Subject(s)
Graft vs Host Disease , Insulin , Ophthalmic Solutions , Adult , Female , Humans , Male , Middle Aged , Chronic Disease , Eye Diseases/etiology , Eye Diseases/drug therapy , Graft vs Host Disease/drug therapy , Hematopoietic Stem Cell Transplantation , Insulin/administration & dosage , Ophthalmic Solutions/therapeutic useABSTRACT
Recent data link the incidence of intestinal GvHD (iGvHD) after allogeneic haematopoietic stem cell transplantation (aSCT) to exposure with piperacillin-tazobactam or imipenem-cilastatin. To assess relevance of timing, duration, sequence and combination of antibiotic treatment in this setting, we applied a time-dependent model to our aSCT cohort. Patients from the prospective Cologne Cohort of Neutropenic Patients (CoCoNut) undergoing aSCT from January 2007 to April 2013 were included into a time-dependent multivariate Cox proportional hazards regression model with backward-stepwise selection. In 399 eligible patients, cumulative antibiotic exposure (hazard ratio (HR) 2.46; 95% confidence interval (95% CI) 1.59-3.81; P<0.001) and exposure to sequential treatment with penicillin derivatives and carbapenems (HR 6.22, 95% CI 1.27-30.31), but not to the individual classes, were associated with iGvHD at day 100. Glycopeptides were assessed as a risk factor (HR 3.73, 95% CI 1.51-9.19), but not considered independent, since their use was dependent on previous exposure to penicillin derivatives and carbapenems. Patients with iGvHD presented with increased non-relapse mortality at day 365 (HR 3.51; 95% CI 2.10-5.89; P<0.001). We identified sequential exposure to penicillin derivatives and carbapenems as well as overall exposure to antibiotics as independent risk factors for iGVHD. Confirmation of these findings in larger, prospective cohorts is necessary.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Transplantation, Homologous/methods , Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Treatment Outcome , Young AdultABSTRACT
The EBMT risk score is an established tool successfully used in the prognosis of survival post-HSCT and is applicable for a range of haematological disorders. One of its main advantages is that score generation involves summation of clinical parameters that are available pretransplant. However, the EBMT risk score is recognized as not being optimal. Previous analyses, involving patients with various diagnoses, have shown that non-HLA gene polymorphisms influence outcome after allogeneic HSCT. This study is novel as it focuses only on patients having acute leukaemia (N = 458) and attempts to demonstrate how non-HLA gene polymorphisms can be added to the EBMT risk score in a Cox regression model to improve prognostic ability for overall survival. The results of the study found that three genetic factors improved EBMT risk score. The presence of MAL (rs8177374) allele T in the patient, absence of glucocorticoid receptor haplotype (consisting of rs6198, rs33389 and rs33388) ACT in the patient and absence of heat-shock protein 70-hom (+2437) (rs2227956) allele C in the patient were associated with decreased survival time. When compared to the EBMT risk score, the scores combining EBMT risk score with the genetic factors had an improved correlation with clinical outcome and better separation of risk groups. A bootstrapping technique, involving repeated testing of a model using multiple validation sets, also revealed that the newly proposed model had improved predictive value when compared to the EBMT risk score alone. Results support the view that non-HLA polymorphisms could be useful for pretransplant clinical assessment and provide evidence that polymorphisms in the recipient genotype may influence incoming donor cells, suppressing the initiation of the graft versus leukaemia effect and reducing survival.
Subject(s)
Graft vs Host Disease/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Leukemia/genetics , Leukemia/immunology , Adult , Female , Genomics , Genotype , HSP70 Heat-Shock Proteins/genetics , Haplotypes/genetics , Histocompatibility Testing , Humans , Leukemia/pathology , Leukemia/therapy , Male , Middle Aged , Prognosis , Risk Factors , Transplantation, Homologous/adverse effectsABSTRACT
Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.
Subject(s)
Adrenal Cortex Hormones/pharmacology , Drug Resistance, Neoplasm/drug effects , Graft vs Host Disease/drug therapy , Hematologic Neoplasms/complications , Hematopoietic Stem Cell Transplantation/adverse effects , Pyrazoles/therapeutic use , Salvage Therapy , Adult , Aged , Animals , Disease Models, Animal , Female , Follow-Up Studies , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Hematologic Neoplasms/therapy , Humans , Janus Kinases/antagonists & inhibitors , Male , Mice , Middle Aged , Neoplasm Staging , Nitriles , Prognosis , Pyrimidines , Recurrence , Retrospective Studies , Survival Rate , Transplantation, Homologous , Young AdultABSTRACT
Allogeneic stem cell transplantation is a treatment option for patients with poor risk CLL. We conducted a retrospective analysis of all CLL patients allografted at our institution, the University Hospital of Cologne, Germany. Data was collected on 40 patients from 2004 to 2012. The mean age was 54, and the majority were male (75 %). On average, the patients were diagnosed 6 years (range 2-12) prior to transplant with an average of 4 years (range 1-8) from time of first-line therapy to transplant. The remission states at the time of transplant were complete remission (CR) (n = 4), stable disease (n = 10), partial remission (n = 20) and progressive disease (n = 6). Only reduced intensity conditioning regimens were employed. The average CD34(+) cell dose was 4.16 × 10(6)/kg. Neutrophil engraftment was seen by day +17 (range 10-23) post-transplant, and 88 % achieved 95-100 % donor chimerism by day 100. Overall survival, progression-free survival and non-relapse mortality at 2 years post-transplant were 65, 52.5 and 27.5 %, respectively. A total of 51 % of patients were found to be minimal residual disease (MRD)-negative at 1 year post-transplant. Our single-centre experience confirms the valuable role of allogeneic stem cell transplantation (allo-SCT) in the treatment of poor risk CLL patients with promising long-term survival and acceptable transplant-related mortality. The advent of newer therapeutic agents should not hinder the consideration of allo-SCT for this patient cohort as it remains the only curative option for these patients.
Subject(s)
Hematopoietic Stem Cell Transplantation/mortality , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Adult , Aged , Female , Hematopoietic Stem Cell Transplantation/trends , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Male , Middle Aged , Morbidity , Mortality/trends , Retrospective Studies , Transplantation, Homologous/mortality , Transplantation, Homologous/trends , Treatment OutcomeABSTRACT
Previous studies of non-histocompatibility leukocyte antigen (HLA) gene single-nucleotide polymorphisms (SNPs) on subgroups of patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) revealed an association with transplant outcome. This study further evaluated the association of non-HLA polymorphisms with overall survival in a cohort of 762 HSCT patients using data on 26 polymorphisms in 16 non-HLA genes. When viewed in addition to an already established clinical risk score (EBMT-score), three polymorphisms: rs8177374 in the gene for MyD88-adapter-like (MAL; P=0.026), rs9340799 in the oestrogen receptor gene (ESR; P=0.003) and rs1800795 in interleukin-6 (IL-6; P=0.007) were found to be associated with reduced overall survival, whereas the haplo-genotype (ACC/ACC) in IL-10 was protective (P=0.02). The addition of these non-HLA polymorphisms in a Cox regression model alongside the EBMT-score improved discrimination between risk groups and increased the level of prediction compared with the EBMT-score alone (gain in prediction capability for EBMT-genetic-score 10.8%). Results also demonstrated how changes in clinical practice through time have altered the effects of non-HLA analysis. The study illustrates the significance of non-HLA genotyping prior to HSCT and the importance of further investigation into non-HLA gene polymorphisms in risk prediction.
Subject(s)
Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/mortality , Polymorphism, Single Nucleotide , Risk Assessment/methods , Adolescent , Adult , Aged , Allografts , Cause of Death , Child , Estrogen Receptor alpha/genetics , Female , Follow-Up Studies , Genotype , Graft vs Host Disease/mortality , Haplotypes , Hematologic Neoplasms/mortality , Histocompatibility , Humans , Infections/mortality , Interleukin-10/genetics , Interleukin-6/genetics , Kaplan-Meier Estimate , Male , Membrane Glycoproteins/genetics , Middle Aged , Multiple Organ Failure/mortality , Prognosis , Proportional Hazards Models , Receptors, Interleukin-1/genetics , Transplantation Conditioning/adverse effects , Treatment OutcomeABSTRACT
Allogeneic haematopoietic stem cell transplantation is an effective treatment option for chemotherapy-refractory or relapsed haematological malignancies such as leukaemias and lymphomas. After conditioning with chemotherapy with or without total body irradiation, donor cells are infused to reconstitute haematopoiesis. Donor-derived immune cells induce immune reactions to control or eradicate the underlying disease, thereby going beyond the effect of chemotherapy. This graft-versus-tumour effect (GvT) is often accompanied by detrimental graft-versus-host reactions (graft-versus-host disease, GvHD), which substantially influence the mortality and morbidity after transplantation. The balance between GvHD and GvT, implementing various parameters such as donor selection, stem cell source, conditioning, immune reconstitution and immunosuppressive regimens, represents the challenge in the field of allogeneic stem cell transplantation.
Subject(s)
Eye Diseases/immunology , Graft vs Host Disease/immunology , Graft vs Tumor Effect/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Leukemia/immunology , Leukemia/therapy , Lymphoma/immunology , Lymphoma/therapy , Transplantation Conditioning/methods , Allografts , Chronic Disease , Eye Diseases/prevention & control , Eye Diseases/therapy , Graft vs Host Disease/prevention & control , Graft vs Host Disease/therapy , Humans , Risk FactorsABSTRACT
Meibomian gland loss in ocular GvHD was described as a mechanism contributing to dry eye and severe damage to the ocular surface. Infrared images of upper eyelid meibomian glands from 86 ocular GvHD patients, from 10 patients after allogeneic stem cell transplantation (aSCT) without ocular GvHD, from 32 patients prior to aSCT and from 30 healthy controls were analyzed retrospectively and evaluated using two grading schemes. The upper meibomian gland area (uMGA) was calculated and set in relation to the total tarsal area of the lid. Results demonstrate that meibomian gland loss is significantly increased in patients with ocular GvHD as well as in patients prior to aSCT in comparison with controls (P between 0.05 and <0.001). Patients after aSCT without ocular GvHD had no significant difference in uMGA in comparison with controls. This study suggests that meibomian gland loss in GvHD patients is likely to be a multifactorial process that also occurs prior to aSCT, possibly due to underlying diseases and/or secondary to chemotherapy or irradiation. In addition, the question has to be addressed whether meibomian gland loss could serve as a predictor for the development of ocular GvHD. Overall, infrared meibography should be included in routine examination of patients undergoing aSCT and during follow-up.
Subject(s)
Graft vs Host Disease/complications , Hematopoietic Stem Cell Transplantation/adverse effects , Meibomian Glands/growth & development , Transplantation Conditioning/adverse effects , Transplantation, Homologous/adverse effects , Adult , Female , Graft vs Host Disease/metabolism , Humans , Male , Middle Aged , Young AdultABSTRACT
The number of hematopoietic stem cell transplantations is continuously increasing. On the one hand reduced intensity conditioning and improved supportive therapies allow for transplantations in patients with significant comorbidities and up to their eighth decade of life. Due to this development the number of complex and critically ill patients in need of intensive care is constantly growing. Recent developments in general critical care such as sepsis bundles and non-invasive ventilation contribute to a better outcome of these patients. However, treatment algorithms that identify patients potentially benefitting from intensive care but also reduce overtreatment of moribund patients represent a central multidisciplinary challenge not only for the treating transplant physician and intensivist.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cell Transplantation/trends , Multiple Organ Failure/therapy , Evidence-Based Medicine , Humans , Treatment OutcomeSubject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Bone Marrow Transplantation , Cyclophosphamide/therapeutic use , Graft vs Host Disease/prevention & control , Leukemia/therapy , Lymphoma/therapy , Adult , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Salvage Therapy , Siblings , Survival Rate , Tissue Donors , Treatment Outcome , Young AdultABSTRACT
Extracorporeal photopheresis (ECP) has been used for over 30 years in the treatment of erythrodermic cutaneous T-cell lymphoma (CTCL) and over 20 years for chronic graft-versus-host disease (cGVHD). The lack of prospective randomized trials has led to different centres having different patient selection criteria, treatment schedules, monitoring protocols and patient assessment criteria. ECP for CTCL and cGVHD is available only at six specialized centres across the U.K. In the recent Improving Outcomes Guidance the National Institute for Health and Clinical Excellence endorsed the use of ECP for CTCL and because of the complexity of treatment supported its use in specialized centres and also suggested the need for expansion of this service. In 2005 consultants and senior nurses from all U.K. sites and from Scandinavia formed a Photopheresis Expert Group. This group's first aim was to produce a consensus statement on the treatment of CTCL and cGVHD with ECP using evidence-based medicine and best medical practice, in order to standardize ECP eligibility, assessment and treatment strategies across the U.K.
Subject(s)
Graft vs Host Disease/drug therapy , Lymphoma, T-Cell, Cutaneous/drug therapy , Photopheresis/methods , Skin Neoplasms/drug therapy , Dose-Response Relationship, Drug , Evidence-Based Medicine , Humans , Photopheresis/adverse effects , Practice Guidelines as Topic/standards , Reference StandardsABSTRACT
Classical Hodgkin lymphoma (cHL) is a distinct malignancy of the immune system. Despite the progress made in the understanding of the biology of cHL, the transforming events remain to be elucidated. Recently, we demonstrated that the Janus kinase inhibitor AG490 blocked cellular proliferation and STAT3 phosphorylation in cHL. To explore the potential of constitutively activated STAT3 as a drug target and its role in cHL pathogenesis, different cHL cell lines were analyzed. Treatment of cHL cells by the protein tyrosine kinase inhibitor AG17 was associated with inhibition of cellular proliferation and cell cycle arrest. AG17 treatment was accompanied by decreased levels of STAT3 phosphorylation, whereas NF-kappaB and p38/SAPK2 signaling were not inhibited. Incubation with AG17 or AG490 sensitized cHL cells to CD95/Fas/Apo-1 or staurosporine-mediated apoptosis. Coincubation of tyrphostins with staurosporine was accompanied by rapid complete inhibition of STAT3 phosphorylation. RNA interference directed against STAT3 in L428 and L1236 cHL cells demonstrated that STAT3 is essential for cell proliferation of these cHL cells. In conclusion, these findings support the concept that STAT3 signaling is important in the pathogenesis of cHL and tyrphostins are agents for developing new therapeutic strategies.
Subject(s)
Apoptosis/drug effects , DNA-Binding Proteins/metabolism , Hodgkin Disease/drug therapy , Trans-Activators/metabolism , Tyrphostins/pharmacology , Cell Division/drug effects , DNA-Binding Proteins/genetics , Enzyme Inhibitors/pharmacology , Gene Expression , Hodgkin Disease/metabolism , Hodgkin Disease/pathology , Humans , Jurkat Cells , Nitriles , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacology , RNA, Small Interfering , STAT3 Transcription Factor , Signal Transduction/drug effects , Staurosporine/pharmacology , Trans-Activators/genetics , fas Receptor/metabolismABSTRACT
Hodgkin-Reed Sternberg (H-RS) cells harbour clonal immunoglobulin gene (Ig) rearrangements in almost all cases of classical Hodgkin's disease but lack Ig gene expression. In the H-RS cell line L1236, a somatic mutation of the Ig heavy-chain gene promoter octamer motif has been described as a putative reason for absence of Ig gene expression. We addressed transcriptional activity of this mutated promoter by performing reporter gene studies and gel retardation assays. The results showed that the mutation outside the coding region of the rearranged Ig gene in L1236 cells leads to downregulation of Ig gene expression in H-RS cells.
Subject(s)
Genes, Immunoglobulin , Hodgkin Disease/genetics , Reed-Sternberg Cells/immunology , Transcription, Genetic , Gene Rearrangement , Genes, Reporter , Hodgkin Disease/immunology , Humans , Promoter Regions, Genetic , Tumor Cells, CulturedABSTRACT
Hodgkin disease (HD) represents a malignant lymphoma in which the putative malignant Hodgkin and Reed-Sternberg cells are rare and surrounded by abundant reactive nonmalignant cells. It has been suggested that cytokines such as interleukin-6 (IL-6) are involved in the pathogenesis of the disease. The expression of the IL-6 receptor (IL-6R) complex and its link to the activation of signal transducers and activators of transcription (STAT) molecules in HD cell lines was investigated. Gel retardation and Western blot analyses revealed a high level of constitutively activated STAT3 in 5 of 7 HD cell lines, which could not be detected in Burkitt lymphoma cell lines. Different levels of IL-6R protein were measured in various HD cell lines: L428 and Dev cells were characterized by very low levels of gp80 and gp130, on KMH2 cells only gp130 but no gp80 was detected, whereas L540, L591, HDLM2, and L1236 were positive for both gp80 and gp130, suggesting a possible autocrine stimulation of STAT3. However, a further increase in STAT3 activation on IL-6 or IL-6/soluble IL-6R stimulation was not observed. Neutralizing monoclonal antibodies against IL-6, gp80, gp130, or both receptor subunits did not affect the proliferation or the constitutive activation of STAT molecules in HD cell lines. However, the tyrosine kinase inhibitor AG490 blocked the constitutive activation of STAT3 and inhibited spontaneous growth of HD tumor cells. The evidence suggests abnormal STAT signaling and growth regulation in Hodgkin cell lines. (Blood. 2001;98:762-770)
Subject(s)
DNA-Binding Proteins/metabolism , Hodgkin Disease/pathology , Trans-Activators/metabolism , Antibodies, Monoclonal/pharmacology , Antigens, CD/immunology , Antigens, CD/metabolism , Antigens, CD/pharmacology , Cell Division/drug effects , Cytokine Receptor gp130 , DNA-Binding Proteins/drug effects , Enzyme Inhibitors/pharmacology , Hodgkin Disease/etiology , Hodgkin Disease/metabolism , Humans , Interleukin-6/immunology , Interleukin-6/physiology , Leukemia/metabolism , Lymphoma/metabolism , Membrane Glycoproteins/immunology , Membrane Glycoproteins/metabolism , Membrane Glycoproteins/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Receptors, Interleukin-6/immunology , STAT1 Transcription Factor , STAT3 Transcription Factor , Trans-Activators/drug effects , Tumor Cells, CulturedABSTRACT
Hodgkin and Reed Sternberg (H-RS) cells represent the malignant cells in classical Hodgkin's disease. Although derived from germinal center B cells, they do not express surface immunoglobulin. This has been explained by the presence of crippling mutations within the immunoglobulin genes in numerous cases of Hodgkin's disease. As immunoglobulin gene expression in B cells requires an interaction between octamer sites and the transactivating factors Oct-2 and Bob-1, this study addresses the expression of the transcription factors Oct-2 and Bob-1 in H-RS cells. In Hodgkin's disease-derived cell lines, low levels of Oct-2 transcripts but no Oct-2 protein were detected. Transcripts of Bob-1, a B-cell-specific co-factor of Oct-2, could not be observed in these cell lines. Absence of Oct-2 and Bob-1 protein expression in primary H-RS cells was demonstrated by performing immunohistochemistry in 20 cases of classical Hodgkin's disease. H-RS cells stained negative for both proteins in all of the cases analyzed. In conclusion, absence of functional Oct-2 and Bob-1 cells represents a novel mechanism for immunoglobulin gene deregulation in H-RS cells. Lack of Oct-2 and Bob-1 points to a defect in transcription machinery in H-RS cells and is associated with lack of immunoglobulin gene expression in these cells.