Higher Risk Of Graft Failure Research Articles

Significant impact of mesenchymal stromal cell co-transplantation in a challenging hematopoietic engraftment scenario comparing two administration routes

Background & Aim Previous studies have shown that the co-infusion of mesenchymal stromal cells (MSCs) with hematopoietic stem cells (HSCs) enhances HSC engraftment in animal models and even in human transplants with a high risk of graft failure. These studies suggest that MSCs interact with HSCs and transport them towards the bone marrow. Although in conventional hematopoietic transplants HSCs are infused by the intravenous route (IV), some studies propose the intrabone route (IB) as an effective alternative procedure to improve HSCs homing. However, few studies have been published comparing the effectiveness of both alternatives in co-transplantation of HSCs with MSCs and the results are inconclusive. For that reason, the aim of this study was to go into detail about the comparison of both administration routes in order to enhance the hematopoietic engraftment. Methods, Results & Conclusion We investigated the possible beneficial effect of 500,000 human adipose tissue-derived MSCs improving the engraftment of a very limited number of human cord blood HSCs (4,000 CD34+ HSCs) in a xenogeneic transplant model in NSG mice, comparing both routes of transplant administration: IV and IB. Analyzing the percentage of human CD45+ cells in peripheral blood, bone marrow and spleen, the results revealed that co-transplantation with MSCs improved hematopoietic engraftment in NSG recipients conditioned with a submyeloablative irradiation dose, regardless of the route used for transplantation. In all instances, engrafted cells were also able to differentiate towards the lymphoid and myeloid linages. Furthermore, we showed that, in this model, the most efficient route of transplant administration is the IV route, obtaining higher levels of human hematopoietic engraftment in all the organs analyzed compared to those obtained by the IB route. Finally, we demonstrated that HSCs transplanted by IB route were not retained in the transplantation site and could migrate to the contralateral leg and also to the spleen. This observation could reveal that IB transplantation directly into the bone marrow niche is not preventing the recirculation and the systemic loss of the HSCs that occur when cells are IV transplanted. Taken together, our results demonstrate that IV co-transplantation of MSCs significantly increase the engraftment of very low numbers of HSCs, suggesting that this approach could be relevant in the clinics, particularly in gene therapy clinical trials in which a limited amount of HSCs is available. Previous studies have shown that the co-infusion of mesenchymal stromal cells (MSCs) with hematopoietic stem cells (HSCs) enhances HSC engraftment in animal models and even in human transplants with a high risk of graft failure. These studies suggest that MSCs interact with HSCs and transport them towards the bone marrow. Although in conventional hematopoietic transplants HSCs are infused by the intravenous route (IV), some studies propose the intrabone route (IB) as an effective alternative procedure to improve HSCs homing. However, few studies have been published comparing the effectiveness of both alternatives in co-transplantation of HSCs with MSCs and the results are inconclusive. For that reason, the aim of this study was to go into detail about the comparison of both administration routes in order to enhance the hematopoietic engraftment. We investigated the possible beneficial effect of 500,000 human adipose tissue-derived MSCs improving the engraftment of a very limited number of human cord blood HSCs (4,000 CD34+ HSCs) in a xenogeneic transplant model in NSG mice, comparing both routes of transplant administration: IV and IB. Analyzing the percentage of human CD45+ cells in peripheral blood, bone marrow and spleen, the results revealed that co-transplantation with MSCs improved hematopoietic engraftment in NSG recipients conditioned with a submyeloablative irradiation dose, regardless of the route used for transplantation. In all instances, engrafted cells were also able to differentiate towards the lymphoid and myeloid linages. Furthermore, we showed that, in this model, the most efficient route of transplant administration is the IV route, obtaining higher levels of human hematopoietic engraftment in all the organs analyzed compared to those obtained by the IB route. Finally, we demonstrated that HSCs transplanted by IB route were not retained in the transplantation site and could migrate to the contralateral leg and also to the spleen. This observation could reveal that IB transplantation directly into the bone marrow niche is not preventing the recirculation and the systemic loss of the HSCs that occur when cells are IV transplanted.

Terminally Differentiated Effector Memory CD8+ T Cells Identify Kidney Transplant Recipients at High Risk of Graft Failure.

Identifying biomarkers to predict kidney transplant failure and to define new therapeutic targets requires more comprehensive understanding of the immune response to chronic allogeneic stimulation. We investigated the frequency and function of CD8+ T cell subsets-including effector memory (EM) and terminally differentiated EM (TEMRA) CD8+ T cells-in blood samples from 284 kidney transplant recipients recruited 1 year post-transplant and followed for a median of 8.3 years. We also analyzed CD8+ T cell reactivity to donor-specific PBMCs in 24 patients who had received living-donor kidney transplants. Increased frequency of circulating TEMRA CD8+ T cells at 1 year post-transplant associated with increased risk of graft failure during follow-up. This association remained after adjustment for a previously reported composite of eight clinical variables, the Kidney Transplant Failure Score. In contrast, increased frequency of EM CD8+ T cells associated with reduced risk of graft failure. A distinct TEMRA CD8+ T cell subpopulation was identified that was characterized by expression of FcγRIIIA (CD16) and by high levels of proinflammatory cytokine secretion and cytotoxic activity. Although donor-specific stimulation induced a similar rapid, early response in EM and TEMRA CD8+ T cells, CD16 engagement resulted in selective activation of TEMRA CD8+ T cells, which mediated antibody-dependent cytotoxicity. At 1 year post-transplant, the composition of memory CD8+ T cell subsets in blood improved prediction of 8-year kidney transplant failure compared with a clinical-variables score alone. A subpopulation of TEMRA CD8+ T cells displays a novel dual mechanism of activation mediated by engagement of the T-cell receptor or of CD16. These findings suggest that TEMRA CD8+ T cells play a pivotal role in humoral and cellular rejection and reveal the potential value of memory CD8+ T cell monitoring for predicting risk of kidney transplant failure.

Association Between Living Kidney Donor Postdonation Hypertension and Recipient Graft Failure.

Recipients of kidneys from living donors who subsequently develop end-stage renal disease (ESRD) also have higher graft failure, suggesting the 2 donor kidneys share risk factors that could inform recipient outcomes. Given that donor ESRD is rare, an earlier and more common postdonation outcome could serve as a surrogate to individualize counseling and management for recipients. Hypertension is a frequent event before donor ESRD; thus, early postdonation hypertension might indicate higher risk of graft failure. We studied Scientific Registry of Transplant Recipients data to quantify the association between early postdonation hypertension and recipient graft failure using propensity score-weighted Cox proportional hazards regression. We also examined the association between postdonation systolic blood pressure and graft failure. Of 37 901 recipients, 2.4% had a donor who developed hypertension within 2 years postdonation. Controlling for donor and recipient characteristics, recipients whose donors developed hypertension had no higher risk for graft failure (adjusted hazard ratio [aHR] 1.03, 95% confidence interval [CI] 0.85-1.25, P = 0.72). This was consistent among subgroups of recipients at higher risk for adverse outcomes due to hyperfiltration: African American recipients (aHR 1.10, 95% CI 0.70-1.73, P = 0.68) and those with ESRD caused by hypertension (aHR 1.10, 95% CI 0.65-1.85, P = 0.73) or diabetes (aHR 0.80, 95% CI 0.56-1.13, P = 0.20). However, graft failure was associated with postdonation systolic blood pressure (per 10 mm Hg, aHR 1.05, 95% CI 1.03-1.08, P < 0.001). Although postdonation systolic blood pressure is associated with graft failure, the reported diagnosis of hypertension as determined by the requirement for blood pressure treatment early postdonation did not portend a higher risk of recipient graft failure in the same way as eventual postdonation ESRD.

SUN-308 URINARY EPIDERMAL GROWTH FACTOR/CREATININE RATIO AND GRAFT FAILURE IN KIDNEY TRANSPLANT RECIPIENTS: A PROSPECTIVE COHORT STUDY

Graft failure remains a major clinical challenge to improving long-term outcomes in kidney transplant recipients (KTR). Early identification of KTR at higher risk of graft failure is key to potentially improve this outcome. Epidermal growth factor (EGF) is involved in kidney tissue proliferation and integrity, with a reduction of its urinary excretion being associated with early fibrotic processes and a wide range of kidney diseases. We aimed to investigate whether, in KTR, urinary EGF (uEGF) is prospectively associated with graft failure. In this prospective cohort study, KTR with a functioning allograft ≥1-year were recruited and followed-up for three years. uEGF was measured at baseline by ELISA in 24-hours urine samples and normalized by urinary creatinine (Cr). Its association with risk of graft failure was assessed by multivariable Cox-regression analyses and its predictive ability by C-statistic. In 706 patients, uEGF/Cr ratio at enrollment was 6.43 (IQR, 4.07–10.77) ng/mg. During follow-up, 41 (6%) KTR developed graft failure. uEGF/Cr ratio was inversely associated with the risk of GF (HR 0.68, 95% CI 0.59‒0.78; P<0.001), which remained independent of adjustment for several potential confounders including immunosuppressive therapy, human leukocyte antigen mismatch, estimated glomerular filtration rate and proteinuria. C-statistic of uEGF/Cr ratio for graft failure was 0.81 (P<0.001) and when added to urinary protein excretion significantly improved its predictive ability (C-statistic from 0.76 to 0.81; P<0.00 1). Kaplan Meier curves by tertiles of uEGF/Cr on graft failure. Tertile 1:<4.78 ng/mg; Tertile 2:4.78-8.80 ng/mg; Tertile 3:>8.80 ng/mg. P value was obtained from the log-rank (Mantel cox) test. uEGF/Cr, urinary epidermal growth factor/creatinine ratio. In KTR, uEGF/Cr ratio is independently and inversely associated with the risk of graft failure and depicts strong prediction ability for this outcome. Further studies seem warranted to elucidate whether uEGF might be a promising biomarker for clinical uptake post-kidney transplantation.

Quantification of T Cell Binding Polyclonal Rabbit Anti-thymocyte Globulin in Human Plasma with Liquid Chromatography Tandem-Mass Spectrometry

The addition of rabbit anti-human thymocyte globulin (ATG) to the conditioning regimen prior to allogeneic hematopoietic cell transplantation has significantly reduced the risk of graft-versus-host disease (GvHD) and graft failure. However, ATG has a small therapeutic window. Overexposure of ATG post-HCT hampers T cell immune reconstitution and has been associated with increased relapse rates and viral reactivations, whereas underexposure has been associated with an increased incidence of GvHD, both of which lead to increased mortality. Therapeutic drug monitoring of T cell binding ATG plasma levels provides a means to optimize dosing for patients at high risk for graft failure to ensure timely T cell immune reconstitution and subsequently increase survival chances. This manuscript describes the first liquid chromatography tandem-mass spectrometry (LC-MS/MS) method to quantify the pharmacologically active fraction of polyclonal ATG in plasma. This was achieved through immunoaffinity purification of active ATG from plasma with Jurkat T cells. After the binding and washing, samples were eluted, denatured, and trypsin-digested. Signature peptides originating from the IgG constant chain were measured with LC-MS/MS. Critical method parameters were optimized, and the method was successfully validated following European Medicines Agency (EMA) guidelines. The method covered the therapeutic range of ATG and was validated at a lower limit of quantification (LLOQ) of 1 AU/mL with an overall CV and bias of 11.8% and − 2.5%, respectively. In conclusion, we developed a LC-MS/MS-based method to quantify active polyclonal rabbit ATG in human plasma. We suggest that this novel assay can be used to monitor and optimize dosing of ATG in clinical practice.

Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide for Severe Aplastic Anemia

Severe aplastic anemia is a life-threatening disease usually treated with immunosuppression or HSCT. This is a multicenter retrospective study that included 78 patients who have undergone haploidentical HSCT with PTCy for severe aplastic anemia in Brazil between 2010 and 2019. Median age was 14 y/o (range: 1-69), and most patients had been heavily transfused. Conditioning regimen was FluCyTBI-based, and GVHD prophylaxis consisted of PTCy, MMF, and tacrolimus (13%) or cyclosporine (87%). Most grafts (92%) were bone marrow. One-year OS was 81%, and it was lower in females (HR=4.6; P=0.007) and in those who had graft failure or poor graft function (HR=10.3; P 30 y/o and lower TNC dose. In conclusion, we have shown that haploidentical transplantation for SAA is feasible. The incidence of graft failure/poor graft function was high, and increasing the TBI dose to 300-400 cGy or Cy to 50 mg/kg in the conditioning regimen may overcome graft failure, but not the addition of ATG. Patients who had not been previously exposed to ATG or alemtuzumab might be at high risk of graft failure. High cellular bone marrow grafts should be pursued.

Can Planned CD34+ Stem Cell Boost Prevent Poor Graft Function after Peripheral Blood Haploidentical Hematopoietic Transplantation?

<h3>Introduction</h3> Traditional outcome measurements for hematopoietic recovery after Haploidentical HCT (haplo-HCT) with post-transplant cyclophosphamide (PTCy) may not capture a subset of patients who meet engraftment milestones, and have full donor chimerism, but subsequently suffer poor graft function (PGF) resulting in prolonged cytopenias and requiring transfusion support. This is termed secondary PGF, occurs in 5-26% of patients, and is associated with significant morbidity and mortality. CD34+ selected donor cell infusions have been employed in this setting without causing graft versus host disease (GVHD). <h3>Objectives</h3> We hypothesized that planned CD34+ stem cell boost (SCB) after PTCy could be used to prevent PGF after haplo-HCT. <h3>Methods</h3> Full donor chimerism was defined as ≥ 95% donor chimerism from bone marrow on day +30. Poor graft function was defined as transfusion dependence with ≥ two cytopenic lines (ANC < 1500 cells/mm3, platelets < 30 000/mm3 and Hgb < 8.5 g/dL) in the presence of full donor chimerism and in the absence of severe GVHD, CMV infection, and relapse. Patients underwent haplo-HCT per institutional protocol. Part of the donor product underwent CD34+ selection and cells were cryopreserved. On day 5-6, CD34+ selected donor product was infused. <h3>Results</h3> Between February 1, 2018 and August 30, 2018, nine patients underwent planned SCB after haplo-HCT. All patients received GVHD prophylaxis with PtCY, tacrolimus, and mycophenolate per institutional guidelines. The comparison cohort consisted of all patients who have undergone haplo-HCT at our institution between July 7^th, 2009 and October 8^th, 2018. All nine SCB patients had neutrophil engraftment (NE) with a median time of 16 days (13 – 25) compared with 17 days (12 – 78) in the comparison cohort (p = 0.40). Six of eight evaluable SCB patients had platelet engraftment (PE) with a median time of 22.5 days (12 – 55) compared with 26 days (9 – 134) in the comparison cohort (p = 0.675). One patient was censored due to death prior to PE on day +19. None of the 8 surviving patients developed secondary PGF. Two patients in the planned SCB group developed grade III acute GVHD involving the GI tract. The remaining seven had no GVHD. <h3>Conclusion</h3> These patients were selected on the basis of being high risk for graft failure or poor graft function. Two patients had active disease at the time of transplant and five of the nine patients were undergoing their second HCT. Time to NE and PE in the SCB group were 1 and 3.5 days faster than in the comparison group. This equivalency is notable given that the SCB patients were specifically selected for being high risk or graft failure. None of the SCB patients had secondary graft failure, compared with published rates between 5.6% and 26%. This approach appears to be safe with acceptable incidence of severe acute GVHD.

Mgta-456, a Cell Therapy Utilizing Expansion of CD34+ Hematopoietic Stem Cells (HSC), Improves HLA Matching for Adult Recipients, Promotes Faster Hematopoietic Recovery and Enables Uniform Engraftment with Less Acute Graft-Vs-Host Disease (GVHD)

<h3>Background</h3> HSC dose and HLA match are risk factors that impact mortality using cord blood units (CBU) in transplant. Low CD34+ doses result in prolonged cytopenia and higher graft failure risk. A minimum cell dose of 3.0 × 10⁷ total nucleated cells (TNC)/kg has generally been required in CBU selection; however, cell dose limits often require the use of a 2^nd unit and markedly limits the availability of 7-8/8 HLA-matched units in larger patients. MGTA-456 is a cell therapy product utilizing an aryl hydrocarbon receptor antagonist for expansion of CD34+ HSCs <i>in vitro</i>. In prior studies with fresh MGTA-456, 36 patients with hematologic malignancies demonstrated rapid neutrophil recovery and 100% engraftment. This study (NCT03674411) will evaluate the safety and efficacy of cryopreserved MGTA-456 and the effectiveness of lowering the TNC threshold of the selected CBU to 1.0 × 10⁷ TNC/kg before expansion to improve HLA match. <h3>Methods</h3> 13 patients aged 2-47 years (12-159 kg) with high-risk hematologic malignancy were enrolled with 11 transplanted to date. Patients received cyclophosphamide 120 mg/kg, fludarabine 75 mg/m2 and total body irradiation 1320 cGy or a busulfan-based regimen for children ≤3 years of age prior to MGTA-456 with cyclosporine/mycophenolate mofetil prophylaxis. G-CSF began the day after infusion until the neutrophil count exceeded 2500/uL for 3 days. <h3>Results</h3> MGTA-456 contained a median 2.3 × 10⁹ CD34+ cells (range, 0.65-8.0) after expansion (422-fold expansion of CD34+ cells [range, 219-1313]). Neutrophil recovery occurred in all patients with a median of 15 days (range, 0-31), similar to recipients of fresh MGTA-456 in a prior study (median 14 days) and significantly faster than in recipients of unmodified CBUs (median 25 days). Median platelet recovery was 41 days (range 24-49) vs 64 days with unmodified CBUs. MGTA-456 CD34+CD90+ content strongly correlated with speed of neutrophil recovery (Fig. 1), consistent with preclinical murine data showing CD34+CD90+ cells represent the true engraftable HSC population. Lowering the TNC requirement to 1.0 × 10⁷ TNC/kg for CBU selection pre-expansion improved HLA match and/or eliminated the need for double CBU transplant in all 5 patients weighing >80 kg. Three patients received 8/8 grafts who would have otherwise received 1 or 2 6/8 units (n=2) or two 7/8 units (n=1) which may account for the low incidence of aGVHD overall (3 cases of Grade 1-2 and no Grade 3-4). With a follow-up of 5.2 months (0.4-8.5 months), all patients are alive. <h3>Conclusion</h3> Cryopreserved MGTA-456 cell therapy resulted in rapid and 100% engraftment with speed of neutrophil recovery correlating with CD34+CD90+ cell dose in patients with high risk hematologic malignancy. Expansion of smaller CBUs increases the chance of finding a better HLA match, particularly for adults, thus reducing the barriers associated with low cell dose and poor HLA match in CBU transplantation.

The presence and impact of herpes virus DNA in recipient cornea and aqueous humor on graft survival following penetrating keratoplasty

Reactivation of herpes viruses poses threat to corneal graft survival. This study evaluated the presence of herpes simplex virus type 1 (HSV-1), HSV type 2 (HSV-2), and cytomegalovirus (CMV) DNA in recipient corneas and the aqueous humor of patients undergoing penetrating keratoplasty (PKP), and the impact on graft survival. This retrospective study reviewed 90 eyes of 71 patients underwent PKP between 2008 and 2016. Cornea and aqueous humor samples were sent for polymerase chain reaction (PCR) testing for viral DNA. The main outcomes were PCR results and graft survival. Recipient corneas tested positive for HSV-1 in 47 eyes (52.2%), for HSV-2 in 24 eyes (26.7%), and for CMV in seven eyes (7.8%). Aqueous humor tested positive for HSV-1 in 44 eyes (48.9%), for HSV-2 in 25 eyes (27.8%), and for CMV in eight eyes (8.9%). The presence of aqueous HSV-1 DNA was associated with higher risk of graft failure (p=0.005), whereas corneal HSV-1 DNA was not. The presence of HSV-2 DNA had no significant impact on graft survival. Aqueous CMV DNA was associated with higher risk of graft failure in univariate model, but not in multivariate model. There were high positive rates of HSV-1, HSV-2, and CMV DNA in recipient corneas and aqueous humor at the time of PKP, even among patients not suspected of latent viral infection. The presence of aqueous HSV-1 DNA was associated with higher risk of graft failure.

Long-term Results of Endovascular Aneurysm Sealing in Treatment of Infrarenal Abdominal Aortic Aneurysm With Unfavourable Morphology

Introduction: Endovascular aneurysm repair (EVAR) is a less invasive alternative of treatment of patients with abdominal aortic aneurysm (AAA). Its applicability however is limited by the AAA anatomy. Endovascular aneurysm sealing originally emerged as an endovascular solution for AAA repair with very promising early results. The purpose of this study was to report long-term results of EVAS of AAAs with unfavourable anatomy for EVAR. Methods: A prospectively maintained database of 42 patients with EVAR-unfavourable anatomy treated by EVAS was analysed. The median age of the patients was 74 (IQR 67-80) years. The median diameter of AAA was 61 (IQR 56-71) mm. The EVAS consisted of implantation of two balloon expandable aorto-iliac stent-grafts surrounded by polymer filled endobags. In case of proximal AAA neck shorter than 5 mm chimney grafts were implanted. The final angiographic result, intra- and early post-operative complications were noted. A follow-up included a clinical assessment angio-CT 4-6 weeks and 12 months after the procedure and duplex Doppler at 12 months intervals thereafter. In case of any abnormalities detected in either clinical or duplex Doppler examination an angio-CT was performed. Patency of the aorto-iliac stents and chimney grafts, occurrence of graft failure and all additional interventions and/or events were noted in the database. The graft failure was defined as AAA growth of more than 5mm, type I endoleak, occlusion of the stent-graft or chimney graft or aneurysm rupture. All-cause mortality (ACM) and aneurysm related mortality (ARM) were analysed with Kaplan-Meier estimates. Results: The procedure was completed in all patients. Twenty-eight chimney grafts were implanted in 19 patients. There were two intraoperative ruptures, one of an aortic neck that required conversion to an open repair and one of an external iliac artery that was successfully treated with implantation of a self-expandible covered stent. One patient died in an early postoperative period. The median follow-up period was 24 (IQR 12-34) months. The cumulative ACM was 15, 21 and 35% at 12, 24 and 36 months respectively and the cumulative ARM was 8, 11 and 27% at 12, 24 and 36 months respectively. Three out of five aneurysm related deaths were due to a secondary aorto-duodenal fistula. The cumulative incidence of graft failure was 20, 27 and 42% at 12, 24 and 36 months, respectively. Cumulative incidence of endoleak was 5, 9 and 23% at 12, 24 and 36 months, respectively.The graft failure increased significantly both ACM (p = 0,012) and ARM (p = 0,00003). The implantation of chimney grafts at the initial procedure increased significantly ARM (p=0,008). The presence of endoleak did not have any significant influence on ACM and ARM. Conclusion: Patients treated with EVAS for AAA with EVAR-unfavourable anatomy, especially those with chimney grafts, have a high risk of graft failure and subsequent death. These patients require more rigorous monitoring than patient after standard EVAR. Disclosure: Nothing to disclose

Mgta-456, an Aryl Hydrocarbon Receptor (AHR) Antagonist Based Expansion of CD34+ Hematopoietic Stem Cells (HSC), Permits Selection of Better HLA Matched Cord Blood Units (CBUs) and Promotes Faster Neutrophil Recovery and Uniform Engraftment with Potentially Less Acute Graft-Vs-Host Disease (GVHD)

Mgta-456, an Aryl Hydrocarbon Receptor (AHR) Antagonist Based Expansion of CD34+ Hematopoietic Stem Cells (HSC), Permits Selection of Better HLA Matched Cord Blood Units (CBUs) and Promotes Faster Neutrophil Recovery and Uniform Engraftment with Potentially Less Acute Graft-Vs-Host Disease (GVHD)

Unmanipulated haploidentical transplantation for adult patients with hematological malignancies.

Unmanipulated haploidentical transplantation for adult patients with hematological malignancies.

PB2322 SPLEEN SIZE AS CLINICAL RISK FACTOR FOR GRAFT FAILURE FOLLOWING ALLOGENEIC STEM CELL TRANSPLANTATION IN ACUTE LEUKEMIA PATIENTS

Background:Primary and secondary graft failure (GF) following allogeneic hematopoietic stem cell transplantation (allo‐HSCT) leads to prolonged neutropenia, infection complications and as a consequence lowered overall survival. Bone marrow as a graft source, HLA‐mismatched donor is a main factors which can influence GF in acute leukemia patients (pts) during first six months after allo‐HSCT. Nevertheless not all GF episodes can be explained by this factors. Here we report data about influence of spleen size (length width) assessed by transabdominal ultrasound on graft failure in first 6 months in acute leukemia patients in CR who underwent allo‐HSCT.Aims:Identify risk factors for GF in patients with acute leukemia remission.Methods:We analyzed medical records of 143 pts with acute leukemia (AML n = 100 (69.9%), ALL n = 43 (30.1%)) who underwent allo‐HSCT between 2013 and 2018 at National Research Center for Hematology and was alive for more than 28 days after allo‐HSCT. A median age of patients was 34 (19‐66) years, 66 (46.2%) males and 77 (53.8%) females. At the time of transplantation 124 (86.7%) pts were in complete remission and 19 (13.3%) pts had advanced disease. Most pts (n = 112; 78.3%) received reduced intensity conditioning regimen (RIC) and 31pts (21.7%) underwent myeloablative conditioning (MAC). Donors were: HLA‐matched unrelated (MRD) – 43.4% (n = 62); mismatched unrelated donor (MMUD) 27.3% (n = 39); matched related donor (MRD) ‐25.9% (n = 37); haploidentical (excluding TCR ab‐depletion) – 3.4% (n = 5), Bone marrow (BM) was used as a graft source in 60.1% (86 pts) and peripheral blood stem cell (PBSC) ‐ in 39.9% (57 pts). Spleen size was routinely evaluated before allo‐HSCT using transabdominal sonography. Cox Proportional‐Hazards model was used to identify influence of spleen size (≥3600 mm2 vs &lt;3600 mm2) as independent prognostic factor (conditioning regimen, donor type, graft source, HLA‐disparity were also entered as covariates as well known risk factors for GF).Results:Results of Cox Proportional‐Hazards model are shown on Figure 1. According to our data spleen size (length width) ≥3600 mm2 assessed by transabdominal sonography before allo‐HSCT was associated with high risk of GF within six months of follow up period after allo‐HSCT.HR‐3.67 (95% Cl, 1.05‐12.74, p = 0.04).Figure 1. Results of Cox Proportional‐Hazards modelSummary/Conclusion:HLA‐disparity, BM as a graft source is characterized by increased probability of GF. In addition we identify that spleen size ≥3600 mm2 assessed by transabdominal sonography before allo‐HSCT also increased GF (up to 3.67 times). Due to that fact it's not recommended to use BM as a graft source for acute leukemia patients who underwent allo‐HSCT especially from MMUD.image

Temporal Changes in the Impact of HLA Mismatching Among Pediatric Kidney Transplant Recipients.

Allocation for pediatric deceased-donor kidney transplantation (pDDKT) in the United States now de-emphasizes HLA matching to improve equality in access to transplantation, but other national systems still consider HLA matching due to concerns about graft survival. We hypothesized that the impact of HLA mismatching has decreased over time due to advances including improved immunosuppression. Using Scientific Registry of Transplant Recipient data, we analyzed whether the association between the number of HLA mismatches and outcomes of first-time pDDKTs changed between 2 eras: 1995 to 2004 (N = 2854) and 2005 to 2014 (N = 4643). Between eras, the median number of mismatches increased from 4 to 5 (P < 0.001). Overall graft failure risk was higher among HLA-mismatched versus HLA-matched transplants (adjusted hazard ratio 1.211.431.69 for 3-6 versus 0-2 mismatches; P < 0.001), and this association was similar pre-2005 and post-2005 (Pinteraction = 0.5). Median panel-reactive antibody change at relisting increased from 79 to 85 (P = 0.01), but the association between number of HLA mismatches and panel-reactive antibody change was similar between eras (Pinteraction = 0.6). Our finding that increased HLA mismatching continues to impact graft survival, with 43% higher risk of graft failure, highlights the tradeoff between transplant access equity and outcomes and calls into question the deemphasis on HLA matching in pDDKT allocation in the United States.

Accuracy of Kidney Failure Risk Equation in Transplant Recipients

Accuracy of Kidney Failure Risk Equation in Transplant Recipients

The Stability study: a protocol for a multicenter randomized clinical trial comparing anterior cruciate ligament reconstruction with and without Lateral Extra-articular Tenodesis in individuals who are at high risk of graft failure

BackgroundThe purpose of anterior cruciate ligament reconstruction (ACLR) is to restore stability to the knee. Persistent rotational laxity following ACLR has been correlated with poor outcome and graft failure. We hypothesize that anterolateral complex reconstruction by way of a Modified Lemaire Lateral Extra-articular Tenodesis (LET) in combination with single bundle ACLR would reduce the risk of persistent rotatory laxity in young individuals who are deemed as being at high risk of failure. We will conduct a pragmatic, multicenter, randomized clinical trial comparing standard single bundle hamstring ACLR with combined ACLR and LET.MethodsSix-hundred patients (300 per group) aged 25 years or less with an ACL deficient knee that meet two of the following three criteria will be included: 1) Grade 2 pivot shift or greater; 2) Returning to high risk cutting or pivoting sports; 3) Generalized ligamentous laxity. Participants will be seen at 3-months, 6-months, 12-months and 24-months post-operatively. The primary outcome measure is graft failure requiring revision ACLR or symptomatic instability associated with a positive asymmetric pivot shift indicating persistent rotational laxity. Patients will complete secondary outcome measures at each follow-up visit including patient-reported outcome measures, functional and biomechanical testing, and magnetic resonance imaging.DiscussionThis protocol is the first adequately powered randomized clinical trial investigating the effects of augmenting ACLR with an LET in patients at high-risk of graft failure. The successful completion of this trial has the potential to change surgical practice and provide evidence for the role of the LET in ACLR.Trial registrationThe trial is registered at ClinicalTrials.gov: NCT02018354, 23-12-2013.

Sex differences in preformed panel-reactive antibody levels and outcomes in patients undergoing heart transplantation.

Sex differences in panel-reactive antibody (PRA) levels in heart transplant recipients and their association with transplant-related outcomes are mostly unknown. In 20181 (24.7% women) first-time heart transplant recipients included from July 2004 to March 2015 in the prospective Organ Procurement and Transplantation Network (OPTN), we studied sex differences in most recent (mr) and peak (p)PRA and outcomes (graft failure, rejection, cardiac allograft vasculopathy [CAV], retransplantation, and mortality). Median follow-up (all-cause mortality) was 6years. Analyses are based on OPTN data (March 6, 2017). MrPRA levels were associated with all-cause mortality (hazard ratio, 95% confidence interval: class I 1.03, 1.01-1.04, P<0.001) and acute rejection (class II 1.08, 1.03-1.14, P=0.0044). PPRA levels were associated with all-cause mortality (class I 1.02, 1.00-1.04, P=0.015) and CAV (class II 1.03, 1.01-1.06, P=0.020). Sex interactions were seen for the association of pPRA and graft failure with a higher risk in women, and for pPRA and CAV with a higher risk in men. PRA were associated with different transplant-related outcomes in both sexes. However, women with elevated pPRA were shown to be at higher risk for graft failure, whereas higher levels of pPRA were more hazardous for men in developing CAV.

Programmed Cell Death 1 (PD-1) Inhibitors in Renal Transplant Patients with Advanced Cancer: A Double-Edged Sword?

Given advancements in cancer immunity, cancer treatment has gained breakthrough developments. Immune checkpoint inhibitors, such as programmed cell death 1 (PD-1) inhibitors, are the most promising drugs in the field and have been approved to treat various types of cancer, such as metastatic melanoma, head and neck squamous cell carcinoma, and urothelial carcinoma. However, whether PD-1 inhibitors should be administered to renal transplant patients with advanced cancer remains unclear because the T-cells produced after administration of these inhibitors act against not only tumor antigens but also donor alloantigens. Thus, the use of PD-1 inhibitors in kidney-transplanted patients with advanced cancer is limited on account of the high risk of graft failure due to acute rejection. Hence, finding optimal treatment regimens to enhance the tumor-specific T-cell response and decrease T-cell-mediated alloreactivity after administration of a PD-1 inhibitor is necessary. Thus far, no recommendations for the use of PD-1 inhibitors to treat cancer in renal transplant patients are yet available, and very few cases reporting kidney-transplanted patients treated with PD-1 inhibitors are available in the literature. Therefore, in this work, we review the published cases and suggest feasible approaches for renal transplant patients with advanced malignancy treated by a PD-1 inhibitor. Of the 22 cases we obtained, four patients maintained intact grafts without tumor progression after treatment with a PD-1 inhibitor. Among these patients, one maintained steroid dose before initiation of anti-PD1, two received immunosuppressive regimens with low-dose steroid and calcineurin inhibitor (CNI)-elimination with sirolimus before initiation of anti-PD-1 therapy, and one received combined anti-PD-1, anti-vascular endothelial growth factor (VEGF), and chemotherapy with unchanged immunosuppressive regimens. mammalian target of rapamycin (mTOR) inhibitors and anti-VEGF may act as regulators of tumor-specific and allogenic T-cells. However, more studies are necessary to explore the optimal therapy and ensure the safety and efficacy of PD-1 inhibitors in kidney-transplanted patients.

Nonadherence after pediatric renal transplantation: detection and treatment.

Nonadherence is a problem in adolescents and young adults. Risk factors are classified as those of the individual, family, health-care-system, or community. I present the latest reports and how to tackle nonadherence. Nonadherence risk is independent of one's origin in a high-poverty or low-poverty neighborhood or having private or public insurance in respect to African Americans. Females with male grafts have higher graft-failure risks than do males. Female recipients aged 15-24 with grafts from female donors have higher graft-failure risk than do males. In study of nonadherence risks, such findings must be taken into account. Antibody-mediated rejection is seen in nonadherence. The sirolimus and tacrolimus coefficient of variation is associated with nonadherence, donor-specific antibodies, and rejection. Adolescents had electronically monitored compliance reported by e-mail, text message or visual dose reminders and meetings with coaches. These patients had significantly greater odds of taking medication than did controls. Transition programs have an impact on renal function and rejection episodes. Individual risk factors are many, and methods for measuring nonadherence exist. Each transplant center should have a follow-up program to measure nonadherence, especially in adolescence, and a transition program to adult care.

Molecular Microscope Determinants of Graft Survival in the INTERHEART Study

Purpose In heart and kidney transplants, rejection is a major cause of graft loss. In kidneys, antibody-mediated rejection (ABMR) is more important than T cell-mediated rejection (TCMR), and molecules predict graft loss better than histology (JASN 26 (7):1711-1720, 2015). We examined the relative importance of ABMR vs TCMR in heart transplant endomyocardial biopsies (EMBs), and the molecules predicting graft survival. Methods The INTERHEART population includes 1219 transplant biopsies from 8 centers in Canada, USA, Australia and Europe. Gene expression was studied using microarrays, selecting the most recent biopsy per patient. Random forest classifiers were used to assess predictive accuracy and determine the importance of molecular predictors, including gene sets and scores from analyses in a reference set of 889 EMBs. Results We studied 3-year survival in 484 patients with follow-up times. Graft failure occurred in 60 patients. Median follow-up was 435 days; biopsies were mainly for indications. Surprisingly, TCMR was a greater short-term hazard than ABMR. The molecular archetype clusters for TCMR and injury (Fig. 1) had the highest risk of graft failure. Fig. 2 combines these clusters since they have similar characteristics. Conclusion Unlike kidneys, graft loss (particularly within one year) after EMB is highly associated with TCMR but not ABMR. TCMR may reflect failure of immunosuppression or non-adherence. This difference between the heart and renal transplant populations raises the possibility that TCMR is relatively more destructive, and ABMR less destructive, in heart than in kidney transplants. ClinicalTrials.gov # NCT02670408