Abstract
Although drug-induced agranulocytosis is infrequent, it is of concern as the mortality rate ranges from 6 to 10%. Since the approval of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), these drugs have been increasingly used in the management of drug-induced agranulocytosis. Unfortunately, most of the data regarding the use of these agents in patients with drug-induced agranulocytosis comes from case reports. In light of the low incidence of drug-induced agranulocytosis, the large variety of offending drugs with potentially different toxic mechanisms and the wide range of neutropenia duration among patients with agranulocytosis, randomised, double-blind studies are unlikely to be performed.
Case reports provide promising results with a shortening in the duration of agranulocytosis, a possible reduction in the duration of hospitalisation and the fatality rate in patients treated with haematopoietic growth factors (HGF) compared with historical controls. A therapeutic effect is also suggested by reports of reductions in the neutrophil count after HGF discontinuation following an initial increase.
The results of recent case series are less positive, with only a moderate, but usually not significant, reduction in the duration of neutropenia in patients treated with HGF, as compared with those receiving routine care. A Japanese study indicated that G-CSF was effective in patients with mild-to-moderate antithyroid drug-induced neutropenia, whereas no clear benefit was apparent in those with severe neutropenia.
Several factors, for example, early recognition and improved management of individual cases with better supportive care, have contributed to a decrease in the overall mortality of drug-induced agranulocytosis. HGF are expected to further reduce mortality. Guidelines for the use of HGF in patients with febrile neutropenia, as established by the American Society of Clinical Oncology, are probably valuable for the management of drug-induced agranulocytosis. In accordance with these recommendations, the use of HGF may be recommended in patients with severe neutropenia and/or poor prognostic factors. Whether the absence of myeloid precursors or presence of promyelocytes or myelocytes in bone marrow examination represents optimal conditions for HGF treatment is still unknown. Most authors agree that treatment should be administered early in the course of the disease. An interesting approach, in which treatment decisions are based on the granulocyte count 4 hours after a single dose of G-CSF in patients with anthithyroid drug-associated neutropenia should be more extensively evaluated.
Similar content being viewed by others
References
Schultz W. Über eigenartige Halserkrankungen. Dtsch Med Wochenschr 1922; 48: 1965–50
Standardization of definitions and criteria of causality assessment of adverse drug reactions: drug-induced cytopenia [editorial]. Int J Clin Pharmacol Ther Toxicol 1991; 29 (2): 75-81
Wiholm BE, Emanuelsson S. Drug-related blood dyscrasias in a Swedish reporting system, 1985-1994. Eur J Haematol 1996; 57 Suppl.: 42–6
Heimpel H. When should the clinician suspect a drug-induced blood dyscrasia, and how should he proceed. Eur J Haematol 1996; 57 Suppl.: 11–5
Kaufman DW, Kelly JP, Levy M, et al. The drug etiology of agranulocytosis and aplastic anaemia: monographs in epidemiology and biostatistics. No 18. New York: Oxford University Press, 1991
Heimpel H. Drug-induced agranulocytosis. Med Toxicol 1988; 3: 449–62
Kaufman DW, Kelly JP, Jurgelon JM, et al. Drugs in the aetiology of agranulocytosis and aplastic anaemia. Eur J Haematol 1996; 57 Suppl.: 23–30
Haas WK, Easton JD, Adams HP, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501–7
Mendelowitz AT, Gerson SL, Alvir JMJ, et al. Clozapine-in-duced agranulocytosis; risk factors, monitoring and management. CNS Drugs 1995; 4(6): 412–21
Bertolet BD, White BG, Pepine CJ. Neutropenia occurring during treatment with vesnarinone (OPC-8212). Am J Cardiol 1994; 74: 968–70
Furusawa S, Ohashi Y, Asanoi H. Vesnarinone-induced granulocytopenia: incidence in Japan and recommendations for safety. J Clin Pharmacol 1996; 36(5): 477–81
D’Antonio D, Iacone A, Fioritoni G, et al. Patterns of infections in 41 patients with idiosyncratic drug-induced agranulocytosis. Ann Hematol 1991; 63: 84–8
Julia A, Olona M, Bueno J, et al. Drug-induced agranulocytosis: prognostic factors in a series of 168 episodes. Br J Haematol 1991; 79: 366–71
Abt C, Dietrich M, Niethammer D, et al. Akute Arzneimittel induzierte Agranulocytosis. Dtsch Med Wochenschr 1978; 103: 108–13
Jick H, Myers MW, Dean AD. The risk of sulfasalazine- and mesalazine- associated blood disorders. Pharmacotherapy 1995; 15(2): 176–81
Vial T, Pofilet C, Pham E, et al. Agranulocytoses aïgues mëdicamenteuses: expërience du Centre Rëgional de Pharmacovigilance de Lyon sur 7 ans. Thërapie 1996; 51(5): 508–15
Salama A, Schutz B, Kiefel V, et al. Immune mediated agranulocytosis related to drugs and their metabolites: mode of sensitization and heterogeneity of antibodies. Br J Haematol 1989; 72: 127–32
Irvine AE, French A, Daly A, et al. Drug-induced neutropenia due to direct effects on CFU-C: ten years of culture experience. Eur J Haematol 1994; 52: 21–7
Parent-Massin DM, Sensëbë L, Lëglise MC, et al. Relevance of in vitro studies of drug-induced agranulocytosis: report of 14 cases. Drug Saf 1993; 9(6): 463–9
Uetrecht JP, Spielberg SP. Mechanisms of neutropenia: the role of neutrophil-specific pathways of drug metabolism. Phar-macoepidemiol Drug Saf 1993; 2 Suppl.: 37–42
Neftel KA, Hauser SP, Müller MR. Inhibition of granulopoiesis in vivo and in vitro by betalactam antibiotics. J Infect Dis 1985; 1: 90–8
Rouveix B, Lassoued K, Vittecoq D, et al. Neutropenia due to β-lactamine antibodies. Lancet 1983; 287: 1832–4
Bodensteiner DC, Doolittle GC. Adverse haematological complications of anticancer drugs: clinical presentation, management and avoidance. Drug Saf 1993; 8(3): 213–24
Tamai H, Mukuta T, Matsubayashi S, et al. Treatment of meth-imazole-induced agranulocytosis using recombinant human granulocyte colony-stimulating factor (rhG-CSF). J Clin Endocrinol Metab 1993; 77(5): 1356–60
Patton WN, Duffull SB. Idiosyncratic drug-induced haematological abnormalities: incidence, pathogenesis, management and avoidance. Drug Saf 1994; 11(6): 445–62
Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (first of two parts). N Engl J Med 1992; 327: 28–35
Delannoy A, Gëhenot M. Colony-stimulating factor and drug-induced agranulocytosis. Ann Intern Med 1989; 110(11): 942–3
Heinrich B, Gross M, Goebel FD. Methimazole-induced agranulocytosis and granulocyte-colonystimulating factor. Ann Intern Med 1989; 111(7): 621–2
Muroi K, Ito M, Sasaki R, et al. Treatment of drug-induced agranulocytosis with granulocyte-colony stimulating factor [letter]. Lancet 1989; II: 55
Groopman JE, Feder D. Hematopoietic growth factors in AIDS. Semin Oncol 1992; 19: 408–14
Fukuta S, Murakami Y, Kuma K, et al. G-CSF levels during spontaneous recovery from drug-induced agranulocytosis [letter]. Lancet 1993; 342: 1495
Tajiri J, Noguchi S, Okamura S, et al. Granulocyte colony-stimulating factor treatment of antithyroid drug-induced granulocytopenia. Arch Intern Med 1993; 153: 509–14
Demuynck H, Zachëe P, Verhoef GEG, et al. Risks of rhG-CSF treatment in drug-induced agranulocytosis. Ann Hematol 1995; 70: 143–7
Delannoy A. GM-CSF therapy for drug-induced agranulocytosis. J Intern Med 1992; 231: 269–71
Pasquale D, Newton M, Goss JB, et al. Granulocyte colony-stimulating factor treatment of clozapine-induced agranulocytosis. Am J Psychiatry 1996; 153(11): 1503–4
Yokoyama K, Sato T, Nakajima S, et al. Successful treatment of methimazole-induced agranulocytosis by granulocyte colony-stimulating factor. Am J Hematol 1992; 40: 76–7
Miyasaka Y, Yoshimura M, Tabata S, et al. Successful treatment of a patient with Graves’ disease on hemodialysis complicated by antithyroid drug-induced granulocytopenia and angina pectoris. Thyroid 1997; 7(4): 621–4
Sperner-Unterweger B, Czeipek I, Gaggl S, et al. Treatment of severe clozapine-induced neutropenia with granulocyte colony-stimulating factor (G-CSF): remission despite continuous treatment with clozapine. Br J Psychiatry 1998, 172: 82–4
Hunault M, Dombret H, Gardin C, et al. Hematopoietic growth factors in drug-induced agranulocytosis. Leukemia 1995; 9: 1286–7
Hurtado MR, Candelaria MH, Majluf-Cruz A, et al. Drug-induced agranulocytosis treated with granulocyte-macrophage colony-stimulating factor. Rev Invest Clin 1994; 46(1): 59–61
Teitelbaum AH, Bell AJ, Brown SL. Filgrastim (r-metHuG-CSF) reversal of drug-induced agranulocytosis. Am J Med 1993; 95: 245–6
Hunt KA, Resnick MP. Clomipramine-induced agranulocytosis and its treatment with G-CSF. Am J Psychiatry 1993; 150(3): 522–3
Sprikkelman A, De Wolf JTM, Vellenga E. The application of hematopoietic growth factors in drug-induced agranulocytosis: a review of 70 cases. Leukemia 1994; 8(12): 2031–6
Mani S, Barry M, Concato J. Granulocyte-colony stimulating factor therapy in drug-induced agranulocytosis. Arch Intern Med 1993; 153: 2500–1
Patton WN, Holyoake TL, Yates JM, et al. Accelerated recovery from drug-induced agranulocytosis following G-CSF therapy. Br J Haematol 1992; 80: 564–5
Kendra JR, Rugman FP, Flaherty TA, et al. First use of G-CSF in chlopromazine-induced agranulocytosis: a report of two cases. Postgrad Med J 1993; 69: 885–7
Means RT, Sandidge DR, Rankin KM, et al. Treatment of phenothiazine-induced agranulocytosis with recombinant granulocyte colony-stimulating factor [letter]. Am J Hematol 1992; 41: 296
Weiss M, Gross-Weege W, Wernet P. Rapid neutrophil recovery from acquired agranulocytosis by recombinant human granulocyte-macrophage colony-stimulating factor in an intensive care patient. Crit Care Med 1992; 20: 1490–1
Bauduer F, Mignard D, Ducout L, et al. GM-CSF et agranulocytoses mëdicamenteuses. Sem Hop 1996; 72(11–12): 370–2
Ellman MH, Telfer MC, Turner AF. Benefit of G-CSF for methotrexate-induced neutropenia in rheumatoid arthritis. Am J Med 1992; 92: 337–8
Chia HM, Kalra L, Lakhani AK, et al. Filgrastim for lowdose, captopril-induced agranulocytosis [letter]. Lancet 1993; 342: 304
Wallach FR, Zirn J, Murray HW, et al. Use of granulocyte-macrophage colony-stimulating factor for treatment of drug-induced agranulocytosis [letter]. Rev Infect Dis 1991; 13: 523
Miyagawa S, Shiomi Y, Fukumoto T, et al. Recombinant granulocyte colony-stimulating factor for dapsone-induced agranulocytosis in leukocytoclastic vasculitis. J Am Acad Dermatol 1993; 28(4): 659–61
Martino R, Martinez E, Sureda A, et al. A favorable response to the granulocyte colony-stimulating factor in a patient with agranulocytosis associated with the use of intravenous immunoglobulin. Med Clin 1993; 100: 358–9
Gora Tybor J, Krykowski E, Robak T. Treatment of drug-induced agranulocytosis with colony-stimulating factors (G-CSF or GM-CSF). Arch Immunol Ther Exp 1996; 44(4): 255–8
Nand S, Bayer R, Prinz RA, et al. Granulocyte-macrophage colony stimulating factor for the treatment of drug induced agranulocytosis. Am J Hematol 1991; 37: 267–9
Cappellari G, Gaio A, Cavallaro A, et al. Use of colony stimulating factors for the treatment of drug-induced agranulocytosis. Br J Haematol 1993; 84: 183–4
Gales BJ, Gales MA. Granulocyte colony-stimulating factor for sulfasalazine-induced agranulocytosis. Ann Pharmacother 1993; 27(9): 1052–4
Kuipers EJ, Vellenga E, de Wolf JTM, et al. Suffasalazine induced agranulocytosis treated with granulocyte-macrophage colony stimulating factor. J Rheumatol 1992; 19(4): 621–2
Palmblad J, Jonson B, Kanerud L. Treatment of drug-induced agranulocytosis with recombinant GM-CSF. J Intern Med 1990; 228: 537–9
Roddie P, Dorrance H, Cook MK, et al. Treatment of sulphasalazine-induced agranulocytosis with granulocyte macrophage-colony stimulating factor. Aliment Pharmacol Ther 1995; 9: 711–2
Rospond RM, Glowacki RC, Mailliard JA. Sargramostim for sulfasalazine-induced agranulocytosis [letter]. Clin Pharm 1993; 12(3): 179
Wyatt S, Joyner MV, Daneshmend TK. Filgrastim for mesalaz-ine-associated neutropenia [letter]. Lancet 1993; 341: 1476
Barète S, Bissuel F, Longuet P, et al. Agranulocytosis caused by treatment with terbinafine. Rev Mëd Interne 1997; 18(3): 258–9
Kovacs MJ, Alshammari S, Guenther L, et al. Neutropenia and pancytopenia with oral terbinafine [letter]. J Am Acad Dermatol 1994; 31: 806
Ruiz-Irastorza G, Alonso JJ, Iglesias JJ, et al. Granulocyte colony-stimulating factor for neutropenia secondary to ticlopidine. Acta Haematol 1994; 91(2): 106–7
Katz R, Chuang LC, Sutton JD. Use of granulocyte colonystimulating factor in the treatment of pancytopenia secondary to colchicine overdose. Ann Pharmacother 1992; 26(9): 1087–8
Lopez-Karpovitch X, Ulloa-Aguirre A, von Eiff C, et al. Treatment of methimazole-induced severe aplastic anemia with recombinant human granulocyte-monocyte colony-stimulating factor and glucocorticosteroids. Acta Haematol 1992; 27: 148–50
Rawanduzy A, Sarkis A, Rovit RL. Severe phenytoin-induced bone marrow depression and agranulocytosis treated with human recombinant granulocyte-macrophage colony-stimulating factor. J Neurosurg 1993; 79: 121–4
Tsatalas C, Chalkia P, Garyfallos A, et al. Ticlopidine-induced aplastic anaemia: case report and review of the literature. Clin Drug Invest 1995; 9(2): 127–30
De Jaureguiberry JP, Galzin M, Talard P, et al. Aplasie mëdullaire associëeà la ticlopidine. Rev Mëd Interne 1996; 17: 1032–6
Escobar-Morreale HF, Bravo P, Garcia-Robles R, et al. Methimazole-induced severe aplastic anemia: unsuccessful treatment with recombinant human granulocyte-monocyte macrophage colony stimulating factor. Thyroid 1997; 7(1): 67–70
Kao TW, Hung CC, Chen YC, et al. Ticlopidine-induced aplastic anemia: report of three Chinese patients and review of the literature. Acta Haematol 1997; 98: 211–3
Khelif A, Assouline D, Ffrench M, et al. Ticlopidine and aplastic anemia. Br J Haematol 1993; 83: 678–9
Mallet L, Mallet J. Ticlopidine and fatal aplastic anemia in an elderly woman. Ann Pharmacother 1994; 28(10): 1169–71
Shapiro CM, Walk D. Aplastic anemia associated with ticopid-ine. Neurology 1996; 47: 300
Delannoy A, Ravoet C. Hematopoietic growth factors in drug-induced agranulocytosis. Leukemia 1995; 9: 1289–90
Feldman AM, Bristow MR, Parmley WW, et al. Effects of vesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med 1993; 329: 149–55
Alvir JMJ, Lieberman JA, Safferman AZ, et al. Clozapine-in-duced agranulocytosis. N Engl J Med 1993; 329: 162–7
Miller PR, Cutten AEC. Haematological side effects of clozapine: patient characteristics. NZ Med J 1997; 110: 125–7
Barnas C, Zwierzina H, Hummer M, et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis: a case report. J Clin Psychiatry 1992; 53(7): 245–7
Bradford CR, Ong EL, Hendrick DJ, et al. Use of colony stimulating factors for the treatment of drug-induced agranulocytosis. Br J Haematol 1993; 84: 182–3
Geibig CB, Marks LW. Treatment of clozapine- and molindone-induced agranulocytosis with granulocyte colony-stimulating factor. Ann Pharmacother 1993; 27(10): 1190–2
Grüner U, Pesch S, Spittler S, et al. Treatment of clozapine-induced agranulocytosis with granulocyte colony-stimulating factor. Dtsch Med Wochenschr 1994; 119: 1467–70
Gullion G, Yeh HS. Treatment of clozapine-induced agranulocytosis with recombinant granulocyte colony-stimulating factor. J Clin Psychiatry 1994; 55(9): 401–5
Lamberti JS, Bellnier TJ, Schwarzkopf SB, et al. Filgrastim treatment of three patients with clozapine-induced agranulocytosis. J Clin Psychiatry 1995; 56(5): 256–9
Nielsen-H. Recombinant human granulocyte colony-stimulating factor (rhG-CSF; filgrastim) treatment of clozapine-induced agranulocytosis. J Intern Med 1993; 234: 529–31
Oren R, Granat E, Shtussberg S, et al. Clozapine-induced agranulocytosis treated with granulocyte macrophage colony stimulating factor. Br J Psychiatry 1993; 162: 686–7
Raison CL, Guze BH, Kissell-RL. Successful treatment of clozapine-induced agranulocytosis with granulocyte colony-stimulating factor. J Clin Psychopharmacol 1994; 14(4): 285–6
Valevski A, Modai I, Lahav M, et al. Clozapine-lithium combined treatment and agranulocytosis. Int Clin Psychopharmacol 1993; 8: 63–5
Weide R, Köppler H, Heymanns J, et al. Successful treatment of clozapine induced agranulocytosis with granulocyte colony-stimulating factor (G-CSF). Br J Haematol 1992; 80: 557–9
Gerson SL, Gullion G, Yeh HS, et al. Granulocyte colony-stimulating factor for clozapine-induced agranulocytosis [letter]. Lancet 1992; 340: 1097
Chengappa KNR, Gopalani A, Haught MK, et al. The treatment of clozapine-associated agranulocytosis with granulocyte colony-stimulating factor (G-CSF). Psychopharmacol Bull 1996; 32(1): 111–21
Bartalena L, Bogazzi F, Martino E. Adverse effects of thyroid hormone preparations and antithyroid drugs. Drug Saf 1996; 15(1): 53–63
Balkin MS, Buchholtz M, Ortiz J, et al. Propylthiouracil (PTU)-induced agranulocytosis treated with recombinant human granulocyte colony-stimulating factor (G-CSF). Thyroid 1993; 3(4): 305–9
Björkholm M, Pisa P, Arver S, et al. Haematologic effects of granulocyte-macrophage colony stimulating factor in a patient with thiamazole-induced agranulocytosis. J Intern Med 1992; 232: 443–5
Freebairn RC, Young RJ, Gomersall CD, et al. Successful treatment of carbimazole-induced agranulocytosis and severe sepsis with granulocyte macrophage colony stimulating factor. Anaesth Intensive Care 1995; 23(4): 510–2
Genet P, Pulik M, Lionnet F, et al. Use of colony-stimulating factors for the treatment of carbimazole-induced agranulocy-tosis. Am J Hematol 1994; 47: 334–5
Gerl A, Gerhartz H, Wilmanns W. GM-CSF for agranulocytosis. J Intern Med 1991; 230: 90–1
Magner JA, Snyder DK. Methimazole-induced agranulocytosis treated with recombinant human granulocyte colony-stimulating factor (G-CSF). Thyroid 1994; 4(3): 295–6
Somogyi A, Rosta A, Lang I, et al. Treatment of drug-induced bone marrow suppression with recombinant human granulo-cyte/monocyte colony stimulating factor. Adverse Drug React Toxicol Rev 1996; 15(2): 119–24
Willfort A, Lorber C, Kapiotis S, et al. Treatment of drug-induced agranulocytosis with recombinant granulocyte colony-stimulating factor (rh G-CSF). Ann Hematol 1993; 66: 241–4
Vial T, Descotes J. Clinical toxicity of cytokines used as haemopoietic growth factors. Drug Saf 1995; 13(6): 371–406
Schilero GJ, Oropello J, Benjamin E. Impairment in gas exchange after granulocyte colony-stimulating factor (G-CSF) in a patient with the adult respiratory distress syndrom. Chest 1995; 107: 276–8
Devereux S, Linch DC, Campos Costa D, et al. Transient leucopenia induced by granulocyte-macrophage colony-stimulating factor. Lancet 1987; II: 1523–4
Bregni M, Siena S, Di Nicola M, et al. Comparative effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor after high dose cyclophos-phamide cancer therapy. J Clin Oncol 1996; 14(2): 628–35
Cabalerro MD, Vazques L, Barragnan JM, et al. Randomised study of filgrastim versus molgramostim after peripheral stem cell transplant in breast cancer. Haematologica 1998; 83: 514–8
Gerson SL. G-CSF and the management of clozapine-in-duced agranulocytosis. J Clin Psychiatry 1994; 55 (9 Suppl. B): 139–42
Tajiri J, Noguchi S, Murakami N. Usefulness of granulocyte count measurement four hours after injection of granulocyte colony-stimulating factor for detecting recovery from antithyroid drug-induced granulocytopenia. Thyroid 1997; 7(4): 575–8
American Society of Clinical Oncology. Recommendations for the use of hematopoietic colony-stimulating factors: evi-denced-based, clinical practice guidelines. J Clin Oncol 1994; 12(11): 2471–508
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Vial, T., Gallant, C., Choquet-Kastylevsky, G. et al. Treatment of Drug-Induced Agranulocytosis with Haematopoietic Growth Factors. BioDrugs 11, 185–200 (1999). https://doi.org/10.2165/00063030-199911030-00005
Published:
Issue Date:
DOI: https://doi.org/10.2165/00063030-199911030-00005