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410 Part IV Disorders of Hematopoietic Cell Development

Therapy for Aplastic Anemia
After the diagnosis of acquired aplastic anemia (AA) has been estab- 6 months at a dose of 12 mg/kg. Corticosteroids are added in moderate
lished, treatment options must be identified, considered carefully, doses (1 mg/kg of prednisone or methylprednisolone) during the first 2
and chosen with alacrity (see box on Treatment Algorithm in Aplastic weeks to ameliorate serum sickness. Improvement should be expected
Anemia). For patients with moderate disease, an expectant approach can within 6 months. This regimen has produced hematologic responses
be chosen based on a stable course and adequate blood counts, or for in approximately 65% of treated patients, who then have an excellent
patients dependent on transfusion support, horse antithymocyte globulin 5-year survival rate.
(ATG; 40 mg/kg/day for 4 days) can be given. After assessment of the Although immunosuppressive therapy is generally well tolerated,
response, patients who improve should be monitored for hematologic patients frequently relapse and require further treatment; however,
signs of relapse, and nonresponders can be offered alternative therapy, relapse is not associated with a poor prognosis. More serious is the devel-
such as androgens or cyclosporine. In severe disease for which the opment of late-onset hematologic clonal diseases, paroxysmal nocturnal
prognosis with blood transfusion and antibiotic support alone is poor, hemoglobinuria (which may not be clinically significant), myelodysplastic
bone marrow (BM) transplantation from a histocompatible sibling or syndrome, and acute myeloid leukemia.
immunosuppression are accepted and effective therapies. Although For patients in whom immunosuppressive therapy fails, there are a
large, retrospective analyses have shown that long-term survival rates number of options. For children, alternative donor BM transplantation
from transplantation or immune therapy are equivalent, each has its should be considered early; at the best centers, survival rates now are
own advantages and disadvantages. For children, BM transplantation almost as good as with sibling donors. In children and adults, well
remains the treatment of choice if an appropriate family donor is avail- matched unrelated donor stem cells provide similar long-term survival as
able, because these patients have a low rate of graft-versus-host disease do matched sibling donors, but the rate of chronic and severe chronic
(GVHD), and the BM disease is cured by stem cell replacement. The GVHD is higher. Patients with AA and telomere disease can respond to
risk of therapy-related cancers can be increased, especially in children, androgen therapy. Repeated immunosuppression in a patient in whom a
after BM transplantation, and is ameliorated by avoiding radiation in first course of ATG and cyclosporine has failed is successful in about 30%
the conditioning regimen. Adults with AA also successfully receive of cases. Eltrombopag is approved for use in patients with refractory AA.
transplants, although the risk and severity of chronic GVHD and other Patients with severe AA should not be subjected to useless early trials of
treatment-related complications increase with age. BM transplantation corticosteroids or hematopoietic growth factors as the primary treatment.
has been performed in patients older than 50 years of age, and it is a For the occasional patient who must decide between BM transplantation
reasonable approach in a younger adult, less than 40 years old, espe- and immunosuppression, the advice of experts familiar with this disease
cially with more severe degrees of neutropenia. Most studies show that and careful counseling of the patient are advisable. Age and severity of
transplant early in the course of disease, within 6 months of diagnosis, is neutropenia are decisive factors. A limited number of transfusions can
desirable. be necessary to optimize the patient’s condition before definitive therapy
Most patients with AA do not have a human leukocyte antigen (HLA)– and are acceptable. Single-donor platelets should be given and can be
matched sibling donor, and immunosuppression is the treatment of obtained from HLA-compatible donors. In severely neutropenic patients,
choice in these cases. Patients with severe disease should receive a com- granulocyte colony-stimulating factor therapy can decrease the risk of
bination of ATG and cyclosporine. We recommend a regimen consisting life-threatening infections. In the absence of overt bleeding, platelet
of 40 mg/kg/day of horse ATG on days 1–4, followed by cyclosporine for counts as low as 5000 cells/µL appear to be safe.

A B

Fig. 30.11 CUTANEOUS ERUPTIONS OF SERUM SICKNESS. (A) On the hand, (B) on the foot.

received antilymphocyte serum as conditioning for BM transplanta- treatment. Continued improvement without further therapy com-
tion. Observations and formal studies in Europe showed that 40% monly occurs after 3 months; nevertheless, clinical status by 3 months
to 70% of patients responded with hematologic improvement and is strongly correlated with long-term survival. Blood counts above the
improved survival. Similar results were also obtained in US random- critical values for severity and platelets and reticulocyte counts of
ized and multicenter protocols, in which about one-half of patients more than 50,000 cells/µL are highly prognostic. Reticulocyte count,
treated with ATG or ALG showed hematologic improvement, broadly perhaps reflecting the stem cell reserve, has been the best predictor
defined as an end to transfusion dependence and an improvement in of response and survival. With new and better tolerated antifungal
a neutrophil number to a level protective against infection. drugs, survival even of nonresponders has improved and a very low
The putative cause of AA is not a factor that predicts response. neutrophil count may no longer have prognostic value.
Virus- and drug-induced aplasia and posthepatitis AA respond simi- ATG has three major toxic effects: immediate allergic phenomena,
larly compared with idiopathic disease. Cytogenetic abnormalities do serum sickness, and transient blood cell count depression (Fig.
not preclude a response because AA with chromosomal abnormalities 30.11). Fever, rigors, and an urticarial cutaneous eruption are
and some cases of frank myelodysplasia improve after ATG. The common on the first or second day of ATG therapy, and these
response rate to ATG or ALG is not improved by the addition of symptoms respond to antihistamines and meperidine. Anaphylaxis is
androgens or very high doses of corticosteroids. rare but can be fatal. Corticosteroids are administered in moderate
A hematologic response to ATG is usually apparent within a few doses (1 mg/kg of prednisone or methylprednisolone) during the first
months of therapy; in some cases, all blood counts rise dramatically, 2 weeks to ameliorate the symptoms of serum sickness. Doses of ATG
and in others, increases in platelets or RBCs can be delayed (see box and ALG have varied from 5 to 50 mg/kg, and the duration of
on Treatment Algorithm in Aplastic Anemia). The average time to administration has varied from 4 to 28 days. It is more rational to
improvement in neutrophil number is 1–2 months; transfusion administer equivalent doses of horse ATG by the schedule originally
independence occurs approximately 2–3 months after initiation of used in Europe (40 mg/kg/day for 4 days); antiserum will then have