Novel treatment for Diamond-Blackfan anemia?

Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia that usually presents early in infancy and is inherited in 10% to 20% of cases. The illness is characterized by a moderate-to-severe macrocytic or normocytic anemia, usually normal neutrophil and platelet counts, a normocellular bone marrow with erythroid hypoplasia, and an increased risk of developing leukemia. Congenital anomalies, particularly of the thumb and face, as well as short stature, may be present. Surprisingly, mutations in the RPS19 gene, which encodes a protein that binds to the small ribosomal subunit, account for about 25% of cases. The mechanism by which mutations in this gene affect erythropoiesis and mesenchymal tissues are not understood. The majority of patients (60%-70%) respond to prednisone, and erythropoiesis can then be maintained, in some cases with almost homeopathic doses of the drug.

Abkowitz and colleagues (page 2687) describe a remarkable adult patient whose anemia, present since a teenager, remitted during pregnancy; the remission was sustained during breast-feeding, raising the possibility that prolactin mediated the beneficial effect. Treatment with metoclopramide, known to induce prolactin release, led to a marked improvement of the anemia. In contrast to the rapid response seen in patients treated successfully with steroids, metoclopramide treatment was required for 15 weeks. A subsequent metoclopramide trial in 15 patients showed a partial response in 3 of the 9 patients who completed 16 weeks of therapy.

This study raises a number of interesting questions, the first of which is whether the diagnosis of DBA is correct? Most DBA patients present in infancy, although it is true that a few present later in life, even as adults. Furthermore the bone marrow aspirate did show the presence of erythroid precursors, and the red cell adenosine deaminase, a useful marker of DBA, was not abnormally increased. On the other hand, the MCV and HbF levels, other features of stress erythropoiesis observed in DBA and in all chronic failures of erythropoiesis, were abnormally increased.

If one accepts this case as one of DBA, the next intriguing question is the mechanism by which prolactin mediates a beneficial effect. Interestingly, the prolonged time to remission, and the author's observations that prolactin had no effect on erythroid progenitors in culture and that no prolactin receptors were present on BFU-Es suggest that the effect is indirect. But these results are controversial, as previously published work (Bellone et al, J Cell Physiol. 1995;163:221-231) suggests that prolactin receptors are present on a proportion of CD34⁺ cells and that prolactin can enhance erythropoiesis in vitro, possibly by increasing expression of the erythropoietin receptor (Epor). It is intriguing that the prolactin receptor has structural and functional similarities to the Epor (eg, in signaling through stat5), and indeed it can substitute for the Epor in Epor^−/− progenitors to fully reconstitute their ability to make red cells in vitro (Socolovsky et al, Blood. 1998;92: 1491-1496).

Steroid nonresponders are usually transfusion-dependent, although responses to IL-3, androgen, or cyclosporin A have been rarely observed. If a histocompatible sibling donor is available, the results of bone marrow transplantation are very good. Karlsson and colleagues (page 2724) show in a small study of 4 patients that the transfer ofRPS19 into RPS19-mutant erythroid progenitors can improve erythroid colony formation. The investigators FACS-selected RPS19 retrovirus–infected cells on the basis of GFP coexpression. Interestingly, despite purification of the corrected progenitor cells, colony formation and BFU-E size still remained subnormal; further data suggested that the corrective effect may be dependent on the level of RPS19 expression. Another point of interest is that the improvement in erythroid colony numbers was observed in the presence of Epo alone or, in 3 of the 4 patients, with Epo plus stem cell factor (SCF), a growth factor known to correct colony formation in a proportion of DBA patients.

In summary, 2 novel forms of treatment for DBA patients are explored in this issue. Although the results are still preliminary, they are provocative; gene therapy may be a long-term goal, but in the meantime one might be tempted to try metoclopramide in steroid-resistant patients.