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The Centre for International Blood and Marrow Transplant Registry (CIBMTR) score has been shown to be prognostic for overall survival (OS) and nonrelapse mortality (NRM) but has been shown in several single-center studies to classify a large proportion of patients with chronic graft-versus-host disease (cGVHD) in the lower risk groups (RG1 to RG2), thereby limiting its prognostic utility for those patients. We evaluate the CIBMTR score, the Global Severity Score (GSS), and a novel risk score developed to improve on the limitations of the CIBMTR with respect to clinically relevant outcomes, including failure-free survival (FFS), in patients receiving frontline systemic treatment for cGVHD. We identified 277 patients between 2002 and 2012 at the Princess Margaret Cancer Centre in Toronto, Canada, who developed cGVHD and were treated with at least 1 line of systemic therapy. cGVHD was graded by GSS, and patients were stratified by CIBMTR. We evaluated OS, NRM, relapse, and FFS within GSS grade groups, as well as CIBMTR RGs, and used a novel prognostic risk score. The median FFS duration was 164 days in the severe GSS group versus 238 days in the moderate-grade group and 304 days in mild-grade group (P= .001). The median FFS duration was 501 days in CIBMTR RG1 versus 291 days in RG2 and 166 days in RG3 to RG6 (Pâ¯=â¯.003). A novel risk score combining the GSS and CIBMTR scores was prognostic of OS, NRM, and FFS and was able to subdivide patients with cGVHD in CIBMTR RG1 to RG2 into distinct prognostic risk categories. The CIBMTR risk score and the GSS are well correlated with FFS, OS, and NRM following frontline systemic treatment for cGVHD. A new risk score model combining the CIBMTR risk score and the GSS could enhance risk stratification in the lower CIBMTR risk groups.
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Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/terapia , Sistema de Registros , Índice de Gravidade de Doença , Adulto , Idoso , Doença Crônica , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
PURPOSE OF REVIEW: The monitoring of minimal residual disease (MRD) has important clinical implications in both the pre and postallogeneic stem cell transplant (SCT) setting in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Next-generation sequencing (NGS) is a rapidly improving technology whose application to the monitoring of MRD is an active area of research. We aim to describe existing methods of MRD in AML and MDS, with a focus on the utility of NGS in patients undergoing SCT. RECENT FINDINGS: Flow cytometry and quantitative PCR have been recommended by the European Leukemia Net as the preferred methods of MRD in AML and MDS, but these methods have limitations in cases without a disease-defining phenotype and genotype. Clinical trials are currently ongoing to assess the use of NGS in the setting of SCT for MDS and AML. Few studies have so far assessed the optimal method of MRD monitoring in the posttransplant setting. SUMMARY: The optimal method for the monitoring of MRD in AML and MDS both pre and post transplant may require more than one technology. NGS holds great promise for the monitoring of MRD, with prospective trials currently ongoing to evaluate its efficacy in this regard.
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Transplante de Células-Tronco Hematopoéticas , Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Neoplasia Residual/terapia , Citometria de Fluxo , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Reação em Cadeia da Polimerase em Tempo Real , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
For patients undergoing allogeneic hematopoietic cell transplantation (alloHCT), HLA-matched related donors (MRDs) have traditionally been the preferred donor source. However, as the age of recipients increases, their sibling donors are aging as well. In this study, we investigated whether younger matched unrelated donors (MUDs) might be a better donor source than similarly aged sibling donors for patients age >60 years with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). A total of 499 patients age 60 to 70 years with AML or MDS who underwent alloHCT from an older MRD (donor age ≥50 years) or a younger MUD (donor age ≤35 years) between 2010 and 2022 were evaluated. Of these, 360 patients (72%) received an MUD graft and 139 (28%) received an MRD graft. The median recipient age was 64 years in the MRD group and 66 years in the MUD group. With a median follow-up among survivors of 53 months (range, 9 to 147 months ), the 4-year progression-free survival was 40% in the MRD group and 41% in the MUD group (P = .79) and the 4-year overall survival was 50% and 44%, respectively (P = .15), with no between-group differences in nonrelapse mortality, relapse, and acute or chronic graft-versus-host disease. In the MUD group, we also compared the effect of donor age 18 to 24 years and donor age 25 to 35 years and found no differences in outcomes between the groups. We conclude that outcomes are comparable between the use of older MRDs and use of younger MUDs for elderly patients with AML or MDS, that there is no donor age effect among younger MUDs, and that the use of either donor type is reasonable.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Transplante Homólogo , Doadores não Relacionados , Humanos , Síndromes Mielodisplásicas/terapia , Síndromes Mielodisplásicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/mortalidade , Pessoa de Meia-Idade , Feminino , Idoso , Masculino , Fatores Etários , Adulto , Doença Enxerto-HospedeiroRESUMO
Acute kidney injury (AKI) is a frequent complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), but few studies have focused on AKI treated with kidney replacement therapy (AKI-KRT), particularly among critically ill patients. We investigated the incidence, risk factors, and 90-day mortality associated with AKI-KRT in 529 critically ill adult allo-HSCT recipients admitted to the ICU within 1-year post-transplant at two academic medical centers between 2011 and 2021. AKI-KRT occurred in 111 of the 529 patients (21.0%). Lower baseline eGFR, veno-occlusive disease, thrombotic microangiopathy, admission to an ICU within 90 days post-transplant, and receipt of invasive mechanical ventilation (IMV), total bilirubin ≥5.0 mg/dl, and arterial pH <7.40 on ICU admission were each associated with a higher risk of AKI-KRT. Of the 111 patients with AKI-KRT, 97 (87.4%) died within 90 days. Ninety-day mortality was 100% in each of the following subgroups: serum albumin ≤2.0 g/dl, total bilirubin ≥7.0 mg/dl, arterial pH ≤7.20, IMV with moderate-to-severe hypoxemia, and ≥3 vasopressors/inotropes at KRT initiation. AKI-KRT was associated with a 6.59-fold higher adjusted 90-day mortality in critically ill allo-HSCT vs. non-transplanted patients. Short-term mortality remains exceptionally high among critically ill allo-HSCT patients with AKI-KRT, highlighting the importance of multidisciplinary discussions prior to KRT initiation.
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Injúria Renal Aguda , Transplante de Células-Tronco Hematopoéticas , Humanos , Adulto , Estado Terminal/terapia , Bilirrubina , Terapia de Substituição Renal/efeitos adversos , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Estudos RetrospectivosRESUMO
Post-transplantation cyclophosphamide (PTCy) is an effective strategy for graft-versus-host disease (GVHD) prophylaxis and is the standard of care for haploidentical hematopoietic cell transplantation (HCT). It is increasingly used for matched and mismatched unrelated donor (MUD/MMUD) HCT, but infections remain a concern. The objective of this study was to evaluate the characteristics and risk factors for infections in haploidentical and unrelated donor HCT recipients treated with PTCy-based GVHD prophylaxis. This single-center retrospective study examined 354 consecutive adults undergoing HCT with PTCy-based GVHD prophylaxis (161 MUD/MMUD; 193 haploidentical) between 2015 and 2022. Opportunistic infections (OIs), including cytomegalovirus (CMV), adenovirus (AdV), Epstein-Barr virus (EBV), and invasive fungal disease (IFD), were assessed from day 0 through day +365. The 1-year cumulative incidence functions of OIs and nonrelapse mortality (NRM) were calculated using dates of relapse and repeat HCT as competing risks. Secondary analysis evaluated risk factors for OIs and NRM using univariate and multivariable Cox regression models. Haploidentical HCT recipients had an increased risk of OIs compared to unrelated donor allograft recipients (39% for haploidentical versus 25% for MUD/MMUD; hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.16 to 2.49; P = .006). On multivariable analysis, haploidentical donor (HR, 1.50; 95% CI, 1.01 to 2.23; P = .046), prior HCT (HR, 1.99; 95% CI, 1.29 to 3.09; P = .002), and diagnosis of aGVHD (HR, 1.47; 95% CI, 1.02 to 2.14; P = .041) were associated with increased risk of OIs. NRM within the first year was not significantly different between the 2 cohorts (HR, 1.11; 95% CI, .64 to 1.93; P = .70). Overall, haploidentical donor was a significant risk factor for OIs in patients receiving PTCy, although 1-year NRM was not different between haploidentical HCT and MUD/MMUD HCT recipients. CMV and AdV infections were significantly increased among haploidentical HCT recipients, whereas the incidences of EBV infection and IFD were similar in the 2 cohorts. Our findings may have implications for infection monitoring and prophylaxis in the setting of PTCy, particularly in haploidentical HCT recipients.
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Infecções por Citomegalovirus , Infecções por Vírus Epstein-Barr , Doença Enxerto-Hospedeiro , Infecções Oportunistas , Adulto , Humanos , Doadores não Relacionados , Estudos Retrospectivos , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Herpesvirus Humano 4 , Recidiva Local de Neoplasia/complicações , Ciclofosfamida/uso terapêutico , Aloenxertos , Infecções Oportunistas/epidemiologia , Infecções Oportunistas/etiologia , Infecções Oportunistas/prevenção & controle , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/prevenção & controleRESUMO
BACKGROUND: The use of CD34+ selected stem cell boost (SCB) post allogeneic hematopoietic cell transplant (alloHCT) has been increasing. Predictors of treatment failure following SCB, both in the context of poor graft function (PGF) or other settings, are not well-characterized. We report among the largest single center retrospective experiences of the use of SCB and evaluate potential predictors of response and outcomes. METHODS: 58 patients who underwent HCT between 2015 and 2022 and who received SCB were identified. The indication for SCB was predominantly PGF, defined as the presence of 2 or more cytopenias for at least two consecutive weeks beyond day +14 after alloHCT in the presence of ≤ 30% bone marrow cellularity and ≥ 90% donor myeloid chimerism in the absence of morphological disease. RESULTS: The median dose of infused CD34+ selected SCB products was 3.88 x 106 CD34+ cells/kg (range: 0.99-9.92). The median 2-year OS and NRM following SCB was 47% and 38%, respectively. The cumulative incidences of 6-month grade III-IV acute and 2-year moderate-severe chronic GVHD following SCB were 3.4% and 12%, respectively. Overall response (CR + PR) was attained in 36/58 (62%) patients, and in 69% with PGF. On multivariable analysis, an active infection at the time of SCB was the greatest predictor of poor response and survival (p=0.013) following SCB. CONCLUSION: SCB can restore hematopoiesis in the majority of patients, particularly for those with poor graft function in whom there is no active infection at infusion.
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ABSTRACT: We conducted a phase 1 trial assessing safety and efficacy of prophylactic maintenance therapy with venetoclax and azacitidine (Ven/Aza) for patients with high-risk myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) undergoing reduced intensity allogeneic stem cell transplantation (allo-SCT) after Ven and fludarabine/busulfan conditioning (Ven/FluBu2 allo-SCT) with tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Among 27 patients who underwent Ven/FluBu2 allo-SCT (55.6% with prior Ven exposure, and 96% with positive molecular measurable residual disease), 22 received maintenance therapy with Aza 36 mg/m2 intravenously on days 1 to 5, and Ven 400 mg by mouth on days 1 to 14 per assigned dose schedule/level (42-day cycles × 8, or 28-day cycles × 12). During maintenance, the most common grade 3-4 adverse events were leukopenia, neutropenia, and thrombocytopenia, which were transient and manageable. Infections were uncommon (n = 4, all grade 1-2). The 1-year and 2-year moderate/severe chronic GVHD rates were 4% (95% confidence interval [CI], 0.3%-18%) and 22% (95% CI, 9%-40%), respectively. After a median follow-up of 25 months among survivors, the median overall survival (OS) was not reached. Among the 22 patients who received Ven/Aza maintenance, the 2-year OS, progression-free survival, nonrelapse mortality, and cumulative incidence of relapse rates were 67% (95% CI, 43%-83%), 59% (95% CI, 36%-76%), 0%, and 41% (95% CI, 20%-61%), respectively. Immune monitoring demonstrated no significant impact on T-cell expansion but identified reduced B-cell expansion compared with controls. This study demonstrates prophylactic Ven/Aza maintenance can be safely administered for patients with high-risk MDS/AML, but a randomized study is required to properly assess any potential benefit. This trial was registered at www.clinicaltrials.gov as #NCT03613532.
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Compostos Bicíclicos Heterocíclicos com Pontes , Doença Enxerto-Hospedeiro , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Condicionamento Pré-Transplante , Transplante Homólogo , Azacitidina/uso terapêuticoRESUMO
Given the safety, tumor tropism, and ease of genetic manipulation in non-pathogenic Escherichia coli (E. coli), we designed a novel approach to deliver biologics to overcome poor trafficking and exhaustion of immune cells in the tumor microenvironment, via the surface display of key immune-activating cytokines on the outer membrane of E. coli K-12 DH5α. Bacteria expressing murine decoy-resistant IL18 mutein (DR18) induced robust CD8+ T and NK cell-dependent immune responses leading to dramatic tumor control, extending survival, and curing a significant proportion of immune-competent mice with colorectal carcinoma and melanoma. The engineered bacteria demonstrated tumor tropism, while the abscopal and recall responses suggested epitope spreading and induction of immunologic memory. E. coli K-12 DH5α engineered to display human DR18 potently activated mesothelin-targeting CAR NK cells and safely enhanced their trafficking into the tumors, leading to improved control and survival in xenograft mice bearing mesothelioma tumor cells, otherwise resistant to NK cells. Gene expression analysis of the bacteria-primed CAR NK cells showed enhanced TNFα signaling via NFkB and upregulation of multiple activation markers. Our novel live bacteria-based immunotherapeutic platform safely and effectively induces potent anti-tumor responses in otherwise hard-to-treat solid tumors, motivating further evaluation of this approach in the clinic.
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Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological cancers. Cytokine-induced memory-like (CIML) natural killer (NK) cells have shown promising results in preclinical and early-phase clinical trials. In the current study, CIML NK cells demonstrated superior antitumor responses against a panel of EOC cell lines, increased expression of activation receptors, and up-regulation of genes involved in cell cycle/proliferation and down-regulation of inhibitory/suppressive genes. CIML NK cells transduced with a chimeric antigen receptor (CAR) targeting the membrane-proximal domain of mesothelin (MSLN) further improved the antitumor responses against MSLN-expressing EOC cells and patient-derived xenograft tumor cells. CAR arming of the CIML NK cells subtanstially reduced their dysfunction in patient-derived ascites fluid with transcriptomic changes related to altered metabolism and tonic signaling as potential mechanisms. Lastly, the adoptive transfer of MSLN-CAR CIML NK cells demonstrated remarkable inhibition of tumor growth and prevented metastatic spread in xenograft mice, supporting their potential as an effective therapeutic strategy in EOC.
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Células Matadoras Naturais , Mesotelina , Neoplasias Ovarianas , Receptores de Antígenos Quiméricos , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Animais , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Feminino , Camundongos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Linhagem Celular Tumoral , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/genética , Imunoterapia Adotiva/métodos , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/terapia , Memória Imunológica , Domínios ProteicosRESUMO
The translation of natural killer (NK) cells to the treatment of malignant disease has made significant progress in the last few decades. With a variety of available sources and improvements in both in vitro and in vivo NK cell expansion, the NK cell immunotherapy platform has come into its own. The enormous effort continues to further optimize this platform, including ways to enhance NK cell persistence, trafficking to the tumor microenvironment, and cytotoxicity. As this effort bears fruit, it is translated into a plethora of clinical trials in patients with advanced malignancies. The adoptive transfer of NK cells, either as a standalone therapy or in combination with other immunotherapies, has been applied for the treatment of both liquid and solid tumors, with numerous early-phase trials showing promising results. This review aims to summarize the key advantages of NK cell immunotherapy, highlight several of the current approaches being taken for its optimization, and give an overview of the landscape of clinical trials translating this platform into clinic.
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Células Matadoras Naturais , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/patologia , Imunoterapia , Imunoterapia Adotiva/métodos , Microambiente TumoralRESUMO
Background: Fifty years of hematopoietic cell transplantation (HCT) has ushered in an exciting era of cellular therapy and has led to enormous progress in improving the outcomes of patients with both malignant and non-malignant hematologic disease. As the survival of transplanted patients has increased, so has the recognition of long-term complications related to this therapy. Purpose: The goal of this review is to highlight some of the most common long-term complications of HCT. Data sources: To this end, we have conducted a review of the published literature on the long-term complications of HCT encompassing the past 50 years. Study selection: We have endeavored to include long-term complications reported in research articles, case series and case reports, reviews, and abstracts. We have focused primarily on adult allogeneic HCT, but have included some data from studies of pediatric allogeneic HCT as well. We have also prioritized the literature published in the last 15 years. Data extraction: Key data supporting the onset and prevalence of the most common long-term complications was extracted. Limitations: While the list of long-term complications extracted and reported was comprehensive, it was not exhaustive. Conclusions: We have endeavored to highlight some of the most common long-term complications of HCT, the recognition and management of which constitutes an important part of HCT survivorship care.
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Cytokine release syndrome (CRS) following haploidentical hematopoietic cell transplantation (HCT) resembles CRS after chimeric antigen receptor-T therapy. We conducted this single-center retrospective study to evaluate the association of posthaploidentical HCT CRS with clinical outcomes and immune reconstitution. One hundred sixty-nine patients who underwent haploidentical HCT between 2011 and 2020 were identified. Of these, 98 patients (58%) developed CRS after HCT. CRS was diagnosed based on the presence of fever within the first 5 days after HCT without evidence of infection or infusion reaction and was graded according to established criteria. The development of posthaploidentical HCT CRS was associated with a lower incidence of disease relapse (P = .024) but with an increased risk of chronic graft-versus-host disease GVHD (P = .01). The association of CRS with a lower incidence of relapse was not confounded by graft source or disease diagnosis. Neither CD34 nor total nucleated cell dose was associated with CRS independently of graft type. In patients developing CRS, CD4+ Treg (P < .0005), CD4+ Tcon (P < .005), and CD8+ T cells (P < .005) increased 1 month after HCT compared with those who did not develop CRS, but not at later time points. The increase in CD4+ regulatory T cells 1 month after HCT was most notable among patients with CRS who received a bone marrow graft (P < .005). The development of posthaploidentical HCT CRS is associated with a reduced incidence of disease relapse and a transient effect on post-HCT immune reconstitution of T cells and their subsets. Therefore, the validation of these observations in a multicenter cohort is required.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Síndrome da Liberação de Citocina/etiologia , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/epidemiologiaRESUMO
The ability of posttransplant cyclophosphamide (PTCY) to facilitate haploidentical transplantation has spurred interest in whether PTCY can improve clinical outcomes in patients with HLA-matched unrelated donors undergoing peripheral blood stem cell transplantation (PBSCT). We investigated our institutional experience using PTCY-based graft-versus-host disease (GVHD) prophylaxis compared with conventional tacrolimus-based regimens. We compared overall survival, progression-free survival (PFS), relapse, nonrelapse mortality, and acute and chronic GVHD in 107 adult patients receiving a PTCY-based regimen vs 463 patients receiving tacrolimus-based regimens for GVHD prophylaxis. The 2 cohorts were well balanced for baseline characteristics except that more patients in the PTCY cohort having received 7-of-8-matched PBSCT. There was no difference in acute GVHD. All-grade chronic GVHD and moderate-to-severe chronic GVHD were substantially reduced in patients receiving PTCY compared with in those receiving tacrolimus-based regimens (2-year moderate-to-severe chronic GVHD: 12% vs 36%; P < .0001). Recipients of PTCY-based regimens also had a lower incidence of relapse compared with recipients of tacrolimus-based regimens (25% vs 34% at 2-years; P = .027), primarily in patients who received reduced intensity conditioning. This led to improved PFS in the PTCY cohort (64% vs 54% at 2 years; P = .02). In multivariable analysis, the hazard ratio was 0.59 (P = .015) for PFS and the subdistribution hazard ratio was 0.27 (P < .0001) for moderate-to-severe chronic GVHD and 0.59 (P = .015) for relapse. Our results suggest that PTCY prophylaxis is associated with lower rates of relapse and chronic GVHD in patients who receive HLA-matched unrelated donor PBSCT.
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Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Tacrolimo/uso terapêutico , Incidência , Transplante de Células-Tronco Hematopoéticas/métodos , Doadores não Relacionados , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Ciclofosfamida/uso terapêutico , RecidivaRESUMO
The Blood and Marrow Transplant Clinical Trials Network study 1101 (BMT CTN 1101; ClinicaTrials.gov identifier NCT01597778) was a multicenter phase III randomized trial comparing the clinical outcomes and quality of life (QoL) of patients with hematologic malignancies undergoing double umbilical cord blood transplantation (dUCBT) or HLA-haploidentical bone marrow transplantation (haplo-BMT) after reduced-intensity conditioning. At a 5-year follow-up, there were no significant differences in progression- free survival (PFS) or overall survival (OS) between the 2 cohorts. The impact of alternative donor source on QoL is unknown, however. English- and Spanish-speaking patients completed the Functional Assessment of Cancer Therapy-General (FACT-G), Short Form 36 (SF-36), EuroQoL-5 Dimensions EQ-5D, and Global QoL patient-reported outcome (PRO) assessments pretransplantation and at 12 and 24 months post-transplantation. We compared longitudinal QoL measures between the dUCBT and haplo-BMT cohorts and investigated the association of QoL and clinical outcomes using an inverse probability weighted-independent estimating equations method, accounting for missingness and baseline variables. We found no significant differences between the 2 cohorts in any of the QoL scores pretransplantation and at 12 and 24 months post-transplantation. Pretransplantation scores were the only significant predictors of post-transplantation QoL scores. Relapse and grade III-IV acute graft-versus-host disease (GVHD) were associated with significant declines in mean FACT-BMT and SF-36 Physical Component scores, and chronic GVHD was associated with a decline in mean EQ-5D utility scores. There were no significant associations between pretransplantation QoL scores and OS or PFS. Donor type did not impact post-transplantation QoL. Pretransplantation QoL scores and clinical events of GVHD and relapse were the only predictors of post-transplantation QoL. QoL was not associated with survival in either treatment arm. PROs may be valuable tools in pretransplantation risk assessment strategies to improve QoL outcomes.
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Transplante de Medula Óssea , Doença Enxerto-Hospedeiro , Humanos , Transplante de Medula Óssea/métodos , Medula Óssea , Sangue Fetal , Qualidade de Vida , Recidiva Local de Neoplasia , Doença Enxerto-Hospedeiro/epidemiologia , Doença CrônicaRESUMO
Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative therapy for patients with hematologic malignancies but is associated with acute kidney injury (AKI). To date, few studies have examined risk factors for AKI at engraftment, or the relationship between AKI and clinical outcomes. This study examined the incidence and risk factors for periengraftment AKI, as well as the association between AKI and overall survival (OS) and nonrelapse mortality (NRM). We conducted a retrospective analysis of adult patients undergoing reduced-intensity conditioning (RIC) allogeneic HCT at the Dana-Farber Cancer Institute between 2012 and 2019. Periengraftment (day 0 to day 30) AKI incidence and severity were defined using modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria. Factors associated with periengraftment AKI risk were examined using Cox regression analysis. The impact of periengraftment AKI on OS and NRM (defined as death without recurrent disease after HCT), was evaluated using Cox regression and the Fine and Gray competing risks model, respectively. Kidney recovery, defined as a return of serum creatinine (SCr) to within 25% of baseline or liberation from kidney replacement therapy (KRT), was examined at day 90 post-HCT. Periengraftment AKI occurred in 330 of 987 patients (33.4%) at a median of 13 days (interquartile range, 4 to 30 days) post-transplantation. Factors associated with a higher multivariable-adjusted risk of AKI were supratherapeutic rapamycin (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.20 to 2.03; P < .001), fludarabine/melphalan conditioning (HR, 1.35, 95% CI, 1.01 to 1.81; P = .05, compared to fludarabine/busulfan and fludarabine, cyclophosphamide, and total body irradiation), HCT Comorbidity Index ≥4 (HR, 1.43; 95% CI, 1.14 to 1.79; P = .002), albumin <3.4 g/dL (HR, 2.04; 95% CI, 1.33 to 3.12; P = .001), hemoglobin ≤12 (HR, 1.96; 95% CI, 1.38 to 2.78; P < .001), supratherapeutic tacrolimus (HR, 1.45; 95% CI, 1.07 to 1.95; P = .02), and baseline SCr >1.1 mg/dL (HR, 1.87; 95% CI, 1.48 to 2.35; P < .001). Periengraftment AKI was associated with worse OS (HR, 1.40; 95% CI, 1.16 to 1.71; P < .001) and NRM (subdistribution HR, 2.10; 95% CI, 1.52 to 2.89; P < .001). Kidney recovery occurred in 18%, 15%, and 30% of patients with stage 1, stage 2, and stage 3 AKI without KRT, respectively, and 4 of 16 patients (25%) were liberated from KRT. Periengraftment AKI is common among RIC allogeneic HCT recipients. We identified several important risk factors for periengraftment AKI. Its association with worse OS and NRM underscores the importance of timely recognition and management.
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Injúria Renal Aguda , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adulto , Humanos , Estudos Retrospectivos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Condicionamento Pré-Transplante/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologiaAssuntos
Entorpecentes/efeitos adversos , Neutropenia/sangue , Sepse/sangue , Abuso de Substâncias por Via Intravenosa/sangue , Adulto , Feminino , Humanos , Entorpecentes/administração & dosagem , Neutropenia/induzido quimicamente , Neutropenia/terapia , Sepse/induzido quimicamente , Sepse/terapia , Abuso de Substâncias por Via Intravenosa/complicações , Abuso de Substâncias por Via Intravenosa/terapiaRESUMO
Ex vivo feeder-free autologous NK cell expansion is an efficient modality for clinical translation. In this issue of Cell Reports Medicine, Nahi et al. describe the use of this approach as consolidation therapy for multiple myeloma,1 thereby reviving an alternate avenue for NK cell therapy.
Assuntos
Mieloma Múltiplo , Terapia Baseada em Transplante de Células e Tecidos , Quimioterapia de Consolidação , Humanos , Células Matadoras Naturais , Mieloma Múltiplo/terapia , Transplante de Células-TroncoRESUMO
Natural killer cells constitute a part of the innate immune system that mediates an effective immune response towards virus-infected and malignant cells. In recent years, research has focused on exploring and advancing NK cells as an active immunotherapy platform. Despite major advances, there are several key challenges that need to be addressed for the effective translation of NK cell research to clinical applications. This review highlights some of these challenges and the innovative strategies being developed to overcome them, including in vitro expansion, in vivo persistence, infiltration to the tumor site, and prevention of exhaustion.
Assuntos
Imunoterapia , Neoplasias , Humanos , Fatores Imunológicos , Células Matadoras Naturais , Neoplasias/terapiaRESUMO
The use of haploidentical donor hematopoietic cell transplantation (haploHCT) has expanded, but recent reports raise concern for increased rates of infectious complications. The incidence and risk factors for invasive fungal disease (IFD) after haploHCT have not been well elucidated. This study aimed to evaluate the incidence and risk factors for IFD after haploHCT. The identification of key risk factors will permit targeted prevention measures and may explain elevated risk for other infectious complications after haploHCT. This single-center retrospective study included all adults undergoing haploHCT between May 2011 and May 2021 (n = 205). The 30-day and 1-year cumulative incidences of proven or probable IFD and 1-year nonrelapse mortality (NRM) were assessed. Secondary analyses evaluated risk factors for invasive yeast infection (IYI) using univariate and multivariable Cox regression models. Twenty-nine patients (14%) developed IFD following haploHCT. Nineteen (9.3%) developed IYI in the first year, 13 of which occurred early, with a 30-day cumulative incidence of 6.3% (95% confidence interval [CI], 2.9% to 9.6%) and increased NRM in patients with IYI (53.9% versus 10.9%). The majority of yeast isolates (17 of 20; 85%) were fluconazole- susceptible. The incidence of IYI in the first 30 days after haploHCT was 10% in the 110 patients (54%) who developed cytokine release syndrome (CRS) and 21% in the 29 patients (14%) who received tocilizumab. On multivariable analysis, acute myelogenous leukemia (hazard ratio [HR], 6.24; 95% CI, 1.66 to 23.37; P = .007) and CRS (HR, 4.65; 95% CI, 1.00 to 21.58; P = .049) were associated with an increased risk of early IYI after haploHCT. CRS after haploHCT is common and is associated with increased risk of early IYI. The identification of CRS as a risk factor for IYI raises questions about its potential association with other infections after haploHCT. Recognition of key risk factors for infection may permit the development of individualized strategies for prevention and intervention and minimize potential side effects.