Chapter 5 – Imatinib

Imatinib mesylate (Gleevec, Glivec, Novartis) is a selective inhibitor of ABL, ARG, KIT, PDGFR, and some oncogenic forms, most notably BCR-ABL. Accelerated approval was initially granted by the Food and Drug Administration (FDA) in 2001 for the treatment of Ph+CML after the failure of IFNα therapy. Approval was extended later that year to pediatric CML resistant to IFNα treatment, or recurring after stem cell transplantation. Concomitantly, imatinib was approved for KIT-positive gastrointestinal stromal tumors (GIST), and in 2006 the indications were extended to newly diagnosed pediatric CML, adult relapsed/refractory Ph+ALL, dermatofibrosarcoma protuberans (DFSP), adult myelodysplastic syndrome/myeloproliferative disease (MDS/MPD) associated with PDGFR gene rearrangements, adult aggressive systemic mastocytosis (ASM) without the D816V c-439 KIT mutation or with KIT mutational status unknown, and adult hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL) with/without or unknown FIP1L1-PDGFRα fusion kinase status. The European Medicines Agency (EMA) approved imatinib in 2001 for Ph+CML, Ph+ALL, MDS/MDP, HES, and GIST, and in the following year the treatment was extended to adult patients with unresectable and recurrent and/or metastatic DFSP; the Agency also included imatinib as orphan treatment for Ph+ALL integrated with chemotherapy, or as monotherapy for relapsing/refractory Ph+ALL. Within the same year, extensions to MDS/MDP associated with PDGFR gene rearrangements and HES in adult patients were approved. In 2009, the EMA included the adjuvant treatment of adult patients following resection of KIT-positive GIST, and in 2013, the Agency approved the extension of treatment to pediatric patients with newly diagnosed Ph+ALL integrated with chemotherapy. Imatinib is the first tyrosine kinase inhibitor (TKI) approved for human therapy, and it is a milestone for the development of the entire class of kinase inhibitors; its history of drug development, approval, efficacy, and safety has become paradigmatic in the whole field of targeted medicines. The overall safety profile is characterized by edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain. More concerning events include severe fluid retention, myelosuppression, CHF, left ventricular ejection dysfunction, severe hepatotoxicity, hemorrhage, GI perforation, severe cutaneous toxicities including Stevens-Johnson syndrome (SJS) and erythema multiforme, hypothyroidism, fetal arm and growth retardation, and tumor lysis syndrome (TLS). Differences, mostly in the incidence of these events, were observed in relation to the treated underlying disease according to specific dosage and therapeutic regimens.