• aplastic anaemia;
  • pegylated rHuMGDF;
  • haematological response

We read with interest the recent paper by Kizaki et al (2003) describing the long-term administration of pegylated recombinant human megakaryocyte growth and development factor (rHuMGDF) for a female myelodysplastic syndrome (MDS) patient. They reported that the patient's platelet count increased, and her haemoglobin level increased dramatically, exceeding 13 g/dl without additional transfusion. They suggested that rHuMGDF might have clinical benefits for patients with MDS. We wish to report a patient with aplastic anaemia (AA) treated with rHuMGDF.

A Japanese man was diagnosed with severe AA in February 1997 in another hospital. At that time, the patient was 46-years old and a healthy carrier of the hepatitis B virus. Laboratory tests showed a haemoglobin of 4·0 g/dl, platelet count of 0·4 × 109/l, leucocyte count of 3·0 × 109/l and neutrophil count of 0·45 × 109/l. He required both red cell and platelet transfusions and was treated with a combination therapy of ciclosporin  A (CyA) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) from March 1997. Although he showed no haematological response, this combination therapy was continued. He was referred to our hospital in September 1997. At that time, his bone marrow (BM) showed hypocellularity without dysplastic changes. Cytogenetic analysis of BM cells revealed a normal karyotype. He refused allogeneic stem cell transplantation and was thus treated with a combination therapy of antithymocyte globulin (ATG; day 1–5), CyA and rhG-CSF from November 1997. Administration of rhG-CSF was discontinued in February 1998, and CyA treatment was discontinued in July 1999. He showed a minimal haematological response. Laboratory tests showed a haemoglobin of 7·6 g/dl, platelet count of 3·0 × 109/l, and neutrophil count of 1·3 × 109/l in February 1999, and he did not require transfusion. However, his cytopenias gradually worsened again. Therefore, we decided to register him in clinical trial of phase I/II rHuMGDF for AA and MDS. He was treated with 2·5 μg/kg rHuMGDF (KRN9000; Kirin Brewery, Tokyo, Japan) by daily intravenous injection for 14 d according to the protocol of this trial from November 1999. He showed a trilineage response, especially in the erythroid line, at 6–16 weeks from the start of treatment. Although this early effect might have been transient, he gradually showed continued trilineage response, especially in the erythroid line. His haemoglobin levels increased beyond 10 g/dl without additional transfusion or treatment (Fig 1). No adverse events or neutralizing antibodies were observed.


Figure 1. Peripheral blood changes of an aplastic anaemia patient treated with intravenous rHuMGDF. The patient was treated with 2·5 μg/kg/d rHuMGDF by intravenous injection for 14 d.

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Tanimukai et al (1997) reported that thrombopoietin (TPO) acts not only on megakaryocyte progenitors but also on erythroid and multipotential progenitors in vitro. Yagi et al (1999) reported that TPO supports the self-renewal and expansion of human primitive haematopoietic stem cells. Kizaki et al (2003) reported that administration of rHuMGDF dramatically ameliorated cytopenias, especially anaemia, in a MDS patient. In our AA patient, rHuMGDF showed a trilineage response. We think that both our findings and those of Kizaki et al (2003) support these previous reports (Tanimukai et al, 1997; Yagi et al, 1999). The remarkable erythroid response of our AA patient was similar to that of the MDS patient reported by Kizaki et al (2003), who showed an erythroid response after the long-term administration of rHuMGDF. However, our AA patient showed a long-lasting erythroid response despite no treatment after the short-term administration of rHuMGDF. This finding was different from that reported by Kizaki et al (2003). The haematological response of our patient occurred more than 2 years after the start of a combination therapy of ATG, CyA and G-CSF. Therefore, we think that it is not a late response to intensive immunosuppressive therapy (IST). We considered the following hypothesis. Although the immune abnormalities leading to AA were improved by treatment with ATG and CyA, the reduction of haematopoitic stem cells persisted. The short-term administration of rHuMGDF became a trigger for the expansion of haematopoietic stem cells. Approximately 20% of AA patients do not respond to intensive IST. The strategy for AA patients who do not respond to intensive IST is very difficult, and they have a poor prognosis. Our experience suggests that rHuMGDF may have clinical benefits for patients with AA who do not show sufficient response under intensive IST.


  1. Top of page
  2. Acknowledgment
  3. References

We thank Kirin Brewery Company for providing pegylated rHuMGDF.


  1. Top of page
  2. Acknowledgment
  3. References
  • Kizaki, M., Miyakawa, Y. & Ikeda, Y. (2003) Long-term administration of pegylated recombinant human megakaryocyte growth and development factor dramatically improved cytopenias in a patient with myelodysplastic syndrome. British Journal of Haematology, 122, 764767.
  • Tanimukai, S., Kimura, T., Sakabe, H., Ohmizono, Y., Kato, T., Miyazaki, H., Yamagishi, H. & Sonoda, Y. (1997) Recombinant human c-Mpl ligand (thrombopoietin) not only acts on megakaryocyte progenitors, but also on erythroid and multipotential progenitors in vitro. Experimental Hematology, 25, 10251033.
  • Yagi, M., Ritchie, K.A., Sitnicka, E., Storey, C., Roth, G.J. & Bartelmez, S. (1999) Sustained ex vivo expansion of hematopoietic stem cells mediated by thrombopoietin. Proceedings of the National Academy of Sciences of the United States of America, 96, 81268131.