Patients Experienced Graft Rejection Research Articles

Epstein-Barr Virus-Associated Smooth Muscle Tumor After Kidney Transplantation: A French Multicenter Retrospective Study.

Epstein-Barr virus (EBV) is a herpesvirus linked to nine different human tumors and lymphoproliferative disorders. Immunosuppression promotes EBV-driven malignancies. The most frequent EBV-induced malignancies are lymphomas and nasopharyngeal carcinoma. By promoting smooth muscle proliferation, EBV can induce EBV-associated smooth muscle tumors (EBV-SMT). EBV-SMT is a rare oncological entity for which no current guideline for diagnosis or management exists. Data on posttransplant EBV-SMT (PT-SMT) are scarce in kidney transplant recipients. We conducted a national multicentric retrospective study and collected cases among transplantation centers in France. Kidney transplant recipients experiencing histologically proven PT-SMT were included. We collected data on demographic characteristics of patient, history of kidney transplantation, history of PT-SMT, evolution of graft function, and patient survival. Eight patients were included. The median age at PT-SMT diagnosis was 31 years (range 6.5-40). PT-SMT occurred after a median delay of 37.8 months after transplantation (range 6-175). PT-SMT management consisted in immunosuppressive regimen minimization in all patients. Introduction of mTOR inhibitors was performed in two patients. Four patients (50%) needed chemotherapy. Surgical resection was performed in four patients. At last follow-up after PT-SMT diagnosis (median 33 months (range 17-132)), five patients were considered in complete remission, and two patients had died. Two patients experienced graft rejection; two resumed dialysis (25%). All patients with available data presented with impaired graft function at last follow-up. PT-SMT is a subacute and progressive disease during kidney transplantation. Even if the risk of developing PT-SMT is low in kidney transplant recipients (0.07% in our cohort), PT-SMT is associated with significant graft loss, possibly due to reduced immunosuppression. Developing guidelines could help transplantation teams better manage these patients.

Incidence, characteristics and outcomes in relapsed and refractory CD20+ PTLD: An institutional retrospective cohort study.

e19078 Background: Post-transplant lymphoproliferative disorder (PTLD) is a malignancy with significant morbidity and mortality after solid organ transplant (SOT). Frontline treatment of CD20+ PTLD is well established; however, there is a lack of data on the treatment of relapsed/refractory (R/R) PTLD, especially in the era of novel therapies approved since 2017 for diffuse large B-cell lymphoma. Methods: We conducted a single institution retrospective study of adult SOT patients with CD20+ PTLD. Inclusion criteria were age ≥18 and use of an adult regimen that included rituximab for frontline therapy. Baseline and pathologic characteristics, frontline and subsequent treatments, response rates, and toxicities were collected. Results: 71 cases of CD20+ PTLD were diagnosed between 01/01/2012 to 12/31/2022. The median age at diagnosis was 46. SOTs included kidney (46.5%), liver (21.1%), lung (16.9%), heart (14.1%), and pancreas (1.4%). Pathologically, 47 cases were monomorphic (12 germinal center B-cell-like [GCB] subtype, 26 non-GCB subtype, 9 cases indeterminate), 12 were polymorphic, 2 were non-destructive, and 10 were unclassified. 38 cases (53.5%) were Epstein-Barr virus positive. Frontline treatments included rituximab followed by R-CHOP (38.0%), rituximab monotherapy (16.9%), R-EPOCH (4.2%), and R-miniCHOP (2.8%). Toxicities included acute kidney injury (21.1%) and perforation (9.8%) and rejection (7%). The median overall survival (OS) was 62 months. 21 (29.6%) patients relapsed (N = 13) or were refractory (N = 8) to frontline treatment. Median time to relapse was 12.0 months. Systemic treatments included RCHOP, R-miniCHOP, RICE, R-Gemcitabine and oxaliplatin (R-GemOx), lenalidomide/tafasitamab (len/tafa), and R-ibrutinib with an overall response rate (ORR) of 72.2% in the second line setting; 50% of patients required dose reductions. Median OS was 17 months. Progression-free survival (PFS) was 4.5 months. The. ORR, median PFS and OS among those who received novel therapy (N=3) was 100%, 4.4 months, and not reached compared to 66.7%, 8 months, and 4.6 months with traditional cytotoxic therapy (N=15), respectively. 6 patients received a third line of therapy, which included polatuzumab-BR, CAR-T cell therapy, R-GemOx, len/tafa, and loncastuximab. ORR was 80%. 33% of patients required dose reductions. At data cutoff, 2 patients who received a third line of therapy were alive with stable disease on therapy. Causes of death in third line treatment included perforation (N=1), COVID (N = 1), fungemia (N=1), and cardiac arrest likely unrelated to PTLD (N = 1). 3 patients who died had active PTLD at time of death. No patients experienced graft rejection during treatment for R/R PTLD. Conclusions: R/R CD20+ PTLD after SOT remains a therapeutic challenge. Better understanding of cytotoxic versus novel therapies can help guide clinical decision making.

Intrabone Transplantation of a Single Unwashed Umbilical Cord Blood Unit with Antithymocyte Globulin-Free and Sirolimus-Based Graft-versus-Host Disease Prophylaxis: Fast Immune Reconstitution and Long-Term Disease Control in Patients with High-Risk Diseases

Several strategies have been explored with the attempt of improving the safety and feasibility of umbilical cord blood transplantation (UCBT) in adults. The aim of this retrospective analysis was to examine the safety and efficacy of intrabone transplantation of a single unwashed cord blood unit in an antithymocyte globulin-free, sirolimus-based graft-versus-host disease prophylaxis platform. We collected data for all consecutive UCBTs infused intrabone (IB) and unwashed at San Raffaele Hospital in Milan between 2012 and 2021. Thirty-one consecutive UCBTs were identified. All but 3 UCB units had a high-resolution HLA typing on 8 loci at the time of selection. At the time of cryopreservation, the median CD34+ cell count was 1 × 105/kg (range, .6 to 12.0 × 105/kg) and the median total nucleated cell (TNC) count was 2.8 × 107/kg (range, 1.48 to 5.6 × 107/kg). Eighty-seven percent of patients received myeloablative conditioning, and 77% underwent transplantation for acute myeloid leukemia. The median duration of follow-up among survivors was 38.2 months (range, 10.4 to 123.6 months). No adverse events were related to the IB infusion at bedside under short-conscious periprocedural sedation or to the no wash technique. After thawing, median CD34+ cell and TNC counts were .8 × 105/kg (range, .1 to 2.3 × 105/kg) and 1.42 × 107/kg (range, .69 to 3.2 × 107/kg). The median time to engraftment was 27 days for neutrophils and 53 days for platelets. One patient experienced graft rejection and was subsequently rescued with a salvage transplantation. The median time to a CD3+ cell count >100/μL was 30 days. The 100-day cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) was 12.9% (95% confidence interval [CI], 4% to 27.3%), and the 2-year cumulative incidence of moderate-to-severe chronic GVHD (cGVHD) was 11.8% (95% CI, 2.7% to 28.3%). At 2 years, overall survival (OS) was 52.7% (95% CI, 33% to 69%), relapse incidence was 30.7% (95% CI, 13.7% to 49.6%), and transplantation-related mortality was 29% (95% CI, 14.3% to 45.6%). In univariate analysis, infused CD34+ cell count did not impact transplantation outcomes. In patients who underwent transplantation in first complete remission, relapse rate was 13%, with a 2-year OS >90%. In our cohort, IB infusion of a single cord blood unit was feasible, with no adverse reactions related to the no wash/IB infusion, low rates of cGVHD and disease relapse, and rapid immune reconstitution.

Tissue presentation of human pegivirus infection in liver transplanted recipients

Human pegivirus-1 (HPgV-1) is known for its protective role in HIV co-infected individuals. This immunomodulatory effect raised questions concerning the possible role of HPgV-1 infection and the risk of rejection in liver transplanted patients. We aimed to evaluate the possible protective effect of HPgV-1 on graft outcome of liver transplanted patients. A total of 283 patients were recruited. Formalin-fixed paraffin-embedded tissue samples were collected from the explanted liver. HBV-DNA, HCV-RNA, and HPgV-1-RNA were determined using PCR and multiplex RT-PCR assays. The clinical course of patients including the occurrence of acute cellular rejection was compared between HPgV-1-infected vs. uninfected patients. HBV-DNA, HCV-RNA and HPgV-1-RNA were detected in 42.6%, 4.9%, and 7.8% of samples, respectively. None of the HPgV-1-infected patients experienced graft rejection. Group LASSO logistic regression revealed that HPgV-1 infection was the only factor which significantly reduced the odds of graft rejection (OR = 0.5, 95% CI = 0.29–0.89). No significant association was found between the presence of HPgV-1 with HBV and HCV infections. The lack of graft rejection in HPgV-1-infected liver transplanted patients might indicate a possible role of this virus for graft surveillance. Since these are still preliminary findings, prospective studies should further elucidate the role of HPgV-1 in liver transplantation outcomes.

Safety and Efficacy of SGLT2i Post Orthotopic Heart Transplantation

<h3>Purpose</h3> Diabetes mellitus is common after orthotopic heart transplantation (OHT) due to steroid-induced hyperglycemia. Traditionally, it has been treated using parenteral insulin therapy. The use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in OHT recipients is not well established. <h3>Methods</h3> A retrospective chart review was performed on all the patients who underwent OHT at our center to identify patients on SGT2i post OHT. Clinical outcomes pre and post SGLT2i therapy were compared using the student t-test. <h3>Results</h3> Out of the 455 patients who had OHT at our single institution, 26 patients were on SGLT2i post OHT (1 patient was dual organ recipient - heart and liver transplant). The baseline characteristics are reported in Table 1. The median days from OHT to initiation of SGLT2i was 780 days (range 40-4986 days), and the median duration of therapy post-OHT was 169 days (range 38-2474 days). There was a statistically significant improvement in the average hemoglobin A1c, weight, and body mass index after starting SGLT2i (Results table). There was a trend towards improving renal function. There was no incidence of systemic infection, hypoglycemia, amputation, or euglycemic diabetic ketoacidosis while on SGLT2i. Two patients were able to discontinue insulin therapy after starting SGLT2i. There was no incidence or progression of cardiac allograft vasculopathy during the therapy. Two patients experienced graft rejection (1Antibody Mediated Rejection and 1 Acute Cellular Rejection) with drop in left ventricular systolic function that recovered after appropriate treatment. <h3>Conclusion</h3> SGLT2i can be used safely in OHT recipients. The renal protective mechanism of SGLT2i could be helpful to combat the nephrotoxicity of calcineurin inhibitors (CNI) used for immunosuppression and help prolong the use of CNI. Further randomized studies are required to explore the complete benefits of SGLT2i in OHT recipients

Encouraging the outcomes of children with beta-thalassaemia major who underwent fresh cord blood transplantation from an HLA-matched sibling donor

ABSTRACT Background Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is currently the only curative treatment for thalassaemia major (TM). Cord blood (CB) from a sibling has different characteristics from marrow and has potential advantages and disadvantages as a stem cell source. Methods We retrospectively analyzed 68 children with beta-thalassaemia major (β-TM) who underwent fresh cord blood transplantation (F-CBT) from an HLA-matched sibling donor (MSD) between June 2010 and July 2018 in the Department of Pediatrics, Nanfang Hospital and Haematology-Oncology, Shenzhen Children’s Hospital. Results The median infused doses of total nucleated cells (TNCs) and CD34 + cells were 8.51×107/kg and 3.16×105/kg, respectively. The median time to neutrophil and platelet engraftment were, respectively, 27 and 31 days. The cumulative probabilities of acute and chronic graft-versus-host disease (GVHD) were very low after F-CBT (7.8% and 0.0%, respectively). Of the 68 paediatric patients, 67 patients survived during a median follow-up period of 61 months. The estimated 5-year probability of overall survival (OS) and disease-free survival (DFS) were 98.5% and 87.9%, respectively. Three patients experienced graft rejection (GR) (4.5%), and we identified CD34 + cell dose as a significant risk factor for graft failure (p = 0.036) in stratify analysis. Conclusions The above results indicate that patients with β-TM have excellent outcomes after F-CBT from an HLA-MSD.

MO992RABBIT ANTITHYMOCYTE GLOBULIN (RATG) AS INDUCTION THERAPY IN INDIAN PATIENTS UNDERGOING RENAL TRANSPLANTATION: CLINICAL EXPERIENCE FROM RISE REGISTRY

Abstract Background and Aims Induction therapy with rabbit anti-thymocyte globulin (rATG) in patients with renal transplantation prevents early graft failure due to immunologic rejection. In India, due to the lack of a robust national transplant registry, limited real-world evidence is available on induction immunosuppression. The RISE study aimed to evaluate the safety and effectiveness of induction immunosuppression using rATG in patients undergoing renal transplantation in India. Method In this multicenter, prospective, observational cohort study (CTRI/2017/09/009/009700) adult patients (≥18 years) were included if they were due to have a renal transplant and physicians’ decision to use rATG as an induction therapy was independent of this registry and based on routine clinical practice. Acute rejection and infections over 12 months, graft survival and renal function at the end of 6 and 12 months and safety (adverse events [AEs] and serious AEs [SAEs]) were evaluated over 12 months. Results Of the 325 patients enrolled, 314 met the eligibility criteria, 313 patients received at least one dose of rATG (safety population) and 299 patients (evaluable population) received at least one dose of rATG and had no critical protocol deviation (ongoing infection, transplantation date deviation, and ABO incompatibility). Of the 299 donors, 81.3% were live donors and the remaining 18.7% deceased. The mean (SD [standard deviation]) age of participants was 42.8 (11.7) years and 76.3% of patients were men. The cumulative mean (SD) rATG dose was 155.06 (91.12) mg. A total of 23 (7.7%) patients experienced graft rejection; of which 21 (91.3%) patients reported acute rejections; one patient had a hyperacute rejection and another patient had accelerated rejection. These rejections occurred within a median time duration of 0.49 months (range: 0.1 to 7.75 months). The diagnosis of graft rejection was most often done by renal biopsy (n=21, 91.3%; 20 of these patients had acute rejection) and clinical diagnosis in two patients. Cellular rejection was the predominant pathology (n=17, 77.3%), followed by mixed rejection (n=3) and antibody-mediated rejection (n=2). The corresponding mean (SD) time to first graft rejection were 5.45 (1.59) and 10.37 (3.58) months, respectively. The graft survival was 93.3% (n=279) at 6 months and 92.3% (n=276) at 12 months (Figure). The mean (SD) glomerular filtration rate was 64.59 (19.57) and 64.93 (20.26) mL/min/1.73m2 at 6 and 12 months, respectively, suggesting normal post-transplant kidney function. Fifty-three patients (17.7%) reported a total of 74 infections, the most common being bacterial (n=37) followed by viral (n=8) and fungal infections (n=5). Urinary tract infection was the most common site of infection (25 events in 23 patients) followed by sepsis (3 events in 2 patients). A total of 342 AEs were reported in 154 (49.2%) patients during 12 months. The majority of AEs (n=195) were of mild intensity, followed by 124 and 22 events of moderate and severe intensity, respectively. SAEs (n=111) were reported in 56 patients. Pyrexia was the most commonly reported SAE in 10 patients (12 events). A total of seven deaths were reported during the study (acute coronary syndrome, left ventricular dysfunction, neutropenic sepsis, septic shock, sudden sepsis, n=1 each and undetermined, n=2). Conclusion The study demonstrated low rejection rate, better survival and function at 6 months and 1 year and an acceptable safety profile of rATG with overall infection incidence less than 18%. Additional follow-up data is warranted to understand factors associated with rejection of graft. This study was funded by Sanofi, India.

Course of renal allograft function after diagnosis and treatment of post-transplant lymphoproliferative disorders in pediatric kidney transplant recipients.

Post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication in renal transplant recipients. Immunomodulatory and chemotherapeutic treatment potentially affect allograft function. The aim of this study was to evaluate graft function of pediatric kidney transplant recipients following diagnosis and standardized treatment of PTLD. Patients were identified from the German Ped-PTLD registry, and data on renal function were retrospectively retrieved from patient charts. For PTLD treatment, immunosuppressive therapy was reduced and all children received rituximab (375mg/m2 ) for up to six doses. Two patients required additional low-dose chemotherapy. Renal allograft function was monitored by consecutive measurements of estimated glomerular filtration rate (eGFR) at defined time points. Follow-up was up to 60months after PTLD. Twenty patients were included in this cohort analysis. Median time from transplantation to PTLD was 2.4years. Histopathology showed monomorphic lesions in 16 and polymorphic in 4 patients. Two patients experienced PTLD relapse after 2 and 14months. Range-based analysis of variance showed stable allograft function in 17 of 20 patients (85%). Mean eGFR increased during early treatment phase. One patient experienced graft rejection 5.3years after diagnosis of PTLD. Another patient developed recurrence of primary renal disease (focal-segmental glomerulosclerosis) and lost his renal allograft 3.8years post-transplant (2.0years after PTLD diagnosis). Treatment of PTLD with rituximab with or without low-dose chemotherapy in combination with reduced immunosuppression, mostly comprising of an mTOR inhibitor-based, calcineurin inhibitor-free regimen, is associated with stable graft function and favorable graft survival in pediatric renal transplant patients.

The Role of Immunotherapy in Hepatocellular Carcinoma: A Systematic Review and Pooled Analysis of 2,402 Patients.

Immune checkpoints inhibitors (ICIs) have emerged as a treatment option for several malignancies. Nivolumab, pembrolizumab, nivolumab plus ipilimumab, and atezolizumab plus bevacizumab have been approved for the management of advanced-stage hepatocellular carcinoma (HCC). We aimed to systematically review the literature and summarize the characteristics and outcomes of patients with HCC treated with ICIs. A systematic literature search of PubMed, the Cochrane Library, and ClinicalTrials.gov was performed according to the PRISMA statement (end of search date: November 7, 2020). Quality of evidence assessment was also performed. Sixty-three articles including 2,402 patients were analyzed, 2,376 of whom received ICIs for unresectable HCC. Response to ICIs could be evaluated in 2,116 patients; the overall objective response rate (ORR) and disease control rate (DCR) were 22.7% and 60.7%, respectively, and the mean overall survival (OS) was 15.8 months. The ORR, DCR, and OS for nivolumab (n = 846) were 19.7%, 51.1%, and 18.7 months, respectively; for pembrolizumab (n = 435) they were 20.7%, 64.6% and 13.3 months, respectively. The combination of atezolizumab/bevacizumab (n = 460) demonstrated an ORR and DCR of 30% and 77%, respectively. The overall rate of treatment discontinuation because of adverse events was 14.9%. Fifteen patients received ICIs in the liver transplant (LT) setting (one pre-LT for bridging, 14 for post-LT recurrence); fatal graft rejection was reported in 40.0% (n = 6/15) and mortality in 80.0% (n = 12/15). ICIs are safe and effective against unresectable HCC, but caution is warranted regarding their use in the LT setting because of the high graft rejection rate. This systematic review pooled the outcomes from studies reporting on the use of immune checkpoint inhibitors (ICIs) for the management of 2,402 patients with advanced-stage hepatocellular carcinoma (HCC), 2,376 of whom had unresectable HCC. The objective response rate and disease control rate were 22.7% and 60.7%, respectively, and the mean overall survival was 15.8 months. The overall rate of treatment discontinuation because of adverse events was 14.9%. Fifteen patients received ICIs in the liver transplant (LT) setting (one pre-LT for bridging, 14 for post-LT recurrence). Six of these patients experienced graft rejection (40.0%).

EFFICACY AND SAFETY OF ISLET TRANSPLANTATION IN PATIENTS WITH TYPE 1 DIABETES: A JAPANESE SINGLE-CENTER EXPERIENCE

Background: Pancreatic islet transplantation (ITx) provides a treatment option for patients with type 1 diabetes (T1D); the clinical results have improved with the introduction of improved immunosuppressive therapies. In Japan, the number of ITxs is small because of donor shortage, and ITx has been performed using the pancreas provided by “marginal” donors, such as donors after cardiac death (DCD) and elderly donors. We report the efficacy and safety of ITx at a single-center in Japan. Methods: Five C-peptide negative T1D patients with severe hypoglycemic events (SHE) received 2–3 intraportal allogeneic ITxs and received immunosuppressive agents, including antithymocyte globulin, tacrolimus, and mycophenolate mofetil from 2012 to 2019. We assessed sustained islet graft function duration, glycemic control, SHE, and post-transplant complications. Results: Thirteen islet isolations were performed from two DCD and 11 who were donors after brain death, and 12 preparations met the transplant criteria. The mean age of the donors was 45.5 years, and the cold ischemia time was 387 ± 89 min. Patients received a mean total number of islet equivalent (IEQ)/body weight(kg) of 19,406 IEQ/kg in 2 (n = 3) or 3 (n = 2) ITxs. The portal vein pressure after transplantation was 10.8 ± 4.4 mmHg (change in portal vein pressure was + 2.6 ± 1.7 mmHg). No complications associated with intraportal transplantation, such as liver dysfunction, intraperitoneal hemorrhage, or portal vein embolism was observed. One patient experienced graft rejection at 26 months after the transplantation, with islet graft survival being observed in the other 4 patients (follow-up: 16–54 months). It is noteworthy that these patients had almost normal glycosylated hemoglobin and creatinine levels. Moreover, 2 patients (40%) in the recent ITx group achieved insulin independence, and SHE was resolved in all recent ITx group recipients. As an adverse event, severe leukopenia was temporarily observed in one patient. No infectious complications occurred in any patient. Conclusion: ITx is considered a highly safe treatment with good clinical results, even in Japan, where there are few donors, and donor conditions are marginal. The future goal is to achieve a higher insulin independent rate and evaluate the long-term outcomes.

Renal transplantation for lupus nephritis: non-adherence and graft survival

Poor adherence to immunosuppressive treatment is common in patients with systemic lupus erythematosus and may identify those with lupus nephritis (LN) who have a poorer prognosis. Non-adherence has also been reported to be a potential adverse outcome predictor in renal transplantation (rTp). We investigated whether non-adherence is associated with increased rTp graft rejection and/or failure in patients with LN. Patients with LN undergoing rTp in two major London hospitals were retrospectively included. Medical and electronic records were reviewed for documented concerns of non-adherence as well as laboratory biochemical drug levels. The role of non-adherence and other potential predictors of graft rejection/failure including demographics, comorbidities, age at systemic lupus erythematosus and LN diagnosis, type of LN, time on dialysis prior to rTp and medication use were investigated using logistic regression. Out of 361 patients with LN, 40 had rTp. During a median follow-up of 8.7 years, 17/40 (42.5%) of these patients had evidence of non-adherence. A total of 12 (30.0%) patients experienced graft rejection or failure or both. In the adherent group 2/23 (8.7%) had graft rejection, whilst in the non-adherent this rose to 5/17 (29.4%, p = 0.11). Graft failure was seen in 5/23 (21.7%) patients from the adherent group and 4/17 (23.5%) in the non-adherent group ( p = 0.89). Non-adherent patients had a trend towards increased graft rejection, hazard ratio 4.38, 95% confidence interval = 0.73-26.12, p = 0.11. Patients who spent more time on dialysis prior to rTp were more likely to be adherent to medication, p = 0.01. Poor adherence to immunosuppressive therapy is common and has been shown to associate with a trend towards increased graft failure in patients with LN requiring rTp. This is the first paper to report that shorter periods on dialysis prior to transplantation might lead to increased non-adherence in lupus patients.

Outcomes of Children with Hemophagocytic Lymphohistiocytosis Given Allogeneic Hematopoietic Stem Cell Transplantation in Italy

We report on 109 patients with hemophagocytic lymphohistiocytosis (HLH) undergoing 126 procedures of allogeneic hematopoietic stem cell transplantation (HSCT) between 2000 and 2014 in centers associated with the Italian Pediatric Hematology Oncology Association. Genetic diagnosis was FHL2 (32%), FHL3 (33%), or other defined disorders known to cause HLH (15%); in the remaining patients no genetic abnormality was found. Donor for first transplant was an HLA-matched sibling for 25 patients (23%), an unrelated donor for 73 (67%), and an HLA-partially matched family donor for 11 children (10%). Conditioning regimen was busulfan-based for 61 patients (56%), treosulfan-based for 21 (20%), and fludarabine-based for 26 children (24%). The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 71% and 60%, respectively. Twenty-six patients (24%) died due to transplant-related causes, whereas 14 (13%) and 10 (9%) patients experienced graft rejection and/or relapse, respectively. Twelve of 14 children given a second HSCT after graft failure/relapse are alive and disease-free. Use of HLA-partially matched family donors was associated with higher risk of graft failure and thus with lower EFS (but not with lower OS) in multivariable analysis. Active disease at transplantation did not significantly affect prognosis. These data confirm that HSCT can cure most HLH patients, active disease not precluding successful transplantation. Because in HLH patients HLA-haploidentical HSCT performed through CD34+ cell positive selection was found to be associated with poor sustained engraftment of donor cells, innovative approaches able to guarantee a more robust engraftment are warranted in patients given this type of allograft.

Treosulfan and Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Children with Primary Immunodeficiency: UK Experience

We previously published results for 70 children who received conditioning with treosulfan and cyclophosphamide (n = 30) or fludarabine (n = 40) before undergoing hematopoietic stem cell transplantation (HSCT) for primary immunodeficiency (PID). Toxicity was lower and T cell chimerism was better in the patients receiving fludarabine, but cohort numbers were relatively small and follow-up was short. Here we report outcomes of 160 children who received homogeneous conditioning with treosulfan, fludarabine, and, in most cases, alemtuzumab (n = 124). The median age at transplantation was 1.36 years (range, .09 to 18.25 years). Donors included 73 matched unrelated, 54 1 to 3 antigen-mismatched unrelated, 12 matched sibling, 17 other matched family, and 4 haploidentical donors. Stem cell source was peripheral blood stem cells (PBSCs) in 70, bone marrow in 49, and cord blood in 41. Median duration of follow-up was 4.3 years (range, .8 to 9.4 years). Overall survival was 83%. No patients had veno-occlusive disease. Seventy-four patients (46%) had acute GVHD, but only 14 (9%) greater than grade II. Four patients underwent successful retransplantation for graft loss or poor immune reconstitution. Another patient experienced graft rejection and died. There was no association between T cell chimerism >95% and stem cell source, but a significant association was seen between myeloid chimerism >95% and use of PBSCs without an increased risk of significant GVHD compared with other sources. All 11 patients with severe combined immunodeficiency diagnosed at birth were alive at up to 8.7 years of follow-up. Long-term studies are needed to determine late gonadotoxic effects, and pharmacokinetic studies are needed to identify whether specific targeting is advantageous. The combination of treosulfan, fludarabine, and alemtuzumab is associated with excellent results in HSCT for PID.

Azacitidine As Post-Allograft Maintenance Helps Reduce Relapse Risk in High-Risk MDS and AML

Purpose: Relapse after allogeneic hematopoietic SCT (allo-SCT) for AML or myelodysplastic syndrome (MDS) remains the main cause of treatment failure and is associated with a very poor prognosis and a short survival despite the type of the salvage therapy. Options include reductions of immunosuppressive therapy, chemotherapy with or without infusion of donor lymphocytes (DLI) or second allo-SCT, but results remain disappointing. Other studies (C Jabbour et al, and Craddock Charlie et al) demonstrated the efficacy and safety of 5-azacytidine (Vidaza) maintenance post Allo-SCT.Patients and Methods: The aim of our observational study was to evaluate the anti-leukemic effect of 5-azacytidine (Vidaza) as post-transplantation prophylactic therapy to prevent relapse in patients with high risk AML or MDS in our center. We identified 16 patients, 13 AML and 3 MDS. Twelve patients (75%) received a risk-adapted intensity of busulfan at 130mg/m2/day for either 2, 3 or 4 days, with a fixed dose of fludarabine (30mg/m2/day for 5 days), and thymoglobulin (2.5mg/kg/day for 2 days). Our algorithm was based on age, co-morbidity (ies) and disease risk.Twelve patients (75%) received peripheral blood stem cells (PBSC) from HLA identical siblings, 3 patients (19%) from haplo-identical donor and 1 patient from matched unrelated donor. Azacitidine was started after a median of 60 days post-transplant with a reduced dose of 32 mg/m2/day for 5 days monthly for 5 years. None of the patients experienced graft rejection. Patient and transplant characteristics are outlined in Table 1.Results: Nine patients (56%) had either a monosomal karyotype or a complex karyotype. Patients received a median number of 8 cycles (1-37) of vidaza. None of our patients stopped definitively vidaza for toxicity reasons. Three patients (19%) discontinued their treatment: one for 3 months because of pneumonia, one for acute GvHD grade II then resumed Azacitidine therapy after 6 months, the third stopped for 2 weeks because of neutropenia. After a median follow-up of 10 months (1-56) from allo-SCT, 13 patients (81%) still alive and 3 patients died; one because of CMV infection, one from disease progression and one from cardiac infarct. At the last follow up 13 patients (81%) remain in complete remission.Conclusions: Azacitidine prophylactic maintenance therapy appears to reduce the risk of relapse by helping consolidate post-allograft responses in high risk AML or MDS. The toxicity related to this dose of azacitidine was very low. Our findings require validation in a large prospective multicenter randomized study.Legend: AML, Acute Myeloid Leukemia; MDS, Myelodysplastic Syndrome; CR, Complete Remission; FB2 Fludarabine 2 days Busulfan,;FB3 Fludarabine 3 days Busulfan; FB4 Fludarabine 4 days Busulfan; TBF Fludarabine Busulfan. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Donor Lymphocytes Depleted of Alloreactive T-Cells (ATIR101) Reduce Transplant Related Mortality and Improve Overall Survival in Haploidentical HSCT for Patients with AML and ALL, Using an Immunosuppressant-Free Transplant Regimen

IntroductionHaploidentical family donors are becoming an effective alternative for patients in need of an hematopoietic stem cell transplantation (HSCT) but lacking an HLA-matched donor. However, to prevent graft-versus-host disease (GVHD), intensive in-vivo or ex-vivo T-cell depletion is often utilised, resulting in slow immune reconstitution, frequent and often lethal infectious complications and/or high relapse rates, thus decreasing overall survival.To overcome these limitations, we have developed a strategy that allows additional donor lymphocytes to be infused post-HSCT without the risk of inducing severe GVHD and maintaining the ability to react against infections and leukemic cells.Patients and MethodsIn this open-label, multi-centre phase 2 clinical trial (CR-AIR-007; NCT01794299), 23 patients with high-risk AML or ALL were enrolled. Patients underwent myeloablative conditioning and were given a CD34+ selected stem cell graft from a haploidentical family donor. In addition, donor lymphocytes from the same donor were processed using a selective photodepletion technology, creating a donor lymphocyte product depleted of alloreactive T-cells (ATIR101). ATIR101 was to be given to patients at 28-32 days post-HSCT at a fixed dose of 2x106 CD3+ cells/kg. No post-transplant GVHD prophylaxis was administered.The primary endpoint of the study is transplant-related mortality at 6 months post-HSCT. Patients are followed to determine disease-free and overall survival.Patients undergoing a similar T-cell depleted haploidentical HSCT without ATIR infusion (CR-AIR-006; NCT02188290) were used as controls. Most centers providing the historic control data also participate in this phase 2 trial with ATIR101.ResultsTwenty-three patients, median age of 41 years (range 21 - 64), have been enrolled into this study. Seventeen patients, 7 male and 10 female, had AML, 12 in CR1 and 5 in CR2 at the time of HSCT. Six patients, 5 male and 1 female, had ALL, 4 in CR1 and 2 in CR2 at the time of HSCT.Conditioning regimen consisted of a] TBI (1200 cGy; n=10) or b] melphalan (120 mg/m2; n=12), along with thiotepa (10 mg/kg), fludarabine (30 mg/m2 x 5d) and ATG (2.5mg/kg x 4d). No patient experienced graft rejection, with neutrophil and platelet engraftment achieved at a median of 11 and 12 days, respectively (range 8-18, range 9-35). 21 patients to date received ATIR101, at a fixed dose of 2x106 CD3+ cells/kg at a median of 28 days (range: 28-73 days) post-transplant. Median follow-up is 270 Days post-HSCT.No patient developed grade III-IV acute GVHD. Two cases of grade II acute GVHD were reported thus far. The onset of these two acute GVHD cases was delayed, at day 173 and day 247 post-HSCT, 145 and 219 post ATIR respectively.No patient died within the first 100 days post-HSCT. There are 3 deaths as a result of transplant related mortality within 6 months post-HSCT (primary endpoint).When compared to the matched historic control group (N=35), TRM was significantly lower in patients given ATIR101 after a T-cell depleted haplotransplant with a 6-month TRM for HSCT + ATIR101 of 17% versus 34% for HSCT only (Figure 1a).Figure 1a: Kaplan Meier of Transplant related mortality: HSCT + ATIR101 vs HSCT alone (p=0.0075), data as per 3 August 2015.Thus far, in CR-AIR-007 study, only one patient experienced a relapse, which occurred at 90 days post-HSCT and resulted in death of the patient on day 122.The overall survival of patients given ATIR101 is significantly improved, compared to the control group, with a 1-year survival of 67% in the HSCT + ATIR101 group and 20% in the control group (Figure 1b).Figure 1b: Kaplan Meier of Overall Survival: HSCT + ATIR101 vs HSCT alone (p=0.0032), data as per 3 August 2015.ConclusionsAddition of ATIR101 to a T-cell depleted haploidentical HSCT protocol significantly improves transplantation outcome, with reduced TRM and improved OS. Specifically, no patient died during the first 100 days post-HSCT. Administration of ATIR101 at the dose of 2x106 cells/kg does not induce severe GVHD, confirming the efficacy of alloreactive T-cell elimination from the donor lymphocyte infusion. We attribute the reduced TRM (mainly infections in the control group) to the additive immunological protection afforded by ATIR101. Moreover, the low number of relapses observed thus far is most encouraging and supports the preservation within ATIR101 of T-cells able to recognize leukemic antigens. [Display omitted] [Display omitted] DisclosuresRoy:Kiadis Pharma: Consultancy, Research Funding; Novartis: Honoraria. Rudiger:Kiadis Pharma: Employment. Velthuis:Kiadis Pharma: Employment. Reitsma:Kiadis Pharma: Employment. Gerez:Kiadis Pharma: Employment. Rovers:Kiadis Pharma: Employment.

Allogeneic Hematopoietic Stem Transplantation in Patients with Transfusion Dependent Beta Thalassemia: A Single-Center Experience from India

Introduction:The thalassemias are the most common of the inherited abnormalities of hemoglobin, typically characterized by a quantitative defect in the synthesis of either the alpha or beta globin chain, resulting in reduced or absent synthesis of either of the globin chains followed by ineffective erythropoiesis with hemolysis. Beta thalassemia is prevalent in the populations of the Mediterranean region, the Middle East, India, Pakistan, and Southeast Asia.Patients are treated with red blood cell transfusions and iron chelation to prevent organ iron overload. Currently, the only cure for thalassemia is allogeneic bone marrow transplantation which corrects the genetic defect in the hematopoietic system by the use of allogeneic stem cells.Methods:We retrospectively and prospectively analyzed the outcomes in transfusion dependant beta Thalassemia patients, who underwent allogeneic HSCT between June 2004 and June 2014. The patients were classified into Class 1, 2 and 3 as per the Pesaro criteria.Results:Sixty seven patients (Males n=40; females n=27) with a median age of 7 years (range 2 to 22 years) underwent HSCT during this time. Fifty seven patients were classified as Class 2, 8 as Class 3 and 2 as Class 1. The conditioning regimens used consisted of Bu-Cy-ATG (n=30), Bu-Cy (n=2), Flu-Bu-Cy-ATG (n=23), Treo-Flu-Thio (n=8), Treo-Flu-Thio-ATG(n=3) and Flu-Bu-Cy-Thio-ATG(n=1) with cyclosporine and methotrexate as GVHD prophylaxis. Stem cell source was marrow, peripheral stem cells and cord in 50, 17 and 1 patients respectively. Sixty four patients had matched sibling transplant and three non-sibling donors (one unrelated cord, one matched unrelated and one haplo-identical ). One patient received both both marrow as well as peripheral stem cells. The median TC cell dose was 6.4x108/kg (range 3 to 16.3 x108/kg) and median CD34 cell dose of 2.4 x106/kg (range 0.6 to 19.6 x106/kg). Hematological recovery was seen in all patients except three patients, who died before engraftment. Neutrophil and platelet engraftment occurred at a median of 14 days (range, 10-22 days) and 22 days (range, 10-35 days), respectively. Twenty four patients developed veno-occlusive disease, 20 patients developed Gr II-IV acute graft-versus-host disease (GVHD), and 3 patients had chronic GVHD. At day +28, thirty five patients showed more than 90% donor chimersim and rest had mixed chimerism. Four patients experienced graft rejection. Treatment-related mortality (TRM) for the whole cohort was 10.4% at 100 days and 14.9% at 6 months post transplant. TRM was 12.28% and 37.5% for Class 2 and class 3 patients respectively. At a median follow up of 416 days, overall survival and thalassemia free survival are 82.1%, and 74.6% respectively.Conclusion: Similar outcomes have been reported from developed countries. Outcome of Class 3 patients still continues to be poor and VOD rates are high in this patient group. DisclosuresNo relevant conflicts of interest to declare.

Haploidentical Hematopoietic Stem Cell Transplantation in Pediatric Patients: Comparison of Early Post-Transplant Outcome According to in Vitro Depletion Method

Currently, haploidentical hematopoietic cell transplantation (HHCT) is considered an established option for patients who have diseases curable with HCT but who lack a suitable donor. We compared the early post-transplant outcomes of the two transplant groups using different in vitro depletion method.Between July 2008 and June 2014, 49 pediatric patients underwent in vitro T cell-depleted HHCT. Of 49 patients, 28 received CD3-depleted stem cells (CD3-HHCT) and 21 received TCRαβ-depleted grafts (TCRαβ-HHCT). Among 28 patients of CD3-HHCT, nine had hematologic malignancy [HM, one with ALL in non-CR, six with AML (3 CR1, 2 CR2, 1 non-CR), and two with MDS-RCMD], 18 had non-malignant disease (one with Fanconi anemia, 16 with acquired SAA, and one with CDA), and one had refractory neuroblastoma. Among 21 patients of TCRαβ-HHCT, 16 had HM [five with ALL (2 CR1, 2 CR2, 1 CR3), five with AML (2 CR1, 2 CR2, 1 non-CR), one with mixed lineage leukemia in non-CR, one with MDS-RCC, two with JMML, and two with NHL (1 CR2, 1 CR3)], two had SAA, and three had solid tumors [two with RMS (1 CR2, 1 refractory), and one with Ewing sarcoma in CR3].Of 28 patients who received CD3-HHCT, two patients failed to achieve primary engraftment, and five patients experienced graft rejection (GR) within 28 days post-transplant. No patients of TCRαβ-HHCT experienced graft failure (GF). Early GF (primary GF and GR) was more common in CD3-HHCT compared to TCRαβ-HHCT (P=0.011). The cumulative incidence of acute GVHD ≥ grade II was comparable between two groups (33.3% for CD3-HHCT and 27.0% for TCRαβ-HHCT). Extensive chronic GVHD occurred in three patients from CD3-HHCT and one from TCRαβ-HHCT. T and T4 cell counts at 2 months post-transplant were higher in TCRαβ-HHCT than that of CD3-HHCT (P=0.007 for T and P=0.074 for T4). In CD3-HHCT, four patients died of non-relapse causes (two of CMV disease, one of encephalopathy, and one of autoimmune hemolytic anemia) and one died of leukemia. In contrast, five patients from TCRαβ-HHCT died of disease but, none died of non-relapse cause.Of 20 patients (18 from CD3-HHCT and two from TCRαβ-HHCT) with non-malignant disease, only one patient of CD3-HHCT died of TRM. As for 29 patients (10 from CD3-HHCT and 19 from TCRαβ-HHCT) with malignant disease, the EFS at 1 year for CD3-HHCT and TCRαβ-HHCT were 60.0% and 56.6%, respectively (P>0.05).In this study, TCRαβ-depleted HHCT showed a better early post-transplant outcome in terms of engraftment, immune recovery, and NRM, compared to CD3-HHCT. However, further study is warranted to evaluate the efficacy of TCRαβ-HHCT in preventing relapse in advanced malignancy. DisclosuresNo relevant conflicts of interest to declare.

No Effect of Birth Order on Relapse, Graft-Versus-Host Disease or Transplant Related Mortality in Matched Sibling Donor Bone Marrow Transplant in Pediatric Patients with Leukemia

Introduction: The impact of birth order of patient and donor in matched sibling hematopoietic stem cell transplantation (HSCT) has not been fully defined. It has been postulated that as a result of fetomaternal trafficking donors who are younger than the transplant patient may develop in utero tolerance to patient cells. A large registry study of adult and pediatric patients found that using a donor younger than the recipient (R>D) was associated with decreased acute GVHD; single center studies found this to be correlated with decreased relapse and improved overall survival as well. We hypothesized that in pediatric patients with hematologic malignancies and a presumed low incidence of acute GVHD that birth order would not have an impact on relapse incidence.Methods: We performed an IRB -approved retrospective chart review of consecutive patients with acute leukemia undergoing matched sibling transplant bone marrow transplantation at Dana Farber/ Boston Children’s Hospital between 1/1/2001 and 10/31/ 2013. All patients were conditioned ablatively with a Busulfan or TBI based regimen. No product underwent T cell depletion. Patients with twin donors or with secondary leukemia were excluded. Basic patient demographics were collected including development of Grade II-IV acute GVHD, relapse and transplant-related mortality (TRM). Patients were assigned a Low Risk (HSCT in 1st remission) or High Risk (all others) disease status. Patients were then divided into 2 groups: those with donor older than recipient (D>R) and those with donor younger (R>D). Chi-Square test was used to assess for significant differences in relapse between patients.Results:We reviewed 91 patients with AML or ALL. Age range was 7 months to 24 years (median 11 years). 43 patients were D>R and 48 were R>D. The overall incidence of acute GVHD (Grade II-IV) was 16 % and TRM 4%; neither was significantly different between the two cohorts. Only 1 patient experienced graft rejection (R>D/ALL). For the population as a whole the relapse incidence was not statistically different - 35% in the R>D cohort vs 25% in the D>R cohort (p=0.46). There was also no difference detected in relapse rate when AML and ALL were evaluated separately (p=0.45 and p=0.57 respectively). We also compared the relapse rate by disease risk status. While previous data (Dobbelstein, ASH abstract 2008) suggested fewer relapses in R>D patients, our data revealed a similar trend but only in high risk patients (24% vs 41%), and statistical significance was not achieved (p=0.25). For low risk patients birth order had no effect on relapse incidence (p=0.88).Conclusion:Previous studies, primarily involving adult patients, have demonstrated an effect of birth order in matched sibling transplants for hematologic malignancies. A decrease in acute GVHD when the donor in younger than recipient (R>D) has been the most consistent finding although single center studies have shown an effect on relapse rate and overall survival as well. In our single institution retrospective study of a similarly treated cohort of pediatric patients we saw no effect of birth order on GVHD, TRM or relapse. Perhaps in the pediatric setting when the incidence of significant GVHD and TRM is low, maternally induced donor tolerance or sensitization to patient cells has less impact and other factors including disease status or patient age predominate. Thus our results suggest that birth order need not be considered as an important factor in matched sibling donor selection for pediatric patients with acute leukemias. DisclosuresNo relevant conflicts of interest to declare.

Long-term outcome of HLA-haploidentical hematopoietic SCT without in vitro T-cell depletion for adult severe aplastic anemia after modified conditioning and supportive therapy

HLA-haploidentical hematopoietic SCT (HSCT) is an option for severe aplastic anemia (SAA) patients. Here, we evaluated the outcomes of 26 adult-SAA patients who received HLA-haploidentical HSCT in five transplant centers in southwestern China. Most of the patients in this study failed prior therapy and were transfused heavily before the transplantation. The patients received fludarabine+cyclophosphamide+antithymocyte globulin as conditioning regimens and then unmanipulated peripheral blood plus marrow transplantation. Micafungin, i.v. Ig and recombinant human TPO were used for post-grafting infection prevention and supportive care. Of 26 patients, 25 achieved engraftment at a median of 13 days (range, 11-19 days) after HSCT. One of 25 patients experienced graft rejection and did not achieve sustained engraftment after second HSCT. Therefore, the final engraftment rate was 92.3%. Three of 25 (12%) patients developed acute GVHD, 10 of 25 (40%) patients developed chronic GVHD (9 with limited whereas the other with extensive). The OS rate was 84.6% and the average follow-up time was 1313.2 (738-2005) days for surviving patients. This encouraging result suggests that HLA-haploidentical HSCT is an effective therapeutic option for adults with acquired SAA if an HLA-identical donor is not available.

Use Of Unrelated Donors In Elderly Patients (age >60 years) Undergoing Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation For Hematologic Malignancies

ObjectivesThe lower morbidity and mortality of reduced-intensity conditioning (RIC) regimens have allowed allogeneic hematopoietic cell transplantation (HCT) in older patients. However, there are only limited data on the feasibility and outcomes of URD HCT in elderly patients.The aim of the study was to compare the outcome in OS and PFS for patients transplanted using unrelated donor (URD) in patients age 60 or older. Patients and methodsWe retrospectively analyzed outcomes in 62 consecutive hematologic malignancy patients aged > or =60 years (median, 62 years; range: 60-70 years) undergoing reduced intensity conditioning regimens (RIC) from URD. In this study, URD was used only when a MRD was not available.Then we compared the outcome of 17 elderly patients (age >65 years) with 44 younger patients aged between 60 and 65 years. Patient, disease and transplant characteristics are shown in Table 1. ResultsNo patients experienced graft rejection. The median HCT comorbidity index score was 2 (range, 0 to 6). With a median follow up of 36 months (range, 5-74), the cumulative incidence of grades II to IV acute GVHD was 28% and of grades III to IV acute GVHD, 13%. At 2 years, the cumulative incidence of chronic GVHD was 27%, progression-free survival (PFS) was 62%, overall survival (OS) was 63%, and relapse was 14%. Non relapse mortality (NRM) was 24% at 2 years.The cumulative incidence of grade II–IV Acute GVHD was 43% for the younger group and 17% for the older group (P = 0.056). The cumulative incidence of chronic GVHD was not different between the two groups (23% vs. 45% (p=0.3), respectively). Two-year OS and PFS was 57% versus 86% (P = 0.059) and 55% versus 86% (P = 0.03), in the younger and the older group respectively. The 2-year NRM and relapse was 26% versus 14% (P = 0.4) and 19% versus 0% (P = 0.04), in the younger and older group respectively. ConclusionsThis retrospective study suggest that RIC HCT from URD is a safe and effective option for patients aged > or =60 years or older, and in the absence of suitable related donors, well-matched URD may offer a very reasonable alternative, and that does not appear to be associated with a detrimental outcome. However these results are encouraging showing once again that with an adequate selection, age is not a definitive limitation. Disclosures:No relevant conflicts of interest to declare.