Efficacy of Lenalidomide in Myelodysplastic Syndromes

University of South Florida, Tampa, Florida, United States
New England Journal of Medicine (Impact Factor: 55.87). 03/2005; 352(6):549-57. DOI: 10.1056/NEJMoa041668
Source: PubMed


Ineffective erythropoiesis is the hallmark of myelodysplastic syndromes. Management of the anemia caused by ineffective erythropoiesis is difficult. In patients with myelodysplastic syndromes and symptomatic anemia, we evaluated the safety and hematologic activity of lenalidomide, a novel analogue of thalidomide.
Forty-three patients with transfusion-dependent or symptomatic anemia received lenalidomide at doses of 25 or 10 mg per day or of 10 mg per day for 21 days of every 28-day cycle. All patients either had had no response to recombinant erythropoietin or had a high endogenous erythropoietin level with a low probability of benefit from such therapy. The response to treatment was assessed after 16 weeks.
Neutropenia and thrombocytopenia, the most common adverse events, with respective frequencies of 65 percent and 74 percent, necessitated the interruption of treatment or a dose reduction in 25 patients (58 percent). Other adverse events were mild and infrequent. Twenty-four patients had a response (56 percent): 20 had sustained independence from transfusion, 1 had an increase in the hemoglobin level of more than 2 g per deciliter, and 3 had more than a 50 percent reduction in the need for transfusions. The response rate was highest among patients with a clonal interstitial deletion involving chromosome 5q31.1 (83 percent, as compared with 57 percent among those with a normal karyotype and 12 percent among those with other karyotypic abnormalities; P=0.007) and patients with lower prognostic risk. Of 20 patients with karyotypic abnormalities, 11 had at least a 50 percent reduction in abnormal cells in metaphase, including 10 (50 percent) with a complete cytogenetic remission. After a median follow-up of 81 weeks, the median duration of transfusion independence had not been reached and the median hemoglobin level was 13.2 g per deciliter (range, 11.5 to 15.8).
Lenalidomide has hematologic activity in patients with low-risk myelodysplastic syndromes who have no response to erythropoietin or who are unlikely to benefit from conventional therapy.

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Available from: Robert Douglas Knight, Oct 26, 2015
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    • "The karyotype is a strong and independent risk factor for disease progression according to prognostic scoring systems (IPSS, WPSS and IPSS-R) (Greenberg et al., 1997, 2012; Haase et al., 2007; Malcovati et al., 2007; Schanz et al., 2011, 2012). Recently, there has been an increasing evidence about the impact of distinct common aberrations on the outcome and clinical course in MDS patients, such as del(5q), del(7q)/-7 or trisomy 8 (Sol e et al., 2000, 2005; List et al., 2005; Haase et al., 2007; Mallo et al., 2011; Schanz et al., 2011, 2012, 2014; Saumell et al., 2012; S anchez-Garc ıa et al., 2014). A deletion of the short arm of chromosome 12 (del(12p)) is a characteristic, but rare, abnormality in MDS patients. "
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    ABSTRACT: In myelodysplastic syndromes (MDS), deletion of the short arm of chromosome 12 (del(12p)) is usually a small abnormality, rarely detected as a single aberration by chromosome banding analysis (CBA) of bone marrow metaphases. Del(12p) has been described in 0.6 to 5% of MDS patients at initial diagnosis and is associated with a good to intermediate prognosis as a sole anomaly according to current scoring systems. Here, we present the results of a systematic del(12p) testing in a German prospective diagnostic study (clinicaltrials.gov: NCT01355913) on 367 MDS patients in whom CD34+ peripheral blood cells were analysed for the presence of del(12p) by sequential fluorescence in situ hybridization (FISH) analyses. A cohort of 2,902 previously published MDS patients diagnosed by CBA served as control. We demonstrate that, using a sensitive FISH technique, 12p deletion occurs significantly more frequently in MDS than previously described (7.6% by CD34+ PB-FISH vs. 1.6% by CBA, P < 0.001) and is often associated with other aberrations (93% by CD34+ PB-FISH vs. 60% by CBA). Additionally, the detection rate can be increased by repeated analyses in a patient over time which is important for the patient´s prognosis to distinguish a sole anomaly from double or complex aberrations. To our knowledge, this is the first study to screen for 12p deletions with a suitable probe for ETV6/TEL in 12p13. Our data suggest that the supplement of a probe for the detection of a 12p deletion to common FISH probe panels helps to avoid missing a del(12p), especially as part of more complex aberrations. © 2015 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 09/2015; 54(12). DOI:10.1002/gcc.22292 · 4.04 Impact Factor
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    • "The thalidomide structural backbone was used as a template by chemists to design and synthesize compounds with increased immunological and anticancer properties, but lacking the toxicity associated with the parent compound (Bartlett et al. 2004). Lenalidomide (LEN), obtained by this way (LEN, known as Revlimid) was proven to be effective in the treatment of patients with low-risk MDS, particularly in MDS del(5q) (List et al. 2005). However, it is important to identify prognostic factors to better risk-stratify patients for more effective treatment (Ma 2012). "
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    ABSTRACT: A specific type of myelodysplastic syndrome (MDS) is associated with isolated deletion on the long arm of chromosome 5 i.e., 5q-syndrome (del(5q)). The treatment approaches for MDS del(5q) include the immunomodulating drug lenalidomide (LEN). Thirteen MDS del(5q) patients were included in this study. We found elevated activities of lactate dehydrogenase (LDH) and matrix metalloproteinase 9 (MMP-9) in the blood plasma of MDS del(5q) patients as compared with healthy controls. This was stabilized to control values after LEN treatment. Similar behavior we registered also for the thioredoxin and calnexin contents in blood plasma. Peripheral blood mononuclear cells (PBMC) from patients with MDS del(5q) prior to and after treatment with LEN did not exhibit any detectable amount of P-glycoprotein (P-gp) gene transcript. However, we detected a measurable amount of multidrug resistance associated protein 1 (MRP1) mRNA in PBMCs from three patients prior to LEN treatment and in one patient during LEN treatment but it was not present prior to treatment. These data indicated on usefulness of applied protein markers estimation for monitoring of MDS del(5q) patient treatment effectiveness by LEN. Expression of MRP1 seems to be independent on LEN treatment and reflects probably the molecular variability in the ethiopathogenesis of MDS del(5q).
    General Physiology and Biophysics 05/2015; DOI:10.4149/gpb_2015012 · 1.17 Impact Factor
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    • "Lenalidomide represents the first therapeutic agent in MDS, which targets a cytogenetically defined disease subset. The initial evidence of its clinical activity was based on a high clinical and cytogenetic response rate in del(5q) MDS patients in the initial safety and efficacy study (11). Lenalidomide was approved by the Food and Drug Administration (FDA) in 2005 for the treatment of transfusion-dependent IPSS low or intermediate (int)-1 risk, del(5q) MDS. "
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    ABSTRACT: Myelodysplastic syndromes (MDS) represent a hematologically diverse group of myeloid neoplasms, however, one subtype characterized by an isolated deletion of chromosome 5q (del(5q)) is pathologically and clinically distinct. Patients with del(5q) MDS share biological features that account for the profound hypoplastic anemia and unique sensitivity to treatment with lenalidomide. Ineffective erythropoiesis in del(5q) MDS arises from allelic deletion of the ribosomal processing S-14 (RPS14) gene, which leads to MDM2 sequestration with consequent p53 activation and erythroid cell death. Since its approval in 2005, lenalidomide has changed the natural course of the disease. Patients who achieve transfusion independence and/or a cytogenetic response with lenalidomide have a decreased risk of progression to AML and an improved overall survival compared to non-responders. Elucidation of the mechanisms of action of lenalidomide in del(5q) MDS has advanced therapeutic strategies for this disease. The selective cytotoxicity of lenalidomide in del(5q) clones derives from inhibition of a haplodeficient phosphatase whose catalytic domain is encoded within the common deleted region on chromosome 5q, i.e., protein phosphatase 2A (PP2Acα). PP2A is a highly conserved, dual specificity phosphatase that plays an essential role in regulation of the G2/M checkpoint. Inhibition of PP2Acα results in cell cycle arrest and apoptosis in del(5q) cells. Targeted knockdown of PP2Acα using siRNA is sufficient to sensitize non-del(5q) clones to lenalidomide. Through its inhibitory effect on PP2A, lenalidomide stabilizes MDM2 to restore p53 degradation in erythroid precursors, with subsequent arrest in G2/M. Unfortunately, the majority of patients with del(5q) MDS develop resistance to lenalidomide over time associated with PP2Acα overexpression. Targeted inhibition of PP2A with a more potent inhibitor has emerged as an attractive therapeutic approach for patients with del(5q) MDS.
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