Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study

Adès, Lionel; Boehrer, Simone; Prébet, Thomas; Beyne‐Rauzy, Odile; Legros, Laurence; Ravoet, Christophe; Dreyfus, François; Stamatoullas, Aspasia; Chaury, M.P.; Delaunay, Jacques; Guy, Laurent; Vey, Norbert; Burcheri, Sara; Mbida, Rose-Marie; Hoarau, Natacha; Gardin, Claude; Fenaux, Pierre

doi:10.1182/blood-2008-08-175778

Cited by 141 publications

(103 citation statements)

References 26 publications

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“…8 A recent study evaluated the effect of lenalidomide 10 mg/day for 21/28 days in patients with intermediate-risk 2 and high-risk MDS and del(5q). 3,9 Thirteen of 47 patients achieved a hematologic response, including seven who had cytogenetic responses. Most responses were seen in patients with isolated del(5q), and none of the 27 patients with a complex karyotype responded to treatment.…”

Section: Introductionmentioning

confidence: 99%

Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

Möllgård¹,

Saft²,

Treppendahl³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundPatients with chromosome 5 abnormalities and high-risk myelodysplastic syndromes or acute myeloid leukemia have a poor outcome. We hypothesized that increasing doses of lenalidomide may benefit this group of patients by inhibiting the tumor clone, as assessed by fluorescence in situ hybridization for del(5q31). Design and MethodsTwenty-eight patients at diagnosis or with relapsed disease and not eligible for standard therapy (16 with acute myeloid leukemia, 12 with intermediate-risk 2 or high-risk myelodysplastic syndrome) were enrolled in this prospective phase II multicenter trial and treated with lenalidomide up to 30 mg daily for 16 weeks. Three patients had isolated del(5q), six had del(5q) plus one additional aberration, 14 had del(5q) and a complex karyotype, four had monosomy 5, and one had del(5q) identified by fluorescence in situ hybridization only. ResultsMajor and minor cytogenetic responses, assessed by fluorescence in situ hybridization, were achieved in 5/26 (19%) and 2/26 (8%) patients, respectively, who received one or more dose of lenalidomide, while two patients achieved only a bone marrow response. Nine of all 26 patients (35%) and nine of the ten who completed the 16 weeks of trial responded to treatment. Using the International Working Group criteria for acute myeloid leukemia and myelodysplastic syndrome the overall response rate in treated patients with acute myeloid leukemia was 20% (3/15), while that for patients with myelodysplastic syndrome was 36% (4/11). Seven patients stopped therapy due to progressive disease and nine because of complications, most of which were disease-related. Response rates were similar in patients with isolated del(5q) and in those with additional aberrations. Interestingly, patients with TP53 mutations responded less well than those without mutations (2/13 versus 5/9, respectively; P=0.047). No responses were observed among 11 cases with deleterious TP53 mutations. ConclusionsOur data support a role for higher doses of lenalidomide in poor prognosis patients with myelodysplastic syndrome and acute myeloid leukemia with deletion 5q. (Clinicaltrials.gov identifier NCT00761449).Key words: lenalidomide, myelodysplastic syndrome, acute myeloid leukemia, P53 mutation.Citation: Möllgård L, Saft L, Treppendahl MB, Dybedal I, Nørgaard JM, Astermark J, Ejerblad E, Garelius H, Dufva IO, Jansson M, Jädersten M, Kjeldsen L, Linder O, Nilsson L, Vestergaard H, Porwit A, Grønbaek K, and

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Section: Introductionmentioning

confidence: 99%

Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

Möllgård¹,

Saft²,

Treppendahl³

et al. 2011

Haematologica

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“…Although a precise cellular target has not been identified, recent investigations indicate that LEN purportedly works through inhibition of phosphatase activity in the common deleted region (CDR) of 5q that plays a key role in cell cycle regulation, through a defect in ribosomal protein function. Accordingly, LEN acts via direct cytotoxic mechanisms in patients with the del (5q) cytogenetic abnormality, and supposedly through effects on the bone marrow microenvi- Lenalidomide in non-del(5q) Myelodysplastic Syndromes ª 2011 Blackwell Publishing Ltd ronment in patients who do not have this lesion, via abrogation of the effects of pro-apoptotic, pro-inflammatory cytokines (List et al, 2005List, 2007;Ades et al, 2009). In the present cohort of lower-risk non-del(5q) MDS refractory to ESA, 48% of the patients obtained an erythroid response with LEN (according to IWG 2006 criteria), and 37% of RBC-TD patients achieved RBC-TI.…”

Section: Discussionmentioning

confidence: 99%

Lenalidomide in lower‐risk myelodysplastic syndromes with karyotypes other than deletion 5q and refractory to erythropoiesis‐stimulating agents

et al. 2011

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SummaryLenalidomide (LEN) has been shown to yield red blood cell (RBC) transfusion independence in about 25% of lower risk myelodysplastic syndromes (MDS) without del(5q), but its efficacy in patients clearly refractory to erythropoiesis‐stimulating agents (ESA) is not known. We report on 31 consecutive lower‐risk non‐del(5q) MDS patients with anaemia refractory to ESA and treated with LEN in a compassionate programme, 20 of whom also received an ESA. An erythroid response was obtained in 15 patients (48%), including 10 of the 27 (37%) previously transfusion‐dependent (RBC‐TD) patients, who became transfusion‐independent (RBC‐TI). Nine of the responders relapsed, whereas 6 (40%) were still responding and transfusion‐free after 11+–31+ months. Median response duration was 24 months. The erythroid response rate was lower in refractory cytopenia with multilineage dysplasia (27% vs. 60%) and tended to be higher in patients treated with LEN + ESA (55% vs. 36%). Response duration was significantly longer in responders who obtained RBC‐TI and in patients treated with LEN after primary resistance to ESA. The main toxicity of LEN was cytopenias. We confirm that, in a patient population of lower risk MDS without del 5q clearly resistant to ESA, LEN is an interesting second line therapeutic option. Its combination with ESAs in this context warrants prospective studies.

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“…For patients resistant to hypomethylating agents use of clofarabine has shown initial promising results . Lenalidomide alone has been used to treat higher risk MDS patients but with low response rates (15% complete responses), virtually all occurring in those with del(5q) alone and <20% marrow blasts (Adès et al, 2009).…”

Section: Management Of Higher Risk Diseasementioning

confidence: 99%

Current therapeutic approaches for patients with myelodysplastic syndromes

Greenberg

2010

Br J Haematol

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SummaryThe myelodysplastic syndromes (MDS) are a heterogeneous spectrum of disorders requiring selective therapy based on patients' specific clinical features, predominantly their prognostic subgroups, age and performance status. Guidelines for management of patients with MDS have been generated by a number of national panels. This review focuses on evidencebased data supporting therapeutic approaches, which have also been recommended by the US National Comprehensive Cancer Network MDS Panel, with discussion of accessibility of recommended drugs in the US and in other countries. For lower risk disease (International Prognostic Scoring System Low and Intermediate-1) therapy is aimed at haematological improvement whereas for higher risk disease (Intermediate-2 and High) treatment focuses on altering disease natural history. Recent information regarding additional clinical and biological features has provided useful parameters for assessing disease prognosis that aid risk-based management decisions. The rationale for use of low versus high intensity therapies with these agents, including allogeneic haematopoietic stem cell transplantation, is discussed in detail.

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Efficacy and safety of lenalidomide in intermediate-2 or high-risk myelodysplastic syndromes with 5q deletion: results of a phase 2 study

Cited by 141 publications

References 26 publications

Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

Clinical effect of increasing doses of lenalidomide in high-risk myelodysplastic syndrome and acute myeloid leukemia with chromosome 5 abnormalities

Lenalidomide in lower‐risk myelodysplastic syndromes with karyotypes other than deletion 5q and refractory to erythropoiesis‐stimulating agents

Current therapeutic approaches for patients with myelodysplastic syndromes

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