RESUMEN
The doubling time (DT) of the BCR-ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re-growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT was calculated as x = ln(2)/K, where x is the DT and K is the fold BCR-ABL1 change from the previous value divided by the number of days between each measurement. The optimal DT value was determined as 12·75 days at two months using a recursive partitioning method. The patients were stratified into three groups: the high-risk group (DT<12·75 days but >0, with rapidly proliferating chronic myeloid leukaemia (CML) cells; n = 26) showed the lowest molecular relapse-free survival (mRFS) of 7·7% at 12 months, compared to 53·6% in the intermediate-risk group (DT≥12·75 days, with slowly proliferating CML cells; n = 16) or 90·0% in the low-risk group (DT≤0, i.e., without proliferating CML cells; n = 71; P < 0·001). Monthly assessment of DT helps identify high-risk patients for treatment-free remission failure with an imminent risk of molecular recurrence, and to define low-risk patients who can be spared the frequent monitoring of monthly molecular tests.
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Proteínas de Fusión bcr-abl/genética , Regulación Leucémica de la Expresión Génica , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/genética , Adulto , Anciano , Biomarcadores de Tumor , Niño , Femenino , Humanos , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/efectos adversos , Leucemia Mieloide de Fase Crónica/diagnóstico , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Reacción en Cadena en Tiempo Real de la Polimerasa , Recurrencia , Inducción de Remisión , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
PURPOSE: Chronic myeloid leukemia (CP-CML) patients can achieve undetectable minimal residual disease (UMRD) and discontinue tyrosine kinase inhibitors (TKIs). Cellular immunity plays an important role in CML disease control. We conducted a randomized, non-blinded phase II trial of adjuvant immunotherapy with TKIs to facilitate TKI discontinuation. METHODS: TKI-treated patients with CP-CML were randomized to receive the K562/GM-CSF vaccine (vaccine) OR Interferon-α + Sargramostim (IFN). If UMRD was achieved, then all treatment was stopped. Patients who did not achieve UMRD within one year, had a molecular relapse, or discontinued therapy for toxicity could crossover. RESULTS: Thirty-four patients were randomized to IFN (n = 18) or vaccine (n = 16), and 21 patients crossed over (IFNâ¶vaccine: n = 9, vaccineâ¶IFN, n = 12). TKIs at enrollment included imatinib (n = 31), nilotinib (n = 2), and dasatinib (n = 1). No patients discontinued vaccine due to side effects, while 33 % of IFN-treated patients discontinued treatment. More patients randomized to IFN (47.4 %, 95 % CI: 16.7-66.7 %) versus vaccine (25.0 %, 95 % CI: 0.5-43.5 %) achieved UMRD within one year. Seven patients randomized to IFN discontinued treatment with 28.6 % (95 % CI: 8.9-92.2 %) sustaining treatment-free remission (TFR) at 1 year, while three patients randomized to vaccine discontinued treatment with none sustaining TFR. Including crossover, there was a cumulative discontinuation success rate of 36.4 % (95 % CI: 16.6 %-79.5 %) after adjuvant IFN. Patients who sustained TFR received a median of 29 months of imatinib prior to discontinuation. CONCLUSION: Adjuvant IFN led to durable TFRs with limited prior TKI exposure with comparable success to prior discontinuation trials, but many patients stopped IFN early.
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Adyuvantes Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Vacunas contra el Cáncer/administración & dosificación , Inmunoterapia/mortalidad , Leucemia Mieloide de Fase Crónica/mortalidad , Adulto , Anciano , Estudios Cruzados , Dasatinib/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Mesilato de Imatinib/administración & dosificación , Interferones/administración & dosificación , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/inmunología , Leucemia Mieloide de Fase Crónica/patología , Masculino , Persona de Mediana Edad , Pronóstico , Pirimidinas/administración & dosificación , Tasa de Supervivencia , Adulto JovenRESUMEN
ABSTRACT: The aim of this study was to evaluate the ability of the red blood cell distribution width (RDW) to predict prognosis and treatment response in chronic myeloid leukemia (CML)-chronic phase (CP) patients treated with tyrosine kinase inhibitor (TKIs).We retrospectively enrolled 93 newly diagnosed CML-CP patients treated with TKIs from 2009 to 2018 at the First Hospital of Lanzhou University. Patients were divided into 2 groups using an RDW of 18.65% determined by receiver operating characteristic curve analysis. We analyzed the correlation of treatment responses and the RDW compared to common scoring systems, as well as the correlation of the RDW with disease outcome, including overall survival (OS) and progression-free survival (PFS), and demographic and laboratory factors affecting outcome. Univariate analysis and Cox regression analysis were used.The median age of patients was 40 years, and 51 patients (54.8%) were men. A high RDW could predict treatment response at 3 months (Pâ=â.03) and 6 months (Pâ=â.02). The RDW was significantly lower in patients who achieved molecular response by 3 months (Pâ<â.001) and complete cytogenetic response by 6 months (Pâ=â.001) than in those who did not respond. Patients with a high RDW (>18.65%, nâ=â35) had significantly worse 5-year OS (77.1% vs 96.6%; Pâ=â.008) and PFS (80.0% vs 98.3%; Pâ=â.002) than those with a low RDW (≤18.65%, nâ=â58). Multivariate analysis demonstrated that a high RDW was an adverse predictor of OS (Pâ=â.005, HR (hazard ratio)â=â9.741) and PFS (Pâ=â.009, HRâ=â16.735).The RDW is a readily available prognostic marker of outcome in patients with CML-CP and can predict treatment response to TKIs. Further larger and prospective studies are required.
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Índices de Eritrocitos , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Leucemia Mieloide de Fase Crónica/sangre , Leucemia Mieloide de Fase Crónica/diagnóstico , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
The ENESTfreedom trial assessed the feasibility of treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) following frontline nilotinib treatment. Results for long-term outcomes after a 5-year follow-up are presented herein. Patients who had received ≥2 years of frontline nilotinib therapy and achieved MR4.5 underwent a 1-year nilotinib treatment consolidation phase before attempting TFR. At the 5-year data cut-off, 81/190 patients entering the TFR phase (42.6%) were still in TFR, with 76 (40.0%) in MR4.5. Patients who lost major molecular response (MMR) entered a treatment re-initiation phase; 90/91 patients entering this phase (98.9%) regained MMR and 84/91 patients (92.3%) regained MR4.5. The Kaplan-Meier estimated treatment-free survival rate at 5 years was 48.2%. No disease progression or CML-related deaths were reported. Whereas the incidence of adverse events (AEs) declined from 96 weeks following the start of TFR, an increase in AE frequency was observed for patients in the treatment re-initiation phase. Low Sokal risk score, BCR-ABL1IS levels at 48 weeks of TFR and stable MR4.5 response for the first year of TFR were associated with higher TFR rates. Overall, these results support the efficacy and safety of attempting TFR following upfront nilotinib therapy of >3 years in patients with CML-CP.
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Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Early molecular response is associated with improved probability of deep molecular response and superior survival in patients with CML-CP. However, ~1 in 3 patients on first-line imatinib do not achieve this threshold. The phase 2b DASCERN trial (NCT01593254) assessed the outcome of early switch to dasatinib in patients with suboptimal response to first-line imatinib. Adult patients with CML-CP were randomized (2:1) to receive 100 mg dasatinib (n = 174) or continue imatinib at ≥400 mg (n = 86). The primary endpoint was the rate of major molecular response (MMR) at 12 months, which was 29% (dasatinib) and 13% (imatinib; P = 0.005). After ≥2 years of follow-up, 45 patients (52%) randomized to continue imatinib had crossed over to dasatinib. Considering treatment crossover, the 2-year cumulative MMR rate was 64% with dasatinib and 41% with imatinib (66% and 67%, respectively by intent-to-treat). Adverse events were consistent with the established safety profiles of both drugs. The results of this first prospective study support early monitoring of patients treated with first-line imatinib, and suggest that switching to dasatinib in cases of suboptimal response may offer clinical benefit. Further follow-up is needed to assess the long-term clinical benefit of early switching.
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Dasatinib/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Dasatinib/efectos adversos , Femenino , Humanos , Mesilato de Imatinib/efectos adversos , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: Dasatinib is a second-generation tyrosine kinase inhibitor that, when used as frontline therapy, produces more and faster cytogenetic and molecular responses compared with imatinib. The authors report the long-term follow-up from the first study using dasatinib as initial therapy for chronic-phase chronic myeloid leukemia. METHODS: Between November 2005 and August 2014, patients were randomly assigned to receive 100 mg daily or 50 mg twice daily. After June 2009, all patients started with 100 mg daily. RESULTS: With a median follow-up of 6.5 years, 94 of 149 treated patients (63%) were still receiving dasatinib on study. The median patient age was 48 years (interquartile range, 37-55 years), and 9% of patients had a high risk Sokal risk score. The cumulative complete cytogenetic response rate at 11 years was 92.6%, the major molecular response (MR) rate was 88.2%, and the MR4.5 rate (indicating a ≥4.5-log reduction in BCR-ABL1 transcripts) was 79.5%. The median time to a major MR and MR4.5 was 6 and 23 months, respectively. A sustained MR4.5 (≥2 years) was achieved in 82 patients (55%). The 10-year overall survival, transformation-free survival, event-free survival, and failure-free survival rates were 89%, 95%, 86%, and 65%, respectively. Univariate analysis showed that the achievement of a complete MR was associated with improved overall survival. The most common reasons for treatment discontinuation were toxicity and elective discontinuation. The most common treatment-emergent grade 3 and 4 adverse events were fatigue, thrombocytopenia, and infections. CONCLUSIONS: After this long-term follow-up, dasatinib continues to show an excellent safety profile and produces rapid cytogenetic responses and MRs, durable deep MRs, and excellent long-term survival outcomes in patients with chronic-phase chronic myeloid leukemia.
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Antineoplásicos/uso terapéutico , Dasatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Adulto , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Tiempo , Resultado del TratamientoRESUMEN
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) improve the survival rate of patients with chronic myeloid leukemia (CML). However, elderly patients often experience adverse events and require dose adjustments, leading to dose interruptions or treatment discontinuation. We therefore investigated TKI dosing patterns and subsequent outcomes in elderly CML patients. PATIENTS AND METHODS: Using the National Health Information Database, we identified patients with CML aged ≥ 70 years who were prescribed TKIs (imatinib, dasatinib, nilotinib, or radotinib) during 2007-2013. Data on age, sex, prescribed medication, and date of death were extracted. RESULTS: Among the 378 patients, the median age was 75 (range, 70-92) years; the median follow-up period was 53 (range, 1-133) months. Imatinib, dasatinib, nilotinib, and radotinib were prescribed to 324 (85.7%), 110 (29.1%), 93 (24.6%), and 15 (4.0%) patients, respectively. In 42 patients (12.2%), the initial dose was lower than the recommended dose for chronic-phase CML. At last follow-up, 249 patients (65.9%) were receiving a reduced dose. The mean ± standard deviation dose densities of imatinib, dasatinib, nilotinib, and radotinib were 207 ± 121.6, 29 ± 26.7, 235 ± 197, and 123 ± 95.4 mg/day, respectively. The estimated 5-year overall survival probability was 61.0%. Initial TKI dose or dose reduction within first year did not affect the overall survival (P = .0571 and .1826, respectively). CONCLUSION: Dose reduction was observed in 65.9% of the patients at their last visit; except for imatinib, TKI dose densities were < 50% of the recommended dose for the chronic phase. Therefore, the recommended TKI doses might be too high for elderly patients with CML.
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Antineoplásicos/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Factores de Edad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mieloide de Fase Crónica/diagnóstico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Terapia Molecular Dirigida , Pronóstico , Modelos de Riesgos Proporcionales , Vigilancia en Salud Pública , República de Corea/epidemiología , Resultado del TratamientoAsunto(s)
Antineoplásicos/efectos adversos , Enfermedad de Gilbert/complicaciones , Glucuronosiltransferasa/genética , Hiperbilirrubinemia/inducido químicamente , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Sustitución de Medicamentos , Femenino , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Estudios de Asociación Genética , Genotipo , Enfermedad de Gilbert/genética , Glucuronosiltransferasa/antagonistas & inhibidores , Enfermedades Hematológicas/inducido químicamente , Humanos , Hiperbilirrubinemia/genética , Leucemia Mieloide de Fase Crónica/complicaciones , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/antagonistas & inhibidores , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/uso terapéutico , TATA Box/genética , Adulto JovenRESUMEN
Forty-three chromosomal abnormalities in Philadelphia-negative metaphases (Ph-CAs) appeared in 35 of 432 patients in chronic phase chronic myeloid leukemia (CP-CML) undergoing tyrosine kinase inhibitor (TKI) treatments. These CAs were mostly common in trisomy-8 (16 cases), trisomy-Y (five cases), and monosomy-7 (five cases). Furthermore, Ph- CAs were significantly associated with higher platelet count (494 × 109/L vs. 326 × 109/L, p = .006), and higher incidence of true clonal evolution in Ph-positive metaphase (22.9% vs. 9.1%, p = .017). Additionally, patients with Ph- CAs had worse rates of complete cytogenetic remission (76% vs. 86%, p = .0091), major molecular remission (55% vs. 76%, p = .001), progression-free survival (47% vs. 86%, p < .001), but a similar overall survival rates compared to those in patients without Ph- CAs. In conclusion, Ph- CAs may predict worse response to TKI therapies and survival in patients with CP-CML, thus requiring close cytogenetic monitoring.
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Aberraciones Cromosómicas/inducido químicamente , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/mortalidad , Metafase , Cromosoma Filadelfia , Inhibidores de Proteínas Quinasas/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Análisis Citogenético , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenAsunto(s)
Biomarcadores de Tumor/genética , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Humanos , Leucemia Mieloide de Fase Crónica/diagnóstico , Leucemia Mieloide de Fase Crónica/mortalidad , Reacción en Cadena de la Polimerasa , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inducción de Remisión , Resultado del TratamientoRESUMEN
Imatinib, the first BCR/ABL kinase inhibitor approved for the treatment of chronic myeloid leukemia (CML), has changed the long-term outcome of patients affected by this disease. The aim of our analysis was to report, after a median follow-up of 10.2 years (range 5.8-14.8), the long-term outcome, efficacy, and safety of imatinib treatment (frontline and after interferon failure) in a single institution cohort of 459 patients with CML in chronic phase treated outside of clinical trials. The 10-year overall survival of the whole cohort was 77.1%, while the 10-year probability of dying due to CML and other causes was 7.8% and 16%, respectively. The prognostic value of the BCR-ABL1 ratio at 3 months (⩽ 10%) and of complete cytogenetic response and major molecular response at 1 year was confirmed also in the real-life practice. The EUTOS long-term survival score better stratified the baseline risk of dying of CML compared with other risk scores. Two hundred thirty-six (51.4%) patients achieved a deep molecular response during imatinib treatment after a median time of 4.57 years, and 95 (20.6%) had a stable deep molecular response maintained for at least 2 consecutive years. Imatinib was associated with a low rate of serious cardiovascular events and second neoplasia. This 10-year real-life follow-up study shows that imatinib maintains efficacy over time and that long-term administration of imatinib is not associated with notable cumulative or late toxic effects.
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Antineoplásicos/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/mortalidad , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Interferones/administración & dosificación , Leucemia Mieloide de Fase Crónica/complicaciones , Leucemia Mieloide de Fase Crónica/diagnóstico , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Inducción de Remisión , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Considering the risk of arterio-thrombotic adverse events (AEs), ponatinib trials in previously untreated chronic myeloid leukemia chronic phase (CML-CP) were terminated. We conducted a retrospective CML-CP outcome study of patients who discontinued frontline-ponatinib. Among 51 patients who received frontline ponatinib, 38 discontinued because of FDA request and 13 due to AEs. At ponatinib discontinuation, all patients remained in CP with deepest response being CCyR, n = 7; PCyR, n = 4; MMR, n = 14; MR4.5, n = 26. Of the four patients in PCyR at ponatinib discontinuation, two improved response to CCyR on subsequent TKI. Of seven patients, in CCyR at discontinuation, five improved response to MMR or deeper, one was inevaluable, and another lost response due to treatment noncompliance. With a median follow-up of 39 months, 3-year EFS and OS were 92% and 96%, respectively, indicating favorable long-term outcomes. The cardiac/vascular system AEs with subsequent TKI occurred in patients with prior similar events on ponatinib. AEs occurred up to 9 months post-ponatinib.
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Imidazoles/administración & dosificación , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridazinas/administración & dosificación , Trombosis/epidemiología , Privación de Tratamiento , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Imidazoles/efectos adversos , Estimación de Kaplan-Meier , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Piridazinas/efectos adversos , Estudios Retrospectivos , Trombosis/inducido químicamente , Trombosis/prevención & control , Adulto JovenRESUMEN
Objective: In clinical trials of second-line therapies for chronic phase chronic myeloid leukemia (CP-CML), to date, only single-arm trials have been conducted for the available tyrosine kinase inhibitor treatments (bosutinib, dasatinib and nilotinib). These trials included heterogeneous patient populations in terms of disease and baseline characteristics. These hamper the use of standard network meta-analyses for indirect treatment comparison of relative efficacy. In this situation, a matching-adjusted indirect comparison (MAIC) in second-line CP-CML was performed. The aim was to compare the relative efficacies of bosutinib, dasatinib and nilotinib in second-line CP-CML patients.Methods: The MAIC was preceded by a systematic literature review that ensured inclusion of the underlying data for the analyses. The outcomes were measured in terms of overall survival (OS), progression-free survival (PFS) and major cytogenetic response (MCyR). The treatments were quantitatively compared based on Cox proportional hazard ratio (HR) regressions, on restricted mean survival (RMST, when the proportionality assumption showed evidence of violation) and on odds ratios (for response measures).Results: Comparing with dasatinib, bosutinib resulted in HRs for PFS and OS of 0.63 (0.44-0.90, p < .05) and 0.82 (0.54-1.26, p = .37) respectively, and resulted in an OR for MCyR of 0.78 (0.53-1.16). Although the proportionality of hazards assumption was violated for PFS, the RMST analyses confirmed the findings of the Cox regression. When compared with nilotinib, bosutinib showed a significant HR of 0.54 (0.38-0.76, p < .01) in favor of bosutinib for PFS, a non-significant HR of 0.72 (0.46-1.13, p = .16) for OS and a non-significant OR of 0.98 (0.71-1.35) for MCyR.Conclusions: Bosutinib had a significantly greater PFS than both dasatinib and nilotinib. For OS, the findings were numerically in favor of bosutinib, but not statistically significant. For MCyR, the findings were numerically in favor of dasatinib and nilotinib, but not statistically significant.
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Compuestos de Anilina/uso terapéutico , Dasatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Nitrilos/uso terapéutico , Pirimidinas/uso terapéutico , Quinolinas/uso terapéutico , Análisis Citogenético , Femenino , Humanos , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Supervivencia sin ProgresiónRESUMEN
For patients with chronic myeloid leukemia in chronic phase with sustained deep molecular responses on long-term tyrosine kinase inhibitor (TKI) therapy, treatment-free remission (TFR) feasibility has been established. TFR is now a treatment goal for patients meeting specific criteria; NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for CML have developed criteria for attempting TFR outside clinical trials, and TFR was added to the US Food and Drug Administration-approved nilotinib label. Importantly, TFR studies vary in design and characteristics of participating patients. We discuss key study design elements to consider when assessing results from TFR trials, including criteria for attempting TFR, characteristics of enrolled patients, use of a consolidation phase (whereby patients continue TKI treatment on study before attempting TFR), and criteria for restarting TKI therapy. Finally, we review the criteria outlined in the NCCN Guidelines® for TFR outside clinical trials and compare to criteria used in TFR studies.
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Ensayos Clínicos como Asunto , Leucemia Mieloide de Fase Crónica/diagnóstico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Biomarcadores de Tumor , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Humanos , Leucemia Mieloide de Fase Crónica/mortalidad , Guías de Práctica Clínica como Asunto , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inducción de Remisión , Proyectos de Investigación , Resultado del TratamientoAsunto(s)
Antineoplásicos/uso terapéutico , Proteína 11 Similar a Bcl2/genética , Biomarcadores de Tumor/genética , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Valor Predictivo de las Pruebas , Pronóstico , Eliminación de Secuencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Bosutinib is a Src/Abl tyrosine kinase inhibitor indicated for adults with newly-diagnosed Philadelphia positive chronic myeloid leukemia or with resistant/intolerant disease. We report the final results of a phase I/II study of second-line bosutinib in chronic phase chronic myeloid leukemia patients after imatinib failure (n=284). Median follow up and treatment durations were 54.8 (range 0.6-96.3) and 25.6 (0.2-96.3) months, respectively. At years 2 and 5, 54% and 40% of patients, respectively, remained on bosutinib. Cumulative major cytogenetic response and complete cytogenetic response rates (newly-attained or maintained from baseline) were 58% and 46%, respectively, by year 2 and 60% and 50% by year 5. Kaplan-Meier probability of maintaining major and complete cytogenetic response was 76% and 78%, respectively, at year 2 and 71% and 69% at year 5. Cumulative incidence of on-treatment disease progression/death was similar at years 5 (19%) and 2 (15%); Kaplan-Meier overall survival was 91% at year 2 and 84% at year 5. Of 169 patients who had discontinued bosutinib by year 5, 38 did so after year 2, most commonly for disease progression (n=11). Most adverse events initially occurred within two years. Overall, gastrointestinal events were the most common (diarrhea 86%, nausea 46%, vomiting 37%); the most common grade 3/4 toxicity was thrombocytopenia (25%). None of the 4 on-treatment deaths in years 3-5 were related to bosutinib. Bosutinib demonstrated durable efficacy and manageable toxicity through year 5 confirming its importance in the treatment of chronic phase chronic myeloid leukemia patients resistant/intolerant to prior imatinib. This trial was registered at clinicaltrials.gov identifier: 00261846.
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Compuestos de Anilina/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Nitrilos/uso terapéutico , Quinolinas/uso terapéutico , Adolescente , Adulto , Anciano , Compuestos de Anilina/efectos adversos , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Estudios de Seguimiento , Humanos , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/complicaciones , Leucemia Mieloide de Fase Crónica/mortalidad , Persona de Mediana Edad , Nitrilos/efectos adversos , Fragmentos de Péptidos/uso terapéutico , Quinolinas/efectos adversos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: This multicenter cooperative study aimed to analyze the adverse events (AEs) associated with tyrosine kinase inhibitors (TKIs) used as initial treatment for chronic-phase chronic myeloid leukemia (CML-CP) and their impact on outcome. METHODS: We retrospectively evaluated 450 patients with CML-CP who received TKIs between 2004 and 2014. RESULTS: The 5-year overall survival (OS) and event-free survival (EFS) rates were 95.1% and 89.0%, respectively. Patients with comorbidities (46.4%) and aged ≥60 years (50.4%) at diagnosis had significantly inferior OS to those without comorbidities and aged <60. Patients achieved higher rates of major molecular response (MMR) at 6 and 12 months after initial treatment with dasatinib or nilotinib compared to imatinib, but final MMR rates were almost the same. Sixty-six percent of patients required treatment modifications from first-line TKI therapy; the main reasons were AEs (48.4%) and failure (18%). Grade III-IV AEs in first-line TKI therapy were significantly correlated to inferior OS/EFS compared to grade 0-II AEs. CONCLUSION: Although long-term outcomes were similar in CML-CP patients treated with each TKI regardless of first-line TKI selection, severe AEs in first-line TKI therapy decreased their survival rates. Early change in TKIs is recommended, when faced with severe AEs of specific TKIs.
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Antineoplásicos/efectos adversos , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide de Fase Crónica/diagnóstico , Inhibidores de Proteínas Quinasas/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Niño , Preescolar , Dasatinib/administración & dosificación , Dasatinib/efectos adversos , Femenino , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/efectos adversos , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/mortalidad , Leucemia Mieloide de Fase Crónica/patología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Chronic, low-grade adverse events are common in patients with chronic myeloid leukemia who are treated with imatinib. These events may decrease patient quality of life and adherence, and may ultimately contribute to a suboptimal response. Alternative, second-generation tyrosine kinase inhibitors, such as dasatinib, are available with the potential to reduce adverse events, improve tolerability, and support long-term treatment goals. We present the final, primary analysis of DASPERSE/CA180-400 (NCT01660906), an open-label, multicenter, phase IV study designed to determine whether chronic, low-grade nonhematologic adverse events in imatinib-treated patients improve after switching to dasatinib, without affecting efficacy. Of the 121 chronic, grade 1/2, imatinib-related adverse events identified at baseline in 39 patients, 77% resolved or improved within 3 months after switching to dasatinib. Dasatinib maintained a consistent safety profile; headache (33%), pleural effusion (26%), fatigue (23%), and rash (23%) were the most common treatment-related adverse events after the switch. Patients either maintained (56%) or improved (44%) their molecular response on dasatinib. Patients who switched to dasatinib also experienced improved patient-reported symptom burden from baseline as assessed by the MD Anderson Symptom Inventory for chronic myeloid leukemia (on a 1-10 scale, mean change in disease-specific score was - 2.24 and core symptom severity score was - 1.06). Overall, the efficacy and quality of life/symptom burden improved in many patients, despite the onset of dasatinib-related adverse events in most patients. This suggests that imatinib-treated patients with chronic, low-grade adverse events could benefit from switching to treatment with dasatinib.
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Dasatinib/uso terapéutico , Sustitución de Medicamentos , Mesilato de Imatinib/efectos adversos , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Dasatinib/administración & dosificación , Dasatinib/efectos adversos , Femenino , Humanos , Leucemia Mieloide de Fase Crónica/mortalidad , Leucemia Mieloide de Fase Crónica/patología , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
This prospective, observational study enrolled 150 adult patients with chronic myeloid leukaemia (CML) in chronic phase (CP) treated with nilotinib as second-line after imatinib, in a real life setting in France. Two-thirds of patients switched to nilotinib treatment due to lack of imatinib efficacy. Of 146 evaluable patients, 16 (11·0%) (95% confidence interval: 6·4-17·2%) achieved uMR4 , defined as undetectable molecular disease in cDNA with MR4 sensitivity (≥10 000 ABL1 transcripts) at 18 months and confirmed at 24 months (primary endpoint). Among patients without major molecular response (MMR) or deep molecular response (DMR) at study entry, 66·3% achieved MMR and 44·2% DMR within a median of 5·7 and 6·24 months, respectively. Fifty-three patients (36·3%) have prematurely terminated the study before 24 months of follow-up, primarily due to nilotinib treatment discontinuation (n = 43; 29·5%), mainly motivated by treatment intolerance (n = 27; 18·5%) and inefficacy (n = 10; 6·8%). The most frequent extra-haematological adverse events (AEs) reported as related to treatment with nilotinib were pruritus (16·4%), asthenia (13·7%) and dry skin (13·0%). Ischaemic cardiovascular AEs were reported in 18 patients (12·3%). This French nationwide large cohort adds valuable information to the body of evidence on the efficiency and safety of nilotinib in the treatment of patients with CP-CML.
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Antineoplásicos/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Estudios de Cohortes , Resistencia a Antineoplásicos , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/efectos adversos , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/mortalidad , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Retratamiento , Resultado del TratamientoRESUMEN
Ponatinib is a pan-tyrosine kinase inhibitor (TKI) with efficacy in multirefractory CML patients who have failed other TKIs. Despite excellent response rates, resistance or intolerance may develop. We conducted a retrospective review of the outcome of patients with chronic (CP) and accelerated (AP) phase CML refractory to prior TKI who discontinued ponatinib for resistance or intolerance. Nineteen CP patients, discontinued due to resistance (n = 13), toxicity (n = 5) and to pursue stem cell transplantation (n = 1). At discontinuation, 14 were still in CP, three had progressed to AP and two to blast phase (BP). Three CP patients improved their cytogenetic response (CyR) to complete CyR (CCyR), two after SCT and one on omacetaxine. None of the 12 patients, without a major cytogenetic response at ponatinib discontinuation, including all patients treated with subsequent TKIs, responded to therapy. Seventeen AP patients, stopped ponatinib due to resistance (n = 15) or intolerance (n = 2). At discontinuation, 14 were still in AP and three had progressed to BP. Four patients were treated with SCT and one achieved major molecular response. None of the 12 patients treated with non-SCT approaches responded to subsequent therapy. Median survival for all patients was 16.6 months after ponatinib discontinuation (31, 9 and 13 months for patients in CP, AP and BP, respectively). Median survival was 60 months for patients who discontinued ponatinib for toxicity and 11 months for those who discontinued for resistance. Long-term outcome of patients with ponatinib failure are poor with estimated one-year OS and EFS rates of 54% and 40%, respectively. New treatment options are required for this subset of patients.