Chronic myeloid leukemia-clinical, experimental and health economic studies with special reference to imatinib treatment

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 (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-α 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

Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase : clinical results from a randomised phase-2 study (NordCML006)

Peer reviewe

Real-world cost-effectiveness in chronic myeloid leukemia: the price of success during four decades of development from non-targeted treatment to imatinib

Imatinib has revolutionized the treatment of chronic myeloid leukemia (CML). We evaluated clinical outcome and cost-effectiveness, using Swedish registry data based on patients with CML diagnosed 1973-2008. Outcome from three time periods (I: 1973-1979; II: 1991-1997; III: 2002-2008) associated with symptomatic treatment, interferon-alpha/stem cell transplant and implementation of imatinib, respectively, were compared and a lifetime cost-effectiveness model developed. Survival data from population registries, estimated resource use from clinical practice and quality of life estimates were employed. Substantial health gains were noted over time, paralleled by increased treatment costs. Median survival was 1.9, 4.0 and 13 years during the respective time periods. The incremental cost-effectiveness ratio (ICER) between periods III and II was (sic)52 700 per quality-adjusted life year (QALY) gained. An estimated 80% price reduction of imatinib, related to patent expiry, would reduce this ICER to (sic)22 700. Our data from four decades reveal dramatically improved survival in CML, paralleled by ICER levels generally accepted by health authorities

Cardiovascular events associated with use of tyrosine kinase inhibitors in chronic myeloid leukemia

Background: Tyrosine kinase inhibitors (TKIs) have increased survival dramatically for patients with chronic myeloid leukemia (CML), but continuous administration of these drugs may elicit long-term toxicity. Objective: To investigate the incidence of vascular events in patients with CML treated with first-and second-generation TKIs. Design: Retrospective cohort study using nationwide population-based registries. Setting: Sweden. Patients: All patients diagnosed with chronic-phase CML in Sweden from 2002 to 2012 and treated with a TKI, and 5 ageand sex-matched control individuals per patient. Measurements: Relative risks, expressed as incidence rate ratios comparing patients with control individuals, were calculated. Events per 1000 person-years were assessed in interdrug comparisons. Results: 896 patients, 94.4% with documented TKI treatment, were followed for a median of 4.2 years. There were 54 arterial and 20 venous events in the CML cohort, corresponding to relative risks of 1.5 (95% CI, 1.1 to 2.1) and 2.0 (CI, 1.2 to 3.3), respectively. The event rate for myocardial infarction was higher in patients treated with nilotinib or dasatinib (29 and 19 per 1000 person-years, respectively) than in those receiving imatinib (8 per 1000 person-years), although data are limited and the CIs were wide and overlapped. Among 31 patients treated with a TKI who had myocardial infarction, 26 (84%) had at least 1 major cardiac risk factor diagnosed before the event occurred. Limitations: Patients may have been exposed to multiple TKIs. Data on second-and third-generation TKIs were limited. Conclusion: An increased risk for arterial and venous vascular events was seen in patients with CML treated with a TKI. Further study is needed to determine whether the risk for myocardial infarction increases with second-generation drugs

Success Story of Targeted Therapy in Chronic Myeloid Leukemia: A Population-Based Study of Patients Diagnosed in Sweden From 1973 to 2008

PURPOSE Chronic myeloid leukemia (CML) management changed dramatically with the development of imatinib mesylate (IM), the first tyrosine kinase inhibitor targeting the BCR-ABL1 oncoprotein. In Sweden, the drug was approved in November 2001. We report relative survival (RS) of patients with CML diagnosed during a 36-year period. PATIENTS AND METHODS Using data from the population-based Swedish Cancer Registry and population life tables, we estimated RS for all patients diagnosed with CML from 1973 to 2008 (n = 3,173; 1,796 males and 1,377 females; median age, 62 years). Patients were categorized into five age groups and five calendar periods, the last being 2001 to 2008. Information on use of upfront IM was collected from the Swedish CML registry. Results Relative survival improved with each calendar period, with the greatest improvement between 1994-2000 and 2001-2008. Five-year cumulative relative survival ratios (95% Cls) were 0.21 (0.17 to 0.24) for patients diagnosed 1973-1979, 0.54 (0.50 to 0.58) for 1994-2000, and 0.80 (0.75 to 0.83) for 2001-2008. This improvement was confined to patients younger than 79 years of age. Five-year RSRs for patients diagnosed from 2001 to 2008 were 0.91 (95% CI, 0.85 to 0.94) and 0.25 (95% CI, 0.10 to 0.47) for patients younger than 50 and older than 79 years, respectively. Men had inferior outcome. Upfront overall use of IM increased from 40% (2002) to 84% (2006). Only 18% of patients older than 80 years of age received IM as first-line therapy. CONCLUSION This large population-based study shows a major improvement in outcome of patients with CML up to 79 years of age diagnosed from 2001 to 2008, mainly caused by an increasing use of IM. The elderly still have poorer outcome, partly because of a limited use of IM

Tyrosine kinase inhibitor usage, treatment outcome, and prognostic scores in CML: report from the population-based Swedish CML registry

Clinical management guidelines on malignant disorders are generally based on data from clinical trials with selected patient cohorts. In Sweden, more than 95% of all patients diagnosed with chronic myeloid leukemia (CML) are reported to the national CML registry, providing unique possibilities to compile population-based information. This report is based on registry data from 2002 to 2010, when a total of 779 patients (425 men, 354 women; median age, 60 years) were diagnosed with CML (93% chronic, 5% accelerated, and 2% blastic phase) corresponding to an annual incidence of 0.9/100 000. In 2002, approximately half of the patients received a tyrosine kinase inhibitor as initial therapy, a proportion that increased to 94% for younger (80 years) patients during 2007-2009. With a median follow-up of 61 months, the relative survival at 5 years was close to 1.0 for patients younger than 60 years and 0.9 for those aged 60 to 80 years, but only 0.6 for those older than 80 years. At 12 months, 3% had progressed to accelerated or blastic phase. Sokal, but not European Treatment and Outcome Study, high-risk scores were significantly linked to inferior overall and relative survival. Patients living in university vs nonuniversity catchment areas more often received tyrosine kinase inhibitors up front but showed comparable survival

Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia

Biologic and clinical observations suggest that combining imatinib with IFN-alpha may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-alpha 2b (Peg-IFN-alpha 2b) 50 mu g weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-alpha 2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-alpha 2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg-IFN-alpha 2b treatment ( 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-alpha 2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg-IFN-alpha 2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent. (Blood. 2011;118(12):3228-3235