RESUMEN
Therapy-related acute myeloid leukemia is an unfortunate complication of cancer treatment, particularly for patients with highly curable primary malignancies and favorable life expectancy. The risk of developing therapy-related acute myeloid leukemia also applies to patients with non-malignant conditions, such as autoimmune diseases treated with cytotoxic and/or immunosuppressive agents. There is considerable evidence to suggest that there is an increased occurrence of hematologic malignancies in patients with autoimmune diseases compared to the general population, with a further increase in risk after exposure to cytotoxic therapies. Unfortunately, studies have failed to reveal a clear correlation between leukemia development and exposure to individual agents used for the treatment of autoimmune diseases. Given the dismal outcome of secondary acute myeloid leukemia and the wide range of available agents for treatment of autoimmune diseases, an increased awareness of this risk and further investigation into the pathogenetic mechanisms of acute leukemia in autoimmune disease patients are warranted. This article will review the data available on the development of acute myeloid leukemia in patients with autoimmune diseases. Possible leukemogeneic mechanisms in these patients, as well as evidence supporting the association of their primary immunosuppressive status and their exposure to specific therapies, will also be reviewed. This review also supports the idea that it may be misleading to label leukemias that develop in patients with autoimmune diseases who are exposed to cytotoxic agents as 'therapy-related leukemias'. A better understanding of the molecular defects in autoimmune disease patients who develop acute leukemia will lead to a better understanding of the association between these two diseases entities.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Esclerosis Múltiple/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Artritis Reumatoide/complicaciones , Artritis Reumatoide/inmunología , Citotoxinas/administración & dosificación , Citotoxinas/efectos adversos , Estudios Epidemiológicos , Humanos , Terapia de Inmunosupresión , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/inmunología , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/inmunología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/inmunología , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/inmunología , RiesgoRESUMEN
The role of allogeneic stem cell transplant in advanced acute promyelocytic leukemia patients who received standard first- and second-line therapy is still unknown. We report the outcome of 31 acute promyelocytic leukemia patients (median age 39 years) who underwent allogeneic transplant in second remission (n=15) or beyond (n=16). Sixteen patients were real-time polymerase chain reaction positive and 15 negative for PML/RARA pre-transplant. The 4-year overall survival was 62% and 31% for patients transplanted in second remission and beyond, respectively (P=0.05), and 64% and 27% for patients with pre-transplant negative and positive real-time polymerase chain reaction, respectively (P=0.03). The 4-year cumulative incidence of relapse was 32% and 44% for patients transplanted in second remission and beyond, respectively (P=0.37), and 30% and 47% for patients transplanted with negative and positive real-time polymerase chain reaction, respectively (P=0.30). Transplant-related mortality was 19.6%. In conclusion, allogeneic transplant is effective in advanced acute promyelocytic leukemia in the all-trans-retinoic acid and arsenic trioxide era, and should be considered once relapse is diagnosed.
Asunto(s)
Antineoplásicos/administración & dosificación , Arsenicales/administración & dosificación , Leucemia Promielocítica Aguda/mortalidad , Leucemia Promielocítica Aguda/terapia , Óxidos/administración & dosificación , Trasplante de Células Madre , Tretinoina/administración & dosificación , Adolescente , Adulto , Trióxido de Arsénico , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante HomólogoAsunto(s)
Nucleótidos de Adenina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Arabinonucleósidos/uso terapéutico , Citarabina/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Adolescente , Adulto , Clofarabina , Esquema de Medicación , Femenino , Expresión Génica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Distribución Aleatoria , Inducción de Remisión , Factores de Riesgo , Análisis de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Overexpression, polymorphisms, and mutations of the WT1 gene have been reported in several human tumors including acute myeloid leukemia (AML) and variably correlated with prognosis. Acute promyelocytic leukemia (APL) represents the AML subset disclosing higher WT1 expression levels; however, no WT1 studies specifically focused on APL have been conducted. We screened for the presence of mutations, SNP rs16754, and expression levels of WT1 gene in 103 adult patients with newly diagnosed APL. Fms-like tyrosine kinase (FLT3) mutations were analyzed as well. WT1 mutations were identified in four (4 %) patients. At least one copy of the minor SNP rs16754 allele (WT1(AG) or WT1(GG)) was detected in 30 (29 %) patients. Six patients (6 %) were homozygous for the minor allele (WT1(GG)) and this genotype was associated with higher WT1 mRNA copies (p = 0.018). FLT3 mutations were found in 37 % of patients and correlated with high WT1 mRNA expression (p = 0.004). Patients heterozygous or homozygous for the minor allele and patients homozygous for major (WT1(AA)) allele did not differ in terms of presenting features. In adult APL, WT1 gene mutational and polymorphic profile shows similarities with pediatric AML rather than with adult AML.
Asunto(s)
Regulación Leucémica de la Expresión Génica , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/fisiopatología , Mutación , Proteínas de Neoplasias/genética , Polimorfismo de Nucleótido Simple , Proteínas WT1/genética , Adulto , Codón sin Sentido , Estudios de Cohortes , Mutación del Sistema de Lectura , Estudios de Asociación Genética , Heterocigoto , Homocigoto , Humanos , Leucemia Promielocítica Aguda/metabolismo , Mutación Missense , Proteínas de Neoplasias/metabolismo , ARN Mensajero/metabolismo , Recurrencia , Ciudad de Roma , España , Análisis de Supervivencia , Proteínas WT1/metabolismoRESUMEN
We report the clinical features and treatment outcome of 33 patients with multiple sclerosis who developed acute promyelocytic leukemia. Thirty patients were previously exposed to mitoxantrone. The median latency period between treatment initiation and acute promyelocytic leukemia diagnosis was 32 months. The PML-RARA bcr1 iso-form was identified in 87% of cases. Twenty-nine (90%) patients achieved hematologic remission after all-trans retinoic acid and chemotherapy (n = 31) or arsenic trioxide and all-trans retinoic acid. Consolidation included modified chemotherapy or arsenic trioxide. At a median follow up of 26 months, 23 patients are in complete remission, 4 relapsed and one developed secondary leukemia. The 5-year cumulative incidence of relapse and overall survival were 23% and 68%, respectively. Although treatment heterogeneity and suboptimal post-remission therapy must be taken into account, overall results and development of secondary leukemia in one patient suggest that effective and less toxic agents like arsenic trioxide warrants further investigation in this context.
Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Promielocítica Aguda/complicaciones , Leucemia Promielocítica Aguda/tratamiento farmacológico , Esclerosis Múltiple/complicaciones , Adulto , Anciano , Antineoplásicos/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
We report the outcomes of secondary acute myeloid leukemia (s-AML) patients included in one of 13 European Organisation for Research and Treatment of Cancer (EORTC) collaborative AML trials using intensive remission-induction chemotherapy. Among 8858 patients treated between May 1986 and January 2008, 960 were identified as having s-AML, either after MDS (cohort A; n = 508), occurring after primary solid tumors or hematologic malignancies other than MDS (cohort B; n = 361), or after non-malignant conditions or with a history of toxic exposure (cohort C; n = 91). Median age was 64 years, 60 years and 61 years in cohort A, B and C, respectively. Among patients ≤60 years and classified in the cohorts A or B (n = 367), the 5-year overall survival (OS) rate was 28%. There was a systematic improvement in the 5-year OS rate over three time periods (p < 0.001): 7.7% (95% CI: 1.3-21.7%) for patients treated before 1990 (period 1: n = 26), 23.3% (95% CI: 17.1-30.0%) for those treated between 1990 and 2000 (period 2: n = 188) and 36.5% (95% CI: 28.7-44.3%) for those treated in 2000 or later (period 3: n = 153). In multivariate analysis, male gender (HR = 1.39; p = 0.01), WBC ≥ 25 × 109/L (HR = 2.00; p < 0.0001), age 46-60 years (HR = 1.65; p < 0.001) and poor-risk cytogenetics (HR = 2.17; p < 0.0001) were independently associated with shorter OS, while being treated during period 2 (HR = 0.50, p = 0.003) or period 3 (HR = 0.43; p = 0.0008). Having received high-dose cytarabine (HD-AraC) (n = 48) in the induction chemotherapy (HR = 0.54, p = 0.012) was associated with a longer OS. In contrast, among patients >60 years of age (n = 502), the OS was dismal, and there was no improvement over time.
Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Tretinoina/uso terapéutico , Femenino , Humanos , Leucemia Promielocítica Aguda/patología , Leucemia Promielocítica Aguda/fisiopatología , Leucemia Promielocítica Aguda/prevención & control , Recurrencia , Inducción de Remisión , Resultado del TratamientoRESUMEN
BACKGROUND: Despite aggressive local therapy, patients with locally advanced bladder cancer have a significant risk of distant metastases. This study evaluated the role of neoadjuvant combination chemotherapy with gemcitabine/cisplatin (GC) in improving the outcome of this group of patients over radical cystectomy alone. PATIENTS AND METHODS: A total of 114 patients with newly diagnosed bladder cancer (T3-4, N0-2, M0) were randomized to radical cystectomy alone or initial 3 cycles of GC, then managed according to response. Patients who achieved complete response completed 6 cycles of GC followed by local radiation therapy (RT) only. If tumors were downstaged to T1, complete transurethral resection was done, followed by 3 cycles of GC and then RT. Patients with partial response underwent radical cystectomy followed by 3 cycles of GC. Patients with stable disease or disease progression underwent radical cystectomy. RESULTS: The overall response rate to GC was 55.1%, and complete response was achieved in 28.6%. The 3-year overall survival (OS) was 51.9% versus 51.2% in the chemotherapy and surgery arms, respectively (P = .399). The 3-year disease-free survival was 31.8% in the chemotherapy arm and 45.1% in the surgery arm (P = .06). Bladder preservation was achieved in 22.5% of patients in the neoadjuvant arm. OS was 78% in responding patients and 100% in patients with complete response. CONCLUSION: Neoadjuvant GC did not improve survival in locally advanced bladder cancer over radical cystectomy alone. However, bladder preservation was feasible, and OS in responding patients was impressive. Therefore, predictive models to select patients are needed. This is the largest prospective study of squamous cell carcinoma and transitional cell carcinoma using neoadjuvant GC.
Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Transicionales/tratamiento farmacológico , Cisplatino/uso terapéutico , Desoxicitidina/análogos & derivados , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Transicionales/cirugía , Cisplatino/efectos adversos , Cistectomía , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Estudios Prospectivos , Resultado del Tratamiento , Vejiga Urinaria/patología , Vejiga Urinaria/cirugía , Neoplasias de la Vejiga Urinaria/cirugía , GemcitabinaRESUMEN
The current study reports the clinical features and treatment outcome of 67 patients with acute promyelocytic leukemia (APL) treated at National Cancer Institute (NCI-Cairo), in Egypt from January 2007 to January 2011. The median age at presentation was 29 years. Bleeding was the most common presenting symptom (79%). Most patients had an intermediate risk Sanz score (49%) and 34% had a high risk score. The median follow-up time was 36 months. All evaluable patients were treated for induction with the simultaneous administration of all-trans retinoic acid (ATRA) and an anthracycline. The original AIDA treatment protocol was modified due to resource limitations at the NCI-Cairo by replacing of idarubicin with daunorubicin or doxorubicin in most of the cases and the inclusion of cytarabine during the consolidation phase only in pediatric patients. All patients who achieved molecular complete remission after consolidation received two-year maintenance treatment with low dose chemotherapy composed of 6 mercaptopurine, methotrexate and intermittent ATRA courses. Five patients died before treatment initiation due to bleeding, three died during induction chemotherapy due to infectious complications (n=2) and bleeding (n=1) and one patient died during consolidation therapy due to infection. The main therapeutic complications during the induction phase were febrile neutropenia (42%), bleeding (18%) and differentiation syndrome (11%). All patients achieved molecular CR at end of consolidation therapy at a median time of 100 days. The 3-year OS was 89%. Two patients relapsed at 13 and 24 months, respectively. Adapting standard AIDA treatment protocols to limited resources by reducing dose-intensity during consolidation, using ATRA in the consolidation phase and alternative anthracyclin (doxorubicin) may be a valid treatment option for APL in developing countries. In spite of the increased incidence of high and intermediate risk disease in our cohort, we reported an acceptable CR rate, toxicity and OS.
RESUMEN
The treatment and survival outcome of acute leukemia in women is generally similar to that of men. However, acute leukemia in women poses additional challenges in clinical practice. In addition to important precautions during therapy, such as prevention of abnormal uterine bleeding in premenopausal women and therapy during pregnancy, women who are survivors of acute leukemia face unique and potentially long-term health-related problems. In this review, we address the aforementioned issues, as well as the various health and psychosocial challenges faced by women who survive childhood leukemia during their path to adulthood. Finally, we address the issue of therapy-related acute leukemia in the category of women who are survivors of breast and ovarian cancer.