Targeted oncological therapies (mAB and tyrosine kinase inhibitors)

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Imatinib Gleevec

Pharmacological Group: Antineoplastic, selective inhibitor of the tyrosine kinase of the BCR-ABL receptor.

Mechanism of Action: It is a small molecule competitive inhibitor that selectively binds to the ATP binding pocket in the kinase domain of the aberrant oncoprotein BCR-ABL (formed after the reciprocal chromosome translocation t(9;22), which gives rise to the Philadelphia chromosome in leukemias). By competitively blocking ATP access, it prevents autophosphorylation and activation of downstream mitogenic signaling cascades (JAK-STAT, PI3K-Akt, Ras-MAPK), inducing mitotic arrest and apoptotic cell death. It also potently inhibits the kinase domains of the c-KIT (CD117) and PDGFR receptors.

Clinical Pearl: Mutational Resistance and T315I Domain

Despite the excellent initial response to imatinib in CML, patients can develop secondary resistance due to point mutations in the kinase domain of BCR-ABL. The most important and feared mutation is T315I (substitution of threonine for isoleucine at position 315, also called the "gatekeeper" mutation). This mutation eliminates an essential hydrogen bond and creates a steric hindrance that blocks the coupling of imatinib and second-generation inhibitors (dasatinib, nilotinib). It requires a therapeutic change to third-generation inhibitors such as ponatinib.

Dosage and Adjustment of Imatinib

Dosage Adults: CML in chronic phase: 400 mg PO once daily. CML in accelerated phase or blast crisis: 600 mg PO once daily. Advanced GIST: 400 mg or up to 800 mg PO daily.
Enzyme Interactions: Avoid the simultaneous use of strong CYP3A4 inhibitors (e.g. voriconazole, erythromycin) or inducers (rifampicin, dexamethasone) to prevent dangerous fluctuations in plasma concentrations.

Pregnancy: Category D (Demonstrated risk of bone and craniofacial malformations) Breastfeeding: Not recommended Pembrolizumab Keytruda

Pharmacological Group: Oncological immunotherapy, anti-PD-1 monoclonal antibody (immune checkpoint inhibitor).

Mechanism of Action: It is a highly selective monoclonal antibody directed against the PD-1 (Programmed Death-1) receptor of human T lymphocytes. Tumor cells frequently express PD-1 ligands (PD-L1 and PD-L2) on their surface as an immune evasion mechanism; The PD-1/PD-L1 interaction slows down and deactivates the cytotoxic function and cytokine secretion of the T lymphocyte (state of lymphocyte anergy). By physically blocking the binding of PD-1 to its ligands, pembrolizumab "releases the brakes" on the host's immune system, reactivating the proliferation of antigen-specific cytotoxic T cells and promoting immune recognition and destruction of the tumor.

Management of Immune-mediated Toxicities (irAEs) and Dexamethasone

Unlike conventional chemotherapy, pembrolizumab ADRs are purely autoimmune due to excess lymphocyte activity. If moderate pneumonitis or colitis is suspected (Grade 2), the drug should be temporarily suspended and systemic corticosteroids (methylprednisolone or prednisone 1-2 mg/kg/day) initiated to attenuate the autoimmune aggression. In severe or steroid-refractory cases (Grade 3 or 4), pembrolizumab is permanently suspended and second-line immunosuppressive therapy such as infliximab may be associated to control inflammation.

Fixed Dosage of Pembrolizumab

Usual Dose: 200 mg IV every 3 weeks, or alternatively 400 mg IV administered every 6 weeks by slow intravenous infusion over 30 minutes.
Organ Adjustment: No adjustment is required in patients with mild to moderate renal or hepatic impairment.

Pregnancy: Risk of intrauterine fetal loss due to allogeneic placental rejection Breastfeeding: Not recommended