What’s the price for the best? Pharmacoeconomic comparison of asciminib and imatinib in first line of chronic myelogenous leukemia treatment

Outcomes of Second-Line Tyrosine Kinase Inhibitors after First-Line Imatinib in Chronic Myelogenous Leukemia: A Retrospective Cohort Study

11532 Background: IM is the standard first-line therapy in advanced GIST, with a median progression-free survival (PFS) of 30 months. Recent multi-kinase inhibitors (MKIs) such as nilotinib, dasatinib or masitinib have been tested as first-line therapies in phase II/III studies. This might theoretically result in increased PFS (by the addition of a new line of treatment), or in early emergence of resistance to approved MKIs. Methods: A retrospective chart review was performed in GIST pts who received investigational MKIs (in phase II/III trials) as first-line treatment, followed by IM as second line. Data on demographics, molecular profile, PFS, and overall survival (OS) were collected in two French referral centers. Results: Of 47 pts, (57% females), 22 (47%) had a KIT exon 11 mutation, one a KIT exon 9 mutation (2%), one a PDGFR D842V mutation (2%). Five patients were wild-type for KIT and PDGFR. The mutational status was unknown in 18 pts (38 %). From 2005 to 2011, 21 pts (45%) received masitinib, 18 (38%) received dasatinib and 8 pts (17%) received nilotinib. Median PFS on first-line treatment was 18.9 months [95%IC: 9.0-26.0]. Median time-to-failure (TTF) with IM was 19.7 months [95%IC: 14.8-53.4]. Median time to second relapse was 50.2 months [95%IC: 31.2-92.2]. Thirty-five patients (74.5%) were dead at the end of follow-up. The median OS from time of initial diagnosis was 5.9 years [95%IC: 4.5-8.2]. Conclusions: GIST pts who received MKIs other than IM as first-line treatment and IM as second-line had a time to second relapse longer than that observed historically with IM in first line. This suggests that using MKIs other than IM in first line does not decrease IM efficacy in second line. Further comparative studies are needed to confirm these findings, but this is encouraging to further develop studies with other MKIs in the first line setting.

Adherence to Chronic Myeloid Leukemia Monitoring and Treatment Guidelines in Canadian Registries

17068 Background: Patients receiving imatinib had a significant survival advantage compared with patients receiving IFN therapy (Roy et al. Blood 2006; Kantarjian et al. Blood 2006). Although reimbursed as second line therapy for CP CML patients who did not respond to INF-a, IM was not considered for public reimbursement as first line treatment in Brazil based on drug costs. An economic evaluation considering the mortality risk reduction with first line IM versus INF was performed under the Brazilian Public Healthcare System perspective, comparing the costs to avoid one death of a chronic phase CML patient over a 5-year period. Methods: Risk of death in 5 years was defined by survival rates in the 60 month follow-up of IRIS for IM (Rim= 10%) (Druker et al. JCO 2006), MD Anderson cohort of CML patients treated with INF-a for INF-a (RINF-a= 38%) (Cortes et al. American J. Med 1996) and a population based-survey in Norway for the natural course of the disease (Rnon-treatment= 67%). IRIS INF group survival rate was not used due to high crossover to IM in the trial. Risk of death in the natural course of the disease was the basis for the absolute risk reduction (ARR) calculation (ARRim= 57%; ARRINF-a= 29%). Number need to treat (NNT) was obtained by the inverse of ARR value for each first line treatment (NNT =1/ARR). Costs were estimated based on the Brazilian public healthcare reimbursement payment (APAC-SUS) for chronic phase CML treatment. A base case economic model of 100 patients for each treatment option was constructed focused on drug costs and adverse events (AE) from the IRIS study for both groups. Clinical guidelines from two public hematology centers were used to estimate AE treatment costs. Costs were discounted at a 6% annual rate. Results: The treatment costs and NNTs for a 5-year period are US$ 62,135 and 3.45 for INF-a, and US$ 93,397 and 1.75 for IM, respectively. The costs to avoid one death over a 5-year period are US$ 214,368 for INF-a and US$ 163,445 for IM. Conclusions: The costs for avoiding one death of a chronic phase CML patient over a 5-year period is US$ 50,923 higher with first line INF-a than it would be with first line imatinib. [Table: see text]

First-Line Treatment and Management of Chronic Myeloid Leukemia (CML) in Clinical Practice: Update of > 1800 Patients (Pts) in the WORLD CML Registry

Frequency of Molecular Monitoring Correlates with Long Term Outcomes in Chronic Phase Chronic Myelogenous Leukemia Treated with First-Line Imatinib: Results of a Community Survey

Retrospective review of imatinib monitoring through electronic health records (EHR) can provide valuable insight into the current management of chronic myelogenous leukemia (CML). This study retrospectively reviewed EHRs from 2001 to 2010 of patients with chronic phase CML (CP-CML) treated with first-line imatinib. Chart evaluations included a review of cytogenetic and molecular testing, overall survival, adverse drug events (ADEs), and therapy modifications. A total of 54 patients with CP-CML were treated with first-line imatinib and had either cytogenetic or molecular testing within 18 months of imatinib initiation. Within the first 18 months of treatment, 33 of 45 patients (73%) undergoing cytogenetic testing experienced a complete cytogenetic response (median, 241 days; range, 110-542 days) and 24 of 48 patients (50%) receiving molecular testing achieved at least a major molecular response (median, 253 days; range, 99-546 days). The average number of cytogenetic and molecular tests conducted within the first 18 months was 2.5 and 3.8, respectively. Nineteen of 54 (35%) had a dose increase of imatinib (>400 mg; median, 329 days; range, 21-1968 days). The 5-year estimated overall survival rate was 88.5%. Between 2006 and 2010 (n=30; 56%), 7 patients (23%) transitioned to dasatinib or nilotinib (median, 399 days from diagnosis; range, 180-1046 days) because of suboptimal response or treatment failure (n=5) and imatinib ADEs (n=2). Forty-six imatinib-associated ADEs occurred in 31 patients (57%), of which 10 (32%) received dose reductions (median, 52 days) and 6 (19%) had discontinuations (median, 139 days). Closely monitored patients with CML treated with imatinib at an NCCN Member Institution experienced outcomes comparable to those reported in key clinical trials.

Nilotinib and dasatinib are now being considered as alternative treatments to imatinib as a first-line treatment of chronic myeloid leukaemia (CML). This technology assessment reviews the available evidence for the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of Philadelphia chromosome-positive CML. Databases [including MEDLINE (Ovid), EMBASE, Current Controlled Trials, ClinicalTrials.gov, the US Food and Drug Administration website and the European Medicines Agency website] were searched from search end date of the last technology appraisal report on this topic in October 2002 to September 2011. A systematic review of clinical effectiveness and cost-effectiveness studies; a review of surrogate relationships with survival; a review and critique of manufacturer submissions; and a model-based economic analysis. Two clinical trials (dasatinib vs imatinib and nilotinib vs imatinib) were included in the effectiveness review. Survival was not significantly different for dasatinib or nilotinib compared with imatinib with the 24-month follow-up data available. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were higher for patients receiving dasatinib than for those with imatinib for 12 months' follow-up (CCyR 83% vs 72%, p < 0.001; MMR 46% vs 28%, p < 0.0001). The rates of CCyR and MMR were higher for patients receiving nilotinib than for those receiving imatinib for 12 months' follow-up (CCyR 80% vs 65%, p < 0.001; MMR 44% vs 22%, p < 0.0001). An indirect comparison analysis showed no difference between dasatinib and nilotinib for CCyR or MMR rates for 12 months' follow-up (CCyR, odds ratio 1.09, 95% CI 0.61 to 1.92; MMR, odds ratio 1.28, 95% CI 0.77 to 2.16). There is observational association evidence from imatinib studies supporting the use of CCyR and MMR at 12 months as surrogates for overall all-cause survival and progression-free survival in patients with CML in chronic phase. In the cost-effectiveness modelling scenario, analyses were provided to reflect the extensive structural uncertainty and different approaches to estimating OS. First-line dasatinib is predicted to provide very poor value for money compared with first-line imatinib, with deterministic incremental cost-effectiveness ratios (ICERs) of between £256,000 and £450,000 per quality-adjusted life-year (QALY). Conversely, first-line nilotinib provided favourable ICERs at the willingness-to-pay threshold of £20,000-30,000 per QALY. Immaturity of empirical trial data relative to life expectancy, forcing either reliance on surrogate relationships or cumulative survival/treatment duration assumptions. From the two trials available, dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML, i.e. assuming the use of second-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY were used, compared with imatinib and nilotinib. Uncertainty in the cost-effectiveness analysis would be substantially reduced with better and more UK-specific data on the incidence and cost of stem cell transplantation in patients with chronic CML. The Health Technology Assessment Programme of the National Institute for Health Research.

Pharmacoeconomic Analysis of the Real World Treatment of Chronic Myeloid Leukemia in Chronic Phase of a Brazilian Private Institution Considering the Use of Generic Drugs and Eventual Discontinuation of Treatment

Early molecular response at 3 months is predictive of improved overall survival and progression-free survival in patients with chronic myeloid leukemia in the chronic phase. Although about one-third of patients treated with first-line imatinib do not achieve an early molecular response, long-term overall survival and progression-free survival are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved an early molecular response after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib than those randomized to imatinib (77% vs. 44%, P<0.001). The median time to MMR was 13.9 months with dasatinib versus 19.7 months with imatinib. The safety profile was consistent with previous reports. These results demonstrate that switching to dasatinib after a suboptimal response to imatinib at 3 months leads to faster MMR, provides earlier deep molecular responses, and improves some outcomes in patients with chronic myeloid leukemia in the chronic phase.

First-line treatment of chronic myeloid leukemia (CML) with imatinib mesylate leads to hematologic remission in >95% of cases by 12 months and a normal life expectancy in chronic phase (CP)-CML patients.1, 2 Despite excellent prognosis, treatment failure is possible. Second- and third-generation tyrosine kinase inhibitors (TKIs) achieve a complete cytogenetic response (CCyR) rate of 40%-60% in imatinib-resistant patients. Recently, additional genetic alterations were detected in CP-CML samples at diagnosis, including ASXL1, DNMT3A, RUNX1, TET2, and JAK2 mutations3 and chromosomal abnormalities such as trisomy of chromosomes 8 and 19, monosomy of chromosome 7 and loss of chromosome Y,4 through targeted resequencing or conventional cytogenetics. We applied a global, unbiased approach to CML mutational landscape at diagnosis with bioinformatic analyses to the identification of the risk of failing first-line imatinib therapy. Nineteen consecutive CP-CML patients referred to our center were prospectively studied between 2007 and 2013 after obtaining informed consent (median age 49 years; Supporting Information Table S1). The Institutional Ethics Committee approved the study. The cytogenetic profile and BCR-ABL1 transcript level were periodically examined in accordance with NCCN/ELN Clinical Practice Guidelines. Myeloid cells were collected at diagnosis from bone marrow or peripheral blood (tumor sample). Normal lymphocytes were expanded in vitro with IL-2 as controls. All patients were prescribed imatinib (400 mg) as first-line TKI treatment. Six patients were subsequently shifted to second- and third-line TKI therapy because of primary or acquired resistance to imatinib. Only 1 patient eventually progressed to AP/BC. To test whether additional abnormalities co-exist along with BCR-ABL1 fusion gene in the Ph+ clone at onset, we performed whole-exome sequencing on matched tumor/normal pairs, at mean exon coverage of 84-fold per sample. Variants were called when present in >35% of tumor reads and <10% of control reads. Synonymous substitutions, non-coding changes and known SNPs were discarded. All candidate somatic mutations identified by WES were confirmed by Sanger sequencing. We identified a total of 81 non-synonymous mutations (median 4 per patient, range 0–11; Supporting Information Table S2). All mutations were not previously described in CP-CML, with the exception of ASXL1 (Q829*) in 1 patient. A weak positive correlation between the number of mutations and patients' age was found (r = 0.4179; P = .075), suggesting that some variants may be passengers. Unfortunately, unless biological data are available, it is not easy to discriminate between true oncogenic mutations and passenger events expanded by neoplastic transformation. In order to evaluate the oncogenic potential of each mutation, we applied OncoScore, a recently developed cancer scoring system based on automatic literature data mining.5 Genes with a score >22 were considered as potential cancer-causing genes. Using these settings, 45% of the mutations (37/81) were predicted to be driver variants (OncoScore >22), with some of them such as ASXL1, KAT6A, PATZ1, DLG5, TEP1, and KAT7 showing very high scores. The oncogenic potential in each patient was calculated either by annotating the sum of OncoScores of all the identified somatic variants (total OncoScore, tOS); or considering only those genes passing the driver threshold (OS22 score); or by 2topOS, which is the sum of scores from the 2 highest-ranking mutated genes in each patient. We found a positive correlation between tOS and Sokal score,6 suggesting that somatic variants of oncogenic potential may be associated with high-risk patients (Figure 1A). Indeed, patients in the high-risk Sokal group had significantly higher tOS compared to patients in the low-risk group (mean ± SEM, 126 ± 20 vs. 63 ± 9, P = .0473). (A) Pearson correlation and linear regression analysis of tOS versus Sokal score in 19 consecutive CP CML patients. (B) Box-and-whiskers graph of OncoScore and Sokal score values from patients who remained on imatinib therapy (IM) and patients who were shifted to second/third line TKI therapy (second) because of resitance to imatinib. The boxes extend from the 25th to 75th percentiles; the middle line represents the median; whiskers show the range (min to max). tOS, sum of the OncoScores of all mutated genes; OS22, sum of all the OncoScores from genes with score >22; 2topOS, sum of the OncoScores derived from the 2 top-scoring genes. Statistical analysis was run by unpaired 2-tailed t-test, where P < .05 was considered as statistically significant. (C) Scatter dot plot of OS22 scores from the 2 group of patients, showing the cut-off value calculated by Jouden's analysis. (D) Kaplan-Meyer curves showing time to loss of response to imatinib for patients showing OS22 > 66.4 (red, n = 8) or < 66.4 (blue, n = 11); P value represents the log-rank test. (E) Box-and-whiskers graphs analysis according to cytogenetic status at long-term follow-up in 19 patients on first-line imatinib: the distribution of OS22 and 2topOS scores is shown for patients with (CCyR, n = 17) and without (non-CCyR, n = 2) complete cytogenetic remission at 2 years of follow-up. A significance test was calculated by 2-tailed unpaired t-test method. P < .05 is considered as statistically significant Next, we asked whether mutations with high OncoScore could affect response to treatment. At 3 months following diagnosis, no significant differences were observed between patients with (10/19, 52.6%) or without CCyR, in average number of mutations or mean oncogenic scores, and no correlation was detected between quantitative real-time PCR values at 3 months and OncoScores. On long-term follow-up (median 5 years, range 2–8), 13/19 patients remained on imatinib while 6 were shifted to another regimen (either second-generation TKIs or imatinib dose increase). We found that the 6 imatinib-resistant patients possessed significantly higher OncoScores than the 13 patients still on imatinib therapy (Figure 1B). The distribution of OS22 values (48.1 ± 11.6 vs. 130.4 ± 14.4 for imatinib responding and resistant patients, respectively; P = .0007) allowed the definition of a cut-off threshold to discriminate between the 2 groups of patients, by ROC curve analysis (Figure 1C). An OS22 cut-off value of 66.4 correctly detects 17/19 outcomes (sensitivity 100%, specificity 85%, accuracy 89%; Youden index J = 0.8462, area under the ROC curve = 0.897; 95% CI = 0.672–0.988; P < .0001). Indeed, the 8 patients with OS22 > 66.4 had a markedly increased probability to lose response to imatinib, compared to those with a low OS22 (median time to loss of response, 15 months vs. not reached; Figure 1D). In contrast, we found no significant difference in Sokal score between imatinib-resistant and responding patients, indicating that Sokal score was less accurate than OncoScore as a prognostic factor in our patients population. These results were maintained also when we repeated all statistical analyses including genes that were found mutated at lower frequency (>25%) in the tumor sample. Interestingly, using this lower threshold, we identified recurrent mutations in the BCLAF1 gene in 2 patients. Whether this finding is significant for disease progression is unknown. At the same time point, 2 patients who never achieved CCyR had ∼2-fold higher mean OncoScores than patients (17/19) who eventually achieved CCyR (OS22, 158.9 ± 31.3 vs. 64.1 ± 11.7, P = .017; 2topOS, 125.0 ± 2.7 vs. 57.5 ± 7.8, P = .011; Figure 1E). Only 1 patient progressed to AP/BC and therefore no comparison was possible with nonprogressing patients. In conclusion, we found that additional mutations were present in BCR-ABL1 positive CP-CML patients at diagnosis, and that patients resistant to first-line imatinib treatment had an increased burden of mutations in cancer-related genes, which could be relevant to treatment response and possibly to the progression of CML. Prioritization of mutated genes by in silico scoring allowed the identification of high-risk patients. Interestingly, Sokal score could not differentiate between the 2 populations, suggesting that genetic analyses may have superior value compared with clinical scoring in identifying patients at high-risk of imatinib failure. If confirmed in larger cohorts these data could allow a better stratification of patients at diagnosis and potentially a more rational treatment selection. We thank Ms Michela Viltadi for assistance in the collection of samples. The authors declare that they have no conflicts of interest with the contents of this article. Additional Supporting Information may be found online in the supporting information tab for this article. Supporting Information Table 1 Supporting Information Table 2 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

The availability of different tyrosine kinase inhibitors (TKIs) with distinct anti-leukemic potency enables optimization of current therapeutic regimens; however, some patients lose their therapy response and acquire TKI resistance. In this study, we describe a single-center experience of monitoring BCR-ABL1 kinase domain (KD) mutations and discuss the impact of treatment on mutation selection. Chronic myelogenous leukemia (CML) patients treated with TKIs at the Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital Brno during 2003-2011 were included in this study. A total number of 100 patients who did not achieve an optimal therapy response or who lost their therapy response were screened for the presence of BCR-ABL1 KD mutations, using direct sequencing. Our data show that pretreatment with non-specific non-TKI drugs prior to TKI therapy does not preferentially select for initial BCR-ABL1 KD mutations, in contrast to first-line imatinib therapy, which shows a clear predominance of T315I or P-loop mutations compared with mutations located in other KD regions. In addition, the median time to detection of P-loop mutations was substantially shorter in patients treated with first-line imatinib than in those pretreated with non-TKI drugs. Furthermore, analysis of CML patients who had recurrent resistance to TKI therapy revealed possible therapy-driven selection of BCR-ABL1 KD mutations. Finally, we confirm the previously described poor prognosis of CML patients with mutations in the BCR-ABL1 KD, since 40.0% of our CML patients who harbored a BCR-ABL1 KD mutation died from CML while receiving TKI treatment. Moreover, among the patients who are still on treatment, 27.8% have already progressed. Our data also confirm the unique position of the T315I mutation with respect to its strong resistance to currently approved TKIs. On the basis of the 'real-life' data described in this study, it is possible that the therapy itself results in its failure and selects the most resistant mutations under the selective pressure of the applied therapy regimen in some CML patients who harbor BCR-ABL1 KD mutations.

Chronic opioid treatment of the mouse thymoma cell lines R1.G1 and R1EGO leads to down-regulation of the kappa opioid receptor without desensitization of adenylyl cyclase activity

Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapy. These studies included patients selected according to many inclusion-exclusion criteria, particularly age and comorbidities, with specific treatment obligations. In daily clinical practice (real-life), inclusion-exclusion criteria do not exist, and the treatment outcome does not only depend on the choice of first-line TKI but also on second- and third-line TKIs. To investigate in a real-life setting the response and the outcome on first-line imatinib, with switch to second generation TKIs in case of unsatisfying response or intolerance, we analyzed all newly diagnosed patients (N = 236), living in two Italian regions, registered in a prospective study according to population-based criteria and treated front-line with imatinib. A switch from imatinib to second-generation TKIs was reported in 14% of patients for side effects and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The 5-year overall survival (OS) and leukemia-related survival (LRS) were 85% and 93%, respectively; the 4-year rates of MR3.0 and MR4.0 were 75% and 48%, respectively. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients receiving nilotinib as second-line. Older age (≥70 years) affected OS, but not LRS. These data provide an unbiased reference on the CML management and on the results of TKI treatment in real-life, according to ELN recommendations, using imatinib as first-line treatment and second-generation TKIs as second-line therapy. Am. J. Hematol. 92:82-87, 2017. © 2016 Wiley Periodicals, Inc.

A Population-Based Study of Chronic Myeloid Leukemia Treated with Imatinib in First Line