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Chapter 30 Aplastic Anemia 409

survival difference between patients 21–30 years old and those 31–55 eradicate immune cells responsible for GVHD, has apparently been
years old. Young adults have fared better in other series, although successful, although the literature describing the results is currently
morbidity from severe GVHD disease was more prevalent in the sparse; small case series from China and Brazil describe about 70%
young adults than in children (43% versus 10%). Overall, the acute survival and remarkably low rates of GVHD.
GVHD rate between 1991 and 1997 was approximately 20% for
patients younger than 20 years of age and 40% for those over 40
years of age. In general, similar numbers have been cited for chronic Late Complications of Bone Marrow Transplantation
GVHD. In more recent reports, the Seattle team’s regimen of cyclo-
phosphamide, ATG, cyclosporine, and methotrexate in children A study published in 2011 analyzing outcomes of children with AA
produced 100% 5-year survival, with low rates of graft rejection, 7%; over the 4 decades indicates that the majority of long-term survivors
high-grade acute GVHD, 3%, and chronic GVHD, 10%; the after transplantation during childhood can have a normal productive
European collective experience is similar for first-line transplant in life with 30-year survival of 82%. 24
very young children (91% long-term survival; 2% rejection, 8% acute Very late complications after transplantation include effects on
GVHD, and 6% chronic GVHD). In contrast, patients over the age gonadal function, growth and development, avascular necrosis, as
of 40 years (who are often transplanted after failing immunosuppres- well as compromised function of endocrine, neurologic, or other
sive treatment), have three- to fourfold higher probabilities of organ systems. About 10% of long-term survivors have significant
developing acute and chronic GVHD. late effects after matched sibling transplant, and a higher proportion
In summary, excellent survival rates and low morbidity in younger after MUD. A high rate of secondary malignancies has been recorded
patients make allogeneic BM transplantation the treatment of choice after transplantation. In a National Cancer Institute retrospective
for children and adolescents. Older adults have a higher risk of analysis of almost 20,000 transplantations, the risk of late-onset
transplant-related morbidity and mortality. Younger adults have a cancer was eightfold higher at 10 years than in the general population
good opportunity for cure with transplantation but face more com- and even higher for young patients, for whom the risk of malig-
plications than do children. In addition to age, a prolonged interval nancy was increased approximately 40-fold. For AA, multivariate
between diagnosis and transplantation, multiple transfusions, and analyses repeatedly implicate radiation as the major risk factor for the
serious infections before transplantation are poor risk factors. development of malignancies, usually solid cancers. For AA, among
320 patients who received transplants in Seattle, four developed
cancer, leading to a calculated risk seven times higher than for normal
Transplant From Alternative Donors controls. In a recent update, 12% of patients who survived more than
2 years after transplantation developed solid tumors. In a French
Haplotype sharing between parents occasionally has allowed identi- survey, four of 147 AA patients developed solid tumors, an 8-year
fication and successful transplantation between phenotypically cumulative incidence rate of 22%. In an analysis of 700 transplanta-
matched relatives. Long-term survival after even one-locus-mis- tion patients with AA and FA, the risk of developing a secondary
matched family donation is inferior to genotypically matched trans- malignancy was 14% at 20 years. The hazard of lymphoid malignan-
plants, mainly because of graft rejection and GVHD. In the large cies decreased with the time after transplantation, whereas the risk of
European experience, for phenotypically identical family matches, the solid tumors progressively increased. In general, the rates of secondary
actuarial survival rate was 45%; for patients with a single-locus malignancies after BM transplantation for AA and other diseases are
mismatch, it was 25%; and for those with two to three loci mis- similar. Immune events such as acute GVHD, treatment with ATG
matched, the survival rate was 11%. In a report from Seattle although or monoclonal antibodies, in addition to total-body irradiation have
all patients who received fully HLA-matched transplants survived, been linked to the development of secondary malignancies. Patients
those with mismatches at one or more loci had a much poorer with these secondary cancers, except for carcinoma of the skin, have
outcome, and even with total-body irradiation added to the condi- a poor prognosis. The risk of cancer after BM transplantation must
tioning regimen, the survival rate was only 50%. be evaluated in the context of other therapeutic options, especially
Until recently, most large studies of matched unrelated donor immunosuppression, because a significant risk of late malignancy
transplants (MUD) have shown inferior long-term survival and exists in AA patients independent of transplantation therapy. The risk
higher rates of complications as compared with matched sibling of malignancy in the large registry of the EGBMT was equivalent
transplants. Even more than in standard sibling transplants, age is a for patients who received immunosuppression and for those who
crucial risk factor in unrelated transplants. The degree of match underwent transplantation. Compared with the general European
clearly impacts the outcome of the unrelated BM transplantation, population, the relative risk of malignancy was calculated at 5.15
and selection of donors based on high resolution typing is a factor in for AA patients treated with immunosuppression (confidence inter-
improving outcomes. Different conditioning regimens have been val [CI]: 3.2–7.9) and at 6.67 (CI: 3–12.6) for patients receiving
used at various centers, and results are often difficult to compare transplants. Overall, the rate of malignancy after BM transplantation
between institutions because of the large number of variables. Nev- has been calculated to be 3.8-fold higher than in the age-matched
ertheless, in a recent summary of the large European experience of population.
transplants performed between 2005 and 2009, overall survival was
equivalent to matched sibling procedures (76% versus 83%), although
with rates of high-grade GVHD (10% versus 5%) and chronic Immunosuppression
extensive GVHD (11% versus 6%). Factors predictive of a favorable
MUD outcome were transplant using BM as a source of stem cells, Antithymocyte Globulins
transplant within 180 days of diagnosis, patient age, use of ATG in
19
the conditioning regimen, and CMV status. MUDs are sufficiently Immunosuppressive therapy is an effective alternative treatment for
effective in children that they have been tested as first-line therapy in patients who are not candidates for BM transplantation (see box on
pilot trials, with good outcomes. Treatment Algorithm in Aplastic Anemia). 1
Retrospective analysis of 71 AA patients treated with umbilical Immunoglobulin preparations made from the sera of horses
cord transplantation showed the estimated probability of 3-year immunized against human thymocytes are the mainstays of current
overall survival of 38% (median follow-up of 35 months; the cell dose regimens. Horse ATG is licensed for use in the United States as
23
appeared to be the most important factor impacting survival. While ATGAM and SAA is an approved indication. Thymoglobulin, a
umbilical cord transplants have become less frequent, increasingly rabbit ATG, is more available worldwide.
popular is the use of stem cells from haploidentical family members, The efficacy of antilymphocyte globulin (ALG) in BM failure was
who are almost always available. As with MUDs, early experience was discovered serendipitously in the late 1960s, when Mathé observed
poor, but the addition of cyclophosphamide posttransplant, to recovery of autologous hematopoietic function in patients who