Imatinib: Targeted Tyrosine Kinase Inhibitor Transforming Cancer Treatment

Imatinib (brand names Gleevec [oral tablet], Imkeldi [oral solution]) is used to treat certain types of leukemia (blood cancer), bone marrow disorders, and skin cancer. Imatinib's mechanism of action involves targeting BCR-ABL tyrosine kinase and some other kinases, particularly ones responsible for uncontrolled cell growth. By preventing these enzymes from working properly, it slows cancer growth and spread. It belongs to the drug class called BCR-ABL tyrosine kinase inhibitors. This medicine gained FDA approval on May 10, 2001, under the brand name Gleevec. A generic Gleevec is available known as imatinib mesylate. Imatinib is also available under the brand name Imkeldi which is an oral solution. There is no Imkeldi generic. It can lower blood cells that help your body fight infections and help your blood to clot. You may get an infection or bleed more easily. Call your doctor if you have unusual bruising or bleeding, or signs of infection (fever, chills, body aches). Imatinib may increase the risk of liver problems. Tell your doctor if you have upper stomach pain, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).

Imatinib: A Breakthrough of Targeted Therapy in Cancer

Imatinib (also known as “Gleevec” or “Glivec”), a tyrosine kinase inhibitor, was called as “magical bullet,” when it revolutionized the treatment of chronic myeloid leukemia (CML) in 2001. Imatinib was invented in the late 1990s by biochemist Nicholas Lyndon then working for Ciba-Geigy (now Novartis), and its use to treat CML was driven by Brian Druker, an oncologist at the Dana-Farber Institute. The first clinical trial of Imatinib took place in 1998 and the drug received FDA approval in May 2001. Deregulated protein tyrosine kinase activity is central to the pathogenesis of human cancers. Targeted therapy in the form of selective tyrosine kinase inhibitors (TKIs) has transformed the approach to management of various cancers and represents a therapeutic breakthrough. Lyndon, Druker, and the other colleagues were awarded the Lasker-DeBakey Clinical Medical Research Award in 2009 for “converting a fatal cancer into a manageable condition” and the Japan Prize in 2012 for their part in “the development of a new therapeutic drug targeting cancer-specific molecules.” Encouraged by the success of Imatinib in treating CML patients, scientists explored its effect in other cancers and it was found to produce a similar miracle effect in other cancers where tyrosine kinases were overexpressed.[1]

The tyrosine kinase (TK) inhibitor, Imatinib, has revolutionized the therapy of malignancies that are addicted to one of its target kinases, c-ABL, c-KIT, and PDGFR. Currently, Imatinib is the standard of care in CML and GIST as it has dramatically changed the outlook of these diseases. Its use has extended to various other cancers and has achieved first-line position in cancers like Ph+ ALL, advanced dermatofibrosarcoma protuberans, hypereosinophilic syndrome, and systemic mastocytosis. Imatinib has also provided a valuable option in patients with SR-cGVHD who cannot access other treatments like extracorporeal photopheresis. No other targeted therapies have contributed so much to therapeutic armamentarium in oncology as Imatinib. Various studies are ongoing to explore its benefits in other cancers also. The major drawback with it is development of resistance which is therapeutically challenging. Second- and third-generation TKIs have come up to overcome this resistance. Despite these limitations, Imatinib has contributed immensely to the field of oncology so that it should still be called a “wonder drug.”

Imatinib in Chronic Myeloid Leukemia

Imatinib binds to BCR-ABL kinase domain, which is in an inactive conformation in a pocket reserved for the ATP binding site, thus preventing the transfer of a phosphate group to tyrosine on the protein substrate and the subsequent activation of phosphorylated protein. As the result, the transmission of proliferative signals to the nucleus is blocked and leukemic cell apoptosis is induced. Imatinib directly inhibits the constitutive tyrosine kinase activity, which results in the modification of the function of various genes involved in the control of the cell cycle, cell adhesion, cytoskeleton organization and finally in the apoptotic death of Ph(+) cells. The first phase I trial was initiated in June 1998 and enrolled patients suffering from CML in chronic phase (CP) who were resistant to or intolerant of interferon alpha (IFN alpha). Almost all patients (98%) treated with at least 300 mg imatinib per day achieved complete hematological response (CHR). Major and complete cytogenetic response (MCyR, CCyR) were obtained by 31% and 13% of patients respectively. Of note, the responses were durable, only 2 relapses (out of 53 patients) were noted after a median follow-up of 265 days.[2]

Preclinical data and some observations from single – arm studies suggested that higher dosages of imatinib could be more effective than standard 400 mg once daily dose, and may provide a better disease control. The amplification of the BCR-ABL gene or overexpression of bcr-abl protein kinase are two known mechanisms of relative resistance to imatinib which could be overcome by dosages of 600 mg or 800 mg daily. Allogeneic – haematopoietic stem cell transplantation (Allo-HSCT) has been and is still considered as the sole treatment able to cure CML. Monitoring of residual disease by more sensitive conventional qRT-PCR within STIM1 study also does not allow the prediction of relapse after imatinib cessation. Importantly some fluctuations in BCR-ABL levels detected by conventional qRT-PCR method (in 33% patients in STIM2 study) could be observed after discontinuation without confirmation of a molecular relapse. 41 patients (33%) in STIM2 study experienced a BCR- ABL qRT-PCR fluctuation without molecular relapse, confirming that BCR-ABL reappearance does not mean automatically clinical relapse and reinforcing the concept of “operational cure”.

Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that is characterized by the Philadelphia (Ph) chromosome and driven by its product, the BCR-ABL1 tyrosine kinase. In 2001, imatinib was introduced as a BCR-ABL1 tyrosine kinase inhibitor and was approved for the treatment of CML on the basis of a high level of activity in phase 2 studies. Early results from the phase 3 International Randomized Study of Interferon and STI571 (IRIS) showed that the medicine at a dose of 400 mg once daily was more active and was associated with fewer side effects than interferon alfa plus cytarabine in patients with newly diagnosed CML in the chronic phase. A retrospective analysis that compared patients in the imatinib group of IRIS with those in a historical cohort of patients who had been treated with interferon alfa plus cytarabine in an earlier trial showed that imatinib therapy resulted in a higher rate of overall survival.[3]

With more than 10 years of follow-up in IRIS, the long-term outcomes in imatinib-treated patients that we describe here confirm and extend earlier findings. No new safety signals and few drug-related serious adverse events were observed during the later years of follow-up, and molecular and cytogenetic response rates were high among the patients who could be evaluated. Several new questions have arisen, such as the relative benefits and risks of imatinib versus newer tyrosine kinase inhibitors and the role and effect of second-line inhibitor therapy. Approximately half the patients in the imatinib group discontinued the trial early, which suggests that the high rate of overall survival must be attributed to the use of commercially available imatinib or effective second-line therapies in these patients.

References

[1]Iqbal N, Iqbal N. Imatinib: a breakthrough of targeted therapy in cancer. Chemother Res Pract. 2014;2014:357027. doi: 10.1155/2014/357027. Epub 2014 May 19. PMID: 24963404; PMCID: PMC4055302.

[2]Sacha T. Imatinib in chronic myeloid leukemia: an overview. Mediterr J Hematol Infect Dis. 2014 Jan 2;6(1):e2014007. doi: 10.4084/MJHID.2014.007. PMID: 24455116; PMCID: PMC3894842.

[3]Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S, Ortmann CE, Menssen HD, Kantarjian H, O'Brien SG, Druker BJ; IRIS Investigators. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med. 2017 Mar 9;376(10):917-927. doi: 10.1056/NEJMoa1609324. PMID: 28273028; PMCID: PMC5901965.