Risk Of Acute Graft-versus-host Disease Research Articles

Role of thymoglobulin in matched sibling allogeneic hematopoietic stem cell transplantation with busulfan and fludarabine conditioning in myeloid malignanicies.

In vivo T-cell depletion using anti-thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation (HSCT) for prophylaxis of GvHD. We investigated the influence of thymoglobulin dose (an ATG) on GvHD following matched sibling donor (MSD) HSCT with a busulfan and fludarabine preparative regimen. Medical records of 180 patients who received MSD HSCT with a conditioning regimen of busulfan, fludarabine, and ATG (BuFluATG) were reviewed retrospectively. The median age was 53 years (range 18-68). Initial diagnoses were acute myeloid leukemia (73.3%) and myelodysplastic syndrome (26.7%). Forty-four and 68 patients (24.4 and 37.7%) experienced acute and chronic GvHD of any grade, respectively. High-dose (⩾4.5 mg/kg) ATG was independently associated with decreased risk of acute GvHD (hazard ratio=0.36, 95% confidence interval (CI): 0.15-0.84, P=0.019) compared to low-dose ATG (<4.5 mg/kg). Although ATG dose was associated with the risk of acute GvHD, it was not associated with the risk of chronic GvHD in our study. A higher dose (⩾4.5 mg/kg) of ATG decreases the risk of acute GvHD but had no significant impact on disease-free survival in MSD HSCT patients conditioned with BuFluATG. The optimal dose of ATG should be further investigated in a large prospective study context.

The effect of CCR5Δ32 on the risk of grade 3-4 acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis.

Many studies have showed that CCR5 was involved in the pathological process of acute graft-versus-host disease (aGVHD). However, the relationship between CCR5Δ32, a frameshift mutation, and grade 3-4 acute GVHD risk has not been well established. We performed a meta-analysis to explore the effects of CCR5 gene polymorphisms on grade 3-4 aGVHD. PubMed, Embase, Web of Science, and Cochrane Library were searched to collect relevant articles. Studies about association between CCR5 genotype in recipients or donors of allo-HSCT and aGVHD risk were included. All pooled analyses were based on fixed effects models. The effects were assessed from odd ratios (ORs) with 95% confidence intervals (CIs). A total of three studies comprising 937 recipients and 914 donors of allo-HSCT met the inclusion criteria. Compared with the wild-type CCR5 homozygotes, the pooled odd ratios (ORs) for CCR5Δ32 mutation (both homozygous and heterozygous) was 0.71 (95% CI, 0.40-1.26; P=.24) for donors, and 0.79 (95% CI, 0.35-1.81; P=.58) for recipients. No relationship was found between the presence of the CCR5Δ32 mutation and grade 3-4 aGVHD. Larger clinical investigations and retrospective studies are needed to explore the association of CCR5 gene polymorphisms with aGVHD risk as well as the outcome of HSCT.

Reconstitution of Th17, Tc17 and Treg cells after paediatric haematopoietic stem cell transplantation: Impact of interleukin-7

Successful reconstitution of T lymphocytes after allogeneic haematopoietic stem cell transplantation (HSCT) is needed to establish the graft-versus-leukaemia effect and an effective anti-microbial defense, but the ratio between functionally different T-cell subsets needs to be balanced to avoid graft-versus-host disease (GVHD).IL-7 is essential for T-cell generation in the thymus and peripheral T-cell homeostasis. High IL-7 levels have been associated with impaired T-cell reconstitution, increased risk of acute GVHD and treatment-related mortality, but the underlying cellular mechanisms behind these associations have not been investigated previously. We hypothesized that increased levels of IL-7 post-transplant alters the balance between immune-regulatory T cell subsets during the post-transplant lymphocyte recovery towards a more pro-inflammatory profile.We quantified Th17 cells, Tc17 cells and Tregs in 29 children following HSCT. Th17 cell and Treg counts rose significantly from day +90 to +180 post-HSCT, and prior acute GVHD was associated with significant changes in the concentration of Tregs (9.4×106/L vs. 1.3×106/L, P=0.0052) and the Th17/Treg ratio (1.5 vs. 4.2, P=0.025). The plasma level of IL-7 at day +90 correlated inversely with Th17 cell counts (rs=−0.65, P=0.0002) and the proportion of Tc17 cells (rs=0.64, P=0.0005) at day +90, but not with Tregs. Furthermore, high IL-7 levels at day +7 were predictive of a less naïve T-cell phenotype at day +90.These findings add further evidence that IL-7 is a key regulatory factor that may tune the balance between functionally different T-cell subsets following HSCT.

Single Step Multiple Genotyping by MALDI-TOF Mass Spectrometry, for Evaluation of Minor Histocompatibility Antigens in Patients Submitted to Allogeneic Stem Cell Transplantation from HLA-Matched Related and Unrelated Donor

The outcome of patients underwent to allogeneic stem cell transplantation (allo- SCT) is closely related to graft versus host disease (GvHD) and graft versus leukemia (GvL) effects which can be mediated by mHAgs. 23 mHAgs have been identified and reported to be differently correlated with GVHD or GVL and the aim of this work was develop a method to genotype the mHAgs described so far. For this study we used MALDI-TOF iPLEX Gold Mass Array technology. We tested 46 donor/recipient matched pairs that underwent allo-SCT because of Philadelphia positive (Ph+) chronic myeloid leukemia (n = 29) or Ph+ acute lymphoblastic leukemia (n =17). Our data show that sibling pairs had a lesser number of mHAgs mismatches compared to MUD pairs. Notably, donor/recipient genomic mismatch on DPH1 was correlated with an increased risk of acute GvHD and LB-ADIR-1R mismatch on graft versus host direction was correlated with a better RFS with no increase of GvHD risk. Our work provides a simple, accurate and highly automatable method for mHAgs genotyping and suggest the role of mHAgs in addressing the immune reaction between donor and host.

Early blood stream infection following allogeneic hematopoietic stem cell transplantation is a risk factor for acute grade III-IV GVHD in children and adolescents.

Graft-versus-host disease (GVHD) remains a major cause of mortality and morbidity in allogeneic hematopoietic stem cell transplantation (HSCT). In adults, early blood stream infection (BSI) and acute GVHD (AGVHD) have been reported to be related. The impact of BSI on risk for AGVHD, however, has not been assessed in pediatric patients. We conducted a retrospective analysis to test the hypothesis that early BSI (before day +30) predisposes allogeneic pediatric transplant patients to severe AGVHD. We analyzed 293 allogeneic HSCT performed at Children's Healthcare of Atlanta between 2005 and 2014 that met eligibility criteria. The cumulative incidence of acute grade III-IV GVHD at 100 days after HSCT was 17.1%. In multivariate analysis, risk for acute grade III-IV GVHD was associated with HLA-mismatched donor (hazard ratio [HR]=4.870, P<0.001), and BSI between day 0 and +30 prior to AGVHD (HR=3.010, P=0.001). These results indicate that early BSI appears to be a risk factor for acute grade III-IV GVHD. Further research is needed to determine if the link is causal.

HLA-DPB1 mismatch induces a graft-versus-leukemia effect without severe acute GVHD after single-unit umbilical cord blood transplantation.

Although it is known that human leukocyte antigen (HLA)-DPB1 disparity has a strong impact on outcomes in unrelated hematopoietic transplantation with induction of acute graft-versus-host disease (GVHD) and a graft-versus-leukemia (GVL) effect, its role in unrelated umbilical cord blood transplantation (UR-CBT) has yet to be fully clarified. Our current study is being conducted to elucidate the impact of HLA-DPB1 mismatch, along with the effect of other HLA loci mismatches at the allele level. HLA six loci alleles were retrospectively typed in 1157 Japanese donors and patients with leukemia or myelodysplastic syndrome who underwent transplantation with a single unit of cord blood. HLA-DPB1 mismatch was associated with a significant reduction in leukemia relapse (hazard ratio 0.61, P<0.001), whereas the other HLA loci allele-level mismatches did not. No significant effect of HLA-DPB1 mismatch was observed in the risk of acute GVHD, engraftment or mortality. This HLA-DPB1 GVL effect without induction of severe acute GVHD or deterioration of survival rate has not been reported in unrelated bone marrow or peripheral blood stem cell transplantations, suggesting apparent advantages of UR-CBT. Accordingly, selection of an HLA-DPB1 mismatch cord blood might be the preferable choice for single-unit UR-CBT.

GvHD prophylaxis after single-unit reduced intensity conditioning cord blood transplantation in adults with acute leukemia.

To investigate better GVHD prophylaxis in reduced intensity conditioning umbilical cord blood transplantation (RIC-UCBT), we compared transplant outcomes after UCBT among GvHD prophylaxes using the registry data. We selected patients transplanted for AML or ALL with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 748 first RIC-UCBT between 2000 and 2012 (MTX+ group, 446, MMF+ group, 302) were included. The cumulative incidence of neutrophil and platelet counts higher than 50 000/μL was significantly better in the MMF+ group (relative risk (RR), 1.55; P<0.001: RR, 1.34; P=0.003, respectively). In multivariate analyses, the risk of grade II-IV and III-IV acute GvHD was significantly higher in the MMF+ group than in the MTX+ group (RR, 1.75; P<0.001: RR, 1.97; P=0.004, respectively). In disease-specific analyses of AML, the risk of relapse of high-risk disease was significantly lower in the MMF+ group (RR, 0.69; P=0.009), whereas no significant difference was observed in the risk of relapse-free and overall survival in high-risk disease. In patients with standard-risk disease, no significant differences were noted in the risk of relapse or survival between the MTX+ and MMF+ groups. Collectively, these results suggest that MMF-containing prophylaxis may be preferable in RIC-UCBT, particularly for high-risk disease.

Bortezomib, rituximab, and risk of graft-versus-host disease (GVHD) after BEAM conditioning for allogeneic stem cell transplantation (alloSCT).

e18543 Background: GVHD remains the main limitation of alloSCT and is exacerbated by the intensity of the conditioning regimen. In a recent study, the risk of acute grade II-IV GVHD and extensive chronic GVHD (cGVHD) after a nonmyelobaltive (NMA) regimen was 11%, and 26%, respectively (Khouri I. Blood 2014 124:2306). Higher rates were previously observed (32% and 54%, respectively) with the BEAM regimen. Based on clinical data showing a reduction in GVHD with the use of rituximab or bortezomib, we conducted a phase I/II study evaluating the addition of bortezomib to rituximab+BEAM in patients (pts.) who were not eligible for NMA alloSCT. Methods: Bortezomib was administered at 1.3 mg/m2 IV on days -13, -6, -1 and +2. The dose was later reduced to 1 mg/m2 after the occurrence of C. Difficile colitis in the first 3 pts. leading to 2 deaths. Rituximab was given on day -13 at a dose of 375 mg/m2, then at 1000 mg/m2 on days -6, +1, and +8 of alloSCT. BEAM was administered between days -6 and -1. All pts. received our standard GVHD prophylaxis with tacrolimus and methotrexate. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving matched unrelated donor (MUD) or mismatched (MM) transplants. Results: Thirty-nine pts. were studied. Median age was 54 yrs. Thirteen (33%) and 26 (67%) pts. had indolent or aggressive lymphoma histologies, respectively. Sixteen (41%) pts. were refractory. Twenty-two (56%) received alloSCT from HLA-compatible siblings, 16 (41%) from MUDs and 1 (3%) from mm donors. Peripheral blood was the source of stem cells in 97% of pts. ABO and CMV-mismatch rates were 56% had 50%, respectively. Median follow up surviving patients was 65 mos. Five-year OS and PFS rates were 35% and 28%, respectively. The CI of acute grade II-IV, III-IV, and cGVHD were 55%, 34%, and 41%, respectively. No predictor for acute GVHD was identified. Instead, we found that sex-mismatched transplants were predictive of a higher risk of cGVHD ( P= 0.01). Conclusions: The current trial is the first one evaluating the safety and efficacy of bortezomib plus rituximab as a part of the BEAM regimen for alloSCT. A better prophylaxis regimen is needed to lessen the risk of GVHD in this setting. Clinical trial information: NCT00439556.

Impact of Alemtuzumab Scheduling on Graft-versus-Host Disease after Unrelated Donor Fludarabine and Melphalan Allografts

Alemtuzumab conditioning is highly effective at reducing the incidence of acute and chronic graft-versus-host disease (GVHD) in reduced-intensity fludarabine and melphalan transplantation with cyclosporine monotherapy. Less frequent and lower dose scheduling may be used with sibling donors, but an optimal regimen for matched unrelated donors has not been defined. In this retrospective observational study of 313 patients, the incidence and severity of GVHD was compared in patients receiving 3 different dose schedules: the standard 100-mg regimen (20 mg on days –7 to –3), 60 mg (30 mg on days –4 and –2), or 50 mg (10 mg on days –7 to –3). Patients treated with 100 mg, 60 mg, or 50 mg developed acute GVHD grades I to IV with an incidence of 74%, 65%, and 64%, respectively, whereas 36%, 32%, and 41% developed chronic GHVD. An excess of severe acute grades III/IV GVHD was observed in the 50-mg cohort (15% versus 2% to 6%; P = .016). The relative risk of severe acute grade GVHD remained more than 3-fold higher in the 50-mg cohort compared with the 100-mg cohort after adjustment for differences in HLA match, age, gender mismatch, cytomegalovirus risk, and diagnosis (P = .030). The findings indicate that the 60-mg alemtuzumab schedule was comparable with the 100-mg schedule, but more attenuated schedules may increase the risk of severe grade GVHD.

Impact of pre-transplant depression on outcomes of allogeneic and autologous hematopoietic stem cell transplantation.

To evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes post-transplantation. We analyzed data from the Center for International Blood and Marrow Transplant Research to compare outcomes after autologous (n = 3786) or allogeneic (n = 7433) HCT for adult patients with hematologic malignancies with an existing diagnosis of pre-HCT depression requiring treatment versus those without pre-HCT depression. Using Cox regression models, we compared overall survival (OS) between patients with or without depression. We compared the number of days alive and out of the hospital in the first 100 days post-HCT using Poisson models. We also compared the incidence of grade 2-4 acute and chronic graft-versus-host disease (GVHD) in allogeneic HCT. The study included 1116 (15%) patients with pre-transplant depression and 6317 (85%) without depression who underwent allogeneic HCT between 2008 and 2012. Pre-transplant depression was associated with lower OS (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.04-1.23; P = 0.004) and a higher incidence of grade 2-4 acute GVHD (HR, 1.25; 95% CI, 1.14-1.37; P < 0.0001), but similar incidence of chronic GVHD. Pre-transplant depression was associated with fewer days-alive-and-out-of-the hospital (means ratio [MR] = 0.97; 95% CI, 0.95-0.99; P = 0.004). There were 512 (13.5%) patients with Pre-transplant depression and 3274 (86.5%) without depression who underwent autologous HCT. Pre-transplant depression in autologous HCT was not associated with OS (HR, 1.15; 95% CI, 0.98-1.34; P = 0.096) but was associated with fewer days alive and out of the hospital (MR, 0.98; 95% CI, 0.97-0.99; P = 0.002). Pre-transplant depression was associated with lower OS and higher risk of acute GVHD among allogeneic HCT recipients and fewer days alive and out of the hospital during the first 100 days after autologous and allogeneic HCT. Patients with pre-transplant depression represent a population that is at risk for post-transplant complications. Cancer 2017;123:1828-1838. © 2017 American Cancer Society.

Increased regulatory T cell graft content is associated with improved outcome in haematopoietic stem cell transplantation: a systematic review.

Allogeneic haematopoietic stem cell transplant (HSCT) recipients are at increased risk of morbidity and mortality, often due to the development of acute or chronic graft-versus-host disease (GVHD). Low numbers or proportions of regulatory T cells (Tregs) have been reported in patients who develop GVHD. We undertook a systematic review of studies that reported the Treg composition of HSCT grafts in patients with haematological malignancies. Fourteen eligible studies were identified, eight of which stratified patients by Tregs (absolute dose or ratio to CD3+ or CD4+ cells). Meta-analyses showed that high levels of Tregs in the grafts were associated with improved overall survival [hazard ratio (HR) 0·42, 95% confidence interval (CI) 0·23-0·74, P=0·003, 2 studies], with a significant reduction in non-relapse mortality (HR 0·30, 95% CI 0·14-0·64, P=0·002, 2 studies) and a reduced risk of acute GVHD (relative risk (RR) 0·59, 95% CI 0·40-0·89, P=0·01, 6 studies). The consistency of these findings strongly suggests that the Treg composition of HSCT grafts has a powerful effect on the success of allogeneic HSCT. The major challenge is to translate these findings into better selection of allografts and future donors to provide a substantial improvement in allogeneic HSCT outcomes and practice.

CD25 Blockade Delays Regulatory T Cell Reconstitution and Does Not Prevent Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation

Daclizumab, a humanized monoclonal antibody, binds CD25 and blocks formation of the IL-2 receptor on T cells. A study of daclizumab as acute graft-versus-host disease (GVHD) prophylaxis after unrelated bone marrow transplantation was conducted before the importance of CD25+FOXP3+ regulatory T cells (Tregs) was recognized. Tregs can abrogate the onset of GVHD. The relation between Tregs and a graft-versus-malignancy effect is not fully understood. An international, multicenter, double-blind clinical trial randomized 210 adult or pediatric patients to receive 5 weekly doses of daclizumab at 0.3 mg/kg (n = 69) or 1.2 mg/kg (n = 76) or placebo (n = 65) after unrelated marrow transplantation for treatment of hematologic malignancies or severe aplastic anemia. The risk of acute GVHD did not differ among the groups (P = .68). Long-term follow-up of clinical outcomes and correlative analysis of peripheral blood T cell phenotype suggested that the patients treated with daclizumab had an increased risk of chronic GVHD (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.0 to 2.3; P = .08) and a decreased risk of relapse (HR, 0.57; 95% CI, 0.3 to 1.0; P = .05), but similar survival (HR, 0.89; 95% CI, 0.6 to 1.3; P = .53). T cells from a subset of patients (n = 107) were analyzed by flow cytometry. Compared with placebo, treatment with daclizumab decreased the proportion of Tregs among CD4 T cells at days 11-35 and increased the proportion of central memory cells among CD4 T cells at 1 year. Prophylactic administration of daclizumab does not prevent acute GVHD, but may increase the risk of chronic GVHD and decrease the risk of relapse. By delaying Treg reconstitution and promoting immunologic memory, anti-CD25 therapy may augment alloreactivity and antitumor immunity.

Circulating Microparticles As Predictive Biomarkers of Acute Graft Versus Host Disease

Background Graft-versus-host disease (GvHD) remains a leading cause of morbidity and mortality among allogeneic stem cell transplantation (SCT) patients. New research focusing on diagnostic methods and therapeutic interventions is required. Microparticles (MP) are structures ranging from 0.1 to 1 µm that are derived from the cell membranes of different cellular subtypes. The majority of circulating microparticles are derived from megakaryocytes (platelets) and erythrocytes. These structures have been described as biomarkers of cellular damage, activation, and intercellular signaling in in several autoimmune and vascular diseases. Whether the biologic events that characterize GvHD can alter the shedding of microparticles has not been described.Methods Patients who underwent allogeneic stem cell transplantation between august 2012 and September 2014 at the Hospital Sirio Libanes (Sao Paulo, Brazil) were included. Adult and pediatric patients were consecutively enrolled if neutrophil engraftment was achieved. Circulating MP were isolated and quantified by flow citometry. Annexin V-positive (total microparticles - TMP), CD61+ platelet-derived microparticles (PMP) and CD235+ erythrocyte-derived microparticles (EMP) were measured at neutrophil engraftment.Results MP were studied in the plasma of 48 patients. The levels of PMP were not associated with the risk of acute GvHD. However, the cumulative incidence (CI) of aGVHD was significantly increased among the patients with EMP counts above 360/µL at engraftment (59% vs. 26%, P=0.04). Higher EMP counts were associated with increased incidence of skin aGVHD (53% vs. 17%,P=0.02) and liver aGVHD (33% vs. 0%, P=0.002). There was no significant association between higher EMP count and incidence of gastrointestinal (GI) aGVHD (42% vs. 20%, P=0.10). The microparticles counts at engraftment were influenced by the intensity of the conditioning regimen. When compared with reduced intensity regimens, myeloablative regimens were associated with significantly higher EMP counts (152 vs. 349/µL, P=0.03). In patients exposed to reduced intensity conditioning regimens, a stronger association of a high EMP count and acute GvHD was observed (89% vs. 23%; p=0.002). A high EMP count was predictive of skin aGVHD (78% vs. 14%, P=0.002), liver aGVHD (67% vs. 0%, P<0.001), and GI aGVHD (72% vs. 20%, P=0.006).Conclusion Our data suggest that higher counts of erythrocyte-derived microparticles at engraftment may be associated with a greater risk of acute GVHD. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Shortened-Duration Tacrolimus after Nonmyeloablative HLA-Haploidentical (NMA haplo) BMT with High-Dose Posttransplantation Cyclophosphamide (PTCy) Facilitates Strategies for Relapse Reduction

▪Background: With PTCy as GVHD prophylaxis, outcomes of NMA haplo and matched BMT are similar, and relapse rather than toxicity is the leading cause of treatment failure. Early discontinuation of IS may augment a graft-versus-tumor effect and permit early implementation of strategies to reduce relapse, but may increase GVHD. We present a completed, prospective single-center trial of stopping tacrolimus (tacro) 3 or 4 months earlier than our Day (D) 180 standard after NMA haplo BMT (ClinicalTrials.gov: NCT01342289). Methods: From 8/2011-11/2015,105 evaluable patients (pts) with hematologic malignancies received NMA haplo BMT on this trial. The primary objective was to evaluate the feasibility and safety of reduced-duration tacro, stopping tacro without taper before D 180.Transplant criteria included age ≤ 75, ECOG PS ≤ 2, LVEF ≥ 35%, FEV1 and FVC ≥ 40% predicted, transaminases < 5 x ULN and no prior allogeneic BMT. All received Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete bone marrow. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and tacro from D 5. Pretransplantation, pts were assigned to stop tacro early if eligible, contingent on having ≥ 5% donor T cells at ~D 56 onward, no relapse and no grade 2-4 acute or significant chronic GVHD. Tacro was first planned through D 90 (n=47), then through D 60 (n=55). A D 120 cohort (n=3) enrolled while D 90 safety data were maturing. For pts ineligible for planned early tacro cessation, IS was individualized and continued to at least D 180. Monitoring rules declared reduced IS feasible if ≥ 33% of pts stopped tacro early as planned. Safety stopping rules for early tacro cessation were based on ≥ 65% probability of a ≥ 20% incidence of grade 3-4 acute plus severe chronic GVHD, ≥ 10% nonrelapse mortality (NRM) or ≥ 5% graft failure, measured from the tacro stop date to ~D 180. Historical data from 212 haplo transplants at our center using the same regimen but tacro until D 180 informed safety risk calculations. Results: Of the 105 pts (median age 61, range 13-74), the most common diagnoses were acute leukemia (50%), MDS (17%), NHL (16%) and HL (8%). By refined Disease Risk Index, 11% were low risk, 70% intermediate and 19% high. Shortened IS was feasible in 63 pts (60%) overall. Ineligibility for shortened IS was due most commonly to GVHD, followed by low donor chimerism or graft failure and early relapse. Of the 47 pts in the D 90 cohort (median follow-up 44 months), 23 (49%) stopped tacro early as planned. Safety stopping criteria were not met. Of these 23 pts, 16 (70%) had no safety events before D 180, 5 (22%) developed grade 2 acute GVHD (1 complicated by severe chronic GVHD) and 2 (9%) developed grade 3-4 acute GVHD. Of the 55 pts in the D 60 cohort (median follow-up 14 months), 38 (69%) stopped tacro early as planned, and safety stopping criteria were likewise not met. Of these 38 pts, 25 (66%) had no safety events before D 180, 1 developed graft failure, 9 (24%) developed grade 2 acute GVHD and 3 (8%) developed grade 3-4 acute GVHD. GVHD outcomes by cohort relative to historical outcomes are shown in Figures A and B. In both cohorts, the D 180 CuI of grade 2-4 acute GVHD was < 40% and was < 10% for grade 3-4 acute GVHD and NRM. The 1-year CuI of any chronic GVHD was 11% for the D 90 arm and 13% for the D 60 arm (12% historically). The 1-year probabilities of PFS, OS and GVHD-free relapse-free survival (GRFS, Figure C) were 40%, 59% and 27% respectively for the D 90 arm and 63%, 77% and 53% respectively for the D 60 arm. Conclusion: These data suggest that reduced-duration tacro is feasible and carries an acceptable safety profile in pts receiving NMA haplo BMT with PTCy. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with tacro until D 180. A larger prospective study is needed to define the optimal duration of IS that balances GVHD risk and relapse risk. However, these data show that many pts (60% in this trial) can discontinue tacro without taper well before D 180. There is even a suggestion of improved PFS and GRFS in the D 60 arm compared to the D 90 arm, although the trial was not powered for these endpoints. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early tacro cessation, provides an ideal setting to incorporate novel posttransplantation approaches for relapse reduction. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Use of Bone Marrow or Peripheral Blood Stem Cell Grafts in Non T Cell Depleted Haploidentical Transplants Using Post-Transplant Cyclophosphamide, an ALWP-EBMT Analysis

▪The use of mobilized peripheral blood (PB) as stem cell source in allogeneic stem cell transplantation (HSCT) from sibling or unrelated donors is associated with higher incidence of chronic graft versus host disease (GVHD) as compared to HSCT with bone marrow (BM). The reported incidence of GVHD in the haploidentical transplants with PT-Cy with BM grafts is low, while GVHD incidence using PB grafts varied between studies between 30% to 40% in single center reports.With the aim to analyze the effect of stem cell (SC) source in the setting of non T cell depleted haploidentical transplant using post-transplant Cyclophosphamide (PT-Cy), we analyzed patients (pts) transplanted for AML or ALL in first or second complete remission (CR) and reported to the EBMT from 2010 to 2014.Four hundred fifty one pts were analyzed, the majority of the pts in both groups were transplanted for AML (73%) in CR1 (67%). BM was the source of SC for 260 pts and PB for 191. Median follow up was longer for pts receiving BM (22.8 vs 18.3 months) and those pts were more likely transplanted with a MAC (61% vs 49%, p=0.008). All pts received PT-Cy as GVHD prophylaxis and prophylaxis was mainly in combination to calcineurin inhibitor and MMF, according to transplant center policy. ATG use was not different for the 2 groups (5% vs 7%, p=0.41).Overall OS, LFS and GRF at 2 year were 55%, 51% and 43%. CI of grade II-IV acute GVHD, chronic GVHD, NRM and Relapse at 2 year were 18%, 35%, 23% and 24%, respectively.Pts transplanted with BM had a longer time to neutrophil engraftment (18 vs 17 days, p= <0.001). In the univariate analysis pts transplanted with BM had a lower incidence of grade II-IV and grade III-IV acute GVHD (12% vs 27%, p=<0.01; and 3%% vs 8%, p=<0.01, respectively). No difference in chronic GVHD (36% vs 32%, p=0.28) was reported according to the SC source (PB vs BM), nor in relapse (26% vs 22%, p=0.38) and NRM (23% vs 23%, p=0.60).At 2 year LFS was 49% vs 54%, p=074 and GRFS was 44% and 42%, p=0.59, for pts receiving BM and PB, respectively. LFS was 53% and 47% (p=0.31) for pts transplanted for AML and ALL, and 56% and 46% (p=0.004) for MAC vs RIC.In the multivariate analysis adjusted for age, diagnosis, disease status, CMV serostatus, conditioning regimen, center effect and SC source, the use of PB was the sole factor associated with an increased risk of grade II-IV acute GVHD (HR 2.2, 95%CI 1.27-3.9, p=0.005). The type of SC (PB vs BM) was not significant associated with grade III-IV aGVHD (HR 2.5, 95%CI 0.9-7.3, p=0.07), cGVHD (HR 1.0, 95%CI 0.57-1.9, p=0.88), relapse (HR 0.7, 95%CI 0.51-1.15, p=0.21), NRM (HR 0.80, 95%CI 0.49-1.32, p=0.4), GRFS (HR 0.90, 95%CI 0.65-1.25, p=0.56), LFS (HR 0.73, 95%CI 0.52-1.04, p=0.08) and OS (HR 0.79, 95%CI 0.54-1.15, p=0.23).For LFS and OS, the use of RIC regimen was the only factor associated with a higher risk of treatment failure, (LFS: HR 1.39, 95%CI 1.01-1.93, p=0.04; OS: HR 1.5, 95%CI 1.06-2.12, p=0.02) and higher risk of relapse (HR 1.61, 95%CI 1.06-2.44, p=0.02).Finally, a center effect was found to be significant for NRM, LFS, GRFS, OS and cGVHD , and entered a frailty variable in the multivariate model.In conclusion, our study indicates that in patients with acute leukemia in first or second CR receiving haploidentical transplant with PT-Cy, the outcomes according to the use of PB or BM are not different. The ultimate choice depends on transplant center experience and policy. DisclosuresBacigalupo:PIERRE FABRE: Speakers Bureau; SANOFI: Speakers Bureau. Ciceri:MolMed SpA: Consultancy.

Post Transplant Cyclophosphamide (PTCy) with Anti-Thymocyte Globulin (ATG) Effectively Reduces the Severe (Grade III-IV) Acute Graft-Versus-Host Disease (GVHD) When Compared to ATG Alone in Matched Unrelated Donor (MUD) Allogeneic Hematopoietic Cell Transplants

Introduction: Acute Graft-versus-Host Disease (aGVHD) is a frequent complication of Allogeneic Hematopoietic cell transplants (allo-HCT). It can be lethal with increased morbidity and mortality and can occur in upto 40-50% of allo-HCT. Various agents such as calcineurin inhibitors, anti-metabolites and anti T cell antibodies, have been variably used for GVHD prophylaxis. Use of Post-transplant Cyclophosphamide (PTCy) has recently been used extensively in haplo-identical transplant setting with promising results, but has mainly been used in patients with BM as a stem cell source. In those patients receiving PBSC as a stem cell source, PTCy alone could reduce the risk of acute and chronic GVHD significantly. Anti-Thymocyte Globulin (ATG) has been associated with decrease in chronic but not acute GVHD. As most of our patients use PBSC as a graft source, we hypothesized that combination of ATG and PTCy can reduce the incidence of both acute and chronic GVHD. Since we had also used ATG for GVHD prophylaxis in a historical cohort, we compared the results of this approach with the current GVHD prophylaxis regimen.Methods: A total of 28 patients with hematological malignancies, who had an unrelated donor underwent allo-HCT at our center from 1 Oct 2015 to 31 Mar 2016. After interim analysis, when increased non-hematological toxicity was observed with myeloablative conditioning, all patients subsequently received reduced intensity conditioning. Peripheral blood was used as a stem cell source in all patients. The GVHD prophylaxis consisted of a combination of ATG-PTCy-CsA, with rabbit ATG administered on Days -3 (0.5 mg/Kg), -2 (2 mg/Kg) and -1 (2 mg/Kg), PTCy at dose of 50 mg/kg on Days +3 and +4 and CsA from Day+5 onwards. Filgrastim was used from day +7 onwards for 13 patients. Emphasis was given to incidence of acute GVHD, especially Steroid Refractory (SR-GVHD).Results: Out of total of 28 patients, aGVHD was seen in 6 (21.4%) patients, five of which had skin involvement (Grade I- II) and one suspected liver involvement (Grade III), all of which responded rapidly to steroids with no cases of SR-GVHD. Secondary graft failure and EBV reactivations; each were seen in 10% of cases. Primary disease relapse was seen in 3 patients, two of which had minimal residual disease prior to transplantation. These results were then compared to the historical cohort of 27 patients who received a combination of ATG-CsA plus Mycophenolate Mofetil (MMf) (Table 1). The incidence of acute GVHD was 26% vs 22% (p=0.99), with severe Grade III-IV aGVHD of 4% vs 20% (p=0.085) in the ATG-PTCy-CsA and ATG-CsA-MMf cohorts, respectively; both were statistically not signifcant. There were five patients with SR-GVHD in the ATG-CsA-MMf cohort and none in the current GVHD prophylaxis arm. In the historical cohort, the main cause of death in 7 out of 11 patients was severe GVHD as compared to 1 out of 9 in the ATG-PTCy-CsA cohort.Conclusions: Combination of ATG-PTCy-CsA is an effective strategy to reduce aGVHD; especially severe Grade III-IV and doesnot increase the risk of SR-GVHD, in unrelated donor transplants as compared to ATG-CsA-MMf. However, a long term follow up is needed to assess relapse and cGVHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Influence of Age on Risk for Acute and Chronic Graft Versus Host Disease in Children Receiving HLA Identical Sibling Bone Marrow Transplantation

Introduction: In adult HLA matched sibling donor (MSD) hematopoietic cell transplantation, both recipient and donor age have been shown to be a risk factors for graft versus host disease (GVHD). While it is widely recognized that pediatric patients are at lower risk for GVHD than adults, the importance of age within the pediatric age group in MSD transplantation has not been examined. We, therefore, assessed the impact of age on GVHD risk after MSD bone marrow transplantation (BMT) in 477 pediatric patients with acute leukemia.Methods: This is a Center for International Blood and Marrow Transplantation registry study. Patients younger than 18 years with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) in 1st or 2nd complete remission (CR), who received myeloablative conditioining, T cell-replete HLA MSD BMT and calcineurin inhibitor based GVHD prophylaxis between 2000-2013 were included. Patients who received a lymphocyte depleting antibody were excluded. Because donor and recipient ages were highly correlated, their effects could not be independently assessed. We, therefore, assessed only recipient age.Results: The transplants were drawn from 101 centers. The median age of the recipients was 10.1 years. 21% had ALL in 1st CR, 24% ALL in 2nd CR, 47% AML in 1st CR and 8% AML in 2nd CR. 73% received cyclosporine and Methotrexate for GVHD prophylaxis. In a preliminary model, using grade 3-4 acute GVHD as the endpoint, we identified two cut points, 2 years and 13 years using the likelihood ratio test. In all final models, three age groups were used to define recipient age: < 2 years (n=60), 2 to 12.99 (n=255) years and 13-17.99 years (n=162). The cumulative incidence of grade 2-4 acute GVHD at 100 days post-transplant was 19% (95% confidence interval, CI, 16-23%); 24% (95% CI 14-35%), 13% (95% CI 9-18%) and 28% (95% CI 21-35%) for recipients <2 years, 2-12.99 years, and 13-17.99 years of age, respectively (p-value=0.001). For grade 3-4 acute GVHD, the cumulative incidence estimate at 100 days was 8% (95% CI 3-17%), 3% (95% CI 1-6%) and 14% (95% CI 9-20%) (p <0.001) and the cumulative incidence estimate for chronic GVHD at 1 year was 15% (95% CI 7-25%), 10% (95% CI 7-14%) and 27% (95% CI 20-34%) (p <0.001) for recipients <2 years, 2-12.99 years, and 13-17.99 years of age, respectively (Figures 1-3). In the multivariate analyses, using age 13-17.99 as the baseline and .01 as the threshold for significance, age 2-12.99 years (HR 0.43, 95% CI 0.26-0.71, p=0.001), but not age < 2 years (HR 0.59, 95% CI 0.3-1.18, p=0.14), was associated with a lower risk for grade 2-4 acute GVHD (after adjustment for GVHD prophylaxis, performance score and year of transplant). For grade 3-4 acute GVHD, again age 2-12.99 years (HR 0.24, 95% CI 0.1-0.56, p=0.001), but not age < 2 years (HR 0.75, 95% CI 0.29-1.94, p=0.55), was associated with a lower risk, after adjustment for year of transplant. For chronic GVHD (after adjustment for donor-recipient birth order, and GVHD prophylaxis), age 2-12.99 years (HR 0.32, 95% CI 0.19-0.54, p<0.001) was associated with lower risk; the effect was similar in age < 2 years, but did not reach significance (HR 0.36, 95% CI 0.16-0.82, p=0.016). Year of transplant had a strong effect on acute, but not chronic GVHD. Its effect did not appear to be mediated by changes in GVHD prophylaxis. Using 2000-2004 as the baseline, the HR for grade 2-4 acute GVHD was 0.38 (95% CI 0.20-0.64, p=0.0006) and 0.28 (95% CI 0.13-0.59, p=0.0008) for 2005-2008 and 2009-2013, respectively. For grade 3-4 acute GVHD, they were 0.23 (95% CI 0.08-0.65, p=0.0057) and 0.23 (95% CI 0.07-0.78, p=0.0183) for these periods, respectively. There was no difference in overall survival, leukemia-free survival or transplant related mortality between the age groups.Conclusion:Our results indicate that children 2-12.99 years have a lower risk for acute and chronic GVHD than those 13 years and older. Children less than 2 years may also have a reduced risk for chronic GVHD, but this possibility needs to be re-examined in a larger sample. It is plausible that pubertal changes underlie the rise in risk for GVHD during adolescence. An important limitation of our study was that we were unable to examine the impact of donor age because of the strong correlation between donor and recipient age. A study with a larger sample is also needed to further investigate this matter. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Analysis of the Impact of KIR B Haplotype Donors on Outcomes after Haploidentical (HI) and Matched Related (MR) Hematopoietic Stem Cell Transplantation (HSCT)

Introduction:Natural killer (NK) cell alloreactivity has been associated with graft versus leukemia effects in HSCT. These effects are in part mediated through killer cell immunoglobulin-like receptors (KIR) on the surface of NK cells. The absence of inhibition of NK cells via inhibitory KIR in KIR ligand mismatched T-cell depleted HI HSCT, and the use of unrelated donors possessing activating KIR haplotypes (KIR-B) have been associated with improved overall survival (OS) due to relapse protection. Inhibitory KIR ligand mismatch in the setting of T-cell replete HI HSCT has not consistently been shown to be beneficial, and data regarding the impact of using KIR-B donors in T-replete HI and MR HSCT is limited. In this preliminary retrospective review, we compared outcomes between patients with KIR-B donors versus KIR A haplotype (KIR-A) donors after HI and MR HSCT to help inform donor selection.Methods:All patients underwent HSCT on our 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 CD 34-selected donor product (step 2). To be included in the analysis, patients had to be alive for at least 1 month post HSCT and be without evidence of graft rejection. Recipients were divided into 2 groups based on whether they were transplanted from a KIR-B (possessing one or more non-framework activating KIR genes) versus a KIR-A donor (genotypically negative for non-framework activating KIR genes). The relationship between the use of a KIR-B donor and the end points of OS, relapse, grades II-IV acute graft versus host disease (GVHD), chronic GVHD and non-relapse mortality (NRM) was examined. Probability of OS was estimated by Kaplan-Meier (KM) method with log-rank analysis and multivariate analyses using Cox proportional hazards. Donor and recipient age and gender, HCT-CI score, Revised Disease Risk Index, presence of any inhibitory KIR ligand mismatch between donor and recipient and CMV reactivation after HSCT were considered as confounding variables. Cumulative incidence functions with competing risk analyses were used to estimate the probabilities of relapse, NRM, acute and chronic GVHD.Results:The study group consisted of 128 consecutive patients with myeloid malignancies (AML=91 MDS=27, CML=1, MPD=9) undergoing HI [n=84] or MR [n=44] HSCT. The median recipient age and follow-up of the study group was 58 (range 19-78) years and 40.6 (range: 1.07-117.27) months respectively. Only 13 (10.2%) patients had grade III or higher acute GVHD and only 7 (5.5%) patients developed severe, chronic GVHD (score of 3) respectively. Seventy-four (58%) and 54 (42%) of recipients had KIR-B versus KIR-A donors respectively. Fifty-five (74.3%) KIR-B donors possessed HLA C1 or C1/2 alleles in the presence of KIR2L2/3/2DS2. On multivariate Cox regression analysis, OS (HR, 0.579; 95% CI, 0.337-0.995; P= 0.048) was significantly higher in patients who received HSCT from KIR-B donors. On competing risk analysis, relapse (HR, 0.756; P=0.403) and NRM (HR, 0.466; P=0.128) were lower in patients who had KIR haplotype B donors though not statistically significant. In contrast, the risk of grades II to IV acute GVHD (with death as a competing event) was higher in patients with KIR-B donors (HR, 1.972; 95% CI, 1.009-3.852; P=0.047). Similarly transplants from KIR-B donors were associated with a higher risk of chronic GVHD (HR, 2.89; P=0.053).Discussion:Our results show that within the context of the 2-step approach, the use of a KIR-B donor is associated with improved OS and an increased risk of acute and chronic GVHD in patients with myeloid neoplasms receiving HI and MR HSCT. While not reaching significance, the results for relapse and NRM suggest that the OS benefit in patients with KIR-B donors was derived from a combination of lower relapse rates and NRM that was not adversely impacted by GVHD which was mostly lower grade in this population. Our findings support the concept of KIR-B donors as more alloreactive than KIR-A donors, specifically those possessing a C1-C1/2/2DL2/3/2DS2 repertoire, the primary type possessed by KIR-B donors in this analysis. The data argues for the continued use of KIR genotyping at our institution and analyses of HSCT outcomes based on donor KIR repertoire and other donor characteristics to optimize donor selection in HI and MR HSCT. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Hematopoietic Cell Transplantation for Elderly Patients: Prognosis Determined By Disease Risk Index

Survival of elderly patients with hematological malignancies remains suboptimal despite many older adults receiving reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT). We studied the impact of disease risk index (DRI) on clinical outcomes of 196 elderly patients (≥60 years old) with hematological malignancies receiving RIC alloHCT between 2000-2013. Median age at transplant was 64.8 years (range, 60-75; 53% age 60-64 and 47% age ≥65). More comorbidities (HCT-CI ≥3) were present in 70 patients (35.7%) and Karnofsky performance score (KPS) was < 80% in 34 patients (17.3%) prior to transplant. Peripheral blood or bone marrow allografting was performed in 100 patients (51.1%) and umbilical cord blood allografting in 96 patients (48.9%). DRI classified 12 patients (6.1%) as low risk (LR), 146 patients (74.5%) as intermediate risk (IR), and 38 patients (19.4%) as high or very high-risk (HR/VHR). Neutrophil engraftment at day 42 did not differ between LR/IR and HR/VHR (95% vs. 100%, p=.40), whereas platelet engraftment at 6 months was significantly lower for HR/VHR (76% vs. 58%, p=.08). Treatment related mortality (TRM) at 2 years was similar in LR/IR and HR/VHR (28% vs. 34%, p=.12). Overall relapse incidence was 30% in the entire cohort and increased in HR/VHR (26% for LR/IR vs. 44% for HR/VHR; p<.01). Notably, 2-year disease free survival (DFS) and overall survival (OS) were both significantly lower in HR/VHR groups. DFS was 39% in entire cohort (44% for LR/IR vs. 21% for HR/VHR; p<.01), and OS in entire cohort was 47% (52% for LR/IR vs. 29% for HR/VHR; p<.01; Figure). For LR/IR and HR/VHR DRI groups, the incidence of grade II-IV acute GVHD was similar (41% and 47% at 6 months, p=.32) and the incidence of chronic GVHD was similar (35% and 31% at 2-years, p=.07). GVHD and relapse free survival (GFRS) at 2-years was significantly worse for HR/VHR DRI group (25% for LR/IR vs. 0% for HR/VHR; p<.01). All clinical outcomes were similar between those 60-64 and ≥65 years of age. In multiple regression analysis, after adjusting for a graft source, platelet recovery was worse for HR/VHR DRI group (HR=0.56; 95% CI 0.35-0.91; p=.02), while neutrophil engraftment was not influenced by DRI. HR/VHR DRI was a risk factor for increased risk of relapse after alloHCT (HR=2.05; 95% CI 1.14-3.69; p=.02). After adjusting for graft source, KPS and year of HCT, treatment failure (inverse of DFS; HR=1.83; 95% CI 1.16-2.87; p=.02) and overall mortality (HR=1.87; 95% CI 1.16-3.02; p=.01) were significantly increased for HR/VHR DRI group. Although DRI did not affect the risk of acute or chronic GVHD, GRFS was significantly worse for patients with HR/VHR DRI (HR=2.13; 95% CI 1.46-3.11; p<.01). We conclude that in this cohort of elderly patients, worse DRI remains a significant prognostic factor for post-transplant relapse, treatment failure, mortality and GRFS. While eligible elderly patients up to age 75 with hematologic malignancies should be considered for RIC alloHCT, alternative or novel therapies should be considered for those with HR/VHR DRI. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PRE-Transplant Positron Emission Tomography (PET) Predicts Outcomes of Patients with Hodgkin disease Undergoing Reduced Intensity Conditioning Haploidentical Transplant

Background. In recent years, the number of Hodgkin Lymphoma (HL) patients submitted to reduced intensity haploidentical allogeneic transplant (RIC haplo SCT) consistently increased. [Sureda et al. Curr Treat Options Oncol 2014] However, with a post alloSCT relapse rate so high as 40-60%, disease control after autoSCT relapse remains a clear unmet medical need. In respect of improving transplant outcome identification of factors influencing outcomes are warrantedMethods.We reviewed outcomes obtained in 44 consecutive HL patients who received RIC haplo SCT between September 2009 and June 2015 at our institution. The donor was haploidentical relative in all cases. All patients had received at least 3 conventional chemotherapy lines before RIC haplo SCT; most of them (72%) were refractory to front-line chemotherapy and all but one had received an autologous SCT. All patients received the same reduced intensity conditiong regime, and GvHD prophilaxis with post-transplant cyclophosphamide (Raiola et al. BBMT 2008). The median age was 31years (range 18-60). Deauville five-points scale were used to interpretate the results of pre-transplant positron-emission tomography (PET) studies, with a threshold of 4 or above considered positive. Survival curve and GvHD incidence were calculated with the method of Kaplan and Meier. Cox regression model was performed to identify pre-transplant factors influencing outcomes.Results. All patients engrafted but 1 who showed autologous recovery. The median day for 500 neutrophils was 15 days (13-23). Three patients died in remission at 8 (cGvHD), 16 (myocarditis) and 51(pneumonia) months from SCT, respectively. Three years non relapse mortality = 8%. Risk of grade II-IV acute GvHD and 3-year chronic GvHD were 22 and 21%, respectively. With a median follow-up for surviving patients of 38 months (range 13-83), 21 relapsed (47%). All relapsed patients were treated with further therapy, mainly immuno-chemotherapy and donor lymphocyte infusion (DLI). The 3-year overall (OS) and progression free survival (PFS) were 77% and 39%, respectively. Pre-transplant PET status was the only factor influencing outcomes of the procedure (OR 5.4; 95% CI 1.7 - 16.6). In the 41 patients with available pre-transplant PET status, 19 were positive and 22 negative. Outcomes accordingly to pre-transplant PET status are shown in the following table.Conclusions.Pre-transplant PET status is a factor influencing outcomes of relapsed/refractory HL submitted to RIC haplo SCT. Grade II-IV aGvHD was markedly reduced in patients with metabolic remission at time of transplantation. [Display omitted] DisclosuresAngelucci:Novartis oncology, celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.