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522 Part VI: The Erythrocyte Chapter 35: Aplastic Anemia: Acquired and Inherited 523

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Survival after allogeneic transplants for SAA, 2001-2011 age 20 years. These guidelines are subject to the unique or special cir-
100 cumstances of an individual case. For example, if patients with aplastic
≤20 y, sibling donor (N = 1,371)
anemia undergo gene sequencing and a mutation known to be a driver
80 >20 y, sibling donor (N = 1,392) mutation for myelodysplasia or AML is found, allogeneic hematopoietic
stem cell transplantation may prove to be a preferred approach.
Probability, % 60 ≤20 y, unrelated donor (N = 703) Components of Anti–T-Lymphocyte (Immunosuppressive)

Therapy
40
>20 y, unrelated donor (N = 704)
Antilymphocyte Serum and Antithymocyte Globulin ATG and ALG
act principally by reducing cytotoxic T cells. This involves ATG-induced
20
apoptosis through both FAS and TNF pathways. Cathepsin B also
161
P < 0.001 plays a role in T-cell cytotoxicity at clinical concentrations of ATG, but
162
0 may involve an independent apoptosis pathway. ATG and ALG also
0 1 2 3 4 5 6 release hematopoietic growth factors from T cells. 163,164 Horse and rabbit
Years ATG are licensed in the United States. Skin tests against horse serum
By donor type and age
should be performed prior to administration. If positive, the patient
165
Figure 35–3. Allogeneic hematopoietic stem cell transplantation is may be desensitized. ATG therapy is given daily for 4 to 10 days with
the principal treatment for young patients with severe aplastic anemia doses of 15 to 40 mg/kg. Fever and chills are common during the first
and available HLA-matched sibling donor. Among the 2763 patients day of treatment. Concomitant treatment with glucocorticoids, such
receiving HLA-matched sibling donor hematopoietic stem cell trans- as methylprednisolone or dexamethasone lessens the reaction to ATG.
plantation for severe aplastic anemia (SAA) between 2001 and 2011, Several studies have compared equine to rabbit ATG in the immuno-
the 3-year probabilities of survival were 88% ± 1% for those younger therapy of aplastic anemia, contemporaneously or using historical com-
than 20 years and 76% ± 1% for those 20 years of age or older. Among parisons. The consensus is that equine ATG is superior to rabbit and, if
the 1407 recipients of unrelated donor hematopoietic stem cell trans- available, is recommended as the first line of therapy (Table 35–6). 166–174
plantation, the corresponding probabilities of survival were 70% ± 2%
and 63% ± 2%. (Reproduced with permission from MC Pasquini, Z Wang: Nevertheless, rabbit ATG is effective and should be considered if equine
Current use and outcome of hematopoietic stem cell transplantation: ATG does not result in a satisfactory outcome (Fig. 35–4).
CIBMTR Summary Slides, 2013. Available at: http://www.cibmtr.org.) ATG treatment may accelerate platelet destruction, reduce the
absolute neutrophil count, and cause a positive direct antiglobu-
lin (Coombs) test. This effect may lead to an increase in transfusion
requirements during the 4- to 10-day treatment interval. Serum sick-
frequency of chronic graft-versus-host disease, which could make it ness, characterized by spiking fevers, skin rashes, and arthralgias, occurs
useful in older patients. 158 commonly 7 to 10 days from the first dose. The clinical manifestations
The longer the delay between diagnosis and transplantation, the of serum sickness can be diminished by increasing the glucocorticoid
less likely is a salutary outcome, probably as a result of a greater number dose from day 10 to day 17 after treatment. Approximately one-third
of transfusions and a higher likelihood of pretransplantation infection. of patients no longer require transfusion support after treatment with
Acute and chronic graft-versus-host disease are serious complications, ATG alone. 175–177
and therapy to prevent or ameliorate them is a standard part of post- Of 358 patients responding to immunosuppressive therapy, prin-
transplantation treatment. 154,157 Transplantations have been performed cipally ATG alone, 74 (21 percent) relapsed after a mean of 2.1 years.
178
using stem cells from partially matched siblings or unrelated, histocom- The actuarial incidence of relapse was 35 percent at 10 years. Similar
patible donors recruited through the National Marrow Donor Program results were observed when 227 patients were treated with immunosup-
179
or similar organizations in other countries. Umbilical cord blood is pression, primarily ATG alone. The actuarial survival at 15 years was
159
an alternative source of stem cells from unrelated donors (or, rarely, sib- 38 percent following immunosuppression. However, a combination of
178
lings) for transplantation in children, but the results are optimal with immunosuppressive agents provides more effective therapy than ATG
matched sibling transplantation. Alternatively, the use of high-resolu- alone (see “Combination Immunotherapy” below).
tion, HLA typing of a matched, unrelated donor markedly improves Twenty-eight (22 percent) of 129 patients treated with ALG devel-
the prognosis for transplantation. High-resolution DNA matching at oped myelodysplasia, leukemia, PNH, or combined disorders. This
180
160
HLA-A, -B, -C, and -DRB1 (8 of 8 alleles) is considered the lowest level tendency to relapse and to develop clonal hematologic disorders was
of matching consistent with the highest level of survival. If there is an reviewed by the European Cooperative Group for Bone Marrow Trans-
181
HLA mismatch at one or more loci, especially HLA-A or -DRB1, the plantation in 468 patients, most of whom received ATG. The risk of
outcome is compromised, and immunosuppression with combined a hematologic complication increased continuously and reached 57
160
therapy may be preferred initially, depending on patient age, CMV sta- percent at 8 years after immunosuppressive therapy. A further survey
tus, and disease severity. Older patients have a much lower favorable found 42 (5 percent) malignancies in 860 patients treated with immu-
response with alternative, non–matched-sibling, donor transplanta- nosuppression, whereas only 9 (1 percent) malignancies were seen in
tions. The use of hematopoietic stem cell transplantation can be con- 748 patients who received marrow transplants. 182
sidered for patients who do not respond or who no longer respond to There are no predictors that augur the risk of clonal evolution in
immunotherapy. If the patient in question is a candidate for stem cell an individual patient, although shorter telomere length at diagnosis and
157
transplantation based on all relevant factors, transplantation could be poorer prognosis are associated. 183
considered at any age for a patient with a syngeneic donor; transplan- Cyclosporine Administration of cyclosporine, a cyclic poly-
tation could be considered as a first-choice therapy up to age 50 years peptide that inhibits IL-2 production by T lymphocytes and pre-
for a patient with an HLA allele-level matched sibling donor; and trans- vents expansion of cytotoxic T cells in response to IL-2, is another
plantation could be considered a first-choice therapy if an allele-level approach to immunotherapy. After the initial report of its ability to
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HLA-matched unrelated donor is available for patients younger than induce remission in 1984, several groups have used cyclosporine as

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