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

therapy, although there were only half the number of severely affected theoretical rationale for use at this time. However, a singular case of
patients in the immunosuppressive therapy group. Thus, immuno- antibody-mediated aplastic anemia responded to rituximab, and the
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suppression may be preferable for patients who are older than 30 years autoantibodies became undetectable. 218,219
of age and in those who may experience a delay in finding a suitable Androgens Randomized trials have not shown efficacy when
donor. Marrow transplants are, however, curative for aplastic anemia, androgens were used as primary therapy for severe aplastic anemia. 220,221
whereas more frequent sequelae have been found after immunosup- Androgens stimulate the production of erythropoietin, and their
pressive therapy, 202–204 notably a substantial rate of evolution to a myel- metabolites stimulate erythropoiesis when added to marrow cultures in
odysplastic syndrome or AML. vitro. High doses of androgens were beneficial in some patients with
A National Institutes of Health protocol was designed to increase moderately severe aplasia. Series of patients were reported in which
220
immune tolerance by specific deletion of activated T lymphocytes that survival seemed improved as compared with historical controls, but
26
target primitive hematopoietic progenitor cells. Concurrent adminis- this could have resulted from improved supportive care. Masculiniza-
141
tration of cyclosporine with ATG may diminish the ATG effect so that tion and other androgen side effects can be severe, especially in female
in this program cyclosporine is introduced at a later time. The addi- patients. Long-term survivors after androgen therapy have essentially
tion of new immunosuppressive agents, such as mycophenolate mofetil, the same progression to clonal hematologic disorders as patients treated
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rapamycin, or monoclonal antibodies, to the IL-2 receptor may be more with immunosuppressive agents. These agents have been replaced by
effective in decreasing cytotoxic T cells, sparing the targeted hemato- immunosuppression or allogeneic hematopoietic stem cell transplanta-
poietic stem cells. 26 tion as a principal approach to treatment.
For the 30 to 40 percent of patients who relapse after immunother- Cytokines Despite their effectiveness in accelerating recovery
apy, retreatment with ATG and cyclosporine is effective in 50 to 60 per- from chemotherapy, these agents have been far less effective in achiev-
cent of them. 205,206 Alternatively, alemtuzumab, a monoclonal anti-CD52 ing long-term benefits in patients with severe aplastic anemia. Daily
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antibody that targets that antigen on T lymphocytes, has been an effec- treatment with G-CSF has improved marrow cellularity and increased
tive immunosuppressive agent in relapsed and in refractory patients, neutrophil counts approximately 1.5- to 10-fold. Unfortunately, in
and it may be administered with cyclosporine. 207–209 nearly all patients, the blood counts return to baseline within several
High-Dose Glucocorticoid Treatment Marrow recovery can days of cessation of therapy. Although occasional patients show evi-
occur after very high doses of glucocorticoids. 210,211 Methylprednisolone dence of trilineage marrow recovery with long-term therapy, the vast
in the range of 500 to 1000 mg daily for 3 to 14 days has been successful, majority do not respond. Therapy with myeloid growth factors is proba-
but the side effects, which include marked hyperglycemia and glyco- bly best reserved for episodes of severe infection or as a preventive mea-
suria, electrolyte disturbances, gastric irritation, psychosis, increased sure prior to dental work or other procedures that would compromise
infections, and aseptic necrosis of the hips, can be severe. Glucocorti- mucosal barriers in patients who have not responded to stem cell trans-
coids at lower doses commonly are used only as a component of combi- plant or immunotherapy. G-CSF in a dose of 5 mcg/kg by subcutaneous
nation therapy for aplastic anemia to ameliorate the toxic effects of ATG injection is easiest to administer and seems to be associated with the
and in providing additional lymphocyte suppression. fewest side effects. The drug can be given daily or fewer times per week
High-Dose Cyclophosphamide Therapy High-dose cyclophos- depending on the response. Newer pegylated preparations have a longer
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phamide has been used as a form of immunosuppression. Although it effect and usually are administered at less frequent, every-other-week
would seem inappropriate to administer high doses of chemotherapy to intervals. The SAA Working Party of the European Group for Blood
patients with severe marrow aplasia, this approach was based on obser- and Marrow Transplant reported that G-CSF added to ATG and cyclo-
vations of autologous recovery after preparative therapy for allogeneic trans- sporine reduces infection early in treatment, but does not affect survival
6
plants not followed by a transplantation. In an early study, 10 patients or length of remission. Generally, prophylactic use of growth factors
223
who received cyclophosphamide at 45 mg/kg per day intravenously is not warranted.
for 4 days with or without cyclosporine for an additional 100 days had IL-1, a potent stimulator of marrow stromal cell production of
gradual neutrophil and platelet recovery over 3 months. Seven patients other cytokines, and IL-3 have been ineffective in small numbers of
responded completely and remained in remission 11 years after treat- patients so treated with severe aplastic anemia. 224,225 These disappointing
ment. High-dose cyclophosphamide treatment may spare hematopoi- results with cytokines are not unexpected, as previous work has found
etic stem cells, which have high levels of aldehyde dehydrogenase and are high serum levels of growth factors in patients with aplastic anemia.
relatively resistant to cyclophosphamide. 213,214 Thus, cyclophosphamide Moreover, the majority of patients have suppression of very primitive
in this situation may be more immunosuppressive than myelotoxic. The progenitors, which may be unresponsive to individual factors that act
most extensive trial of high-dose cyclophosphamide resulted in 65 percent on more mature progenitor cells.
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of patients responding completely at 50 months. However, the role An exception to the poor response to cytokines is the use of eltrom-
of this regimen as initial therapy is not clear because of early toxicity bopag, a TPO receptor agonist that binds to the transmembrane region
that may exceed that of the ATG and cyclosporine combination. The of the TPO receptor and stimulates the Janus kinase (JAK)-signal trans-
216
probability of a durable remission may be superior, but there are insuf- ducer and activator of transcription (STAT) and mitogen-activated pro-
ficient data (comparative clinical trials) to conclude whether high-dose tein (MAP) kinase pathways. TPO may expand stem cell numbers and
cyclophosphamide provides better long-term results than ATG and promote DNA repair. 226–229 Use of this agent in 43 patients with acquired
cyclosporine. The latter approach is favored at this time. aplastic anemia who did not respond to immunotherapy resulted in
Rituximab A case report of the successful use of the anti-CD20 improved hematopoiesis and cell counts in 17 (40 percent) with several
humanized mouse antibody rituximab has provided preliminary evi- having improved bi- or trilineage hematopoiesis and cell counts. Five
217
dence for its potential effectiveness in treating aplastic anemia. patients had near normalization of all blood counts and had therapy
Clinical trials have not examined its efficacy compared to standard stopped after 9 to 37 months with maintenance of their blood counts
230
immunotherapy (ATG and cyclosporine), in patients refractory to stan- for 1 to 13 months of observation. Although many did not normal-
dard therapy, or as a third drug in an immunotherapy regimen. Whether ize their counts, several became red cell and platelet transfusion inde-
B lymphocytes play a role in the pathogenesis of T-cell–mediated aplastic pendent. Eight patients developed new cytogenetic abnormalities (5 of
anemia has not been defined, so rituximab does not appear to have a 8 patients developed −7 or del[7]), but none had progressed to AML.

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