RESUMEN
We previously conducted a randomized phase II trial of OCV-501, a WT1 peptide presented by helper T cells, in elderly AML (acute myeloid leukemia) patients in first remission, indicating no difference in 2-year disease-free survival (DSF) between the OCV-501 and placebo groups. Here, we analyzed 5-year outcome and biomarkers. Five-year DFS was 36.0% in the OCV-501 group (N = 52) and 33.7% in the placebo group (N = 53), with no significant difference (p = 0.74). The peripheral WT1 mRNA levels were marginally suppressed in the OCV-501 group compared with the placebo group. Enhanced anti-OCV-501 IgG response by the 25th week was an independent favorable prognostic factor. Anti-OCV-501 IFNγ responses were less frequent than the IgG reactions. These findings suggest that host immunoreactivity has a significant impact on the prognosis of AML and that further improvement of the WT1 peptide vaccine is needed.
Asunto(s)
Leucemia Mieloide Aguda , Proteínas WT1 , Humanos , Anciano , Estudios de Seguimiento , Pronóstico , Leucemia Mieloide Aguda/genética , Vacunas de Subunidad/uso terapéutico , Inmunoglobulina GRESUMEN
BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL. METHODS: PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20-79 years, had an Eastern Cooperative Group performance status of 0-3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1-5 of cycle one and days 2-6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up. FINDINGS: Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5-5·5). 2-year progression-free survival was 76% (95% CI 58-87). The most frequent adverse events of grade 3-4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment. INTERPRETATION: R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation. FUNDING: The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.
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Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Metotrexato/administración & dosificación , Neoplasias Vasculares/tratamiento farmacológico , Adulto , Anciano , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Estudios Prospectivos , Rituximab/administración & dosificación , Vincristina/administración & dosificación , Adulto JovenAsunto(s)
Anemia Hemolítica Autoinmune , Anemia Hemolítica , Síndromes Mielodisplásicos , Anemia Hemolítica/complicaciones , Anemia Hemolítica Autoinmune/inducido químicamente , Anemia Hemolítica Autoinmune/diagnóstico , Anemia Hemolítica Autoinmune/tratamiento farmacológico , Azacitidina/efectos adversos , Prueba de Coombs , Humanos , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/tratamiento farmacológicoRESUMEN
Chronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase. It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells. Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a(+/+) and Foxo3a(-/-) mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-beta is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-beta inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-beta inhibitor impaired their colony-forming ability in vitro. Our results demonstrate a critical role for the TGF-beta-FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo.
Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Animales , Antineoplásicos/uso terapéutico , Apoptosis , Benzamidas , Diferenciación Celular , Línea Celular Tumoral , Núcleo Celular/metabolismo , Modelos Animales de Enfermedad , Activación Enzimática , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/deficiencia , Factores de Transcripción Forkhead/genética , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Células Madre Neoplásicas/efectos de los fármacos , Fosforilación , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Transporte de Proteínas , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirimidinas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Ensayo de Tumor de Célula MadreRESUMEN
Langerhans cell sarcoma (LCS) is an extremely rare neoplasm of Langerhans cell origin characterized by systemic involvement and a poor prognosis. There are, however, few reports of LCS with central nervous system involvement. We experienced a patient with LCS recurrence in the brain that appeared during systemic chemotherapy. The brains lesions eventually responded to total cranial irradiation. A 60-year-old female presented with systemic lymphadenopathy. LCS was diagnosed based on neck lymph node biopsy findings. Two cycles of ESHAP induced marked regression of her lymphadenopathy, but FDG-PET/CT scan revealed new lesions in the central nervous system and her disorientation gradually worsened. We administered 37.5 Gy of total cranial irradiation which improved her consciousness and shrank the brain tumors as demonstrated by MRI. The patient's clinical course indicates that radiation therapy may be effective for central nervous system involvement of LCS even if the lesion is resistant to systemic chemotherapy.
Asunto(s)
Neoplasias Encefálicas/terapia , Sarcoma de Células de Langerhans/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Neoplasias Encefálicas/patología , Quimioradioterapia , Cisplatino/uso terapéutico , Irradiación Craneana , Citarabina/uso terapéutico , Etopósido/uso terapéutico , Resultado Fatal , Femenino , Humanos , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos XRESUMEN
In HLA haploidentical stem cell transplantation, patients and donors usually share one HLA haplotype and have one different HLA haplotype (hetero-to-hetero). However, there are rare cases of transplantation from HLA homozygous donors to heterozygous recipients (homo-to-hetero), resulting in mismatches only in the graft-versus-host direction. We previously reported that homo-to-hetero transplants have a lower survival rate in a mouse model than hetero-to-hetero transplants due to stronger graft-versus-host disease (GVHD) but inferior graft-versus-leukemia effect. To examine whether homo-to-hetero transplant effects also occur in humans, we retrospectively compared the results of 59 homo-to-hetero and 4,539 hetero-to-hetero cases in the Japanese transplant registry data. The results showed no statistical difference between the homo-to-hetero and hetero-to-hetero groups in the cumulative incidences of neutrophil engraftment (83.1% vs 89.0%), acute GVHD II-IV (36.8% vs 38.8%), III-IV (16.8% vs 17.4%), chronic GVHD (32.7% vs 30.7%), relapse (52.9% vs 49.0%), and non-relapse mortality (31.6% vs 28.2%). In contrast, overall survival was significantly lower in the homo-to-hetero group than in the hetero-to-hetero group (12.6% vs 26.2%, p = 0.0308). The inferior effect of homo-to-hetero transplantation on overall survival remained significant in multivariate analyses.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Animales , Ratones , Humanos , Estudios Retrospectivos , Trasplante Haploidéntico/efectos adversos , Tasa de Supervivencia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/etiologíaRESUMEN
We evaluated the efficacy of in vivo T-cell depletion with alemtuzumab in two prospective studies according to the International Conference on Harmonisation (ICH)-Good Clinical Practice (ICH-GCP) guidelines; one was for patients with aplastic anemia (AA study) and the other was for patients who were undergoing hematopoietic stem cell transplantation (HSCT) from a 2- or 3-antigen-mismatched haploidentical donor (MM study). The final dose of alemtuzumab in these studies was 0.16 mg/kg/day for 6 days. At this dose, all of the 12 and 11 patients in the AA and MM studies, respectively, achieved initial engraftment and the incidences of Grade II-IV acute graft-versus-host disease (GVHD) were 0% and 18%. While cytomegalovirus (CMV) frequently reactivated, none of the patients developed fatal CMV disease. Transplantation-related mortality within 1 year after HSCT was observed in only two and one patients, respectively. The numbers of CD4+ and CD8+ T-cells and T-cell receptor rearrangement excision circles remained low within 1 year after HSCT. These findings suggest that the use of alemtuzumab at this dose in a conditioning regimen enables safe allogeneic HSCT even from a 2- or 3-antigen-mismatched donor. However, the use of a lower dose of alemtuzumab should be explored in future studies to accelerate immune recovery after HSCT.
Asunto(s)
Anemia Aplásica/terapia , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Trasplante de Células Madre Hematopoyéticas , Depleción Linfocítica , Acondicionamiento Pretrasplante , Adulto , Anciano , Alemtuzumab , Anemia Aplásica/inmunología , Anemia Aplásica/patología , Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos/farmacología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , Ciclofosfamida/farmacología , Ciclofosfamida/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Antígenos HLA/inmunología , Haplotipos , Prueba de Histocompatibilidad , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Trasplante Homólogo , Vidarabina/análogos & derivados , Vidarabina/farmacología , Vidarabina/uso terapéuticoRESUMEN
Lymphoproliferative disorders (LPDs) are generally caused by uncontrolled B-cell proliferation induced by the Epstein-Barr virus (EBV) in the setting of impaired EBV-specific T-cell immunity, particularly when there is pharmacological immunosuppression including antithymocyte globulin. We herein present an unusual case of EBV associated with LPD (EBV-LPD) in which LPD occurred 3 weeks after the use of rabbit antithymocyte globulin administered for severe hepatitis-associated aplastic anemia; the patient died of fulminant leukemic lymphoma 5 days after the onset. We also review the pertinent literature on EBV-LPD after immunosuppressive therapy and document the efficacy of EBV viral load monitoring and the need for preemptive therapy.
Asunto(s)
Anemia Aplásica/virología , Suero Antilinfocítico/efectos adversos , Infecciones por Virus de Epstein-Barr/complicaciones , Linfoma de Células B Grandes Difuso/virología , Trastornos Linfoproliferativos/virología , Acidosis Láctica/etiología , Anemia Aplásica/tratamiento farmacológico , Animales , Suero Antilinfocítico/uso terapéutico , Ciclosporina/uso terapéutico , ADN Viral/sangre , Resultado Fatal , Humanos , Masculino , Persona de Mediana Edad , Conejos , Carga ViralRESUMEN
The optimal therapy for relapsed primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS) remains unclear. We herein report a case of relapsed primary DLBCL of the CNS complicated with primary biliary cholangitis, cirrhosis, and pancytopenia that was successfully treated with bridging therapy with tirabrutinib before autologous hematopoietic stem cell transplantation (ASCT). Tirabrutinib is well tolerated and effective for relapsed primary DLBCL of the CNS with comorbidities, including cirrhosis and pancytopenia. Tirabrutinib is a promising option as bridging therapy before ASCT.
RESUMEN
Chronic myeloid leukemia (CML) blast phase (monocytic lineage) is extremely rare. A 39-year-old Japanese man was diagnosed with CML blast phase (monocytic lineage). T315I mutation was positive, ponatinib was initially started, and then, allogenic hematopoietic stem cell transplantation (allo-HSCT) was performed. Seven days after allo-HSCT, hyper-acute graft-versus-host disease developed, and medial temporal lobe encephalitis emerged 24 days after allo-HSCT. He was alive for over 1 year after allo-HSCT. This is the first case report of HSCT for CML blast phase (monocytic lineage) in tyrosine kinase inhibitor era. Further cases should be documented for effective treatment regimen and analysis of clinical features.
RESUMEN
Although autologous hematopoietic cell transplantation (HCT) is an established therapy for patients with relapsed acute promyelocytic leukemia (APL) after returning to complete remission (CR), the role of allogeneic HCT remains unclear for treating relapsed APL. This study aimed to investigate allogeneic HCT outcomes in patients with relapsed APL, focusing particularly on those who underwent transplantation in non-CR and those who had relapsed after prior autologous HCT. We retrospectively analyzed Japanese nationwide transplantation registry data of patients with relapsed APL age ≥16 years who underwent allogeneic HCT between 2006 and 2020. A total of 195 patients were eligible for this analysis, including 69 who underwent transplantation in non-CR and 55 who relapsed after prior autologous HCT. The median duration of follow-up for survivors was 5.4 years. Multivariate analysis revealed that both non-CR at transplantation (hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.12 to 2.71; P = .014) and prior autologous HCT (HR, 2.10; 95% CI, 1.28 to 3.44; P = .013) were associated with higher risks of overall mortality. The 5-year overall survival (OS) rates for patients who underwent transplantation in CR and non-CR were 58% and 39%, respectively (P = .085), if they did not have a history of prior autologous HCT. In the patients who had relapsed after prior autologous HCT, the 5-year OS rate was 47% for those who underwent allogeneic HCT in CR and 6% for those who did so in non-CR (P = .001). Allogeneic HCT still provides an opportunity for long-term survival for certain patients with relapsed APL for whom autologous HCT is unlikely to be effective. The dismal outcome of those with prior autologous HCT who underwent allogeneic HCT in non-CR poses a significant therapeutic challenge.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Promielocítica Aguda , Humanos , Adolescente , Leucemia Promielocítica Aguda/cirugía , Trasplante Homólogo , Estudios Retrospectivos , Trasplante AutólogoRESUMEN
To determine how immunosuppressant agents used for graft-versus-host disease (GVHD) prophylaxis affect natural killer (NK) cells, we examined the effects of cyclosporine (CSP), tacrolimus (TAC), mycophenolic acid (MPA, an active form of mycophenolate mofetil), and methotrexate (MTX) on the proliferation and cytotoxicity of NK cells. The proliferation of NK cells from healthy individuals in the presence of interleukin (IL)-2 and IL-15 was suppressed to 51% ± 16% of that of the controls with CSP, to 31% ± 19% with TAC, to 14% ± 6% with MPA, and to 87% ± 18% with MTX. Both CSP and TAC increased the proportion of CD16(-)CD56(bright) cells, a NK cell subset capable of secreting high amount of cytokines, and also enhanced NKp30 expression, whereas MPA markedly decreased the proportion of CD16(-)CD56(bright) cells and reduced the expression of all activating NK cell receptors, including NKG2D, NKp30, NKp44, and NKp46. MPA also reduced the cytotoxicity against K562 cells from 61% ± 15% to 17% ± 7% and that against Daudi cells from 44% ± 4% to 4% ± 4%, whereas the other 3 drugs did not diminish these cytotoxicities. The inhibition of NK cell proliferation and cytotoxicity against leukemic cell lines by MPA was partially abolished by the inclusion of guanosine in the culture. Similar to the effect of MPA on T cells, MPA inhibited the down-regulation of p27 on NK cells induced by the incubation of NK cells in the presence of IL-2. These results suggest that MPA is a potent inhibitor of NK cells, and that its inclusion in the GVHD prophylaxis regimen might diminish the graft-versus-leukemia effect of NK cells.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Citotoxicidad Inmunológica/efectos de los fármacos , Inmunosupresores/farmacología , Células Asesinas Activadas por Linfocinas/efectos de los fármacos , Células Asesinas Activadas por Linfocinas/fisiología , Ácido Micofenólico/farmacología , Línea Celular Tumoral , Células Cultivadas , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Inhibidores Enzimáticos/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Efecto Injerto vs Leucemia/efectos de los fármacos , Guanosina/metabolismo , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , IMP Deshidrogenasa/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Activación de Linfocitos/efectos de los fármacos , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapéutico , Profármacos/uso terapéutico , Receptores de Células Asesinas Naturales/metabolismo , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/metabolismoRESUMEN
Although some studies have suggested the effectiveness of hyperbaric oxygen (HBO) therapy for hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (HSCT), the role of HBO has not been established. We compared the treatment outcomes of 8 patients with viral HC (adenovirus [ADV], n = 2; BK virus [BKV], n = 6) treated with HBO (HBO[+]) and 8 patients (ADV, n = 2; BKV, n = 6) treated with conventional therapy (HBO[-]), such as urinary catheterization and intravenous cidofovir. HBO therapy was performed at 2.1 atmospheres for 90 min/day until clinical improvement was achieved. The median number of HBO treatments was 10 (range 8-12). The median duration of HBO treatment was 19.5 days (range 10-23 days). All 8 HBO(+) patients achieved complete remission (CR) at a median of 14.5 days (range 5-25 days). Of the 8 HBO(-) patients, 5 (62.5%) obtained CR and 3 remained symptomatic for 2-6 months. The cumulative incidence of transplant-related mortality at day 100 after allogeneic HSCT was significantly higher in the HBO(-) patients than in the HBO(+) patients (14.2 vs. 0%, P < 0.05). No severe HBO-related adverse effects were observed. In conclusion, HBO is a feasible option for treating viral HC after allogeneic HSCT.
Asunto(s)
Cistitis/terapia , Cistitis/virología , Trasplante de Células Madre Hematopoyéticas , Hemorragia/terapia , Hemorragia/virología , Oxigenoterapia Hiperbárica , Adenoviridae/aislamiento & purificación , Infecciones por Adenoviridae/complicaciones , Adulto , Virus BK/aislamiento & purificación , Cistitis/etiología , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hemorragia/etiología , Humanos , Oxigenoterapia Hiperbárica/métodos , Masculino , Persona de Mediana Edad , Infecciones por Polyomavirus/complicaciones , Trasplante Homólogo/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Valproic acid (VPA), a histone deacetylase inhibitor, upregulates NKG2D ligands (NKG2DLs) on some monocytic and lymphoid leukemic cells. However, its effect on myeloid leukemia cells and synergistic agents that can augment the effect of VPA remains unknown. Of the various myeloid cell lines examined, OUN-1, a chronic myelogenous leukemia cell line, showed the most prominent upregulation of MICA/B and ULBP2 in response to VPA. The NKG2DL upregulation was observed only in leukemic cells without apoptosis and the effect was abrogated by pretreatment of cells with caffeine, an inhibitor of ATM/ATR. Several activators of ATM/ATR were screened for their effect on NKG2DL expression, but only hydroxyurea (HU) efficiently upregulated both MICA/B and ULPB2 expression on the cell line. VPA and HU synergistically upregulated the NKG2DLs on OUN-1 cells as well as primary leukemic cells from some patients with acute myeloid leukemia. The upregulation of NKG2DLs by VPA and/or HU was associated with increased transcription of each NKG2DL gene. OUN-1 cells treated with VPA + HU were more susceptible to killing by natural killer (NK) cells than untreated cells and the enhanced cytotoxicity of NK cells was blocked by the treatment of NK cells with anti-NKG2D monoclonal antibodies. The same concentrations of VPA and HU did not affect the cytotoxicity of NK cells against OUN-1 cells. These data suggest that VPA and HU might enhance the NK cell-mediated antileukemia effect by increasing the susceptibility of myeloid leukemic cells to NK cells.
Asunto(s)
Citotoxicidad Inmunológica/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Hidroxiurea/farmacología , Péptidos y Proteínas de Señalización Intercelular/genética , Células Asesinas Naturales/inmunología , Leucemia Mieloide/inmunología , Ácido Valproico/farmacología , Cafeína/farmacología , Línea Celular Tumoral , Sinergismo Farmacológico , Proteínas Ligadas a GPI , Humanos , Leucemia Mieloide/patología , Regulación hacia ArribaRESUMEN
A small population of CD55(-)CD59(-) blood cells was detected in a patient who developed donor-type late graft failure after allogeneic stem cell transplantation (SCT) for treatment of aplastic anemia (AA). Chimerism and PIGA gene analyses showed the paroxysmal nocturnal hemoglobinuria (PNH)-type granulocytes to be of a donor-derived stem cell with a thymine insertion in PIGA exon 2. A sensitive mutation-specific polymerase chain reaction (PCR)-based analysis detected the mutation exclusively in DNA derived from the donor bone marrow (BM) cells. The patient responded to immunosuppressive therapy and achieved transfusion independence. The small population of PNH-type cells was undetectable in any of the 50 SCT recipients showing stable engraftment. The de novo development of donor cell-derived AA with a small population of PNH-type cells in this patient supports the concept that glycosyl phosphatidylinositol-anchored protein-deficient stem cells have a survival advantage in the setting of immune-mediated BM injury.
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Rechazo de Injerto/etiología , Rechazo de Injerto/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Proteínas de la Membrana/genética , Mutación , Anemia Aplásica/genética , Anemia Aplásica/terapia , Células Madre Hematopoyéticas/metabolismo , Hemoglobinuria Paroxística/genética , Hemoglobinuria Paroxística/terapia , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Donantes de Tejidos , Quimera por Trasplante/genética , Trasplante HomólogoRESUMEN
To identify factors affecting responsiveness to eltrombopag (EPAG), we retrospectively analyzed 38 aplastic anemia patients treated with EPAG who were refractory (n = 29) or showed an inadequate response (n = 9) to conventional therapies. The efficacy was evaluated at 16 weeks after starting EPAG and at any given time when the best response was achieved. Hematologic responses were observed in 15 patients (39%) at week 16 and in 25 (66%) at any given time. Ten of 19 (53%) achieved transfusion independence. A univariate analysis revealed the presence of PNH-phenotype cells and the relatively higher platelet counts as associated with a good response to EPAG.
RESUMEN
Immunotherapy targeting leukemia-associated antigens has shown promising results. Because of the heterogeneity of leukemia, vaccines with a single peptide have elicited only a limited immune response. Targeting several peptides together elicited peptide-specific cytotoxic T lymphocytes (CTLs) in leukemia patients, and this was associated with clinical responses. Thus, the discovery of novel antigens is essential. In the current study, we investigated cyclin E as a novel target for immunotherapy. Cyclin E1 and cyclin E2 were found to be highly expressed in hematologic malignancies, according to reverse transcription polymerase chain reaction and western blot analysis. We identified two HLA-A*0201 binding nonameric peptides, CCNE1M from cyclin E1 and CCNE2L from cyclin E2, which both elicited the peptide-specific CTLs. The peptide-specific CTLs specifically kill leukemia cells. Furthermore, CCNE1M and CCNE2L CTLs were increased in leukemia patients who underwent allogeneic hematopoietic stem cell transplantation, and this was associated with desired clinical outcomes. Our findings suggest that cyclin E1 and cyclin E2 are potential targets for immunotherapy in leukemia.
Asunto(s)
Antígenos de Neoplasias/metabolismo , Vacunas contra el Cáncer/inmunología , Ciclina E/inmunología , Ciclinas/inmunología , Antígeno HLA-A2/inmunología , Leucemia/inmunología , Proteínas Oncogénicas/inmunología , Adulto , Anciano , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/farmacología , Epítopos de Linfocito T/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linfocitos T Citotóxicos/inmunología , Adulto JovenRESUMEN
The global, randomized, open-label KEYNOTE-185 study closed early after an interim analysis showed an unfavorable benefit-risk profile with pembrolizumab plus lenalidomide and low-dose dexamethasone (Rd) versus Rd alone in treatment-naive, transplant-ineligible multiple myeloma. This subgroup analysis reported outcomes in the Japanese population. Patients were randomly assigned (1:1) to pembrolizumab plus Rd or Rd alone, stratified by age and International Staging System. The primary end point was progression-free survival (PFS). Fifty-two Japanese patients were randomly assigned to pembrolizumab plus Rd (n = 27) or Rd (n = 25). The median follow-up was 7.2 months (range, 0.4-13.8). The median PFS was not reached (NR); 6-month PFS was 91.2% versus 86.2% with pembrolizumab plus Rd versus Rd [hazard ratio (HR), 0.31; 95% CI, 0.06-1.63]. The median overall survival (OS) was NR; 6-month OS was 96.2% versus 95.7% with pembrolizumab plus Rd versus Rd (HR, 0.33; 95% CI, 0.03-3.72). With pembrolizumab plus Rd versus Rd, grade 3-5 adverse events occurred in 70.4% versus 69.6% of patients; serious adverse events occurred in 40.7% versus 52.5%. Although in the Japanese subgroup of KEYNOTE-185 adding pembrolizumab to Rd did not show an unfavorable risk-benefit, the analysis is limited by short follow-up and small sample size, affecting generalizability of the results.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dexametasona/administración & dosificación , Lenalidomida/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Pueblo Asiatico , Biosimilares Farmacéuticos , Supervivencia sin Enfermedad , Femenino , Humanos , Lenalidomida/efectos adversos , Masculino , Mieloma Múltiple/mortalidadRESUMEN
Peripheral blood from 489 recently diagnosed patients with aplastic anaemia (AA) and 316 with refractory anaemia (RA) of myelodysplastic syndrome was evaluated to characterize CD55(-)CD59(-) [paroxysmal nocturnal haemoglobinuria (PNH)]-type blood cells associated with bone marrow (BM) failure. PNH-type cells were detected in 57% and 20% of patients with AA and RA, respectively. The percentages of PNH-type granulocytes ranged from 0.003% to 94.2% and the distribution was log-normal with a median of 0.178%. Serial analyses of 75 patients with PNH-type cells over 5 years revealed that the percentage of PNH-type cells constantly increased in 13 (17%), persisted in 44 (59%), disappeared in the remaining 18 (24%) although even in the 'Disappearance' group, PNH-type granulocytes persisted for at least 6 months. A scattergram profile of PNH-type cells unique to each patient persisted regardless of the response to immunosuppressive therapy and only single PIGA mutations were detected in PNH-type granulocytes sorted from four patients. These findings suggest that the PNH-type cells in patients with BM failure are derived from single PIGA mutant haematopoietic stem cells even when their percentages are <1% and their fate depends on the proliferation and self-maintenance properties of the individual PIGA mutants.
Asunto(s)
Glicosilfosfatidilinositoles/deficiencia , Hemoglobinuria Paroxística/sangre , Anciano , Anciano de 80 o más Años , Anemia Aplásica/sangre , Anemia Aplásica/genética , Estudios de Seguimiento , Glicosilfosfatidilinositoles/sangre , Granulocitos/metabolismo , Hemoglobinuria Paroxística/genética , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/genéticaRESUMEN
OBJECTIVES: Some patients with myelodysplastic syndrome (MDS) show a marked increase in the percentage of immature platelet fraction (IPF%) despite the absence of severe thrombocytopenia. To determine the significance of such an unbalanced increase in the IPF%, we investigated the IPF% and other laboratory findings of 51 patients recently diagnosed with MDS. METHOD: Subjects consisted of 80 healthy males, 90 healthy females, and 51 patients with MDS and 20 patients with idiopathic thrombocytopenic purpura (ITP). The IPF and IPF% were determined using a Sysmex XE-2100 system loaded with IPF Master software (XE IPF Master, Sysmex). Platelet counts were measured simultaneously. RESULTS: IPF% and platelet counts of these patients ranged from 1.1% to 25.1% (median, 5.3%) and from 6 to 260 x 10(9)/L (median, 71 x 10(9)/L), respectively. Twelve patients showed platelet counts more than 50 x 10(9)/L with 10% or more IPF%. All of the 12 patients had chromosome abnormalities including monosomy 7 and complex abnormalities involving 7 or 5q. In the other 39 patients who did not show the aberrant IPF% increase, chromosomal abnormalities were seen only in seven patients and none of them had chromosome 7 abnormalities. The IPF% of two patients increased to more than 10% in association with the appearance of monosomy 7. CONCLUSIONS: These findings suggest that a high IPF% in MDS patient may be a marker for karyotypic abnormalities with a poor prognosis, including chromosome 7 abnormalities.