What are the potential side effects of lenalidomide (Generic name for Revlimid) in adult patients with a history of cancer or hematological disorders, such as multiple myeloma or myelodysplastic syndromes?

Side Effects of Lenalidomide

Hematologic Toxicities (Most Common and Clinically Significant)

Myelosuppression is the most frequent and dose-limiting adverse effect of lenalidomide, requiring mandatory blood count monitoring throughout treatment.

Neutropenia

• Grade 3 or 4 neutropenia occurs in 30-77% of patients, with the highest rates observed in MDS patients with del(5q) abnormalities (77% in the 5-mg arm, 75% in the 10-mg arm) 1
• In non-del(5q) MDS patients, grade 3/4 neutropenia occurs in 30-62% of patients depending on the study population 1
• Neutropenic fever is uncommon, occurring in approximately 6% of patients 1
• Careful monitoring of complete blood counts is mandatory during treatment, particularly in patients with renal dysfunction due to lenalidomide's renal excretion route 1

Thrombocytopenia

• Grade 3 or 4 thrombocytopenia occurs in 13-38% of patients, with rates of 37-38% in MDS patients with del(5q) receiving lenalidomide versus only 2-3% with placebo 1
• In non-del(5q) MDS patients, grade 3/4 thrombocytopenia occurs in 25-36% of patients 1
• Treatment interruption or dose reduction is frequently required (in approximately 50% of patients) due to potentially serious but generally transient cytopenias 1

Anemia

• Grade 3 or 4 anemia occurs in 11% of patients receiving lenalidomide compared to 6% with placebo 2

Thrombotic Complications (Critical Safety Concern)

Venous thromboembolism is a serious and potentially life-threatening complication that requires mandatory thromboprophylaxis in high-risk combinations.

Deep Vein Thrombosis and Pulmonary Embolism

• DVT occurs in 9% of patients and pulmonary embolism in 4% when lenalidomide is combined with dexamethasone, compared to 4% and 1% respectively with placebo 2
• VTE rates reach 11-19% with lenalidomide/high-dose dexamethasone combinations without routine thromboprophylaxis 3
• Without prophylaxis, DVT incidence reaches 26% when lenalidomide is combined with high-dose dexamethasone or multiagent chemotherapy 3
• Grade 3 or 4 deep vein thrombosis occurred in 3 patients receiving lenalidomide 10-mg and 1 patient receiving placebo in MDS trials 1

Mandatory Thromboprophylaxis Requirements

• Anticoagulation is mandatory when lenalidomide is combined with high-dose dexamethasone or multiagent chemotherapy 3
• Patients must receive either low molecular weight heparin (LMWH) or warfarin when receiving high-risk combinations 3
• Aspirin 81-325 mg daily is adequate prophylaxis for patients with ≤1 VTE risk factor receiving lenalidomide with low-dose dexamethasone, melphalan, or as monotherapy 3

Tumor-Specific Reactions (Unique to Hematologic Malignancies)

Tumor Flare Reactions

• Tumor flare occurs in 30-60% of patients with relapsed/refractory CLL and 50-90% in the first-line setting, though reactions are typically grade 1 or 2 1
• Tumor flare is more frequent in patients with enlarged lymph nodes >5 cm at baseline 1
• Manifestations include painful enlargement of lymph nodes, spleen enlargement, low-grade fever, rash, and/or bone pain 1, 4
• Management requires steroids for lymph node enlargement/inflammation and antihistamines for rash/pruritus 1
• Dose delays or reductions are usually not required for tumor flare reactions 4
• For patients with bulky (>5 cm) lymph nodes, tumor flare prophylaxis with steroids may be considered for the first 10-14 days of therapy 1

Tumor Lysis Syndrome

• Tumor lysis syndrome can complicate treatment, particularly in patients with high lymphocyte counts before therapy 1
• Signs include shortness of breath, peripheral edema, generalized weakness, sweating, fever, and tachycardia 4
• Untreated tumor lysis syndrome can result in renal impairment and congestive heart failure 4
• Allopurinol prophylaxis during cycle 1 (or first 3 cycles in some protocols) is recommended 1

Cardiovascular Toxicities

Cardiac Arrhythmias

• Atrial fibrillation occurs in 18% of patients receiving lenalidomide versus 11% with placebo 2
• Lenalidomide has no QT prolongation risk at approved doses 5

Gastrointestinal and Constitutional Symptoms

• Gastrointestinal disturbance is a common adverse event 6
• Asthenia (generalized weakness) occurs with lenalidomide treatment 6
• Fatigue is a recognized adverse effect 4

Dermatologic Toxicities

• Skin toxicity and rash occur with lenalidomide treatment 6, 4
• Unlike thalidomide, lenalidomide does not appear to cause peripheral neuropathy 2

Renal Considerations

• Approximately 82% of an oral dose is excreted as lenalidomide in urine within 24 hours 5
• Renal function is the only important factor affecting lenalidomide plasma exposure 5
• AUC-matched dose adjustment is recommended for patients with renal impairment at the start of therapy 5
• Lenalidomide requires dose reduction in renal impairment but is not contraindicated 3
• LMWH should be used with caution and may require anti-Xa monitoring in renal dysfunction 3

Pharmacokinetic Factors Affecting Toxicity

• Higher plasma exposure to lenalidomide is associated with increased risk of neutropenia and thrombocytopenia 5
• Lenalidomide has a short half-life (3-4 hours) and does not accumulate in plasma upon repeated dosing 5
• Interindividual variability in plasma exposure is low to moderate 5
• No dose adjustment is needed based on age, ethnicity, mild hepatic impairment, or drug-drug interactions 5

Other Adverse Effects

• Decreased peripheral blood stem cell yield during stem cell collection when lenalidomide is used after a long period of time 6
• Treatment-related mortality was 2.5% in both lenalidomide and placebo groups in MDS trials 1

Critical Monitoring Requirements

All patients receiving lenalidomide require:

• Regular complete blood count monitoring throughout treatment 1
• Assessment for signs of thrombosis, particularly with high-risk combinations 3
• Evaluation for tumor flare reactions in patients with CLL or lymphoma 1
• Renal function monitoring, especially in patients with baseline renal impairment 5