Chronic myeloid leukemia-clinical, experimental and health economic studies with special reference to imatinib treatment
Sammanfattning: CML is a malignant disease that originates in the bone marrow stem cell, carrying the Philadelphia chromosome with the BCR-ABL fusion gene. This gene translates into an active tyrosine kinase, Bcr-Abl, affecting hematopoiesis, particularly resulting in increased numbers of white blood cells in the peripheral blood. Left untreated, CML progresses from a silent chronic phase (CP) to a life-threatening blastic phase (BP). After the millennium shift imatinib was introduced for the treatment of CML. Specifically targeting the Bcr-Abl oncoprotein, it was the first tyrosine kinase inhibitor (TKI) employed in cancer. It induced spectacular responses among CML-CP patients, strikingly reducing the risk of disease progression, combined with excellent tolerability. In this thesis we have studied various aspects of imatinib treatment in CML. In a cohort of 45 newly diagnosed CML-CP patients initiated on imatinib, we consecutively assessed treatment responses by FISH, PCR and chromosome banding analysis (CBA). In a landmark analysis, an early favourable response, defined as less than 10% BCR-ABL-positive cells by FISH after 3 months of treatment, was identified as a predictive marker of an improved long-term clinical outcome. Among evaluable patients 51% achieved this response. A large majority, 95% of such responders, reached complete cytogenetic response within 12 months and 100% an event-free survival at 48 months. We assessed the effect of imatinib treatment on neutrophil leukotriene (LT) signaling to evaluate its possible role as a clinical biomarker predictive of treatment response. Increased LT signaling has previously been suggested as a driver of leukocytosis in CML. The activity and expression of LTC4S, catalyzing formation of LTC4 from LTA4, were determined in neutrophils from 11 CML-CP patients during their initial phase of imatinib treatment, and the results related to the parallel development of BCR-ABL-expression. CD16+ neutrophils were isolated, their LTC4S activity measured and LTC4S expression determined at the protein and mRNA levels. In parallel, BCR-ABL expression was assessed by bone marrow CBA and by FISH on peripheral blood cells, including a combined May Grünewald Giemsa staining and FISH technique (MGG-FISH) to score neutrophilic cells. An aberrant expression of LTC4S in CML neutrophils was typically found, but it was rapidly normalized after initiation of imatinib treatment, later paralleled by a decreasing expression of BCR-ABL. The findings indicate that increased expression and activity of LTC4S in CML is a down-stream step of BCR-ABL activity, i.e. the Bcr-Abl protein directly or indirectly causes an upregulation of LTC4S. It is possible that an early evaluation of LTC4S expression during imatinib treatment could serve as a more rapid way of assessing treatment response than the current methods identifying BCR-ABL expression through CBA, FISH or qRT- PCR. We also defined real life outcome of patients with CML in Sweden during four decades and related the relative survival (RS) patterns to imatinib treatment and other management strategies. We assessed trends in survival and short-and long-term excess mortality among all patients (n=3,173) regardless of clinical trial enrollment. Patients were categorized into five age groups (<50, 50-59, 60-69, 70-79 and >79 years) and five calendar periods (1973- 1979, 1980-1986, 1987-1993, 1994-2000 and 2001-2008). We found that throughout all calendar periods, age was a strong predictor of survival, with superior survival for the youngest patients. In analyses including age and period of diagnosis, RS improved with calendar period in all age groups, but most markedly in patients younger than 79 years of age, particulary those 70-79 years of age. Survival among all age groups was greatest in the last calendar period, mainly as a result of an increasing use of imatinib. However, elderly patients still do poorly. The Swedish CML registry data show that patients diagnosed 2002-2008, at the age of 70-79 years received TKI in 66% and patients >80 years in only 18% of the cases. Finally, we compared the costs during the last decades with earlier decades treatment regimens and related the costs to the expected improved survival. Using Swedish real world national data from CML patients diagnosed in the country from 1973 to 2008 (n=1,778), we evaluated the incremental cost-effectiveness ratio (ICER) between three periods associated with broad implementation of imatinib (III), interferon-? and allogeneic stem cell transplantation (II), and symptomatic treatment (I), respectively. We observed substantial health gains over time, paralleled by increased treatment costs. The mean survival was 2.9, 9.2 and 18.5 years during periods I-III, respectively. The resulting ICER was £45 700 per QALY gained comparing periods III and II using a societal perspective. In a separate analysis by groups of age at diagnosis showed lower ICERs for individuals <50 years at diagnosis: £38 500 for the societal perspective. Since the prevalence of CML patients is increasing and assuming that 75% of each incident cohort was to receive imatinib at current prices, the imatinib budget would need to double by 2050. A future potential discontinuation of imatinib for selected excellent responders would reduce the ICER per QALY gained. Reduced drug cost of imatinib linked to the patent expiry of the drug will probably have a greater impact on ICER per QALY. An estimated price reduction of 80% (global competition) or 30% (expected change for biological drugs) would be associated with an ICER of £20 000 and £36 000, respectively, per QALY gained.
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