Low Counts of Plasmacytoid Dendritic Cells After Engraftment Are Associated with Higher Early Transplantation-Related Mortality in Patients Receiving Unrelated HSCT

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4541-4541
Author(s):  
Matheus Vescovi GonÇalves ◽  
Mihoko Yamamoto ◽  
Vergílio Antônio Rensi Colturato ◽  
Mair Pedro de Souza ◽  
Marcos Mauad ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Stem Cell ◽  
Nk Cells ◽  
Hematopoietic Stem Cell ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Innate Defense ◽  
Common Diagnosis ◽  
The Impact

Abstract Abstract 4541 Background: The heterogeneous status of host immune defenses may influence the risk of infection and graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT). In such defense, dendritic cells (DC) which act as specialized antigen-presenting cells that bridge the innate and adaptive immune systems, and NK-cells, responsible for the innate defense against infections and residual tumor cells, are essential cell components. Objectives: To monitor the recovery of different subsets of DC and NK cells after unrelated umbilical cord blood (UCB), bone marrow (BM), and peripheral blood (PBSC) HSCT and to evaluate the impact of the distribution of these cell subsets on the outcome of the transplant. Methods: Overall, 34 patients (median age 13y; range 1–63y) receiving a UCB (n=15), BM (n=14) or PBSC (n=5) unrelated HSCT were studied. The most common diagnosis was acute leukemia (ALL, 12 cases; AML, 10; CML, 5; aplastic anemia, 4; MDS, 2; Hodgkin lymphoma, 1; SCID, 1), a majority of patients were males (56%), and received myeloablative conditioning (MAC) regimens (73%). Antithymocyte globulin (ATG) was used in 38% and total body irraditation (TBI) in 41% of cases. Median time to neutrophil engraftment was 18 days (range: 12–45). T-cell (CD4+, CD8+, CD4−8−, CD4+8+), DC [CD123+ plasmacytoid(p)DC, CD11c+ myeloid(m)DC, and CD16+ monocytoid(mo)DC] and NK cell subsets (CD3−/CD19− 56++16− and 56+16++) were quantified by multiparametric flow cytometry at 7 sequential time points (pre-transplant, at engraftment, and at days 3, 7, 14, 21 and 60 after engraftment). Results: As compared to BM/PBSC, UCB was associated with a delayed neutrophil recovery (28 days vs. 17 days; p=0.01), and a trend to lower counts of all T-, NK- and pDC subsets, particularly for the CD4+ and CD4−/CD8− T-cells during the first 3 weeks after recovery. Conversely, no significant differences were observed between both groups as regards the distribution of mDC and moDC. The use of TBI, MAC or ATG were not associated with the reconstitution of the studied cell subsets. In contrast, patients who died from transplantation-related causes (TRM) had significantly lower counts of pDC and mDC during the first 3 weeks after HSCT. At day 21 after engraftment, the median number of pDC and mDC was 0.9 and 2.0/uL among patients who died from TRM vs. 7.1 (p=.006) and 8.4/uL (p=.01) in the remainder, respectively). Patients presenting grade II-IV acute GVHD also had significantly lower pDC counts at days 14 and 21. There was no significant association of both the hematopoietic stem cell source and the conditioning regimen on the risk of TRM or acute GVHD. Conclusion: Low pDC counts in the first weeks after unrelated HSCT are associated with an increased incidence of GVHD and mortality. The precise mechanisms that might explain the role of pDC on immunity early after HSCT deserve further investigations. Disclosures: No relevant conflicts of interest to declare.

Rapid Immune Reconstitution after a Reduced-Intensity Conditioning Regimen and a CD3-Depleted Haploidentical Stem Cell Graft for Pediatric Refractory Hematologic Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5311-5311
Author(s):  
Xiaohua Chen ◽  
Gregory A. Hale ◽  
Raymond C. Barfield ◽  
Ely Benaim ◽  
Wing H. Leung ◽  
...  
Keyword(s):  
Stem Cell ◽  
Nk Cells ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Hematologic Malignancies ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity Conditioning Regimen ◽  
Reduced Intensity

Abstract Haploidentical hematopoietic stem cell transplantation (HaploHSCT) from a mismatched family member (MMFM) donor offers an alternative option for patients who lack an HLA-matched donor. The main obstacles to successful haploidentical hematopoietic stem cell transplantation from a mismatched family member donor are delayed immune reconstitution, vulnerability to infections, and severe graft-versus-host disease (GvHD). Method: We designed a reduced-intensity conditioning regimen that excluded total body irradiation and anti-thymocyte globulin. The graft was immunomagnetically depleted of CD3+ T-cells (CD3 negative selection) and contained a large number of both CD34+ and CD34− stem cells and most other immune cells especailly NK cells. This protocol was used to treat 22 pediatric patients with refractory hematologic malignancies. Results and Discussion: After transplantation, 91% of the patients achieved full donor chimerism. They also showed rapid recovery of CD3+ T-cells, T-cell receptor excision circle counts, TCRβ repertoire diversity and NK-cells during first four months post-transplantation. The incidence and extent of viremia were limited and no lethal infection was seen. Only 9% of patients had grade 3 acute GvHD, while 27% patients had grade 1 and another 27% had grade 2 acute GvHD. This well-tolerated regimen appears to accelerate immune recovery and shorten the duration of early post-transplant immunodeficiency, thereby reducing susceptibility to viral infections. Rapid T-cell reconstitution, retention of NK-cells in the graft, and induction of low grade GvHD may also enhance the potential anti-cancer immune effect.

scholarly journals The Impact of Age in Allogeneic Stem Cell Transplantation with Thiotepa Busulfan and Fludarabine (TBF) for Myelofibrosis : A Retrospective Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4858-4858
Author(s):  
Federica SORA ◽  
Patrizia Chiusolo ◽  
Sabrina Giammarco ◽  
Idanna Innocenti ◽  
Francesco Autore ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Total Dose ◽  
Cell Transplantation ◽  
Older Patients ◽  
Research Funding ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Allogeneic hematopoietic stem-cell transplantation (HSCT) currently remains the only curative therapy for intermediate or high risk disease.myelofibrosis (MF). We are reporting 56 patients (pts) who underwent an allogeneic HSCT in our Centre between 2016 and 2020, and assessed factors predictive of outcome. The median age was 59 years (36-72). Most patients (72%) were JAK2+ and had int2-high DIPSS (92%). The conditioning regimen consisted of thiotepa, busulfan , fludarabine (TBF). All pts received thiotepa 10 mg/kg and fludarabine 150 mg/m^2. The dose of busulfan was adjusted considering the age and the comorbidity score. One pt received 3 days of busulfan (total dose 9.6 mg/kg); 47 received 2 days (total dose 6.4 mg/kg) and 8 received one day of busulfan iv (3.2 mg/kg). Donor was an identical sibling in 13 pt, haploidentical in 18, matched unrelated donor (UD) in 18 and a mismatchedUD in 7. Thus we had 31 HLA matched and 25 HLA mismatched grafts. Fortytwo patients received post-transplant cyclophosphamide (PTCy)-based GVHD (Graft versus host disease ) prophylaxis with cyclosporine and mycophenolate mofetil , and 14 patients received a standard GvHD prophylaxis (CSA+MTX+ATG). The 2 year survival (OS) was 73 % and disease free survival (DFS) was 66 % and the cumulative incidence (CI) of TRM was 23% and of relapse 11%. The incidence of acute GvHD grade II-IV was 22% in HLA matched and 50% in HLA mismatched pts (p=0.022), grade III-IV was 6% and 25% respectively (p=0.042) . The incidence of moderate-severe chronic GvHD was 25% in HLA matched and 36% in HLA mismatched grafts (p=0.36). HLA had a major impact on survival : 85% vs 49% survival for matched vs mismatched patients (p=0.01). Patients age >60 years had a major impact on outcome, with a 2 year survival of 51% vs 88% in patients over (n=24) or under 60 years of age (n=32) (p=0.007; the DFS was 46 % and 80% respectively and the CI of TRM was 42% vs 9% (p=0.003). As to the total dose of busulfan, we found 26% TRM in patients receiving busulfan for 2 days (total doe 6.4 mg/kg) (n=47) and 0% in older patients receiving 1 day only (total dose 3.2 mg/kg) (n=8) ; relapse rate was 10% and 20% respectively. In multivariate cox analysis including age, spleen size ,DIPSS score, number of transfusion received and donor type, only HLA matching influenced the incidence of acute GvHD; transfusion burden and age plays a role in NRM and OS; DIPSS predicts relapse . In conclusion: older patients with MF have a high NRM and need to be prepared with a milder conditioning regimen. Disclosures Laurenti: Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria; BeiGene: Honoraria. Sica: Pfizer: Honoraria.

scholarly journals Masp-2 Levels Following Allogeneic Hematopoietic Stem Cell Transplantation in Adults: Correlation with Development of a Thrombotic Microangiopathy and Implications for Therapy with Anti-Complement Agents

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3305-3305
Author(s):  
Jeffrey Laurence ◽  
Koen Van Besien ◽  
Jasimuddin Ahamed ◽  
Sonia Elhadad
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Conditioning Regimen ◽  
Clinical Manifestations ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
The Impact

Introduction: 8500 adult allogeneic hematopoietic stem cell transplants (alloHSCT) are performed annually in the U.S. and 17,000 in Europe. HSCT-associated thrombotic microangiopathy (TMA), defined by thrombocytopenia, microangiopathic hemolytic anemia, and organ dysfunction in the absence of disseminated intravascular coagulation, complicates some 20% of these procedures. About half of post-alloHSCT TMAs may resolve when GvHD immunoprophylaxis is modified, but three year survival rates for those with severe HSCT-TMAs are a dismal 11%. Clinical manifestations are similar to other TMAs, but their pathophysiology may be distinct. Damage to vascular endothelium, independent of loss of ADAMTS13 activity, is thought to be critical. Fibrin-rich microthrombi, often accompanied by C4d and C5b-9 (membrane attack complex) deposition, occur in the microvasculature of multiple organs (Clin Adv Hematol Oncol 2014;12:565-573; Transplantation. 2013;96:217-223). This supports a role for complement activation in HSCT-TMA, but the importance of the various complement activation pathways is unclear. Recently, narsoplimab (OMS721), a monoclonal antibody inhibitor of MBL-associated serine protease-2 (MASP-2), a principal component of lectin-dependent complement activation, received Breakthrough Therapy Designation for HSCT-TMA, based on improved survival compared to historical controls in a phase 2 study. A phase 3 program is ongoing. Chemotherapy in association with autologous HSCT is linked to a marked increase in serum MASP-2 levels, persisting for about 4 weeks post-transplant (Front Immunol 2018;9:2153). However, TMAs are rare in autologous transplants, and circulating levels of MASP-2 following alloHSCT, and the impact of TMA development on those levels, are unknown. Methods: All individuals >18 years of age scheduled to undergo alloHSCT for hematologic malignancy at New York Presbyterian Hospital-Cornell were approached to participate in this study (NCT02604420). 100 of the first 101 subjects, age 58.3 +14 yrs, were enrolled and followed for >1.5 years post-transplant. This interval is consistent with the median time to HSCT-TMA diagnosis in adults of 90 days (range 32-733 days). Plasma was obtained at baseline (defined as between the time of consent and beginning of conditioning regimen), and at each regularly scheduled visit post-transplant-day 28 +5 days; day 100 +28 days; day 180 +28 days; and day 365 +28 days-as well as at the time of TMA diagnosis, based on the Consensus Criteria of Cho et al. (Transplantation 2010;90:918-926). A commercial ELISA (MyBioSource) was used to assess MASP-2 concentrations. Results: 20 subjects met study criteria for a HSCT-TMA diagnosis, occurring a median of 69 days (range 33-289) post-transplant. Three resolved following discontinuation of GvHD prophylaxis (mTOR or calcineurin inhibitor) and switch to mycophenolate and increased corticosteroid doses, and 7 had an intercurrent infection, 6 of whom expired with ongoing severe TMA despite a change in GvHD prophylaxis (Figure). TMAs persisted in the remaining 10 subjects. Median MASP-2 levels were significantly elevated in all subjects post-transplant, assessed at the time of TMA development or, in those not developing a TMA, at day 100 + 28 days post-transplant vs. controls (n=36, 86.2ng/ml (23.3-210.9): persistent TMA (n=9 (one plasma unavailable), 154ng/ml (range 82-209)); alloHSCT subjects who did not experience a TMA (n=40 evaluated to date, 113.5ng/ml (56-430.3)). (Figure). Lack of a significant rise in MASP-2 levels in patients with persistent TMAs vs. those who did not develop a TMA, combined with a significant decrease in variance of MASP-2 levels in the former group (p=0.005), may reflect consumption of product at sites of disease activity, i.e., the microvasculature. Conclusions: There is a significant increase in MASP-2 levels, with a wide variance, in post-alloHSCT patients evaluated at a time post-transplant typical of HSCT-TMA development. At time of development of a HSCT-TMA that persists despite withdrawal of GvHD prophylaxis, MASP-2 levels remain elevated over controls, but with a significantly lower variance vs. those not developing TMA. A study of additional samples, including longitudinal specimens, from this cohort is underway to determine if a change in MASP-2 levels correlates with HSCT-TMA development post-alloHSCT. Disclosures Van Besien: Miltenyi Biotec: Research Funding.

Single Center Experience of Allogenic Hematopoietic Stem Cell Transplantation in 100 Patients with Myelodysplasia: The Impact of Graft-Versus-Host Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5537-5537
Author(s):  
Colombe Saillard ◽  
Raynier Devillier ◽  
Sabine Furst ◽  
Jérome Rey ◽  
Angela Granata ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Donor Type ◽  
The Impact ◽  
Disease Free

Abstract Introduction Allogenic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment for patients with myelodysplasia (MDS). However, because of age, MDS patients represent a challenging population for such an intensive treatment. Additionally, the low rate of HLA-identical donor has represented a major limitation in this strategy. Recently, reduced-intensity conditioning (RIC) regimens have made feasible Allo-HSCT in the elderly, although relapse rate might be increased. Additionally, the development of HSCT using alternative donors overcomes HLA-compatibility limitations. Graft-versus-host disease (GVHD) is a major post-transplant event, graft-versus-leukemia effect being counterbalanced by toxicity and impaired quality of life. The aim of this retrospective study was to report outcome of patients with MDS who underwent Allo-HSCT and to study the impact of GVHD. Methods Between 2003 and 2014, 100 consecutive patients presenting with MDS, or MDS-secondary AML, underwent Allo-HSCT in our institution. At diagnosis, 58 patients had ≥ 2 cytopenias. IPPS was low/intermediate-1 in 46% and intermediate-2/high in 54%, R-IPSS was very low/low in 25%, intermediate in 20% and high/very high in 55%. Cytogenetics, according to Disease Risk Index (DRI), was intermediate in 79% and adverse in 21%. Secondary MDS represented 27% of our cohort. Before Allo-HSCT, 42% received 5-Azacytidine, 27% intensive chemotherapy and 9% were transplanted upfront. At the time of Allo-HSCT, the median recipient age was 61 (19-71) years. Median time between diagnosis and Allo-HSCT was 12 months (1-131). After excluding patients transplanted upfront, 31 patients still had ≥5% blasts after treatment. Donors were HLA-matched in 70% (41% related, 29% unrelated), 30% were not HLA-matched (10% unrelated, 7% cord blood, 13% T-repleted haplo-HSCT). Stem cell source was peripheral blood stem cells in 90%. Twelve percent of patients received non-myeloablative (NMA) conditioning regimen, 75% RIC and 13% reduced-toxicity conditioning (RTC) regimens. Post-graft immunosuppression consisted in cyclosporine A (CSA) in 58%, CSA-Mycophenolate Mofetil (MMF) in 15%, CSA-Methotrexate in 14% and CSA-MMF-Cyclophosphamide for haplo-HSCT (13%). Results Median follow-up was 37 months (3-197). The incidence of 3-4 acute GVHD at day 100 was 7% (95% CI = 2-12). The incidence of severe chronic GVHD at 3 years was 19% (95% CI = 11-27). One and 3-year non-relapse mortality (NRM) were 23 and 29% respectively. The cumulative incidence of relapse (CIR) at 1 year and 3 years 24% and 33% respectively. One and 3-year progression-free survival (PFS) were 52% (95% CI = 43-63) and 37% (95% CI = 28-49). One and 3-year overall survival (OS) were 60% (95% CI = 51-71) and 48% (95% CI = 39-60). At one year, 51 patients were alive and disease-free, including 61% (n=31) without immunosuppression. At the end of follow-up, 39 patients were alive and disease-free, including 85% (n=33) without immunosuppression and 77% (n=30) GVHD-free. Time-dependent analysis of GVHD impact (Table 1), adjusted on age, donor-type, DRI and conditioning regimen, revealed that acute GVHD strongly impacts on OS (HR 3.8, 95% IC = 2-7, p<0.01), PFS (HR 3.1, 95% CI = 1.7-5.6, p<0.01) and NRM (HR 12, 95% CI = 5.2-28, p<0.01). Chronic GVHD was statistically significant on CIR (HR 0.16, 95% CI = 0.04-0.7, p=0.02) and NRM (HR 2.8, 95% CI = 1-8, p=0.05). Pre-transplant disease characteristics did not have any impact by univariate analysis. Multivariate analysis did not find any impact of age, donor type, DRI and conditioning regimen in terms of OS, PFS, NRM and CIR. Conclusion Our results suggest that GVHD highly influences outcome, regardless of MDS and Allo-HSCT characteristics. It should be quoted that a significant number of patients are alive, long-term survivors, disease-free and GVHD-free suggesting good quality of life. These results invite defining better strategies of GVHD prevention while retaining disease control magnifying the existing graft-versus-leukemia effect. Table 1. Time-dependent analysis of the impact of acute and chronic GVHD, adjusted on age (< or > 60), donor-type (HLA-matched or not matched), DRI and conditioning regimen (NMA, RIC or RTC). HR 95% CI p Acute GVHD OS PFS NRM CIR 3.8 3.1 12 0.4 2-7 1.7-5.6 5.2-28 0.09-1.7 <0.01 <0.01 <0.01 0.2 Chronic GVHD OS PFS NRM CIR 0.7 0.8 2.8 0.2 0.3-1.5 0.4-1.8 1.01-8 0.04-0.8 0.4 0.6 0.050.02 Disclosures Vey: Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria.

scholarly journals Analysis of the Impact of Donor-Recipient ABO Mismatch on Outcomes of HLA-Haploidentical (HI) Hematopoietic Stem Cell Transplantation (HSCT)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3215-3215
Author(s):  
Praveen Ramakrishnan Geethakumari ◽  
Thomas R. Klumpp ◽  
Rachael Grosso ◽  
Ashok Mandala ◽  
Neal Flomenberg ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Acute Gvhd ◽  
Statistical Significance ◽  
Chronic Gvhd ◽  
Competing Risk ◽  
Fixed Dose ◽  
Hematopoietic Stem ◽  
Abo Incompatibility ◽  
The Impact

Abstract Background: It is estimated that 30-50% of allogeneic hematopoietic stem cell transplants (HSCT) have some type of ABO incompatibility. There are inconsistencies in the literature regarding the impact of recipient/donor ABO mismatch (MM) on HSCT outcomes including overall (OS), event-free survival (EFS), relapse, and acute and chronic graft-versus-host disease (GVHD) in conventional myeloablative or reduced intensity settings. This may be a consequence of heterogeneity in treatment approaches and patient populations studied. In addition, little is known about the effect of ABO MM on outcomes after HI HSCT. To address these issues, we analyzed the effects of various recipient/donor ABO combinations on post HI HSCT outcomes in a population of patients treated on the uniformly designed Jefferson 2-step HSCT method. In this approach, after conditioning, patients received fixed dose of T cells (step 1), followed 2-3 days later by cyclophosphamide (CY) for bidirectional tolerization. Two days after CY, patients received the CD 34-selected donor product (step 2). Our goal was to elucidate the impact of various ABO recipient/donor combinations on outcomes in a homogeneous HI HSCT setting. Methods: This is a preliminary, retrospective evaluation of 167 patients with hematologic malignancies undergoing a 2 step HI HSCT between 2006 and 2015. Patients were divided into 3 ABO groups: major MM (MM in recipient to graft direction), minor MM (MM in graft to recipient direction) and matched. The groups were analyzed for the primary statistical end point, the association of ABO incompatible HI HSCT with EFS (death from disease progression or relapse). Secondary end points were the association of ABO incompatibility with OS, non-relapse mortality (NRM) and acute and chronic GVHD. The probabilities of EFS and OS were estimated by Kaplan-Meier (KM) method with log-rank analysis. Multivariate analysis to assess impact of ABO group on EFS and OS controlling for confounding variables (age, disease status at HSCT, conditioning intensity, interval from diagnosis to HSCT) was performed using Cox proportional hazards. Cumulative incidence functions with competing risk analyses were used to estimate probabilities of relapse, NRM, acute and chronic GVHD. Results: The median age and follow-up of the study group was 55 years and 33.8 months (range: 0.83-97.67 months) respectively. A total of 103 (61.7%) donor-recipient pairs were ABO identical, 28 (16.8%) major MM, and 36 (21.5%) minor MM. KM analysis showed that patients with minor MM had higher EFS but lower OS as compared with matched or major MM groups. This was recapitulated on multivariate Cox analysis, where EFS (HR=0.70, CI 0.30-1.66, p=0.43) was higher, but OS (HR=1.13, CI 0.65-1.97, p= 0.65) was lower in patients with minor MM. On competing risk analysis, NRM was higher (HR=1.67, CI 0.83-3.38, p=0.15) while relapse was lower (HR=0.59, CI 0.27-1.30, p=0.19) in minor MM group. The risk of grades 2 to 4 acute GVHD was significantly lower in patients with minor MM (HR=0.29, CI 0.10-0.88, p=0.02). Risks of acute GVHD grades 3 to 4 and chronic GVHD were not significantly different for any group, possibly due to few events in these categories. Discussion: To the best of our knowledge, this is the first assessment of the impact of ABO incompatibility on outcomes after HI HSCT. The strength of this study is the uniformity of treatment protocol and testing group. The analysis suggests that ABO minor MM has different effects on outcomes than major MM or matched groups which were surprisingly similar to each other. These findings were highlighted by the association of minor MM with decreased incidence of acute GVHD, the only finding that reached statistical significance. That minor MM was associated with less relapse and greater EFS may be indicative of a decreased need for immunosuppression in the group, but this relationship does not explain the lower OS and higher NRM in this group. The weakness of the analysis is the small sample size, especially in some subgroups. While most findings failed to reach statistical significance, the analysis was uniform in that minor ABO MM was different from other categories, possibly due to less alloreactivity in this group, thus impacting rates of acute GVHD and survival. These findings support the need for prospective research in this area with larger groups of patients. Non-relapse Mortality Acute GVHD 2-4 Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of Natural Killer Cells Reconstitution on Outcomes after Allogenic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4880-4880
Author(s):  
Moazzam Shahzad ◽  
Amna Y Shah ◽  
Muhammad Usman Zafar ◽  
Ezza Tariq ◽  
Anam Hamid ◽  
...  
Keyword(s):  
Stem Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Hematopoietic Stem Cell Transplant ◽  
Acute Gvhd ◽  
Meta Analysis ◽  
Cell Transplant ◽  
Hematopoietic Stem

Abstract Background: Natural killer (NK) cells are the first cells to recover following allogeneic hematopoietic stem cell transplant (HSCT) and play a crucial role in enabling engraftment, preventing post-transplant infection and tumor relapse. In addition, NK cells also reduce the risk of graft versus host disease (GvHD) and increase the graft versus leukemia effect (GVL). The purpose of this systematic review and meta-analysis is to know the impact of NK cells reconstitution on outcomes of allogeneic HSCT. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane Library, and ClinicalTrials.gov through January 2021. We used MeSH terms and keywords for "hematologic malignancies" OR "hematopoietic stem cell transplantation" AND "natural killer cells." No filters or publication time limits were applied for the search. A total of 13 studies were included after screening 988 records and excluding duplicates, review, and non-relevant articles. An arbitrary value of NK cell count of 22.2 cell/ul was set as a cut-off to divide between high and low groups of NK where applicable. Quality evaluation was done using the NIH quality assessment tool and Inter-study variance was calculated using Der Simonian-Laird Estimator. Pooled analysis was done using the 'meta' package (Schwarzer et al. R programming language), and proportions with 95% confidence intervals (CI) were computed. Results: A total of 1623 patients were evaluated from 13 studies. (Table 1) The median age of patients was 44 (8.6-63) years and 33.5% were males. The median duration of follow-up was 18 (0.3-122) months. The median 2-year overall survival (OS) for high NK cohort and low NK cohort was 77% (95%CI 0.70-0.83, I 2 =82%, n=982) and 52%(95%CI 0.38-0.67, I 2 =95%, n=982), respectively. The pooled rate of relapse in high NK group was 8% (95%CI 0.01-0.19, I 2 =83%, n=226) and it was 20% (95%CI 0.06-0.39, I 2 =90%, n=226) for low NK group. The pooled incidence of acute GvHD was 24% (95%CI 0.09-0.42, I 2 =91%, n=336) and 44% (95%CI 0.26-0.62, I 2 =91%, n=336) for high and low NK cohorts, respectively. The pooled incidence for viral infection for high NK group was 17% (95%CI 0.01-0.47, I 2 =98%, n=508) while it was 29% (95%CI 0.04-0.65, I 2 =98%, n=508) for low NK group, respectively. Conclusion: Higher reconstitution of NK cells after allogeneic hematopoietic stem cell transplant has a favorable impact on outcomes, including better overall survival and low incidence of relapse, acute GvHD, and viral infections. Our findings suggest the need for further prospective studies to investigate utility of NK cells infusion early post-transplant to improve clinical outcomes and survival. Figure 1 Figure 1. Disclosures McGuirk: Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; EcoR1 Capital: Consultancy; Astelllas Pharma: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding.

Impact of Activating Killer Immunoglobulin-Receptor Genotype of the Donor on Outcome of Unrelated Donor - Hematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5206-5206
Author(s):  
Sebastian Giebel ◽  
Izabela Nowak ◽  
Tomasz Kruzel ◽  
Jerzy Wojnar ◽  
Miroslaw Markiewicz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Function of NK cells is regulated by a balance between inhibitory and activating signals transmitted through killer immunoglobulin-like receptors (KIR). The goal of the present analysis was to evaluate the impact of donor activating KIR genotype (KIR2DS1 and KIR2DS2 loci) on outcome of unrelated donor-hematopoietic stem cell transplantation (URD-HSCT). Fourty-two URD-HSCT recipients with haematological malignancies, aged 28 (14–48) years (male/female - 26/16) were included in the analysis. The conditioning regimen was myeloablative and based on chemotherapy alone (n=33) or total body irradiation (n=9). Graft-vs-host disease (GVHD) prophylaxis consisted of cyclosporin, methotrexate, and pre-transplant anti-thymocyte globulin. Patients were grouped according to their donors’ activating KIR genotype including two loci: KIR2DS1 and KIR2DS2. The overall survival at 2.5 years with respect of the donors’ activating KIR genotype was as follows: KIR2DS1(−)DS2(−) (n=15) − 82% (+/−12%), KIR2DS1(+)DS2(−) (n=9) − 78% (+/−14%), KIR2DS1(−)DS2(+)− (n=7) 86% (+/−13%), KIR2DS1(+)DS2(+) (n=11) − 0%. The OS rate differed significantly between KIR2DS1(+)DS2(+) group and the remaining patients: 0% vs. 82% (+/−7%), p=0.03. The difference resulted mainly from higher cumulative incidence of non-relapse mortality in the KIR2DS1(+)DS2(+) group: 100% vs. 18% (+/−8%), p=0.098. The reasons of death in patients with KIR2DS1(+)DS2(+) donors were chronic GVHD (n=4) and acute GVHD (n=1). We conclude that the concomitance of both KIR2DS1 and KIR2DS2 in the donor is associated with high risk of mortality following URD-HSCT, resulting mainly from the incidence of severe GVHD. Whether this effect is associated with the activity of NK cells or KIR-bearing T lymphocytes requires further investigation.

Higher Counts Of Plasmacytoid Dendritic Cells In The Allograft Are Associated Increased Risk Of Acute Gvhd After Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4626-4626
Author(s):  
Matheus Vescovi Gonçalves ◽  
Mihoko Yamamoto ◽  
Eliza Y. S. Kimura ◽  
Vergilio Antonio Renzi Colturato ◽  
Maura Valerio Ikoma ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Plasmacytoid Dendritic Cells ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Increased Risk ◽  
Common Diagnosis

Background Recent studies suggest that higher circulating dendritic cell counts after hematopoietic stem cell transplantation (HSCT) may be associated with lower risk of graft versus host disease (GVHD) and mortality. Plasmacytoid dendritic cells (pDC) have tolerogenic properties and may explain such results. However, only a few studies with conflicting results analyzed pDC counts in the allograft, mainly in the related HSCT setting. Objectives To compare pDC counts among different cell sources [umbilical cord blood (UCB), bone marrow (BM), and peripheral blood (PBSC)] and to correlate the pDC content on the graft with main HSCT outcomes. Methods Plasmacytoid dendritic cells (pDC: lineage negative, HLA-DR+ and CD123+) were quantified by multiparametric flow cytometry in the graft just before its infusion. Overall, 77 patients (49 male; median age 21y, range 1-74y) receiving UCB (n=26), BM (n=34) or PBSC (n=17) HSCT from unrelated (n=67) or related donors (n=10) were studied. The most common diagnosis was acute leukemia (ALL, 30 cases; AML, 22). Most patients received myeloablative conditioning regimens (n=47, 61%). Antithymocyte globulin was used in 30 patients (39%) and total body irradiation in 41 (53%). Median follow up time was 15 months (4-33). Results Median time to neutrophil engraftment was 19 days (range: 11-49) and 35 days to platelet engraftment (range 2-176). The median percentage of pDC on the graft was 0.20% of non erythroid nucleated cells (range: 0.02-0.67) and no differences were noticed among sources. Cumulative incidence (CI) of grade II-IV acute GVHD at 100 days was higher on patients receiving grafts with higher percentages of pDC (22% for patients with less than 0.15%pDC graft content vs. 52% for patients receiving grafts with higher counts, p=0.026). There was no impact of graft pDC content on mortality, relapse, chronic GVHD or overall survival. In a multivariate analysis, graft pDC content remains an independent risk factor for acute GVHD [HR: 3.0, CI (95%): 1.15-7.8]. Conclusion Higher pDC graft percentages were associated with increased risk of acute GVHD, but had no impact on non-relapse mortality or survival. The precise role of pDC on immunity after HSCT deserves further investigation and might be related not only to pDC biology itself but to the chronology of the pDC interaction with host antigens. Disclosures: No relevant conflicts of interest to declare.

scholarly journals NK Cell and CD4+FoxP3+ Regulatory T Cell Based Therapies for Hematopoietic Stem Cell Engraftment

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Antonio Pierini ◽  
Maite Alvarez ◽  
Robert S. Negrin
Keyword(s):  
Stem Cell ◽  
Nk Cells ◽  
Hematopoietic Stem Cell ◽  
Immune Reconstitution ◽  
Hematopoietic Cell Transplantation ◽  
Opportunistic Infections ◽  
Nk Cell ◽  
Severe Toxicity ◽  
Hematopoietic Stem ◽  
The Impact

Allogeneic hematopoietic cell transplantation (HCT) is a powerful therapy to treat multiple hematological diseases. The intensive conditioning regimens used to allow for donor hematopoietic stem cell (HSC) engraftment are often associated with severe toxicity, delayed immune reconstitution, life-threatening infections, and thus higher relapse rates. Additionally, due to the high incidence of graft versus host disease (GvHD), HCT protocols have evolved to prevent such disease that has a detrimental impact on antitumor and antiviral responses. Here, we analyzed the role of host T and natural killer (NK) cells in the rejection of donor HSC engraftment as well as the impact of donor regulatory T cells (Treg) and NK cells on HSC engraftment. We review some of the current strategies that utilize NK or Treg to improve allogeneic HCT therapy in order to accomplish better HSC engraftment and immune reconstitution and achieve a lower incidence of cancer relapse, opportunistic infections, and GvHD.

scholarly journals Impact of Omitting Prophylactic Antibiotics, to Preserve Gut Microbiota, on the Incidence of Bacteraemia during the Pre-Engraftment Period of Allogenic Hematopoietic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2094-2094
Author(s):  
Claudie Roy ◽  
Simon Frédéric Dufresne ◽  
Miguel Chagnon ◽  
Silvy Lachance
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Conditioning Regimen ◽  
Prophylactic Antibiotics ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Gram Negative ◽  
Febrile Episodes ◽  
The Impact

Abstract Introduction Prophylactic antibiotic (ATB) administration has been shown to reduce febrile episodes and infections in neutropenic patients undergoing high dose chemotherapy or hematopoietic stem cell transplant (HSCT) in large meta-analyses (Gafter-Gvili, Cochrane, 2012; Kimura, J Infect Dis, 2014). This practice is supported by current guidelines in high-risk patients including those undergoing HSCT. However, ATB use has also been associated with adverse outcomes such as decreased microbiota diversity (Taur, Blood, 2014) and increased resistance (Magesic, Transpl Inf Dis, 2014). Recently, our group participated in a multicenter retrospective cohort of patients undergoing allogeneic (a) HSCT that demonstrated an increased incidence of acute graft versus host disease (aGVHD) and lower overall survival in patients receiving antibioprophylaxis (Routy, Oncoimmunology, 2017). To assess the impact of omitting prophylactic ATB, we used the sample from one of the participating centers (Hôpital Maisonneuve-Rosemont) to compare the incidence of bacteraemia and mortality in aHSCT patients who received prophylactic ATB during the pre-engraftment period to those who did not. Methods This retrospective study included patients undergoing aHSCT for hematological malignancy between January 2005 and December 2012 at our center. Exclusion criteria were prior aHSCT, syngenic and haploidentical HSCT. Antibioprophylaxis with fluoroquinolones or trimethoprim-sulfamethoxazole (TMP-SMX)was administered at initiation of the conditioning regimen in patients receiving a myeloablative (MA) and reduced intensity conditioning regimen and discontinued after engraftment. It was omitted in patients with fluoroquinolone or penicillin allergy and in patients receiving a non-myeloablative regimen. Prophylactic ATB were substituted for therapeutic ATB during episodes of febrile neutropenia and documented infection. Bacteraemia occurring during the pre-engraftment period (30 days or less after stem cell infusion) were recorded. Results A total of 377 patients were included, of which 182 (48%) received prophylactic ATB and 195 (52%) did not. In the ATB group, 141 patients received ciprofloxacin, 17 moxifloxacin and 24 TMP-SMX. Baseline characteristics differed in both groups. The ATB group had a younger mean age with 45.2 ±12.3 years compared to 49.5 ±11.3 years (p<0.001) and a higher intensity conditioning regimen with 74% receiving a MA regimen compared with 36% (p<0.001). The incidence of bacteraemia was similar in both groups with 14.3% (95% CI 9.2-19.4%) in those receiving prophylactic ATB compared to 12.3% (95% CI 7.7-17.0%) in those who did not (OR 1.19, 95% CI 0.7-2.2, p 0.57). Expectedly, gram negative bacteremia was less likely (OR 0.24, 95% CI 0.07-0.84, p 0.026) in the ATB group, representing 11.5% of all bacteraemia compared to 52.2%. The incidence of bacteraemia was also reduced by prophylactic ATB in patients receiving a MA conditioning regimen (OR 0.48, 95% CI 0.25-0.96, p 0.036). There was no mortality associated to infectious causes during the pre-engraftment period in either group. Two patients died during the pre-engraftment period, one from hepatic failure and the other from acute respiratory distress syndrome in the context of veno-occlusive disease. Both were in the group that did not receive prophylactic ATB and received MA conditioning. Discussion In this study, the omission of prophylactic ATB did not increase the incidence of bacteraemia in patients undergoing aHSCT. However, the administration of prophylactic ATB did reduce bacteremia in those receiving MA conditioning regimens, as well as gram negative bacteraemia in all patients. Nevertheless, there was no impact on treatment related mortality at day 30 after stem cell infusion. Thus, the benefit of prophylactic ATB must be weighed against the higher risk of aGVHD and shorter overall survival observed in this sample in earlier studies (Routy, Oncoimmunology, 2017) and with the potential risk of selection and resistance. The limitations of this study include its retrospective design, the heterogenicity between the two groups and its omission of febrile episodes and infections without bacteraemia. Further data, preferably from a large prospective, randomised trial, would be useful to reassess the benefits and risks of prophylactic antibiotics in aHSCT. Disclosures Lachance: ExCellThera: Patents & Royalties: Royalities from sales of UM171.

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