CMV Matching Research Articles

Clonal Hematopoiesis Is Common in Unrelated Stem Cell Donors but Has No Impact on Patient Outcome after Hematopoietic Stem Cell Transplantation

Introduction. Clonal hematopoiesis (CH) has been associated with increased mortality mainly due to associations with cardiovascular diseases and hematologic cancer. Previous studies with predominantly related stem cell donors suggest that donor CH modulates graft-versus-host reactions and may augment graft-versus-leukemia effects after allogeneic hematopoietic cell transplantation (alloHCT). The impact of donor CH in the setting of unrelated alloHCT remains to be determined. To address this question, we initiated a joint study of the Transplant Complications Working Party of EBMT and DKMS. Patients and Methods. Donor samples from the time of stem cell donation were taken from the Collaborative Biobank. Patient baseline and outcome data were retrieved from the EBMT registry. Unrelated donor-recipient pairs were selected for a minimum donor age of 35 years. CH analysis was performed with an error-corrected ultra-deep NGS assay for 45 genes with a median sensitivity of 0.2% variant allele frequency (VAF). Accuracy of low frequency CH findings was checked by cross validation with an orthogonal assay. The primary objective was to assess the impact of donor CH on overall survival (OS). Major secondary endpoints were the risk of relapse/progression and non-relapse mortality (NRM), cumulative incidences of acute and chronic GVHD and event-free survival (EFS). All endpoints were evaluated with (cause-specific) multivariable Cox regression models. Adjustment factors were patient and donor age, diagnosis, disease risk index, Karnofsky performance status, conditioning intensity, GVHD-prophylaxis, graft source, HLA-match, sex match and CMV match. We did not adjust for multiple testing. Results. Data from 2584 unrelated donor-recipient pairs were analyzed. Median patient follow-up after alloHCT was 60 months. The median donor age was 46 years (range, 39-61 years). The median patient age was 54 years (range, 0-79 years). Indications for alloHCT were AML (44%), ALL (10%), MDS (10%), MPN (6%), B-cell lymphoma (6%), Multiple Myeloma (5%), CML 3%, inherited disorders (3%), CLL 2% and other (13%). Transplantations were performed between 2005 and 2018. In vivo or ex vivo T-cell depletion (TCD) was used in 81% of transplants, PTCY in 5% and no TCD in 14%. Mutations in DNMT3A, TET2, and ASXL1 defined CH most frequently. The distribution of donor CH across leukemia driver genes was comparable to previous reports (Panel A). With 0.2% (2%) VAF cutoffs, rates of DNMT3A-mutations were 19% (2%) among donors younger than 41 years compared to 37% (6%) among donors aged 55 years and higher. Corresponding rates for 0.2% (2%) VAF cutoffs for total CH were 38% (4%) among donors younger than 41 years compared to 67% (14%) among donors aged 55 years and higher. We tested systematically increasing VAF cutoffs (≥0.2% versus <0.2%, ≥1% versus <1%, ≥2% versus <2%, ≥5% versus <5%, and ≥5% versus <0.2%) for DNMT3A-CH and total CH for associations with clinical endpoints. Panel B shows results for multivariable regression analyses for total donor CH. Although we observed trends towards increased mortality and inferior EFS for some cutoffs, no incremental impact of donor CH with higher VAF was found and no systematic changes of the risk for GVHD and relapse/progression were observed. Conclusions. We conclude that donor CH has no significant impact on the risk for GVHD, relapse and survival in the context of HLA-compatible unrelated donor alloHCT with GVHD-prophylaxis based predominantly on T-cell depletion with ATG.

Superior Outcomes with Fludarabine-Busulfan (Flu/Bu) Based Conditioning for Allogeneic Hematopoietic Cell Transplantation in Myelofibrosis - a Comparative Analysis By CIBMTR

Background:Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative therapeutic modality for patients with myelofibrosis (MF). However, the optimal conditioning regimen for allo-HCT either in the myeloablative conditioning (MAC) or in the reduced intensity conditioning (RIC) setting is not well known.Methods:Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified adults aged ≥18 years with MF who underwent allo-HCT between the years 2008-2018. Donor types included matched sibling donor (MSD), 8/8 matched unrelated donor (MUD), and 7/8 MUD. Outcomes were compared separately in the MAC and RIC cohorts based on the most common conditioning regimens used in each setting - MAC [(Fludarabine/Busulfan (Flu/Bu) vs. Busulfan/cyclophosphamide (Bu/Cy)] or RIC [(Flu/Bu vs. Fludarabine/melphalan (Flu/Mel)]. Overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM), relapse, acute and chronic graft versus host disease (GVHD) and GVHD-free relapse-free survival (GRFS) were evaluated. Survival analysis was done using Kaplan-Meier method and significant predictors were evaluated using Cox-proportional hazard regression method. Multivariable regression model included main effect (conditioning regimen) and covariates (patient age, gender, race, CMV match, disease subtype, DIPSS at HCT, comorbidities score (HCT-CI), Karnofsky performance status, prior therapy (ruxolitinib use/splenic radiation therapy/splenectomy), interval between diagnosis and transplant, conditioning intensity, stem cell source, donor-recipient HLA-match, GVHD prophylaxis, ATG/alemtuzumab use, transplant year, and center affect). All analyses were performed at a two-sided significance level of 0.05.Results:Of 872 patients who met the study criteria, 379 patients underwent allo-HCT using MAC (Flu/Bu=247, Bu/Cy=132) and 493 patients using RIC (Flu/Bu=166, Flu/Mel=327). Key baseline characteristics of the patients are summarized in Table 1. In multivariable analysis, significant differences in outcomes were observed in the MAC and RIC setting based on the choice of conditioning regimen (Table 2). In the MAC setting, Bu/Cy was associated with a higher risk of acute GVHD (grade 2-4 HR 2.33, 95% CI 1.67-3.25, p<0.01; grade 3-4 HR 2.31, 95% CI 1.52-3.52, p<0.01) and inferior GRFS (HR 1.94, 95% CI 1.49-2.53, p<0.01) as compared to Flu/Bu. In the RIC setting, Flu/Mel was associated with inferior OS (HR 1.80, 95% CI 1.15-2.81, p<0.01), higher risk of NRM (HR 1.81, 95% CI 1.12-2.91, p=0.01) and acute GVHD (grade 2-4- HR 1.45, 95% CI 1.03-2.03, p=0.03; grade 3-4 HR 2.21, 95%CI 1.28-3.83, p<0.01) as compared to Flu/Bu. These higher risks associated with Flu/Mel were primarily observed early post-transplant. The results were consistent when the outcomes were evaluated based on the two common melphalan doses employed in the RIC setting (100mg/m 2 vs 140mg/m 2).Conclusions:Our study demonstrates that the choice of conditioning regimen significantly influences the outcomes of allo-HCT in MF. The results favor Flu/Bu based conditioning in the MAC (lesser acute GVHD and better GRFS) and RIC (better OS, lower NRM, lower acute GVHD) setting. Hence, this aspect should be explored in future studies as the modification of conditioning strategies could lead to improved outcomes. [Display omitted] DisclosuresGuru Murthy: TG therapeutics: Other: Advisory board; Cardinal Health Inc.: Honoraria; Qessential: Consultancy; Guidepoint: Consultancy; Techspert: Consultancy; Cancerexpertnow: Honoraria. Sobecks: CareDX: Membership on an entity's Board of Directors or advisory committees. Scott: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Saber: Govt. COI: Other.

Trends in Use and Outcomes of Autologous and Allogeneic Hematopoietic Cell Transplantation in Racial/Ethnic Minorities

BackgroundThere has been an increase in overall utilization as well as improvement in overall survival (OS) after hematopoietic cell transplantation (HCT) for most hematologic disorders over time. It is not known if these changes have impacted racial/ethnic minorities equally. In this study, we describe changes in the volume and rate of autologous (auto) and allogeneic (allo) HCT and examine trends in survival in different racial/ethnic groups from 2009 to 2018.MethodsData were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) which collects patient data on most autologous and allogeneic HCT recipients in the US. We compared the number of auto and allo transplants in 4 different racial/ethnic groups: Non-Hispanic Whites (NHWs), African Americans (AAs), Hispanics and ‘Others’ across five 2-year cohorts from 2009 to 2018. ‘Others’ included Asians, Pacific Islanders and Native Americans as well as non-US residents. Since numbers in individual categories were too low to be meaningful, they were grouped together as ‘Others’. Multi race individuals and those with either race or ethnicity missing were excluded. Cox proportional hazards models were used to examine trends in overall mortality after auto HCT in adult patients (for NHL, HD, and MM), and allo HCT among adult and pediatric patients (for AML, ALL, lymphoma including chronic lymphocytic leukemia, and MDS/MPD) in the 4 different racial ethnic groups over 5 study time periods. These models were adjusted for sociodemographic and clinical variables (age, sex, Karnofsky/Lansky score, HCT-comorbidity index, disease, disease status, geographic region, insurance, marital status, education, distance to the transplant center, median income derived from patient's ZIP code). Graft type, donor, conditioning, GVHD prophylaxis, donor-recipient CMV match and donor-recipient sex match were included for allo HCT models.ResultsA total of 80,080 (59,666 NHWs, 10,683 AAs, 7,110 Hispanics) patients received an auto HCT and 60,412 (44,272 NHWs, 4,964 AAs, 7,826 Hispanics) received an allo HCTs from 2009 to 2018. The volume of auto and allo transplants increased overall, as well as within each race/ethnicity group, over the study periods. In addition, there was a significant change in the proportion of patients in each racial/ethnic group undergoing an auto HCT, with a lower proportion of NHWs and increased proportion of minorities over time (from 78%, 12% and 8% in 2009 -2010 to 71%, 15% and 10% in 2017-2018 for NHWs, AAs and Hispanics respectively; p<0.001). Similar trends were observed for allo HCT: from 76%, 8% and 12% in 2009-2010 to 71%, 9% and 14% in 2017-2018 of all allo HCTs for NHWs, AAs and Hispanics respectively; p<0.001. While there was an increase in the rate of transplants over the years across all racial/ethnic groups, the rate was higher in AAs and Hispanics as compared to NHWs (Table 1).There was no significant difference in overall mortality amongst the three main racial ethnic groups, though there was decrease in mortality over time for auto HCT and adult allo HCT patients. In the allo HCT pediatric group, AAs had higher overall mortality as compared to NHWs across all time periods. (Table 2) Figure 1 shows temporal trends in two-year survival by race and ethnicity.ConclusionsThis large population-based study shows an improvement in the rates and survival of auto and allo HCT in adults over time. Changes in the proportion of different racial/ethnic groups undergoing HCT are higher than rate of change of population growth (3% decline for NHWs, no change in AAs and 2% increase in Hispanics from 2010 to 2019 per William H. Frey analysis of census population estimates released June 25, 2020). Progress is reflected in higher rates of increase in racial/ ethnic minority groups and comparable survival across the racial ethnic groups in our cohort as compared to two prior registry studies (Baker et al. JCO 2005 and Baker et al. BBMT 2009) for most HCT patients. However, in pediatric patients undergoing allo HCT, the gap in survival between NHWs and AAs has continued to persist over the years. With increasing diversity of the US population, we need to strengthen our efforts for improving access to, and outcomes of HCT to narrow the gap for all patients requiring HCT, irrespective of their sociodemographic characteristics. [Display omitted] DisclosuresWood: Koneksa Health: Consultancy, Current equity holder in publicly-traded company; Teladoc: Consultancy; Pfizer: Research Funding. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy. Saber: Govt. COI: Other.

Cytomegalovirus mismatch after heart transplantation: Impact of antiviral prophylaxis and intravenous hyperimmune globulin.

ObjectiveCytomegalovirus (CMV) infections are correlated with complications following heart transplantation (HTx) and impaired outcome. The impact of a serologic mismatch between donor and recipient and the necessity of prophylactic virostatic medication is still a matter of concern.MethodsWe retrospectively reviewed all patients that underwent HTx between 2010 and 2020 in our department. The recipients (n = 176) could be categorized into four risk groups depending on their serologic CMV matching (D+/R − = donor CMV‐IgG positive and recipient CMV‐IgG negative, n = 32; D − /R+, n = 51; D − /R − , n = 35; D+/R+, n = 58). All patients followed the same protocol of CMV prophylaxis with application of ganciclovir/valganciclovir and intravenous CMV hyperimmune globulin.RESULTSIncidence of postoperative morbidity such as primary graft dysfunction, neurological events, infections, and graft rejection were comparable between all groups (p > .05). However, the incidence of postoperative acute kidney injury with hemodialysis was by trend increased in the D−/R+ group (72.0%) compared to the other groups. In‐hospital CMV‐DNAemia was observed in serologic positive recipients only (D+/R−: 0.0%, D−/R+: 25.0%, D−/R−: 0.0%, D+/R+: 13.3%, p < .01). During the first year, a total of 18 patients developed CMV‐DNAemia (D+/R−: 31.6%, D−/R+: 31.9%, D−/R−: 3.4%, D+/R+: 11.1%, p = .03).ConclusionsSeropositive recipients carry an important risk for CMV‐DNAemia. However, we did not observe differences in perioperative morbidity and mortality regarding CMV matching, which might be related to regularly administer prophylactic virostatics and additional CMV‐IVIG for risk constellations. For high‐risk constellation, long‐term application of CMV‐IVIG during the first year after transplant may be beneficial.

Autoimmune Cytopenias (AIC) Following Allogeneic Haematopoietic Stem Cell Transplant for Acquired Aplastic Anaemia: A Joint Study of the Autoimmune Diseases and Severe Aplastic Anaemia Working Parties (ADWP/SAAWP) of the European Society for Blood and Marrow Transplantation (EBMT)

IntroductionAutoimmune cytopenias(AICs) are the most common autoimmune phenomenon encountered following haematopoietic stem cell transplant(HSCT) (Holbro et al. 2012). Mechanisms of autoimmunity post-HSCT may relate to genetic susceptibility(Consolini et al. 2016), failure of central and peripheral immune tolerance(King et al. 2004), and factors such as drugs and inflammation(Lang et al. 2005). The aim of this EBMT study is to describe the incidence, risk factors, diagnosis and treatment of AIC post alloHSCT for acquired aplastic anaemia (aAA), itself a recognized autoimmune disease in most patients.MethodsEBMT centres performing alloHSCT for aAA were invited to participate in the study. Participating centres identified paediatric and adult patients with aAA treated between January 2002 and December 2012 with first alloHSCT, and confirmed whether AIC was diagnosed post-HSCT. Patients diagnosed with AIC prior to HSCT were excluded. Data for patients without AIC were extracted from the EBMT registry. Centres identifying cases of AIC provided additional data on diagnostic criteria and investigations, therapy administered and treatment outcome.Results196 (38%) paediatric and 320 (62%) adult patients were confirmed eligible for study inclusion by 40 participating EBMT centres. Characteristics of n=516 patients are shown in Table 1. 23 patients were diagnosed at a median of 13.0 (range 2.6-91.4) months post alloHSCT with AICs as follows: 30.4% (n=7) immune thrombocytopenia (ITP), 26.1% (n=6) autoimmune haemolytic anaemia(AIHA), 17.4% (n=4) autoimmune immune neutropenia (AIN), and 21.7% (n=5) Evans Syndrome. 1 case (4.3%) was diagnosed both with AIHA and AIN. Cumulative incidence of AIC at 1, 3 and 5 years post AIC was 2.0% (95% CI 0.7-3.2%), 4.1% (2.3-5.9%) and 4.4% (2.6-6.3%) respectively. Cumulative incidence of AIC at 5 years post HSCT did not vary with patient age group (<18 vs ≥18), Interval from aAA diagnosis to transplant (<12 vs ≥12 months), donor/recipient CMV match, donor/recipient gender match, or conditioning with TBI (P>0.5 in all cases). However, 5-year cumulative incidence of AIC was higher amongst patients treated with non-myeloablative conditioning (6.9% vs 2.5%, p=0.03), and conditioning regimens containing Fludarabine (6.2 vs 1.9%, p=0.03) or Alemtuzumab (10.0% vs 2.93%, p=0.003). Conditioning with anti-thymocyte globulin(ATG) was associated with a lower incidence of AIC (1.6 vs 6.2%, p=0.02). Incidence of AIC was also significantly higher in patients receiving PBSC (9.9%) compared with UCB (5.0%) and BM (0.8%) (p=0.002). 2 AIC patients received a second HSCT, one 2.3 months after AIC diagnosis and one 35 months after AIC diagnosis. There were 3 deaths in the AIC group, 2 infection-related to AIC and 1 HSCT-related.Diagnostic investigations varied across centres with direct antiglobulin test (DAT) performed in 6/7 AIHA patients, and bone marrow examination (BME) performed in 5/7 ITP patients. Anti-neutrophil antibodies were screened for in all AIN cases and detected in 1 patient. Multiple lines of therapy were required for patients with ITP, AIHA and Evans syndrome with 42.1%(n=8) of these patients not responding, and a further 26.3% (n=5) relapsing after initial complete response (CR) to first-line therapy. 1 ITP patient exhibited disease refractory to 3 lines of therapy including splenectomy. 2 AIHA patients achieved CR, and 1 patient with Evans syndrome achieved partial response following 4 lines of therapy. 2 AIN patients did not require treatment; 1 AIN patient achieved PR after first line treatment with granulocyte-colony stimulating factor (G-CSF), and a second achieved CR after second-line treatment with G-CSF and Rituximab.ConclusionsWith a cumulative incidence of 4.4% (2.6-6.3%) over 5 years, AICs are a clinically challenging and potentially life-threatening complication of alloHSCT for aAA. Patients receiving non-myeloablative conditioning regimens incorporating Fludarabine and/or Alemtuzumab, and those receiving PBSC are at higher risk of this complication. Diagnosis of AIC should be considered and investigated in cases of new or worsening cytopenia at any stage post alloHSCT for aAA. Standardization of diagnostic and therapeutic approaches, along with data registration (via the EBMT and other databases), is warranted to inform harmonized recommendations for management. [Display omitted] DisclosuresSnowden:Sanofi: Honoraria. Bader:Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding. Peffault De Latour:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

Identifying Risk Factors for Acute and Chronic Graft-Versus-Host Disease in T-Replete HLA-Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide

Introduction: Acute(aGVHD) and chronic graft-versus-host disease (cGVHD) cause significant morbidity and mortality in patients post hematopoietic cell transplantation (HCT). The use of T-replete HLA-haploidentical transplantation (HIDT) with post-transplant cyclophosphamide has become a common donor source for patients lacking a suitably matched donor. In spite of the increase in HIDT, there is paucity of data describing aGVHD and cGVHD outcomes and potential risk factors for developing graft-versus-host disease after HIDT.Methods: The outcomes and the characteristics of 203 patients undergoing first allogeneic transplantation using HIDT with post-transplant cyclophosphamide between 2005 and 2016 were retrospectively assessed to identify the incidence and risk factors for aGVHD and cGVHD. Variables included in the analysis included patient related (age, sex, race, karnofsky, HCT-CI), disease related (diagnosis, disease type, disease risk index DRI, CIBMTR risk status) and transplant related (graft source as marrow vs peripheral blood, donor age, donor/recipient relationship, donor/recipient gender match, donor/recipient CMV match, conditioning intensity, high dose TBI in conditioning intensity, CD34 cell dose, CD3 cell dose and year of transplant). Univariate analysis with Gray's test and log-rank was carried for cumulative incidence and survival respectively. The proportional hazard cox model was used with backward elimination to select significant covariates. Multivariate analyses for developing GVHD, overall survival (OS), disease free survival (DFS), and relapse were conducted.Results: The median age was 51 years (range 19, 75) with a median follow up for survivors of 37 months. Seventy patients (34%) received bone marrow as graft source and 43% had Myeloablative conditioning. All patients received GVHD prophylaxis consisting of post-transplant cyclophosphamide on Days +3 and +4, MMF till day +35 and tacrolimus till day +180. The cumulative incidence for aGVHD grade II-IV and grade III-IV were 45% and 12% respectively. The common organs involved in aGVHD were skin (76% of cases, 39% stage 3 /4), gut (58% of cases, stage 3 /4 11%) and liver (7% of cases, stage 3 /4 of 1%). Subsequent aGVHD flare developed in 6 patients (5 with gut GVHD and 1 skin GVHD). The cumulative incidences of all grade cGVHD and moderate-severe cGVHD were 32% and 24% respectively (table 1). Conditioning intensity was the only risk factor associated with developing grade 2-4 aGVHD (p=0.04). Patients that received myeloablative regimens as compared to those who received a reduced intensity or non-myeloablative regimen had statistically higher rates of grade 2-4 aGVHD (hazard ratio [HR] of 1.52 (95% CI, 1.01-2.29, p=0.04). Risk factors for cGVHD showed that race and hematopoietic cell transplantation-comorbidity index (HCT-CI) had a statistically significant bearing on the likelihood of developing all-grade cGVHD (p=0.004 and 0.01 respectively). Graft source (marrow vs Peripheral blood) was a significant risk factor for developing moderate-severe cGVHD (p=0.03). Multivariate analysis on OS, DFS and relapse showed that Patients aged 55 or older (HR of 1.91, 95% CI 1.22-2.99, p =.005) and High/very high DRI risk (HR 2.06, CI 1.05-4.00, p=0.03) had worse overall survival rates. Older age, not developing chronic GVHD and receiving a transplant between 2005 and 2010 were all associated with a worse DFS (P<0.01 for all). High/very high DRI, male gender and not developing cGVHD were all significant factors for a higher relapse rate.Conclusions: This single center analysis of GVHD incidence and risk factors after HIDT using post-transplant cyclophosphamide showed that conditioning intensity, graft source and HCT-CI to be factors affecting incidence of GVHD. Higher disease risk and older patient age were associated with worse overall survival. [Display omitted] DisclosuresSolh:Amgen: Speakers Bureau; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau.

Association between Esophageal Dysmotility and Long-Term Outcomes in Lung Transplant Recipients

<h3>Purpose</h3> Esophageal dysmotility is very common in patients with end-stage lung disease and post lung transplant and is thought to predispose to allograft injury through higher risk of aspiration. We routinely test lung transplant recipients for esophageal dysmotility with High Resolution Manometry (HRM) at 3 months post-transplant. We hypothesize that lung transplant recipients (LTRs) with significant esophageal dysmotility are more likely to develop lung injury leading to CLAD and death. <h3>Methods</h3> Among 1753 LTRs transplanted at our center between July 2000 and June 2018, we retrospectively analyzed 426 patients who had HRM with a 24 hour-pH impedance study available post-transplantation. Esophageal hypomotility was defined as >= 30% of failed and/or simultaneous esophageal contractions, while esophageal hypermotility was defined as evidence of higher amplitude on HRM. Cox proportional hazards models adjusted for age, sex, native lung disease, CMV matching, and transplant type (single vs double) were used to determine the association between esophageal dysmotility and death/retransplant or CLAD. <h3>Results</h3> Esophageal hypomotility and hypermotility was found in 120 (28%) and 22 (5%) patients, respectively. Mild, moderate, and severe hypomotility was found in 58 (48%), 14 (12%), and 48 (40%) patients, respectively. In multivariate analyses, esophageal hypermotility or hypomotility was not associated with CLAD (HR 0.59 [95% CI 0.21-1.60]; HR 0.79 [95% CI 0.52-1.19]). or death (HR 0.53 [95% CI 0.16-1.68]; HR 0.62 [95% CI 0.37-1.03]). The risk of CLAD or death did not vary by severity of hypomotility. <h3>Conclusion</h3> In a large single-center lung transplant cohort study, we have determined that esophageal dysmotility is not associated with CLAD or death. Concurrent GI co-morbidities, such as reflux and gastroparesis, may play a role in modifying this risk. Additionally, center-specific approaches to patient selection and/or treatment may be related to outcomes and will be further assessed in future studies.

Intra-Subject Variance of Respiratory Oscillometry Reflects Graft Injury and is Associated with Acute Rejection and Chronic Lung Allograft Dysfunction (CLAD) Post Lung Transplant (LTx)

Purpose CLAD occurs in 50-70% of LTx patients by year 5 and is the major obstacle to longterm survival. Multiple factors contribute to CLAD, of which acute rejection (AR) is the most significant. Routine monitoring with spirometry aims to identify and treat AR early. We reported that the oscillometry (Osc) metrics of small airway obstruction and ventilatory inhomogeneity, AX, X5 and R5-19, are more sensitive than spirometry in detecting AR associated graft injury. Hypothesis Osc detects AR associated graft injury and predicts risk of CLAD. Methods All double LTx recipients were enrolled from Dec 2017 onwards for Osc with each routine spirometry. By Mar 13, 2020, 238/287 enrolled patients had follow-up of ≥3 months while 170 had ≥6 months, of whom 32 developed CLAD. We excluded 6 CLAD cases due to insufficient Osc measurements by CLAD-onset date. Cox regression factored in the initial, baseline (the average of 2 best achieved post LTx) and intra-subject variance of AX, X5 and R5-19; demographics, primary diagnosis, CMV match status, HLA status and biopsy A-score, a cumulative index of biopsy-proven ARs. Results Cox analysis in 170 patients with ≥ 6 months follow up found higher A-scores to increase the risk of CLAD (HR 1.60, p Conclusion We provide evidence that 1) Osc metrics of lung function reflect graft injury associated with AR and 2) intra-subject variance in Osc measurements is a marker of ongoing graft injury that provides a risk assessment of subsequent CLAD. As such, post LTx graft monitoring with Osc can improve early detection of CLAD.

Effect of Mycophenolate Mofetil Dosing on 6-month Risk of Acute Cellular Rejection, Leukopenia and CMV Viremia in Heart Transplant

<h3>Purpose</h3> Mycophenolate mofetil (MMF) is a cornerstone of heart transplant (HT) therapy. MMF dose is associated with leukopenia and infections (eg CMV). Despite widespread use, the optimal MMF dose to balance risk of rejection with leukopenia and infection is unknown. Our center recently transitioned from a high-dose (HD) 3g/day to low-dose (LD) 2g/day MMF protocol. We tested whether LD-MMF is associated with: i) lower rates of leukopenia and CMV, and ii) comparable rates/severity of acute cellular rejection (ACR) at 6-months after HT. <h3>Methods</h3> 108 pts who received HT between 6/16 to 8/20 were included. Pts were categorized based on LD- vs HD-MMF. ACR was defined according to ISHLT criteria. A total rejection score (TRS) was calculated as follows: 0R=0, 1R=1, 2R=2, 3R=3 by dividing summed scores by total number of biopsies during study period. Leukopenia = WBC<4.0x10⁹/L. Between-group differences in freedom from ACR, leukopenia and CMV at 6-months were evaluated by KM method. Adjusted Hazard Ratios (HRs) were calculated from Cox proportional models. <h3>Results</h3> Baseline characteristics of HD- (n=71) vs LD-MMF (n=37) pts were similar including WBC and CMV match status; 80% vs 86% of pts were discharged at target doses. 59 ACR, 71 leukopenia and 10 CMV events occurred at 6-months. Freedom from first ACR, leukopenia and CMV in HD- vs L`D-MMF are shown in Fig 1a-c. Total ACR events in HD- vs LD- MMF group were 50/722 (6.9%) biopsies in 71 pts vs 9/272 (3.3%) biopsies in 37 pts. However, ACR events in HD-MMF group were less likely to be high grade (≥2R): 12% vs 55% (<i>p</i>=.002). TRS did not differ between groups: .075±.12 vs .05±.11, <i>p</i>=.08. After multivariable adjustments, HD-MMF was associated with higher risk of any ACR (HR=2.23, <i>p=</i>.043) and higher risk of leukopenia (HR=1.71 <i>p</i>=.049) (Fig 1d). <h3>Conclusion</h3> LD-MMF was associated with less leukopenia. However this came at the cost of more clinical significant ≥2R rejections. Further studies are warranted to address the long-term implications of these findings.

Chromosomal Aberrations in Pre-HCT Blood Samples and Outcomes after Transplantation in Patients with Myelofibrosis

Introduction: Allogeneic hematopoietic cell transplantation (HCT) is curative for myelofibrosis (MF). However, prognosis post HCT is variable. Identifying subsets of patients who can greatly benefit from HCT is important for clinical decision-making and patient counseling. The Dynamic International Prognostic Scoring System (DIPSS) score includes cytogenetic abnormalities provides important prognostic information. Here, we used high-resolution single nucleotide polymorphism (SNP) arrays to characterize chromosomal aberrations in pre-HCT blood samples from patients with MF and evaluated their added value in patient risk stratification for post HCT survival. Methods: We used the Illumina Global Screening Array to detect somatic copy number alterations (SCNAs) sized ≥2Mb (by calculating the log2 R ratio and B allele frequency and leveraging haplotype information) in pre-HCT blood samples (collected 2-4 weeks prior to HCT conditioning regimen administration) from 923 MF patients who underwent HCT between 2000-2016. Clinical data and blood samples were obtained from the Center for International Blood and Marrow Transplant Research. We used Kaplan-Meier survival analysis and multivariable Cox regression to evaluate the prognostic significance of observed SCNAs on survival after HCT. Results: Median age at HCT was 58 years (range=0.7-76). About 58% were males (N=536), 85% received unrelated donor HCT (N=787), 90% received peripheral blood stem cell grafts (N=826), 47% (N=429) received myeloablative conditioning (MAC), 34% (N=312) received HCT within 1 year from diagnosis, and 537 patients (58%) had known DIPSS score at HCT (47% of them were intermediate II or high). A high frequency of SCNAs were noted in MF (N=623; 67.5%), most commonly on chromosome (chr) 9p (N=224, 24%), chr13q (N=104, 11%), and chr20q (N=102, 11%) (Figure 1). Aberrations noted on chromosomal regions harboring the known MF genes (MPL, DNMT3A, TET2, EZH2, JAK2, SRSF2, CALR, ASXL1, U2AF1) accounted for 28% of all detected (40% of the patients), including JAK2 (9p24.1, N=253, 27%), MPL (1p34.2, N=30, 3.3%) and CALR (19p13.13, N=23, 2.5%). Multivariable models including all MF genes (adjusted for DIPSS score, KPS, year of HCT, hemoglobin count, splenectomy, age, sex, time from diagnosis to HCT, and stratified on CMV match, graft type and conditioning regimen) showed an association between SCNAs on TET2 or SRSF2 regions and poor survival (HR for TET2 =2.40, 95% CI=1.33-4.32, p=0.004; and HR for SRSF2= 2.22, 95% CI=1.26-3.89, p=0.006). TET2 region aberrations were associated with an increased risk of transplant-related mortality (TRM) (HR=2.97, 95% CI=1.53-5.78, p=0.001), worse disease-free survival (DFS; HR=2.22, 95% CI=1.33-3.69, p=0.002), but not the risk of relapse (p=0.12). SRSF2 region aberrations were associated with DFS (HR=1.94, 95% CI=1.11-3.37, p=0.02); no statistically significant association was noted with the risk of relapse (p=0.07) or TRM (p=0.44). These associations were predominant in patients receiving reduced intensity (RIC) or non-myeloablative regimens (Figure 2). Further univariate analyses focusing on all frequently affected chromosomes (affecting ≥10 patients) showed poor OS with SCNAs on chr17p (log-rank p&amp;lt;0.0001), 12p (p&amp;lt;0.0001), 5q (p&amp;lt;0.0001), 13q (&amp;lt;0.001), 8q (p=0.004), 18q (p=0.02) and 4q (p=0.03). In multivariable models stratified on conditioning regimens, chr17p aberrations showed a significant association with excess risk of relapse independent of regimen intensity (HR=5.31, p=0.01 in MAC, and HR=2.70, p=0.02 in RIC). The HR for OS was 2.55, p=0.09, and 2.86, p=0.002, respectively. Other chromosomal aberrations that showed significant associations with inferior OS in patients receiving RIC were SCNAs on chr8q (HR=5.55, p&amp;lt;0.001) (Figure 3), with excess risk of TRM (HR=5.09, p=0.002) but not relapse (p=0.34). In patients that received MAC, elevated risk of mortality was noted with chr5q SCNAs (HR=2.83, p=0.02) with a suggestive association with relapse (HR=2.72, p=0.08) but not with TRM (p=0.59). Conclusion: This study highlights the prognostic ability of pre-HCT detected SCNAs in patients with myelofibrosis, independent on DIPSS score. Relapse risk in patients with aberrations affecting TP53 region was not eliminated by MAC. Follow-up studies to confirm the poor prognosis of those chromosomal changes are warranted. Disclosures Lee: Incyte: Consultancy, Research Funding; Syndax: Research Funding; Kadmon: Research Funding; AstraZeneca: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Research Funding; Novartis: Research Funding.

Younger HLA-Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplantation (allo-HCT) for Myelodysplastic Syndromes (MDS) Is Associated with Superior Disease-Free Survival Compared to Older HLA-Identical Sibling Donors: CIBMTR Analysis

Background: When older MDS patients present for allo-HCT, HLA-identical sibling donors who are eligible to donate are usually the preferred choice. The age of the HLA-identical sibling donor is likely to be advanced as well. However, the choice between an older HLA-identical sibling donor and younger HLA-matched unrelated donor remains unclear. Methods: Using the center for international blood and marrow transplant research (CIBMTR) database, we identified adults aged ≥50 years with MDS who underwent allo-HCT from older HLA-identical sibling donor (age ≥50) or younger 8/8 (HLA-A, -B, -C and -DRB1) well matched unrelated donor (MUD) (age ≤ 35) between the years 2011-2017. In prior studies, compared to older MUD, allo-HCT from MUD younger than age 35 was associated with superior outcomes (Shaw BE et al. BBMT 2018, Kollman C et al. Blood 2016, CIBMTR internal data). Hence, in the current analysis, the MUD arm was restricted to those aged ≤35. Key exclusion criteria were allo-HCT from mismatched unrelated donor, haploidentical donor, cord blood donor and ex-vivo T-cell depleted grafts. Overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM), relapse, acute and chronic graft versus host disease (GVHD) were evaluated. Survival analysis was done using Kaplan-Meier method and significant predictors were evaluated using Cox-proportional hazard regression method. Multivariate regression model included main effect (donor age group) and covariates (patient age, gender match, CMV match, disease subtype, R-IPSS at HCT, comorbidities score (HCT-CI), Karnofsky performance status, prior therapy, interval between diagnosis and transplant, conditioning intensity, stem cell source, GVHD prophylaxis, ATG/campath use, transplant year, and center affect). Fine and Gray (F-G) model for competing risks was used for analysis of NRM and relapse. Results: Of 1761 patients who met the study criteria, 646 patients received allo-HCT from older HLA-identical sibling and 1115 patients from younger MUD. Cohorts were similar for age, sex, Karnofsky performance status, HCT-CI, R-IPSS at HCT, time from diagnosis to transplant, prior therapy, graft type and conditioning intensity. Notable differences between donor groups included donor age (HLA identical sibling donor- median age 61.3 years vs. MUD- median age 25.2 years) and use of ATG/campath (HLA identical sibling donor 14% vs MUD 37%). In multivariable analysis, there was a significant difference in DFS (p=0.01) but not OS (p=0.14) among donor groups. Compared to MUD ≤35 years, DFS was inferior in HLA identical sibling donor age ≥60 but not in HLA-identical sibling donor age 50-59 (Table 1) (Figure 1A). In multivariate analysis using Fine and Gray model, the risk of relapse was significantly higher in patients receiving allo-HCT from HLA-identical sibling donor compared to MUD≤35 (Table 1, figure 1B). There was no significant difference in NRM between HLA-identical sibling donors and MUD ≤35 (overall p=0.07, table 1). HLA-identical sibling donor cohort was associated with lower risk of acute GVHD (p&amp;lt;0.001) and chronic GVHD (overall p=0.007) as compared to MUD ≤35 cohort (table 1). Results were consistent across all subgroups. Conclusions: Our results demonstrate a superior DFS that is mediated by superior disease control for MDS patients undergoing allo-HCT from younger MUD compared to older HLA-identical sibling donors. Our results should inform donor selection algorithms for older MDS patients undergoing allo-HCT. Disclosures Nakamura: Alexion: Other: Support on a meeting presentation; Kadmon Corporation: Other: Advisory board meeting; Kyowa-Kirin: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; Magenta Therapeutics: Other: Advisory board meeting; Viracor: Consultancy; Celgene: Other: Support on seminar; NapaJen Pharma: Consultancy. Oran:Celgene: Consultancy; ASTEX: Research Funding; Arog Pharmaceuticals: Research Funding. Scott:BMS, Novartis: Research Funding; Alexion, Incyte, Novartis, Regeneron: Consultancy; Agios, BMS: Honoraria.

Association between Esophageal Dysmotility and Long-Term Outcomes in Lung Transplant Recipients

Esophageal dysmotility is very common in lung transplant recipients and is thought to predispose to allograft injury through higher risk of aspiration. At our center, we routinely test lung transplant recipients for esophageal dysmotility with High Resolution Manometry (HRM) at 3 months post-transplant. We hypothesize that lung transplant recipients (LTRs) with significant esophageal dysmotility are more likely to develop lung injury leading to CLAD and death. Among 1753 LTRs transplanted at our center between July 2000 and June 2018, we retrospectively analyzed 426 patients who had HRM with a 24 hour-pH impedance study available post-transplantation. Esophageal hypomotility was defined as >=30% of failed and/or simultaneous esophageal contractions, while esophageal hypermotility was defined as evidence of higher amplitude on HRM. Cox proportional hazards models adjusted for age, sex, native lung disease, CMV matching, and transplant type (single vs double) were used to determine the association between esophageal dysmotility and death/retransplant or CLAD. Esophageal hypomotility and hypermotility was found in 120 (28%) and 22 (5%) patients, respectively. Mild, moderate, and severe hypomotility was found in 58 (48%), 14 (12%), and 48 (40%) patients, respectively. In multivariate analyses, esophageal hypermotility or hypomotility was not associated with CLAD (HR 0.59 [95% CI 0.21-1.60]; HR 0.79 [95% CI 0.52-1.19]). or death (HR 0.53 [95% CI 0.16-1.68]; HR 0.62 [95% CI 0.37-1.03]). The risk of CLAD or death did not vary by severity of hypomotility. In a large single-center lung transplant cohort study, we have determined that esophageal dysmotility is not associated with CLAD or death. Concurrent GI co-morbidities, such as reflux and gastroparesis, may play a role in modifying this risk. Additionally, center-specific approaches to patient selection and/or treatment may be related to outcomes and will be further assessed in future studies.

Significantly Increased Risk of Grade II-IV Acute Gvhd in Adolescent and Young Adult (AYA) Recipients (ages ≥13 years) Vs Childhood Recipients (ages 2-12 years) with Acute Leukemia Following Matched Unrelated Donor (MUD) Stem Cell Transplantation (SCT): The Children's Oncology Group Experience

<h3>Background</h3> Adolescent and young adult (AYA) acute leukemia patients have inferior outcomes in comparison to their younger counterparts, related to higher risk disease and increased toxicity (Hochberg J, et al., BJH, 2013). AYA recipient age (≥13 years) vs children (ages 2-12 years) has been associated with increased acute and chronic graft versus host disease (GVHD) in matched sibling donor SCT (Qayed M, et al., BBMT, 2017). <h3>Objective</h3> To determine the association between recipient age (age ≥13 years vs age 2-12 years) and risk of acute grade II-IV and chronic GVHD following MUD SCT in acute leukemia recipients. <h3>Methods</h3> We reviewed all pediatric and young adult recipients receiving a MUD SCT enrolled on Children's Oncology Group clinical trials ASCT0431, AAML03P1, AAML0531, AAML1031 from 2004-present. Variables assessed included age at transplant, sex, race, performance score, leukemia type (ALL vs AML), remission (CR1 vs CR2), stem cell source, donor/recipient ABO, CMV, and sex matching, GVHD prophylaxis, year of transplant, time from diagnosis to transplant. Overall survival (OS), event-free survival (EFS), acute and chronic GVHD were assessed with Kaplan-Meier curves, cumulative incidence curves, and multivariable Cox proportional hazard models. <h3>Results</h3> Four-hundred eighty-six children and young adults underwent transplant on these trials, including 205 patients undergoing MUD SCT. For the MUD population, 8% were under age 2 years, 58% were age 2-12, and 34% were age 13-29. Seventy-one percent of patients had AML in CR1; 8% had ALL in CR1; 21% had ALL in CR2. Stem cell source included bone marrow (48%), peripheral blood stem cells (14%), and cord blood (38%). Complete HLA match in 60%, 1 allele HLA mismatch in 27%, 2+ HLA mismatches in 13%. Five-year OS and EFS rates (± standard error) for MUD were 48.4±3.8% and 44.6±3.6%, respectively. In multivariable analysis, older recipient age was associated with a significant increase in grade II-IV acute GVHD, hazard ratio or HR (95% CI) =2.03(1.28, 3.22) for age ≥13 vs age 2-12, p=0.004 (see Figure 1). HLA mismatches (≥2) were associated with grade II-IV acute GVHD, HR=2.35(1.30, 4.24) for ≥2 HLA mismatches vs matched, p=0.039 (see Figure 2). Older recipient age was not associated with chronic GVHD (p=0.83). However, significant association was found between chronic GVHD vs leukemia type and remission status (p=0.007; see Figure 3), with ALL in CR2 having more chronic GVHD than did AML in CR1 (HR=3.54(1.56, 8.03)). Acute GVHD, as expected, was a risk factor for the development of chronic GVHD (HR=2.18(1.03, 4.60), p=0.040). <h3>Conclusion</h3> Older recipient age (ages ≥13 years vs ages 2-12 years) was associated with significantly increased risk of grade II-IV acute GVHD in patients with acute leukemia following MUD SCT. Further evaluations of differential toxicity of AYA vs younger pediatric patients undergoing MUD SCT are underway.

Hematopoietic Cell Transplantation Donor Selection Reimagined: KIR-KIR Ligand Interactions and a Formalized Donor Risk Index Effective at Predicting Survival

When selecting a human leukocyte antigen (HLA) matched unrelated donor (URD) for hematopoietic cell transplantation (HCT) it is generally accepted that donor age, sex, ABO blood group and viral serologic status should be considered. However, the inter-relationship among these variables is not well established and a consensus on how strongly to consider each variable has not been reached. Selection of the optimal donor gets more complicated as new donor recipient pair (DRP) selection parameters, including killer immunoglobulin-like receptors (KIR) haplotypes are included. In this study we seek to develop a logic-based method to reduce the inconsistencies in donor selection in the HLA matched HCT. Retrospective review of eligible adults with known KIR genotyping receiving HLA-A, B, C & DRB1 allelically matched URD HCT for hematologic malignancy. Donor recipient pairs were selected based on donor age, sex match, CMV sero-status match, and ABO compatibility when possible; KIR genotype was not considered in DRP selection. KIR-KIR ligand interactions were calculated for each DR pair and interaction unit values were ascribed as previously described and each DRP IM KIR score (eq. 1) was calculated. IM KIR Score = |iKIR| + |mKIRL| [1] Weights of each donor risk variable (age, sex, CMV & ABO match) contribution were ascribed using Cox regression methods and summed up to determine donor risk parameter. Donor risk parameters and reciprocal-IM-KIR were finally combined into a donor risk index. Ninety-eight DRP with known HLA & KIR genotyping were studied. A higher IM-KIR score describes a DRP with increased iKIR-KIR ligand interactions and missing KIR ligand interactions; which was associated with a favorable survival after HCT, HR of 0.44 (95%CI: 0.26 to 0.73; P=0.002). Univariate analysis of overall survival for donor age, sex match, ABO compatibility and CMV status were all statistically insignificant (p>0.05). Donor risk parameter was predictive of mortality with a hazard ratio (HR) of 2.76 (95% CI: 1.22-6.18, p=0.014). Combining the two into a donor risk index was predictive of survival with a HR of 2.38 (1.44-3.92, p=0.001). ROC-AUC comparison of survival for IM-KIR score and donor risk parameter showed AUCs of 0.63 and 0.67 respectively. Further, the combined donor risk index shows improved sensitivity and specificity over the donor risk parameter with AUCs of 0.72 and 0.67 respectively. A novel IM-KIR score independently predicts survival in HLA matched DRP, as does a formalized donor risk parameter which includes non-HLA donor characteristics. Moreover, their addition enhanced the specificity and sensitivity of predicting survival in these patients. If validated in a larger exploration and validation cohort this method of donor selection may improve the donor selection process, decreasing variability in clinical outcomes and improve overall survival.

A study of selected hematopoietic stem cell donors provided by an intermediate size registry.

Planning new hematopoietic stem cell (HSC) donor recruitment strategies requires a sound understanding of the factors underlying donor selection, especially considering HLA-matching criteria. A total of 182 consecutive workups of Swiss donors performed from 2014 to 2017 were analyzed for HLA match level, locus disparities, number of potentially 10/10 matched donors in the international database, donor ranking on the lists, donor date of registration, age, ABO, CMV, gender matching, patient genotype frequency, and country performing the search. Matching status of the selected donors was 10/10 for 38.5%, 10-12/12 for 35.1%, and 8-9/10 for 26.4% donors, without differences in average donor age in the three categories. HLA-A and -C mismatches were most frequent and -DRB1 very rare. 8.2% patients were matched for HLA-DPB1 (12/12). ABO matching was 46.3%, and CMV matching was 59.1%. Based on "HaploStat"-derived genotype frequencies, 50.3% patients belonged to the "good," 38.5% to the "fair," and 11.2% to the "poor" search prognosis categories. 37.9% of transplants were gender-mismatched, and 42.3% of donors were female. HLA typing quality (high resolution, all loci typed), great diversity of haplotypes and donor age are main factors impacting the selection of Swiss donors, while gender and ABO matching seem to be of secondary importance.

Outcomes of Salvage Haploidentical Transplant with Post-Transplant Cyclophosphamide for Rescuing Primary Graft Failure Patients : A Report By the SFGM-TC

Abstract Prognosis of graft failure patients is dismal, and another transplant is the sole option for long-term survival. Currently, there is no consensus concerning the best option for treating patients undergoing primary graft failure and finding a new donor within an acceptable delay is challenging. In the last years, haploidentical transplants with post-transplant cyclophosphamide (PT-Cy) have shown acceptable results in the treatment of many hematological diseases, including some cases of graft failure. To address the interest of haploidentical transplants as a salvage option in this context, we retrospectively collected and analyzed data from 26 primary graft failure (PGF) patients transplanted between 2011 and 2017 in 15 centers belonging to the Francophone Society for Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). Inclusion criteria were the occurrence of PGF defined as non-achievement of a minimum absolute neutrophil count of 500/μL without evidence of disease relapse at D+28 after transplantation and the use of a haploidentical transplantation with PT-Cy as graft-versus-host-disease (GvHD) prophylaxis. Continuous variables are presented as medians and inter-quartile range. They were compared between groups using the Wilcoxon rank sum. Categorical variables are presented with counts and percentages and were compared using the Fisher exact test. All tests were 2-sided, and a p-value below 0.05 was considered to be significant. Analyses were performed using the R statistical platform (version 3.4.1). This study was performed according to the Declaration of Helsinki and was approved by the SFGM-TC scientific council. Nineteen patients had a diagnosis of myeloid malignancy (8 acute myeloid leukemias, 4 myelodysplastic syndromes, 4 myeloproliferative neoplasms, 1 unclassified myeloid disorder), 3 had a lymphoid neoplasm, and 4 had a bone marrow failure syndrome (2 acquired and 2 congenital). Twenty-four patients had previously received an allogeneic transplantation, and 2 had already failed two previous allogeneic transplants. Male/female ratio was 2.25. Median age at haploidentical transplant was 42 years (2-58). Fifteen patients received peripheral blood as stem cell source, and 11 received bone marrow. Eleven transplants were female to male. Twelve patients received an ABO-matched graft, 6 had a major ABO-incompatibility, 7 a minor incompatibility and one missing data. The median number of infused CD34+ cells was 5.2 x106/kg (1.2 - 12.5). There was no ex-vivomanipulation of cells. CMV matching was available for 22 transplantations, of which 6 were high-risk (seropositive recipient with a seronegative donor). Fludarabine-based reduced intensity conditioning was used in all but one patient who received clofarabine + 4Gy TBI. Twenty patients received TBI 2Gy. Three patients received ATG. Fourteen patients received the Baltimore regimen (53%). The median delay between the previous and the salvage transplantation was 77 days (39-1161). All patients received PT-Cy associated with cyclosporine, and 24 patients also received MMF for GvHD prophylaxis. Median follow up was 487 (16-2010) days. The cumulative incidence (CI) of neutrophil recovery at day 30 was 81%, and the median time to neutrophil engraftment was 19 (13-34) days. Four patients (15%) presented primary graft failure and died within a median time of 5 (3-8) weeks after transplantation of infectious complications. Cumulative incidence of grade II-IV aGvHD at day-100 was 13%, and 1-year CI of cGvHD was 32%. One-year CI of relapse was 16%. Overall survival was 58% at 1 year (Figure 1; confidence interval: 39-85). Among the 22 patients who engrafted, 6 patients died. HSCT complications accounted for 80% of the causes of deaths (4 multiorgan failure, 1 GvHD, 1 interstitial pneumonitis, 1 bacterial infection, 1 post-transplant lymphoproliferative disorder). To the best of our knowledge, this is the first cohort describing the outcomes of haploidentical transplants with PT-Cy rescuing patients with primary graft failure. Our cohort presents promising outcomes in a particularly challenging situation, suggesting that haploidentical transplants with PT-Cy might appear as a valid salvage strategy for patients with PGF. Prospective well-designed trials are urgently needed before the inclusion of Haplo-PT-Cy in the treatment strategy of patients with PGF. Figure 1. Figure 1. Disclosures Mohty: MaaT Pharma: Consultancy, Honoraria. Peffault De Latour:Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Classification of Donor KIR-Genotype Information to Predict Outcome after Unrelated Hematopoietic Stell Cell Transplantation: The Jury Is Still out

Introduction:A series of studies suggest that harnessing natural killer (NK) cell reactivity by killer cell immunoglobulin-like receptor (KIR) genotype based unrelated donor selection could further improve outcome after allogeneic hematopoietic cell transplantation (alloHCT). A Receptor-Ligand model has been proposed for donor selection which aims at augmenting NK cell activation while minimizing inhibition. Information on education of KIR2DS1-positive NK cells (Venstrom et al, NEJM 2012) and the predicted Receptor-Ligand interaction of KIR3DL1-positive NK cells is utilized for this algorithm. By combining this information donors can be classified as KIR-advantageous or disadvantageous. Patients with donors, characterized by activating KIR2DS1 and weak/non-inhibiting KIR3DL1, experienced less relapse and improved survival compared to patients with donors, characterized by lacking an activating KIR2DS1 but presence of strong-inhibiting KIR3DL1. This study aimed at validating this predictor in an independent cohort of patients.Methods:Donor samples were retrieved from the Collaborative Biobank (Dresden, Germany) and mapped to patient outcome data extracted from the German Registry for Stem Cell transplantation. KIR typing was performed using a high resolution amplicon-based next generation sequencing method. KIR typing at the allele level was based on sequencing of exons 3, 4, 5, 7, 8, and 9. The patient population was restricted to patients with AML or MDS. Donor and patient mapping was cross-checked by HLA-typing of the donor sample. The impact of the predictor on overall survival was tested in a Cox regression model adjusted for patient age, a modified disease risk index, performance status, donor age, HLA-match, sex match, CMV match, conditioning intensity, type of T-cell depletion and graft type.Results:Clinical data from 2314 patients were analyzed. The median age at alloHCT was 59.4 years (range, 18.1 to 79.6 years). The indication for alloHCT was AML for 80% of patients and MDS for 20% of patients. Disease risk was assessed as low, intermediate, high or very high in 1%, 52%, 42%, and 5%, respectively. Patient and donor were 10/10 matched in 78% of pairs, whereas a one locus mismatch was reported for 21% of pairs. Myeloablative, reduced-intensity and non-myeloablative conditioning regimens were used in 29%, 67%, and 4% of patients, respectively. ATG was administered in 77% and alemtuzumab in 3% of patients. Twenty percent of patients received no T-cell depletion.In total, 535 patients experienced relapse and 945 patients died. This number of events translated into a power of the confirmatory analysis for the predictor of KIR2DS1 and KIR3DL1 of 67%. Two-year overall and event-free survival for the whole cohort was 51% (95%-CI 48% to 53%) and 44% (95%-CI 42% to 47%) and the 2-year incidence of relapse and non-relapse mortality was 28% (95%-CI 26% to 30%) for both endpoints. In univariate analysis, overall survival (54% versus 56%) and the cumulative incidence of relapse of patients with a KIR-advantageous donor were comparable to patients with KIR-disadvantageous donors. The adjusted hazard ratio from the multivariable Cox regression model for the comparison of patients with KIR-advantageous versus KIR-disadvantageous donors was 0.99 (Wald-test, p=0.95) for overall survival and 1.12 (Wald-test, p=0.41) for relapse incidence.When evaluated separately, the two components of the predictor (degree of inhibition by KIR3DL1 & presence of activating KIR2DS1) did not have an impact on overall survival or the incidence of relapse (see Figure). Also, evaluation of the combined predictor in subsets of patients by disease, type of T-cell depletion and HLA-compatibility did not allow prediction of these outcomes.Conclusions:Relapse incidence and overall survival after unrelated donor alloHCT could not be predicted using information on activating KIR2DS1 and inhibiting KIR3DL1 donor genes in an independent cohort of predominantly Caucasian patients. The predictor had been developed in a cohort of patients with AML who were younger and predominantly had received myeloablative conditioning based on total-body irradiation, ATG was administered less often, but donors often were only partially HLA-compatible. The different outcome in the current analysis thus points at potential interactions between NK-cell mediated allo-reactivity and procedural variations of alloHCT. [Display omitted] DisclosuresSchetelig:Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Roche: Honoraria; Abbvie: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Stelljes:Novartis: Honoraria; MSD: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; JAZZ: Honoraria; Amgen: Honoraria. Ayuk:Therakos (Mallinckrodt): Honoraria; Novartis: Honoraria; Celgene: Consultancy; Gilead: Consultancy. Bethge:Neovii GmbH: Honoraria, Research Funding; Miltenyi Biotec GmbH: Consultancy, Honoraria, Research Funding. Bug:Neovii: Other: Travel Grant; Novartis Pharma: Honoraria, Research Funding; Janssen: Other: Travel Grant; Celgene: Honoraria; Amgen: Honoraria; Astellas Pharma: Other: Travel Grant; Jazz Pharmaceuticals: Other: Travel Grant. Kobbe:Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding; Amgen: Honoraria, Research Funding. Beelen:Medac: Consultancy, Other: Travel Support. Fleischhauer:GENDX: Research Funding.

Analysis of 10,462 8/8 HLA- Matched Unrelated Donor Transplants Could Not Identify a Donor Selection Score, As Younger Age Is the Only Significant Donor Characteristic Associated with Survival

▪Background. There is no hierarchical algorithm that weights the characteristics of individual donors against each other in a quantitative manner to facilitate donor selection when multiple potential equally HLA-matched unrelated donors (URD) are available. Donor factors, such as age, sex, CMV status, ABO type, and matching of secondary HLA loci (DQB1, DPB1), have been associated with recipient survival in URD hematopoietic cell transplantation (HCT) although the impact of specific factors has varied among studies. The goal of this study was to develop and validate a donor selection score that prioritizes donor characteristics associated with better survival in 8/8 HLA-matched URD transplantation.Methods. Two large CIBMTR patient datasets were studied: HCT from 1999-2011 (n=5952) and 2012-2014 (n=4510). Patients were adults (>18), transplanted for acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), or myelodysplastic syndrome (MDS). Each dataset was randomly split for the analysis. Cohort 1 (c1): 2/3 (n=3969) for modeling/score development (training) and 1/3 (n=1983) for testing and similarly for cohort 2 (c2): 2/3 (n=3051) and 1/3 (n=1459). Thus, two independent models were built and tested, adjusting for significant patient characteristics associated with survival. Interactions between donor characteristics, and donor and recipient characteristics were tested. The following donor characteristics were considered for the donor score: HLA-DQB1 matching, HLA-DPB1 matching (using the T-cell epitope matching categorization), age, sex matching, parity, CMV matching, ABO matching and race matching.Results. In the final survival model (training set from 1999-2011, c1) we found significant negative associations with survival for three donor risk factors: non-permissive DPB1 matching (HR 1.13; 95% CI 1.01, 1.26; p-value=0.032), older donor age (as a linear effect, HR 1.07 per decade increase in age; 95% CI 1.02, 1.12, p-value=0.004), and CMV mismatching for CMV+ recipients (HR 1.14; 95% CI 1.02, 1.27; p-value=0.022). For CMV- recipients, a CMV+ donor was not significantly associated with an increase in mortality (HR=1.03; 95% CI 0.89-1.20; p-value=0.68), so this was not included in the score. ABO mismatching (any type: major, minor or bidirectional) was associated with mortality in initial modelling, but the effect was not present in more recent transplants (HR for ABO mismatch among patients transplanted since 2007: 1.04; 95% CI 0.91-1.19; p-value=0.638), so it was not included in the final model and donor score. Based on these results a donor risk score was constructed, however this score was not validated in the testing set (c1), nor were any of the individual component donor factors significantly associated with worse overall survival. In the second cohort (c2), only donor age was significantly associated with worse survival, and it validated in the independent test set from c2. Since donor age was significant in 3 of the 4 cohorts, we quantified the impact of donor age in the validation set of the most recent cohort, c2. We found that choosing a donor 2, 5, 10 or 20 years older was associated with a 1%, 2%, 3% or 7% decrease in 2 year OS, adjusted for patient characteristics.Conclusion. Despite data on over 10,000 URD transplants, we were unable to develop a valid donor selection score. The only donor characteristic associated with better survival was younger age, with 2-year survival being 3% better when a donor is 10 years younger. We did not test other endpoints; it is possible that separate scores could be generated to predict the risk of other outcomes (e.g. graft failure, graft-versus-host disease), however, unless the adverse donor characteristics are identical for these outcomes, centers will still have to prioritize the various donor characteristics to select from a pool of potential donors. This large data set shows that none of the other easily available donor clinical and genetic factors tested were reproducibly associated with survival and hence, flexibility in selecting URD based on these characteristics is justified. These data support a simplified URD selection process and have significant implications for URD registries. DisclosuresPorter:Incyte: Honoraria; Genentech/Roche: Employment, Other: Family member employment, stock ownship - family member; Servier: Honoraria, Other: Travel reimbursement; Novartis: Honoraria, Patents & Royalties, Research Funding; Immunovative Therapies: Other: Member DSMB. Lee:Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Mallinckrodt: Honoraria; Kadmon: Other: One-time advisory board member.

Outcomes of Kidney Transplantation with a CMV Matching Allocation Schema

BackgroundCytomegalovirus (CMV) infection continues to be a major cause of morbidity in kidney transplant recipients. The CMV donor-positive (D+)/recipient-negative (R−) serostatus pairing poses highest risk for CMV disease.MethodsIn September 2012, we adopted a CMV matching allocation policy at the centers served by our organ procurement organization, the Pacific Northwest Transplant Bank. CMV serostatus was used as a criterion in determining deceased donor kidney allocation, whereby R− kidney transplant recipients were preferentially paired with a D− organ, and R+ recipients with an R+ organ. We performed a retrospective analysis of CMV-related outcomes for 400 consecutive kidney recipients, 196 prior to (January 1, 2010– August 31, 2012) and 204 following (September 1, 2012–December 3, 2014) implementation of the CMV matching allocation schema at our center. We also looked at waitlist time for patients transplanted during the same period.ResultsThe percentage of D+/R− transplants performed decreased from 17.3% to 2.5% (P < 0.001) after implementation of the CMV matching allocation strategy (Figure 1). CMV viremia decreased from 13.3% to 5.9% (P = 0.0118), and CMV syndrome or disease decreased from 9.2% to 2.9% (P = 0.00859) (Table 1). The percentage of patients treated for CMV infection overall decreased from 10.7% to 5.4% (P = 0.0498). Median days on the waitlist prior to transplantation increased from 793 (PRE) to 944 (POST) due to growing wait list size, but neither R− nor R+ patients appeared to be disadvantaged: wait times increased from 808.5 to 958 for the R− subset and from 777.5 to 933 for the R+ subset (Figure 2).ConclusionCMV disease occurred infrequently in our cohort, in the context of 6 months of valganciclovir prophylaxis post-transplant and post-prophylaxis pre-emptive monitoring strategy for our D+/R− recipients. Following implementation of an allocation schema that took CMV serostatus into account, the rate of CMV infection and antiviral treatment decreased significantly.Table 1.Pre n (%)Post n (%)CMV viremia26 (13.3)12 (5.9)CMV syndrome13 (6.6)1 (0.05)7 D+/R– 4 D+/R+ 2 D–/R+1 D+/R−CMV disease5 (2.5)5 (2.5)4 D+/R+ 1 D+/R−4 D+/R+ 1 D−/R−# treated for CMV21 (10.7)11 (5.4)Lymphocyte depleting immune suppression91 (46.4)46 (22.5)Disclosures L. Strasfeld, Merck: Independent Contractor, Salary

Recipient/donor HLA and CMV matching in recipients of T-cell-depleted unrelated donor haematopoietic cell transplants.

Improving haematopoietic cell transplantation outcomes by selection of an HLA-matched unrelated donor is best practice; however, donor selection by secondary characteristics is controversial. We studied 1271 recipients with haematological malignancies who underwent T-cell-depleted allografts and had complete data on HLA-matching status for six loci (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1) and clinical outcome data. Five-year overall survival was 40.6%. HLA mismatching (at HLA-A, -B, -C, -DRB1, -DQB1) relative risk (RR) 1.22, 95% confidence interval (CI) 1.2-1.5, P=0.033 for 1 mismatch and RR 1.46, 95% CI 1.1-1.9, P=0.009 for >1 mismatch) and CMV mismatching (RR 1.37, 95% CI 1.2-1.6, P<0.001) were significantly associated with inferior survival. Donors aged <30 years showed a trend towards better survival. The multivariate model for mortality, combining CMV and HLA-match status, found an RR of 1.36 (95% CI 1.1-1.7, P=0.003) for HLA matched/CMV mismatched, an RR of 1.22 (95% CI 0.99-1.5, P=0.062) for HLA mismatched/CMV matched and an RR of 1.81 (95% CI 1.4-2.3, P=<0.001) for HLA/ CMV mismatched, compared with the HLA/CMV-matched recipients. These data suggest that HLA and CMV matching status should be considered when selecting unrelated donors and that CMV matching may abrogate the effect of an HLA mismatch.