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Chapter 29 Inherited Bone Marrow Failure Syndromes 359

harvested and fertilized with the father’s sperm in vitro, resulting in been observed to occur. Most patients on long-term androgens
a number of blastomeres. Using single-cell polymerase chain reaction eventually become refractory to therapy as BM failure progresses.
(PCR) technology, isolated cells from several blastomeres can be Potential side effects include masculinization, which is especially
tested for an HLA match and for absence of biallelic FANC mutation. troublesome in female patients, and elevated hepatic enzymes, cho-
The selected HLA-compatible normal blastomeres can then be lestasis, peliosis hepatis, and liver tumors. Five complications of
transferred and implanted in utero, resulting in a successful pregnancy androgen therapy require consideration.
and subsequent birth of a matched unaffected sibling. Cord blood
from the PGD-selected healthy infant sibling can be banked for an 1. Peliosis hepatis is a cystic dilation of hepatic sinusoids that fill with
HSCT for the affected sibling. The notion of “designer babies” is still blood and can be life-threatening if they rupture. They may be
debated in ethical circles. clinically silent or produce right upper quadrant pain. Liver func-
Despite the successes of HSCT in correcting the BM failure of tion test results are normal. Ultrasonographic examination is a safe
patients with FA, there is a subset of survivors who develop cancers, way to diagnose the abnormality. The lesions may regress after
particularly squamous cell carcinoma of the head and neck. These stopping the androgens.
malignancies reflect the ongoing genetic susceptibility of FA nonhe- 2. Androgens also damage hepatocytes nonspecifically. This may be
matopoietic tissue to cancer despite successful transplantation for manifest as cholestatic jaundice or elevated liver enzymes. Stop-
aplastic anemia, MDS, or AML. Published data comparing cancer ping androgen therapy usually leads to complete resolution.
risks in transplanted and nontransplanted patients with FA show a Hepatic cirrhosis may develop in patients on continued androgen
4.4-fold increase in age-specific hazard rate of squamous cell carci- therapy. If resolution of enzyme elevation does not occur after
noma in the transplanted cohort. The causes for the increased cancer androgen withdrawal, a liver biopsy is indicated.
risk above the baseline seen in patients with FA who have not been 3. Hepatocellular adenomas are associated with androgen therapy.
transplanted are not proven, but GVHD, especially chronic, and the These are benign, noninvasive tumors. They can, however,
preparative regimens of chemotherapy and irradiation are highly rupture, leading to life-threatening bleeding. Patients with FA
suspect. T-cell depletion has been introduced in some protocols to may develop these tumors rapidly, but they can be readily detected
reduce GVHD, and irradiation has been reduced or eliminated in by imaging. The tumor may regress after stopping the androgens.
others to address this issue. If persistent, surgical resection or radiofrequency ablation may be
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G-CSF mobilization and collection of peripheral blood CD34 necessary.
cells from patients with FA before the onset of severe pancytopenia 4. Hepatocellular carcinoma (HCC; hepatoma) occurs with androgen
has not attained broad application. These cells in theory can be used use, and some studies have suggested that patients with FA on
as targets for gene therapy; however, their cryopreservation and infu- treatment may be at increased risk for HCC. The HCC associated
sion later when severe BM failure ensues or as an autologous rescue with androgens characteristically does not produce α-fetoprotein
after chemotherapy in the event of leukemic transformation is in serum, distinguishing it from de novo HCC. Patients develop-
unlikely to reconstitute the hematopoietic system or confer a survival ing HCC should discontinue androgen therapy.
benefit. 5. Androgen therapy for patients with FA is recognized as an adverse
prognostic factor for those receiving a transplant by a European
Androgens study. Consequently, several investigators recommended that
Androgen therapy has been used to treat FA for decades. The overall androgens be given to patients with FA only if a suitable donor
response rate in the literature is about 50% heralded by reticulocytosis cannot be identified. Unfortunately, comparative studies between
and a rise in hemoglobin within 1 to 2 months. If the other lineages androgen administration and HSCT from related or unrelated
respond to androgens, white blood cells increase next and then donors are not available, and are probably not feasible because of
platelets, but it may take many months to achieve the maximum the rarity of the disease. The cause of the association is unknown
response. Accepted indications for treating with androgens are one but may be related to delay in HSCT rather than the drug itself.
or more of the following: hemoglobin level less than 8 g/dL or
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symptoms from anemia, platelet count less than 30,000/mm , and Those receiving androgens should be evaluated serially with liver
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neutrophil count less than 500/mm . Oxymetholone, an oral 17-α enzyme profiles every 2 to 3 months and ultrasonography of the liver
alkylated androgen, is used most frequently at 1 to 5 mg/kg once a every 6 to 12 months. If liver enzymes increase to above normal or
day. The author’s practice is to start with 0.5 mg/kg/day and increase if abnormalities appear on imaging, the androgen dose should be
it monthly if there are no major side effects and an insufficient decreased or stopped.
response. Although unproven, some clinicians add corticosteroids to
offset androgen-induced growth acceleration and to prevent throm- Hematopoietic Growth Factors
bocytopenic bleeding by promoting vascular stability. For this Both G-CSF and GM-CSF can induce a neutrophil response in
purpose, 5 to 10 mg of prednisone is given orally every second day. neutropenic patients with FA. G-CSF is indicated for a patient with
There are increasing data on the efficacy of the attenuated androgen, recurrent or serious bacterial infection, especially if the neutrophil
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danazol, in FA; however, there are no comparative data with oxy- counts are less than 500/mm . In a published clinical trial of G-CSF
metholone. Claims of reduced masculinizing side effects in female in 12 patients with FA, all 12 had an increase in absolute neutrophil
patients with FA treated with danazol compared with those treated numbers, five had a significant increment in hemoglobin levels, and
with oxymetholone have not yet been substantiated in clinical trials. four had an increase in platelet counts. Concurrent with the impres-
A maintenance danazol dose of 1 to 5 mg/kg/day is probably suffi- sive improvements in blood counts, 8 of 10 patients who finished
cient to maintain good blood counts in those who respond. A danazol 40 weeks of G-CSF treatment showed elevations in the percentage
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clinical trial for FA at Children’s Hospital Boston is underway. of BM and peripheral blood CD34 cells. The starting dose for
Another androgen, oxandrolone, is also in clinical trial for FA at subcutaneous G-CSF is 5 µg/kg/day, and after a neutrophil response
Cincinnati Children’s Hospital. If an injectable androgen is preferred occurs, the dose can be decreased to every second day or 2 to 3
to decrease the risk of liver toxicity and growth of hepatic tumors, times a week. Long-acting pegylated G-CSF has not been studied
nandrolone decanoate, 1 to 2 mg/kg/week, is given intramuscularly in FA.
followed by the application of local pressure and ice packs to prevent In another published clinical trial, combination cytokine therapy
the development of hematomas. When the response is deemed consisting of subcutaneous G-CSF 5 µg/kg once daily with erythro-
maximal or sufficient, the androgens should be slowly tapered but poietin 50 units/kg administered subcutaneously or intravenously
not stopped entirely. three times a week was given to patients with FA. Androgen therapy
Almost all patients relapse when androgens are stopped. The few was added if the response was inadequate. Of 20 patients treated, 19
who successfully discontinue treatment are often in the puberty age had improved neutrophil numbers, 6 had an increase in hemoglobin
range when temporary “spontaneous hematologic remissions” have levels, and 4 achieved a sustained rise in platelets.