Abstract

Lenalidomide is the first drug to consistently induce transfusion independence and complete cytogenetic remissions in MDS patients with deletion of 5q. However, recently concerns were raised whether lenalidomide treatment may increase the risk of leukemic transformation. The selective activity of lenalidomide against the deletion 5q clone may allow pre-existing aberrant clones to expand if the dominant deletion 5q clone is eradicated in a circumstance in which few normal stem cells remain. This conditional selection of pre-existing clones (

M. Cazzola,
Haematologica
2008
;
93
:
967
–72
) could represent a potential mechanism for leukemic transformation. We therefore analyzed 22 European patients with transfusion-dependent anemia due to low- or intermediate-1-risk deletion 5q MDS treated with lenalidomide who were enrolled in the MDS-003 (CC-5013-MDS-003) study between 12/2003 and 2/2004. For these patients, sufficient cytogenetic, morphologic and clinical follow-up data were available. Ten of these patients achieved a complete (n = 6, 3/6 transiently) or partial (n = 4, 3/4 transiently) cytogenetic remission and 11 patients (5/11 transiently) achieved an erythroid response resulting in transfusion independence. Seven of the 22 patients (32%) developed complex clones containing typical aberrations like der(7q), +8, del(12p), del(17p) and +21 within 5 to 42 months (median 19 months) after study entry, and within 15 and 72 months (median 44 months) after diagnosis. Among these 7 patients, the findings at baseline included that 2 patients had the deletion 5q plus additional chromosomal aberrations, i.e. del(12p) and trisomy 21, respectively, 2 patients had an isolated deletion 5q karyotype and low-risk MDS, and 3 patients had an elevated blast count ≥ 5%. Six of the these 7 patients progressed to AML, and one patient lost the complex clone with continued lenalidomide treatment, showing the isolated deletion 5q again, and achieved a partial remission from RAEB-1 to RCMD. Both patients with low risk MDS and isolated deletion 5q developed complex clones 12 and 9 months after study entry and 19 and 24 months after diagnosis, respectively, and progressed into AML. Moreover, two patients without cytogenetic response progressed to AML 5 and 6 months after study entry, and 15 and 72 months after diagnosis, respectively. In total, 8 patients (36%), 2 of them with 5q- syndrome, 4 with RCMD and 2 with RAEB-1 according to the WHO classification, progressed into AML. FISH analyses were performed retrospectively to clarify whether complex karyotypes were already present at the time of diagnosis. In no case were such aberrations detected. The FISH data also showed that 13% to 84% (median 50%) of the cells contained a del (5q) abnormality, demonstrating that in all patients who underwent karyoptypic evolution, a substantial number of normal cells was present in the bone marrow. Overall, these data show that karyotypic evolution of 5q- clones into complex clones plays a significant role in the progression of low and int-1 MDS with 5q- into AML. No evidence of conditional selection by FISH analyses was observed. However, the presence of small complex clones at baseline may have been missed because FISH has a detection limit of up to 10%. It remains unclear whether the development of complex clones occurs during the natural course of the disease, whether lenalidomide treatment increases chromosomal instability or whether pre-existing clones are selected during treatment. Clearly, these findings warrant careful follow-up of MDS patients treated with lenalidomide and show that a multi-center, double-blind, placebo-controlled study with a long observation time is needed to define long-term safety and efficacy of lenalidomide.

Topics:
chief complaint, clone cells, cytogenetics, follow-up, lenalidomide, transfusion, cytopenia, refractory, with multilineage dysplasia, disease remission, karyotype determination procedure, refractory anemia with excess blasts

Disclosures: Göhring:Celgene Corporation: cytogenetic reference lab for Celgene MDS-004 study. Giagounidis:Celgene Corporation: Speakers Bureau. Aul:Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees. Büsche:Celgene Corporation: histology reference lab for Celgene MDS-004 study. Kreipe:Celgene Corporation: histology reference lab for Celgene MDS-004 study. Hellström-Lindberg:Celgene Corporation: Consultancy, Research Funding. Knight:Celgene Corporation: Employment. Schlegelberger:Celgene Corporation: cytogenetic reference lab for Celgene MDS-004 study.

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2008, The American Society of Hematology
2008