Results from a retrospective analysis of a randomized, international phase III study (MDS-004) of lenalidomide (Revlimid?, Celgene International S?rl) for the treatment of patients with low/int-1 risk myelodysplastic syndromes (MDS) with a del(5q) chromosome abnormality confirmed that the cumulative three-year risk of progression to acute myeloid leukaemia (AML) rate was 25.1%, and the three-year overall survival rate was 56.0% for patients receiving lenalidomide in the study.

These results were presented during the 52nd Annual Meeting of the American Society of Hematology in Orlando (December 4 ? 7, 2010).

Myelodysplastic syndromes (MDS) are a group of hematologic malignancies that affect approximately 300,000 people worldwide. Myelodysplastic syndromes occur when blood cells remain in an immature or ?blast? stage within the bone marrow and never develop into mature cells capable of performing their necessary functions. Eventually, the bone marrow may be filled with blast cells suppressing normal cell development.

For most patients, standard treatment includes reliance on blood transfusions to manage symptoms of anemia and fatigue which, in turn, and may lead to the development of life-threatening iron overload and/or toxicity from frequent transfusions, which may lead to cardiac, hepatic, and endocrine dysfunction.[1] Recent studies suggest an adverse effect of RBC transfusion dependence on survival, predominantly in lower-risk MDS [2]. This effect was sufficiently significant that RBC transfusion dependence was incorporated into the World Health Organization Prognostic Scoring System (WPSS) for MDS [3], underscoring the critical need for new therapies targeting the cause of the condition rather than simply managing its symptoms, which, for many MDS patients remains supportive/palliative care. Some studies encouraging studies have resulted in transfusion-dependent MDS patients becoming transfusion independent in response to thalidomide. [3]

Chromosomal (cytogenetic) abnormalities are detected in more than half of patients with MDS, and involve a deletion in all or part of one or more specific chromosomes. The most common cytogenetic abnormalities in MDS are deletions in the long arm of chromosomes 5, 7, and 20. Another common abnormality is an extra copy of chromosome 8. A deletion involving the 5q chromosome may be involved in 20 to 30% of all MDS patients. The World Health Organization (WHO) has also recently identified a unique subset of MDS patients with a ?5q- Syndrome? where the only chromosomal abnormality is a specific portion of the 5q chromosome.

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The results from the retrospective analysis presented during the annual meeting showed that patients achieving red blood cell transfusion independence (RBC-TI) for at least 26 weeks were associated with 41% and 47% reductions in risk of AML progression or death (p=0.046) and death (p=0.019), respectively, compared to patients who did not achieve RBC-TI. Factors associated with an increased risk of AML progression and deaths were higher baseline ferritin levels, older age, and higher transfusion burden.

Additionally, a landmark analysis showed that patients achieving RBC-TI for at least 26 weeks were associated with longer AML-free survival times compared with non-responders (P = 0.021)

The retrospective analysis evaluated 138 patients with RBC transfusion-dependent low-or-int-1-risk del(5q) MDS who were randomized to receive either lenalidomide 5 mg on days 1-28 (n=69) or lenalidomide 10 mg on days 1-21 (n=69), both in 28-day cycles. Median time since diagnosis of MDS was 2.7 years (0.2-29.2 years), median RBC transfusion requirement at baseline was 6 units/8 weeks (range, 1-25 units/8 weeks), and median duration of lenalidomide treatment was 12.9 months (range, 0.3-36.7 months). First response was assessed at 16 weeks, and responders continued double-blind treatment for up to 52 weeks, until erythroid relapse or disease progression. Patients who completed 52 weeks of therapy could enter an open-label (OL) extension phase at their current lenalidomide dose. Patients receiving placebo or 5 mg lenalidomide who did not respond by week 16 or who had erythroid relapse could receive lenalidomide 5 mg or 10 mg, respectively, in the OL phase.

This analysis included data through completion of the OL phase for patients randomized in the double-blind phase to lenalidomide 5 mg and 10 mg combined. Patients randomized to placebo were excluded, as all except 11 patients crossed over to lenalidomide 5 mg after 16 weeks of treatment.

The most common grade three or higher adverse events in the 5 mg and 10 mg arms were neutropenia (74%, 51/69 and 75%, 52/69, respectively), thrombocytopenia (33%, 23/69; 41%, 28/69) and leukopenia (13%, 9/69; 9%, 6/69).

Lenalidomide, a thalidomide analogue and IMiDs? compound, is indicated for patients with transfusion-dependent anemia due to Low- or Intermediate-1?risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

Research presented during the 2010 meeting of American Society of Clinical Oncology shows that the drug has a predictable and manageable safety profile. Most Adverse Events generally occur early in therapy. The risk/benefit profile supports 10 mg as starting dose. Anticipation of lenalidomide,-associated hematologic Adverse Events, and use of dose modifications and supportive care as needed, should help achieve optimal clinical benefit from lenalidomide.[4]

[1] J. B. Porter, Practical management of iron overload, British Journal of Haematology, vol. 115, no. 2, pp. 239?252, 2001.
[2] Malcovati L, Della Porta MG, Pascutto C, et al., Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making, Journal of Clinical Oncology, vol. 23, no. 30, pp. 7594?7603, 2005.
[3] Malcovati L, Germing U, Kuendgen G, et al., Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes, Journal of Clinical Oncology , vol. 25, no. 23, pp. 3503?3510, 2007
[4] Raza A, Meyer P, Dutt D, Zorat F, Lisak L, Nascimben F, du Randt M, Kaspar C, Goldberg C, Loew J, Dar S, Gezer S, Venugopal P, Zeldis J. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood. 2001 Aug 15;98(4):958-65
[5] Fenaux P, Giagounidis A, Selleslag DL, Beyne-Rauzy O, Mittelman M, Muus P, Knight RD, Fu T, Hellstrom-Lindberg E. Safety of lenalidomide (LEN) from a randomized phase III trial (MDS-004) in low-/int-1-risk myelodysplastic syndromes (MDS) with a del(5q) abnormality J Clin Onco, 2010 ASCO Annual Meeting Proceedings (Post-Meeting Edition) vol 28, No 15_suppl (May 20 Supplement), 2010: 6598.<</body>

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