RESUMEN
In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.
Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT/genética , Mutación de Línea Germinal , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Adolescente , Adulto , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Linaje , Adulto JovenRESUMEN
A retrospective case-matched study was conducted to compare the oral regimen CTD (cyclophosphamide - thalidomide - dexamethasone) and infusional CVAMP (cyclophosphamide - vincristine - doxorubicin - methylprednisolone) as induction therapy followed by autologous peripheral blood stem-cell transplantation (PBSCT) for newly diagnosed multiple myeloma patients. The response rate after three cycles of treatment was statistically higher with CTD (n = 27) compared to CVAMP (n = 27) (89% vs. 56%, P = 0.016). Toxicity studies showed more neutropenia (grade 3/4) (4% vs. 60%, P = 0.0002) with CVAMP and more thrombotic episodes with CTD (11% vs. 4%). CTD may emerge as the superior induction regimen prior to PBSCT, in terms of high efficacy and better tolerability.
Asunto(s)
Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/epidemiología , Trasplante de Células Madre de Sangre Periférica , Adulto , Anciano , Antineoplásicos/efectos adversos , Estudios de Casos y Controles , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Dexametasona/uso terapéutico , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Masculino , Metilprednisolona/efectos adversos , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Mieloma Múltiple/patología , Mieloma Múltiple/cirugía , Talidomida/uso terapéutico , Trasplante Autólogo , Vincristina/efectos adversos , Vincristina/uso terapéuticoRESUMEN
The aim of this retrospective study conducted between H.U. Marques de Valdecilla (Spain) and the Royal Marsden NHS Trust (UK) was to analyse the outcome of patients who underwent haemopoietic progenitor cell transplantation (HPCT) after a previous history of Invasive fungal infections (IFI). This study includes 27 patients (15 autologous, 12 allogeneic). The diagnosis of IFI was microbiologically proven in 21 cases and only radiologically in six. Pre-HPCT treatment included intravenous antifungals in all and surgical excision in eight cases. All patients received post-HPCT antifungal prophylaxis. Median time from diagnosis of IFI to HPCT was 131 days. At median follow-up of 193 days, three patients (two allogeneic, one autologous) had relapse of IFI resulting in death in all cases. One of them had received TBI and two were receiving treatment for graft versus host disease. Each patient was receiving a different form of prophylaxis. Overall, seven patients are alive and disease-free. Ten patients died from disease progression and 10 from transplant-related toxicity, including IFI. In our experience, the risk of post-HPCT reactivation of a previous IFI is low (11%), so IFI should not be an absolute contraindication for HPCT. The combination of aggressive antifungal treatment for IFI and antifungal prophylaxis throughout HPCT reduces the probability of reactivation.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide/complicaciones , Mieloma Múltiple/complicaciones , Micosis/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Enfermedad Aguda , Adolescente , Adulto , Anciano , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/tratamiento farmacológico , Micosis/diagnóstico , Micosis/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
A relationship between dose of granulocyte colony-stimulating factor (G-CSF) and maturational stage of the progenitors mobilized in healthy adult donors has been suggested. In this study we characterize the progenitors mobilized by 2 different dosages of G-CSF in children receiving autologous grafts after intensive treatment for solid tumors.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Células Madre Hematopoyéticas/inmunología , Neoplasias/tratamiento farmacológico , Adulto , Antígenos CD , Antígenos CD34 , Antígenos de Diferenciación Mielomonocítica , Niño , Humanos , Neoplasias/inmunología , Lectina 3 Similar a Ig de Unión al Ácido SiálicoRESUMEN
One-hundred-twenty consecutive adult patients aged 15-69 years (median 40) with acute myeloid leukemia (AML) excluding t(15;17) received induction therapy comprising idarubicin, high-dose cytarabine and etoposide. Planned post-induction treatment included two courses of moderate-intensity consolidation therapy followed by stem cell transplantation. 11 patients (9%) died during induction therapy. The complete remission (CR) rate with a single cycle of induction therapy was 71%. The overall CR rate, after salvage chemotherapy but excluding allogeneic transplantation for primary refractory disease, was 82%. CR rates with one cycle of therapy for patients with good, intermediate and poor karyotype were 96, 72 and 41%, respectively (P<0.0001). The impact of karyotype on the overall CR rate was also significant (96 vs. 88 vs. 59%; P=0.001). Overall, 84 of 98 patients (86%) attaining CR underwent autologous (n=59), allogeneic (n=23) or syngeneic (n=2) hematopoietic stem cell transplantation in first CR. The 5-year overall survival (OS) of 43% (95% CI: 34-52%) was significantly influenced by the karyotype: good 73%, intermediate 41%, and poor 18% (P=0.0001). These data suggest that the sequence of therapy employed is active in AML, but additional steps are needed to improve the outcome of patients with intermediate- and high-risk cytogenetic abnormalities.
Asunto(s)
Citarabina/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Aberraciones Cromosómicas , Etopósido , Humanos , Idarrubicina , Cariotipificación , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Persona de Mediana Edad , Inducción de Remisión/métodos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
The aim of the study was to evaluate whether adequate stem cells (CD34+) could be harvested at presentation in myeloma patients such that high dose melphalan (HDM) with autologous stem cell rescue can be offered as primary therapy. The regimes either involved no prior cytoreductive chemotherapy (steroids only, n = 31) or a single course of VAD (n = 22). The median number of CD34 cells collected with steroids was 1.3 x 10(6) (0.2-5.6) compared to 4.6 x 10(6) (0.3-19.2) cells/kg with VAD (P < 0.0001). We conclude that it is possible to collect stem cells from myeloma patients at presentation with minimal prior therapy. Using this strategy, of a single prior course of chemotherapy followed by immediate harvest, it is feasible to offer early high-dose therapy in clinical situations where this is important.
Asunto(s)
Movilización de Célula Madre Hematopoyética/métodos , Mieloma Múltiple/sangre , Trasplante de Células Madre de Sangre Periférica , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recuento de Células Sanguíneas , Ciclofosfamida/farmacología , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Esquema de Medicación , Estudios de Factibilidad , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/farmacología , Humanos , Lenograstim , Leucaféresis , Masculino , Melfalán/uso terapéutico , Metilprednisolona/farmacología , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/cirugía , Proteínas Recombinantes/farmacología , Inducción de Remisión , Factores de Tiempo , Vincristina/administración & dosificaciónRESUMEN
If standard infusional therapy (IC) has been used to treat myeloma at presentation, it is a matter of debate whether patients should receive the original induction therapy or a different drug combination in first relapse. Instinctively, most clinicians may switch treatment, particularly since the advent of new drugs for the treatment of myeloma. Hitherto, there has been no data on the efficacy of repeating standard IC in the salvage setting. We studied 62 myeloma patients whose initial treatment consisted of C-VAMP and a single high dose melphalan procedure and who were retreated with C-VAMP at the time of first relapse. Response to salvage C-VAMP was seen in 50% (95% confidence interval = 0.37-0.62) but we were unable to identify any predictors for response to salvage C-VAMP. Only patients resistant to salvage C-VAMP benefited from a second autograft. The survival of patients who responded to salvage C-VAMP was not prolonged by a second transplant. In conclusion, our data supports the use of C-VAMP for patients with myeloma in first relapse and suggest that only patients resistant to salvage C-VAMP should be offered a second autograft.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Melfalán/administración & dosificación , Mieloma Múltiple/terapia , Terapia Recuperativa , Adulto , Anciano , Estudios de Cohortes , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Masculino , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Recurrencia , Estudios Retrospectivos , Terapia Recuperativa/métodos , Trasplante Autólogo , Vincristina/administración & dosificaciónRESUMEN
Induction chemotherapy followed by high-dose melphalan (HDM) is the standard treatment for fitter patients with myeloma. The place of bortezomib and the thalidomide analogues within this treatment paradigm is yet to be established. We sought to identify patients who may benefit from the introduction of novel agents during their initial management. An intention-to-treat analysis was performed on 383 patients with newly diagnosed myeloma eligible for HDM to determine whether the extent of response to induction therapy and HDM correlated with long-term survival. Early response [complete response (CR) and partial response (PR)] to induction therapy was predictive of overall survival (OS) [median OS, 7.47 years for responders (CR and PR) versus 4.89 years for non-responders; P = 0.035]. The attainment of CR at 3 months post-HDM correlated with a prolonged progression-free survival (PFS) (median PFS, 7.4 years in CR group versus 5.3 years in non-CR group; P = 0.023). This data suggests that, at every stage of treatment, the aim should be to achieve CR. Patients with suboptimal responses could be offered alternative therapy. We propose a multiparametric risk-adapted model that includes response to induction chemotherapy and HDM, for identifying patients who may benefit from novel approaches to treatment.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Melfalán/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea , Esquema de Medicación , Estudios de Seguimiento , Humanos , Melfalán/uso terapéutico , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Inducción de Remisión , Riesgo , Tasa de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Hyperhaemolysis syndrome is well recognised in patients with sickle cell disease and beta-thalassaemia major, but has not been described in patients with other haematological diseases. We describe a case of fatal post-transfusion hyperhaemolysis occurring in a lady with myelofibrosis evolving into acute myeloid leukaemia. No free antibodies were identified in either pre- or post-transfusion serum samples. Since her haemoglobin (Hb) level after the reaction was very much lower, than of would have been the case if only the transfused red cells had haemolysed, it seems likely that this severe haemolytic transfusion reaction was an example of the so-called hyperhaemolysis syndrome.
Asunto(s)
Hemólisis , Trastornos Mieloproliferativos/complicaciones , Mielofibrosis Primaria/complicaciones , Reacción a la Transfusión , Anemia/etiología , Médula Ósea/patología , Femenino , Humanos , Persona de Mediana Edad , Mielofibrosis Primaria/patologíaRESUMEN
Extending the principle of conventional acute lymphoblastic leukemia (ALL) therapy to transplantation, 77 adult patients receiving autografts in first remission after melphalan with or without total body irradiation were scheduled to receive 6-mercaptopurine (6MP), methotrexate (MTX), and vincristine-prednisone (VP) for 2 years after transplantation to reduce relapse. Seventy-one percent of patients received 6MP, 57% received MTX, and 38% received VP. Thirty patients had a relapse at 1.5 to 80 months (median, 12.5 months), 15 in the first year and 7 beyond 3 years. The cumulative incidence of relapse at 10 years was 42% (95% CI, 31%-55%). The 10-year probabilities of disease-free survival (DFS) and overall (OS) survival were 50% (95% CI, 38%-62%) and 53% (95% CI, 41%-65%), respectively. Age older than 30 years, more than 4 weeks to attain remission, and high-risk karyotypes, for example, t(9;22) or t(4;11), were adverse features contributing to the identification of 3 prognostic risk groups with 0, 1, and 2 adverse features, respectively: standard (47%), intermediate (36%), and high (17%). The 10-year cumulative incidences of relapse (20%, 48%, 85%; P <.0001) and probabilities of DFS (72%, 41%, 10%; P =.0003) were significantly different among these groups. In Cox analysis of the 71 patients alive and well 120 days after transplantation, those receiving 2 or 3 maintenance chemotherapy agents had significantly lower relapse rates and superior DFS compared with those receiving 0 or 1 agent. Our data suggest that maintenance chemotherapy improves the outcome of patients with ALL undergoing autografting. However, it is unlikely that autograft-based strategies are optimal for the high-risk group of patients who should be considered for alternative-donor allograft procedures.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Mercaptopurina/administración & dosificación , Metotrexato/administración & dosificación , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Prednisona/administración & dosificación , Estudios Prospectivos , Prevención Secundaria , Análisis de Supervivencia , Trasplante Autólogo , Vincristina/administración & dosificaciónRESUMEN
We undertook a randomised prospective observational study to identify the true prevalence of dermatological problems on an acute in-patient haemato-oncology unit treating patients with myeloma and leukaemia (median age 52 years), that could be used to plan for optimum dermatological servicing of such a unit. As a snap-shot, beds were randomly selected each week and the patients in them examined to identify the prevalence and identity of mucocutaneous problems for in-patients. Primary endpoints were the prevalence of integument reactions, prevalence and type of rash. Eighty-four leukaemia and myeloma patients were seen on 200 episodes. Integument changes were seen in 88% of episodes. Predictable changes such as hair loss (74%) and mucositis (38%) were seen commonly. Rashes were seen in 38% of episodes. The most common rash was palm and sole erythema (10% of all episodes) which was associated with allogeneic BMT (20%; p=0.0009). Flexural erythema with subsequent desquamation occurred in 4% of episodes, more commonly in males (p=0.09). Drug allergies were seen in 14 of 200 episodes and were significantly associated with antibiotics (p=0.003). Patients' perceived their skin problems as moderate or severe in 19% of the episodes. The impact on resources in the haematology practice was large; 45% of inpatients were receiving topical or systemic skin treatment, in 5% of patients the oncology treatment was compromised, 11% of patients required extra nursing and 3% of patients stayed longer in hospital. This volume of mucocutaneous problems makes dermatological input to haemato-oncology units vital.