Transplant-related Mortality In Patients Research Articles

Endothelial Activation and Stress Index (EASIX) Measured Pre-Transplant Identifies a Subgroup with High Transplant Related Mortality in Patients with Thalassemia Undergoing Stem Cell Transplantation Using Thiotepa-Treosulfan-Fludarabine Conditioning

Allogeneic stem cell transplantation (SCT) is a curative treatment for beta-thalassemia major. The Pesaro risk stratification classifies patients with thalassemia into three groups (class I, II, and III) to predict the transplant-related mortality (TRM) and graft rejection after myeloablative conditioning with busulfan and cyclophosphamide. However, in developing countries, where inadequate chelation therapy prior to transplant is common, most patients would fall under the class III category. There is heterogeneity in the clinical outcomes in this group. Hence, our center introduced a further refinement in this risk stratification, identifying a subset of “class III high risk” as those with age greater than or equal to 7 years and liver size > 5cm (Mathews V et al. BBMT 2007). Subsequently, we showed that the use of a conditioning regimen containing thiotepa, treosulfan, and fludarabine (TTF) along with a peripheral blood stem cell graft led to improved outcomes in this subset with a reduction in early TRM from 46% (with busulfan-cyclophosphamide) to 13% (Mathews V et al. PLoS One 2013). There is still a need to identify predictors of poor clinical outcomes to optimize further the clinical outcomes of these class III high-risk thalassemia patients. Endothelial activation and stress index (EASIX) is a simple biomarker calculated using lactate dehydrogenase, creatinine, and platelet counts. EASIX has been shown to be predictive of overall survival in various settings like GVHD following reduced-intensity transplants for malignancies in adults, veno-occlusive disease, and nonrelapse mortality following SCT (Luft T et al. Lancet Haem 2017; Jiang S et al. Haematologica 2021; Luft T et al. BMT 2020). Here, we evaluated the role of EASIX (measured before conditioning therapy) as a biomarker in predicting early TRM in patients with thalassemia major who have undergone SCT with a uniform conditioning regimen using TTF at our center. During the study period from January 2012 to December 2019, 281 patients with thalassemia major underwent SCT with a uniform TTF protocol at our center. The median age was nine years (range 1 to 25 years). One hundred and nine (38.8%) were females. As per Pesaro classification (with Vellore modification), three (1.1%) were class I, 34 (12.1%) were class II, 134 (47.7%) were class III low risk, and 110 (39.1%) were class III high risk. The stem cell donors were matched sibling (n=218, 77.6%), matched related non-sibling (n=23, 8.2%), or matched unrelated donors (n=40, 14.2%). The stem cell donor was HLA matched in all cases except 21 (7.5%), wherein there was a mismatch at one locus. Five (1.8%) had a bone marrow graft, while others had peripheral blood stem cell grafts. Thirty-eight (13.5%) patients had transplant-related mortality by day 100 (TRM100). The median follow-up of the cohort was 31 months (range 0 to 103 months). EASIX score pre-transplant was available for 184 (65.5%) patients. There was no difference in the rate of TRM100 in patients where EASIX was available compared to those where EASIX was not available (14.7% versus 11.3%, p 0.47). Also, there was no difference in overall mortality rate in patients where EASIX was available compared to those where EASIX was not available (21.2% versus 17.5%, p 0.53). Among patients with TRM100 vis-à-vis those who did not, the median EASIX score was significantly higher (1.09 versus 0.75, p 0.008). We then plotted a receiver operating characteristics (ROC) curve for predicting TRM100 using the EASIX score. The area under the curve was 0.661 (Figure 1a). A cut-off of 0.85 for the EASIX score had a 70.4% sensitivity and 62% specificity for predicting TRM100. The TRM100 for patients with EASIX above 0.85 was significantly higher than those with EASIX less than 0.85 (24.4% versus 7.5%, p 0.003). On multivariable logistic regression analysis, the factors independently predicting TRM100 were pre-transplant EASIX score, pre-transplant ferritin, unrelated donor source, and chimerism at day 60 (Figure 1b). In patients with thalassemia major undergoing SCT using a uniform TTF conditioning, EASIX score measured pre-transplant can identify patients at greater risk for Day100 TRM. [Display omitted] DisclosuresMathews: Christian Medical College: Patents & Royalties: US 2020/0345770 A1 - Pub.Date Nov.5, 2020; AML: Other: Co-Inventor.

BEAM-Campath Allogeneic Stem Cell Transplant for Patients with Relapsed/Refractory Lymphoma: High Incidence of Long-Term Mixed Donor-Recipient Chimerism and the Response to Donor Lymphocyte Infusions

BiCNU (carmustine), etoposide, Ara-C, melphalan (BEAM) and Campath conditioning was developed to reduce the high transplant-related mortality in patients with lymphoma while delivering intensive antilymphoma immunotherapy, as well as to some extent a platform for allogeneic stem cell engraftment. Significant numbers of patients appeared to have persistent recipient-derived hematopoiesis, and therefore we retrospectively analyzed patients with lymphoma undergoing BEAM-Campath conditioned allogeneic stem cell transplantation at our center (2003 to 2017) to characterize the patterns of chimerism and patient outcomes. Chimerism was analyzed with short tandem repeat PCR. Mixed donor-recipient chimerism (MDRC) was defined as 5% to 94.9% donor. Fifty-two patients (n=30 male), with a median age of 45 years, were identified with histologic diagnoses of Hodgkin lymphoma (n=13), diffuse large B cell lymphoma (n=7), low-grade non-Hodgkin lymphoma (n=16), mantle cell lymphoma (n=10), and T cell lymphoma (n=6). Pretransplant, 93% achieved complete response (52%) or partial response (41%) with a median of 3 prior therapies (n=3 prior autologous stem cell transplantation). Donors were Matched sibling donors (MSD) (n=21), matched unrelated donors (MUD) (n=24), miss-matched unrelated donors (MMUD) (n=6), and syngeneic (n=1). Acute graft-versus host disease (GVHD) developed in 52% (81% grade I to II) and chronic GVHD (83% extensive) in 12%. MDRC of T cells (MDRCt) developed in 62% (n=32), and 29% (n=15) developed MDRC of myeloid cells (MDRCm) at a median onset of 100 days. Donor lymphocyte infusion (DLI) was given to 17 patients, with a median starting dose of 1×106/kg. The first DLI was given at a median of 225 days post-transplant (range, 99 days to 5.3 years). Of these, 9 developed acute post-DLI GVHD and 2 limited chronic GVHD. Conversion to full donor occurred in 47% MDRCt and 50% MDRCm. Multivariate analysis identified sibling donor type as associated with increased MDRCt (P=.035; hazard ratio [HR], 0.17) and reduced total nucleated cell dose with increased MDRCm (P=.021; HR, 0.76). The median follow-up was 6 years, and 2-year NRM cumulative incidence was 16% (95% confidence interval [CI], 7% to 27%). Ten-year progression and extensive GVHD-free survival was 45% (95% CI, 28% to 61%), and overall survival was 66% (95% CI, 50% to 78%). One-year landmark analysis identified no increased GVHD or relapse risk with MDRCt or MDRCm but reduced nonrelapse mortality (NRM) risk with MDRCt (P=.001). BEAM-Campath allografts for high-risk lymphoma achieve long-term disease-free survival with low rates of GVHD and transplant-related mortality. The frequent development of myeloid MDRC demonstrates that BEAM-Campath is a nonmyeloablative conditioning regimen in almost a third of patients. MDRCt is associated with reduced NRM, but neither MDRCt or MDRCm is associated with increased GVHD or relapse.

HLA-Haploidentical Hematopoietic Cell Transplantation for Treatment of Nonmalignant Diseases Using Nonmyeloablative Conditioning and Post-Transplant Cyclophosphamide.

Allogeneic hematopoietic cell transplant (HCT) is often the only curative therapy for patients with nonmalignant diseases; however, many patients do not have an HLA-matched donor. Historically, poor survival has been seen after HLA-haploidentical HCT because of poor immune reconstitution, increased infections, graft-versus-host disease (GVHD), and graft failure. Encouraging results have been reported using a nonmyeloablative T cell-replete HLA-haploidentical transplant approach in patients with hematologic malignancies. Here we report the outcomes of 23 patients with various nonmalignant diseases using a similar approach. Patients received HLA-haploidentical bone marrow (n=17) or granulocyte colony-stimulating factor-mobilized peripheral blood stem cell (n=6) grafts after conditioning with cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, and 2 or 4 Gy total body irradiation. Postgrafting immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, tacrolimus, ± sirolimus. Median patient age at HCT was 10.8 years. Day 100 transplant-related mortality (TRM) was 0%. Two patients died at later time points, 1 from intracranial hemorrhage/disseminated fungal infection in the setting of graft failure and 1 from infection/GVHD. The estimated probabilities of grades II to IV and III to IV acute GVHD at day 100 and 2-year National Institutes of Health consensus chronic GVHD were 78%, 26%, and 42%, respectively. With a median follow-up of 2.5 years, the 2-year overall and event-free rates of survival were 91% and 78%, respectively. These results are encouraging and demonstrate favorable disease-specific lineage engraftment with low TRM in patients with nonmalignant diseases using nonmyeloablative conditioning followed by T cell-replete HLA-haploidentical grafts. However, additional strategies are needed for GVHD prevention to make this a viable treatment approach for patients with nonmalignant diseases.

Capsule Endoscopy after Hematopoietic Stem Cell Transplantation Can Predict Transplant-Related Mortality

Background and Objectives: Allogenic hematopoietic stem cell transplantation (allo-SCT) is a curative therapy for hematological malignancies, but transplant-related mortality (TRM) remains a concern. This study aimed to determine the efficacy of capsule endoscopy (CE) by evaluating the correlation between inflammatory findings on CE and TRM. Methods: The data of patients after allo-SCT were retrospectively collected. The association between findings on CE and TRM at 100 days from the CE was evaluated. Results: Of the 94 patients included in the study, 47 showed inflammatory findings on CE. The findings were diagnosed as graft-versus-host disease (GVHD; n = 17), cytomegalovirus (CMV) infection (n = 14), and GVHD with CMV infection (n = 16). Of the 47 patients, 13 (28%) had TRM. Endoscopic diagnoses of these TRM cases were GVHD (n = 4), CMV infection (n = 0), and GVHD with CMV infection (n = 9). In contrast, in the remaining 47 patients who showed no inflammatory findings on CE, 2 patients (4%) had TRM. The proportion of TRM was higher in patients with inflammatory findings than in those without it (28 vs. 4%, p < 0.01). Conclusions: CE may predict TRM in patients who developed gastrointestinal symptoms after allo-SCT.

Donor IFNL4 Genotype Is Associated with Transplant-Related Mortality after Unrelated Donor Myeloablative Hematopoietic Cell Transplantation in Patients with Acute Leukemia

Introduction. Interferon Lambda 4 gene (IFNL4) encodes IFN-λ4 protein, a new member of the type-III interferon family. IFNL4 genotype (rs368234815-dG allele), defines the genetic ability to produce IFN-λ4 and has been associated with reduced clearance of hepatitis C virus (HCV) infection. Given antiviral activity and immune modulation properties of IFN-λ4, we hypothesized that IFNL4 genotype of recipient and/or donor may modulate post-transplant survival outcomes, possibly through control of viral infections, and/or alloreactivity.Methods. From the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we randomly selected 627 patients who received unrelated hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML, N=449) or acute lymphocytic leukemia (ALL, N=178). The patients had to match the following criteria: 1) HCT between 2004 and 2012, 2) available pre-HCT blood sample for the donor and recipient, 3) 8/8 HLA matching, and 3) myeloablative conditioning. IFNL4 genotyping was completed for 619 donors and 522 recipients using a custom-designed TaqMan assay for rs368234815. Multivariable Cox proportional hazard models were used for statistical analyses. Follow-up ended in November 2017.Results. Median age at HCT was 40 years (range=<1-68). Most patients (66%, N=411) were in first complete remission, had a Karnofsky Performance Score (KPS) between 90-100% (70%, N=436), and received peripheral blood stem cell grafts (70%, N=439). The median post-HCT follow-up was 68 months (range=5-122). Donor IFNL4 genotype was associated with risk of transplant-related mortality (TRM); with 5 years probabilities=19%, 27%, and 30% for donor TT/TT (n=286), TT/dG (n=267), and dG/dG (n=64) genotypes, respectively, p=0.02. The results remained significant in multivariable analysis (p=0.002); compared with patients receiving HCT from donors with TT/TT genotype, with the HR=1.59 (95% CI=1.13-2.23, p=0.007) for TT/dG donors and HR=1.95 (95% CI=1.18-3.23, p=0.009) for dG/dG donors. The data suggested that donor IFNL4 genotype may also predict risk of disease-free survival (DFS; HR=1.43, 95% CI=1.02-2.00, p=0.03), and overall survival (OS; HR=1.40 (95% CI=0.98-1.99, p=0.06) for donor dG/dG genotype (Table1). No association between recipient genotype and any survival outcome was observed (p>0.05 for OS, DFS, and TRM)Conclusions. Donor IFNL4 genotype is associated with risk of transplant-related mortality in patients with acute leukemia. The data suggest that avoiding donors with dG/dG genotype will improve HCT outcomes without limiting the potential donor pool. A validation study is needed; if confirmed, IFNL4 genotype may provide an added value to donor selection criteria. DisclosuresLee:Onyx: Research Funding; Kadmon: Research Funding; Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Takeda: Research Funding.

Prognostic analysis of allogeneic hematopoietic stem-cell transplantation in 47 patients with acute myeloid leukemia and MLL rearrangement

目的研究混合谱系白血病（MLL）基因重排阳性急性髓系白血病（AML）患者行异基因造血干细胞移植（allo-HSCT）的预后特点。方法回顾性分析2009年9月至2016年5月于苏州大学附属第一医院行allo-HSCT的47例MLL基因重排阳性AML患者的临床资料。结果全部47例MLL重排阳性AML患者中男24例，女23例，中位年龄30（15~58）岁，M4/M5共36例（76.6%）。移植后2年总生存（OS）率为（64.4±8.4）%，无病生存（DFS）率为（47.3±9.3）%，复发率为41.0%，移植相关死亡率为17.9%。45例患者检出11q23易位，2例染色体核型正常患者检出MLL部分串联重复。t（6;11）组（16例）、t（9;11）组（15例）、其他类型组（16例）的2年OS率差异无统计学意义（χ2=1.509，P=0.472）。多因素分析显示，移植时年龄>45岁是影响OS的独立危险因素[HR=4.454（95%CI 1.314~15.099），P=0.016]，移植前MRD阳性是影响患者DFS[HR=4.236（95%CI 1.238~14.495），P=0.021]、复发[HR=5.491（95% CI 1.371~21.995），P=0.016]的独立不良预后因素，移植前疾病处于非CR状态患者移植相关死亡风险增高[HR=10.370（95%CI 1.043~103.110），P=0.046]。结论移植时年龄>45岁、移植前疾病处于非CR状态、移植前MRD阳性为影响allo-HSCT治疗MLL基因重排阳性AML患者预后的危险因素。

Thiotepa-Based Intensified Reduced-Intensity Conditioning Adult Double-Unit Cord Blood Hematopoietic Stem Cell Transplantation Results in Decreased Relapse Rate and Improved Survival Compared with Transplantation Following Standard Reduced-Intensity Conditioning: A Retrospective Cohort Comparison

The “Minnesota” reduced-intensity conditioning (RIC) cord blood transplantation (CBT) regimen (standard RIC) of fludarabine (Flu) (200 mg/m2), cyclophosphamide (Cy) (50 mg/kg), and 200- or 300-cGy total body irradiation (TBI) is the most published RIC CBT regimen. Though well tolerated, high relapse rates remain a concern with this regimen. Intensification of conditioning may reduce relapse without increasing transplant-related mortality (TRM). We performed a retrospective cohort comparison of outcomes in adult patients who underwent first double-unit CBT with standard RIC as compared with the intensified regimen of Flu 150 mg/m2, Cy 50 mg/kg, thiotepa 10 mg/kg, and 400-cGy TBI (intensified RIC). Of the 99 patients studied, 47 received intensified RIC. Acute myelogenous leukemia was the major indication for transplant. The median age at transplant was 67 years (range, 24 to 74 years) and 54 years (range, 25 to 67 years) in standard RIC and intensified RIC, respectively. Median hematopoietic stem cell transplantation comorbidity index was 3 (range, 0 to 5) and 1 (range, 0 to 6) in the standard RIC and intensified RIC groups, respectively. Median follow-up among survivors was 22 months (range, 3.7 to 79 months) following standard RIC and 15 months (range, 2.8 to 36 months) following intensified RIC. The cumulative incidence (CI) of relapse was significantly lower following intensified RIC compared with standard RIC (P = .0013); this finding maintained significance in multivariate analysis (P = .045). TRM was comparable between the 2 groups (P = .99). Overall survival (OS) was significantly improved following intensified RIC as compared with standard RIC (P = .03). Median OS was 17 months following standard RIC versus not reached followed intensified RIC. The CI of grade II to IV acute graft-versus-host disease (GVHD) was significantly higher in the intensified RIC cohort than the standard RIC-cohort (P = .007), while CI of grade III to IV acute GVHD, any chronic GVHD, and moderate-to-severe chronic GVHD was comparable in each cohort (P = .20, P = .21, and P = .61, respectively). This retrospective analysis shows an improvement in OS and decreased relapse without increase in TRM in patients receiving intensified RIC as compared with standard RIC. Our data suggest that consideration of thiotepa-based intensified RIC may improve outcomes in fit, older patients undergoing double-unit CBT.

The EBMT Score Predicts Transplant Related Mortality and Overall Survival after Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes

Introduction: Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) is still the only curative treatment for myelodysplastic syndromes (MDS). However, the so far perceived high transplant related mortality (TRM) limits the number of patients referred for alloSCT.Materials (or patients) and methods: We retrospectively analyzed 9741 consecutive patients diagnosed with primary or secondary MDS aged 18 or older undergoing allogeneic transplantation at EBMT centers between 1997 and 2013. Cord blood and haploidentical donors and second or further transplants were excluded.Results: Patients´ characteristics: Median age at time of transplant was 54.9 years (18-79) with 5804 patients (60%) being male. WHO classification at transplant (available from 2009) in 4033 patients showed: 634 (16%) patients with RA/RARS/del5q, 406 (10%) with RCMD (+/-RS), 964 (24%) with RAEB-1, 1707 (42%) with RAEB-2 and 322 (8%) with secondary AML. A total of 1437 (19%) patients had secondary MDS.Transplant characteristics: Peripheral blood was the preferred source of stem cells (82.5%).The conditioning was reduced intensity in 4987 (53%) and myeloablative in 4492 (47%). The reasons for RIC included institutional protocol (44%), patient age (38%) and co-morbidities (14%).Donor was unrelated in 5475 (56%) patients and an HLA-identical sibling in 4266 (44%). GvHD prophylaxis consisted of cyclosporine and short-course MTX with (1585 patients - 16%) or without (1906- 20%) in vivo T-cell depletion with alemtuzumab or ATG. In addition, MMF was used instead of MTX in 1320 (14%) and 751 (8%) patients respectively. The EBMT risk score reported by Gratwohl et al. was calculated in our cohort (Table 1). The EBMT score separated patients into 3 groups: low risk (0-2 points, n=1949, 22%), intermediate risk (3-4 points, n=4795, 53%) and poor risk (5-7 points, n=2229, 25%).Primary and secondary graft failure was reported in 419 (4%) and 71 (0.7%) patients respectively. Grade 0-I GvHD developed in 6314 (69%) and grade II-IV in 2789 (31%). 2270 (23%) patients relapsed during follow-up. At time of analysis, 4390 (45%) patients were alive without relapse and 4902 (50%) of patients had died, of whom 3081 (32%) never relapsed. We analyzed the cause of death of this latter population: 1004 (33%) died of GvHD, 996 (32%) due to infections, 86 (3%) of haemorrhages, 130 (4%), due to multi-organ failure, 69 (2%) of secondary malignancies and 796 (26%) from other causes.The overall survival was 60% at 12 months and 41% at 5 years. The EBMT score strongly separated patients with good (50%), intermediate (41%) and poor (31%) survival at 5 years (p<0.001). TRM was 27% at 12 months and 37% at 5 years. TRM for patients with a low EBMT score was 20% at 12 months compared with 26% and 35% for intermediate and poor-risk EBMT scores respectively (p<0.001). No differences in the cumulative incidence of relapse among the three EBMT score risk groups (CI at 3 years for low was 27%, intermediate 25% and poor risk 26%). For patients with RA/RARS/del5q and low-risk EBMT score, the TRM was 23% at 5 years.We found small but statistically significance differences in TRM in favor of patients who received reduced intensity vs myeloablative conditionings (p=0). In addition, the overall TRM at 12 months has slightly improved (p=0.008): 1997-2001 (32%), 2002-2006 (27%) and 2007-2013 (26%).Conclusion: The EBMT Score accurately predicts OS and TRM but does not correlate with the relapse risk. The TRM for MDS patients after alloHSCT is lower than previously described and this should no longer be an obstacle for referring patients for transplantation. Patients with low risk MDS (RA/RARS/del5q) who are otherwise candidates for alloHSCT, should expect a low TRM of 23% at 5 years from transplant if their EBMT score is low.Table 1EBMT Risk ScoreRISK FACTORPOINTSPATIENTS (%)AGE OF PATIENT (years)<200129 (1%)20-4011542 (16%)>4028070 (83%)DISEASE STATUSEarly (first CR, untreated)05575 (62%)Intermediate (second CR, PR)11163 (13%)Late (other)22283 (25%)TIME INTERVAL DIAGNOSIS-TRANSPLANT (months)* Does not apply if CR<1206154 (63%)>1213587 (37%)DONOR TYPEHLA-identical sibling04266 (44%)Unrelated, other15475 (56%)DONOR RECIPIENT SEX COMBINATIONAll other07679 (81%)Female donor, male recipient11847 (19%) [Display omitted] [Display omitted] DisclosuresNiederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Schönland:Janssen, Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Age-Adjusted Telomere Length May Predict Treatment-Related Mortality in Children Undergoing Hematopoietic Stem Cell Transplantation

IntroductionTelomeres are specialized DNA structures found at the end of linear chromosomes. In humans, they contain the repetitive sequence (TTAGGG)nalong with its complementary strand and associated proteins. With each cell division, the telomere shortens due to incomplete replication of the lagging strand, a phenomenon known as the end replication problem. Oxidative damage, as well as the action of nucleases also leads to telomere attrition. Once the telomere reaches a critically short length, cells enter senescence or apoptosis. In the general population, telomere length (TL) varies greatly, and is seen to decline with age. Patients with Dyskeratosis Congenita (DC) have inherently short telomeres, which leads to multiple organ dysfunction. These patients suffer increased organ toxicity when given standard myeloablative conditioning regimens during hematopoietic stem cell transplantation (HSCT). This is most likely due to the reduced ability of their cells to replicate and recover following cytotoxic treatment. It is not known whether patients without DC, who have telomere lengths at the lower end of the normal spectrum also suffer increased rates of toxicity. Thus we undertook a retrospective analysis to determine if there was an association between short TL and increased transplant-related mortality (TRM) following HSCT in children.MethodMedical records of patients who underwent allogeneic HSCT at the Children's Hospital at Westmead (Sydney, Australia) between 2002 to 2013 were examined and demographic, prior treatment, transplant, toxicity and transplant information was extracted. The primary outcome measured was TRM, while overall survival, relapse and graft versus host disease (GVHD) being secondary outcomes of interest. Stored DNA, extracted from bone marrow, taken within 3 months prior to HSCT was used for telomere length testing, as a surrogate marker for TL in other tissues in the body. Quantitative PCR was carried out to determine relative telomere length, which was converted to an age adjusted TL (AATL) by subtracting the expected relative TL (i.e. 50th percentile for age of the patient) from the measured relative TL, so that patients of all ages could be analyzed together.ResultsBetween 2002 and 2013, there were 121 patients who underwent allogeneic HSCT at our institution. Of these, 78 had DNA stored, with appropriate consent and ethics approval to be used in our study. Most children were undergoing HSCT for hematological malignancies (acute lymphoblastic leukemia 52%, acute myeloid leukemia 39%), with 55% having relapse or refractory disease. Matched sibling donors made up 46% of cases. At a median follow up of 3.2 years, 64% of patients remained alive. The single leading cause of death was relapse (48%) with 52% of deaths attributable to transplant-related causes.The median AATL for the entire cohort was -0.21 (range -0.61-0.28). Telomere length was not associated with relapse or refractory disease. There was no correlation between AATL and specific organ toxicity, relapse or overall survival. When the cohort was divided into 2 groups based on AATL, there was a trend (p=0.055) towards increased TRM in patients who had AATL below the median for the cohort (Figure 1). Multivariate analysis adjusting for age at transplant, CMV status, disease status and HLA matching showed a reduced risk (HR 0.33; p value 0.072) of TRM in patients with AATL above the median for the cohort.ConclusionAATL was shorter in patients pre-HSCT compared with age matched controls. There was a trend towards increased TRM in patients with shorter telomere length, however most likely due to small sample size, this did not achieve significance. If extended to a larger cohort of patients, TL may prove to be a significant marker for children at increased risk of TRM prior to HSCT. This could influence the choice to use less myeloablative conditioning in these patients.Support: NHMRC GNT1056667 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Busulfan-Dose Escalation in Reduced Intensity Stem Cell Transplantation (RIC-HSCT) Results in Good Outcomes for Patients with MDS and AML without Increased Toxicity

Current evidence indicates that patients receiving myeloablative HSCT have decreased relapse rates but higher transplant-related mortality (TRM) than patients receiving RIC-HSCT. It is well established that there is wide variation in intensity within protocols considered RIC. We have pioneered the use of an alemtuzumab based HSCT with two doses of busulfan (bu) (8mg PO or 6.4mg IV), however it is noted that relapse rates within this context are high (Potter V. et al, BBMT, Jan 2014). Targeted dose escalation of bu in allogeneic transplant conditioning regimens has the potential to reduce relapse rates. We therefore adopted an intensification strategy by increasing the total bu dose (16mg PO or 12.8mg IV) administered during conditioning.Ninety-five consecutive patients with a median follow-up for survivors of 1083 days (204 - 4627) received FB4C HSCT between 2000 and 2014. The protocol included fludarabine 150mg/m2, bu 12.8mg/kg and alemtuzumab (FB4C) as previously described. Patients received pre-emptive DLI for low (<50%) or falling CD3 chimerism. The median age of the cohort was 59 years (19 - 70). Diagnosis included RCMD (n=14), RAEB (n=18), de novo AML (n= 21), AML with multi-lineage dysplasia (AML-MLD) (n=34) and CMML (n= 8). Patients received PBSC (n=89) or BM (n=6) with a respective median cell dose of 6.8 and 2.5 x106CD34/kg. Neutrophil and platelet engraftment occurred at medians of 13 and 16 days respectively. Graft failure occurred in only 6% of patients.Five year overall survival (OS) for the entire cohort was 56% with a TRM at 100 days of 9.7% and 30% at 5 years. Disease free survival (DFS) at 1 year was 65% and 39% at 5 years. Relapse rates were 24% at 1 and 44% at 5 years. There was no significant difference in outcome for patients receiving sibling vs matched unrelated, 10/10 HLA vs 9/10 HLA matched or BM vs PBSC stem cell source. OS for patients with de novoAML was 62% compared to 43% for MDS-AML, 69% for RCMD, 25% for CMML and 70% for RAEB. These differences were not significant. Twenty patients receiving pDLI did particularly well with a 5 year OS of 79%.Patients were stratified by age group: <50 years (n= 28), 51-60 years (n= 33) and >60 years (n= 34). These patients were equivalent in terms of disease status at transplantation, IPSS-R, HCT-CI and cytogenetic risk groups. In contrast to our previous results there was no adverse effect of advanced age. Patients <50 years had a 5 year OS of 66% compared to 47% for 50-60 and 51% age >60 (p=NS). TRM in patients <50 years was 25%, 30% for in those aged 50-60 and 36% in those >60 at 5 years. The DFS for those <50 at 5 years was 48%, 35% for 50-60 and 29% for those >60. When compared with patients with a HCT-CI of 0, patients with a HCT-CI score of 1-2 (p=0.04), or ≥3 (0.05), did significantly worse. OS for these groups was 65%, 48% and 50% respectively. The TRM for these groups was not significantly difference suggesting that bu dose intensification can be safely used even in those with additional comorbidities.Cytogenetics were classified as low (n=5), intermediate (n=61) and poor (n=22) according to NCCN and IPSS-R categories. The small numbers of patients in the very poor and poor IPSS-R groups were grouped together for the final analysis. There was a trend toward significantly worse outcomes for those with poor cytogenetics compared to intermediate (p=0.06) with 5 year OS of 40% vs 62%. Five year DFS was significantly different at 21% vs 45% (p=0.03). OS at 5 years for patients with residual cytogenetic disease pre-HSCT was 41% compared to 63% for those without cytogenetic disease at 63% at the time of transplant (p=0.04). On multivariate analysis this was the only variable to retain significance (HR 1.6, (95% CI 1.02-2.6)). Rates of severe GvHD were low with a cumulative incidence of acute GvHD grade III-IV of 22%. Chronic GvHD rates were low overall at 33% and with NIH severe GvHD occurring in only 13.7%.These results compare favourably with our previous publication of lower dose bu which demonstrated 5 year OS and DFS of 44% and 33% respectively. Relapse rate was also improved at 44% compared with 51% at five years. The lack of difference in TRM with regard to age and HCT-CI suggests that this protocol is potentially an effective method of optimising outcomes in high risk and older patients with MDS/AML without an increase in toxicity. Although these results are encouraging prospective randomised trials are required to identify the most appropriate setting for bu dose intensification. DisclosuresNo relevant conflicts of interest to declare.

Abstract 5079: Adjudicating complex phenotypes for use in GWAS: A study of transplant-related mortality (TRM) after unrelated donor hematopoietic cell transplantation (URD-HCT)

Abstract As a first step in a 2-phase GWAS of TRM in patients with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after URD-HCT, a consensus panel (CP), composed of BMT physicians and epidemiologists, reviewed all cause-specific deaths (CSDs) reported by 151 US transplant centers (TC) from 2000-11. Agreement measures, statistics and models were used to compared CP and TC CSD and the factors impacting the determination of CSDs. Less affected by prevalence and marginal probabilities than Cohen's K, Gwet's Agreement Coefficient (AC1) measured the agreement between TC and CP CSD and the 95% confidence intervals were generated by bootstrapping the conditional distributions of the CSDs. For each CSD (disease, graft versus host (GvHD), infection, organ failure, other) we determined the proportion of agreement (PA) between the TC and CP and the Bias Index (BI, the proportion of cases the CP moved into or out of a CSD category). Logistic and log-linear models identified factors significantly associated with TC/CP odds of agreement and dependencies between covariates and TC/CP CSD, respectively. The discovery cohort (c1) includes 2609 10/10 HLA matched URD-HCT patients from 2000-8, reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) by TCs. The validation cohort (c2) includes 920 10/10 or 8/8 HLA matched URD-HCT patients from 2000-11. The CP adjudicated CSDs in c1 using in-person meetings and teleconferences over 1 year; c2 cases were reviewed during a 2-day in-person meeting. A total of 1116 (c1) and 388 patients (c2) died ≤1-yr post-URD-HCT. External and internal validity showed &amp;gt;96% agreement. The AC1 statistic was .751 (.726, .801) and .658 (.567, .682), for c1 and c2 respectively. The PA for GvHD was 12% lower in c2 than c1 but the proportion of GvHD cases was higher in c2; these same differences were also seen for organ failure CSD. BI showed the rate of movement between CSDs was almost identical in both cohorts. In c1, TC and CP were &amp;gt;2 fold less likely to agree on CSD for both ALL and MDS (p&amp;lt;.05) when URD-HCT was in the early 2000s. The log-linear models also showed c1 cohort effects, as well as dependencies in both cohorts between age and TC CSD and CP CSD and disease status (early/advanced). The cohort effect and age dependencies with TC CSD in c1 were not present when a systematic review of cases by the CP was performed. In c2 the TC CSD did not show evidence of a cohort effect; however a greater understanding of the lower AC1 in c2 vs. c1 was gained through use of PA. In both cohorts the BI and log-linear models show consistency in CSDs as determined by the CP. Our work illustrates that CPs are a worthwhile part of genomic studies of complex multi-factorial phenotypes, and the use of agreement statistics and dependency models is imperative to monitor CP phenotype reliability and understand data structure for subsequent analyses. Citation Format: Lara Sucheston-Campbell, Theresa Hahn, Leah Preus, Kenan Onel, Xiaochun Zhu, Song Liu, Li Yan, Alyssa Clay, David Tritchler, Marcelo Pasquini, Philip McCarthy. Adjudicating complex phenotypes for use in GWAS: A study of transplant-related mortality (TRM) after unrelated donor hematopoietic cell transplantation (URD-HCT). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5079. doi:10.1158/1538-7445.AM2014-5079

Outcomes of autologous or allogeneic stem cell transplantation for non-Hodgkin lymphoma

Transplant outcomes of autologous or allogeneic stem cell transplantation (SCT) have not been elucidated as a single cohort in non-Hodgkin lymphoma (NHL). We analyzed the outcomes of 270 adult recipients receiving autologous (auto) SCT (n = 198) or allogeneic (allo) SCT (n = 72) for NHL between the years 2000 and 2010. Five-year overall survival rates for B and T cell NHL were 58% and 50%, respectively (allo-SCT 51% vs. 54% for B and T-cell NHL, and auto-SCT 60% vs. 47% for B and T cell lymphoma, respectively). In multivariate analysis, the number of chemotherapy regimens and disease status pre-SCT were independently associated with long-term outcome after SCT (for both auto- and allo-SCT). We conclude that the type of transplantation offered to patients, based on patient selection and disease-related factors, can achieve long-term survival, highlighting the importance of further improvement in disease control and reducing procedure-related mortality. The role of transplantation needs to be reevaluated in the era of targeted therapy.

Evaluating CD8+ Memory Stem T Cells Dynamics After Allogeneic Bone Marrow Transplantation: Impact On GvHD Occurrence

Abstract 4179Graft-versus-host disease (GvHD) is caused by alloreactive donor T cells that target host tissues. GvHD develops over weeks or months, suggesting a requirement for persistent alloreactive T cells able to sustain the alloresponse. With this respect, long-living memory stem T cells (TSCM) with the ability to self-renew and the plasticity to differentiate into potent effectors, may represent important targets influencing GvHD when bearing specificities for alloantigens. We have demonstrated that CD8+ TSCM are characterized by the CD45RA+ CD62L+ CD95+ phenotype and are able to mediate a potent xenogeneic GvHD when infused into immunodeficient mice, preserving their xenoreactivity even across serial transplants (Cieri et al., Blood (ASH Annual Meeting Abstracts) 118: 2052). Importantly, we found that requirements for TSCM generation are CD3/CD28 engagement in the presence of IL-7 and IL-15 starting from naïve precursors. Accordingly, in hematopoietic stem cell transplantation (HSCT), the conditioning regimen favors systemic inflammation, leading to the activation of antigen presenting cells, which become costimulation competent and could then provide CD3/CD28 stimuli to allogeneic naïve T cells. On the other hand, conditioning causes also severe host lymphopenia, creating a milieu in which infused allogeneic naïve T lymphocytes are exposed to elevated levels of IL-7 and IL-15 (Dean et al., 2008; Thiant et al., 2011). We hypothesize that this dynamic environment may support the in vivo generation of TSCM. To verify this hypothesis and assess the impact of TSCM on post-transplant immune reconstitution and GvHD incidence, peripheral blood lymphocytes from 10 patients transplanted after myeloablative conditioning at San Raffaele Scientific Institute between 2011 and 2012 were analyzed one month after transplant (median day post-HSCT: 32 days; range 14–46). A 11-color flowcytometric panel was established to evaluate TSCM and was tested in ten healthy individuals. In patients, we documented a selective accumulation of TSCM one-month post-HSCT, since the majority of circulating CD45RA+CD62L+ CD8+ T lymphocytes expressed CD95 (HSCT patients: 92.37 ± 21.03%, healthy individuals: 9.911 ± 3.931%; P < 0.0001), and represented a higher fraction of total CD8+ T cells compared to healthy controls (HSCT patients: 24.80 ± 15.76%, healthy individuals: 4.669 ± 1.727%; P = 0.0025). Moreover, the percentage of TSCM not only correlated with aGvHD occurrence (P = 0.0148), but was also significantly higher in patients who experienced aGvHD grade III-IV compared to those with aGvHD ≤ grade II (P = 0.009). Furthermore, TSCM percentages one-month after HSCT were also predictive for the subsequent development of cGvHD (P = 0.007). Overall, patients with higher percentages of circulating TSCM required a more profound immunosuppressive therapy (> 2 lines) compared to those with less circulating TSCM (P = 0.012). Accordingly, there was also a trend towards higher transplant related mortality in patients bearing higher TSCM frequencies. Of note, the extent of TSCM accumulation one month after transplant did not correlate with the dose of CD3+ or CD45+ cells present in the graft, nor with the degree of mismatch between donors and recipients. Finally, in 4 patients we had the opportunity to evaluate circulating TSCM at a later time-point after HSCT (median day post-HSCT: 197 days; range 57–250). In one patient who did not experience GvHD we found that the proportion of TSCM on CD8+ T cells remained stable over time, while in the remaining three patients, who instead experienced GvHD, a drastic reduction of TSCM percentage after GvHD resolution was observed (P = 0.046). Our studies evaluated for the first time TSCM dynamics after allogeneic HSCT and suggest that TSCM frequencies observed early after transplant may represent biomarkers to predict subsequent development of GvHD. To this aim, we are currently starting a prospective longitudinal study of circulating TSCM lymphocytes after HSCT in a larger cohort of patients. Hopefully, if a causative role for TSCM in GvHD will be demonstrated, new therapies to selectively target this T-cell population may be designed with the final aim of relieving GvHD morbidity and mortality. Disclosures:Bonini:MolMed S.p.A.: Consultancy.

Association Between Genetic Variants in Immune Response Genes and Outcomes After Hematopoietic Cell Transplantation

Abstract 3049 Background:Despite rapid advances in allogeneic hematopoietic cell transplant (HCT) techniques, the procedure continues to be associated with a high morbidity and mortality with transplant related mortality (TRM) ranging from 15% to as high as 50%. Acute graft versus host disease (GvHD) remains a major cause of morbidity and an important cause of early TRM in patients undergoing allogeneic HCT. Though variations in major histocompatibiliy (MHC) genes are well known determinants of acute GvHD, there is increasing evidence that genetic variation in immune/cytokine response pathways also contributes significantly to the pathogenesis of acute GvHD. Methods:We evaluated the association of single nucleotide polymorphisms (SNPs) in non-MHC dependent immune/cytokine response pathways (n= 77 SNPs in recipients and donors) with acute GvHD and TRM at one year in a cohort of 425 recipient-donor pairs who underwent allogeneic HCT for treatment of hematologic malignancies at the University of Minnesota between 1998 and 2007. We used a Fine and Gray proportional hazards model adjusted for competing risk to evaluate the association between the genetic variants and time to acute GvHD and time to TRM. Results:After adjustment for recipient age at transplant, race, diagnosis, disease status at transplant, gender mismatch, CMV serostatus of recipient and donor, recipient and donor sex, donor type, conditioning regimen (myeloablative or reduced intensity) and year of transplant, one recipient SNP, rs646005 in the TIRAP gene and one donor SNP, rs2232596 in the LBP gene were marginally associated with increased risk for grade II-IV acute GvHD (Hazard ratio (HR) = 1.33 (95% Confidence interval (CI): 1.07 – 1.62) and 1.32 (1.07 – 1.66) respectively; p =0.01). Similar analyses for TRM showed recipient SNP rs5498 in the ICAM1 gene was associated with a decreased risk of TRM (HR: 0.67(95% CI: 0.50 – 0.89); p=0.0006) while recipient SNPs rs1739654 in the LBP gene and rs3804100 in the TLR2 gene were associated with an increased TRM risk (HR: 1.86 (95% CI: 1.16 – 2.97) and 1.66 (95% CI: 1.11 – 2.48) respectively; p =0.01). Conclusions:These findings are consistent with previous reports that support a role for genetic variants in the innate immune response pathways among both recipients and donors can influence the risk of acute GvHD and TRM among patients undergoing allogeneic HCT. These findings indicate that a systematic search for genetic variants in the innate immune response pathways may identify novel biomarkers that can be used to identify patients at high risk for acute GvHD and TRM. Disclosures:Weisdorf:Genzyme: Consultancy, Research Funding.

CMV Infection after Transplant from Cord Blood Compared to Other Alternative Donors: The Importance of Donor-Negative CMV Serostatus

Cytomegalovirus (CMV) infection and disease are important complications after hematopoietic stem cell transplant, particularly after transplant from alternative donors. Allogeneic cord blood transplantation (CBT) is being increasingly used, but immune recovery may be delayed. The aim of this study was to compare CMV infection in CBT with transplants from unrelated or mismatched related donors, from now on defined as alternative donors. A total of 165 consecutive transplants were divided in 2 groups: (1) alternative donors transplants (n = 85) and (2) CBT recipients (n = 80). Donor and recipient (D/R) CMV serostatus were recorded. The incidence of CMV infection, its severity, timing, and outcome were compared. Median follow-up was 257 days (1-1328). CMV infection was monitored by CMV antigenemia and expressed as CMV Ag positive cell/2 × 10(5) polymorphonuclear blood cells. There was a trend toward a higher cumulative incidence of CMV infection among CBT than alternative donor transplant recipients (64% vs 51%, P = .12). The median time to CMV reactivation was 35 days, and was comparable in the 2 groups (P = .8). The maximum number of CMV-positive cells was similar in the 2 groups (11 versus 16, P = .2). The time interval between the first and the last positive CMV antigenemia was almost 4 times longer in CBT compared with alternative donor transplants (109 vs 29 days, respectively, P = .008). The incidence of late CMV infection was also higher in CBT (62% vs 24%, P < .001). The incidence of early and late CMV infection in CBT was similar to D-/R+ alternative transplants, and higher than in D+/R+ alternative transplants: early infection, 72% in CBT versus 69% in D-/R+ alternative versus 55% in D+/R+ alternative (P = .21); and late infection, 67% in CBT versus 60% in D-/R+ alternative versus 7% in D+/R+ alternative (P < .001). Transplant-related mortality and overall survival were similar between the groups: 34% versus 36% (P = .6) and 54% versus 46% (P = .3) for alternative transplant and CBT, respectively. Longer duration and higher incidence of late CMV infection was seen in CBT patients, when compared with alternative donor transplants, whereas no difference in mortality was observed. The duration and incidence of late CMV infection were similar when D-/R+ CBT were compared with D-/R+ alternative donor transplants.

Antithymocyte Globulin (ATG) for Graft-Versus-Host-Disease (GvHD) Prophylaxis In Patients Undergoing Allogeneic Hematopoietic Cell Transplantation (allo-HCT): a Systematic Review and Meta-Analysis.

AbstractAbstract 1513 Introduction:Despite advances in high resolution HLA typing, GvHD remains a major complication after allo-HCT and results in significant mortality and morbidity. Transplant related mortality (TRM) in patients with severe acute GvHD has been estimated to be in the range of 28 to 92%. The 3-year risk for TRM in patients with chronic GVHD ranges from 28 to 48% depending on the extent of GVHD (limited versus extensive). Effective GvHD prophylaxis is key to prevention of GvHD. ATG is one of several immunosuppressive agents widely used for GvHD prophylaxis following allo-HCT. The effect of ATG for the prevention of GVHD has been evaluated in several randomized controlled trials (RCTs). However, data on the efficacy of ATG for the prevention of GvHD has been conflicting across RCTs. Informed clinical decision-making requires synthesis of all research evidence. Therefore, we have performed a systematic review to assess effect of ATG for GvHD prophylaxis in patients undergoing allo-HCT for various hematologic diseases. Methods:All completed phase III RCTs comparing use of ATG versus control for the prevention of GVHD in patients undergoing allo-HCT were eligible for inclusion. Medline (PubMed), and Cochrane database of RCTs published through April 2010 were searched to identify potentially relevant studies. Abstracts from the annual proceedings of the American Society of Hematology (2008-2009), American Society for Clinical Oncology (2008-2009) were also searched. Data were extracted on benefits and harms associated with compared treatments (ATG versus “no ATG”). Outcomes analyzed included: (i) GvHD incidence (ii) overall survival and (iii) TRM. Data on the methodological quality of included RCTs were also extracted to assess the robustness of the findings. Any discrepancies in data extraction were resolved by consensus. Data were pooled under a random effects model. A formal statistical test for heterogeneity using the chi square and I2 test was performed. The meta-analysis was performed using Review Manager Software. Results:Initial search of Pubmed, Cochrane database of RCTs and ASH and ASCO meeting abstracts yielded 141 citations of which 7 RCTs met the pre-defined inclusion criteria. Altogether these RCTs enrolled a total of 733 patients. The pooled results showed a statistically non-significant benefit for overall survival (7 RCT, 733 patients) with use of ATG for the prevention of GVHD. The combined hazard ratio (HR) for the comparison of ATG versus no ATG was 0.91 (95%CI, 0.75 to 1.10; p=0.32). There was no heterogeneity among included studies. The results did not change when data was analyzed according to the source of ATG (horse versus rabbit). There was a statistically significant benefit associated with ATG use for the prevention of severe grade III-IV acute GVHD (5 RCTs, 609 patients). The risk ratio (RR) was 0.56 (95%CI, 0.38 to 0.82; p=0.003). There was a statistically significant heterogeneity among included trials. However, there was no benefit with use of ATG for the prevention of either grade II (3 RCTs, 238patients; RR=0.78; 95%CI, 0.47 to 1.29; p=0.33) or grade I acute GVHD (2 RCTs, 185 patients; RR=1.42; 95%CI, 0.75 to 2.69; p=0.28). Use of ATG was not associated with any significant effect on TRM. The risk ratio was 0.74 (95%CI, 0.53 to 1.03; p=0.08). The results were not affected by methodological quality of studies. Conclusion:This comprehensive assessment of the effect of ATG in preventing GvHD in patients undergoing allo-HCT suggests that ATG has a beneficial effect on the prevention of severe grade III-IV acute GvHD. However, the available research evidence does not show a significant impact on overall survival. Additional prospective trials with adequate sample size are still needed to provide a more definitive answer. Disclosures:No relevant conflicts of interest to declare.

Graft-Versus-Tumor Effect In Patients with Graft-Versus-Host Disease Defined by NIH Consensus Criteria

AbstractAbstract 2343 Background.The National Institutes of Health consensus criteria (NCC) for chronic graft-versus-host disease (GVHD) are based on clinical manifestations rather than onset time after transplantation. Previous studies about the feasibility of the new criteria have been performed in patients who survived beyond 100 days after transplantation and had GVHD presenting after day 100. In order to investigate and compare the clinical impact of acute and chronic GVHD by NCC on survival, a cohort including patients with GVHD presenting ‘before’ as well as ‘after’ day 100 is needed. Additionally, a proper statistical tool should be applied to clarify the effect of GVHD on survival outcomes, because the occurrence of GVHD is a well known time-dependent event. In this context, we examined a cohort including all patients who underwent allogeneic stem cell transplantation (SCT) in order to investigate clinical impact of acute or chronic GVHD by NCC on survival outcomes. Methods.We retrospectively investigated 771 patients who underwent allogeneic SCT between January 2002 to December 2008. To study a homogenous cohort, patients received 2 allogeneic SCT and/or donor-lymphocyte-infusion was excluded. We used time-dependent analyses to reveal the effect of GVHD on survival outcomes. In particular, to approach the effects of GVHD as a time-dependent covariate on competing risks [relapse or transplant-related mortality (TRM)], we analyzed cause-specific hazards by Cox proportional hazards regression model (Cartese G, Andersen PK. Biometrical Journal 2009;51:138–158). Results.The median age was 36 years (range, 15–68). Patients had various hematologic malignancies (AML/ALL/CML/MDS/MM, 361/226/86/67/31, respectively) and were transplanted from matched sibling (n=485), well-matched unrelated donors (n=154), partially-matched unrelated donors (n=101), and mismatched unrelated donors (n=31). Conditioning regimens consisted of myeloablative (n=536) and reduced-intensity regimens (n=235). GVHD prophylaxis consisted of cyclosporine and short-course methotrexate for related SCT and tacrolimus and short-course methotrexate for unrelated SCT. Among 771 patients, 540 patients were diagnosed with GVHD after transplantation. According to onset time of GVHD, in 348 patients GVHD developed within 100 days after SCT, whereas in 156 patients GVHD occurred more than 100 days after SCT. Using the NCC, we classified patients as three categories regardless of onset time: (1) acute GVHD (n=215), if patients had only acute features (no chronic features) during the course of GVHD, (2) acute GVHD with following chronic GVHD (n=118), if patients had any chronic features after the occurrence of acute GVHD, and (3) chronic GVHD (n=207), if patients had any chronic features at the onset of GVHD. Multivariate analyses using cause-specific hazards revealed that acute GVHD was significantly associated with lower relapse incidence [HR (95% CI) 0.65 (0.44–0.94), P=0.023]. However, it did not influence disease-free survival (DFS, P=0.602) and overall survival (OS, P=0.294) due to higher TRM in patients with acute GVHD [HR (95% CI) 1.74 (1.15–2.61), P=0.008]. Acute GVHD with following chronic GVHD was also associated with lower relapse incidence [HR (95% CI) 0.31 (0.15–0.66), P=0.002] and higher TRM [HR (95% CI) 2.89 (1.65–5.04), P<0.001], which did not influence DFS (P=0.567) and OS (P=0.820). On the other hand, the occurrence of chronic GVHD significantly reduced relapse rates [HR (95% CI) 0.46 (0.29–0.75), P=0.002] without increasing TRM (P=0.177). Indeed, this effect was translated into improved DFS [HR (95% CI) 0.67 (0.48–0.95), P=0.023]. Conclusions.Our data show that both acute and chronic GVHD by NCC reduced the risk of relapse, demonstrating the presence of graft-versus-tumor (GVT) effect by the occurrence of GVHD and no difference according to the clinical features (acute or chronic) by NCC. However, survival benefit was only observed in chronic GVHD by NCC compared to acute GVHD with/without following chronic GVHD by NCC due to higher TRM. This study represents the first one demonstrating the GVT effect of GVHD defined by NCC in a cohort including GVHD presenting ‘before’ as well as ‘after’ day 100 using appropriate time-dependent analyses by cause-specific hazards by Cox proportional hazards regression model. Disclosures:No relevant conflicts of interest to declare.

Reduced-intensity conditioning with Fludarabin, oral Busulfan, and thymoglobulin allows long-term disease control and low transplant-related mortality in patients with hematological malignancies

The development of reduced-intensity conditioning regimens rather than myeloablative regimens for allogeneic stem cell transplantation has led to decreased treatment-related mortality and increased use of this treatment modality, especially in older patients with hematological malignancies. No randomized controlled trials have been performed resulting in determining effectiveness on phase II studies, which rarely report on long-term survival. In an attempt to address this limitation, we analyzed a single-center cohort of 100 consecutive patients with hematological malignancies undergoing allogeneic stem cell transplantation from a human leukocyte antigen-matched related donor with median follow-up of 60 months. The reduced-intensity conditioning regimen consisted of oral Busulfan, rabbit anti-thymocyte globulin, and Fludarabin. Median age was 50 years (range, 18-64 years). The incidences of acute and chronic graft-vs.-host disease were 43% and 81%, respectively. The probability of nonrelapse mortality at 1 and 5 years was 15% and 25%, respectively. Nonrelapse mortality was adversely associated with acute graft-vs.-host disease (hazard ratio = 6; p = 0.0002). Of the 52 patients with measurable disease, 37 (71%) achieved a response. Relapse/progression occurred at a median of 11 months (range 1-52 months) in 21 patients, for a cumulative incidence of 22%. The probability of overall survival and progression-free survival at 5 years were 60% and 54%, respectively. Overall survival and progression-free survival were favorably influenced by having had previous autologous stem cell transplantation and a low CD34(+) cell dose. Overall survival, progression-free survival, and nonrelapse mortality improved over time in this cohort of patients. These results are encouraging for populations different in term of age, diagnosis, and disease status.

Response of 864 Patients to Steroids as Primary Therapy for Acute Gvhd at a Single Institution: Day 28 Response Is the Best Endpoint to Predict Transplant-Related Mortality.

Abstract 1134Poster Board I-156The optimal primary endpoint for acute GVHD treatment trials has not been established. In a retrospective analysis, we examined the response of 864 patients who received prednisone 60 mg/m2 for 14 days, followed by an 8 week taper, as initial therapy for acute GVHD from 1990-2007 at a single institution. Complete response (CR), partial response (PR), very good partial response (VGPR), and no response (NR) were scored at day 14, day 28 and day 56 after initiation of steroids. To determine the best endpoint, an index of concordance, the c-statistic (C), was performed to estimate the probability that patients with the better GVHD response will have lower transplant related mortality (TRM) than patients with a worse response. Median patient age was 32 (range, 0.2-69) years; 35% were <18 years old. Patients received grafts of HLA-matched sibling bone marrow (BM) or peripheral blood (PB, n=315), partially matched sibling BM or PB (n=24), unrelated donor (URD) BM or PB (n=313), single umbilical cord blood (sUCB, n=89) or double UCB (dUCB, n=123). Prior to initiation of steroid therapy, initial GVHD grades were grade I in 230 (27%), grade II in 504 (58%), grade III in 119 (14%), and grade IV in 11 (1%). Initial GVHD organ involvement was skin only (57%), gut only (17%), liver only (1%) or multiorgan (25%). Day 28 responses were similar to day 56 responses (p=0.14) and better than day 14 responses (p=0.03) in predicting TRM. In multiple regression analysis, patients with NR at day 28 were 2.77 times more likely to have TRM than patients with CR, VGPR or PR while any response favored lower TRM (table). Factors associated with significantly worse 2 year TRM in patients with acute GVHD include: NR to steroids, partially matched BM/PB, high risk disease, older age and skin only GVHD. Factors not associated with TRM include CMV serostatus, conditioning therapy, GVHD prophylaxis, days to steroid treatment, and initial grade of GVHD.Table:Factors associated with 2 year TRM: multiple regression analysisFactorRelative RiskP valueOverall P ValueDay 28 Response (% patients)..<0.001CR (53%)1.0.VGPR (7%)0.630.13PR (4%)1.220.45NR (31%)2.77<0.001Donor Type..<0.01MSD BM/PBSC1.0.URD well matched BM/PBSC1.350.17URD partial matched BM/PBSC1.540.03URD or sibling MM BM/PBSC1.77<0.001Single UCB1.060.83Double UCB0.790.36Disease Risk..0.02Standard1.0.High1.350.02Age1.00.020.02<18 years1.40318 yearsAffected Organs (skin only)..0.05Yes1.0.No1.360.05Grade at Start of Steroid Therapy..0.11I1.0.II1.080.60III-IV1.510.10These data suggest that responses at day 28 or 56 are equally effective endpoints for acute GVHD trials. Day 14 responses cannot as accurately predict TRM. As patients with NR require further therapy in a timely manner, early progression or response by day 28 is the best endpoint to assess efficacy of initial therapy for acute GVHD. Prospective trials are still required to determine the best therapy for different subgroups of patients with acute GVHD, especially those identified to have predictably poor responses and high TRM. DisclosuresNo relevant conflicts of interest to declare.

363: Early Detection of Severe Acute Graft-Versus-Host Disease using Plasma Markers of T-cell Activation

Severe acute graft-versus-host disease (GVHD) is a significant cause of transplant related mortality in patients that receive allogeneic hematopoietic stem cell transplantation (HSCT). Treatment of grade III and IV GVHD is frequently ineffective. Preemptive treatment based on the early detection of cytokines associated with T-cell activation and subclinical GVHD might be a more effective strategy, similar to the monitoring of CMV infection after HSCT.