Page 552 - Williams Hematology ( PDFDrive )

526 Part VI: The Erythrocyte Chapter 35: Aplastic Anemia: Acquired and Inherited 527

Splenectomy Removal of the spleen does not increase hemato- Treatment with high-dose cyclophosphamide produces early
poiesis but may increase neutrophil and platelet counts two- to threefold results similar to that seen with the combination of ATG and cyclospo-
and improve survival of transfused red cells or platelets in highly sen- rine. 247,248 However, cyclophosphamide has greater early toxicity and
sitized individuals. The surgical morbidity and mortality in patients slower hematologic recovery, but may generate more durable remis-
231
with few platelets and white cells makes this a questionable therapeutic sions. Its use has been too limited to reach a firm conclusion on its rel-
procedure. Because there are more successful methods of therapy that ative merits and it is rarely used as the first choice of immunotherapy.
attack the fundamental problem, this approach is not recommended.
Other Therapy High doses of intravenous γ-globulin have been
given to small numbers of patients with severe aplastic anemia 232,233 HEREDITARY APLASTIC ANEMIA
because of its success in treating certain cases of antibody-mediated
pure red cell aplasia. Some improvement was noted in 4 of 6 patients FANCONI ANEMIA
treated. Another treatment that is occasionally successful is lymphocy- Definition and History
tapheresis to deplete T cells. 234,235 Agents that target other T-cell func- Fanconi anemia is the most common form of constitutional aplas-
tions, such as alefacept, a CD2-directed leukocyte function antigen-3 tic anemia and was initially described in three brothers by Fanconi in
(LFA-3)/Fc fusion protein that consists of the extracellular CD2-binding 1927. It is inherited as an autosomal recessive condition that results
249
portion of the human LFA-3 linked to the Fc (hinge, CH2 and CH3 from defects in genes that modulate the stability of DNA.
domains) portion of human immunoglobulin (Ig) G are being tested as
l
immunosuppressive drugs in acquired aplastic anemia. 236 Epidemiology
Fanconi anemia is an uncommon disorder and is estimated to be pres-
Course and Prognosis ent in 1 in 1 million individuals. It is far more frequent in Afrikaners of
At diagnosis, the prognosis is largely related to the absolute neutrophil European descent. This unusually high frequency has been attributed
250
and platelet count. The absolute neutrophil count is the most impor- to a founder effect.
tant prognostic feature, with a count of fewer than 500/μL (0.5 × 10 /L)
9
considered severe aplastic anemia and a count of fewer than 200/μL Etiology and Pathogenesis
(0.2 × 10 /L) very severe aplastic anemia, the latter associated with a Sixteen complementation groups, defined by somatic cell hybridization,
9
poor response to immunotherapy and usually a dire prognosis, if early are associated with the development of Fanconi anemia (FA). 251,252 A
successful allogeneic transplant is not available. In the past, the progno- complementation group is a genetic subgroup. Identifying a comple-
sis appeared worse when the disease followed hepatitis. 72,73 But, more mentation group requires adding a gene to the genome of a cell to cor-
comprehensive results with immunosuppression or hematopoietic rect (complement) the genetic defect. This procedure can be done by
210
stem cell transplantation show an equivalent response to that seen cell fusion studies. After fusing two cells together, thereby joining their
237
with idiopathic or drug-induced cases. genetic material, one can test the cells for the genetic defect. In the case
Before marrow transplantation and immunosuppressive ther- of Fanconi anemia, this would be with the diepoxybutane test. In this
apy, more than 25 percent of the patients with severe aplastic anemia test, diepoxybutane results in chromosome fragmentation in the cells of
died within 4 months of diagnosis; half succumbed within 1 year. 235,239 patients with Fanconi anemia. Hybrids in which the hypersensitivity to
Marrow transplantation is curative for approximately 80 to 90 percent diepoxybutane is corrected (complemented) can be assumed to result
of patients younger than 20 years of age, approximately 70 percent if from the fusion of cells from different genetic subgroups (complemen-
between the ages of 20 and 40 years, and approximately 50 percent if tation groups), whereas hybrids that still show the sensitivity are the
older than age 40 years. 157,240 Unfortunately, as many as 40 percent of result of fusion of cells from the same subgroup. Because one can deter-
transplant survivors suffer the deleterious consequences of chronic mine the complementation group without knowing the gene involved,
graft-versus-host disease, and the risk of subsequent cancer can be this approach is the first step in understanding the genetic basis of a
157
as high as 10 percent in older patients or after immunotherapy prior to disease. Once the genes are known, one does not need to use cell fusion
hematopoietic stem cell transplantation. 241,242 The best outcomes occur studies; rather, retroviral vectors can be used to insert corrected genes
in those patients who have an allele-based HLA-matched sibling; have into the cells.
not been exposed to immunosuppressive therapy prior to transplanta- The complementation groups have been designated FANCA, B, C,
tion; have not been exposed and sensitized to blood cell products; have D1, D2, E, F, G, I, J, L, M, N, O, P, and Q. Table 35–8 lists the gene muta-
had a marrow rather than a blood stem cell donor product; and have not tions corresponding to these complementation groups, and Fig. 35–5
been subjected to high-dose radiation in the conditioning regimen for summarizes the functions of the known Fanconi anemia proteins.
252
transplantation. 157,241,243,244 The great majority of patients have mutations of FANCA, FANCC, or
Combination immunosuppressive therapy with ATG and cyclo- FANCG. It has been proposed that the A and C gene products, which
253
sporine leads to a marked improvement in approximately 70 percent are cytoplasmic proteins, form an “FA core complex” with the prod-
of the patients; a higher initial absolute reticulocyte and lymphocyte ucts of genes B, E, F, G, L, and M, which are adaptors or phosphoryla-
counts are predictive of the response to therapy. Although some tors. 253,254 The complex translocates to the nucleus, where it is required
245
patients regain normal blood counts, many continue with moderate for the ubiquitination of FANCD2 and protects the cell from DNA
anemia or thrombocytopenia. In as many as 40 percent of patients crosslinking and participates in DNA repair (Fig. 35–6). DNA dam-
initially responding to immunosuppressive therapy, their disease may age initiates activation of the FA/BRCA pathway and ubiquitination of
relapse or progress to PNH, a myelodysplastic syndrome, or AML over FANCD2, which is targeted to the altered DNA and facilitates repair
10 years of observation. 178–186,214–216 Moreover, the beneficial effects of by interacting with DNA repair proteins, BRCA1, FANCD1/BRCA2,
immunotherapy are often lost 10 years after treatment. In 168 trans- FANCN/PALB2, and RAD51. In the presence of a mutant gene prod-
planted patients the actuarial survival at 15 years was 69 percent, and in uct, the normal protective and repair functions are disturbed leading
227 patients receiving immunosuppressive therapy it was 38 percent. to damaging effects in sensitive tissues, including hematopoietic cells.
178
The long-term survival in pediatric patients younger than age 18 years The genetic damage appears related to the adverse effects of reactive
appears better, with approximately one-third relapsing at 10 years. 246 oxygen radicals, such as superoxide and hydrogen peroxide as well as

Kaushansky_chapter 35_p0513-0538.indd 527 9/19/15 12:24 AM