Lenalidomide

Lenalidomide

Systematic (IUPAC) name
(RS)-3-(4-Amino-1-oxo 1,3-dihydro-2H-isoindol- 2-yl)piperidine-2,6-dione
Clinical data
Trade names	Revlimid
AHFS/Drugs.com	monograph
MedlinePlus	a608001
Pregnancy cat.	X
Legal status	℞-only (US)
Routes	Oral
Pharmacokinetic data
Protein binding	30%
Metabolism	Undetermined
Half-life	3 h
Excretion	Renal (67% unchanged)
Identifiers
CAS number	191732-72-6 Y
ATC code	L04AX04
PubChem	CID 216326
DrugBank	DB00480
ChemSpider	187515 Y
UNII	F0P408N6V4 Y
KEGG	D04687 Y
ChEMBL	CHEMBL848 Y
Chemical data
Formula	C13H13N3O3
Mol. mass	259.261 g/mol
SMILES O=C1NC(=O)CCC1N3C(=O)c2cccc(c2C3)N
InChI InChI=1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18) Y Key:GOTYRUGSSMKFNF-UHFFFAOYSA-N Y
Y (what is this?)  (verify)

Lenalidomide /lɛnəˈlɪdɵmaɪd/ (Revlimid) is a derivative of thalidomide introduced in 2004.

It was initially intended as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic treatment. Lenalidomide has also shown efficacy in the class of hematological disorders known as myelodysplastic syndromes (MDS). Lenalidomide has significantly improved overall survival in myeloma (which generally carries a poor prognosis), although toxicity remains an issue for users. ^[1] It costs $163,381 per year for the average patient.^[2]

Medical uses

Multiple myeloma

Multiple myeloma is a cancer of the blood, characterized by accumulation of a plasma cell clone in the bone marrow.^[3] Lenalidomide is one of the novel drug agents used to treat multiple myeloma. It is a more potent molecular analog of thalidomide, which inhibits tumor angiogenesis, tumor secreted cytokines and tumor proliferation through the induction of apoptosis.^[4][5][6]

Compared to placebo, lenalidomide is effective in induring complete or "very good partial" response, and progression-free survival is improved. Adverse events more common in people receiving lenalidomide for myeloma were neutropenia (a decrease in the white blood cell count), deep vein thrombosis, infections, and an increased risk of other hematological malignancies.^[7] The risk of second primary hematological malignancies does not outweigh the benefit of using lenalidomide in relapsed or refractory multiple myeloma.^[8] It may be more difficult to mobilize stem cells for autograft in people who have received lenalidomide.^[9]

On June 29, 2006, lenalidomide received U.S. Food and Drug Administration (FDA) clearance for use in combination with dexamethasone in patients with multiple myeloma who have received at least one prior therapy.^{[citation needed]}

On 23 April 2009, The National Institute for Health and Clinical Excellence (NICE) issued a Final Appraisal Determination (FAD) approving lenalidomide, in combination with dexamethasone, as an option to treat patients who suffer from multiple myeloma who have received two or more prior therapies in England and Wales.^[10]

Myelodysplastic syndromes

With myelodysplastic syndromes (MDS), the best results of lenalidomide were obtained in patients with deletion 5q.^[11]

It was approved by the FDA on December 27, 2005 for patients with low or intermediate-1 risk MDS with 5q- with or without additional cytogenetic abnormalities. A completed Phase II, multi-centre, single-arm, open-label study evaluated the efficacy and safety of Revlimid monotherapy treatment for achieving haematopoietic improvement in red blood cell (RBC) transfusion dependent subjects with low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality.

63.8% of subjects had achieved RBC-transfusion independence accompanied by a median increase of 5.8 g/dL in blood Hgb concentration from baseline to the maximum value during the response period. Major cytogenetic responses were observed in 44.2% and minor cytogenetic responses were observed in 24.2% of the evaluable subjects. Improvements in bone marrow morphology were also observed. The results of this study demonstrate the efficacy of Revlimid for the treatment of subjects with Low- or Intermediate-1-risk MDS and an associated del 5 cytogenetic abnormality.^[11][12][13]

Lenalidomide was approved on June 17, 2013 by the European Medicines Agency for use in low- or intermediate-1-risk myelodysplastic syndromes (MDS) patients who have the deletion 5q cytogenetic abnormality and no other cytogenetic abnormalities, are dependent on red blood cell transfusions, and for whom other treatment options have been found to be insufficient or inadequate.^[14]

Other cancers

Lenalidomide is undergoing clinical trial as a treatment for Hodgkin's lymphoma,^[15] as well as non-Hodgkin's lymphoma, chronic lymphocytic leukemia and solid tumor cancers, such as carcinoma of the pancreas.^[16] One Phase 3 clinical trial being conducted by Celgene in elderly patients with B-cell chronic lymphocytic leukemia was halted in July 2013 when a disproportionate number of cancer deaths were observed during treatment with lenalidomide versus patients treated with chlorambucil.^[17]

Adverse effects

Lenalidomide is related to thalidomide which is known to be teratogenic. Recent tests in monkeys have suggested lenalidomide is also teratogenic. It therefore has the pregnancy category X and cannot be prescribed for women who are pregnant or who might be conceiving. For this reason, the drug is only available in the United States (under the name Revlimid) through a restricted distribution system called RevAssist.

Other potential side effects are thrombosis, pulmonary embolus, and hepatotoxicity, as well as bone marrow toxicity resulting in neutropenia and thrombocytopenia. Myelosuppression is the major dose-limiting toxicity, which is contrary to experience with thalidomide.^[18]

Venous thromboembolism

Nonetheless, lenalidomide, like its parent compound thalidomide, may cause venous thromboembolism (VTE), a potentially serious complication with their use. Bennett et al. have reviewed incidents of lenalidomide-associated VTE among patients with multiple myeloma.^[19] They have found that there are high rates of VTE when patients with multiple myeloma received thalidomide or lenalidomide in conjunction with dexamethasone, melphalan, or doxorubicin. When lenalidomide and dexamethasone are used to treat multiple myeloma, a median of 14% of patients had VTE (range,3-75%). Patients who took prophylaxis to treat lenalidomide-associated VTE, such as aspirin, thromboembolism rates were found to be lower than without prophylaxis, frequently lower than 10%. Clearly, thromboembolism is a serious adverse drug reaction associated with lenalidomide, as well as thalidomide. In fact, a black box warning is included in the package insert for lenalidomide, indicating that lenalidomide-dexamethasone treatment for multiple myeloma is complicated by high rates of thromboembolism.

Currently, clinical trials are underway to further test the efficacy of lenalidomide to treat multiple myeloma and how to prevent the lenalidomide associated venous thromboembolism.

Stevens-Johnson syndrome

In March 2008, the U.S. Food and Drug Administration (FDA) included lenalidomide on a list of 20 prescription drugs under investigation for potential safety problems. The drug is being investigated for possibly increasing the risk of developing Stevens–Johnson syndrome, a life-threatening condition affecting the skin.^[20]

FDA ongoing safety review

As of 2011, the FDA has initiated an ongoing review of Revlimid. The review focuses on clinical trials which found that Revlimid caused an increased risk of developing new malignancies such as acute myelogenous leukemia (AML) and B-cell lymphoma.^[2] The FDA is currently advising all patients on Revlimid to continue their treatment.^[21]

Mechanism of action

Lenalidomide has been used to successfully treat both inflammatory disorders and cancers in the past 10 years. There are multiple mechanisms of action, and they can be simplified by organizing them as mechanisms of action in vitro and in vivo.^[22]In vitro, lenalidomide has three main activities: direct anti-tumor effect, inhibition of angioenesis, and immunomodulatory role. In vivo, lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity. Lenalidomide has a broad range of activities that can be exploited to treat many hematologic and solid cancers.

See also

• Discovery and development of thalidomide and its analogs

References

Further reading

• Chang DH, Liu N, Klimek V, et al. (July 2006). "Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications". Blood 108 (2): 618–21. doi:10.1182/blood-2005-10-4184. PMC 1895497. PMID 16569772. 
• Anderson KC (October 2005). "Lenalidomide and thalidomide: mechanisms of action--similarities and differences". Seminars in Hematology 42 (4 Suppl 4): S3–8. doi:10.1053/j.seminhematol.2005.10.001. PMID 16344099. 

External links

• Official website Includes list of adverse reactions
• Prescribing Information
• International Myeloma Foundation article on Revlimid
• multiplemyeloma.org Revlimid April 2007 Summary