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Transplantation Sep 2019Limited published data exist to guide the treatment of pancreas transplant rejection.
BACKGROUND
Limited published data exist to guide the treatment of pancreas transplant rejection.
METHODS
We reviewed the treatment and outcomes of 158 first episodes of biopsy-proven pancreas rejection between 1 January 1997 and 31 December 2016. Within each Banff grade of rejection, we compared response rates and long-term outcomes with steroids alone versus steroids plus antithymocyte globulin (ATG).
RESULTS
Of 158 pancreas recipients with rejection, 65 were treated with steroids alone. Eighty-three percent of patients with grade I, 60% with grade II, and 33.33% with grade III rejection responded to treatment with steroids alone. Ninety-three patients were treated with steroids plus ATG. The response rates were 69% in grade I, 76% in grade II, and 73% in grade III. Response rates and graft survival were not different with grade I rejection treated with steroids alone versus steroids plus ATG. However, response rates and graft survival were significantly better with grade III rejection treated with the addition of ATG, and graft survival rates were significantly better with grade II rejection treated with the addition of ATG.
CONCLUSIONS
Grade I pancreas rejection can usually be successfully treated with steroids alone, whereas grade II and III rejection should usually be treated with steroids plus ATG, as the addition of ATG improves both response rates and graft survival.
Topics: Adult; Antilymphocyte Serum; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunocompromised Host; Immunosuppressive Agents; Male; Middle Aged; Opportunistic Infections; Pancreas Transplantation; Plasma Exchange; Risk Factors; Severity of Illness Index; Steroids; Time Factors; Treatment Outcome
PubMed: 31233481
DOI: 10.1097/TP.0000000000002694 -
Clinical Transplantation Nov 2022We provide a contemporary consideration of long-term outcomes and trends of induction therapy use following lung transplantation in the United States. (Review)
Review
OBJECTIVES
We provide a contemporary consideration of long-term outcomes and trends of induction therapy use following lung transplantation in the United States.
METHODS
We reviewed the United Network for Organ Sharing registry from 2006 to 2018 for first-time, adult, lung-only transplant recipients. Long-term survival was compared between induction classes (Interleukin-2 inhibitors, monoclonal or polyclonal cell-depleting agents, and no induction therapy). A 1:1 propensity score match was performed, pairing patients who received basiliximab with similar risk recipients who did not receive induction therapy. Outcomes in matched populations were compared using Cox, Kaplan-Meier and Logistic regression modeling.
MEASUREMENTS AND MAIN RESULTS
22 025 recipients were identified; 8003 (36.34%) were treated with no induction therapy, 11 045 (50.15%) with basiliximab, 1556 (7.06%) with alemtuzumab and 1421 (6.45%) with anti-thymocyte globulin. Compared with those who received no induction, patients receiving basiliximab, alemtuzumab or anti-thymocyte globulin were found on multivariable Cox-regression analyses to have lower long-term mortality (all p < .05). Following propensity score matching of basiliximab and no induction populations, analyses demonstrated a statistically significant association between basiliximab use and long- term survival (p < .001). Basiliximab was also associated with a lower risk of acute rejection (p < .001) and renal failure (p = .002).
CONCLUSION
Induction therapy for lung transplant recipients-specifically basiliximab-is associated with improved long-term survival and a lower risk of renal failure or acute rejection.
Topics: Adult; Humans; Antilymphocyte Serum; Immunosuppressive Agents; Graft Rejection; Antibodies, Monoclonal; Basiliximab; Lung Transplantation; Alemtuzumab; Renal Insufficiency; Recombinant Fusion Proteins
PubMed: 35848518
DOI: 10.1111/ctr.14782 -
Transplantation Proceedings May 2022Alloantibodies are significant biomarkers of posttransplant kidney rejection. With solid-phase assays, the presence of alloantibodies and complement-binding capacities...
Alloantibodies are significant biomarkers of posttransplant kidney rejection. With solid-phase assays, the presence of alloantibodies and complement-binding capacities can be tested. It has been noted that complement-binding anti-HLA (C1q) correlates well with high titers of anti-HLA antibodies (single antigen bead, SAB), but we have recently shown that lower SAB titers may be associated with complement in the complement cytotoxicity test. If so, low titers of donor-specific antibodies could be stratified for complement binding and used for better donor-recipient matching. To study this, we tested 268 patients awaiting kidney transplantation for SAB and C1q and stratified them into positive (Allo+) and negative (Allo-) cohorts. Next, all assayed specificities of SAB were matched with the corresponding C1q in order to correlate mean fluorescence intensity levels. We found a strong correlation between SAB and C1q for all HLA loci apart from HLA-DP. Moreover, there was no strict cutoff for C1q prediction on SAB mean fluorescence intensity level. In addition, an unusual laboratory phenotype was found; that is, a positive C1q result without corresponding SAB specificity. We tested this phenomenon and found positive IgM SAB. CONCLUSIONS: Simultaneous C1q and SAB testing may serve as a tool for in-depth analysis of alloantibodies before transplantation.
Topics: Antilymphocyte Serum; Complement C1q; Graft Rejection; HLA Antigens; Humans; Immunoglobulin G; Isoantibodies; Kidney Transplantation; Tissue Donors
PubMed: 35534279
DOI: 10.1016/j.transproceed.2022.02.054 -
Bone Marrow Transplantation Nov 2023Post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophylaxis, but it may cause dose-dependent toxicities, particularly in frail...
Post-transplant cyclophosphamide (PT-Cy) is effective for graft-versus-host disease (GVHD) prophylaxis, but it may cause dose-dependent toxicities, particularly in frail patients. Therefore, we compared the outcomes with a reduced PT-Cy total dose (70 mg/kg) to those with the standard PT-Cy dose (100 mg/kg) in haploidentical hematopoietic cell transplantation (HCT) patients aged ≥ 65 years and those with cardiac comorbidities. All consecutive patients with a hematological malignancy receiving peripheral blood stem cells (PBSCs) after a thiotepa-based conditioning with low-dose antithymocyte globulin were included. Thirty-three patients received PT-Cy at 70 mg/kg and 25 at 100 mg/kg. PT-Cy dose reduction did not increase the risk of GVHD and was associated with faster neutrophil and platelet recovery, and lower cumulative incidences of bacteremia (38% versus 72%, p = 0.004) and cardiac complications (12% versus 44%, p = 0.028). At 2 years, GVHD-free, relapse-free survival (GRFS) was higher with the reduced dose compared to the standard dose (60% versus 33%, p = 0.04). In conclusion, reducing PT-Cy total dose to 70 mg/kg is a safe and valid approach for elderly patients and those with cardiac comorbidities underdoing haploidentical HCT with PBSCs and low-dose antithymocyte globulin. The reduced PT-Cy dose was associated with improved hematological count recovery, lower incidence of toxicities, and higher GRFS.
Topics: Aged; Humans; Antilymphocyte Serum; Peripheral Blood Stem Cells; Transplantation, Haploidentical; Neoplasm Recurrence, Local; Cyclophosphamide; Peripheral Blood Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Transplantation Conditioning; Retrospective Studies
PubMed: 37596473
DOI: 10.1038/s41409-023-02085-2 -
Transplantation and Cellular Therapy May 2022The implementation of dual T-cell depletion comprising 4.5 mg/kg of antithymocyte globulin (ATG), post-transplantation cyclophosphamide, and cyclosporine A for...
The implementation of dual T-cell depletion comprising 4.5 mg/kg of antithymocyte globulin (ATG), post-transplantation cyclophosphamide, and cyclosporine A for reduced-intensity allogeneic hematopoietic cell transplantation (HCT) independent of donor source in 2015 significantly improved graft-versus-host disease (GVHD) control at our Institution. Further advances were made between 2017 to 2020 in supportive care of allogeneic HCT recipients and were the subject of this study, with 651 adults included. Transplant outcomes were compared between patients who underwent transplantation during Period 1 (2017-2018) and Period 2 (2019-2020). Main changes implemented during the study period were reduction of ATG dose from 4.5 to 2 mg/kg in matched unrelated donor transplants, abandoning of dual T-cell depletion in matched related donor transplants, combining dual T-cell depletion with myeloablative conditioning for selected patients, and reduction of the target therapeutic cyclosporine level from 200 to 400 ng/L to 150 to 250 ng/L. Other improvements included addition of ursodiol until day 100, implementation of a double responsible physician model, and personalized patient supportive care plan focused on activity and calorie intake. The reduction in intensity of GVHD prophylaxis provided comparable acute GVHD and moderate-severe chronic GVHD between both time periods. Altogether the described improvements in transplant methodology and supportive care showed that compared to Period 1, patients transplanted in Period 2 had superior 1-year overall survival, relapse-free survival, and non-relapse mortality and showed a trend toward better GVHD- and relapse-free survival, without an increase in relapse risk. This study reports the results of outcomes-directed improvements in transplantation design, GVHD prophylaxis, and supportive care, highlighting how transplantation outcomes can be improved through careful modifications in response to meticulously monitored outcomes.
Topics: Adult; Antilymphocyte Serum; Cyclosporine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Transplantation Conditioning; Transplantation, Homologous
PubMed: 35139398
DOI: 10.1016/j.jtct.2022.02.001 -
Blood Advances Feb 2022Traditional weight-based dosing results in variable rabbit antithymocyte globulin (rATG) clearance that can delay CD4+ T-cell immune reconstitution (CD4+ IR) leading to...
Traditional weight-based dosing results in variable rabbit antithymocyte globulin (rATG) clearance that can delay CD4+ T-cell immune reconstitution (CD4+ IR) leading to higher mortality. In a retrospective pharmacokinetic/pharmacodynamic (PK/PD) analysis of patients undergoing their first CD34+ T-cell-depleted (TCD) allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area under the curve (arbitrary unit per day/milliliter [AU × day/mL]) using a validated population PK model. We related rATG exposure to nonrelapse mortality (NRM), CD4+ IR (CD4+ ≥50 cells per µL at 2 consecutive measures within 100 days after HCT), overall survival, relapse, and acute graft-versus-host disease (aGVHD) to define an optimal rATG exposure. We used Cox proportional hazard models and multistate competing risk models for analysis. In all, 554 patients were included (age range, 0.1-73 years). Median post-HCT rATG exposure was 47 AU × day/mL (range, 0-101 AU × day/mL). Low post-HCT area under the curve (<30 AU × day/mL) was associated with lower risk of NRM (P < .01) and higher probability of achieving CD4+ IR (P < .001). Patients who attained CD4+ IR had a sevenfold lower 5-year NRM (P < .0001). The probability of achieving CD4+ IR was 2.5-fold higher in the <30 AU × day/mL group compared with 30-55 AU × day/mL and threefold higher in the <30 AU × day/mL group compared with the ≥55 AU × day/mL group. In multivariable analyses, post-HCT rATG exposure ≥55 AU × day/mL was associated with an increased risk of NRM (hazard ratio, 3.42; 95% confidence interval, 1.26-9.30). In the malignancy subgroup (n = 515), a tenfold increased NRM was observed in the ≥55 AU × day/mL group, and a sevenfold increased NRM was observed in the 30-55 AU × day/mL group compared with the <30 AU × day/mL group. Post-HCT rATG exposure ≥55 AU × day/mL was associated with higher risk of a GVHD (hazard ratio, 2.28; 95% confidence interval, 1.01-5.16). High post-HCT rATG exposure is associated with higher NRM secondary to poor CD4+ IR after TCD HCT. Using personalized PK-directed rATG dosing to achieve optimal exposure may improve survival after HCT.
Topics: Antigens, CD34; Antilymphocyte Serum; Hematopoietic Stem Cell Transplantation; Humans; Neoplasm Recurrence, Local; Retrospective Studies; T-Lymphocytes
PubMed: 34788361
DOI: 10.1182/bloodadvances.2021005584 -
International Journal of Hematology Sep 2020Recently, several studies have been conducted to generate considerable evidence regarding unique treatments for severe aplastic anemia (SAA) in China. Haploidentical... (Review)
Review
Recently, several studies have been conducted to generate considerable evidence regarding unique treatments for severe aplastic anemia (SAA) in China. Haploidentical donor hematopoietic stem cell transplantation (HID-HSCT) showed an overall survival rate (80.3-86.1%) comparable to those with immunosuppressive therapy (IST) and matched related donor (MRD)- and matched unrelated donor (MUD)-HSCT. Failure-free survival of HID-HSCT was also comparable (76.4-85.0%) to those of MRD- and MUD-HSCT and better than IST in patients < 40 years. Although these results are promising, HID-HSCT should be regarded as a salvage therapy when young patients fail to respond to IST. Porcine anti-human lymphocyte immunoglobulin (pALG) showed similar or superior overall response at 6 months compared to rabbit anti-human thymocyte immunoglobulin (rATG) (64.0-79.4% in the pALG-group vs.48.1-64.7% in the rATG-group) as a first-line IST. Promising hematological response (28.4-33.3%) was observed in patients with refractory AA following infusion of the mesenchymal stromal cells (MSCs) derived from the bone marrow of allogeneic donors. pALG can replace rATG as an immunosuppressive drug and MSCs infusion can be used as a second-line treatment for refractory SAA. We believe that this review contributes to refine the global practices for SAA treatment.
Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Animals; Antilymphocyte Serum; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Mesenchymal Stem Cell Transplantation; Middle Aged; Prognosis; Salvage Therapy; Severity of Illness Index; Survival Rate; Swine; Transplantation, Haploidentical; Unrelated Donors; Young Adult
PubMed: 32748215
DOI: 10.1007/s12185-020-02955-1 -
Diabetes Care Feb 2024Low-dose antithymocyte globulin (ATG) (2.5 mg/kg) preserves C-peptide and reduces HbA1c in new-onset stage 3 type 1 diabetes, yet efficacy in delaying progression from...
OBJECTIVE
Low-dose antithymocyte globulin (ATG) (2.5 mg/kg) preserves C-peptide and reduces HbA1c in new-onset stage 3 type 1 diabetes, yet efficacy in delaying progression from stage 2 to stage 3 has not been evaluated.
RESEARCH DESIGN AND METHODS
Children (n = 6) aged 5-14 years with stage 2 type 1 diabetes received off-label, low-dose ATG. HbA1c, C-peptide, continuous glucose monitoring, insulin requirements, and side effects were followed for 18-48 months.
RESULTS
Three subjects (50%) remained diabetes free after 1.5, 3, and 4 years of follow-up, while three developed stage 3 within 1-2 months after therapy. Eighteen months posttreatment, even disease progressors demonstrated near-normal HbA1c (5.1% [32 mmol/mol], 5.6% [38 mmol/mol], and 5.3% [34 mmol/mol]), time in range (93%, 88%, and 98%), low insulin requirements (0.17, 0.18, and 0.34 units/kg/day), and robust C-peptide 90 min after mixed meal (1.3 ng/dL, 2.3 ng/dL, and 1.4 ng/dL).
CONCLUSIONS
These observations support additional prospective studies evaluating ATG in stage 2 type 1 diabetes.
Topics: Child; Humans; Antilymphocyte Serum; Blood Glucose; Blood Glucose Self-Monitoring; C-Peptide; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Hypoglycemic Agents; Insulin; Prospective Studies
PubMed: 38117469
DOI: 10.2337/dc23-1750 -
[Rinsho Ketsueki] the Japanese Journal... 2020Graft-versus-host disease (GVHD) is one of the most important complications after an allogeneic hematopoietic stem cell transplantation (allo-SCT). The current National...
Graft-versus-host disease (GVHD) is one of the most important complications after an allogeneic hematopoietic stem cell transplantation (allo-SCT). The current National Institutes of Health's (NIH) consensus is that clinical manifestations, and not the time to symptomatic onset after transplantation, determine whether the clinical syndrome of GVHD is considered acute or chronic. In the past decade, peripheral blood stem cell transplantation from an unrelated donor can be performed in Japan. Furthermore, poor-risk patients without human leukocyte antigen (HLA)-matched donor can receive allo-SCT from HLA haploidentical donor. Therefore, severe or steroid-refractory GVHD would be increased. Corticosteroid, at a dose of 2 mg/kg, is a standard first-line therapy for acute GVHD. If there is no improvement after the first-line therapy, second-line therapy should be administered immediately. Although anti-thymocyte globulin and mesenchymal stem cells are covered by health insurance in Japan, another treatment options should be determined for steroid-refractory acute GVHD. Furthermore, severe chronic GVHD increases patients' mortality and decreases their quality of life. A number of novel drugs targeting specific biological pathways for GVHD are under development. Currently, more than 60 clinical trials are carried out for the treatment of steroid-refractory GVHD worldwide for drug approval. The accumulation of novel evidence for GVHD treatment is expected to be established.
Topics: Antilymphocyte Serum; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Japan; Quality of Life; Transplantation Conditioning
PubMed: 33162541
DOI: 10.11406/rinketsu.61.1395 -
Plastic and Reconstructive Surgery Jun 2023Although vascularized composite allotransplantation (VCA) has been the focus of many animal studies, further research is needed to determine the potential for a...
BACKGROUND
Although vascularized composite allotransplantation (VCA) has been the focus of many animal studies, further research is needed to determine the potential for a generalized model and immunosuppression regimen that applies across different donor-recipient combinations. In this study, the authors evaluated the outcome of VCAs performed on reciprocal rodent donor-recipient combinations.
METHODS
VCA was performed in rats using Lewis and Brown Norway (BN) donor-recipient pairs, under the previously reported antilymphocyte serum/cyclosporine/adipose-derived stem cell regimen. Similarly, a published co-stimulatory blockade/rapamycin regimen was performed on the mouse VCA model between Balb/C and C57BL/6 strains.
RESULTS
To accommodate the active behaviors of BN recipients, the allograft had to be modified and inset to the neck instead of to the groin. The tolerogenic regimen did not provide the same benefits for BN rats as it did for Lewis recipients. Increasing antilymphocyte serum dose and extending the duration of cyclosporine administration from 10 to 21 days significantly prolonged allograft survival and induced donor-specific tolerance. In mice, the co-stimulatory blockade/rapamycin regimen produced inferior VCA outcomes in BALB/c recipients than in C57BL/6 recipients. In both rats and mice, the authors identified an association between the tolerance outcome and the peripheral chimerism measured on postoperative day 30.
CONCLUSIONS
Reciprocal donor-recipient combinations led to different responses toward the immunosuppression regimen and varied VCA outcomes. Sustained donor chimerism that remained in circulation for 1 month after surgery supported long-term VCA survival. Modification of the model and immunosuppression regimen accordingly is recommended.
CLINICAL RELEVANCE STATEMENT
Various donor-recipient combinations respond differently to the immunosuppression regimens. Maintaining donor chimerism for 30 days after surgery improves VCA survival. It is recommended to tailor the immunosuppression regimen based on the recipient's background to optimize outcomes.
Topics: Animals; Mice; Rats; Antilymphocyte Serum; Cyclosporins; Graft Rejection; Graft Survival; Immunosuppressive Agents; Mice, Inbred C57BL; Rats, Inbred BN; Rats, Inbred Lew; Rodentia; Sirolimus; Vascularized Composite Allotransplantation
PubMed: 36508453
DOI: 10.1097/PRS.0000000000010099