Myelodysplastic syndrome in the new millennium. How to classify and cure patients?

Česká verzia

Authors: J. Čermák ¹; A. Vítek ¹; K. Michalová ¹; J. Březinová ¹; Z. Zemanová ²
Authors place of work: Ústav hematologie a krevní transfuze, Praha, ředitel prof. MUDr. Pavel Klener, DrSc. ¹; Centrum nádorové cytogenetiky Ústavu klinické biochemie a laboratorní diagnostiky 1. LF UK a VFN, Praha, ředitel prof. MUDr. Tomáš Zima, DrSc. ²
Published in the journal: Vnitř Lék 2005; 51(1): 20-30
Category: Original Contributions

Summary

Aim of the study and methods:
A retrospective analysis of the relationship between the initial classification according to either FAB or WHO classification and survival was performed in a group of 197 patients with primary myelodysplastic syndrome (MDS), who were also subdivided into risk groups according to the International Prognostic Scoring System (IPSS). The influence of stem cell transplantation (SCT) or supportive therapy on survival of different subgroups of patients was also studied.

Results:
A classification of 107 patients on the base of WHO criteria revealed a significant difference in median survival between patients with „pure“ RA and RCMD (78.2 months vs. 42.3 months, P = 0.001). Molecular cytogenetics methods (fluorescent in situ hybridization – FISH) were crucial for classification and prognosis of patients with 5q deletion and enabled us to discriminate patients with additional karyotype abnormalities and adverse prognosis from those with isolated deletion of 5q. In patients with advanced MDS (RAEB, RAEB-T), SCT substantially prolonged median survival in both patients with RAEB and RAEB-T (38.4 months vs. 11.5 months, p < 0.001) and patients with intermediate II. and high risk according to IPSS (36.8 months vs. 12.0 months, p < 0.001) in comparison to supportive treatment or/and chemotherapy only. On the other hand, SCT did not significantly prolong median survival either in RA patients (62.3 months vs. 62.4 months, P > 0.8) or in those with low or intermediate I. IPSS risk (57.2 months vs. 60.8 months, P = 0.8), mainly because of a high rate of SCT related mortality. Classification of RA patients according to the WHO criteria showed no benefit from SCT for survival in both RA and RCMD subgroups. Only more detailed subclassification on the base of combined WHO morphologic and IPSS cytogenetic criteria revealed a subgroup of non-transplanted RCMD patients and „poor“ karyotype, who survived only 9.2 months in contrast to transplanted with median survival of 81.8 months. Presence of adverse karyotype abnormalities was the most important independent variable determining survival and leukemic transformation in multivariate regression analysis.

Conclusion:
Combination of classical morphology with molecular cytogenetics methods may improve identification of risk patients within RA subgroup, who may benefit from early SCT despite a high risk of SCT related complications.

Key words:
myelodysplastic syndrome – classification – prognosis – treatment – transplantation – karyotype

Zdroje

1. Anderson JE Bone marrow transplantation for myelodysplasia. Blood Reviews 2000; 14: 63-77.

2. Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51: 189-199.

3. Cox DR. Regression models and life-tables. J R Stat Soc 1972; 34: 187.

4. Cutler C, Lee S, Greenberg P et al. A decision analysis of allogeneic stem cell transplantation for MDS: Delayed transplantation for low risk MDS is associated with improved outcome. Blood 2002; 100: 74a.

5. Čermák J Myelodysplastický syndrom. In: Mayer J, Starý J. Leukémie. Grada 2002: 221-234.

6. De Witte T, Zwaan F, Hermans J et al. Allogeneic bone marrow transplantation for secondary leukemia and myelodysplastic syndrome:a survey by the Leukemia Working Party of the European Bone marrow Transplantation Group (EBMTG). Br J Haematol 1990; 74: 151-155.

7. De Witte T, Suciu S, Verhoef G et al. Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS. Blood 2002; 98: 2326-2331.

8. Germing U, Gattermann N, Strupp C et al. Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. Leuk Res 2000; 24: 983-992.

9. Greenberg P, Cox C, Le Beau MM et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079-2088.

10. Harris NL, Jaffe ES, Diebold J et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee Meeting - Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17: 3835-3849.

11. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-481.

12. Parker JE, Shafi T, Pagliuca A et al. Allogeneic stem cell transplantation in the myelodysplastic syndromes: interim results of outcome following reduced-intensity conditioning compared with standard preparative regimens. Br J Haematol 2002; 119: 144-154.

13. Raza A, Gregory A, Preisler HD. The myelodysplastic syndromes in 1996: complex stem cell disorders confounded by dual actions of cytokines. Leukemia Res 1996; 20: 881-890.

14. Sierra J, Pérez WS, Rozman C et al. Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood 2002; 100: 1997-2004.

15. Steensma DP, Tefferi A The myelodysplastic syndrome(s): a perspective and review highlighting current controversies. Leuk Res 2003; 27: 95-120.

16. Sutton L, Chastang C, Ribaud P et al. Factors influencing outcome in de novo myelodysplastic syndromes treated by allogeneic bone marrow transplantation: a long term study of 71 patients. Blood 1996; 88: 358-365.

17. Van Den Berghe H, Cassiman JJ, David G et al. Distinct hematological disorder with deletion of long arm of No. 5 chromosome. Nature 1974; 251: 437.

18. Wijermans P, Lubbert M, Verhoef G et al. Low-dose 5-Aza-2,-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol 2000; 18: 956-962.