Bethesda Handbook of Clinical Oncology, 2nd Edition

Supportive Care

35

Hematopoietic Growth Factors

Philip M. Arlen

James L. Gulley

Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Hematologic toxicity from chemotherapy is the most prevalent serious side effect encountered in medical oncology clinical practice. Reduction in all three cell lineages (i.e., white blood cells, red blood cells, and platelets) can lead to complications such as fever, which complicates neutropenia and requires patient hospitalization, and severe anemia or thrombocytopenia, which may necessitate transfusion.

All three cell lines arise from differentiation of totipotent hematopoietic stem cells; the fully differentiated cells are mature leukocytes, erythrocytes, or platelets (the breakdown product of megakaryoctes). Hematopoietic growth factors are the regulatory molecules for all three cell lines. Several hematopoietic growth factors have been identified, synthesized, and approved for use in clinical practice to mitigate hematologic toxicity caused by chemotherapy. Recommendations in this chapter come primarily from the evidence-based clinical practice guidelines of the American Society of Clinical Oncology (ASCO) (1,2,3).

In many clinical situations, hematopoietic growth factor is used both judiciously (4) and in a cost-effective manner (5,6). New agents continue to be sought, developed, and evaluated in clinical trials.

MYELOID GROWTH FACTORS: GRANULOCYTE COLONY-STIMULATING FACTOR AND GRANULOCYTE MACROPHAGE COLONY-STIMULATING FACTOR

Currently, two myeloid growth factors have been approved for clinical use by the U.S. Food and Drug Administration (FDA). They are filgrastim (granulocyte colony-stimulating factor [G-CSF; Neupogen and Neulasta (Pegfilgrastim)]; Amgen, Inc. and sargramostim (granulocyte macrophage colony-stimulating factor [GM-CSF, Leukine; Berlex Laboratories (Schering AG)]. Whereas G-CSF is specific for the production of neutrophils, GM-CSF stimulates the production of monocytes and eosinophils in addition to neutrophils. There is no firm clinical evidence to indicate that one agent produces a superior clinical benefit over the other. Although exogenous myeloid growth factor decreases the duration of absolute neutropenia, it does not affect the extent of the neutropenia. FDA-recommended doses of growth factors are listed in Table 35.1.

TABLE 35.1. Summary of Growth Factor Indications

Drug/FDA-recommended dosing

Indications

FDA, U.S. Food and Drug Administration; pts, patients; ANC, absolute neutrophil count; BMT, bone marrow transplant; AML, acute myelogenous leukemia.

Filgrastim

·         5 µg/kg/d s.c.—initiated 24 h after completion of chemotherapy—continued daily until the postchemotherapy ANC is = 10 × 109 cells/L—may require as many as 10–14 daily injections.

·         For stem cell mobilization and transplant—10 µg/kg/d s.c. may be used.

·         Cancer pts receiving myelosuppressive chemotherapy.

·         Pts with nonmyeloid malignancy following BMT

·         Pts with severe chronic neutropenia following induction chemotherapy for AML mobilization of stem cells for transplant

Pegfilgrastim

·         Single 6-mg fixed dose, once per chemotherapy cycle

Cancer pts receiving myelosuppressive chemotherapy

Sargramostim

·         Dose for chemotherapy-induced neutropenia is 250 µg/m2/d s.c

·         Following autologous bone marrow transplant—250 µg/m2/d given by a 2-hour i.v. infusion

·         Following autologous BMT

·         Delay or failure of BMT engraftment

·         Following induction chemotherapy for AML in older pts

·         Mobilization of stem cells for transplant

Epoetin α

chemotherapy for nonmyeloid malignancies

·         current FDA-approved recommended dose—150 U/kg s.c. three times a wk—can be increased to 300 U/kg three times weekly if an adequate response (rise in hemoglobin = 1 g/dL) does not occur after 4 wk of therapy.

·         40,000 units s.c. weekly—well tolerated and as effective as a three times a week dosing.

Chemotherapy induced anemia

Darbopoetin α

Same as epoetin α

·         approved recommended starting dose is 2.25 µg/kg s.c.—dose should be adjusted to maintain a target hemoglobin level
– for a < 1.0 g/dL increase in hemoglobin after 6 wk of therapy, dose should be increased up to 4.5 µg/kg
– if hemoglobin increases by more than 1.0 g/dL in a 2-wk period or exceeds 12 g/dL, the dose should be reduced by 25%
– if hemoglobin exceeds 13 g/dL, doses should be temporarily withheld until the hemoglobin falls to 12 g/dL

 

Oprelvekin

·         dose in adult is 50 µg/kg s.c. once daily

·         therapy begins 6–24 h after chemotherapy is completed

·         continues until the postnadir platelet count is = 50,000 µL.

Pts undergoing myelosuppressive chemotherapy for nonmyeloid malignancies who are at high risk for developing severe thrombocytopenia

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INDICATIONS

Primary Prophylaxis

Myeloid growth factors were initially recommended as primary prophylaxis after a first cycle of chemotherapy for patients with a more than 40% probability of experiencing febrile neutropenia (FN). This was based upon the Lyman study that examined the cost of hospitalization and the point at which G-CSF became a cost-effective option in preventing FN (5). ASCO guidelines are currently being updated to reflect the threshold value of the probability of experiencing FN as being greater than 20% to 25%, the value at which it currently becomes cost effective to use growth factors to prevent hospitalization. This probability includes patients who are receiving high-dose chemotherapeutic regimens. The use of growth factors may be strongly considered in patients who are thought to be at higher risk for chemotherapy-induced infectious complications because of (a) preexisting neutropenia caused by disease, (b) extensive earlier chemotherapy, (c) previous irradiation to areas containing large amounts of bone marrow, (d) a history of FN during earlier myelosuppressive treatments that have been equally or less myelosuppressive, or (e) conditions that potentially increase the risk of a serious infection (e.g., poor performance status, decreased immune function, open wounds, and preexisting active tissue infections).

Secondary Prophylaxis

To date, there have been no published regimens demonstrating a benefit of either disease-free survival or overall survival to patients when CSF support is implemented as a secondary prophylaxis along with dose-intense chemotherapy. Therefore, in the absence of clinical data or other compelling reasons for maintaining the dose intensity of chemotherapy, CSF support should be administered following FN or severe or prolonged neutropenia after a previous chemotherapy cycle while implementing conventional chemotherapy doses.

Treatment of Neutropenic Patients

A number of clinical trials strongly support the recommendation that growth factors should not be used routinely for uncomplicated fever and neutropenia, which are defined as fever for at least 10 days; when there is no evidence of pneumonia, cellulitis, abscess, sinusitis, hypotension, multiorgan dysfunction, or invasive fungal infection; and in the absence of uncontrolled malignancies (7,8,9,10,11,12,13,14). Although a decrease in the period of neutropenia [absolute neutrophil count (ANC) <500 per µL] has been demonstrated with growth factors, no clinical benefit has been consistently noted. Growth factors, however, may be considered along with antibiotics in some patients with FN who are at a higher risk for infection-associated complications and in those who have prognostic factors that are predictive of a poor clinical outcome. These factors include absolute neutropenia, ANC < 100 per µL, uncontrolled primary disease, hypotension, multiorgan dysfunction (sepsis syndrome), and invasive fungal infection. It is important to note that the benefits of CSF in these circumstances have not been proven.

Transplantation and Peripheral Blood Stem Cell Mobilization

CSFs are used to mobilize peripheral blood stem cells (PBSCs) and after PBSC infusion. Using both G-CSF and GM-CSF can lead to rapid hematopoietic recovery, shorter hospitalization, and, possibly, reduced costs (15,16,17).

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Leukemias and Myelodysplastic Syndrome

CSFs can be given after induction chemotherapy to patients with acute myelogenous leukemia (AML) if the benefits in reducing the length of hospitalization outweighs the costs of administering the growth factor (18,19). Patients who are 55 years or older are more likely to benefit from the use of growth factors. Despite concerns that myeloid growth factors might actually induce the growth of the underlying leukemia, clinical studies have not shown any detrimental effect from their use in this setting. Data on the use of growth factors in leukemic patients younger than 55 years are limited.

There are sufficient data to recommend the administration of G-CSF in patients with acute lyphoblastic leukemia (ALL) after the completion of the first few days of initial induction chemotherapy or after the first postremission course, thereby shortening the duration of neutropenia (ANC <1000 per µL) by approximately 1 week (20,21). However, data are not sufficient to recommend CSF in patients with refractory or relapsed ALL.

In myelodysplastic syndrome (MDS), there are no data about the safety of long-term use of myeloid growth factors; however, its intermittent use may be considered in patients with MDS who have severe disease-related neutropenia and recurrent infections.

ERYTHROCYTIC GROWTH FACTOR: EPOETIN

Indication: Anemia in Cancer Patients

Erythropoietin is specific for differentiation of erythrocytes (Table 35.1). Anemia is multifactorial in patients with cancer. Before initiating supportive treatment with agents such as erythropoietin stimulating proteins (ESP), the selection of patients is important to ensure the cost-effectiveness of the treatment. Patients who have anemia before commencing the antineoplastic treatment and those who experience a decrease in hemoglobin level by more than 2 g per dL after the first cycle of chemotherapy are at greatest risk for transfusion of anemia.

American Society of Hematology and American Society of Clinical Oncology Clinical Practice Guidelines

The recommendations for using erythropoietin in chemotherapy-induced anemia are summarized in Table 35.2 (22). Recently, the FDA approved the use of darbepoetin-α for the treatment of chemotherapy-induced anemia. It has a longer half-life than epoetin-α and requires less frequent dosing. The recommended dosage of epoetin-α and darbepoetin-α is listed in Table 35.1.

TABLE 35.2. American Society of Hematology/American Society of Clinical Oncology (ASH/ASCO) Practice Guidelines for Anemia in Cancer Patients

ESP, erythropoietin stimulating proteins; Hgb, hemoglobin; MDS, myelodysplastic syndrome; TIBC, total iron-binding capacity.
Blood transfusion is also a therapeutic option
If anemia persists despite optimal treatment of underlying disease, ESP may be indicated.

ESP use in chemotherapy-associated anemia

ESP is indicated

Hgb = 12 g/dLa

ESP is used on the basis of clinical circumstance

Hgb 10–12 g/dLa

Insufficient data to suggest ESP use

Hgb = 12 g/dL

ESP use in hematologic disease states

ESP is indicated

Low-risk MDS

Insufficient data to suggest ESP use

Multiple myeloma, non-Hodgkin lymphoma, or chronic lymphocytic leukemia in absence of chemotherapyb

Response to ESP Treatment

Goal Hgb 10–12 g/dL

 

If no response is seen in 6–8 wk (= 1 g/dL rise) with appropriate dose escalation, discontinue ESPa

Monitoring during ESP Treatment

Periodic total iron, TIBC, transferrin, and ferritin, with iron replacement as indicated

 

PLATELET GROWTH FACTOR: INTERLEUKIN-11

Thrombocytopenia can be a life-threatening consequence of antineoplastic treatments and requires monitoring of platelet counts, and platelet transfusions are required when it is necessary to prevent or mitigate hemorrhagic complications. Patients who are at high risk for bleeding or who experience delays in receiving planned chemotherapy include those with poor bone marrow reserve or a previous history of bleeding, those who receive regimens highly toxic to bone marrow, and those with a potential bleeding site (e.g., necrotic tumor) (23).

Although several thrombopoietic agents are in clinical development, oprelvekin (Neumega; Genetics Institute, Inc.) is the only thrombocytopoietic agent that has received FDA approval for clinical use. Oprelvekin is a product of recombinant DNA technology and is nearly homologous with native interleukin-11 (IL-11), lacking only an amino-terminal proline residue. Oprelvekin promotes the proliferation of hematopoietic stem cells, induces the maturation of megakaryocytes, and has clinically been shown to shorten the duration of thrombocytopenia and reduce the need for platelet transfusions in patients who develop

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platelet counts of <20 × 103 per µL after prior antineoplastic treatments (24). Table 35.1 provides the recommended dose of IL-11.

Fortunately, iatrogenic thrombocytopenia that requires platelet transfusion or causes major bleeding is relatively uncommon, although its occurrence tends to increase with cumulative cycles of chemotherapy that are toxic to hematopoietic progenitor cells. At present, neither the ASCO nor the National Comprehensive Cancer Network (NCCN) has published formal guidelines for using thrombopoietic growth factors, although they are under development. The results of clinical trials and economic analyses with this class of agents will aid in determining their optimal clinical use.

REFERENCES

  1. Ozer H, Armitage JO, Bennett CL et al. American Society of Clinical Oncology. Update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol2000;20(18):3558–3585.
  2. Rizzo JD, Lichtin AE, Woolf SH, et al. Use of ESP in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol2002;20(19):4083–4107.
  3. Bennett CL, Smith TJ, Weeks JC, et al. Use of hematopoietic colony-stimulating factors: the American Society of Clinical Oncology survey. J Clin Oncol1996;14:2511–2520.
  4. Croockewit AJ, Bronchud MH, Aapro MS, et al. A European perspective on haematopoietic growth factors in haemato-oncology: report of an expert meeting of the EORTC. Eur J Cancer1997;33:1732–1746.
  5. Lyman GH, Kuderer M, Grene J, et al. The economics of febrile neutropenia: implications for the use of colony-stimulating factors. Eur J Cancer1998;34:1857–1864.
  6. Schulman KA, Dorsainvil D, Yabroff KR, et al. Prospective economic evaluation accompanying a trial of GM-CSF/IL-3 in patients undergoing autologous bone marrow transplantation for Hodgkin's and non-Hodgkin's lymphoma. Bone Marrow Transplant1998;21:607–614.
  7. Maher DW, Lieschki 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.

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  1. Mitchell PLR, Morland B, Stevens MCG, et al. Granulocyte colony-stimulating factor in established febrile neutropenia: a randomized study of pediatric patients. J Clin Oncol1997;15:1163–1170.
  2. 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.
  3. Anaissie E, Vartivarian S, Bodey GP, et al. Randomized comparison between antibiotics alone and antibiotics plus granulocyte-macrophage colony-simulating factor (Escherichia coli-derived) in cancer patients with fever and neutropenia. Am J Med1996;100:17–23.
  4. 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.
  5. Ravaud A, Chevreau C, Cany L, et al. Granulocyte-macrophage colony-stimulating factor inpatients 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.
  6. Riikonen P, Saarinen UM, Makipernaa A, et al. Recombinant human granulocyte-macrophage colony-stimulating factor in the treatment of febrile neutropenia: a double-blind placebo-controlled study in children. Pediatr Infect Dis J1994;13:197–202.
  7. Biesma B, de Vries EG, Willemse PH, et al. Efficacy and tolerability of recombinant human granulocyte-macrophage colony-stimulating factor in patients with chemotherapy-related leukopenia and fever. Eur J Cancer1990;26:932–936.
  8. Ho AD, Young D, Maruyama M, et al. Pluripotent and lineage-committed CD34+ subsets in leukapheresis products mobilized by G-CSF, GM-CSF vs. a combination of both. Exp Hematol1996;24:1460–1468.
  9. Meisenberg B, Brehm T, Schmeckel A, et al. A combination of low-dose cyclophosphamide and colony-stimulating factors is more cost-effective than granulocyte-colony-stimulating factors alone in mobilizing peripheral blood stem and progenitor cells. Transfusion1998;38:209–215.
  10. Cesana C, Carlo-Stella C, Regazzi E, et al. CD34+ cells mobilized by cyclophosphamide and granulocyte colony stimulating factor (G-CSF) are functionally different from CD34+ cells mobilized by G-CSF. Bone Marrow Transplant1998;21:561–568.
  11. Bennett CL, Stinson TJ, Laver JH, et al. Cost analyses of adjunct colony stimulating factors for acute leukemia: can they improve clinical decision-making. Leuk Lymphoma2000;37:65–70.
  12. Bennett DL, Hynes D, Godwin J, et al. Economic analysis of granulocyte colony-stimulating factor as adjunct therapy for older patients with acute myelogenous leukemia (AML): estimates from a Southwest Oncology Group clinical trial. Cancer Invest2001;19(6):603–610.
  13. Pui C, Boyett JM, Hughes WT, et al. Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia. N Engl J Med1997;336:1781–1787.
  14. Laver J, Amylon M, Desai S, et al. Effects of r-met HuG-CSF in an intensive treatment for T-cell leukemia and advanced stage lymphoblastic lymphoma of childhood: a Pediatric Oncology Group pilot study. J Clin Oncol1998;16:522–526.
  15. Rizzo JD, Lichtin AE, Woolf SH, et al. American Society of Clinical Oncology. American Society of Hematology. Use of ESP in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol2002;20(19):4083–4107.
  16. Rubenstein EB, Elting L. Incorporating new modalities into practice guidelines: platelet growth factors. Oncology1998;12:381–386.
  17. Tepler I, Elias S, Smith JW II, et al. A randomized placebo-controlled trial of recombinant human IL-11 in cancer patients with severe thrombocytopenia due to chemotherapy. Blood1996;87:3607–3614.