Pocket Oncology (Pocket Notebook Series), 1st Ed.

IMMUNOMODULATORS/EPIGENETIC MODIFIERS

Kristen Beyer

Drug Classification

Interferon Alfa-2b (Intron A)

Mechanism of action: ↑ activity of cellular & innate immune responses

Dosing/dose adjustments: 2–30 million units/ m2 typically 3 × weekly, given IM/SQ/IV, dose adjustments for tox (hematologic, HSR, neuropsychiatric) & according to indication

PK/PD: Bioavailability IM 83%, SQ 90%, does not penetrate CSF, primarily renal metabolism, T1/2: IV ∼2 h, IM/SQ ∼2–3 h

Adverse effects: Neuropsychiatric (DLT), neutropenia,↑ AST/ALT

DDI: Inhibits CYP1A2 (weak), theophylline (↓ theophylline clearance), ribavirin (risk of worsening mental depression)

Interleukin-2 (Aldesleukin, Proleukin)

Mechanism of action: ↑ lymphocyte mitogenesis & cytotoxicity

Dosing/dose adjustments: 600000 units/kg IV every 8 h, repeat after 9 d (total 28 doses/course), SCr <1.5 mg/dL before starting Rx, hold for signs of hepatic failure, dose adjustments for tox (CV disease, CNS, dermatologic, GI, infxn, respiratory)

PK/PD: Renally metabolized, T1/2 IV initial ∼10 min, renally excreted

Adverse effects: Capillary leak syndrome (BBW, onset immediately after tx initiation), CNS tox (BBW), infxn (BBW), GI bleeding/intestinal perforation, ↑ Tbili, renal insufficiency

DDI: Live vaccines (vaccinial infxn may develop), glucocorticoids (counteract immunostimulant effects)

Ipilimumab (Yervoy)

Mechanism of action: Binds to cytotoxic T-lymphocyte associate antigen 4 (CTLA-4) allowing for ↑ T-cell activation & proliferation

Dosing/dose adjustments: 3 mg/kg IV every 3 wks × 4 doses, no renal dose adjustments recommended. Hepatic impairment during tx: AST or ALT > 2.5 to ≤ 5 × ULN or Tbili > 1.5 to ≤ 3 × ULN: Temporarily hold, AST or ALT > 5 × ULN or Tbili > 3 × ULN: D/C. Adjust dose or D/C for tox (immune rxns, endocrine disorder, CNS, dermatologic, GI, ophthalmic).

PK/PD: T1/2 ∼15 d

Adverse effects: Immune-mediated adverse effects (BBW, commonly includes: Dermatitis, endocrine disorders, enterocolitis, hepatitis)

DDI: No significant drug interactions

Clinical pearls: Check LFTs & TFTs before each dose, initiate high-dose corticosteroid (prednisone 1–2 mg/kg/d) for sev. immune-mediated rxns

Lenalidomide (Revlimid)

Mechanism of action: Displays immunomodulatory, antiangiogenic, & antineoplastic characteristics by: ↓ proinflammatory cytokines & signals to angiogenic factors, ↑ cell-mediated immunity, & induces cell cycle arrest

Dosing/dose adjustments: 10–25 mg PO daily, renal adjustments required for CrCl <60 mL/min, no hepatic dose adjustments recommended, dose adjustments for tox (thrombocytopenia, neutropenia, dermatologic)

PK/PD: Rapid absorption, protein binding ∼30%, T1/2 3–5 h (threefold ↑ in mod.-to-sev. renal impairment), renally excreted, HD removes ∼40% of a dose in a single session

Adverse effects: BM suppression (BBW), thromboembolic events (BBW), peripheral edema, peripheral neuropathy, GI upset, rash

DDI: Digoxin (↑ digoxin conc. ∼14%)

Clinical pearls: Must be registered w/REMS program (RevAssist), consider anticoagulation ppx when used w/dexamethasone after assessment of RFs.

Pomalidomide (Pomalyst)

Mechanism of action: Displays immunomodulatory & antineoplastic characteristics by: ↓ proliferation, ↓ angiogenesis, ↑ apoptosis, ↑ NK cells/T-cell-mediated immunity, ↓ production of proinflammatory cytokines

Dosing/dose adjustments: 4 mg PO daily, avoid if SCr > 3 mg/dL or Tbili > 2 mg/dL & AST/ALT > 3 × ULN. Adjust dose for tox (neutropenia, thrombocytopenia).

PK/PD: Hepatically metabolized, T1/2 ∼8 h, excreted in urine & feces

Adverse effects: Neutropenia, anemia, thrombocytopenia, neuropathy, VTE

DDI: CYP3A4/1A2 or P-gp inhibitors/inducers (↑/↓ conc. of pomalidomide)

Clinical pearls: Must be registered w/REMS program (POMALYST REMS), consider anticoagulation ppx after assessment of RFs

Thalidomide (Thalomid)

Mechanism of action: Displays immunomodulatory & antiangiogenic characteristics by: ↑ NK cells/interleukin-2/IFN, ↓ angiogenesis, ↓ free-radical–mediated DNA damage, ↑ cell-mediated cytotoxic effects

Dosing/dose adjustments: 50–800 mg PO daily, no renal or hepatic dose adjustments recommended. Adjust dose for tox (ANC ≤ 750/mm3, constipation, oversedation, peripheral neuropathy).

PK/PD: Bioavailability ∼90%, protein binding ∼60%, metabolized by nonenzymatic hydrolysis in plasma, T1/2 ∼6 h, renally excreted

Adverse effects: Thromboembolic events (BBW), leukopenia, peripheral neuropathy, diarrhea, constipation, orthostatic HoTN, rash

DDI: Dexamethasone (↑ thrombogenic effect of thalidomide)

Clinical pearls: Must be registered w/REMS program (STEPS), consider anticoagulation ppx after assessment of RFs.

Drug Classification

Romidepsin (Istodax)

Mechanism of action: Inhibits HDAC enzymes causing termination of cell growth & apoptosis

Dosing/dose adjustments: 14 mg/m2 IV d 1, 8, & 15 of 28-d cycle, no renal dose adjustments recommended, use w/caution in sev. hepatic impairment. Adjust dose for tox.

PK/PD: Protein binding ∼94%, T1/2 ∼3 h, metabolism via CYP3A4 or P-gp

Adverse effects: Pancytopenia, diarrhea, QTc prolongation, electrolyte wasting, hyperuricemia, hyperglycemia

DDI: CYP3A4/P-gp inhibitors/inducers (↑/↓ conc. of romidepsin), QTc-prolonging medications (↑ QTc-prolonging effect)

Clinical pearls: Monitor serum electrolytes (K & Mg) & ECG in pts w/significant CV disease

Vorinostat (Zolinza)

Mechanism of action: Inhibits HDAC enzymes causing termination of cell growth & apoptosis

Dosing/dose adjustments: 400 mg PO daily, no renal dose adjustments recommended, mod. hepatic impairment (Tbili >1.5 to 3 × ULN): 200 mg daily & contraindicated in sev. impairment (Tbili > 3 mg/dL). Adjust dose for tox (↑ SCr, ↓ appetite, ↓ K, N/V, neutropenia, leukopenia, thrombocytopenia)

PK/PD: Bioavailability fasting ∼43%, protein binding ∼71%, glucuronidated & hydrolyzed, T1/2 ∼2 h, renally excreted

Adverse effects: Thrombocytopenia, anemia, QTc prolongation, ↑ SCr, diarrhea, hyperglycemia, electrolyte wasting, proteinuria, thrombosis

DDI: Oral anticoagulants (↑ risk of bleeding), valproic acid (risk of sev. thrombocytopenia & GI bleeding), QTc-prolonging medications (↑ QTc-prolonging effect)

Clinical pearls: Encourage oral hydration as pts may develop diarrhea, monitor electrolytes (K & Mg), SCr, & glu.

Information based on publicly available drug inserts from Merck, Novartis, Bristol-Myers Squibb, and Celgene.