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1.
Leukemia ; 23(12): 2222-32, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19741729

RESUMEN

Although outcomes for patients with multiple myeloma (MM) have improved over the past decade, the disease remains incurable and even patients who respond well to induction therapy ultimately relapse and require additional treatment. Conventional chemotherapy and high-dose therapy with stem cell transplantation (SCT) have historically been utilized in the management of relapsed MM, but in recent years the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, as well as the proteasome inhibitor bortezomib, have assumed a primary role in this setting. This review focuses on the role of thalidomide, lenalidomide and bortezomib in relapsed and refractory MM, with additional discussion dedicated to emerging drugs in relapsed MM that may prove beneficial to patients with this disease.


Asunto(s)
Factores Inmunológicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Terapia Recuperativa/métodos , Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Bortezomib , Humanos , Inmunosupresores/uso terapéutico , Lenalidomida , Pirazinas/uso terapéutico , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Resultado del Tratamiento
3.
Oncogene ; 26(16): 2374-80, 2007 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-17016430

RESUMEN

Bcl-2 or Bcl-X(L) confers resistance to chemotherapy in multiple myeloma (MM). Here we characterized the effects of ABT-737, a potent small-molecule inhibitor of antiapoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w with markedly higher affinity than previously reported compounds, on human MM cells. ABT-737 induces apoptosis in MM cells, including those resistant to conventional therapy. Examination of purified patient MM cells demonstrated similar results, without significant toxicity against normal peripheral blood mononuclear cells and MM bone marrow stromal cells. Importantly, ABT-737 decreases the viability of bortezomib-, dexamethasone-(Dex) and thalidomide-refractory patient MM cells. Additionally, ABT-737 abrogates MM cell growth triggered by interleukin-6 or insulin-like growth factor-1. Mechanistic studies show that ABT-737-induced apoptosis is associated with activation of caspase-8, caspase-9 and caspase-3, followed by poly(ADP-ribose) polymerase cleavage. Combining ABT-737 with proteasome inhibitor bortezomib, melphalan or dexamethasone induces additive anti-MM activity. Taken together, our study provides the rationale for clinical protocols evaluating ABT-737, alone and together with botezomib, mephalan or dexamethasone, to enhance MM cell killing, overcome drug resistance conferred by Bcl-2 and improve patient outcome in MM.


Asunto(s)
Antineoplásicos/farmacología , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Compuestos de Bifenilo/farmacología , Mieloma Múltiple/tratamiento farmacológico , Nitrofenoles/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Sulfonamidas/farmacología , Proteína bcl-X/antagonistas & inhibidores , Antineoplásicos/toxicidad , Células de la Médula Ósea/efectos de los fármacos , Ácidos Borónicos/toxicidad , Bortezomib , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Mieloma Múltiple/patología , Piperazinas/farmacología , Pirazinas/toxicidad , Células Tumorales Cultivadas
4.
Bone Marrow Transplant ; 35(1): 77-83, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15502851

RESUMEN

The diagnosis and treatment of cancer is often associated with high levels of psychosocial distress, yet exploration of these issues is rarely included in routine oncologic care. We conducted a pilot study to evaluate the feasibility of screening for psychosocial distress after autologous and allogeneic stem cell transplantation. A total of 80 adults were enrolled in Boston, MA, USA. Subjects completed self-administered assessments prior to hospital admission, at their first clinic visit after hospital discharge, and at 100 days post transplant. Assessments included validated instruments assessing psychosocial distress and quality of life (QOL). Elevated levels of anxiety and/or depression were detected in 55% of those providing pre-transplant assessments and were associated with compromised QOL. Post transplant screening was successfully performed in 69% of subjects and identified that 44% had symptoms of depression, anxiety or post traumatic stress disorder. Pre-transplant distress was associated with detection of distress after transplantation (81 vs 13%, P< 0.0001). In summary, we detected high levels of distress in transplant patients using self-administered tools. Pre-transplant distress appears to be highly predictive of distress post transplant and is a feasible marker to target screening and intervention programs.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Estrés Psicológico/diagnóstico , Adaptación Psicológica , Adulto , Ansiedad , Depresión , Emociones , Femenino , Humanos , Acontecimientos que Cambian la Vida , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Proyectos Piloto , Calidad de Vida , Rol del Enfermo , Trasplante de Células Madre/efectos adversos , Trasplante de Células Madre/psicología , Trastornos por Estrés Postraumático , Encuestas y Cuestionarios , Factores de Tiempo
5.
Bone Marrow Transplant ; 32(12): 1145-51, 2003 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-14647268

RESUMEN

A total of 228 patients with multiple myeloma (MM), 166 patients receiving autologous transplantation (124 PBSC and 38 BM) and 66 patients receiving T-cell-depleted allogeneic transplantation were analyzed to compare overall survival (OS), progression-free survival (PFS) and risk of relapse. Patients receiving autologous transplantation had a significantly improved OS (P=0.006) and PFS (P=0.002) at 2 years with OS and PFS for autologous transplant 74% and 48%, respectively, compared with 51% and 28% for allogeneic transplantation. By 4 years after transplantation, outcome was similar with OS and PFS for autologous transplantation 41% and 23%, respectively, compared with 39% and 18% for allogeneic transplantation. The 4-year cumulative incidence of nonrelapse mortality was significantly higher in patients receiving allogeneic transplantation (24% vs 13%) (P=0.004). Relapse was the principle cause of treatment failure for both groups; however, there was a significantly reduced risk of relapse associated with allogeneic transplantation at 4 years: 46% for allograft vs 56% for autograft (P=0.02). Despite a lower risk of relapse after allogeneic transplantation, autologous transplantation is associated with improved OS and PFS compared with allogeneic transplantation in patients with MM. Strategies focused on reducing nonrelapse mortality in allogeneic transplantation may translate into an improved outcome for patients receiving allogeneic transplantation.


Asunto(s)
Efecto Injerto vs Tumor , Mieloma Múltiple/terapia , Trasplante de Células Madre de Sangre Periférica/métodos , Trasplante Autólogo , Trasplante Homólogo , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Tablas de Vida , Depleción Linfocítica , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Trasplante de Células Madre de Sangre Periférica/mortalidad , Trasplante de Células Madre de Sangre Periférica/estadística & datos numéricos , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Riesgo , Análisis de Supervivencia , Acondicionamiento Pretrasplante
6.
Biol Blood Marrow Transplant ; 8(3): 139-44, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-11939603

RESUMEN

Prior studies of non-T-cell-depleted (TCD) transplantation have demonstrated a reduction in relapse in patients receiving escalated doses of TBI; however, overall survival in these studies was not significantly improved due to increased treatment-related toxicity seen at the higher doses of irradiation. Toxicity was in part related to an increased incidence of GVHD. Because T-cell depletion of donor bone marrow reduces the incidence of GVHD and other treatment-related complications after allogeneic bone marrow transplantation, it was postulated that TBI dose may be safely escalated in this setting and may decrease the risk of relapse following TCD BMT. Herein, we report the results of a trial assessing the safety and impact of escalated doses of TBI after TCD BMT. Two hundred adults with hematologic malignancies were treated in consecutive cohorts defined by increasing doses of TBI (1400, 1480, and 1560 cGy) in combination with cyclophosphamide. In vitro T-cell depletion using anti-CD6 monoclonal antibody was used for GVHD prophylaxis. The incidence of grade II or greater acute GVHD in patients receiving 1560 cGy (36%) was significantly higher than in patients receiving 1400 cGy (18%) (P = .04) or 1480 cGy (13%) (P = .01). Two-year treatment-related mortality was significantly higher in patients who received 1560 cGy of TBI (33%) than in those who received 1400 cGy (20%) (P = .04) or 1480 cGy (19%) (P = .05). The increased dose of TBI did not reduce the rates of relapse, with the estimated 2-year risk of relapse being 24% (1400 cGy), 24% (1480 cGy), and 31% (1560 cGy) for the 3 cohorts of patients. Overall survival at 2 years was inferior for patients receiving 1560 cGy of TBI (36%) compared with those who received 1400 cGy (55%) or 1480 cGy (58%) (P = .01). We conclude that dose escalation of TBI is associated with increased GVHD and inferior survival following TCD BMT. Future efforts to reduce the risk of relapse after TCD BMT should focus on immunologic methods to induce the graft-versus-leukemia effect after BMT rather than intensification of the ablative regimen by escalation of irradiation dose.


Asunto(s)
Trasplante de Médula Ósea/métodos , Irradiación Corporal Total/métodos , Adolescente , Adulto , Anciano , Relación Dosis-Respuesta en la Radiación , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Enfermedades Hematológicas/complicaciones , Enfermedades Hematológicas/radioterapia , Enfermedades Hematológicas/terapia , Humanos , Depleción Linfocítica , Masculino , Persona de Mediana Edad , Prevención Secundaria , Análisis de Supervivencia , Tasa de Supervivencia , Trasplante Isogénico/métodos , Resultado del Tratamiento , Irradiación Corporal Total/efectos adversos , Irradiación Corporal Total/normas
7.
Semin Oncol ; 28(6): 607-12, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11740818

RESUMEN

Novel therapies in multiple myeloma (MM) target not only the tumor cell but also the bone marrow (BM) microenvironment. Thalidomide (Thal), as well as derivative immunomodulatory drugs (IMiDs), directly induce apoptosis or G1 growth arrest in MM cell lines and patient's MM cells which are resistant to melphalan (Mel), doxorubicin (Dox), and dexamethasone (Dex). Although Thal and IMiDs do not alter adhesion of MM cells to bone marrow stromal cells (BMSCs), they inhibit the upregulation of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion triggered by the binding of MM cells to BMSCs. Proteasome inhibitors represent another potential anticancer therapy targeting the MM cell and the BM microenvironment. The proteasome inhibitor PS-341 directly inhibits proliferation and induces apoptosis in both human MM cell lines and freshly isolated patient's MM cells which are resistant to Mel, Dox, and Dex. PS-341 inhibits p44/42 mitogen-activated protein kinase (MAPK) growth signaling triggered by IL-6 and induces apoptosis, despite induction of p21 and p27, in p53 wild-type and p53 mutant MM cells. PS-341 adds to the anti-MM activity of dexamethasone and overcomes IL-6-mediated protection against dexamethasone-induced apoptosis. PS-341 blocks the paracrine growth of human MM cells by decreasing their adherence to BMSCs and related NF-kappaB-dependent induction of IL-6 secretion in BMSCs. Moreover, proliferation and MAPK growth signaling of those residual adherent MM cells is also inhibited. Tumor necrosis factor-alpha (TNF-alpha), which is produced by some MM cells, induces only low-level MM proliferation and MAPK activation in MM cells, but markedly upregulates IL-6 secretion from BMSCs and upregulates expression of adhesion molecules (VLA-4 and LFA-1) on MM cells and their receptors (VCAM-1 and ICAM-1) on BMSCs, with resultant increased binding of MM cells to BMSCs. Inhibition of TNF-alpha-induced NF-kappaB activation with PS-341 inhibits both the upregulation of these molecules on MM cells and BMSCs and the resultant increased adhesion. Therefore, inhibiting TNF-alpha and its sequelae may be useful treatment strategies in MM. Our data show that VEGF causes proliferation and enhances migration of MM as well as plasma cell leukemia (PCL) cells. VEGF induced twofold activation of cell migration in MM cells and more than 100-fold activation of cell migration in PCL cells, suggesting an important role of VEGF in the progression of MM to PCL. These data indicate that VEGF plays a pivotal role not only in neoangiogenesis in MM BM but also in proliferation and migration of tumor cells.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Médula Ósea/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Talidomida/uso terapéutico , 3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Adyuvantes Inmunológicos/uso terapéutico , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Médula Ósea/irrigación sanguínea , Ciclo Celular/efectos de los fármacos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Cisteína Endopeptidasas , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Factores de Crecimiento Endotelial/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Humanos , Linfocinas/antagonistas & inhibidores , Complejos Multienzimáticos/antagonistas & inhibidores , Mieloma Múltiple/patología , Neovascularización Patológica , Inhibidores de Fosfodiesterasa/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Complejo de la Endopetidasa Proteasomal , Talidomida/análogos & derivados , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
8.
Leukemia ; 15(12): 1950-61, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11753617

RESUMEN

Increased angiogenesis has recently been recognized in active multiple myeloma (MM). Since vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are two key mediators of angiogenesis, we characterized the production of VEGF, b-FGF and interleukin-6 (IL-6) (a MM growth and survival factor) in MM cell lines and Epstein-Barr virus (EBV) transformed B cell lines from MM patients, patient MM cells, as well as bone marrow stromal cells (BMSCs) from normal healthy donors and MM patients. We detected secretion of VEGF, but no bFGF and IL-6, in MM cell lines (MM.1S, RPMI 8226 and U266); EBV transformed B cell lines from MM patients (IM-9, HS-Sultan and ARH77); MM cell lines resistant to doxorubicin (RPMI-DOX40), mitoxantrone (RPMI-MR20), melphalan (RPMI-LR5) and dexamethasone (MM.1R); and patient MM cells (MM1 and MM2). BMSCs from MM patients and normal donors secreted VEGF, b-FGF and IL-6. Importantly, when MM cells were adhered to BMSCs, there was a significant increase in VEGF (1.5- to 3.1-fold) and IL-6 (1.9- to 56-fold) secretion. In contrast, the bFGF decreased in co-cultures of BMSCs and MM cells. Paraformaldehyde fixation of BMSCs or MM cells prior to adhesion revealed that VEGF was produced both from BMSCs and MM cells, though it may come primarily from BMSCs in some cultures. IL-6 was produced exclusively in BMSCs, rather than MM cells. Moreover, when MM cells were placed in Transwell insert chambers to allow their juxtaposition to BMSCs without cell to cell contact, induction of VEGF and IL-6 secretion persisted, suggesting the importance of humoral factors. Addition of exogenous IL-6 (10 ng/ml) increased VEGF secretion by BMSCs. Conversely, VEGF (100 ng/ml) significantly increased IL-6 secretion by BMSCs. Moreover, anti-human VEGF (1 microg/ml) and anti-human IL-6 (10 microg/ml) neutralizing antibodies reduced IL-6 and VEGF secretion, respectively, in cultures of BMSCs alone and co-cultures of BMSCs and MM cells. Finally, thalidomide (100 microM) and its immunomodulatory analog IMiD1-CC4047 (1 microM) decreased the upregulation of IL-6 and VEGF secretion in cultures of BMSCs, MM cells and co-cultures of BMSCs with MM cells. These data demonstrate the importance of stromal-MM cell interactions in regulating VEGF and IL-6 secretion, and suggest additional mechanisms whereby thalidomide and IMiD1-CC4047 act against MM cells in the BM millieu.


Asunto(s)
Factores de Crecimiento Endotelial/metabolismo , Linfocinas/metabolismo , Mieloma Múltiple/patología , Células del Estroma/citología , Inhibidores de la Angiogénesis/farmacología , Células de la Médula Ósea/citología , Células de la Médula Ósea/fisiología , Adhesión Celular , Comunicación Celular/fisiología , Técnicas de Cocultivo , Interacciones Farmacológicas , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Humanos , Interleucina-6/metabolismo , Mieloma Múltiple/metabolismo , Mieloma Múltiple/fisiopatología , Células del Estroma/metabolismo , Células del Estroma/fisiología , Talidomida/farmacología , Células Tumorales Cultivadas , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
9.
J Clin Oncol ; 19(17): 3771-9, 2001 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-11533101

RESUMEN

PURPOSE: Although high-dose chemotherapy supported by autologous peripheral-blood progenitor-cell (PBPC) transplantation improves response rates and survival for patients with multiple myeloma, all patients eventually develop progressive disease after transplantation. It has been hypothesized that depletion of malignant plasma cells from autografts may improve outcome by reducing infused cells contributing to relapse. PATIENTS AND METHODS: A randomized phase III study using the CEPRATE SC System (Cellpro, Bothell, WA) to enrich CD34(+) autograft cells and passively purge malignant plasma cells was completed in 190 myeloma patients randomized to receive an autograft of CD34-selected or unselected PBPCs. RESULTS: After CD34 selection, tumor burden was reduced by 1.6 to 6.0 logs (median, 3.1), with 54% of CD34-enriched products having no detectable tumor. Median time to count recovery, number of transfusions, transplantation-related mortality, and days in hospital were equivalent between the two transplantation arms. With a median follow-up of 37 months, 33 patients (36%) in the selected and 34 patients (35%) in the unselected arm had died (P =.784). Median overall survival in the selected arm was reached at 50 months and is not reached at this time in the unselected arm (P =.78). Median disease-free survival was 100 versus 104 weeks (P =.82), with 67% of patients in the selected arm and 66% of patients in the unselected arm relapsing. CONCLUSION: This phase III trial demonstrates that although CD34 selection significantly reduces myeloma cell contamination in PBPC collections, no improvement in disease-free or overall survival was achieved.


Asunto(s)
Antígenos CD34/análisis , Purgación de la Médula Ósea/métodos , Mieloma Múltiple/terapia , Adulto , Anciano , Antineoplásicos/uso terapéutico , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/inmunología , Mieloma Múltiple/mortalidad , Células Neoplásicas Circulantes/inmunología , Reacción en Cadena de la Polimerasa , Modelos de Riesgos Proporcionales , Tasa de Supervivencia
10.
Oncogene ; 20(33): 4519-27, 2001 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-11494147

RESUMEN

In this study we demonstrate that tumor necrosis factor alpha (TNFalpha) triggers only modest proliferation, as well as p44/p42 mitogen-activated protein kinase (MAPK) and NF-kappaB activation, in MM.1S multiple myeloma (MM) cells. TNFalpha also activates NF-kappaB and markedly upregulates (fivefold) secretion of interleukin-6 (IL-6), a myeloma growth and survival factor, in bone marrow stromal cells (BMSCs). TNFalpha in both a dose and time dependent fashion induced expression of CD11a (LFA-1), CD54 (intercellular adhesion molecule-1, ICAM-1), CD106 (vascular cell adhesion molecule-1, VCAM-1), CD49d (very late activating antigen-4, VLA-4), and/or MUC-1 on MM cell lines; as well as CD106 (VCAM-1) and CD54 (ICAM-1) expression on BMSCs. This resulted in increased (2-4-fold) per cent specific binding of MM cells to BMSCs, with related IL-6 secretion. Importantly, the proteasome inhibitor PS-341 abrogated TNFalpha-induced NF-kappaB activation, induction of ICAM-1 or VCAM-1, and increased adhesion of MM cells to BMSCs. Agents which act to inhibit TNFalpha may therefore abrogate the paracrine growth and survival advantage conferred by MM cell adhesion in the BM microenvironment.


Asunto(s)
Mieloma Múltiple/fisiopatología , Proteínas de Neoplasias/fisiología , Factor de Necrosis Tumoral alfa/fisiología , Antígenos CD/biosíntesis , Antígenos CD/genética , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Ácidos Borónicos/farmacología , Bortezomib , Adhesión Celular , División Celular/efectos de los fármacos , Cisteína Endopeptidasas , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Integrina alfa4 , Molécula 1 de Adhesión Intercelular/biosíntesis , Molécula 1 de Adhesión Intercelular/genética , Interleucina-6/metabolismo , Antígeno-1 Asociado a Función de Linfocito/biosíntesis , Antígeno-1 Asociado a Función de Linfocito/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteína Quinasa 1 Activada por Mitógenos/biosíntesis , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/biosíntesis , Proteínas Quinasas Activadas por Mitógenos/genética , Modelos Biológicos , Mucina-1/biosíntesis , Mucina-1/genética , Complejos Multienzimáticos/antagonistas & inhibidores , Mieloma Múltiple/genética , Mieloma Múltiple/patología , FN-kappa B/fisiología , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Inhibidores de Proteasas/farmacología , Complejo de la Endopetidasa Proteasomal , Pirazinas/farmacología , Células del Estroma/citología , Células del Estroma/metabolismo , Células Tumorales Cultivadas/metabolismo , Células Tumorales Cultivadas/patología , Molécula 1 de Adhesión Celular Vascular/biosíntesis , Molécula 1 de Adhesión Celular Vascular/genética
11.
Blood ; 98(4): 934-9, 2001 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-11493435

RESUMEN

Previous trials of allogeneic bone marrow transplantation (BMT) in patients with multiple myeloma (MM) have demonstrated high response rates but also high transplantation-related mortality (TRM) and high relapse rates. Exploitation of this strategy remains of interest because donor lymphocyte infusions (DLIs) can induce a potent graft-versus-myeloma (GVM) effect. CD6 T-cell--depleted allogeneic BMT was combined with prophylactic CD4(+) DLI administered 6 to 9 months after BMT in an effort to reduce TRM and to induce a GVM response after BMT. Twenty-four patients with matched sibling donors and chemotherapy-sensitive disease underwent BMT. CD6 T-cell depletion of donor bone marrow was the sole method of graft-versus-host disease (GVHD) prophylaxis. GVHD after BMT was minimal, 1 (4%) grade III and 4 (17%) grade II GVHD. Fourteen patients received DLI, 3 in complete response and 11 with persistent disease after BMT. Significant GVM responses were noted after DLI in 10 patients with persistent disease, resulting in 6 complete responses and 4 partial responses. After DLI, 50% of patients developed acute (> or = II) or extensive chronic GVHD. Two-year estimated overall survival and current progression-free survival (PFS) for all 24 patients is 55% and 42%, respectively. The 14 patients receiving DLI had an improved 2-year current PFS (65%) when compared with a historical cohort of MM patients who underwent CD6-depleted BMT survived 6 months with no GVHD and did not receive DLI (41%) (P =.13). Although this study suggests that prophylactic DLI induces significant GVM responses after allogeneic BMT, only 58% of patients were able to receive DLI despite T-cell--depleted BMT. Therefore, less toxic transplantation strategies are needed to allow a higher proportion of patients to receive DLI and the benefit from the GVM effect after transplantation. (Blood. 2001;98:934-939)


Asunto(s)
Trasplante de Médula Ósea/métodos , Depleción Linfocítica/normas , Transfusión de Linfocitos/normas , Mieloma Múltiple/terapia , Análisis Actuarial , Adulto , Antígenos CD/análisis , Antígenos de Diferenciación de Linfocitos T/análisis , Trasplante de Médula Ósea/efectos adversos , Linfocitos T CD4-Positivos/trasplante , Supervivencia sin Enfermedad , Femenino , Efecto Injerto vs Tumor/fisiología , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Pronóstico , Linfocitos T/inmunología , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/métodos
12.
Blood ; 98(3): 795-804, 2001 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-11468181

RESUMEN

Multiple myeloma (MM) remains incurable and novel treatments are urgently needed. Preclinical in vitro and in vivo evaluations were performed to assess the potential therapeutic applications of human recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) in MM. TRAIL/Apo2L potently induced apoptosis of MM cells from patients and the majority of MM cell lines, including cells sensitive or resistant to dexamethasone (Dex), doxorubicin (Dox), melphalan, and mitoxantrone. TRAIL/Apo2L also overcame the survival effect of interleukin 6 on MM cells and did not affect the survival of peripheral blood and bone marrow mononuclear cells and purified B cells from healthy donors. The status of the TRAIL receptors (assessed by immunoblotting and flow cytometry) could not predict TRAIL sensitivity of MM cells. The anti-MM activity of TRAIL/Apo2L was confirmed in nu/xid/bg mice xenografted with human MM cells; TRAIL (500 microg intraperitoneally daily for 14 days) was well tolerated and significantly suppressed the growth of plasmacytomas. Dox up-regulated the expression of the TRAIL receptor death receptor 5 (DR5) and synergistically enhanced the effect of TRAIL not only against MM cells sensitive to, but also against those resistant to, Dex- or Dox-induced apoptosis. Nuclear factor (NF)-kappaB inhibitors, such as SN50 (a cell-permeable inhibitor of the nuclear translocation and transcriptional activity of NF-kappaB) or the proteasome inhibitor PS-341, enhanced the proapoptotic activity of TRAIL/Apo2L against TRAIL-sensitive MM cells, whereas SN50 reversed the TRAIL resistance of ARH-77 and IM-9 MM cells. Importantly, normal B lymphocytes were not sensitized to TRAIL by either Dox, SN50, or PS-341. These preclinical studies suggest that TRAIL/Apo2L can overcome conventional drug resistance and provide the basis for clinical trials of TRAIL-based treatment regimens to improve outcome in patients with MM. (Blood. 2001;98:795-804)


Asunto(s)
Apoptosis/efectos de los fármacos , Glicoproteínas de Membrana/farmacología , Mieloma Múltiple/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/farmacología , Animales , Proteínas Reguladoras de la Apoptosis , Linfocitos B/efectos de los fármacos , Dexametasona/farmacología , Dexametasona/uso terapéutico , Evaluación Preclínica de Medicamentos , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Humanos , Interleucina-6/farmacología , Glicoproteínas de Membrana/administración & dosificación , Ratones , FN-kappa B/antagonistas & inhibidores , FN-kappa B/farmacología , Trasplante de Neoplasias , Plasmacitoma/tratamiento farmacológico , Receptores del Factor de Necrosis Tumoral/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF , Trasplante Heterólogo , Células Tumorales Cultivadas/efectos de los fármacos , Factor de Necrosis Tumoral alfa/administración & dosificación
13.
J Immunother ; 24(3): 272-9, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11394506

RESUMEN

Waldenstrom's macroglobulinemia (WM, lymphoplasmacytic lymphoma) is a B-cell lymphoproliferative disorder in which CD20 is expressed on tumor cells from most patients. Several small studies have suggested a benefit from the anti-CD20 monoclonal antibody rituximab (Rituxan, MabThera) in patients with WM. In this retrospective study, we examined the outcome of 30 previously unreported patients with WM who received treatment with single-agent rituximab (median age 60; range 32-83 years old). The median number of prior treatments for these patients was 1 (range 0-6), and 14 patients (47%) received a nucleoside analogue before rituximab therapy. Patients received a median of 4.0 (1-11.3) infusions of rituximab (375 mg/m2). Three patients received steroids with their infusions for prophylaxis of rituximab-related infusion syndrome. Overall, treatment was well tolerated. Median immunoglobulin M (IgM) levels for all patients declined from 2,403 mg/dL (range 720-7639 mg/dL) to 1,525 mg/dL (range 177-5,063 mg/dL) after rituximab therapy (p = 0.001), with 8 of 30 (27%) and 18 of 30 (60%) patients demonstrating >50% and >25% decline in IgM, respectively. Median bone marrow lymphoplasmacytic (BM LPC) cell involvement declined from 60% (range 5-90%) to 15% (range 0-80%) for 17 patients for whom pre- and post-BM biopsies were performed (p < 0.001). Moreover, 19 of 30 (63%) and 15 of 30 (50%) patients had an increase in their hematocrit (HCT) and platelet (PLT) counts, respectively. Before rituximab therapy, 7 of 30 (23.3%) patients were either transfusion or erythropoietin dependent, whereas only 1/30 (3.3%) patients required transfusions (no erythropoietin) after rituximab. Overall responses after treatment with rituximab were as follows: 8 (27%) and 10 (33%) of the patients achieved a partial (PR) and a minor (MR) response, respectively, and an additional 9 (30%) of patients demonstrated stable disease (SD). No patients attained a complete response. The median time to treatment failure for responding (PR and MR) patients was 8.0 months (mean 8.4: range 3-20+ months), and 5.0 months (mean 6.1; range 3-12+ months) for patients with SD. These studies therefore demonstrate that rituximab is an active agent in WM. Marked increases in HCT and PLT counts were noted for most patients, including patients with WM who had MR or SD. A prospective clinical trial to more completely define the benefit of single-agent rituximab in patients with WM has been initiated by many of our centers.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos CD20/metabolismo , Macroglobulinemia de Waldenström/inmunología , Macroglobulinemia de Waldenström/terapia , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales de Origen Murino , Médula Ósea/patología , Femenino , Humanos , Inmunoglobulina M/sangre , Inmunoterapia , Enfermedades Linfáticas/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Rituximab , Esplenomegalia/terapia , Macroglobulinemia de Waldenström/sangre , Macroglobulinemia de Waldenström/patología
14.
J Immunother ; 24(3): 263-71, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11394505

RESUMEN

The anti-CD20 chimeric monoclonal antibody rituximab (Rituxan) is used to treat patients with various B-cell tumors, including patients with plasma cell dyscrasias who have CD20+ disease. Many patients with CD20+ disease have either primary unresponsive disease or progress after initially responding to rituximab; therefore, understanding how tumor cells are, or become, resistant to rituximab is of clinical relevance. In this report, we determined whether tumor cells express antigens that block complement-mediated lysis or antibody-dependent cell-mediated cytotoxicity (ADCC) and thereby contribute to rituximab resistance. We demonstrate that expression of the complement regulator CD59 is associated with resistance to rituximab-mediated complement lysis of multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) cell lines. Moreover, neutralization of CD59 using a blocking monoclonal antibody reversed resistance to rituximab-mediated complement lysis of CD20++ CD59++ ARH-77 MM cells. In addition, we demonstrate the presence of CD59 and rituximab binding on viable tumor cells from patients with MM and Waldenstrom's macroglobulinemia with progressive disease despite rituximab therapy. Last, we also examined MM and NHL B-cell lines, as well as patient tumor cells, for the expression of other antigens that may have a role in blocking ADCC activity, such as Fas ligand (FasL), MUCI, or TRAIL. FasL, MUC1, and/or TRAIL were coexpressed with complement regulators on many of these cells. These studies therefore show that complement regulators, particularly CD59 and antigens that may block ADCC, are present on various B-cell tumors and associated with rituximab resistance in patients. A prospective, clinical study is assessing the role of these antigens in mediating rituximab resistance.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos CD59/metabolismo , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Animales , Anticuerpos Monoclonales de Origen Murino , Citotoxicidad Celular Dependiente de Anticuerpos , Antígenos CD20/metabolismo , Proteínas Reguladoras de la Apoptosis , Linfocitos B/inmunología , Proteína Ligando Fas , Humanos , Técnicas In Vitro , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/terapia , Glicoproteínas de Membrana/inmunología , Ratones , Mucina-1/inmunología , Mieloma Múltiple/inmunología , Mieloma Múltiple/terapia , Pruebas de Neutralización , Fragmentos de Péptidos/inmunología , Rituximab , Ligando Inductor de Apoptosis Relacionado con TNF , Células Tumorales Cultivadas , Factor de Necrosis Tumoral alfa/inmunología , Macroglobulinemia de Waldenström/inmunología , Macroglobulinemia de Waldenström/terapia
15.
Blood ; 98(1): 210-6, 2001 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-11418482

RESUMEN

The antiangiogenic activity of thalidomide (Thal), coupled with an increase in bone marrow angiogenesis in multiple myeloma (MM), provided the rationale for the use of Thal in MM. Previously, the direct anti-MM activity of Thal and its analogues (immunomodulatory drugs, IMiDs) on MM cells was demonstrated, suggesting multiple mechanisms of action. In this study, the potential immunomodulatory effects of Thal/IMiDs in MM were examined. It was demonstrated that Thal/IMiDs do not induce T-cell proliferation alone but act as costimulators to trigger proliferation of anti-CD3-stimulated T cells from patients with MM, accompanied by an increase in interferon-gamma and IL-2 secretion. However, an increase in autologous T-cell killing of patient MM cells could not be demonstrated. A role for natural killer (NK)- and LAK-cell-mediated killing is suggested because IL-2-primed peripheral blood mononuclear cells (PBMCs) treated with Thal/IMiDs demonstrated significantly increased lysis of MM cell lines. Cold target inhibition assays suggested NK- rather than LAK-cell-mediated killing. Furthermore, this killing was not major histocompatibility complex-class restricted, and the depletion of CD56(+) cells blocked the drug-induced MM cell lysis. It was significant that increased killing of patient MM cells by autologous PBMCs treated with Thal/IMiDs was also observed. Although the in vivo relevance of NK-cell-mediated MM cell killing is unknown, phenotypic analysis performed in MM patients receiving Thal therapy demonstrated an increase in CD3(-)CD56(+) cells in patients responding to therapy. Thus in vitro and in vivo data support the hypothesis that Thal may mediate its anti-MM effect, at least in part, by modulating NK cell number and function.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Células Asesinas Naturales/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Talidomida/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Estudios de Casos y Controles , Citotoxicidad Inmunológica/efectos de los fármacos , Humanos , Inmunofenotipificación , Células Asesinas Naturales/inmunología , Recuento de Linfocitos , Mieloma Múltiple/sangre , Mieloma Múltiple/inmunología , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Talidomida/administración & dosificación , Células Tumorales Cultivadas/efectos de los fármacos
16.
J Clin Oncol ; 19(4): 1152-9, 2001 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-11181681

RESUMEN

PURPOSE: The role of donor marrow T-cell depletion (TCD) in preventing graft-versus-host disease (GVHD) after transplantation of unrelated allogeneic marrow remains undefined. Because different TCD methodologies differ in the degree and specificity with which T cells are removed, it is likely that transplant outcomes would depend on which technique is used. Herein, we report results in the first 48 recipients of unrelated marrow using CD6+ TCD as the sole form of GVHD prophylaxis. PATIENTS AND METHODS: Median age of patients was 46 years (20 to 58 years). Donors were matched at A/B HLA loci. Ablation consisted of cyclophosphamide and fractionated total-body irradiation (TBI; 14 Gy). To facilitate engraftment, patients also received 7.5 Gy (22 patients) [corrected] or 4.5 Gy (26 patients) [corrected] of total lymphoid irradiation (TLI) before admission. No additional immune suppressive prophylaxis was administered. Granulocyte colony-stimulating factor was administered daily from day +1 to engraftment. RESULTS: All 48 patients demonstrated neutrophil engraftment. An absolute neutrophil count of 500 x 10(6)/L was achieved at a median of 12 days (range, 9 to 23 days). There were no cases of late graft failure. The number of CD34+ cells infused/kg was associated with speed of platelet and neutrophil recovery. The dose of TLI did not influence engraftment. Grades 2-4 acute GVHD occurred in 42% of patients (95% confidence interval [CI], 0.28 to 0.57). Mortality at day 100 was 19%. There have been only five relapses. Estimated 2-year survival was 44% (95% CI, 0.28 to 0.59) for the entire group, 58% for patients less than 50 years of age. In multivariable analysis, age less than 50 years (P =.002), cytomegalovirus seronegative status (P =.04), and early disease status at bone marrow transplant (P =.05) were associated with superior survival. CONCLUSION: CD6+ TCD does not impede engraftment of unrelated bone marrow after low-dose TLI, cyclophosphamide, and TBI. CD6+ TCD as the sole form of GVHD prophylaxis results in an incidence of GVHD that compares favorably with many adult studies of unrelated transplantation using unmanipulated marrow and immune-suppressive medications, especially in light of the median age of our patients (46 years). Although event-free survival in patients less than 50 years of age is very encouraging, older patients experience frequent transplantation-related complications despite TCD.


Asunto(s)
Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea/efectos adversos , Enfermedad Injerto contra Huésped/prevención & control , Depleción Linfocítica/métodos , Linfocitos T/inmunología , Adulto , Terapia Combinada , Femenino , Humanos , Leucemia/terapia , Subgrupos Linfocitarios , Masculino , Persona de Mediana Edad
17.
J Clin Oncol ; 19(1): 242-52, 2001 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-11134219

RESUMEN

PURPOSE: Although the number of autologous and allogeneic stem-cell transplantations (SCT) is increasing, relatively little information about recovery after transplantation is available. Quantitative information appropriate for patient counseling is difficult to discern from the literature. We sought to suggest reasonable expectations for recovery and symptoms after SCT for hematologic malignancies and other disorders using the following measures: (1) objective measures of health status, such as frequency of clinic visits, need for rehospitalization, medication usage, work status, and overall and event-free survival; (2) qualitative assessment of quality of life, such as returning to a normal life, resumption of normal activities, satisfaction with appearance, and whether recovery has occurred; and (3) quantification of specific bothersome symptoms. PATIENTS AND METHODS: Autologous and allogeneic SCT recipients at a tertiary-care transplant center participated in the prospective, longitudinal questionnaire study. RESULTS: Three hundred twenty patients were studied. Questionnaire response rates at 6, 12, and 24 months range from 85% to 88% among survivors. Although autologous patients had better event-free and overall survival, fewer symptoms, and more complete recovery at 6 months, these advantages had largely equalized by 12 months. Specific bothersome symptoms were reported by less than 24% of patients after transplantation, except for fatigue and financial and sexual difficulties, which were more prevalent. CONCLUSION: These findings may help counsel patients considering transplantation and educate them about reasonable expectations for recovery. Overall, the low level of bothersome symptoms and continued recovery through the first year after transplantation are encouraging.


Asunto(s)
Enfermedades Hematológicas/rehabilitación , Enfermedades Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Recuperación de la Función , Actividades Cotidianas , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Estado de Salud , Enfermedades Hematológicas/mortalidad , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Calidad de Vida , Estadísticas no Paramétricas , Tasa de Supervivencia , Trasplante Autólogo , Trasplante Homólogo , Resultado del Tratamiento , Estados Unidos/epidemiología
18.
Blood ; 96(9): 2943-50, 2000 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-11049970

RESUMEN

Although thalidomide (Thal) was initially used to treat multiple myeloma (MM) because of its known antiangiogenic effects, the mechanism of its anti-MM activity is unclear. These studies demonstrate clinical activity of Thal against MM that is refractory to conventional therapy and delineate mechanisms of anti-tumor activity of Thal and its potent analogs (immunomodulatory drugs [IMiDs]). Importantly, these agents act directly, by inducing apoptosis or G1 growth arrest, in MM cell lines and in patient MM cells that are resistant to melphalan, doxorubicin, and dexamethasone (Dex). Moreover, Thal and the IMiDs enhance the anti-MM activity of Dex and, conversely, are inhibited by interleukin 6. As for Dex, apoptotic signaling triggered by Thal and the IMiDs is associated with activation of related adhesion focal tyrosine kinase. These studies establish the framework for the development and testing of Thal and the IMiDs in a new treatment paradigm to target both the tumor cell and the microenvironment, overcome classical drug resistance, and achieve improved outcome in this presently incurable disease.


Asunto(s)
Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Resistencia a Múltiples Medicamentos , Inmunosupresores/toxicidad , Mieloma Múltiple/patología , Talidomida/toxicidad , Talidomida/uso terapéutico , Ciclo Celular/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , Dexametasona/toxicidad , Doxorrubicina/toxicidad , Femenino , Fase G1/efectos de los fármacos , Humanos , Masculino , Melfalán/toxicidad , Talidomida/análogos & derivados , Células Tumorales Cultivadas
19.
Biol Blood Marrow Transplant ; 6(4): 375-86, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-10917573

RESUMEN

Donor lymphocyte infusions (DLIs) have been demonstrated to induce clinical responses in patients with relapsed multiple myeloma after allogeneic bone marrow transplantation, but the immunologic mechanisms involved have not been well characterized. In patients with chronic myelocytic leukemia (CML), remissions following DLI are invariably associated with conversion to complete donor hematopoiesis, suggesting that the target antigens of this response are expressed on both normal and CML-derived hematopoietic stem cells. In the present study, we examined hematopoietic chimerism and the complexity of the T-cell receptor (TCR) repertoire in 4 patients with relapsed multiple myeloma who received infusions of donor CD4+ lymphocytes. Three of 4 patients had a clinical response that began 1 to 2 months after DLI. All 3 responding patients developed lymphocytosis at the initiation of response that was due to a 2- to 4.5-fold increase in the number of CD3+ T cells. In 1 patient, this was due primarily to increases in CD3+ and CD8+ cells; in 2 patients, to increased numbers of CD3+ and CD8+ and CD3+ and CD4+ T cells. In all responding patients, conversion to complete donor hematopoiesis occurred in the first 2 months after DLI. The single nonresponding patient remained it 100% recipient hematopoiesis. The TCR repertoire complexity was examined by polymerase chain reaction amplification of complementary-determining region 3 (CDR3) derived from 24 Vbeta gene subfamilies. In 2 patients, the initiation of myeloma response and conversion to complete donor hematopoiesis was associated with normalization of TCR complexity. Complete donor chimerism and normal TCR complexity remained stable in all patients and did not change with subsequent relapse or development of graft-versus-host disease (GVHD). Thus, conversion to full donor chimerism was temporally associated with the antimyeloma effect of DLI but not with the development of GVHD. Nevertheless, the maintenance of stable donor hematopoiesis did not prevent disease relapse and was not associated with prolonged remission. The selective relapse of myeloma cells without concomitant return of mixed hematopoietic chimerism suggests that myeloma tumor cells in some patients develop resistance to immune destruction.


Asunto(s)
Efecto Injerto vs Tumor/inmunología , Transfusión de Linfocitos , Mieloma Múltiple/terapia , Quimera por Trasplante/sangre , Animales , Antígenos CD/sangre , Donantes de Sangre , Trasplante de Médula Ósea , Linfocitos T CD4-Positivos , Estudios de Seguimiento , Enfermedad Injerto contra Huésped , Hematopoyesis , Humanos , Inmunofenotipificación , Linfocitosis/etiología , Mieloma Múltiple/complicaciones , Mieloma Múltiple/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/análisis , Recurrencia , Factores de Tiempo
20.
Bone Marrow Transplant ; 25(6): 623-32, 2000 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10734296

RESUMEN

Recent reports of clinical responses following donor lymphocyte infusions (DLI) in patients with relapsed multiple myeloma (MM) after allogeneic BMT have demonstrated the ability of allogeneic cells to mediate a graft-versus-myeloma (GVM) effect, but the mechanisms involved have not been determined. To identify changes in the T cell compartment associated with DLI, we performed a molecular analysis of the T cell receptor (TCR) repertoire in four patients with relapsed MM who received infusions of CD4+ lymphocytes from HLA-identical sibling donors. Three of the four patients demonstrated a clinical anti-myeloma response following DLI but also developed graft-versus-host disease (GVHD). The TCR repertoire was examined after PCR amplification of 24 Vbeta gene subfamilies. This method determines the relative utilization of each Vbeta gene subfamily and also allows the identification of clonal and oligoclonal T cell populations through analysis of CDR3 regions for each TCR Vbeta gene subfamily. Serial blood samples were obtained over at least a 1 year period before and after DLI and results compared to 10 normal donors. Serial analysis of CDR3 size profiles demonstrated the appearance of clonal T cell populations after DLI in each of the three responding patients. The appearance of some clones was noted within the first 3 months after DLI and coincided with decreasing levels of monoclonal paraprotein indicating an ongoing GVM response. Other T cell clones appeared at later time points and coincided with the development of GVHD. These findings demonstrate that T cell clones with different patterns of onset can be identified in the peripheral blood of MM patients following DLI. Further functional characterization of these distinct clonal expansions will be required to determine whether these T cell clones are mediators of either anti-myeloma or anti-host activity.


Asunto(s)
Regiones Determinantes de Complementariedad , Enfermedad Injerto contra Huésped/inmunología , Efecto Injerto vs Tumor/inmunología , Transfusión de Linfocitos/efectos adversos , Mieloma Múltiple/etiología , Receptores de Antígenos de Linfocitos T/inmunología , Adulto , Trasplante de Médula Ósea , Células Clonales/inmunología , Femenino , Humanos , Región Variable de Inmunoglobulina/química , Región Variable de Inmunoglobulina/inmunología , Masculino , Persona de Mediana Edad , Mieloma Múltiple/terapia , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Linfocitos T/inmunología , Trasplante Homólogo
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