tanaka S, Takayama H, et al: A mesenteric liposarcoma with production of granulocyte colony-stimulating factor. Intern Med1998; 37:884-890.
- Ahn HJ, Park YH, Chang YH, et al: A case of uterine cervical cancer presenting with granulocytosis. Korean J Intern Med2005; 20:247-250.
- Kaushansky K: Thrombopoietin: the primary regulator of platelet production [see comments]. Blood1995; 86:419-431.
- Kuter DJ, Begley CG: Recombinant human thrombopoietin: basic biology and evaluation of clinical studies. Blood2002; 100:3457-3469.
- Sitnicka E, Lin N, Priestley GV, et al: The effect of thrombopoietin on the proliferation and differentiation of murine hematopoietic stem cells. Blood1996; 87:4998-5005.
- Nandurkar HH, Robb L, Tarlinton D, et al: Adult mice with targeted mutation of the interleukin-11 receptor (IL11Ra) display normal hematopoiesis. Blood1997; 90:2148-2159.
- Nandurkar HH, Robb L, Begley CG: The role of IL-II in hematopoiesis as revealed by a targeted mutation of its receptor. Stem Cells1998; 2:53-65.
- Begley CG, Basser RL: Biologic and structural differences of thrombopoietic growth factors. Semin Hematol2000; 37(Suppl 4):19-27.
- Gainsford T, Nandurkar H, Metcalf D, et al: The residual megakaryocyte and platelet production in c-mpl-deficient mice is not dependent on the actions of interleukin-6, interleukin-11, or leukemia inhibitory factor. Blood2000; 95:528-534.
- Scott CL, Robb L, Nandurkar HH, et al: Thrombopoietin signaling is required for in vivo expansion of IL-11-responsive hematopoietic progenitor cells in the steady state. Exp Hematol2001; 29:138-145.
- Robb L, Li R, Hartley L, Nandurkar HH, et al: Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation. Nat Med1998; 4:303-308.
- Katsumata Y, Suzuki T, Kuwana M, et al: Anti-c-Mpl (thrombopoietin receptor) autoantibody-induced amegakaryocytic thrombocytopenia in a patient with systemic sclerosis. Arthritis Rheum2003; 48:1647-1651.
- Kuwana M, Okazaki Y, Kajihara M, et al: Autoantibody to c-Mpl (thrombopoietin receptor) in systemic lupus erythematosus: relationship to thrombocytopenia with megakaryocytic hypoplasia. Arthritis Rheum2002; 46:2148-2159.
- Gordon MS, McCaskill-Stevens WJ, Battiato LA, et al: A phase I trial of recombinant human interleukin-11 (neumega rhIL-11 growth factor) in women with breast cancer receiving chemotherapy. Blood1996; 87:3615-3624.
- Tepler I, Elias L, Smith JW, et al: A randomized placebo-controlled trial of recombinant human interleukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy. Blood1996; 87:3607-3614.
- Isaacs C, Robert NJ, Bailey FA, et al: Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin. J Clin Oncol1997; 15:3368-3377.
- Orazi A, Cooper RJ, Tong J, et al: Effects of recombinant human interleukin-11 (Neumega rhIL-11 growth factor) on megakaryocytopoiesis in human bone marrow. Exp Hematol1996; 24:1289-1297.
- Harker LA, Hunt P, Marzec UM, et al: Regulation of platelet production and function by megakaryocyte growth and development factor in nonhuman primates. Blood1996; 87:1833-1844.
- Vadhan-Raj S, Murray LJ, Bueso-Ramos C, et al: Stimulation of megakaryocyte and platelet production by a single dose of recombinant human thrombopoietin in patients with cancer. Ann Intern Med1997; 126:673-681.
- Vadhan-Raj S, Verschraegen CF, Bueso-Ramos C, et al: Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer. Ann Intern Med2000; 132:364-368.
- Vadhan-Raj S, Kavanagh JJ, Freedman RS, et al: Safety and efficacy of transfusions of autologous cryopreserved platelets derived from recombinant human thrombopoietin to support chemotherapy-associated severe thrombocytopenia: a randomised crossover study. Lancet2002; 359:2145-2152.
- Vadhan-Raj S, Patel S, Bueso-Ramos C, et al: Importance of predosing of recombinant human thrombopoietin to reduce chemotherapy-induced early thrombocytopenia. J Clin Oncol2003; 21:3158-3167.
- O'Malley CJ, Rasko JE, Basser RL, et al: Administration of pegylated recombinant human megakaryocyte growth and development factor to humans stimulates the production of functional platelets that show no evidence of in vivo activation. Blood1996; 88:3288-3298.
- Basser RL, Rasko JE, Clarke K, et al: Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor with filgrastim after dose-intensive chemotherapy in patients with advanced cancer. Blood1997; 89:3118-3128.
- Fanucchi M, Glaspy J, Crawford J, et al: Effects of polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor on platelet counts after chemotherapy for lung cancer. N Engl J Med1997; 336:404-409.
- Basser RL, Underhill C, Davis I, et al: Enhancement of platelet recovery after myelosuppressive chemotherapy by recombinant human megakaryocyte growth and development factor in patients with advanced cancer. J Clin Oncol2000; 18:2852-2861.
- Li J, Yang C, Xia Y, et al: Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood2001; 98:3241-3248.
- Wang B, Nichol JL, Sullivan JT: Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther2004; 76:628-638.
- Rice L: Drug evaluation: AMG-531 for the treatment of thrombocytopenias. Curr Opin Investig Drugs2006; 7:834-841.
- Newland A, Caulier MT, Kappers-Klunne M, et al: An open-label, unit dose-finding study of AMG 531, a novel thrombopoiesis-stimulating peptibody, in patients with immune thrombocytopenic purpura. Br J Haematol2006; 135:547-553.
- Bussel JB, Kuter DJ, George JN, et al: AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med2006; 355:1672-1681.
- Erickson-Miller CL, DeLorme E, Tian SS, et al: Discovery and characterization of a selective, nonpeptidyl thrombopoietin receptor agonist. Exp Hematol2005; 33:85-93.
- Aledort LM, Hayward CP, Chen MG, et al: Prospective screening of 205 patients with ITP, including diagnosis, serological markers, and the relationship between platelet counts, endogenous thrombopoietin, and circulating antithrombopoietin antibodies. Am J Hematol2004; 76:205-213.
- Haznedaroglu IC, Buyukasik Y, Kosar A, et al: Thrombopoietin, interleukin-6, and P-selectin at diagnosis and during post-steroid recovery period of patients with autoimmune thrombocytopenic purpura. Ann Hematol1998; 77:165-170.
- Emmons RV, Reid DM, Cohen RL, et al: Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood1996; 87:4068-4071.
- von dem Borne A, Folman C, van den Oudenrijn S, et al: The potential role of thrombopoietin in idiopathic thrombocytopenic purpura. Blood Rev2002; 16:57-59.
- Kappers-Klunne MC, de Haan M, Struijk PC, van Vliet HH: Serum thrombopoietin levels in relation to disease status in patients with immune thrombocytopenic purpura. Br J Haematol2001; 115:1004-1006.
- Kosugi S, Kurata Y, Tomiyama Y, et al: Circulating thrombopoietin level in chronic immune thrombocytopenic purpura. Br J Haematol1996; 93:704-706.
- Gu J, Lu L, Xu R, Chen X: Plasma thrombopoietin levels in patients with aplastic anemia and idiopathic thrombocytopenic purpura. Chin Med J2002; 115:983-986.
- Mukai HY, Kojima H, Todokoro K, et al: Serum thrombopoietin (TPO) levels in patients with amegakaryocytic thrombocytopenia are much higher than those with immune thrombocytopenic purpura. Thromb Haemost1996; 76:675-678.
- Zent CS, Ratajczak J, Ratajczak MZ, et al: Relationship between megakaryocyte mass and serum thrombopoietin levels as revealed by a case of cyclic amegakaryocytic thrombocytopenic purpura. Br J Haematol1999; 105:452-458.
- Nagasawa T, Hasegawa Y, Shimizu S, et al: Serum thrombopoietin level is mainly regulated by megakaryocyte mass rather than platelet mass in human subjects. Br J Haematol1998; 101:242-244.
- Nomura S, Dan K, Hotta T, et al: Effects of pegylated recombinant human megakaryocyte growth and development factor in patients with idiopathic thrombocytopenic purpura. Blood2002; 100:728-730.
- Kuter DJ: The promise of thrombopoietins in the treatment of ITP. Clin Adv Hematol Oncol2005; 3:464-466.
- Hwang SJ, Luo JC, Li CP, et al: Thrombocytosis: a paraneoplastic syndrome in patients with hepatocellular carcinoma. World J Gastroenterol2004; 10:2472-2477.
- Stebler C, Tichelli A, Dazzi H, et al: High-dose recombinant human erythropoietin for treatment of anemia in myelodysplastic syndromes and paroxysmal nocturnal hemoglobinuria: a pilot study. Exp Hematol1990; 18:1204-1208.
- Bowen D, Culligan D, Jacobs A: The treatment of anaemia in the myelodysplastic syndromes with recombinant human erythropoietin. Br J Haematol1991; 77:419-423.
- Bessho M, Jinnai I, Matsuda A, et al: Improvement of anemia by recombinant erythropoietin in patients with myelodysplastic syndromes and aplastic anemia. Int J Cell Cloning1990; 8:445-458.
- Hellstrom E, Birgegard G, Lockner D, et al: Treatment of myelodysplastic syndromes with recombinant human erythropoietin. Eur J Haematol1991; 47:355-360.
- Stein RS, Abels RI, Krantz SB: Pharmacologic doses of recombinant human erythropoietin in the treatment of myelodysplastic syndromes. Blood1991; 78:1658-1663.
- Anonymous : A randomized double-blind placebo-controlled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes. Italian Cooperative Study Group for rHuEpo in Myelodysplastic Syndromes. Br J Haematol1998; 103:1070-1074.
- Cazzola M, Ponchio L, Beguin Y, et al: Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Results of a phase I/II clinical trial [see comments]. Blood1992; 79:29-37.
- Rafanelli D, Grossi A, Longo G, et al: Recombinant human erythropoietin for treatment of myelodysplastic syndromes. Leukemia1992; 6:323-327.
- Goy A, Belanger C, Casadevall N, et al: High doses of intravenous recombinant erythropoietin for the treatment of anaemia in myelodysplastic syndrome. Br J Haematol1993; 84:232-237.
- Stone RM, Bernstein SH, Demetri G, et al: Therapy with recombinant human erythropoietin in patients with myelodysplastic syndromes. Leuk Res1994; 18:769-776.
- Musto P, Lanza F, Balleari E, et al: Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. Br J Haematol2005; 128:204-209.
- Stasi R, Abruzzese E, Lanzetta G, et al: Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1-risk myelodysplastic syndromes. Ann Oncol2005; 16:1921-1927.
- Patton JF, Sullivan T, Mun Y, et al: A retrospective cohort study to assess the impact of therapeutic substitution of darbepoetin alfa for epoetin alfa in anemic patients with myelodysplastic syndrome. J Support Oncol2005; 3:419-426.
- Mannone L, Gardin C, Quarre MC, et al: High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study. Br J Haematol2006; 133:513-519.
- Negrin RS, Stein R, Vardiman J, et al: Treatment of the anemia of myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor in combination with erythropoietin [see comments]. Blood1993; 82:737-743.
- Negrin RS, Stein R, Doherty K, et al: Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: evidence for in vivo synergy. Blood1996; 87:4076-4081.
- Hansen PB, Johnsen HE, Hippe E, et al: Recombinant human granulocyte-macrophage colony-stimulating factor plus recombinant human erythropoietin may improve anemia in selected patients with myelodysplastic syndromes. Am J Hematol1993; 44:229-236.
- Hellstrom-Lindberg E, Ahlgren T, Beguin Y, et al: Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients. Blood1998; 92:68-75.
- Stasi R, Pagano A, Terzoli E, Amadori S: Recombinant human granulocyte-macrophage colony-stimulating factor plus erythropoietin for the treatment of cytopenias in patients with myelodysplastic syndromes. Br J Haematol1999; 105:141-148.
- Mantovani L, Lentini G, Hentschel B, et al: Treatment of anaemia in myelodysplastic syndromes with prolonged administration of recombinant human granulocyte colony-stimulating factor and erythropoietin. Br J Haematol2000; 109:367-375.
- Thompson JA, Gilliland DG, Prchal JT, et al: Effect of recombinant human erythropoietin combined with granulocyte/macrophage colony-stimulating factor in the treatment of patients with myelodysplastic syndrome. GM/EPO MDS Study Group. Blood2000; 95:1175-1179.
- Jadersten M, Montgomery SM, Dybedal I, et al: Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood2005; 106:803-811.
- Casadevall N, Durieux P, Dubois S, et al: Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: a randomized, controlled trial. Blood2004; 104:321-327.
- Vadhan-Raj S, Keating M, LeMaistre A, et al: Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. N Engl J Med1987; 317:1545-1552.
- Antin JH, Smith BR, Holmes W, Rosenthal DS: Phase I/II study of recombinant human granulocyte-macrophage colony-stimulating factor in aplastic anemia and myelodysplastic syndrome. Blood1988; 72:705-713.
- Ganser A, Volkers B, Greher J, et al: Recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes—a phase I/II trial. Blood1989; 73:31-37.
- Negrin RS, Haeuber DH, Nagler A, et al: Treatment of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor. A phase I-II trial. Ann Intern Med1989; 110:976-984.
- Negrin RS, Haeuber DH, Nagler A, et al: Maintenance treatment of patients with myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor. Blood1990; 76:36-43.
- Gradishar WJ, Le Beau MM, O'Laughlin R, et al: Clinical and cytogenetic responses to granulocyte-macrophage colony-stimulating factor in therapy-related myelodysplasia. Blood1992; 80:2463-2470.
- Yuo A, Kitagawa S, Okabe T, et al: Recombinant human granulocyte colony-stimulating factor repairs the abnormalities of neutrophils in patients with myelodysplastic syndromes and chronic myelogenous leukemia. Blood1987; 70:404-411.
- Verhoef G, Boogaerts M: In vivo administration of granulocyte-macrophage colony stimulating factor enhances neutrophil function in patients with myelodysplastic syndromes. Br J Haematol1991; 79:177-184.
- Estey E, Thall P, Andreeff M, et al: Use of granulocyte colony-stimulating factor before, during, and after fludarabine plus cytarabine induction therapy of newly diagnosed acute myelogenous leukemia or myelodysplastic syndromes: comparison with fludarabine plus cytarabine without granulocyte colony-stimulating factor [see comments]. J Clin Oncol1994; 12:671-678.
- Estey EH, Thall PF, Pierce S, et al: Randomized phase II study of fludarabine + cytosine arabinoside + idarubicin ± all-trans retinoic acid ± granulocyte colony-stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome. Blood1999; 93:2478-2484.
- Ohno R, Tomonaga M, Kobayashi T, et al: Effect of granulocyte colony-stimulating factor after intensive induction therapy in relapsed or refractory acute leukemia. N Engl J Med1990; 323:871-877.
- Dombret H, Chastang C, Fenaux P, et al: A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group [see comments]. N Engl J Med1995; 332:1678-1683.
- Rowe JM, Andersen JW, Mazza JJ, et al: A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (aged 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood1995; 86:457-462.
- Stone RM, Berg DT, George SL, et al: Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J Med1995; 332:1671-1677.
- Estey E, Thall PF, Kantarjian H, et al: Treatment of newly diagnosed acute myelogenous leukemia with granulocyte-macrophage colony-stimulating factor (GM-CSF) before and during continuous-infusion high-dose ara-C + daunorubicin: comparison to patients treated without GM-CSF. Blood1992; 79:2246-2255.
- Lowenberg B, van Putten W, Theobald M, et al: Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med2003; 34:743-752.
- Welte K, Zeidler C, Reiter A, et al: Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia. Blood1990; 75:1056-1063.
- Dale DC, Bonilla MA, Davis MW, et al: A randomized controlled phase III trial of recombinant human granulocyte colony-stimulating factor (filgrastim) for treatment of severe chronic neutropenia. Blood1993; 81:2496-2502.
- Hammond WP, Price TH, Souza LM, et al: Treatment of cyclic neutropenia with granulocyte colony-stimulating factor. N Engl J Med1989; 320:1306-1311.
- Mempel K, Pietsch T, Menzel T, et al: Increased serum levels of granulocyte colony-stimulating factor in patients with severe congenital neutropenia. Blood1991; 77:1919-1922.
- Dong F, Brynes RK, Tidow N, et al: Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia. N Engl J Med1995; 333:487-493.
- Freedman MH, Bonilla MA, Fier C, et al: Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy. Blood2000; 96:429-436.
- Jeha S, Chan KW, Aprikyan AG, et al: Spontaneous remission of granulocyte colony-stimulating factor-associated leukemia in a child with severe congenital neutropenia. Blood2000; 96:3647-3649.
- Bellanne-Chantelot C, Clauin S, Leblanc T, et al: Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register. Blood2004; 103:4119-4125.
- Rosenberg PS, Alter BP, Bolyard AA, et al: The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood2006; 107:4628-4635.
- Peters C, Minkov M, Matthes-Martin S, et al: Leucocyte transfusions from rhG-CSF or prednisolone stimulated donors for treatment of severe infections in immunocompromised neutropenic patients. Br J Haematol1999; 106:689-696.
- Price TH, Bowden RA, Boeckh M, et al: Phase I/II trial of neutrophil transfusions from donors stimulated with G-CSF and dexamethasone for treatment of patients with infections in hematopoietic stem cell transplantation. Blood2000; 95:3302-3309.
- Adkins DR, Goodnough LT, Shenoy S, et al: Effect of leukocyte compatibility on neutrophil increment after transfusion of granulocyte colony-stimulating factor-mobilized prophylactic granulocyte transfusions and on clinical outcomes after stem cell transplantation. Blood2000; 95:3605-3612.
- Elias AD, Ayash L, Anderson KC, et al: Mobilization of peripheral blood progenitor cells by chemotherapy and granulocyte-macrophage colony-stimulating factor for hematologic support after high-dose intensification for breast cancer. Blood1992; 79:3036-3044.
- Brugger W, Birken R, Bertz H, et al: Peripheral blood progenitor cells mobilized by chemotherapy plus granulocyte-colony stimulating factor accelerate both neutrophil and platelet recovery after high-dose VP16, ifosfamide and cisplatin. Br J Haematol1993; 84:402-407.
- Chao NJ, Schriber JR, Grimes K, et al: Granulocyte colony-stimulating factor “mobilized” peripheral blood progenitor cells accelerate granulocyte and platelet recovery after high-dose chemotherapy. Blood1993; 81:2031-2035.
- Kritz A, Crown JP, Motzer RJ, et al: Beneficial impact of peripheral blood progenitor cells in patients with metastatic breast cancer treated with high-dose chemotherapy plus granulocyte-macrophage colony-stimulating factor. A randomized trial. Cancer1993; 71:2515-2521.
- Demuynck H, Delforge M, Verhoef G, et al: Comparative study of peripheral blood progenitor cell collection in patients with multiple myeloma after single-dose cyclophosphamide combined with rhGM-CSF or rhG-CSF [see comments]. Br J Haematol1995; 90:384-392.
- Kawano Y, Takaue Y, Watanabe T, et al: Efficacy of the mobilization of peripheral blood stem cells by granulocyte colony-stimulating factor in pediatric donors. Cancer Res1999; 59:3321-3324.
- Negrin RS, Kusnierz-Glaz CR, Still BJ, et al: Transplantation of enriched and purged peripheral blood progenitor cells from a single apheresis product in patients with non-Hodgkin's lymphoma. Blood1995; 85:3334-3341.
- Williams SF, Lee WJ, Bender JG, et al: Selection and expansion of peripheral blood CD34+ cells in autologous stem cell transplantation for breast cancer. Blood1996; 87:1687-1691.
- Lopez M, Lemoine FM, Firat H, et al: Bone marrow versus peripheral blood progenitor cells CD34 selection in patients with non-Hodgkin's lymphomas: different levels of tumor cell reduction. Implications for autografting. Blood1997; 90:2830-2838.
- Paquette RL, Dergham ST, Karpf E, et al: Ex vivo expanded unselected peripheral blood: progenitor cells reduce posttransplantation neutropenia, thrombocytopenia, and anemia in patients with breast cancer. Blood2000; 96:2385-2390.
- Lee SM, Radford JA, Dobson L, et al: Recombinant human granulocyte colony-stimulating factor (filgrastim) following high-dose chemotherapy and peripheral blood progenitor cell rescue in high-grade non-Hodgkin's lymphoma: clinical benefits at no extra cost. Br J Cancer1998; 77:1294-1299.
- Ringden O, Labopin M, Gorin NC, et al: Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versus-host disease and death: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol2004; 22:416-423.
- Khoury HJ, Loberiza FR, Ringden O, et al: Impact of posttransplantation G-CSF on outcomes of allogeneic hematopoietic stem cell transplantation. Blood2006; 107:1712-1716.
- Grigg AP, Roberts AW, Raunow H, et al: Optimizing dose and scheduling of filgrastim (granulocyte colony-stimulating factor) for mobilization and collection of peripheral blood progenitor cells in normal volunteers [see comments]. Blood1995; 86:4437-4445.
- Bensinger WI, Clift R, Martin P, et al: Allogeneic peripheral blood stem cell transplantation in patients with advanced hematologic malignancies: a retrospective comparison with marrow transplantation. Blood1996; 88:2794-2800.
- Prosper F, Stroncek D, Verfaillie CM: Phenotypic and functional characterization of long-term culture-initiating cells present in peripheral blood progenitor collections of normal donors treated with granulocyte colony-stimulating factor. Blood1996; 88:2033-2042.
- Tanaka R, Matsudaira T, Aizawa J, et al: Characterization of peripheral blood progenitor cells (PBPC) mobilized by filgrastim (rHuG-CSF) in normal volunteers: dose-effect relationship for filgrastim with the character of mobilized PBPC. Br J Haematol1996; 92:795-803.
- Zeng D, Dejbakhsh-Jones S, Strober S: Granulocyte colony-stimulating factor reduces the capacity of blood mononuclear cells to induce graft-versus-host disease: impact on blood progenitor cell transplantation. Blood1997; 90:453-463.
- Anderlini P, Donato M, Lauppe MJ, et al: A comparative study of once-daily versus twice-daily filgrastim administration for the mobilization and collection of CD34+ peripheral blood progenitor cells in normal donors. Br J Haematol2000; 109:770-772.
- Bensinger WI, Martin PJ, Storer B, et al: Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med2001; 344:175-181.
- Morton J, Hutchins C, Durrant S: Granulocyte-colony-stimulating factor (G-CSF)-primed allogeneic bone marrow: significantly less graft-versus-host disease and comparable engraftment to G-CSF-mobilized peripheral blood stem cells. Blood2001; 98:3186-3191.
- Storek J, Dawson MA, Storer B, et al: Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood2001; 97:3380-3389.
- Lapierre V, Auperin A, Tayebi H, et al: Increased presence of anti-HLA antibodies early after allogeneic granulocyte colony-stimulating factor-mobilized peripheral blood hematopoietic stem cell transplantation compared with bone marrow transplantation. Blood2002; 100:1484-1489.
- Guardiola P, Runde V, Bacigalupo A, et al: Retrospective comparison of bone marrow and granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells for allogeneic stem cell transplantation using HLA identical sibling donors in myelodysplastic syndromes. Blood2002; 99:4370-4378.
- Morris ES, MacDonald KP, Hill GR: Stem cell mobilization with G-CSF analogs: a rational approach to separate GVHD and GVL?. Blood2006; 107:3430-3435.
- Arpinati M, Green CL, Heimfeld S, et al: Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. Blood2000; 95:2484-2490.