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Chronic idiopathic neutropenia (CIN):what we know & don’t know

Siobán B. Keel, M.D.Acting Instructor of Medicine

Division of HematologyUniversity of Washington

Chronic idiopathic neutropenia (CIN):what we know & don’t know

• How to diagnosis & theories about its cause

• Natural history (what to expect)

• Treatment: GCSF & safety considerations

• Background on blood

Blood cell development

..

Neutrophil Maturation

Image modified from PeripheralBloodTUTOR software. Wood B, et al. University of WA, 1998.

These are seen in the blood

Hereditary neutropenia

Absolute neutrophil count < 2 standard deviations below the population average

(generally <1500/uL)

Acquiredneutropenia

What causes an isolated low neutrophil count ?

Neonatal alloimmmune (babies) Primary autoimmune (kids)Drug inducedSecondary autoimmune & LGL leukemiaChronic idiopathic (CIN)

CyclicSevere congenital

CIN: a diagnosis of exclusion

• Patient history and physical exam– Old blood counts (acquired neutropenia ?)– Consider underlying illness (autoimmune disorder, cancer,

infection)– Drug history

• Laboratory data– Blood counts (are other cell counts abnormal) ?

± anemia, low platelets, & increased monocyte count*

- Antineutrophil antibody testing (controversial)- Consider imaging scans (looking for underlying cause)- Consider bone marrow biopsy

* Palmblad J, et al. Current Opinion in Hematology 15: 2008.

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CIN: a diagnosis of exclusion

As there are no specific diagnostic findings inCIN, this diagnosis may reflect a mixture ofdiseases.

Chronic “nonimmune” idiopathic neutropenia:strict diagnostic criteria*

• ANC < 1500/uL for African Americans and<1800/uL for Caucasians

• Absence of clinical, laboratory, or imagingstudies suggesting any underlying diseasethat could cause neutropenia

• No drug exposures or radiation exposure• Normal bone marrow chromosomes• Negative antineutrophil antibodies

Papadaki H, et al. Eur J Haematol 67: 2001.

Antineutrophil antibody testing Bone marrow aspirate & biopsy

Riley S et al. An illustrated guide to performing the bone marrow aspiration and biopsy.

Bone marrow aspirate & biopsy

Core biopsyAspirate smearThere is no unique finding in the marrow in CIN.

Bone marrow studies1. Morphology (visual appearance)

2. Specialized tests

• Chromosomes (cytogenetics)

• Flow cytometry

The cause of CIN is poorly understood:likely has an autoimmune component

Decreased production of neutrophils in thebone marrow

Movement of neutrophilsfrom the blood intotissues or organs

Destruction of neutrophils(or precursors) in bonemarrow or blood

Reviewed in ASH Education Book 2004: Congenital and Acquired Neutropenia.

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Neutropenia lessons fromT-cell large granular lymphocytic leukemia

Normal lymphocyte LGL lymphocyte

• Leukemia of mature T cells, indolent disease• Usually presents ≈ 60 yo with neutropenia ± anemia ± enlarged spleen• 1/3 of patients are asymptomatic at presentation

Diagnosis requires that you find an expanded population ofclonal large granular T lymphocytes.

Images modified from the American Society of Hematology Image Bank 2003.

Virus infected cell

No accumulation of cytotoxic

T lymphocytes.

Cytotoxic T lymphocyte (CTL)

Virus- infected cell

dies

CTL celldies

Accumulation of cytotoxicT lymphocytes.This leads to neutropenia.

Normally

T cell LGL

• Studies in some CIN patients identifyincreased number of activated T lymphocyteswith increased inflammatory mediators thatsuppress neutrophils in the bone marrow.1-3

The cause of CIN (cont).

1. Wlodarski M, et al. Exp Hem 36: 2008. 2. Papadaki H, et al. Blood 101: 2003.3. Papadaki H, et al. BJH 128: 2005.

• The cause of neutropenia in some CIN casesmay be similar to the cause of neutropenia inlarge granular lymphocytic leukemia.

Natural history (what to expect)• Original report of 15 patients with CIN

– 14/15 were female, no large spleens– Initial ANC < 1000/uL in all patients

• < 250/uL in 9/15 patients– Marrow showed absence of mature neutrophils

• Median follow-up 15 years (8-31 years)– 9/15 patients had persistent ANC <1000– No reported increase risk of infection

• This was with NO THERAPY• Another study of 41 patients with CIN f/up 6 years showed ahigher rate of minor to moderate infections in patients withANC <500/uL vs. 500-1000 (56% vs. 8%).3

1. Kyle R. NEJM 279: 1968. 2. Kyle R. NEJM 302: 1980. 3. Greenberg P et al. Blood 55: 1980.

• 238 cases of idiopathic neutropenia– Adult and child-onset neutropenia– ANC < 500/uL– No evidence of cancer, autoimmune disorder, or

drug exposure– Likely includes CIN & autoimmune neutropenia

Idiopathic Neutropenia Patients on the Severe ChronicNeutropenia International Registry

1994-1999*

* Dale D, et al. Amer Journ Hemat 72: 2003.

- 69.3% female- GCSF increased mean ANC from ~ 390/uL to 3840/uL

SCNIR 1994-1999 cont.

0.0116.67

0.1710.14

0.25190

MinimumMaximum

1.082.035.00Median

2.422.2819.03SD

1.852.7210.19Mean

Idiopathicn = 117

Cyclic n = 79

Congenitaln = 169

GCSF dose(ug/kg/day)

* Dale D, et al. Amer Journ Hemat 72: 2003.

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• No cases of leukemia or Myelodysplastic Syndrome• Did not report details on infectious complications

Idiopathic neutropenia patients on the SCNIR 1994-19991

1. Dale D, et al. Amer Journ Hemat 72: 2003. 2. Palmblad J, et al. Curr Opinion Hemat 15: 2008.

Development of acute leukemia is very rare inCIN (6 reported cases).2 CIN patients are notthought to be at higher risk of leukemia.

Therapy

Treat the patient & not the numbers!

GCSF should be reserved for those patients with significantrecurrent infectious complications and considered in those withsevere neutropenia.

Neutrophil Production & where GCSF acts

Marrow STEM CELL CFU-GM 7 Days

PeripheralBlood

MYELOBLASTMYELOCYTENEUTROPHILGM-CSF G-CSF

14 DaysGM-CSF G-CSF

PeripheralBlood

Marrow

GM-CSF G-CSF

STIMULUS

CIRCULATING POOL (50%)

MARGINAL POOL (50%)6 - 10 Hours

STEM CELL CFU-GM

MYELOBLASTMYELOCYTENEUTROPHIL 14 Days

7 Days

Neutrophil Production & where GCSF acts

GM-CSF G-CSF

PeripheralBlood

Marrow

CIRCULATING POOL (50%)

MARGINAL POOL (50%)

NEUTROPHILTissue

GM-CSF G-CSF

STIMULUS

PHAGOCYTOSISRESPIRATORY BURST

CYTOKINE RELEASE CHEMOTAXIS

6 - 10 Hours

STEM CELL CFU-GM

MYELOBLASTMYELOCYTENEUTROPHIL 14 Days

7 Days

Neutrophil Production & where GCSF actsGCSF & safety:

adverse events reported in different populations

• Bone pain is the most commonly reported adverseevent in peripheral blood stem cell donors (PBSC).1– Generally treated with acetaminophen or ibuprofen

1. Tigue C, et al. Bone marrow transplant 40: 2007. 2. Stroncek D, et al. Transfusion 43, 2003.

• Splenic rupture– Spleen size increased in 95% of PBSC donors (meanlength increase of 13%) and size returned to baseline10 days after GCSF stopped.2– 11 cases of splenic rupture (reviewed in 1)

• 4 healthy PBSC donors, 7 hematologic disorders orcancer patients• All receiving short course of GCSF

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• Rare reported events1

– Serious skin rash (cutaneous vasculitis)– Lung injury– Thyroid dysfunction

GCSF & safety:adverse events reported in different populations

• No studies to date proving GSCF-therapycauses leukemia or myelodysplastic syndrome– Thus far, no association in PBSC donors established.1– In severe congenital neutropenia the dose of G-CSF is

associated with the risk of leukemia andmyelodysplastic syndrome, but this does not proveGCSF has a role in leukemia.2

1. Tigue C, et al. Bone marrow transplant 40: 2007. 2. Rosenberg P, et al. Blood 107: 2006.

The End