Lenalidomide-Mechanism of Action, Indications, Dose, Side Effects

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lenalidomide

Structure

Added amino group at position 4 of the phthaloyl ring and removal of a carbonyl. It is more potent than its parent drug Thalidomide.

Pharmacokinetics

It is rapidly absorbed after oral administration, and reaches peak plasma concentrations at 60–90 minutes. It undergoes limited metabolism and elimination is primarily renal and 66% of  the dose is excreted unchanged in the urine. T1/2 is 3hrs.

Indications

  1. Multiple Myeloma
  2. MDS – associated with the del 5q with or without additional cytogenetic abnormalities. (low- or intermediate-1-risk)
  3. Mantle Cell Lymphoma (MCL) – relapsed  or  progressed after two prior therapies, one of which included bortezomib.
  4. Other – CLL, Follicular lymphoma, DLBCL

Dosing and administration

  1. Myelodysplastic syndrome: 10 mg PO daily.
  2. Multiple myeloma and MCL : 25 mg PO daily on days 1–21 of a 28-day cycle.

Available as 2.5, 5, 10, 15, 20, 25mg capsule in bottle containing 21 or 100 capsules.

Dosing Instructions

  • Once daily, with or without food.
  • If the patient miss a dose, dose can be taken upto 12 hrs of schedule dose.
  • If more than 12 hours have elapsed, patient should be instructed to skip the dose for that day and take drug the next day at the usual time.

Side Effects

  • Severe or fatal teratogenic effect.
  • Myelosuppression with neutropenia (30-50%) and thrombocytopenia (20-30%)- usually reversible.
  • Thromboembolic complications – DVT and PE.(5-10%). Prophylaxis with low molecular weight heparin or aspirin recommended.
  • GI side effects (30-40%) – Nausea/vomiting, diarrhea, and constipation.
  • Neurologic side effects(5-10%)
  • Peripheral neuropathy are rare with almost no sedation.

Allergic Reactions

  • Angioedema, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) – discontinue.
  • Prior history of Grade 4 rash associated with thalidomide – do not give lenalidomide.
  • Interruption or discontinuation – Grade 2-3 skin rash.

Hepatotoxicity

  • Incidence – 15%
  • Fatal cases – in combination with dexamethasone.
  • Monitor liver enzymes periodically.

Tumor Flare Reaction

  • May occur during use for CLL and lymphoma.
  • Tender lymph node swelling, fever, and rash.
  • T/t – corticosteroids, NSAIDs and/or narcotic analgesics.
  • Grade 3 or 4 – withhold treatment until TFR resolves to ≤ Grade 1.

Second Primary Malignancies

  • Incidence – 1-3%
  • AML and Hodgkin lymphoma
  • Patients treated with lenalidomide with melphalan and stem cell transplantation had a higher incidence.
  • Monitor patients for the development of second malignancies.

Dose Modification

PLATELET COUNT RECOMMENDED COURSE (MM)
< 30,000 Interrupt t/t

follow CBC weekly

Return to >30,000 Resume dose at 15mg/day
For each subsequent drop <30,000/mc Interrupt treatment
Return to ≥30,000/mcL Resume at 5 mg less than the previous dose.

Do not dose below 5 mg daily

 

ABSOLUTE NEUTROPHIL COUNT RECOMMENDED COURSE (MM)
Fall to <1000/mcL Interrupt treatment

follow CBC weekly

Return to ≥1,000/mcL

and neutropenia is the only toxicity

Resume at 25 mg daily
Return to ≥1,000/mcL

and if other toxicity present

Resume at 15 mg daily
For each subsequent drop <1,000/mcL Interrupt  treatment
Return to ≥1,000/mcL Resume at 5 mg less than the previous dose.

Do not dose below 5 mg

 

GFR DOSE IN MM/MCL DOSE IN MDS
30-60mL/min 10mg/d 5mg/d
<30mL/min

not requiring dialysis

15mg/48hr 2.5mg/d
<30mL/min

requiring dialysis

5mg/d 2.5mg/d

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