Page 518 - Hematology_ Basic Principles and Practice ( PDFDrive )

438 Part IV Disorders of Hematopoietic Cell Development

implementation of prophylactic antibiotics and/or hematopoietic counts in some patients, but a significant proportion of patients will
growth factors. Neutropenia in childhood may be caused by con- be refractory. Of interest is the observation that high-dose therapy
genital diseases, be associated with viral infections, or be immune with typical lymphoma regimens may be ineffective and therefore
mediated. These three causes are usually self-limiting. In adults, most should not be used. Cases refractory to bone marrow transplantation
neutropenias are secondary to other conditions, including hema- have been described. Monotherapy with prednisone may relieve some
tologic or systemic diseases. In general, drug reactions are a very of the symptoms and improve neutropenia, but remissions are usually
common cause of neutropenia. Idiopathic or AIN as a primary disease not durable. CsA represents a reasonable first-line therapy; however,
is a diagnosis of exclusion. The pathogenesis involves T-lymphocyte/ a course of sufficient duration has to be given, with a response
NK–mediated inhibition of myelopoiesis or ANAs. Immunosup- expected after 8 to 10 weeks of therapy. Weekly oral methotrexate
pressive therapy may be used and includes prednisone, methotrexate, has been used successfully. A prospective phase II multicenter clinical
CsA, IVIg, cyclophosphamide or rituximab or in conjunction with trial analyzing treatment of 59 patients found a response rate of 38%
myeloid growth factors. to frontline methotrexate therapy (Table 32.8). Patients with LGL
T-LGL leukemia is a chronic, often indolent clonal lymphopro- leukemia–associated PRCA may be better treated with oral cyclo-
liferation of cytotoxic T cells associated with immune-mediated phosphamide instead of methotrexate with a dose between 50 and
cytopenias. It may be a part of a continuum of reactive cytotoxic 100 mg/day. In LGL leukemia with associated PRCA, responses may
T-cell responses ranging from polyclonal, oligoclonal, to monoclonal be delayed, and the PRCA may recur after discontinuation of cyclo-
expansions as seen in T-LGL leukemia. The pathophysiology of phosphamide therapy, or if insufficient treatment (<6–8 weeks) was
cytopenias includes cytokine effects and direct antigen-specific administered. In the above-mentioned trial, overall response rate to
cytotoxicity. Most patients present with neutropenia. PRCA and
pancytopenia are less common. Hemolytic anemia and pancytopenia
may be the result of splenomegaly present in a significant minority T-LGL
of patients. B symptoms and lymphadenopathy are uncommon, and
many patients remain asymptomatic. The diagnosis is established
according to the presence of characteristic LGL lymphocytosis, but
in some patients the LGL count may not be very high. The immuno-
+
+
−
+
−
+
phenotype is CD3 , CD8 , CD57 , CD16 , CD56 , and CD28 . Asymptomatic Symptomatic
CD56 antigen–expressing LGL may be characterized by a more Observe Cytopenia
aggressive course. Some cases may coexpress CD4 and CD8. The Infections
diagnosis includes detection of a TCR rearrangement. In most Systemic symptoms
instances, expansion of the involved Vβ family may be detected using
Vβ flow cytometric clonotyping. T-LGL is often associated with First-line therapy Second-line therapy
autoimmune diseases, including rheumatoid arthritis and Felty syn-
drome. T-LGL can accompany myelodysplasia and, in rare instances, Neutropenia CsA ± prednisone
aplastic anemia or PNH. Reactive, often viral infection–associated, Methotrexate Cyclophosphamide/G-CSF
CTL proliferation may be difficult to document. Asymptomatic cases ± prednisone
are monitored, and development of systemic symptoms or symptom- If no response
atic cytopenias may prompt therapy. Current treatments include CsA ± prednisone after 3-month
immunosuppressive agents such as prednisone, CsA, oral methotrex- PRCA cyclophosphamide trial
ate, or cyclophosphamide. Chronic long-term therapy may be more ± prednisone
effective than high-dose combination chemotherapy applied in B-cell
lymphomas. Second-line treatments may involve alemtuzumab or Other salvage therapies
ATG. The prognosis is generally good, and transformation to a more Response
aggressive lymphoproliferative disorder is rare. Alemtuzumab (Campath)
Unless additional hematologic diseases, such as MDS, are sus- ATG
pected, bone marrow examination may not be required. Bone marrow Yes No Fludarabine, 2-CdA
biopsy and aspirate should be obtained in cases of pancytopenia or Continue/taper G-CSF
involvement of several lineages. Morphologic hallmarks of MDS and
cytogenetic analysis may help establish a diagnosis of MDS. Fig. 32.8 THERAPY OF T-CELL LARGE GRANULAR LYMPHOCYTE
LEUKEMIA. ATG, Antithymocyte globulin; 2-CdA, 2-chlorodeoxyadenosine;
CsA, cyclosporine A; G-CSF, granulocyte colony-stimulating factor; PRCA,
DIFFERENTIAL DIAGNOSIS pure red cell aplasia; T-LGL, T-cell large granular lymphocyte.
Differential diagnostic considerations include reactive processes such
as viral infections. Occasionally MDS may be present simultaneously TABLE Metaanalyses of Studies for Response to Therapy in
or serve as an alternative diagnosis; T-cell oligoclonality may accom- 32.8 Large Granular Lymphocyte Leukemia
pany MDS. MTX CsA CPM
Study N (N) OR (%) (N) OR (%) (N) OR (%)
THERAPY French Registry a 229 62 34 (55) 24 5 (21) 32 21 (66)
Battiwalla et al b 25 25 14 (56)
A significant proportion of patients will be asymptomatic, and in Moignet et al a 45 45 32 (71)
such cases therapy may be delayed. Lymphocytosis may be significant, Osuji et al a 29 8 6 (85) 23 18 (78) 4 1 (25)
but absolute lymphocyte counts more than 40,000/µL is unusual. b
Symptomatic splenomegaly may be an indication for splenectomy. Dhodapkar 68 2 2 (100) 16 11 (69)
Pancytopenia may be a result of splenomegaly, and the procedure aids Loughran c 59 55 21 (38) 14 9 (64)
in the treatment of a hemolytic anemia that can be present in some a Retrospective analysis from multiple centers.
patients. b Retrospective analysis in single center.
Patients may tolerate significant degrees of neutropenia for many c Multicenter phase 2 trial.
years. Indications for treatment include neutropenic complications CPM, Cyclophosphamide; CsA, cyclosporine A; MTX, methotrexate; OR, overall
response.
or transfusion dependence (Fig. 32.8). G-CSF therapy will increase