Haematologica 2002; 87:(03)ELT18
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Efficacy of thalidomide in the treatment of myelodysplastic syndromes
Pier Paolo Piccaluga, Giuseppe Visani,* Carlo Finelli, Tiziana Grafone, Michele Baccarani, Sante Tura
Institute of Haematology and Clinical Oncology "L. e A. Seràgnoli", University of Bologna, Italy; *Department of Hematology, San Salvatore Hospital, Pesaro, Italy

Correspondence: Pier Paolo Piccaluga, MD. Institute of Haematology and Clinical Oncology "L. e A. Seràgnoli", University of Bologna, Policlinico S. Orsola, via Massarenti 9, 40138 Bologna, Italy.
Phone: international+39.051.6363680. Fax: international +39.051.6364037.E-mail: ppiccaluga@hotmail.com
Recent data suggest that neoangiogenesis is involved in the development of some hematologic malignancies. We, therefore, treated 2 patients with myelodysplastic syndrome with thalidomide, an antiangiogenic drug, and evaluated angiogenic parameters. Both had a clinical benefit and a concomitant reduction in basic fibroblast growth factor plasma level. We conclude that thalidomide can be useful in myelodysplastic syndrome, probably via an antiangiogenic action.

Angiogenesis probably plays a significant role in the development and progression of hematopoietic malignancies. In fact, higher microvascular density (MVD) and/or increased plasma or serum levels of angiogenic factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been reported in multiple myeloma (MM), acute leukemias, chronic myeloproliferative disorders and lymphomas, sometimes having a prognostic relevance. In particular, increased MVD has been recently described also in myelodysplastic syndromes (MDS).1

Thalidomide, an immunomodulatory agent, has shown antiangiogenic activity in experimental in vitro and in vivo models,2-3 with clinical relevance in the approach to MM3; preliminary data suggest potential efficacy also in myelofibrosis with myeloid metaplasia4,5 and MDS.6

Case 1. We treated with thalidomide a 63-year old woman diagnosed as having a myelodysplastic syndrome. The patient, affected by refractory anemia and carrying a 5q- abnormality, had been treated with conventional drugs, such as corticosteroids, androgens, erythropoietin and vitamins since 1996. In spite of these therapies, she developed an important transfusion dependency, requiring 4 to 5 red blood cell (RBC) units every month. In June 2000, we decided to evaluate neoangiogenesis. MVD, estimated on a bone marrow biopsy with qualitative and quantitative methods, appeared definitely increased. bFGF plasma level was higher than that in normal controls. We treated the patient with thalidomide at a dose of 600 mg. Before treatment, the patient's peripheral blood (PB) count was: hemoglobin (Hb) 6.5 g/dL; white blood cells (WBC) 4.6 x 109/L; platelets (PLT) 139 x 109/L. After 12 weeks of treatment we observed an improvement in hemoglobin level from 6.5 to 8 g/dL. Her WBC count was 4.8 x 109/L and PLT 352 x 109/L with a reduction of the transfusion dependency to only 1 RBC unit every 40 days. After 8 months, at the time of writing this, the patient's PB count is: Hb 8.1 g/dL; WBC 5.6 x 109/L; PLT 299 x 109/L (Figure 1). No significant adverse effects have been recorded. A bone marrow biopsy performed after 6 months documented a reduction of MVD and bFGF level was also decreased (Figure 1).

Case 2. The patient, a 65-year old woman, was diagnosed as having refractory anemia with an excess of blasts in 1999. In the last 6 months, her hemoglobin dropped to 8 g/dL, and she was transfused with two RBC units every month, despite standard therapy. We then administered thalidomide at a dose of 300 mg. Higher doses were not well tolerated, since the patient developed a peripheral neuropathy. Before treatment, her peripheral blood count was: Hb 8.6 g/dL; WBC 1.9 x 109/L; PLT 45 x 109/L. After six weeks, her hemoglobin level increased up to 15 g/dL with concomitant reduction of bFGF plasma level (Figure 1). Her WBC count was 3.2 x 109/L and PLT 133 x 109/L. The patient is now transfusion independent, with a follow-up of 6 months, and has the following blood count: Hb 15.5 g/dL; WBC 4.2 x 109/L; PLT 155 x 109/L (Figure 1).

We have found that thalidomide has both biological and clinical effects in refractory anemia. The reduction of MVD and plasma levels of angiogenic growth factors seems to suggest that antiangiogenic activity had a significant role in these effects, but we cannot exclude that other mechanisms are involved such as in other malignancies. In fact, thalidomide shows not only antiangiogenic properties, both in vitro and in vivo, but also immunomodulatory activities, modifying the expression of several adhesion molecules and cytokines, able to explain this drug's effectiveness in hematologic tumors. One of our patients experienced a minor HI-E and the other a major one, according to the IWG classification,7 with a relevant benefit in the quality of life. Adverse effects were mild: both patients developed moderate constipation and peripheral neuropathy (grade I in one case and grade II in the other, according to the WHO scheme). We conclude that thalidomide may be useful in the treatment of refractory anaemia, also in patients resistant to conventional therapies. Further studies regarding thalidomide and other antiangiogenic drugs are now warranted in order to define the role of these new strategies in the approach to hematologic malignancies.

References

  1. Pruneri G, Bertolini F, Soligo D, Carboni N, Cortelezzi A, Ferrucci PF, et al. Angiogenesis in myelodysplastic syndromes. Br J Cancer 1999; 81:1398-401.
  2. D'Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Nat Acad Sci USA 1994; 91:4082-5.
  3. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Eng J Med 1999; 341:1565-71.
  4. Barosi G, Grossi A, Comotti B, Musto P, Gamba G, Marchetti M. Safety and efficacy of thalidomide in patients with myelofibrosis with myeloid metaplasia. Br J Haematol 2001; 114:78-83
  5. Piccaluga PP, Finelli C, Ricci P, Cavo M, Pileri SA, Isidori A, et al. Antiangiogenic therapy with thalidomide improves anemia, thrombocytopenia, hyperleucocytosis, splenomegaly in idiopathic myelofibrosis. Blood 2000; 96:688-III.[abstract 3224]
  6. Raza A, Mejer P, Dutt D, Zorat F, Lisak L, Nascimben F, et al. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndrome. Blood; 2001; 98:958-65.
  7. Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 2000; 96:3671-4.