Extrapolation from observations in animal models is difficult as inhibition of kinase function in a mature animal will clearly not produce the range of developmental anomalies seen in germline knockout studies

Extrapolation from observations in animal models is difficult as inhibition of kinase function in a mature animal will clearly not produce the range of developmental anomalies seen in germline knockout studies. for stem cell factor. KIT is important in cell cycle regulation and critically important in haematopoiesis. Two receptors for platelet-derived growth factor (PDGF) are sensitive to imatinib. PDGF is involved in cell cycle regulation, angiogenesis, and fibroblast proliferation (Claesson-Welsh, 1994). Despite similarities in structure and function, PDGFR and are encoded on different chromosomes and differ in their affinity for individual isotypes of PDGF. We review the current evidence regarding efficacy and safety of imatinib in Philadelphia-positive (Ph+) haematological disorders and in other disorders with evidence for imatinib sensitivity. We also review the available data on imatinib resistance. We then consider the broader implications for anticancer treatment based on kinase inhibitors. EFFICACY Chronic myeloid leukaemia CML is a disorder of the haematopoietic stem cell consistently associated with the fusion gene. It is characterised by the proliferation Rabbit Polyclonal to MOBKL2B of the myeloid series, although lymphoid cells may also arise from the malignant clone. Three phases of the disease are recognised. In the chronic phase, there is indolent leukocytosis with infiltration of the liver and spleen. In the accelerated phase, there may also be acquisition of additional cytogenetic abnormalities and an increase in the proportion of immature cells in the blood or marrow. In blast crisis, which may be of lymphoid or myeloid lineage, the clinical picture resembles acute leukaemia and carries a very poor prognosis. Imatinib in newly diagnosed chronic phase Prior to the introduction of imatinib, the accepted standard therapy for newly diagnosed CML in the chronic phase was interferon and cytarabine. A recently published study (O’Brien 56%), complete cytogenetic response (CCR: 76 15%) and freedom from progression to accelerated phase or blast crisis (97 92%), all showed a statistically significant improvement in the imatinib group. Imatinib in chronic phase after interferon failure Patients with prior exposure to interferon are mostly in the late chronic phase (?12 months from diagnosis). Of 454 late RIPK1-IN-7 chronic phase patients started on imatinib at 400?mg RIPK1-IN-7 daily, 95% achieved CHR and 41% CCR with freedom from progression in 89% at 18 months (Kantarjian Ph+ ALL, BCR-ABL retains sensitivity to imatinib, but additional genetic abnormalities conferring drug resistance are common. In patients with relapsed or refractory Ph+ ALL or lymphoid blast crisis (Ottmann fusion gene (Baxter (a regulatory gene that may be translocated in acute leukaemia) and (Apperley fusion were treated with imatinib 400?mg daily. All achieved CHR after 4 weeks and cytogenetic remission after 9 months. Idiopathic hypereosinophilic syndrome is characterised by persistent peripheral blood eosinophilia with evidence of end-organ damage (usually cardiac or sinopulmonary infiltration RIPK1-IN-7 or neuropathy) without an identifiable cause. In a series of 16 patients with idiopathic hypereosinophilic syndrome, a novel fusion of and has been reported (Cools fusion received imatinib treatment. The doses of imatinib ranged from 100 to 400?mg daily. CHR of at least 3 months duration was achieved in all but two patients, neither RIPK1-IN-7 of whom carried the fusion gene. Efficacy at lower doses than in CML is supported RIPK1-IN-7 by data, indicating that the IC50 (drug concentration required to inhibit proliferation by 50%) for imatinib of PDGFRreport on five patients treated with imatinib. Four patients achieved CHR. The starting dose was 100?mg daily and maintenance doses were as low as 200?mg per week. These results imply that another cryptic rearrangement involving PDGFR (or another imatinib-sensitive kinase) may be present in some patients. Systemic mastocytosis is a rare myeloproliferative disorder with an increase in mast cells in the marrow and evidence of visceral and cutaneous infiltration. A syndrome related to histamine release may also occur. Imatinib inhibition of KIT phosphorylation in mast cell lines correlates with the inhibition of cellular proliferation (Zermati D816V, occurs in the catalytic region of the enzyme, and also prevents binding of imatinib. Most cases of mastocytosis are therefore resistant to imatinib. However, patients with mutations in the juxtamembrane region of the KIT molecule may retain sensitivity (Zermati antisense oligonucleotides.