RESUMO
Anti-thymocyte globulin (ATG) is an established approach to decrease chronic GVHD (cGVHD), yet the exact mechanism is uncertain. To better understand the mechanism of action of ATG in preventing cGVHD, we evaluated the day 100 immune reconstitution of known cGVHD cellular biomarkers using patients from the randomized Canadian Bone Marrow Transplant Group (CBMTG) 0801 trial, which demonstrated a significant impact of ATG on cGVHD. In a separate companion biology study, we evaluated the impact of ATG prophylaxis on cGVHD cellular markers at day 100 in 40 CBMTG 0801 patients. Analysis focused on previously identified cGVHD cellular biomarkers, including naive helper T (Th) cells, recent thymic emigrant (RTE) Th cells, CD21low B cells, CD56bright NKreg cells, and Treg cells ST2, osteopontin, soluble B-cell activating factor (sBAFF), Interleukin-2 receptor alpha (sCD25), T-cell immunoglobulin and mucin domain-3 (TIM-3), matrix metallopeptidase 3, ICAM-1, C-X-C motif chemokine 10 (CXCL10), and soluble aminopeptidase N. The ATG-treated group had a >10-fold decrease in both RTE naive Th and naive Th cells (P < .0001) and a 10-fold increase in CD56bright NKreg cells (P < .0001). Treg cells, conventional Th cells, CD21low B cells, and all plasma markers were not affected. In the populations most affected by ATG, changes in naive Th cells were associated with the later development of cGVHD. This analysis suggests that ATG primarily impacts on cGVHD through suppression of naive Th cell expansion after transplantation. These associations need to be validated in additional studies.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Soro Antilinfocitário/uso terapêutico , Canadá , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Condicionamento Pré-TransplanteRESUMO
Chronic graft-versus-host disease (cGVHD) remains one of the most significant long-term complications after allogeneic blood and marrow transplantation. Diagnostic biomarkers for cGVHD are needed for early diagnosis and may guide identification of prognostic markers. No cGVHD biomarker has yet been validated for use in clinical practice. We evaluated both previously known markers and performed discovery-based analysis for cGVHD biomarkers in a 2 independent test sets (total of 36 cases ≤1 month from diagnosis and 31 time-matched controls with no cGVHD). On the basis of these results, 11 markers were selected and evaluated in 2 independent replication cohorts (total of 134 cGVHD cases and 154 controls). cGVHD cases and controls were evaluated for several clinical covariates, and their impact on biomarkers was identified by univariate analysis. The 2 replications sets were relatively disparate in the biomarkers they replicated. Only sBAFF and, most consistently, CXCL10 were identified as significant in both replication sets. Other markers identified as significant in only 1 replication set included intercellular adhesion molecule 1 (ICAM-1), anti-LG3, aminopeptidase N, CXCL9, endothelin-1, and gelsolin. Multivariate analysis found that all covariates evaluated affected interpretation of the biomarkers. CXCL10 had an increased significance in combination with anti-LG3 and CXCL9, or inversely with CXCR3(+)CD56(bright) natural killer (NK) cells. There was significant heterogeneity of cGVHD biomarkers in a large comprehensive evaluation of cGVHD biomarkers impacted by several covariates. Only CXCL10 strongly correlated in both replication sets. Future analyses for plasma cGVHD biomarkers will need to be performed on very large patient groups with consideration of multiple covariates.
Assuntos
Biomarcadores/sangue , Quimiocina CXCL10/metabolismo , Doença Enxerto-Hospedeiro/diagnóstico , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Receptores CXCR3/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/sangue , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Daclizumab, a humanized monoclonal antibody, binds CD25 and blocks formation of the IL-2 receptor on T cells. A study of daclizumab as acute graft-versus-host disease (GVHD) prophylaxis after unrelated bone marrow transplantation was conducted before the importance of CD25+FOXP3+ regulatory T cells (Tregs) was recognized. Tregs can abrogate the onset of GVHD. The relation between Tregs and a graft-versus-malignancy effect is not fully understood. An international, multicenter, double-blind clinical trial randomized 210 adult or pediatric patients to receive 5 weekly doses of daclizumab at 0.3 mg/kg (n = 69) or 1.2 mg/kg (n = 76) or placebo (n = 65) after unrelated marrow transplantation for treatment of hematologic malignancies or severe aplastic anemia. The risk of acute GVHD did not differ among the groups (P = .68). Long-term follow-up of clinical outcomes and correlative analysis of peripheral blood T cell phenotype suggested that the patients treated with daclizumab had an increased risk of chronic GVHD (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.0 to 2.3; P = .08) and a decreased risk of relapse (HR, 0.57; 95% CI, 0.3 to 1.0; P = .05), but similar survival (HR, 0.89; 95% CI, 0.6 to 1.3; P = .53). T cells from a subset of patients (n = 107) were analyzed by flow cytometry. Compared with placebo, treatment with daclizumab decreased the proportion of Tregs among CD4 T cells at days 11-35 and increased the proportion of central memory cells among CD4 T cells at 1 year. Prophylactic administration of daclizumab does not prevent acute GVHD, but may increase the risk of chronic GVHD and decrease the risk of relapse. By delaying Treg reconstitution and promoting immunologic memory, anti-CD25 therapy may augment alloreactivity and antitumor immunity.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoglobulina G/farmacologia , Subunidade alfa de Receptor de Interleucina-2/antagonistas & inibidores , Linfócitos T Reguladores/efeitos dos fármacos , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Daclizumabe , Método Duplo-Cego , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunoglobulina G/uso terapêutico , Lactente , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/citologia , Transplante Homólogo , Adulto JovemRESUMO
Randomized trials have conclusively shown higher rates of chronic graft-versus-host disease with filgrastim-stimulated apheresis peripheral blood as a donor source than unstimulated bone marrow. The Canadian Blood and Marrow Transplant Group conducted a phase 3 study of adults who received either filgrastim-stimulated apheresis peripheral blood or filgrastim-stimulated bone marrow from human leukocyte antigen-identical sibling donors. Because all donors received the identical filgrastim dosing schedule, this study allowed for a controlled evaluation of the impact of stem cell source on development of chronic graft-versus-host disease. One hundred and twenty-one evaluable filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow patient donor products were immunologically characterized by flow cytometry and tested for their association with acute and chronic graft-versus-host disease within 2 years of transplantation. The immune populations evaluated included, regulatory T cells, central memory and effector T cells, interferon γ positive producing T cells, invariate natural killer T cells, regulatory natural killer cells, dendritic cell populations, macrophages, and activated B cells and memory B cells. When both filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow were grouped together, a higher chronic graft-versus-host disease frequency was associated with lower proportions of CD56bright natural killer regulatory cells and interferon γ-producing T helper cells in the donor product. Lower CD56bright natural killer regulatory cells displayed differential impacts on the development of extensive chronic graft-versus-host disease between filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow. In summary, while controlling for the potential impact of filgrastim on marrow, our studies demonstrated that CD56bright natural killer regulatory cells had a much stronger impact on filgrastim-stimulated apheresis peripheral blood than on filgrastim-stimulated bone marrow. This supports the conclusion that a lower proportion of CD56bright natural killer regulatory cells results in the high rate of chronic graft-versus-host disease seen in filgrastim-stimulated apheresis peripheral blood. clinicaltrials.gov Identifier: 00438958.
Assuntos
Antígeno CD56/metabolismo , Filgrastim/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Doença Crônica , Feminino , Filgrastim/farmacologia , Doença Enxerto-Hospedeiro/diagnóstico , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunofenotipagem , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Irmãos , Condicionamento Pré-Transplante , Adulto JovemRESUMO
BACKGROUND: Pretreatment with anti-thymocyte globulin (ATG) decreases the occurrence of chronic graft-versus-host disease (CGVHD) after haemopoietic cell transplantation from an unrelated donor, but evidence of patient benefit is absent. We did a study to test whether ATG provides patient benefit, particularly in reducing the need for long-term immunosuppressive treatment after transplantation. METHODS: We did a phase 3, multicentre, open-label, randomised controlled trial at ten transplant centres in Canada and one in Australia. Eligible patients were aged 16 to 70 years with any haematological malignancy and a Karnofsky score of at least 60 receiving either myeloablative or non-myeloablative (or reduced intensity) conditioning preparative regimens before haemopoietic cell transplantation from an unrelated donor. We allocated patients first by simple randomisation (1:1), then by a minimisation method, to either pretransplantation rabbit ATG plus standard GVHD prophylaxis (ATG group) or standard GVHD prophylaxis alone (no ATG group). We gave a total dose of ATG of 4·5 mg/kg intravenously over 3 days (0·5 mg/kg 2 days before transplantation, 2·0 mg/kg 1 day before, and 2·0 mg/kg 1 day after). The primary endpoint was freedom from all systemic immunosuppressive drugs without resumption up to 12 months after transplantation. Analysis was based on a modified intention-to-treat method. This trial was registered at ISRCTN, number 29899028. FINDINGS: Between June 9, 2010, and July 8, 2013, we recruited and assigned 203 eligible patients to treatment (101 to ATG and 102 to no ATG). 37 (37%) of 99 patients who received ATG were free from immunosuppressive treatment at 12 months compared with 16 (16%) of 97 who received no ATG (adjusted odds ratio 4·25 [95% CI 1·87-9·67]; p=0·00060. The occurrence of serious adverse events (Common Terminology Criteria grades 4 or 5) did not differ between the treatment groups (34 [34%] of 99 patients in the ATG group vs 41 [42%] of 97 in the no ATG group). Epstein-Barr virus reactivation was substantially more common in patients who received ATG (20 [one of whom died-the only death due to an adverse event]) versus those who did not receive ATG (two [no deaths]). No deaths were attributable to ATG. INTERPRETATION: ATG should be added to myeloblative and non-myeloblative preparative regimens for haemopoietic cell transplantation when using unrelated donors. The benefits of decreases in steroid use are clinically significant. Epstein-Barr virus reactivation is increased, but is manageable by prospective monitoring and the use of rituximab. Future trials could determine whether the doses of ATG used in this trial are optimum, and could also provide additional evidence of a low relapse rate after non-myeloablative regimens. FUNDING: The Canadian Institutes of Health Research and Sanofi.
Assuntos
Soro Antilinfocitário/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Fatores Imunológicos/uso terapêutico , Condicionamento Pré-Transplante/métodos , Ativação Viral/efeitos dos fármacos , Adulto , Aloenxertos , Animais , Soro Antilinfocitário/efeitos adversos , Doença Crônica , Feminino , Herpesvirus Humano 4/fisiologia , Humanos , Fatores Imunológicos/efeitos adversos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios/métodos , Coelhos , Adulto JovemRESUMO
In adult hematopoietic cell transplantation (HCT), filgrastim-mobilized peripheral blood (G-PB) has largely replaced unstimulated marrow for allografting. Although the use of G-PB results in faster hematopoietic recovery, it is also associated with more chronic graft-versus-host disease (cGVHD). A potential alternative allograft is filgrastim-stimulated marrow (G-BM), which we hypothesized may be associated with prompt hematopoietic recovery but with less cGVHD. We conducted a phase 3, open-label, multicenter randomized trial of 230 adults with hematologic malignancies receiving allografts from siblings after myeloablative conditioning to compare G-PB with G-BM. The primary endpoint was time to treatment failure, defined as a composite of extensive cGVHD, relapse/disease progression, and death. With a median follow-up of 36 months (range, 9.6 to 48), comparing G-BM with G-PB, there was no difference between the 2 arms with respect to the primary outcome of this study (hazard ratio [HR], .91; 95% confidence interval [CI], .68 to 1.22; P = .52). However, the cumulative incidence of overall cGVHD was lower with G-BM (HR, .66; 95% CI, .46 to .95; P = .007) and there was no difference in the risk of relapse or progression (P = .35). The median times to neutrophil recovery (P = .0004) and platelet recovery (P = .012) were 3 days shorter for recipients allocated to G-PB compared with those allocated to G-BM, but there were no differences in secondary engraftment-related outcomes, such as time to first hospital discharge (P = .17). In addition, there were no graft failures in either arm. This trial demonstrates that, compared with G-PB, the use of G-BM allografts leads to a significantly lower rate of overall cGVHD without a loss of the graft-versus-tumor effect and comparable overall survival. Our findings suggest that further study of this type of allograft is warranted.
Assuntos
Transplante de Medula Óssea/métodos , Medula Óssea/efeitos dos fármacos , Filgrastim/farmacologia , Neoplasias Hematológicas/terapia , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco de Sangue Periférico/métodos , Adolescente , Adulto , Idoso , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Irmãos , Taxa de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Treatment of chronic graft-versus-host disease is intended to produce a sustainable benefit by reducing symptom burden, controlling objective manifestations of disease activity, preventing damage and impairment, and improving overall survival without causing disproportionate harms related to the treatment itself. Successful management can control the disease until systemic treatment is no longer needed. The complexity of the disease, the extended duration of follow-up needed to observe disease resolution and withdrawal of immunosuppressive treatment, and the lack of fully developed shorter term endpoints impede progress in the field. Identification and characterization of primary endpoints demonstrating clinical benefit without requiring years of follow-up is urgently needed, with the understanding that clinical benefit encompasses not only the self-evident benefit of the primary endpoint but also any other associated benefits. This report discusses regulatory considerations, eligibility criteria, the value of controlled trial designs, the merits of proposed primary endpoints, and key considerations elaborated from experience and progress during the past decade. The report concludes by mapping an overall approach that could support and lead to maximally informative clinical trials, especially those that seek to demonstrate clinical benefit along a pathway to regulatory review and approval.
Assuntos
Ensaios Clínicos como Assunto/métodos , Doença Enxerto-Hospedeiro/prevenção & controle , História do Século XXI , Humanos , National Institutes of Health (U.S.) , Estados UnidosRESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive myeloid malignancy of the dendritic cell lineage that affects patients of all ages, though the incidence appears to be highest in patients over the age of 60 years. Diagnosis is based on the presence of plasmacytoid dendritic cell precursors expressing CD123, the interleukin-3 (IL-3) receptor alpha, and a distinct histologic appearance. Timely diagnosis remains a challenge, due to lack of disease awareness and overlapping biologic and clinical features with other hematologic malignancies. Prognosis is poor with a median overall survival of 8 to 14 months, irrespective of disease presentation pattern. Historically, the principal treatment was remission induction therapy followed by a stem cell transplant (SCT) in eligible patients. However, bridging to SCT is often not achieved with induction chemotherapy regimens. The discovery that CD123 is universally expressed in BPDCN and is considered to have a pathogenetic role in its development paved the way for the successful introduction of tagraxofusp, a recombinant human IL-3 fused to a truncated diphtheria toxin payload, as an initial treatment for BPDCN. Tagraxofusp was approved in 2018 by the United States Food and Drug Administration for the treatment of patients aged 2 years and older with newly diagnosed and relapsed/refractory BPDCN, and by the European Medicines Agency in 2021 for first-line treatment of adults. The advent of tagraxofusp has opened a new era of precision oncology in the treatment of BPDCN. Herein, we present an overview of BPDCN biology, its diagnosis, and treatment options, illustrated by clinical cases.
Assuntos
Neoplasias Hematológicas , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Adulto , Humanos , Pessoa de Meia-Idade , Subunidade alfa de Receptor de Interleucina-3 , Interleucina-3/uso terapêutico , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/tratamento farmacológico , Medicina de Precisão , Doença Aguda , Transtornos Mieloproliferativos/patologia , Neoplasias Cutâneas/patologia , Células Dendríticas/patologia , BiologiaRESUMO
This is a consensus-based Canadian guideline whose primary purpose is to standardize and facilitate the management of chronic graft-versus-host disease (cGvHD) across the country. Creating uniform healthcare guidance in Canada is a challenge for a number of reasons including the differences in healthcare authority structure, funding and access to healthcare resources between provinces and territories, as well as the geographic size. These differences can lead to variable and unequal access to effective therapies for GvHD. This document will provide comprehensive and practical guidance that can be applied across Canada by healthcare professionals caring for patients with cGvHD. Hopefully, this guideline, based on input from GvHD treaters across the country, will aid in standardizing cGvHD care and facilitate access to much-needed novel therapies. This consensus paper aims to discuss the optimal approach to the initial assessment of cGvHD, review the severity scoring and global grading system, discuss systemic and topical treatments, as well as supportive therapies, and propose a therapeutic algorithm for frontline and subsequent lines of cGvHD treatment in adults and pediatric patients. Finally, we will make suggestions about the future direction of cGvHD treatment development such as (1) a mode-of-action-based cGvHD drug selection, according to the pathogenesis of cGvHD, (2) a combination strategy with the introduction of newer targeted drugs, (3) a steroid-free regimen, particularly for front line therapy for cGvHD treatment, and (4) a pre-emptive approach which can prevent the progression of cGvHD in high-risk patients destined to develop severe and highly morbid forms of cGvHD.
Assuntos
Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Consenso , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/patologia , Doença Crônica , CanadáRESUMO
PURPOSE: Pneumatosis intestinalis is a radiologic diagnosis that manifests in a variety of clinical settings. We report 4 cases of pneumatosis intestinalis in patients undergoing cancer treatments that included cytotoxic agents and/or tyrosine kinase inhibitors. These reports aim to provide insight into the clinical interpretation and pathogenesis of pneumatosis intestinalis in the setting of cancer treatments and demonstrate a potential association with tyrosine kinase inhibitors. METHODS: Radiologists responsible for the interpretation of adult imaging at our tertiary care centre were surveyed to identify cases of pneumatosis intestinalis arising in the midst of cancer treatment. The case histories were reviewed by physicians with expertise in cancer treatment. RESULTS: Four cases of chemotherapy-related pneumatosis intestinalis were identified. The diagnosis was made in 1 patient during investigations undertaken for non-life-threatening abdominal symptoms and incidentally in 2 patients by abdominal imaging used to measure chemotherapy response. A fourth patient presented in a life-threatening manner, and abdominal imaging was symptom guided. Interestingly, 3 of the 4 patients were receiving treatments that included a tyrosine kinase inhibitor, and this agent was the only identifiable potential etiology in 1 patient. CONCLUSIONS: The significance of pneumatosis intestinalis arising during cancer treatments is difficult to interpret because of the complex nature of the diseases and the treatments that often include combinations of cytotoxic agents and/or novel therapies. These reports demonstrate the importance of classifying this radiologic finding according clinical severity rather than etiology and underscore the need for continued observation for unexplained adverse effects when using novel therapies.
Assuntos
Carcinoma de Células Renais/complicações , Neoplasias Renais/complicações , Leucemia Mieloide Aguda/complicações , Linfoma não Hodgkin/complicações , Pneumatose Cistoide Intestinal/diagnóstico por imagem , Pneumatose Cistoide Intestinal/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adulto , Idoso , Carcinoma de Células Renais/tratamento farmacológico , Evolução Fatal , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pneumatose Cistoide Intestinal/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: von Willebrand factor (VWF) is synthesized by vascular endothelial cells and megakaryocytes. The VWF propeptide is critical for multimerization and acts as an intra-molecular chaperone for mature VWF in sorting to its storage organelles, Weibel-Palade bodies (WPBs). In the Canadian Type 3 VWD study, almost half of the identified variants were in the VWF propeptide and these were associated with an increased bleeding phenotype. OBJECTIVE: To investigate VWF propeptide variants that cause quantitative von Willebrand disease (VWD) by utilizing patient-derived endothelial colony-forming cells (ECFCs). PATIENTS/METHODS: Endothelial colony-forming cells were isolated from five Type 3 VWD patients from four families with the following variants: (1) homozygous p.Asp75_Gly178del (deletion of exons 4 and 5 deletion; Ex4-5del), (2) homozygous p.Cys633Arg, (3) homozygous p.Arg273Trp, and (4) p.Pro293Glnfs*164 and p.Gln419* inherited in the compound heterozygous state. Additionally, ECFCs were isolated from six family members (two Type 1 VWD, four unaffected). RESULTS: Endothelial colony-forming cells from the Type 3 patient with the compound heterozygous genotype exhibited a true null VWF cellular phenotype, with negligible VWF detected. In contrast, the other three propeptide variants presented a similar expression pattern in homozygous ECFCs where VWF was synthesized but not packaged in WPBs, and variant VWF had an increased association with the endoplasmic reticulum (ER) marker, protein disulfide-isomerase (PDI), indicating an ER-retention phenotype. The biosynthetic phenotype was similar but to a lesser degree in heterozygous ECFCs expressing the non-null variants. CONCLUSION: This study further elucidates the importance of the VWF propeptide in the VWD phenotype using patient-derived cells.
Assuntos
Doença de von Willebrand Tipo 3 , Doenças de von Willebrand , Canadá , Retículo Endoplasmático/metabolismo , Células Endoteliais/metabolismo , Humanos , Doenças de von Willebrand/genética , Fator de von Willebrand/metabolismoRESUMO
Overcoming graft-versus-host disease (GvHD) without increasing relapse and severe infections is a major challenge after allogeneic hematopoietic stem-cell transplantation (HSCT). ATIR101 is a haploidentical, naïve cell-enriched T-cell product, depleted of recipient-alloreactive T cells to minimize the risk of GvHD and provide graft-versus-infection and -leukemia activity. Safety and efficacy of ATIR101 administered after T-cell-depleted haploidentical HSCT (TCD-haplo + ATIR101) without posttransplant immunosuppressors were evaluated in a Phase 2, multicenter study of 23 patients with acute leukemia and compared with an observational cohort undergoing TCD-haplo alone (n = 35), matched unrelated donor (MUD; n = 64), mismatched unrelated donor (MMUD; n = 37), and umbilical cord blood (UCB; n = 22) HSCT. The primary endpoint, 6-month non-relapse mortality (NRM), was 13% with TCD-haplo + ATIR101. One year post HSCT, TCD-haplo + ATIR101 resulted in lower NRM versus TCD-haplo alone (P = 0.008). GvHD-free, relapse-free survival (GRFS) was higher with TCD-haplo + ATIR101 versus MMUD and UCB (both P < 0.03; 1-year rates: 56.5%, 27.0%, and 22.7%, respectively) and was not statistically different from MUD (1 year: 40.6%). ATIR101 grafts with high third-party reactivity were associated with fewer clinically relevant viral infections. Results suggest that haploidentical, selective donor-cell depletion may eliminate requirements for posttransplant immunosuppressors without increasing GvHD risk, with similar GRFS to MUD. Following these results, a randomized Phase 3 trial versus posttransplant cyclophosphamide had been initiated.
Assuntos
Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia Mieloide Aguda/mortalidade , Depleção Linfocítica/mortalidade , Doadores não Relacionados/estatística & dados numéricos , Adulto , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Condicionamento Pré-Transplante , Adulto JovemRESUMO
PURPOSE: Evidence regarding red blood cell (RBC) transfusion practices and their impact on hematopoietic cell transplantation (HCT) outcomes are poorly understood. PATIENTS AND METHODS: We performed a noninferiority randomized controlled trial in four different centers that evaluated patients with hematologic malignancies requiring HCT who were randomly assigned to either a restrictive (hemoglobin [Hb] threshold < 70 g/L) or liberal (Hb threshold < 90 g/L) RBC transfusion strategy between day 0 and day 100. The noninferiority margin corresponds to a 12% absolute difference between groups in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) score relative to baseline. The primary outcome was health-related quality of life (HRQOL) measured by FACT-BMT score at day 100. Additional end points were collected: HRQOL by FACT-BMT score at baseline and at days 7, 14, 28, 60, and 100; transplantation-related mortality; length of hospital stay; intensive care unit admissions; acute graft-versus-host disease; Bearman toxicity score; sinusoidal obstruction syndrome; serious infections; WHO Bleeding Scale; transfusion requirements; and reactions to therapy. RESULTS: A total of 300 patients were randomly assigned to either restrictive-strategy or liberal-strategy treatment groups between 2011 and 2016 at four Canadian adult HCT centers. After HCT, mean pre-transfusion Hb levels were 70.9 g/L in the restrictive-strategy group and 84.6 g/L in the liberal-strategy group (P < .0001). The number of RBC units transfused was lower in the restrictive-strategy group than in the liberal-strategy group (mean, 2.73 units [standard deviation, 4.81 units] v 5.02 units [standard deviation, 6.13 units]; P = .0004). After adjusting for transfusion type and baseline FACT-BMT score, the restrictive-strategy group had a higher FACT-BMT score at day 100 (difference of 1.6 points; 95% CI, -2.5 to 5.6 points), which was noninferior compared with that of the liberal-strategy group. There were no significant differences in clinical outcomes between the transfusion strategies. CONCLUSION: In patients undergoing HCT, the use of a restrictive RBC transfusion strategy threshold of 70 g/L was as effective as a threshold of 90 g/L and resulted in similar HRQOL and HCT outcomes with fewer transfusions.
Assuntos
Transfusão de Eritrócitos/métodos , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Unidades de Terapia Intensiva/estatística & dados numéricos , Adulto , Canadá , Transfusão de Eritrócitos/efeitos adversos , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do TratamentoRESUMO
This collaborative initiative aimed to provide recommendations on the use of polyclonal antithymocyte globulin (ATG) or anti-T lymphocyte globulin (ATLG) for the prevention of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). A comprehensive review of articles released up to October, 2018 was performed as a source of scientific evidence. Fourteen clinically relevant key questions to the domains indication, administration, and post-transplant management were developed and recommendations were produced using the Delphi technique involving a Panel of 14 experts. ATG/ATLG was strongly recommended as part of myeloablative conditioning regimen prior to matched or mismatched unrelated bone marrow or peripheral blood allogeneic HSCT in malignant diseases to prevent severe acute and chronic GvHD. ATG/ATLG was also recommended prior to HLA-identical sibling peripheral HSCT with good but lesser bulk of evidence. In reduced intensity or nonmyeloablative conditioning regimens, ATG/ATLG was deemed appropriate to reduce the incidence of acute and chronic GvHD, but a higher risk of relapse should be taken into account. Recommendations regarding dose, application, and premedication were also provided as well as post-transplant infectious prophylaxis and vaccination. Overall, these recommendations can be used for a proper and safe application of polyclonal ATG/ATLG to prevent GvHD after allogeneic HSCT.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Animais , Soro Antilinfocitário/uso terapêutico , Consenso , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Recidiva Local de Neoplasia , Coelhos , Condicionamento Pré-TransplanteRESUMO
BACKGROUND: Previous trials testing prevention strategies for chronic graft versus host disease (GVHD) have measured its cumulative incidence. In this trial of anti-thymocyte globulin, we measured treatment-independence at a long-term timepoint as the primary endpoint. METHODS: This was a randomised, open-label, multicentre, phase 3 trial done at ten centres in Canada and one in Australia. Eligible patients had a haematological malignancy (leukaemia, myelodysplastic syndrome, or lymphoma), were between 16 and 70 years of age, eligible for transplantation with a Karnofsky score of at least 60, and received an unrelated donor (fully matched or one-locus mismatched at HLA-A, HLA-B, HLA-C, or DRB1 loci) graft following myeloablative or non-myeloablative-reduced intensity conditioning. Patients were randomly assigned to receive anti-thymocyte globulin 4·5 mg/kg plus standard GVHD prophylaxis (cyclosporine or tacrolimus plus methotrexate or mycophenolate) or standard GVHD prophylaxis alone. The primary endpoint, freedom from immunosuppressive therapy without resumption at 12 months, was previously reported. Here we report on the prespecified 24-month analysis. Analyses were per-protocol, excluding those patients who did not proceed to transplantation. This trial is registered as ISRCTN 29899028 and NCT01217723, status completed. FINDINGS: Between June 9, 2010, and July 8, 2013, we recruited and randomly assigned 203 eligible patients to receive anti-thymocyte globulin (n=101) or no additional treatment (n=102) along with standard GVHD prophylaxis. 7 (3%) patients did not receive a transplant and were excluded from the analysis. 38 (38%) of 99 evaluable patients in the anti-thymocyte globulin plus GVHD prophylaxis group were free from immunosuppressive therapy at 24 months compared with 18 (19%) of 97 patients in the standard GVHD prophylaxis group (adjusted odds ratio [OR] 3·49 [95% CI 1·607·60]; p=0·0016). At 24 months, the cumulative incidence of relapse was 16·3% (95% CI 8·923·7) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 17·5 (9·925·1) in the standard GVHD prophylaxis group (p=0·73) and non-relapse mortality was 21·2% (95% CI 13·229·2) versus 31·3% (21·940·7; p=0·15). The cumulative incidence of chronic GVHD at 24 months was 26·3% (95% CI 17·535·1) in the anti-thymocyte globulin group and 41·3% (31·351·3) in the standard GVHD prophylaxis group (p=0·032). Overall survival at 24 months was 70·6% (95% CI 60·678·6) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 53·3% (42·862·8) in the standard GVHD prophylaxis group (adjusted hazard ratio [HR] 0·56, 95% CI [0·350·90]; p=0·017). Symptoms of chronic GVHD by the Lee Scale were more prevalent in the standard GVHD prophylaxis group, with scores of 13·27 (SD 10·94) in the anti-thymocyte globulin plus GVHD prophylaxis group and 20·38 (SD 14·68) in the standard GVHD prophylaxis group (p=0·040). Depressive symptoms were more prominent in the standard GVHD prophylaxis group, the mean Center for Epidemiological Studies Depression scale (CES-D) scores were 10·40 (SD 9·88) in the anti-thymocyte globulin group and 14·62 (SD 12·26) in the standard GVHD prophylaxis group (p=0·034). Serious adverse events (CTCAE grade 4 or 5) occurred in 38 (38%) patients in the anti-thymocyte globulin group and in 49 (51%) in the standard GVHD prophylaxis group, the most common being infection and GVHD. One patient in the anti-thymocyte globulin plus GVHD prophylaxis group died of Epstein-Barr virus hepatitis, but no deaths were attributable to anti-thymocyte globulin. INTERPRETATION: The results of this prespecified 24-month analysis suggest that pretreatment with anti-thymocyte globulin provides clinically meaningful benefits when added to standard GVHD prophylaxis in patients undergoing unrelated donor transplantation, including decreases in use of immunosuppressive therapy, chronic GVHD and its symptoms, depressive symptoms, and improved overall survival. Anti-thymocyte globulin should be included in the preparative regimens of patients with haematological malignancies selected for unrelated donor transplantation. FUNDING: Canadian Institutes of Health Research and Sanofi.
Assuntos
Soro Antilinfocitário/uso terapêutico , Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/terapia , Imunossupressores/uso terapêutico , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Adolescente , Adulto , Idoso , Ciclosporina/administração & dosagem , Ciclosporina/uso terapêutico , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Humanos , Imunossupressores/administração & dosagem , Estimativa de Kaplan-Meier , Masculino , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Ácido Micofenólico/administração & dosagem , Ácido Micofenólico/uso terapêutico , Medidas de Resultados Relatados pelo Paciente , Linfócitos T/imunologia , Tacrolimo/administração & dosagem , Tacrolimo/uso terapêutico , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Doadores não Relacionados , Adulto JovemRESUMO
PURPOSE: To provide evidence-based recommendations on the treatment of multiple myeloma to practicing physicians and others. METHODS: ASCO and Cancer Care Ontario convened an Expert Panel of medical oncology, surgery, radiation oncology, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and some phase II studies published from 2005 through 2018. Outcomes of interest included survival, progression-free survival, response rate, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 124 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS: Evidence-based recommendations were developed for patients with multiple myeloma who are transplantation eligible and those who are ineligible and for patients with relapsed or refractory disease.
Assuntos
Oncologia/normas , Mieloma Múltiplo/terapia , Ensaios Clínicos Fase II como Assunto , Humanos , Oncologia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisões Sistemáticas como AssuntoRESUMO
A systematic review and meta-analysis was performed to determine the efficacy and toxicity of thalidomide in previously untreated patients with myeloma. Medline, Embase, Cochrane Controlled Trials Register, and abstracts from the American Society of Hematology and the American Society of Clinical Oncology were searched for randomized controlled trials (RCTs) of either induction or maintenance thalidomide in adults with previously untreated myeloma. Nine RCTs of induction thalidomide, three RCTs of maintenance thalidomide, and one RCT of induction and maintenance thalidomide were identified, involving a total of 4144 subjects. When thalidomide was added to standard, non-transplantation myeloma therapy, overall survival (OS) improved (HR 0.67; 95% CI 0.56-0.81). When thalidomide was given as maintenance following autologous transplantation (ASCT), there was a trend to improved OS (HR 0.61, 95% CI 0.37-1.01); when the only trial which combined induction and maintenance thalidomide was excluded from this analysis, a significant survival advantage emerged (HR 0.49, 95% CI 0.32-0.74). The relative risk of venous thromboembolism (VTE) with induction thalidomide was 2.56 (95% CI 1.88-3.49). A meta-analysis of trials/sub-groups administering low molecular weight heparin (LMWH) as VTE prophylaxis, suggested a persistently increased relative risk of VTE with induction thalidomide (RR 1.54, 95% CI 1.07-2.22). The relative risk of VTE was substantially lower, but still elevated, when thalidomide was given as maintenance therapy following ASCT (RR 1.95, 95% CI 1.15-3.30). In summary, thalidomide appears to improve the overall survival of patients with newly diagnosed myeloma both when it is added to standard, non-transplantation therapy, and when it is given as maintenance therapy following ASCT. However, thalidomide is associated with toxicity, particularly a significantly increased risk of VTE.
Assuntos
Imunossupressores/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/uso terapêutico , Progressão da Doença , Humanos , Mieloma Múltiplo/patologia , Resultado do TratamentoRESUMO
The effectiveness of erythropoiesis-stimulating agents (ESAs) for the treatment of anemia in patients with non-myeloid hematological malignancies needs to be assessed as the response to their administration is not uniform and their cost is high. We conducted a systematic review (SR) of the literature to identify reports of the effect of ESAs on survival, quality of life (QOL), transfusion requirements, and anemia. The entries to MEDLINE, EMBASE, and the Cochrane Library databases, and abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology and the American Society of Hematology were searched. Seventeen reports and five abstracts of randomized trials fulfilled prospective criteria for inclusion. Five trials reported on survival; three failed to detect differences between groups and two demonstrated inferior survival in patients allocated to an ESA. Seven trials and three abstracts reported on QOL with four articles and three abstracts describing improvements in patients allocated to erythropoietin. However, important methodologic limitations were identified in these reports. Seven randomized controlled trials reported a reduction in the proportion of patients transfused. The absolute risk reduction in transfusions ranged from 15% to 24%. This is the only SR that assesses the use of erythropoiesis-stimulating agents specifically in patients with hematological malignancies. We conclude that available data evaluating ESAs in patients with hematologic malignancies demonstrate that these agents reduce transfusion requirements. Limitations of these data preclude conclusions that these agents improve QOL. More data are required to confirm the inferior survival associated with ESAs.
Assuntos
Anemia/tratamento farmacológico , Anemia/etiologia , Hematínicos/uso terapêutico , Linfoma/complicações , Mieloma Múltiplo/complicações , Eritropoetina , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes , Análise de SobrevidaRESUMO
The majority of patients with TKI failure respond to HCT. However, the relapse risk remains high. This study has evaluated transplant outcomes in 223 CML patients with TKI failure due to resistance (n = 132) or intolerance (n = 29), as well as those that were TKI naïve/responding with advanced disease (n = 35) or with chronic phase (CP, n = 27). We studied outcomes according to post-transplant BCR-ABL transcript level within 3 months. With respect to transplant outcomes according to the post-transplant BCR/ABLtranscript level within 3 months, the group failing to achieve a 1.3 log reduction (n = 14, 12.4%) showed the highest relapse rate of 78.6% at 5 years, compared to 26.2% and 24.1% in the groups achieving 1.3-4.0 log reduction (n = 45, 39.8%), and ≥4.1 log reduction (n = 54, 47.8%) respectively (p < 0.001). Multivariate analysis confirmed that the group failing to achieve a 1.3 log reduction had a 2.3-fold higher risk of death and 6.6 times higher risk of relapse. Poor overall survival after HCT was associated with advanced disease at diagnosis, but not disease status prior to HCT. Of 61 patients who relapsed after HCT, 47 were treated with post-transplant TKI therapy; those receiving TKI after loss of MR2 or MMR showed higher rates of response and survival compared to those receiving TKI after hematologic relapse (p < 0.001). QPCR log reduction level within 3 months post transplantation is prognostic in this population.