scholarly journals Elimination of Acute GvHD with Three Doses of Abatacept Prophylaxis Combined with Post-Transplant Cyclophosphamide after Myeloablative Treosulfan-Based Conditioning in the HLA Identical Sibling and Unrelated (10-12/12) Peripheral Blood Stem Cell Donor Setting: Improved Safety and Efficacy Compared to Alemtuzumab Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4540-4540
Author(s):  
Amit Patel ◽  
Jun Yong
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Safety And Efficacy ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Secondary Outcomes ◽  
Cmv Reactivation

Background. Acute graft versus host disease (GvHD) remains a major cause of treatment failure post allogeneic stem cell transplantation (HSCT). CD28-CD80/CD86 axis T cell co-stimulation blockade with CTLA4-Ig using abatacept (AB) is an emerging acute GvHD prophylaxis strategy1. After myeloablative conditioning (MAC), together with methotrexate and calcineurin inhibition, four doses of AB commencing day (d)-1 is being investigated in the unrelated HLA 7/8 and 8/8 mismatched/matched donor settings, mostly in children2. It is unknown if AB can be de-escalated in adults to three doses for HLA matched sibling (SIB) or unrelated 10-12/12 donors (MUD), or combined with post-transplant cyclophosphamide (PT-CY) GvHD prophylaxis3, or combined with treosulfan (TREO)-based MAC4, which are other emerging transplant strategies. We investigated the safety and efficacy of this combination, and compared outcomes to a standard anti-CD52 directed IgG1 alemtuzumab (CH) prophylaxis regimen5 in a reduced intensity conditioning (RIC). Methods. We report a single centre consecutive cohort study using peripheral blood stem cells from SIB or HLA 10-12/12 MUDs, for HSCT in adults with blood cancer indications (intuitional registration: 1920-31). One group received AB GvHD prophylaxis while the other group received CH. During 2018-2019, the AB cohort received MAC with IV fludarabine 150 mg/m2, IV TREO 42 mg/m2, and 2 Gy total body irradiation (TBI). GvHD prophylaxis comprised three doses of IV AB 10 mg/kg on d+5, +14, and +28. This was combined with IV PT-CY 50 mg/kg on d+3 and +4, IV tacrolimus 0.03 mg/kg/d infusion from d+5, and IV mycophenolate mofetil 15 mg/kg tds from d+53. The MAC AB cohort was compared to a RIC CH cohort, chosen to be biased against AB. During 2017-2018 the CH cohort received RIC with IV fludarabine 150 mg/m2and IV melphalan 140 mg/m2. GvHD prophylaxis comprised IV CH 10 mg on d-7 to d-3, and IV ciclosporin 1.5 mg/kg bd from d-1. The primary outcome measure was the incidence of acute GvHD6 at d100 and 180 post HSCT. Secondary outcomes measures were the incidence of graft failure, mixed donor chimerism, donor lymphocyte infusion (DLI), CMV reactivation, relapse, overall survival, at d100 and 180. The AB and CH cohorts were indirectly compared. Results. A total of 39 patients were included in this study, with 15 consecutive patients in the AB group (Table). The AB group had a median Karnofsky score of 70% and HCT-CI of 6; significant comorbidity greater than other reports1,2. The major cancer indications were acute leukaemia and myelodysplastic syndrome (MDS). The AB and CH groups were largely balanced. There were no AB related infusion reactions. As expected for MAC, the AB group had a numerically but not clinically significantly slower time to engraftment relative to the RIC CH group. There was no AB group graft failure. Remarkably, the AB group did not experience acute GvHD compared to the CH group by d100 (P=0.03) and d180 (P<0.01). In contrast, by d100, 29% in the CH group experienced acute GvHD after a median of 59 days post HSCT. No AB group patients experienced mixed donor chimerism (P<0.01), nor required a DLI (P<0.01) compared to the CH group, where all had <99% T cell or whole blood values at d100. Consequently, 45% of the CH cohort without acute GvHD were treated with DLI, with all patients experiencing acute GvHD at a median of 39 days post DLI (Table). Other secondary outcomes were similar. The AB group experienced a CMV reactivation rate of 67% in IgG seropositive patients. Unfortunately, 93% of CMV IgG positive patients in the CH group experienced CMV reactivation. No relapses were observed by d180 in the AB group, whereas in the CH group, 8% of patients experienced relapse. Mortality at d180 was 20% in the MAC AB group, and 21% in the RIC CH group. Conclusions. Acute GvHD prophylaxis with only three doses of AB and PT-CY post TREO-based MAC appears to be safe and efficacious in the SIB and MUD settings, in a highly co-morbid adult blood cancer population. This AB approach seems favourable compared to CH despite RIC, where acute GvHD without DLI or post DLI remains significant. A prospective multicentre clinical trial with AB in this setting seems warranted to confirm these remarkable findings of patient benefit. References. 1. Biol Blood Marrow Transplant (BBMT) 2013;19:1638-49. 2. NCT01743131. 3. Lancet Haematol 2019;6:e132-43. 4. Cancer 2017;123:2671‐79. 5. BBMT 2017;23:805-12. 6. BBMT 2016;22:4-10. Table Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Abatacept, alemtuzumab, cyclophosphamide all the for the indication of graft versus host disease (GvHD) prophylaxis.

Ruxolitinib during Peritransplant Period for Myelofibrosis Patients Undergoing Allogeneic Stem Cell Transplantation Reduces Acute Graft-Versus-Host Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2242-2242 ◽  
Author(s):  
Nicolaus Kröger ◽  
Sharifah Shahnaz Syed Abd Kadir ◽  
Tatjana Zabelina ◽  
Christine Wolschke ◽  
Francis A. Ayuk ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Cmv Reactivation

Abstract Introduction Allogeneic stem cell transplantation is a curative treatment approach for patients with myelofibrosis, but associated with a high risk of therapy related complications such as graft versus host disease (GvHD). Ruxolitinib is the first approved drug for treatment of myelofibrosis. Major effects are reduction in spleen size and improvement of constitutional symptoms, which may be useful in order to reduce transplant related complications. Therefore, the EBMT/ELN guidelines recommend to administer Ruxolitinib prior to allogeneic stem cell transplantation (Leukemia 2015). Because of the immunosuppressive properties, Ruxolitinib has been shown to be active in steroid refractory graft versus host disease (GvHD). While in transplant setting Ruxolitinib is usually stopped at time of conditioning, data of Ruxolitinib during peritransplant period are lacking. Patients and methods From 171 myelofibrosis patients(pts) who underwent allogeneic stem cell transplantation 58 pts (34%) received Ruxolitinib at any time point prior to ASCT and 12 did not stop Ruxolitinib at start of conditioning, but continued during Busulfan based reduced conditioning and after stem cell transplantation until stable engraftment. For those 12 pts (male n=6, female n=6), the median age was 63 years (range 43-71 years) and disease status according DIPSS was intermediate 1 (n=1), intermediate 2 (n=9) and high risk (n=2). Nine patients were JAK2V617F positive, 4 were CALR positive and 1 was triple negative. The median duration of Ruxolitinib was 163 days (range 61-1268 days) and all patients showed at least improvement in spleen size and constitutional symptoms. CMV serostatus was positive in 6 patients. Pts received peripheral blood stem cells from HLA-identical sibling (n=2), matched (n=8) or mismatched (n=2) unrelated donors. The dose of Ruxolitinib during condition therapy was 2 x 5mg and continued until stable engraftment, then tapered and stopped around day 28 post transplantation. GvHD prophylaxis consisted of cyclosporine A from day -1 and MMF from day +1 until day 28. All patients received anti-lymphocyte globulin (ATG Neovii®) at dose of 30mg for related and 60mg/kg for unrelated stem cell grafts. Results No major toxicity was observed during conditioning therapy. ATG treatment was well tolerated without any SIRS syndrome. We observed no graft failure. Leukocyte engraftment was achieved after a median of 12 days (r., 11-18). Overall, only 1 patients experienced acute GvHD grade III , resulting in an incidence of aGvHD grade II-IV and of 8%. Complete donor cell chimerism was achieved in 11 patients after a median of 40 days and molecular clearance was noted in 10 patients after a median of 32 days. CMV reactivation in the CMV positive patients was seen in 67% (n= 4) and one of them has CMV colitis as well. The onset of CMV reactivation is earlier as observed in a historical non Ruxolitinib treated cohort (median 22 vs 54 days, respectively). In two patients, Ruxolitinib was discontinued on day 17 and 18 after ASCT due to cytopenia after engraftment. After a short median follow up of 112 days (range 42-191) all patients are alive, with one progessing disease and no NRM. One patients developed fever of unknown origin after discontinuation of Ruxolitinib , otherwise no case of withdrawal syndrome was observed. Conclusions These results suggest that Ruxolitinib given during peritransplant period in patients with myelofibrosis is well tolerated and ensure safe and fast engraftment and leads to a low incidence of acute GvHD. Ruxolitinib should be further investigated as GvHD prophylaxis. Disclosures Kröger: Novartis: Honoraria, Research Funding.

scholarly journals Post-Transplant Cyclophosphamide and Thymoglobulin, a Graft-Versus-Host Disease Prophylaxis in Matched Sibling Donor Peripheral Blood Stem Cell Transplantations

2020 ◽  
Vol 29 ◽  
pp. 096368972096590
Author(s):  
Chutima Kunacheewa ◽  
Weerapat Owattanapanish ◽  
Chutirat Jirabanditsakul ◽  
Surapol Issaragrisil
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Chronic Gvhd ◽  
Survival Rates ◽  
Free Survival ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Matched Sibling

Post-transplant cyclophosphamide (PTCy) has been explored in several types of stem cell transplantations (SCTs) and it proved highly effective in controlling graft-versus-host disease (GvHD) without aggravating relapsed disease. However, PTCy alone has resulted in inferior outcomes in matched sibling donor (MSD) employing peripheral blood (PB) SCTs. We hypothesized that adding thymoglobulin to PTCy would be able to control GvHD effectively. We retrospectively compared the use of standard GvHD prophylaxis encompassing a combination of PTCy and thymoglobulin (ATG) in patients with myeloid malignancies in a myeloablative conditioning MSD PBSCT. Forty-two patients underwent PBSCT using either methotrexate and cyclosporine (MTX/CSA, 21 patients) or PTCy and ATG (21 patients) as a GvHD prophylaxis. With median follow-ups of 71 months, the 1-year GvHD-free, relapse-free survival rates and chronic GvHD-free survival rate of the standard and PTCy/ATG groups were similar: 24% versus 37% ( P = 0.251) and 29% versus 43% ( P = 0.095), respectively. When focusing on chronic GvHD we observed that 17/35 patients (48.6%) suffered from this, 5/18 (27.8%) treated with MTX/CSA had extensive chronic GvHD, but 0/17 PTCy/ATG did. Twenty-one patients required additional GvHD treatment; 7/21 in the PTCy/ATG received only corticosteroid, while 8/14 MTX/CSA required at least 2 drugs. The 5-year overall survival rates were 52% and 52% ( P = 0.859), and the 5-year disease-free survival rates were 52% and 52% ( P = 0.862) for the MTX/CSA and PTCy/ATG groups, respectively. We conclude that PTCy in combination with ATG without immunosuppression of a calcineurin inhibitor can effectively control GvHD.

Selective Depletion of Alloreacting CD25+ Cells from Stem Cell Allografts Can Reduce Acute Graft-Versus-Host Disease Following Matched Related Donor Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 426-426
Author(s):  
Scott R. Solomon ◽  
Thao Tran ◽  
Charles S. Carter ◽  
Nancy Hensel ◽  
Laura Wisch ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Cell Transplant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Donor T Cells ◽  
Related Donor

Abstract Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplant (SCT), especially in older patients. We previously showed that host-reactive donor T cells are selectively depleted (SD) from an allograft ex vivo, following a short co-culture of donor cells with irradiated T cell stimulators from the recipient and subsequent treatment with an anti-CD25 immunotoxin. We report a pilot study to test the hypothesis that GVHD could be decreased in a cohort of elderly patients receiving SD allografts from HLA-identical sibling donors. Sixteen patients, median age 65 years (range 51–73), with advanced hematologic malignancies were transplanted following reduced-intensity conditioning with fludarabine and either cyclophosphamide (n=5), melphalan (n=5), or busulfan (n=6). Cyclosporine was used as the only additional GVHD prophylaxis. SD allografts contained a median CD34 dose of 4.5x106/kg (range 3.5–7.3) and an SD CD3 dose of 1.0x108/kg (range 0.2–1.5). Fifteen patients achieved sustained engraftment. The helper T lymphocyte precursor (HTLp) frequency assay demonstrated depletion of host-reactive donor T cells in 9/11 cases tested from a mean of 1/182,089 to 1/822,354 (mean 5.5-fold depletion), while third party responses were conserved. Kaplan-Meier estimates of probability of grade II-IV and grade III-IV acute GVHD were lower than those seen in a historical control group of patients receiving cyclosporine alone for GVHD prophylaxis (35±13% vs. 57±10%, p=0.34) and (7±6% vs. 38±6%, p=0.05), respectively. Of note, the two patients who developed visceral (gut ± liver) GVHD showed ineffective allodepletion by HTLp (figure). Chronic GVHD occurred in five of 14 evaluable patients. At a median follow-up of 212 days (range 60 – 690), seven of sixteen patients remain alive and in remission. Relapse deaths occurred in four patients (refractory AML [2], therapy-related MDS [1], and CMML [1]). Non-relapse mortality in this high-risk cohort of patients included graft failure [1], GVHD [2], infection [1], and myocardial infarction [1]. In summary, CD25-directed allodepletion of stem cell allografts can reduce clinically relevant acute GVHD following matched related donor transplantation. Figure Figure

A Randomized, Double Blind Trial, of Hydroxychloroquine for the Prevention of Graft-Versus-Host Disease after Allogeneic Peripheral Blood Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1800-1800
Author(s):  
Tom Fong ◽  
Kim Trinkaus ◽  
Douglas R. Adkins ◽  
Ravi Vij ◽  
Steven Devine ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Peripheral Blood Stem Cell ◽  
Chronic Gvhd ◽  
Double Blind ◽  
Graft Versus Host ◽  
Blood Stem Cell Transplantation

Abstract Hydroxychloroquine (HCQ) is an immunosuppressive lysosomotropic amine that has activity against graft-versus-host disease (GVHD). We previously reported low incidences of acute GVHD in unrelated donor transplant recipients who received prophylactic HCQ in addition to standard GVHD prophylaxis (BBMT2003; 9: 714–721). We herein report results of a single-institution phase III trial, in which 95 recipients of matched sibling allogeneic peripheral blood stem cell transplantation were randomized to receive, in a double-blind fashion, and in addition to prophylactic cyclosporine A (CSA), HCQ or placebo starting 21 days pre-transplant and continued until d+365. HCQ was very well tolerated and not associated with side effects. The addition of HCQ had no effects on lymphocyte subsets both pre- and post-transplant. Overall, the incidence of acute GVHD was 59% in both arms, and severe acute GVHD occurred in 11% (HCQ) and 14% (placebo) (p=0.76). Sixty-one and 46% of patients developed chronic GVHD in the placebo and the HCQ arms, respectively (p = 0.15). With a median follow-up of 18 months, relapse-free and overall survivals were comparable in both groups. In summary, in this randomized trial, the addition of HCQ to single agent CSA was not associated with a reduction of either acute or chronic GVHD; additionally, no significant effects on relapses or survival were observed.

The Bidirectional Relationship Between Cytomegalovirus Replication and Graft-Versus-Host Disease - a Retrospective Single Center Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2236-2236
Author(s):  
Nathan Cantoni ◽  
Hans H Hirsch ◽  
Nina Khanna ◽  
Dominik Heim ◽  
Joerg Halter ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Time Dependent ◽  
Cmv Infection ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Cmv Reactivation ◽  
Multiple Episodes

Abstract Abstract 2236 Poster Board II-213 Cytomegalovirus (CMV) infection and graft-versus host disease (GVHD) are important complications after allogeneic HSCT with a clear link. Multiple studies show that GVHD and its treatment put patients at risk for CMV reactivation. Data on CMV infection as a cause of GVHD, in contrast, are controversial. The association of pre-transplant CMV serology with GVHD development and reduced rates of chronic GVHD after preemptive CMV treatment are indicative of such an association. However, analyses of the direct impact of CMV infection on GVHD are rare; a recent small study found no effect of CMV replication on subsequent development of acute GVHD (Wang et al, BMT 2008). We analyzed in a single centre study the association of CMV reactivation with acute GVHD in 517 patients treated between 1993 and 2008. 59% of patients were male, median age was 42 years (range 16 to 70). Diagnoses were AML (31%), ALL (16%), CML (15%), MDS/MPN (13%), lymphoma (21%), and other (4%). Conditioning regimens were Cy/TBI ±/- etoposide (49%), Cy/Bu (17%), fludarabine and TBI (16%), or others (18%). GVHD prophylaxis consisted of CyA/MTX (78%) or CyA/MMF (21%). Donors were HLA-identical siblings (65%), other family members (4%), or unrelated donors (31%). We made use of a standardized CMV policy over the last decades. CMV reactivation was monitored using real-time polymerase chain reaction or pp65 antigenemia assay weekly in patients without infection, twice weekly in patients with CMV replication. CMV was preemptively treated with gancyclovir or foscarnet. To determine the correlation of CMV infection with acute GVHD, we used a stringent Cox regression model, in which CMV replication was modeled as a time-dependent covariate becoming positive on the day of the first detection of CMV and negative on the first negative assay thereafter. Multiple episodes of CMV replication were considered. Acute GVHD was modeled as a time-dependent covariate in models with CMV infection as endpoint. Hazard ratios (HR) were adjusted for patient age, disease, disease stage, donor type, stem cell source, conditioning regimen and GVHD prophylaxis. The analysis was restricted to the time from transplant to day 100. CMV reactivation was detected at least once in 16% (84/517) of patients at a median of 33 (range 1-95) days after HSCT. Median duration of CMV reactivation was 8.5 days (range 2-62). 19 patients showed multiple episodes of CMV replication. Donor and recipient serostatus significantly influenced the day 100 cumulative incidence of CMV infection: D-/R- (N=173) 6%; D±/R- (N=61) 10%; D±/R± (N=128) 25%; and D-/R± (N=99) 37%, p<0.001. The cumulative incidence for any acute GVHD (grade I-IV) was 67% (95% CI 56-78%) with a median onset time at day 14 (range day 5-94); the cumulative incidence for severe acute GVHD (grade II-IV) was 48% (95% CI 40-56%). When both endpoints (CMV, GVHD) were combined, 150 patients (29%) experienced neither GVHD nor CMV reactivation, 281 (54%) GVHD only, 19 (4%) CMV reactivation only, and 67 (13%) both CMV reactivation and GVHD. Of the 67 patients with both GVHD and CMV, 46 (69%) developed GVHD prior to CMV reactivation, 17 (25%) developed GVHD during CMV reactivation, and 4 (6%) developed GVHD after CMV reactivation. Cox modeling revealed that presence of GVHD grade II-IV increased the risk of CMV infection (HR 1.61, 95% CI 1.03-2.52, p=0.04). Similarly, patients were at increased risk of developing acute GVHD during phases of CMV replication (grades I-IV: HR 2.23, 95% CI 1.39-3.81, p=0.001; grades II-IV: HR 2.00, 95% CI 1.08-3.72, p=0.03). GVHD grade was not influenced by concomitant CMV reactivation (median grade II, in patients with or without CMV reactivation). The overall proportion of GVHD that occurred during phases of CMV replication was small (3% versus 64% occurring in CMV non replicating patients). Even if GVHD occurring after resolution of CMV reactivation was additionally taken into account, the majority of GVHD occurred without preceding CMV infection (63% versus 4%). These data describe the complex relationship between CMV infection and GVHD. We confirm previous studies that GVHD (and GVHD therapy) can induce CMV infection. We describe as well that patients with active CMV replication have a significantly higher risk of developing GVHD compared to patients without CMV replication. However, the proportion of GVHD that could be linked to CMV reactivation was small in this population with a low overall incidence of CMV reactivation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis

Blood ◽  
2007 ◽  
Vol 110 (2) ◽  
pp. 490-500 ◽  
Author(s):  
Francisco M. Marty ◽  
Julie Bryar ◽  
Sarah K. Browne ◽  
Talya Schwarzberg ◽  
Vincent T. Ho ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Graft Versus Host Disease ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Cmv Reactivation

AbstractSirolimus-based immunosuppressive regimens in organ transplantation have been associated with a lower than expected incidence of cytomegalovirus (CMV) disease. Whether sirolimus has a similar effect on CMV reactivation after allogeneic hematopoietic stem cell transplantation (HSCT) is not known. We evaluated 606 patients who underwent HSCT between April 2000 and June 2004 to identify risk factors for CMV reactivation 100 days after transplantation. The cohort included 252 patients who received sirolimus-tacrolimus for graft-versus-host disease (GVHD) prophylaxis; the rest received non–sirolimus-based regimens. An initial positive CMV DNA hybrid capture assay was observed in 225 patients (37.1%) at a median 39 days after HSCT for an incidence rate of 0.50 cases/100 patient-days (95% confidence interval [CI], 0.44-0.57). Multivariable Cox modeling adjusting for CMV donor-recipient serostatus pairs, incident acute GVHD, as well as other important covariates, confirmed a significant reduction in CMV reactivation associated with sirolimus-tacrolimus–based GVHD prophylaxis, with an adjusted HR of 0.46 (95% CI, 0.27-0.78; P = .004). The adjusted HR was 0.22 (95% CI, 0.09-0.55; P = .001) when persistent CMV viremia was modeled. Tacrolimus use without sirolimus was not significantly protective in either model (adjusted HR, 0.66; P = .14 and P = .35, respectively). The protective effect of sirolimus-containing GVHD prophylaxis regimens on CMV reactivation should be confirmed in randomized trials.

A Possible Association between the Presence of Interleukin-4-Secreting Cells and a Reduction in the Risk of Acute Graft-Versus-Host Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4968-4968
Author(s):  
Maki Takabayashi ◽  
Heiwa Kanamori ◽  
Hirotaka Takasaki ◽  
Satoshi Yamaji ◽  
Hideyuki Koharazawa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Interleukin 4 ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract We monitored interleukin-4 (IL-4), interferon-gamma (IFN-g), and tumor necrosis factor alpha (TNF-a)-secreting cells using an enzyme-linked immunospot (ELISPOT) assay in a prospective study to assess the cytokine network after transplantation. Peripheral blood mononuclear cells were collected from 23 patients who received allogeneic stem cell transplantation, from before the preconditioning regimen to 56 days after transplantation. The frequency of IL-4-secreting cells was significantly higher in 5 patients receiving peripheral blood stem cell transplantation (PBSCT) than that in 18 patients who received bone marrow transplantation (BMT). Based on IFN-g and TNF-a release, there was a trend toward a decrease in the number of cytokine-secreting cells in PBSCT. Furthermore, patients who did not develop acute graft-versus-host disease (GVHD, n = 5) showed a significantly higher number of IL-4-secreting cells compared with those who developed acute GVHD (n = 18). These results indicate that the high percentage of IL-4-secreting cells may be responsible for the inhibition of acute GVHD. In addition, the increased percentage of IL-4-secreting cells may be responsible for the unexpected low incidence of acute GVHD in PBSCT, despite the presence of large numbers of mature T cells in the donor infusion.

Graft Versus Host Disease (GVHD) Prophylaxis with Everolimus and Tacrolimus Is Associated with a High Incidence of Sinusoidal Obstruction Syndrome and Microangiopathy – Results of the EVTAC Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1172-1172
Author(s):  
Uwe Platzbecker ◽  
Malte Bonin ◽  
Eray Goekkurt ◽  
Joergen Radke ◽  
Alexander Kiani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Prophylactic Regimen ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Abstract Beyond disease biology, the success of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with hematological malignancies is mainly determined by the occurrence and extent of graft versus host disease (GVHD). Therefore, prevention of GVHD is the major goal and challenge in clinical HSCT. A calcineurin-inhibitor combined with methotrexate is the standard graft versus host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (HSCT). Everolimus is a derivative of sirolimus, which also seems to mediate anti-leukemia effects. Given the potential synergism and favourable toxicity profile of everolimus and tacrolimus (EVTAC) after allogeneic HSCT we sought to investigate the efficacy of this combination in patients with either myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). We report a combination of everolimus (days 0–56) and Tacrolimus (from day −1 on) in 24 patients (pts, median age 62 years) with either MDS (n=17) or AML (n=7) undergoing intensive busulfan-based conditioning followed by HSCT from related (n=4) or unrelated matched (n=12) or 1-allele mismatched (n=8) donors. All pts engrafted and only one experienced grade IV mucositis. However, although everolimus was scheduled to be administered up to day 56, patients received the drug a median of 44 days (range 10–56) only. The reason for premature discontinuation (50%) were either occurrence of early-onset (day 6) GVHD associated hyperbilirubinemia CTC grade 4 (n=1), transplantation-associated microangiopathy (TMA, n=3), sinusoidal obstructive syndrome (SOS) of the liver (n=6) or a drop of platelets after engraftment by at least 50% (n=2). Nine pts (37%) developed grade II–IV acute GVHD, however, chronic extensive GVHD was observed in 11 of 17 (64%) evaluable pts. TMA occurred in 7 pts (29%) with two cases of acute renal failure. In five out of seven patients with TMA either tacrolimus (n=4) or everolimus (n=1) blood through levels were slightly above the upper target level at the time of TMA appearance. The study was terminated prematurely because additional 6 pts (25%) developed SOS, which was fatal in two cases. With a median follow-up of 26 months, the 2-year overall survival rate is 47%. In conclusion, although this new combination appears to be effective as prophylactic regimen for acute GVHD, the incidence of TMA and SOS seems to be higher compared to other regimens. As a result this combination cannot be recommended as prophylactic regimen after busulfan-based intensive conditioning. However, studies in the context of TBI-based or reduced-intensity conditioning regimens might come to a different conclusion.

Severe Gut Acute Graft Versus host Disease (GVHD) Influence Thrombotic Microangiopathy in 86 Allogeneic Hematopoietic Stem Cell Recipients Who Received Tacrolimus-Based Regimen for GVHD Prophylaxis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1955-1955
Author(s):  
Jorge Labrador ◽  
Oriana López-Godino ◽  
Lucía López-Corral ◽  
Estefanía Pérez-López ◽  
Mónica Cabrero-Calvo ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Thrombotic Microangiopathy ◽  
Acute Gvhd ◽  
Host Disease ◽  
Allogeneic Hsct ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Acute Graft

Abstract Abstract 1955 Background and aims: Transplantation-associated thrombotic microangiopathy (TA-TMA) is a significant complication of allogeneic stem cell transplantation (HSCT). Although endothelial injury represents the final common pathway of disease, the exact pathophysiology of TA-TMA remains unclear. A variety of potential risk factors have been proposed such as different conditioning regimens, the development of acute graft versus host disease (GVHD), concomitant infection, or the use of calcineurin inhibitor (cyclosporine, tacrolimus) and sirolimus. The recent use of both tacrolimus and sirolimus for GVHD prophylaxis suggest increasing the risk of TA-TMA, especially in patients receiving busulfan and cyclophosphamide. However, there are little studies in which tacrolimus/sirolimus GVHD prophylaxis was compared with other tacrolimus-based regimens in order to determine the really increased incidence of TA-TMA. The purpose of this study was to determine the incidence and risk factors of TA-TMA in 86 allogeneic-HSCT recipients who received tacrolimus-based regimens (with sirolimus or with methotrexate) for GVHD prophylaxis. Patients and Methods: We conducted a retrospective cohort study of 86 consecutive allogeneic-HSCT recipients (aged over 18 years) transplanted in our unit between September 2007 and July 2012; GVHD prophylaxis consisted on tacrolimus and methotrexate (N = 19) or tacrolimus and sirolimus (N= 64); 3 patients received tacrolimus and sirolimus for acute GVHD treatment. Median age was 51 years (range 20–68) and 59.3% male. 40.7% of patients were diagnosed of acute leukemia, 23.3% myelodisplastic syndrome, 23.2% lymphoproliferative disorders, 7% multiple myeloma, 5.9% other hematological malignancies. The EBMT status at the moment of HSCT was intermediate/advanced in 63% of patients. The source of stem cells was peripheral blood in 87.2% and bone marrow in 12.8%. 57% of patients receiving an unrelated donor transplant. Nineteen patients (22.1%) received a HLA-mismatch graft. Reduced intensity conditioning was administered in 74.4%. 67.4% developed acute GVHD, 58.1% grade II-IV acute GVHD. Median follow-up was 248 days (range 16–1357). The diagnosis of TA-TMA was considered according to probable TMA criteria as defined by validation study by Cho et al. Results: TA-TMA occurred in 9/86 patients (10,5%): 2/19 patients in the tacrolimus-methotrexate regimen group (10.5%) and 7/67 in the tacrolimus/sirolimus regimen group (10.4%). Median time until diagnosis of TA-TMA was 67 days (range, 37 – 405 days), and 8/9 patients were diagnosed before the day +110 post-HSCT; none of them developed chronic GVHD previously to the diagnosed of TA-TMA. Several variables have been analyzed but only acute GVHD (p=0.026) and acute gut GVHD (p=0.007) were significantly associated with TA-TMA in the univariate analysis. Of note, in the tacrolimus/sirolimus group, only acute gut GVHD (p=0.04) but not acute GVHD, was associated with TA-TMA. In the multivariate analysis, only grade ≥2 acute gut GVHD retained their association with TA-TMA development (OR = 13.33, 95% CI = 1.51 – 117.38). Conclusions: In contrast to previously published evidence, these data support that the use of tacrolimus/sirolimus GVHD prophylaxis does not increase the risk of TA-TMA compared to tacrolimus/methotrexate regimen. However, none of the patients included in our study have received busulfan-cyclophosphamide conditioning. On the other hand, the most important risk factor for TA-TMA in allogeneic-HSCT recipients who received tacrolimus-based GVHD prophylaxis regimens was grade ≥2 acute gut GVHD. Consequently we propose especially close monitoring for TA-TMA in these patients. Disclosures: No relevant conflicts of interest to declare.

Does Donor Epstein-Barr Virus (EBV) Seropositivity Affect Recipient's Risk of Graft Versus Host Disease (GVHD) in Allogeneic Hematopoietic Stem Cell Transplantation (Allo-HSCT)?

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5766-5766
Author(s):  
Erden Atilla ◽  
Esmanur Kaplan ◽  
Pinar Ataca Atilla ◽  
Selami Kocak Toprak ◽  
Pervin Topcuoglu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Abstract Introduction: EBV seropositivity in general population is 80%. Reactivation of latent infection in pre-transplant seropositive patients causes post-transplant lenfoproliferative disease (PTLD) following Allo-HSCT. The effect of donor EBV positivity on recipient's risk of graft versus host disease is not clear. Our aim is to present EBV seroprevalence and PTLD incidence as well as demonstrating the relation of EBV seropositivity with GVHD. Patients and Methods: A total of 364 allogeneic stem cell transplant recipients and donors were evaluated retrospectively from 2006 to 2015. During Allo-HSCT preparation procedures all recipients and donors were serologically tested. EBV specific IgG (VCA-IgG, EBNAIgG, EA-IgG) and IgM (VCA-IgM) antibodies were determined by Chemiluminescence by ARCHITECT lab analyzers using commercially available kits (Abbott, USA). All patients were followed for reactivation. Results: EBV IgG positivity was detected in 338 of recipients (92.8%) and 283 of donors (77.7%). There was no statistically difference detected between related or unrelated transplants. The mean age was 37 (range 16-67). 217 recipients were male (60%). 295 (81%) patients were transplanted for malign hematological diseases. The majority of patients were grafted from full-matched related donors (258, 71%). The most common source of stem cell was peripheral blood in 299 patients (82%) followed by bone-marrow in 56 patients (15%), bone-marrow plus peripheral blood in 9 patients (3%). 273 (75%) patients received myeloablative conditioning regimen. All patients received prophylactic acyclovir (in related transplants 400mg 3 times daily, in un-related transplants 800mg 3 times daily) starting from conditioning and up to three months posttranplant period. One pretransplant seropositive 26 year-old aplastic anemia patient had PTLD with EBV IgM positivity within 3 months posttransplant. He received 4 cycles of rituximab and prednisolone and achieved complete response. Three patients had EBV IgM positivity in posttransplant 4, 9 and 24th months with symptoms of infectious mononucleosis. The seropositivity resolved without treatment. Acute GVHD developed in 223 patients (61%) whereas chronic GVHD was detected in 285 (78%) of patients. The incidence of acute GVHD was similar when donor was EBV seropositive compared to seronegative (78% vs 22%, p=0.72). Chronic GVHD incidence was similar between donor EBV seropositive group compared to seronegative group (80% vs 20%, P=0.199). Conclusion: EBV seropositivity is common detected in 92.8% of our allo-HSCT recipient cohort. Donor EBV status did not have an effect on developing acute or chronic GVHD. Disclosures No relevant conflicts of interest to declare.

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