Cumulative clinical experience from a decade of use: imatinib as first-line treatment of chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is a malignant disease that originates in the bone marrow and is designated by the presence of the Philadelphia (Ph+) chromosome, a translocation between chromosomes 9 and 22. Targeted therapy against CML commenced with the development of small-molecule tyrosine kinase inhibitors (TKIs) exerting their effect against the oncogenic breakpoint cluster region (BCR)-ABL fusion protein. Imatinib emerged as the first successful example of a TKI used for the treatment of chronic-phase CML patients and resulted in significant improvements in response rate and overall survival compared with previous treatments. However, a significant portion of patients failed to respond to the therapy and developed resistance against imatinib. Second-generation TKIs nilotinib and dasatinib were to have higher efficiency in clinical trials in imatinib- resistant or intolerant CML patients compared with imatinib. Identification of novel strategies such as dose escalation, drug combination therapy, and use of novel BCR-ABL inhibitors may eventually overcome resistance against BCR-ABL TKIs. This article reviews the history of CML, including the treatment strategies used prediscovery of TKIs and the preclinical and clinical data obtained after the use of imatinib, and the second-generation TKIs developed for the treatment of CML.

Chronic Myeloid Leukemia Presenting with Priapism

“…-Less Common; not a medical emergency. ABL fusion gene which is produced by a reciprocal chromosomal translocation between the ABL oncogene on chromosome 9 and the BCR gene on chromosome 22 [8][9][10][11][12]. The disease is often discovered accidentally when the patient presents with an elevated WBC count and/or an enlarged spleen.…”

“…The most common clinical manifestations of CML are: anorexia, malaise, weight loss, sweating, bleeding episodes due to platelet dysfunction, abdominal fullness and pain or dragging sensation in the abdomen due to progressive enlargement of the spleen. Involvement of extramedullary tissues or sites such as liver, lymph nodes and skin is generally limited to patients having progressive disease [10]. At times, patients may present with leukostatic complications of hyperleukocytosis such as thromboembolic phenomena, hearing loss or priapism [4,[13][14][15].…”

“…However, imatinib at dose of 400mg per day is still the gold standard first-line treatment for CML [17]. If the patient has a suboptimal response whilst on imatinib therapy, shifting to a second generation TKI such as dasatinib or nilotinib is justified in order to have a more optimal response as these agents have shown higher efficacy in clinical trials in imatinib-resistant or intolerant CML patients compared to imatinib treatment [10,18]. Other therapeutic options in case of suboptimal response to imatinib include: (1) escalation of the dose of imatinib, (2) allogeneic hematopoietic stem cell transplantation (HSCT), and (3) the use of agents that are being evaluated in clinical trials.…”

“…These patients require alternative therapies. Therefore, it is vital to identify high risk patients at presentation of CML and start them on appropriate alternative therapies as early as possible [10,19]. Patients with CML harboring specific mutations such as T315 I remain resistant not only to first line but also to second line TKIs and require additional third generation inhibitors such as ponatinib to overcome resistance induced by these point mutations [8,18].…”

Bcr-Abl tyrosine kinase inhibitors: a patent review

“…2.1 Bcr-Abl inhibitors approved for CML therapy As just reported, imatinib, 1 (Figure 1) has been the first TK inhibitor entered in cancer therapy [20]. Nilotinib, 2 (Figure 1) is an orally active Bcr-Abl inhibitor structurally related to imatinib, approved for the treatment of CML patients with resistance to imatinib [21].…”