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434 Part IV Disorders of Hematopoietic Cell Development

hypergammaglobulinemia and hypogammaglobulinemia and T- and hematologic disorder requires a bone marrow examination that may
NK-cell abnormalities of various causes (both inherited and acquired) be consistent with an early form of aplastic anemia or MDS.
can also be associated with neutropenia.
THERAPY
Other Iatrogenic Forms of Neutropenia
For secondary neutropenias, the therapy is aimed at the primary
Hemodialysis can result in neutropenia. One important mechanism disease. If potentially offending drugs are present, they should be
postulated is through activation of the plasma complement pathway discontinued. G-CSF may be used for severe cases of both primary
by dialyzer cellophane membranes and generation of C5a (desarg) and secondary neutropenias. It may help to speed up recovery, but if
that causes reversible neutrophil aggregation, resulting in transient the primary cause persists, it will have only a temporary effect.
neutropenia. Similar mechanisms to explain neutropenia have been Primary or idiopathic neutropenias most often have an autoimmune
suggested in other clinical settings, including leukapheresis and car- cause. Prednisone may be used as first-line therapy, but other B
diopulmonary bypass surgery. cell–targeted agents may be needed, including rituximab. IVIg is
effective in certain cases of PWCA. Finally, similar to the treatments
applied for T-LGL leukemia, T cell–targeted approaches, such as
LABORATORY EVALUATION CsA, can be used. A trial of at least 6 weeks is recommended. Similarly
use of ATG has also been effective for cases of PWCA and other
Laboratory studies aim at the identification of the primary causes of idiopathic forms of neutropenia. Weekly oral methotrexate is effective
neutropenia, as outlined in Fig. 32.4. Idiopathic and AIN remain, in in treating neutropenia related to Felty syndrome and T-LGL leuke-
most instances, diagnoses of exclusion. A careful history, including mia. Of note, is that in many instances, isolated neutropenias may
family history and initial age of first abnormal counts, help to distin- be asymptomatic, and therapy may not be needed. Alemtuzumab has
guish familial neutropenias (see Chapter 29). Should primary causes been used with success in treating thymoma-associated PWCA and
such as drugs or systemic diseases be identified, the diagnostic evalu- other cases of neutropenias.
ation will concentrate on disease-specific tests. In addition to a
complete blood cell count and differential, which will help establish
the severity of neutropenia, and tests to diagnose a specific disorder LARGE GRANULAR LYMPHOCYTE LEUKEMIA
such as T-LGL leukemia, a bone marrow examination is required.
Lack of morphologic or cytogenetic signs of primary hematologic LGL leukemia is a chronic clonal lymphoproliferation of cytotoxic T
diseases (e.g., MDS or aplastic anemia) and peripheral destruction cells (T-LGL) or NK cells (NK-LGL), often associated with cytope-
will be supported by the observation of left shift and myeloid pre- nias, including neutropenia, red cell aplasia, and thrombocytopenia.
dominance. Inhibition of myeloid production is exemplified by an Pancytopenia is less frequently encountered and may be related to
increased erythroid:myeloid ratio. splenomegaly. T-LGL leukemia may be an indolent disorder and
In some instances, auxiliary tests may help identify the cause of present with leukopenia or with lymphocytosis. LGLs observed on a
the neutropenia, including vitamin B 12 , zinc, folate, or copper levels. peripheral smear are characteristic of T-LGL leukemia, but their
Determination of immunoglobulin levels may be helpful to establish- frequency can vary.
ing the presence of immunodeficiency. Detection of ANAs has a T-LGL leukemia results from a proliferation of CTLs and often
limited significance because most of the currently available tests are resembles reactive CTL expansion. It is associated with rheumatoid
not very sensitive and may not be specific. The presence of antibodies, arthritis (11–36%) and B-cell malignancies (5–7%) and to a lesser
however, may be helpful and supports the diagnosis of autoimmune extent with other autoimmune diseases such as Sjögren syndrome,
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forms of neutropenia. celiac disease, pulmonary hypertension, hematologic malignancies
like MDS and HSCT. Most reactive processes are polyclonal, but
immunodominant CTL clones may be present, making a distinction
DIFFERENTIAL DIAGNOSIS between true T-LGL and a reactive process difficult (Fig. 32.5). A

Differential diagnostic consideration aims to distinguish primary
from secondary forms of neutropenia and to exclude familial hema- CTL responses
tologic diseases. Suspicion of neutropenia secondary to a primary

Chronic versus acute Isolated neutropenia TCR
Age of presentation
Rule out familial Clonal Polyclonal
complex
Rule out neutropenias polarity
drugs
systemic diseases
Left shift versus No dysplasia
Bone marrow exam decreased Normal cytogenetics
myelopoiesis

Neutrophil antibody Rule out T-LGL
LGL AIN, PRCA
Idiopathic/autoimmune
neutropenia Fig. 32.5 PATHOPHYSIOLOGY OF CYTOTOXIC T-LYMPHOCYTE
RESPONSES. AIN, Autoimmune neutropenia; CTL, cytotoxic T lympho-
Fig. 32.4 EVALUATION OF PRIMARY AND SECONDARY NEUTRO- cyte; LGL, large granular lymphocyte; PRCA, pure red cell aplasia; TCR,
PENIA. T-LGL, T-cell large granular lymphocyte. T-cell receptor.