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1.
Leukemia ; 28(8): 1573-85, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24496300

RESUMEN

In this report, a panel of European myeloma experts discuss the role of pomalidomide in the treatment of relapsed and refractory multiple myeloma (RRMM). Based on the available evidence, the combination of pomalidomide and low-dose dexamethasone is a well-tolerated and effective treatment option for patients with RRMM who have exhausted treatment with lenalidomide and bortezomib. The optimal starting dose of pomalidomide is 4 mg given on days 1-21 of each 28-day cycle, whereas dexamethasone is administered at a dose of 40 mg weekly (reduced to 20 mg for patients aged >75 years). The treatment should continue until evidence of disease progression or unacceptable toxicity. Dose-modification schemes have been established for patients who develop neutropenia, thrombocytopaenia and other grade 3-4 adverse events during pomalidomide therapy. Guidance on the prevention and management of infections and venous thromboembolism is provided, based on the available clinical evidence and the experience of panel members. The use of pomalidomide in special populations, such as patients with advanced age, renal impairment or unfavourable cytogenetic features, is also discussed.


Asunto(s)
Factores Inmunológicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Talidomida/análogos & derivados , Factores de Edad , Ensayos Clínicos como Asunto , Dexametasona/administración & dosificación , Esquema de Medicación , Humanos , Infecciones/inducido químicamente , Mieloma Múltiple/genética , Mieloma Múltiple/psicología , Neutropenia/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Calidad de Vida , Talidomida/administración & dosificación , Talidomida/efectos adversos , Talidomida/farmacología , Talidomida/uso terapéutico , Tromboembolia Venosa/inducido químicamente
2.
Leukemia ; 28(1): 155-65, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23588715

RESUMEN

The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50<200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.


Asunto(s)
Carioferinas/antagonistas & inhibidores , Mieloma Múltiple/terapia , Osteoclastos/patología , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Humanos , Mieloma Múltiple/patología , Proteína Exportina 1
4.
Leuk Res ; 32(1): 55-9, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17416416

RESUMEN

Waldenström's Macroglobulinaemia (WM) is an uncommon B-cell lymphoproliferative disorder defined as a predominately inter-trabecular bone marrow infiltration of small lymphocytes with an IgM monoclonal gammopathy. There are little reliable incidence and survival data for the disease in the UK since epidemiological studies have usually grouped it with other plasma cell dyscrasias. This study uses data from the South Thames Haematology Register and the Thames Cancer Registry for South East England to describe the incidence and survival of WM, and the influence of selected clinical factors on survival. Between 1999 and 2001, there were 152 new cases of WM recorded in the South Thames Haematology Register, giving an age standardised rate of 0.55 per 100,000 European standard population (0.73 for males and 0.42 for females). The incidence increased with age, and the median age at diagnosis was 75 years (range 45-93 years). The estimated 5 year survival was 57% (95% CI: 47-66%). Age over 70, haemoglobin less than 10 g/L and the Eastern Cooperative Oncology Group (ECOG) Performance Status grade 3-4 at diagnosis were associated with worse survival. Between 1985 and 2002, the Thames Cancer Registry recorded 750 cases of WM occurring in the wider area of South East England. The relative 5 year survival for patients aged less than 70 years was 70% (95% CI: 60-81%) and for patients aged 70 and over it was 50% (95% CI: 41-60%).


Asunto(s)
Macroglobulinemia de Waldenström/epidemiología , Adulto , Factores de Edad , Anciano , Inglaterra , Femenino , Hemoglobinas/análisis , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pronóstico , Sistema de Registros , Análisis de Supervivencia , Macroglobulinemia de Waldenström/mortalidad
5.
Br J Haematol ; 127(3): 299-304, 2004 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-15491289

RESUMEN

Epidemiology data on multiple myeloma (MM) occurrence and outcome is inconsistent whilst a major limitation of randomized controlled trials is selection bias. We present a population-based analysis of patients diagnosed with MM in the South Thames area, which comprises 5.4 million adult inhabitants. A total of 855 cases of MM were ascertained between 1999 and 2000 in a collaborative project involving haematologists and the Thames Cancer Registry. The age-standardized rate was 3.29 per 100 000 and 4.82 cases per 100 000 (World Standard and European Population respectively). The median age was 73 years. The median survival for the whole group was 24 months whist it was 42 and 18 months in those aged less than 65 years and greater than 65 years respectively (P < 0.001). This population study has shown a higher incidence than previously reported in the UK and Europe and provides a benchmark for future studies. If survival is to be improved, future clinical trials and health care planning should consider patients over 65 years of age.


Asunto(s)
Mieloma Múltiple/epidemiología , Distribución por Edad , Anciano , Inglaterra/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Tasa de Supervivencia
6.
J Clin Oncol ; 22(16): 3269-76, 2004 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-15249589

RESUMEN

PURPOSE: To assess the safety, efficacy, and immunomodulatory effects of CC-4047 (Actimid; Celgene, San Diego, CA) in patients with relapsed or refractory myeloma. PATIENTS AND METHODS: Twenty-four relapsed or refractory patients were treated with a dose-escalating regimen of oral CC-4047. Clinical responses and adverse effects were identified, and peripheral T-cell subsets, serum cytokines, and proangiogenic factors were evaluated. RESULTS: CC-4047 was tolerated with no serious nonhematologic adverse events. All patients were eligible for analysis. Toxicity criteria during the initial 4 weeks of study were used to define the maximum-tolerated dose (MTD). During this period, one patient withdrew with a deep vein thrombosis (DVT) probably caused by an undiagnosed primary melanoma with lymphadenopathy in the groin, one patient withdrew because of progressive disease (PD), and three patients discontinued with neutropenia. Nineteen of 24 patients continued on treatment beyond 4 weeks to PD or development of a serious adverse event. Three further patients developed a DVT at 4, 9, and 11 months. Treatment resulted in a greater than 25% reduction in paraprotein in 67% of patients, 13 patients (54%) experienced a greater than 50% reduction in paraprotein, and four (17%) of 24 patients entered complete remission. The MTD was 2 mg/d. All patients showed increased CD45RO expression on CD4(+) and CD8(+) cells, with a concomitant decrease in CD45RA(+) cells. CC-4047 treatment was associated with significantly increased serum interleukin (IL)-2 receptor and IL-12 levels, which is consistent with activation of T cells and monocytes and macrophages. CONCLUSION: This study demonstrates the safety and efficacy of CC-4047. The MTD of CC-4047 orally was 2 mg/d. This is the first report demonstrating in vivo T-cell costimulation by this class of compound, supporting a potential role for CC-4047 as an immunostimulatory adjuvant treatment.


Asunto(s)
Mieloma Múltiple/tratamiento farmacológico , Talidomida/análogos & derivados , Talidomida/farmacología , Administración Oral , Anciano , Citocinas/sangre , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mieloma Múltiple/patología , Recurrencia , Talidomida/administración & dosificación , Talidomida/efectos adversos
7.
Bone Marrow Transplant ; 33(11): 1131-5, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15094743

RESUMEN

The prognosis for patients with non-Hodgkin's lymphoma (NHL) and advanced Hodgkin's disease (HD) who relapse following autologous transplant is poor. We report on a pilot study designed to evaluate the feasibility of using Cyclosporin A and interferon alpha to induce autologous GVHD following a second autologous transplant for relapsed lymphoma. In all, 10 patients entered the study with median age 46.5 years. Diagnosis was NHL (n=7) or Hodgkin's lymphoma (n=3). All had relapsed from a prior autologous transplant. The second transplant was well tolerated by all patients. Histological changes consistent with cutaneous GVHD developed in 30% of patients at a median of 22.5 days from transplant and settled spontaneously in all cases. Five patients have died (four from progressive disease) at a median 7 months from second transplant. Five patients are still alive and in complete remission at a median of 20 months from transplant. Median overall survival for the group is 13.5 months and median relapse-free survival has not been reached at 42 months. This is a well-tolerated regimen for use in this poor-risk group of patients with lymphoma. The overall survival and event-free survival are encouraging, however further studies are necessary.


Asunto(s)
Ciclosporina/farmacología , Enfermedad Injerto contra Huésped/inducido químicamente , Interferón-alfa/farmacología , Linfoma/terapia , Trasplante de Células Madre de Sangre Periférica/métodos , Terapia Recuperativa/métodos , Trasplante Autólogo , Adulto , Ciclosporina/administración & dosificación , Femenino , Reacción Injerto-Huésped , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/terapia , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/farmacología , Interferón-alfa/administración & dosificación , Linfoma/mortalidad , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/terapia , Masculino , Persona de Mediana Edad , Proyectos Piloto , Análisis de Supervivencia , Resultado del Tratamiento
8.
Leuk Res ; 27(10): 909-14, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12860011

RESUMEN

Myeloma remains incurable with conventional treatment in the vast majority of patients. The introduction of thalidomide in 1999 for the treatment of relapsed disease offers the opportunity to treat patients who have developed myelotoxicity or who are refractory to conventional chemotherapy. The optimal schedule remains unresolved and only two studies have reported long term follow-up data. We report a phase II low dose escalation study of thalidomide with long term follow-up showing overall survival (OS) of 19 months and progression free survival (PFS) of 14 months. In addition we report on the side effects and toxicity and give recommendations for the use of thalidomide in the relapsed setting based upon these findings.


Asunto(s)
Mieloma Múltiple/tratamiento farmacológico , Talidomida/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/mortalidad , Guías de Práctica Clínica como Asunto , Inducción de Remisión , Terapia Recuperativa , Tasa de Supervivencia , Talidomida/toxicidad
9.
Hematology ; 7(5): 291-9, 2002 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-12850816

RESUMEN

The discovery that multiple myeloma is associated with new vessel formation and is correlated with survival and proliferation led initially to the use of thalidomide for patients with relapsed or refractory disease. The outcome with conventional chemotherapy in this setting has historically been very poor. New insights into the biology of the disease suggests that thalidomide may work via a number of other mechanisms and the advent of the thalidomide analogues with their differential effects on survival and proliferation pathways has opened up a new era in the understanding and treatment of the disease. The encouraging results from phase I/II trials of these agents has meant that for the first time in 50 years there is the opportunity to improve outcome. Further work is in progress to define how best to use these drugs and their role in treatment at different stages of the disease.


Asunto(s)
Mieloma Múltiple/tratamiento farmacológico , Talidomida/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Manejo de la Enfermedad , Humanos , Mieloma Múltiple/etiología , Talidomida/farmacología , Resultado del Tratamiento
10.
Clin Lab Haematol ; 23(2): 125-9, 2001 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11488852

RESUMEN

High dose chemoradiotherapy with autologous peripheral blood progenitor cell transplantation (PBPCT) may improve outcome in myeloma. Melphalan is an effective drug in the treatment of myeloma, but is potentially toxic to progenitor cells. We studied 8 patients receiving intermittent intravenous melphalan (25 mg/m2) as induction therapy before PBPCT to assess engraftment characteristics post-transplantation. Comparison was made with an age-matched control group of patients with non-Hodgkins lymphoma who had not received melphalan during induction therapy. There was correlation (P=0.037) between the dose of melphalan per kg body weight given, premobilization, and days to neutrophil engraftment, but no significant difference between the two groups in neutrophil recovery. The study group had delayed platelet recovery (P=0.01) and required more platelet support post-transplantation (P=0.05). 3-4 weekly melphalan (25 mg/m2) up to 6 courses was delivered to patients who went on to PBPCT without significantly influencing neutrophil recovery but with a negative impact on platelet recovery.


Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Melfalán/uso terapéutico , Mieloma Múltiple/terapia , Antineoplásicos Alquilantes/farmacología , Terapia Combinada , Femenino , Movilización de Célula Madre Hematopoyética , Humanos , Masculino , Melfalán/farmacología , Persona de Mediana Edad , Mieloma Múltiple/patología , Trasplante Autólogo
11.
Br J Haematol ; 110(4): 894-6, 2000 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-11054077

RESUMEN

Bone marrow or stem cell transplantation is an established therapy for haematological malignancies. We report a cytomegalovirus (CMV) IgG +ve 56-year-old patient who underwent autologous rescue with CD34(+) selected peripheral blood stem cells as part of consolidation therapy for multiple myeloma and subsequently developed CMV colitis. In contrast to infection secondary to human immunodeficiency virus (HIV), CMV colitis has not previously been described in this context. We discuss this case and issues arising from it related to the use of CD34+ selected stem cells for transplantation.


Asunto(s)
Antígenos CD34 , Infecciones por Citomegalovirus/complicaciones , Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/inmunología , Mieloma Múltiple/terapia , Antivirales/uso terapéutico , Purgación de la Médula Ósea/efectos adversos , Colitis/tratamiento farmacológico , Colitis/virología , Infecciones por Citomegalovirus/tratamiento farmacológico , Ganciclovir/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/virología , Trasplante Autólogo
12.
Hematology ; 5(4): 265-273, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-11399621

RESUMEN

The failure of conventional chemotherapy to eradicate chronic lymphocytic leukaemia cells and induce cure has led many clinicians to investigate the use of high dose chemotherapy and haemopoietic stem cell rescue in this disease. The selection of patients remains a major problem because this is a disease of elderly patients with a median overall survival of 7 years and will only therefore be applicable to a minority of patients. However transplantation is the most likely therapeutic option at this time to lead to cure in this condition. The best type of transplant is not known and not all patients will be able to mobilise adequate numbers of stem cells or have a suitable donor identified. Autologous transplantation relies on the ability of high doses of chemotherapy to eradicate disease whilst allogeneic transplantation attempts to harvest the graft versus leukaemia effect that has been identified in chronic granulocytic leukaemia. However, the high treatment related mortality and morbidity of allogeneic transplants has led to interest in the use of non-myeloablative allografts which hope to maximise the immunological effects of transplantation to achieve durable remissions. To date there have been no randomised clinical trials to compare the efficacy of combination chemotherapy, autologous or allogeneic transplants and this is unlikely to happen in the near future. Other issues that need to be addressed include the timing of transplantation, the source of stem cells, the optimal conditioning regimen and the role of immunomodulation post transplantation. This review attempts to answer some of these questions.

13.
Br J Haematol ; 105(4): 901-11, 1999 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10554799

RESUMEN

Fluconazole is widely used as antifungal prophylaxis but it is ineffective against Aspergillus. Itraconazole has a broader spectrum of activity but the capsules give erratic bioavailability in neutropenic patients. We compared itraconazole oral solution (which has an improved pharmacokinetic profile) with fluconazole for antifungal prophylaxis. Adults with haematological malignancies receiving chemotherapy or bone marrow transplants were randomly allocated 5 mg/kg/d itraconazole (itra) solution (288 episodes) or 100 mg fluconazole suspension (flu) (293 episodes) from before the onset of neutropenia until neutrophil recovery or suspected fungal infection. Outcomes were assessed by independent reviewers unaware of the prophylaxis allocation. More proven systemic fungal infections occurred in flu (Aspergillus four, Candida tropicalis one, C. krusei one) than itra (C. albicans one) and more of these were fatal (four versus nil). This difference reached statistical significance when first study episodes were considered separately (six flu versus nil itra, P = 0.03). Significantly more deaths of presumed fungal origin occurred in flu than itra (seven versus nil, P = 0.024). There were significantly more cases of proven aspergillosis in flu than itra (six versus nil, P = 0.038, 5/6 cases were fatal) if those occurring outside the study period are included. Significantly more patients receiving flu required amphotericin B (58 v 39, P = 0.043) but this may have been affected by the fact that the study was not blinded. There were 11 proven mucosal candidal infections in flu and four in itra. Itraconazole solution and fluconazole provide effective prophylaxis against Candida but itraconazole affords greater protection against fatal aspergillosis.


Asunto(s)
Antifúngicos/uso terapéutico , Fluconazol/uso terapéutico , Neoplasias Hematológicas/complicaciones , Itraconazol/uso terapéutico , Micosis/prevención & control , Adolescente , Adulto , Anciano , Antineoplásicos Fitogénicos/uso terapéutico , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Micosis/complicaciones , Infecciones Oportunistas/complicaciones , Vincristina/uso terapéutico
14.
Eur J Haematol ; 61(5): 306-10, 1998 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-9855245

RESUMEN

The variable absorption of melphalan from the gastrointestinal tract results in response rates between 40 and 60%. High dose melphalan increases response rates but at the cost of increased morbidity and mortality. We have investigated intravenous intermediate dose melphalan and dexamethasone in the treatment of patients presenting with de novo multiple myeloma with the object of reducing toxicity while preserving an improved response rate compared to oral melphalan and prednisolone. The results show that this treatment can be delivered safely on an outpatient basis in patients up to the age of 78 yr; 82% of patients achieved an objective response and 30% a complete haematological and clinical remission. Median overall survival for the whole group is 37 months.


Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Dexametasona/administración & dosificación , Melfalán/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Mieloma Múltiple/fisiopatología , Estudios Prospectivos
15.
Bone Marrow Transplant ; 20(9): 793-5, 1997 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-9384485

RESUMEN

A 40-year-old woman underwent allogeneic peripheral blood stem cell transplantation for relapsed AML-M6. She developed graft-versus-host disease on day +15 post-transplant, for which she was treated with cyclosporin A and methyl prednisolone. On day +19 she developed cortical blindness, headache and convulsions which were associated with white matter changes on MRI scanning of the head and elevated cyclosporin A levels. A diagnosis of cyclosporin A encephalopathy was made and cyclosporin A was discontinued. Her vision recovered completely after 48 h and the other symptoms resolved. This is the first case of cyclosporin A encephalopathy to be reported in an allogeneic PBSC recipient.


Asunto(s)
Ceguera Cortical/inducido químicamente , Ciclosporina/efectos adversos , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/efectos adversos , Convulsiones/inducido químicamente , Adulto , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Humanos , Leucemia Eritroblástica Aguda/terapia , Metilprednisolona/uso terapéutico
19.
Eur J Cancer ; 29A(1): 140-2, 1992.
Artículo en Inglés | MEDLINE | ID: mdl-1445731

RESUMEN

We have measured serum osteocalcin, a vitamin K-dependent glycoprotein synthesised by osteoblasts in 62 patients, 49 with myeloma, 26 at presentation and 23 previously treated, 7 with Waldenstrom's macroglobulinaemia (WM), and 6 with monoclonal gammopathy of uncertain significance (MGUS). Osteocalcin levels were normal in WM and MGUS. High values were found in 5/26 (19%) patients with myeloma at presentation. There was no relationship between serum osteocalcin and stage of disease. Osteocalcin was normal in all patients in plateau phase, falling to low levels in relapsed patients who failed to respond to further treatment. Serum osteocalcin may be a useful indicator of bone metabolism in myeloma.


Asunto(s)
Osteocalcina/sangre , Paraproteinemias/sangre , Adulto , Humanos , Persona de Mediana Edad , Mieloma Múltiple/sangre , Estadificación de Neoplasias , Paraproteinemias/patología , Paraproteinemias/terapia , Factores de Tiempo , Macroglobulinemia de Waldenström/sangre
20.
J Clin Pathol ; 38(8): 897-903, 1985 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-2993372

RESUMEN

The intracytoplasmic inclusions seen in most cells from a patient with B prolymphocytic leukaemia were analysed using both light and electron microscopy. They consisted of a dense homogeneous structure and were surrounded by a membrane, which had no continuity with the Golgi cisternae or the endoplasmic reticulum; some inclusions had a clear association with small lysosomal granules. Immunofluorescence and immunoperoxidase studies using light microscopy failed to elucidate completely the nature of the inclusions, but immunocytochemical reactions performed using electron microscopy suggested an immunoglobulin nature. All inclusions were negative for acid phosphatase and periodic acid Schiff. The nature of the inclusions described in the prolymphocytes of this patient were compared with those previously recorded in B prolymphocytic leukaemia.


Asunto(s)
Linfocitos B/ultraestructura , Citoplasma/ultraestructura , Cuerpos de Inclusión/ultraestructura , Leucemia Linfoide/patología , Anciano , Linfocitos B/inmunología , Citoplasma/inmunología , Humanos , Inmunoglobulinas/análisis , Leucemia Linfoide/inmunología , Masculino , Microscopía Electrónica
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