RESUMEN
Tyrosine kinase inhibitors (TKIs), the backbone of treatment for chronic phase chronic myeloid leukemia patients (CP-CML), have changed the long-term outcome of the disease. Nonetheless, over 20% of patients fail front-line therapy due to intolerance or resistance. A head-to-head comparison of dasatinib and nilotinib as second-line treatment outside of sponsored clinical trials has not been reported. We retrospectively analyzed 131 CP-CML patients who, after front-line imatinib failure, switched to a second-line therapy with nilotinib (59, 45%) or dasatinib (72, 55%). Median duration of second-line treatment was 33 months (range 2-100). The reason for switching therapy was resistance in 83.2% and intolerance in 16.8% of patients. The overall survival of the entire cohort at 7 years was 78.9%, while it was 72% and 85.6% for patients treated with dasatinib and nilotinib, respectively (p=0.287). With regard to efficacy after 12 months of treatment, 108 patients were evaluable for molecular response: 47% achieved a major molecular response and 18.2% a deep molecular response with dasatinib, compared to 38% and 16.2% with nilotinib (p=ns). We observed 35% of grade 3-4 adverse events, more frequently in the dasatinib group (47%) compared to the nilotinib group (22%), without affecting molecular responses. Our study suggests that, in the real-life setting, dasatinib and nilotinib used as second-line treatment in CP-CML are equally effective, with high molecular response rates and an acceptable tolerability.
Asunto(s)
Antineoplásicos/uso terapéutico , Dasatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Pirimidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Resistencia a Antineoplásicos , Femenino , Humanos , Mesilato de Imatinib/uso terapéutico , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
We report the long-term outcome of 139 patients treated with imatinib in late chronic phase after IFN failure. Median follow-up was 16.6 years and the estimated 18-year OS was 64.8%. 18-year EFS and PFS were 69% and 64.4%, respectively. Fifty (36%) patients stopped imatinib, 72% received a second line. b2a2 transcript was associated with a significantly inferior 18-year OS (p = 0.008), FFS (p = 0.036), PFS (p = 0.013) compared to the b3a2 type, whilst the type of transcript did not influence the time to response achievement. Failure to achieve MMR at 12 months significantly reduced the chance of reaching a DMR (p = 0.001). Imatinib discontinuation after achieving a sustained deep molecular response was attempted in 14 patients; 12 (86%) are still in treatment-free remission (TFR) at the last follow-up. Our experience confirms the long-term efficacy of imatinib after IFNα failure in real-life setting and documents the possibility of attempting a TFR in this subset of patients.
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Antineoplásicos , Leucemia Mieloide de Fase Crónica , Antineoplásicos/uso terapéutico , Estudios de Seguimiento , Proteínas de Fusión bcr-abl , Humanos , Mesilato de Imatinib/uso terapéutico , Interferón-alfa/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del TratamientoAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Nitrilos/uso terapéutico , Mielofibrosis Primaria/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Escamosas/complicaciones , Humanos , Masculino , Mielofibrosis Primaria/complicaciones , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Cutáneas/complicacionesRESUMEN
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
BACKGROUND: According to 2008/2016 classification of the World Health Organization (WHO), a platelet (PLT) count ≥ 450 × 109/L, reduced from the previously published WHO 2001 indicated level ≥ 600 × 109/L, was considered the new PLT threshold for the diagnosis of essential thrombocythemia (ET). PATIENTS AND METHODS: To validate this important diagnostic change in a setting of current clinical practice, we retrospectively analyzed clinical and hematologic features at diagnosis and during follow-up of 162 patients with ET, diagnosed in our center from January 2008 to December 2017. We subdivided patients according to PLT value at baseline into Group A (PLT ≥ 600 × 109/L) (124 patients; 76.5%) and Group B (PLT ≥ 450 × 109/L < 600 × 109/L) (38 patients; 23.5%). RESULTS: Among clinical features, only the median value of leukocytes (P < .001) was significantly higher in Group A. Cytostatic treatment was administered in 103 patients, with a significantly higher rate in patients of group A (P < .001). After a median follow-up of 42.4 months (interquartile range, 22.1-70.6 months), 8 thrombotic events were recorded in the entire cohort, without differences between the 2 groups (P = .336). The 5-year overall survival (OS) of the entire cohort was 96.9% (95% confidence interval, 92.6%-100%), without differences between the 2 groups (P = .255). CONCLUSIONS: Our data indicate a substantial homogeneity among patients with ET regardless of the PLT count at diagnosis, thus confirming the usefulness of the 2008/2016 WHO diagnostic criteria.
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Citostáticos/administración & dosificación , Recuento de Plaquetas/normas , Trombocitemia Esencial/diagnóstico , Trombosis/epidemiología , Anciano , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Pronóstico , Valores de Referencia , Estudios Retrospectivos , Factores de Riesgo , Trombocitemia Esencial/sangre , Trombocitemia Esencial/complicaciones , Trombocitemia Esencial/tratamiento farmacológico , Trombosis/sangre , Trombosis/etiología , Trombosis/prevención & control , Organización Mundial de la SaludRESUMEN
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.
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Antineoplásicos/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Esquema de Medicación , Monitoreo de Drogas , Proteínas de Fusión bcr-abl/análisis , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Metaanálisis como Asunto , Dolor Musculoesquelético/inducido químicamente , Estudios Observacionales como Asunto , Pronóstico , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , ARN Mensajero/análisis , ARN Neoplásico/análisis , Recurrencia , Inducción de Remisión , Síndrome de Abstinencia a Sustancias/etiología , Privación de TratamientoRESUMEN
BACKGROUND AND OBJECTIVE: In the last decades, the chronic myeloid leukemia (CML) therapeutic landscape has changed dramatically with the introduction of tyrosine kinase inhibitors (TKIs), with 10-year survival rates improving to up to 80%. Long-lasting TKI treatment, in particular with second-generation TKIs, has enabled clinicians to manage the onset of several side effects and other co-morbidities, such as atrial fibrillation or venous thromboembolism (VTE). METHODS: We retrospectively evaluated nine CML patients treated with TKIs between 2017 and 2020 who experienced atrial fibrillation or VTE and received concomitant administration of TKIs and direct oral anticoagulants (DOACs) outside clinical trials, to evaluate the efficacy and safety of this combination. RESULTS: Median age was 66 years at CML diagnosis (range 52-73 years) and 69 years at the time of starting DOACs. A female predominance was observed. The median follow-up of concomitant DOAC and TKI administration was 8.5 months; edoxaban was administered in six patients and apixaban in two patients, and one patient received rivaroxaban. Regarding CML treatment, four patients received imatinib, two patients bosutinib, and three nilotinib. In eight patients DOACs were started for atrial fibrillation and in one patient for VTE. In none of the patients treated with the combination were additional symptomatic thrombotic adverse events or major bleedings reported. CONCLUSION: In this small case series, the use of DOACs in CML patients seemed feasible. Additional data on long-term outcomes including a larger cohort of CML patients treated with DOACs are, however, needed.
Asunto(s)
Anticoagulantes/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Administración Oral , Adulto , Anciano , Compuestos de Anilina , Estudios de Cohortes , Femenino , Hemorragia/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Pirimidinas , Quinolinas , Estudios Retrospectivos , Tromboembolia VenosaRESUMEN
INTRODUCTION: Patients with cancer may be more susceptible to and have higher morbidity and mortality rates from COVID-19 than the general population, while epidemiologic data specifically addressed to hematologic patients are limited. To investigate whether patients with hematologic diseases undergoing therapy are at increased risk for acquiring SARS CoV-2 infection compared to the general population, a retrospective study was carried out at a referral hematologic center in Rome, Italy, during the period of the greatest epidemic spread (March 8 to May 14, 2020). METHODS: All adult and pediatric patients with a diagnosis of a neoplastic or a nonneoplastic hematologic disease who underwent treatment (chemotherapy or immunosuppressive or supportive therapy) during the study period or in the previous 6 months were considered. The prevalence of COVID-19 in the overall outpatient and inpatient population undergoing hematologic treatment compared to that of the general population was analyzed. The measures taken to manage patients during the epidemic period are described. RESULTS: Overall, 2,513 patients with hematological diseases were considered. Out of 243 (9.7%) patients who were screened for SARS CoV-2, three of 119 (2.5%) outpatients with fever or respiratory symptoms and none of 124 asymptomatic patients were diagnosed with COVID-19. Three further patients were diagnosed with COVID-19 and managed in other hospitals in Rome. As of May 14, 2020, the prevalence of COVID-19 in our hematologic population accounted for 0.24% (95% CI 0.23-0.25; 6 of 2,513 patients: 1 case in every 419 patients) as compared to 0.12% (7,280 of 5,879,082 residents; 1 case in every 807 residents) in the general population (p = 0.14). Three of 6 patients diagnosed with COVID-19 required critical care and 2 died while still positive for SARS CoV-2. Out of 225 healthcare providers on duty at our Institution during the study period, 2 (0.9%) symptomatic cases were diagnosed with COVID-19. CONCLUSION: In our experience, the prevalence of COVID-19 in hematologic patients, mainly affected by malignancies, was not significantly higher compared to that of the general population. Definition of adapted strategies for healthcare services, while continuing to administer the standard hematologic treatments, represents the crucial challenge for the management of hematologic diseases in the COVID-19 era.
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COVID-19/diagnóstico , Enfermedades Hematológicas/complicaciones , Adolescente , Adulto , Anciano , COVID-19/complicaciones , COVID-19/epidemiología , COVID-19/virología , Niño , Femenino , Enfermedades Hematológicas/tratamiento farmacológico , Enfermedades Hematológicas/terapia , Humanos , Inmunosupresores/uso terapéutico , Italia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , SARS-CoV-2/aislamiento & purificación , Centros de Atención Terciaria , Adulto JovenRESUMEN
INTRODUCTION: Polycythemia vera is a myeloproliferative neoplasm characterized by an increased red blood cell mass, risk of thromboembolic events, and of transformation into secondary myelofibrosis and acute leukemia. The goal of treatment is to reduce the risk of fatal cardiovascular events reducing the hematocrit level with phlebotomies and low-dose aspirin. In high-risk patients (age >60 years or previous thromboembolic events) cytoreductive therapy is indicated. In this setting, resistance and/or intolerance is common. AREAS COVERED: Authors searched Medline, Embase, archives from the EHA and the ASH annual congresses from 2014 onward about ruxolitinib treatment in PV patients. Two trials (RESPONSE and RESPONSE2) have documented the efficacy and safety of ruxolitinib. The drug is able to persistently control the hematocrit level and symptoms (due to increased cytokine levels, increased viscosity, and increased splenomegaly), to reduce WBC counts and the rate of thromboembolic events, to increase the quality of life. EXPERT OPINION: Although ruxolitinib has entered into the clinical practice, the real-life incidence of resistant/intolerant patients, the long-term safety, and the activity on thromboembolic events (associated or not to a reduction of the molecular burden) remains to be conclusively determined. More information extrapolated by registries are required to shed light on the missing information.
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Inhibidores de las Cinasas Janus/uso terapéutico , Policitemia Vera/tratamiento farmacológico , Pirazoles/uso terapéutico , Ensayos Clínicos como Asunto , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Resistencia a Antineoplásicos , Humanos , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Inhibidores de las Cinasas Janus/farmacología , Terapia Molecular Dirigida , Mutación , Nitrilos , Policitemia Vera/diagnóstico , Policitemia Vera/etiología , Pronóstico , Pirazoles/farmacología , Pirimidinas , Resultado del TratamientoRESUMEN
Predictive factors of response to hypomethylating agents (HMA) in elderly acute myeloid leukemia (AML) patients remain unclear in the real-life setting and no direct comparison between azacitidine (AZA) and decitabine (DEC) has been carried out. We retrospectively evaluated 110 AML patients treated with HMA (78 AZA, 32 DEC) as first-line therapy outside of clinical trials. Median age was 75 years (range 58-87). The median overall survival (OS) of the entire cohort was 8.0 months (95% CI 6.1-10), without significant differences among the subgroups: AZA 8.8 months vs DEC 6.3 months (p = 0.291). HMA treatment yielded an overall response rate (ORR) of 40% (AZA 37% vs DEC 47%, p = 0.237). A stable disease (SD) after 4 HMA cycles was not associated with a worse survival outcome compared with an early optimal response. Factors independently associated with a better OS were transfusion independence during treatment (p = 0.049), achievement of an optimal response to treatment (p < 0.001), and a baseline hemoglobin level ≥ 9.25 (p = 0.018). A bone marrow (BM) blast count ≥ 30% (p < 0.001) and a therapy-related AML (p = 0.008) remain poor survival predictors. Of the available biologic features, an adverse risk category according to the ELN classification was significantly associated with a shorter survival over the intermediate risk category (p = 0.034). Disease progression remains the primary cause of death. Infectious complications were more severe (p = 0.036) and occurred earlier (p = 0.006) in the DEC group compared with that of the AZA group. In conclusion, clinical prognostic factors associated to response and survival have been identified without significant associations concerning overall outcomes between the two HMAs.
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Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Metilación de ADN/efectos de los fármacos , ADN de Neoplasias/efectos de los fármacos , Decitabina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Médula Ósea/patología , Causas de Muerte , Recuento de Células , ADN de Neoplasias/química , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Hemoglobinas/análisis , Humanos , Infecciones/etiología , Infecciones/mortalidad , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Células Madre Neoplásicas , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
The role of positron emission tomography/computed tomography (PET/CT) in identifying Richter Syndrome (RS) is well established, while its impact on the survival of patients with chronic lymphocytic leukemia (CLL) has been less explored. The clinical characteristics and PET/CT data of 40 patients with a biopsy-proven CLL who required frontline chemoimmunotherapy, FCR (fludarabine, cyclophosphamide, rituximab) in 20 patients, BR (bendamustine, rituximab) in 20, were retrospectively analyzed. Standardized uptake volume (SUVmax) values ≥ 5 were observed more frequently in patients with deletion 11q (p = 0.006) and biopsies characterized by a rate of Ki67 positive cells ≥ 30% (p = 0.02). In the multivariate analysis, the presence of large and confluent PCs emerged as the only factor with a negative impact on progression-free survival (PFS), and overall survival (OS). Deletion 11q also revealed a significant and independent effect on PFS. SUVmax values ≥ 5 showed no statistical impact on PFS while in multivariate analysis, they revealed a significant adverse impact on OS (median survival probability not reached vs. 56 months; p = 0.002). Moreover, patients with higher SUVmax values more frequently developed Richter Syndrome (p = 0.015). Our results show that higher SUVmax values identify CLL patients with a pronounced rate of proliferating cells in the lymph-node compartment, inferior survival, and an increased risk of developing RS.
RESUMEN
Since July 2017, different generic imatinib formulations have been introduced in Italy for the treatment of patients with chronic myeloid leukemia (CML). We analyzed 168 chronic phase CML patients treated with branded imatinib for a median of 12 years (range 1-16) at a single institution who switched to a single generic formulation in order to assess the safety and impact on molecular response. The Sokal risk was low/intermediate/high in 63%, 33%, and 4% of patients, respectively. The median duration of generic imatinib treatment was 19 months (range 4-22). Twenty-seven percent of patients were in MMR and 73% were in deep molecular responses (MR4-4.5) at the time of the switch. After 12 months of treatment with generic imatinib, 140 patients were evaluable for response: 23.6% and 76.4% were respectively in MMR and in deep molecular response. When the degree of response was compared with the best molecular response observed with branded imatinib, it was found that 84% of patients maintained the response previously achieved, 6% improved it, and 10% of patients had a molecular fluctuation from the previous deep molecular response to MMR. Only 1 patient lost the MMR and no patient switched to another TKI for inefficacy. In terms of safety, 20% of patients reported new or worsening side effects, but only 2 patients returned to branded imatinib for toxicity. Our data show that the switch to generic imatinib in patients who have been previously treated with branded imatinib appears to maintain efficacy, although a proportion of patients experience new or worsening side effects.
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Antineoplásicos/administración & dosificación , Sustitución de Medicamentos/métodos , Medicamentos Genéricos/administración & dosificación , Mesilato de Imatinib/administración & dosificación , Leucemia Mieloide de Fase Crónica/diagnóstico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Sustitución de Medicamentos/efectos adversos , Medicamentos Genéricos/efectos adversos , Dispepsia/inducido químicamente , Femenino , Humanos , Mesilato de Imatinib/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Many epidemiological, biological and therapeutic studies have extensively investigated the etiological link between HCV infection and B-cell Non-Hodgkin Lymphoma (NHL). Large experiences in the literature demonstrated HCV-related indolent NHL regression after antiviral therapy. While the response to interferon-ribavirin-based antiviral therapy is well documented, evidence of the efficacy of interferon-free Direct-Acting Antivirals (DAAs) in this subset of lymphoma is also currently increasing. Splenic and Nodal Marginal zone Lymphoma (MZL) are frequently associated with HCV chronic infection. In this article we report two cases of HCV-related MZL with an unusual presentation, subcutaneous "lipoma-like" nodules, treated with DAAs. Both patients, a 59-years-old woman and a 72-years-old man, were affected by HCV chronic infection since several years and were referred to our Institute for a diagnosis of MZL with subcutaneous presentation. Given the possible etiological link with HCV infection, both patients were treated with DAAS. A Sustained virological response (SVR) was reached after few weeks of therapy and at the end of treatment a clinically and radiologically documented reduction of MZL localizations, persisting to date, were obtained in both patients. The two clinical cases presented in this article confirm the efficacy of DAA's as first-line treatment in HCV related NHL, also in this rare entity of MZL with subcutaneous presentation.