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368 Part IV Disorders of Hematopoietic Cell Development

The median survival in the cases reported in the past decade was regimens appear to be well tolerated and allow prompt engraftment
estimated at 49 years. without significant complications. However, the benefit in reducing
the risk of nonhematologic disease-related complications, such as
bleeding from vascular lesions and respiratory failure caused by pul-
Therapy monary fibrosis, is not clear. Posttransplant deaths among published
cases in which reduced intensity transplant regimens were incorpo-
Androgens rated include such complications. All the three Toronto patients
reported in 2003 did develop these complications 7 to 14 years after
Management of aplastic anemia is similar to treatment for FA. transplant. Also, the role of these conditioning regimens in increasing
Androgens improve BM function in about 70% of patients. If a the additive risk of cancer caused by HSCT is still to be
response is achieved and deemed to be sufficient or maximal, the determined.
minimal androgen dose to maintain this response should be consid-
ered. As in FA, patients typically become refractory to androgens as
aplastic anemia progresses. Immunosuppressive therapy is not effec- Future Directions
tive for this disorder, and a portion of the patients with DC are only
diagnosed after failure to respond to immunosuppressive therapy for So far, about 75% of the patients with DC can be genotyped. Clearly,
severe aplastic anemia. Since androgens have been shown to activate there is a need to discover additional DC genes. Furthermore, the
telomerase activity, the question whether they can alleviate symptoms mechanism by which impaired activity, transport, and stability of
related to nonhematologic complications of DC needs to be answered. telomerase and other ribonucleoprotein complexes influence HSC
function requires clarification. The complete spectra of disorders and
G-CSF phenotypes caused by mutations in these genes are still to be defined.
A small number of patients were reported who responded to G-CSF Effective therapies with reduced toxicity are necessary to prevent
therapy with significant increases in absolute neutrophil counts devastating complications such as BM failure, pulmonary fibrosis,
(ANCs). Similarly, two other patients received GM-CSF therapy that and vascular anomalies. Last, there is a need for studies focusing on
resulted in improved neutrophil numbers. G-CSF with erythropoi- translating this genetic knowledge into gene therapy.
etin resulted in a trilineage hematologic response in one patient.
G-CSF plus androgens has led to splenic peliosis and rupture in DC
and is not recommended as a long-term treatment if a donor for Congenital Amegakaryocytic Thrombocytopenia
HSCT is available. Although the reports are scanty, cytokine therapy
appears to offer potential benefit, at least in the short term, especially Background
for improving granulopoiesis.
CAMT is an autosomal recessive syndrome that typically presents in
Hematopoietic Stem Cell Transplantation infancy with isolated thrombocytopenia caused by reduced or absent
Publications focusing on HSCT in DC are mostly isolated case BM megakaryocytes with preservation initially of granulopoietic and
reports or a small series that limit one’s ability to make meaningful erythroid lineages. Aplastic anemia subsequently ensues in the vast
correlations of the types of regimens, donors, and indications with majority of the patients, usually in the first few years of life. Most
outcome. The older literature consists of patients who received patients do not have physical malformations; therefore, the diagnosis
myeloablative regimens resulting in a median survival of approxi- depends on the exclusion of other acquired and inherited causes of
mately 3 years after HSCT. Causes of death include unusual compli- thrombocytopenia in early life. Mutations of the thrombopoietin
cations related to DC that are not prevented by HSCT such as receptor, MPL, have been identified and confirm that sporadic and
vascular lesions of the gut, kidneys, liver, and lung (≈50% of patients) familial cases are inherited in an autosomal recessive manner. CAMT
and fibrosis involving the lung and liver (≤40% of patients). A recent is a distinct genetic entity, but mutations in several other genes have
review of the CIBMTR database identified 34 patients with DC who been described in a number of inherited thrombocytopenias that
had been transplanted between 1981 and 2009. The overall 10-year must be considered in the differential diagnosis (Table 29.5).
survival among this group was 30%. Early posttransplant deaths were
caused by graft failure and other transplant-related complications.
Late mortality was related to pulmonary failure. These striking Epidemiology
complications after HSCT probably reflect the natural history of the
disease. However, it is not known whether HSCT can accelerate their More than 100 cases have been reported in the literature. However,
course. These unusual complications, uniquely seen in DC, have not some patients might be reported more than once. On the other hand,
been reported in other IBMFSs such as FA. with the recent identification of patients with MPL mutations and
DC is a disorder with chromosomal instability caused by flawed relatively late presentation, it is possible that the incidence is higher
telomere maintenance. This might explain the hypersensitivity to and includes a portion of the patients with aplastic anemia who do
irradiation and chemotherapy. The increased hypersensitivity of not respond to immunosuppressive therapy. The incidence of diag-
patients with DC to transplant conditioning can be related to the nosed cases is estimated at one case per million births per year.
telomere shortening from DC combined with the accelerated telo-
mere shortening that occurs after HSCT. Further, because of the high
degree of mucocutaneous involvement, patients with DC may be Pathobiology
more susceptible to endothelial damage, which occurs after HSCT
as a result of various factors, including the conditioning regimen, The defect in CAMT is directly related to mutations in MPL, the
cyclosporine A, infectious diseases, GVHD, and cytokine storm. The gene for the thrombopoietin receptor that maps to 1p34 in 94% of
increased predisposition to posttransplant complications and the patients. Heterozygote carriers of the mutant gene have normal blood
tendency to develop tumors highlight the need to avoid certain cell counts. Affected individuals have mutations in both alleles in
conditioning agents such as busulfan and irradiation and possibly either homozygous or compound heterozygous state. Mutations have
reduce the intensity of the transplant preparative regiments. been found throughout the MPL gene, including nonsense, missense,
The strategy of using low-intensity fludarabine-based protocols frameshift, and splicing mutations. The mutations cause either
for HSCT has produced encouraging results for patients with DC. reduced cell surface receptor expression or defective TPO binding
From 2002–2013, 25 patients were transplanted using reduced and receptor activation. A genotype–phenotype correlation has been
intensity protocols (mostly fludarabine-based). Overall, 20 of the 25 identified in CAMT patients and two prognostic groups were estab-
were reported alive at 10 to 212 months posttransplant. These lished, types I and II.