How I Diagnose and Treat Neutropenia

REVIEW

CURRENT OPINION How I diagnose and treat neutropenia

David C. Dale

Purpose of review Neutropenia absolute neutrophil count (ANC) less than 1.5 Â 109/l is a common hematological finding, and severe neutropenia, that is, ANC less than 0.5 Â 109/l is a well known risk factor for susceptibility to bacterial infections. This review provides a succinct clinical approach to the diagnosis and treatment of neutropenia with specific recommendations on the treatment of severe chronic neutropenia with the myeloid growth factor, granulocyte colony-stimulating factor (G-CSF). Recent findings Experts agree that patients with acute febrile neutropenia should be treated with antibiotics and that patients at high risk of severe neutropenia (>20% risk) after myelosuppressive chemotherapy should be treated prophylactically with a myeloid growth factor, usually G-CSF. The diversity of causes and consequences of chronic neutropenia make the diagnosis and management of these patients more complicated. Summary The review provides a stepwise approach to neutropenia focusing first on reaching a provisional diagnosis and treatment plan then steps to a final diagnosis. It also provides specific recommendations on the treatment of severe chronic neutropenia with G-CSF. Keywords diagnosis, granulocyte colony-stimulating factor, neutropenia, treatment

INTRODUCTION (b) Are there previous blood cell counts (CBCs)? I have been interested in the diagnosis and treat- Establish whether neutropenia is acute (days ment of neutropenia for nearly 50 years, from to weeks) or chronic (months to years). when we had just a few antibiotic choices for (c) What is the clinical context? A newborn? managing febrile neutropenia to the present era Possibly a reaction to a drug? Associated with a huge array of testing strategies, worries with cancer chemotherapy? Part of an about antibiotic resistance and options for growth ongoing autoimmune, infectious, or inher- factor treatments. ited disease? Several experts have recently recommended (d) What clinical events have occurred: fevers, approaches to acute and chronic neutropenia in mouth ulcers, gingivitis, cellulitis, rectal children and adults [1&&,2&&,3–9] and managing che- ulcers, pneumonia, abscesses, and/or bac- motherapy-induced neutropenia, including anti- teremia? What is the frequency? Is there biotic therapy [10&&,11,12,13&&,14]. In this brief a pattern? review, I suggest a stepwise clinical approach to (e) Do any family members have similar ill- diagnose and treat neutropenia. nesses or symptoms?

CLINICAL APPROACH TO NEUTROPENIA

(1) Always get a complete medical history. The key Department of Medicine, University of Washington, Seattle, Washington, questions are: USA (a) Is neutropenia part of an acute illness or was Correspondence to David C. Dale, MD, Department of Medicine, Uni- it found on routine examination? If it was versity of Washington, Box 356422, 1959 NE Pacific St., Seattle, WA found on routine examination and the 98195, USA. Tel: +1 206 543 7215; e-mail: [email protected] patient is not ill, making the diagnosis Curr Opin Hematol 2016, 23:1–4 can be deliberative. DOI:10.1097/MOH.0000000000000208

usually required. I do not hesitate to recom- KEY POINTS mend myeloid growth factor treatment, that is, G-CSF, especially if the patient has The study provides a stepwise approach to making the && && diagnosis in patients presenting with neutropenia. not received it previously [1 ,2 ,3– 9,10&&,11,12,13&&]. Patients with fever and severe neutropenia should (c) If the patient is not acutely ill or has chronic always have a careful examination and receive neutropenia, consider out-patient anti- antibiotics as soon as possible. biotics and a deliberative work-up Patients with severe chronic neutropenia benefit from [1&&,2&&,3–9,10&&,11,12,13&&]. treatment with granulocyte colony-stimulating factor (G- (5) Make a specific diagnosis: CSF); this review gives specific guidelines for treatment (a) Before a marrow exam: if the diagnosis is of these patients. not known: (i) Consider antineutrophil antibody testing in children; it is generally not very (2) Do a careful exam: helpful in adults. If ordered, it is very (a) Focus on evidence of infection in skin, respir- important to identify a specialized atory tract, abdominal, and perirectal area. laboratory for this testing. Remember, (b) Determine whether there is lymphadenop- positive test results may occur in athy or hepatosplenomegaly. patients with congenital as well as (c) Examine carefully for congenital nabnor- autoimmune neutropenia [3–4]. malities. (ii) Consider fluorescence-activated cell (3) Gather laboratory data: sorting analysis to identify a causal (a) If neutropenia appears to be acute, see when clonal hematological disease, for counts were last normal and patterns of example, large granular lymphocyte decline. If neutropenia may be chronic, syndrome [8]. get CBCs back to early childhood. Usually (iii) Consider antinuclear antibody tests. 20 counts over a 40- to 50-day period are The antinuclear antibody reflexive necessary to diagnose cyclic neutropenia. panel will help to identify patients (b) Evaluate each hematological cell lineage, if with autoimmune diseases. counts are stable or drifting upward or down- (iv) Consider measuring vitamin B12, ward. Neutropenia combined with anemia folate and other vitamin levels; trans- and/or thrombocytopenia suggests an auto- cobalamin deficiency is a very rare immune or infectious disease or perhaps a cause of neutropenia [2&&]. generalized marrow failure disorder. Neutro- (v) Consider genetic sequencing to identify penia and thrombocytopenia are common mutations in genes associated with neu- with splenic enlargement. Neutropenia and tropenia. Mutations in elastase, neutro- lymphocytopenia occur in autoimmune dis- phil expressed gene (ELANE) are by far eases and idiopathic neutropenia. Severe the most common cause of cyclic and neutropenia and lymphocytopenia occur congenital neutropenia. Use evidence in warts, hypogammaglobulinemia, infec- of autosomal or recessive inheritance tions and myelokathexis syndrome. and clinical clues, that is, cardiac or (c) Review other laboratory data and imaging urogenital abnormalities suggest glu- studies. cose 6-phosphatase, catalytic, 3 gene (4) Form a provisional clinical diagnosis and give (G6PC3) mutation, malabsorption, initial therapy: short stature suggest Shwachman– (a) Examples are: Diamond syndrome, etc. Testing for a (i) Acute neutropenia associated with a broad panel of genetic causes for neu- new medication. tropenia [Hematopoietic cell-specific (ii) Acute febrile neutropenia after cancer lyn substrate1-Associated protein X-1 chemotherapy. (HAX1), G6PC3, Wiskott-Aldrich Syn- (iii) Newly recognized fever and severe neu- drome gene (WAS), Shwachman-Bod- tropenia in infant. ian-Diamond Syndrome gene (SBDS), (iv) Chronic mild neutropenia in asympto- etc.] is appropriate in children with matic adult woman. no associated anomalies to guide test- (b) If the patient is febrile and acutely ill, anti- ing or when a panel is less expensive biotics, fluids, and urgent hospital care are than several individual tests [2&&,3–7].

(b) Marrow examination: median 2.4; congenital: median 7.3. (i) A marrow examination is not routinely Patients with SCN presenting with a serious done for acute chemotherapy or drug- infection should be administered both G- associated neutropenia. It is also not CSF and antibiotics immediately. necessary when patients have a long (c) Patients should be advised that the acute history of mild to moderate-isolated adverse events associated with initiation of neutropenia. It is very important to G-CSF are primarily bone pain, arthralgias, diagnose myelodysplasia, acute leuke- myalgias, and headache with onset a few mia, severe neutropenia, or generalized hours after the injections [16]. There are marrow failure. less common adverse events including (ii) The differential cell count and cytoge- thrombocytopenia, skin rash, injection si- netics are useful tests. In the congenital te reactions, vasculitis, and glomerulo- neutropenias, ‘maturation arrest’ is the nephritis. Decreased bone density and expected finding, but it is not always osteoporosis are also reported but patho- present, especially if the patient is ill logical fractures are uncommon [16]. The when the test is performed. potential for increasing the risk of myeloid Usually these tests are sufficient for leukemia should also be discussed with making the diagnosis. If not and the each patient. Severe congenital neutrope- patient is not very ill, it is best to nia patients have a high risk of evolving to observe at intervals of 3–6 months myelodysplastic syndrome and acute or refer. myeloid leukemia [17]. Certain ELANE (6) Make treatment plan for acute neutropenia: mutations appear to carry a much higher (a) Broad spectrum antibiotics are the critical risk [18&&]. for acutely ill patients with severe neutro- (d) For most patients with chronic neutropenia penia. The specifics depend on the patient’s and infections, I recommend: diagnosis, the severity of illness and the (i) Start with a low daily dose of G-CSF. I results of microbial cultures [11,12,13&&]. recommend daily dose for idiopathic (b) The availability of G-CSF is the most import- 1.0 mg/kg/day, cyclic 2.0 mg/kg/day, ant advance in the management of neutro- and congenital 3.0 mg/kg/day. penia. There are recent evidence-based (ii) Use daily therapy initially, the guidelines for prevention of infections advantage of daily treatment is to associated with chemotherapy-induced avoid or minimize bone pain and neutropenia [10&&,13&&,14]. other acute adverse effects. (7) Make treatment plan for chronic neutropenia: (iii) Switch to every other day on a Mon- The use of G-CSF to prevent and treat infections day/Wednesday/Friday schedule for in patients with severe chronic neutropenia good responders (daily dose 3 mg/kg/ differs significantly from the use of this myeloid day or less). growth factor for prevention of infection in (iv) If initial therapy is insufficient to patients with chemotherapy-induced neutrope- reach target median count, increase nia. My recommendations are: dose by 1–2 mg/kg/day at 1- to 2-week (a) For chronic neutropenia, the minimal intervals; above 10 mg/kg/day criteria for G-CSF are: absolute neutrophil increase the dose by 3–5 mg/kg/day count repeatedly less than 0.5 Â 109/l with to maximum dose of 20–30 mg/kg/ recurrent mouth ulcers and gum disease. day. Consult with a neutropenia The goal is to prevent pain and loss of specialist in all nonresponding or permanent teeth. Recurrent fevers, celluli- poorly responding patients to con- tis, abscesses, sinusitis, pneumonia, perirec- sider alternate strategies, including tal infections are stronger criteria for hematopoietic transplantation. recommending long-term G-CSF treatment. (v) Monitor CBC at least weekly in the (b) The use of G-CSF for preventing infections initial 2 months on treatment, at least in idiopathic, cyclic, and congenital neutro- once per month for the first 6 months penia is based on a randomized controlled and quarterly thereafter for stable trial [15]. Effective doses of G-CSF vary by patients. diagnosis (expressed as mg/kg/day and given (vi) For severe congenital neutropenia daily, alternate day, or three times per patients, evaluate with bone week): idiopathic: median 1.2; cyclic: marrow aspirate and cytogenetics

pretreatment and annually. Forothers, 2. Palmblad J, Dufour C, Papadaki HA. How we diagnose neutropenia in the && adult and elderly patient. Haematologica 2014; 99:1130–1133. consult with a neutropenia specialist. A practical review of the diagnosis and treatment of acute and chronic neutropenia in adults, particularly the elderly, following step by step evaluation and diagnosis in (vii) Other than G-CSF, hematopoietic a speciﬁc case. transplantation is the only other pre- 3. Walkovich K, Boxer LA. How to approach neutropenia in childhood. Pediatr Rev 2013; 34:173–184. dictablyeffectivetreatmentforcongen- 4. Newburger PE, Dale DC. Evaluation and management of patients with ital, cyclic, or idiopathic neutropenia. isolated neutropenia. Sem Hematol 2013; 50:198–206. 5. Fioredda F, Calvillo M, Bonanomi S, et al. Neutropenia Committee of the (viii) Patients with autoimmune neutrope- Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato- nia will respond to G-CSF, similar to Oncologia Pediatrica). Congenital and acquired neutropenias consensus guidelines on therapy and follow-up in childhood from the Neutropenia idiopathic neutropenia. Committee of the Marrow Failure Syndrome Group of the AIEOP (Associa- zione Italiana Emato-Oncologia Pediatrica). Am J Hematol 2012; 87:238– 243. 6. Fioredda F, Calvillo M, Bonanomi S, et al. Congenital and acquired neu- CONCLUSION tropenia consensus guidelines on diagnosis from the Neutropenia Commit- Neutropenia is no longer the challenge it once was teeoftheMarrowFailureSyndromeGroupoftheAIEOP(Associazione Italiana Emato-Oncologia Pediatrica). Pediatr Blood Cancer 2011; 57:10– to clinicians. The greatest challenge now is to pro- 17. vide truly useful ‘point of care’ information to clini- 7. Donadieu J, Fenneteau O, Beaupain B, et al. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis 2011; cians, patients, and families when they need it. 6:26. 8. Lamy T, Loughran TP Jr. How I treat LGL leukemia. Blood 2011; 117:2764– Acknowledgements 2774. 9. Andre`s E, Zimmer J, Mecili M, et al. Clinical presentation and management We would like to thank Audrey Anna Bolyard for her of drug-induced agranulocytosis. Expert Rev Hematol 2011; 4:143– 151. review of the manuscript. 10. Vehreschild JJ, Bo¨ hme A, Cornely OA, et al. Prophylaxis of infectious && complications with colony-stimulating factors in adult cancer patients under- Financial support and sponsorship going chemotherapy-evidence-based guidelines from the Infectious Dis- eases Working Party AGIHO of the German Society for Haematology and The work was supported by a National Institutes of Medical Oncology (DGHO). Infectious Diseases Working Party of the Health, NIAID grant for the Severe Chronic Neutropenia Society for Haematology and Medical Oncology. Ann Oncol 2014; 25:1709–1718. International Registry, grant # 5R 24AI049393-11, the Evidence-based guidelines for the use on myeloid growth factors to prevent Amgen Foundation and the Ella Jewell Foundation. infections associated with chemotherapy-induced neutropenia. 11. Averbuch D, Orasch C, Cordonnier C, et al. ECIL4, a joint venture of EBMT, EORTC, ICHS, ESGICH/ESCMID and ELN. European guidelines for empiri- Conflicts of interest cal antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in D.C.D. serves as a consultant for Amgen, the manufac- Leukemia. Haematologica 2013; 98:1826–1835. turer of granulocyte colony-stimulating factor (G-CSF) 12. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malig- products, Neupogen and Neulasta. G-CSF is used for the nancy: American Society of Clinical Oncology clinical practice guideline. J treatment of neutropenia. The UW has a contract with Clin Oncol 2013; 31:794–810. 13. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC Amgen. D.C.D. is the PI for this contract. Amgen && growth factors: American Society of Clinical Oncology Clinical Practice supplies G-CSF through a research pharmacy directly Guideline Update. J Clin Oncol 2015; 33:319–212. The most recent evidence-based guidelines for prevention of infections with to patients who are in the NIH sponsored Registry. All myeloid growth factors for patients receiving cancer chemotherapy. of these relationships have been previously revealed in 14. Crawford J, Armitage J, Balducci L, et al. Myeloid growth factors. J Natl Compr Canc Netw 2013; 11:1266–1290. UW GIM 10 forms. 15. Dale DC, Bonilla MA, Davis MW, et al. ArandomizedcontrolledphaseIII trial of recombinant human granulocyte colony-stimulating factor (ﬁlgras- tim) for treatment of severe chronic neutropenia. Blood 1993; 81:2496– 2502. REFERENCES AND RECOMMENDED 16. Dale DC, Bolyard AA, Schwinzer BG, et al. The severe chronic neutropenia READING international registry: 10-year follow-up report. Support Cancer Ther 2006; Papers of particular interest, published within the annual period of review, have 3:220–231. been highlighted as: 17. Rosenberg PS, Zeidler C, Bolyard AA, et al. Stable long-term risk of leukaemia & of special interest in patients with severe congenital neutropenia maintained on G-CSF therapy. && of outstanding interest Br J Haematol 2010; 150:196–199. 18. Makaryan V, Zeidler C, Bolyard AA, et al. The diversity of mutations and clinical 1. Gibson C, Berliner N. How we evaluate and treat neutropenia in adults. Blood && outcomes for ELANE-associated neutropenia. Curr Opin Hematol 2015; && 2014; 124:1251–1258. 22:3–11. A timely review and practical approach to the evaluation of adult neutropenia The genotype–phenotype relationships for mutations in the gene for neutrophil patients, focusing on the outpatient setting. elastase, ELANE, and outcomes for severe chronic and cyclic neutropenia.