Lenalidomide (Revlimid)

A 4-amino-glutaramide analog of thalidomide.

Immunomodulatory drug similar to thalidomide but more potent inhibition of tumor necrosis factor alpha and other inflammatory cytokines with greater capacity to promote T cell activation, angiogenesis and with reduced neurological and sedative properties.

Has pleitropic antitumor effects, including stimulation of T cell and natural killer cell expansion, inhibits tumor associated angiogenesis and lymphangioangiogenesis and induction of lymphoma cell apoptosis through the down regulation of cyclin D1.

In contrast to thalidomide, lacks significant neurosedative toxicity, but shares the risk of venous thromboembolism.

Venous thrombus prophylaxis should be considered with this drug.

Harvesting of peripheral blood stem cells should be done before prolonged exposure to lenalidomide.

Aspirin is recommended as thromoboprophylaxis and therapeutic anticoagulation is recommended for those at high-risk for thrombosis.

Response rate with dexamethasone in relapsed or refractory multiple myeloma about 50%.

A trial of 198 patients with newly diagnosed multiple myeloma treated with this agent and dexamethasone vs. dexamethasone alone or dexamethasone plus placebo revealed an 84% overall response rate in the combination of lenalidomide plus dexamethasone with 22% complete remission and 62% partial response rate compared to a 53% response rate for dexamethasone alone. :in the above trial, patients with dexamethasone alone crossed over to the combination of drugs had an overall response rate of 70%.: estimated one year progression free survival was 77% in the combination group compared to 55% with dexamethasone alone.

Reinforces activity of dexamethasone and bortezomib, probably via capase 8 and 9 mediated apoptotic pathway.

Adverse effects include anemia, thrombocytopenia, neutropenia, neuropathy, constipation, deep vein thrombosis and fatigue.

Lenalidomide induced diarrhea can be due to bile acid malabsorption and can be treated effectively with bike acid sequestrants.

As much as 100-50,000 times higher potency than thalidomide as inhibitor of cytokines.

Treatment of the 5q deletion syndrome results in approximately 70% response rate with patients becoming RBC transfusion independent, with most responses within 4-6 weeks of treatment.

Yields transfusion independence responses in 67% of patients, complete cytogenetic remissions in 44% and a duration of transfusion independence lasts a median of 2 years (List A).

Can result rapid reduction in neutrophil and platelet counts because of suppression of hematopoiesis from the 5q clone.

Overall response rates in relapsed or refractory CLL 32-47%.

Phase II studies suggest significant activity in untreated CLL patients with dramatic reductions in lymphocytes with 70% partial response rates by the end of cycle 2, utilizing 5mg/day or less dosage.

Actively inhibits proliferation of NHL cells.

Stimulates activity against CD4+ and CD8+ T cells utilized as a marker of the prognosis of NHL.

Phase II study of monotherapy in 43 refractory or relapsed patients with NHL resulted in 26% response rate with 2 patients having a complete remission, with a progression free survival of approximately 5 months and responding patients exhibiting a survival of approximately 8 months (Witzig).

In patients with relapsed/refractory aggressive non-Hodgkin’s lymphoma 28% of patients had an objective response, and 22% had stable disease. (Wiernik).

In combination with dexamethasone in 23 patients with primary amyloidosis resulted in 10 responses at a median follow-up of 17 months (Dispenzieri).

Oral formulation and is given every 21 to 28 days of monthly cycles.

Dose modification is recommended for patients with renal impairment as the drug is excreted primarily through the kidneys.

A combination of Lenalidomide and rituximab in mantle cell lymphoma results in a response rate of 92%, a complete response rate of 64%, with a medium progression free survival that had not been reached as initial treatment.

Reports show a higher incidence of secondary malignancies when used as a maintenance therapy post stem cell transplant or in a melphalan containing regimen.

There is an increased risk for secondary cancers, especially post stem cell transplant or after treatment with melphalan containing regimens.

In a meta-analysis of a median follow-up of 79.5 months on lenalidomide maintenance the rates of a secondary primary hematologic and solid malignancies were 5.3 and 5.8% respectively.

Lenalidomide alone is the best therapy for maintenance therapy for myeloma according to a meta analysis.

Lenalidomide Improves Efficacy of Rituximab in Recurrent Indolent Lymphoma

Use of lenalidomide in combination with rituximab is safe and improves the efficacy of rituximab in patients with recurrent indolent lymphoma.

In a Phase 3, multi-center clinical trial of lenalidomide plus rituximab versus placebo plus rituximab in patients with relapsed/refractory follicular or marginal zone lymphoma.

Lenalidomide or placebo was administered for 12 cycles along with rituximab given once weekly for 4 weeks in cycle 1 and on day 1 of cycles 2 through 5.

The primary end point of the trial was progression-free survival.

Lenalidomide plus rituximab demonstrated a significantly improved PFS over placebo plus rituximab.

The median PFS was 39.4 months with lenalidomide plus rituximab versus 14.1 months with rituximab alone.

It is suggested that lenalidomide plus rituximab should replace rituximab monotherapy as a standard of care for patients with relapsed or refractory indolent NHL.

Estimated 4,400 people in the U.S. diagnosed with smoldering myeloma each year.

Lenalidomide can reduce the risk of smoldering myeloma progressing to overt multiple myeloma in high-risk patients, and may also reduce the risk of smoldering myeloma from progressing to cancer in intermediate-risk patients.

Every risk group benefits from intervention.

In a study of 86,000 people with multiple myeloma and found that 13.7 percent were first diagnosed as having smoldering myeloma, with a median age of 67 years at diagnosis.

Estimated 4,400 people in the U.S. diagnosed with smoldering myeloma each year.

In half of those diagnosed with smoldering myeloma, the condition progresses to multiple myeloma in the first 5 years.

In the phase II trial, after 3 years, 87 percent of the patients were alive without progressing to multiple myeloma.

In the phase III trial, after 1, 2 and 3 years on the trial, respective progression-free survival rates were 98 percent, 93 percent, and 91 percent for those who received lenalidomide and 89 percent, 76 percent, and 66 percent, respectively, for those who did not receive the treatment.

About 80 percent of patients in the phase II trial and 51 percent of those in phase III trial discontinued lenalidomide due to toxicity: fatigue and non-blood or bone-related side effects.

A 2015 Spanish trial, named PETHEMA, demonstrated that the combination of lenalidomide and dexamethasone lengthened the time before people with smoldering myeloma developed multiple myeloma and extended survival.

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