Rabbit Anti-human Thymocyte Immunoglobulin Research Articles

Single non-blood-related umbilical cord blood transplantation using a reduced-intensity conditioning regimen for the treatment of severe aplastic anemia

Objective: To evaluated the clinical efficacy of a reduced-intensity preconditioning regimen for single non-blood-related umbilical cord blood transplantation (sUCBT) in the treatment of severe aplastic anemia (SAA) . Methods: The clinical data of 63 patients with SAA who underwent sUCBT from January 2021 to July 2023 at the Department of Hematology of the First Affiliated Hospital of USTC were retrospectively analyzed. Fifty-two patients received total body irradiation/total bone marrow irradiation (TMI) combined with fludarabine or a cyclophosphamide- conditioning regimen (non-rATG group) , while 11 patients received rabbit anti-human thymocyte immunoglobulin (rATG) combined with TMI, fludarabine, or the cyclophosphamide-conditioning regimen (rATG group) . All patients received cyclosporine A and mycophenolate mofetil for graft-versus-host disease (GVHD) prophylaxis. Complications post-transplantation and long-term survival were compared between the two groups. Results: The baseline parameters were balanced between the two groups (P>0.05) . In the rATG group, all patients achieved stem cell engraftment, and in the non-rATG group, five patients had primary graft failure. There was no significant difference in the cumulative incidence of neutrophil engraftment at 42 days after transplantation or platelet engraftment at 60 days between the two groups. The incidence of grade Ⅱ-Ⅳ acute GVHD in the rATG group was significantly lower than in the non-rATG group (10.0% vs. 46.2% , P=0.032) , and the differences in the cumulative incidences of grade Ⅲ/Ⅳ acute GVHD and 1-year chronic GVHD were not statistically significant (P=0.367 and P=0.053, respectively) . There were no significant differences in the incidences of pre-engraftment syndrome, bacterial bloodstream infections, cytomegalovirus viremia, or hemorrhagic cystitis between the two groups (P>0.05 for all) . The median follow-up time for surviving patients was 536 (61-993) days, and the 1-year transplantation related mortality (TRM) of all patients after transplantation was 13.0% (95% CI 6.7% -24.3% ) . Among the patients in the non-rATG and rATG groups, 15.5% (95% CI 8.1% -28.6% ) and 0% (P=0.189) , respectively, had mutations. The 1-year overall survival (OS) rate of all patients after transplantation was 87.0% (95% CI 75.7% -93.3% ) . The 1-year OS rates in the rATG group and non-rATG group after transplantation were 100% and 84.5% , respectively (95% CI 71.4% -91.9% ) (P=0.198) . Conclusion: The preliminary results of sUCBT with a low-dose irradiation-based reduced-intensity conditioning regimen with fludarabine/cyclophosphamide for the treatment of patients with SAA showed good efficacy. Early application of low-dose rATG can reduce the incidence of acute GVHD after transplantation without increasing the risk of implantation failure or infection.

Porcine Anti-Lymphocyte Globulin, Cyclosporine A Plus Thrombopoietin Receptor Agonists Achieved Similar Efficacy and Survival Compared to Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Aplastic Anemia.

Immunosuppressive therapy (IST) with horse or rabbit anti-human thymocyte immunoglobulin (h-/r-ATG) and hematopoietic stem cell transplantation (HSCT) are two baseline treatments for severe aplastic anemia (SAA) and transfusion-dependent non-severe aplastic anemia (TD-NSAA) patients. Addition of thrombopoietin receptor agonists (TPO-RAs) to standard IST therapy (h-/r-ATG) has greatly improved the survival of SAA, whereas porcine anti-lymphocyte globulin (p-ALG) combined with TPO-RAs still had a matter of debate. We retrospectively compared the data of 48 AA patients in our center between 2020 and 2022, 23 AA patients received with p-ALG ± TPO-RAs, 25 AA patients underwent matched sibling donor (MSD-) or haploidentical (haplo-) HSCT. For patients in the HSCT group, the ORR was 90.9% which was significantly higher than that in the IST±TPO-RAs group (45.5%, P = 0.001) at 3 months; moreover, patients who underwent HSCT achieved faster transfusion independence, better CR rate, shorter time of recovery normal blood routine, and the percentage of normal blood routine (all P < 0.05) compared with IST±TPO-RAs group. However, the ORR were similary at 6 months in the two groups (95.5% vs 81.8% P = 0.342), with a median follow up of 19.8 months (range, 0.3-38.2 months), the 2-year FFS and OS in the two cohorts has no different. Subgroup analysis further indicated that the 2-year FFS and OS were similar between IST+TPO-RAs and haplo-HSCT subgroups, as well as in IST+TPO-RAs and MSD-HSCT cohorts. Moreover, the first-time hospitalizations were much more expensive in the HSCT group than in the IST±TPO-RAs group (402 756 vs. 292 902 yuan, P = 0.002). P-ALG-based-IST±TPO-RAs is a good treatment option with similar FFS and OS compared to allo- HSCT for AA patients without the opportunity of HSCT.

Current trends in the treatment of aplastic anemia

Aplastic anemia is a syndrome characterized by reduced hematopoietic stem cells, bone marrow hypoplasia, and pancytopenia, and is often considered a T-cell-mediated autoimmune disease. It is predominantly treated with hematopoietic stem cell transplantation and immunosuppressive therapy with anti-human thymocyte immunoglobulin (ATG) and cyclosporine. Only rabbit ATG was previously available in Japan, but equine ATG was recently approved for use in 2023. Thrombopoietin receptor agonists available in Japan are oral eltrombopag and injectable romiplostim. In hematopoietic stem cell transplantation for aplastic anemia, a conditioning regimen of reduced-dose cyclophosphamide and fludarabine has been used to reduce cardiotoxicity. Human leukocyte antigen haploidentical stem cell transplants have also been developed, and their use in patients without a donor is increasingly reported. Future advancements in novel drugs and transplantation therapies could revolutionize the management of aplastic anemia.

Clinical characteristics of 15 cases of renal transplantation with pre-exsiting donor-specific antibody.

Currently, patients with pre-exsiting donor-specific antibody (DSA) are prone to antibody-mediated rejection (AMR) after surgery and are at a relatively high risk of postoperative complications and graft failure. The risk of postoperative complications and graft failure is relatively high. This study aims to discuss the clinical outcome of DSA-positive kidney transplantation and analyze the role and safety of preoperative pretreatment in DSA-positive kidney transplantation, providing single-center treatment experience for DSA-positive kidney transplantation. We retrospectively analyzed the clinical data of 15 DSA-positive kidney transplants in the Department of Renal Transplantation of First Affiliated Hospital of Zhengzhou University from August 2017 to July 2022. Eight cases were organ donation after citizen's death (DCD) kidney transplant recipients, of which 3 cases in the early stage were not treated with preoperative desensitisation therapy (DCD untreated group, n=3), and 5 recipients were treated with preoperative rituximab desensitisation (DCD preprocessing group, n=5). The remaining 7 cases were living related donors recipients (LRD) who received preoperative desensitisation treatment with rituximab and plasma exchange (LRD preprocessing group, n=7). We observed and recorded the incidence of complications with changes in renal function and DSA levels in the recipients and the survival of the recipients and transplanted kidneys at 1, 3 and 5 years, and to compare the differences in recovery and postoperative complications between 3 groups. All 15 recipients were positive for preoperative panel reactive antibody (PRA) and DSA and were treated with methylprednisolone+rabbit anti-human thymocyte immunoglobulin induction before kidney transplantation. DCD untreated group all suffered from DSA level rebound, delayed renal graft function (DGF) and rejection reaction after surgery. After the combined treatment, DSA level was reduced and the graft renal function returned to normal. The DCD preprocessing group were all without antibody rebound, 1 recipient developed DGF and the renal function returned to normal after plasmapheresis, and the remaining 4 recipients recovered their renal function to normal within 2 weeks after the operation. In the LRD preprocessing group, 2 cases had antibody rebound and 1 case had rejection, but all of them recovered to normal after treatment, and DSA was maintained at a low level or even disappeared. The incidence of DGF and rejection in the DCD untreated group were significantly higher than that in the DCD preprocessing group and the LRD preprocessing group; and there were no significant difference in the incidence of postoperative haematuria, proteinuria, bacterial and fungal infections, and BK virus infection between the 3 groups (all P>0.05). A total of 11 of the 15 recipients were followed up for more than 1 year, 6 for more than 3 years, and 1 for more than 5 years, and the survival rates of both the recipients and the transplanted kidneys were 100%. Effective preoperative pretreatment with desensitization therapy can effectively prevent antibody rebound in DSA-positive kidney transplantation and reduce perioperative complications.

Efficacy analysis of anti-thymocyte globulin regimens with different timing strategies for matched sibling donor hematopoietic stem cell transplantation

Objective: To compare the effects of two administration time strategies for rabbit antihuman thymocyte immunoglobulin (rATG) of 5mg/kg total dose in matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) . Methods: This study retrospectively analyzed the clinical data of 32 patients who received MSD-HSCT with 5 mg/kg rATG conditioning regimen at the Department of Hematology of the First Medical Center of the People's Liberation Army General Hospital from October 2020 to April 2022. The patients were classified into two groups: the 4d-rATG group (16 cases), who received antithymocyte globulin (ATG) from day -5 to day -2, and the 2d-rATG group (16 cases), who received ATG from day -5 to day -4. Between the two groups, the transplantation outcomes, serum concentrations of active antithymocyte globulin (ATG) in patients from -4 days to 28 days after graft infusion (+28 days), and the reconstitution of lymphocyte subsets on days +30, +60, and +90 were compared. Results: The cumulative incidences of acute graft-versus-host disease at 100 days after graft infusion were 25.0% (95% CI 7.8% -47.2% ) and 18.8% (95% CI 4.6% -40.2% ) (P=0.605) in the 4d-rATG group and 2d-rATG group, respectively. The 1-year cumulative incidences of chronic graft-versus-host disease were 25.9% (95% CI 8.0% -48.6% ) and 21.8% (95% CI 5.2% -45.7% ) (P=0.896). The 1-year cumulative incidence of relapse was 37.5% (95% CI 18.9% -65.1% ) and 14.6% (95% CI 3.6% -46.0% ) (P=0.135), and the 1-year probabilities of overall survival were 75.0% (95% CI 46.3% -89.8% ) and 100% (P=0.062). The total area under the curve (AUC) of serum active ATG was 36.11 UE/ml·d and 35.89 UE/ml·d in the 4d-rATG and 2d-rATG groups, respectively (P=0.984). The AUC was higher in the 4d-rATG group than that in the 2d-rATG group (20.76 UE/ml·d vs 15.95 UE/ml·d, P=0.047). Three months after graft infusion, the average absolute count of CD8(+) T lymphocytes in the 4d-rATG group was lower than that in the 2d-rATG group (623 cells/μl vs 852 cells/μl, P=0.037) . Conclusion: The efficiencies of GVHD prophylaxis in MSD-PBSCT receiving 4d-ATG regimen and the 2d-rATG regimen were found to be similar. The reconstruction of CD8(+)T lymphocytes in the 2d-rATG group was better than that in the 4d-rATG group, which is related to the lower AUC of active ATG after transplantation.

#6011 VIRAL INFECTION AND DE NOVO PRODUCTION OF DONOR SPECIFIC ANTIBODIES IN KIDNEY TRANSPLANTATION: DCD VS DBD

Abstract Background and Aims Viruses are among the most common causes of opportunistic infection after transplantation and an accurate screening and follow-up is needed in order to prevent related complication as systemic damages and worsening of kidney function. On the other hand, in the first years after transplantation, antibody-mediated rejection (ABMR) is one of the first cause of graft lost and de novo production of donor specific antibody (dnDSAs) is the main source. In this monocentric study we analysed data of 255 patient transplanted from January 2016 to February 2022. We studied the incidence of viral infection and dnDSAs in the first one year after transplantation in different sub-groups of patients. Method Data was obtained from our monocentric registry, from January 2016 to February 2022. Starting from 299 kidney transplantation we obtained 255 patients with a complete annual follow-up for viral infection and DSA monitoring. We compared the incidence of viral infection and dnDSAs in different sub-group: transplanted from donation after brain-death treated with Basiliximab as induction therapy (DBDb), transplanted from donation after brain-death treated with rabbit anti-human thymocyte immunoglobulin (rATG) as induction therapy (DBDt), transplanted from donation after circulatory death treated with rATG as induction therapy (DCD) and transplanted treated with rATG as induction (DBDt+DCD). Results Global incidence of viral infection was 73% and dnDSAs formation was present in 12,5% of all patients. DBDs showed an incidence of 69% of viral infection and 10% of dnDSAs while in DBDt these values were 77,4% and 25%, respectively. In DCD data of viral infection was higher (96,7%) whereas dnDSAs was 14%. rATG (DBDt+DCD) displayed 87,1% of viral infection and 19% of dnDSAs. Conclusion Viral infection and dsDNAs are two paramount aspects in kidney transplantation and demonstrate different incidences depending on donation profile and immunosuppressive induction therapy. Specifically rATG seems to be associated to an higher rate of viral infection and DCD is the more relevant sub-group. Furthermore, rATG was associated with higher dsDNAs rate, especially in DBD treated with rATG. On the best of our knowledge, this data was never observed before. These data, due to the low number of cases, need to be confirmed from larger cohorts. Moreover our study underlines how significant is to develop a personalized approach in order to reduce complications associated to immunosuppressive therapies.

Porcine anti-human lymphocyte immunoglobulin depletes the lymphocyte population to promote successful kidney transplantation.

Porcine anti-human lymphocyte immunoglobulin (pALG) has been used in kidney transplantation, but its impacts on the lymphocyte cell pool remain unclear. We retrospectively analyzed 12 kidney transplant recipients receiving pALG, and additional recipients receiving rabbit anti-human thymocyte immunoglobulin (rATG), basiliximab, or no induction therapy as a comparison group. pALG showed high binding affinity to peripheral blood mononuclear cells (PBMCs) after administration, immediately depleting blood lymphocytes; an effect that was weaker than rATG but stronger than basiliximab. Single-cell sequencing analysis showed that pALG mainly influenced T cells and innate immune cells (mononuclear phagocytes and neutrophils). By analyzing immune cell subsets, we found that pALG moderately depleted CD4+T cells, CD8+T cells, regulatory T cells, and NKT cells and mildly inhibited dendritic cells. Serum inflammatory cytokines (IL-2, IL-6) were only moderately increased compared with rATG, which might be beneficial in terms of reducing the risk of untoward immune activation. During 3 months of follow-up, we found that all recipients and transplanted kidneys survived and showed good organ function recovery; there were no cases of rejection and a low rate of complications. In conclusion, pALG acts mainly by moderately depleting T cells and is thus a good candidate for induction therapy for kidney transplant recipients. The immunological features of pALG should be exploited for the development of individually-optimized induction therapies based on the needs of the transplant and the immune status of the patient, which is appropriate for non-high-risk recipients.

The impact of donor-to-recipient gender compatibility on outcomes of haploid hematopoietic stem cell transplantation in patients with hematological malignancies

Objective: To investigate how gender differences between the donor and the recipient affect the effectiveness of antithymocyte globulin (ATG) and pure peripheral blood stem cell (PBSC) hematopoietic stem cell transplantation (haplo-HSCT) in the treatment of malignant hematological diseases. Methods: From February 2015 to September 2020, 648 hematological malignancies patients underwent myeloablative condition regimen haplo-HSCT treatment at the Bone Marrow Transplant Center of the First Affiliated Hospital of Zhejiang University. The median age was 32 (14-62) years, with 363 males (56.0% ) and 285 females (44.0% ) present. 242 cases of acute lymphoblastic leukemia (ALL) (37.3% ) , 293 cases of acute myeloid leukemia (AML) (45.2% ) , 56 cases of myelodysplastic syndrome (MDS) (8.7% ) , 27 cases of non-Hodgkin's lymphoma (NHL) (4.2% ) , and 30 cases of other hematological malignancies (4.6% ) . Results: ① The 3-year overall survival (OS) , DFS, the incidence of Ⅱ-Ⅳ grade acute graft-versus-host disease (aGVHD) , the incidence of Ⅲ-Ⅳ grade aGVHD, the 3-year incidence of moderate & severe chronic GVHD (cGVHD) , severe cGVHD, the 3-year incidence of relapse, and NRM of the whole group were (73.10±1.90) % , (70.80±1.90) % , (33.96±1.87) % , (13.08±1.33) % , (35.10±2.14) % , (10.66±1.38) % , (19.43±1.67) % , and (9.80±1.24) % , respectively. ②There was no statistically significant difference between the donor-recipient gender match and donor-recipient gender mismatch groups in the 28-day cumulative neutrophil engraftment rate, 28-day cumulative platelet engraftment rate, the incidence of Ⅱ-Ⅳ grade aGVHD, the incidence of Ⅲ-Ⅳ grade aGVHD, 3-year OS, 3-year DFS, the cumulative incidence of relapse, NRM, and incidence of moderate & severe cGVHD, severe cGVHD. ③The 28-day cumulative neutrophil engraftment rate did not differ statistically between the male-female, female-female, male-male, and female-male groups (P=0.148) . The incidence of Ⅱ-Ⅳ grade aGVHD, the incidence of Ⅲ-Ⅳ grade aGVHD, 3-year OS, 3-year DFS, cumulative relapse rate, and NRM, and the incidence of cGVHD were not statistically different among the four groups (P>0.05) . The 28-day cumulative platelet engraftment rate of the female-male group was significantly lower than male-female group, and the female-female group [ (91.45±2.63) % vs. (94.77±1.75) % , P=0.004; (91.45±2.63) % vs. (95.54±2.05) % , P=0.005]. No significant difference existed in the 28-day cumulative platelet engraftment rate between the female-male group and the male-male group [ (91.45±2.63) % vs. (95.08±1.41) % , P=0.284]. ④Among patients ≤35 years old, the 3-year incidence of severe cGVHD patients receiving sister donors and sibling donors were (26.71±5.90) % and (10.33±4.43) % , respectively (P=0.054) . Patients accepting daughter donors and son donors had a 3-year incidence of moderate and severe cGVHD that was 40.07% vs. 27.41% , respectively, among those over 35 (40.07±6.65) % vs. (27.41±4.54) % (P=0.084) . ⑤Female donors to male recipients had a significantly lower 28-day cumulative platelet engraftment rate compared to the other groups [ (91.45±2.63) % vs. (95.08±0.95) % , P=0.037]. ⑥ Female donors to male recipients had a significantly lower 28-day cumulative platelet engraftment rate than the other groups in the ATG-Fresenius (ATG-F) 10 mg/kg group [ (89.29±4.29) % vs. (94.49±1.45) % , P=0.037]. But when compared to the other groups in the Rabbit Antihuman Thymocyte Immunoglobulin (rATG-T) 6 mg/kg group, the 28-day cumulative platelet implantation rate between female donors and male recipients was not significantly different [ (93.44±3.38) % vs. (95.62±1.26) % , P=0.404]. Conclusion: The main clinical outcomes of patients with malignant blood diseases following transplantation are unaffected by the gender combination of the donor and patient in the haplo-HSCT mode based on ATG and PBSC sources. Female donors to male recipients have a lower 28-day cumulative platelet engraftment rate and longer platelet engraftment times.

Safety of rabbit anti-human thymocyte immunoglobulin in second allogeneic hematopoietic stem cell transplantation for patients with hematological diseases

Objective: To look into the security of a second allogeneic hematopoietic stem cell transplantation (allo-HSCT) using rabbit anti-human thymocyte immunoglobulin (rATG) . Methods: Twenty-seven patients who used rATG in the first and second allo-HSCT at the Institute of Hematology, Peking University were enrolled in the study. Experienced toxicities associated with the conditioning protocol within 10 days (-5 d to +3 d) following the beginning of the rATG application, including fever, diarrhea, arrhythmia, reduced blood pressure, liver damage, seizures, and other problems. Results: The overall incidence of conditioning regimen early adverse reactions during the first transplantation and the second allo-HSCT conditioning regimen was 96.3% and 77.8% (P=0.043) . Fever rates were 81.5% and 63.0% (P=0.129) , diarrhea rates were 59.3% and 25.9% (P=0.013) , liver damage rates were 22.2% and 25.9% (P=0.75) , and the rates of other events (cardiac arrhythmia, low blood pressure, and epilepsy) were 3.7% and 18.5% (P=0.083) . Adverse reactions that occurred during both the first and second course of rATG applications have been improved with symptomatic treatment, and no treatment interruptions occurred. Conclusion: Reusing rATG in a second transplant was risk-free and did not result in higher early toxicities.

Current insights into the treatments of severe aplastic anemia in China.

Recently, several studies have been conducted to generate considerable evidence regarding unique treatments for severe aplastic anemia (SAA) in China. Haploidentical donor hematopoietic stem cell transplantation (HID-HSCT) showed an overall survival rate (80.3-86.1%) comparable to those with immunosuppressive therapy (IST) and matched related donor (MRD)- and matched unrelated donor (MUD)-HSCT. Failure-free survival of HID-HSCT was also comparable (76.4-85.0%) to those of MRD- and MUD-HSCT and better than IST in patients < 40years. Although these results are promising, HID-HSCT should be regarded as a salvage therapy when young patients fail to respond to IST. Porcine anti-human lymphocyte immunoglobulin (pALG) showed similar or superior overall response at 6months compared to rabbit anti-human thymocyte immunoglobulin (rATG) (64.0-79.4% in the pALG-group vs.48.1-64.7% in the rATG-group) as a first-line IST. Promising hematological response (28.4-33.3%) was observed in patients with refractory AA following infusion of the mesenchymal stromal cells (MSCs) derived from the bone marrow of allogeneic donors. pALG can replace rATG as an immunosuppressive drug and MSCs infusion can be used as a second-line treatment for refractory SAA. We believe that this review contributes to refine the global practices for SAA treatment.

Novel Improvement of Haploidentical Hematopoietic Stem Cell Transplantation for Advanced Refractory/Relapsed Acute Leukemia

Introduction The advanced refractory/relapsed acute leukemia has a very dismal prognosis even with the salvage allogeneic hematopoietic stem cell transplantation (allo-HSCT). To develop a novel transplant protocol to achieve a rapid engraftment and quick graft-versus leukemia (GVL) effect is crucial. Based on previous observation, the G-CSF primed bone marrow (BM) plus peripheral blood mononuclear cells (PBMNCs) could not only increase mononuclear cells and CD34 cells, but also change T-cell biology by down-regulating the expression of adhesion and CD28/B7 molecules and increase the absolute number of D2APCS, which promotes a T-cell shift from T1 to T2 subset to secrete a higher anti-inflammatory cytokines of IL-4 and IL-10. After going through a rigorous conditioning, the recipients' T-cells are incapable to attack host. We propose that reinfusion of G-CSF primed donor PBMNCs to recipient on transplant day + 6 may cross mismatched MHC barrier thus accelerating engraftment. Patients and Methods From April 2018 to June 2019, 30 advanced-stage patients with refractory/relapsed acute leukemia were enrolled and underwent a salvage haploidentical (haplo)-HSCT. The median age was 12 (2-63) years with M/F ratio of 17/13. There were 21 patients with acute myelocytic leukemia (AML, 70%), 4 -cell acute lymphoblastic leukemia (B-ALL, 13%), 2 biphenotypic acute leukemia (BAL, 7%), 1 juvenile myelomonocytic leukemia (JMML, 3%), and 2 T-lymphoblast leukemia (T-LBL, 7%). The median BM blasts were 40% (5%-90%). Twenty-eight patients received a conditioning regimen including fludarabine 30mg/m2/d×4 day, cytarabine 2.0g/m2/d×4 days, busulfan 3.2mg/kg/d Q6h×4days, cyclophosphamide 1.5g/m2/d×2 days and melphalan 110mg/m2/d×1 day. Two patients with T-LBL received BCNU+Etoposide+Cytarabine+Melphalan (BEAM) regimen. Graft-versus-host disease (GVHD) prophylaxis contained methotrexate (MTX), cyclosporine A (CsA) and mycophenolate mofetil (MMF), plus ATG (Rabbit anti-human thymocyte immunoglobulin, Sangstat) 1.5mg/kg/d iv daily from day -4 to -1 and additional 1.5mg/kg on day +7 (total dose of 7.5 mg/kg). In addition, anti-CD25 monoclonal antibody (basiliximab) 20 mg on day+1 and +4 was given iv. Donors were primed with G-CSF at 3-4 ug/kg/d sq d1-5. On day 4 of G-CSF, donor BM cells were harvested and were infused unmanipulated on the same day to patient on transplant day 01. On day 5 of G-CSF injection, donor primed PBMNCs were harvested, part of which were immediately infused unmanipulated to recipient on transplant day 02. Part of the cells were cryopreserved and stored in the liquid nitrogen, which were then thawed and reinfused unmanipulated to recipient on day +6 (Table 1). Results All patients achieved a trilineage engraftment with a median time of 13.5 (5-16) days. The median neutrophil and platelet engraftment were 13 (11-19) days and 10 (5-22) days respectively (Fig.1). Among 29 evaluable patients, acute GVHD occurred in 10 (34.5%, Fig. 2) with a median time of 32 (14-60) days, including 5 cases (17%) of grade Ⅱ, 3 (10%) of grade Ⅲ and 2 (7%) of grade Ⅳ. Among the 28 evaluable patients for chronic GVHD, only 6 (21.4%, Fig.3) developed limited chronic GVHD with a median time of 103 (90-180) days. Twenty seven out of thirty (90%) patients achieved disease-free survival (DFS) with a median follow-up time of 6 (5-14) months. Three patients died from transplant related complication, including infection for 2 and GVHD for 1 respectively. Conclusion In this study, with an intensive myeloablative condition and salvage haplo-HSCT, by reinfusing additional unmanipulated donor PBMNCs to recipients on day +6 during their transplantation, a short engraftment time without engraftment failure, low lethal GVHD incidence, and a lower infection rate were able to be achieved. More importantly, most patients remain DFS at a median follow-up time of 6 months. Despite short-term follow-up. the outcomes are particularly encouraging. Disclosures No relevant conflicts of interest to declare.

Clinical observation of 12 patients with refractory/relapsed acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation containing cladribine regimen

目的评估含克拉屈滨序预处理异基因造血干细胞移植（allo-HSCT）治疗难治/复发急性髓系白血病（AML）的疗效。方法回顾性分析12例接受含克拉屈滨预处理allo-HSCT难治/复发AML患者的临床资料。结果①12例患者中，男9例，女3例，中位年龄36（27~50）岁。亲缘全相合供者移植3例，无关供者移植1例，单倍型移植8例。移植前部分缓解9例，未缓解3例，移植前化疗中位疗程6（2~13）个。②预处理：司莫司汀250 mg·m−2·d−1，−7 d；克拉屈滨5 mg·m−2·d−1，−6 d~−2 d；阿糖胞苷2 g·m−2·d−1，−6 d~−2 d；白消安3.2 mg·m−2·d−1，−6 d~−3 d；兔抗人胸腺细胞免疫球蛋白（ATG）1.5 mg·m−2·d−1（无关供者移植）或2.0~2.5 mg·m−2·d−1（单倍型移植），−4 d~−1 d。③11例患者获得造血重建，1例发生原发植入失败。可评估患者中，中性粒细胞植入时间为15（15~21）d，中位血小板植入时间为19（17~30）d。④预处理过程中，12例患者均未发生肝静脉闭塞病，2例患者发生出血性膀胱炎。移植过程中8例出现发热，均经抗感染治疗后好转。3例患者发生Ⅱ度急性GVHD。至随访截止9例存活患者中8例发生慢性局限型GVHD。⑤中位随访时间为8（4~12）个月，2例患者分别在移植后6、12个月复发。预期1年总生存率为（71.1±1.8）%，无病生存率为（62.2±1.8）%。结论含克拉屈滨预处理allo-HSCT可作为难治/复发AML患者的可选治疗方案。

Correction to: Rabbit anti-human thymocyte immunoglobulin for the rescue treatment of chronic antibody-mediated rejection after pediatric kidney transplantation.

The article "Rabbit anti-human thymocyte immunoglobulin for the rescue treatment of chronic antibody-mediated rejection after pediatric kidney transplantation", written by Yasemen Cihan, Nele Kanzelmeyer, Jens Drube, Martin Kreuzer, Christian Lerch, Imke Hennies, Kerstin Froede, Murielle Verboom.

Comparative study of porcine anti-human lymphocyte immunoglobulin and rabbit anti-human thymocyte immunoglobulin as a first-line treatment of acquired severe aplastic anemia

Porcine anti-human lymphocyte immunoglobulin (pALG) and rabbit anti-human thymocyte immunoglobulin (rATG) are the only two ATGs for severe aplastic anemia (SAA) treatment in China. 148 treatment-naïve SAA patients who received ATG combined with cyclosporine A (CsA) therapy were analysed retrospectively. The patients were divided into a pALG group (n = 114) and a rATG group (n = 34). After three months, the pALG and rATG groups had an overall response (OR) of 65.8% and 44.1%, respectively (P = 0.023); after six months, the OR reached 74.6% and 64.7%, respectively (P = 0.361). The pALG group had markedly better time-related efficacy than the rATG group (P = 0.03). The overall survival (OS) and event-free survival (EFS) between groups had no significant difference (P > 0.1). The pALG and rATG groups did not significantly differ in terms of recurrence (8.8% vs. 5.9%, P = 0.734) or PNH clonal transformation (5.3% vs. 2.9%, P = 1.000), whereas a significant difference was found in the incidence of MDS/AML transformation (2.6% vs. 11.8%, P = 0.049). We found that pALG achieved a better time-related efficacy than rATG for the treatment of SAA; nonetheless, no significant difference in the OS or EFS of pALG compared with rATG.

Rabbit anti-human thymocyte immunoglobulin for the rescue treatment of chronic antibody-mediated rejection after pediatric kidney transplantation.

Chronic antibody-mediated rejection (cAMR) is the leading cause of late kidney graft loss, but current therapies are often ineffective. Rabbit anti-human thymocyte immunoglobulin (rATG) may be helpful, but its use is virtually undocumented. Data were analyzed retrospectively from nine pediatric kidney transplant patients with cAMR were treated with rATG (1.5mg/kg × 5days) at our center after non-response to pulsed prednisolone, intravenous immunoglobulin, rituximab, and increased immunosuppressive intensity (including switching to belatacept in some cases), with or without bortezomib. The median time from diagnosis to cAMR was 179days. rATG was started 5-741days after diagnosis. Median estimated glomerular filtration rate (eGFR) increased from 40mL/min/1.73m2 when rATG was started to 62mL/min/1.73m2 9months later (p=0.039). Four patients showed substantially higher eGFR after 9months and 2 patients showed a small improvement; eGFR continued to decline in 3 patients after starting rATG. No grafts were lost during follow-up. At last follow-up, donor-specific antibodies (DSAs) were no longer detectable in 4 out of 8 patients for whom data were available, median fluorescence intensity had decreased substantially in 1 out of 8 patients; anti-HLA DQ DSAs persisted in 2 out of 8 patients. No adverse events with a suspected relation to rATG, including allergic reactions, leukocytopenia or infections, were observed in any of the patients. In this small series of patients, rATG appears a promising treatment for unresponsive cAMR. Further evaluation, including earlier introduction of rATG, is warranted.

Two Cases Report of Haploid Hematopoietic Stem Cell Transplantation Treatment of Adrenal Leukodystrophy

Background: Adrenal leukodystrophy is one of the beta oxidation peroxidase disease, an x-linked recessive heredity, can lead to very long chain fatty acids in tissue accumulation, result in adrenal and cerebral white matter of the progressive deterioration. Hematopoietic stem cell transplantation (HSCT) is a curative treatment for early childhood cerebral type of X-ALD. We report two cases of haploid hematopoietic stem cell transplantation for the treatment of adrenal leukodystrophy.Methods: Two patients were male, 5 years old, 6 years old, respectively, by the gene diagnosis of adrenal leukodystrophy.Case 1 received father haploid bone marrow and peripheral blood stem cell(HLA7/10 match)combine with unrelated umbilical cord blood(HLA 9/10 match). Case 2 received sister haploid bone marrow and peripheral blood stem cell(HLA5/10 match)combine with unrelated umbilical cord blood(HLA 7/10 match).Case 1 conditioning regimen use cyclophosphamide, fludarabine and thiotepa.Case 2 conditioning regimen use cyclophosphamide , busulfan ,fludarabine , rabbit anti-human thymocyte immunoglobulin and thiotepa.Case 1 bone marrow infused total nucleated cell dose was 2×108/kg (CD34+:0.75%,CD3+:1.67%), peripheral blood stem cell infused total nucleated cell dose was 29×108/kg (CD34+:0.19%,CD3+:4.96%), unrelated umbilical cord blood infused total nucleated cell dose was 1.16×108/kg (CD34+:0.44%). Case 2 bone marrow infused total nucleated cell dose was 0.89×108/kg (CD34+:0.74%,CD3+:2.29%), peripheral blood stem cell infused total nucleated cell dose was 25.85×108/kg (CD34+:0.5%,CD3+:15.23%), unrelated umbilical cord blood infused total nucleated cell dose was 0.39×108/kg (CD34+:0.93 %). GVHD prophylaxis Case 1 used mycophenolate mofetil,sirolimus,while Case 2 used mycophenolate mofetil,tacrolimus and sirolimus.Results: The absolute neutrophil count (ANC) greater than 0.5×109/L of two patients were 21 and 23 days , case 1 had a successful engraftment with father donor-derived as case 2 had a successful engraftment with umbilical cord blood donor-derived.Follow-up time of 35 months and 3 months respectively,Case 1 Check head MRI again show a smaller lesionswhile Case 2 progression-free.Two cases’ C24:0, C26:0, C24:0 / C22:0, C26:0 / C22:0 of plasma decline than before transplantation.Conclusion: In the absence of HLA-match donor, haploid bone marrow and peripheral blood stem cell combined unrelated umbilical cord transplantation is a effective method of treatment of adrenal leukodystrophy, but which will successful engraftment need more further studies. DisclosuresNo relevant conflicts of interest to declare.

Effect of Rabbit Anti-human Thymocyte Immunoglobulin Combined with Cyclosporin A on Severe Aplastic Anemia

To study the efficacy and safety of anti-human thymocyte immunoglobulin(ATG-F) combined with cyclosporin A(CsA) on patients with severe aplastic anemia (SSA), so as to provide support for clinical work. From January 2010 to December 2015, 78 patients with SAA admitted in our hospital were divided into 2 groups: ATG-F+CsA group(40 cases) and ATG-F group(38 cases). After treatment for 6 months, the effective rate, side reaction rate and time of effect initiation were compared between 2 groups. The follow-up results were compared between 2 groups. The effective rate and side reaction rate in ATG-F+CsA group were 100.00% and 32.50% respectively, those in ATG-F group were 94.74% and 44.74% respectively and without statistical significant difference(P>0.05). In ATG-F+CsA group, the time of effect initiation in cured patients, remission and obvious inprovement were (44.9±15.4) d, (68.8±15.9) d and (85.4±17.6) d; in ATG-F group, patients with those were (59.6±11.5) d, (94.7±17.8) d and (119.8±21.4) d respectively, the difference showed statistical significance(P<0.05). The follow-up results were not statistically significantly different between 2 groups(P>0.05). ATG-F combined with CsA can shorten the time of effect initiation, and demonstrates reliable safety.

Non-T-Cell Depleted HLA Haploidentical Hematopoietc Stem Cell Transplantation for Refractory or Relapsed Pediatric Solid Tumor

Abstract 4470 Background:Despite intensive multi-modal therapies, prognosis of refractory or relapsed pediatric solid tumor is dismal because majority of those tumors already get acquired chemo-resistance. Therefore new break through approaches are expected in order to improve their survival. The efficacy of allogeneic hematopoietic stem celltransplantation(SCT) is primarily attributed to a T/NK- cell-mediated response to HLA disparity between donor and tumor cell. Non–T-cell depleted (non TCD) haploidentical hematopoietc stem cell transplantation as immunothrapy is attractive challenge for refractory tumor, however, there are several reports describing graft-versus-tumor (GVT) effects in patients with solid tumors. The major problems of non-TCD haplo-SCT are lethal graft-versus-host disease (GVHD), graft failure (GF) and high-risk of early death. Previously we reported the safety profile from the retrospective study assessing GVHD prophylaxis that was conducted with anti-human thymocyte immunoglobulin (ATG), tacrolimus, methotrexate and prednisolone in non-TCD haplo-SCT (Mochizuki, Kikuta, Clin Transplant,2010 DOI:10.1111/j.1399-0012.2010.01352.x). We started clinical study of non-TCD HLA haploidentical hematopoietc stem cell transplantation for refractory or relapsed pediatric solid tumor as cell-mediated immune therapy since July, 2007. Objectives/Methods:This study presents a series of transplant experiments aiming to evaluate the efficacy and feasibility of non-TCD HLA haploidentical hematopoietc stem cell transplantation for refractory or relapsed pediatric solid tumor. Seven cases (3males, 4females) with refractory or relapsed pediatric solid tumor were enrolled on this study between July 2007 to December 2010. One patient had second transplantation due to tumor progression 1year after transplantation. Among 7 patients, there are 3 cases of relapsed neuroblastoma, 1 case of relapsed Mesenchymal Chondrosarcoma, 1 case of relapsed Ewing sarcoma family tumor, 1 case of refractory alveolar soft part sarcoma with multiple lung metastasis, and 1 case of refractory primitive neuroectodermal tumor. Conditioning regimens consisted with fludarabine30mg/m2 at day-9 to -5+Melphalan70mg/m2 at day-4 to-3+rabbit ATG 1. 25mg/kg at day-2 to -1. The GVHD prophylaxis was conducted with tacrolimus (0.03mg/kg/day, start on day-1), methotrexate (10mg/m2, 7mg/m2, 7mg/m2 on day+1, +3, +6) and predonisolone (1mg/kg/day, day 0–29, taper on day30 without GVHD). HLA disparities were 3/8 in 3, 4/8 in 5. Donors included father(1), mothers(5), siblings(1), mother's younger brother(1). Four pts received peripheral blood stem cells and 4 pts received bone marrow. Result:All of seven patients achieved primary engraftment but secondary graft rejection was observed in one patients. Median follow up period after transplantation were 14 months (range 11–40 months). Incidence of acute GvHD was 3/7 cases (grade±:1, gradeII:1, grade III:1), chronic GvHD was observed in 5(83%) of 6 evaluable patients. Three cases were underwent DLI for tumor progression. Treatment-related mortality(TRM) was not observed and reactivation of VZV, interstitial pneumonia, and HHV6 related limbic system encephalitis were recognized as major complication within 100 days after transplantation. Five cases of patients had tumor progression after transplantation, and two children were dead by tumor progression, other 3 cases had additional treatment. Two cases are alive and well, with no evidence of disease 13 and 14 months after transplantation. Graft versus Tumor effect was clearly observed in three cases. Conclusion:The survival rate of relapsed or refractory pediatric solid tumor is under 20%, however, the two-year probability of overall survival was 71.4% with no TRM in this study. These results indicated the feasibility and the possibility of efficacy of non-TCD HLA haploidentical hematopoietc stem cell transplantation for relapsed or refractory pediatric solid tumor. Disclosures:No relevant conflicts of interest to declare.

Anti-thymocyte globulin induced non-cardiogenic pulmonary edema during renal transplantation

Non-cardiogenic pulmonary edema (NCPE) is a clinical syndrome characterized by simultaneous presence of severe hypoxemia, bilateral alveolar infiltrates on chest radiograph, without evidence of left atrial hypertension/congestive heart failure/fluid overload. The diagnosis of drugrelated NCPE relies upon documented exclusion of other causes of NCPE like gastric aspiration, sepsis, trauma, negative pressure pulmonary edema. We describe a 28year-old, 50 kg male with ASA risk III posted for laparoscopic renal transplantation, who developed NCPE after 4 hours of administration of rabbit anti-human thymocyte immunoglobulin (ATG). He was successfully treated with mechanical ventilatory support and adjuvant therapy. This report emphasizes that this fatal complication may occur with use of ATG.

A Case of Successful Treatment of Cutaneous Aspergillosis with Voriconazole at the Low Cyclosporine Trough Level in a Renal Transplant

Aspergillosis is a serious infectious complication with high mortality in transplant recipients. Voriconazole is a broad spectrum triazole antifungal agent, but it has a drug-drug interaction with immunosuppressants. Herein we report a case of the use of a small dose of cyclosporine (CsA) with coadministration of voriconazole. A 23 year old woman received a kidney transplant from a deceased donor. The initial immunosuppressant was tacrolimus, mycophenolate mofetil, steroids, and basiliximab. Thirty-two days after kidney transplantation, because of hemolytic uremic syndrome, she received Rabbit anti-human thymocyte immunoglobulin and plasmapheresis. Cyclosporine was used instead of tacrolimus. Three months after transplantation, she was admitted to the hospital because of an erythematous nodule on her trunk and a dry cough. Skin biopsy revealed an Aspergillus species and tissue culture showed that it was A. fumigatus. We treated her with itraconazole and subsequently with amphotericin B. Afterwards, her condition got worse. So we changed amphotericin B to voriconazole and a minimum dose of CsA (25 mg bid) at the peril of graft failure. Eventually, she recovered and maintained good graft function. The trough level of CsA ranged from 3.2 to 27.9 ng/mL.