Revlimid (lenalidomide)

Revlimid (lenalidomide) is an orally available thalidomide analog, exerting both anti-angiogenic and immunomodulatory/anti-inflammatory properties.

Revlimid is specifically indicated for the treatment of 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.

Revlimid is supplied as an opaque capsule for oral administration. Recommended dosing is 10 mg daily with water. Dosing may be reduced (to 5 mg once daily or once every other day) or temporarily suspended if incidence of thrombocytopenia or neutropenia is observed (see Side Effects, below).

FDA Approval
Approval of Revlimid was based on results of an open-label, single arm, multi-center study that enrolled 148 patients with red-blood-cell-transfusion dependent anemia due to low-or intermediate-1- risk MDS associated with a 5 q (q31-33) cytogenetic abnormality in isolation or with additional cytogenetic abnormalities. Subjects received 10 mg Revlimid once daily either continuously or for 21 of every 28 days. Sequential dose reductions, to 5 mg daily and 5 mg every other day, were permitted to mitigate toxicities. The drug was shown to be efficacious in reducing the need for red-blood cell transfusions: 67% (n=99/148) of patients experienced a period of at least 8 weeks during which no transfusion was needed, and the median duration of transfusion independence was maintained for a median 44 weeks. 90% of responders experienced onset of transfusion independence within 3 months. Dose interruption or reduction due to toxicity was necessary in 79.7% of patients (n=118/148).

Ongoing Study Commitments

• The embryo-fetal toxicity assessment of Revlimid has not been adequately addressed. Celgene has agreed to provide adequate information for this assessment in appropriate models designed to fully assess the possible toxicity of Revlimid. Celgene plans to conduct these studies in two different species that are appropriate to assess the full range of thalidomide embryo-fetal effects. As discussed, the rat is not an acceptable model. If the study with lenalidomide in the first species shows clear evidence of teratogenesis, than a confirmatory study will not be necessary. Although not generally considered definitive test systems for pharmaceutical products, additional studies of an exploratory nature on the embryo-fetal effects of lenalidomide may be useful.
  Protocol Submission: June 2006
  Study Start: September 2006
  Final Report Submission: December 2007
• Celgene has agreed to submit the study report and data from the ongoing study, CC-5013-MDS-004, a randomized, double-blind, placebo-controlled, multicenter, 3-arm study of the efficacy and safety of 2 doses of lenalidomide (5 mg daily versus 10 mg day 21 days of a 28 day cycle) versus placebo in red blood cell (RBC) transfusion-dependent patients with low-or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality when completed.
  Protocol Submission: March 2005
  Study Start: August 2005
  Final Report Submission: December 2008
• Following Revlimid dosing, approximately 2/3 of lenalidomide is excreted as unchanged drug in urine. In multiple myeloma patients with mild renal impairment, exposure (plasma AUC) was 56% higher than in similar patients with normal renal function who received the same dose. Based on these data, Celgene has agreed to conduct a study to determine the pharmacokinetics of lenalidomide in subjects with renal impairment.
  Protocol Submission: November 2004
  Study Start: March 2006
  Final Report Submission: December 2007
• Regarding the Evaluation/Surveillance Plan:
  Celgene has agreed to submit a Pregnancy Exposure follow-up plan which will document their plan to follow-up pregnancy exposures to their outcome. This plan may be submitted as a post-marketing commitment.
  Plan submission: June 1, 2006

  Celgene has agreed to submit an Evaluation Plan of RevAssist to FDA within 3 to 6 months of approval, including, at a minimum, plans to study the Pharmacy Audit Plan, Outcomes of Pregnancy Exposures, and the Knowledge Surveys of physicians, nurses, and patients.
  Plan submission: June 1, 2006

• Celgene has agreed to submit all exposed pregnancies within 15 days of receipt as 15 day expedited reports.

Adverse events associated with the use of Revlimid may include, but are not limited to, the following:

• Thrombocytopenia
• Neutropenia
• Diarrhea
• Pruritus
• Rash
• Fatigue
• Constipation
• Nausea
• Nasopharyngitis
• Arthralgia
• Back Pain
• Pyrexia
• Peripheral Edema

Thrombocytopenia and neutropenia were the most frequently observed all-grade (61.5% and 58.8% of patients, respectively) and serious (Grade 3/4) adverse events (53.4% and 50.0% of patients). Resolution of these events was usually achieved by suspension of Revlimid dosing until cell counts stabilized, followed by a reduced dosing regimen (5 mg once daily or once every other day) on resumption of treatment. Close monitoring of platelet and neutrophil counts, both prior to and during treatment, should be performed.

In addition, as an analogue of thalidomide, Revlimid is presumed to carry serious teratogenic risk Use of the drug in women who are pregnant or who may become pregnant during Revlimid treatment or within 4 months of treatment termination is strongly discouraged. The drug is only available through a closely monitored distribution and education program, dubbed RevAssist, designed to minimize the chance that Revlimid is administered to a pregnant patient. Prior to beginning treatment, female patients are required to have 2 negative pregnancy tests 10-14 days and 24 hours prior to initiation of treatment, and receive at least 4 weeks of effective birth control. Female patients are also required to use two forms of reliable birth control during treatment and dose interruption, and should produce a negative pregnancy test once weekly for the first 4 weeks and then once every 4 weeks (every 2 weeks for patients with irregular menstrual cycles) for the duration of treatment and during treatment interruptions. It is unknown if Revlimid enters the semen of male patients. As such, all male patients (including those who have undergone successful vasectomy) are required to use latex condoms throughout treatment and during treatment interruptions.

Finally, Revlimid has been associated with increased risk of deep vein thrombosis and pulmonary embolism. Patients should receive education on the symptoms associated with these conditions, and seek medical help immediately if symptoms appear. It is unknown if prophylactic anticoagulant therapy is effective in reducing this risk; any such treatment course should be administered under the close supervision of a medical professional.

The exact mechanism of Revlimid's activity has not been fully detailed. In-vitro and in-vivo studies indicated that the drug both inhibited the secretion of pro inflammatory cytokines and promoted the secretion of anti inflammatory cytokines from peripheral blood mononuclear cells. The drug also inhibited expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro. Additional antiproliferative activity was noted in some, but not all, human cell lines. The drug effectively inhibited growth of Namalwa cells, a human B cell lymphoma cell line with a deletion of one chromosome 5, but was much less effective in inhibiting the KG-1 human myeloblastic cell line (which also has a deletion of one chromosome 5), and other cell lines without chromosome 5 deletions.

Naing A, Sokol L, List AF. Developmental therapeutics for myelodysplastic syndromes Journal of the National Comprehensive Cancer Network 2006 Jan;4(1):78-82

Giagounidis AA, Germing U, Aul C. Biological and prognostic significance of chromosome 5q deletions in myeloid malignancies Clinical Cancer Research 2006 Jan 1;12(1):5-10

Anderson KC. Lenalidomide and thalidomide: mechanisms of action-similarities and differences Seminars in Hematology 2005 Oct;42(4 Suppl 4):S3-8

Giagounidis AA, Germing U, Strupp C, Hildebrandt B, Heinsch M, Aul C. Prognosis of patients with del(5q) MDS and complex karyotype and the possible role of lenalidomide in this patient subgroup Annals of Hematology 2005 Sep;84(9):569-71. Epub 2005 May 13.

Dredge K, Horsfall R, Robinson SP, Zhang LH, Lu L, Tang Y, Shirley MA, Muller G, Schafer P, Stirling D, Dalgleish AG, Bartlett JB. Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro Microvascular Research 2005 Jan;69(1-2):56-63

List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes New England Journal of Medicine 2005 Feb 10;352(6):549-57

For additional information regarding Revlimid or myelodysplastic syndromes, please visit the Revlimid web page.