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 EMA Assessment of Asciminib for the Treatment of Adult Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase Who Were Previously Treated With at Least Two Tyrosine Kinase Inhibitors.

Asciminib is an allosteric high-affinity tyrosine kinase inhibitor (TKI) of the BCR-ABL1 protein kinase. This kinase is translated from the Philadelphia chromosome in chronic myeloid leukemia (CML). Marketing authorization for asciminib was granted on August 25, 2022 by the European Commission. The approved indication was for patients with Philadelphia chromosome-positive CML in the chronic phase which have previously been treated with at least 2 TKIs. Clinical efficacy and safety of asciminib were evaluated in the open-label, randomized, phase III ASCEMBL study. The primary endpoint of this trial was major molecular response (MMR) rate at 24 weeks. A significant difference in MRR rate was shown between the asciminib treated population and the bosutinib control group (25.5% vs. 13.2%, respectively, P = .029). In the asciminib cohort, adverse reactions of at least grade 3 with an incidence ≥ 5% were thrombocytopenia, neutropenia, increased pancreatic enzymes, hypertension, and anemia. The aim of this article is to summarize the scientific review of the application which led to the positive opinion by the European Medicines Agency's Committee for Medicinal Products for Human Use.

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.

Tyrosine kinase inhibitors and reduced-dose chemotherapy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia.

Objectives: To compare the outcomes of tyrosine kinase inhibitors (TKIs) in combination with reduced-dose chemotherapy with those of standard induction chemotherapy, as well as the outcomes between chemotherapy and transplantation, in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).Methods: We retrospectively reviewed cases of Ph+ ALL treated with TKIs and combination chemotherapy. The patients were allocated to either the TKIs with reduced-dose chemotherapy group or the TKIs with standard chemotherapy group. In additions, patients were further stratified into either the transplant group or the non-transplant group.Results: The complete remission rate (88.7% vs. 83.9%, p = 0.372), major molecular response (58.9% vs. 56.0%, p = 0.750), molecular complete response (20.5% vs. 22.0%, p = 0.891), and early mortality rate (3.2% vs. 3.5%, p = 0.922) were similar between the TKIs with reduced-dose chemotherapy group and the TKIs with standard chemotherapy group. The proportions of lung infections, bloodstream infections, patients with >21 days of hospitalization, the total costs, transfusion costs, and antimicrobial costs were higher in the standard chemotherapy group than in the TKIs with reduced-dose chemotherapy group. The 3-year overall survival rates (59.0% [95% CI, 46.6-74.7%] vs. 38.4% [95% CI, 29.9-49.4%]) and disease-free survival rates (48.6% [95% CI, 34.2-69.1%] vs. 32.0% [95% CI, 23.5-43.7%]) were significantly better in the transplant group than in the non-transplant group.Conclusion: An induction regimen combining TKIs with reduced-dose chemotherapy and transplantation during the first complete remission remains a suitable and effective option for patients with Ph+ ALL.

Decision Analysis for Unrelated Bone Marrow Transplantation or Immediate Cord Blood Transplantation for Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Complete Remission.

An HLA-matched relative is the first-choice donor for patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1). The most promising alternative donor is thought to be an HLA-matched unrelated donor (MUD) in patients who do not have an HLA-matched related donor. Cord blood transplantation (CBT) is an alternative option. Higher rates of engraftment failure and nonrelapse mortality (NRM) are significant problems, but the ready availability of cord blood can be an advantage, because patients can immediately undergo transplantation before progression. This study was conducted to identify an appropriate alternative donor in patients with Ph-negative ALL in CR1 who do not have an HLA-matched related donor (MRD). Decision analyses using a Markov model were performed to compare immediate CBT, in which CBT was performed at 1 month after the achievement of CR1, with elective unrelated bone marrow transplantation (uBMT) from an 8/8 MUD (8/8 uBMT) or uBMT from a 7/8 MUD (7/8 uBMT), in which uBMT was performed at 4 months, in patients age 16 to 55 years with Ph-negative ALL in CR1 who did not have an MRD. We constructed a decision tree. The cycle length was set at 3 months, and analyses were performed for 19 cycles for uBMT and 20 cycles for CBT, resulting in evaluation of the 5-year life expectancy after both decisions. Transition probabilities (TPs) and utilities were estimated from prospective and retrospective Japanese studies and the registry database of Japan. Subgroup analyses were performed according to risk stratification based on WBC count and cytogenetics at diagnosis and according to age stratification, with a cutoff of 25 years. One-way sensitivity analyses for TPs and utilities were performed as well. The baseline analyses showed that 8/8 uBMT or 7/8 uBMT had superior results to CBT, with quality-adjusted life years (QALYs) of 2.86 in 8/8 uBMT, 2.84 in 7/8 uBMT, and 2.75 in CBT. One-way sensitivity analyses showed that the results of the baseline analyses were reversed if the probability of NRM in CBT improved. Subgroup analyses showed similar results in younger, older, and high-risk patients. However, QALY was worse in 8/8 uBMT compared with CBT in standard-risk patients. In one-way sensitivity analyses, the probabilities of NRM in uBMT and CBT affected the baseline results in all analyses except for comparisons between 8/8 uBMT and CBT in younger and high-risk patients. In these 2 populations, the superiority of 8/8 uBMT was consistently demonstrated throughout the one-way sensitivity analyses. For patients with Ph-negative ALL in CR1 who decide to undergo transplantation from an alternative donor, elective uBMT from either an 8/8 MUD or a 7/8 MUD is expected to yield a better outcome than immediate CBT. Nonetheless, CBT is a viable option, and improvements to reduce the risk of NRM in CBT may change these results.

Newly proposed threshold and validation of white blood cell count at diagnosis for Philadelphia chromosome-positive acute lymphoblastic leukemia: risk assessment of relapse in patients with negative minimal residual disease at transplantation-a report from the Adult Acute Lymphoblastic Leukemia Working Group of the JSTCT.

White blood cell count (WBC) at diagnosis is the conventional prognostic factor in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Nevertheless, little is known about the impact of WBC at diagnosis considering the minimal residual disease (MRD) status at allogeneic hematopoietic cell transplantation (HCT). We evaluated adult patients with Ph+ ALL who achieved negative-MRD and received HCT in first complete remission between 2006 and 2018. The entire cohort was temporally divided into derivation (n = 258) and validation cohorts (n = 366). Using a threshold of 15,000/µL, which was determined by a receiver operating characteristic curve analysis in the derivation cohort, high WBC was associated with an increased risk of hematological relapse in both the derivation cohort (25.3% vs. 11.6% at 7 years, P = 0.004) and the validation cohort (16.2% vs. 8.5% at 3 years, P = 0.025). In multivariate analyses, high WBC was a strong predictor of hematological relapse in the derivation cohort (HR, 2.52, 95%CI 1.32-4.80, P = 0.005) and in the validation cohort (HR, 2.32, 95%CI, 1.18-4.55; P = 0.015). In conclusion, WBC at diagnosis with a new threshold of 15,000/µL should contribute to better risk stratification in patients with negative-MRD at HCT.

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.

Ultra-accurate Duplex Sequencing for the assessment of pretreatment ABL1 kinase domain mutations in Ph+ ALL.

Mutations of ABL1 are the dominant mechanism of relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). We performed highly accurate Duplex Sequencing of exons 4-10 of ABL1 on bone marrow or peripheral blood samples from 63 adult patients with previously untreated Ph + ALL who received induction with intensive chemotherapy plus a BCR-ABL1 TKI. We identified ABL1 mutations prior to BCR-ABL1 TKI exposure in 78% of patients. However, these mutations were generally present at extremely low levels (median variant allelic frequency 0.008% [range, 0.004%-3.71%] and did not clonally expand and lead to relapse in any patient, even when the pretreatment mutation was known to confer resistance to the TKI received. In relapse samples harboring a TKI-resistant ABL1 mutation, the corresponding mutation could not be detected pretreatment, despite validated sequencing sensitivity of Duplex Sequencing down to 0.005%. In samples under the selective pressure of ongoing TKI therapy, we detected low-level, emerging resistance mutations up to 5 months prior to relapse. These findings suggest that pretreatment ABL1 mutation assessment should not guide upfront TKI selection in Ph + ALL, although serial testing while on TKI therapy may allow for early detection of clinically actionable resistant clones.

Molecular profiling refines minimal residual disease-based prognostic assessment in adults with Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia.

Minimal residual disease (MRD) assessment is an essential tool in contemporary acute lymphoblastic leukemia (ALL) protocols, being used for therapeutic decisions such as hematopoietic stem cell transplantation in high-risk patients. However, a significant proportion of adult ALL patients with negative MRD still relapse suggesting that other factors (ie, molecular alterations) must be considered in order to identify those patients with high risk of disease progression. We have identified partial IKZF1 gene deletions and CDKN2A/B deletions as markers of disease recurrence and poor survival in a series of uniformly treated adolescent and adult Philadelphia chromosome-negative B-cell progenitor ALL patients treated according to the Programa Español de Tratamientos en Hematología protocols. Importantly, CDKN2A/B deletions showed independent significance of MRD at the end of induction, which points out the need for treatment intensification in these patients despite being MRD-negative after induction therapy.

Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.

Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10-3 and 36/67 (53%) and 53/67 (79%) at 10-4BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.

Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring.

DISEASE OVERVIEW: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100 000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. DIAGNOSIS: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR-ABL1 oncoprotein. Frontline therapy: Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, and bosutinib are approved by the United States Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses; this has not translated into improved long-term survival, because of the availability of effective salvage therapies. Salvage therapy: For patients who fail frontline therapy, second-line options include second and third generation TKIs. Second and third generation TKIs, although potent and selective, exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities, disease stage, and BCR-ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least 2 TKIs, and for all patients in CML advanced phases.

Quantitative assessment of JAK2 V617F and CALR mutations in Philadelphia negative myeloproliferative neoplasms.

BACKGROUND: Philadelphia negative myeloproliferative neoplasms (MPNs) are characterized by frequent mutations of driver genes including JAK2, CALR and MPL. While the influence of JAK2 V617F mutant allele burden on the clinical phenotype of MPN patients is well-described, the impact of CALR mutant allele burden on clinical features needs further investigation. PATIENTS AND METHODS: Quantitative assessment of JAK2 and CALR mutations was performed on diagnostic DNA samples from 425 essential thrombocythemia (ET) and 227 primary myelofibrosis patients using real-time quantitative PCR and fragment length analysis. Characterization of CALR mutations and detection of MPL mutations were performed by Sanger sequencing. RESULTS: Twelve novel CALR mutations have been identified. ET patients with CALRmut load exceeding the median value exhibited lower hemoglobin values (12.0 vs. 13.6 g/dL), higher LDH levels (510 vs. 351 IU/L) and higher rate of myelofibrotic transformation (19% vs. 5%). The CALRmut load was higher among ET patients presenting with splenomegaly compared to those without splenomegaly (50.0% vs. 43.5%). CONCLUSION: Our study confirms the clinical significance of driver mutational status and JAK2mut load in MPNs; in addition, unravels a novel clinical association between high CALRmut load and a more proliferative phenotype in ET.

Impact of clinical utility of MRD assessment with different techniques on survival in acute B lymphoblastic leukemia.

We investigated the impact of minimal residual disease (MRD) obtained from different approaches on the outcomes of 141 B lymphoblastic leukemia (B-ALL) patients. Among 169 samples with more than 5% blasts by morphology, 3.6% (6/169) were Flow-MRD negative. Of the 212 positive molecular-MRD samples from Ph+ ALL patients, 55 (25.9%) were Flow-MRD negative. Before consolidation or allogeneic stem cell transplantation (allo-HSCT), negative Flow-MRD was associated with improved survival (p = .019 and .041, respectively) for Ph- ALL patients, but not for Ph+ ALL (p = .111 and .812, respectively). There was no difference in overall survival (OS) by achievement of complete molecular response at complete remission (CR, p = .333 and .863, respectively). Our results indicated that the results of MRDs detected with different methods varied. Flow-MRD can be used as a reliable prognostic marker for Ph- ALL patients. MRD either by flow cytometry or quantitative reverse transcription-polymerase chain reaction (qRT-PCR) at CR did not affect OS or DFS for Ph+ ALL.

Cost-effectiveness of blinatumomab versus salvage chemotherapy in relapsed or refractory Philadelphia-chromosome-negative B-precursor acute lymphoblastic leukemia from a US payer perspective.

OBJECTIVE: To evaluate the cost-effectiveness of blinatumomab (Blincyto) vs standard of care (SOC) chemotherapy in adults with relapsed or refractory (R/R) Philadelphia-chromosome-negative (Ph-) B-precursor acute lymphoblastic leukemia (ALL) based on the results of the phase 3 TOWER study from a US healthcare payer perspective. METHODS: The Blincyto Global Economic Model (B-GEM), a partitioned survival model, was used to estimate the incremental cost-effectiveness ratio (ICER) of blinatumomab vs SOC. Response rates, event-free survival (EFS), overall survival (OS), numbers of cycles of blinatumomab and SOC, and transplant rates were estimated from TOWER. EFS and OS were estimated by fitting parametric survival distributions to failure-time data from TOWER. Utility values were based on EORTC-8D derived from EORTC QLQ-C30 assessments in TOWER. A 50-year lifetime horizon and US payer perspective were employed. Costs and outcomes were discounted at 3% per year. RESULTS: The B-GEM projected blinatumomab to yield 1.92 additional life years and 1.64 additional quality-adjusted life years (QALYs) compared with SOC at an incremental cost of $180,642. The ICER for blinatumomab vs SOC was estimated to be $110,108/QALY gained in the base case. Cost-effectiveness was sensitive to the number and cost of inpatient days for administration of blinatumomab and SOC, and was more favorable in the sub-group of patients who had received no prior salvage therapy. At an ICER threshold of $150,000/QALY gained, the probability that blinatumomab is cost-effective was estimated to be 74%. LIMITATIONS: The study does not explicitly consider the impact of adverse events of the treatment; no adjustments for long-term transplant rates were made. CONCLUSIONS: Compared with SOC, blinatumomab is a cost-effective treatment option for adults with R/R Ph - B-precursor ALL from the US healthcare perspective at an ICER threshold of $150,000 per QALY gained. The value of blinatumomab is derived from its incremental survival and health-related quality-of-life (HRQoL) benefit over SOC.

Nilotinib versus dasatinib as second-line therapy in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase who are resistant or intolerant to imatinib: a cost-effectiveness analysis based on real-world data.

OBJECTIVE: To evaluate the cost-effectiveness of second-line nilotinib vs dasatinib among patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) who are resistant or intolerant to imatinib, from a US third-party perspective. METHODS: A lifetime partitioned survival model was developed to compare the costs and effectiveness of nilotinib vs dasatinib, which included four health states: CP on treatment, CP post-discontinuation, progressive disease (accelerated phase [AP] or blast crisis [BC]), and death. Time on treatment, progression-free survival, and overall survival of nilotinib and dasatinib were estimated using real-world comparative effectiveness data. Parametric survival models were used to extrapolate outcomes beyond the study period. Drug treatment costs, medical costs, and adverse event costs were obtained from the literature and publicly available databases. Utilities of health states were derived from the literature. Incremental cost-effectiveness ratios, including incremental cost per life-year (LY) gained and incremental cost per quality-adjusted life-year (QALY) gained, were estimated comparing nilotinib and dasatinib. Deterministic sensitivity analyses were performed by varying patient characteristics, cost, and utility inputs. RESULTS: Over a lifetime horizon, nilotinib-treated patients were associated with 11.7 LYs, 9.1 QALYs, and a total cost of $1,409,466, while dasatinib-treated patients were associated with 9.5 LYs, 7.3 QALYs, and a total cost of $1,422,122. In comparison with dasatinib, nilotinib was associated with better health outcomes (by 2.2 LYs and 1.9 QALYs) and lower total costs (by $12,655). Deterministic sensitivity analysis results showed consistent findings in most scenarios. LIMITATIONS: In the absence of long-term real-world data, the lifetime projection could not be validated. CONCLUSIONS: Compared with dasatinib, second-line nilotinib was associated with better life expectancy, better quality-of-life, and lower costs among patients with Ph+ CML-CP who were resistant or intolerant to imatinib.

Patients' perceptions about diagnosis and treatment of chronic myeloid leukemia: a cross-sectional study among Brazilian patients / Percepções dos pacientes sobre diagnóstico e tratamento da leucemia mieloide crônica: estudo transversal entre pacientes brasileiros

CONTEXT AND OBJECTIVES: Chronic myeloid leukemia (CML) requires strict daily compliance with oral medication and regular blood and bone marrow control tests. The objective was to evaluate CML patients' perceptions about the disease, their access to information regarding the diagnosis, monitoring and treatment, adverse effects and associations of these variables with patients' demographics, region and healthcare access. DESIGN AND SETTING: Prospective cross-sectional study among CML patients registered with the Brazilian Lymphoma and Leukemia Association (ABRALE). METHODS: CML patients receiving treatment through the public healthcare system were interviewed by telephone. RESULTS: Among 1,102 patients interviewed, the symptoms most frequently leading them to seek medical care were weakness or fatigue. One third were diagnosed by means of routine tests. The time that elapsed between first symptoms and seeking medical care was 42.28 ± 154.21 days. Most patients had been tested at least once for Philadelphia chromosome, but 43.2% did not know the results. 64.8% had had polymerase chain reaction testing for the BCR/ABL gene every three months. 47% believed that CML could be controlled, but 33.1% believed that there was no treatment. About 24% reported occasionally stopping their medication. Imatinib was associated with nausea, cramps and muscle pain. Self-reported treatment adherence was significantly associated with normalized blood count, and positively associated with imatinib. CONCLUSIONS: There is a lack of information or understanding about disease monitoring tools among Brazilian CML patients; they are diagnosed quickly and have good access to treatment. Correct comprehension of CML control tools is impaired in Brazilian patients.

CONTEXTO E OBJETIVOS: Leucemia mieloide crônica (CML) exige estrita adesão à medicação oral e ao monitoramento do sangue e da medula. O objetivo foi avaliar percepções de pacientes com leucemia mieloide crônica (LMC) sobre a doença, seu acesso à informação sobre diagnóstico, monitoramento e tratamento, efeitos adversos e a associação destes com dados demográficos, geográficos e de acesso a tratamento. DESENHO E LOCAL: Estudo prospectivo transversal realizado com pacientes de LMC cadastrados na Associação Brasileira de Leucemia e Linfoma (Abrale). MÉTODOS: Pacientes com LMC recebendo tratamento do sistema público de saúde foram entrevistados por telefone. RESULTADOS: Entre os 1.102 pacientes entrevistados, os sintomas mais frequentemente levando à busca de consulta foram fraqueza e fadiga. Um terço foi diagnosticado por exames de rotina. O tempo entre sintoma inicial e procura por ajuda foi de 42,28 ± 154,21 dias. A maioria foi testada pelo menos uma vez para o cromossomo Filadélfia, mas 43,2% não sabiam os resultados. 64,8% fizeram exame de reação em cadeia da polimerase para o gene BCR/ABL a cada três meses. 47% acreditavam que LMC pode ser controlada, mas 33,1% acham que não há tratamento. Cerca de 24% disseram que ocasionalmente interrompem o tratamento. Imatinibe associou-se com náusea, câimbra e dor muscular. Aderência auto-reportada associou-se significativamente com hemograma normal e positivamente com uso de imatinibe. CONCLUSÕES: Falta informação ou compreensão sobre monitoramento entre pacientes com LMC; eles recebem diagnóstico rapidamente e têm bom acesso ao tratamento. A correta compreensão das ferramentas de controle em LMC está prejudicada entre eles.

Patients' perceptions about diagnosis and treatment of chronic myeloid leukemia: a cross-sectional study among Brazilian patients.

CONTEXT AND OBJECTIVES: Chronic myeloid leukemia (CML) requires strict daily compliance with oral medication and regular blood and bone marrow control tests. The objective was to evaluate CML patients' perceptions about the disease, their access to information regarding the diagnosis, monitoring and treatment, adverse effects and associations of these variables with patients' demographics, region and healthcare access. DESIGN AND SETTING: Prospective cross-sectional study among CML patients registered with the Brazilian Lymphoma and Leukemia Association (ABRALE). METHODS: CML patients receiving treatment through the public healthcare system were interviewed by telephone. RESULTS: Among 1,102 patients interviewed, the symptoms most frequently leading them to seek medical care were weakness or fatigue. One third were diagnosed by means of routine tests. The time that elapsed between first symptoms and seeking medical care was 42.28 ± 154.21 days. Most patients had been tested at least once for Philadelphia chromosome, but 43.2% did not know the results. 64.8% had had polymerase chain reaction testing for the BCR/ABL gene every three months. 47% believed that CML could be controlled, but 33.1% believed that there was no treatment. About 24% reported occasionally stopping their medication. Imatinib was associated with nausea, cramps and muscle pain. Self-reported treatment adherence was significantly associated with normalized blood count, and positively associated with imatinib. CONCLUSIONS: There is a lack of information or understanding about disease monitoring tools among Brazilian CML patients; they are diagnosed quickly and have good access to treatment. Correct comprehension of CML control tools is impaired in Brazilian patients.

Identifying and addressing unmet clinical needs in Ph-neg classical myeloproliferative neoplasms: a consensus-based SIE, SIES, GITMO position paper.

This article presents the results of group discussion among experts from SIE, SIES and GITMO societies aimed at highlighting unmet challenges in the management of Ph-neg myeloproliferative neoplasms (MPNs). The issues analyzed were: diagnosis of prefibrotic myelofibrosis; diagnosis of Ph-neg MPNs in the setting of splanchnic vein thrombosis (SVT); management of low-risk PV and low-risk ET patients with JAK2V617F mutation; molecular biomarkers in the prognostic evaluation of myelofibrosis (MF); ruxolitinib therapy in low-risk MF; therapy in patients with SVT-associated Ph-neg MPN; indications of splenectomy in MF. For each of these issues, proposals for advancement in clinical research were addressed.