Chronic Myeloid Leukemia Targeted Therapy Treatment

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Chronic Myeloid Leukemia Targeted Therapy Treatment

Most patients (>95%) with CML have a well-characterized genetic abnormality – Philadelphia (Ph) chromosome that gives rise to the BCR-ABL-1 fusion gene. The defective fusion gene encodes for a protein that has intrinsic tyrosine kinase activity responsible for the uncontrolled proliferation of the CML cells.

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This well-established mechanism of CML etiology paved the way for the development of tyrosine kinase inhibitors, the targeted drugs for CML treatment. In 2002, the first successful targeted drug for any cancer, i.e. imatinib, was approved for the first-line treatment of patients with CML.

Since the approval of imatinib, various other targeted agents have been developed and approved for the treatment of CML, which include dasatinib, bosutinib, nilotinib, ponatinib, and Omacetaxine. The treatment landscape of CML has been completely transformed by these targeted agents. The targeted drugs are now considered the standard-of-care for the management of most CML patients. F

ollowing is the list of various TKIs currently approved for the treatment of patients with CML:

Imatinib is the only first-generation tyrosine kinase inhibitor (TKI) that inhibits the abnormal activity of BCR-ABL1. It is the first targeted drug approved for the treatment of CML in first-line setting due to significantly improved clinical outcome and overall survival (OS) observed in clinical studies. Side effects of imatinib include nausea, diarrhea, muscle pain, fatigue, skin rash, and fluid build-up in different body parts.

Dasatinib is a second-generation TKI that has about 350 times more potency than imatinib for inhibition of BCR-ABL tyrosine kinase. It was found effective in some patients who were resistant to imatinib treatment. It has also been approved for the treatment of patients with CML in first-line settings owing to better response and fewer chances of disease progression observed in large clinical studies. Side effects of dasatinib include edema, low blood cell counts, nausea, diarrhea, and skin rashes.

Nilotinib is another second-generation TKI that is a structural analog of imatinib but is about 50 times more potent than imatinib. Similar to dasatinib, nilotinib may be effective against some cases that are resistant to imatinib. Also, compared to imatinib, it showed a better response to treatment and fewer chances of disease progression when employed in the first-line setting. It has also been approved for the first- and second-line treatment of CML patients.

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Bosutinib is another second-generation TKI that is a potent inhibitor of BCR-ABL1 kinase activity. Although it was initially approved to be used in the second-line setting, it has recently been approved to be used in the first-line settings for the treatment of patients with CML. Side effects include nausea, vomiting, diarrhea, abdominal pain, fever, fatigue, low blood cell counts, and liver damage.

Ponatinib is the third-generation TKI that is a potent inhibitor of BCR-ABL and is the only TKI active against the T315I mutation. It is approved for the treatment of patients who are not responding to prior therapy or have T315I mutation. Side effects of the drug include abdominal pain, headache, skin problems, fatigue, high blood pressure, and other heart-related problems.

Based on the results obtained from various clinical research studies following inferences have been drawn:

    • First-generation TKI–Imatinib, and second-generation TKIs–bosutinib, dasatinib, and nilotinib are generally employed for the treatment of most of CML patients due to their proven effective in patients with newly diagnosed chronic phase (CP)-CML. The second generation TKIs are preferred over imatinib in patients with high-risk disease, and in women who want to achieve quick response for fertility-related reasons. Of note, the overall survival rate with second-generation TKI remain comparable to imatinib.
    • The selection of the most appropriate TKI drug (among the second-generation agents) also depends upon the side-effects associated with the drug.

Selection of Second-line Treatment based on the Response to First-Line TKI Treatment

The response to first-line treatment with TKIs is one of the key prognostic indicators of the clinical outcome in CML patients. The response to treatment is usually assessed by assessing the level of BCR-ABL1 transcript in the blood or bone marrow with the help of reverse transcriptase- polymerase chain reaction (RT-PCR) technique.
The requirement for continuation of the same treatment regimen or a change in treatment regimen is then assessed based on the level of BCR-ABL1 achieved at different time points as shown in the table below:

Time of Response Assessment BCR-ABL1 Level Clinical Consideration
3 months </=10% Disease is sensitive to the current treatment regimen and there is no need to change the current treatment regimen.
>10% There are chances of resistance development on the current treatment regimen. Assessment of compliance to treatment and mutational analysis is recommended for these patients.
6 months </=10% Disease is sensitive to the current treatment regimen and there is no need to change the current treatment regimen.
>10% Disease is resistant to the current treatment regimen. Second-line treatment regimen should be selected based on results from mutational analysis and considering other factors.
12 months </=1% Disease is sensitive to the current treatment regimen and there is no need to change the current treatment regimen.
>1% but </=10% There are chances of resistance development on the current treatment regimen. Assessment of compliance to treatment and mutational analysis is recommended for these patients.
>10% Disease is resistant to the current treatment regimen. Second-line treatment regimen should be selected based on results from mutational analysis and considering other factors.
15 months or more </=1% Disease is sensitive to the current treatment regimen and there is no need to change the current treatment regimen.
>1% Disease is resistant to the current treatment regimen. Second-line treatment regimen should be selected based on results from mutational analysis and considering other factors.

 

Mutational Analysis:

CML patients who do not achieve a predefined response to the first-line TKI therapy or who progressed on the initial TKI-therapy are recommended to undergo a mutation analysis. This is performed by next-generation sequencing method or conventional sequencing method.

The mutational analysis help in detection of specific mutation(s) that may have played a role in the resistance development to the initial TKI used. In case a mutation is detected, appropriate second-line therapy with an alternate TKI agent can be started based on the detected mutation. Following table indicate the most appropriate second-line TKI agents for different mutations detected in the mutational analysis.

Mutation Treatment Recommendation
Y253H, E255K/V, or F359V/C/I Dasatinib
F317L/V/I/C, T315A, or V299L Nilotinib
E255K/V, F317L/V/I/C, F359V/C/I, T315A, or Y253H Bosutinib
T315I Ponatinib, Omacetaxine

 

In case of the absence of any mutation, a second line treatment therapy is selected based on the overall health of the patient and risk score.

Second generation TKIs are generally preferred over imatinib for second-line treatment due to the lower risk of disease progression, especially in patients with an intermediate- to high-risk score.

Ponatinib, a third-generation TKI, is the only active TKI against the T315I mutation. It is recommended for patients with T315I mutation. Omacetaxine, a chemotherapeutic agent, can also be employed for the treatment of patients with the T315I mutation and for patients who have progressed on 2 or more prior TKIs.

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