Impact of hematopoietic stem cell transplantation on T cytotoxic and T helper cells subsets in children with β-thalassemia major

Nonpharmacologic Treatment of Chronic Graft-versus-Host Disease in Children and Adolescents

Premature Aging of Hematopoietic Cells in Long Term Survivors after HSCT with Chronic GVHD and a Female Donor.

Background: Reconstitution of the immune system following allogeneic hematopoietic stem cell transplantation (HSCT) is important for transplantation outcome. Quantitative measurement of the lymphocyte subset (LST) by flow cytometry has been used for analysis of the immune system. However, the association of each lymphocyte subset with transplantation has not been fully elucidated. Here, we investigated the relevance of each lymphocyte fraction as a predictor for HSCT outcome. Methods: A total of 70 patients who received allogeneic HSCT at national cancer center were included. The median age was 42 years (range 20-64) with 34 males (49%). The enrolled diseases included acute myeloid leukemia (n=33, 47%), acute lymphoblastic leukemia (n=13, 19%), myeloid dysplastic syndrome (n=9, 13%), non-hodgkin lymphoma (n=5, 7%), severe aplastic anemia (n=4, 6%), chronic myeloid leukemia (n=3, 4%), and multiple myeloma (n=3, 4%). LST measurements for CD3, CD4, CD8, CD19, and CD16/CD56-positive cells were performed at 7 days before and 30 days after HSCT. The absolute counts of lymphocyte subsets were evaluated for acute graft-versus-host disease (GVHD), infection (bacterial, viral, and fungal) and complications during 100 days post HSCT. GVHD was pathologically validated and determination of infection was based on microbiology results including culture, cytomegalovirus antigenemia and virus PCR. Moreover, the association between LST and treatment failure as relapse or death during any period was analyzed. Results: The number of each fraction of lymphocyte subsets at 7 days before and 30 days after HSCT were as following (mean ± SD/uL): CD3 (804.5 ± 564.6, 862.1 ±890.0, p =0.719), CD4 (339.74 ± 284.8, 223.5 ± 189.9, p =0.009, CD8 (430.6 ± 362.9, 576.9 ± 703.1, p = 0.169, CD19 (39.7 ± 72.3, 19.1 ± 22.9, p =0.035), NK (86.6 ± 86.8, 272.5 ± 192.2, p < 0.001). Each lymphocyte fraction does not show any association with complications and increased risk for infection. However, the decreased number of NK cells at 30 days after HSCT represented association with an increased risk of GVHD (n=21) (GVHD group vs. non-GVHD group: 206.4±195.2 vs. 310.1 ± 182.5, p = 0.033). When the NK cell level was divided as median value (219/µL), the group of lower level has correlation decreased overall survival (p = 0.018). Moreover, decreased number of NK cells at 90 days after HSCT was also associated with an increased risk of GVHD (145.3±107.9 vs. 370.2±265.8, p = 0.043). Conclusion: These results suggest that measuring the early recovery of NK cells at 30 days and analyzing the trend of LST can be a useful predictor of clinical outcome including GVHD in allogeneic HSCT. Citation Format: Seo Yeon Kim, Hyewon Lee, Hyoeun Shim, Hyeon-Seok Eom, Sun-Young Kong. Post-transplantation NK cell is a useful predictor of graft-versus-host-disease in allogeneic hematopoietic stem cell transplantation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2536. doi:10.1158/1538-7445.AM2014-2536

Impact of anti-HLA antibodies on allogeneic hematopoietic stem cell transplantation outcomes after reduced-intensity conditioning regimens

Objective To explore the clinical significance of the relationship between the immune function and the pathogenesis of aplastic anemia in children with aplastic anemia(AA), along with the incidence of graft versus host disease (GVHD) by monitoring the changes of T lymphocyte subsets dynamically in + 1, + 3, + 6, + 12 months for blood disease patients after allogeneic hematopoietic stem cell transplantation. Methods Twelve AA patients received allogeneic hematopoietic stem cell transplantation in Department of Hematology, the Affiliated General Hospital of Beijing Military Region of Anhui Medical University, from January 2013 to January 2014, including 4 male and 8 female, with average age of 7.92 years old(3-14 years old) with 5 cases of human leukocyte antigen(HLA) matched and 7 cases of HLA mismatched.The level of T lymphocyte subsets including CD3+ , CD4+ , CD8+ , CD4+ /CD8+ , CD56+, CD4+ CD25high+ FOXP3+ were monitored with flow cytometry before transplantation and in + 1, + 3, + 6, + 12 months after transplantation dynamically in the peripheral blood.While in the same period the level of T lymphocyte subsets was monitored in 12 cases of healthy children at the same period as the healthy control group. Results Followed up to March 2015, 10 cases had abnormal cellular immunity (CD4+ /CD8+ ratio inversion) in the 12 AA patients.Compared with the control group, in the AA group, CD3+ was slightly higher, (66.79±7.35)% and (62.74±5.58)% respectively(P=0.043), CD4+ was decreased by (33.73±7.26)% and (39.54±3.46)% respectively(P=0.037), CD8+ was increased by (35.69±6.78)% and (25.34±4.36)%, respectively (P=0.000), CD4+ /CD8+ decreased by 1.23±0.56 and 1.78±0.34 respectively(P=0.001) and CD56+ was decreased by (7.46±2.80)% and (16.73±3.70)% respectively(P=0.000), CD4+ CD25high+ FOXP3+ was decreased by (3.3±1.5)% and (8.1±1.3)% respectively (P=0.003), whose difference was statistically significant (P<0.05). The lever of CD3+ , CD4+ , CD8+ , CD4+ /CD8+ , CD56+, CD4+ CD25high+ FOXP3+ had a different degree of recovery after transplantation for all cases and returned to normal in + 12 months basically. In + 1, + 3, + 6, + 12 months after transplantation, the levels of CD4+ CD25high+ FOXP3+ in GVHD positive group and negative group were (0.4±0.6)% and (1.6±0.7)% respectively, (0.7±0.3)% and (2.7±0.4)% respectively, (1.1±0.5)% and (2.9±0.7)% respectively, (1.4±0.3)% and (3.6±0.2)% respectively, which had statistical significance (P<0.05). Conclusions There was abnormal cell immune function in some cases with AA.After transplantation, the level of CD4+ CD25high+ FOXP3+ is closely related to the acute GVHD, which can be used to predict the occurrence of GVHD. Key words: Aplastic anemia; Allogeneic hematopoietic stem cell transplantation; Cellular immune function; T lymphocyte subsets; Graft versus host disease

Vitamin D deficiency, autoimmunity, and graft-versus-host-disease risk: Implication for preventive therapy

Predictive factors for outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Société Française de Greffe de Moelle et de Thérapie Cellulaire

Cellular Immunotherapies for Leukemia Patients

Hematopoietic stem cell transplantation (HSCT) serves as a therapeutic intervention for various pediatric diseases. Acute and chronic graft-versus-host disease (GVHD) are decisive determinants of successful allogeneic HSCT. The immunosuppressive agent cyclosporin A (CsA) is most often used to prevent GVHD in pediatric patients, but it is known to be nephrotoxic. Acute kidney injury (AKI) affects 17% to 47% of pediatric HSCT recipients, compromising clinical outcomes. This retrospective single-institution analysis scrutinized the practice of substituting nephrotoxic CsA with an everolimus/mycophenolate mofetil (MMF) combination as GVHD prophylaxis in 57 patients with AKI (n = 53) or central nervous system side effects due to calcineurin inhibitor (CNI) treatment (n = 4) following first allogeneic HSCT. This retrospective cohort study analyzed the clinical courses of 57 children who were switched from CNI-based GVHD prophylaxis (CsA or tacrolimus in single cases) to the everolimus/MMF combination (n = 48) or everolimus alone (n = 9) after undergoing their first allogeneic HSCT at the Charité University Medicine Berlin. Serving as a control group were 74 patients undergoing their first allogeneic HSCT during the same period who did not receive everolimus at any time post-transplantation. Patients undergoing mismatched family donor transplantation without subsequent CNI treatment for GVHD prophylaxis were excluded. Study endpoints encompassed the retention parameter course subsequent to the GVHD prophylaxis switch, overall survival (OS), and incidences of underlying disease relapse and acute and chronic GVHD in both treatment groups. Renal function improved significantly after switching from CsA to the everolimus/MMF combination. Crucially, the transition to everolimus did not adversely affect OS following HSCT (hazard ratio [HR], 1.6; 95% confidence interval [CI], 0.74 to 3.5; P = .23), especially for patients with nonmalignant diseases (HR, 1.4; 95% CI, 0.34 to 5.9; P = .64). The incidences of grade III-IV acute GVHD (HR, 1.82; 95% CI, 0.45 to 7.4; P = .40) and severe chronic GVHD (HR, 2.76; 95% CI, 0.69 to 11.0; P = .15) were comparable in patients treated with the everolimus/MMF combination and those receiving standard CsA treatment in the control group. OS in patients with malignant underlying diseases was lower in the everolimus group (HR, 2.7; 95% CI, 1.1 to 6.9; P = .03), however, event-free survival was similar in patients with an underlying malignant disease treated with either the everolimus/MMF combination or CsA (HR, 0.87; 95% CI, 0.39 to 1.9; P = .73). Renal function improved significantly in patients who switched their immunosuppression regimen from CsA to everolimus with or without MMF cotreatment after diagnosis of AKI. Patient outcomes in the everolimus group were comparable to those in the control group. This study provides compelling real-world clinical evidence to support replacing CsA with the everolimus/MMF combination in the management of AKI following HSCT in children.

First Successful Allogeneic Hematopoietic Stem Cell Transplantation in Children with Chronic Myeloid Leukemia, Preceded by Imatinib Prior Transplantation.

Homeostatic Reconstitution of CD4+ Regulatory and Conventional T Cell Subsets in Adult Patients after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Diverse T Cell Responses Lead To The Different Manifestations Of Cutaneous Graft-Versus-Host Disease

Acute promyelocytic leukemia is a rare indication for hematopoietic stem cell transplantation. Usually it is indicated as consolidation of salvage regimens following relpase. Here we report our experience with stem cell transplantation in acute promyelocytic leukemia patients. Between 1989 and 2011, we performed 40 hematopoietic stem cell transplantation in first complete remission or relapsed acute promyelocytic leukemia patients. Median age of patients was 23.5 years. Patients received 11 autologous and 29 allogeneic hematopoietic stem cell transplantation from their HLA fully-matched sibling donors. Different conditioning regimens were applied. A total of 24 patients received hematopoietic stem cell transplantation who were in first complete remission and the remainder with a second or more complete remission. Hematopoietic stem cell engraftment was observed in all cases. There were no deaths prior to 100 days after hematopoietic stem cell transplantation. Acute graft versus host disease was mild to moderate in the majority of patients, whereas it was grade III in 4 patients. Chronic graft versus host disease was extensive in 2 cases. With a 4-year median follow up, the relapse rate was 25%. A total of 26 patients are alive. Five year overall survival was 65.5% and 46.8% for allogeneic and autologous hematopoietic stem cell transplantation, respectively. Hematopoietic stem cell transplantation is an acceptable treatment for acute promyelocytic leukemia. Although there is a statistical difference for overall survival between allogeneic or autologous hematopoietic stem cell transplantation, the choice between autologous or allogeneic transplantation needs to have reliable methods for the detection of molecular remission before hematopoietic stem cell transplantation as well as close, reliable follow up of patients with clinical and molecular parameters.

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

Translational Research Efforts in Biomarkers and Biology of Early Transplant-Related Complications