The Combination of Tacrolimus (T), Sirolimus (S), and Rabbit Anti-Thymocyte Globulin (Thymoglobulin Thymo) to Prevent Acute Graft-Vs-Host Disease (aGVHD) in Patients (pts) Receiving Unrelated Hematopoietic Stem Cell Transplantation (UHSCT).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2239-2239
Author(s):  
Zaid S Al-Kadhimi ◽  
Zartash Gul ◽  
Lawrence G. Lum ◽  
Lois Ayash ◽  
Muneer H. Abidi ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Immune Suppression ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Viral Infections ◽  
Disease Relapse ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Abstract 2239 Poster Board II-216 Background: Acute graft versus host disease aGVHD continues to affect approximately 60% or more of patients undergoing UHSCT, with significant mortality and morbidity. Furthermore viral infections such as Cytomegalo virus (CMV) affect approximately two thirds of these patients. Methods: In a phase II trial, we prospectively evaluated whether adding Thymo (4.5 mg/kg divided doses on days -1,-2, and -3) to Tacrolimus and Sirolimus combination for aGVHD prophylaxis in recipients of UHSCT would decrease the rate of aGVHD. The primary endpoint is aGVHD, which is calculated as cumulative incidence. Since infections are a concern after T cell depletion, the incidence of infections and adverse events were monitored closely. Results: There were 25 patients (pts) with median age of 51(20-70) years enrolled in the protocol, 10 females and 15 males. There were 10 AML (5CR1, 5CR2), 7 MDS (untreated), 2 ALL (CR1), 1 ALL/AML (uCR1), 1 CML (CP), 1 CMML (untreated), 1 granulocytic Sarcoma (CR1), 1 NKT cell lymphoma (CR3), and 1 DLBCL(CR2). Preparative regimens included Bu/Flu (21 pts), VP16/TBI (2 pts) R-BEAM (1 pt), and Flu/MEL (1 pt). All patients received peripheral blood hematopoietic stem cells (PBHSC) mobilized with granulocyte colony stimulating factor G-CSF with an average CD34+ dose of 8.24×10 6/kg (3.7-14.3). All patients received daily G-CSF starting day +6 till engraftment. After molecular typing, 11 of 25 patients received HLA fully matched graft, 11 of 25 received a 1 antigen (Ag) mismatched graft, and 3 of 25 received a 2 Ag mismatched unrelated PBHSC graft. All patients' engrafted. Median engraftment day is 12 (9,13). Eighteen patients had passed the day 100 time point; seven pts did not reach day 100. Three deaths occurred, due to: relapse (1), multi organ failure (1), and pneumonia (1). Two patients experienced disease relapse. Both went into complete remission once immune suppression was withdrawn, demonstrating clear graft versus Leukemia (GVL) effect, before day 100. Seven of 25 pts developed aGVHD, 1 developed aGVHD after relapse. Three developed grade 1 aGVHD, 3 pts developed grade 2 aGVHD. One pt developed grade 4 aGVHD after immune suppression withdrawal due to disease relapse. Five patients needed systemic steroids, maximum duration 36 days. All aGVHD cases have responded to therapy. The cumulative incidence rate for aGVHD at 100 days is 0.258 ( 0.101, 0.448); the cumulative incidence rates of competing events: relapse is 0.146 (0.034, 0.334) and death without GVHD or relapse 0.050 (0.003, 0.212). Patients tolerated Thymo well. Two patients developed thrombotic thrombocytopenic purpura (TTP), one patient after day 100 that required discontinuation of tacrolimus and sirolimus. Four patients developed CMV PCR sub-clinical activation 16% (95% CI 5.7-33.6%), which resolved with treatment. Six patients developed PCR sub-clinical Epstien-barr virus (EBV) activation 20% (95% CI 8.2-38.4), 5/6 needed Rituximab. Three patients developed Herpese simplex virus (HSV) stomatitis, two rhinovirus upper respiratory tract infections, and 3 BK viral cystitis. 14 patients had a documented bacterial infection all resolved. Apart from 2 oral candidiasis, no fungal infections observed. All infections have resolved. Conclusion: These early results suggest that the combination of Tacrolimus/Sirolimus and Thymo in pts undergoing unrelated HSCT is well tolerated and is associated with a low rate and severity of acute GVHD, and early GVL effect as demonstrated in two patients. Low rates of CMV viral infections were seen. Further accrual and a longer follow-up will be needed to confirm these encouraging results. Disclosures: Al-Kadhimi: Genzyme pharmacutical: Research Funding. Off Label Use: Thymoglobulin is used to prevent graft versus host disease in unrelated transplant in this protocol. That is an off lable drug use.. Abidi:Merck Pharmaceuticals: Research Funding.

scholarly journals Ruxolitinib for Steroid-Refractory Acute Graft-Versus-Host Disease: A Single Centre Retrospective Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4878-4878
Author(s):  
Yuan Suo ◽  
Jiapei Liu ◽  
Yiming Sun ◽  
Qiaoyuan Wu ◽  
Hua Jin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Retrospective Study ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Second Line ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Background Acute graft-versus-host disease (aGVHD) is the major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation(allo-HSCT). But only 40% of the patients will respond to first-line therapies Corticosteroids. Ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, reduces the incidence and severity of GVHD while preserving graft-versus-leukemia effects in preclinical models. The retrospective study evaluated the efficacy of ruxolitinib compared with other second-line therapies for steroid-refractory aGVHD (SR-aGVHD) in a single-center. Methods A total of 90 patients who developed SR-aGVHD after HSCT were evaluated in this retrospective study.They were treated with ruxolitinib (n=45) or other salvage-therapies (n=45) including MTX, basiliximab, etanercept and MSC at our institution. The primary endpoint was the overall response rate (ORR) at Day 28. Additional endpoints included overall survival (OS), cumulative incidence rates of failure-free survival (FFS), relapse, non-relapse mortality (NRM) and cGVHD. Treatment failure was defined as 1) addition of new systemic therapy for aGVHD, 2) NRM, 3) relapse, 4) progression of hematologic disease. FFS and OS were calculated from the day of starting the use of second-line treatments for aGVHD. Results The median age was 34 years (range 14-69). At the time of enrollment 25 patients had grade Ⅱ disease, 39 with grade Ⅲ disease, 26 with grade IV disease. The skin was involved in 54.4%, lower gastrointestinal (GI) tract in 78.9% and liver in 20.2%. With a median follow-up of 1.33 years, the ORR at day 28 was higher in ruxolitinib group than non-ruxolitinib group (62.2% [95% CI, 47.5%-77.0%] vs. 26.7% [95% CI, 13.2%-40.1%], P=0.001) (Table 1). The 1-year OS was 64.4 % and 45.5% in the two groups, respectively (P=0.0382). Ruxolitinib treatment also improved the 1-year cumulative incidence of FFS (57.8% vs. 26.6%, P=0.002), while the 1-year cumulative incidence of relapse did not differ significantly (9.6% vs. 20.0%, P=0.195). The 1-year cumulative incidence of NRM was lower in the ruxolitinib group than the non-ruxolitinib group (24.4% vs. 45.3%, P=0.023). The 1-year and 3-year cumulative incidence of cGVHD were 17.8% vs. 33.3% and 26.8% vs. 44.4% between the ruxolitinib group and non-ruxolitinib group (P=0.10 and P=0.04). Conclusions Our study demonstrated that ruxolitinib is effective than other second-line treatments in patients with SR-aGVHD due to the higher response rates and the improvement of prognosis. Furthermore, ruxolitinib could reduce the incidence and severity of chronic GVHD in aGVHD patients. Keywords: Ruxolitinib; Steroid-refractory; Acute graft-versus-host disease; Haploidentical hematopoietic stem cell transplantation Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effect of Early Post-Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 613
Author(s):  
Nidhi Sharma ◽  
Qiuhong Zhao ◽  
Bin Ni ◽  
Patrick Elder ◽  
Marcin Puto ◽  
...  
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Tacrolimus Concentration ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
The Impact ◽  
Risk Of Relapse ◽  
Acute Graft

Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as a GVHD prophylaxis. However, there is variability in the serum concentrations of TAC, and little is known on the impact of early TAC levels on aGVHD. We retrospectively analyzed 673 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002 and 2016. Week 1 TAC was associated with a lower risk of aGVHD II–IV at TAC level ≥10.15 ng/mL (p = 0.03) compared to the lowest quartile. The cumulative incidence of relapse at 1, 3 and 5 years was 33%, 38% and 41%, respectively. TAC levels at week 2, ≥11.55 ng/mL, were associated with an increased risk of relapse (p = 0.01) compared to the lowest quartile. Subset analysis with acute myeloid leukemia and myelodysplastic syndrome patients showed significantly reduced aGVHD with TAC level ≥10.15 ng/mL at week 1 and a higher risk of relapse associated with week 2 TAC level ≥11.55 ng/mL (p = 0.02). Hence, achieving ≥10 ng/mL during the first week of HCT may mitigate the risk of aGVHD. However, levels (>11 ng/mL) beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse.

scholarly journals 1075. Absolute Lymphocyte Count as a Predictor of Cytomegalovirus (CMV) Infection and Recurrence in Hematopoietic Stem Cell Transplant (HSCT) Recipients

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S565-S565
Author(s):  
Joanne Reekie ◽  
Marie Helleberg ◽  
Christina Ekenberg ◽  
Mark P Khurana ◽  
Isabelle P Lodding ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Lymphocyte Count ◽  
Absolute Lymphocyte Count ◽  
Cell Transplant ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Increased Risk ◽  
Acute Graft

Abstract Background Cytomegalovirus (CMV) is a serious complication following Hematopoietic Stem Cell Transplant (HSCT) and can lead to serious organ disease and mortality. This study aimed to investigate the association between absolute lymphocyte count (ALC) and CMV to determine whether ALC could help to identify those at an increased risk of CMV infection and recurrence Methods Adults undergoing HSCT between 2011 and 2016 at Rigshospitalet, Denmark were included. Cox proportional hazards models investigated risk factors, including ALC, for CMV infection in the first year post-transplant and recurrent CMV infection 6 months after clearance and stopping CMV treatment for the first infection. For the primary outcome ALC was investigated as a time-updated risk factor lagged by 7 days, and for recurrent CMV, ALC measured at the time at the time of stopping treatment for the first CMV infection was investigated (+/- 7 days). Results Of the 352 HSCT recipients included, 57% were male, 40% received myeloablative conditioning, 42% had high risk (D-R+) CMV IgG serostatus at transplant and the median age was 56 (IQR 43-63). 143 (40.6%) patients had an episode of CMV DNAemia a median of 47 days after transplant (IQR 35-62). A lower current ALC (≤ 0.3 x109/L) was associated with a higher risk of CMV infection in univariate analysis compared to a high current ALC (> 1 x109/L). However, this association was attenuated after adjustment, particularly for acute graft versus host disease (Figure). 102 HSCT recipients were investigated for risk of recurrent CMV of which 41 (40.2%) had a recurrent CMV episode a median of 27 days (IQR 16-50) after stopping CMV treatment for the first infection. A lower ALC (≤ 0.3 x109/L) at the time of stopping CMV treatment was associated with a significantly higher risk of recurrent CMV after adjustment (Figure). A higher peak viral load (> 1500 IU/ml) during the first episode of CMV infection was also associated with an increased risk of recurrent CMV (aHR 2.47, 95%CI 1.00-6.10 compared to < 750 IU/ml). Association between absolute lymphocyte count (ALC) and risk of CMV infection and recurrent CMV within 6 months. **First CMV infection multivariable model also adjusted for sex, CMV serostatus, age, year of transplant, Charlson Comorbidity Index, Anti-thymocyte globulin (ATG) given, HLA donor-recipient matching, and acute graft versus host disease (time-updated) *Recurrent CMV infection multivariable model also adjusted for conditioning regimen, sex, CMV serostatus, age, year of transplant Anti-thymocyte globulin (ATG) given, HLA donor-recipient matching, and acute graft versus host disease and peak CMV viral load during the first CMV infection Conclusion A lower ALC at the time of stopping treatment for the first CMV infection was associated with an increased risk of recurrent CMV and could be used to help guide decisions for augmented CMV surveillance and clinical awareness of CMV disease symptoms in these patients. Disclosures All Authors: No reported disclosures

scholarly journals Tissue immune profiles supporting response to mesenchymal stromal cell therapy in acute graft-versus-host disease—a gut feeling

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Caroline Gavin ◽  
Erik Boberg ◽  
Lena Von Bahr ◽  
Matteo Bottai ◽  
Anton Törnqvist Andrén ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Mesenchymal Stromal Cell ◽  
Stromal Cell ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Profile ◽  
Acute Graft

AbstractAcute graft-versus-host disease (aGvHD), post-allogeneic hematopoietic stem cell transplantation, is associated with high mortality rates in patients not responding to standard line care with steroids. Adoptive mesenchymal stromal cell (MSC) therapy has been established in some countries as a second-line treatment.Limitations in our understanding as to MSC mode of action and what segregates patient responders from non-responders to MSC therapy remain. The principal aim of this study was to evaluate the immune cell profile in gut biopsies of patients diagnosed with aGvHD and establish differences in baseline cellular composition between responders and non-responders to subsequent MSC therapy.Our findings indicate that a pro-inflammatory immune profile within the gut at the point of MSC treatment may impede their therapeutic potential. These findings support the need for further validation in a larger cohort of patients and the development of improved biomarkers in predicting responsiveness to MSC therapy.

Impact of clostridiodes difficile infection on acute graft-versus-host disease in allogenic transplant patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19027-e19027
Author(s):  
Prasanth Lingamaneni ◽  
Vatsala Katiyar ◽  
Rohit Kumar ◽  
Maha A.T. Elsebaie ◽  
Hashim Mann ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Lymphoblastic Leukemia ◽  
Index Admission ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Hospitalization Costs ◽  
Acute Graft

e19027 Background: Clostridiodes difficile infection (CDI) is reported to occur up to 9-fold higher in allogenic hematopoietic stem cell transplant (HSCT) recipients compared to the general population of hospitalized patients. This is attributed to disruption of gut microbiome by antibiotics, myeloablative regimens, neutropenia, prolonged hospitalization, and immunosuppressive regimens administered to prevent acute graft-versus-host disease (aGVHD). CDI by disruption of the intestinal microbiome may trigger gastrointestinal aGVHD. Previous studies from HSCT centers have reported conflicting data on the relationship between CDI and subsequent development of aGVHD. Methods: The Nationwide Readmissions Database was queried for admissions of adult allogenic HSCT patients between 2016 and 2018. Those with and without CDI during index admission were compared. Multivariable logistic regression was used to evaluate the primary outcome of risk of aGVHD in the index admission or within 100 days post-engraftment. Results: A total of 13518 allogenic HSCT patients were included in the study. Mean age was 52.4 years. 57.2% of patients were female. The most common underlying diagnoses were acute myeloid leukemia (38%), myelodysplastic syndrome (17%) and acute lymphoblastic leukemia (14%). 11.1% of the index admissions were complicated by CDI. Rates of aGVHD during the index admission or 100 days post-engraftment were similar between CDI and non-CDI groups: 13.8% vs. 12.1%, p=0.19 during index admission and 29.2% vs. 26.1%, p=0.09 during 100 days post-engraftment. Nonetheless, patients with CDI had longer length of hospital stay (34.6 vs 29.8 days, p<0.0001), higher hospitalization costs ($608K vs $506K USD) and greater rate of inpatient mortality (7.3% vs 4.6%, p<0.001). In the multivariate regression analysis, CDI during index admission was not associated with risk of development of aGVHD (Adjusted Odds Ratio 1.14, 95% Confidence Interval 0.87-1.48, p=0.34). Age and unrelated donor HSCT were predictive of risk of aGVHD. Conclusions: CDI during index admission was not predictive of aGVHD during the first 100 days post-allogenic HSCT. HSCT patients are frequency colonized with C.difficile. Diarrhea secondary to CDI may resemble gastrointestinal aGVHD. Therefore, overdiagnosis of CDI in this population is a concern. Antimicrobial stewardship and use of clinical decision support tools have been advocated recently to decrease testing of HSCT patients with C.difficile colonization. Multivariable analysis of risk factors of aGVHD.[Table: see text]

scholarly journals An investigation of the diagnostic, predictive, and prognostic impacts of three colonic biopsy grading systems for acute graft versus host disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256543
Author(s):  
Andreas Kreft ◽  
Katrin Hippe ◽  
Eva Maria Wagner-Drouet ◽  
Isabelle Ries ◽  
Arne Kandulski ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Steroid Therapy ◽  
Graft Versus Host Disease ◽  
Steroid Treatment ◽  
Systemic Steroid ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grading Systems ◽  
Acute Graft

Acute graft versus host disease (aGvHD) is an important, life-threatening complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). To investigate the value of multiple simultaneous colon biopsies in improving diagnostic accuracy in patients with aGvHD, we retrospectively analyzed 157 patients after alloHSCT. The biopsies were evaluated individually using three established histological grading systems (Lerner, Sale, and Melson). The maximum, minimum, median, and mean histological aGvHD grades were calculated for each patient, and the results were correlated with the Glucksberg grade of clinical manifestation of GvHD, steroid therapy status, and outcome. We found that multiple colon biopsies enhanced diagnostic sensitivity. Moreover, higher histological grades correlated with steroid therapy initiation and refractoriness; the latter particularly occurred when advanced damage was present in all samples and healthy colon mucosa was reduced or absent. On multivariate analysis, the minimal Lerner and Glucksberg grades for intestinal aGvHD were significantly associated with steroid treatment failure. Ninety-nine patients died. The median survival was 285 days after the biopsies were taken. Fifteen patients died from relapse of their underling disorder and 84 from other causes, mostly infection (53 patients) and GvHD (14 patients). Multivariate analysis revealed a significant association between none-relapse mortality and the mean Lerner grade, minimum Melson grade, Glucksberg organ stage, and platelet counts. Thus, we found the Lerner system to be superior to the other grading methods in most instances and histologic evaluation of multiple simultaneously obtained biopsies from the colon to result in a higher diagnostic yield, which helps plan systemic steroid treatment while predicting treatment response and outcome.

scholarly journals Low cyclosporine concentrations in children and time to acute graft versus host disease 

2020 ◽  
Author(s):  
Eun Kyung Chung ◽  
Jeong Yee ◽  
Jae Youn Kim ◽  
Hye sun Gwak
Keyword(s):  
Graft Versus Host Disease ◽  
Careful Attention ◽  
Target Concentration ◽  
Blood Concentrations ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Time Periods ◽  
Initial Target ◽  
Acute Graft

Abstract Background: Achievement of target blood concentrations of cyclosporine (CsA) early after transplantation is known to be highly effective for reducing the incidence of acute graft versus host disease (aGVHD). However, no research has been conducted for predicting aGVHD occurrence with low CsA concentrations at different time periods. The objective of this study was to investigate the risk of aGVHD according to low CsA concentrations at lag days in children with allogenic hematopoietic stem cell transplantation (HSCT). Methods: The records of 61 consecutive children who underwent allogeneic HSCT and received CsA as prophylaxis against aGVHD between May 2012 and March 2015 were retrospectively evaluated. The main outcome was any association between low CsA concentrations at lag days and aGVHD occurrence, which was examined for the first month after transplantation. Mean CsA concentrations at three lag periods were calculated: lag days 0-6, 7-13, and 14-20 before aGVHD occurrence.Results: Patients whose mean CsA concentrations at lag days 0-6 did not reach the initial target concentration had 11.0-fold (95% confidence interval [CI]: 2.3-51.9) greater incidence of aGVHD. In addition, the AORs of low CsA concentrations at lag days 7-13 and 14-20 for developing aGVHD were 108.2 (95% CI: 7.7-1515.5) and 12.1 (95% CI: 1.1-138.1), respectively. Conclusions: After low CsA concentrations are detected, careful attention needs to be paid to prevent aGVHD.

Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Blood ◽  
2004 ◽  
Vol 104 (4) ◽  
pp. 1224-1226 ◽  
Author(s):  
Vincent T. Ho ◽  
David Zahrieh ◽  
Ephraim Hochberg ◽  
Eileen Micale ◽  
Jesse Levin ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Phase 1 ◽  
Interleukin 2 ◽  
Maximum Tolerated Dose ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Denileukin Diftitox ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Denileukin diftitox (Ontak), a recombinant protein composed of human interleukin 2 (IL-2) fused to diphtheria toxin, has selective cytotoxicity against activated lymphocytes expressing the high-affinity IL-2 receptor. We conducted a phase 1 study of denileukin diftitox in 30 patients with steroid refractory acute graft-versus-host disease (GVHD). Seven patients received 9 μg/kg intravenously on days 1 and 15; 18 received 9 μg/kg intravenously on days 1, 3, 5, 15, 17, and 19; and 5 received 9 μg/kg intravenously on days 1 to 5 and 15 to 19. Hepatic transaminase elevation was the dose-limiting toxicity (DLT), and dose level 2 was the maximum tolerated dose (MTD). Overall, 71% of patients responded with complete resolution (12 of 24; 50%) or partial resolution (5 of 24; 21%) of GVHD. Eight of 24 patients (33%) are alive at 6.3 to 24.6 months (median, 7.2 months). Denileukin diftitox is tolerable and has promising activity in steroid-refractory acute GVHD. (Blood. 2004;104:1224-1226)

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