RESUMEN
BACKGROUND: We conducted a retrospective study to categorize the cord blood unit (CBU)s to identify the optimal units. METHODS: A total of 8503 adults (female, n = 3592; male, n = 4911) receiving their first single cord blood transplantation (CBT) in 2000-2019 were analyzed. Factors associated with CBUs affecting overall survival (OS) and neutrophil engraftment were selected to create ranked categorization for each outcome, followed by comparison with transplantation using HLA-matched bone marrow (BMT)/peripheral blood stem cell (PBSCT) from unrelated (n = 6052) and related donors (n = 4546). RESULTS: Sex-mismatch, CD34+ cell and CFU-GM counts were selected in the OS analysis. Considering the strong interaction between sex mismatch and CD34+ cell counts, we analyzed females and males separately. For females, female CBU with CD34+ cell counts {greater than or equal to} 0.5 × 10e5/kg and CFU-GM counts {greater than or equal to} 15 × 10e3/kg offered the best OS (Group I), followed by other groups with any (Groups II-IV) or all (Group V) of the risk factors. Group I consistently showed favorable OS (Group IV: HR1.22, P = 0.027; Group V: HR1.31, P = 0.047), comparable to those of rBMT/PBSCT (OS: HR1.02, P = 0.654) and uBM/PBSCT in patients with higher rDRI (HR1.07, P = 0.353). Male patients lacked significant factors affecting OS. Categorization for neutrophil engraftment consisting of CD34+ cell and CFU-GM counts, sex-mismatch, presence of donor-specific antibodies, and the number of HLA-mismatches was effective but not predicted OS. CONCLUSION: Our ranked categorizations sufficiently predicted female OS and engraftment. The best-ranked CBUs offered preferable outcomes comparable to conventional BM/PB donors in female but not in male patients.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Masculino , Femenino , Trasplante de Médula Ósea/efectos adversos , Estudios Retrospectivos , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Sangre Fetal , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Antígenos CD34 , Enfermedad Injerto contra Huésped/etiologíaRESUMEN
Despite the remarkable initial efficacy of CD19 chimeric Ag receptor T (CAR-T) cell therapy, a high incidence of relapse has been observed. To further increase treatment efficacy and reduce the rate of escape of Ag-negative cells, we need to develop CAR-T cells that target other Ags. Given its restricted expression pattern, CD37 was considered a preferred novel target for immunotherapy in hematopoietic malignancies. Therefore, we designed a CD37-targeting CAR-T (CD37CAR-T) using the single-chain variable fragment of a humanized anti-CD37 Ab, transmembrane and intracellular domains of CD28, and CD3ζ signaling domains. High levels of CD37 expression were confirmed in B cells from human peripheral blood and bone marrow B cell precursors at late developmental stages; by contrast, more limited expression of CD37 was observed in early precursor B cells. Furthermore, we found that human CD37CAR-T cells with longer spacer lengths exhibited high gene transduction efficacy but reduced capacity to proliferate; this may be due to overactivation and fratricide. Spacer length optimization resulted in a modest transduction efficiency together with robust capacity to proliferate. CD37CAR-T cells with optimized spacer length efficiently targeted various CD37+ human tumor cell lines but had no impact on normal leukocytes both in vitro and in vivo. CD37CAR-T cells effectively eradicated Raji cells in xenograft model. Collectively, these results suggested that spacer-optimized CD37CAR-T cells could target CD37-high neoplastic B cells both in vitro and in vivo, with only limited interactions with their normal leukocyte lineages, thereby providing an additional promising therapeutic intervention for patients with B cell malignancies.
Asunto(s)
Antígenos CD19 , Recurrencia Local de Neoplasia , Antígenos CD19/genética , Antígenos de Neoplasias , Antígenos CD28 , Línea Celular Tumoral , Humanos , Linfocitos T/inmunología , TetraspaninasRESUMEN
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) grafts have expanded from related human leukocyte antigens (HLA)-matched donors to unrelated HLA-matched donors and umbilical cord blood. Either one of these grafts is now available for almost all patients who need allo-HSCT. Furthermore, an allo-HSCT from an HLA one haplo-mismatched donor can be safely performed with cyclophosphamide administration after transplantation. Graft-versus-host disease (GVHD) and graft-versus-leukemia effects are inextricably linked in allo-HSCT, and a transplant with more GVHD-associated complications is not necessarily a worse transplant as a graft selection indicator. Transplants with severe GVHD have fewer relapses, which offset the negative effects. This study presents data to guide graft selection by comparing transplant outcomes from different donor sources. The current position of post-transplant cyclophosphamide haplo from HLA-one haplo mismatched donor is also discussed based on data presented to date.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Donante no Emparentado , Ciclofosfamida/uso terapéutico , Trasplante Homólogo/efectos adversos , Estudios RetrospectivosRESUMEN
The number of cases of chimeric antigen receptor T (CAR-T) cell therapy has been rapidly increasing in Japan since Tisagenlecleucel was approved in March 2019, and clinical experience with CAR-T therapy for CD19 has demonstrated that the therapy can be performed safely than initially expected. The current challenge for CAR-T therapy is insufficient response, as about 50% of patients who receive CD19 CAR-T therapy eventually relapse or become refractory. The causes can be generally classified as CAR-T cell exhaustion and lack of sufficient effector function, loss of the target antigen, and extremely rapid tumor growth, and countermeasures are being investigated and developed for each of these causes. Additionally, the development of novel CAR-T therapies is also desired. In this article, we discuss the current status and future prospects of these issues, including our own efforts.
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Neoplasias , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/uso terapéutico , Receptores de Antígenos de Linfocitos T , Inmunoterapia Adoptiva , Neoplasias/tratamiento farmacológico , Recurrencia , Antígenos CD19RESUMEN
CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promise as treatment of relapsed or refractory B-cell malignancies. However, the clinical utility of early CAR-T monitoring within 1 month after infusion has not been elucidated. In this study, we quantitatively measured CAR-T kinetics in peripheral blood on days 2, 4, 7, 9, 11, 14, 21, and 28 post-infusion using flow cytometry and quantitative polymerase chain reaction in 13 patients with relapsed refractory diffuse large B-cell lymphoma (DLBCL) treated with tisagenlecleucel (tisa-cel). No relationships were identified between bulk CAR-T kinetics and treatment outcomes. Interestingly, the magnitude of CD4+ CAR-T expansion was higher in responders than in nonresponders, while CD8+ CAR-T expansion was minimal in responders. Additionally, CAR-T proliferation was more pronounced in patients with cytokine release syndrome. Our results suggest that CD4+ CAR-T cellular kinetics within 1 month after CAR-T infusion may predict its efficacy after tisa-cel therapy in adult patients with DLBCL.
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Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Adulto , Humanos , Receptores Quiméricos de Antígenos/uso terapéutico , Receptores de Antígenos de Linfocitos T/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfocitos T , Inmunoterapia Adoptiva/métodos , Antígenos CD19/uso terapéuticoRESUMEN
Adoptively transferred CD19 chimeric antigen receptor (CAR) T cells have led to impressive clinical outcomes in B cell malignancies. Beyond induction of remission, the persistence of CAR-T cells is required to prevent relapse and provide long-term disease control. To improve CAR-T cell function and persistence, we developed a composite co-stimulatory domain of a B cell signaling moiety, CD79A/CD40, to induce a nuclear translocating signal, NF-κB, to synergize with other T cell signals and improve CAR-T cell function. CD79A/CD40 incorporating CD19CAR-T cells (CD19.79a.40z) exhibited higher NF-κB and p38 activity upon CD19 antigen exposure compared with the CD28 or 4-1BB incorporating CD19CAR-T cells (CD19.28z and CD19.BBz). Notably, we found that CD19.79a.40z CAR-T cells continued to suppress CD19+ target cells throughout the co-culture assay, whereas a tendency for tumor growth was observed with CD19.28z CAR-T cells. Moreover, CD19.79a.40z CAR-T cells exhibited robust T cell proliferation after culturing with CD19+ target cells, regardless of exogenous interleukin-2. In terms of in vivo efficiency, CD19.79a.40z demonstrated superior anti-tumor activity and in vivo CAR-T cell proliferation compared with CD19.28z and CD19.BBz CD19CAR-T cells in Raji-inoculated mice. Our data demonstrate that the CD79A/CD40 co-stimulatory domain endows CAR-T cells with enhanced proliferative capacity and improved anti-tumor efficacy in a murine model.
Asunto(s)
Antígenos CD19/inmunología , Antígenos CD40/metabolismo , Antígenos CD79/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores Quiméricos de Antígenos/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Técnicas de Cocultivo , Humanos , Inmunoterapia Adoptiva , Células K562 , Activación de Linfocitos , Ratones , FN-kappa B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Despite a strong association between acute graft-versus-host disease (GVHD) and cytomegalovirus reactivation (CMVR), the joint effect of acute GVHD and CMVR on nonrelapse mortality (NRM) has not been well studied. METHODS: We evaluated the impact of CMVR on NRM stratified according to the development of acute GVHD using a landmark method. This study included 6078 patients who received their first allogeneic hematopoietic cell transplantation (HCT) with a preemptive strategy for CMVR between 2008 and 2017. RESULTS: The cumulative incidences of grade 2-4 acute GVHD (G24GVHD), CMVR by day 100, and CMV disease by day 365 were 37.3%, 52.1%, and 2.9%, respectively. Patients with G24GVHD were associated with the subsequent development of CMVR, and the presence of CMVR also increased the risk of G24GVHD. In a landmark analysis at day 65, the cumulative incidence of NRM at 1 year was 5.4%, 10.0%, 13.9%, and 19.7% in patients with G24GVHD-/CMVR-, G24GVHD-/CMVR+, G24GVHD+/CMVR-, and G24GVHD+/CMVR+, respectively. In a multivariate analysis, CMVR was respectively associated with an increased risk of NRM by day 365 in patients without G24GVHD (hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.24-2.05; Pâ <â .001) and with G24GVHD (HR, 1.34; 95% CI, 1.06-1.70; Pâ =â .014), but the interaction between G24GVHD and CMVR was not significant (Pâ =â .326). Subgroup analyses suggested that the joint effect of acute GVHD and CMVR might vary according to the baseline characteristics. CONCLUSIONS: These data regarding the close relationship between acute GVHD and CMVR should provide important implications for the treatment strategy after HCT.
Asunto(s)
Infecciones por Citomegalovirus , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Citomegalovirus , Infecciones por Citomegalovirus/epidemiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Acondicionamiento PretrasplanteRESUMEN
To overcome the delayed or failed engraftment after unrelated cord blood transplantation (CBT), we conducted a multicenter phase II study of intrabone single-unit CBT without antithymocyte globulin (ATG) for adult patients with hematological malignancies (UMIN-CTR, UMIN000020997). Sixty-four patients received an intrabone injection of unwashed (n = 61) or washed (n = 3) cord blood after local anesthesia. All injection-related adverse events were mild and resolved spontaneously. Sixty-two patients were evaluable for the efficacy of intrabone CBT of serological HLA-A, -B, and -DR ≥ 4/6 matched cord blood with a median number of 2.57 × 107/kg cryopreserved total nucleated cells. The probability of survival with neutrophil engraftment on day 28 was 77.4% (95% confidence interval, 67.0-85.8%), which exceeded the threshold value. The cumulative incidences of neutrophils ≥ 0.5 × 109/L on day 60 was 80.6% (68.2-88.6%), with a median time to recovery of 21 days after transplantation. The cumulative incidences of platelets ≥ 20 × 109/L and platelets ≥ 50 × 109/L on day 100 were 75.8% (62.6-84.9%) and 72.6% (59.4-82.1%), respectively, with median time to platelets ≥ 20 × 109/L and platelets ≥ 50 × 109/L of 38 and 45 days after transplantation, respectively. The cumulative incidences of grade II-IV and III-IV acute graft-versus-host disease were 29.0% and 6.5%, respectively. All responded to steroid therapy, and secondary treatments were not required. The present study suggests the efficacy of intrabone single-unit CBT without ATG in terms of early engraftment and controllable acute graft-versus-host disease.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Neoplasias Hematológicas/terapia , Infusiones Intraóseas/métodos , Adolescente , Adulto , Anciano , Suero Antilinfocítico , Huesos , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Femenino , Sangre Fetal/fisiología , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/patología , Neoplasias Hematológicas/epidemiología , Humanos , Incidencia , Infusiones Intraóseas/efectos adversos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The outcomes of 7/8 allele-matched unrelated bone marrow transplantation (7/8 UBMT) and umbilical cord blood transplantation (UCBT) have been improving. We retrospectively analyzed adults with acute leukemia who underwent their first 7/8 UBMT or UCBT in Japan. Between January 2008 and December 2017, a total of 4150 patients were recorded, including 488 who underwent 7/8 UBMT and 3662 who underwent UCBT. Only 32 patients with 7/8 UBMT had graft-versus-host-disease (GVHD) high-risk HLA mismatched pairs. Overall survival at 3 years was 54% for 7/8 the UBMT group and 46% for the UCBT group, a nonsignificant difference in multivariate analysis (hazard ratio [HR], 1.01; 95% confidence interval [CI], .88 to 1.17; P = .89). The 7/8 UBMT and UCBT groups showed a similar nonrelapse mortality rate (HR, 1.16; 95% CI, .96 to 1.45; P = .16) and relapse rate (HR, .85; 95% CI, .71 to 1.02; P = .08). However, the UCBT group had a lower risk of grade II-IV acute GVHD (HR, .76; 95% CI, .65 to .88; P < .001) and chronic GVHD (HR, .77; 95% CI, .66- .91; P = .002) compared with the 7/8 UBMT group. In stratified analyses combining disease risk with conditioning intensity, 7/8 UBMT showed superior overall survival to UCBT in standard risk and myeloablative conditioning (HR, .72; 95% CI, .56 to .93; P = .014). Both 7/8 UBMT and UCBT are appropriate alternative donor procedures. The stem cell source can be selected on the basis of disease risk, patient tolerability, or concerns regarding GVHD.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped , Adulto , Alelos , Trasplante de Médula Ósea , Humanos , Japón , Estudios Retrospectivos , Donante no EmparentadoRESUMEN
Almost comparable transplantation outcomes have been reported with HLA-matched unrelated donor transplantation (UDT) and cord blood transplantation (CBT). We conducted a prospective phase 2 study to assess the efficacy and safety of single-unit myeloablative CBT in adult leukemia and myelodysplastic syndrome. Because the day 180 survival of UDT was approximately 80%, we determined the alternative hypothesis of expected day 180 survival with a successful engraftment rate of 80% and set the null hypothesis of threshold rate at 65%. Sixty-two patients (median age, 37 years) were registered, including 28 with acute myelogenous leukemia, 25 with acute lymphoblastic leukemia, and 9 with myelodysplastic syndrome. Of 61 eligible patients, 52 were successfully engrafted and survived at day 180 (85%; 95% confidence interval, 74% to 93%). Single-unit CBT was judged to be effective because the null hypothesis was rejected (P < .001). Furthermore, neutrophil engraftment was observed in 57 patients (92%); the incidences of grade II-IV acute and chronic graft-versus-host disease were 30% and 32%, respectively; and the cumulative incidences of nonrelapse mortality and relapse at 2 years were 18% and 13%, respectively. The present study showed favorable survival outcomes with single-unit CBT. Therefore, this method may be considered if a well-HLA-matched UDT cannot be obtained.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped , Leucemia , Síndromes Mielodisplásicos , Enfermedad Aguda , Adolescente , Adulto , Aloinjertos , Enfermedad Crónica , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Leucemia/mortalidad , Leucemia/terapia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Estudios Prospectivos , Tasa de Supervivencia , Factores de TiempoRESUMEN
Owing to the difficulty in isolating T cells from human biopsy samples, the characteristics of T cells that are infiltratinghuman acute graft-versus-host disease (GVHD) tissues remain largely uninvestigated. In the present study, TCR-ß deep sequencing of various GVHD tissue samples and concurrent peripheral blood obtained from transplant recipients was performed in combination with functional assays of tissue-infiltrating T cell clones. The T cell repertoire was more skewed in GVHD tissues than in the peripheral blood. The frequent clonotypes differed from tissue to tissue in the same patient, and the frequent clonotypes in the same tissue differed from patient to patient. Two T cell clones were successfully isolated from GVHD skin of a patient. In a cytotoxicity assay, both Tcell clones lysed patient peripheral blood mononuclear cells, but not donor-derived Epstein-Barr virus-transformed lymphoblastoid cells. Their clonotypes were identical to the most and second most frequent T cell clonotypes in the original GVHD skin and accounted for almost all of the skin-infiltrating T cells. These results suggest that human acute GVHD may result from only a few different alloreactive cytotoxic T cell clones, which differ from tissue to tissue and from patient to patient. The characterization of T cells infiltrating human GVHD tissues should be further investigated.
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Enfermedad Injerto contra Huésped/patología , Linfocitos T Citotóxicos/citología , Movimiento Celular , Células Clonales/citología , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Piel/inmunología , Piel/patología , Trasplante HomólogoRESUMEN
Wilms' tumor 1 (WT1) is constantly expressed in leukemic cells of acute leukemia and myelodysplastic syndrome (MDS). A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A*24:02 has been identified. We conducted a first-in-human trial of TCR-gene transduced T-cell (TCR-T-cell) transfer in patients with refractory acute myeloblastic leukemia (AML) and high-risk MDS to investigate the safety and cell kinetics of the T cells. The WT1-specific TCR-gene was transduced to T cells using a retroviral vector encoding small interfering RNAs for endogenous TCR genes. The T cells were transferred twice with a 4-week interval in a dose-escalating design. After the second transfer, sequential WT1 peptide vaccines were given. Eight patients, divided into 2 dose cohorts, received cell transfer. No adverse events of normal tissue were seen. The TCR-T cells were detected in peripheral blood for 8 weeks at levels proportional to the dose administered, and in 5 patients, they persisted throughout the study period. The persisting cells maintained ex vivo peptide-specific immune reactivity. Two patients showed transient decreases in blast counts in bone marrow, which was associated with recovery of hematopoiesis. Four of 5 patients who had persistent T cells at the end of the study survived more than 12 months. These results suggest WT1-specific TCR-T cells manipulated by ex vivo culture of polyclonal peripheral lymphocytes survived in vivo and retained the capacity to mount an immune reaction to WT1. This trial was registered at www.umin.ac.jp as #UMIN000011519.
Asunto(s)
Genes Codificadores de los Receptores de Linfocitos T , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Linfocitos T/metabolismo , Transducción Genética , Proteínas WT1/genética , Traslado Adoptivo , Anciano , Médula Ósea/patología , Femenino , Humanos , Cinética , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Péptidos/farmacologíaRESUMEN
A 47-year-old man with acute myeloid leukemia and myelodysplastic-related changes relapsed after an allogenic bone marrow transplant and received a cord blood transplant as salvage therapy. The patient developed febrile neutropenia that was resistant to broad-spectrum antibiotics and multiple, painful, nodular skin lesions on his trunk and extremities before engraftment. A skin biopsy and blood culture found mold, and the subsequent microscopic examination, mass spectrometry, and DNA sequencing of the fungal colonies identified Fusarium solani. The patient's fever and skin lesions began to improve with the administration of liposomal amphotericin B at 5 mg/kg/day. Neutrophilic engraftment occurred on day 19. Stage 3 acute skin graft-versus-host disease was cured by the application of topical steroid. Unexpectedly, a change from liposomal amphotericin B to voriconazole on day 38 exacerbated the Fusarium infection. The Fusarium infection was finally cured by the administration of liposomal amphotericin B for a total of 19 weeks. Neutrophilic engraftment, an immediate definitive diagnosis, the sufficient and long-term administration of appropriate antifungal medication, and avoidance of the systemic administration of steroids might have contributed to the successful outcome of this patient.
Asunto(s)
Anfotericina B/uso terapéutico , Trasplante de Células Madre de Sangre del Cordón Umbilical , Fusariosis , Antifúngicos , Fusariosis/terapia , Humanos , Masculino , Persona de Mediana EdadRESUMEN
An 18-year-old man was diagnosed with Epstein-Barr virus (EBV) -associated hemophagocytic syndrome (HPS) and treated with prednisolone (PSL) at a previous hospital. During PSL tapering, the HPS symptoms reappeared, and the patient was referred to our hospital. Increased PSL improved the symptoms, but the EBV infection remained unresolved. At age 20, he was admitted to our hospital for newly developed pneumonia and diagnosed with myelodysplastic syndrome (refractory cytopenia with multilineage dysplasia) (MDS-RCMD; normal karyotype, IPSS: Int-1) by bone marrow examination. MDS remission was achieved following bone marrow transplantation from an unrelated donor, and he is currently alive without relapse. The patient's father had also been diagnosed with MDS when he was young and died from leukoencephalopathy at approximately 50 years old. These observations support a diagnosis of familial MDS. GATA2 mutation p.R230Hfs*44 was identified in both bone marrow and control cells (buccal swab) at MDS diagnosis, and he was diagnosed with monocytopenia and mycobacterial infection (MonoMAC) syndrome. Furthermore, an acquired STAG2 mutation (splicing site change, c.820-2A>G) in the bone marrow cells was also identified, which might contribute to MDS progression.
Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Deficiencia GATA2/complicaciones , Síndromes Mielodisplásicos/etiología , Adolescente , Médula Ósea , Trasplante de Médula Ósea , Análisis Mutacional de ADN , Factor de Transcripción GATA2/genética , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapia , Inducción de Remisión , Adulto JovenRESUMEN
The outcomes of cord blood transplantation with non-irradiated reduced-intensity conditioning for hematological malignancies need to be improved because of graft failure and delayed engraftment. Intrabone infusion of cord blood cells has the potential to resolve the problems. In this phase II study, 21 adult patients with hematological malignancy received intrabone transplantation of serological HLA-A, B, and DR ≥4/6 matched single cord blood with a median number of cryopreserved total nucleated cells of 2.7 × 107 /kg (range, 2.0-4.9 × 107 /kg) following non-irradiated fludarabine-based reduced-intensity conditioning. Short-term methotrexate and tacrolimus were given as graft-versus-host disease prophylaxis, and granulocyte colony-stimulating factor was given after transplantation. No severe adverse events related to intrabone injection were observed. The cumulative incidences of neutrophils ≥0.5 × 109 /L, reticulocytes ≥1%, and platelets ≥20 × 109 /L recoveries were 76.2%, 71.4%, and 76.2%, respectively, with median time to recoveries of 17, 28, and 32 days after transplantation, respectively. The probability of survival with neutrophil engraftment on day 60 was 71.4%, and overall survival at 1 year after transplantation was 52.4%. The incidences of grade II-IV and III-IV acute graft-versus-host disease were 44% and 19%, respectively, with no cases of chronic graft-versus-host disease. The present study showed the safety of direct intrabone infusion of cord blood. Further analysis is required to confirm the efficacy of intrabone single cord blood transplantation with non-irradiated reduced-intensity conditioning for adult patients with hematological malignancy. This study was registered with UMIN-CTR, number 000000865.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Enfermedad Injerto contra Huésped/epidemiología , Neoplasias Hematológicas/terapia , Vidarabina/análogos & derivados , Adolescente , Adulto , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Criopreservación , Femenino , Neoplasias Hematológicas/sangre , Humanos , Inyecciones , Masculino , Persona de Mediana Edad , Neutrófilos/citología , Recuento de Plaquetas , Recuento de Reticulocitos , Análisis de Supervivencia , Acondicionamiento Pretrasplante , Resultado del Tratamiento , Vidarabina/administración & dosificación , Adulto JovenRESUMEN
The effectiveness of chimeric Ag receptor (CAR)-transduced T (CAR-T) cells has been attributed to supraphysiological signaling through CARs. Second- and later-generation CARs simultaneously transmit costimulatory signals with CD3ζ signals upon ligation, but may lead to severe adverse effects owing to the recognition of minimal Ag expression outside the target tumor. Currently, the threshold target Ag density for CAR-T cell lysis and further activation, including cytokine production, has not yet been investigated in detail. Therefore, we determined the threshold target Ag density required to induce CAR-T cell responses using novel anti-CD20 CAR-T cells with a CD28 intracellular domain and a CD20-transduced CEM cell model. The newly developed CD20CAR-T cells demonstrated Ag-specific lysis and cytokine secretion, which was a reasonable level as a second-generation CAR. For lytic activity, the threshold Ag density was determined to be â¼200 molecules per target cell, whereas the Ag density required for cytokine production of CAR-T cells was â¼10-fold higher, at a few thousand per target cell. CD20CAR-T cells responded efficiently to CD20-downregulated lymphoma and leukemia targets, including rituximab- or ofatumumab-refractory primary chronic lymphocytic leukemia cells. Despite the potential influence of the structure, localization, and binding affinity of the CAR/Ag, the threshold determined may be used for target Ag selection. An Ag density below the threshold may not result in adverse effects, whereas that above the threshold may be sufficient for practical effectiveness. CD20CAR-T cells also demonstrated significant lytic activity against CD20-downregulated tumor cells and may exhibit effectiveness for CD20-positive lymphoid malignancies.
Asunto(s)
Antígenos de Superficie/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antígenos CD20/inmunología , Antígenos CD20/metabolismo , Antígenos de Superficie/metabolismo , Antígenos CD28/inmunología , Antígenos CD28/metabolismo , Complejo CD3/inmunología , Complejo CD3/metabolismo , Línea Celular Tumoral , Citocinas/biosíntesis , Citotoxicidad Inmunológica , Expresión Génica , Orden Génico , Genes Reporteros , Humanos , Inmunofenotipificación , Espacio Intracelular , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/metabolismo , Activación de Linfocitos , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/genética , Linfoma de Células B/inmunología , Linfoma de Células B/metabolismo , Unión Proteica , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Rituximab , Transducción de Señal , Especificidad del Receptor de Antígeno de Linfocitos T/genética , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Transducción GenéticaRESUMEN
Malignant lymphoma with cardiac involvement is difficult to diagnose and treatment selection decisions can be challenging, because patients usually present with atypical disease involvement and the incidence is low. Herein, we describe the clinical characteristics and courses of three non-Hodgkin lymphoma patients showing cardiac involvement. All three patients were male, ages 32, 74 and 64 years. All three patients had presented with cardiac involvement mainly in the right heart system. We promptly performed needle biopsies for patients 1 and 3, and open-heart biopsy for patient 2, which showed PMBL for patient 1, DLBCL for patients 2 and 3. Since we were concerned regarding possible transient exacerbation of heart failure or the occurrence of fatal arrhythmia, we chose to start with relatively low dose chemotherapeutic interventions or pre-phase steroid therapy. After one course of chemotherapy or pre-phase steroid therapy, symptoms associated with heart failure almost completely subsided, and we further administered full-dose chemotherapy thereafter, resulting in complete responses in 2 cases. This case series demonstrates that malignant lymphoma with cardiac involvement is a treatable disease, despite widespread involvement. Furthermore, rapid and appropriate diagnostic imaging and biopsy are important when this disease is suspected.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Cardíacas/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Adulto , Anciano , Neoplasias Cardíacas/diagnóstico , Humanos , Linfoma/diagnóstico , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
To investigate an up-to-date alternative donor selection strategy, we compared the transplantation outcomes of 8/8 and 7/8 allele-matched unrelated bone marrow transplantation (UBMT) with those of umbilical cord blood transplantation (UCBT) and redefined the role of UCBT with extended analysis. Using Cox and competing risk regression analyses, we analyzed the transplantation outcomes in adult patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). A total of 2472 first myeloablative transplantations between 2000 and 2010 were included (8/8 UBMT, 1001; 7/8 UBMT, 656; UCBT, 815). For acute and chronic graft-versus-host disease (GVHD) and nonrelapse mortality (NRM), we applied the combined analyses including both AML and ALL data. In the multivariate analyses, severe acute GVHD and NRM after UCBT were comparable with 8/8 UBMT, whereas those after 7/8 UBMT were significantly higher. The incidence of extensive chronic GVHD was significantly lower with UCBT compared with after 8/8 and 7/8 UBMT. With adjusted analyses for AML, UCBT and 8/8 UBMT showed similar overall survival (OS), whereas 7/8 UBMT showed inferior OS. For ALL, we found no significant difference in OS among the 3 groups. Cord blood may be the first choice alternative to 8/8 UBMT for both AML and ALL.
Asunto(s)
Trasplante de Médula Ósea/métodos , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Alelos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
We retrospectively compared the transplantation outcomes for patients 50 years or older who received umbilical cord blood transplantation (UCBT) with those who received unrelated bone marrow transplantation (UBMT) for hematologic malignancies. A total of 1377 patients who underwent transplantation between 2000 and 2009 were included: 516 received 8/8 HLA allele-matched UBMT, 295 received 7/8 HLA allele-matched UBMT, and 566 received 4/6 to 6/6 HLA-matched UCBT. Adjusted overall survival (OS) was significantly lower in those who underwent UCBT than those who underwent 8/8 HLA-matched UBMT but was similar to that of 7/8 HLA-matched UBMT (the 2-year OS after 8/8 HLA-matched UBMT, 7/8 HLA-matched UBMT, and UCBT were 49% [95% confidence interval (CI), 45% to 55%], 38% [95% CI, 32% to 45%], and 39% [95% CI, 34% to 43%], respectively). However, adjusted OS was similar between 8/8 HLA-matched UBMT and UCBT receiving ≥.84 × 10(5) CD34(+) cells/kg among those with acute myeloid leukemia and those with acute lymphoblastic leukemia (the 2-year OS was 49% [95% CI, 43% to 55%], and 49% [95% CI, 41% to 58%], respectively). These data suggest that UCB is a reasonable alternative donor/stem cell source for elderly patients with similar outcomes compared with UBM from 8/8 HLA-matched unrelated donors when the graft containing ≥.84 × 10(5) CD34(+) cells/kg is available.
Asunto(s)
Trasplante de Médula Ósea , Trasplante de Células Madre de Sangre del Cordón Umbilical , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Donante no Emparentado , Anciano , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Little is known regarding the chimerism status after reduced-intensity conditioning transplantation when bone marrow is used as a stem cell source. We prospectively analyzed lineage-specific chimerism and retrospectively evaluated clinical outcomes in 80 adult patients who underwent unrelated donor bone marrow transplantation (URBMT) with fludarabine plus melphalan (FM) as the conditioning regimen. Mixed donor chimerism (MDC) was seen in 43 and 10 % of patients at days 14 and 28, respectively. Melphalan at ≤130 mg/m(2) was associated with an increased incidence of MDC at day 28 (P = 0.03). Patients with MDC at day 14 showed a marginally increased risk of primary graft failure and a marginally decreased risk of graft-versus-host disease. In multivariate analysis, MDC at day 14 was associated with higher overall mortality (hazard ratio (HR) = 2.1; 95 % confidence interval (CI), 1.1-4.2; P = 0.04) and relapse rate (HR = 3.0; 95 % CI, 1.2-7.5; P = 0.02), but not with non-relapse mortality (HR = 1.8; 95 % CI, 0.70-4.6; P = 0.23). Thus, the FM regimen yields prompt complete donor chimerism after URBMT, but the melphalan dose significantly impacts the kinetics of chimerism. Chimerism status evaluation at day 14 may be instrumental in predicting relapse after URBMT with the FM regimen.