Asunto(s)

Acetilcisteína/uso terapéutico , Anemia de Células Falciformes/patología , Dolor/prevención & control , Acetilcisteína/efectos adversos , Acetilcisteína/farmacología , Adolescente , Adulto , Anemia de Células Falciformes/tratamiento farmacológico , Antioxidantes , Niño , Femenino , Humanos , Masculino , Cumplimiento de la Medicación , Resultado del Tratamiento , Adulto Joven

RESUMEN

This retrospective multicenter study in patients with chronic myeloid leukemia in chronic phase was undertaken to confirm the clinical relevance of imatinib plasma concentrations monitoring in daily practice. Forty-one patients, with 47 imatinib plasma measurements, were analyzed during treatment with imatinib given at a fixed 400mg daily dose. A significant inverse relationship of imatinib concentration with the patients' weight was observed (Pearson's test: p=0.02, R2=0.1). More interestingly, patients with poor response (switched to another tyrosine kinase inhibitor because of imatinib failure, or because of disease progression after an initial response) displayed a significantly lower mean imatinib concentration as compared to patients maintained on imatinib (822ng/mL vs 1099ng/mL; Student's t-test, p=0.04). Failure or disease progression occurred more often in patients in the lowest quartile of imatinib concentrations compared to patients in the highest quartile (p=0.02, logrank test). No correlation could be established with other biological or clinical parameter, including complete cytogenic response and major molecular response. IN CONCLUSION: in patients treated with imatinib at a fixed daily dose of 400mg, imatinib plasma concentrations decreased with increasing body weight and were lower in patients switched to another tyrosine kinase inhibitor due to imatinib failure. Systematic determination of imatinib plasma trough levels should be encouraged in such patients.

Asunto(s)

Monitoreo de Drogas/métodos , Mesilato de Imatinib/farmacocinética , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bélgica , Femenino , Humanos , Mesilato de Imatinib/administración & dosificación , Masculino , Persona de Mediana Edad , Estudios Retrospectivos

RESUMEN

Prognosis of Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another potent tyrosine kinase inhibitor, in combination with low-intensity chemotherapy. Patients older than age 55 years were included in the European Working Group on Adult ALL (EWALL) study number 01 for Ph(+) ALL (EWALL-PH-01 international study) and were treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. Seventy-one patients with a median age of 69 years were enrolled; 77% had a high comorbidity score. Complete remission rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. Only 7 patients underwent allogeneic hematopoietic stem cell transplantation. At 5 years, overall survival was 36% and up to 45% taking into account deaths unrelated to disease or treatment as competitors. Thirty-six patients relapsed, 24 were tested for mutation by Sanger sequencing, and 75% were T315I-positive. BCR-ABL1(T315I) was tested by allele-specific oligonucleotide reverse transcription-quantitative polymerase chain reaction in 43 patients and detection was associated with short-term relapses. Ten patients (23%) were positive before any therapy and 8 relapsed, all with this mutation. In conclusion, dasatinib combined with low-intensity chemotherapy was well-tolerated and gave long-term survival in 36% of elderly patients with Ph(+) ALL. Monitoring of BCR-ABL1(T315I) from diagnosis identified patients with at high risk of early relapse and may help to personalize therapy.

Asunto(s)

Antineoplásicos/uso terapéutico , Dasatinib/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Dasatinib/efectos adversos , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Masculino , Persona de Mediana Edad , Mutación , Cromosoma Filadelfia/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pronóstico , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/efectos adversos

RESUMEN

Warm antibody hemolytic anemia is the most common form of autoimmune hemolytic anemia. When therapy is needed, corticosteroids remain the cornerstone of initial treatment but are able to cure only a minority of patients (<20%). Splenectomy is usually proposed when a second-line therapy is needed. This classical approach is now challenged by the use of rituximab both as second-line and as first-line therapy. Second-line treatment with rituximab leads to response rates similar to splenectomy (∼70%), but rituximab-induced responses seem less sustained. However, additional courses of rituximab are most often followed by responses, at the price of reasonable toxicity. In some major European centers, rituximab is now the preferred second-line therapy of warm antibody hemolytic anemia in adults, although no prospective study convincingly supports this attitude. A recent randomized study strongly suggests that in first-line treatment, rituximab combined with steroids is superior to monotherapy with steroids. If this finding is confirmed, rituximab will emerge as a major component of the management of warm antibody hemolytic anemia not only after relapse but as soon as treatment is needed.

Asunto(s)

Anemia Hemolítica Autoinmune/tratamiento farmacológico , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Factores Inmunológicos/uso terapéutico , Adulto , Humanos , Rituximab

RESUMEN

PURPOSE: The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. PATIENTS AND METHODS: In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). RESULTS: N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). CONCLUSION: These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.

Asunto(s)

Proteínas de Ciclo Celular/genética , Análisis Mutacional de ADN , Proteínas F-Box/genética , GTP Fosfohidrolasas/genética , Eliminación de Gen , Proteínas de la Membrana/genética , Mutación , Fosfohidrolasa PTEN/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogénicas/genética , Receptor Notch1/genética , Ubiquitina-Proteína Ligasas/genética , Proteínas ras/genética , Adulto , Supervivencia sin Enfermedad , Proteína 7 que Contiene Repeticiones F-Box-WD , Femenino , Predisposición Genética a la Enfermedad , Humanos , Estimación de Kaplan-Meier , Masculino , Análisis Multivariante , Fenotipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/clasificación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas p21(ras) , Factores de Riesgo , Factores de Tiempo , Adulto Joven

RESUMEN

We report here the results of the GRAAPH-2003 trial with long-term follow-up in 45 patients with de novo Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Imatinib-based strategy improved the 4-year overall survival (OS) up to 52% versus 20% in the pre-imatinib LALA-94 trial (P = .0001). Despite the selection in patients who actually underwent transplantation, these results suggest that allogeneic or autologous stem cell transplants (SCTs) still have a place in overcoming the poor prognosis of Ph+ ALL in the era of imatinib therapy. OS was 50% after allogeneic SCT (24 patients), 33% in patients without a transplantation (9 patients), and 80% after autologous SCT (10 patients without allogeneic donor or >55 years, including 7 patients in complete molecular response).

Asunto(s)

Antineoplásicos/administración & dosificación , Benzamidas/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Cromosoma Filadelfia , Piperazinas/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pirimidinas/administración & dosificación , Adolescente , Adulto , Factores de Edad , Antineoplásicos/efectos adversos , Benzamidas/efectos adversos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Piperazinas/efectos adversos , Pirimidinas/efectos adversos , Tasa de Supervivencia , Factores de Tiempo , Trasplante Autólogo , Trasplante Homólogo , Donante no Emparentado

RESUMEN

In this article, the evidence on the clinical use of monoclonal antibodies in the treatment of immune-mediated hematologic disorders is described. Insights into pathogenic mechanisms have revealed a major role of both B and T cells. Controlled trials have shown conflicting results, necessitating further research regarding pathogenesis, mechanism of action, and resistance. Although the use of more potent and specific monoclonal antibody therapy, mainly targeting costimulation signals, may improve response rates and long-term outcome, its use should be carefully balanced against potential side effects.

Asunto(s)

Enfermedades Hematológicas/inmunología , Enfermedades Hematológicas/terapia , Alemtuzumab , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales de Origen Murino/farmacología , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antígenos CD20/inmunología , Basiliximab , Daclizumab , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunoglobulina G/farmacología , Inmunoglobulina G/uso terapéutico , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Infliximab , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/uso terapéutico , Rituximab

RESUMEN

The genetic background of mature B-cell neoplasms with villous lymphocytes is poorly understood. We identified a novel breakpoint region at 14q32.13 that was rearranged together with IGH/14q32.33 in four cases of BRAF/V600E-negative leukemia/lymphoma with villous lymphocytes carrying either t(14;14)(q32.13;q32.33) (three patients) or del(14)(q32.13q32.33) (one patient). The 14q32.13 breakpoints were mapped by fluorescence in situ hybridization (FISH) in the region harboring the TCL1A/TCL1B/TCL6 genes, known to be affected by TCRA/D-mediated t(14;14)(q11;q32)/inv(14)(q11q32) occurring in T-cell leukemia/lymphoma. To identify the target of t(14;14)(q32.13; q32.33) and del(14)(q32.13q32.33), quantitative real-time polymerase chain reaction (qRT-PCR) analysis of 25 candidate genes located centromerically and telomerically to the 14q32.13 breakpoint was performed. Any of the analyzed genes was commonly overexpressed in the presented cases. Of note, up-regulated transcription of TCL1A was observed in two cases. In summary, we provide evidence that IGH-mediated chromosomal aberrations affecting the 14q32.13/TCL1A-TCL6 region are recurrent in mature B-cell neoplasms with villous lymphocytes. Despite extensive qRT-PCR studies, molecular consequences of these novel aberrations remain elusive.

Asunto(s)

Linfocitos B/metabolismo , Aberraciones Cromosómicas , Cromosomas Humanos Par 14/genética , Proteínas Proto-Oncogénicas/genética , Anciano , Linfocitos B/patología , Puntos de Rotura del Cromosoma , Deleción Cromosómica , Cromosomas Humanos Par 4/genética , Resultado Fatal , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/genética , Linfoma de Células B/genética , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Translocación Genética

RESUMEN

The main characteristic of acute lymphoblastic leukaemia (ALL) in the elderly is its dismal prognosis. However, other than a lower incidence of T-cell ALL and a greater likelihood of unfavourable chromosomal abnormalities, the clinical and biological characteristics of Philadelphia chromosome-negative (Ph-) ALL in the elderly at diagnosis are no different from those observed in younger adults, and do not account, per se, for its poor prognosis. Rather, the latter is explained to a large extent by a high rate of treatment-induced mortality and/or by the use of less toxic but comparatively less effective drug regimens. Ph- ALL patients are offered treatments ranging from palliative care to intensive chemotherapy, but the survival of patients given palliative or minimally active chemotherapy is extremely poor. However, a valid comparison with patients given more intensive chemotherapy is lacking, as, in most cases, minimally active chemotherapy is used in patients with poor performance status at diagnosis. When more intensive chemotherapy is used, unacceptably high early mortality rates (up to 50%) have been reported, with complete-response rates ranging from 40% to 80% and 5-year survival consistently below 20%. Clearly, the results of therapy are unsatisfactory in Ph- ALL patients, which should encourage the development of innovative approaches, such as the use of new monoclonal antibodies. On the other hand, the availability of imatinib and second-generation tyrosine kinase inhibitors (TKIs) has improved the prognosis of Philadelphia-positive (Ph+) ALL in older patients. Impressive response rates have been reported, even in patients given imatinib and corticosteroids without additional chemotherapy, at the cost of manageable toxicity. Paradoxically, in the imatinib era, elderly patients with Ph+ leukaemia (which is clearly associated with an adverse prognosis in younger adults) seem to survive longer than Ph- elderly patients, although long-term survivors still remain relatively few. Whether new TKIs, such as dasatinib or nilotinib, will improve the prognosis of Ph+ ALL in the elderly is being prospectively assessed in several countries.

Asunto(s)

Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Anciano , Humanos , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/prevención & control , Pronóstico , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-bcr/metabolismo

RESUMEN

A cutaneous infiltrate composed of plasmacytoid dendritic cells may occasionally occur in a patient suffering from a myeloid neoplasm. To date, the clinical and pathological features associated with this event remains poorly characterized. Herein, we report a patient with acute myeloid leukemia who developed pruritic papules or erythematous plaques scattered on the skin. Microscopic examination showed a dermal infiltrate rich in plasmacytoid dendritic cells expressing CD4, CD43, CD68, granzyme B, CD123, CD303 [blood dendritic cell antigen 2 (BDCA-2)], CD2-associated protein (CD2AP) and T-cell leukemia/lymphoma oncogene 1 (TCL1). Our observation illustrates further that cutaneous lesions associated with some myeloid neoplasms, especially those featuring a monocytic component, may be composed of plasmacytoid dendritic cells. Because of differences in clinical, pathological and genetic features, this rare condition should be distinguished from blastic plasmacytoid dendritic cell neoplasm.

Asunto(s)

Células Dendríticas/patología , Leucemia Mieloide Aguda/diagnóstico , Células Plasmáticas/patología , Plasmacitoma/diagnóstico , Neoplasias Cutáneas/diagnóstico , Anciano , Biomarcadores de Tumor/metabolismo , Células Dendríticas/metabolismo , Dermis/metabolismo , Dermis/patología , Diagnóstico Diferencial , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Células Plasmáticas/metabolismo , Plasmacitoma/metabolismo , Neoplasias Cutáneas/metabolismo

RESUMEN

There is very limited data on isolated systemic relapses of primary central nervous system lymphomas (PCNSL). We retrospectively reviewed the clinical characteristics and outcome of 10 patients with isolated systemic disease among 209 patients with PCNSL mainly treated with methotrexate-based chemotherapy (CT) with or without radiation therapy (RT). Isolated systemic relapse remained rare (4.8%, 10/209 patients). Median time from initial diagnosis to relapse was 33 months (range, 3-94). Sites of relapse were mostly extranodal. Three patients presented with early extra-cerebral (EC) relapse 3, 5 and 8 months from the beginning of initial treatment, respectively, and 7 patients had later relapses (range, 17-94 months). Treatment at relapse included surgery alone, RT alone, CT with or without radiotherapy, or CT with autologous stem cell transplantation (ASCT). Median overall survival (OS) after relapse was 15.5 months (range, 5.8-24.5) compared to 4.6 months (range, 3.6-6.5) for patients with central nervous system (CNS) relapse (p = 0.35). In conclusion, isolated systemic relapses exist but are infrequent. Early EC relapse suggests the presence of systemic disease undetectable by conventional evaluation at initial diagnosis. Patient follow-up must be prolonged because systemic relapse can occur as late as 10 years after initial diagnosis. Whether EC relapses of PCNSL have a better prognosis than CNS relapses needs to be assessed in a larger cohort.

Asunto(s)

Neoplasias del Sistema Nervioso Central/terapia , Linfoma no Hodgkin/terapia , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Nervioso Central/mortalidad , Terapia Combinada , Femenino , Humanos , Linfoma no Hodgkin/mortalidad , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Recurrencia , Resultado del Tratamiento

RESUMEN

Autoimmune hematological disorders encompass a broad group of hematological conditions characterized by the loss of self-tolerance to a variety of antigens. Despite good response to first-line therapy in the majority of patients, relapses are common, necessitating new and safe therapeutic options. The anti-CD20 monoclonal antibody rituximab has led to substantial improvement in the treatment of malignant and immune-mediated disorders involving B cells. Although experience with rituximab in immune-mediated hematological disorders is rarely supported by randomized trials, there is now substantial experience with rituximab suggesting that anti-CD20 therapy is an effective and well-tolerated alternative to immunosuppressive therapy in these disorders. However, caution is needed based on recent reports describing-sometimes severe-rituximab-related complications.

Asunto(s)

Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Hematológicas/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Antígenos CD20/inmunología , Antineoplásicos , Enfermedades Autoinmunes/complicaciones , Enfermedades Hematológicas/complicaciones , Humanos , Rituximab

RESUMEN

BACKGROUND: The prognosis of acute lymphoblastic leukemia in the elderly is poor. The GRAALL-SA1 phase II, randomized trial compared the efficacy and toxicity of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in patients 55 years or older with Philadelphia chromosome-negative acute lymphoblastic leukemia. DESIGN AND METHODS: Sixty patients received either continuous-infusion doxorubicin (12 mg/m(2)/day) and continuous-infusion vincristine (0.4 mg/day) on days 1-4 or pegylated liposomal doxorubicin (40 mg/m(2)) and standard vincristine (2 mg) on day 1, accompanied by dexamethasone, followed at day 28 by a second cycle, reinforced by cyclophosphamide. End-points were safety, outcome and prognostic factors. RESULTS: Myelosuppression was reduced in the pegylated liposomal doxorubicin arm with shorter severe neutropenia (P=0.05), shorter severe thrombocytopenia (P=0.03), and fewer red blood cell transfusions (P=0.04). Grade 3/4 infections and Gram-negative bacteremia were reduced in the pegylated liposomal doxorubicin arm (P=0.04 and P=0.02, respectively). There was a trend towards fewer cardiac events among the patients who received pegylated liposomal doxorubicin (1/29 versus 6/31). The complete remission rate was 82% and, with a median follow-up of 4 years, median event-free survival and overall survival were 9 and 10 months, respectively. Despite the better tolerance of pegylated liposomal doxorubicin, no differences in survival were observed between the two arms, due to trends towards more induction refractoriness (17 versus 3%, P=0.10) and a higher cumulative incidence of relapse (52% versus 32% at 2 years, P=0.20) in the pegylated liposomal doxorubicin arm. CONCLUSIONS: With the drug schedules used in this study, pegylated liposomal doxorubicin did not improve the outcome of elderly patients with acute lymphoblastic leukemia despite reduced toxicities.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Femenino , Humanos , Liposomas , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Polietilenglicoles/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Tasa de Supervivencia , Resultado del Tratamiento , Vincristina/administración & dosificación

Asunto(s)

Anemia Hemolítica Autoinmune/tratamiento farmacológico , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Humanos , Estudios Retrospectivos , Rituximab , Terapia Recuperativa/métodos

RESUMEN

The prognostic significance of CD20 expression in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been mostly studied in children and yielded conflicting results. In 143 adults with Philadelphia chromosome-negative BCP-ALL treated in the multicentric GRAALL 2003 trial, CD20 positivity over 20% was observed in 32% of patients. While not influencing complete remission achievement, CD20 expression was associated with a higher cumulative incidence of relapse (CIR) at 42 months (P=0.04), independently of the ALL high-risk subset (P=0.025). Notably, the negative impact of CD20 expression on CIR was only observed in patients with a white blood cell count (WBC) over 30x10(9)/L (P=0.006), while not in those with a lower WBC. In the former subgroup, this impact translated into lower event-free survival (15% vs. 59% at 42 months, P=0.003). CD20 expression thus appears to be associated with a worse outcome, which reinforces the interest of evaluating rituximab combined to chemotherapy in CD20-positive adult BCP-ALL. ClinicalTrials.gov ID, NCT00222027.

Asunto(s)

Antígenos CD20/genética , Expresión Génica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Enfermedad Aguda , Adolescente , Adulto , Ensayos Clínicos como Asunto , Humanos , Recuento de Leucocitos , Persona de Mediana Edad , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Pronóstico , Recurrencia , Adulto Joven

RESUMEN

The JAK2(V617F) mutation does not elucidate the phenotypic variability observed in myeloproliferative neoplasm (MPN) families. A putative tumor suppressor gene, TET2, was recently implicated in MPN and myelodysplastic syndromes through the identification of acquired mutations affecting hematopoietic stem cells. The present study analyzed the TET2 gene in 61 MPN cases from 42 families. Fifteen distinct mutations were identified in 12 (20%) JAK2(V617F)-positive or -negative patients. In a patient with 2 TET2 mutations, the analysis of 5 blood samples at different phases of her disease showed the sequential occurrence of JAK2(V617F) and TET2 mutations concomitantly to the disease evolution. Analysis of familial segregation confirmed that TET2 mutations were not inherited but somatically acquired. TET2 mutations were mainly observed (10 of 12) in patients with primary myelofibrosis or patients with polycythemia vera or essential thrombocythemia who secondarily evolved toward myelofibrosis or acute myeloid leukemia.

Asunto(s)

Neoplasias de la Médula Ósea/genética , Proteínas de Unión al ADN/genética , Trastornos Mieloproliferativos/genética , Proteínas Proto-Oncogénicas/genética , Adulto , Anciano , Células Cultivadas , Análisis Mutacional de ADN , Dioxigenasas , Familia , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo

RESUMEN

PURPOSE: Retrospective comparisons have suggested that adolescents or teenagers with acute lymphoblastic leukemia (ALL) benefit from pediatric rather than adult chemotherapy regimens. Thus, the aim of the present phase II study was to test a pediatric-inspired treatment, including intensified doses of nonmyelotoxic drugs, such as prednisone, vincristine, or L-asparaginase, in adult patients with ALL up to the age of 60 years. PATIENTS AND METHODS: Between 2003 and 2005, 225 adult patients (median age, 31 years; range, 15 to 60 years) with Philadelphia chromosome-negative ALL were enrolled onto the Group for Research on Adult Acute Lymphoblastic Leukemia 2003 protocol, which included several pediatric options. Some adult options, such as allogeneic stem-cell transplantation for patients with high-risk ALL, were nevertheless retained. RESULTS: were retrospectively compared with the historical France-Belgium Group for Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) trial experience in 712 patients age 15 to 55 years. Results Complete remission rate was 93.5%. At 42 months, event-free survival (EFS) and overall survival (OS) rates were 55% (95% CI, 48% to 52%) and 60% (95% CI, 53% to 66%), respectively. Age remained an important bad prognostic factor, with 45 years of age as best cutoff. In older versus younger patients, there was a higher cumulative incidence of chemotherapy-related deaths (23% v 5%, respectively; P < .001) and deaths in first CR (22% v 5%, respectively; P < .001), whereas the incidence of relapse remained stable (30% v 32%, respectively). Complete remission rate (P = .02), EFS (P < .001), and OS (P < .001) compared favorably with the previous LALA-94 experience. CONCLUSION: These results suggest that pediatric-inspired therapy markedly improves the outcome of adult patients with ALL, at least until the age of 45 years.

Asunto(s)

Antineoplásicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Selección de Paciente , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven

RESUMEN

In recent years, there has been a tremendous increase in the number of clinical studies with monoclonal antibodies and small molecules in the treatment of hematological malignancies. Clinical observations have shown that some of these molecules may also aid in the treatment of immune-mediated hematological disorders. Moreover, immunotherapy has become an important treatment cornerstone in other, non-hematological, auto-immune diseases. This paper reviews the current state of the use of these new molecules in the treatment of the most frequently encountered immune-mediated hematological disorders: auto-immune hemolytic anemia (AIHA), idiopathic thrombocytopenic purpura (ITP), and thrombotic thrombocytopenic purpura (TTP).

Asunto(s)

Enfermedades Hematológicas/tratamiento farmacológico , Enfermedades Hematológicas/inmunología , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Corticoesteroides/uso terapéutico , Anemia Hemolítica Autoinmune/tratamiento farmacológico , Anemia Hemolítica Autoinmune/inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Ensayos Clínicos como Asunto , Quimioterapia Combinada , Medicina Basada en la Evidencia , Humanos , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/inmunología , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Púrpura Trombocitopénica Trombótica/inmunología , Rituximab , Esplenectomía , Resultado del Tratamiento

RESUMEN

Outcome of adult acute lymphoblastic leukemia (ALL) with central nervous system (CNS) involvement is not clearly defined. We studied 104 patients presenting with CNS involvement at diagnosis among 1493 patients (7%) included into the LALA trials, and 109 patients presenting CNS disease at the time of first relapse among the 709 relapsing patients (15%). Eighty-seven patients (84%) with CNS leukemia at diagnosis achieved complete remission (CR). Fifty-three patients underwent stem cell transplantation (SCT): 25 allogeneic SCT, 28 autologous SCT, while 34 continued with chemotherapy alone. Seven-year overall survival (OS) and disease-free survival (DFS) were 34% and 35%, respectively. There were no significant differences in terms of CR, OS and DFS among patients with CNS involvement at diagnosis and those without CNS disease. There were also no differences among the two groups regarding T lineage ALL, B lineage ALL, and among those who underwent SCT. After a first relapse, 38 patients with CNS recurrence (35%) achieved a second CR. The median OS was 6.3 months. Outcome was similar to that of relapsing patients without CNS disease. CNS leukemia in adult ALL is uncommon at diagnosis as well as at the time of first relapse. With intensification therapy, patients with CNS leukemia at diagnosis have a similar outcome than those who did not present with CNS involvement. CNS leukemia at first relapse remains of similar poor prognosis than all other adult ALL in first relapse.

Asunto(s)

Neoplasias del Sistema Nervioso Central/etiología , Recurrencia Local de Neoplasia/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Nervioso Central/patología , Terapia Combinada , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pronóstico , Inducción de Remisión , Trasplante de Células Madre , Resultado del Tratamiento

RESUMEN

An estimation of the incidence and demographic picture of the major hemoglobinopathies in Belgium has been approached through a confidential inquiry sent to 228 pediatric and adult hematological departments. Forty-two percent of responses showed that 417 patients are known in Belgium: 83% with sickle cell disease, 13% with beta-thalassemia (beta-thal) major, 2% with beta-thal intermedia, and 1% with Hb H disease. Twenty-five percent of the sickle cell disease patients and 54% of those suffering from a beta-thal major were older than 20 years. Three hospitals ensure the follow-up of 70% of the patients and are situated in Brussels, Belgium; a follow-up of less than 20 patients was reported at 21 centers. These results confirm that sickle cell disease is the major hemoglobinopathy in Belgium; it concerns mostly pediatricians but adult hematologists are also confronted with these pathologies. Therefore, it is necessary to implement integrated programs of prevention and treatment.

Asunto(s)

Hemoglobinopatías/epidemiología , Bélgica/epidemiología , Demografía , Femenino , Estudios de Seguimiento , Humanos , Masculino