Low Dose ATG Research Articles

Significance of HLA 1-locus mismatch and ATG administration in unrelated hematopoietic stem cell transplantation

HLA 1-locus-mismatched unrelated donors (1MMUD) are used in allogeneic hematopoietic stem cell transplantation (allo-HCT) for patients who lack an HLA-matched donor. Here we retrospectively reviewed 3,313 patients with acute leukemia or myelodysplastic syndrome who underwent bone marrow transplantation from an HLA allele-matched unrelated donor (MUD) or 1MMUD in 2009-2014. We compared the outcomes of MUD (n＝2,089) and 1MMUD with antithymocyte globulin [ATG; 1MM-ATG (＋) ; n＝109] with those of 1MMUD without ATG [1MM-ATG (-) ; n＝1,115]. In the 1MM-ATG (＋) group, the median total dose of ATG (thymoglobulin) was 2.5 (range, 1.0-11.0) mg/kg. The rates of grade III-IV acute GvHD, non-relapse mortality (NRM), and overall mortality were significantly lower in the MUD group than in the 1MM-ATG (-) group [hazard ratio (HR) 0.77; P＝0.016; HR, 0.74, P<0.001; and HR, 0.87, P＝0.020, respectively]. Similarly, the rates of grade III-IV acute GvHD, NRM, and overall mortality were significantly lower in the 1MM-ATG (＋) group than in the 1MM-ATG (-) group (HR, 0.42, P＝0.035; HR, 0.35, P<0.001; and HR, 0.71, P＝0.042, respectively). Even in the recent cohort, the outcome of allo-HCT from 1MM-ATG (-) was inferior to that of allo-HCT from MUD. Nevertheless, the negative impact of 1MMUD disappeared with the use of low-dose ATG without exacerbating the risk of relapse.

Differential depletion of total T cells and regulatory T cells and prolonged allotransplant survival in CD3Ɛ humanized mice treated with polyclonal anti human thymocyte globulin.

Thymoglobulin (ATG) is a polyclonal rabbit antibody against human thymocytes used as a T cell-depleting agent to prevent or treat allotransplant rejection. The aim of the present study was to investigate the effect of low dose ATG treatment exclusively on T cells using a humanized BALB/c human CD3Ɛ transgenic mouse model expressing both human and murine T cell receptors (TCR). Mice received a single intravenous (i.v.) injection of ATG. Blood and peripheral lymphoid organs were obtained after different time points. We found a significant T cell depletion in this mouse model. In addition, regulatory T cells (Tregs) proved to be less sensitive to depletion than the rest of T cells and the Treg:non-Treg ratio was therefore increased. Finally, we also investigated the effect of ATG in a heterotopic allogenic murine model of heart transplantation. Survival and transplant function were significantly prolonged in ATG-treated mice. In conclusion, we showed (a) an immunosuppressive effect of ATG in this humanized mouse model which is exclusively mediated by reactivity against human CD3Ɛ; (b) provided evidence for a relative resistance of Tregs against this regimen; and (c) demonstrated the immunomodulatory effect of ATG under these experimental circumstances by prolongation of heart allograft survival.

Low Dose Antithymocyte Globulin (ATG) for Graft-Versus-Host Disease (GVHD) Prophylaxis

ATG appears to reduce the incidence of acute and chronic GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). Potential risks of this strategy include viral reactivation, delayed immune recovery and increased relapse rates. The ideal dosing of rabbit ATG in this context is largely unknown. We therefore hypothesized that low dose ATG would reduce the incidence of acute and chronic GVHD in matched unrelated donor (MUD) transplants without compromising survival and relapse rate. A retrospective analysis was performed of a cohort of high-risk MUD HSCT recipients treated since year 2013, when our practice changed to include rabbit ATG at 3 mg/Kg for all MUD transplants at the Case Medical Center in Cleveland, Ohio. Herein we present the results of this analysis.Methods. 58 MUD transplants were performed between years 2013 and 2016, with a median follow up of 262 days post-transplant. All donor-recipient pairs were matched by high resolution HLA typing at HLA-A, -B, -C, and DRB1, (8/8 matches) with the exception of 4 pairs (7/8 matches. Median age was 56 years (range, 53-64). Underlying diagnoses were AML (n=26), MDS (13), CML (n=5), NHL (n=9), Hodgkin's lymphoma (n=2), Multiple Myeloma (n=1) and myeloproliferative disorders (n=2). Preparative regimens were ablative in 26 cases (45 %) and of reduced intensity in 31 cases (55 %). Graft source was bone marrow (n=5) and peripheral blood (n=53). All but 4 pts received GVHD prophylaxis with tacrolimus, and mini-methotrexate (5 mg/m2 on days +1, +3, +6 and +11), in addition to rabbit ATG 3 mg/Kg divided in two doses on days -2 and -1 pre HSCT. Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Human Herpes Virus (HHV6) PCR were conducted thrice weekly during the first 100 days after HSCT.Results. The 100-day cumulative incidence of grade II-IV acute GVHD was 41% (95% CI: 29-57; Fig 1), while the cumulative incidence of grade III-IV acute GVHD was 18% (95% CI: 9-35; Fig 2). 1-year cumulative incidence of chronic GVHD was 27% (95% CI: 17-42; Fig 3). At 180 days, the incidence of CMV viremia (defined as more than 1,000 copies/mL) was 25% (95% CI: 16-40), while the incidence of EBV and of HHV6 viremia was 35% (95% CI: 24-51) and 14% (95% CI: 8-27), respectively. There was no instance of EBV-related lymphoproliferative disorder.3-year overall survival estimate is 48% (95% CI: 34-62). Cumulative incidence of Non-relapse mortality (NRM) and relapse at 1 year was 21% (95% CI: 12-37) and 44% (95% CI: 29-65), respectively.Conclusion. Our study shows that low dose rabbit ATG appears to reduce chronic GVHD rates without a major effect on acute GVHD incidence. CMV, EBV and HHV6 reactivation did occur, albeit at rates that are somewhat lower than those historically reported, without EBV-driven lymphoproliferative disorder. [Display omitted] [Display omitted] [Display omitted] DisclosuresCaimi:Genentech: Speakers Bureau; Roche: Research Funding; Novartis: Consultancy; Gilead: Consultancy.

Potential Value of Low-Dose ATG Treatment for Steroid-Resistant Acute GVHD

Potential Value of Low-Dose ATG Treatment for Steroid-Resistant Acute GVHD

Low Dose ATG (Thymoglobulin) Induction for Older Kidney Transplant Recipients - Single Centre Experience Over 8 Years.

Low Dose ATG (Thymoglobulin) Induction for Older Kidney Transplant Recipients - Single Centre Experience Over 8 Years.

Immune Phenotyping and Efficacy of Low Dose ATG in Non-Sensitized Kidney Recipients Undergoing Early Steroid Withdrawal: A Randomized Pilot Study.

Immune Phenotyping and Efficacy of Low Dose ATG in Non-Sensitized Kidney Recipients Undergoing Early Steroid Withdrawal: A Randomized Pilot Study.

Late-onset hemorrhagic cystitis after haploidentical hematopoietic stem cell transplantation in patients with advanced leukemia: differences in ATG dosage are key

Late-onset hemorrhagic cystitis (LOHC) is a common complication following allogeneic hematopoietic stem cell transplantation (HSCT), but its cause remains obscure. More attention to risk factors for LOHC is needed. We retrospectively analyzed patients with advanced leukemia who had been treated with ATG-containing conditioning regimens to evaluate the influence of different doses of ATG on LOHC after haploidentical HSCT. Seventy-five patients undergoing haploidentical HSCT from January 2003 to February 2011 were evaluated. A total of 39 patients receiving transplantation before June 2008 were treated with high-dose ATG (10 mg/kg), whereas 36 patients received low-dose ATG (6 mg/kg) thereafter. LOHC occurred in 16.7% of the patients with low-dose ATG, and in 38.5% of the patients with high-dose ATG (P = 0.027). Univariate analysis showed high-dose ATG, male gender and cytomegalovirus reactivation to be significant risk factors for LOHC. However, only high-dose ATG (HR 2.96, 95% CI 1.143-7.663, P = 0.025) and male gender (HR 4.033, 95% CI 1.355-12.008, P = 0.012) were independent risk factors, as shown by multivariate analysis. In the setting of haploidentical HSCT, we concluded that LOHC is more prevalent in recipients of high-dose ATG and male patients. Future studies should focus on immune reconstitution and virus infection after haploidentical HSCT with 6 mg/kg or 10 mg/kg ATG.

National, Retrospective, Multi-Centre Comparison of Alemtuzumab- Versus ATG-Based Conditioning Regimens in Hematopoietic Stem Cell Transplantation for Aplastic Anemia: A Study From the British Society for Blood and Marrow Transplantation (BSBMT) (CTCR 09-03)

Abstract 52▪▪This icon denotes a clinically relevant abstract Background:The ideal conditioning regimen for HSCT in AA is one that achieves engraftment, absence of GVHD and minimal toxicity. Standard conditioning for young patients undergoing matched sibling donor (MSD) HSCT for AA is cyclophosphamide (CY) 200mg/kg and ATG as T-cell depletion (TCD), with ciclosporin (CSA) and methotrexate (MTX) as post graft immunosuppression. For patients who are > 30–40years old receiving MSD HSCT a fludarabine (FLUD)-based regimen with low dose CY (1200mg/m2) and ATG is commonly used. For unrelated donor (UD) HSCT, in Europe, a similar FLUD-based regimen with low dose CY and ATG is commonly used, with addition of low dose TBI (2Gy) for older patients. Long term survival for MSD HSCT is 80–90%, but only 50% for patients aged > 50 years. For UD HSCT, survival is around 75–80%. Chronic GVHD remains a problem, in 30–40% of MSD and up to 50% of UD HSCT. A recent retrospective study of 50 patients transplanted with Alemtuzumab instead of ATG, with CY (1200mg/m2), FLUD, and CSA alone as post graft immunosuppression, showed overall survival at 2 years was 95% for MSD and 83% for UD HCT and only two patients (4%) developed chronic GVHD. Patients:We analyzed data from 159 patients with acquired AA transplanted in the UK, who received either Alemtuzumab or ATG pre-transplant, as part of the conditioning for a first allograft. Patients who received their graft between 1999 and 2009 and had a minimum follow-up of 6months were included in this study. Median age was 20yr (range 1– 67) and M: F ratio was 86: 73. MSD HSCT was performed in 88 (55%) patients, UD HSCT in 65 (41%) including 2 mis-matched, and 6 patients were transplanted from other related donors of which 3 were mis-matched. Source of stem cells was BM in 108 (68%), PB in 39 (25%), BM+PB in 8 (5%) and cord blood in 4 (2%) patients. Conditioning was with Alemtuzumab in 103 (65%) and ATG in 55 (35%), and one patient had received both. CY +/− FLUD was used in 148 and FLUD +/− Melphalan in 11 patients, with addition of TBI in 11 (7%) patients. Median time from diagnosis to HSCT was 6 months (range 0.5–300). Results:Of 159 patients, 137 (86%) are alive at a median follow up of 3.3yr (range 3 months – 10.4 yr). Twenty two patients have died from the following causes of death (not mutually exclusive): infection (n = 15, 68%), GVHD (n = 6, 27%), multi-organ failure (n = 4), lymphoproliferative disorder (n = 1), relapse of breast cancer (n = 1) and one unknown. For all patients, the 1 yr, 5 yr and 10 yr overall survival (OS) were 89% (95% C.I. = 83–93%), 85% (78–90%) and 85% (78–90%), respectively. There was no difference in the 1 yr OS in relation to the method of TCD (Alemtuzumab 91% (84–95%) versus ATG 84% (71–91%), p = 0.1578). Graft failure was observed in 15 (9%) patients. Median time to neutrophil engraftment, defined as ANC > 0.5 × 109/l on first of 3 consecutive days, was 20 days (range 10–89) and platelet engraftment, defined as platelet count > 20 × 109/l on first of 3 consecutive days and no platelet transfusions 7 days prior, was 21 days (range 0–275). Chimerism was full donor in 70 (46%), mixed in 41 (27%), not performed in 37 (24%) and unknown or not evaluable in 2 patients. Acute GVHD grade I-II occurred in 35 (25%) evaluable patients, grade III-IV in 8 (6%). Chronic GVHD was seen in 23 (16%) evaluable patients, limited in 14, extensive in 6 and unknown in 3. Conclusions:From this national study, we report excellent outcomes for HSCT in SAA during the last decade. There was a trend, not significant, for better survival with Alemtuzumab instead of ATG in the conditioning regimen. This is the first reported study comparing outcomes after Alemtuzumab versus ATG based conditioning regimens for SAA. Further analyses, comparing graft failure, acute and chronic GVHD, probability of survival and event - free survival, and patient-related, disease-related and treatment related variables, between Alemtuzumab and ATG-based conditioning regimens, are currently in progress. Disclosures:Marsh:Genzyme: Research Funding. Off Label Use: ATG used as part of conditioning regimen for HSCT in aplastic anaemia. Alemtuzumab used as part of the conditioning regimen for HSCT in aplastic anemia. Pagliuca:Genzyme: Speakers Bureau. Mufti:Celgene: Consultancy, Research Funding.

Prior High Dose Chemotherapy and a Higher “Intensity” of the Preparative Regimen Can Influence Outcome after Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukemia (AML) in First Complete Remission (CR1).

In the setting of AML, RIC regimens have emerged as an attractive modality to decrease toxicity. However, toxicity might represent only one aspect of the problem, since AML encompasses a group of chemosensitive diseases, raising concerns that significant reduction of the intensity of the preparative regimen, while increasing immunosuppression, may have a negative impact on long-term outcome. This report describes the comparative results of 31 AML patients in CR1 receiving RIC allo-SCT from an HLA-identical sibling in 2 institutions (Nantes, n=13; and Marseille, n=18) using 2 different “global” treatment approaches (Table below). After achievement of CR1, the “Nantes” approach included administration of one or two courses of consolidation with high-dose cytarabine (HDC), followed immediately by allo-SCT conditioned with a genuine nonmyeloablative, but highly immunosuppressive RIC regimen including fludarabine, low dose busulfan (4 mg/Kg), ATG (5 mg/Kg) and both CsA and corticosteroids for GVHD prophylaxis (“FB1A2” group). The “Marseille” program aimed to deliver after CR1, in addition to HDC, an autologous SCT followed by allo-SCT conditioned with fludarabine, an intermediate dose of busulfan (8 mg/Kg), low dose ATG (2.5 mg/Kg) and CsA alone for GVHD prophylaxis (“FB2A1” group). In the “FB2A1” group, 12 patients (67%) could actually receive the planned auto-SCT. With a median follow-up of 47 months, leukemia-free survival (LFS) in the whole study population was 56% at 5 years. However, the KM estimate of LFS was significantly higher in the “FB2A1” group as compared to the “FB1A2” group (P=0.01; 72% vs. 31% at 5 years). Overall, 8 patients (26%; 95%CI, 11–41%) had relapsed at a median of 320 (range, 241–707) days after diagnosis, and the significant difference between the 2 groups in terms of LFS was likely due to a higher risk of leukemia relapse in the “FB1A2” group (6/13, vs. 2/18; P=0.07). Five patients died from toxicity, for an overall incidence of TRM of 16% (95%CI, 6–34%), with this being comparable between the 2 groups (2/13 vs. 3/18; P=NS). Such comparable TRM despite a more “intensive” approach, translated towards a higher overall survival in the “FB2A1” group as compared to the “FB1A2” group (72% vs. 42% at 5 years; P=0.07). After controlling for relevant factors, in the multivariate analysis, actual performance of auto-SCT prior to RIC allo-SCT (P=0.04; RR=4.9; 95%CI, 1.1–22.4), was significantly predictive of an improved LFS. We conclude that RIC allo-SCT from an HLA-matched related donor represents a valid option for AML patients not eligible for standard allo-SCT. However, in order to achieve optimal results, a comprehensive treatment “package” including some form of high dose therapy prior to RIC allo-SCT and/or semi-intensive cytoreduction/myeloablation incorporated within the RIC regimen is likely necessary to allow sufficient time for the GVL effect. [Display omitted]

Risk factors for acute graft-versus-host disease grades II–IV after reduced intensity conditioning allogeneic stem cell transplantation with unrelated donors—a single centre study

We analysed factors associated with moderate to severe acute GVHD in 111 patients treated with fludarabin-based reduced intensity conditioning (RIC) and allogeneic haematopoietic stem cell transplantation (HSCT). Most patients had a haematological malignancy. Donors were 97 HLA-A, -B and -DRbeta1 identical unrelated and 14 HLA-A, -B or -DRbeta1 allele mismatched unrelated donors. In the univariate analysis, we found ten factors associated with acute GVHD. These were diagnosis (P=0.06), GVHD prophylaxis with combinations other than CsA+MTX (P=0.006), graft nucleated (P<0.001) and CD34 (P<0.001) cell-dose, bidirectional ABO mismatch (P=0.001), conditioning (P=0.002), hospital vs home-care (P=0.06), ATG dose (P<0.001), donor herpes virus serology (P=0.07) and an immunized female donor to male recipient (P=0.05). In the multivariate analysis, three factors remained significant: a high CD34 cell dose (P<0.001), low dose (4 mg/kg) ATG (P<0.001), and an immunized female donor to male recipient (P<0.01). Patients receiving a CD34 cell dose > or =17.0 x 10(6) per kg had a higher incidence of GVHD, 53.7%, compared to 22.3% in patients receiving a lower dose (P=0.002). In patients without any of these risk factors (n=70), the incidence of acute GVHD was 14.1%, while it was 38.0 and 85.0% in patients with one (n=29) or two (n=10) risk factors (P<0.001). We concluded that risk factors for acute GVHD using RIC are similar as using myeloablative conditioning.

Low Dose Busulfan and ATG with Fludarabine as Conditioning Regimen Was Effective in Sibling and Unrelated Donor HSCT in CML Patients.

Allogeneic hematopoietic stem cell transplantation offers complete remission in CML patients. However, transplant related mortality and long term consequences especially associated with cGvHD make patients reluctant to accept this treatment modality especially in the era of Imatinib. Therefore, in 1999 we started a transplant program for CML patients characterized with a reduced dose of Busulfan to 8 mg/kg of. b.w., Fludarabine (120 mg/m2 in sibiling and 150 mg/m2 in MUD setting) and ATG to facilitate engraftement. At the beginning ATG cumulative dose was 40 mg/kg of b.w. (5 patients), or 20 mg/kg of b.w (13 patients). In this high dose ATG group 6 patients had CMV or EBV reactivation what prompted us to decrease ATG dose to 2.5 mg/kg of b.w. given in three consecutive days and then on day 4 the dose was increased to 5 mg/kg of b.w. if patients lymphocyte count did not reach the target values (≤300/ul of WBC and < 0.1% of CD3+ cells in nucleated blood cells population).With the use of the above program 52 adults and two children (F/M: 22/32, age from 11 to 55 yrs (median: 34) were transplanted from sibling (20 patients) and alternative (33 MUD and 1 related haploidentical) donors. Thirty nine and 15 patients received PBPC and marrow, respectively. Seven patients died by + 100 days post transplant (6 infectious complications including 1 case with viral encephalitis and 1 blast crisis). One patient had marrow failure, 15 patients developed ≥ IIo aGvHD, 23 patients had cGvHD and 14 of them extensive form. Thirty four patients (63%) are alive with an observation time from 1 to 81 months post transplant (median 22 months). Survival was better in sibling than in MUD transplanted patients (77% vs 50%, p=0.03, Cox analysis). In alive patients group STR technique proved complete chimerism in 26 out of 31 examined patients. Five cases lacking full chimerism include: 1 patient with hematological relapse, and 4 with molecular relapse. All other cases were bcr/abl negative.In conclusion: low dose ATG was sufficient to secure the take and the employed reduced intensity conditioning was associated with:low rate of transplant related mortality,aGvHD was infrequent and mild,cGvHD was the main cause of late complications,full chimerism and bcr/abl free status were observed in a vast majority (84%) of long term survivors.

Long Term Infectious Complications Following Reduced Intensity Conditioning (RIC) Allogeneic HLA-Identical Sibling Transplantation (allo-SCT).

In the setting of RIC for allo-SCT, long term outcomes are still poorly defined. Of note, the epidemiology of long term transplant-related infections is still sparse. This prospective report describes infectious complications occurring beyond 6 months after allo-SCT, in 159 consecutive patients who received a RIC allo-SCT from an HLA-identical sibling. Patients characteristics are as follow: median age was 50 (range, 18–68) years. 68 patients (43%) had a myeloid malignancy, whereas 66 patients (41%) had a lymphoid malignancy. The remaining 25 patients (16%) were treated for metastatic non-hematological malignancies. The majority of patients (n=126, 79%) had an advanced disease with high risk features precluding the use of myeloablative allo-SCT. 24 patients (15%) received donor bone marrow (BM), while the remaining 135 patients (85%) received PBSCs. In addition to fludarabine and busulfan, the RIC regimen included high dose ATG in 20 patients (13%) and low dose ATG in 95 (60%). 24 patients (15%) received fludarabine, busulfan and TLI, while the remaining 24 patients (15%) received fludarabine and low dose TBI. With a median follow-up of 19 (range, 6–90) months, 120 patients (75%) experienced at least one infectious episode (total number of episodes, 366) beyond the first six months after allo-SCT developing at a median of 8 (range, 6–34) months. In all, 212 infectious episodes (58%) required hospitalization (7% in the intensive care unit) for a median duration of 10 (1–91) days. 144 episodes (39%) could be documented (bacterial, n=48; viral, n=78; fungal, n=18). Microbiologically documented infections were distributed as follow: gram negative bacteria (18%), other bacteria (15%), CMV positive antigenemia (17%), HSV (19%), VZV (15%), other viruses (3%), aspergillus (6%), candida species (6%), other (1%). 76% of patients with an infection were under systemic immunosuppressive therapy for chronic GVHD at time of infection. Moreover, 85 patients (71%) experienced more than one infectious episode (median, 2; range, 1–12). In multivariate analysis, active or prior history of extensive chronic GVHD and the use of a BM graft were the strongest factors significantly associated with an increased risk of long term infections (P=0.0003; RR=2.04; 95%CI, 1.4–3.0; and P=0.005; RR=2; 95%CI, 1.2–3.2 respectively), highlighting the raising concern about the deleterious impact of severe chronic GVHD occurring after RIC allo-SCT, but also the protective effect of donor origin immunity based on graft origin and content. In this series of patients surviving at least 6 months after RIC allo-SCT, the overall long term transplant-related mortality was 11% (n=18), of whom 12 deaths were attributed to chronic GVHD and its complications including infections, and 5 deaths solely attributed to infections. In all, these results suggest that, despite reduction in early toxicity associated with the use of RIC regimens, long term debilitating chronic GVHD and its corollary of continuous immunosuppression and subsequent infections are still a matter of concern. Prospective efforts to develop optimal antimicrobial preventive strategies are needed to further improve the safety of the procedure and the overall benefits of RIC preparative regimens before allo-SCT.

Fludarabine-Busulfan Conditioning and In Vivo T-Cell Depletion with Reduced Dose of ATG Followed by Allografting Induces Durable Responses in Patients with Advanced Multiple Myeloma with No Grade III-IV aGvHD.

Background: We have investigated a conditioning regimen with Fludarabine and intravenous Busulfan with reduced ATG dose in patients with advanced and poor prognosis myeloma exploring the possibility that a low dose ATG may be sufficient enough to prevent severe GvHD without completely suppressing the graft vs myeloma effect.Methods: 15 patients received a conditioning regimen consisting of fludarabine 50mg/m2 on days -6 to -2 and IV BU (Busulfex, ESP Pharma) at a “myeloablative” dose of 3.2 mg/kg daily days -5 to -2 inclusive. All pts received Thymoglobulin (Genzyme) 4.5 mg/kg in divided doses over 3 consecutive days pre-transplant finishing D0, cyclosporine A and methotrexate with folinic acid.Results: The median age was 49 years (range 40–61). 14 (93.3%) patients had stage III (DS) disease with a median β2-microglobulin 3.12 mg/dl (1.82–5.75) and 7/11 (63.6%) in whom FISH studies were available had deletion 13, 5/15 (33.3%) patients had relapsed or progressed within 2 years of prior autologous stem cell transplant and 4 (26.6%) had progressed while on thalidomide /Dex salvage treatment. The disease status prior to allogeneic transplant was partial response (PR) in 6/15 (40%) and progressive disease (PD) in 9/15 (60%). 2/15 had plasma cell leukemia. The median number of bone marrow plasma cells prior to allo-transplant was 16% (range 3%-85%). Donors were matched siblings (MRD) for 13 (86.7%) and alternate donors in 2 (13.3%, unrelated with 2 C antigen mismatch). Cell source was blood in 14/15 (93.3%). Acute GVHD grade II-IV occurred in only 1 patient (6.6%) with no grade III-IV acute GVHD. Chronic GVHD occurred in 9/15 (60%). The TRM was 6.6%. Among 14/15 patients evaluable for response, the overall response rate (CR+PR) was 53.3% (2 CR, 6 PR, 1 MR and 5 PD); 37.5% (1CR, 2PR, 1MR and 4PD) for pts with PD at the time of the transplant and 71.4% (4PR, 1MR and 1PD) for pts with del13. After a median follow-up of 40.9 months (range 36–65.2), the estimated OS and PFS at 4 years for all patients is 38.9% (CI 95%: 13.1–64.7%) and 20.0% (CI 95%: 0–40.3%) respectively. For patients with del13 the estimated OS and PFS at 4 years is 38.1% (CI 95%: 0–77.9%) and 0% respectively.Conclusion: In vivo T-cell depletion with ATG results in a low rate of severe aGvHD with low treatment-related mortality and a substantial number of long-term survivors among patients with advanced multiple myeloma. The detection of deletion 13 by FISH however remains a predictor of short progression free survival. [Display omitted]

In vivo T-cell depletion with low-dose ATG is effective in reducing cGVHD after peripheral blood stem cell myeloablative sibling transplants in CML: results from a prospective phase II study

In vivo T-cell depletion with low-dose ATG is effective in reducing cGVHD after peripheral blood stem cell myeloablative sibling transplants in CML: results from a prospective phase II study

Long term infectious complications following reduced intensity conditioning (RIC) allogeneic HLA-identical sibling transplantation (allo-SCT)

In the setting of RIC for allo-SCT, promising results have been reported in regards to decreased early transplant-related complications. However, long term outcomes are still poorly defined. Of note, the epidemiology of long term transplant-related infections is still sparse. Our current knowledge of long term infectious complications after RIC allo-SCT is still primarily based on results of analyses performed in the standard myeloablative allo-SCT setting. This prospective report describes infectious complications occurring beyond six months after allo-SCT, in 81 consecutive patients who received a RIC regimen prior to allo-SCT from HLA-identical siblings. Patients’ characteristics are as follow: median age: 49 (range, 18–63) y. 33 patients (41%) had a myeloid malignancy, 34 (42%) had a lymphoid malignancy, and 14 patients (17%) were treated for metastatic non-hematological malignancies. 21 patients (26%) from this series received donor bone marrow (BM), while the remaining 60 patients (74%) received peripheral blood stem cells (PBSC). In addition to fludarabine and busulfan, the RIC regimen included high dose ATG in 20 patients (25%) and low dose ATG in 50 patients (62%). The remaining 11 patients (13%) received a low dose irradiation-based RIC. With a median follow-up of 26 (range, 9–68) months, 67 patients (83%) experienced at least one infectious episode (microbiologically documented, n=33; or non-documented infections, n=34) beyond the first six months after allo-SCT developing at a median of 8 (range, 6–34) months. A total number of 221 infectious episodes was observed, of which 123 (56%) required hospitalization and systemic anti-microbial therapy. 94 episodes (43%) could be documented (bacterial, n=28; viral, n=56; fungal, n=10). Microbiologically documented infections were distributed as follow: gram negative bacteria (16%), other bacteria (14%), CMV positive antigenemia (17%), HSV (25%), VZV (15%), other viruses (3%), aspergillus (4%), candida species (6%). 81% of patients (n=54) with an infection were under systemic immunosuppressive therapy for chronic GVHD. In a univariate analysis performed in the 33 patients with a documented infection, age <50 (P=0.06), the use of PBSCs as stem cell source (P=0.03) and a history of DLI administration (P=0.002), exerted a protective effect against infection occurrence. Interestingly, in a multivariate analysis, DLI administration (for progressive disease or mixed chimerism) was the strongest factor significantly associated with a decreased risk of long term infections (P=0.002; RR=0.23; 95%CI, 0.1–0.6), indirectly highlighting the protective effect of donor origin immunity after allo-SCT. In this series of patients surviving at least 6 months after RIC allo-SCT, the overall long term transplant-related mortality was 14% (n=11), of whom 6 deaths were attributed to infections (3 bacterial septicemia, 2 aspergillosis, 1 pneumocystosis), giving a cumulative incidence of long term-infectious related mortality of 7% (95%CI, 1.4–12.6%). Obviously, prospective efforts to develop optimal antimicrobial preventive strategies after RIC allo-SCT are still needed. However, the results from this analysis compare favorably with data from the standard myeloablative allo-SCT setting, further underlining the overall benefits of RIC preparative regimens before allo-SCT.

Long Term Infectious Complications Following Reduced Intensity Conditioning (RIC)Allogeneic HLA-Identical Sibling Transplantation (allo-SCT).

In the setting of RIC for allo-SCT, promising results have been reported in regards to decreased early transplant-related complications. However, long term outcomes are still poorly defined. Of note, the epidemiology of long term transplant-related infections is still sparse. Our current knowledge of long term infectious complications after RIC allo-SCT is still primarily based on results of analyses performed in the standard myeloablative allo-SCT setting. This prospective report describes infectious complications occurring beyond six months after allo-SCT, in 81 consecutive patients who received a RIC regimen prior to allo-SCT from HLA-identical siblings. Patients' characteristics are as follow: median age: 49 (range, 18–63) y. 33 patients (41%) had a myeloid malignancy, 34 (42%) had a lymphoid malignancy, and 14 patients (17%) were treated for metastatic non-hematological malignancies. 21 patients (26%) from this series received donor bone marrow (BM), while the remaining 60 patients (74%) received peripheral blood stem cells (PBSC). In addition to fludarabine and busulfan, the RIC regimen included high dose ATG in 20 patients (25%) and low dose ATG in 50 patients (62%). The remaining 11 patients (13%) received a low dose irradiation-based RIC. With a median follow-up of 26 (range, 9–68) months, 67 patients (83%) experienced at least one infectious episode (microbiologically documented, n=33; or non-documented infections, n=34) beyond the first six months after allo-SCT developing at a median of 8 (range, 6–34) months. A total number of 221 infectious episodes was observed, of which 123 (56%) required hospitalization and systemic anti-microbial therapy. 94 episodes (43%) could be documented (bacterial, n=28; viral, n=56; fungal, n=10). Microbiologically documented infections were distributed as follow: gram negative bacteria (16%), other bacteria (14%), CMV positive antigenemia (17%), HSV (25%), VZV (15%), other viruses (3%), aspergillus (4%), candida species (6%). 81% of patients (n=54) with an infection were under systemic immunosuppressive therapy for chronic GVHD. In a univariate analysis performed in the 33 patients with a documented infection, age <50 (P=0.06), the use of PBSCs as stem cell source (P=0.03) and a history of DLI administration (P=0.002), exerted a protective effect against infection occurrence. Interestingly, in a multivariate analysis, DLI administration (for progressive disease or mixed chimerism) was the strongest factor significantly associated with a decreased risk of long term infections (P=0.002; RR=0.23; 95%CI, 0.1–0.6), indirectly highlighting the protective effect of donor origin immunity after allo-SCT. In this series of patients surviving at least 6 months after RIC allo-SCT, the overall long term transplant-related mortality was 14% (n=11), of whom 6 deaths were attributed to infections (3 bacterial septicemia, 2 aspergillosis, 1 pneumocystosis), giving a cumulative incidence of long term-infectious related mortality of 7% (95%CI, 1.4–12.6%). Obviously, prospective efforts to develop optimal antimicrobial preventive strategies after RIC allo-SCT are still needed. However, the results from this analysis compare favorably with data from the standard myeloablative allo-SCT setting, further underlining the overall benefits of RIC preparative regimens before allo-SCT.

Low-dose ATG is effective in treatment of acute rejection episodes

Low-dose ATG is effective in treatment of acute rejection episodes

Prospective randomized trial to evaluate the efficacy of single low dose ATG induction in renal transplant recipient with spousal kidney

Prospective randomized trial to evaluate the efficacy of single low dose ATG induction in renal transplant recipient with spousal kidney

A randomized prospective study comparing low-dose 0KT3 to low-dose ATG for the treatment of acute steroid-resistant rejection episodes in kidney transplant recipients

A randomized prospective study comparing low-dose 0KT3 to low-dose ATG for the treatment of acute steroid-resistant rejection episodes in kidney transplant recipients

Xenotransplantation of pig kidneys to nonhuman primates: I. Development of the model

Abstract: Long‐term survival of discordant xenografts will require control of both humoral and cellular aspects of the immune response. Because cellular responses to xenografts appear to be more potent than those encountered by allografts, recipients of xenogeneic tissues are likely to require more immunosuppression, with potential for unacceptably high complication rates. We have therefore directed our attention toward the induction of tolerance to some or all of the xenogeneic antigens recognized in the primate anti‐pig cellular immune response, utilizing mixed lymphohematopoietic chimerism as the means for tolerance induction. We report here our initial series of 16 animals in which the conditions for application of this treatment regimen were established. In 14 cynomolgus monkey recipients, induction therapy consisted of low dose whole body irradiation, thymic irradiation, and ATG, followed by infusion of pig bone marrow and a pig kidney transplant. Other aspects of the regimen included splenectomy and removal of monkey anti‐porcine natural antibodies by extracorporeal perfusion of the recipient's blood through a pig liver. Two control animals received either no treatment or extracorporeal perfusion but no additional induction therapy. Five of the experimental animals were treated posttransplant with an anti‐IgM monoclonal antibody, five with Cyclosporin A, and two with a combination of both immunosuppressants. Both IgM and IgG natural antibodies were removed effectively by liver perfusion in all but one monkey, as determined by flow cytometry. Antibody liters remained low for 5–7 days, but increased progressively thereafter. The longest kidney survival in this series was 13 days, in an animal which maintained excellent kidney function for the first 11 days posttransplant. Peripheral chimerism was detected only transiently on day 10 in the peripheral blood of this recipient. We conclude that extracorporeal perfusion by this technique removes natural antibodies and prevents hyperacute rejection, permitting maintenance of excellent renal xenograft function for at least 11 days. Additional manipulations appear to be required to achieve mixed chimerism and tolerance of the cellular immune system in this model.