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Chapter 29 Inherited Bone Marrow Failure Syndromes 379

responses. In general, a corticosteroid dose equivalent of prednisone, widely considered as not indicated. In properly transfused and ade-
0.5 mg/kg/day, is suggested as a maximum “maintenance” dose after quately chelated patients who do not have severe thrombocytopenia,
the initial dose of 2 mg/kg/day. About one-third of patients can severe neutropenia, severe aplastic anemia or MDS/AML, HSCT is
maintain a response at a low prednisone dose. The rest are usually ultimately a choice made by the parents and patients. With the
managed with chronic RBC transfusions. advances in the management of patients who need chronic transfu-
There are several patterns of response to corticosteroid therapy, sion (e.g., developing of oral chelators and MRI-based imaging of
some of which may occur at different times in the same patient. Most iron overload) the quality of life of these patients substantially
children who respond to steroids cannot be completely weaned off improves; hence it is possible that HSCT for DBA patients will be
the medication and become steroid dependent. About one-third of applied less frequently in the future.
these patients, however, enter steroid-free remission after a prolonged Experience has broadened since the first HSCT was performed for
period of treatment. Between 1% and 5% of responders immediately DBA in 1976. Preparative regimens, supportive measures, and
enter a durable steroid-independent remission. However, late relapses, GVHD management have progressively become more refined, thereby
sometimes precipitated by an infectious illness or by hormonal reducing the overall risks of the procedure. For consideration in the
changes such as in pregnancy or with the use of birth control pills, decision-making process, though, there are still lethal risks, including
are common. In other cases, a progressive resistance to steroids occurs, sepsis, fatal complications associated with chronic GVHD, graft
requiring escalating doses of prednisone or alternative therapy. After failure, graft rejection, interstitial pneumonia, and cardiac failure.
a relapse, some patients are responsive to steroids again, but others Results from the International Bone Marrow Transplant Registry
are refractory to subsequent trials. Initial refractoriness to steroids is show a 64% 3-year probability of overall survival of 61 transplanted
observed in 36% of cases. In more than 60% of patients, long-term DBA patients. The American DBA Registry and the Aplastic Anemia
steroid therapy is hampered by the development of resistance or by Committee of the Japanese Society of Pediatric Hematology report an
side effects of the treatment. In adolescent responders on long-term 87.5% and an 85% survival, respectively, but express caution that
steroids, an option is to stop prednisone temporarily to allow a alternative donors pose a much higher risk than matched sibling
normal growth spurt. Infants with DBA on high doses of steroids are donors. From the American DBA Registry database, the survival rate
at risk for pneumocystis pneumonia and should be given prophylactic for patients younger than the age of 10 years receiving matched
antibiotics. related HSCT is greater than 90%. A report from the Italian Associa-
Megadose steroid therapy for DBA patients who were refractory tion of Pediatric Haematology and Oncology Registry from 2014
to conventional-dose prednisone has been reported to induce a sus- indicated 80.4% 5-year survival for HSCT from matched sibling
tained erythroid response leading to transfusion independence in 8 donor and 69.9% for matched unrelated donor without statistically
of 13 cases. Eleven had been treated with 100 mg/kg/day intrave- significant difference between the groups. Umbilical cord blood as a
nously, and two additional patients had been treated with 30 mg/kg/ stem cell source has been used for DBA HSCT with favorable results.
day orally. Another report showed only a transient response in one Given the generally favorable results with related donors, this
of eight patients after intravenous treatment with 30 mg/kg/day and procedure can now be offered to patients approximately after the age
a sustained response after a higher dosage (100 mg/kg/day) in three of 5 years when no spontaneous remission is apparent. However,
of eight patients, but side effects were weight gain, oral moniliasis, HSCT from an unrelated donor is not recommended unless the
increase in hepatic transaminases, transient hyperglycemia, and bac- patient has severe thrombocytopenia, severe neutropenia, severe
teremia related to a central venous catheter. A conclusive study of aplastic anemia, MDS, or leukemia or as part of a clinical trial.
nine refractory DBA patients using megadose oral methylpredniso- This success with related donors has sparked interest in PGD with
lone showed no response in five cases and a partial or complete in vitro fertilization to “create” HLA-matched sibling donors without
response in the other four during the initial 4 to 8 weeks of therapy, a mutated DBA gene, and a number of patients worldwide have been
but all of these patients relapsed with a taper and became transfusion successfully transplanted using umbilical cord–derived stem cells
dependent. Thus none of the cases exhibited a clinically significant from donors produced in this way. The religious, ethical, and eco-
or durable response. nomic questions generated by PGD to find a healthy matched donor
for DBA and other inherited BM failure transplantations are ongoing.
Cytokine Therapy
Because of the “corrective” effect on erythropoiesis by IL-3 in vitro, Other Therapeutic Options
clinical trials were introduced for steroid-refractory and steroid- Based on the role of the DBA genes in ribosome biogenesis and global
dependent DBA patients and for those in whom HSCT was consid- protein translation and in vitro studies aimed to stimulate translation
ered too risky. The early enthusiasm generated by sustained remissions in BM cells, a trial was performed in which the branched amino acid
in some patients was tempered by the realization that IL-3 is effective leucine was administered to a patient with DBA. The patient had an
in only a very small number of cases of steroid-refractory, transfusion- impressive response. Based on this, two leucine trials are ongoing in
dependent DBA. Of 49 patients treated with IL-3 in a European the United States and Europe. Leucine stimulates translation by
multicenter compassionate-need study, only three children had a enhancing the activation of translation initiation factors that regulate
significant response with sustained remissions off therapy. A compari- mRNA binding to the ribosomal complex and by activation of the
son of individual patient characteristics confirmed that patients who ribosomal protein S6 kinase and the mTOR (mammalian target of
had never achieved significant in vivo erythropoiesis in response to rapamycin) pathway. Thus far, the efficacy of leucine has been docu-
steroids or during a spontaneous remission were highly unlikely to mented in cellular models of DBA, in several ribosomal protein
respond to IL-3. Thus the overall response rate in all published deficient zebrafish models and in a RPS19-knockdown mouse model
studies averaged 10–20%. Currently, there are no IL-3 or other where doxycycline-regulatable specific shRNA was used.
growth factor clinical trials in North America for DBA. Serum A number of uncontrolled therapeutic trials have been performed
erythropoietin levels are elevated in DBA, and attempts at treatment in steroid-refractory patients using various medications and treat-
with high-dose erythropoietin have been ineffective. ments with varying anecdotal successes in a few patients. The medica-
tions include cyclosporine, metoclopramide, lenalidomide, androgens,
Hematopoietic Stem Cell Transplantation riboflavin, vitamin B 12, folate, iron and other “hematinic” agents,
Hematopoietic stem cell transplantation is a therapeutic option for 6-mercaptopurine, cyclophosphamide with antilymphocyte globulin,
DBA, but the risks must be weighed against the benefits on a case- and antithymocyte globulin alone. There is a case report claiming
by-case basis. The fundamental issue centers on the defined mortality efficacy of valproic acid for DBA and another report of an 8-month
rate with HSCT when used for a nonlethal medical disorder, at least transfusion-free remission after rituximab therapy. Plasmapheresis has
a disorder that is nonlethal in the short term. In steroid-responsive also been tried. Splenectomy, used in the past, shows no effect on
patients on low-dose maintenance, quality of life is not threatened erythropoiesis but may be helpful in transfused patients with proven
by life-threatening complications. Thus in this setting HSCT is hypersplenism.