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

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2071-2071 ◽  
Author(s):  
David Jared Kobulnicky ◽  
Roy T Sabo ◽  
Allison F Scalora ◽  
David Portier ◽  
Devon Fletcher ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Unrelated Donor ◽  
Cell Recovery ◽  
Ebv Reactivation ◽  
Stem Cell Source ◽  
Cell Source

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

Related Vs Unrelated Donors After Auto-Allo Tandem Stem Cell Transplantation for Newly Diagnosed Patients with Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1201-1201
Author(s):  
Nicolaus Kröger ◽  
Tatjana Zabelina ◽  
Marion Heinzelmann ◽  
Georgia Schilling ◽  
Christine Wolschke ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Unrelated Donor ◽  
Newly Diagnosed ◽  
Stem Cell Source ◽  
Cell Source ◽  
Unrelated Donors

Abstract Abstract 1201 Poster Board I-223 Introduction: Autologous stem cell transplantation followed by a dose-reduced conditioning and allogeneic stem cell transplantation from HLA-identical siblings has become a treatment option for patients with multiple myeloma. However, only a minority of the patients with multiple myeloma has an HLA-identical sibling and the experience using unrelated donor in this setting is limited. Patients and Methods: From 1997 to 2007, 73 patients (male:45; female:28) with multiple myeloma stage II/III and a median age of 49 years (r, 29-64) were included in a prospective trial to determine the efficacy of a tandem auto-allogeneic stem cell transplantation SCT) from HLA-identical sibling (n=24) or unrelated donors (n=45). Unrelated donor were either fully HLA matched (n=29) or had one mismatch (n=16).Deletion 13q14 could be analyses in 64 pts was found to be positive in 66% of the pts. Del13q14 was more present in patient with unrelated (n=42) than with related (n=22) donors. Stem cell source was PBSC (n=69) or bone marrow (n=4). Induction-chemotherapy consisted of a median of 4 cycles anthracycline-based therapy in 60 pts, or of thalidomide- (n=3) or bortezomib- (n=8) based regimen. 6 pts did not respond to induction therapy and received salvage chemotherapy before autologous SCT. Conditioning prior auto SCT consisted of melphalan 200mg/m2. After a median of 110 days (range 39-228) patients received a reduced intensity regimen with melphalan (140 mg/m2)/fludarabine regimen followed by allogeneic SCT from related (n=24) or unrelated (n=45) donors. GvHD prophylaxis consisted of anti-lymphocyte globulin (ATG-Fresenius®), cyclopsorin A and short course of MTX. Results: No primary or secondary graft failure was observed and leukocyte engraftment was achieved after a median of 15 days (range, 9-27), respectively. Acute graft-versus-host disease (GvHD) grade II to IV occurred in 38% and chronic GvHD in 22% of the patients. Limited GvHD was seen in 16 % and extensive GvHD was seen in 6 % of the patients. There was no difference regarding incidence of GvHD between HLA-identical sibling and unrelated donors. Overall response rate at day 100 was 94% including 55% complete remission (CR) and did not differ between related and unrelated SCT. Cumulative incidence (CI) of non-relapse mortality at one year was 20% (95% CI:11-29%) and did not differ between MUD and MRD (21 vs 17%, p 0.35). The cumulative incidence of relapse at 3 and 5 years was 30% (95% CI:19-41%) and 42% (95% CI: 29-55%), respectively with no difference between related and unrelated SCT at 5 years: 36 vs 44%(p= 0.6). The only significant factor for higher relapse incidence at 5 years was the presence of del13q14 (60 vs 20%, p= 0.007). After a median follow up of 40 months (r., 26-100), the estimated 5-year progression-free (PFS) and overall survival (OS) rates were 31% (95%CI: 19-43%) and 54% (95% CI: 42-64%), respectively, with no difference between related and unrelated SCT. Due to the higher relapse incidence only presence of del13q resulted in a significant worse 5- year OS and DFS (45 vs 77%, p=0.02 and 18 vs 57%, p=0.04). Conclusions: Unrelated donors as stem cell source for auto-allogeneic tandem stem cell transplantation for newly diagnosed myeloma patients resulted in similar NRM, relapse-incidence, DFS and OS than HLA-identical sibling transplantation and can therefore be used as alternative stem cell source. Outcome after transplantation is better for patients lacking del 13q14. Disclosures: No relevant conflicts of interest to declare.

Donor Stem Cell Source Does Not Impact Outcome of High Risk (HR) Acute Myeloblastic Leukaemia (AML) Patients After Reduced Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation (RIC-ALLO).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4339-4339
Author(s):  
Sabine Furst ◽  
Luca Castagna ◽  
Thomas Prébet ◽  
Claude Lemarie ◽  
Jean El Cheikh ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Unrelated Donor ◽  
Special Focus ◽  
Hematopoietic Stem ◽  
Stem Cell Source ◽  
Significant Difference ◽  
Cell Source ◽  
Donor Type

Abstract Abstract 4339 Allogeneic Stem Cell Transplantation (ASCT) offers a potential curative treatment approach of HR AML patients (pts). Over years, the use of umbilical cord blood (UCB) has become an attractive alternative stem cell source for those pts lacking a suitable HLA matched related or unrelated donor. The aim of this analysis was to assess the outcome of 50 pts who received a RIC-ALLO in our centre between 2005 and 2008 with a special focus on three different donor sources: identical sibling, unrelated donor or UCB. All pts had HR AML in complete remission (CR) at time of transplant. HR features were defined as at least one of the following criteria: CR1 with unfavourable cytogenetics, secondary AML, more than one induction chemotherapy for obtaining CR or CR2 and above. Reasons for RIC regimen were older age, unfit physical condition, comorbidities or prior autologous transplant. All pts received a Fludarabine-based RIC regimen with GVHD prophylaxis consisting in CSA alone or CSA and MMF. The median age of all pts was 51 (range, 19-70) years. 28 pts had identical sibling donors, 7 pts had a matched 10/10 (5 pt) or mismatched 9/10 (2 pt) unrelated donors and 15 pt received a single or double UCBT. Pts characteristics were comparable between the three groups but for pt age [identical sibling group: 52 (range, 35-70) years; unrelated donor group: 61 (range, 50-66) years; UCB group: 44 (range, 19-61) years]. After a median follow-up of 886 (range, 336-1528) days, 20 pts have died (disease=6, treatment related=14) and 8 pts have experienced relapse. Four year OS and EFS for all pts were 57% and 54%, respectively with no significant difference between the 3 groups (2 year OS: 61%, 54% and 66%; 2 year EFS: 59%, 54% and 45% respectively). One year TRM was 20% for the entire group and did not significantly differ between the 3 groups. Despite the obvious limitations of this small series, results seem to indicate that in this population, donor type does not highly influence outcome. This is quite encouraging as most of the pts lack a compatible sibling donor. This may invite to consider privileging a rapid identification of an alternative donor rather than a given donor type when a match sibling is not available. Thus concomitant search for both graft type should be undertaken in order to perform allo SCT in a larger number of pts otherwise not treated because of early progression as illustrated in the underrepresentation of alternative transplant as compared with familial transplant in this retrospective study (28 familial vs 22 alternative). Disclosures: No relevant conflicts of interest to declare.

scholarly journals Improving Cytomegalovirus-Specific T Cell Reconstitution after Haploidentical Stem Cell Transplantation

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Xiao-Hua Luo ◽  
Ying-Jun Chang ◽  
Xiao-Jun Huang
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cmv Infection ◽  
Graft Versus Host ◽  
Stem Cell Source ◽  
Haploidentical Stem Cell Transplantation ◽  
Donor T Cells ◽  
Conditioning Regimens

Cytomegalovirus (CMV) infection and delayed immune reconstitution (IR) remain serious obstacles for successful haploidentical stem cell transplantation (haplo-SCT). CMV-specific IR varied according to whether patients received manipulated/unmanipulated grafts or myeloablative/reduced intensity conditioning. CMV infection commonly occurs following impaired IR of T cell and its subsets. Here, we discuss the factors that influence IR based on currently available evidence. Adoptive transfer of donor T cells to improve CMV-specific IR is discussed. One should choose grafts from CMV-positive donors for transplant into CMV-positive recipients (D+/R+) because this will result in better IR than would grafts from CMV-negative donors (D−/R+). Stem cell source and donor age are other important factors. Posttransplant complications, including graft-versus-host disease and CMV infection, as well as their associated treatments, should also be considered. The effects of varying degrees of HLA disparity and conditioning regimens are more controversial. As many of these factors and strategies are considered in the setting of haplo-SCT, it is anticipated that haplo-SCT will continue to advance, further expanding our understanding of IR and CMV infection.

scholarly journals Association between preconditioning absolute lymphocyte count and transplant outcomes in patients undergoing matched unrelated donor allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning and anti-thymocyte globulin

2021 ◽  
Vol 12 ◽  
pp. 204062072110637
Author(s):  
Jeongmin Seo ◽  
Dong-Yeop Shin ◽  
Youngil Koh ◽  
Inho Kim ◽  
Sung-Soo Yoon ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
Reduced Intensity Conditioning ◽  
Matched Unrelated Donor ◽  
T Cell Depletion ◽  
Reduced Intensity

Background: Allogeneic stem cell transplantation (alloSCT) offers cure chance for various hematologic malignancies, but graft- versus-host disease (GVHD) remains a major impediment. Anti-thymocyte globulin (ATG) is used for prophylactic T-cell depletion and GVHD prevention, but there are no clear guidelines for the optimal dosing of ATG. It is suspected that for patients with low absolute lymphocyte counts (ALCs), current weight-based dosing of ATG can be excessive, which can result in profound T-cell depletion and poor transplant outcome. Methods: The objective of the study is to evaluate the association of low preconditioning ALC with outcomes in patients undergoing matched unrelated donor (MUD) alloSCT with reduced-intensity conditioning (RIC) and ATG. We conducted a single-center retrospective longitudinal cohort study of acute leukemia and myelodysplastic syndrome patients over 18 years old undergoing alloSCT. In total, 64 patients were included and dichotomized into lower ALC and higher ALC groups with the cutoff of 500/μl on D-7. Results: Patients with preconditioning ALC <500/μl were associated with shorter overall survival (OS) and higher infectious mortality. The incidence of acute GVHD and moderate-severe chronic GVHD as well as relapse rates did not differ according to preconditioning ALC. In multivariate analyses, low preconditioning ALC was recognized as an independent adverse prognostic factor for OS. Conclusion: Patients with lower ALC are exposed to excessive dose of ATG, leading to profound T-cell depletion that results in higher infectious mortality and shorter OS. Our results call for the implementation of more creative dosing regimens for patients with low preconditioning ALC.

New Developments in Allotransplant Immunology

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 350-371 ◽  
Author(s):  
A. John Barrett ◽  
Katayoun Rezvani ◽  
Scott Solomon ◽  
Anne M. Dickinson ◽  
Xiao N. Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Cytokine Gene ◽  
Post Transplant ◽  
Cytokine Milieu ◽  
Cytokine Gene Polymorphisms

Abstract After allogeneic stem cell transplantation, the establishment of the donor’s immune system in an antigenically distinct recipient confers a therapeutic graft-versus-malignancy effect, but also causes graft-versus-host disease (GVHD) and protracted immune dysfunction. In the last decade, a molecular-level description of alloimmune interactions and the process of immune recovery leading to tolerance has emerged. Here, new developments in understanding alloresponses, genetic factors that modify them, and strategies to control immune reconstitution are described. In Section I, Dr. John Barrett and colleagues describe the cellular and molecular basis of the alloresponse and the mechanisms underlying the three major outcomes of engraftment, GVHD and the graft-versus-leukemia (GVL) effect. Increasing knowledge of leukemia-restricted antigens suggests ways to separate GVHD and GVL. Recent findings highlight a central role of hematopoietic-derived antigen-presenting cells in the initiation of GVHD and distinct properties of natural killer (NK) cell alloreactivity in engraftment and GVL that are of therapeutic importance. Finally, a detailed map of cellular immune recovery post-transplant is emerging which highlights the importance of post-thymic lymphocytes in determining outcome in the critical first few months following stem cell transplantation. Factors that modify immune reconstitution include immunosuppression, GVHD, the cytokine milieu and poorly-defined homeostatic mechanisms which encourage irregular T cell expansions driven by immunodominant T cell–antigen interactions. In Section II, Prof. Anne Dickinson and colleagues describe genetic polymorphisms outside the human leukocyte antigen (HLA) system that determine the nature of immune reconstitution after allogeneic stem cell transplantation (SCT) and thereby affect transplant outcomethrough GVHD, GVL, and transplant-related mortality. Polymorphisms in cytokine gene promotors and other less characterized genes affect the cytokine milieu of the recipient and the immune reactivity of the donor. Some cytokine gene polymorphisms are significantly associated with transplant outcome. Other non-HLA genes strongly affecting alloresponses code for minor histocompatibility antigens (mHA). Differences between donor and recipient mHA cause GVHD or GVL reactions or graft rejection. Both cytokine gene polymorphisms (CGP) and mHA differences resulting on donor-recipient incompatibilities can be jointly assessed in the skin explant assay as a functional way to select the most suitable donor or the best transplant approach for the recipient. In Section III, Dr. Nelson Chao describes non-pharmaceutical techniques to control immune reconstitution post-transplant. T cells stimulated by host alloantigens can be distinguished from resting T cells by the expression of a variety of activation markers (IL-2 receptor, FAS, CD69, CD71) and by an increased photosensitivity to rhodamine dyes. These differences form the basis for eliminating GVHD-reactive T cells in vitro while conserving GVL and anti-viral immunity. Other attempts to control immune reactions post-transplant include the insertion of suicide genes into the transplanted T cells for effective termination of GVHD reactions, the removal of CD62 ligand expressing cells, and the modulation of T cell reactivity by favoring Th2, Tc2 lymphocyte subset expansion. These technologies could eliminate GVHD while preserving T cell responses to leukemia and reactivating viruses.

scholarly journals Haploidentical Hematopoietic Stem-Cell Transplantation in Adults

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Salem Alshemmari ◽  
Reem Ameen ◽  
Javid Gaziev
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Hematopoietic Stem

Haploidentical hematopoietic stem-cell transplantation is an alternative transplant strategy for patients without an HLA-matched donor. Still, only half of patients who might benefit from transplantation are able to find an HLA-matched related or unrelated donor. Haploidentical donor is readily available for many patients in need of immediate stem-cell transplantation. Historical experience with haploidentical stem-cell transplantation has been characterised by a high rejection rate, graft-versus-host disease, and transplant-related mortality. Important advances have been made in this field during the last 20 years. Many drawbacks of haploidentical transplants such as graft failure and significant GVHD have been overcome due to the development of new extensive T cell depletion methods with mega dose stem-cell administration. However, prolonged immune deficiency and an increased relapse rate remain unresolved problems of T cell depletion. New approaches such as partial ex vivo or in vivo alloreactive T cell depletion and posttransplant cell therapy will allow to improve immune reconstitution in haploidentical transplants. Results of unmanipulated stem-cell transplantation with using ATG and combined immunosuppression in mismatched/haploidentical transplant setting are promising. This paper focuses on recent advances in haploidentical hematopoietic stem-cell transplantation for hematologic malignancies.

Sign in / Sign up

Export Citation Format

Share Document