ABSTRACT
Idecabtagene vicleucel (ide-cel), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen (BCMA), received early access program (EAP) authorization in France in April 2021 for relapsed/refractory multiple myeloma (RRMM). We conducted a real-world registry-based multicentre observational study in 11 French hospitals to evaluate ide-cel outcomes. Data from 176 RRMM patients who underwent apheresis between June 2021 and November 2022 were collected from the French national DESCAR-T registry. Of these, 159 patients (90%) received ide-cel. Cytokine release syndrome occurred in 90% with 2% grade ≥3, and neurotoxicity occurred in 12% with 3% grade ≥3. Over the first 6 months, the best overall response and ≥complete response rates were 88% and 47% respectively. The median progression-free survival (PFS) from the ide-cel infusion was 12.5 months, the median overall survival (OS) was 20.8 months and the estimated OS rate at 12 months was 73.3%. Patients with extra-medullary disease (EMD) had impaired PFS (6.2 months vs. 14.8 months). On multivariable analysis, EMD and previous exposure to BCMA-targeted immunoconjugate or T-cell-redirecting GPRC5D bispecific antibody were associated with inferior PFS. Our study supports ide-cel's feasibility, safety and efficacy in real-life settings, emphasizing the importance of screening for EMD and considering prior treatments to optimize patient selection.
Subject(s)
Allografts/physiopathology , Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cells/physiology , Reoperation/methods , Adult , Aged , Antigens, CD34/analysis , Antigens, CD34/metabolism , Cohort Studies , Delayed Graft Function/physiopathology , Delayed Graft Function/therapy , Female , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cells/metabolism , Humans , Male , Middle Aged , Transplantation Conditioning/methods , Young AdultABSTRACT
Biomarkers are increasingly used for diagnosis and treatment of transplant-related complications including the first biomarker-driven interventional trials of acute graft-versus-host disease (GvHD). In contrast, the development of biomarkers of chronic GvHD (cGvHD) has lagged behind due to a broader variety of manifestations, overlap with acute GvHD, a greater variation in time to onset and maximum severity, and lack of sufficient patient numbers within prospective trials. An international workshop organized by a North-American and European consortium was held in Marseille in March 2017 with the goal to discuss strategies for future biomarker development to guide cGvHD therapy. As a result of this meeting, two areas were prioritized: the development of prognostic biomarkers for subsequent onset of moderate/severe cGvHD, and in parallel, the development of qualified clinical-grade assays for biomarker quantification. The most promising prognostic serum biomarkers are CXCL9, ST2, matrix metalloproteinase-3, osteopontin, CXCL10, CXCL11, and CD163. Urine-proteomics and cellular subsets (CD4+ T-cell subsets, NK cell subsets, and CD19+CD21low B cells) represent additional potential prognostic biomarkers of cGvHD. A joint effort is required to verify the results of numerous exploratory trials before any of the potential candidates is ready for validation and subsequent clinical application.
Subject(s)
Biomarkers/metabolism , Graft vs Host Disease/diagnosis , Chronic Disease , Female , Graft vs Host Disease/pathology , Humans , Male , PrognosisABSTRACT
Transplant-eligible patients with multiple myeloma (MM) now have extended survival after diagnosis owing to effective modern treatment strategies that include new agents in induction therapy, autologous stem cell transplant (ASCT), consolidation therapy and posttransplant maintenance therapy. Standard of care for newly diagnosed, fit patients includes ASCT and, often nowadays, posttransplant maintenance. Several large studies have shown the efficacy of maintenance with thalidomide, lenalidomide and bortezomib in the treatment scheme of MM with regards to prolonging progression-free survival and, to a lesser degree, overall survival. Herein we discuss the data currently available to support the use of maintenance therapy in patients after ASCT as well as the newer available agents that may be a part of its changing landscape in the years to come.
Subject(s)
Multiple Myeloma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bortezomib/administration & dosage , Bortezomib/adverse effects , Bortezomib/therapeutic use , Hematopoietic Stem Cell Transplantation , Humans , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , Immunologic Factors/therapeutic use , Lenalidomide , Maintenance Chemotherapy , Molecular Targeted Therapy , Multiple Myeloma/mortality , Multiple Myeloma/pathology , Postoperative Care , Thalidomide/administration & dosage , Thalidomide/adverse effects , Thalidomide/analogs & derivatives , Thalidomide/therapeutic use , Transplantation, Autologous , Treatment OutcomeABSTRACT
Over the past decade, significant advances have been made in the field of multiple myeloma. Introduction of the so-called novel agents, proteasome inhibitors (PI) and immunomodulatory drugs (IMiD), and improved supportive care have resulted in significantly better outcome. Standard first line treatment in fit patients include PI and IMiD based induction, high dose melphalan with autologous hematopoietic stem cell transplantation (ASCT) and consolidation/maintenance. However, despite these progresses MM remains incurable for the majority of patients and most patients will relapse. Next generation PI (carfilzomib, ixazomib) and IMiD (pomalidomide) and new therapeutic classes: monoclonal antibody (elotuzumab, daratumumab) and pan-deacetylase inhibitors (panobinostat) have been successfully evaluated in relapse multiple myeloma. Some of these new agents are now approved for multiple myeloma treatment at relapse. However choosing the most appropriate treatment at relapse may be difficult. This review sum up the most important studies and provide evidence to choose the most relevant therapeutic strategy for relapse after ASCT, based on disease, patient and previous treatment related parameters.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/therapy , Stem Cell Transplantation/methods , Clinical Trials, Phase III as Topic , Combined Modality Therapy , Humans , Male , Middle Aged , Multiple Myeloma/drug therapy , Precision Medicine/methods , Randomized Controlled Trials as Topic , Transplantation, AutologousABSTRACT
Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life threatening complication that can develop after hematopoietic cell transplantation. Although SOS/VOD progressively resolves within a few weeks in most patients, the most severe forms result in multi-organ dysfunction and are associated with a high mortality rate (>80%). Therefore, careful attention must be paid to allow an early detection of SOS/VOD, particularly as drugs have now proven to be effective and licensed for its treatment. Unfortunately, current criteria lack sensitivity and specificity, making early identification and severity assessment of SOS/VOD difficult. The aim of this work is to propose a new definition for diagnosis, and a severity-grading system for SOS/VOD in adult patients, on behalf of the European Society for Blood and Marrow Transplantation.
Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Hepatic Veno-Occlusive Disease/diagnosis , Adult , Biomarkers , Early Diagnosis , Hepatic Veno-Occlusive Disease/etiology , Hepatic Veno-Occlusive Disease/therapy , Humans , Risk Factors , Sensitivity and Specificity , Severity of Illness IndexABSTRACT
Allogeneic stem cell transplantation (allo-SCT) is a curative therapy for different life-threatening malignant and non-malignant hematologic disorders. Acute graft-vs.-host disease (aGVHD) and particularly gastrointestinal aGVHD remains a major source of morbidity and mortality following allo-SCT, which limits the use of this treatment in a broader spectrum of patients. Better understanding of aGVHD pathophysiology is indispensable to identify new therapeutic targets for aGVHD prevention and therapy. Growing amount of data suggest a role for T helper (Th)17 cells in aGVHD pathophysiology. In this review, we will discuss the current knowledge in this area in animal models and in humans. We will then describe new potential treatments for aGVHD along the Th17 axis.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Gastrointestinal Tract/drug effects , Graft vs Host Disease/prevention & control , Hematologic Diseases/therapy , Hematopoietic Stem Cell Transplantation , Th17 Cells/drug effects , Acute Disease , Animals , Clinical Trials as Topic , Cytokines/antagonists & inhibitors , Cytokines/biosynthesis , Cytokines/immunology , Disease Models, Animal , Gastrointestinal Tract/immunology , Gastrointestinal Tract/pathology , Graft vs Host Disease/immunology , Graft vs Host Disease/pathology , Hematologic Diseases/immunology , Hematologic Diseases/pathology , Humans , Liver/drug effects , Liver/immunology , Liver/pathology , Mice , Molecular Targeted Therapy , Skin/drug effects , Skin/immunology , Skin/pathology , Th17 Cells/immunology , Th17 Cells/pathology , Transplantation, HomologousABSTRACT
Acute graft-versus-host disease (aGVHD) remains a major complication following allogeneic hematopoietic cell transplantation, limiting the success of this therapy. We previously reported that interleukin-22 (IL-22) participates to aGVHD development, but the underlying mechanisms of its contribution remain poorly understood. In this study, we analyzed the mechanism of the pathological function of IL-22 in intestinal aGVHD. Ex-vivo colon culture experiments indicated that IL-22 was able to induce Th1-like inflammation via signal transducer and activator of transcription factor-1 (STAT1) and CXCL10 induction in the presence of type I interferon (IFN). To evaluate a potential synergy between IL-22 and type I IFN in aGVHD, we transplanted recipient mice, either wild-type (WT) or type I IFN receptor deficient (IFNAR(-/-)), with bone marrow cells and WT or IL-22 deficient (IL-22(-/-)) T cells. We observed a decreased GVHD severity in IFNAR(-/-) recipient of IL-22(-/-) T cells, which was associated with a lower level of STAT1 activation and reduced CXCL10 expression in the large intestine. Finally, immunohistochemistry staining of STAT1 performed on gastrointestinal biopsies of 20 transplanted patients showed exacerbated STAT1 activation in gastrointestinal tissues of patients with aGVHD as compared with those without aGVHD. Thus, interfering with both IL-22 and type I IFN signaling may provide a novel approach to limit aGVHD.
Subject(s)
Bone Marrow Transplantation , Chemokine CXCL10/immunology , Graft vs Host Disease/immunology , Interferon Type I/immunology , Interleukins/immunology , Intestine, Large/immunology , STAT1 Transcription Factor/immunology , Animals , Bone Marrow/immunology , Bone Marrow/pathology , Chemokine CXCL10/genetics , Gene Expression Regulation , Graft vs Host Disease/genetics , Graft vs Host Disease/pathology , Hematologic Neoplasms/genetics , Hematologic Neoplasms/immunology , Hematologic Neoplasms/pathology , Hematologic Neoplasms/therapy , Humans , Interferon Type I/genetics , Interleukins/deficiency , Interleukins/genetics , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Intestine, Large/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/immunology , STAT1 Transcription Factor/genetics , Signal Transduction , Th1 Cells/immunology , Th1 Cells/pathology , Tissue Donors , Transplantation, Homologous , Whole-Body Irradiation , Interleukin-22Subject(s)
Carbon Monoxide/metabolism , Hematologic Diseases , Hematopoietic Stem Cell Transplantation , Nitric Oxide/metabolism , Adult , Aged , Allografts , Female , Hematologic Diseases/metabolism , Hematologic Diseases/mortality , Hematologic Diseases/physiopathology , Hematologic Diseases/therapy , Humans , Lung Volume Measurements , Male , Middle AgedABSTRACT
BACKGROUND: Hemorrhagic cystitis (HC) is a common complication after hematopoietic allogeneic stem cell transplantation (HSCT) associated with intensity of the conditioning regimen, cyclophosphamide (Cy) therapy, and BK polyomavirus (BKPyV) infection. METHODS: We analyzed 33 consecutive haploidentical (haplo) HSCT recipients transplanted for hematologic diseases. Eleven patients had a previous transplant. Median follow-up was 11 months. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine + mycophenolate mofetil and post-HSCT Cy. RESULTS: Thirty-two of 33 patients achieved neutrophil recovery. Cumulative incidence (CI) of platelet recovery was 65%. CI grade II-IV acute GVHD was 44%. Twenty patients developed HC in a median time of 38 days. CI of HC at day 180 was 62%. BKPyV was positive in blood and urine of 91% of patients at HC onset. HC resolved in 18/20 patients. Factors associated with HC were previous transplant (P = 0.01) and occurrence of cytomegalovirus reactivation before HC (P = 0.05). Grade II-IV acute GVHD was not associated with HC (P = 0.62). CI of day 180 viral infections was 73%. Two-year overall survival (OS) was 50%; HC did not impact OS (P = 0.29). CONCLUSION: The incidence of HC after haplo with post-HSCT Cy is high and is associated with morbidity, especially in high-risk patients such as those with a previous transplant history and with impaired immune reconstitution.
Subject(s)
Cystitis/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Adolescent , Adult , Aged , Graft vs Host Disease/prevention & control , Haplotypes , Hemorrhage , Humans , Immunosuppressive Agents/pharmacology , Incidence , Middle Aged , Risk Factors , Young AdultSubject(s)
Hematopoietic Stem Cell Transplantation , Receptors, Fc/administration & dosage , Recombinant Fusion Proteins/administration & dosage , Thrombocytopenia/drug therapy , Thrombopoietin/administration & dosage , Adolescent , Adult , Aged , Allografts , Female , Humans , Male , Middle Aged , Recombinant Fusion Proteins/adverse effects , Thrombocytopenia/etiology , Thrombopoietin/adverse effectsABSTRACT
Acute myeloid leukemia (AML) with 11q23/MLL rearrangement (MLL-r AML) is allocated to the intermediate- or high-risk cytogenetic prognostic category depending on the MLL fusion partner. A more favorable outcome has been reported in patients receiving an allogeneic hematopoietic stem-cell transplantation (alloHSCT), but this has not been confirmed in large series. We analyzed the outcome of alloHSCT among adult patients reported to the Acute Leukemia Working Party between 2000 and 2010. We identified 159 patients with 11q23/MLL rearranged AML allografted in first complete remission (CR1, n=138) or CR2, mostly corresponding to t(9;11), t(11;19), t(6;11) and t(10;11) translocations. Two-year overall survival (OS), leukemia-free survival (LFS), relapse incidence and non-relapse mortality were 56±4%, 51±4%, 31±3% and 17±4%, respectively. The outcome differed according to 11q23/MLL rearrangement, being more favorable in patients with t(9;11) and t(11;19) compared with t(10;11) and t(6;11) (2-year OS: 64±6% and 73±10% vs 40±13% and 24±11%, respectively; P<0.0001). Multivariate analysis for OS identified t(6;11), t(10;11), age>40 years and CR2 as unfavorable features, whereas t(6;11), t(10;11), CR2 and the use of reduced-intensity conditioning regimen affected poorly the LFS. This study confirms the potential role of alloHSCT for adult patients with 11q23/MLL rearranged AML in CR1.
Subject(s)
Gene Rearrangement , Hematopoietic Stem Cell Transplantation , Histone-Lysine N-Methyltransferase/genetics , Leukemia, Myeloid, Acute/therapy , Myeloid-Lymphoid Leukemia Protein/genetics , Adult , Aged , Chromosome Aberrations , Chromosomes, Human, Pair 11 , Female , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Recurrence , Retrospective Studies , Transplantation, Homologous , Treatment OutcomeABSTRACT
Sinusoidal obstruction syndrome or veno-occlusive disease (SOS/VOD) is a potentially life-threatening complication of hematopoietic SCT (HSCT). This review aims to highlight, on behalf of the European Society for Blood and Marrow Transplantation, the current knowledge on SOS/VOD pathophysiology, risk factors, diagnosis and treatments. Our perspectives on SOS/VOD are (i) to accurately identify its risk factors; (ii) to define new criteria for its diagnosis; (iii) to search for SOS/VOD biomarkers and (iv) to propose prospective studies evaluating SOS/VOD prevention and treatment in adults and children.
Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Postoperative Complications , Vascular Diseases , Adult , Biomarkers/blood , Humans , Postoperative Complications/blood , Postoperative Complications/diagnosis , Postoperative Complications/physiopathology , Postoperative Complications/therapy , Risk Factors , Vascular Diseases/blood , Vascular Diseases/diagnosis , Vascular Diseases/etiology , Vascular Diseases/physiopathology , Vascular Diseases/therapyABSTRACT
Lung function decline is a well-recognized complication following allogeneic SCT (allo-SCT). Reduced-intensity conditioning (RIC) and in vivo T-cell depletion by administration of antithymocyte globulin (ATG) may have a protective role in the occurrence of late pulmonary complications. This retrospective study reported the evolution of lung function parameters within the first 2 years after allo-SCT in a population receiving the same RIC regimen that included fludarabine and i.v. BU in combination with low-dose ATG. The median follow-up was 35.2 months. With a median age of 59 years at the time of transplant, at 2 years, the cumulative incidences of non-relapse mortality was as low as 9.7%. The cumulative incidence of relapse was 33%. At 2 years, the cumulative incidences of extensive chronic GVHD (cGVHD) and of pulmonary cGVHD were 23.1% and 1.9%, respectively. The cumulative incidences of airflow obstruction and restrictive pattern were 3.8% and 9.6%, respectively. Moreover, forced expiratory volume (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio remained stable from baseline up to 2 years post transplantation (P=0.26, P=0.27 and P=0.07, respectively). These results correspond favorably with the results obtained with other RIC regimens not incorporating ATG, and suggest that ATG may have a protective pulmonary role after allo-SCT.
Subject(s)
Hematologic Diseases/therapy , Lung Diseases/prevention & control , Lymphocyte Depletion/methods , Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Administration, Intravenous , Adult , Aged , Antilymphocyte Serum/administration & dosage , Busulfan/administration & dosage , Female , Follow-Up Studies , Hematologic Diseases/mortality , Humans , Immunosuppressive Agents/administration & dosage , Lung Diseases/etiology , Male , Middle Aged , Myeloablative Agonists/administration & dosage , Respiratory Function Tests , Retrospective Studies , Stem Cell Transplantation/adverse effects , Stem Cell Transplantation/mortality , Transplantation Conditioning/mortality , Transplantation, Homologous , Vidarabine/administration & dosage , Vidarabine/analogs & derivatives , Young AdultABSTRACT
The contribution of Th17 cells to chronic GVHD (cGVHD) has been demonstrated in cGVHD mouse models. However, their contribution to human liver cGVHD remains unclear. We evaluated Th17 cells in biopsies from a cohort of 17 patients with liver cGVHD. We observed a significant increase in Th17 cells in the liver of patients with cGVHD, as demonstrated by an increase in CCR6+, CD161+ and RORγt+ T cells (P=0.03, P=0.0001 and P=0.03, respectively). We also assessed the presence of Th1 and regulatory (Treg) T cells: the numbers of Th1 and Treg cells were very low, with no difference between the two groups (P=0.88 and P=0.12, respectively). Furthermore, Th17/Th1 and Th17/Treg ratios were significantly increased in the liver of patients with liver cGVHD (P=0.005 and P=0.002, respectively). This study provides evidence for an infiltration by Th17 cells in the liver of patients with cGVHD and an increased Th17/Treg ratio, suggesting a defect in the regulatory mechanism driven by Treg cells or an inappropriate activation of effectors cells, especially Th17 cells, or both mechanisms, in human liver cGVHD.
Subject(s)
Graft vs Host Disease/immunology , Liver Diseases/immunology , T-Lymphocytes, Regulatory/pathology , Th17 Cells/pathology , Adult , Aged , Animals , Biopsy , Female , Graft vs Host Disease/pathology , Humans , Liver Diseases/pathology , Male , Mice , Middle Aged , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunologyABSTRACT
This prospective pilot study aimed to evaluate the predictive value of (18)F-FDG PET/CT for early diagnosis of acute gastrointestinal GVHD (GI-GVHD). In all, 42 consecutive patients who received allo-SCT were included. (18)F-FDG PET/CT was systematically performed at a median of 28 (range, 24-38) days after allo-SCT. (18)F-FDG PET/CT data review was positive in 15 cases (36%) (9 true positive (TP) cases and 6 false positive (FP) cases) and negative in 27 cases (64%; 26 true negative (TN) cases and 1 false negative (FN) case) at visual analysis. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of (18)F-FDG PET/CT for the diagnosis of acute GI-GVHD were, respectively, 81%, 90%, 60%, 96% and 83%. There were no significant differences of SUVmax values between grade 1-2 GI-GVHD and severe grade 3-4 GI-GVHD. Overall, these preliminary findings suggested that the inflammatory activity of the gastrointestinal tract associated with acute GI-GVHD could be assessed by (18)F-FDG PET/CT suggesting that noninvasive (18)F-FDG PET/CT could become a valuable examination to be performed shortly before endoscopy to map acute GI-GVHD lesions, guide the biopsy sites and choose the appropriate endoscopic procedure, especially in those asymptomatic patients with a positive (18)F-FDG PET/CT.
Subject(s)
Fluorodeoxyglucose F18 , Gastrointestinal Diseases/diagnostic imaging , Graft vs Host Disease/diagnostic imaging , Hematologic Diseases/therapy , Adult , Aged , False Negative Reactions , False Positive Reactions , Female , Hematologic Diseases/complications , Humans , Male , Middle Aged , Multimodal Imaging , Pilot Projects , Positron-Emission Tomography , Prospective Studies , Radiopharmaceuticals , Reproducibility of Results , Sensitivity and Specificity , Tomography, X-Ray Computed , Transplantation Conditioning , Young AdultABSTRACT
The potentially important role of northern microrefugia during postglacial dispersal is challenging the view of southern Europe as a refuge and source area of European biota. In groundwaters, large geographic ranges of presumably good dispersers are increasingly suspected to consist of assemblages of cryptic species with narrow ranges. Moreover, a large species range, even when confirmed by molecular evidence, tells us little about the spatiotemporal dynamics of dispersal. Here, we used phylogenetic inferences, species delineation methods and Bayesian phylogeographic diffusion models to test for the likelihood of postglacial colonization from distant refugia among five morphospecies of Proasellus (Isopoda, Asellidae). All morphospecies except one were monophyletic, but they comprised a total of 15-17 cryptic species. Three cryptic species retained ranges that spanned a distance >650 km, similar to that of the nominal morphospecies. Bayesian diffusion models based on mitochondrial markers revealed considerable spatiotemporal heterogeneity in dispersal rates, suggesting that short-time dispersal windows were instrumental in shaping species ranges. Only one species was found to experience a recent, presumably postglacial, range expansion. The Jura and Alpine foothills probably played a major role in maintaining diversity within Proasellus in northern regions by acting both as diversification hotspots and Pleistocene refugia. Gaining insight into the spatiotemporal heterogeneity of dispersal rates revealed contrasting colonization dynamics among species that were not consistent with a global postglacial colonization of Europe from distant refugia.