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

John Glaspy

SUMMARY OF KEY POINTS

  

   

Anemia is very common in oncology patients and is multifactorial.

  

   

Many patients with cancer have in part the anemia of chronic disease.

  

   

The anemia of chronic disease is associated with decreased absorption of oral iron and decreased ability to access storage iron pools.

  

   

Iron-restricted erythropoiesis may limit the efficacy of erythropoietic agents for the treatment of anemia in these patients and can be overcome with parenteral iron.

  

   

Treatment of anemia in cancer patients reduces transfusions and improves quality of life.

  

   

The safety of increasing hemoglobin levels to greater than 13 g/dL is not established, and the target hemoglobin level during treatment should be 12 g/dL.

  

   

Neutropenia in oncology is usually due to treatment.

  

   

Myeloid growth factors can be used to reduce infection risk in patients in whom the risk is unacceptably high, and this is preferable to delaying or reducing the dose of chemotherapy when cure is the intent.

  

   

There are new agents for the stimulation of platelet production in clinical development.

INTRODUCTION

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,[1] 5×1010 neutrophils,[2] and 2.5×1011 platelets,[3] 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[4] 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

Pathophysiology

Anemia is common in cancer patients [5] [6] 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.[7]More recently, it has been shown that inflammation is frequently associated with increased production of the iron-regulatory peptide, hepcidin, by the liver. [8] [9] [10] [11] Hepcidin binds to and inactivates the iron transporter, ferroportin, impairing both absorption of dietary iron and access to storage iron pools. [12] [13] 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.

 

 

Management

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.[14] 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,[15] which has a longer half-life. In randomized, placebo-controlled trials, both epoetin alfa [16] [17] [18] [19] [20] and darbepoetin alfa [21] [22] 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.[23] 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. [24] [25] [26] [27] 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.[28] 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.[29] 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. [30] [31] When analysis of data from randomized trials confirmed that ESP therapy for anemia is associated with improvements in fatigue in cancer patients, [16] [20] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] 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. [47] [48] 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[49] or 500 mg[50]; every-3-week dosing on the same day as chemotherapy seems to be as effective as asynchronous dosing.[51] 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.[52] 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.[53] Moreover, later intervention will probably result in more fatigue for cancer patients. Both of the recently developed guidelines by the National Comprehensive Cancer Network[54] and the European Organization for Research and Treatment of Cancer (EORTC)[55] 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.[56] When patients are treated with ESPs, evidence of iron-restricted erythropoiesis can develop, even in the presence of apparently adequate body iron stores.[57] 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.[58] 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. [59] [60] [61] 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

Preparation

Brand Name

Administration

Low-molecular-weight dextran

Infed

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
dose (mL) = 0.0442 (desired Hb - observed Hb) × LBW + (0.26 × LBW)
is feasible in one session.[*] Premedication with corticosteroids will decrease the frequency of myalgia and arthralgias following TDI.[†]

High-molecular-weight dextran

Dexferrum

Similar to low-molecular-weight dextran, although reported rates of adverse drug reaction are greater [60] [61] and the use of this preparation with ESP therapy in cancer patients cannot be supported.

Ferric gluconate complex

Ferrlecit

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.

Iron sucrose

Venofer

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.[62] Similar results have been reported in trials using ferric gluconate[14] 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. [63] [64]

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.[65] 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[66]; 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. [67] [68] [69] Two parameters that can be reliably determined using flow cytometric techniques available in some hemogram autoanalyzers include the percentage of hypochromic red cells [70] [71] [72] and the reticulocyte hemoglobin content. [71] [73] [74] [75] [76] [77] 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.[78] 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,[79] 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. [80] [81] 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. [82] [83] 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.[84] There is in vitro evidence that ESPs may synergize with endogenous thrombopoietin in inducing platelet activation[85] and that platelets may be activated through interaction with young red blood cells.[86] 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[87] or with head and neck cancer undergoing radiation therapy,[88] 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. [89] [90] [91] [92] 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.[93]

It is important to bear in mind that anemia is associated with cellular hypoxia, especially in tumor cells, [94] [95] [96] [97] [98] [99] [100] and that tumor cell hypoxia has been associated with both enhanced mutation rates and selection of more apoptosis-resistant or invasive phenotypes [97] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] and with resistance to both radiation [103] [118] [119] [120] [121] [122] [123] and chemotherapy. [124] [125] [126] Anemia is an independent negative prognostic factor across a wide range of malignancies[127]; 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, [97] [128] [129] 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. [98] [99] [100] [130] 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. [131] [132] [133] [134] 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.[135] 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. [136] [137]

Polycythemia

Paraneoplastic polycythemia is an uncommon syndrome observed in a variety of human cancers[138] including renal cell carcinoma, [139] [140] hepatocellular cancers, [141] [142] [143] Wilms’ tumor [144] [145]and, rarely, other malignancies. [146] [147] [148] [149] The mechanism is usually ectopic production of EPO, [147] [148] [150] [151] [152] although increased EPO levels are not always observed[139] and other mechanisms, such as ectopic renin secretion, have been suggested.[149] 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.[140] 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.[139]

DISORDERS OF WHITE CELLS

Neutropenia

Pathophysiology

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.[153] 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 [154] [155] [156] [157] [158] as well as mature neutrophil function. [2] [159] [160] [161] GM-CSF plays a critical role in pulmonary homeostasis, [162] [163] [164] [165] and a defect in this function seems to be involved in the pathogenesis of pulmonary alveolar proteinosis. [165] [166] [167] There are also negative regulatory factors of neutrophil production that are less well understood, including neutrophil elastase[168] and the src family kinases.[169] 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.[170]

Management

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. [171] [172] [173] [174] 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, [175] [176] others not demonstrating an impact on febrile neutropenia, [177] [178] [179] and some demonstrating an effect on febrile neutropenia only during the first chemotherapy cycle. [180] [181] 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.[182] [183] 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.[184] 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.[185]

Pegfilgrastim has a longer half life than filgrastim, particularly following the administration of chemotherapy.[186] 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. [187] [188] [189] 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.[190] 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. [191] [192] The issue of the cost effectiveness of myeloid growth factors used to prevent febrile neutropenia remains controversial. [193] [194] [195] [196] [197] 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.[198] 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.[199] 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. [200] [201] 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.[202] In animal models of sepsis, the addition of G-CSF to antibiotic treatment results in improved outcomes as compared with antibiotics alone.[203] 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,[204] although the authors raise questions regarding the cost-effectiveness of filgrastim in this setting.[205] The clinician has two options in the managing a cancer chemotherapy patient at risk of infection: prophylactic antibiotics[206] 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.[184] 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. [207] [208] [209] [210] [211] [212] 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[213] and lymphoma treatment[214] 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,[215] 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. [216] [217] [218] [219] 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

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 [220] [221] [222] [223] [224] [225] The pathophysiology of this syndrome seems to be production of parathyroid hormone-like peptides coupled with G-CSF. [226] [227] [228] [229] Isolated production of G-CSF can occur in any tumor and produce a neutrophilic leukocytosis [230] [231] [232]; 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

Thrombocytopenia

Pathophysiology

The primary regulator of the platelet count in humans is thrombopoietin, [233] [234] a glycoprotein that is produced primarily in the liver and cleared primarily by platelets and their precursors. Thrombopoietin induces growth and development of megakaryocytes[235]; 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 [236] [237] [238] [239] [240]; its primary constitutive role seems to be the maintenance of female fertility. [234] [241] 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. [242] [243]

Management

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. [244] [245] [246] [247] 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) [234] [238] [248] were introduced into clinical trials. Therapy with either rTPO [249] [250] [251] [252] or MGDF [253] [254] [255] [256] 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,[257] 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. [258] [259] [260] [261]Eltrombopag is an orally bioavailable member of a new class of small molecule thrombopoietin receptor agonists.[262] 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, [263] [264] [265] [266] [267] [268] [269] [270] presumably because of increased clearance of this factor by the expanded platelet precursor pool. [271] [272] 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.[273] Both AMG 531 and eltrombopag have shown promising results in the treatment of immune thrombocytopenic purpura. [261] [274] 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.

 

 

Thrombocytosis

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,[275] 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

Myelodysplastic Syndrome

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 [276] [277] [278] [279] [280] [281] [282] [283] [284] [285] and darbepoetin alfa [286] [287] [288] [289] 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, [290] [291] [292] [293] [294] [295] [296] [297] although the cost-effectiveness of this approach has been questioned.[298] 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 [299] [300] [301] [302] [303] [304] and improve neutrophil function [305] [306] in neutropenic patients with MDS. Myeloid growth factors have also been used to support myelosuppressive therapy for MDS. [307] [308] 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.[309] 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. [310] [311] [312] Attempts to utilize myeloid growth factors to recruit AML cells into cycle and enhance their sensitivity to chemotherapy have met with mixed results. [307] [313] [314]

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. [315] [316] [317] Patients with severe congenital neutropenia frequently require relatively high doses of filgrastim,[318] 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. [319] [320] [321] [322] [323]

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, [324] [325] although in the postmarrow transplant setting human lymphocyte antigen incompatibility may limit the benefit.[326] 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. [327] [328] [329] [330] [331] [332] 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. [333] [334] [335] [336] 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. [337] [338] [339] The use of peripheral blood progenitor cells as an alternative to marrow is feasible in the allogeneic transplant setting as well. [340] [341] [342] [343] [344] [345] [346] [347] [348] [349] [350] [351] Finally, myeloid growth factors can be used to mobilize and harvest dendritic cell precursors for cancer vaccine applications.[352]

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