Imatinib

May cause bone marrow suppression (anemia, neutropenia, and thrombocytopenia), usually occurring within the first several months of treatment. Median duration of neutropenia is 2 to 3 weeks; median duration of thrombocytopenia is 2 to 4 weeks. Monitor blood counts weekly for the first month, biweekly for the second month, and as clinically necessary thereafter. In chronic myeloid leukemia (CML), cytopenias are more common in accelerated or blast phase than in chronic phase.

Severe heart failure (HF) and left ventricular dysfunction (LVD) have been reported (occasionally). Cardiac adverse events usually occur in patients with advanced age or comorbidities. Carefully monitor patients with preexisting cardiac disease or risk factors for HF or history of renal failure. With initiation of imatinib treatment, cardiogenic shock and/or LVD have been reported in patients with hypereosinophilic syndrome (HES) and cardiac involvement (reversible with systemic steroids, circulatory support and temporary cessation of imatinib). Echocardiogram and serum troponin monitoring may be considered in patients with HES/chronic eosinophilic leukemia (CEL) and in patients with myelodysplastic/myeloproliferative (MDS/MPD) disease or aggressive systemic mastocytosis associated with high eosinophil levels. Patients with high eosinophil levels and an abnormal echocardiogram or abnormal serum troponin level may benefit from prophylactic systemic steroids (for 1 to 2 weeks) with the initiation of imatinib. In a scientific statement from the American Heart Association, imatinib has been determined to be an agent that may either cause direct myocardial toxicity (rare) or exacerbate underlying myocardial dysfunction (magnitude: moderate) (AHA [Page 2016]).

Severe bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported; recurrence has been described with rechallenge. Case reports of successful resumption at a lower dose (with corticosteroids and/or antihistamine) have been described; however, some patients may experience recurrent reactions. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported. Symptoms of DRESS include fever, severe skin eruption, lymphadenopathy, hematologic abnormalities (eosinophilia or atypical lymphocytes), and internal organ involvement. If symptoms of DRESS occur, interrupt therapy and consider permanently discontinuing; symptoms regressed upon discontinuation of therapy, however, symptoms recurred in all cases when rechallenged.

Caution is recommended while driving/operating motor vehicles and heavy machinery when taking imatinib; advise patients regarding side effects such as dizziness, blurred vision, or somnolence. Reports of accidents have been received, but it is unclear if imatinib has been the direct cause in any case.

Imatinib is commonly associated with fluid retention, weight gain, and edema (risk increases with higher doses and age >65 years); may be occasionally serious and lead to significant complications, including pleural effusion, pericardial effusion, pulmonary edema, and ascites. Monitor regularly for rapid weight gain or other signs/symptoms of fluid retention; rapid unexpected weight gain should be evaluated and managed appropriately. Use with caution in patients where fluid accumulation may be poorly tolerated, such as in cardiovascular disease (HF or hypertension) and pulmonary disease.

Imatinib is associated with a moderate emetic potential; antiemetics may be recommended to prevent nausea and vomiting (Dupuis 2011, Hesketh 2017, Roila 2016). May cause GI irritation; take with food and water to minimize irritation. There have been rare reports (including fatalities) of GI perforation.

Severe hemorrhage (grades 3 and 4) has been reported with use, including GI hemorrhage and/or tumor hemorrhage. The incidence of hemorrhage is higher in patients with gastrointestinal stromal tumors (GIST) (GI tumors may have been hemorrhage source). Gastric antral vascular ectasia (a rare cause of gastrointestinal bleeding) has also been reported (Alshehry 2014; Saad Aldin 2012). Monitor for GI symptoms with treatment initiation.

Hepatotoxicity may occur; fatal hepatic failure and severe hepatic injury requiring liver transplantation have been reported with both short- and long-term use; monitor liver function (transaminases, bilirubin, and alkaline phosphatase) prior to initiation and monthly or as needed thereafter; therapy interruption or dose reduction may be necessary. Transaminase and bilirubin elevations, and acute liver failure have been observed with imatinib in combination with chemotherapy.

Imatinib is associated with a decline in renal function; may be associated with duration of therapy. The median estimated GFR declined from 85 mL/minute/1.73 m2 at baseline to 75 mL/minute/1.73 m2 at 12 months and to 69 mL/minute/1.73 m2 at 60 months (in patients with newly diagnosed chronic myeloid leukemia and malignant GIST). Evaluate renal function prior to imatinib initiation and monitor during therapy. Patients with risk factors for renal dysfunction (eg, preexisting renal impairment, diabetes mellitus, hypertension, congestive heart failure) may be at higher risk for nephrotoxicity.

Tumor lysis syndrome (TLS), including fatalities, has been reported in patients with acute lymphoblastic leukemia (ALL), CML eosinophilic leukemias, and GIST. Risk for TLS is higher in patients with a high tumor burden or high proliferation rate; monitor closely. Correct clinically significant dehydration and treat high uric acid levels prior to initiation of imatinib. Disease-related concerns:

Use with caution in patients with hepatic impairment; dosage adjustment recommended in patients with severe impairment.

Imatinib exposure may be reduced in patients who have had gastric surgery (eg, bypass, major gastrectomy, or resection); monitor imatinib trough concentrations (Liu 2011; Pavlovsky 2009; Yoo 2010).

Use with caution in patients with renal impairment; dosage adjustment recommended for moderate and severe renal impairment (CrCl • Thyroid disease: Hypothyroidism has been reported in thyroidectomy patients who were receiving thyroid hormone replacement therapy prior to initiation of imatinib; monitor thyroid function. The average onset for imatinib-induced hypothyroidism is 2 weeks; consider doubling levothyroxine doses upon initiation of imatinib (Hamnvik 2011). Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

The incidence of edema was increased with age older than 65 years in CML and GIST studies.

Growth retardation has been reported in children receiving imatinib for the treatment of CML; generally where treatment was initiated in prepubertal children; growth velocity was usually restored as pubertal age was reached (Shima 2011). Monitor growth closely. Other warnings/precautions:

Determine PDGFRb gene rearrangements status (for MDS/MPD), D816V c-Kit mutation status (for aggressive systemic mastocytosis [ASM]), Philadelphia chromosome status for acute lymphoblastic leukemia and chronic myeloid leukemia, Kit (CD117)-positivity for GIST, and FIP1L1–platelet-derived growth factor (PDGF) receptor status for HES or CEL prior to initiating treatment.