RESUMO
Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell-specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ-dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.
Assuntos
Transplante de Medula Óssea , Infecções por Citomegalovirus , Imunidade Humoral , Interleucina-6 , Antivirais , Transplante de Medula Óssea/efeitos adversos , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/metabolismo , Imunoglobulina G , Interleucina-6/metabolismo , Animais , CamundongosRESUMO
Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML.
Assuntos
Ferroptose , Leucemia Mieloide Aguda , Oligonucleotídeos , Telomerase , Humanos , Telomerase/genética , Telomerase/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Ácidos GraxosRESUMO
There is a limited body of evidence for haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in older patients. Previous studies have used a high proportion of bone marrow-derived grafts and a variety of conditioning regimens. In Australia and New Zealand, haplo-HCST is predominantly performed using peripheral blood (PB) with universal use of post-transplantation cyclophosphamide (PTCy). To characterize the outcomes of older recipients undergoing haplo-HSCT for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Data were collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients aged 65 or older receiving a PB haplo-HSCT for AML/MDS between January 2010 and July 2020. A total of 44 patients were included in the analysis. The median follow-up time was 377 days. The median age was 68 (range 65-74) with a median Karnofsky performance status of 90. Thirty patients (68.2%) had AML, whereas 14 (31.8%) had MDS. The median donor age was 40. The most common conditioning regimen was nonmyeloablative fludarabine, cyclophosphamide, and total body irradiation (75%); the remainder of the patients received either melphalan- or busulfan-based regimens, and the majority were reduced intensity, with only 2 patients undergoing myeloablative conditioning. All patients received post-transplantation cyclophosphamide and mycophenolate mofetil, with the majority also receiving tacrolimus (90.5%) and the remainder receiving cyclosporine (9.5%). No patients received anti-thymocyte globulin. Neutrophil engraftment was achieved in 97.6% of patients at a median of 18 days, whereas platelet engraftment was achieved in 92.7% of patients at a median of 28 days. The cumulative incidences of cytomegalovirus (CMV) reactivation and CMV disease were 52.5% and 5.1% at 1 year. The incidence of grade 2-4 acute Graft Versus Host Disease (GVHD) was 18.2%. The incidence of chronic GVHD at 2 years was 40.7%, with extensive chronic GVHD occurring in 17.7% of patients. The incidences of relapse and non-relapse mortality (NRM) at 2 years were 8.8% and 20.7% respectively. The leading causes of death were infection (64.7%) followed by relapse (14.2%). The 2-year overall survival was 74%. Relapse free survival and GVHD free, relapse free survival at 2 years was 70% and 48%. Haplo-HSCT using a peripheral blood graft and PTCy GVHD prophylaxis demonstrates long-term disease control with acceptable rates of NRM for older patients with AML/MDS.
Assuntos
Infecções por Citomegalovirus , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Transplante de Células-Tronco de Sangue Periférico , Humanos , Idoso , Nova Zelândia/epidemiologia , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Síndromes Mielodisplásicas/terapia , RecidivaRESUMO
PURPOSE: Oral mucositis (OM) is a common complication in haematopoietic stem cell transplantation (HSCT). Polaprezinc, an anti-ulcer drug, has been shown to be effective to prevent OM in several studies when administered topically and systemically. This study aimed to evaluate the effectiveness of topical polaprezinc in patients undergoing HSCT. METHODS: This was an open-label randomised clinical trial comparing polaprezinc and sodium bicarbonate mouthwashes for the prevention of severe OM in HSCT patients. Adult patients who received conditioning regimens at moderate to high risk of developing OM were included. The primary endpoint was the incidence of severe (WHO grades 3-4) OM. The secondary endpoints included duration of grades 3-4 OM, incidence and duration of grades 2-4 OM, patient-reported pain and functional limitations. RESULTS: In total, 108 patients (55 test arm and 53 control arm) were randomised. There was no difference in the incidence of grades 3 to 4 OM (35% test arm versus 36% control arm). The secondary endpoints were not significantly different. In both arms, patients reported more throat pain compared to mouth pain. CONCLUSIONS: Topical polaprezinc had no effect in the prevention of OM in HSCT patients. Further research is required to evaluate the effects of systemic polaprezinc. The OM assessment tool needs to be reviewed as throat mucositis was a main issue in this study. TRIAL REGISTRATION: ACTRN12320001188921 (Date Registered: 10th November 2020).
Assuntos
Carnosina , Transplante de Células-Tronco Hematopoéticas , Estomatite , Adulto , Humanos , Carnosina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Dor/etiologia , Estomatite/etiologia , Estomatite/prevenção & controle , Estomatite/tratamento farmacológicoRESUMO
Acute gastrointestinal graft versus host disease (GI-GVHD) is a common complication following allogeneic haematopoietic cell transplantation (HCT), and is characterised by severe morbidity, frequent treatment-refractoriness, and high mortality. Early, accurate identification of GI-GVHD could allow for therapeutic interventions to ameliorate its severity, improve response rates and survival; however, standard endoscopic biopsy is inadequately informative in terms of diagnostic sensitivity or outcome prediction. In an era where rapid technological and laboratory advances have dramatically expanded our understanding of GI-GVHD biology and potential therapeutic targets, there is substantial scope for novel investigations that can precisely guide GI-GVHD management. In particular, the combination of tissue-based biomarker assessment (plasma cytokines, faecal microbiome) and molecular imaging by positron emission tomography (PET) offers the potential for non-invasive, real-time in vivo assessment of donor:recipient immune activity within the GI tract for GI-GVHD prediction or diagnosis. In this article, we review the evidence regarding GI-GVHD diagnosis, and examine the potential roles and translational opportunities posed by these novel diagnostic tools, with a focus on the evolving role of PET.
Assuntos
Gastroenteropatias , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Doença Enxerto-Hospedeiro/diagnóstico por imagem , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Trato Gastrointestinal/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/efeitos adversos , Biópsia/efeitos adversos , Doença Aguda , Gastroenteropatias/diagnóstico por imagem , Gastroenteropatias/etiologiaRESUMO
Sorafenib maintenance improves outcomes after hematopoietic cell transplant (HCT) for patients with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML). Although promising outcomes have been reported for sorafenib plus intensive chemotherapy, randomized data are limited. This placebo-controlled, phase 2 study (ACTRN12611001112954) randomized 102 patients (aged 18-65 years) 2:1 to sorafenib vs placebo (days 4-10) combined with intensive induction: idarubicin 12 mg/m2 on days 1 to 3 plus either cytarabine 1.5 g/m2 twice daily on days 1, 3, 5, and 7 (18-55 years) or 100 mg/m2 on days 1 to 7 (56-65 years), followed by consolidation and maintenance therapy for 12 months (post-HCT excluded) in newly diagnosed patients with FLT3-ITD AML. Four patients were excluded in a modified intention-to-treat final analysis (3 not commencing therapy and 1 was FLT3-ITD negative). Rates of complete remission (CR)/CR with incomplete hematologic recovery were high in both arms (sorafenib, 78%/9%; placebo, 70%/24%). With 49.1-months median follow-up, the primary end point of event-free survival (EFS) was not improved by sorafenib (2-year EFS 47.9% vs 45.4%; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.51-1.51; P = .61). Two-year overall survival (OS) was 67% in the sorafenib arm and 58% in the placebo arm (HR, 0.76; 95% CI, 0.42-1.39). For patients who received HCT in first remission, the 2-year OS rates were 84% and 67% in the sorafenib and placebo arms, respectively (HR, 0.45; 95% CI, 0.18-1.12; P = .08). In exploratory analyses, FLT3-ITD measurable residual disease (MRD) negative status (<0.001%) after induction was associated with improved 2-year OS (83% vs 60%; HR, 0.4; 95% CI, 0.17-0.93; P = .028). In conclusion, routine use of pretransplant sorafenib plus chemotherapy in unselected patients with FLT3-ITD AML is not supported by this study.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Sorafenibe , Tirosina Quinase 3 Semelhante a fms/genética , Estudos Retrospectivos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genéticaRESUMO
PURPOSE: Oral mucositis is a common complication during haematopoietic stem cell transplantation (HSCT). This study aimed to assess the incidence of severe mucositis in patients undergoing different HSCT regimens. METHODS: This single-centre retrospective study reviewed daily oral assessment for 467 consecutive patients who underwent different transplant regimens for matched unrelated or related allogeneic HSCT with post-transplant methotrexate, haploidentical or mismatched HSCT with post-transplant cyclophosphamide (PTCy), or autologous HSCT. Oral care and cryotherapy with melphalan were used. Patient demographic data, oral mucositis WHO grade, use of total parenteral nutrition (TPN) and patient-controlled analgesia (PCA) were collected. RESULTS: Grade 3-4 oral mucositis was common in myeloablative total body irradiation (TBI)-based regimens cyclophosphamide/ TBI (CyTBI) (71%) and fludarabine/ TBI (FluTBI) with PTCy (46%), as well as reduced-intensity fludarabine/melphalan (FluMel) (43%) and carmustine/etoposide/cytarabine/melphalan (BEAM) autologous HSCT (41%). In contrast, grade 3-4 oral mucositis was less common in reduced-intensity haploidentical regimen melphalan/fludarabine/TBI with PTCy (19%), all non-myeloablative regimens (0-9%) and high-dose melphalan autologous HSCT (26%). TPN and PCA use were correlated to oral mucositis severity. CONCLUSIONS: Severe oral mucositis was associated with myeloablative TBI, methotrexate and melphalan in combination with methotrexate and in BEAM. Use of PTCy was preferable over methotrexate to prevent oral mucositis.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Estomatite , Humanos , Melfalan/efeitos adversos , Estudos Retrospectivos , Incidência , Metotrexato/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Estomatite/epidemiologia , Estomatite/etiologia , Estomatite/prevenção & controle , CiclofosfamidaAssuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Infecções Fúngicas Invasivas , Humanos , Doença Enxerto-Hospedeiro/etiologia , Incidência , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante Homólogo/efeitos adversos , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/epidemiologia , Infecções Fúngicas Invasivas/etiologia , Doença AgudaRESUMO
PURPOSE: Oral mucositis is a common complication in patients undergoing hematopoietic stem cell transplantation. Accurate oral mucositis grading is essential for both clinical practice and oral mucositis research. This study aimed to evaluate the accuracy of daily oral mucositis grading by nurses in a tertiary hospital in Australia. METHODS: A retrospective study was undertaken to review the daily patient oral assessment record, including diet, pain, erythema, ulceration and the oral mucositis grade based on World Health Organization (WHO) oral mucositis grading scale. The accuracy of the grade was determined by the observations recorded, and reasons for inaccuracy were documented. Any repetition of the same error in the same patient was noted. RESULTS: In total, 6841 oral assessments in 373 patients, conducted between 2017 and 2020, were reviewed. A total of 70% (N = 4781) were graded correctly. Of these, 64% (N = 3043) were grade 0. When the grade 0 scores were excluded, the accuracy of grading was reduced to 46% (N = 1738). Common reasons for incorrect grading included: unable to grade due to diet not specified, no ulceration and no pain was scored grade 1, no ulceration was scored as grade 2-4, oral intake was not taken into account, and pain without ulcer was scored 0. A total of 77% of the errors were repeated in the same patient on consecutive days. CONCLUSIONS: Our results suggest there is frequent inaccurate evaluation of oral mucositis and a need for nurse training to accurately assess oral mucositis.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Estomatite , Austrália/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Dor , Estudos Retrospectivos , Estomatite/diagnóstico , Estomatite/epidemiologia , Estomatite/etiologiaRESUMO
PURPOSE: Patients who undergo haematopoietic stem cell transplantation (HSCT) often have multiple health issues following hospital discharge. In many centres, outpatient follow-up is solely conducted by specialist physicians. We aimed to implement and describe the outcomes of a nurse-allied health multidisciplinary clinic. METHODS: The clinic consisted of six disciplines-nursing, pharmacy, dietetics, physiotherapy, occupational therapy and social work. All allogeneic and high risk autologous HSCT patients were reviewed at 2 weeks after discharge and on day 100 post HSCT, with additional reviews as needed. Occasions of service, interventions, readmission data and physician satisfaction survey were collected prior to and after implementation. Additionally, patient feedback and quality of life survey (FACT-BMT) were collected during the first 6 months. RESULTS: From July to December 2019, 57 patients were reviewed in the clinic (475 reviews, average 8.3 reviews per patient). Common interventions included the following: exercise programs by physiotherapist (n = 111), diet prescription (n = 103), counselling by social worker (n = 53), medication lists provision (n = 51), fatigue management (n = 43) and nurse education (n = 22). The clinic did not reduce patients' readmission rate; however, positive feedback from patients and physicians were reported. FACT-BMT results demonstrated that there are unmet needs, particularly fatigue management, sexual education and support, body images, back to work support and quality of life improvement. From discharge to day 100, there was no significant improvement in quality of life. CONCLUSIONS: This clinic provides an innovative approach to patient-centred care in HSCT. It has been well received by patients who were supported by multidisciplinary interventions.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Qualidade de Vida , Humanos , Alta do Paciente , Readmissão do Paciente , Transplante AutólogoRESUMO
We determined the efficacy of tocilizumab (TCZ) in preventing grade 2-4 acute graft-versus-host disease (aGVHD) in patients with acute leukemia or myelodysplasia undergoing matched sibling donor (MSD) or volunteer unrelated donor (VUD) allogeneic stem cell transplantation after myeloablative or reduced-intensity conditioning across 5 Australian centers. A total of 145 patients (50 MSD, 95 VUD) were randomly assigned to placebo or TCZ on day -1. All patients received T-cell-replete peripheral blood stem cell grafts and graft-versus-host disease (GVHD) prophylaxis with cyclosporin/methotrexate. A planned substudy analyzed the VUD cohort. With a median follow-up of 746 days, the incidence of grade 2-4 aGVHD at day 100 for the entire cohort was 36% for placebo vs 27% for TCZ (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.26; P = .23) and 45% vs 32% (HR, 0.61; 95% CI, 0.31-1.22; P = .16) for the VUD subgroup. The incidence of grade 2-4 aGVHD at day 180 for the entire cohort was 40% for placebo vs 29% for TCZ (HR, 0.68; 95% CI, 0.38-1.22; P = .19) and 48% vs 32% (HR, 0.59; 95% CI, 0.30-1.16; P = .13) for the VUD subgroup. Reductions in aGVHD were predominantly in grade 2 disease. For the entire cohort, transplant-related mortality occurred in 8% vs 11% of placebo-treated vs TCZ-treated patients, respectively (P = .56), and overall survival was 79% vs 71% (P = .27). Median day to neutrophil and platelet engraftment was delayed by 2 to 3 days in TCZ-treated patients, whereas liver toxicity and infectious complications were similar between groups. In this phase 3 randomized double-blind trial, TCZ showed nonsignificant trends toward reduced incidence of grade 2-4 aGVHD in recipients from HLA-matched VUDs but no improvements in long term-survival.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Ciclosporina/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Humanos , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Efeito Placebo , Transplante Homólogo , Resultado do TratamentoRESUMO
Donor registries and transplantation societies recommend cryopreservation of unrelated donor hemopoietic progenitor cell (HPC) products before the recipient commences conditioning therapy to mitigate the donor and travel risks associated with the COVID-19 pandemic. However, little is known regarding the postthaw quality of such allogeneic products or the effect of precryopreservation storage and processing on these characteristics. We investigated the postthaw CD34+ cell recovery and viability of 305 allogeneic HPC products cryopreserved at 9 laboratories across Australia. Median postthaw CD34+ cell recovery was 76% and ranged from 6% to 122%. Longer transit time before cryopreservation, white cell count (WCC) during storage, and complex product manipulation before cryopreservation were independently associated with inferior postthaw CD34+ cell recovery. Longer precryopreservation transit time and WCC were also associated with inferior postthaw CD34+ cell viability. We conclude that although postthaw CD34+ cell recovery and viability of cryopreserved allogeneic HPC is generally acceptable, there is a significant risk of poor postthaw product quality, associated with prolonged storage time, higher WCC, and complex product manipulation precryopreservation. Awareness of expected postthaw recovery and practices that influence it will assist collection, processing, and transplant centers in optimizing outcomes for transplant recipients.
Assuntos
Antígenos CD34/análise , Criopreservação , Células-Tronco Hematopoéticas/citologia , COVID-19 , Sobrevivência Celular , Infecções por Coronavirus/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Transplante HomólogoRESUMO
We have previously reported that haematopoietic progenitor cell transplantation recipients with biopsy-negative acute Gastrointestinal Graft versus Host Disease (Discordant GVHD) demonstrate superior survival compared to "True Positive" cases. We aimed to elucidate this discrepancy by examining clinical and laboratory predictors of survival among patients treated for True Positive or Discordant GVHD. Data were obtained by retrospective chart review. At diagnosis, the incidence of severe symptoms, hypoalbuminaemia, hyperbilirubinaemia, and poor performance status were recorded. Following treatment, the incidence of non-response to first-line corticosteroids was assessed. Differences between cohorts were compared using Fisher's exact test. 74 patients were identified, comprising 55 (74%) True Positive and 19 (26%) Discordant GVHD cases. True Positive cases were significantly more likely to have baseline severe symptoms (84% vs. 36%; p = 0.0002) and hypoalbuminaemia (94% vs. 75%; p = 0.023). There was no significant difference between cohorts in terms of hyperbilirubinaemia or performance status. Non-response to corticosteroid therapy was observed significantly more frequently in the True Positive cohort (55% vs. 11%; p = 0.001). In summary, the superior survival observed in Discordant GVHD is explained by a less severe GI-GVHD phenotype at diagnosis and a greater likelihood of response to corticosteroids. Further research is warranted to explain biological mechanisms for these findings.
Assuntos
Trato Gastrointestinal , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/mortalidade , Doença Aguda , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idoso , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Taxa de Sobrevida , Adulto JovemRESUMO
Erythropoietic protoporphyria (EPP) is an inherited metabolic disorder of heme synthesis resulting from overproduction of protoporphyrin IX (PPIX), which can lead to progressive liver disease characterized by recurrent EPP crises and end-stage liver disease. We used the Australian Transplant Registry to identify 5 patients referred for liver transplantation between 2008 and 2017. A total of 4 patients had EPP secondary to ferrochelatase deficiency, and 1 patient had X-linked EPP. No patient had follow-up with a specialist prior to the diagnosis of progressive liver disease. There were 3 patients who underwent orthotopic liver transplantation, whereas 2 died while on the transplant waiting list. Parenteral PPIX-lowering therapy was used in 4 patients and was effective in 3 patients, although 2 of these had rebound porphyria and worsening liver function following a decrease in the intensity of therapy. Early disease recurrence in the allograft following transplantation occurred in 2 patients requiring red cell exchange (RCE) to successfully attain and maintain low PPIX levels, but RCE was associated with hemosiderosis in 1 patient. Allogeneic stem cell transplantation (AlloSCT) was performed in 2 patients. One failed engraftment twice, whereas the second rejected the first graft but achieved full donor chimerism with a second graft and increased immunosuppression. In conclusion, our observations suggest that progressive liver disease needs parenteral PPIX-lowering treatment with the intensity adjusted to achieve a target Erc-PPIX level. Because EPP liver disease is universally recurrent, AlloSCT should be considered in all patients with adequate immunosuppression to facilitate engraftment. RCE appears to be effective for recurrent EPP liver disease but is associated with an increased risk of iron overload.
Assuntos
Doença Hepática Terminal/terapia , Rejeição de Enxerto/epidemiologia , Transplante de Fígado , Protoporfiria Eritropoética/patologia , Transplante de Células-Tronco , Listas de Espera/mortalidade , Adolescente , Adulto , Aloenxertos/patologia , Progressão da Doença , Doença Hepática Terminal/mortalidade , Doença Hepática Terminal/patologia , Feminino , Rejeição de Enxerto/patologia , Humanos , Lactente , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Protoporfiria Eritropoética/mortalidade , Protoporfiria Eritropoética/terapia , Recidiva , Sistema de Registros/estatística & dados numéricos , Transplante Homólogo , Adulto JovemRESUMO
PURPOSE: Inducible caspase 9 (iCasp9) is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of iCasp9-transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies. PATIENTS AND METHODS: Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.5-1.0 × 106/kg donor-derived iCasp9-transduced T cells on day +25 or 26 post-transplant, with additional doses allowed for disease relapse, infection, or mixed chimerism. RESULTS: Three patients were enrolled. iCasp9-transduced T cells were readily detectable by 4 weeks post-infusion in all patients and remained at high level (114 cells/µL, 11% of T cells) in 1 patient alive at 3.6 years. One patient developed donor-derived Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD), which was followed by a marked expansion of iCasp9 T cells and cytokine release syndrome (CRS). These iCasp9-transduced T cells infiltrated the affected lymph nodes and secreted IFNγ and IL-10. They peaked at 1,848 cells/µL and were found to be monoclonal by T-cell receptor (TCR) clonotype and oligoclonal by viral integrant analysis, representing a 6-log in vivo expansion of the dominant T-cell clone. These T cells were not autonomous and contracted with the resolution of EBV-PTLD, which did not recur. CONCLUSIONS: iCasp9-transduced T cells could persist long-term. They retained very high in vivo clonotypic proliferative capacity and function, and could cause CRS in response to de novo lymphoma development.
Assuntos
Caspase 9/metabolismo , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Agonistas Mieloablativos/administração & dosagem , Linfócitos T/transplante , Adolescente , Adulto , Caspase 9/genética , Caspase 9/imunologia , Feminino , Neoplasias Hematológicas/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Depleção Linfocítica/efeitos adversos , Depleção Linfocítica/métodos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/efeitos adversos , Recidiva Local de Neoplasia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo , Condicionamento Pré-Transplante/métodos , Transplante Haploidêntico/efeitos adversos , Transplante Haploidêntico/métodos , Resultado do Tratamento , Adulto JovemRESUMO
The key complications of allogeneic bone marrow transplantation (BMT) remain graft-versus-host disease (GVHD) and opportunistic infection. We have analyzed the blood stream infections (BSIs) occurring between day -7 and day 100 in a cohort of 184 adult patients undergoing allogeneic BMT in our center. A total of 167 of the 184 patients (91%) had blood cultures collected, and 69 (38%) patients had a confirmed BSI. Enterobacteriaceae, Pseudomonas aeruginosa, Enterococcus spp., and viridans Streptococcus spp. were the most commonly isolated organisms. Gender, conditioning (myeloablative versus reduced intensity), and donor type (sibling versus unrelated) did not differ significantly between those with and without confirmed BSI. Elevated temperature (>38°C) at the time of culture collection was associated with an almost 2-fold increased likelihood of returning a positive blood culture. The absence of a BSI was associated with a significant improvement in overall survival at 2 years, due to a significant reduction in nonrelapse mortality predominantly unrelated to the primary BSI. The presence of a BSI before engraftment was associated with the dysregulation of IL-6 and IL-8. Our findings suggest that BSI early after BMT defines a group of high-risk patients with enhanced cytokine dysregulation and poor transplant outcome.
Assuntos
Bacteriemia/etiologia , Transplante de Medula Óssea/efeitos adversos , Adolescente , Adulto , Idoso , Bacteriemia/mortalidade , Bacteriemia/patologia , Citocinas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Adulto JovemRESUMO
Acute gastrointestinal graft-versus-host disease (GI-GVHD) after hematopoietic progenitor cell transplantation (HPCT) is a common and life-threatening complication. Endoscopic biopsy of the GI tract (GIT) is required for diagnosis. However, clear evidence to optimize this diagnostic approach is lacking, leading to variation in diagnostic sensitivity between institutions. We aimed to assess the clinical, endoscopic, and histologic findings of endoscopies performed for suspected acute GI-GVHD at our institution to better define the optimal use of this strategy. We performed a retrospective cohort study of adults who had undergone endoscopy for suspected acute GI-GVHD within 180 days after allogeneic HPCT for hematologic malignancy between 2011 and 2016. Details included symptoms at time of referral for endoscopy, type of procedure performed, macroscopic findings on endoscopy, and histologic findings after gut biopsy. Correlation was made with clinical GVHD severity scores. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated and compared for each procedure. Predictors of histologic GVHD and overall survival were also compared. Of the 123 patients included, acute GI-GVHD occurred in 59 (48%). Lower endoscopy demonstrated greater sensitivity than upper endoscopy (50% versus 39%). Single upper endoscopy for upper symptoms alone had the lowest yield of GI-GVHD (14%). Combination upper and lower endoscopy demonstrated strong histologic concordance between upper and lower procedures. The addition of upper endoscopy to lower endoscopy only identified an extra 2 (4%) cases of GVHD. Advanced age and the presence of lower GIT symptoms were the only pre-endoscopy predictors of histologic GVHD on multivariate analysis. Patients with isolated upper histologic GVHD showed similar survival to patients with negative biopsies. Endoscopy and biopsy only identified 74% of those ultimately requiring treatment for acute GI-GVHD. Acute GI-GVHD remains a clinical diagnosis supported by available histologic evidence. Isolated upper GI-GVHD is rare, and in the absence of lower GIT symptoms, routine upper endoscopy does not significantly improve diagnostic yield for histologic GVHD. Overall, endoscopy and biopsy underdiagnoses 26% of clinical GI-GVHD, highlighting a need for research into novel diagnostic strategies.