Adequate Immune Reconstitution in Recipients of Unrelated Donor Hematopoietic Cell Transplants Given Rabbit Anti-Thymocyte Globulin During Conditioning.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2234-2234
Author(s):  
Devon Fletcher ◽  
John M. McCarty ◽  
Harold M Chung ◽  
Kathryn Candler ◽  
Catherine H Roberts ◽  
...  
Keyword(s):  
Immune Reconstitution ◽  
Hematopoietic Cell ◽  
First Year ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Cell Counts ◽  
Number Of Patients ◽  
Cellular Immune ◽  
Cmv Reactivation

Abstract Abstract 2234 Poster Board II-211 Anti-thymocyte globulin (ATG) is known to reduce the risk of developing acute graft vs host disease following allogeneic hematopoietic cell transplant (HCT). Its effects on long-term immune reconstitution are less well defined, particularly in the adult population undergoing unrelated donor (URD) HCT. Since 2004, rabbit ATG (Thymoglobulin, Genzyme Inc, Cambridge, MA) has been used at our institution during the conditioning of patients undergoing URD HCT. We performed a retrospective landmark analysis to compare immune reconstitution in patients who received ATG during conditioning vs. those who did not. Patients had to have completed at least 6 months of follow-up post transplant. Eighty six patients were eligible, and underwent analysis of immune reconstitution in the first year post transplant. Fifty six patients underwent matched related donor HCT and did not receive ATG (no ATG cohort); 30 patients received an URD HCT (ATG cohort). The median age for no ATG cohort was 49 years and for the ATG cohort was 48. There were 40 females in the combined cohorts. The no ATG cohort included patients with the diagnosis of AML (34%), NHL (21%), MM (16%), ALL (9%), along with CML, CLL, MDS, MF and HD (20%). The ATG cohort was comprised of AML (43%), MDS (23%), ALL (13%), CML (13%), along with NHL & SAA (8%). Conditioning regimens used in the no ATG vs. ATG cohorts were 12-Gy TBI-Cy in 18% vs. 47%, Bu-Cy in 42% vs. 40%, and others in 40% vs. 13% (Flu-Mel, Bu-Flu, Flu-Cy, 2-Gy TBI,TBI-VP16). Stem cells were GCSF mobilized PBSC in 95% of the no ATG cohort and in 44% of the ATG cohort. The ATG dose administered was either 7.5 or 10 mg/kg in 3 divided doses, given from day -3 to day -1. With a median follow up of 727 days in the no ATG cohort and 480 days in the ATG cohort, 82% of the patients survived in the no ATG cohort compared to 73% in the ATG cohort (Fisher's exact test P=0.41). Absolute lymphocyte counts at 6, 9 and 12 months following transplantation were (mean ± SD) 1.2 ± 0.6×10 3 /μL vs. 1.0 ± 0.8 (T-Test, P=0.44), 1.5 ± 0.9 vs. 1.3 ± 1.0 (P=0.51) and 1.6 ± 0.9 vs. 1.3 ± 0.9 (P=0.23) respectively in the no ATG cohort vs. ATG cohort. Lymphocyte subset enumeration data was obtained during the first year following HCT at the time of cessation of immunosuppression and was available for 32 and 12 patients in the no ATG and ATG cohorts respectively. Absolute CD3+ cell counts measured at a median of 278 days were 1226 ± 773 vs. 981 ± 442 /μL in the no ATG vs. ATG cohorts (P=0.52). Simultaneously measured absolute CD3+/4+ cell counts were 483 ± 231 vs. 242 ± 122 (P=0.001), CD3+/8+ were 717 ± 627 vs. 701 ± 444 (P=0.94), CD19+ were 250 ± 239 vs. 351 ± 233 (P=0.25) and CD56+ were 181 ± 97 vs. 178 ± 67 (P=0.75) in the no ATG vs. ATG cohorts. Surveillance for EBV and CMV reactivation was performed using PCR. No statistically significant difference was noted in rate of CMV reactivation between the two cohorts in the 6-12 month post-transplant period indicating equivalent functional cellular immune reconstitution. EBV reactivation did not occur in either cohort. During the same time period the incidence of culture proven fungal infections and viral infections was equivalent between the two groups, however there was a significantly higher number of patients who experienced bacterial infection episodes in the ATG group. We are investigating the impact of ATG administration on the relative rate of relapse in these two cohorts. We conclude that ATG administered during conditioning did not adversely impact cellular immune reconstitution in this cohort of patients, even though these high-risk patients had undergone URD HCT with bone marrow as the stem cell source in the majority. This effect may be explained by a reduction in the incidence of acute GVHD secondary to ATG use, which in turn reduces the overall immunosuppressive exposure these patients experience following transplantation. T helper cell reconstitution appears to be delayed and may contribute to the higher number of patients experiencing bacterial infections in the ATG cohort. Disclosures: Off Label Use: Thymoglobulin for GVHD prophylaxis. McCarty:Celgene: Honoraria; Genzyme: Honoraria.

Sequential Therapy with Allogeneic Transplant Followed by Low-Dose Azacitidine for CML Patients That Failed Multiple Tyrosine Kinase Inhibitors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3106-3106
Author(s):  
Marcos De Lima ◽  
Sairah Ahmed ◽  
Elizabeth J Shpall ◽  
Gabriela Rondon ◽  
Julienne Chen ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Low Dose ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Sequential Therapy ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Number Of Patients ◽  
Preparative Regimen

Abstract Abstract 3106 Background Allogeneic stem cell transplantation (SCT) is potentially curative for patients with CML who fail tyrosine kinase inhibitor (TKIs) treatment but remain in chronic phase (CP). In addition, TKI may ‘downstage’ advanced disease, creating a window of opportunity for SCT in second CP (CP2). Sequential therapy, as proposed by Champlin et al (ASH 2009), using a reduced intensity preparative regimen, followed by low dose donor lymphocyte infusion (DLI) is well tolerated and associated with prolonged disease control, especially for patients in CP1. There is preclinical and clinical evidence that hypomethylating agents have immunomodulatory effects when given after SCT (de Lima, Cancer 2010). We then hypothesized that low dose 5-azacitidine (AZA) given early after SCT will induce a more rapid and durable molecular complete remission (molCR). Patients and Methods Objective: To increase the frequency of achievement of molCR following reduced intenstity allogeneic SCT. Eligibility: CML in CP who had failed to respond to treatment with one or more TKI. Patients received a preparative regimen of fludarabine 40 mg/m2 × 4 days, busulfan 130 mg/m2 × 2 days, and thymoglobulin 2.5 mg/kg daily × 3 days followed by allogeneic SCT from an HLA matched related or unrelated donor. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and mini-methotrexate (5 mg/m2 on SCT days 1, 3 and 6 and 11). Those not in molCR 30 days after SCT receive AZA 32 mg/m2 every 28 days for four cycles starting on day +35. Patients were required to have engraftment and initial hematologic recovery, stable organ function and no active GVHD to start AZA treatment. Patients were treated between 2/09 - 9/10, and those with at least 6 months of follow-up are presented here. Results 15 patients were entered on study. Eight patients received AZA for a median of 4 cycles. Seven patients did not receive AZA: two were in molCR post transplant, 2 had hematologically progressive disease, 2 were cytopenic, which precluded AZA and 1 patient declined. AZA was administered outpatient with minimal, reversible toxicity: grade I/II/III thrombocytopenia (37.5%), grade I nausea (25%) and grade I fatigue (25%). Grade II-IV acute GVHD occurred in 10 pts. Four AZA patients subsquently received DLI (1 × 107 CD3 cells/Kg) and 75% (3 of 4) converted to MolCR and cytogenetic CR. 7 of the 8 patients that received AZA achieved a MolCR with median follow-up of 12.6 months (range, 3.4–24), compared with MolCR of 57% for those that didn't receive AZA. (Figure 1: cumulative incidence of MolCR) (Table 1). Thirteen patients are alive with a median of 25 months of follow-up (Figure 2) and two died of CML. One patient with overt relapse of chronic phase CML received a second transplant and is alive in MolCR. Conclusion Azacitidine is well tolerated post nonmyeloablative SCT and may contribute to achieveent of molCR. Larger number of patients and longer follow-up are necessary to define the efficacy of this intervention. Disclosures: De Lima: Celgene: Research Funding. Off Label Use: azacitidine used post transplant.

CMV reactivation in allogeneic hematopoietic stem cell transplant patients receiving post-transplant cyclophosphamide.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18533-e18533
Author(s):  
Paul Markowski ◽  
Dale G. Schaar ◽  
Catherine Wei ◽  
Anne Tyno
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Published Data ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Transplant Patients ◽  
Number Of Patients ◽  
Cmv Reactivation

e18533 Background: Post transplant cyclophosphamide (PTCY) has been shown to be an effective treatment for prevention of graft versus host disease (GVHD). However, this increased immune suppression rates may increase the risk of CMV reactivation. There is limited published data addressing CMV reactivation in this patient population. Additionally there is no data on the efficacy of prophylactic letermovir in the patients who have received PTCY. In this study we analyzed the incidence of CMV reactivation in patients treated with PTCY and those not treated with PTCY, as well as the efficacy of letermovir in preventing CMV reactivation in the PTCY population. Methods: We conducted a retrospective review of MUD, MRD, and haploidentical stem cell transplant patients at our institution from 1/1/2014 until 12/10/2018. We analyzed the incidence of CMV reactivation (PCR > 137 DNA IU/ml), peak of CMV PCR titer and time to reactivation within the first 100 days post-transplant. Results: There were 150 patients with at least 60 days of follow-up that were included in this study. These patients were split into three groups: No post-transplant cyclophosphamide (NPTCY) (N = 64), received post-transplant cyclophosphamide (PTCY) (N = 70), and received PTCY and letermovir prophylaxis. (L-PTCY) (N = 15). The incidence of CMV reactivation was increased in the PTCY patients when compared to the NPTCY (44% vs 29%). In the NPTCY patients the donor (D) serostatus increased the risk of CMV reactivation (Recipient (R)+ D+ 73% vs R+D-36%) conversely in the PTCY group the donor CMV status did not influence reactivation rates (R+D+ 52% vs R+D- 81%). The CMV reactivation rate in the L-PTCY patients was lower when compared to the PTCY patients (21% vs 44%), additionally the L-PTCY patients had much lower peak CMV titers compared to PTCY group (445 vs 2112 IU/ml). Conclusions: This study demonstrates that there is an increased incidence of CMV reactivation in patients who receive PTCY. Additionally, the donor CMV serostatus does not appear to influence the incidence of CMV reactivation in patients receiving post-transplant CY. Although the number of patients in the L-PTCY group is small, it does appear to be an effective prophylactic treatment in patients receiving PTCY.

Kinetics of Immune Reconstitution in Event-Free Patients: Establishing Reference Values for Immune Recovery of Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5772-5772
Author(s):  
Xu-Ying Pei ◽  
Yu Wang ◽  
Lan-Ping Xu ◽  
Xiao-Hui Zhang ◽  
Xiang-Yu Zhao ◽  
...  
Keyword(s):  
Reference Values ◽  
Immune Reconstitution ◽  
Immune Cell ◽  
First Year ◽  
Immune Recovery ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Cell Counts ◽  
Healthy Donors ◽  
Immune Cell Subsets

Abstract Background: Immune reconstitution (IR) is strongly associated with clinical outcomes after hematopoietic stem cell transplantation (HSCT). So far, there are no optimal reference values for recovered immune cell subsets after HSCT, and approaches to enhance post-transplant IR based on data from health donors have their limitations. Therefore, reference values need to be established for immune cell counts to monitor IR and identify high-risk patients needing aggressively supportive treatment. Methods: Between January 2011 and December 2013, 706 consecutive patients who received HLA-matched sibling transplantation (MSDT) or haploidentical transplantation (haplo-SCT) modality participated in this study. Finally a total of 144 patients who did not experience transplant complications such as poor graft function, grades II-IV acute graft-versus-host disease (GVHD), serious chronic GVHD, serious bacterial infection, invasive fungal infection, relapse or death in the first year after transplant were available for immune cell subset testing between day 30 and 365, and were analyzed in this study. To provide reference values that could be used for all recipients, the effects of recipient age, gender, and underlying disease on IR were investigated. In addition, 41 healthy donors underwent single time-point immune analysis, and the data were used as a normal control. Results: The 4-year probability of relapse, non-relapse mortality, leukemia-free survival, and overall survival was 5% (95% CI: 1%-9%), 1% (95% CI: 0%-2%), 95% (95% CI: 90%-99%), and 98% (95% CI: 96%-100%), respectively. Monocytes recovered rapidly and persisted at higher levels than normal during the first year after transplantation. The total CD3+ T cell counts were very low in the first 30 days but normalized by 90 days post-transplant. CD4+ helper T cells recovered very slowly and did not reach normal range by 1 year after transplantation. The absolute numbers of CD8+ T cells were higher after 90 days post-transplant compared to healthy donors. The recovery of CD19+ B cells was delayed during 1 year after transplantation. All immune cell subsets except monocytes recovered faster after MDST than haplo-SCT. By univariate and multivariate analysis, the haplo-SCT modality was confirmed to be associated with immune recovery. So the reference values for recovered immune cell subgroups were provided for MSDT and haplo-SCT, respectively. Conclusion: Our results suggest that patients with IR comparable to the reference values could have superior survival and the immune cells may not have to recover to healthy donor levels in the first year after transplantation. We emphasize that data from this recipient cohort should be understood as reference values for immune cell counts post-transplant for patients receiving HSCT. Acknowledgments: This work was supported, in part, by the National High Technology Research and Development Program of China (Program 863; Grant No. 2013AA020401) and the National Natural Science Foundation of China (Grant No. 81470342). We thank the faculty members who collected samples and analyzed the flow cytometry data. Disclosures No relevant conflicts of interest to declare.

Ex-Vivo Expansion and Prophylactic Infusion of CMV pp65 Specific CTL Following Haemopoietic Stem Cell Transplantation (HSCT).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3244-3244
Author(s):  
David J. Gottlieb ◽  
Anna M. Hansen ◽  
Ken P. Micklethwaite ◽  
Aaron E. Foster ◽  
Cameron J. Turtle ◽  
...  
Keyword(s):  
Stem Cell ◽  
Late Onset ◽  
Ex Vivo ◽  
Simple Method ◽  
Post Transplant ◽  
Number Of Patients ◽  
Cmv Reactivation

Abstract CMV reactivation in patients after HSCT is common and life threatening. Current pharmaceutical prophylaxis involves significant side effects, namely myelosuppression and an increased incidence of late onset CMV reactivation. One attractive approach to the problem is rapid reconstitution of CMV immunity post-transplant using adoptively transferred cells derived from transplant donors. Previous reports have described infusions of CMV-specific CTL raised using a CMV lysate, an approach no longer considered acceptable in the current regulatory environment due to the potential transmission of infectious CMV virions or other infectious agents in immunocompromised hosts. An alternative approach using tetramer selection of CMV specific cells cannot be widely applied due to the high cost and limited availability of appropriate reagents. CTL generated by these methods have been effective when given at the time of CMV reactivation but there are no reports of the efficacy of CMV-specific CTL when given prophylactically in preventing CMV reactivation or disease. To address these issues, we have developed a simple method for generating donor-derived CMV-specific CTL and commenced a phase I clinical trial of prophylactic infusion following HSCT. CMV-specific CTL are generated in vitro using the immunogenic HLA-A2 restricted epitope of the CMV pp65 protein NLVPMVATV (NLV). CMV seropositive donor monocyte-derived dendritic cells (MoDC) are pulsed with NLV and used to stimulate donor PBMC. Two stimulations with MoDC at one week intervals are followed by cell expansion in IL-2. After a total of 21 days culture, a dose of 2 x 107/m2 is infused at least 28 days post HSCT. With starting frequencies of around 1% CMV specific NLV tetramer+ CTL expansion of between 400–8000 fold occurs over 3 weeks of culture. The resulting infusion is predominantly CD3+CD8+, the majority of which are CMV-specific. Cells secrete IFNγ in response to CMV antigen. To date, 4 CMV seropositive and 2 seronegative patients (5 nonmyeloablative, 1 Bu/Cy conditioning) have received CTL from day 28–83 post-HSCT. Patients have been followed up from 7–798 days post transplant. There have been no infusion related adverse effects. Two of six patients have demonstrated increases in CMV-specific cells in the peripheral circulation following CTL infusion but we have not observed consistent expansion of CMV-specific CTL in vivo using this form of prophylactic treatment in the absence of CMV viremia. One patient receiving CMV CTL reactivated CMV during follow up while on treatment with corticosteroids for GVHD. Two patients receiving CMV-specific CTL have developed grade 3 GVHD and one patient has experienced graft failure requiring a second stem cell infusion. The use of donor NLV-pulsed MoDC to stimulate donor PBMC is a simple method for generating CMV-specific CTL for post-transplant adoptive immunotherapy. CMV-specific CTL given prophylactically after transplant do not expand in vivo in the same manner as CMV-specific CTL given during CMV viremia. No adverse events related to infusion have been observed. A larger number of patients and longer follow up will be required to determine whether prophylactic infusions result in a clinically relevant reduction in the rate of CMV reactivation or infection.

scholarly journals Potent Interaction between CMV Reactivation and Gvhd: Immunologic Evidence for Blunting of CMV-Driven Immune Reconstitution in the Setting of Gvhd

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 50-50
Author(s):  
Yvonne Suessmuth ◽  
Kayla Betz ◽  
Alison Yu ◽  
Brandi Bratrude ◽  
Benjamin Watkins ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Immune Reconstitution ◽  
Hematopoietic Cell Transplantation ◽  
Effector Memory ◽  
Multiparameter Flow Cytometry ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Cell Immunity ◽  
Cmv Reactivation

Allogeneic hematopoietic cell transplantation (HCT) may be curative for patients with marrow and immune disorders, but graft-vs-host-disease (aGVHD) and infections cause significant morbidity and non-relapse mortality. We have conducted a multicenter, double blind, placebo-controlled phase II trial of costimulation blockade with abatacept (Aba) combined with standard GVHD prophylaxis with a calcineurin inhibitor and methotrexate (CNI + MTX) following HLA matched unrelated donor transplant (n=142). In order to assess the effects of Aba on immune reconstitution, and to assess whether this reconstitution is influenced during CMV reactivation, we longitudinally evaluated post-transplant whole blood samples with multiparameter flow cytometry using markers for CD3, CD4, CD8, CD197 and CD45RA to measure reconstitution of CD4 and CD8 T cell populations and their respective memory subsets over time. Results: We observe that post-transplant CMV reactivation induces a marked expansion of CD8 effector memory (EM) cells, which is similar in magnitude for Aba vs placebo patients. We found that development of moderate (gr 2-4) or severe (gr 3-4) GVHD was not associated with an increased frequency of CMV reactivation, but patients with moderate GVHD showed a blunted expansion of CD8 EM cells compared to those without GVHD, and CD8 EM expansion was essentially absent among CMV reactivating patients with severe aGVHD. Clinical correlates will be presented. Conclusions: Our results suggest that adding abatacept to CNI/MTX does not materially affect reconstitution of T cell immunity in the presence or absence of CMV reactivation, but aGVHD remains a major driver of compromised immune recovery after HCT. Disclosures Watkins: Bristol Myers Squibb: Research Funding. Qayed:Mesoblast: Consultancy; Novartis: Consultancy. Horan:Bristol Myers Squib: Honoraria, Research Funding. Kean:gilead: Research Funding; bluebird bio: Research Funding; fortyseven: Consultancy; magenta: Research Funding; regeneron: Research Funding; hifibio: Consultancy; kymab: Consultancy; Bristol Meyers Squibb: Research Funding; novartis: Consultancy. Langston:Kadmon Corporation: Research Funding; Bristol Myers Squib: Research Funding; Incyte: Research Funding; Chimerix: Research Funding; Takeda: Research Funding; Astellas Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding.

MO941CLINICAL OUTCOMES IN KIDNEY RE-TRANSPLANTATION

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Clara Pardinhas ◽  
Rita Leal ◽  
Francisco Caramelo ◽  
Teofilo Yan ◽  
Carolina Figueiredo ◽  
...  
Keyword(s):  
Acute Rejection ◽  
Kidney Transplant ◽  
Graft Survival ◽  
Graft Failure ◽  
Graft Function ◽  
Delayed Graft Function ◽  
First Year ◽  
Kidney Transplant Recipients ◽  
Post Transplant

Abstract Background and Aims As kidney transplants are growing in absolute numbers, so are patients with failed allografts and thus potential candidates for re-transplantation. Re-transplantation is challenging due to immunological barriers, surgical difficulties and clinical complexities but it has been proven that successful second transplantation improves life expectancy over dialysis. It is important to evaluate re-transplantation outcomes since 20% of patients on the waiting list are waiting for a second graft. Our aim was to compare major clinical outcomes such as acute rejection, graft and patient survival, between patients receiving a first or a second kidney transplant. Method We performed a retrospective study, that included 1552 patients submitted to a first (N=1443, 93%) or a second kidney transplant (N=109, 7%), between January 2008 and December 2018. Patients with more than 2 grafts or multi-organ transplant were excluded. Demographic, clinical and histocompatibility characteristics of both groups were registered from our unit database and compared. Delayed graft function was defined has the need of dialysis in the first week post-transplant. All acute rejection episodes were biopsy proven, according to Banff 2017 criteria. Follow-up time was defined at 1st June 2020 for functioning grafts or at graft failure (including death with a functioning graft). Results Recipients of a second graft were significantly younger (43 ±12 vs 50 ± 13 years old, p<0.001) and there were significantly fewer expanded-criteria donors in the second transplant group (31.5% vs 57.5%, p<0.001). The waiting time for a second graft was longer (63±50 vs 48±29 months, p=0.011). HLA mismatch was similar for both groups but PRA was significantly higher for second KT patients (21.6±25% versus 3±9%; p<0.001). All patients submitted to a second KT had thymoglobulin as induction therapy compared to 16% of the first KT group (p<0.001). We found no difference in primary dysfunction or delayed graft function between groups. Acute rejection was significantly more frequent in second kidney transplant recipients (19% vs 5%, p<0.001), being 10 acute cellular rejections, 7 were antibody mediated and 3 were borderline changes. For the majority of the patients (85%), acute rejection occurred in the first-year post-transplant. Death censored graft failure occurred in 236 (16.4%) patients with first kidney transplant and 25 (23%) patients with a second graft, p=0.08. Survival analysis showed similar graft survival for both groups (log-rank p=0.392). We found no difference in patients’ mortality at follow up for both groups. Conclusion Although second graft patients presented more episodes of biopsy proven acute rejection, especially at the first-year post-transplant, we found no differences in death censored graft survival or patients’ mortality for patients with a second kidney transplant. Second transplants should be offered to patients whenever feasible.

scholarly journals Early Immune Reconstitution after Haplo-Identical Hematopoietic Stem Cell Transplantation (HCT) with Post-Transplant Cyclophosphamide (PTCY) Does Not Improve Overall Survival Compared to Matched Unrelated Donor HCT Recipients Receiving Thymoglobulin Prophylaxis (ATG)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5676-5676
Author(s):  
Yasser Khaled ◽  
Joshua Boss ◽  
Poojitha Valasareddy ◽  
Arnel Pallera ◽  
Robert Johnson ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Overall Survival ◽  
T Cell ◽  
Graft Failure ◽  
Immune Reconstitution ◽  
T Cell Proliferation ◽  
First Year ◽  
Post Transplant ◽  
Allogeneic Hct ◽  
Primary Graft Failure

Recent retrospective studies demonstrated similar overall survival (OS) and relapse rate after allogeneic HCT using matched unrelated or haplo-identical donors. However, differences in graft versus host disease (GVHD) prevention protocols using ATG or PTCY may have influenced the results. In addition, there is little knowledge about immune reconstitution after PTCY compared to ATG. We examined the outcomes of 73 consecutive patients who received allogeneic HCT from 5/2015 to 4/2019 (39 Haplo, 34 MUD). Patient's Characteristics shown in table-1. The two groups matched except for donor age, CD34 dose infused and race. Conditioning regimens shown in table-1. MUD recipients received GVHD prophylaxis with Tacrolimus/ Mycophenolate (Tacro/MMF) in addition to ATG (24 Patients) or PTCY (10 Patients) while Haploidentical patient received Tacro/MMF with PTCY. A panel of immune reconstitution markers collected at day 100 post- transplant for CD3, CD4, CD8, Activated T cell ( HLA- DR3+ CD3+)and NK cells ( CD56+) was obtained for 29 MUD and 28 Haploidentical recipients. We observed pronounced proliferation and recovery in all T cell subsets in Haploidentical patients compared to MUD patients at day 100 as shown in Fig-1. This robust T cell recovery in Haploidentical transplant patients with PTCY was statistically significant for CD3, CD4 and CD8. When Immune reconstitution for Haploidentical patients compared to MUD patients who received PTCY, it maintained its robust effect on T cell proliferation (Fig-2) although it did not reach statistical significance. The overall survival at one-year with median duration of follow up of 22.6 months was 61.5% and 82.3% for Haploidentical and MUD recipients respectively; P=0.14. There were 15 deaths during the first year in the Haploidentical patients (3 = relapse, 5 = severe cytokine release syndrome (CRS), 1=Veno-occlusive disease, 3= infection, 2=GVHD and 1 = primary graft failure). In contrast there were only six deaths in MUD patients (2= relapse, 3= GVHD and 1= infection). There was no deaths in MUD PTCY patients in the first year. There was no primary graft failure in either arm, however secondary graft failure occurred in 2 Haploidentical and 1 MUD patients. Median time to engraftment was 18 days for Haploidentical (range, 12-57) and 11.6 days for MUD (range, 10-18). Acute GVHD grade 2-4 developed in 35% in MUD and 23% in Haploidentical patients. Conclusions: We found robust early immune recovery after Haploidentical HCT compared to MUD HCT. The degree of HLA mismatch with Haploidentical HCT and antigen presentation may have contributed to pronounced T cell proliferation as the same effects was not observed in MUD HCT with PTCY. Despite the early recovery of T cells after Haploidentical HCT the overall survival did not exceed the overall survival with MUD HCT. Severe CRS contributed to the increased mortality seen in Haploidentical HCT patients. Further strategies are needed to decrease treatment related mortality with Haploidentical HCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of Different T Cell Depletion Protocols on Immune Reconstitution Following Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Amandine Pradier ◽  
Adrien Petitpas ◽  
Anne-Claire Mamez ◽  
Federica Giannotti ◽  
Sarah Morin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Reconstitution ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
The Impact

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic modality for a variety of hematological malignancies and congenital disorders. One of the major complications of the procedure is graft-versus-host-disease (GVHD) initiated by T cells co-administered with the graft. Removal of donor T cells from the graft is a widely employed and effective strategy to prevent GVHD, although its impact on post-transplant immune reconstitution might significantly affect anti-tumor and anti-infectious responses. Several approaches of T cell depletion (TCD) exist, including in vivo depletion using anti-thymocyte globulin (ATG) and/or post-transplant cyclophosphamide (PTCy) as well as in vitro manipulation of the graft. In this work, we analyzed the impact of different T cell depletion strategies on immune reconstitution after allogeneic HSCT. Methods We retrospectively analysed data from 168 patients transplanted between 2015 and 2019 at Geneva University Hospitals. In our center, several methods for TCD are being used, alone or in combination: 1) In vivo T cell depletion using ATG (ATG-Thymoglobulin 7.5 mg/kg or ATG-Fresenius 25 mg/kg); 2) in vitro partial T cell depletion (pTCD) of the graft obtained through in vitro incubation with alemtuzumab (Campath [Genzyme Corporation, Cambridge, MA]), washed before infusion and administered at day 0, followed on day +1 by an add-back of unmanipulated grafts containing about 100 × 106/kg donor T cells. The procedure is followed by donor lymphocyte infusions at incremental doses starting with 1 × 106 CD3/kg at 3 months to all patients who had received pTCD grafts with RIC in the absence of GVHD; 3) post-transplant cyclophosphamide (PTCy; 50 mg/kg) on days 3 and 4 post-HSCT. Absolute counts of CD3, CD4, CD8, CD19 and NK cells measured by flow cytometry during the first year after allogeneic HSCT were analyzed. Measures obtained from patients with mixed donor chimerism or after therapeutic DLI were excluded from the analysis. Cell numbers during time were compared using mixed-effects linear models depending on the TCD. Multivariable analysis was performed taking into account the impact of clinical factors differing between patients groups (patient's age, donor type and conditioning). Results ATG was administered to 77 (46%) patients, 15 (9%) patients received a pTCD graft and 26 (15%) patients received a combination of both ATG and pTCD graft. 24 (14%) patients were treated with PTCy and 26 (15%) patients received a T replete graft. 60% of patients had a reduced intensity conditioning (RIC). 48 (29%) patients received grafts from a sibling identical donor, 94 (56%) from a matched unrelated donor, 13 (8%) from mismatched unrelated donor and 13 (8%) received haploidentical grafts. TCD protocols had no significant impact on CD3 or CD8 T cell reconstitution during the first year post-HSCT (Figure 1). Conversely, CD4 T cells recovery was affected by the ATG/pTCD combination (coefficient ± SE: -67±28, p=0.019) when compared to the T cell replete group (Figure 1). Analysis of data censored for acute or chronic GVHD requiring treatment or relapse revealed a delay of CD4 T cell reconstitution in the ATG and/or pTCD treated groups on (ATG:-79±27, p=0.004; pTCD:-100±43, p=0.022; ATG/pTCD:-110±33, p<0.001). Interestingly, pTCD alone or in combination with ATG resulted in a better reconstitution of NK cells compared to T replete group (pTCD: 152±45, p<0.001; ATG/pTCD: 94±36, p=0.009; Figure 1). A similar effect of pTCD was also observed for B cells (pTCD: 170±48, p<.001; ATG/pTCD: 127±38, p<.001). The effect of pTCD on NK was confirmed when data were censored for GVHD and relapse (pTCD: 132±60, p=0.028; ATG/pTCD: 106±47, p=0.023) while only ATG/pTCD retained a significant impact on B cells (102±49, p=0.037). The use of PTCy did not affect T, NK or B cell reconstitution when compared to the T cell replete group. Conclusion Our results indicate that all TCD protocols with the only exception of PTCy are associated with a delayed recovery of CD4 T cells whereas pTCD of the graft, alone or in combination with ATG, significantly improves NK and B cell reconstitution. Figure 1 Disclosures No relevant conflicts of interest to declare.

Outcomes of low-intensity biopsy surveillance for rejection in paediatric cardiac transplantation

2019 ◽  
Vol 29 (7) ◽  
pp. 910-916
Author(s):  
Patrick D. Evers ◽  
Neal Jorgensen ◽  
Borah Hong ◽  
Erin Albers ◽  
Mariska Kemna ◽  
...  
Keyword(s):  
Cardiac Transplantation ◽  
Graft Loss ◽  
Cardiac Allograft ◽  
First Year ◽  
Safety Measures ◽  
Post Transplant ◽  
Low Intensity ◽  
Clinical Surveillance ◽  
Biopsy Protocol

AbstractBackground:Significant inter-centre variability in the intensity of endomyocardial biopsy surveillance for rejection following paediatric cardiac transplantation has been reported. Our aim was to determine if low-intensity biopsy surveillance with two scheduled biopsies in the first year would produce outcomes similar to published registry outcomes.Methods:A retrospective study of paediatric recipients transplanted between 2008 and 2014 using a low-intensity biopsy protocol consisting of two surveillance biopsies at 3 and 12–13 months in the first post-transplant year, then annually thereafter. Additional biopsies were performed based on echocardiographic and clinical surveillance. Excluded were recipients that were re-transplanted or multi-organ transplanted or were followed at another institution.Results:A total of 81 recipients in the first 13 months after transplant underwent an average of 2 (SD ± 1.3) biopsies, 24 ± 6.8 echocardiograms, and 17 ± 4.4 clinic visits per recipient. During the 13-month period, 19 recipients had 24 treated rejection episodes, with the first at an average of 2.8 months post-transplant. The 3-, 12-, 36-, and 60-month conditional on discharge graft survival were 100%, 98.8%, 98.8%, and 90.4%, respectively, comparable to reported figures in major paediatric registries. At a mean follow-up of 4.7 ± 2.1 years, four patients (4.9%) developed cardiac allograft vasculopathy, three (3.7%) developed a malignancy, and seven (8.6%) suffered graft loss.Conclusion:Rejection surveillance with a low-intensity biopsy protocol demonstrated similar intermediate-term outcomes and safety measures as international registries up to 5 years post-transplant.

Alemtuzumab (Campath 1-H) Exposure Correlates with Risk of Chronic Graft vs Host Disease and CMV Viremia after Allogeneic Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1818-1818
Author(s):  
Justin P. Kline ◽  
Rajiv Swamy ◽  
Dezheng Huo ◽  
Laura Michaelis ◽  
Richard A. Larson ◽  
...  
Keyword(s):  
At Risk ◽  
Half Life ◽  
Immune Reconstitution ◽  
Chronic Gvhd ◽  
Absolute Lymphocyte Count ◽  
Enzyme Linked Immunosorbent Assay ◽  
Unrelated Donor ◽  
Increased Risk ◽  
Cmv Reactivation

Abstract Conditioning regimens using in vivo alemtuzumab (Campath-1H, humanized anti-CD52) are characterized by low rates of acute and chronic GVHD, but may also result in delayed immune reconstitution. Optimization of such regimens will depend on an understanding of the relation between alemtuzumab exposure, immune reconstitution and GVHD. We have conducted a prospective study of fludarabine 30 mg/m2/d x 5 days, melphalan 140 mg/m2 x 1 day and alemtuzumab 20 mg/d x 5 days as conditioning for related and unrelated allografts. Using an enzyme-linked immunosorbent assay (ELISA), we determined serum free and total Campath levels in 46 patients with hematologic malignancies (45) or sickle cell disease (1) on day 0, day 7, day 14, day 28, day 50, day 75, day 100, day 150 and at one year after transplant (HSCT). 26 (57%) had a matched sibling donor, 16 (35%) a matched unrelated donor (MUD) and 4 (9%) a mismatched related or unrelated donor. 44 pts engrafted and are included in the analysis. Median follow up for survivors was 2.8 years. Grade II–IV aGVHD occurred in 8 pts after a median of 42 days (range 22 to 60). Eight pts developed cGVHD after a median of 107 days (range 89–140). 15/41 (37%) at risk pts developed CMV reactivation. The half-life of free alemtuzumab (fA) was 26 days after HSCT with wide interpatient variation in fA pharmacokinetics (e.g. Coefficient of variation was 138% on day 0). On day 0, 1 patient had an undetectable level of fA. By day 28, 50, and 100, there were 6 (14.6%), 12 (35.3%), and 13 (52%) pts with undetectable fA, respectively. Figure 1 shows the fitted means and 95% confidence intervals of fA over time. Using log-rank and Cox proportional hazard models, there was no association between fA on day 0, day 28, or the last available fA, and development of acute GVHD. However, pts with higher average free and total Campath levels in the first month had a lower risk of developing cGVHD (p=0.02). The median fA concentration in the first month for pts with cGVHD was 0.32 (inter-quarter range IQR: 0.22–0.41), as compared with 0.97 (IQR: 0.23–3.31) in those without cGVHD. No significant association between absolute lymphocyte count and fA concentration was found after adjusting for time (p=0.28). Finally, among pts at risk, a higher fA concentration on day 0 (p=0.002), and in the first month (p=0.003) was significantly associated with CMV viremia. In summary, the estimated half-life of serum fA is 26 days after HSCT, but with considerable interpatient variability. Higher concentrations of fA were associated with a decreased incidence of cGVHD, but an increased risk of CMV reactivation. In contrast to a previous preliminary analysis, no association existed between fA and lymphocyte reconstitution. Variation in alemtuzumab pharmacokinetics may predict important clinical outcomes, such as cGVHD and CMV reactivation. Future studies are warranted to determine an optimal alemtuzumab exposure that hastens immune reconstitution while minimizing chronic GVHD. Fig 1. Fitted Mean Free Campath and 95% CI Fig 1. Fitted Mean Free Campath and 95% CI

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