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Chronic myeloid leukemia is a progressive cancer of the bone marrow and the blood 1. This cancer is mainly characterized by the excessive production of immature white blood cells which lack the ability to differentiate into its functional stage <1>. Currently, it is estimated that around 3,000 Canadians are suffering from CML and that approximately 510 people in Canada are expected to be diagnosed with CML each year <1, 2>.
The cause of CML is believed to be due to the fusion of the Abelson murine leukemia (ABL) gene on chromosome 9 with the breakpoint cluster region (BCR) on chromosome 22 <3>. This fusion results in expression of a chimeric protein termed BCR-ABL <3>. The BCR-ABL protein is a constitutively active form of the ABL tyrosine kinase and promotes replication and growth via multiple downstream signaling pathways <4>.
Diagnosis and Symptoms
CML can be categorized into three disease phases: chronic phase, accelerate phase and blast phase. CML diagnosis is commonly made during the chronic phase <4>. Common signs and symptoms of CML in the chronic phase occur due to anemia and splenomegaly <4>. These include fatigue, unexplained weight loss, shortness of breath during normal physical activity, night sweats and general discomfort or pain <1, 4>. However, up to 50% of patients are asymptomatic and are diagnosed with CML in the chronic phase mainly from routine blood test or physical examination <4>.
The majority of CML patients in the chronic phase will transform into accelerate phase before the blast phase <4>. During the CML accelerated phase, patients may experience severe anemia, splenomegaly and organ infiltration <4>. However, 20% of CML patients automatically transform into the blast phase without any warning signs <4>. During the blast phase, CML patients will experience acute leukemia with worsening of symptoms, fever, infections and bleeding <4>.
CML ââ‚¬" Past Treatments
Initially, CML drug treatment was limited to non-specific agents such as hydroxyurea, busulfan and interferon-alpha <5>. For example, the authors demonstrated that interferon-alpha improved survival rate and decreased disease progression <5>. However, its use was avoided due to its toxicities <5>. Another treatment option for CML patient is receiving allogeneic stem cell transplantation <5>. Although this treatment is curative intervention, there is a high risk of mortality and morbidity <5>.
Tyrosine Kinase Inhibitors Development
Due to advancement in molecular biology, the development of small molecule tyrosine kinase inhibitors (TKIs) utilized the presence of the abnormal BCR-ABL protein expression in CML cells <4>. This particular target method significantly improved 10 year overall survival from 20% to 80-90% <6, 7>.
First and Second Generation TKIs
Imatinib is the first TKI approved for treatment of CML <8>. It inhibits the ABL tyrosine kinase activity resulted from the BCR-ABL protein fusion with moderate affinity (in the range of 100nmol/L) <8>. Imatinib is highly specific to the ABL kinases and only inhibits a few other enzymes <8>. However, BCR-ABL mutations related with imatinib resistance cluster in certain regions of the kinase domain (Table 1) <8,9>. With the majority of the BCR-ABL mutations, the degree of imatinib resistance is relatively mild <8.9>. Despite a mild resistance, it is enough to re-establish BCR-ABL tyrosine kinase activity in CML cells that have a kinase domain mutation <8,9>.
G250E, Q25H, Y253H/F, E255K/V
T315I (gatekeeper residue)
M244V, F317L, M351T, E355G, F359V
To combat against imatinib resistant BCR-ABL mutants, second generation TKIs dasatinib and nilotinib were developed <9, 10, 11>. Dasatinib inhibits BCR-ABL tyrosine kinase activity up to 20 fold lower concentrations than nilotinib, which is still 10 to 20 fold more potent than imatinib <10,11>. Currently, both second generation TKIs are considered first-line drug therapy of CML in chronic and accelerated phases in imatinib resistance patients <9>. Although both second generation TKIs efficiently inhibit all common imatinib resistance BCR-ABL mutations, it has been unsuccessful against the BCR-ABL T315I gatekeeper mutant <9, 10, 11>.
Third Generation TKIs
In the last decade, there have been numerous pre-clinical candidates against the BCR-ABL T315I gatekeeper mutant but it has only been recently that three third generation TKIs targeting the this T315I mutant have entered clinical evaluations <9>.
A study conducted by Oââ‚¬â„¢Hare et al. demonstrated that SGX393 is a potent inhibitor of the BCR-ABL T315I mutant <12>. Exposing SGX393 with peripheral blood mononuclear cells from a CML patient with the T315I mutation, the investigators observed a reduction in the level of phosphorylation of the BCR-ABL substract via immunoblot analysis <12>. Furthermore, when SGX393 was included with dasatinib or nilotinib in vitro, the growth of resistance clones was reduced to zero <12>. Hence, the authors concluded that SGX393 can inhibit BCR-ABL T315I tyrosine kinase activity in CML cells and also that the combination of SGX393 with the current second generation TKIs could be potentially helpful in reducing BCR-ABL mutations in CML patients <12>.
Ponatinib is also another third generation TKI targeting BCR-ABL T315I mutants <13>. Investigators demonstrated via biochemical assays that ponatinib was able to decrease the catalytic activity of both native BCR-ABL and BCR-ABL T315I mutants <13>. Furthermore, using Ba/F3 transfected cells with BCR-ABL mutations, this study indicated that ponatinib can also inhibit the growth of cells of all BCR-ABL mutants (IC50: 0.5-36nM) including BCR-ALB T315I mutants (IC50: 11nM) <13>.
Currently, ponatinib is undergoing phase II clinical trial (PACE Trial) and initial results showed high response rates in all populations: patients with tyrosine kinase domain mutations, including the T315I mutant, in patients with no mutations and in all CML phases (chronic, accelerated and blast) <14>. Furthermore, it was indicated by the investigators that there is a promising early safety profile in all CML patients <14>.
Recently, another TKI inhibitor of BCR-ABL T315I mutants, DCC-2036, was developed showing similar characteristics to both SGX393 and Ponatinib <15>. The authors illustrated that DCC-2036 can strongly inhibit the ABL tyrosine kinase and is effective against the majority of clinically relevant CML mutations included the T315I mutants <15>. Moreover, DCC-2036 inhibits BCR-ABL T315I transfected calls and prolongs survival in mouse models of CML T315I mutants <15>.
Without a doubt, the development of TKIs has significantly changed the prognosis of CML patients. CML originally was considered a life-threatening leukemia with up to 20% mortality per year <4>. Since the arrival of targeted drug therapy such as TKIs, CML considered as treatable chronic disease with 2% mortality per year <4>. Furthermore, even with BCR-ABL mutations, such as the T315I gatekeeper mutant, researchers have improved TKIs agents that could potentially help all CML patients. Ultimately, a better understanding of the disease is essential to developing new agents. Hopefully, this will eventually lead to a cure to CML and improve the quality of life of patients.