Cost-effectiveness analysis of imatinib versus dasatinib in the treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia when combined with conventional chemotherapy in China.

BACKGROUND: Tyrosine kinase inhibitors combined with conventional chemotherapy (CC) in treating Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) has achieved promising efficacy and safety outcomes. The study was conducted to compare the cost-effectiveness between imatinib (HANSOH Pharma, Jiangsu, China) and dasatinib (CHIATAI TIANQING Pharma, Jiangsu, China) in treating pediatric Ph-positive ALL when combined with CC from the perspective of the health system in China. METHODS: A Markov model was established to simulate a hypothetical cohort of pediatric Ph-positive ALL patients receiving imatinib or dasatinib, combined with CC. The model was designed using a 10-year horizon, a 3- month cycle, and a 5% discount rate. Three health states were included: alive with progression-free survival, progressed disease, and death. Patient characteristics and transition probabilities were estimated based on clinical trials. Other relevant data, such as direct treatment costs and health utility data were extracted from published literature and Sichuan Province's centralized procurement and supervision platform. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the results. The willingness-to-pay (WTP) was set as three times China's GDP per capita in 2021. RESULTS: In the base-case analysis, the total medical costs were $89,701 and $101,182, and the quality-adjusted life years (QALYs) gained were 1.99 and 2.70, for imatinib and dasatinib regimens, respectively. The incremental cost-effectiveness ratio for dasatinib versus imatinib was $16,170/QALY. The probabilistic sensitivity analysis indicated that treatment with dasatinib combined with CC achieved a 96.4% probability of cost-effectiveness at a WTP threshold of $37,765/QALY. CONCLUSIONS: Dasatinib combined with CC is likely to be a cost-effective strategy compared to imatinib combination therapy for pediatric Ph-positive ALL in China at a WTP threshold of $37,765/QALY.

The Economic Burden of Chronic Myeloid Leukemia in Patients with Later Lines: Findings from a Real-World Analysis in Italy.

INTRODUCTION: Chronic myeloid leukemia (CML) is a hematopoietic myeloproliferative disorder that accounts for 20% of all leukemias of adults. The introduction of tyrosine kinase inhibitors (TKIs) (imatinib, bosutinib, dasatinib, nilotinib, ponatinib) has yielded significant benefits for patients with CML in terms of survival and quality of life. This real-world analysis evaluated the economic burden for managing patients with CML in 2nd or ≥ 3rd TKI lines in Italian settings of clinical practice. METHODS: A retrospective observational analysis was performed exploiting the administrative databases of a sample of entities covering around 15 million inhabitants. From 2015 to 2018, the study included adult patients with at least one prescription for TKIs, (and for some TKI with at least one hospitalization discharge diagnosis for CML, or at least one prescription for BCR-ABL examination). The index date was the first TKI prescription. Healthcare resource consumption and costs for patients with CML in 2nd and ≥ 3rd line treatment with TKIs were analyzed for drug prescriptions, hospitalizations, specialist visits, and diagnostic services. RESULTS: In total 635 patients were included, 491 in 2nd line and 144 in 3rd line with TKIs. Dasatinib was the most frequently prescribed drug in 2nd line (28.9%) and imatinib in later lines (26.4%). With progressing lines of treatment, healthcare consumption showed a trend towards increased non-TKI prescriptions per patient (8 for 2nd line and 9.7 for ≥ 3rd line). The management of patients with CML in later lines resulted in increased overall healthcare burden, with hospitalizations accounting for about half of total expenditure, whatever the treatment line and type of TKI. CONCLUSIONS: This analysis in Italian real-life clinical practice reported economic expenditure for patients with CML in 2nd or ≥ 3rd lines with TKIs, mostly burdened by hospitalizations. Such clinical complexity suggests that further efforts are needed to improve the therapeutic management of later lines of CML.

Cost-effectiveness analysis of dasatinib versus imatinib in pediatric philadelphia chromosome-positive acute lymphoblastic leukemia patients in China.

BACKGROUND: Dasatinib and imatinib are the recommended tyrosine kinase inhibitors (TKIs) for treating pediatric Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL), and the one which has been approved indication in China is imatinib. Recently, clinical demand for Ph + ALL treatment is becoming unmet gradually with the increasing resistance of imatinib. There are some studies reporting the better efficacy and comparative safety of dasatinib compared with imatinib, but no economic comparison has been published. This study aims to supplement economic evidence by comparing the cost-effectiveness between imatinib and dasatinib in treating pediatric patients with Ph+ ALL in China, and to help clinical rational drug use via multi-dimensional value assessment. METHODS: A decision tree model combined with a 10-year Markov model were established based on the disease progression. The parameters were collected from published literatures and our hospital's electronic medical records. From the health system perspective, the incremental cost-effectiveness ratio (ICER) between the two treatment groups was calculated through cost-effectiveness analysis and then compared with the willingness-to-pay (WTP) threshold. The set WTP threshold in this study was 1 times per capita gross domestic product (GDP) of China, as recommended by the World Health Organization. Direct medical costs and quality-adjusted life years (QALYs) were calculated and discounted at 5%. The sensitivity analyses were conducted to assess the uncertainty and robustness of the results. RESULTS: The total costs were CNY 1,020,995.35 and CNY 1,035,788.50 in imatinib group and dasatinib group during the 10-year simulation, and the total QALYs were 2.59 and 4.84. Compared with the imatinib treatment group, the ICER was around CNY 6,575.78/ QALY, which was less than the set threshold CNY 70,892/ QALY. The sensitive analyses indicated the robustness of the results. CONCLUSIONS: The cost-effectiveness analysis shows the potential cost-effective advantages of adding dasatinib comparing with adding imatinib for pediatric Ph + ALL patients in China under the set WTP threshold, which indicates that those patients could achieve more QALYs by paying acceptable fee.

Inequality in Drug Utilization among Chronic Myeloid Leukaemia Patients in Malaysia: A Cost-Utility Analysis.

BACKGROUND: The burden of chronic myeloid leukaemia (CML) is increasing due to longer patient survival, better life expectancy of the general population, and increasing drug prices. Funding is one of the main concerns in the choice of CML medication used worldwide; thus, patient assistance programmes were introduced to ensure accessibility to affordable treatment. In this study, we evaluated CML drug distribution inequality in Malaysia through patient assistance programmes, using pharmaco-economics methods to evaluate CML treatment from the care provider's perspective. METHODS: Patients with CML were recruited from outpatient haematological clinics at the national centre of intervention and referral for haematological conditions and a public teaching hospital. The health-related quality of life or utility scores were derived using the EuroQol EQ-5D-5L questionnaire. Costing data were obtained from the Ministry of Health Malaysia Casemix MalaysianDRG. Imatinib and nilotinib drug costs were obtained from the administration of the participating hospitals and pharmaceutical company. RESULTS: Of the 221 respondents in this study, 68.8% were imatinib users. The total care provider cost for CML treatment was USD23,014.40 for imatinib and USD43,442.69 for nilotinib. The governmental financial assistance programme reduced the total care provider cost to USD13,693.51 for imatinib and USD19,193.45 for nilotinib. The quality-adjusted life years (QALYs) were 17.87 and 20.91 per imatinib and nilotinib user, respectively. Nilotinib had a higher drug cost than imatinib, yet its users had better life expectancy, utility score, and QALYs. Imatinib yielded the lowest cost per QALYs at USD766.29. CONCLUSION: Overall, imatinib is more cost-effective than nilotinib for treating CML in Malaysia from the care provider's perspective. The findings demonstrate the importance of cancer drug funding assistance for ensuring that the appropriate treatments are accessible and affordable and that patients with cancer use and benefit from such patient assistance programmes. To establish effective health expenditure, drug distribution inequality should be addressed.

A Systematic Literature Review of the Economic Evaluations of Treatments for Patients with Chronic Myeloid Leukemia.

BACKGROUND AND OBJECTIVES: The management of chronic myeloid leukemia is associated with an extensive economic burden, and as novel interventions are being tested in this disease, understanding the comparative effectiveness is of interest. Findings and conclusions of this important issue continue to evolve with improvements in clinical research and economic understanding. This systematic literature review aims to conduct a comprehensive assessment of economic evaluations in chronic phase chronic myeloid leukemia. METHODS: Embase®, MEDLINE®, and the National Health Service Economic Evaluation Database were searched on 4 July, 2022 to identify economic evaluations of chronic myeloid leukemia. Health technology assessment websites and key conference proceedings were also searched. Economic evaluations comparing treatment options in adult patients with chronic phase chronic myeloid leukemia were included. The quality of the studies were assessed using Drummond's checklists. RESULTS: The search retrieved 47 studies and 16 health technology assessments that fulfilled the eligibility criteria. Most were cost-utility analyses (23 studies and 11 health technology assessments) and were from the USA (n = 15) and China (n = 7). Twenty-seven studies and six health technology assessments included only patients with chronic phase chronic myeloid leukemia. Most models had a Markov structure, a 1 year to lifetime time horizon, and a 1-month cycle length. Commonly assessed treatments were various tyrosine kinase inhibitors (imatinib, nilotinib, dasatinib, bosutinib, and ponatinib) and other interventions such as interferon-α, hydroxyurea, and allogeneic stem cell transplant. CONCLUSIONS: In patients with newly diagnosed chronic myeloid leukemia, imatinib regimens were cost effective, mostly owing to the availability of generics. Nilotinib and dasatinib were generally cost effective as second-line agents for patients who were resistant or intolerant to imatinib. Though progress has been made to better characterize the cost effectiveness of first-line and second-line chronic myeloid leukemia therapies, the paucity of published cost-effectiveness studies of third-line treatments increases the uncertainty associated with economic evaluations of later lines of therapy.

Ex vivo assessment of cancer drug sensitivity in epithelial ovarian cancer and its association with histopathological type, treatment history and clinical outcome.

Epithelial ovarian cancer (EOC) is divided into type I and type II based on histopathological features. Type I is clinically more indolent, but also less sensitive to chemotherapy, compared with type II. The basis for this difference is not fully clarified. The present study investigated the pattern of drug activity in type I and type II EOC for standard cytotoxic drugs and recently introduced tyrosine kinase inhibitors (TKIs), and assessed the association with treatment history and clinical outcome. Isolated EOC tumor cells obtained at surgery were investigated for their sensitivity to seven standard cytotoxic drugs and nine TKIs using a short­term fluorescent microculture cytotoxicity assay (FMCA). Drug activity was compared with respect to EOC subtype, preoperative chemotherapy, cross­resistance and association with progression­free survival (PFS). Out of 128 EOC samples, 120 samples, including 21 type I and 99 type II, were successfully analyzed using FMCA. Patients with EOC type I had a significantly longer PFS time than patients with EOC type II (P=0.01). In line with clinical experience, EOC type I samples were generally more resistant than type II samples to both standard cytotoxic drugs and the TKIs, reaching statistical significance for cisplatin (P=0.03) and dasatinib (P=0.002). A similar pattern was noted in samples from patients treated with chemotherapy prior to surgery compared with treatment­naive samples, reaching statistical significance for fluorouracil, irinotecan, dasatinib and nintedanib (all P<0.05). PFS time gradually shortened with increasing degree of drug resistance. Cross­resistance between drugs was in most cases statistically significant yet moderate in degree (r<0.5). The clinically observed relative drug resistance of EOC type I, as well as in patients previously treated, is at least partly due to mechanisms in the tumor cells. These mechanisms seemingly also encompass kinase inhibitors. Ex vivo assessment of drug activity is suggested to have a role in the optimization of drug therapy in EOC.

Experimental and computational assessment of the synergistic pharmacodynamic drug-drug interactions of a triple combination therapy in refractory HER2-positive breast cancer cells.

The development of innate and/or acquired resistance to human epidermal growth factor receptor type-2 (HER2)-targeted therapy in HER2-positive breast cancer (HER2 + BC) is a major clinical challenge that needs to be addressed. One of the main mechanisms of resistance includes aberrant activation of the HER2 and phosphatidylinositol 3-kinase/AKT8 virus oncogene cellular homolog/mammalian target of rapamycin (PI3K/Akt/mTOR) pathways. In the present work, we propose to use a triple combination therapy to combat this resistance phenomenon. Our strategy involves evaluation of two targeted small molecule agents, everolimus and dasatinib, with complementary inhibitory circuitries in the PI3K/Akt/mTOR pathway, along with a standard cytotoxic agent, paclitaxel. Everolimus inhibits mTOR, while dasatinib inhibits Src, which is a protein upstream of Akt. An over-activation of these two proteins has been implicated in approximately 50% of HER2 + BC cases. Hence, we hypothesize that their simultaneous inhibition may lead to enhanced cell-growth inhibition. Moreover, the potent apoptotic effects of paclitaxel may help augment the overall cytotoxicity of the proposed triple combination in HER2 + BC cells. To this end, we investigated experimentally and assessed computationally the in vitro pharmacodynamic drug-drug interactions of the various dual and triple combinations to assess their subsequent combinatorial effects (synergistic/additive/antagonistic) in a HER2-therapy resistant BC cell line, JIMT-1. Our proposed triple combination therapy demonstrated synergism in JIMT-1 cells, thus corroborating our hypothesis. This effort may form the basis for further investigation of the triple combination therapy in vivo at a mechanistic level in HER2-therapy resistant BC cells.

Eficacia y seguridad de dasatinib en pacientes adultos con leucemia linfoblástica aguda philadelphia positivo resistente o intolerante a quimioterapia más imatinib / Efficacy and safety of dasatinib in adult patients with philadelphia-positive acute lymphoblastic leukemia resistant or intolerant to chemotherapy plus imatinib

ANTECEDENTES : El presente dictamen expone la evaluación de la eficacia y seguridad de dasatinib con o sin quimioterapia, comparado con quimioterapia, en pacientes adultos con leucemia linfoblástica aguda, philadelphia positivo, resistente o intolerante a quimioterapia más imatinib. En la literatura se señala que, la leucemia linfoblástica aguda (LLA) cromosoma Philadelphia positivo (Ph+) representa entre el 20.0 al 30 % de los casos de LLA. En el Perú, no se conoce el número de casos de LLA Ph+; sin embargo, se conoce que, en el 2019, la tasa de incidencia de LLA en personas mayores de 20 años fue de 1.04 casos por cada 100,000 personas y la tasa de mortalidad fue de 0.79 muertes por cada 100,000 personas.  Luego de la terapia de inducción con un inhibidor de la tirosina quinasa (TKI, por sus siglas en inglés), entre el 10 y 20 % de los pacientes desarrolla LLA resistente. Debido a la aparición de casos de resistencia o intolerancia a los TKI de primera generación (imatinib), se han desarrollado otros TKI, como dasatinib. En EsSalud, se cuentan con varias opciones de medicamentos que pueden ser empleados en diferentes esquemas de quimioterapia en este grupo de pacientes con resistencia o intolerancia a TKI. Actualmente, dasatinib se encuentra disponible en EsSalud para el tratamiento de pacientes con leucemia mieloide crónica (LMC), Ph+ resistente o intolerante a tratamientos previos a dosis altas a imatinib y sin mutación T315l. No obstante, algunos especialistas de EsSalud solicitan que se amplíe el uso de dasatinib a pacientes adultos con LLA Ph+ resistente o intolerante, aduciendo que dasatinib (con o sin quimioterapia) podría mejorar la sobrevida libre de progresión (SLP) del paciente. Así, el presente dictamen preliminar expone la evaluación de la eficacia y seguridad de dasatinib, con o sin quimioterapia, en pacientes adultos con LLA Ph+ resistente o intolerante a quimioterapia más imatinib. METODOLOGÍA: Tras la búsqueda de la literatura científica, se identificaron dos guías de práctica clínicas (GPC) elaboradas por The National Comprehensive Cancer Network (NCCN) y The European Society for Medical Oncology (ESMO), y dos evaluaciones de tecnologías sanitarias (ETS) elaboradas por The Scottish Medicines Consortium (SMC) y Comissão Nacional de Incorporação de Tecnologías no Sistema Único de Saúde (CONITEC). Además, se encontraron dos estudios de fase II; sin grupo de comparación, el estudio START-L (Ottman et al., 2007), empleado para sustentar la aprobación acelerada de uso de dasatinib por parte de la Food and Drug Administration (FDA) y la aprobación de la European Medicines Agency (EMA) en pacientes con LLA Ph+ y resistencia o intolerancia a una terapia previa, y el estudio de Sakamaki et al., 2009. RESULTADOS: Se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: En el presente documento, se evaluó la mejor evidencia científica disponible hasta la actualidad, sobre la eficacia y seguridad de dasatinib con o sin quimioterapia, comparado con quimioterapia, en pacientes adultos con LLA Ph+y resistencia o intolerancia a la quimioterapia más imatinib. La búsqueda sistemática de la evidencia culminó con la selección de dos GPC (NCCN 2021; Hoelzer et al. 2016), dos ETS (CONITEC 2020; SMC 2007), el estudio de fase II START-L, pivotal de dasatinib (Ottmann et al. 2007), y el estudio de fase II de Sakamaki et al. (Sakamaki et al. 2009). Las GPC del NCCN y ESMO coinciden en señalar que la evidencia disponible sobre el uso de dasatinib para el tratamiento de los pacientes con LLA Ph+ y resistencia o recaída no es de calidad. Por ello, la ESMO resalta que no hay una terapia estándar de reinducción y el NCCN recomienda, especialmente, la participación en un ensayo clínico. Las ETS del SMC y del CONITEC coinciden en dar una recomendación en contra del uso de dasatinib en pacientes con LLA Ph+ con resistencia/recaída a una terapia previa o al mesilato de imatinib. La SMC basó en que la terapia con dasatinib no sería costo-efectiva en este grupo de pacientes; y la CONITEC, en la alta incidencia de EAS, y las altas tasas de abandono del tratamiento y de reducción de dosis observadas en la evidencia analizada. Los estudios START-L y de Sakamaki et al., de fase II, presentaron limitaciones (e.g. falta de un grupo de comparación, pequeño tamaño de la muestra y la falta de acceso al protocolo del estudio) que afectan la validez de sus resultados. Aun así, sus resultados sugieren que el perfil de seguridad de dasatinib no puede ser considerado como favorable para los pacientes (altas tasas de eventos adversos, reducción de dosis de dasatinib y descontinuación del tratamiento). Actualmente, en EsSalud, se cuentan con varias opciones de medicamentos que pueden ser empleados en diferentes esquemas de quimioterapia para pacientes con LLA Ph+ resistente o intolerante a quimioterapia más imatinib. Por lo expuesto, el IETSI no aprueba el uso de dasatinib con o sin quimioterapia en pacientes adultos con LLA Ph+ resistente o intolerante a quimioterapia más imatinib.

Assessment of Dasatinib Versus Nilotinib as Upfront Therapy for Chronic Phase of Chronic Myeloid Leukemia in Qatar: A Cost-Effectiveness Analysis.

BACKGROUND: The economic outcome research of approved tyrosine kinase inhibitors for treating the chronic phase of chronic myeloid leukemia in developing is scarce. The aim of this study was to assess the cost-effectiveness of dasatinib and nilotinib for newly diagnosed chronic myeloid leukemia patients. METHODS: A decision tree model was developed linking clinical effectiveness (defined as major molecular response) and/or complete cytogenetic response, utility, and cost data over a 12-month period. Patients are recruited from Qatar Cancer Registry. The probability of primary clinical outcome is calculated from DASISION (dasatinib) and ENESTnd (nilotinib) trials. Direct healthcare costs were derived from the national healthcare payer system, whereas adverse effects data were derived from local incident reporting system. RESULTS: In the first-line treatments of chronic myeloid leukemia patients, nilotinib has greater major molecular response (39% nilotinib vs 12% dasatinib) and complete cytogenetic response (24% nilotinib vs 16% dastinib) response outcomes, and more adverse effects than dasatinib (13.3% vs 4%). Moreover, nilotinib is more cost-effective with annual costs (USD63,589.59) and after 12 months of follow-up. Despite the lower acquisition annual cost of dasatinib (USD59,486.30), the incremental cost-effectiveness ratio of nilotinib (vs dasatinib) per major molecular response/complete cytogenetic response achieved was USD15,481.10 per year. There were no cases in both arms that progressed to accelerated or blast phase. At a threshold of 3 times gross domestic product per capita of Qatar and according to World Health Organization recommendation, the nilotinib use is still cost-effective. CONCLUSION: Upfront therapy of chronic myeloid leukemia-chronic phase patients by nilotinib plan appears to be more cost-effective than dasatinib.

Dasatinibe para adultos com leucemia linfoblástica aguda cromossomo Philadelphia positivo resistentes/Intolerantes ao mesilato de imatinibe / Dasatinib for Adults with Acute Lymphoblastic Leukemia Philadelphia Chromosome Positive Resistant/Intolerant to Imatinib Mesylate

INTRODUÇÃO: A leucemia linfoblástica aguda (LLA) é uma doença hematológica altamente agressiva, resultante da proliferação e expansão de explosões linfoides no sangue, medula óssea e outros órgãos. A LLA ocorre com uma distribuição bimodal, com um pico precoce nas crianças de 4 a 5 anos, seguido de um segundo pico aos 50 anos de idade, sendo que a incidência mundial é cerca de 1 a 4,75 / 100.000 indivíduos. A proporção entre homens e mulheres é de aproximadamente 1,3:1. A LLA cromossomo Filadélfia positivo (LLA Ph+) é uma variante biologicamente distinta de LLA, classificada pela Organização Mundial da Saúde como LLA com t (9; 22) (q34; q11.2); BCR-ABL1. A LLA Ph+ representa cerca de 20 a 30% das LLA em adultos, e 2 a 3% das LLA em crianças. Quando tratados com quimioterapia isoladamente, os pacientes com LLA Ph+ apresentam um prognóstico ruim com poucos sobreviventes aos cinco anos após o tratamento. O transplante de células hematopoiéticas alogênicas (allo-TMO) proporciona melhores resultados, curando aproximadamente 30 a 60 % dos pacientes com LLA Ph+. A utilização de inibidores da tirosina quinase (ITQ) do BCR-ABL1 (imatinibe, dasatinibe, nilotinibe) no regime de tratamento resultou em taxas de resposta superiores, permitindo assim que mais pacientes procedam ao allo-TMO. No entanto, os pacientes podem adquirir resistência ou intolerância ao tratamento com ITQ, principalmente com mesilato de imatinibe. PERGUNTA: Qual a eficácia (resposta hematológica, reposta citogenética, sobrevida) e a segurança (eventos adversos, toxicidade) do dasatinibe como tratamento de segunda linha em pacientes adultos com LLA Ph+ resistentes ou intolerantes ao mesilato de imatinibe? TECNOLOGIA: dasatinibe (Sprycel). EVIDÊNCIAS CLÍNICAS: Foram avaliados três estudos, sendo um ensaio clínico randomizado de fase III e dois estudo de fase 1/2. Dasatinibe 140 mg uma vez ao dia proporcionou uma sobrevida global mediana (IC95%) de 6,5 (4,6-9,8) meses, e dasatinibe 70 mg duas vezes ao dia proporcionou uma sobrevida de 9,1 (4,8-13,2) meses. A diferença entre os grupos foi não significativa ­ HR: 1,26 (IC95% 0,78-2,04). Houve uma sobrevida livre de progressão mediana (IC95%) de 4,0 (2,9-5,6) meses com o uso de dasatinibe 140 mg uma vez ao dia, e de 3,0 (2,0-4,2) meses com o uso de dasatinibe 70 mg duas vezes ao dia. Esse resultado confere ausência de diferença significante entre os grupos avaliados (0,92; IC95%: 0,58-1,47). Mais de 30% dos indivíduos, independente do estudo em questão, atingiram resposta hematológica principal (MaHR). Em geral, os indivíduos levaram pouco mais de um mês para atingir a MaHR. A resposta hematológica completa (CHR) foi alcançada por 33% dos pacientes que receberam dasatinibe 140 mg/1x dia, e por 25% dos participantes que receberam dasatinibe 70 mg 2x ao dia. A taxa de ausência de leucemia foi variável a depender do estudo (5 a 41%). Resposta citogenética principal (MCyR) foi alcançada por mais de 50% dos indivíduos avaliados, independentemente do estudo em questão. Os eventos adversos de graus 3 ou 4 mais frequentes foram os hematológicos: anemia, leucopenia, trombocitopenia e neutropenia. Conforme avaliação pela abordagem GRADE, a qualidade da evidência foi muito baixa para todos os desfechos avaliados, devido ao grave risco de viés dos estudos individuais e a pequena amostra, o que conferiu baixa precisão nas estimativas. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Foi elaborado uma análise de impacto orçamentário para estimar os gastos decorrentes da incorporação do dasatinibe no SUS em um horizonte temporal de cinco anos (2021 a 2025). Considerando a população aferida por demanda de quimioterapia de primeira linha para LLA no DATASUS, o impacto orçamentário variou de R$ 7.632.203,49 a R$ 82.217.665,35, a depender da taxa de difusão e fonte de valor de custo (Banco de Preços em Saúde ­ BPS/Sistema Integrado de Administração de Serviços Gerais ­ SIASG ou Câmara de regulação do mercado de Medicamentos ­ CMED). Considerando população estimada com dados epidemiológicos, o impacto orçamentário variou de R$ 4.647.425,94 a R$ 49.310.733,59, a depender da taxa de difusão e fonte de valor de custo (BPS/SIASG e CMED). MONITORAMENTO DO HORIZONTE TECNOLÓGICO (MHT): Os medicamentos flumatinibe (fase 3), inotuzumabe ozogamicin (fase 4) e ponatinibe (fase 3) foram detectados no MHT para pacientes adultos com LLA Ph+ resistentes/intolerantes ao mesilato de imatinibe. CONSIDERAÇÕES FINAIS: As evidências apresentadas mostram que o dasatinibe proporciona boa resposta hematológica e citogenética, podendo apresentar uma mediana de sobrevida global de até 9 meses, em pacientes com LLA Ph+ e resistentes ao mesilato de imatinibe. No entanto, os eventos adversos graves não são raros e os principais são de origem hematológica (leucopenia, neutropenia, anemia, trombocitopenia). Também não foram raros os eventos de interrupção de tratamento ou de redução de dose. Os estudos são pequenos, com baixo rigor metodológico (elevado risco de viés) e não são comparativos. Ademais, a qualidade da evidência foi avaliada como muito baixa para a totalidade dos desfechos, devido ao grave risco de viés e pequena amostra dos estudos individuais, o que conferiu baixa precisão na estimativa dos desfechos, conforme avaliado pela abordagem GRADE. Levando em conta o número de pacientes elegíveis ao tratamento (313 a 522 pacientes a depender do cenário), após a resistência/intolerância ao mesilato de imatinibe, o incremento orçamentário para a ampliação do uso de dasatinibe pode variar entre R$ 20.921.668,18 e R$ 98.479.559,89 em um horizonte temporal de cinco anos (2021-2025). RECOMENDAÇÃO PRELIMINAR DA CONITEC: A Conitec, em sua 91ª reunião ordinária, realizada no dia 07 de outubro de 2020, deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar não favorável à ampliação de uso no SUS do dasatinibe para adultos com leucemia linfoblástica aguda cromossomo Philadelphia positivo resistentes/intolerantes ao mesilato de imatinibe. Considerou-se, entre outrosfatores, que, os estudos apresentados são de baixa qualidade e não possuem comparador, pois são estudos de doses. Além disso, a maioria das agências internacionais não recomendaram a incorporação do medicamento. CONSULTA PÚBLICA: A maioria das contribuições foram de desacordo com a recomendação inicial da Conitec. A ideia central das contribuições é favorável à incorporação do dasatinibe de forma que os pacientes tenham resposta adequada a terapia com ITQ para, então, serem encaminhados ao transplante. A sociedade se manifesta descontente com relação à percebida falta de assistência aos pacientes com LLA Ph+ intolerantes ou com resistência ao imatinibe, em caso de recomendação contrária à incorporação do dasatinibe para esta indicação. RECOMENDAÇÃO FINAL: Os membros da Conitec presentes na 93ª reunião ordinária, no dia 08 de dezembro de 2020, deliberaram por unanimidade recomendar a não ampliação de uso do dasatinibe em adultos com leucemia linfoblástica aguda cromossomo Philadelphia positivo resistentes/intolerantes ao mesilato de imatinibe. Os membros presentes entenderam que não houve mudança no direcionamento da evidência clínica que justificasse uma alteração entre a recomendação preliminar e a recomendação final. Foi assinado o Registro de Deliberação nº 579/2020. DECISÃO: Não ampliar o uso do dasatinibe em adultos com leucemia linfoblástica aguda cromossomo Philadelphia positivo resistentes/intolerantes ao mesilato de imatinibe, no âmbito do Sistema Único de Saúde - SUS, conforme Portaria nº 67, publicada no Diário Oficial da União nº 250, seção 1, página 770, em 31 de dezembro de 2020.

Cost-Effectiveness of First-Line Tyrosine Kinase Inhibitor Therapy Initiation Strategies for Chronic Myeloid Leukemia.

OBJECTIVES: Overall survival in chronic myeloid leukemia (CML) in chronic phase is not significantly different by treatment with first-line tyrosine kinase inhibitors (TKIs), but emerging evidence reveals differences in costs and safety profiles. We evaluated the 1-year cost-effectiveness of TKI initiation with imatinib, dasatinib, or nilotinib among a hypothetical cohort of incident patients with CML from a US payer's perspective. METHODS: We constructed a decision analytic model to assess quality-adjusted life years (QALYs), healthcare costs, net monetary benefit, and incremental cost-effectiveness of treatment strategies. We used published studies and data from the IBM Watson Health MarketScan database for model parameters. To calculate TKI costs, we used the 2018 Federal Supply Schedule estimates for generic imatinib and branded second-generation TKIs. We evaluated cost-effectiveness under various willingness-to-pay thresholds. We accounted for uncertainty with deterministic and probabilistic sensitivity analyses. RESULTS: In the base-case analysis, imatinib was favored over dasatinib and nilotinib at a lower cost per QALY gained. Imatinib remained the favored strategy after 1-way variations in TKI costs, TKI switching, QALYs, adverse event risk, and CML progression. When we assessed model uncertainty with prespecified parameter distributions, imatinib was cost-saving compared with dasatinib in 40% of 100 0000 simulations and was favored over all simulations compared with nilotinib. First-line treatment with second-generation TKIs was cost-effective in 50% of simulations at a $200 000/QALY willingness-to-pay threshold. CONCLUSIONS: Generic availability of imatinib provides a more cost-effective treatment approach in the first year compared with other available TKIs for newly diagnosed patients with CML.

Tyrosine Kinase Inhibitors and the Relationship With Adherence, Costs, and Health Care Utilization in Commercially Insured Patients With Newly Diagnosed Chronic Myeloid Leukemia: A Retrospective Claims-Based Study.

OBJECTIVE: To examine the association among tyrosine kinase inhibitor (TKI) out-of-pocket costs, adherence, and health care costs and utilization in a large group of commercially insured patients with chronic myeloid leukemia (CML). MATERIALS AND METHODS: Patients with CML aged 18 to 64 years were identified using IBM MarketScan Commercial Database between April 1, 2011 and December 31, 2014. Patients were required to be continuously enrolled 3 months before and 12 months after TKI (imatinib, dasatinib, or nilotinib) initiation. TKI adherence is estimated using the proportion of days covered (PDC), defined as the percentage of the PDC by the prescription fill during the 12-month study period (adherent patients have PDC ≥80%). Health care cost differences between adherent and nonadherent patients were estimated using generalized linear models. Health care utilization was compared using negative binomial regression models. All models were controlled for potential confounding factors. RESULTS: The study sample consisted of 863 patients, where 355 (41.1%) patients were classified as adherent. Over the study period, nonadherent patients incurred US$10,974 more in medical costs (P<0.001), and US$1663 more in non-TKI pharmacy costs (P<0.01). Adherent patients incurred US$28,184 more in TKI pharmacy costs (P<0.001) that resulted in US$18,305 more in overall total health care costs (P<0.001). Adherent patients, however, were estimated to be less likely to have all-cause hospitalizations (incidence rate ratio, 0.32; P<0.001), or CML-specific hospitalizations (incidence rate ratio, 0.31; P<0.01). CONCLUSIONS: Patients with CML with better adherence experienced fewer hospitalizations, resulting in medical service cost savings. These lower medical costs, however, were more than offset by higher TKI medication costs observed during the first year of TKI therapy.

Paediatric chronic myeloid leukaemia: Is it really a different disease?

Paediatric chronic myeloid leukaemia (CML) has biological and clinical differences from adult CML. Management of paediatric CML presents unique challenges in growing children, and there are no specific guidelines for paediatric CML. This review focusses on the clinical characteristics, diagnostic issues and management of paediatric CML. Major studies that provide the basis of managing paediatric CML are summerized here. Studies conducted on adult CML patients were used to guide the management of places where studies were lacking in paediatric CML. Recently, dasatinib and nilotinib have been approved for treatment of paediatric CML, and their role has been discussed in the current management perspective. Allogeneic transplant, fertility and vaccination in paediatric CML, have also been discussed.

Budget Impact of Treatment-Free Remission in Treating Chronic-Phase Philadelphia-Positive Chronic Myeloid Leukemia in Lebanon.

PURPOSE: Chronic myeloid leukemia (CML) ranks second in terms of disease-related health care expenditures at the Lebanese Ministry of Public Health (MoPH) after breast cancer. With the introduction of tyrosine kinase inhibitors (TKIs), survival of patients with CML has dramatically improved and approached that of the normal population. In recent years, several studies demonstrated that patients who achieve a deep molecular response while receiving TKI therapy could safely attempt treatment-free remission (TFR), the new treatment goal in patients with CML. The objective is to estimate the budget impact of TFR at the MoPH. METHODS: Analyses were done on 162 patients with CML receiving imatinib, nilotinib, or dasatinib, as first-line or second-line therapy, over a 4-year time horizon using MoPH drug pricing. The model assumed that patients could attempt TFR after 36 months of TKI therapy, where the last 24 months were at stable molecular response as per MoPH and National Comprehensive Cancer Network guidelines. Duration of TFR was based on European Stop Kinase Inhibitor treatment-free survival curve. RESULTS: Out of the 162 patients, 83 were eligible to attempt TFR, 36 patients were not eligible, 32 patients were lost to follow-up, two patients died as a result of CML progression, and five died as a result of other causes. The total cost of CML treatment with TFR from the time of analysis and over 4 years can be reduced by more than 7 million US dollars (57%). CONCLUSION: The model can be used to inform health care decision makers on the importance of TFR and the potential savings.

Economic Evaluations of Tyrosine Kinase Inhibitors for Patients with Chronic Myeloid Leukemia in Middle- and High-Income Countries: A Systematic Review.

OBJECTIVES: The objective of this systematic review was to conduct a comprehensive assessment of economic evaluations of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML) in middle- and high-income countries. METHODS: A literature search was conducted in Embase, MEDLINE (via PubMed) and the Cochrane library on March 3, 2018 to identify economic evaluations of chronic myeloid leukemia that met the inclusion criteria. Data on such parameters as patient characteristics, cost components, and main outcomes were extracted from eligible studies. RESULTS: The literature review retrieved 798 studies, 17 of which fulfilled the eligibility criteria. Eight studies included an economic analysis on newly diagnosed patients with CML. Seven studies investigated people with CML who were resistant or intolerant to standard-dose imatinib. One article focused on chronic phase (CP)-CML patients who experienced failure with first-line treatment for interferon-α. The last study investigated advanced stages of CML patients. Most studies (n = 70.6%) were conducted in high-income countries. Only five studies (n = 29.4%) were performed in middle-income countries. Most studies used a Markov model. The time horizon varied from six months to life-time. CONCLUSIONS: Despite high costs, the included studies indicate that imatinib regimens are cost effective in newly diagnosed patients with CP-CML. For people with CML who are resistant or intolerant to standard-dose imatinib, dasatinib is likely to be a more cost-effective strategy in middle-income countries. More studies are necessary to assess the long-term efficacy and cost effectiveness of novel treatment options.

Out-of-Pocket Spending Not Associated with Oral Oncolytic Survival Benefit.

BACKGROUND: With total and out-of-pocket spending for oral oncolytics rising, there is increased interest in choosing oncology treatments based on their clinical value relative to cost. OBJECTIVE: To determine if out-of-pocket spending varied for higher versus lower benefit oral oncology drugs reimbursed by commercial insurers. METHODS: This study was a retrospective analysis of commercial insurer prescription drug claims filed between 2007 and 2014 for 13 oral oncolytics approved before 2009. We calculated mean monthly out-of-pocket payment for each fill by patient. We then categorized oral oncolytics by their overall and progression-free survival benefits for each FDA-approved indication, using evidence from published studies. We assessed the relationship of survival benefit with mean monthly out-of-pocket payment, adjusting for demographic and plan characteristics. RESULTS: Our population included 44,113 patients aged 18-65 years (mean 52.5 [SD 9.4]) with a cancer diagnosis who filled 731,354 prescriptions. The most commonly represented oncolytics were imatinib (37.4% of fills), lenalidomide (17.7% of fills), and dasatinib (10.0% of fills). Approximately 32.3% of fills were for drug-indication pairs with an overall survival benefit of 4+ years. In adjusted analyses, there was no clear pattern to suggest that out-of-pocket payments differed with drug indication-specific survival benefits. Drugs for indications providing > 0 to 1 year of overall survival benefit were significantly more likely to have a lower out-of-pocket payment versus those prescribed off-label, but there were no significant differences in out-of-pocket payments between drugs and associated indications in any other survival category versus drugs used off-label. CONCLUSIONS: Out-of-pocket payments for oral oncolytics were not clearly related to indication-specific value in commercially insured patients. This finding suggests that despite increased attention to value- and indication-based drug pricing, cost sharing for oral oncolytics does not currently reflect these goals. DISCLOSURES: This project was supported by Research Scholar Grant RSGI-14-030-01-CPHPS from the American Cancer Society; the NIH Building Interdisciplinary Research Careers in Women's Health (BIRCWH) K12 Program; the North Carolina Translational and Clinical Sciences Institute (UL1TR001111) Grant; and K24CA181510 from the National Cancer Institute. The authors have no disclosures. Data from this study were presented at the 2017 American Society for Clinical Oncology Annual Meeting on June 5, 2017, in Chicago, Illinois.

Generic Price Competition For Specialty Drugs: Too Little, Too Late?

The case of generic imatinib demonstrates several potential barriers to effective generic price competition for specialty prescription drugs, including fewer market entrants, smaller-than-expected price reductions, shifts in prescribing toward more expensive brand-name treatments, and limited uptake of the generic product.

Impact of Genetic Mutations and Health Plan Access to Therapies on Treatment Response and Drug Costs Related to Tyrosine Kinase Inhibitor Treatment Among Patients With Chronic Myelogenous Leukemia.

OBJECTIVES: This study assessed treatment responses and economic consequences of limiting access to the second-generation BCR-ABL1 tyrosine kinase inhibitors (2G-TKI), dasatinib and nilotinib, for treatment of chronic myelogenous leukemia, while taking into account frequencies of genetic mutations that exhibit different sensitivities to the 2G-TKIs. METHODS: Frequencies of BCR-ABL1 mutations and the impact of mutations on responses to 2G-TKIs were obtained from published literature and used as inputs in a decision analytics model. Complete hematologic response (CHR) and major cytogenetic response (MCyR) were estimated after 12 months of 2G-TKI treatment. Total annual 2G-TKI drug costs per CHR and MCyR were estimated and compared among 3 2G-TKI access scenarios: (1) open access to both 2G-TKIs; (2) access restricted to dasatinib (DASA-only); and (3) access restricted to nilotinib (NILO-only). RESULTS: Among a hypothetical cohort of 1000 2G-TKI-treated chronic myelogenous leukemia patients, the percentage of patients with CHR and MCyR were greatest for the open access plan (CHR: 93%, MCyR: 56%), followed by DASA-only (88%, 53%) and NILO-only (67%, 47%). Compared with the 2G-TKI costs per CHR in open access ($120,706/CHR), the costs were 5% higher ($126,753/CHR) in DASA-only and 41% higher ($169,990/CHR) in NILO-only. Likewise, compared with the 2G-TKI costs per MCyR in open access ($198,284/MCyR), the costs were 6% higher ($209,259/MCyR) in DASA-only and 22% higher ($241,515/MCyR) in NILO-only. CONCLUSION: Open access to both 2G-TKIs is associated with improved clinical and economic outcomes: greater treatment response rates (CHR and MCyR) and lower drug costs compared with restricted access to 2G-TKIs.

Cost Effectiveness of Imatinib, Dasatinib, and Nilotinib as First-Line Treatment for Chronic-Phase Chronic Myeloid Leukemia in China.

BACKGROUND AND OBJECTIVE: Tyrosine kinase inhibitors (TKIs) have obvious effects on chronic myeloid leukemia (CML), but they are expensive in China. Moreover, the overall cost of treatment of CML is high and the medical economic burden of patients with CML on the government is heavy. This study tested the cost effectiveness of imatinib, nilotinib, and dasatinib as first-line treatment in Chinese patients who were first diagnosed with chronic myeloid leukemia in the chronic phase (CML-CP). METHODS: A state-transition Markov model combining clinical effectiveness, utility, and cost data was used. Sensitivity analyses were conducted to determine the robustness of the model outcomes. RESULTS: The imatinib-first, dasatinib-first, and nilotinib-first strategy offered patients 9.76, 9.87, and 9.72 quality-adjusted life years (QALYs) at a cost of US$303,502.42, US$381,681.03, and US$305,509.92 over 20 years, respectively. The nilotinib-first strategy exhibited the lowest utility and highest price and was thus eliminated. An incremental cost-effectiveness analysis of the imatinib-first strategy and the dasatinib-first strategy showed that the dasatinib-first strategy yielded an incremental cost-utility ratio (ICER) of 710,714.64 $/QALY compared with the imatinib-first strategy, which exceeded the threshold; hence, the dasatinib-first strategy was not cost effective and was eliminated. The results were robust for multiple sensitivity analyses. CONCLUSION: From the perspective of the Chinese medical system, imatinib is likely to be more cost effective than dasatinib and nilotinib for patients who were first diagnosed with CML-CP.