Patients with del(5q) MDS who fail to achieve sustained erythroid or cytogenetic remission after treatment with lenalidomide have an increased risk for clonal evolution and AML progression
- 606 Downloads
Lenalidomide consistently induces transfusion independence and complete cytogenetic response in patients with myelodysplastic syndromes with 5q deletion. Only limited information on long-term outcome is currently available. We performed a long-term follow-up analysis of 42 patients with low or intermediate risk myelodysplastic syndromes and 5q deletion treated with lenalidomide. At a median follow-up of 40 months, 58% of the patients achieved an erythroid response and 48% a cytogenetic response. Thirty-six percent of patients progressed into acute myeloid leukaemia. Most of them (87%) acquired chromosome aberrations in addition to the 5q deletion, i.e. underwent clonal evolution during leukaemogenesis. There were no clinical, cytological or cytogenetic markers at study entry that allowed prediction of increased risk of leukaemic transformation. However, erythroid and cytogenetic responders had a significantly decreased risk of progression to acute myeloid leukaemia (p = 0.001 and p = 0.009, respectively) compared to non-responders. Three and 5 years after study entry, the cumulative incidence of acute myeloid leukaemia for patients with a cytogenetic response was 10% and 21%, respectively, and for patients without cytogenetic response, it was 46% and 60%. Patients with del(5q) myelodysplastic syndromes without erythroid or cytogenetic remission after treatment with lenalidomide have a high risk for clonal evolution and acute myeloid leukaemia progression. In refractory, or relapsing, patients, genetic instability and clonal evolution seem to be the driving forces of leukaemic transformation. Regular follow-up investigations of del(5q) myelodysplastic syndrome patients treated with lenalidomide may help to identify patients requiring alternative treatment strategies.
KeywordsMyelodysplastic syndrome Acute myeloid leukaemia 5q deletion Clonal evolution Complex karyotype Leukaemia transformation Lenalidomide
The authors would like to thank Lana Harder, Claudia Haferlach, Brigitte Mohr and Stefan Bohlander for providing cytogenetic data and Gillian Teicke for her help in preparing the manuscript. Finally, we thank Dr. Robert Knight, Celgene, for allowing us to use data obtained within the Celgene MDS-003 clinical trial.
Authorship and disclosures
GG, AG and BS were the principal investigators and take primary responsibility for the paper. AG and CA recruited the patients. GG, GB and HHK performed the laboratory work for this study. MZ participated in the statistical analysis. AG, EHL and BS co-ordinated the research. GG, AG and BS wrote the paper. The authors reported no potential conflicts of interest.
This study was supported by the BMBF (German Competence Network Acute and Chronic Leukaemias).
- 1.Jaffe ES, Harris NL, Stein H, Vardiman JW (2001) World health organization classification of tumours vol. 3. Pathology and genetics: tumours of haematopoietic and lymphoid tissues. IARC, LyonGoogle Scholar
- 11.Schlegelberger B, Metzke S, Harder S, Zühlke-Jenisch R, Zhang Y, Siebert R (1999) Classical and molecular cytogenetics of tumor cells. In: Wegener R (ed) Diagnostic cytogenetics. Springer, Heidelberg, pp 151–185Google Scholar
- 12.ISCN (1995) Guidelines for cancer cytogenetics, supplement to an international system for human cytogenetic nomenclature. Mitelman F (ed) S Karger, BaselGoogle Scholar
- 15.Cox DR (1972) Regression models and life tables. J R Stat Soc 34:187Google Scholar
- 17.Kalbfleisch JD, Prentice RL (1980) The statistical analysis of failure time data (ed 1). Wiley, New YorkGoogle Scholar
- 18.Farag SS, Archer KJ, Mrozek K, Ruppert AS, Carroll AJ, Vardiman JW et al (2006) Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. Blood 108(1):63–73CrossRefPubMedGoogle Scholar
- 22.List A (2008) Immunomodulatory drugs in myelodysplastic syndromes: long-term outcome. Hematol Educ 2(1):91–94Google Scholar
- 25.Jädersten MS, Saft L, Pellagatti P, Göhring G, Nilsson L, Wainscoat JS, Boultwood J, Porwit A, Schlegelberger B, Hellström-Lindberg E (2009) Clonal heterogeneity in the 5q- syndrome: p53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression. Haematologica (in press)Google Scholar
- 26.Göhring G, Schlegelberger B, Hellström-Lindberg E (2008) Myelodysplastic syndromes. In: Stilgenbauer S, Döhner H (eds) Molecular diagnostics in hematological oncology. UNI-MED, Bremen, pp 117–125Google Scholar