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Zhongguo Shi Yan Xue Ye Xue Za Zhi Dec 2023Graft-versus-host disease (GVHD) is one of the major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which seriously affects the...
Graft-versus-host disease (GVHD) is one of the major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which seriously affects the prognosis of patients. At present, a new regimen of post-transplantation cyclophosphamide (PTCy) combined with antithymocyte globulin (ATG) has been used to prevent GVHD, indicating that PTCy combined with ATG may have a good effect on the prevention of GVHD in different types of transplantation. However, the mechanism of this regimen, its effect on immune reconstitution and viral reactivation still needs to be further studied. Therefore, this article briefly reviews the research progress of PTCy combined with ATG in preventing GVHD after HSCT.
Topics: Humans; Antilymphocyte Serum; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Transplantation, Homologous; Retrospective Studies
PubMed: 38071080
DOI: 10.19746/j.cnki.issn.1009-2137.2023.06.047 -
Hematology. American Society of... Dec 2023Chimeric antigen receptor T-cell therapy and bispecific T-cell recruiting antibodies have transformed the treatment landscape for relapsed/refractory multiple myeloma,... (Review)
Review
Chimeric antigen receptor T-cell therapy and bispecific T-cell recruiting antibodies have transformed the treatment landscape for relapsed/refractory multiple myeloma, with B-cell maturation antigen being the most common target and other targets in clinical development. However, these therapies are associated with unique and severe toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), delayed neurotoxicity, cytopenias, and infection. In addition, immune effector cell-associated hemophagocytic lymphohistiocytosis (HLH)-like syndrome (IEC-HS), which exhibits overlap between CRS and HLH, can be challenging to diagnose and treat. In this review, we provide an overview of toxicities associated with novel immunotherapies for treatment of multiple myeloma and describe management recommendations. The pathophysiology and risk factors behind these toxicities are not yet comprehensively understood. Based on consensus recommendations, treatment for CRS consists of tocilizumab and steroids, while treatment for ICANS includes steroids and anakinra in severe cases. Management of cytopenias and infection is similar to post-hematopoietic cell transplantation principles with antimicrobial prophylaxis, growth factor support, immunoglobulin replacement, and vaccinations. In contrast, effective treatments for delayed neurotoxicity and IEC-HS are lacking, although steroids and anakinra are commonly used. Management of all these toxicities should include a broad differential and multidisciplinary collaboration with infectious diseases, neurology, and/or critical care providers.
Topics: Humans; Multiple Myeloma; Interleukin 1 Receptor Antagonist Protein; Immunotherapy; Immunotherapy, Adoptive; Antilymphocyte Serum; Cytokine Release Syndrome; Cytopenia; Lymphohistiocytosis, Hemophagocytic; Steroids
PubMed: 38066898
DOI: 10.1182/hematology.2023000435 -
Acta Biomaterialia Jan 2024There is currently no specific and effective treatment for bacteremia-mediated sepsis. Hence, this study engineered a combinatorial nanosystem containing...
There is currently no specific and effective treatment for bacteremia-mediated sepsis. Hence, this study engineered a combinatorial nanosystem containing neutrophil-targeted roflumilast-loaded nanocarriers and non-targeted fusidic acid-loaded nanoparticles to enable the dual mitigation of bacteremia-associated inflammation and methicillin-resistant Staphylococcus aureus (MRSA) infection. The targeted nanoparticles were developed by conjugating anti-lymphocyte antigen 6 complex locus G6D (Ly6G) antibody fragment on the nanoparticulate surface. The particle size and zeta potential of the as-prepared nanosystem were about 200 nm and -25 mV, respectively. The antibody-conjugated nanoparticles showed a three-fold increase in neutrophil internalization compared to the unfunctionalized nanoparticles. As a selective phosphodiesterase (PDE) 4 inhibitor, the roflumilast in the nanocarriers largely inhibited cytokine/chemokine release from the activated neutrophils. The fusidic acid-loaded nanocarriers were vital to eliminate biofilm MRSA colony by 3 log units. The nanoparticles drastically decreased the intracellular bacterial count compared to the free antibiotic. The in vivo mouse bioimaging demonstrated prolonged retention of the nanosystem in the circulation with limited organ distribution and liver metabolism. In the mouse bacteremia model, the multifunctional nanosystem produced a 1‒2 log reduction of MRSA burden in peripheral organs and blood. The functionalized nanosystem arrested the cytokine/chemokine overexpression greater than the unfunctionalized nanocarriers and free drugs. The combinatory nanosystem also extended the median survival time from 50 to 103 h. No toxicity from the nanoformulation was found based on histology and serum biochemistry. Furthermore, our data proved that the active neutrophil targeting by the versatile nanosystem efficiently alleviated MRSA infection and organ dysfunction caused by bacteremia. STATEMENT OF SIGNIFICANCE: Bacteremia-mediated sepsis poses a significant challenge in clinical practice, as there is currently no specific and effective treatment available. In our study, we have developed a novel combinatorial nanosystem to address this issue. Our nanosystem consists of neutrophil-targeted roflumilast-loaded nanocarriers and non-targeted fusidic acid-loaded nanoparticles, enabling the simultaneous mitigation of bacteremia-associated inflammation and MRSA infection. Our nanosystem demonstrated the decreased neutrophil activation, effective inhibition of cytokine release, elimination of MRSA biofilm colonies, and reduced intracellular bacterial counts. In vivo experiments showed prolonged circulation, limited organ distribution, and increased survival rates in a mouse bacteremia model. Importantly, our nanosystem exhibited no toxicity based on comprehensive assessments.
Topics: Mice; Animals; Methicillin-Resistant Staphylococcus aureus; Neutrophils; Fusidic Acid; Staphylococcal Infections; Survival Rate; Anti-Bacterial Agents; Bacteremia; Disease Models, Animal; Cytokines; Chemokines
PubMed: 38061677
DOI: 10.1016/j.actbio.2023.11.040 -
Blood Jan 2024B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells are the most potent treatment against multiple myeloma (MM). Here, we review the increasing body... (Review)
Review
B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells are the most potent treatment against multiple myeloma (MM). Here, we review the increasing body of clinical and correlative preclinical data that support their inclusion into firstline therapy and sequencing before T-cell-engaging antibodies. The ambition to cure MM with (BCMA-)CAR T cells is informed by genomic and phenotypic analysis that assess BCMA expression for patient stratification and monitoring, steadily improving early diagnosis and management of side effects, and advances in rapid, scalable CAR T-cell manufacturing to improve access.
Topics: Humans; Immunotherapy, Adoptive; Multiple Myeloma; Receptors, Chimeric Antigen; B-Cell Maturation Antigen; Antilymphocyte Serum
PubMed: 38033289
DOI: 10.1182/blood.2023021221 -
Clinical Case Reports Nov 2023This report describes a rare case of developing Guillain-Barre syndrome (GBS) following receiving rabbit antithymocyte globulin (ATG) after kidney transplantation to...
This report describes a rare case of developing Guillain-Barre syndrome (GBS) following receiving rabbit antithymocyte globulin (ATG) after kidney transplantation to prevent acute allograft rejection in a 34-year-old man. The patient presented severe pain in the right temporomandibular joint, fever, chills, myalgia, polyarthralgia, and bone pain. Twelve hours later, he developed quadriplegia, paresthesia, and a limited range of active motions in all extremities. No antecedent viral or bacterial infection was identified. The EMG/NCV evaluation displayed acute inflammatory sensory-motor polyneuropathy. After the administration of GBS treatment, the neurologic symptoms started to improve. Over a few days, the reflexes came back completely, and the patient was able to walk. To our knowledge, this is the second case report of ATG-related GBS after kidney transplantation.
PubMed: 38028101
DOI: 10.1002/ccr3.8184 -
British Journal of Haematology Jan 2024To compare the clinical efficacy of porcine anti-lymphocyte globulin (p-ALG) and rabbit anti-thymocyte globulin (r-ATG) in the treatment of haematological malignancies...
Effectiveness of in vivo T-cell-depleted regimen containing porcine anti-lymphocyte globulin or rabbit anti-thymocyte globulin in preventing acute graft-versus-host disease after haploidentical haematopoietic stem cell transplantation.
To compare the clinical efficacy of porcine anti-lymphocyte globulin (p-ALG) and rabbit anti-thymocyte globulin (r-ATG) in the treatment of haematological malignancies using haploidentical haematopoietic stem cell transplantation (haplo-HSCT), this study was conducted. The incidences of neutrophil and platelet engraftment, respectively, were 100%, 93.6% and 94.4%; 100%, 93.6% and 90.3% in p-ALG 75 mg/kg (n = 57), p-ALG 90 mg/kg (n = 49), and r-ATG 7.5 mg/kg (n = 72). The median time to neutrophil engraftment and platelet engraftment were 11, 12 and 12 days (p = 0.032); 13, 14 and 13 days (p = 0.013), respectively. The incidence of grades II-IV acute graft-versus-host disease and cumulative incidence of chronic graft-versus-host disease were 16.7% versus 12.5% versus 13.3% (p = 0.817) and 14.7% versus 12.1% versus 19.5% in p-ALG 75 mg/kg, p-ALG 90 mg/kg and r-ATG groups. Notably, the cytomegalovirus infection rate in the p-ALG 75 mg/kg group was significantly lower than the other two groups. The cumulative incidence of 2-year relapse and 2-year overall survival rates were similar (p = 0.901, p = 0.497). The lower dose of p-ALG (75 mg/kg) had a similar efficacy and safety profile compared with r-ATG (7.5 mg/kg) in the setting of haplo-HSCT. Therefore, p-ALG (75 mg/kg) may be an appropriate alternative to r-ATG in the conditioning regimen of haplo-HSCT.
Topics: Animals; Swine; Antilymphocyte Serum; T-Lymphocytes; Neoplasm Recurrence, Local; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Transplantation Conditioning; Retrospective Studies
PubMed: 37984846
DOI: 10.1111/bjh.19205 -
Frontiers in Immunology 2023The novel low-dose anti-thymocyte (ATG, 5 mg/kg) plus low-dose post-transplant cyclophosphamide (PTCy, 50 mg/kg) (low-dose ATG/PTCy)-based regimen had promising activity...
Low-dose anti-thymocyte globulin plus low-dose post-transplant cyclophosphamide-based regimen for prevention of graft-versus-host disease after haploidentical peripheral blood stem cell transplants: a large sample, long-term follow-up retrospective study.
INTRODUCTION
The novel low-dose anti-thymocyte (ATG, 5 mg/kg) plus low-dose post-transplant cyclophosphamide (PTCy, 50 mg/kg) (low-dose ATG/PTCy)-based regimen had promising activity for prevention of graft-versus-host disease (GVHD) in haploidentical-peripheral blood stem cell transplantation (haplo-PBSCT), but its impacts on long-term outcomes remain to be defined.
METHODS
We performed a large sample, long-term follow-up retrospective study to evaluate its efficacy for GVHD prophylaxis.
RESULTS
The study enrolled 260 patients, including 162 with myeloid malignancies and 98 with lymphoid malignancies. The median follow-up time was 27.0 months. For the entire cohort, the cumulative incidences (CIs) of grade II-IV and III-IV acute GVHD (aGVHD) by 180 days were 13.46% (95% CI, 9.64%-17.92%) and 5.77% (95% CI, 3.37%-9.07%); while total and moderate/severe chronic GVHD (cGVHD) by 2 years were 30.97% (95% CI, 25.43%-36.66%) and 18.08% (95% CI, 13.68%-22.98%), respectively. The 2-year overall survival (OS), relapse-free survival (RFS), GVHD-free, relapse-free survival (GRFS), non-relapse mortality (NRM), and CIs of relapse were 60.7% (95% CI, 54.8%-67.10%), 58.1% (95% CI, 52.2%-64.5%), 50.6% (95% CI, 44.8-57.1%), 23.04% (95% CI, 18.06%-28.40%), and 18.09% (95% CI, 14.33%-23.97%, respectively. The 1-year CIs of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation were 43.46% (95% CI, 37.39%-49.37%) and 18.08% (95% CI, 13.68%-22.98%), respectively. In multivariate analysis, the disease status at transplantation was associated with inferior survivor outcomes for all patients and myeloid and lymphoid malignancies, while cGVHD had superior outcomes for all patients and myeloid malignancies, but not for lymphoid malignancies.
DISCUSSION
The results demonstrated that the novel regimen could effectively prevent the occurrence of aGVHD in haplo-PBSCT.
Topics: Humans; Antilymphocyte Serum; Peripheral Blood Stem Cell Transplantation; Follow-Up Studies; Retrospective Studies; Hematopoietic Stem Cell Transplantation; Epstein-Barr Virus Infections; Peripheral Blood Stem Cells; Herpesvirus 4, Human; Cyclophosphamide; Graft vs Host Disease; Neoplasms
PubMed: 37954615
DOI: 10.3389/fimmu.2023.1252879 -
European Journal of Haematology Mar 2024Pneumocystis jirovecii pneumonia (PJP) is a rare complication of hematopoietic stem cell transplantation (HSCT). Primary prophylaxis for 6-12 months post-HSCT is the...
INTRODUCTION
Pneumocystis jirovecii pneumonia (PJP) is a rare complication of hematopoietic stem cell transplantation (HSCT). Primary prophylaxis for 6-12 months post-HSCT is the standard approach. However, there is no consensus regarding the optimal duration of prophylaxis.
METHODS
We identified patients who developed PJP more than 1-year post-HSCT. All patients had previously received 12 months of PJP prophylaxis. PJP was diagnosed based on clinical findings and the detection of P. jirovecii in bronchoalveolar lavage (BAL) using polymerase chain reaction (PCR). The CD4 T-cell percentage was determined using flow cytometry. Data expressed as median (interquartile range).
RESULTS
Ten patients developed PJP at 17.5 months (16-24 months) post-HSCT. PJP diagnosis occurred 5.5 months (3-15 months) after discontinuing prophylaxis. Eight patients received anti-thymocyte globulin (ATG) as graft versus host disease (GVHD) prophylaxis. At diagnosis, only one patient had lymphopenia; all patients had CD4 T-lymphocyte counts ≥0.2 × 10 /L (median 0.337 × 10 /L). Three patients had concomitant bacterial infections. The clinical presentation was mild; only three required hospitalization, none of them required intensive care and there were no deaths.
CONCLUSION
There is a need to develop risk-adapted prophylactic strategies in the contemporary era using ATG-based GVHD prophylaxis.
Topics: Humans; Pneumonia, Pneumocystis; Pneumocystis carinii; Antilymphocyte Serum; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Retrospective Studies
PubMed: 37947314
DOI: 10.1111/ejh.14133 -
Pediatric Transplantation Feb 2024The study purpose was to add to limited literature assessing anti-HLA donor-specific antibody (DSA) appearance, clearance, specificity, and impact in...
BACKGROUND
The study purpose was to add to limited literature assessing anti-HLA donor-specific antibody (DSA) appearance, clearance, specificity, and impact in intestinal/multivisceral (MV) transplant as well as the value of serial monitoring following an institutional protocol shift implementing serial monitoring.
METHODS
This single-center retrospective review included intestinal/MV recipients transplanted 1/1/15-9/31/17 with completed DSA testing. Patients were divided into groups based on DSA presence post-transplant. The primary outcome was biopsy-proven acute rejection (BPAR). Secondary outcomes included graft loss and death. Descriptive analysis of DSA was completed.
RESULTS
Of the 35 intestinal/MV recipients (60% pediatric) with DSA testing, 24 patients had post-transplant DSA. Fifteen patients in the DSA(+) group had T-cell-mediated BPAR versus five in the DSA(-) group (63% vs 45%, p = .47). Days to BPAR were 25 [IQR 19-165] (DSA(+) group) versus 232 [IQR 25.5-632.5] (DSA(-) group) (p = .066). There were no differences between groups for graft loss or death. One hundred and five DSA were identified in the DSA(+) group with 63% being class II, and 54% cleared during follow-up. DSA were directed against 50 different HLA alleles, with the most common being directed against HLA- DQ (35%). Time to first DSA and to clearance did not differ between class I and II.
CONCLUSION
Findings confirm previous data that suggest post-transplant DSA in this population may lead to increased BPAR or shorter time to BPAR, although not statistically significant. Most DSA were identified within the first month after transplant, and ahead of rejection identification on biopsy. DSA therefore may have utility as an early rejection biomarker and use may be considered in place of early protocol biopsies, particularly in pediatric patients. We identified novel findings of DSA directed against a large breadth of HLA in intestinal/MV patients.
Topics: Adult; Humans; Child; Transplant Recipients; HLA Antigens; Kidney Transplantation; Antibodies; Tissue Donors; Retrospective Studies; Antilymphocyte Serum; Graft Rejection; Graft Survival; Isoantibodies
PubMed: 37942670
DOI: 10.1111/petr.14638 -
Journal of Oncology Pharmacy Practice :... Mar 2024Alpha-gal syndrome (AGS) is a hypersensitivity disorder in which tick bites-most commonly from the lone star tick ()-trigger immunoglobulin E-mediated hypersensitivity...
INTRODUCTION
Alpha-gal syndrome (AGS) is a hypersensitivity disorder in which tick bites-most commonly from the lone star tick ()-trigger immunoglobulin E-mediated hypersensitivity reaction upon exposure to oligosaccharide galactosse-alpha-1,3-galactose (α-gal). α-gal is most notorious for being found in "red meat" products but is present in mammalian meats such as beef, pork, lamb, rabbit, and others. Manifestations of AGS hypersensitivity are variable. There is currently no data describing allergic reactions against rabbit products in patients with AGS.
CASE REPORT
Here, we describe a case of a 44-year-old male with myelodysplastic syndrome and a known history of AGS undergoing allogeneic hematopoietic cell transplantation (allo-HSCT) with the use of rabbit antithymocyte globulin (rATG) for graft-versus-host disease (GVHD) prophylaxis.
MANAGEMENT AND OUTCOME
The risk of cross-reactivity against rATG in our patient with AGS could not be ruled out and, therefore, a test dose was administered. The patient tolerated the test dose with no signs of anaphylaxis. After demonstrating tolerance to the test dose, rATG was utilized for GVHD prophylaxis.
DISCUSSION
Due to the heterogeneity of AGS manifestations in patients, the use of rATG in patients with known AGS should be considered on a case-by-case basis. The administration of a test dose may help predict the occurrence of severe hypersensitivity reactions. The limited data surrounding the risk of AGS with rabbit-containing products and the various indications for the use of rATG warrants more in-depth study of the reactivity of this medication in this population.
Topics: Adult; Animals; Humans; Male; Antilymphocyte Serum; Food Hypersensitivity; Galactose; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Mammals; Rabbits
PubMed: 37936368
DOI: 10.1177/10781552231212648