CMV Serological Status Research Articles

A Prospective, Multi-Center, Randomized, Controlled Clinical Trial to Explore the Role of Mesenchymal Stem Cells in Preventing Graft Versus Host Disease

Background: There are few studies currently available on the prevention of GVHD by mesenchymal stem cells (MSCs) that use a systematic approach to prevent both aGVHD and cGVHD simultaneously. The clinical investigation of MSCs preventing either aGVHD or cGVHD independently is the main focus of the earlier studies. Aim:Using the strategy of co-transplantation of MSCs and HSCs and phased application of MSCs after transplantation (MSCs 100-day scheme), we seek to develop a secure and dependable system that can avoid both aGVHD and cGVHD based on our preliminary research. Method:Patients undergoing haploidentical adult hematopoietic stem cell transplantation will receive unaltered, fourth-generation UC-MSCs(Umbilical Cord). In addition to the usual GVHD preventive measures, UC-MSCs are given four hours before the transplantation of peripheral blood stem cells on day 0. UC-MSCs are administered once weekly for 1-4 weeks, once every 2-8 weeks, and once every 4-12 weeks after transplantation. The dose needed for each transfusion is 1 10 6/kg. Our research will look at how well UC-MSCs prevent GVHD following haplo-HSCT, as well as recurrence rates after transplantation, transplant-related issues, and the state of immunological reconstruction. the frequency, severity, 1- and 2-year survival rates, cumulative death rates, and the occurrence of aGVHD and cGVHD.Real-time tracking will be performed to monitor the occurrence of aGVHD and cGVHD, as well as their severity, frequency, 1-year and 2-year survival rates, and cumulative mortality rates. The analysis of the differences between the control group and the experiment will take into account the pre-transplant ferritin levels, CMV serological status of the donor-recipient, blood type matching situation, HLA locus matching situation, disease remission status, residual disease conditions, recipient age, donor-recipient gender matching situation, stem cell quantities (nucleated cells and CD34+ cell counts), and stem cell numbers (nucleated cells and CD34+ cell counts). Results: 96 patients from the MSCs group and 96 patients from the control group are now accessible for statistical purposes. Demographic factors for age and gender distribution do not differ considerably. Acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome-EB2, and acute mixed cell leukemia,which were all classified as having the same level of risk. The cumulative incidence of aGVHD grades II to IV is 19.8% in the MSCs group, while grades III to IV is 0%. Comparable indications for the control group are 43.8% and 9.3%, respectively. The overall incidence of aGVHD differs between the two groups in a statistically significant way (P=0.0047). The rates of moderate and severe cGVHD in the control group were 10.4% and 9.4%, respectively, whereas they were 13.5% and 4.2% in the MSCs group. Over the course of 1 year, the cumulative incidence of cGVHD for the MSCs group was 36.5%, compared to 39.6% for the control group. Regarding the overall two-year OS, there is no discernible difference between the MSCs group and the control group (P=0.43).While the MSCs group outperformed the control group in terms of GRFS (GVHD free and relapse free survival). Conclusion: The strategy of MSCs 100-day scheme infusion can successfully lower the incidence of acute and chronic GVHD and is beneficial for enhancing patient GRFS.

The Presence of Recipient CMV Immunodominant Human Leukocyte Antigen (HLA) Alleles Affect Outcomes after Haploidentical (HI) Hematopoietic Stem Cell Transplantation (HSCT)

CMV reactivation is associated with increased treatment-related mortality (TRM), decreased overall survival (OS), and in some analyses, protection from relapse after HSCT. We previously showed that CMV reactivation was significantly higher in HI versus matched related HSCT recipients receiving an identical preparatory regimen, implicating HLA mismatch as a contributor to reactivation. It is known that specific CMV immunodominant HLA alleles (CMV ID alleles) are associated with more efficient antigen presentation and protection from CMV. We hypothesized that a match at a CMV ID allele in the shared haplotype of the donor and recipient pairs may overcome the disadvantage proffered by HI HSCT with respect to CMV. As a control, we tested whether the presence of a CMV ID allele in either the donor or recipient, as opposed to a match at the CMV ID allele, was the more important impactor of outcomes. This information would potentially impact donor selection and identify HI recipients with greater risk for CMV-related complications.MethodsThis is a retrospective, analysis of 138 HI HSCT recipients at risk for CMV reactivation as defined by the presence of positive CMV serologic status in the recipient, donor, or both. All recipients were treated on the Jefferson 2 step approach in which after conditioning, a fixed T cell dose (2 x 108/kg) is administered (step 1), followed 2-3 days later by cyclophosphamide (CY) for bidirectional tolerization. Two days after CY, patients receive a CD34-selected donor product (step 2). To be included in the analysis, patients had to successfully engraft and be alive for at least 1 month post HSCT. Outcomes related to CMV, 1) reactivation incidence, 2) peak copy number of initial CMV reactivation occurring by d+100, 3) TRM, 4) relapse related mortality (RRM), and 5) OS, were tested in 3 contexts: the presence vs the absence of a CMV ID allele in the recipient or the donor, or the presence or absence of a donor/recipient (R/D) match at the same CMV ID allele. CMV ID alleles were defined as HLA A01:01, A02:01, A24:02, B07:02, B08:01, B35:01 and C07:02. Statistics used: incidence of CMV reactivation=Chi-Square; comparison of peak CMV copy numbers=T-test; assessment of RRM and NRM=cumulative incidence (CI); OS=Kaplan-Meier method.Results:A CMV ID allele was present in 68.1% recipients and 66.7% donors. 41.7% of D/R pairs were matched at the same CMV ID allele. The incidence of CMV reactivation was not associated with a D/R CMV ID allele match or recipient or donor CMV ID allele positivity. Peak CMV levels were lower in the presence of any recipient or donor CMV ID allele, but only approached significance in D/R pairs matched at the same CMV ID allele (p=0.065) with a mean of 8.7 x 10e3 vs 4.1 x10e4 copies/ml by PCR in matched vs non-matched pairs respectively. At 3 years, in recipients who matched their donor at 1 or more CMV ID alleles vs those who had no match, CI of NRM was 28% vs 26% (p=0.48) and 16% vs 32% (p=0.07) for RRM. In recipients with vs without a CMV ID allele CI of NRM was 23% vs 36% (p=0.059) and 20% vs 36% for RRM (p= 0.02) (Figure). In recipients with donors who possessed a CMV ID allele vs not, CI of NRM was 27% vs 28% (p=0.80) and 21% vs 31% for RRM (p= 0.12). OS in recipients who were matched at the same CMV ID allele with their donors or who possessed a CMV ID allele was 51% vs 37% (p=0.062) and 52% vs 27% (p=0.001) respectively as compared to recipients negative for these alleles.Conclusion:This analysis suggests that matching HI D/R pairs at a CMV ID epitope may reduce CMV peak copy number but has no significant effect on post HSCT reactivation. Recipient positivity for a CMV ID allele was strongly associated with improvement in NRM, RRM, and OS. Whether the benefit is specific to improved CMV control or to a more efficient antigen presentation in general by these alleles is unknown, but should be further investigated. This data requires confirmation with multivariate analysis. [Display omitted] DisclosuresWagner:Novartis: Research Funding.

Interpretation of AlloMap® in Clinically Stable Combined Heart-Kidney Transplant Recipients

PurposeAs the number of patients undergoing heart-kidney transplantation (HKT) increases, new strategies for dual organ surveillance emerge. AlloMap® gene expression profiling is a widely adopted non-invasive tool utilized to monitor immune quiescence after heart transplant (HT) with the recommended threshold to rule out cellular rejection being 34. The interpretation of AlloMap® in combined HKT surveillance is not well defined. We aimed to determine the utility of AlloMap® for heart surveillance in stable HKT recipients.MethodsAlloMap® data collected from two transplant centers were reviewed retrospectively. Clinically stable patients with HKT (study group) and HT (control group) were included in the study. The HKT and HT cohorts were matched for age, ethnicity, sex, renal and cardiac function, and CMV serologic status. Serial AlloMap® distributions versus time were analyzed by two-sample Kolmogorov-Smirnov (K-S) analysis.ResultsThe study included 25 HKT recipients and 25 HT recipient matched controls transplanted between 1993 and 2020. Over the observed follow-up period (55 days to 18.4 years), there was no difference in AlloMap® scores between groups. In the time interval from 6 months to 24 months, the median AlloMap® scores were higher for HKT vs HT, 33.00 [95% CI, 29.87-34.08] vs 30.00 [95% CI, 28.99-30.92], p=0.028. The 1-year survival in both cohorts was 100% with no cardiac graft dysfunction or biopsy proven rejection (≥2R).ConclusionAlloMap® scores were slightly higher in HKT vs HT recipients between 6 months and 24 months post-transplant. As the HKT AlloMap® scores are near the threshold for possible acute cellular rejection, further investigation is warranted to define interpretation of AlloMap® in combined HKT surveillance. As the number of patients undergoing heart-kidney transplantation (HKT) increases, new strategies for dual organ surveillance emerge. AlloMap® gene expression profiling is a widely adopted non-invasive tool utilized to monitor immune quiescence after heart transplant (HT) with the recommended threshold to rule out cellular rejection being 34. The interpretation of AlloMap® in combined HKT surveillance is not well defined. We aimed to determine the utility of AlloMap® for heart surveillance in stable HKT recipients. AlloMap® data collected from two transplant centers were reviewed retrospectively. Clinically stable patients with HKT (study group) and HT (control group) were included in the study. The HKT and HT cohorts were matched for age, ethnicity, sex, renal and cardiac function, and CMV serologic status. Serial AlloMap® distributions versus time were analyzed by two-sample Kolmogorov-Smirnov (K-S) analysis. The study included 25 HKT recipients and 25 HT recipient matched controls transplanted between 1993 and 2020. Over the observed follow-up period (55 days to 18.4 years), there was no difference in AlloMap® scores between groups. In the time interval from 6 months to 24 months, the median AlloMap® scores were higher for HKT vs HT, 33.00 [95% CI, 29.87-34.08] vs 30.00 [95% CI, 28.99-30.92], p=0.028. The 1-year survival in both cohorts was 100% with no cardiac graft dysfunction or biopsy proven rejection (≥2R). AlloMap® scores were slightly higher in HKT vs HT recipients between 6 months and 24 months post-transplant. As the HKT AlloMap® scores are near the threshold for possible acute cellular rejection, further investigation is warranted to define interpretation of AlloMap® in combined HKT surveillance.

Genetic T-cell receptor diversity at 1 year following allogeneic hematopoietic stem cell transplantation.

After allogeneic hematopoietic stem cell transplantation (HSCT), immune reconstitution leads to the development of a new T-cell repertoire. Immune reconstitution could be influenced by events such as conditioning, infections, and graft versus host disease (GVHD). Factors influencing the TCR diversity are of great interest to fine-tune the strategy for donor selection and to optimize standard of care. In this work, immunosequencing of the TCR CDR3β region was carried out in a large cohort of 116 full chimeric recipients at 1 year post-HSCT and their respective donors prior to transplantation. The repertoire overlap before and after HSCT was minimal, supporting de novo reconstitution as a primary pathway at any age. Among the parameters investigated, increased patient and/or donor age as well as positive CMV serologic status reinforced by CMV infection/reactivation were the ones significantly associated with a reduced diversity at 1 year post-HSCT. CMV-specific T-cell clones were shown to influence the clonality of the repertoire alongside the expansion of limited numbers of non-CMV T-cell populations. Interestingly, at the exception of CMV infection/reactivation, TCR diversity was not predictive of GVHD, relapse, death, or infections post-HSCT.

The Impact of Cytogenetics on the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed/Refractory Acute Myeloid Leukemia: A Survey from the Acute Leukemia Working Party (ALWP) of EBMT

Abstract Introduction: Diagnostic karyotype is one of the most important determinants of initial response to treatment, remission duration and overall survival in Acute Myelogenous Leukemia (AML). Moreover, risk stratification of AML based on cytogenetic abnormalities is a key parameter for the success rate and outcome of allogeneic stem cell transplantation (allo-SCT) in AML. However, while the prognostic significance of chromosomal abnormalities is well established during frontline therapy, its influence at time of salvage therapy in Primary Refractory (Ref) and Relapsed (Rel) AML and the role of allo-SCT in this subset, remains uncertain. Patients and methods: This was a survey from the EBMT registry which included adult AML patients undergoing allo-SCT for Ref/Rel AML from HLA-matched related or 9/10 - 10/10 unrelated donor (UD) between 2000 and 2017. Patients were stratified according to cytogenetic risk as defined by Grimwade et al. (Blood 2010). Primary endpoint was Leukemia-Free Survival (LFS). Secondary endpoints were relapse cumulative incidence (RI), non-relapse mortality (NRM), overall survival (OS), acute and chronic GVHD and GVHD-relapse-free Survival (GRFS). Results: 2089 patients with Ref AML (n=972) and Rel AML (n=1117) were analyzed: 154 patients had a favorable risk, 1283 were in intermediate risk and 652 had an adverse cytogenetic risk. Median follow-up was 49 months. Patients and transplant characteristics are summarized in table 1. Patients in the favorable risk group were younger and transplanted more frequently in first or second relapse. Patients in the adverse risk group received more frequently transplants from 9/10 UD. FLT3-ITD mutation was present in 18%, 43% and 16% of the favorable, intermediate and adverse risk groups, respectively (p<10-3). The 3 groups were not significantly different in terms of Karnosfky score, patient and CMV serology status and conditioning intensity (myeloablative or reduced). Outcome correlated with cytogenetic category, with a percentage of complete remission within 100 days after transplant of 79%, 69% and 61% (p<10-3), RI at 2 years were 42%, 51% and 61% (p<10-5), LFS and OS rates were 34%, 27%, 18% and 41%, 33%, 22% in favorable, intermediate and adverse risk group (p<10-5 for both LFS and OS), respectively. Non-relapse mortality, on the contrary, did not differ among the three groups (24%, 21% and 21%, respectively; p=NS). We performed a multivariate analysis adjusting for all factors differing between risk groups and factors known as influencing outcome of AML patients after allograft. Compared to the favorable risk group, intermediate risk group was associated with a higher RI (HR=1.58; 95% CI: 1.17-2.14; p=0.003), lower LFS (HR=1.39; 95% CI: 1.09-1.77; p=0.008), lower OS (HR=1;47; 95% CI: 1.14-1.90; p=0.003) and lower GRFS (HR=1;29; 95% CI: 1.03-1.61; p=0.03). The adverse risk group was associated with a higher RI (HR=2.27; 95% CI: 1.65-3.10; p<10-5), lower LFS (HR=1.86; 95% CI: 1.44-2.40; p<10-5), lower OS (HR=1.89; 95% CI: 1.44-2.47; p<10-5) and lower GRFS (HR=1.62; 95% CI: 1.28-2.06; p<10-4; Figure1). In a subgroup analysis of patients in intermediate or adverse risk groups with available information on FLT3-ITD status, adverse cytogenetics remained an important prognostic factor for RI (HR=1.55; 95% CI: 1.22-1.97; p=0.0004), LFS (HR=1.37; 95% CI: 1.12-1.68; p=0.002), OS (HR=1.38; 95% CI: 1.11-1.70; p=0.003) and GRFS (HR=1.31; 95% CI: 1.08-1.59; p=0.006) compared to the intermediate risk group. Other poor prognostic factors in this population were presence of FLT3-ITD mutation, Rel vs Ref status at transplant, Karnofsky score <80%, use of bone marrow as stem cell source and patient CMV serology positivity. In vivo T cell depletion was associated with a lower risk of acute and chronic GVHD and a better GRFS. Conclusion: In Rel and Ref AML karyotype remains an important prognostic factor for those patients undergoing allo-SCT in active disease phase, allowing to separate patients into different risk groups. Moreover, FLT3-ITD mutation remains a negative prognostic factor in this population. Disclosures Beelen: Medac: Consultancy, Other: Travel Support. Tischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Mohty:MaaT Pharma: Consultancy, Honoraria.

1590. A Hybrid CMV Prevention Strategy Is Effective in Preventing CMV Disease Outcomes in Pediatric Solid Organ Transplant Patients

BackgroundOptimal CMV prevention strategies for pediatric solid-organ transplant (SOT) patients have not been clearly defined for early and late post-transplant periods.MethodsWe analyzed CMV prevention strategies in liver, kidney, heart, lung and intestinal SOT patients from 2005 to 2015 in our institution. A hybrid strategy was defined as prophylaxis for ≤6 months post-transplant and then transition to a pre-emptive strategy.ResultsOf 833 patients, 769 were prophylaxis and 62 were hybrid strategies. Compared with prophylaxis, hybrid patients were more likely to have a D−/R− CMV serology status, be ≤1 year old and have a heart transplant (P < 0.001). We found no significant differences in CMV disease frequency, rejection or mortality between hybrid and prophylaxis groups. In total, we found 13 cases of CMV disease, of which 1 was a hybrid and the rest a prophylaxis strategy. The median time to CMV disease was 1.5 years from transplant. We found more allograft rejection (n = 9) in patients with CMV disease compared with patients with CMV infection or no Infection. For the same comparisons, no significant difference was found for age or type of organ transplant. Late rejection was frequent (n = 6/13, 67%) in patients with CMV disease, and the majority were not started on empiric anti-virals with the rejection episode. In contrast, no CMV disease was found in patients who had late rejection and received empiric anti-viral with the rejection episode, even though these patients had increasing CMV DNAemia (P = 0.04).ConclusionIn the early post-transplant period, a hybrid CMV prevention strategy is effective with similar clinical outcomes compared with a prophylaxis strategy, even in younger CMV naïve patients and relatively more immune suppressed heart transplant patients. A hybrid strategy may provide effective long-term control of intermittent CMV replication as suggested by the low frequency of CMV disease in this group compared with prophylaxis. In the late post-transplant period, administering episodic empiric anti-virals with a rejection diagnosis may be necessary to prevent CMV disease associated with late rejection episodes.Disclosures All authors: No reported disclosures.

Irradiation and prolonged storage of red cells are associated with increased adverse events.

Red blood cell (RBC) transfusion is associated with the most transfusion-related adverse events (AE). Recent clinical studies showed no significant difference in transfusion-associated mortality between fresh and older RBCs. However, the impact of storage duration as well as irradiation on nonfatal yet much more common complications has not been fully investigated. In this retrospective study of RBC transfusion-associated AEs, a total of 188,562 units of leucocyte-reduced RBCs were transfused in approximately 5·5 years. After excluding washed, deglycerolized, autologous or directed RBCs and RBCs transfused during a massive transfusion protocol, 149,052 units were analysed. Attributes of RBCs including storage time, collection method, CMV serological status and gamma irradiation, as well as the recipient's gender, were analysed. A total of 358 RBC transfusion AEs were categorized into allergic and non-allergic reactions and analysed. Univariate and multivariate logistic analyses showed that irradiated RBCs were associated with a significantly increased frequency of non-allergic reactions (OR (95% CI): 1·89 (1·52, 2·35); P < 0·001). There was a significant association between the frequency of non-allergic reactions and the storage time of irradiated RBCs (OR (95% CI): 1·024 (1·001, 1·048); P = 0·042). In contrast, there was no association between the frequency of allergic reactions and the storage time of irradiated RBCs or between the age of non-irradiated RBCs and the frequency of non-allergic reactions. Prolonged storage of irradiated RBCs was associated with a significant increase in non-allergic transfusion reactions. Overall, the irradiated RBCs appeared to cause more non-allergic reactions compared with non-irradiated RBCs.

Comparable survival using a CMV-matched or a mismatched donor for CMV+ patients undergoing T-replete haplo-HSCT with PT-Cy for acute leukemia: a study of behalf of the infectious diseases and acute leukemia working parties of the EBMT.

The role of donor CMV serostatus in the setting of non T-cell depleted haplo-HSCT with post-transplant cyclophosphamide (PT-Cy) has not been specifically addressed so far. Here we analyzed the impact of the donor CMV serological status on the outcome of 983 CMV seropositive (CMV+), acute leukemia patients receiving a first, non T-cell depleted haplo-HSCT registered in the EBMT database. The 1-year NRM was 21.3% (95% CI: 18.4-24.8) and 18.8% (95% CI: 13.8-25.5) in the CMV D+/R+ and D-/R+ pairs, respectively (p = 0.40). Similarly, 1-year OS was 55.1% (95% CI: 50.1-58.0) and 55.7% (95% CI: 48.0-62.8) in the same groups (p = 0.50). The other main outcomes were comparable. No difference in NRM nor OS was observed after stratification for the intensity of conditioning and multivariate anaysis confirmed the lack of significant association with NRM or OS. In conclusion, the choice of a CMV-seronegative donor did not impair early survival of CMV-seropositive patients with acute leukemia after a first, non T-cell depleted haploidentical HSCT and PT-Cy among this series of 983 consecutive patients. Future research may focus on the assessment of the hierarchy of all the donor variables.

Clinical Characteristics, Biological Markers and Comorbidity Indexes As Predictors of Transplant-Related Mortality after Allogeneic Hematopoietic Stem Cell Transplantation: Which One Should We Choose?

Treatment-related mortality (TRM) after allogeneic hematopoietic stem cell transplantation (HSCT) is a major concern and remains difficult to predict adequately. Several pre-transplant characteristics of patients and disease are associated with TRM. Comorbidity indexes, including pre-transplant assessment of mortality (PAM) and the hematopoietic cell transplantation comorbidity index (HCT-CI), have been developed in an attempt to predict TRM. Biologic markers, such as ferritin, C-reactive protein (CRP) and, more recently, telomere length, also correlate with TRM. However, the cumulative impact of these factors on TRM has not been addressed. Here, we investigated the impact of pre-transplant clinical factors, comorbidity indexes and biologic markers on TRM in 670 consecutive patients from a single center who received a first allogeneic HSCT between January 2006 and June 2012. Clinical factors considered were: year of transplantation, donor and recipient ages, gender and CMV serological status, disease risk (based on the American Society for Blood and Marrow Transplantation Request for Information 2006 risk scoring schema), stem cell source, and HLA matching. Comorbidities were evaluated by PAM and HCT-CI, and coded prospectively for all patients by a single observer. HCT-CI and PAM scores were ranked into previously published categories (0, 1-2, ≥3 for HCT-CI and 9-16, 17-23, 24-30 and 31-44 for PAM; Sorror, Blood 2005; Parimon, Annals Intern. Med. 2006). Ferritin, CRP and biological data for comorbidity indexes were recorded within 2 weeks prior to HSCT. Recipient telomere lengths were determined in peripheral blood leukocytes by qPCR and adjusted for age by the telomere attrition rate observed in donors.Our analysis categorized the population into quartiles and divided patients into 2 groups: shorter telomeres (first quartile) versus longer telomeres (upper 3 quartiles). The entire patient cohort was subsequently divided into 3 groups by data availability: Group 1 (G1), the entire population (n=670) for whom all clinical data were available; G2, 488 patients with clinical and comorbidity index data (pulmonary function tests were not systematically performed during the early study period); and G3, for whom pre-transplant telomere length was available (n=178). Univariate and multivariate methods developed by Fine and Gray for competing risks studies were used to assess prognostic TRM factors, with relapse as a competing event. Table 1 shows patient characteristics. Significant differences between G1 and G2 were found for mean donor and recipient ages, sex mismatch, HLA matching, stem cell source, disease risk, and year of transplantation. Median follow-up was 36 months, overall survival at 5 years for the entire cohort was 60%, and TRM was 18%. In G1, factors significantly associated with higher TRM in multivariate analysis were: recipient age (HR, 1.02, 95%CI [1.0-1.03], p=0.005), CMV seropositive recipient/seronegative donor (R+/D-) (HR, 1.98, 95%CI [1.34-2.92], p=0.001) and mismatched unrelated donor (MMUD) (HR, 2.28, 95%CI [1.38-3.74], p=0.001). In G2, the same factors [recipient age (HR, 1.01, 95%CI [1.00-1.03], p=0.027), CMV R+/D- (HR, 1.91, 95%CI [1.22-2.99], p=0.005), MMUD (HR, 2.55, 95%CI [1.48-4.42], p=0.001)] were associated with higher rates of TRM, whereas PAM showed a trend for higher TRM (HR, 1.41, 95%CI [0.99-1.99], p=0.05). HCT-CI, ferritin, and CRP were not associated with TRM. In G3, only MMUD (HR, 2.82, 95%CI [1.06-7.46], p=0.037) was associated with higher TRM. However, in analysis restricted to patients transplanted from an HLA-matched related or unrelated donor, recipient age (HR, 1.03, 95%CI [1.00-1.06], p=0.027) and telomere length (HR, 2.45, 95%CI [1.07-5.59], p=0.033) were independently associated with higher TRM. This is the first study to investigate the impact of clinical and biological pre-transplant factors and comorbidity indexes on TRM after allogeneic HSCT in a large cohort of patients. Best results were obtained with young patients transplanted from an HLA-matched donor, with CMV other than R+/D-. High comorbidity scores (evaluated by PAM) were marginally associated with higher TRM. In G3 (pre-transplant telomere length available), only HLA-mismatch was significantly associated with higher TRM. [Display omitted] DisclosuresPeffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding.

The Use of Anti-Thymocyte Globulin Is Associated with Increased Chance of Survival Free from Relapse and Graft-Versus-Host Disease after Allogeneic Peripheral Blood Stem Cell Transplantation for Adults with Philadelphia-Negative Acute Lymphoblastic Leukemia: An Analysis By the Acute Leukemia Working Party of the EBMT

BACKGROUNDAllogeneic hematopoietic stem cell transplantation (allo-SCT) is considered a standard of care for adults with high risk Philadelphia-negative acute lymphoblastic leukemia (Ph-neg ALL). During the last decade mobilized peripheral blood stem cells (PBSCT) has become predominant source of graft for allo-SCT. However, as compared to bone marrow, PBSCT is associated with increased risk of chronic graft-versus-host disease (cGVHD). Attempts to reduce the cGVHD rate include the addition of anti-thymocyte globulin (ATG) to the conditioning regimen. The goal of this registry-based, retrospective study was to analyze the effect of ATG on results of allo-PBSCT in adults with Ph-neg ALL. PATIENTS AND METHODS682 patients, aged 18-74 years, with Ph-neg ALL, treated with un-manipulated allo-PBSCT in first complete remission between 1997-2014 were included in the analysis. Conditioning regimen was myeloablative in 550 (81%) cases. Among 339 transplantations from matched sibling donors, ATG was used in 57 (22%) cases. In the 8/8 HLA-matched unrelated setting 204/343 (78%) patients were treated with ATG. Survival free from grade III-IV acute GVHD, cGVHD and relapse (GRFS) was the primary study end-point. RESULTSIn a univariate analysis the use of ATG was associated with increased probability of GRFS at 3 years (46% vs 38%, p=0.02) as well as decreased incidence of the overall cGVHD (34% vs. 51%, p=0.0001) and extensive cGVHD (12% vs. 25%, p<0.0001). No significant difference could be demonstrated with regard to the incidence of grade II-IV acute GVHD (30% vs. 33%, p=0.41), grade III-IV acute GVHD (8% vs. 11%, p=0.12), relapse (28% vs. 26%, p=0.38) and non-relapse mortality (NRM, 15% vs. 17%, p=0.21) as well as probability of leukemia-free survival (LFS, 57% vs. 57%, p=0.89) and overall survival (OS, 65% vs. 65%, p=0.54).In a multivariate model adjusted for other potential risk factors, the use of ATG was associated with reduced risk of grade II-IV aGVHD (HR=0.64, p=0.007), grade III-IV aGVHD (HR=0.52, p=0.03), overall cGVHD (HR=0.61, p=0.001), extensive cGVHD (HR=0.4, p<0.0001), and NRM (HR=0.62, p=0.04). No significant effect was found with regard to the incidence of relapse (p=0.27), LFS (p=0.7) and OS (p=0.16). GRFS was significantly increased with the use of ATG (HR=0.74; p=0.009). Among other factors a chance of GRFS was significantly decreased with increasing patient age (HR=1.1 for each 10 years, p=0.02), transplantations with reduced-intensity conditioning (HR=1.61, p=0.0009) and positive recipient CMV serological status (HR=1.3, p=0.02). CONCLUSIONSPatients with Ph-neg ALL treated with allo-PBSCT benefit from the use ATG in terms of survival free from GVHD and relapse. The use of ATG should therefore be recommended in this setting. Further studies are needed to explore potential role of the ATG brand and dose. DisclosuresMasszi:Janssen-Cilag: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; Takeda: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees. Maertens:Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy.

Allogeneic Hematopoietic Cell Transplantation for Adult Patients with ALL: Current Results and Prognostic Factors. an Analysis from Acute Leukemia Working Party of the EBMT

BACKGROUNDAllogeneic HCT (alloHCT) with myeloablative conditioning is considered a standard of care for adult patients with high risk acute lymphoblastic leukemia (ALL). However, with improving results of conventional-dose chemotherapy and the introduction of novel agents the indications for alloHCT require re-evaluation, taking into account patient- and procedure-related factors. The aim of this study was to analyze most recent results of alloHCT for adult patients with ALL and to identify factors associated with outcome. PATIENTS562 patients aged 18-55 years (median 35 y) treated with alloHCT from either HLA-matched sibling (n=252) or unrelated (URD, n=310) donors in first complete remission (CR1) during the period 2008-2012 were included in the analysis. The diagnosis was B-ALL (n=430) or T-ALL (n=132). Ph-positive status was present in 225 (40%) cases. RESULTSThe probability of the overall survival (OS) at 2 years was 69%, leukemia-free survival (LFS) - 60%, relapse incidence - 22%, while, non-relapse mortality (NRM) was 17%. The cumulative incidence of grade II-IV acute graft versus host disease (GVHD) and chronic GVHD was 39% and 45%, respectively. In a multivariate analysis, the risk of treatment failure (either relapse or NRM) was increased for patients with high initial tumor burden (WBC >30 x109/L for B-ALL and >100 x109/L for T-ALL, HR=1.45, p=0.01) while, it was reduced for transplantations with conditioning based on total body irradiation (TBI, HR=0.63, p=0.02). The risk of relapse was increased in case of high initial WBC (HR=1.89, p=0.001) and Ph-positive ALL (HR=1.61, p=0.02) while, reduced for TBI-based conditioning (HR=0.48, p=0.004). Finally, the risk of NRM was increased for URD-HCT (HR=2.11, p=0.002) and in case of female donor to male recipient gender combination (HR=1.85, p=0.02). In the URD-HCT setting, a univariate analysis did not reveal significant effects of the level of HLA disparity on outcome. Similarly, other factors, including recipient age, ALL subtype (B vs T), donor/recipient CMV serological status, interval from diagnosis to HCT or the source of stem cells did not affect transplantation outcome. CONCLUSIONSOur registry based study indicates that myeloablative alloHCT performed between 2008-2012 for adult patients with ALL in CR1 result in impressive 2y OS and LFS of 69% and 60%, respectively. Among disease-related risk factors, high initial tumor burden is the strongest predictor of treatment failure. As for procedure-related factors, the choice of conditioning appears most important. Based on our current results, TBI - based regimens should still be strongly recommended. DisclosuresRambaldi:Roche: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene: Research Funding; Pierre Fabre: Honoraria.

(335) - Three Years Outcome of Virtual Crossmatch Strategy in Heart Transplant Recipients

s S131 visits. A novel approach for quantifying dd-cfDNA using targeted amplification and next-generation sequencing was used to quantify dd-cfDNA on 109 plasma samples from these 24 patients. 3 to 10 samples were collected between 2 months and 1 year post-transplantation for each patient. Most plasma samples had endomyocardial biopsy rejection grades and geneexpression profiling (GEP) test scores available from the same clinic visits. Results: Median dd-cfDNA was 0.79% (interquartile range [0.38%, 1.30%]). Total between-patient variability (51% CV) was similar to within-patient variability (45% CV). Analytical variability was 17%. The ratio of betweenpatient variability to within-patient variability was 1.6 times lower for ddcfDNA than for GEP. No effect of recipient gender, age, CMV serologic status, or time post-transplantation was seen on % dd-cfDNA measurements. Conclusion: In this longitudinal study of non-rejecting heart transplant recipients, the withinand between-patient variabilities of dd-cfDNA were shown to be of similar size, and significantly larger than the analytical variability of the assay. The ratio of between-patient variability to within-patient variability was significantly less than in GEP, suggesting that dd-cfDNA does not depend as strongly on patient-specific factors as does GEP. dd-cfDNA showed no dependence on patient age, gender, CMV serologic status, or time since transplant in this cohort. Taken together, these characteristics indicate that dd-cfDNA is a stable analyte in non-rejecting patients. (Study sponsored by CareDx, Inc.)

(337) - Pretransplant Serum BAFF in Heart Transplantation: A Potential New Biomarker for Acute Cellular Rejection Risk

s S131 visits. A novel approach for quantifying dd-cfDNA using targeted amplification and next-generation sequencing was used to quantify dd-cfDNA on 109 plasma samples from these 24 patients. 3 to 10 samples were collected between 2 months and 1 year post-transplantation for each patient. Most plasma samples had endomyocardial biopsy rejection grades and geneexpression profiling (GEP) test scores available from the same clinic visits. Results: Median dd-cfDNA was 0.79% (interquartile range [0.38%, 1.30%]). Total between-patient variability (51% CV) was similar to within-patient variability (45% CV). Analytical variability was 17%. The ratio of betweenpatient variability to within-patient variability was 1.6 times lower for ddcfDNA than for GEP. No effect of recipient gender, age, CMV serologic status, or time post-transplantation was seen on % dd-cfDNA measurements. Conclusion: In this longitudinal study of non-rejecting heart transplant recipients, the withinand between-patient variabilities of dd-cfDNA were shown to be of similar size, and significantly larger than the analytical variability of the assay. The ratio of between-patient variability to within-patient variability was significantly less than in GEP, suggesting that dd-cfDNA does not depend as strongly on patient-specific factors as does GEP. dd-cfDNA showed no dependence on patient age, gender, CMV serologic status, or time since transplant in this cohort. Taken together, these characteristics indicate that dd-cfDNA is a stable analyte in non-rejecting patients. (Study sponsored by CareDx, Inc.)

Pathological mechanisms of antiphospholipid antibodies in trophoblastic cell fusion

Pathological mechanisms of antiphospholipid antibodies in trophoblastic cell fusion

Pregnancy recall in decidual NK cells

Pregnancy recall in decidual NK cells

Donor Characteristics As Pretransplant Predictive Factors of Long-Term Outcomes After Allogeneic Peripheral Blood Stem Cell Transplantation From HLA-Matched Related and Unrelated Donors in Patients with Hematologic Malignancies

Abstract 2000▪▪This icon denotes a clinically relevant abstract Background:Over the past 20 years, allogeneic hematopoietic cell transplantation (HCT) has been increasingly performed with peripheral blood stem cells (PB) and gained benefit from better HLA-typing. Similar long-term survival has been suggested after HLA-matched related and unrelated donor HCT. Till now, the optimal strategy for donor selection is still controversial. We evaluated the impact of donor type (10/10 HLA-matched unrelated (MUD) vs. matched related (MRD)) and other donor traits on long term outcomes of patients with hematologic malignancies after PB HCT. Patients and Methods:We analyzed outcomes of 442 consecutive patients with hematologic malignancies who were transplanted with PB either from MUD (n= 164) or MRD (n=278) at our center from 01/2000 to 12/2010. Median patient age was 48 years (range 7–68). Diseases included 122 acute myelogenous leukemias, 62 non-Hodgkin lymphomas, 60 myelodysplastic syndromes, 57 multiple myelomas, 40 acute lymphoblastic leukemias, 37 myeloproliferative disorders, 29 Hodgkin diseases, 20 chronic myeloid leukemias and 15 chronic lymphocytic leukemias. Two-third of patients underwent HCT following reduced intensity conditioning. Graft-versus-host disease (GVHD) prophylaxis consisted mostly in cyclosporine plus MMF or methotrexate. ATG was used in 19% of HCT. We assessed the impact of donor factors (type, age, gender, CMV serologic status and ABO group) on chronic GVHD (cGVHD), relapse, non relapse mortality (NRM) and overall survival (OS). Concerning donor age, as the upper age limit for voluntary PB donation was usually 60 years, we completed our analysis by performing 3 groups according to donor type and age (MUD, MRD<60y and MRD≥60y) and evaluated their influence on outcomes. Donors:Median donor age was 40 years (range 18–72). Most young donors were MUD (<30y: 70%) while older were mainly MRD (≥50y: 98%). Thirty-six patients were transplanted with MRD≥60y. The proportion of female donors was 42% and 113 HCT were performed from female donor to male recipient. Half of patients were transplanted from CMV seronegative donors. Donor/recipient pairs (D/R) were CMV status mismatched in 38% of cases. D/R were ABO matched, minor and major mismatched in 57%, 19% and 24% of cases. Considering donor type, MUD and MRD HCT were balanced for patient age, disease risk and conditioning. MUD received ATG more frequently than MRD (29% MUD vs. 14% MRD [10% MRD<60y and 25% MRD≥60y], P <.0001). Results:The median follow-up (FU) was 36 months (range 2–133) and 25% of patients had a FU of at least 60 months. The cumulative incidence (CIf) of cGVHD at 2 years was 58%. In multivariate analysis, sex mismatch (female > male) increased risk of cGVHD (HR: 1.41 [95% CI 1.05–1.88], P=.02) while MRD≥60y resulted in lower risk (HR: 0.48 [0.25–0.94], P=.031). Donor type by itself did not impact on cGVHD (58% with MRD and 59% with MUD). At 5 years, the CIf of relapse was 34% and was higher with MRD than MUD (39% vs. 24%, P=.038). Adjusted for disease risk, conditioning and infused cells count, only MRD≥60y resulted in significant higher risk of relapse than MUD (HR 2.41[1.26–4.62], P=.008) while MRD <60y had similar risk. The 5 years NRM was 26%. MUD vs. MRD was associated with higher NRM (HR: 1.84 [1.20–2.83], P=.005). Adjusted for recipient age, conditioning, and infused cells count, only MRD<60y were associated with lower risk of NRM than MUD (0.55 [0.35 to 0.86], P=.008) while MRD≥60y had similar NRM. OS was 46% at 5 years and was similar with MUD and MRD. Considering age, MRD≥60y appeared to have notable low OS at 5 years (6%, SE 6%). Adjusted for recipient age, disease risk and infused cells count, HCT from MRD≥60y was associated with higher risk of late (≥18 months) mortality (HR: 4.44 [1.53–12.9], P=.006) than MUD (Fig. 1). Conclusion:Donor/recipient gender parity, donor type and age appeared as significant predictive factors of long term outcomes after HLA-matched PB HCT. Nor donor CMV status nor ABO group seemed to impact on outcomes in our cohort. The selection of a sex mismatched donor (female>male) was associated with significant higher risk of cGVHD. Using PB as graft source, HLA 10/10 MUD provided higher NRM but better disease control and similar OS than MRD. Having combined donor type and age, we observed notable poor outcome (high relapse rate and low OS) for patients transplanted with MRD≥60y in our cohort. Given those results, one may question HCT with old MRD when a younger MUD is available. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) for HCT Outcomes At US Transplant Centers: A Center for International Blood and Marrow Transplant Research (CIBMTR) Study

AbstractAbstract 733In 2005, the HCT-CI was introduced by a single institution as a weighted scoring system to predict mortality risk following allogeneic HCT. Since then, not all investigators were able to validate the HCT-CI after testing in their respective institutions. In 2007, a new prospective multi-institutional observational study was initiated at the CIBMTR to collect comorbidities from all transplant centers by their respective evaluators and to validate the predictive power of the HCT-CI in a large sample of patients (pts). The HCT-CI was adapted into the Pre-Transplant Essential Data (pre-TED) collection form #2400. Data managers from all institutions attended an education session on comorbidity coding per the HCT-CI at the 2007 Tandem BMT Meeting in Keystone, Colarodo. This session was then made public to all data managers at the CIBMTR website. <>The study accrued 8115 consecutive pts treated with allogeneic HCT from 12/2007 to 12/2009 from related (47%) or unrelated (53%) donors. Median age was 52 [range 1–78) years. Conditioning regimens were high-dose (67%) or either reduced-intensity (RIC) or nonmyeloablative (NST) regimens (34%). Diagnoses were acute (54%) or chronic (12%) leukemia, myelodysplastic syndromes (16%), lymphomas (16%), and others (2%). GVHD prophylaxis regimens were cyclosporine-based (22%), tacrolimus-based (68%), or others (10%). Stem cell source was marrow (17%) or peripheral blood mononuclear cells (83%). Karnofsky performance status scores were <90% (33%), ≥ 90% (62%), or missing (5%). HCT-CI scores were 0 (47%), 1 (15%), 2 (11%), 3 (12%), 4 (7%), 5 (3%), ≥6 (4%), or missing (1%). About 11% of pts with score 0 had other comorbidities listed.Overall, pts experienced cumulative incidence of transplant-related mortality (TRM) of 28% and a survival rate of 48% at 3-years. Pts with HCT-CI scores of 0 vs. 1–2 vs. ≥3 had 3-year TRM incidences of 24%, 28%, and 35% (p <0.001) and 3-year overall survival (OS) rates of 54%, 47%, and 38%, respectively (p <0.001, Figure). Proportional hazards models were used to estimate the hazard ratio (HR) for TRM and OS associated with HCT-CI scores. The models were adjusted for all previously mentioned covariates in addition to disease status, CMV serology status, gender, and race. Increasing HCT-CI scores (1–2 and ≥3 vs. 0) were associated with increases in the HR [95% confidence interval (CI)] for TRM [1.12 (1.00–1.26) and 1.47 (1.31–1.65), respectively, p<0.0001] and OS [1.12 (1.03–1.22) and 1.36 (1.25–1.48), respectively, p<0.0001] in the overall pt population. No statistically significant difference could be detected between pts with score 0 + other comorbidities vs. score 0 for TRM (HR 0.93, p= 0.385) or OS (HR 0.96, p= 0.474). When the HCT-CI was modeled as scores of 0, 1, 2, 3, 4, and ≥5 the HR for TRM were 1.00 vs. 1.12 vs. 1.13 vs. 1.31 vs. 1.52 vs. 1.77, respectively (, p<0.0001) and for OS were 1.00 vs. 1.13 vs. 1.12 vs. 1.22 vs. 1.39 vs. 1.62 (p<0.0001). Likewise, the HCT-CI could discriminate outcomes well among pts given high-dose or RIC/NST regimens and those diagnosed with lymphoid or myeloid diseases (Table 1).The inter-rater reliability (IRR) rate among data managers versus their respective investigators was assessed in 3 institutions. Weighted kappa statistics were 0.54, 0.81, and 0.47 respectively, indicating fair-moderate agreement rate among evaluators.The HCT-CI is a valid tool to discriminate relative risks for TRM and OS after HCT across different institutions, different conditioning intensities, and different diagnoses. The HCT-CI should be used as a standard-of-care health measure in counseling pts for HCT, in clinical trial design, and in adjusting statistical analyses for HCT outcomes. Future efforts will focus on improving the IRR of the HCT-CI.Table 1:Multivariate analysesTRMOSHCT-CI scoresHRp-valueHRp-valueHigh-dose regimens01.00<0.00011.00<0.000111.191.1421.121.1031.341.1941.531.415+1.881.64RIC/NST regimens01.000.0011.00<0.000110.951.1221.101.1231.271.2741.461.395+1.661.65Lymphoid diseases01.00<0.00011.00<0.000111.161.1521.241.1231.371.3242.131.675+2.151.88Myeloid diseases01.00<0.00011.00<0.000111.121.1321.001.0631.251.1441.291.275+1.631.52 [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Post–Renal Transplant Cytomegalovirus Infection: Study of Risk Factors

ObjectivesCytomegalovirus (CMV) is a common opportunistic infection following renal transplantation (RTx). It responds promptly to antiviral treatment. The mortality rate reaches 90% if untreated. Identification of risk factors helps in the early diagnosis of CMV. We studied demographic features, risk factors, and outcomes associated with CMV infection in RTx recipients despite ganciclovir prophylaxis. Materials and methodsWe reviewed 720 RTx recipients between 2007 and 2009. We examined the serostatus of the donor and recipient before transplantation using an enzyme-linked immunosorbent assay, and diagnosed CMV infections in recipients by CMV DNA detection with a polymerase chain reaction. ResultsA total of 42 of 750 (5.6%) patients were identified to display CMV infection (69.1%) or disease (30.9%). Their mean age was 34 ± 13.5 years, with 80.9% men. CMV serologic status was D+/R− in 21.4% and D+/R+ in 59.5% patients. Fever, malaise (76.2%), and leukopenia (52.3%) were the commonest presenting symptoms; diabetes (30.9%) and hepatitis C virus (28.6%) the commonest comorbid conditions. Risk factors were triple drug immunosuppression (47.6%), antithymocyte globulin ATG induction (54.8%), and a rejection episode (26.1%) and methylprednisolone (76.2%) which were more common in CMV disease than infection. Mean CMV DNA at diagnosis was 78,803; 71.2% patients developed CMV within 6 months posttransplantation, the majority occurring after 3 months. With a mean follow-up of 4 ± 1.9 years, patient and graft survival rates were 85.7% and 81% with a mean serum creatinine value of 1.83 ± 12 mg/dL. ConclusionsUniversal CMV prophylaxis was associated with a low incidence (5.6%) and mild form of CMV disease among our patients.

HLA Matching Is More Critical Than CMV Matching in Predicting Non-Relapse-Mortality of Patients Undergoing HSCT From An Unrelated Donor: A Retrospective Monocenter Study.

Abstract 4336 Introductionfor patients in search of an unrelated donor for haematopoietic stem cell transplantation (HSCT), a 10/10 allele-matched donor represents the best option; for a CMV- patient, a CMV- donor is generally preferred to a CMV+ donor due to low risk of CMV infection when both donor and patients are CMV-, however it is not known at the present how the CMV serological status affects transplant outcome compared to patient-donor HLA matching, and this is particularly true when more than one donor is available. The aim of the present study is to analyze the effect of CMV matching with respect to HLA matching on HSCT outcome, in patients who are CMV-. MethodsCMV-patients who underwent a HSCT from an unrelated donor between 1st Jan 2000 and 31st Mar 2009 at our Institution were included in the analysis. Patients receiving HSC from cord blood were excluded. Evaluation of overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM) and acute graft-versus-host disease (GvHD) were performed with Kaplan-Meier method or cumulative incidence analysis; comparisons among groups were performed using log-rank test. Data about most relevant patients' and donors' factors (patients' age, gender matching, AB0 incompatibility, diagnosis, disease status at HSCT, CMV matching, HLA matching, HSCT conditioning, use of ATG, TBI, source of HSCs) were collected and included in a multivariate Cox regression analysis: the relative impact of CMV and HLA matching on HSCT outcomes were expressed as hazard ratio (HR) together with the 95% confidence interval (CI), after adjustment for the above mentioned factors. Resultssixty-six patients were eligible for the analysis, median age was 35 (16-64), diagnoses were acute leukemia (n=33: n=23 CR1 and n=10 CR2 or more), MDS (n=8), multiple myeloma (n=8), non Hodgkin's lymphoma (n=6), CML (n=5: n=2 chronic phase, n=3 acceleterated or acute phase), myeloproliferative syndrome other than CML (n=3), aplastic anemia (n=1), CLL (n=1), Hodgkin's lymphoma (n=1). A high-resolution 10/10 HLA matching was present in 55 (83%) HSCTs while one mismatch (9/10-matched donor) was present in 11 (17%) HSCTs: n=8 at HLA-A, n= 3 at HLA-C. All recipients were CMV-. Donors were CMV- in 40 of 55 (73%) 10/10-matched pairs and in 6 of 11 (54%) 9/10-matched pairs. Median follow-up was 225 days (range: 82-2014). In univariate analysis, no significant survival differences were detected among patients with HLA matched and mismatched donors (1y-OS= 42% and 20% respectively, p=0.23) or with CMV- and CMV+ donors (1y-OS= 34% and 48% respectively, p=0.26); no significant differences in occurrence of grade 2-4, grade 3-4 acute GvHD or PFS were observed as well. However, a significantly increased probability of NRM was seen when a HLA mismatched donor was present (1y-NRM= 80% vs 33%, p=0.03); this was not the case of CMV serological status (p=0.31). Multivariate analysis for NRM showed a HR = 5.22 (95% CI: 1.47-18.56) with p= 0.01 for HLA mismatched vs. matched and HR = 0.72 (95% CI: 0.23-2.24) with p= 0.57 for CMV mismatched vs. matched. Conclusionthese results confirm that HLA matching is critical in determining the incidence of NRM and should continue to be preferred to CMV matching in CMV seronegative patients undergoing HSCT from an unrelated donor. However, a larger, multicenter analysis could better clarify this issue and help to define the relative importance of HLA matching vs. CMV serology in this setting of patients. Disclosures:No relevant conflicts of interest to declare.

Biologic Assignment Clinical Trials in Hematopoietic Stem Cell Transplantation (HSCT) for Multiple Myeloma: Baseline Characteristics by Treatment Allocation from BMT CTN 0102 According to Availability of an HLA-Matched Sibling Donor.

Randomization in clinical trials involving comparison of patients receiving an allogeneic HSCT versus other treatments is challenged by limitated donor availability. Biologic assignment relies on the availability of suitable donors to determine assignment to allogeneic HSCT. BMT CTN 0102 is a phase III multicenter clinical trial that compares tandem autologous HSCT (auto-auto) to an autologous HSCT followed by a nonmyeloablative allogeneic HSCT (auto-allo) for the treatment of multiple myeloma after initial systemic therapy. Transplant arm assignment was determined by the availability of an HLA-matched sibling donor. Patients were stratified into high and standard risk groups. Absence of chromosome 13 deletion by standard karyotyping and beta-2 microglobulin (B2M) ≤ 4mg/L were defined as standard-risk disease (SRD). The trial was powered to detect differences in 3-year progression-free survival in patients with SRD. A total of 710 patients from 43 centers in the U.S. were enrolled from December 2001 to March 2007. Data from 596 patients with SRD were available for this analysis (sibling donor availability for other 28 SRD patients is not yet determined); 30% (n=178) were assigned to the auto-allo arm. The median ages were 55 and 52 years for the auto-auto and auto-allo arms, respectively (p=0.01). The proportions of African-American patients were 17% and 9% in the auto-auto and auto-allo arms, respectively (p=0.006). Most patients were Durie Salmon Stage III (66% and 70%, p=0.6), in partial remission (86% and 83%, p=0.6) and had Karnofsky Performance Scores ≥ 90 (76% and 77%, p=0.5) at time of study entry. Treatment arms were balanced for B2M, baseline cardiac and hepatic functions and CMV serological status. Median times from diagnosis, initiation of systemic therapy and stem cell mobilization to first transplant were 213, 191 and 27 days, respectively and the same in both arms. The interval from the first to second transplant was 98 days for the auto-auto arm and 105 days for the auto-allo arm (p=0.02). We conclude that biologic assignment resulted in two reasonably comparable treatment groups, although statistically significant differences in age, race and interval between first and second transplant were identified. The differences in age between the groups is related to donor availability, since patients younger than 55 years had on average significantly more living siblings than older patients. Importantly, full-sibling donor availability did not account for differences in race distribution. Because the clinical significance of all detectable differences is unknown, the planned statistical analysis will adjust for these discrepancies. These results confirm that biologic assignment is feasible and might be considered when standard randomization is prohibitive, as in allogeneic HSCT clinical trials.