Antithymocyte Globulin-Based Prophylaxis for Graft Versus Host Disease Compared to Post-Transplant Cyclophosphamide-Based Prophylaxis in Matched Unrelated Donor Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2307-2307
Author(s):  
Sara Redondo Velao ◽  
Mi Kwon ◽  
Diana Champ ◽  
MJ Pascual Cascon ◽  
Pascual Balsalobre ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Antithymocyte Globulin ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Abstract INTRODUCTION Post-transplant high-dose cyclophosphamide (PTCy) has shown to prevent graft versus host disease (GvHD) after haploidentical allogeneic hematopoietic cell transplantation (HSCT). Although less extended, its use after matched unrelated donor (MUD) HSCT in combination with additional immunosuppression has been encouraging. The aim of this study was to analyze and compare outcomes of antithymocyte globulin based (ATG) versus PTCy-based GvHD prophylaxis in matched unrelated donor HSCT. MATERIAL AND METHODS We retrospectively analyzed 51 MUD (8/8 HLA-matched) transplants performed in two Spanish centers: 25 received ATG-based prophylaxis and were performed from 2010 to 2013, and 26 received PTCy-based prophylaxis and were performed from 2013 to 2016. RESULTS Characteristics of patients and post-HSCT complications are detailed in Table 1. There were no significant differences in age, gender, diagnosis and Disease risk index. For the ATG group, conditioning regimen consisted of fludarabine combined with busulfan (80%) or melphalan (12%), and TBI plus cyclophosphamide (8%). All patients received ATG 2 mg/kg from day -4 to day -2 followed by methotrexate and cyclosporine (CsA). Conditioning regimen for patients from the PTCy group consisted of fludarabine and busulfan (85%) and thiotepa combined with busulfan and fludarabine (15%). GvHD prophylaxis consisted of PTCy 50 mg/kg on days +3 and +4, combined with: CsA plus MMF in 57%, CsA alone in 31%, or tacrolimus plus MMF or sirolimus in 8%, and tacrolimus alone in 4%. With a median follow-up of 58 months for the ATG group and 12 months for the PTCy group, there were no statistically significant differences in overall survival at 18 months (56% vs 85%, p=0.08), in event free survival (56% vs 68%, p=0.5), and in cumulative incidence of relapse (12% vs 18%, p=0.3). Non-relapse mortality at 12 months was significantly higher in the ATG group (32% vs 10%, p = 0.04). The ATG group presented more cases of hepatic toxicity grades I-IV and hemorrhagic cystitis than PTCy group (Table 1). Cumulative incidence of acute GvHD grades II-IV was higher in the ATG group as well as acute GvHD grades III-IV, with no differences in moderate/severe chronic GvHD incidence (Figure A). CONCLUSION In our experience, albeit differences in follow-up and limited number of patients, we conclude that PTCy combined with additional immunosuppression after MUD allogeneic HSCT offers lower rates of acute GvHD together with less toxicity and non-relapse mortality compared to ATG-based prophylaxis. Further analysis including larger series and follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

A Randomized Study of Cyclosporine and Methotrexate with or without Methylprednisolone for the Prevention of Graft-Versus-Host Disease: Improved Long-Term Survival with the Triple Prophylaxis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2241-2241
Author(s):  
Tapani Ruutu ◽  
Anne Nihtinen ◽  
Riitta Niittyvuopio ◽  
Eeva Juvonen ◽  
Liisa Volin
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Not Given ◽  
Term Survival ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
To Receive

Abstract Background: In a previously published single-center study (Blood 2000) we randomized 108 consecutive adult patients with a malignant hematological disorder undergoing allogeneic bone marrow transplantation from an HLA-identical sibling donor to receive (n=53) or not to receive (n=55) methylprednisolone (MP+ or MP-, respectively) as a part of graft-versus-host disease (GVHD) prophylaxis. All patients received cyclosporine A and methotrexate. MP administration was initiated on day 14 post-transplantation with 0.5 mg/kg, the dose was increased to 1 mg/kg on day 21 and thereafter tapered and discontinued on day 110. The cumulative incidence of acute GVHD was 19 % among the patients given and 56 % among those not given MP prophylaxis (p=0.0001), and that of grade II-IV acute GVHD 13 and 36 %, respectively (p=0.005). There was a non-significant trend toward a lower cumulative incidence of chronic GVHD (cGVHD) and better survival in the MP+ group. There were fewer infections and the stay at hospital was shorter among the patients given MP prophylaxis. No difference was seen in the relapse rate. We have now carried out a long-term follow-up to find out possible late effects of the intensified GVHD prophylaxis. Results: The median follow-up time of living patients was 24.5 (range 22.7-26.9) years; two patients were lost for follow-up at 37 and 80 months. In the MP+ group the overall survival (OS, p=0.021) (Figure 1) and relapse-free survival (RFS, p=0.024) were significantly higher and the non-relapse mortality (NRM) lower (p=0.003) than in the MP- group. There was a trend toward lower cumulative incidence of cGVHD in the MP+ group (36 vs. 48 %, p=0.17). The prevalence of cGVHD, analyzed with data available from ten years of scheduled follow-up, was significantly (p=0.031) lower in the MP+ group and the difference became more marked with time. Among the patients alive at ten years, none in the MP+ group but 28 % of the patients in the MP- group had active cGVHD. There was no difference in the relapse rate between the MP+ and MP- groups, the cumulative incidences were 36 and 38 %, respectively. Seven patients in each group developed a secondary malignancy, one patient in both groups had two secondary tumors. At 15 years, the survival was 55 % in the MP+ group and 47 % in the MP- group, and the NRM 21 and 30 %, respectively. Thereafter there was marked non-relapse mortality in the MP- group, eleven patients died after this time point, whereas there were no deaths during this period in the MP+ arm. At the end of the follow-up, the OS in the MP+ and MP- groups were 55 and 20 % and the RFS 54 and 18 %, respectively. The causes of the late deaths in the MP- group were: bacterial infection 3, obstructive bronchiolitis 1, acute myocardial infarction 1, intracerebral bleeding 1, sudden death of unknown cause 1, lung cancer 2, colon cancer 1, and esophagus cancer 1. Conclusion: The addition of corticosteroid to cyclosporine and methotrexate in GVHD prophylaxis, resulting in a marked decrease in the incidence of acute GVHD, did not cause adverse late effects. Long-term survival was higher among the patients given MP prophylaxis. Unexpectedly, there was marked late non-relapse mortality in the group not given MP prophylaxis, possibly contributed to by the higher prevalence of cGVHD. Disclosures No relevant conflicts of interest to declare.

Comparative Study on Fresenius-ATG Versus Thymoglobuline-ATG for the Graft Versus Host Disease (GVHD) Prophylaxis in Allogeneic Stem Cell Transplantation from Matched Unrelated Donor: A Single Center Experience on 76 Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4601-4601
Author(s):  
Nicola Polverelli ◽  
Michele Malagola ◽  
Alessandro Turra ◽  
Cristina Skert ◽  
Federica Cattina ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Cumulative Incidence ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Immune Recovery ◽  
Matched Unrelated Donor ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Cmv Reactivation

Abstract Introduction . Anti-thymocyte globulin (ATG), has been shown to significantly reduce the incidence and severity of acute and chronic graft versus host disease (GVHD) in pts submitted toallogeneic stem cell transplantation (allo-SCT). Two different ATG formulations, derived from rabbit immunization against T antigens,thymoglobuline-ATG (tATG) andfresenius-ATG (fATG) are usually employed. However, only few retrospective studies are available in order to compare the efficacy and safety of these two drugs. Moreover, the differential impact of the two formulations on immune recovery has been poorly studied. Methods. Clinical and laboratory data of 76 pts receivingfATG (30 mg/kg for 3 days beforeallo-SCT) ortATG (10 mg/Kg for 3 days beforeallo-SCT) as GVHD prophylaxis forallo-SCT from matched unrelated donor (MUD) for hematological malignancies at the Unit of Stem Cells Transplantation ofSpedaliCivili of Brescia between 2009 and 2014, were retrospectively collected. Basic phenotype of circulating lymphocytes was assessed by flow-cytometry at 3-months interval fromallo-SCT. The aims of the study were to compare the two ATG formulations in term of incidence of acute and chronic GVHD, infections, non-relapse mortality, relapse-free survival, overall survival and immune recovery. The study was approved by the local Ethic Committee. Results. Overall, 46 (60%) pts receivedfATG and 30 (40%)tATG as GVHD prophylaxis, in association to cyclosporine andmethotrexate. Baseline characteristics were (median): age, 46 years (range, 17-66); male, 68%; acute leukemia, 53%; complete hematological remission, 51%; HLA full-matched (8/8), 40%; source of stem cells, peripheral blood, 87%;myeloablative conditioning regimen, 49%; median follow-up, 22 months (range, 1-88). No significant differences were observed between the two populations according age, sex, hematological disease, disease status atallo-SCT, HLA match, stem cell source, amount of CD3+ and CD34+ cells infused and conditioning regimen. Overall, 26 (57%)fATGand 19 (61%)tATG-exposed pts developed an acute GVHD (p=0.8); among 18 (24%) pts who developedcGVHD, 2 out of 10 (20%)fATGand 6 out of 8 (75%)tATG-receiving pts evolved towards severecGVHD(p=0.05). In particular, the cumulative incidence of severecGVHD, was 5,2% versus 27,6% at 2 years (p=0.03) infATGandtATGgroup, respectively (Figure 1). Bacterial infections were encountered in 42 (91%) and 25 (81%) (p=0.19), fungal infections in 12 (26%) and 6 (19%) (p=0.58)fATGandtATG-treated pts. CMV reactivation was observed in 28 (61%) and 19 (73%) (p=0.43)fATGandtATG-exposed pts, respectively. However, a trend for a higher incidence of early-CMV reactivation was seen in thetATGgroup, with a cumulative incidence of CMV reactivation at 30 days of 30% versus 52% infATGandtATGcohort, respectively (p=0.09). No differences were observed betweenfATGandtATGpopulations in term of relapse-related mortality (24% versus 40%, p=0.25), non-relapse mortality (28% versus 20%, p=0.48) and overall survival (52% versus 60%, p=0.71). Immunologic reconstitution was evaluated in 48 pts (fATG, 64%). As compared totATG,fATGpts showed a significant lower amount of CD3-/CD16+ NK cells (median, 137/mclvs255/mcl, p=0.05) and a trend for lower CD3+CD4+CD25+CD127- T-regcells (5/mclvs11/mcl, p=0.07) and CD4/CD8 ratio (0.26vs0.57, p=0.08) at 3 months fromallo-SCT. At 6 months CD4/CD8 ratio was significantly lower infATGcompared totATGgroup (0.26vs0.42, p=0.01). At 9 months, lymphoid populations did not differ between the two cohorts. Overall, ATG administration was well-tolerated without grade III-IV adverse events, however an increase in infusion-related events (mainly, fever and chills) was recorded infATGgroup (67%vs32%, p=0.004). Conclusion. This retrospective study, reporting a quite large population ofallo-SCT pts from MUD homogeneously followed in a single Hematology Center, shows thatfATG-treated pts have a lower incidence of severecGVHD compared totATG. On the contrary a slight increase of early CMV reactivation has been observed intATG group. These differences do not result in a higher relapse-related or overall mortality. The distinct immune reconstitution as identified by flow-cytometricanalysis, could justify these observations, that need to be validated by prospective studies. Figure 1 Cumulative incidence of severecGVHD according to type of ATG employed Figure 1. Cumulative incidence of severecGVHD according to type of ATG employed Disclosures No relevant conflicts of interest to declare.

Cannabidiol - An Innovative Strategy For Graft Versus Host Disease Prevention

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3299-3299 ◽  
Author(s):  
Moshe Yeshurun ◽  
Ofer Shpilberg ◽  
Corina Herscovici ◽  
Juliet Dreyer ◽  
Anat Peck ◽  
...  
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Unrelated Donor ◽  
End Points ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Grade 3

Abstract Introduction Acute graft-versus-host disease (aGVHD) is a major life-threatening complication following allogeneic stem cell transplantation (alloSCT), affecting 35%-70% of recipients despite standard prophylaxis regimens. Thus, developing innovative strategies to prevent and treat GVHD is a major unmet need. Cannabidiol (CBD), a safe and non-psychotropic ingredient of marijuana, has been shown to exhibit potent immune-modulatory and anti-inflammatory properties in animal models of various inflammatory diseases. We hypothesized that administration of CBD during alloSCT may significantly decrease GVHD incidence. Methods We conducted a phase I/II trial. All patients were given standard GVHD prophylaxis consisting of cyclosporine and a short course of methotrexate (15 mg/m2 on day +1 and 10 mg/m2 on days +3 and +6). The investigational agent, CBD (STI Pharmaceuticals, Essex, UK), was orally administered at a dosage of 150 mg twice daily from starting of conditioning up to day +30. Primary end points were safety and cumulative incidence of grade 2-4 and grade 3-4 aGVHD by day +100. The secondary end points were cumulative incidence of chronic and chronic extensive GVHD, non-relapse mortality (NRM), relapse incidence, and overall survival (OS). Results Between 9/2012 and 6/2013, 30 consecutive unselected adult patients undergoing alloSCT were enrolled (median age=52, range, 22-71 years). Median follow-up was 4.8 months (range, 1-10.3). Base line diseases were acute leukemia (n=21, 70%), myelodysplastic syndrome (n=2, 7%), lymphoma (n=5, 17%), aplastic anemia (n=1, 3%), and multiple myeloma (n=1, 3%). 73% were in CR/PR at transplantation. The majority of patients were given a myeloablative preparative regimen (n=22, 73%). The donor was either an HLA identical sibling (n=16) or 10/10 matched unrelated donor (n=12) or 1 antigen mismatched unrelated donor (n=2). All patients were given G-CSF mobilized peripheral blood stem cell grafts. There were no documented grade 3-4 toxicities attributed to CBD. There were no cases of graft rejection. In all, 2 patients developed aGVHD by day 100 (grade 2, n=1 and grade 3, n=1) and one patient developed late onset aGVHD (grade 4, n=1). The cumulative incidences of grade 2-4 aGVHD and grade 3-4 aGVHD by day +100 were 8.4% and 4.5%, respectively. Five patients developed chronic GVHD, 4 had limited disease and one extensive disease. There were 4 deaths because of sepsis (n=1), cardiac arrhythmia (n=1), grade 4 aGVHD (n=1) and relapse (n=1). Cumulative incidences of NRM at 3 and 6 months were both 6.9% and incidences of relapse were both 10.7%. OS at 3 and 6 months were both 90%. Conclusion These data suggest that the combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of GVHD. Nevertheless, a well designed prospective controlled study comparing this novel approach with standard GVHD prophylaxis is warranted. Follow-up data on safety, efficacy, and on additional subjects will be presented. Disclosures: No relevant conflicts of interest to declare.

Bortezomib, rituximab, and risk of graft-versus-host disease (GVHD) after BEAM conditioning for allogeneic stem cell transplantation (alloSCT).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18543-e18543
Author(s):  
Kamal Chamoun ◽  
Alison M Gulbis ◽  
Denai Milton ◽  
Elias Jabbour ◽  
Francesco Turturro ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Aggressive Lymphoma ◽  
Unrelated Donor ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Clinical Trial Information

e18543 Background: GVHD remains the main limitation of alloSCT and is exacerbated by the intensity of the conditioning regimen. In a recent study, the risk of acute grade II-IV GVHD and extensive chronic GVHD (cGVHD) after a nonmyelobaltive (NMA) regimen was 11%, and 26%, respectively (Khouri I. Blood 2014 124:2306). Higher rates were previously observed (32% and 54%, respectively) with the BEAM regimen. Based on clinical data showing a reduction in GVHD with the use of rituximab or bortezomib, we conducted a phase I/II study evaluating the addition of bortezomib to rituximab+BEAM in patients (pts.) who were not eligible for NMA alloSCT. Methods: Bortezomib was administered at 1.3 mg/m2 IV on days -13, -6, -1 and +2. The dose was later reduced to 1 mg/m2 after the occurrence of C. Difficile colitis in the first 3 pts. leading to 2 deaths. Rituximab was given on day -13 at a dose of 375 mg/m2, then at 1000 mg/m2 on days -6, +1, and +8 of alloSCT. BEAM was administered between days -6 and -1. All pts. received our standard GVHD prophylaxis with tacrolimus and methotrexate. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving matched unrelated donor (MUD) or mismatched (MM) transplants. Results: Thirty-nine pts. were studied. Median age was 54 yrs. Thirteen (33%) and 26 (67%) pts. had indolent or aggressive lymphoma histologies, respectively. Sixteen (41%) pts. were refractory. Twenty-two (56%) received alloSCT from HLA-compatible siblings, 16 (41%) from MUDs and 1 (3%) from mm donors. Peripheral blood was the source of stem cells in 97% of pts. ABO and CMV-mismatch rates were 56% had 50%, respectively. Median follow up surviving patients was 65 mos. Five-year OS and PFS rates were 35% and 28%, respectively. The CI of acute grade II-IV, III-IV, and cGVHD were 55%, 34%, and 41%, respectively. No predictor for acute GVHD was identified. Instead, we found that sex-mismatched transplants were predictive of a higher risk of cGVHD ( P= 0.01). Conclusions: The current trial is the first one evaluating the safety and efficacy of bortezomib plus rituximab as a part of the BEAM regimen for alloSCT. A better prophylaxis regimen is needed to lessen the risk of GVHD in this setting. Clinical trial information: NCT00439556.

scholarly journals Low-dose antithymocyte globulin plus low-dose posttransplant cyclophosphamide combined with cyclosporine and mycophenolate mofetil for prevention of graft-versus-host disease after HLA-matched unrelated donor peripheral blood stem cell transplantation

2021 ◽  
Author(s):  
Xi Sun ◽  
Jun Yang ◽  
Yu Cai ◽  
Liping Wan ◽  
Chongmei Huang ◽  
...  
Keyword(s):  
Antithymocyte Globulin ◽  
Low Dose ◽  
Peripheral Blood Stem Cell ◽  
Unrelated Donor ◽  
Relapse Free Survival ◽  
Matched Unrelated Donor ◽  
Free Survival ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Blood Stem Cell Transplantation

AbstractThe standard regimens for graft-versus-host disease (GvHD) prophylaxis in matched unrelated donor (MUD) transplantation were based on antithymocyte globulin (ATG) in combination with calcineurin inhibitors (CNIs). To improve the efficiency of GvHD prophylaxis in MUD peripheral blood stem cell transplantation (MUD-PBSCT), 51 patients with hematological malignancies received a novel regimen for GvHD prophylaxis, which is composed of low dose of ATG (5 mg/kg) plus low-dose posttransplant cyclophosphamide (PTCy, 50 mg/kg) (low-dose ATG/PTCy) combined with cyclosporine A (CsA) and mycophenolate mofetil (MMF). The cumulative incidences (CIs) of grades I–IV and II–IV acute GvHD (aGvHD) were 14.5% (95% CI, 9.4–19.6%) and 6.2% (95% CI, 2.8–9.6%) within 100 days after transplantation, respectively. The CI of mild-to-moderate chronic GvHD (cGvHD) within 1 year was 11.5% (95% CI, 6.6–16.4%). The 1-year probabilities of GvHD and relapse-free survival, relapse-free survival, and over survival were 70.6% (95% CI, 64.2–77.0%), 76.5% (95% CI, 70.6–82.4%), and 82.0% (95% CI, 76.5–87.5%), respectively. The CIs of CMV and EBV reactivation by day 180 were 10.4% (95% CI, 1.5–19.4%) and 8.3% (95% CI, 0.2–16.4%), respectively. The results suggested that low-dose ATG/PTCy combined with CsA/MMF as GvHD prophylaxis in MUD-PBSCT had promising activity.

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 Extended CCR5 Blockade in Graft-Versus-Host Disease Prophylaxis – a Phase II Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2491-2491 ◽  
Author(s):  
Ran Reshef ◽  
James K. Mangan ◽  
Selina M. Luger ◽  
Alison Wakoff Loren ◽  
Elizabeth O. Hexner ◽  
...  
Keyword(s):  
Phase Ii ◽  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Phase Ii Study ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade 3 ◽  
Ccr5 Blockade

Abstract Background: Blocking lymphocyte trafficking after allogeneic stem cell transplantation (alloSCT) may prevent graft-versus-host disease (GvHD) without interfering with graft-versus-tumor (GvT) activity. We previously reported that brief (up to day+30) CCR5 blockade using maraviroc (MVC, Pfizer) after reduced-intensity conditioned (RIC) alloSCT resulted in a low incidence of acute GvHD and absence of early liver and gut GvHD, although delayed GvHD still occurred. We designed a phase II study to test the hypothesis that extended administration of MVC would be feasible, safe and provide protection against late-onset GvHD without impairing immune reconstitution or GvT responses. Patients and Methods: In April 2013 we initiated a 37-patient (pt) phase II study to test an extended course of MVC in recipients of RIC alloSCT from unrelated donors. Pts receive fludarabine 120 mg/m2 and busulfan i.v. 6.4 mg/kg followed by peripheral blood stem cells. MVC 300 mg b.i.d. is orally administered from day -3 to day +90 in addition to standard prophylaxis with tacrolimus and methotrexate. The primary endpoint is the cumulative incidence of grade 2-4 acute GvHD by day 180. As of July 2014 we enrolled 20 pts at high risk for transplant-related toxicity by virtue of age (median=64, range 55–72), donor source (matched unrelated 80%, single-antigen mismatch unrelated 20%) or comorbidities (comorbidity index: low 15%, intermediate 35%, high 50%). Underlying diseases were AML (16), MDS, MPD, ALL and CTCL (1 each). Feasibility and Safety: The median follow-up on surviving patients is 5.7 months. The 3-month course of MVC was well tolerated with no increased toxicity; two pts did not complete their treatment due to early disease relapse and one patient discontinued therapy due to a skin reaction with eosinophilia where the histological features favored a drug reaction and the attribution to MVC was possible. Postural hypotension, a known dose-dependent toxicity, was observed in one pt who completed the course with a 50% dose reduction. Engraftment and Immune Reconstitution: The median time to ANC>500/μL was 12 d (range 10-21) and platelets>20k/μL was 14 d (range 9-28). The median whole blood and T-cell donor chimerism levels at day 100 were 95% (range 12–100%) and 80% (range 23–94%) respectively, which are similar to historical rates. Median CD4 counts on day 30 were 341 (range 206-424). Only 3/16 evaluable pts had Ig levels<500 mg/dL in the first 100 days. GvHD: Sixteen pts are evaluable with > 3 mo of follow-up. The day-180 cumulative incidence rates (± s.e.) of grade 2-4 and grade 3-4 acute GvHD are 25 ± 11% and 6 ± 6% respectively (Fig. 1). Of patients who developed acute GvHD in the first 180 days, there have been no cases of liver GvHD, 2 cases of stage 1 steroid-responsive gut GvHD and 1 case of severe diarrhea with combined features of GvHD and leukemic infiltrates in the gut. These results are comparable to the GvHD rates in our phase I/II MVC study (grade 2-4: 23.6% and grade 3-4: 5.9%), which included related and unrelated donor transplants. These results also compare favorably with a 45% day-180 acute GvHD rate seen in similar patients treated with our standard GvHD prophylaxis alone. Notably, there has been no treatment-related mortality. Five patients have relapsed at a median of 2.6 months post-transplant (range 0.93 – 3.5), which is similar to our historical rates after RIC alloSCT. PD analysis: We developed a phosphoflow assay to assess in real-time the activity of MVC in fresh blood samples. The assay quantifies the activation of CCR5 by measuring the phosphorylation of C-terminal serine residues as a result of CCL4 stimulation. In 15 evaluable patients, we observed diminished pCCR5 levels with CCL4 stimulation on day 0 as compared to day -6 (Fig. 2). In summary, our preliminary results support the feasibility, safety and protective activity of the CCR5 antagonist MVC against acute GvHD, with preferential activity against visceral GvHD. Continued pt enrollment and follow-up are ongoing. Updated safety, efficacy and PD results will be presented. A multi-center study (BMT-CTN 1203) will be initiated later this year to further clarify the role of this novel strategy in improving the outcome of alloHSCT. Fig 1. Cumulative Incidence of Acute GvHD Fig 1. Cumulative Incidence of Acute GvHD Fig 2. Phosphoflow shows CCR5 unresponsiveness to CCL4 stimulation on day 0 Fig 2. Phosphoflow shows CCR5 unresponsiveness to CCL4 stimulation on day 0 Disclosures Reshef: Pfizer: Research Funding. Off Label Use: Maraviroc for graft-versus-host disease prophylaxis.

scholarly journals Post-Transplant Cyclophosphamide for Gvhd Prophylaxis in Matched Unrelated Donor Transplantation Compared to ATG-Based Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3285-3285
Author(s):  
Rebeca Bailén ◽  
Mi Kwon ◽  
Maria Jesus Pascual-Cascon ◽  
Anna Torrent ◽  
Christelle M Ferra ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Cumulative Incidence ◽  
High Dose ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Background: Post-transplant high dose cyclophosphamide (PT-CY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT). The use of PT-CY in HLA-identical donor is less explored. In this study, we analyzed the results of PT-CY for GVHD prophylaxis in matched unrelated donor (MUD) HSCT and compared them with those obtained after prophylaxis with anti-thymocyte globulin (ATG), methotrexate (MTX) and cyclosporine (CsA). Methods: 132 matched unrelated donor HSCT from 4 Spanish centers have been analyzed: 60 performed between 2010 and 2018 using ATG-MTX-CsA and 72 performed between 2014 and 2018 using PT-CY. Results: Baseline characteristics and post-transplant complications are shown in Table 1. Peripheral blood was used as graft source in 92% of the patients in the ATG group and in 78% in the PT-CY group. GVHD prophylaxis consisted in rabbit ATG either 2mg/kg days -4 to -2 (41 patients, 68%) or 0.5mg/m2 on day -3 followed by 1mg/kg days -2 and -3 (19 patients, 32%), MTX days +1, +3, +6 and +11, and CsA from day -1 in the ATG group. The PT-CY group received cyclophosphamide 50 mg/kg/d on days +3 and +4, followed by either CsA or tacrolimus plus mycophenolate mofetil (MMF) from day +5 in 30 patients (42%), or cyclophosphamide on days +3 and +5 combined with CsA or tacrolimus in 42 patients (58%; 16 out of them also received sirolimus due to 9/10 HLA-match). Cumulative incidence of grade II-IV (67% vs 46%, p=0.008) and III-IV (34% vs 3%, p=0.003) acute GVHD, were significantly higher in the ATG group (Figure 1). There were no differences in the 2-year cumulative incidence of chronic moderate to severe GVHD (23% vs 24%, p=0.86). After a median follow-up of 78 months for the ATG group and 26 months for the PT-CY group, no differences were found in the 2-year overall survival (58% vs 60%, p=0.475), 2-year event-free survival (51% vs 50%, p=0.961) and the composite endpoint of GVHD-free and relapse-free survival (44% vs 40%, p=0.742). The 2-year cumulative incidence of relapse (22% vs 26%, p=0.67) and non-relapse mortality (NRM) (24% vs 22%, p=0.68) were also similar between both groups. However, NRM in the ATG group was due to GVHD in 9 out of 16 patients, while in the PT-CY group NRM was mostly due to infections and organ toxicity and only 3 out of 15 patients died due to GVHD. The incidence of sinusoidal obstruction syndrome was low in both groups (0% vs 4%, p=0.11). CMV reactivation rates were similar (40% vs 51%, p=0.191). However, both hemorrhagic cystitis and EBV reactivation were higher in the ATG group (56% vs 12%, p=0.00, and 5% vs 0%, p=0.05, respectively). Conclusions: In our experience, GVHD prophylaxis using PT-CY combined with additional immunosuppression after MUD HSCT, using mostly peripheral blood as graft source, resulted in lower incidence of aGVHD compared to prophylaxis based on ATG-MTX-CsA. Although no impact on non-relapse mortality was observed, GVHD associated mortality was higher in the ATG group as well as cystitis and EBV reactivations. Prospective studies with longer follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

Tacrolimus Versus Cyclosporine for Graft-Versus-Host Disease Prophylaxis in Pediatric Patients Undergoing Matched Unrelated Donor Hematopoietic Stem Cell Transplants. A Pediatric Blood and Marrow Transplant Consortium Study..

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2883-2883 ◽  
Author(s):  
Mark P. Atlas ◽  
Gregory Yanik ◽  
Rakesh Goyal
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Ii

Abstract Calcineurin inhibitors form the backbone of graft versus host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation. In the adult literature tacrolimus was demonstrated superior to cyclosporine in preventing grade II–IV acute GVHD in both related and unrelated donor transplants; however, there is no data comparing their efficacy in the pediatric population. In a multi-institutional trial, we prospectively evaluated the clinical data on 102 patients receiving either cyclosporine/methotrexate or tacrolimus/methotrexate based prophylactic regimens for 6/6 matched unrelated donor, transplant. Conditioning regimens were fully ablative; no T-cell depletion was permitted; cord blood donors were excluded. Patients were required to receive either cyclosporine or tacrolimus, but the choice was per investigator preference. The two arms were reasonably balanced: 59.8% of patients received cyclosporine and 40.2% of patients received tacrolimus. Rates for maximum grade II–IV acute GVHD were 37.7% for cyclosporine and 39% for tacrolimus (p = 0.89). Rates for maximum grade III–IV acute GVHD were 19.6% for cyclosporine and 24.4% for tacrolimus (p = 0.57). Incidence of chronic GVHD in 97 evaluable patients was 37.9% in 58 patients who received cyclosporine and 35.8% in 39 patients who received tacrolimus (p = 0.84). Survival at 1 year post-transplant was similar in both groups: 59.2% for cyclosporine and 51.2% for tacrolimus (p= 0.31). Toxicity analysis is ongoing. In pediatric matched unrelated donor transplantation, the efficacy of tacrolimus/methotrexate and cyclosporine/methotrexate based regimens for prophylaxis of GVHD are not significantly different.

scholarly journals Tacrolimus and minidose methotrexate for prevention of acute graft- versus-host disease after matched unrelated donor marrow transplantation

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4383-4389 ◽  
Author(s):  
D Przepiorka ◽  
C Ippoliti ◽  
I Khouri ◽  
M Woo ◽  
R Mehra ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Advanced Disease ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Unrelated Donors ◽  
Acute Graft

Abstract Thirty adults with leukemia or lymphoma undergoing marrow transplantation from HLA-compatible unrelated donors received tacrolimus (FK506), a new immunosuppressive macrolide lactone, and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 36 years (range 21 to 49 years). Twenty-four patients had advanced disease, and 11 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/d intravenously (i.v.) by continuous infusion from day -2, converted to oral at four times the i.v. dose following engraftment, and continued through day 180 posttransplant. Methotrexate 5 mg/m2 was given i.v. on days 1, 3, 6, and 11. All patients engrafted. Grades 2–4 GVHD occurred in 34% (95% CI, 17% to 52%), and grades 3–4 GVHD in 17% (95% CI, 3% to 31%). Mild renal toxicity was common before day 100; 63% of patients had a doubling of creatinine, and 52% had a peak creatinine greater than 2 mg/dL, but only one patient was dialyzed. The median last i.v. dose of tacrolimus was 53% of the scheduled dose, and the median oral dose on day 100 was 41% of that scheduled. Overall survival at 1 year was 47% (95% CI, 27% to 66%). We conclude that tacrolimus can be combined safely with minidose methotrexate, and the combination has substantial activity in preventing acute GVHD after unrelated donor marrow transplantation.

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