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378 Part IV Disorders of Hematopoietic Cell Development

link between DBA and hematologic cancer is more understandable Transfusions for Patients With
from the data described herein that implicate an early pluripotent Diamond-Blackfan Anemia
BM progenitor in the pathobiology of DBA. From published data Before the first transfusion, it is recommended that a full RBC
up to 2011, 10 DBA patients developed AML, 2 developed MDS, 1 phenotype be performed on the patient. This information is valuable
had acute lymphoblastic leukemia, 3 had Hodgkin lymphoma, and 1 for prevention and management of alloantibody formation caused by
had non-Hodgkin lymphoma. Regarding solid tumors, a predilection sensitization. For patients in whom corticosteroids are either ineffec-
to osteosarcoma was reported in 6 of the 11 solid tumors. The other tive or excessively toxic, a regular program of RBC transfusions is
solid tumors included HCC, breast carcinoma, gastric carcinoma, usually required. During the course of this program, a small number
vaginal melanoma, and malignant fibrous histiocytoma. Among of steroid-resistant patients may show responsiveness to corticoste-
patients enrolled in the American DBA Registry, the cumulative roids when retreated or even proceed to a spontaneous transient or
risk of solid tumors and leukemia by the age of 40 years was about prolonged remission. If not, leukocyte-depleted packed RBCs are
5%. Among patients enrolled in the CIMFR none developed clonal given monthly to keep the hemoglobin concentration at a level
and malignant myeloid transformation during childhood. Therefore compatible with normal activity, usually above 9 g/L. CMV-negative
regular surveillance for detection of early MDS/leukemia in DBA is packed cells should be used if HSCT is contemplated. Several com-
probably not indicated during childhood. plications may arise from transfusions such as blood-borne infections
The published cases implicate several possible operative factors, and sensitization, but the major long-term threat is iron overload,
including genetic predisposition, transfusional iron overload, use of which causes delayed puberty, growth retardation, diabetes mellitus,
androgens, immunosuppression from corticosteroids, thymic and hypoparathyroidism, and eventually liver cirrhosis and cardiac failure.
skeletal irradiation during childhood as “therapy” for DBA in one These complications can be delayed and possibly prevented by the
case, and cyclophosphamide “treatment” in another. It is noteworthy early administration of an iron chelator.
that inhibition of ribosome protein genes in zebrafish is associated Two iron chelators are available in North America. The first,
with the development of cancer. deferoxamine (Desferal), is administered by a battery-powered pump
as a daily 12-hour subcutaneous infusion. It has been the main chela-
tor used for the past four decades. Deferasirox (Exjade) is an effective
Natural History and Prognosis oral iron chelator in patients with iron overload and is approved for
children older than 6 years of age (>2 years of age in some countries).
Historically the only treatment for DBA was blood transfusions. The initial dose is 20 to 30 mg/kg by mouth once daily. In a random-
Without this, patients died of anemia. When corticosteroids were ized trial of Desferal versus Exjade in patients with transfusional iron
introduced as an effective therapy for DBA, all patients were assigned overload, the two chelators showed similar efficacy. In an international
to one of the two therapeutic interventions, and the “natural history” multicenter study in which the efficacy of Exjade was assessed in
of the disorder took on a different dimension. patients with anemia of various etiologies, 30 patients with DBA were
A notable phenomenon is spontaneous remission that occurs in included. Successful chelation was observed in 54% of DBA patients
about 20% of cases that allows patients to discontinue whatever as defined by reduction of liver iron concentration by biopsy to less
treatment they are receiving, either chronic transfusion therapy than 7 mg/g dry weight within 1 year. Given its oral route of admin-
or corticosteroids. The American DBA Registry has actuarial istration, Exjade has been replacing Desferal as the iron chelator of
data showing that 75% of these patients remit before their 10th choice if the former is not contraindicated.
birthday, and in most cases, the remission is sustained. It appears There are uncertainties about the optimal age at which to start
that an equal number of patients remit from either corticosteroids patients younger than 2 years old with transfusion-dependent anemia
or transfusions. A relapse of DBA requires reintroduction of with Desferal therapy. There have been reports of abnormal linear
treatment. growth and metaphyseal dysplasia in patients with thalassemia major
The overall actuarial survival for DBA patients greater than 40 treated with Desferal before the age of 3 years. This adverse event has
years of age is 75% ± 4.8%. For those in sustained spontaneous prompted recommendations for starting Desferal later. However, a
remission, it is 100%; for corticosteroid responders, it is 57% ± 8.9%; progressively rising serum ferritin level or, more accurately, excessive
and for transfusion-dependent patients, it is 8.9%. Causes of death hepatic iron concentration obtained by FerriScan (using R2-MRI
mostly relate directly to the development of cancer or its treatment, imaging technology) or biopsy after a period of regular transfusions
complications from corticosteroid-induced immunosuppression, would be an appropriate indication to commence chelation therapy.
HSCT–related complications, and transfusional hemosiderosis. The daily starting subcutaneous infusion dose of Desferal should not
exceed 50 mg/kg. Ascorbate supplementation should be considered
if there is sustained loss of efficacy of deferoxamine, especially if tissue
Therapy ascorbate concentrations are reduced.
In younger children and infants, it is important to determine Corticosteroids
whether the RBC aplasia is DBA or TEC (see Table 29.7). Until Steroid responsiveness occurs in 50% to 75% of DBA patients. Upon
a firm diagnosis is established, the initial treatment in children is administration of prednisone at a dose of 2 mg/kg/day in 2 or 3
almost always transfusions. This allows the flexibility to complete divided doses, reticulocytosis is usually seen within 1 to 4 weeks and
the viral workup and other investigations and to await a spontaneous is followed by a rise in hemoglobin concentration. When the hemo-
remission if the anemia is caused by TEC or another self-limited globin level reaches 9.0 to 10.0 g/dL, prednisone can be slowly
condition. Demonstration of a mutant DBA gene would clinch the tapered by reducing the number of daily doses. If a single daily dose
diagnosis, but negative molecular analysis does not rule out this of prednisone maintains the desired hemoglobin level, the dose can
diagnosis. be doubled and given on alternate days, but this may not prevent
If transfusions are used, it is recommended to aim for a moderate significant steroid toxicity.
but not full correction of anemia so that erythropoiesis is not sup- The dose of prednisone can be further reduced by small decre-
pressed and recovery from TEC not delayed. In general, the nadir ments on a weekly basis or more slowly until the minimal effective
should not be less than 6 g/dL and should not allow the development dose is determined. This dose is extremely variable. A few patients
of significant symptoms. Most patients with TEC usually recover can be maintained on minute, nonpharmacologic doses, but other
within a few weeks after receiving only one transfusion. Occasionally, patients need large doses that preclude long-term therapy because of
recovery from TEC is slow and may mimic DBA in chronicity. If serious side effects such as Cushingoid features, pathologic fractures,
there is confusion about the proper diagnosis, it is appropriate to cataracts, growth failure, diabetes, and avascular necrosis of the
withhold corticosteroids in favor of a further transfusion to allow femoral or humeral heads. There is no known predictor of steroid
more observation time. responsiveness or any way to anticipate the type of individual