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ANALYSIS OF CHRONIC MYELOID LEUKEMIA PHARMACOTHERAPY COSTS IN POLAND

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Paczkowska A., Kus K., Nowicka M., Kopciuch D., Zaprutko T., Komarnicki M., Nowakowska E.

Acta Poloniae Pharmaceutica - Drug Research

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2019

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vol. 76

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issue 1

175-183

EN

The aim of this study was to analyze pharmacotherapy cost of chronic myeloid leukemia from the society’s, the payer’s (National Health Fund), and the patient’s perspective. The study included 55 patients with a diagnosed and treated chronic myeloid leukemia at the selected hematology clinic in the city of Poznan. Retrospective study involved time horizon of one calendar year – 2013. The data required for economic evaluation were obtained from the patients’ case histories and the Department of Organization and Accounting of the selected health care facilities. The total cost of chronic myeloid leukemia pharmacotherapy for 55 patients from the society’s perspective in 2013 amounted to 1,483,416.88 EUR. Average annual cost of medication per patient in 2013 amounted to 26,971.22 EUR (Median – 32,854.22 EUR). Average cost of chronic myeloid leukemia pharmacotherapy for a patient without transplantation was 32,167.34 EUR (Median – 30,623.00 EUR), and for a patient after transplantation amounted to 413.13 EUR (Median – 378.40 EUR). The cost from the payer’s perspective is 99.93% of total costs from the society’s perspective. The cost from the patient’s perspective represents 0.07% of the total cost of chronic myeloid leukemia pharmacotherapy from the society’s perspective. Costs of chronic myeloid leukemia pharmacotherapy are very high and represent a significant burden to society. The highest costs associated with treatment of chronic myeloid leukemia are incurred by the society, and, subsequently, the public payer (NHF), and the patient.

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Deep molecular response (MR4.5) as a target of therapy with tyrosine kinase inhibitors. MR4.5 – goal of CML treatment

100%

Sacha T.

OncoReview

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2014

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vol. 4

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issue 1

A27-32

EN

Chronic myeloid leukemia (CML) accounts for 15% of diagnosed leukemias. The annual incidence in two Polish regions has been calculated for 0.7/100,000 of general population. Introduction of tyrosine kinase inhibitors (TKIs) have substantially improved not only the prognosis of CML, but also changed the treatment goals, and the expectations of patients and physicians. The goals of CML therapy include: to prevent the progression towards accelerated phase and blastic phase, to eliminate the risk of death from leukemia, to prolong the length of survival to comparable of healthy population and to attain a quality of life comparable to healthy people. Patients treated up-front with second generation TKIs (2GTKI) have a better chance to achieve faster and deeper response to therapy. Most of patients receiving 2GTKI in first line or e.g. nilotinib after initial phase of imatinib therapy can achieve very deep molecular response (MR4.5), which is a key criterion for discontinuation studies. The results of stop-trials suggest that substantial proportion of patient could achieve sustained treatment-free survival, and that the disease could be controlled despite of persistence of minimal residual disease, which does not require a clinical intervention. Patients group that could benefit most from discontinuation study include younger people, those who have achieved MR4.5 and patients reporting TKI – associated side effects. Achievement of MR4.5 could be considered as a target of CML therapy for considerable proportion of patients. The question of safe TKI dose reduction or therapy cessation should be addressed in the future planned clinical trials.

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The effect of tyrosine kinase inhibitors used in the treatment of chronic myeloid leukemia on the cardiovascular system

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Sacha T., Góra-Tybor J., Szmit S.

OncoReview

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2019

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vol. 9

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issue 1

3-21

EN

The use of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia has significantly improved the prognosis and outcomes for most patients. Clinical trials indicate that long-term CML therapy requires the introduction of second- or third-generation inhibitors in approximately 40–50% of cases. Effective in the case of imatinib resistance or intolerance, second generation TKI’s can also be used as a first-line treatment, leading to a faster, and deeper molecular response. TKIs, however, have also been observed to cause significant late adverse effects, including cardiovascular complications, which may raise certain safety concerns. The excellent treatment outcomes achieved with tyrosine kinase inhibitors have led to a gradual increase in the number and age of treated patients, and the associated higher incidence and severity of age-related co-morbidities such as diabetes, hypercholesterolemia, atherosclerosis, ischemic heart disease, hypertension, and congestive heart failure, which raise the risk of treatment-related cardiovascular complications. The article discusses the effects of individual TKIs on the pathogenesis of cardiovascular complications and presents the results of clinical trials that studied their impact on the incidence of such events.

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Mitochondrial mutagenesis in BCR-ABL1-expressing cells sensitive and resistant to imatinib

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Blasiak J., Hoser G., Bialkowska-Warzecha J., Pawlowska E., Skorski T.

Acta Biochimica Polonica

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2016

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vol. 63

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issue 2

365-370

EN

Imatinib revolutionized the treatment of chronic myeloid leukemia (CML) with the expression of the BCR-ABL1 tyrosine kinase, but imatinib resistance is an emerging problem. Imatinib can hinder the inhibitory effects of BCR-ABL1 on mitochondrial apoptotic pathway, so mitochondrial mutagenesis can be important for its action. To explore the mechanisms of imatinib resistance we created a mouse-derived CML model cells consisting of parental 32D cells (P) and cells transfected with the BCR-ABL1 gene (S cells) or its variants with the Y253H or T315I mutations (253 and 315 cells, respectively), conferring resistance to imatinib. A fraction of the S cells was cultured in increasing concentrations of imatinib, acquiring resistance to this drug (AR cells). The 253, 315 and AR cells, in contrast to S cells, displayed resistance to imatinib. We observed that the T315I cells displayed greater extent of H2O2-induced mtDNA damage than their imatinib-sensitive counterparts. No difference in the sensitivity to UV radiation was observed among all the cell lines. A decrease in the extent of H2O2-induced mtDNA damage was observed during a 120-min repair incubation in all cell lines, but it was significant only in imatinib-sensitive and T315I cells. No difference in the copy number of mtDNA and frequency of the 3,867-bp deletion was observed and genotoxic stress induced by H2O2 or UV did not change this relationship. In conclusion, some aspects of mtDNA mutagenesis, including sensitivity to oxidative stress and DNA repair can contribute to imatinib resistance in BCR-ABL1-expressing cells.

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Role of anti-apoptotic pathways activated by BCR/ABL in the resistance of chronic myeloid leukemia cells to tyrosine kinase inhibitors

75%

Danisz K., Blasiak J.

Acta Biochimica Polonica

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2013

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vol. 60

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issue 4

503-514

EN

Chronic myeloid leukemia (CML) is a hematological stem cell disorder characterized by the excessive proliferation of the myeloid lineage. In its initial chronic phase, the myeloid progenitor cells expand and demonstrate apparently normal differentiation. The disease may then transform into the accelerated phase, usually associated with resistance to therapy, and finally, into acute leukemic progression phase - blast crisis. Abnormal myeloid cells produce progenitors, which have lost their ability to differentiate, but retain the capacity to proliferate. The molecular hallmark of CML is the Philadelphia chromosome, resulting from reciprocal chromosome translocation, t(9;22)(q34;q11), and containing the BCR/ABL fusion gene, producing the BCR/ABL protein with a constitutive tyrosine kinase activity. BCR/ABL-positive cells have faster growth and proliferation over their normal counterparts and are resistant to apoptosis. Introduction of imatinib (IM), a tyrosine kinase inhibitor, revolutionized the therapy of CML, changing it from a fatal disease into a chronic disorder. However, some patients show a primary resistance to IM, others acquire such resistance in the course of therapy. Therefore, a small number of leukemic stem cells retains self-renewal capacity under IM treatment. Because BCR/ABL is involved in many signaling pathways, some of them may be essential for resistance to IM-induced apoptosis. The PI3K/AKT, Ras and JAK/STAT signaling pathways are involved in resistance to apoptosis and can be activated by BCR/ABL. Therefore, they can be candidates for BCR/ABL-dependent pro-survival pathway(s), allowing a fraction of CML cells to withstand treatment with tyrosine kinase inhibitors.

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Reactive oxygen species in BCR-ABL1-expressing cells - relevance to chronic myeloid leukemia

75%

Antoszewska-Smith J., Pawlowska E., Blasiak J.

Acta Biochimica Polonica

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2017

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vol. 64

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issue 1

1-10

EN

Chronic myeloid leukemia (CML) results from the t(9;22) reciprocal chromosomal translocation producing the BCR-ABL1 gene, conferring growth and proliferation advantages in the CML cells. CML progresses from chronic, often syndrome-free, to blast phase, fatal if not treated. Although the involvement of BCR-ABL1 in some signaling pathways is considered as the cause of CML, the mechanisms resulting in its progression are not completely known. However, BCR-ABL1 stimulates the production of reactive oxygen species (ROS), which levels increase with CML progression and induce BCR-ABL1 self-mutagenesis. Introducing imatinib and other tyrosine kinase inhibitors (TKIs) to CML therapy radically improved its outcome, but TKIs-resistance became an emerging problem. TKI resistance can be associated with even higher ROS production than in TKI-sensitive cells. Therefore, ROS-induced self-mutagenesis of BCR-ABL1 can be crucial for CML progression and TKI resistance and in this way should be taken into account in therapeutic strategies. As a continuous production of ROS by BCR-ABL1 would lead to its self-destruction and death of CML cells, there must be mechanisms controlling this phenomenon. These can be dependent on DNA repair, which is modulated by BCR-ABL1 and can be different in CML stem and progenitor cells. Altogether, the mechanisms of the involvement of BCR-ABL1 in ROS signaling can be engaged in CML progression and TKI-resistance and warrant further study.

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Advances in hematology – research that revolutionized patient care

63%

Wach M., Podhorecka M., Cioch M., Hus I., Wąsik-Szczepanek E., Sokołowska B., Hus M.

Polish Journal of Public Health

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2015

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vol. 125

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issue 1

32-35

EN

In the last decades, substantial strides have been made in the diagnosis, treatment, and prevention of blood diseases. The new drugs to be used in combination with cytostatic therapy have been developed, based on increased understanding of the biology of neoplasia. The diagnosis of several diseases is based exclusively on cytogenetic and molecular analysis which has become a part of routine diagnostic management. Moreover, molecular definition has allowed the introduction of therapy targeted at molecular change characteristic for a given disease. The introduction of novel agents for the treatment of hematological disorders has resulted in a great improvement in response rate and median survival. The aim of this study is to show advances and possible future directions in the treatment of chosen hematological malignancies during the recent decades.

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ANALYSIS OF CHRONIC MYELOID LEUKEMIA PHARMACOTHERAPY COSTS IN POLAND

Deep molecular response (MR4.5) as a target of therapy with tyrosine kinase inhibitors. MR4.5 – goal of CML treatment

The effect of tyrosine kinase inhibitors used in the treatment of chronic myeloid leukemia on the cardiovascular system

Mitochondrial mutagenesis in BCR-ABL1-expressing cells sensitive and resistant to imatinib

Role of anti-apoptotic pathways activated by BCR/ABL in the resistance of chronic myeloid leukemia cells to tyrosine kinase inhibitors

Reactive oxygen species in BCR-ABL1-expressing cells - relevance to chronic myeloid leukemia

Advances in hematology – research that revolutionized patient care