Anti-thymocyte Globulin Recipients Research Articles

Proinflammatory Cytokine Release and Infusional Side-Effects after Anti-Thymocyte Globulin Serotherapy for Graft-Versus-Host Disease Prophylaxis in Allogeneic Hematopoietic Cell Transplantation

Background: Anti-thymocyte globulin (ATG) serotherapy for graft-versus-host disease (GVHD) prophylaxis in allogeneic hematopoietic cell transplantation (HCT) is frequently associated with infusional side-effects (ISEs) including fever, tachycardia, respiratory distress, and hypotension/shock. Although this constellation closely resembles cytokine release syndrome, the mechanism behind ATG ISEs is poorly understood. The aim of this study was to characterize the frequency and severity of ATG ISEs, and determine the association of ISEs with cytokine levels and clinical outcomes. Methods: This study included 118 adult HCT recipients receiving myeloablative conditioning including fludarabine, busulfan, low-dose total body irradiation, and 4.5mg/kg ATG (0.5mg/kg on day -2 and 2mg/kg on days -1 and 0). Patient electronic medical records were retrospectively reviewed for clinical data collection. ISE were classified as thermal (fever/rigors), respiratory (tachypnea/hypoxemia/increased O 2 supplementation), tachycardia, or circulatory (hypotension/fluid resuscitation requirement). ISEs were further characterized into mild or severe (e.g., mild tachycardia = 105-120bpm, severe ≥120bpm). Serum levels of 31 cytokines were determined pre- and post-1 st ATG infusion in all patients (and up to 13 timepoints in select patients) using Luminex. Cox and Fine-Gray regression were used to determine the association of ISEs with clinical outcomes including grade 2-4 acute GVHD (aGVHD), moderate-severe chronic GVHD (cGVHD), cumulative incidence of relapse (CIR), and overall survival (OS). Results: At least one ISE occurred in 74% (87/118) of patients, with a maximum severity of mild in 56 (47%) and severe in 31 (26%). Patients experienced an average of 1.4 ISEs (median 1), most commonly tachycardia (57%) and thermal (50%), while respiratory (26%) and circulatory (7%) ISEs were less frequent. ISE frequency was 62%, 60%, and 35% after the 1 st-3 rd ATG infusions, respectively, with the median time from infusion to first ISE being ~4.5 hours. Compared to pre-infusion levels, there was a >1-fold change in 11/34 cytokines (all P<0.001) [Table 1]. Of greatest interest was IL-6, which demonstrated a progressive increase in median levels between patients with no vs. mild vs. severe ISEs (P<0.05). Severe ISEs were associated with a lower incidence of grade 2-4 aGVHD (SHR=0.12, P=0.032), but not with any other outcomes. Patient age, sex, primary disease, or pre-infusion peripheral blood cell counts (leukocytes, lymphocytes, neutrophils, and monocytes) did not appear to influence ISE frequency or severity. Conclusion: ISEs occur in the majority of ATG recipients, with one-fourth experiencing severe ISEs. The concomitant rise in serum cytokine levels (particularly IL-6) suggests that anti-cytokine antibodies (e.g., tocilizumab) may assist in the prevention or treatment of ISEs, however, the impact this may have on outcomes is unclear and warrants investigation in upcoming clinical studies.

Increased donor inhibitory KIR with known HLA interactions provide protection from relapse following HLA matched unrelated donor HCT for AML.

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated graft versus leukemia effect (GVL) after hematopoietic cell transplant (HCT) for AML. Accounting for known KIR-KIRL interactions may identify donors with optimal NK cell-mediated alloreactivity and GVL. A retrospective study of 2359 donor-recipient pairs (DRP) who underwent unrelated donor (URD) HCT for AML was performed. KIR-KIRL combinations were determined and associations with clinical outcomes examined. Relapse risk was reduced in DRP with both higher inhibitory KIR-KIRL (iKIR) and missing KIRL (mKIR) scores, with HR 0.86 (P = 0.01) & HR 0.84 (P = 0.02) respectively. The iKIR and mKIR score components were summed to give a maximal inhibitory KIR ligand (IM-KIR) score for each donor, which if it was 5, as opposed to <5, was also associated with a lower relapse risk, SHR 0.8 (P = 0.004). All IM = 5 donors possess KIR Haplotype B/x. Transplant-related mortality was increased among those with IM-KIR = 5, HR, 1.32 (P = 0.01). In a subset analysis of those transplanted with 8/8 HLA-matched DRP, anti-thymocyte globulin recipients with IM-KIR = 5, had a lower relapse rate HR, 0.61 (p = 0.001). This study demonstrates that HLA-matched unrelated donors with the highest inhibitory KIR content confer relapse protection, albeit with increased TRM. These donors all have KIR haplotype B. Clinical trials utilizing donors with a higher iKIR content in conjunction with novel strategies to reduce TRM should be considered for URD HCT in recipients with AML to optimize clinical outcomes.

Increased Inhibitory KIR-Ligand Interactions Confer Relapse Protection Following HLA Matched Unrelated Donor HCT for AML

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated graft versus leukemia effect (GVL) after hematopoietic stem cell transplant (HCT) for AML. There is considerable heterogeneity in the KIR gene and KIRL content of individuals, making it difficult to estimate the full clinical impact of NK cell alloreactivity following HCT. Herein, we validate a mathematical model accounting for KIR-KIRL interactions identifying donors with optimal NK cell-mediated alloreactivity and GVL. This retrospective study was performed on de-identified donor and recipient demographic and clinical outcomes data provided by the Center for International Blood and Marrow Transplant Research (CIBMTR). Donor recipient pairs (DRP) who underwent unrelated donor (URD) HCT for early and intermediate AML were included. KIR-KIRL interaction values were assigned as follows; if an inhibitory KIR (iKIR) on the NK cell encounters a ligand on its target, this will give the NK cell an inhibitory signal and this is scored as a single interaction(Figure 1b), as is the case, if there is no ligand for an inhibitory KIR, i.e., missing KIRL (mKIRL) (Figure 1c). Finally, activating KIR (aKIR) interacting with its ligands is similarly scored(Figure 1a). The absolute values of the iKIR and mKIR scores were summed to calculate the composite inhibitory-missing ligand (IM)-KIR score (Figure 1d). The study cohort was comprised of 2365 donor-recipient pairs (DRP) who underwent URD HCT for early or intermediate AML. Mean age was 53 years; 85% of DRPs were high-resolution 8/8 HLA-matched for HLA-A, -B, -C, and -DRB1. All patients received T cell replete grafts; 42% (n=996) received in vivo T cell depletion, 937 (94%) with anti-thymocyte globulin (ATG); 86% received a graft of mobilized peripheral blood stem cells (PBSC), 59% received myeloablative conditioning. This cohort was primarily of Caucasian descent (89%). When adjusted for recipient age, donor age, CMV status, KPS, GVHD prophylaxis, cytogenetics, disease status, conditioning regimen, in vivo T cell depletion, graft source, and sex match, relapse risk was significantly reduced in donor-recipient pairs (DRP) with higher inhibitory KIR-KIRL interaction and missing KIRL (mKIR) scores, with HR=0.86 (P=0.01) &amp; HR=0.84 (P=0.02) respectively. This effect was not observed with activating KIR-KIRL interactions. Chronic GVHD and TRM were not significantly affected by iKIR, mKIR or aKIR. Given the significant individual impact of iKIR and mKIR, the summed inhibitory-missing ligand (IM-KIR) score was next assessed, and when this score was 5 (as opposed to &amp;lt;5), the IM-KIR score was also associated with lower relapse risk, HR 0.8 (P=0.004) (Figure 2a). Acute and chronic graft vs. host disease (GVHD), survival, GRFS, and relapse-free survival were not significantly different, likely due to increased TRM among these patients, HR 1.32 (P=0.01). Interaction analysis indicated that amongst the HLA matched DRP, ATG recipients with IM-KIR=5, had a lower relapse rate compared to those with an IM-KIR&amp;lt;5, HR 0.61 (p=0.001) (Figure 2b), among the cohort who did not receive ATG there was no significant difference in relapse among IM-KIR=5 and IM-KIR&amp;lt;5; thus, the use of ATG significantly modified the effect of IM KIR score in an interaction analysis (p=0.049), suggesting higher NK cell magnitude of KIR-KIRL interaction may compensate for the general increase of relapse in those who receive in vivo T cell depletion. Nevertheless, TRM was also increased in these patients, HR 1.49 (p=0.034), likely abrogating survival advantage from a lower relapse risk. This large international study confirms that unrelated DRPs with greater magnitude of inhibitory KIR-KIRL interactions confer significant relapse protection after MUD HCT in standard-risk AML. This challenges the notion that KIR are irrelevant to donor selection. Future clinical trials evaluating donor selection for URD HCT should include this measure to evaluate its value prospectively in uniformly treated patient cohorts, with adequate GVHD and antiviral prophylaxis to mitigate TRM. Disclosures No relevant conflicts of interest to declare.

Less Chronic Graft-Versus-Host Disease, Immunosuppressive Therapy and Better Survival after Anti-Thymocyte Globulin in Unrelated Donor Stem Cell Transplant Recipients: Longer Follow-up of a Multicentre Cell Therapy Transplant Canada Randomized Trial

Less Chronic Graft-Versus-Host Disease, Immunosuppressive Therapy and Better Survival after Anti-Thymocyte Globulin in Unrelated Donor Stem Cell Transplant Recipients: Longer Follow-up of a Multicentre Cell Therapy Transplant Canada Randomized Trial

In Vivo T Cell Depletion with Myeloablative Regimens on Outcomes after Cord Blood Transplantation for Acute Lymphoblastic Leukemia in Children.

The inclusion of antithymocyte globulin (ATG) in cord blood transplantation is controversial. We evaluated outcomes according to ATG inclusion in 297 children and adolescents with acute lymphoblastic leukemia (ALL) who received myeloablative total body irradiation-based conditioning and either single-unit (74%) or double-unit (26%) grafts. Ninety-two patients (31%) received ATG and 205 (69%) did not. ATG recipients were more likely to be cytomegalovirus seronegative. The incidences of day 100 grades II to IV acute graft-versus-host disease (GVHD; 30% versus 54%, P = .0002) and chronic GVHD (22% versus 43%, P = .0008) were lower with ATG compared with non-ATG regimens. However, day 100 grades III to IV acute GVHD was comparable (11% versus 17%, P = .15). The 3-year incidences of transplant-related mortality (16% versus 17%, P = .98), relapse (17% versus 27%, P = .12), and leukemia-free survival (66% versus 55%, P = .23) in ATG and non-ATG recipients were similar. There were no differences in viral reactivation between treatment groups (60% versus 58%, P = .83). Therefore, the data suggest that incorporation of ATG with myeloablative conditioning regimens may be useful in reducing the risk of acute and chronic GVHD without any deleterious effect on transplant-related mortality, relapse, or leukemia-free survival in children and adolescents with ALL.

Comparable 3-Year Disease-Free Survival Regardless of Anti-Thymocyte Globulin Inclusion in Pediatric Myeloablative Cord Blood Transplantation for Acute Lymphoblastic Leukemia

Background: Cord blood (CB) is routinely used as an alternative stem cell source for the treatment of children with acute leukemia and has been associated with high rates of disease-free survival (DFS). However, one controversial issue in pediatric CB transplantation is the role of anti-thymocyte globulin (ATG) as immunoprophylaxis. While inclusion of ATG in the conditioning may decrease the risk of graft-versus-host disease (GVHD), it could potentially abrogate graft-versus-leukemia effects and increase the risk of opportunistic infections. Thus, we compared outcomes in a uniform group of pediatric patients with acute lymphoblastic leukemia (ALL) who underwent myeloablative CB transplantation with or without ATG.Methods: Patients with ALL in morphologic remission (CR1 n=106, CR2 n=146, CR3 n=45) aged ≤ 20 years transplanted between 01/2007-12/2011 with high-dose total body irradiation-based conditioning and single or double unit CB grafts were eligible for analysis. CB units were 4-6/6 HLA-A,-B at the antigen-level, -DRB1 allele matched to the recipient and had CB unit with cryopreserved total nucleated cell dose of ≥ 2.5 x107/kg/unit. Cox regression models were built to evaluate potential differences in outcome in ATG versus non-ATG CB transplant recipients. The primary endpoint was 3-year DFS.Results: Of 297 patients, 92 received ATG and 205 did not. Age and disease status were similar in each group whereas ATG recipients were less likely to be CMV seropositive and more likely to receive single unit CB grafts. While neutrophil engraftment was similar in each group, the risk of day 100 grade II-IV acute GVHD [30% (95%CI: 21-40) versus 54% (95%CI: 47-61), p = 0.0002] and 3-year chronic GVHD [22% (95% CI: 14-31) versus 43% (95% CI: 36-50), p = 0.0008] were decreased in ATG recipients. However, day 100 grade III-IV aGVHD was comparable: 11% (95%CI: 5-18) in ATG versus 17% (95%CI: 12-23) in non-ATG recipients, p = 0.15]. The 3-year TRM was similar in both groups: 16% (95%CI: 10-25) in ATG versus 17% (95%CI: 13-23) in non-ATG recipients (p = 0.98). Relapse was also similar in ATG and non-ATG recipients: 17% (95%CI: 10-23) versus 27% (95%CI: 21-34, p = 0.12), respectively. In multivariate analysis, negative CMV serostatus was associated with reduced TRM risk [HR 0.55 (95%CI: 0.30-0.98), p = 0.004] whereas remission status CR2 or CR3 significantly increased relapse risk [HR 2.18 (95%CI: 1.22-3.89), p = 0.008], but inclusion of ATG had no effect on either outcome. With a median follow-up of survivors of 36 months (range 5-72), the 3-year DFS was 66% (95%CI: 56-76) and 55% (95%CI: 48-62) in ATG and non-ATG recipients, respectively (p = 0.23, Figure 1). The distribution of causes of death was similar in each group. In multivariate analysis, treatment failure risk was increased in patients transplanted in CR2 or CR3, but the inclusion of ATG had no effect (p = 0.24) (Table 1).Conclusion: Inclusion of ATG in pediatric myeloablative CB transplant for ALL is associated with a decreased risk of grade II-IV acute GVHD and chronic GVHD but not severe grade III-IV acute GVHD. There was no difference in 3-year DFS in each group and multivariate analysis revealed ATG inclusion had no impact upon treatment failure risk. These results indicate that optimization of both ATG and non-ATG conditioning platforms are needed in order to further improve CB transplantation survival in children with ALL. Unanswered questions include the impact of the formulation, dose and timing of ATG administration. These findings cannot be extrapolated for other diagnoses, reduced intensity conditioning, or adults.Table 1Hazard ratio(95% confidence interval)p-valueATG useConditioning without ATG Conditioning with ATG1.00 0.78 (0.52 – 1.18)0.24 Disease statusCR1 CR2, CR31.00 2.01 (1.31 – 3.08)0.001 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The effect of equine antithymocyte globulin on the outcomes of reduced intensity conditioning for AML.

Whether or not the benefits of antithymocyte globulin (ATG) on engraftment and GVHD are offset by increased risk of relapse, delayed T-cell recovery and increased infections remains controversial. We retrospectively studied the effect of ATG in 144 AML patients, 34 of whom received ATG, undergoing reduced intensity conditioning (RIC) umbilical cord blood transplantation (UCB) or HLA-matched sibling PBSC. ATG patients had not received intensive chemotherapy for 3 months before transplantation for UCB, 6 months for PBSC. There were no differences in engraftment between ATG and non-ATG patients. The cumulative incidences of TRM as well as acute and chronic GVHD in ATG-treated patients were not statistically different. ATG patients had significantly more infections between 46 and 180 days post transplantation. Unexpectedly, after adjusting for donor type, relapse was lower among ATG recipients (relative risk (RR) 0.5, 95% confidence interval (CI) 0.3-1.0, P=0.04). In summary, administration of ATG to AML patients undergoing RIC had no adverse impact on major clinical outcomes. ATG may be indicated for patients at higher risk of graft failure after allogeneic hematopoietic cell transplantation (allo-HCT).

Immune Reconstitution In Anti-Thymocyte Globulin Conditioned Unrelated Donor Stem Cell Transplantation

Anti-thymocyte globulin (ATG) is widely used for in vivo T cell depletion and immunomodulation in unrelated donor (URD) stem cell transplantation (SCT) to reduce the risk of graft vs. host disease (GVHD). However, despite the reduction in GVHD risk, outcomes are generally not superior to matched related donor (MRD) SCT conditioned without ATG. This is primarily because of defective immune reconstitution and high rates of opportunistic infections in ATG recipients. We have previously reported equivalent outcomes in URD SCT recipients conditioned with ATG when compared to MRD recipients. We now report immune reconstitution in an expanded cohort of these patients. Patients with AML, ALL, MDS, MPD (n=142) transplanted between 2004 and 2011 were included in this retrospective review. Seventy eight received either bone marrow or peripheral blood stem cell (PBSC) grafts from URD and received either 10 or 7.5 mg/kg rabbit ATG (Thymoglobulin, Sanofi-Aventis) during conditioning, those with MRD did not. Conditioning was myeloablative in all patients. Lymphoid recovery was equivalent in the two cohorts during the first year following SCT except in the first month (Figure), when URD recipients had lower absolute lymphocyte count (μ-URD=0.6x103/ μ L, μ-MRD=1.1; repeated measures mixed model p=0.022). Age, CD3/34 cell dose infused, stem cell source and conditioning intensity were not associated with ALC recovery post transplant. In a subset of patients lymphocyte subset enumeration was performed following withdrawal of immunosuppression, at an average 237 days post-SCT. ATG recipients had significantly lower mean CD4+ counts (μ-URD=267 (n=30), μ-MRD =434/ μ L (n=27); ANCOVA p = 0.003), however no significant differences were observed in CD3+, CD8+, CD19+ or CD56+ cell recovery. ATG recipients were significantly more likely to have complete donor T cell chimerism at 1 (OR = 12.5, CI= 2.4, 66.0, p = 0.001) and 2 months post-SCT (OR = 6.5 , CI=1.5, 27.4, p = 0.013), however by 9 months following SCT this trend had reversed with a greater likelihood of mixed T cell chimerism (OR > 100; p = 0.017), suggesting re-emergence of recipient derived T cell clones. Consequently, donor lymphocyte infusions were given significantly more often to ATG recipients (12/78) than to non-recipients (2/64) (OR = 5.64, CI = 1.21, 26.20, p=0.027). High grade CMV viremia (1000 copies/ μL) was significantly more likely in CMV sero-positive ATG recipients (n=18/55) than in non-recipients (n=7/48) (OR = 2.8, CI 1.1, 7.6, p = 0.032). Reduced intensity conditioning and PBSC were associated with higher CMV reactivation in ATG recipients and there was a lower likelihood of survival in these individuals than in those who did not receive ATG (HR: 0.53, CI: 0.31, 0.92; p = 0.024). EBV reactivation was observed more often in susceptible ATG recipients (n=22/58) than in non-recipients (n=5/43), (OR=4.6, CI=1.6, 13.6, p= 0.003). The median peak EBV viral load in ATG recipients (u=1545 copies/ μL, IQR: 288, 2,302) was significantly higher than in non-recipients (u=120 IQR: 57, 169, p = 0.005). PBSC stem cell source (p = 0.049) and HLA mismatch (p =< 0.001) were associated with EBV reactivation in ATG recipients but not in non-recipients. ATG recipients were also more likely to experience a fungal infection (OR=2.8, CI=1.1, 6.7, p=0.023). 1-month ALC was predictive of disease free survival whereby it had a significant negative effect on relapse (HR = 0.33; 95% CI: 0.16, 0.66; p = 0.002). As 1-month ALC increased by one-tenth, the odds of relapse decreased by over 3% and survival increased by 3%. In conclusion, high doses of ATG used during conditioning are associated with an early retardation of lymphoid recovery post-SCT, and with late mixed T cell chimerism accompanied by a delay in CD4+ T cell recovery. This is associated with a higher rate of viral reactivation in PBSC recipients and of fungal infections in general. Lower doses of ATG should be used in SCT and in ATG conditioned SCT, early intervention with DLI, particularly CD8+ cell depleted DLI as reported by others, may help restore T cell repertoire and improve SCT outcomes and survival. [Display omitted] Disclosures:Toor:Sanofi Avnetis: Research Funding.

Induction Therapy in African American Heart Transplant Recipients: Analysis of the UNOS Database

Purpose Induction therapy (IND) after heart transplant (HTx) remains controversial despite its use in over 50% of programs. No randomized trials exist to suggest benefit. African Americans (AA) are at high risk for allograft rejection. We sought to explore whether the use of Antithymocyte globulin (ATG) or Basiliximab improved survival in AA, using the UNOS database. Methods and Materials We reviewed 2,523 consecutive adult AA HTx patients from the UNOS database from 1/2000 to 3/2011. Data were analyzed using two age groups; younger ages 21-59 years (n=2,037) and older ≥60 years (n=486). Five-year (5-yr) survival was estimated by Kaplan-Meier method. Survival was compared across groups by Log-Rank test. Cox proportion hazards models were used to assess factors related to 5-yr survival and to obtain hazard ratios and their 95% confidence intervals. Results Univariable analysis found younger AA who received ATG had better 5-yr survival compared to Basiliximab (P=0.002) or no IND (P=0.016). Older AA with Basiliximab experienced better 5-year survival than ATG recipients (P=0.019). In multivariable models, adjusting for Creatinine>2mg/dL and PRA>10%, younger AA, had a trends for ATG to be protective vs Basilximab (HR=0.74, P=0.075) and no IND (HR=0.78, P=.076). In older AA, Basiliximab was protective vs ATG (HR=0.46, P=0.022) and there was a trend for no IND to be protective vs ATG(HR=0.72, P=0.16). [ figure 1 ] Conclusions ATG may confer protection in the young AA but worsen survival in AA age 60 and older. For AA of age ≥60 Basiliximab appears protective vs ATG. Age-related differences in immune activation may explain these findings. Randomized trials to assess efficacy of induction therapy are indicated.

Different Outcomes between Cyclophosphamide Plus Horse or Rabbit Antithymocyte Globulin for HLA-Identical Sibling Bone Marrow Transplant in Severe Aplastic Anemia

The standard regimen for HLA-identical sibling bone marrow transplant (BMT) in severe aplastic anemia (SAA) is cyclophosphamide (Cy) and horse antithymocyte globulin (ATG). Horse ATG has been replaced by rabbit ATG in many countries due to the unavailability of the former product. This study was designed to assess if these ATG preparations are interchangeable in the preparative regimen for matched related BMT in SAA. Forty consecutive BMTs were retrospectively analyzed: 20 received Cy plus horse ATG and 20 received Cy plus rabbit ATG as the preparative regimen. Conditioning with rabbit ATG was protective against acute graft-versus-host disease (aGVHD) grades II-IV and moderate-severe chronic GVHD (cGVHD), with incidence rates of 0% versus 35.2% (P = .009) and 0% versus 34.0% (P = .04), respectively. On day +100, the probability of proven/probable invasive fungal disease (IFD) was higher in patients conditioned with rabbit ATG, 31.2% versus 5.5%, respectively (P = .04). Earlier cytomegalovirus (CMV) reactivation (40 versus 50 days; P = .02) was observed with rabbit ATG. An inferior lymphocyte count on days +30 (0.360 versus 0.814 × 10(9)/L; P = .01) and +90 (0.744 versus 1.330 × 10(9)/L; P = .006) was noticed in recipients of rabbit ATG. The incidence of stable mixed chimerism was higher in recipients of rabbit ATG (18.2% versus 80%, respectively; P = .004). These results suggest that horse and rabbit ATG preparations have different biological and clinical properties and should not be used interchangeably in the preparative regimen for related BMT in SAA.

Obesity Adversely Affects Survival of Pediatric Patients with Severe Aplastic Anemia After Hematopoietic Cell Transplantation.

Abstract 652Prevalence of obesity in children has been rapidly rising in the last decade in the US and other industrialized countries (US prevalence, ages 2-19, 16%, NHANES, 2008) and it represents a serious health concern. The impact of recipient's weight on mortality after hematopoietic cell transplantation (HCT) for non-malignant diseases is not well characterized. We studied the effect of body mass (BMI) on transplant outcomes in 1,281 patients aged 2-19 years who underwent HCT for severe aplastic anemia from 1990-2005. The study population was divided in five groups based on age-adjusted BMI percentiles. Patients in the <5th, 5-25th, 26-75th, 76-95th and >95th percentile BMI were classified as underweight, at risk for underweight, normal weight, at risk for overweight, and overweight respectively. Cox proportional hazards regression models for survival and acute graft-versus-host disease grade III-IV (aGVHD) were performed using BMI groups as the main effect and the normal weight (26-75th percentile) as the baseline comparison. Two-year overall survival was lower for overweight children (p<0.001, table). The risk of death, adjusted for significant covariates was higher for overweight compared to normal weight children (p=0.001, table). BMI groups were not associated with excess risk for aGVHD. Other significant factors associated with mortality include race and region of US, donor type, performance score at HCT, recipient age, and year of transplant. Risk of death was higher in African American patients (1.84, p=0.009) compared to Caucasians in the US, donors other than HLA-matched sibling and patients who received HCT before 2002. Among recipients of HLA-matched sibling grafts, use of busulfan-containing regimens (3.13, p<0.001) or cyclophosphamide without antithymocyte globulin (ATG) (1.92, p=0.03) had a higher risk of death compared to recipients of cyclophosphamide and ATG. Conditioning regimens in recipients of unrelated donor HCT were not associated with mortality. Among the reported causes of death, organ failure and infections occurred more frequently in overweight patients compared to the other BMI groups. In conclusion, overweight children with severe aplastic anemia have a higher risk of death after HCT independent of other factors analyzed in the study.BMI percentileN100 day mortality Probability (95% CI)2-y OS Probability (95% CI)RR of death (95% CI)p26-75th152515 (10-20)76 (70-82)1.00-<5th10812 ( 7-19)77 (68-84)1.01 (0.65-1.57)0.975-25th19611 ( 9-14)77 (74-81)1.38 (0.99-1.91)0.0676-95th30417 (13-21)73 (68-78)1.22 (0.93-1.61)0.14>95th14229 (22-36)59 (51-67)1.71 (1.24-2.35)0.0011Baseline group Disclosures:No relevant conflicts of interest to declare.

Infectious complications associated with alemtuzumab use for allogeneic hematopoietic stem cell transplantation: comparison with anti‐thymocyte globulin

To evaluate the incidence of infectious complications after receiving alemtuzumab as part of a conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in Korean patients. From November 2004 to January 2006, 12 patients who received alemtuzumab-based conditioning regimens for allogeneic HSCT were evaluated retrospectively until death or until the end of the follow-up in July 2007; they were compared with 18 patients who received rabbit anti-thymocyte globulin (ATG)-containing conditioning regimens from January 2002 to January 2006. Post-engraftment infections occurred more frequently in the alemtuzumab recipients than in the ATG recipients; the mean number of infections, excluding cytomegalovirus (CMV) infections, per patient during the follow-up period was 2.6+/-1.4 vs. 1.0+/-0.8 (P=0.003), respectively. Although there was no statistical difference in the cumulative incidence of CMV infection between the 2 groups (91.7% vs. 55.6%, P=0.381), the alemtuzumab recipients had a higher incidence of CMV diseases (41.6% vs. 0%, P=0.0006) and a higher recurrence rate of CMV infection (90.0% vs. 27.3%, P=0.008) than did the ATG recipients, irrespective of the dose of alemtuzumab. Hemorrhagic cystitis (HC) (66.7% vs. 16.7%, P=0.009) and BK virus-associated HC (41.7% vs. 5.6%, P=0.026) developed more frequently in the alemtuzumab recipients. The all-cause mortality rate was not significantly different between the alemtuzumab and the ATG recipients (75% vs. 55.6%, P=0.28). Alemtuzumab recipients had a high incidence of CMV disease as well as BK virus-associated HC compared with the ATG recipients. The dose of alemtuzumab should be tailored to patients' risk; in addition, the implementation of the appropriate prophylaxis for CMV and early detection strategies for BK virus are recommended.

Adult Recipients of Matched Related Donor Blood Cell Transplants Given Pretransplant Antithymocyte Globulin Have Less Graft-Versus-Host Disease and Transplant-Related Mortality: Follow-Up of a Matched Pair Analysis.

Because pretransplant antithymocyte globulin (ATG) seems to reduce GVHD and TRM after unrelated donor BMT we have investigated this agent in matched related donor (MRD) blood cell transplant (BCT). Fifty-four adults receiving rabbit ATG (Thymoglobulin, Genzyme), cyclosporine A (CSA) and methotrexate with a first MRD BCT were matched for disease and stage (AML 16 CR1, 2 CR2, 12 advanced, ALL 6 CR1, 1 CR2, 2 advanced, CML 1 AP, 1 CP2, CLL 3 rel/ref, NHL 8 rel/ref, MM 2 rel/ref) with 54 patients not given ATG. Myeloablative conditioning for ATG pts comprised fludarabine (Flu) 50 mg/m 2 x 5 with busulfan (Bu) 4mg/kg PO x 4 (7), Bu 3.2mg. kg IV x 4 (36) or Bu 3.2mg. kg IV x 4 plus TBI 200cGy x 2 (10) and VP16 60mg/kg + TBI 1200cGy (1). Controls were given VP16 60mg/kg + TBI 1200cGy (26) or 500cGy (2), TBI 1200cGy + Cyclophosphamide (Cy) 120mg/kg (2) or Cy 180mg/kg (2), Bu 4mg/kg PO x 4 + Cy 120mg/kg and Bu 4mg/kg PO x 4 + Flu 50 mg/m 2 x 5. The ATG was given at a total dose of 4.5 mg/kg over 3 days finishing day 0. Surviving ATG recipients were followed for 49 to 89 months (median 72) and control pts for 90–137 months (median 110). Rates of acute GVHD (aGVHD) grade II–IV, aGVHD grade III–IV, chronic GVHD (cGVHD) and extensive cGVHD were 15±5% vs. 32±6% (p=0.036), 6±3% vs. 13±5% (p = ns), 67±7% vs. 97±3% (p = 0.035) and 50±7%vs. 95±5% (p = 0.005) in the ATG and control groups respectively. Patients given ATG had fewer sites of involvement by cGVHD than the control group (mean 1.87±0.22 vs 2.72±0.24, p = 0.013). Those ATG pts with cGVHD were treated for a median of 382 days compared with 473 for controls (p = ns). Of 46 ATG recipients with grade 0 - I aGVHD 41 lived beyond 105 days. Twenty-five discontinued CSA at 44 – 890 days (median 75) and 16 developed cGVHD while still on CSA. Of 37 control patients with grade 0 - I aGVHD 31 lived beyond 105 days, 8 stopped CSA at 62 – 145 days (median 110) and 21 developed cGVHD while still taking CSA. Of 35 ATG recipients alive beyond 4 years 11 had never received immunosuppressive treatment for cGVHD compared with one of 27 controls (p = 0.008). Non-relapse mortality with and without ATG respectively was 4±3% vs 17±5% at 100 days and 9±4% vs 34±7% at 4 years (p = 0.002). Three of 9 pts given oral Bu with Flu died of transplant-related causes. Deaths were GVHD related in 3 ATG treated patients vs 14 controls (p=0.007). Despite a trend to more relapse with ATG (43±7% vs. 22±7% at 4 years, p = 0.053) survival was 66±7% in the patients given ATG vs 50±7% in the controls (p=0.046). This study indicates that MRD BCT recipients given regimens including Flu, oral or IV Bu and ATG experience less cGVHD, lower mortality related to both acute and cGVHD and probably improved quality of life in survivors compared with previous protocols. It is unlikely that substituting Flu for Cy with Bu or differences in CSA taper contributed to the improved results but it is possible that IV Bu may have done so to some extent. Attempts to improve outcomes further will need to address the problem of relapse.

Amelioration of Late Complications Following Unrelated Donor Bone Marrow Transplantation When Anti-Thymocyte Globulin Is Used as a Part of Conditioning.

Polyclonal anti-thymocyte globulin (ATG) reduces the risk for primary graft rejection as well as acute graft-versus-host disease (GVHD) by depleting T cells in both the host and the infused allograft. However, the impact of ATG on late outcomes is less certain. We report the results of a retrospective landmark analysis of consecutive patients who underwent an unrelated donor bone marrow transplant at our center between January 2001 and October 2005 (n=45) and survived at least 90 days following transplant. We compared late outcomes in patients who either recieved ATG (n=25) or did not (n=20) as a part of their conditioning regimen. Conditioning was with either busulfan and cyclophosphamide (n= 28; 17 without ATG) or BCNU, etoposide, cytarabine, and melphalan (n=18; 3 without ATG). Most patients (20) received rabbit ATG at a median dose of 3 mg/kg (range: 1.5–9 mg/kg) on day -4 and -3. Others were given equine ATG. GVHD prophylaxis consisted of tacrolimus + methotrexate in both groups. Median age was 42 years (range 18–65; 14 female). Bone marrow from unrelated donors matched at HLA-A, B, C, and DRB1 (7/8 and 8/8 matches) was used as the stem cell source. Diseases treated were CML (11), HD (9), AML (8), MDS (6), NHL (3), MM (3), and other (5). A median of 3 prior therapies had been given before transplant (range 1–5). There was no significant difference (Pearson χ2) in the number of patients beyond CR1/CP1 (n=25) and those having failed a prior autograft (n=17) between the two groups. The median overall survival in the recipients of ATG was 1382 days (95% CI: 373– 2391 days) as opposed to 364 days (95% CI: 0–851) in those not receiving ATG (P=0.125 by Log-Rank test); with a 1-year overall survival of 76% (59%–93%) vs. 50% (28–72) in the ATG vs. no ATG cohorts respectively, and 69% (49–89) vs. 44% (22–66) at 2-years. The 1-year progression free survival was 84% (69–98) vs.90% (77–100) in the ATG vs. no ATG cohorts, and 84% (69–98) vs. 67% (37–97) at 2 years. Chronic GVHD developed in 15/20 (75%) patients not receiving ATG (45% extensive), and in 12/25 (48%) in those recieving ATG (16% extensive) (P=0.06 Pearson χ2). Graft rejection was seen in 2/20 patients in the non-ATG arm and 1/25 patients in the ATG arm. Despite a lower incidence of chronic GVHD, the relapse rate was similar in the two groups (16% in the ATG group vs. 20% in the non-ATG group; P=0.73). Lymphoid recovery was similar in the two groups. The absolute lymphocyte counts at day-90 and day-180 post transplant were 680 vs 800/microL and 1100 vs. 1500/microL in the no ATG vs. ATG cohorts (P=0.275 repeated measures ANOVA). Serious late infections requiring parenteral antimicrobial treatment occured in 8 patients (32%) receiving ATG, and in 9 patients (45%) in the non-ATG arm ((P=0.248). CMV reactivation was seen in 8 patients (32%) receiving ATG, and 7 (35%) in the non-ATG arm. Eleven patients (55%) have died in the no ATG cohort from either relapse (2), GVHD (4) or infection (5); whereas in the ATG cohort 9 (36%) have died of either relapse (4), GVHD (3) or infection (2). In conclusion, ATG appears to reduce delayed transplant related complications, such as chronic GVHD and infections, in patients receiving bone marrow from unrelated donors. This may lead to a favorable trend towards improved survival in patients recieving ATG as a part of non-total body irradiation based conditioning.

A Comparison of Basiliximab and Anti-Thymocyte Globluin as Induction Agents After Lung Transplantation

Interleukin-2 receptor antagonists have supplanted polyclonal antibody preparations as the most frequently used induction agents after lung transplantation, but the relative efficacy of these agents has not been firmly established.We retrospectively analyzed the efficacy of basiliximab compared with antithymocyte globulin among 157 adult lung transplant recipients at our center.At 3, 6, and 12 months after transplantation, the median cumulative acute rejection A scores for the basiliximab group (2, 2, and 3, respectively) were significantly higher than those for the anti-thymocyte globulin group (1, 1, and 2, respectively; p = 0.003, 0.004, and 0.033, respectively). In addition, basiliximab recipients were more likely to develop acute rejection grade > or = A2 than anti-thymocyte globulin recipients; in fact, 60% of basiliximab recipients compared with 38% of anti-thymocyte globulin recipients developed their first episode of acute rejection grade > or = A2 in the first 100 days after transplantation (log-rank p = 0.04). Furthermore, basiliximab recipients were more likely to develop bronchiolitis obliterans syndrome than anti-thymocyte globulin recipients (log-rank p = 0.036). Two years after transplantation, 36% of basiliximab recipients and 26% of anti-thymocyte globulin recipients developed bronchiolitis obliterans syndrome. However, there were no significant differences in the incidences of cytomegalovirus viremia and pneumonitis between the 2 groups (p = 0.86 and 0.89, respectively).Induction with anti-thymocyte globulin is associated with a lower burden of acute rejection and bronchiolitis obliterans syndrome compared with basiliximab, without a significant difference in the incidence of cytomegalovirus infections.

Adult Recipients of Matched Related Donor Blood Cell Transplants (BCT) Given Pretransplant Low-Dose Antithymocyte Globulin (ATG) Have Less Chronic Graft-Versus-Host Disease (cGVHD) and Transplant-Related Mortality (TRM): A Matched Pair Analysis.

Because pretransplant antithymocyte globulin (ATG) seems to reduce graft-versus-host disease (GVHD) and transplant-related mortality (TRM) after unrelated donor bone marrow transplant (BMT) we have investigated this agent in matched related donor (MRD) blood cell transplant (BCT). Of 82 adults receiving myeloablative conditioning and first MRD BCT between 01/99 and 05/02, 54 were matched for disease and stage with 54 patients (pts) not given ATG between 12/94 and 11/98. Median age was 42 (range 18 – 63) for ATG pts and 41 (range 22 – 54) for controls. Included in each group were 22 standard-risk pts (16 AML CR1, 6 ALL CR1), and 14 with high-risk acute leukemia of whom 12 had active AML (7 arising from MDS, 3 induction failures, 1 refractory, 1 relapse), and 2 ALL (1 refractory, 1 relapse). An additional 18 pts included 2 AML CR2, 1 ALL CR2, 2 CML AP/CP2, 2 MM, 8 relapsed/refractory NHL (2 mantle cell, 4 low, 1 intermediate, 1 high-grade) and 3 relapsed/refractory CLL. More control pts had conditioning incorporating TBI (32 vs 11, p<0.0001). All pts were given cyclosporine A and “short course” methotrexate with folinic acid. The study group received Thymoglobulin (Genzyme) (ATG) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing D0. ATG recipients were followed for 22 to 62 months (median 46) and control patients for 65–112 months (median 84). The actuarial incidence of acute GVHD grades II – IV was 25±6% in ATG recipients compared with 37±7% in the controls (p = ns). The figures for grade III – IV disease were 13±5% and 20±7% respectively (p = ns). Incidence of cGVHD at two years was 40±7% with ATG vs 97±3% without ATG (p < 0.0001), figures for extensive disease were 32±7% and 94±3% respectively (p < 0.0001). Sites of involvement by cGVHD were similar apart from gastrointestinal disease which was relatively more frequent in those ATG recipients who developed cGVHD (26% vs 5%, p = 0.03). Non-relapse mortality with and without ATG respectively was 4±3% vs 17±5% at 100 days and 9±4% vs 32±7% at 2 years (p = 0.004). Deaths were GVHD related in 3 ATG treated patients vs 13 controls (p=0.01). In the control group 2 year TRM was 26±8% in 32 TBI recipients compared with 42±11% in 22 patients not given TBI (p = ns). Relapse rate at 2 years was 36±7% for ATG recipients and 23±7% in controls (p = 0.06). Six of 21 relapsing patients in the ATG group survive having achieved another remission (4) or disease stabilization (2) after more treatment. One of 12 control patients who relapsed is currently alive in remission after a second BCT. Survival at 2 years was 70±6% in the patients given ATG vs. 54±7% in the controls (p=0.08) and progression-free survival was 57±7% vs 52±7% respectively. This study indicates that MRD BCT recipients given pretransplant ATG experience less cGVHD, less overall TRM and lower mortality related to both acute and chronic GVHD. These findings are not due to more control pts receiving TBI. Despite a trend to more relapse progression-free survival is unaffected, there is a trend to improved survival and presumably quality of life is generally better in ATG recipients because fewer of them have cGVHD.

Comparison of basiliximab and antithymocyte globulin as induction agents after lung transplantation

Background Interleukin-2 receptor antagonists have supplanted polyclonal antibody preparations as the most frequently used induction agents after lung transplantation, but the relative efficacy of these agents has not been firmly established. Methods We retrospectively analyzed the efficacy of basiliximab compared with antithymocyte globulin among 157 adult lung transplant recipients at our center. Results At 3, 6, and 12 months after transplantation, the median cumulative acute rejection A scores for the basiliximab group (2, 2, and 3, respectively) were significantly higher than those for the anti-thymocyte globulin group (1, 1, and 2, respectively; p = 0.003, 0.004, and 0.033, respectively). In addition, basiliximab recipients were more likely to develop acute rejection grade > or = A2 than anti-thymocyte globulin recipients; in fact, 60% of basiliximab recipients compared with 38% of anti-thymocyte globulin recipients developed their first episode of acute rejection grade > or = A2 in the first 100 days after transplantation (log-rank p = 0.04). Furthermore, basiliximab recipients were more likely to develop bronchiolitis obliterans syndrome than anti-thymocyte globulin recipients (log-rank p = 0.036). Two years after transplantation, 36% of basiliximab recipients and 26% of anti-thymocyte globulin recipients developed bronchiolitis obliterans syndrome. However, there were no significant differences in the incidences of cytomegalovirus viremia and pneumonitis between the 2 groups (p = 0.86 and 0.89, respectively). Conclusions Induction with anti-thymocyte globulin is associated with a lower burden of acute rejection and bronchiolitis obliterans syndrome compared with basiliximab, without a significant difference in the incidence of cytomegalovirus infections.

Basiliximab: a review of its use as induction therapy in renal transplantation.

Basiliximab (Simulect), a chimeric (human/murine) monoclonal antibody, is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents. Basiliximab significantly reduced acute rejection compared with placebo in renal transplant recipients receiving dual- (cyclosporin microemulsion and corticosteroids) or triple-immunotherapy (azathioprine- or mycophenolate mofetil-based); graft and patient survival rates at 12 months were similar. Significantly more basiliximab than placebo recipients were free from the combined endpoint of death, graft loss or acute rejection 3 years, but not 5 years, after transplantation. The incidence of adverse events was similar in basiliximab and placebo recipients, with no increase in the incidence of infection, including cytomegalovirus (CMV) infection. Malignancies or post-transplant lymphoproliferative disorders after treatment with basiliximab were rare, with a similar incidence to that seen with placebo at 12 months or 5 years post-transplantation. Rare cases of hypersensitivity reactions to basiliximab have been reported. The efficacy of basiliximab was similar to that of equine antithymocyte globulin (ATG) and daclizumab, and similar to or greater than that of muromonab CD3. Basiliximab was as effective as rabbit antithymocyte globulin (RATG) in patients at relatively low risk of acute rejection, but less effective in high-risk patients. Numerically or significantly fewer patients receiving basiliximab experienced adverse events considered to be related to the study drug than ATG or RATG recipients. The incidence of infection, including CMV infection, was similar with basiliximab and ATG or RATG. Basiliximab plus baseline immunosuppression resulted in no significant differences in acute rejection rates compared with baseline immunosuppression with or without ATG or antilymphocyte globulin in retrospective analyses conducted for small numbers of paediatric patients. Limited data from paediatric renal transplant recipients suggest a similar tolerability profile to that in adults. Basiliximab appears to allow the withdrawal of corticosteroids or the use of corticosteroid-free or calcineurin inhibitor-sparing regimens in renal transplant recipients. Basiliximab did not increase the overall costs of therapy in pharmacoeconomic studies. Basiliximab reduces acute rejection without increasing the incidence of adverse events, including infection and malignancy, in renal transplant recipients when combined with standard dual- or triple-immunotherapy. The overall incidence of death, graft loss or acute rejection was significantly reduced at 3 years; there was no significant difference for this endpoint 5 years after transplantation. Malignancy was not increased at 5 years. The overall efficacy, tolerability, ease of administration and cost effectiveness of basiliximab make it an attractive option for the prophylaxis of acute renal transplant rejection.

Resolution of red cell compatibility testing problems in patients receiving anti-lymphoblast or anti-thymocyte globulin.

Passively acquired hemagglutinating antibodies may be detected in the serum of patients receiving horse anti-lymphoblast globulin (ALG) or anti-thymocyte globulin (ATG). Thirty-seven patients receiving ALG following renal transplantation were studied. Eight patients monitored daily all developed positive direct antiglobulin tests (DAT) and positive red cell antibody screening tests. Fifteen of 32 recipients developed red cell antibodies reactive at room temperature in saline, 4 of 32 in albumin at 37 degrees C, and 33 of 37 in the antiglobulin test. Horse globulin was detected on the red cells of all six recipients tested with rabbit anti-horse globulin. Ether eluates prepared from the red cells of 20 patients showed no specificity for common red cell antigens. Anti-human globulin (AHG), absorbed with ALG-coated red cells to remove the component in the AHG which was crossreacting with horse globulin, was used successfully for antibody screening and identification, direct antiglobulin testing, and/or the antiglobulin crossmatching of 27 ALG and ATG recipients, including five with red cell alloantibodies.

Cell-mediated immunity to varicella-zoster virus after allogeneic marrow transplant.

The cellular immune response of normal persons and marrow transplant recipients to varicella-zoster virus (VZV) antigen was measured with use of the lymphocyte transformation response. Ninety-nine of 100 normal persons with previous VZV infection had a stimulation index of greater than or equal to 4.8, while 10 susceptible persons had responses of less than or equal to 3.0. Before transplant, responses were lower than normal in patients with leukemia in relapse (P = 0.001), but not in patients with leukemia in remission or with aplastic anemia. Throughout the first 100 days after transplant, lymphocyte response was depressed (P less than 0.0005), especially among recipients of antithymocyte globulin during days 41-80 (P less than 0.05). Patients with aplastic anemia had higher responses than those with leukemia during days 20-60 (P less than 0.02). By one year, most responses were normal. Long-term survivors who had recurrent VZV infection had positive responses more often than those without recurrent infection (P = 0.01). The lymphocyte response to VZV antigen parelleled, and thus may predict, periods of increased susceptibility to VZV infection.