Gleevec use in treating Chronic Myeloid Leukemia

 

Chronic myeloid leukemia (CML)

The Chronic myeloid leukemia (CML) is a category of cancer that begins in some specific cells of the bone marrow that form blood. It accounts for 15% of all leukemias in adults, and it is estimated to be about one case in every ten thousand cancer cases (Kujak & Kolesar, 2016).  Before the advent of Imatinib, the median survival of CML patients was approximately six years meaning that the estimated prevalence was approximately 25,00-30,000. This has however changed with the mortality rates decreasing to 2% annually (Kujak & Kolesar, 2016). In this type of cancer, a genetic change transpires in the immature types of myeloid cells that are responsible for making red blood cells, platelets and most of the white blood cells excluding for the lymphocytes. This alteration leads to the formation of abnormal gene that is known as BCR-ABL that results into the CML cell (Sausville, 2003).

The cells in with leukemia develop and divisions causing an accumulation in the bone marrow and hence a dripping into the blood system. The leukemia is defined to be acute contingent on whether the abnormal cells are developed or undeveloped. In the enduring leukemia, the cells mature partially but not wholly, meaning that the cells may seem like they are standard but they are not (Sausville, 2003). They are not able to battle infections and they tend to live longer and gather out standard cells in the bone marrow. The chronic myeloid leukemia (CML) is branded by unnecessary production and recurring cytogenetic irregularity that is commonly known as Philadelphia chromosome (Ph). This aberration results from a stable translocation amid chromosomes 9 and 22 which ferocities the peak point gathering area gene on chromosome 22 the ABL genetic factor on chromosome 9 (Kujak & Kolesar, 2016).

The risk factors for getting CML include older age where most of the people that are diagnosed are normally around 64 years, males are more prone to the disorder and radiation exposure for instance radiation therapy for other cancer types (Kujak & Kolesar, 2016). The leukemia is not genetic in nature meaning that the chromosome transmutation that clues to the leukemia cannot be passed down from the parents to the children.

Gleevec as a Treatment options for CML

Gleevec also scientifically known as Imatinib mesylate or STI-571 was the leading signal transduction inhibitor (STI) that was used in the scientific background. The drug is recently diagnosed adult and paediatric patients that suffer from PH+ CHL (Philadelphia chromosome positive chronic myeloid leukemia) when it is in the chronic stage (Druker, 2015). The drug is administered as a pill by mouth and it can be taken one time or two in a day liable on the concentration of the disorder and general general well-being of the person. In CML, the drug is given in 400 mg dosage per day  and it may increase after the failure of interferon alpha therapy where it is increased to the dosage of 600 mg per day in the absence of sever adverse drug reaction (Gleevec case study, 2004). The drug should be taken with meal and with lots of water whereby it can also be dispersed in water for the patients that have a problem with swallowing.

History and science of Gleevec

This was the leading STI (signal transduction inhibitor), which was utilized in a scientific background for the management of CML. The medication helps to prevent BCR-ABL protein from applying its function in the oncogenic trail in CML. Imatinib directly constrains the constitutive tyrosine kinase action (Deininger et al., 2009). It fixes to BCR-ABL kinase sphere by averting the transmission of a phosphate assembly to tyrosine on the protein substrate and the succeeding instigation of phosphorylated protein (Gleevec case study, 2004).  As a consequence, the diffusion of proliferative indications to the nucleus is congested and leukemic cell apoptosis is prompted.

Pharmacokinetics of Imatinib is branded by speedy and whole oval biohandiness and a comparative dose revelation association. There is no noteworthy interface of Imatinib with food consumption (Druker, 2015). Its station half-life is roughly 18 hours which permits for once a day quantity. The median top plasma focuses at fixed state of Imatinib directed orally one time every single day at 400 mg dosage and a median through intensities are 5.4 M and 1.43 M correspondingly.  Imatinib is usually processed by the cytochrome P450 system (Druker, 2015). The action of CYP enzyme hinders intrinsic inconsistency which could be the source of elevated inter-patient disproportion in Imatinib coverage. Drugs that are inhibitors or inductors of CYP3A4 isoenzymes have been revealed to modify Imatinib pharmacokinetic action.

Efficacy of Imatinib

Phase i trials

Stage 1 trial was started in the year 1998 and it joined up patients that agonized from CML in chronic point (CP) that were resilient to interferon alpha (IFN alpha) (Gleevec case study, 2004). Practically all patients whose conditions were managed using at least 300 mg Imatinib each day attained comprehensive haematological response (CHR). Major and complete cytogenetic response was acquired by thirty one percent and thirteen percent of the patients correspondingly. The reactions were robust, only two reversions out of the 53 patients was eminent after a trailing of about 263 days (Gleevec case study, 2004).

Phase ii trials

Three trials were instigated in the year 1999. The study populace comprised patients with CML in myeloid BC, reverted PH+ALL, CML in A, and patients who were resilient to IFN alpha. The outcomes attained in patients ailing from BC with myeloid phenotype principally established the outcomes gotten in phase 1 study (Peng et al., 2004). In dissimilarity to patients with myeloid type syndrome, none of the individuals treated for lymphoid blast crisis and for reverted PH+ALL had sturdy reaction to Imatinib. A reflective evaluation amid two dose units that is 400mg and 600 mg exhibited a meaningfully longer time to evolution and generally endurance for the 60 mg unit (Peng et al., 2004). Grounded on this research, the endorsed prescription for the patients in progressive phases of CML was fixed at 600mg every day.

Phase iii trials

A world-wide study equating Imatinib at a single daily prescription of 400 mg and IFN alpha plus cytarabine in recently detected patients with CML in CP was commenced in the year 2002. The outcomes of the study exhibited an exceptional efficiency of Imatinib and its advantage with deference to the charges of CHR, major cytogenetic response (MCyR) and complete cytogenetic response CCyR  (Hughes & Branford, 2006). At 18 months, the degree of CCyR in the patients treated with Imatinib was 76% as equalled to the patients treated with IFN alpha plus cytarabine. An inclusive survival ratio is 85% for patients getting Imatinib and it is actually 93% when only CML linked bereavements and those prior to stem cells transplantation are deliberated (Hughes & Branford, 2006).

Comparison between Imatinib and interferon alpha in treatment of CML

Studies that have been conducted comparing Imatinib and interferon alpha as treatments for CML show that Imatinib brings out much better results (Deininger et al., 2009, O’Brien et al, 2008).  Imatinib at 12 months has been associated with higher complete haematological response which is at the rate of 97% to 69%, in complete cytogenetic responses rates it is at the rates of 76% to 14%. And a rate of 87% to 35% in reference to major cytogenetic response Imatinib is associated with a 56% reduction in mortality as compared with interferon alpha in the overall (O’Brien et al, 2008).

Established chronic-phase patients with CML
	Imatinib 400mg per day N=553	Interferon alpha N=553
Complete hematological response, patients	97 %	69%
Major cytogenetic response,  patients	87%	35%
Complete cytogenetic response, patients	76%	14%

 

One of the side effects of using Imatinib for MCL is that it causes myelosuppression which refers to a disorder in the bone marrow where activity is decreased leading to fewer blood cells, platelets and white blood cells (O’Brien et al, 2008). This can transpire at any interval in the course of Imatinib therapy but it is most common in the leading weeks of treatment. Other side effects that are noted with the use of Imatinib for MCL are nausea and occasional vomiting which are basically dose related and they are also mild (Hochhaus et al., 2009). These are effects that can be eluded in maximum number of the patients when Imatinib is administered with nutrients which do not modify the drugs pharmacokinetics. Diarrhoea is another common toxicity of Imatinib which is most likely caused by local irritant effects, it can however be controlled by anti-diarrheal medications (Hochhaus et al., 2009). Mild fluid retention and edema are also prevalent dose interrelated harmfulness of Imatinib that transpire in about fifty percent to seventy percent of the patients. This can be as a result of reserve of targets that are accountable for the reliability of vessels by Imatinib (Hochhaus et al., 2009).

Conclusion

The results that are obtained with Imatinib mesylate up to the current day are impressive.  Imatinib is a revolution not only for managing CML but also for aiding to comprehend how to improve directed therapies for management of many other menacing syndromes. Even though the therapy for CML is not yet realized by just obstructing the Bcr-Abl kinase, there is high likelihood that other drugs established from Imatinib will permit for testing of ground-breaking theories to finally support realization of this objective. Imatinib is likely to much more effective when used with other therapies and there is also a need for detailed research to determine the optimal treatment pathways.

 

 

 

 

 

 

 

 

 

 

References

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