Health care resource utilization in 3L + patients with chronic phase chronic myeloid leukemia receiving asciminib or bosutinib.

OBJECTIVES: To assess and compare health care resource utilization (HCRU) rates of asciminib and bosutinib at the Week 24, Week 48, and Week 96 cutoffs among 3 L + patients with chronic myeloid leukemia in chronic phase (CML-CP) in the randomized ASCEMBL trial. METHODS: Patients in the ASCEMBL trial (Clinicaltrials.gov: NCT03106779) were randomized to receive asciminib 40 mg twice daily (n = 157) or bosutinib 500 mg once daily (n = 76). At each scheduled visit, investigators conducted HCRU assessment on hospitalization, emergency room visit, general practitioner visit, specialist visit and urgent care visit; duration and type of hospitalization for the hospitalized patients; and reasons for HCRU. The number of patients with HCRU, rate of HCRU per patient-year, and length of hospital stay by ward type were compared at Week 24, Week 48, and Week 96 analyses. RESULTS: Lower proportions of patients receiving asciminib versus bosutinib used any resources including hospitalizations, emergency room visits, general practitioner visits, specialist visits, and urgent care visits (23.6% versus 36.8%, 26.1% versus 39.5%, and 28.6% versus 42.6% at Week 24, Week 48, and Week 96 analyses, respectively). After normalizing for treatment exposure, rates of HCRU for any resource per patient-year were significantly lower for asciminib versus bosutinib: 0.25 (95% CI: 0.18-0.34) versus 0.80 (95% CI: 0.55-1.16) at the Week 24 analysis, 0.20 (95% CI: 0.15-0.27) versus 0.47 (95% CI: 0.32-0.66) at the Week 48 analysis, and 0.17 (95% CI: 0.12-0.22) versus 0.40 (95% CI: 0.27-0.55) at the Week 96 analysis. Among the hospitalized patients, mean length of hospital stay was lower for asciminib than bosutinib for most wards at all three timepoints. CONCLUSIONS: In the ASCEMBL trial, asciminib-treated patients with CML-CP in 3 L + maintained lower resource utilization compared to bosutinib over the long-term.

Efficacy and Safety of Generic Dasatinib in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase: A Multicenter Prospective Study in China.

BACKGROUND: Brand-name dasatinib was approved for newly diagnosed chronic myeloid leukemia-chronic phase (CML-CP) patients due to its deeper and faster molecular response than imatinib. Generics, as the alternative, low-cost forms, are much in demand. This study aimed to evaluate the efficacy and safety of generic dasatinib (Yinishu) as a first-line treatment in CML-CP. MATERIALS AND METHODS: This was a prospective, multicenter, single-arm study from May 2016 to October 2018 with a 2-year follow-up analysis. All patients were given 100 mg/d (initial dose) of the generic dasatinib once a day. The primary endpoint was the major molecular response (MMR) calculated based on the BCR-ABL1 gene mutation rate of ≤ .1% at 12 months. RESULTS: Among 55 patients in CP observed for at least 3 months, 80.4% achieved MMR at 12 months. The cumulative MR4.5 was 58.2% by 24 months. Responses occurred rapidly, with 69.1% of patients achieving complete cytogenetic response (CCyR) by 3 months and 70.9% achieving CCyR by 6 months. The estimated 2-year PFS and OS were both 96%, with a median follow-up time of 24 months. Grade 3 neutropenia occurred in 8.5% of patients, and thrombocytopenia occurred in 11.9% of patients. Nonhematologic toxicity was usually mild and manageable. Pleural effusion occurred in 20.3% of patients, and only 1 patient (1.7%) had a grade 3 pleural effusion. No grade 4 adverse events were observed. CONCLUSION: Generic dasatinib is an effective option for newly diagnosed CML-CP patients, producing an MMR early in a greater number of patients during their therapy.

Comparison of 3-month cytogenetic and molecular assays for early assessment of long-term clinical impact after BCR-ABL1 tyrosine kinase inhibitor treatment in chronic myeloid leukemia.

To compare the clinical significance of 3-month cytogenetic and molecular monitoring, we analyzed 1,410 paired cytogenetic and molecular data from 705 chronic-phase chronic myeloid leukemia patients. Based on early cytogenetic response (ECyR, Ph+≤35 %) and molecular response (EMR, BCR-ABL1IS≤10 %) at 3 months, the patients were divided into four groups (group 1: ECyR + EMR, n = 560; group 2: no ECyR + EMR, n = 27; group 3: ECyR + no EMR, n = 55; group 4: no ECyR + no EMR, n = 63). By 10 years, major molecular response (MMR), deep molecular response (MR4.5), overall survival (OS), and progression-free survival (PFS) rates were significantly high in group 1 (P < 0.001). Comparing groups 2 and 3, the MMR (P = 0.096), MR4.5 (P = 0.945), OS (P = 0.832), and PFS (P = 0.627) rates tended to be higher in group 2, although not significantly. Thus, the cytogenetic assay can not only be useful but its addition may also provide a more precise prediction of MR4.5.

Assessment of estimated glomerular filtration rate in patients with chronic myeloid leukemia following discontinuation of tyrosine kinase inhibitors.

BCR-ABL1 tyrosine kinase inhibitors (TKIs) have dramatically improved survival outcomes in patients with chronic phase chronic myeloid leukemia (CML-CP) and are associated with a manageable safety profile. However, long-term TKI administration can lead to cardiovascular or renal adverse events. One goal in discontinuation of TKIs was reduction of adverse events, but it is unclear whether chronic toxicities are ameliorated as a result. In this study, we evaluated changes in estimated glomerular filtration rate (eGFR) in patients with CML-CP before and after TKI discontinuation. Long-term TKI treatment appears to induce renal toxicity, as eGFR at the time of TKI discontinuation correlated with the duration of TKI treatment (r = - 0.478, p = 0.005). Patients who received imatinib as first-line treatment exhibited lower eGFR levels than those treated with dasatinib or nilotinib, which may be correlated with long-term treatment (p = 0.027). After TKI discontinuation, no significant increases in eGFR were seen either in patients with treatment-free remission (66.8-71.2 ml/min/1.73 m2) or molecular relapse (64.8-68.7 ml/min/1.73 m2, p = 0.666). These data indicate that TKI-induced renal toxicities are associated with long-term TKI treatment, and may be irreversible even following treatment discontinuation.

Cost Effectiveness of the Third-Generation Tyrosine Kinase Inhibitor (TKI) Ponatinib, vs. Second-Generation TKIs or Stem Cell Transplant, as Third-Line Treatment for Chronic-Phase Chronic Myeloid Leukemia.

BACKGROUND AND OBJECTIVES: Third-line treatment options for patients with chronic-phase chronic myeloid leukemia include tyrosine kinase inhibitors and allogeneic hematopoietic stem cell transplantation (alloHSCT). The objective of this study was to develop a Markov model with a lifetime time horizon to assess the cost effectiveness of ponatinib for third-line chronic-phase chronic myeloid leukemia vs. second-generation tyrosine kinase inhibitors (dasatinib, nilotinib, bosutinib) or alloHSCT from the public healthcare system perspective in Germany, Sweden, and Canada. METHODS: Clinical outcomes were derived from the literature, and from patient-level data (phase II PACE trial) for ponatinib. Resource use included drugs, alloHSCT, monitoring and follow-up, adverse events, and end-of-life care; costs were based on national tariffs. Quality-adjusted life-years (QALYs) were calculated using chronic myeloid leukemia health-state utilities from an international time-trade-off study. Costs and benefits were discounted at 3% per annum for Germany and Sweden, and 5% for Canada. RESULTS: Ponatinib yielded more discounted QALYs than any second-generation tyrosine kinase inhibitor/alloHSCT in all three countries, mainly owing to better response rates and longer durations of response. Incremental cost-effectiveness ratios for ponatinib vs. second-generation tyrosine kinase inhibitors were US$21,543-37,755/QALY in Germany, $24,018-38,227/QALY in Sweden, and $43,001-58,515/QALY in Canada. Ponatinib was dominant over alloHSCT in Germany, while incremental cost-effectiveness ratios for ponatinib vs. alloHSCT in Sweden and Canada were $715/QALY and $31,534/QALY, respectively. CONCLUSIONS: Ponatinib may improve outcomes (mainly because of higher response rates and longer response durations) at an acceptable cost level compared with other third-line treatment options for chronic-phase chronic myeloid leukemia in Germany, Sweden, and Canada; however, the lack of an indirect comparison is a limitation of our study.

Results of the European survey on the assessment of deep molecular response in chronic phase CML patients during tyrosine kinase inhibitor therapy (EUREKA registry).

PURPOSE: The advent of tyrosine kinase inhibitor (TKI) therapies has revolutionized the treatment of chronic myeloid leukemia (CML). The European LeukemiaNet (ELN) recommends quantification of BCR-ABL1 transcripts by real-time quantitative PCR every 3 months during TKI treatment. Since a proportion of patients in deep molecular response (DMR: MR4, MR4.5, MR5) maintain remission after treatment stop, assessment of DMR is crucial. However, systematically collected molecular data, monitored with sensitive standardized assays, are not available outside clinical trials. METHODS: Data were collected on the standardized assessment of molecular response in the context of real-life practice. BCR-ABL1 transcript levels after > 2 years of TKI therapy were evaluated for DMR by local laboratories as well as standardized EUTOS laboratories. Since standardized molecular monitoring is a prerequisite for treatment discontinuation, central surveillance of the performance of the participating laboratories was carried out. RESULTS: Between 2014 and 2017, 3377 peripheral blood samples from 1117 CML patients were shipped to 11 standardized reference laboratories in six European countries. BCR-ABL1 transcript types were b3a2 (41.63%), b2a2 (29.99%), b2a2/b3a2 (3.58%) and atypical (0.54%). For 23.72% of the patients, the initial transcript type had not been reported. Response levels (EUTOS laboratory) were: no MMR, n = 197 (6.51%); MMR, n = 496 (16.40%); MR4, n = 685 (22.64%); MR4.5, n = 937 (30.98%); MR5, n = 710 (23.47%). With a Cohen's kappa coefficient of 0.708, a substantial agreement between EUTOS-certified and local laboratories was shown. CONCLUSIONS: Multicenter DMR assessment is feasible in the context of real-life clinical practice in Europe. Information on the BCR-ABL1 transcript type at diagnosis is crucial to accurately monitor patients' molecular response during or after TKI therapy.

The potential health gain and cost savings of improving adherence in chronic myeloid leukemia.

Healthcare costs are rising due to an increase in chronic diseases, including chronic myeloid leukemia (CML) due to improved survival. In CML care, patient adherence and physician adherence are key elements. We assessed the potential health gain and cost savings when both are improved, using a decision analytic model that integrated various sources of evidence. The current situation was compared to a theoretical situation in which either patient or physician adherence is improved, in terms of costs and quality-adjusted life years (QALYs). Current patient adherence rate is 74%, improvement to 100% resulted in 0.1031 QALYs gained and a saving of €17,509 per patient over a 25-year period. Improving physician adherence from 72% to 100%, resulted in 0.0380 QALYs and €7606. Enhancement of either adherence results in substantial health gain and cost savings. Regarding the rising healthcare costs, new strategies should focus on improving adherence to keep healthcare affordable in the future.

First-line therapy for chronic phase CML: selecting the optimal BCR-ABL1-targeted TKI.

Patients diagnosed with chronic myeloid leukemia (CML) and treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs) have long life spans. Selection of an appropriate first-line therapy can be difficult as both the unique characteristics of each TKI and patient need to be taken into account to find the optimal match. Patient characteristics include comorbidities, concomitant medications, lifestyle, risk factors, BCR-ABL1 transcript type (e.g. b2a2 or b3a2) and additional chromosomal abnormalities. Just as patients differ, side effects, drug-drug interactions, administration plans, dosing schedules and treatment-related expenses across TKIs also vary. Alignment of these characteristics with the appropriate TKI is key to successfully initiating CML treatment. Continued success relies on communication between the patient and the healthcare team, adherence and optimization of therapy once it is initiated. In this review, we discuss these factors, in addition to TKI efficacy and safety, the cost of therapy, the future of treating CML and treatment-free remission.

Incidence and management of myelosuppression in patients with chronic- and accelerated-phase chronic myeloid leukemia treated with omacetaxine mepesuccinate.

Omacetaxine mepesuccinate (Synribo) is an inhibitor of protein synthesis indicated for the treatment of patients with chronic- or accelerated-phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors. Myelosuppression is the most common and clinically significant toxicity experienced by patients treated with omacetaxine. Here, we further examine the patterns of hematologic toxicity observed in clinical trials and describe the approach to management as well as resolution of events. Omacetaxine-related myelosuppression typically occurs more frequently during induction cycles. In general, the myelosuppression observed with omacetaxine treatment is manageable and reversible, and long-term administration is feasible. Careful monitoring, dose delays and reduction in administration days, and appropriate supportive care are critical for successful management of hematologic toxicity. Concerns regarding myelosuppression, observed with many cancer treatments, should not prevent eligible patients from receiving omacetaxine, particularly CML patients with unsatisfactory responses to multiple lines of prior treatment.

Practical issues surrounding the explosion of tyrosine kinase inhibitors for the management of chronic myeloid leukemia.

The advent of tyrosine kinase inhibitors (TKIs) has drastically changed the treatment outcome of chronic myeloid leukemia (CML). Imatinib was the first TKI approved, and has been considered the standard of care for more than a decade. Second generation compounds, namely dasatinib and nilotinib, are highly effective in newly diagnosed patients as well as those who fail imatinib. Bosutinib and ponatinib have also become available as second line options. With five agents from which to choose, selecting a TKI has become a challenge. Multiple tests are now available to determine a patient's disease status, making the ideal monitoring strategy unclear. The gold standard for response to TKI therapy remains the achievement of complete cytogenetic response. This review will discuss the practical aspects of selecting a TKI and monitoring a patient once on therapy, including when to consider a treatment change. Other relevant issues, including cost, compliance, role of allogeneic hematopoietic cell transplantation, and discontinuation of TKIs will also be covered.

Cost-utility analysis of dasatinib and nilotinib in patients with chronic myeloid leukemia refractory to first-line treatment with imatinib in Thailand.

BACKGROUND: Recently, the second-generation tyrosine kinase inhibitors dasatinib and nilotinib have emerged as alternative treatments in patients with chronic myeloid leukemia (CML) who are resistant to or intolerant of imatinib. OBJECTIVE: This article aimed to assess the cost utility and budget impact of using dasatinib or nilotinib, rather than high-dose (800-mg/d) imatinib, in patients with chronic phase (CP) CML who are resistant to standard-dose (400-mg/d) imatinib in Thailand. METHODS: A Markov simulation model was developed and used to estimate the lifetime costs and outcomes of treating patients aged ≥38 years with CP-CML. The efficacy parameters were synthesized from a systematic review. Utilities using the European Quality of Life-5 Dimensions tool and costs were obtained from the Thai CML population. Costs and outcomes were compared and presented as the incremental cost-effectiveness ratio in 2011 Thai baht (THB) per quality-adjusted life year (QALY) gained. One-way and probabilistic sensitivity analyses were performed to estimate parameter uncertainty. RESULTS: From a societal perspective, treatment with dasatinib was found to yield more QALYs (2.13) at a lower cost (THB 1,631,331) per person than high-dose imatinib. Nilotinib treatment was also found to be more cost-effective than high-dose imatinib, producing an incremental cost-effectiveness ratio of THB 83,328 per QALY gained. This treatment option also resulted in the highest number of QALYs gained of all of the treatment options. The costs of providing dasatinib, nilotinib, and high-dose imatinib were estimated at THB 5 billion, THB 6 billion, and THB 7 billion, respectively. CONCLUSIONS: Treatment with dasatinib or nilotinib is likely to be more cost-effective than treatment with high-dose imatinib in CP-CML patients who do not respond positively to standard-dose imatinib in the Thai context. Dasatinib was found to be more cost-effective than nilotinib.

Assessment at 6 months may be warranted for patients with chronic myeloid leukemia with no major cytogenetic response at 3 months.

Response to tyrosine kinase inhibitors at three months is a predictor for long-term outcome in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. We analyzed 456 newly diagnosed chronic myeloid leukemia patients treated with tyrosine kinase inhibitors to determine their outcome based on their response at six months. Forty-four (10%) patients did not achieve major cytogenetic response at three months: 18 of 67 (27%) patients treated with imatinib 400; 18 of 196 (9%) with imatinib 800; and 8 of 193 (4%) with 2nd generation tyrosine kinase inhibitors. Among them, 19 (43%) achieved major cytogenetic response at six months and subsequently had an overall outcome similar to the patients who achieved a major cytogenetic response at three months. In conclusion, the response to tyrosine kinase inhibitors at three months is a static, one-time measure. Assessing the response at six months of patients with poor response at three months may provide a better predictor for long-term outcome.

Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid leukaemia: a systematic review and economic evaluation.

BACKGROUND: Chronic myeloid leukaemia (CML) is a form of cancer affecting the blood, characterised by excessive proliferation of white blood cells in the bone marrow and circulating blood. In the UK, an estimated 560 new cases of CML are diagnosed each year. OBJECTIVES: The purpose of this study was to assess the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in the treatment of people with imatinib-resistant (ImR) and imatinib-intolerant (ImI) CML. A systematic review of the clinical effectiveness literature, a review of manufacturer submissions and a critique and exploration of manufacturer submissions for accelerated phase and blast crisis CML were carried out and a decision-analytic model was developed to estimate the cost-effectiveness of dasatinib and nilotinib in chronic phase CML. SYSTEMATIC REVIEW METHODS: Key databases were searched for relevant studies from their inception to June 2009 [MEDLINE (including MEDLINE In-Process & Other Non-Indexed Citations), EMBASE, (ISI Web of Science) Conference Proceedings Citation Index and four others]. One reviewer assessed titles and abstracts of studies identified by the search strategy, with a sample checked by a second reviewer. The full text of relevant papers was obtained and screened against the full inclusion criteria independently by two reviewers. Data from included studies were extracted by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through narrative review. ECONOMIC EVALUATION METHODS: Cost-effectiveness analyses reported in manufacturer submissions to the National Institute of Health and Clinical Excellence were critically appraised and summarised narratively. In addition, the models for accelerated phase and blast crisis underwent a more detailed critique and exploration. Two separate decision-analytic models were developed for chronic phase CML, one simulating a cohort of individuals who have shown or developed resistance to normal dose imatinib and one representing individuals who have been unable to continue imatinib treatment owing to adverse events. One-way, multiway and probabilistic sensitivity analyses were performed to explore structural and parameter uncertainty. RESULTS: Fifteen studies were included in the systematic review. Chronic phase: effectiveness data were limited but dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic response and haematological response in both ImR and ImI populations. In terms of cost-effectiveness, it was extremely difficult to reach any conclusions regarding either agent in the ImR population. All three models (Novartis, PenTAG and Bristol-Myers Squibb) were seriously flawed in one way or another, as a consequence of the paucity of data appropriate to construct robust decision-analytic models. Accelerated and blast crisis: all available data originated from observational single-arm studies and there were considerable and potentially important differences in baseline characteristics which seriously undermined any process for making meaningful comparisons between treatments. Owing to a lack of available clinical data, de novo models of accelerated phase and blast crisis have not been developed. The economic evaluations carried out by the manufacturers of nilotinib and dasatinib were seriously undermined by the absence of evidence on high-dose imatinib in these populations. LIMITATIONS: The study has been necessarily constrained by the paucity of available clinical data, the differences in definitions used in the studies and the subsequent impossibility of undertaking a meaningful cost-effectiveness analyses to inform all policy questions. CONCLUSIONS: Dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic and haematological responses in both ImR and ImI populations. It was difficult to reach any cost-effectiveness conclusions as a consequence of the paucity of the data. Future research should include a three-way, double-blind, randomised clinical trial of dasatinib, nilotinib and high-dose imatinib.

Comprehensive therapeutic outcomes of frontline imatinib mesylate in newly diagnosed chronic phase chronic myeloid leukemia patients in Korea: feasibility assessment of current ELN recommendation.

Optimal responses during imatinib therapy are commonly defined following the European LeukemiaNet (ELN) recommendations. Achievements of these optimal responses have not, however, been comprehensively tested as response-related prognostic factors using single center data sets. We evaluated the parameters using long-term (median 63 months) outcomes from 363 chronic phase chronic myeloid leukemia patients treated with imatinib as frontline therapy at our center. Intention-to-treat analysis showed comparable rates of complete cytogenetic response (86 %), major molecular response (MMR, 54 %), and complete molecular response (MR(4.5), 8 %). Estimated overall survival, progression-free survival, and event-free survival at 7 years were 94, 88 and 84 %, respectively. Achievement of recommended optimal response at 6 months (major cytogenetic response) and 12 months (complete cytogenetic response) yielded significantly better overall, progression-free, and event-free survival. However, achievement of recommended optimal response at 18 months (MMR) provided marginal benefit only in event-free survival. Most ELN criteria were predictive of long-term outcomes, with the exception of the clinical significance of achieving MMR at 18 months. Treatment adherence in the early treatment period was one of the important independent predictors of favorable long-term outcome. Durable cytogenetic and molecular responses were maintained in a majority of patients treated with optimal dose intensity.

Patient adherence to tyrosine kinase inhibitor therapy in chronic myeloid leukemia.

Dramatically improved survival associated with tyrosine kinase inhibitor (TKI) therapy has transformed the disease model for chronic myeloid leukemia (CML) to one of long-term management, but treatment success is challenged with poor medication adherence. Many risk factors associated with poor adherence can be ameliorated by close monitoring, dose modification, and supportive care. Controlling risk factors for poor adherence in combination with patient education that includes direct communication between the health care team and the patient are essential components for maximizing the benefits of TKI therapy.

CML treatment in Asia-Pacific region.

CML in Asia seems to affect the younger age group and more patients are in the high and intermediate Sokal risk group. Cytogenetic study and molecular testing are done mostly at diagnosis, but monitoring the response is limited due to the cost and accessibility. The treatment of chronic phase CML has changed dramatically within the last decade and imatinib has become the standard treatment for CP, CML. Since the cost of imatinib is quite high, most Asian patients cannot afford it. Patients in several countries get imatinib through Glivec International Patient Assistant Program. Patients who are intolerant or resistant to imatinib usually get the second generation tyrosine kinase inhibitors (TKIs), either nilotinib or dasatinib. The National Health Insurance covers all or most of the cost of imatinib in South Korea, Hong Kong and Taiwan. Both nilotinib and dasatinib are partially or fully covered by national insurance in Australia, Japan, Singapore and Taiwan as the second-line therapy. TKIs treatment remains out of reach for many Asian CML patients, especially those in the rural areas and those who are not eligible for patient access programs or covered by the national insurance. The cytogenetic response to imatinib in Asian CML patients varies considerably, from as low as 24% to as high as 96%. The Asia CML Study Alliance was briefly presented.

Utility values for chronic myelogenous leukemia chronic phase health states from the general public in the United Kingdom.

This study estimated time trade-off preference values associated with the four chronic myelogenous leukemia (CML) chronic phase-related health states (i.e. untreated, hematologic response, cytogenetic response and molecular response) among members of the general public in the UK (n = 241). All four health states were associated with decreases in preference values from full health. The molecular response to treatment was the most preferred health state (mean utility of 0.94). The second-most preferred health state was cytogenetic response followed by hematologic response (mean utilities were 0.89 and 0.80, respectively). The least preferred health state was untreated chronic phase CML (mean utility of 0.72). The utility values for each state were significantly different from one another (p < 0.001). This study demonstrated and quantified the impact that more robust treatment responses have on the health-related quality of life of patients with chronic phase CML.

Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors.

PURPOSE: We studied BCR-ABL1 transcript levels in patients with chronic myeloid leukemia in chronic phase (CML-CP) at 3, 6, and 12 months after starting imatinib to identify molecular milestones that would predict for overall survival (OS) and other outcomes more reliably than serial marrow cytogenetics. PATIENTS AND METHODS: We analyzed 282 patients with CML-CP who received imatinib 400 mg/d as first-line therapy followed by dasatinib or nilotinib if treatment with imatinib failed. We used a receiver operating characteristic curve to identify the cutoffs in transcript levels at 3, 6, and 12 months that would best predict patient outcome. We validated our findings in an independent cohort of 95 patients treated elsewhere. RESULTS: Patients with transcript levels of more than 9.84% (n = 68) at 3 months had significantly lower 8-year probabilities of OS (56.9% v 93.3%; P < .001), progression-free survival, cumulative incidence of complete cytogenetic response, and complete molecular response than those with higher transcript levels. Similarly, transcript levels of more than 1.67% (n = 87) at 6 months and more than 0.53% (n = 93) at 12 months identified high-risk patients. However, transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (relative risk, 0.207; P < .001 and relative risk, 0.158; P < .001, respectively). CONCLUSION: A single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.

Cost-effectiveness of dasatinib and nilotinib for imatinib-resistant or -intolerant chronic phase chronic myeloid leukemia.

OBJECTIVES: To estimate the cost-effectiveness of dasatinib and nilotinib compared with high-dose imatinib for people with chronic phase chronic myeloid leukemia, which are resistant to normal-dose imatinib and compared with interferon-α for people intolerant to imatinib, from the perspective of the UK National Health Service. METHODS: An an area under the curve partitioned survival model was developed to estimate the cost-effectiveness of dasatinib and nilotinib. Clinical effectiveness evidence was taken mostly from single-arm trials. RESULTS: Both progression-free survival and overall survival are highly uncertain. In the base case, patients take nilotinib for much less time than dasatinib. Nilotinib is expected to dominate high-dose imatinib, yielding slightly more (0.32) quality-adjusted life years (QALYs) at slightly less cost (£11,100 [pound sterling]) per person. Dasatinib is predicted to provide slightly more (0.53) QALYs at substantially greater cost (£48,900), yielding a very high incremental cost-effectiveness ratio of £91,500 QALY against high-dose imatinib. Cost-effectiveness, however, changes radically under the plausible assumption that the drugs are taken for the same time. For people intolerant to imatinib, nilotinib is expected to yield an incremental cost-effectiveness ratio of £104,700/QALY, and dasatinib £82,600/QALY compared with interferon-α. Further, both drugs represent poor value for money for a range of plausible structural assumptions. CONCLUSIONS: The model should be viewed as an exploratory analysis of the cost-effectiveness of dasatinib and nilotinib because it relies on many assumptions. Whilst clinical data remains immature, the cost-effectiveness of dasatinib and nilotinib for imatinib-resistant people is highly uncertain. Both nilotinib and dasatinib are highly unlikely to be cost-effective versus interferon-α for people intolerant to imatinib.