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INTRODUCTION: Chronic myeloid leukemia (CML) prevalence is currently increasing due to the great efficacy of tyrosine kinase inhibitor (TKI) therapy. Discontinuation of treatment in the long-term, owing to avoid off-target side effects or treatment-free remission (TFR), has become an additional treatment goal in CML patients who achieved a deep molecular response (DMR). Second-generation TKIs (2 G-TKIs) have a significantly higher rate of DMR than imatinib. Hence, especially in young patients with a strategy of TFR, 2 G-TKIs are becoming the most frequently used TKIs and may increase TFR attempts in the future. AREAS COVERED: In this review, the main findings extrapolated from clinical trials and real-life evidence regarding 2 G-TKIs discontinuation were discussed, through broad research on Medline, Embase, and archives from EHA and ASH congresses. EXPERT OPINION: Overall, TFR rate after 2 G-TKIs is ranging from 40% to 60% for selected patients with sustained DMR and it can be considered a safe procedure, that have become, nowadays, a daily practice. However, many crucial aspects regarding treatment choices, timings, as well as predictive factors, patient communication, and optimal strategies need to be better clarified to improve successful TFR rate.
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Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Inducción de Remisión , Humanos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/efectos adversos , Mesilato de Imatinib/farmacologíaAsunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Aprendizaje Automático Supervisado , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , PronósticoRESUMEN
OBJECTIVE: To explore the clinical efficacy and safety of flumatinib mesylate produced in China in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). METHODS: 32 newly diagnosed CML-CP patients admitted to the Hematology Department of the Affiliated Hospital of Southwest Medical University from March 1, 2020 to March 31, 2022, who had never received any tyrosine kinase inhibitor (TKI) were included in the study. The patients were treated by flumatinib mesylate 600mg once daily. The hematologic, cytogenetic and molecular responses were assessed at 3-, 6- and 12-month, and adverse effects of the drug were evaluated. RESULTS: 31 patients were treated with flumatinib for≥3 months, of which 24 patients were treated for ≥6 months and 14 patients were treated for≥12 months. At 3rd month of treatment, 30 out of 31 patients achieved complete hematologic response (CHR); 24 patients underwent cytogenetic testing and 22 cases achieved major cytogenetic response(MCyR), of which 21 cases achieved complete cytogenetic response (CCyR); Among 25 patients who underwent molecular testing, 22 patients had BCR-ABLIS≤10%, including 10 patients with BCR-ABLIS≤0.1%, and 6 patients with BCR-ABLIS≤0.01%. At 6th month of treatment, 23 out of 24 patients achieved CHR; 17 patients underwent cytogenetic testing and all achieved CCyR; Among 23 patients who underwent molecular testing, 20 patients had BCR-ABLIS≤1%, including 16 patients with BCR-ABLIS≤0.1% and 12 patients with BCR-ABLIS≤0.01%. At 12nd month of treatment, all 14 patients achieved CHR and CCyR; Among them, 10 patients had BCR-ABLIS≤0.1%, including 9 patients with BCR-ABLIS≤0.01%. The grade â ¢/â £ leukopenia, thrombocytopenia and anemia rates in the patients were 13.3%, 20.0% and 3.3%, respectively. One patient stopped flumatinib therapy due to severe and persistent hematologic toxicity. The major non-hematologic adverse events were abnormal liver function (20%), diarrhea (10%), bone/joint pain (10%), muscle spasm (10%), rash (6.7%), acute kidney injury (6.7%) and nausea(3.3%), most of which were grade I-II. No patient experienced grade â £ non-hematologic adverse events. No drug toxicity-related death occurred. CONCLUSION: Flumatinib mesglate, as the first-line treatment for newly diagnosed CML-CP, can enable the patients to achieve early and deep molecular and cytogenetic responses, and shows good safety.
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Anemia , Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Trombocitopenia , Humanos , Mesilato de Imatinib/uso terapéutico , Pirimidinas/farmacología , Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Benzamidas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del Tratamiento , Respuesta Patológica Completa , Mesilatos/uso terapéutico , Antineoplásicos/uso terapéuticoRESUMEN
Introduction: Chronic myeloid leukemia (CML) is characterized by the presence of the BCR::ABL1 fusion gene, and the advent of tyrosine kinase inhibitors (TKIs) has revolutionized its therapeutic landscape. Asciminib, a STAMP inhibitor, emerges as a promising option for patients unresponsive or intolerant to multiple conventional TKIs. However, the safety and efficacy of asciminib in individuals with chronic kidney disease remain understudied. Case Presentation: In this report, we detail the case of a 62-year-old patient with CML and stage 3 chronic kidney disease, who faced intolerance to traditional TKIs primarily due to fluid retention. The transition to asciminib therapy resulted in a profound molecular response and did not exacerbate renal function, effectively addressing the fluid retention issue. Conclusion: This case highlights the potential of asciminib as a viable therapeutic alternative for CML patients with chronic kidney disease, particularly those intolerant to standard TKIs. Further research is warranted to establish the broader safety and efficacy profile of asciminib in this patient population.
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BACKGROUND: Typical chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm caused by t(9; 22)(q34; q11) translocation. This chromosomal translocation forms the BCR::ABL1 fusion gene. The tyrosine kinase encoded by the BCR::ABL1 is considered to be the main pathogenic diver. BCR::ABL1 is not only a therapeutic target, but also a monitoring target. Monitoring of BCR::ABL1 reveals the progression of the disease and guides the next treatment. Now for CML, the target of treatment has been focused on treatment-free remission (TFR). METHODS: We conducted a literature review of current developments of treatment-free remission and molecular monitoring methods. RESULTS: More effective and sensitive CML monitoring methods such as digital droplet PCR (ddPCR) and next generation sequencing (NGS) have further studied the measurable residual disease (MRD) and clonal heterogeneity, which provides strong support for the exploration of TFR. We discussed some of the factors that may be related to TFR outcomes at the molecular level, along with some monitoring strategies. CONCLUSION: Currently, predictive indicators for treatment-free remission outcomes and recurrence are lacking in clinical practice. In future, treatment-free remission research should focus on combining the clinical indicators with molecular monitoring and biological markers to personalize patient conditions and guide clinicians to develop individualized treatment plans, so that more patients with CML can achieve safer and stabler treatment-free remission.
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Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Inducción de Remisión , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Proteínas de Fusión bcr-abl/genética , Neoplasia Residual/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Biomarcadores de Tumor/genéticaRESUMEN
Introduction: Early stable deep molecular response (DMR) to nilotinib is associated with goal of treatment-free remission (TFR) in patients with chronic-phase chronic myeloid leukemia (CML-CP). It is important to early distinguish between patients who can achieve a DMR and those who are fit for TFR. Methods: We performed a multicenter study to explore the early cumulative MR4.5 rate at 18 months with nilotinib in patients with newly diagnosed CML-CP (ND-CML-CP) in China. Of the 29 institutes, 106 patients with ND-CML-CP received nilotinib (300 mg BID). Results and discussion: The cumulative MR4.5 rate of nilotinib treatment at 18 months was 69.8% (74/106). The cumulative MMR and MR4.0 rates for nilotinib at 18 months were 94.3% (100/106) and 84.9% (90/106), respectively. Patients with an ultra-early molecular response (u-EMR) at 6 weeks were not significantly different in obtaining DMR or MMR by 24 months compared with those without u-EMR (p = 0.7584 and p = 0.9543, respectively). Our study demonstrated that nilotinib treatment in patients with ND-CML-CP contributed to obtain high early MR4.5.
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Patients with chronic myeloid leukaemia in chronic phase (CML-CP) who have a sustained deep molecular response (DMR) are eligible to discontinue treatment and attempt treatment-free remission (TFR). In the DASFREE study (ClinicalTrials.gov; NCT01850004), the 2-year TFR rate after dasatinib discontinuation was 46%; here we present the 5-year update. Patients with a stable DMR after ≥2 years of dasatinib therapy discontinued treatment and were followed for 5 years. At a minimum follow-up of 60 months, in 84 patients discontinuing dasatinib, the 5-year TFR rate was 44% (n = 37). No relapses occurred after month 39 and all evaluable patients who relapsed and restarted dasatinib (n = 46) regained a major molecular response in a median of 1.9 months. The most common adverse event during the off-treatment period was arthralgia (18%, 15/84); a total of 15 withdrawal events were reported in nine patients (11%). At the 5-year final follow-up, almost half of the patients who discontinued dasatinib after a sustained DMR maintained TFR. All evaluable patients who experienced a relapse quickly regained a DMR after restarting dasatinib, demonstrating that dasatinib discontinuation is a viable and potentially long-term option in patients with CML-CP. The safety profile is consistent with the previous report.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Humanos , Dasatinib/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Resultado del Tratamiento , Recurrencia Local de Neoplasia , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológicoRESUMEN
The prognosis and life expectancy of chronic myeloid leukemia (CML) patients have improved significantly with the launch of first tyrosine kinase inhibitor (TKI), imatinib. Maintaining at least one major molecular response in CML patients without the use of TKI is known as treatment-free remission (TFR). The safety of the first TFR (TFR1) effort has been reported by numerous studies. However, some patients relapse during TFR1. A second TFR (TFR2) can be tried again in those patients. This systematic review aims to evaluate individual patient characteristics for a TFR2, factors predicting successful TFR2, monitoring, consequences of the cessation of TKI, and studies about TFR2. We identified 5 studies related TFR2. The results showed that the first failed TKI discontinuation attempt is not an indicator of a second TKI discontinuation failure. TKIs could safely and successfully be discontinued for a second time in chronic phase CML patients despite a TFR1 failure. The most important factors for estimating TFR2 success are the speed of molecular relapse and the TKI-free duration after the first TKI discontinuation attempt. New trends in the management of CML patients are reducing the side effects of treatment, lessening the financial burden, and improving the quality of life of patients as CML has developed into a manageable chronic disease rather than an aggressive cancer. Although there are many studies and guidelines on TFR1, there are few studies on TFR2 and predictive factors. More data is still needed regarding TFR2 attempt in patients with CML.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Calidad de Vida , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Mesilato de Imatinib/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , RecurrenciaRESUMEN
Superior rates of deep molecular response (DMR) have been reported with the combination of tyrosine kinase inhibitors and pegylated-interferon-alpha (Peg-IFN) in patients with newly diagnosed chronic phase-chronic myeloid leukaemia (CP-CML). In this setting, this study investigated the efficacy and safety of dasatinib combined to Peg-IFN-α2b (Dasa-PegIFN, NCT01872442). A total of 79 patients (age ≤65 years) started dasatinib; 61 were eligible for Peg-IFNα-2b add-on therapy at month 3 for a maximum 21-months duration. Dasatinib was continued thereafter. The primary endpoint was the cumulative rate of molecular response 4.5 log (MR4.5 ) by 12 months. The results are reported for the 5-year duration of the study. Grade 3 neutropenia was frequent with the combination but did not induce severe infection (one of grade 3). Other adverse events were generally low grade (4% of grade 3-4) and expected. Seventy-nine per cent and 61% of patients continued the Peg-IFN until months 12 and 24, respectively. Overall, at these time points, MR4.5 rates were 25% and 38%, respectively. Thereafter, 32% and 46% of patients achieved a sustained (≥2 years) MR4.5 or MR4 , respectively. This work established the feasibility and high rates of achievement of early and sustained DMR (a prerequisite for treatment-free-remission) with dasatinib and Peg-IFNα-2b combination as initial therapy.
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Interferón-alfa , Leucemia Mieloide de Fase Crónica , Humanos , Anciano , Dasatinib/efectos adversos , Interferón-alfa/efectos adversos , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Polietilenglicoles/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: The real-world experience of Swiss chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) is largely unknown, in particular with regard to achievement of response per European Leukemia Net (ELN) criteria and adherence to ELN recommendations. METHODS: This was a retrospective, non-interventional, multicenter chart review of patients with newly diagnosed CML who had received first-line TKI and were solely treated with TKIs between 2010 and 2015, with a minimum follow-up of 18 months, at six Swiss hospitals. Effectiveness was evaluated according to ELN 2013 milestone achievements at 3, 6, 12 and 18 months, and at last follow-up. RESULTS: Data from 63 patients (56% men; median age at diagnosis 55 years) were collected (first-line imatinib [n = 27], nilotinib [n = 27], dasatinib [n = 8], or ponatinib [n = 1]). TKI switches (49 times) and dosing changes (165 times) due to intolerance or insufficient response were frequent. Compared with patients receiving first-line imatinib, a higher proportion of patients receiving first-line nilotinib or dasatinib achieved optimal response at all timepoints, irrespective of subsequent TKI therapy, and a higher proportion of patients treated with first-line nilotinib and dasatinib reached deep molecular response (BCR-ABL1IS ≤ 0.01%) at 18 months (42 and 38%, respectively, versus 27%). Patients who received nilotinib or dasatinib switched therapies less frequently than patients treated with imatinib, irrespective of subsequent TKI therapy. CONCLUSIONS: Although patient numbers were small, this real-world evidence study with patients with CML confirms that ELN guidelines are generally implemented in Swiss clinical practice, with a large proportion of patients achieving ELN 2013 milestones. While TKI use involved all inhibitors approved at the time of the study, an unexpectedly high number of TKI therapy switches suggests a clear difference in TKI use between registration trials and clinical practice.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Humanos , Masculino , Persona de Mediana Edad , Femenino , Mesilato de Imatinib/uso terapéutico , Dasatinib/uso terapéutico , Estudios Retrospectivos , Suiza/epidemiología , Inhibidores de Proteínas Quinasas/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Enfermedad CrónicaRESUMEN
BACKGROUND: Withdrawal syndrome (WS) a musculoskeletal pain after discontinuation of tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML) has been described in the treatment-free remission (TFR) studies. The pathophysiological mechanisms and predisposing factors of WS have not been well established. AIM: Our aim was to evaluate clinical features and factors associated with WS in the Russian cohort of CML patients who discontinued TKI therapy. MATERIALS AND METHODS: WS was evaluated in total of 183 CML patients with chronic phase and sustained deep molecular response (DMR). WS was defined as a musculoskeletal pain newly observed after TKI cessation or as a worsening of previously observed symptoms. RESULTS: DMR loss free survival at 36 months was 49% and 43% in prospective and retrospective groups respectively (p=0.96) with mеdian (Me) time of observation 33 months (range 1136). WS was observed in 49 (27%) patients: grade 12 was in 45 (92%) patients, grade 3 in 4 (8%) patients. Me time to WS occurrence was 2 months (range 17), Ðе duration of WS was 5 months (range 135). WS was resolved in 14 of 15 patients with molecular relapse after 13 months of TKI re-initiation and was decreased in 1 patient. WS was completely resolved in 31 of 34 patients who continued remained in TFR and decreased in 3 patients. WS was resolved spontaneously or with nonsteroidal anti-inflammatory drugs in 14 (45%) and 17 (55%) patients accordingly. Older age (p0.0001), longer duration of TKI therapy (p0.0001) and presence of locomotion system diseases (p=0.022) were observed in patients with WS. No WS was observed in pregnant patients (Ñ0.001). Survival without DMR loss at 12 months after TKI stop was 66 and 42% in patients with and without WS accordingly (Ñ=0.095). CONCLUSION: The rate of WS was 27% that is in a good concordance with the data of the other TFR studies. A longer period of TKI exposure, older age and the history of locomotion system diseases were associated with the development of the WS. We found for the first time that WS was not observed in patients with pregnancy. There was no association of WS development and the rate of molecular relapses.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Dolor Musculoesquelético , Humanos , Estudios Retrospectivos , Estudios Prospectivos , Dolor Musculoesquelético/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Recurrencia , Antiinflamatorios/uso terapéuticoRESUMEN
PURPOSE: We evaluated the plasma exposure and response relationships of nilotinib for patients with newly diagnosed chronic myeloid leukemia (CML) in real-world practice. METHODS: For the 26 patients enrolled in this study, at 3, 6, 12, and 24 months after nilotinib administration, the trough plasma concentrations (Ctrough) of nilotinib were analyzed. The relationships between nilotinib Ctrough and the molecular response to nilotinib treatment at each point (each n = 26) were evaluated. RESULTS: Median nilotinib Ctrough values were significantly higher in patients with a major molecular response (MMR) at 3 months than in patients without an MMR (809 and 420 ng/mL, respectively; P = 0.046). Based on the area under the receiver-operating characteristic curve, the threshold value of the nilotinib Ctrough at 3 months for predicting MMR achievement was 619 ng/mL at the best sensitivity (71.4%) and specificity (77.8%). Patients with a nilotinib Ctrough of above 619 ng/mL had a significantly shorter time to achievement of a deep molecular response (DMR; 9.0 and 18.0 months, respectively; P = 0.020) and higher rates of DMR by 2 years in Kaplan-Meier plots (P = 0.025) compared with that in patients with a nilotinib Ctrough of less than 619 ng/mL. CONCLUSION: For patients with newly diagnosed CML, the nilotinib dose may be adjusted using a Ctrough of above 619 ng/mL as the minimum effective concentration, i.e., the lowest concentration required for MMR or DMR achievement within a shorter time, during early stages after beginning therapy to obtain faster and deeper clinical responses.
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Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Antineoplásicos/uso terapéutico , Enfermedad Crónica , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Resultado del TratamientoRESUMEN
BCR-ABL1 mRNA levels represent the key molecular marker for the evaluation of minimal residual disease (MRD) in chronic myeloid leukemia (CML) patients and real-time quantitative PCR (RT-qPCR) is currently the standard method to monitor it. In the era of tyrosine kinase inhibitors (TKIs) discontinuation, droplet digital PCR (ddPCR) has emerged to provide a more precise detection of MRD. To hypothesize the use of ddPCR in clinical practice, we designed a multicentric study to evaluate the potential value of ddPCR in the diagnostic routine. Thirty-seven RNA samples from CML patients and five from healthy donors were analyzed using both ddPCR QXDxTMBCR-ABL %IS Kit and LabNet-approved RT-qPCR methodologies in three different Italian laboratories. Our results show that ddPCR has a good agreement with RT-qPCR, but it is more precise to quantify BCR-ABL1 transcript levels. Furthermore, we did not find differences between duplicate or quadruplicate analysis in terms of BCR-ABL1% IS values. Droplet digital PCR could be confidently introduced into the diagnostic routine as a complement to the RT-qPCR.
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Following the development of tyrosine kinase inhibitors (TKI), the survival of patients with chronic myeloid leukaemia (CML) drastically improved. With the introduction of these agents, CML is now considered a chronic disease for some patients. Taking into consideration the side effects, toxicity, and high cost, discontinuing TKI became a goal for patients with chronic phase CML. Patients who achieved deep molecular response (DMR) and discontinued TKI, remained in treatment-free remission (TFR). Currently, the data from the published literature demonstrate that 40-60% of patients achieve TFR, with relapses occurring within the first six months. In addition, almost all patients who relapsed regained a molecular response upon retreatment, indicating TKI discontinuation is safe. However, there is still a gap in understanding the mechanisms behind TFR, and whether there are prognostic factors that can predict the best candidates who qualify for TKI discontinuation with a view to keeping them in TFR. Furthermore, the information about a second TFR attempt and the role of gradual de-escalation of TKI before complete cessation is limited. This review highlights the factors predicting success or failure of TFR. In addition, it examines the feasibility of a second TFR attempt after the failure of the first one, and the current guidelines concerning TFR in clinical practice.
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BCR-ABL tyrosine kinase inhibitors (TKIs) dramatically improve the chronic myeloid leukemia (CML) prognosis, and most CML patients in the chronic phase are now able to lead lives that are comparable to those of healthy individuals. However, the high cost and adverse effects associated with long-term treatment remain issues in the treatment of CML patients. At the setout, a clinical study involving the discontinuation of imatinib was conducted in France. Thereafter, several TKI stop studies of first-generation (imatinib) and second-generation TKIs (dasatinib, nilotinib) have shown an earlier response than that with imatinib. These studies revealed that almost 50% of CML patients who were treated with TKIs and achieved a certain period of sustained deep molecular response can stop TKIs safely and obtain sustained treatment-free remission (TFR). Adverse effects of TKI withdrawal and predicting factors for successful discontinuation including immunity are gradually becoming clear via these studies. For superior CML treatment, several promising agents, including ABL001, are being developed. I trust that these efforts will enable CML patients to maintain TFR in the near future.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Dasatinib , Proteínas de Fusión bcr-abl , Humanos , Mesilato de Imatinib , Inducción de Remisión , Resultado del TratamientoRESUMEN
OBJECTIVES: Tyrosine kinase inhibitors (TKIs) account for the vast majority of healthcare expenditure on patients with chronic myeloid leukemia (CML), and it has been demonstrated that TKI discontinuation in patients in long-term deep molecular remission (DMR) is safe and improves quality of life. Our objective was to estimate the budget impact of TKI discontinuation in CML patients in long-term DMR from the perspective of the French healthcare system. METHODS: This analysis was conducted over a 5-year time horizon using a Markov model with cycles of 6 months. Transition probabilities were estimated through systematic reviews and meta-analyses. Costs were estimated from the French National Claims Database. Monte Carlo simulations were performed to take into account the uncertainty surrounding model parameters. Sensitivity analyses were carried out by varying the size of the target population and the cost of TKIs. RESULTS: Over a 5-year period and for a target population of 100 patients each year eligible and agreeing to stop TKI, the TKI discontinuation strategy would save 25.5 million (95% confidence interval -39.3 to 70.0). In this model, the probability that TKI discontinuation would be more expensive than TKI continuation was 12.0%. In sensitivity analyses, mean savings ranged from 14.9 million to 62.9 million. CONCLUSIONS: This study provides transparent, reproducible, and interpretable results for healthcare professionals and policy makers. Our results clearly show that innovative healthcare strategies can benefit both the healthcare system and patients. Savings from generalizing TKI discontinuation in CML patients in sustained DMR should yield health gains for other patients.
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Costos y Análisis de Costo/economía , Atención a la Salud/economía , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas , Calidad de Vida/psicología , Privación de Tratamiento/economía , Francia , Humanos , Revisión de Utilización de Seguros/economía , Modelos Estadísticos , Inhibidores de Proteínas Quinasas/economía , Inhibidores de Proteínas Quinasas/uso terapéutico , Inducción de RemisiónRESUMEN
BACKGROUND: Treatment-free survival (TFS) in chronic myeloid leukemia (CML) is a new goal. This prospective study aims to evaluate imatinib discontinuation's feasibility and safety in patients with deep molecular response MR4 (BCR-ABL1 < 0.01 % IS). METHODS: Study was approved by the ethical committee and registered at Clinicaltrials.gov (NCT03239886). Incluision criteria were: age ≥ 18y, chronic phase, first-line imatinib for 36 months, MR4 for 12 months, no previous transplant or resistance. Imatinib was resumed when two samples confirmed the loss of MMR. The primary endpoint was molecular recurrence-free survival (MRFS) at 24 months. Lymphocyte subpopulations were counted in peripheral blood before discontinuation. RESULTS: 31 patients were included from Dec/2016 until Oct/2017. Median age was 54years, 58 % male, 58 % low Sokal, 65 % b3a2 transcripts, and 61 % were in MR4.5. Imatinib therapy's median time was 9.7y (3-14.9 y), median time of MR4 was 6.9y (1.6-10.3y). MRFS at 24 months was 55 % (95 % CI 39-75). Thirteen patients relapsed, 46 % after six months of discontinuation, and all patients recovered MMR. Median time to recover MMR was one month. MR4.5 was the only factor associated with MRFS. NK cells proportion at baseline was lower in patients with only MR4 who relapsed after discontinuation. CONCLUSION: With a median duration of sustained MR4 above five years, as recommended by most TKI discontinuation guidelines, the TFS was similar to previous studies. Only MR4.5 was associated with lower risk of relapse. Further studies are needed to evaluate whether patients with only MR4 and low NK cell levels are suitable for discontinuation.
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Mesilato de Imatinib/administración & dosificación , Células Asesinas Naturales/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Mesilato de Imatinib/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Recurrencia , Factores de TiempoRESUMEN
Tyrosine kinase inhibitors (TKIs) have drastically changed the outcome of chronic myeloid leukemia (CML) patients. A sustained and deep molecular response achieved over time paves the way to therapy discontinuation, and is a pre-requisite to attempt treatment-free remission. Monitoring of the molecular response during treatment discontinuation is routinely carried out by RQ-PCR, but it may not be the optimal tool to monitor minimal residual disease at the time of stopping treatment and during treatment discontinuation. Different digital PCR platforms (such as droplet dPCR) are available, a method based on water-emulsion droplet technology in which the sample is partitioned into 20,000 droplets and PCR amplification of the template subsequently occurs in each individual droplet. The consequent high sensitivity and precision with a very reliable quantification without the need of a calibration curve and the exquisite reproducibility makes this procedure as an ideal alternative method for the detection of very low levels of disease. Aim of this review is to describe and discuss the recent use of dPCR/ddPCR in CML, focusing in particular on its role in TKI treatment discontinuation strategies.
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Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Neoplasia Residual , Reacción en Cadena de la Polimerasa , Inhibidores de Proteínas Quinasas/uso terapéutico , Reproducibilidad de los ResultadosRESUMEN
Therapy with tyrosine kinase inhibitors (TKI) allows to achieve a deep molecular response in 6070% of patients with chronic myeloid leukemia (CML). According to the current guidelines CML patients receive a long-term treatment with TKI in standard dose. The frequently observed adverse effects (AE) of TKI therapy are mostly dose-dependent. A new treatment approach with TKI use in reduced dose is desirable for the CML patients with existing AE or with a high risk of AE occurrence. We report the two cases of successful long-term treatment of CML patients with reduced doses of second generation TKIs. The aim of the TKI dose reduction was to reduce the clinical manifestations of drug toxicities and to prevent the AE.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Dasatinib , Composición Familiar , Estudios de Seguimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
Introduction: Tyrosine kinase inhibitors (TKIs), which target BCR-ABL1 kinase activity, have significantly prolonged the overall survival of patients affected by chronic myeloid leukemia (CML) and changed drastically the outcome. Evidences from several studies suggest that in patients who have achieved a sustained, stable and deep molecular response, TKI treatment can be safely discontinued with a close subsequent monitoring. Thus, a stable deep molecular response (DMR) has become a feasible treatment goal in CML. Areas covered: In this review, the main findings extrapolated from sponsored and real-life evidences regarding TKI discontinuation were discussed, through a broad research on Medline, Embase and archives from EHA and ASH congresses (including words such as discontinuation, treatment-free remission, TFR, etc). Moreover, suggestions emerged from international guidelines about treatment-free remission (TFR) are presented. Expert opinion: With the growing availability of clinical trials and real-life data on TFR, in recent years the possibility of offering to CML patients a safe, informed and shorter path to TFR, through the achievement of a stable deep molecular response (DMR), has become an increasing option. However, many controversial aspects remain regarding treatment choices and timings, predictive factors, patient communication and optimal strategies aimed at achieving a successful TFR.