Discussion
When it comes to managing patient with CML, the main objectives are to achieve clinical remission, halt disease progression and also providing optimal care for treatment related side effects. In practice so far there are five TKI approved which can be use in chronic phase namely Imatinib, Dasatinib, Nilotininb, Bousitinb, Ponatinib(5).Choice of initial TKI depends upon drug’s toxicity profile, patient co morbid condition as tolerability of side effects depends upon it.
Imatinib was the very first drug approved for newly confirmed case of CML, But, an intention-to-treat analysis demonstrated that approximately 1/3rd of patients treated with diagnosed CML-CP showed inadequate responses or do not experience long-term benefit(6).
Dasatinib is a second line TKI, and considered to be more potent in achieving early molecular response as compare to first line Imatinib(7).It has been approved as first line therapy after DASISION trial(8).Common side effects are cytopenias, GI toxicity including diarrhea ,pleural effusion and Qtc prolongation .Our patient was initially started on Dasatinib as upfront therapy with 100mg daily for four weeks. But it was discontinued because of poor intolerance as he developed severe Diarrhea not responding to symptomatic management. As the patient is already diabetic and immunocompromised because of risk of sever colitis it was decided to terminate Dasatinib. Cases of Dasatinib induced CMV hemorrhagic colitis have been reported in past(9) .
Nilotinib, another 2nd generation TKI is more potent than imatinib, inhibits several imatinib-resistant BCR-ABL1 mutants. It also comes with side effects such as cytopenias, hepatotoxicity, QTc prolongation, pancreatitis, hyperglycemia and long-term Cardiovascular complications(10).Not only it can worsen the preexisting Diabetes mellitus but association of directly causing diabetes have also been demonstrated in the literature(11, 12).In our patient he experienced worsening of his preexisting diabetes that lead to termination of nilotinib in his case.
Bosutinib is a second-generation TKI approved for the treatment of chronic-, accelerated-, and blast-phase CML in patients who are intolerant or resistant to prior therapy(13).
Results from BEFORE trial have successfully demonstrated patients who received bosutinib had significantly higher rates of major molecular response (MMR) and complete cytogenetic response (CCyR) by 12 and 24 months, and achieved responses faster, compared with imatinib-treated patients, for example, MMR and CCyR rates at 12 months were 47 versus 37% and 77 versus 66% for bosutinib and imatinib, respectively(14). .
Bosutinib is an excellent choice for patients who developed resistance or showed intolerance to other TKI. Phase 4 BYOND study showed the efficacy of Bousitinb in achieving higher rates of not only cytogenetic but also molecular responses those with Ph+chronic phase CML and with excellent response in patient’s resistant or tolerant to previous TKI(15).
It not only inhibit the activity of the BCR–ABL kinase but also exhibits activity against Src kinases, which are involved with malignant cell transformation, tumor progression, and metastasis(16).
Bosutinib is one the expensive drug, but affordability was not the issue in his case. He was started on Bosutinib 500mg daily. He achieved major molecular response MR3, bcr-abl/abl ratio 0,013% a(s seen in figure 1)after only 4 months of initiating therapy.
Side effect profile of Bosutinib ranges from mild to moderate which can be managed by symptomatic management dose reduction or temporary stoppage of the drug(17). GI toxicity is the most common non hematological adverse effects in which diarrhea remains the top most which can occur early in the treatment .It is usually mild and can be manage with anti-diarrheal medications(17).Other includes, pleural effusion which can occur not only in patient’s who had previous history of pleural effusion secondary to other TKI(Dasatinib) but also those without any past history. It is usually managed by either reducing the dose or sometime needs interruption of therapy(17).Cardiac and vascular events overall are less in long run in patients treated with bosutinib ,occur mainly in those with preexisting cardiac conditions(17, 18).Myelosuppression is the most common hematological side effect, in which thrombocytopenia is the most frequent.
Our patient tolerated Bosutinib very well as compare to previous TKI .He did experience diarrhea but the severity was less and controlled well with anti-diarrheal.
In conclusion, each TKI come with its on toxicity profile as this needs to be taken in account before starting therapy with particular agent in a patient. Most of the adverse effects related to TKI are mild and can be managed by either symptomatic treatment or either by dose reduction. But some patients can become intolerant and to switch to other TKI remains the only option.Bosutinib can be an excellent choice in not only achieving good molecular and hematological response but also a good option in those who experience intolerance to previous TKI.