scholarly journals A Randomized Phase II Trial Comparing a Calcineurin Inhibitor-Free Graft-Versus-Host Disease Prophylaxis Regimen with Post-Transplantation Cyclophosphamide and Abatacept to Standard of Care

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1816-1816
Author(s):  
Divya Koura ◽  
Dimitrios Tzachanis ◽  
Edward D. Ball ◽  
Caitlin Costello ◽  
Aaron M Goodman ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Standard Of Care ◽  
Post Transplantation ◽  
Transplant Tolerance ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Abstract Background: Graft versus host disease (GVHD) is one the major causes of mortality and morbidity after an allogeneic stem cell transplantation. We hypothesized that we can induce post-transplant tolerance by using the combination of post-transplant cyclophosphamide (PTCy) and abatacept (CTLA4Ig) for GVHD prophylaxis. PTCy when given on Days +3 and +4 can eliminate host-reactive donor T cells. CTLA4Ig blocks the costimulatory signals given through CD28 to naïve donor T cells thus favoring an anergic phenotype that promotes tolerance towards recipient derived antigens. CTLA4Ig gives an activating signal to NK cells and therefore has the ability to preserve the graft-versus-tumor effect. Methods: We have initiated a 50 patient randomized clinical trial. Patients with hematologic malignancies in need of a transplant and with an 8/8 matched donor are randomized 1:1 to tacrolimus and methotrexate for GVHD prophylaxis (standard of care arm) or PTCy on days +3 and +4 followed by CTLA4Ig on days +5, +14,+28, +56, +84, +112, +140 and +168. Patients are stratified by conditioning regimen (myeloablative vs reduced intensity) and by donor type (matched sibling vs matched unrelated donor). The primary endpoint is chronic GVHD at 1 year as a marker of tolerance induction. Secondary endpoints include acute GVHD rate, relapse rate, overall survival, GVHD-relapse-free-survival, transplant related mortality and infection rate. Post-transplantation immune reconstitution studies include measuring T cell and NK cell phenotype, PD-1 expression, and alloreactivity to recipient and third party at predetermined time points. Results: 25 patients have been treated on this study, 10 of which are on the experimental arm. Patients on the experimental arm have been followed for up to 516 days post-transplant. So far no cases of chronic GVHD or grade 3-4 acute GVHD have been observed in the experimental arm. All the patients have engrafted and there have been no treatment related deaths. Conclusions: The combination of PTCy and CTLA4Ig for GVHD prophylaxis is feasible. This ongoing study will examine its ability to induce post-transplant tolerance. Disclosures Tzachanis: Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Partner: Consultancy; Fate Therapeutics: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Incyte: Research Funding; EUSA: Consultancy; Takeda: Consultancy, Speakers Bureau; Magenta: Consultancy; Kyowa Kirin: Consultancy. Goodman: Seattle Genetics: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria. Mangan: Elevate Bio: Other: ad board. OffLabel Disclosure: abatacept: using as part of graft versus host disease prophylaxis

scholarly journals Transplant Outcomes of 9/10 HLA Matched Unrelated Donors (MUD) Treated with Post-Transplant Cyclophosphamide for Prevention of Graft Versus Host Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2486-2486 ◽  
Author(s):  
Sai Ravi Pingali ◽  
Denai Milton ◽  
Uday R. Popat ◽  
Chitra M. Hosing ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Post Transplantation ◽  
Modest Improvement ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Abstract Background: Graft-versus-host disease (GVHD) is a major complication of allogeneic stem cell transplantation (ASCT). The incidence of GVHD with conventional GVHD prevention is higher with HLA mismatched compared to matched donors, with 69% of patients (pts) developing grade 2-4 and 16% grade 3-4 acute (aGVHD) and more than half the pts developing chronic (cGVHD), as previously reported by us(Ciurea SO abstract ASH 2010). Here we report preliminary results of 9/10 MUD transplant pts receiving GVHD prophylaxis with post-transplantation cyclophosphamide (PTCY), in addition to tacrolimus and mycophanolate mofetil (MMF). Methods: Patients were treated prospectively using a 9/10 MUD on a separate arm of a phase II clinical trial (2009-0266). Conditioning regimen consisted of Melphalan 140 mg/m2 on day −8 (100mg/m2 for pts ≥55 years or with comorbidities), Thiotepa 5-10 mg/kg on day −7 and Fludarabine 40 mg/m2/day on days −6, −5, −4, and −3. All patients received T-cell replete bone marrow graft. GVHD prophylaxis included PTCY 50mg/kg on days +3 and +4, MMF was given until day 100 and Tacrolimus until day 180 if no GVHD. Primary objectives were to determine the incidence of acute and chronic GVHD and non-relapse mortality (NRM), while secondary objectives included progression free survival (PFS) and overall survival (OS). Results: 39 patients with median age of 50 years (range 20-64) received a 9/10 MUD with PTCY GVHD prophylaxis. 20 patients (51%) were women and AML/MDS was the most common indication for transplantation in 13(33%), NHL 8(21%), ALL 7(18%), AA in 4(10%) and CLL, CML/MPD, HL and MM constituted rest of the patients. Poor, intermediate and low risk cytogenetics were seen in 6, 8 and 4 patients with leukemia, respectively. 22 patients (56%) were not in complete remission at the time of transplantation. Median follow-up time for survivors was 35.9 months (range: 2.6–123.5). All patients engrafted the donor cells. Day 100 NRM for all pts was 18%.The cumulative incidence (CI) of grade II-IV aGVHD and gr III-IV aGVHD was 42% and 17%, respectively. CI of all cGVHD was only 20% and extensive only cGVHD was 13%. NRM for all pts was 36% at 1 year and 40% at 3 years. OS for all pts at 1 and 3 yr was 57% and 44%, while PFS at 1 and 3 yr was 43% and 39%, respectively. Conclusions: Post-transplant cyclophosphamide for prevention of GVHD which has been successfully used in haploidentical transplantation, resulted in a modest improvement in the rates of grade 2-3 and 3-4 acute GVHD compared to reports of standard GVHD prophylaxis for 9/10 MUD transplants. However, a promising low rate of chronic GVHD was observed. This approach can produce durable remissions for patients with hematologic malignancies who lack an HLA matched donor. Figure 1 Figure 1. Disclosures Andersson: Otsuka Pharmeceuticals: Research Funding, Research funding from Otsuka Pharmeceuticals Other.

scholarly journals Less Chronic Graft-Versus-Host Disease, Immunosuppressive Therapy and Better Survival after Anti-Thymocyte Globulin in Unrelated Donor Stem Cell Transplant Recipients: Longer Follow-up of a Multicentre Cell Therapy Transplant Canada Randomized Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 875-875
Author(s):  
Jean Roy ◽  
Tony Panzarella ◽  
Stephen Couban ◽  
Félix Couture ◽  
Gerald M. Devins ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Control Group ◽  
Unrelated Donor ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
To Receive

Background: We previously reported that pretreatment with rabbit anti-thymocyte globulin (ATG) decreases the use of immunosuppressive therapy (IST) and occurrence of chronic graft-versus-host disease (GVHD) 12 months after allogeneic stem cell transplantation from unrelated donors. We hypothesized these benefits would persist beyond 12 months with a positive clinical impact on patients. Methods: Phase 3, multicentre, open-label, randomized controlled trial at 10 centres in Canada and one in Australia. Patients aged 16-70 years with a hematological malignancy, a matched (HLA-A, B, C and DRB1) or 1-antigen/allele mismatched unrelated donor were eligible. Myeloablative, nonmyeloablative or reduced intensity conditioning regimens were permitted according to center clinical preference. Patients were randomized to receive or not to receive rabbit ATG (Thymoglobulin®, Sanofi Canada) as part of their conditioning. GVHD prophylaxis included either cyclosporine or tacrolimus plus methotrexate or mycophenolate mofetil. The ATG arm received 0.5, 2.0, 2.0 mg/kg of ATG on days -2, -1 and +1, respectively. Analyses were on a modified intention-to-treat basis for patients actually transplanted. Primary endpoint was freedom from all systemic IST without resumption up to 24 months after transplantation. Secondary endpoints included survival, relapse, non-relapse mortality, incidence and symptoms of chronic GVHD according to Lee scale and quality of life using different questionnaires including the Center for Epidemiologic Studies Depression (CES-D) scale. We also aimed to evaluate the recently described endpoints of graft-versus-host disease and relapse-free survival (GRFS) and chronic graft-versus-host disease and relapse-free survival (CRFS) in each cohort. This trial was registered at ISRCTN (#29899028) and clinicaltrials.gov (#NCT01217723). Results: Between 06/2010 and 07/2013, 203 patients were randomized and 196 available for end-points analysis, including 99 patients in the ATG group and 97 in the No ATG (control) group. Datalock was performed on April 1, 2019. The cumulative incidence of chronic GVHD at 24 months was significantly lower in ATG recipients (26.3% versus 41.2%, p=0.032). Similarly, more than twice patients in the ATG group were free from IST at 24 months (adjusted OR of 3.49 [95% CI : 1.60-7.60]; p = 0.002). Most patients retained the same IST status from 12 to 24 months (74.7% in the ATG and 81.4% in the control group). Symptoms of chronic GVHD were also significantly less prevalent in patients receiving ATG, with scores by Lee scale of 13.57 (SE : 1.47) versus 19.90 (SE : 2.15); p=0.017. In contrast, we observed no difference in non-relapse mortality (ATG : 21.2% versus No ATG : 30.9%; p=0.14) and relapse (ATG : 16.2% versus No ATG : 17.5%; p=0.73). Of note, there was no increase in relapse in those receiving either myeloablative or non-myeloablative conditioning (Gray's test p = 0.66 and 0.29, respectively). ATG had a positive impact on survival (Figure 1), with an overall survival at 12 months of 74.8% (SE : 4.4) compared with 64.9% (SE : 4.8) in the control group (adjusted HR 0.56 [95% CI : 0.35-0.90; p=0.017). This benefit of ATG on survival persisted at 24 months, with 70.7% of patients in the ATG group and 53.6% in the control group being alive (p=0.018). GRFS at 12 and 24 months were significantly better in the ATG group, with 45.4% and 37.4% of patients alive and free of ever having had GVHD versus 24.7% and 17.5%, respectively (p = 0.0034). CRFS led to similarly better results in ATG recipients at 12 (57.6%) and 24 (48.5%) months (p=0.01; Figure 2). Depressive symptoms were less frequently reported in the ATG group, the mean CES-D scores being 10.39 (SE : 1.29) compared with 14.63 (SE : 1.48) in the No ATG group (p=0.034). There were no statistically significant differences in other patient-reported outcomes. Conclusions: Pretreatment with rabbit ATG in combination with standard acute GVHD prophylaxis provides long term benefits consisting of decreases in chronic GVHD incidence, use of IST, depression and improved survival. Our trial is the first to demonstrate both a survival advantage and improvement in quality of life in patients receiving ATG for chronic GVHD prophylaxis. Our data support that ATG should be included in the preparative regimens of all unrelated donor transplant recipients receiving standard acute GVHD prophylaxis. Disclosures Roy: Celgene: Consultancy, Honoraria, Research Funding; ExCellThera: Patents & Royalties: Royalties from sales of UM171, Research Funding; Amgen Canada: Honoraria; Janssen Canada: Honoraria; Sanofi Canada: Research Funding. Foley:Celgene: Speakers Bureau; Janssen: Speakers Bureau; Amgen: Speakers Bureau. Kuruvilla:Janssen: Research Funding; Roche: Research Funding; BMS: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Karyopharm: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Amgen: Honoraria; Astra Zeneca: Honoraria; BMS: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Merck: Honoraria; Novartis: Honoraria; Roche: Honoraria; Seattle Genetics: Honoraria. Lee:AstraZeneca: Research Funding; Incyte: Research Funding; Syndax: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Kadmon: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Popradi:Sanofi Canada: Consultancy, Honoraria. Walker:Kiadis Pharma: Other: Grant funding via institution (as a principal investigator). OffLabel Disclosure: Rabbit ATG (Sanofi) for chronic GVHD prophylaxis.

Post-Transplantation Cyclophosphamide Following Busulfan and Fludarabine Myeloablative Conditioning Prevents Severe Acute and Chronic Graft-Versus-Host Disease and Minimizes Duration Of Immunosuppression: Results Of a Multi-Institutional Trial In Patients With High-Risk Hematologic Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3310-3310
Author(s):  
Christopher G. Kanakry ◽  
Paul O’Donnell ◽  
Terry Furlong ◽  
Marcos J de Lima ◽  
Wei Wei ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Post Transplantation ◽  
Myeloablative Conditioning ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
One Year

Abstract Introduction Allogeneic blood or marrow transplantation (alloBMT) involves a multi-faceted platform with each component having significant implications for the overall success of the transplant. However, the optimal transplantation platform is unknown. We combined two promising approaches, intravenous (IV) busulfan (Bu)/fludarabine (Flu) myeloablative conditioning and high-dose, post-transplantation cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis, in a multi-institutional trial for patients receiving HLA-matched related or unrelated bone marrow allografts. We hypothesized that this transplantation platform could prevent severe acute and chronic GVHD, while shortening the duration of post-grafting immunosuppression, having low treatment-related toxicity, and providing effective disease control. Methods Busulfan was given in daily IV doses which were adjusted based on measured pharmacokinetics. Fludarabine was given at 40 mg/m2/day. PTCy (50 mg/kg/day in IV daily dosing) was administered as sole GVHD prophylaxis on days +3 and +4 after infusion of unmanipulated bone marrow. Forty-five (49%) patients received HLA-matched related allografts, while 47 (51%) received HLA-matched unrelated allografts. Seventy-three (79%) patients were transplanted for myeloid diseases, including 53 (58%) with acute myelogenous leukemia and 13 (14%) with myelodysplastic syndrome. Fifteen (16%) patients had acute lymphocytic leukemia. Sixty-seven (73%) patients were in morphologic complete remission (CR) at the time of alloBMT, and the remaining twenty-five (27%) patients had active disease. Eighteen (20%) patients had evidence of minimal residual disease. Twenty-five (27%) patients were males who received allografts from females. The primary endpoint of the study was the cumulative incidence of grade III-IV acute GVHD. Pre-defined secondary endpoints included chronic GVHD, non-relapse mortality, event-free and overall survival, and use and duration of systemic immunosuppressants beyond the originally planned two days of PTCy. GVHD was scored centrally by an independent reviewer. Results The median follow-up was 595 days (1.6 years) for all patients and 794 days (2.2 years) for patients who were alive at last follow-up. The cumulative incidence (CI) of grade II-IV and III-IV acute GVHD were 51% and 15%, respectively, at two years. The CI of chronic GVHD was 14% at two years. Thirty-five percent of all patients and 39% of patients alive at last follow-up never required immunosuppression for any reason beyond day +4 post-transplant. Corticosteroid use occurred in 61% of all patients and 60% of patients alive at last follow-up. A median 98 days (range 10-1221) elapsed from first initiation to final cessation of corticosteroids. Immunosuppression beyond corticosteroids was used for 50% of all patients and 52% of patients alive at last follow-up. A median 167.5 days (range 1-1156) elapsed from first initiation to final cessation of secondary immunosuppression. A calcineurin inhibitor was required for any reason in 45% of patients. Only 16% of patients required additional immunosuppression beyond corticosteroids and/or a second systemic immunosuppressant. Seventy-two percent of patients alive at last follow-up were off all immunosuppression at one year. Non-relapse mortality was 9% and 16% at 100 days and one year, respectively. Event-free survival and overall survival were 62% and 67% at two years and were 80% and 79% at two years for patients in CR without MRD at the time of alloBMT. Multivariate Bayesian analysis showed that having an unrelated donor, being in CR without MRD, and having a higher nucleated cell count all had beneficial effects on EFS. Conclusion Myeloablative IV Bu/Flu conditioning followed by single-agent GVHD prophylaxis with PTCy results in low rates of severe acute and chronic GVHD and effective disease control for patients with high-risk hematologic malignancies undergoing HLA-matched alloBMT even from unrelated donors. Moreover, the use of post-grafting immunosuppression beyond day +4 was not required in a significant subset of patients and was rapidly tapered in others. This study confirms the efficacy of PTCy after myeloablative conditioning and provides further support for future randomized studies comparing PTCy against other GVHD prophylactic approaches. Disclosures: Off Label Use: post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis. Luznik:Otsuka Pharmaceutical: Research Funding.

scholarly journals Outcomes Following Intolerance to Tacrolimus/Sirolimus for Graft-Versus-Host Disease Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplant

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5673-5673
Author(s):  
Sayeef Mirza ◽  
Ankita Tandon ◽  
Dakota Jenneman ◽  
Shu Cao ◽  
Ambuj Kumar ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Research Funding ◽  
Categorical Variables ◽  
Cell Transplant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Allogeneic Hct ◽  
Gvhd Prophylaxis ◽  
Days Of Therapy ◽  
Grade Ii

INTRODUCTION: Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplant (HCT) resulting in significant morbidity and mortality. The combination of tacrolimus and sirolimus (TAC/SIR) has emerged as a GVHD prophylaxis platform preferred by many institutions given its association with rapid engraftment and acceptable transplant-related toxicity. However, overlapping toxicities between the two drugs can lead to intolerance and premature discontinuation in some patients. There is limited literature describing outcomes and subsequent management of such patients. The goal of this study is to investigate the clinical outcomes of patients becoming intolerant to the combination of TAC/SIR prophylaxis. METHODS: We retrospectively evaluated consecutive adult patients (n=100) at the Moffitt Cancer Center who received allogeneic HCT with TAC/SIR for GVHD prophylaxis in 2018. TAC/SIR intolerance was defined as discontinuation due to the toxicity of either TAC or SIR before post-transplant day 100. Survival analyses were estimated from the time of transplant with the Kaplan-Meier method and compared using the log-rank test. Patients intolerant of this prophylaxis regimen were compared to patients who completed >100 days of therapy, using Mann-Whitney U test for continuous variables and Pearson Chi-square tests for categorical variables. All statistical analyses were performed using SPSS v25 and NCSS v11. RESULTS: Demographics and clinical characteristics of all patients are summarized in Table 1A. TAC/SIR intolerance occurred in 25% (24 discontinued TAC, 1 discontinued SIR) of patients at a median duration of therapy of 19 days (range 4-92). The most common TAC/SIR toxicity (Table 1B) was acute kidney injury (AKI, n=11, 44%), followed by thrombotic microangiopathy (TMA, n=3, 12%). Baseline metabolic and clinical variables including creatinine, liver function, and conditioning intensity were not predictive of TAC-SIR intolerance. At a median follow-up of 10 months, the median overall survival (OS) for patients intolerant of TAC/SIR was 10 months versus was not reached for the patients without intolerance (HR 5.42; 95% CI 1.71-17.14; p<0.001). The 1-year PFS was 16% (95% CI 0% - 42%) vs 75% (95% CI 65% - 86%) and OS was 35% (95% CI 8% - 63%) vs. 79% (95% CI 68% - 90%) for patients who were TAC/SIR-intolerant compared to those who were TAC/SIR-tolerant (p<0.01) (Figure 1A). The cumulative incidence (CuI) of non-relapse mortality (NRM) at 1 year in patients intolerant of TAC/SIR was 47% (95% CI: 28% - 81%) and in patients tolerant of TAC/SIR was 4.4% (95% CI: 1.5% - 14%), (p<0.001). The Cul of relapse at 1 year was 45% (95% CI: 20% - 100%) in patients who were TAC/SIR-intolerant compared to 18% (95% CI: 10% - 30%) in patients who tolerated TAC/SIR (p=0.07) (figure 1B). Overall, 31 patients (31%) developed grade II-IV acute GVHD (aGVHD). The Cul of grade II-IV aGVHD at 100 days in patients who were TAC/SIR-intolerant was 29% (95% CI 15% - 58%) compared to 17% (95% CI 10% - 29%) in patients who tolerated TAC/SIR, (p=0.38). The Cul of cGVHD at 1 year in patients who were TAC/SIR-intolerant was 44% (95% CI: 25% - 79%) compared to 52% (95% CI: 40% - 68%) in patients who were TAC/SIR-tolerant (p=0.89). CONCLUSIONS: Outcomes for patients completing over 100 days of TAC/SIR for GVHD prophylaxis following allogeneic HCT are favorable. However, early intolerance of TAC/SIR GVHD prophylaxis occurred in 25% of allogeneic HCT in 2018 alone and predicted a poor prognosis with increased NRM and overall mortality, largely from drug-related toxicities. Notably, premature discontinuation of TAC/SIR did not contribute to higher subsequent risks of GVHD. Strategies to mitigate the risks of TAC/SIR toxicity are warranted. Future studies are also needed to identify the optimal GVHD prophylactic regimen for patients after TAC/SIR intolerance. Disclosures Nishihori: Novartis: Research Funding; Karyopharm: Research Funding. Bejanyan:Kiadis Pharma: Other: advisory board.

scholarly journals Bone marrow transplantation for severe aplastic anemia: influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome

Blood ◽  
1992 ◽  
Vol 79 (1) ◽  
pp. 269-275 ◽  
Author(s):  
E Gluckman ◽  
MM Horowitz ◽  
RE Champlin ◽  
JM Hows ◽  
A Bacigalupo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Graft Versus Host Disease ◽  
Randomized Clinical Trials ◽  
Chronic Gvhd ◽  
Severe Aplastic Anemia ◽  
Term Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Data for 595 patients with severe aplastic anemia receiving HLA- identical sibling bone marrow transplants were analyzed to determine the effect of pretransplant conditioning and graft-versus-host disease (GVHD) prophylaxis on outcome. Transplants were performed between 1980 and 1987 and reported to the International Bone Marrow Transplant Registry. Three conditioning regimens (cyclophosphamide alone, cyclophosphamide plus limited field radiation, and cyclophosphamide plus total body radiation) were studied; none was associated with superior long-term survival. Three GVHD prophylaxis regimens (methotrexate, cyclosporine, and methotrexate plus cyclosporine) were studied. Recipients of cyclosporine with or without methotrexate had a significantly higher probability of 5-year survival (69%, 95% confidence interval 63% to 74%) than patients receiving methotrexate only (56%, 49% to 62%, P less than .003). Higher survival with cyclosporine resulted from decreased risks of interstitial pneumonia (P less than .0002) and chronic GVHD (P less than .005). Additional risk factors adversely associated with survival included infection pretransplant (P less than .004), use of parous or transfused female donors (P less than .005), older patient age (P less than .005), and 20 or more pretransplant transfusions (P less than .006). These data may prove useful in planning randomized clinical trials and in identifying patients at high-risk of treatment failure.

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.

scholarly journals Bone marrow transplantation for severe aplastic anemia: influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome

Blood ◽  
1992 ◽  
Vol 79 (1) ◽  
pp. 269-275 ◽  
Author(s):  
E Gluckman ◽  
MM Horowitz ◽  
RE Champlin ◽  
JM Hows ◽  
A Bacigalupo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Graft Versus Host Disease ◽  
Randomized Clinical Trials ◽  
Chronic Gvhd ◽  
Severe Aplastic Anemia ◽  
Term Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Abstract Data for 595 patients with severe aplastic anemia receiving HLA- identical sibling bone marrow transplants were analyzed to determine the effect of pretransplant conditioning and graft-versus-host disease (GVHD) prophylaxis on outcome. Transplants were performed between 1980 and 1987 and reported to the International Bone Marrow Transplant Registry. Three conditioning regimens (cyclophosphamide alone, cyclophosphamide plus limited field radiation, and cyclophosphamide plus total body radiation) were studied; none was associated with superior long-term survival. Three GVHD prophylaxis regimens (methotrexate, cyclosporine, and methotrexate plus cyclosporine) were studied. Recipients of cyclosporine with or without methotrexate had a significantly higher probability of 5-year survival (69%, 95% confidence interval 63% to 74%) than patients receiving methotrexate only (56%, 49% to 62%, P less than .003). Higher survival with cyclosporine resulted from decreased risks of interstitial pneumonia (P less than .0002) and chronic GVHD (P less than .005). Additional risk factors adversely associated with survival included infection pretransplant (P less than .004), use of parous or transfused female donors (P less than .005), older patient age (P less than .005), and 20 or more pretransplant transfusions (P less than .006). These data may prove useful in planning randomized clinical trials and in identifying patients at high-risk of treatment failure.

Elevated Serum Interleukin-7 Levels Precede the Development of Acute Graft-Versus-Host Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1064-1064
Author(s):  
Robert M. Dean ◽  
Terry Fry ◽  
Crystal Mackall ◽  
Seth M. Steinberg ◽  
Frances T. Hakim ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Multiple Time ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Allogeneic Hsct ◽  
Graft Versus Host ◽  
Post Transplant ◽  
Interleukin 7 ◽  
Gvhd Prophylaxis ◽  
Acute Graft

Abstract BACKGROUND: Despite advances in transplantation immunology, there is no clinically practical tool to predict acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Murine models indicate that aGVHD is promoted by interleukin-7 (IL-7), a homeostatic cytokine for naïve CD4+ and CD8+ T-cells. We hypothesized that serum IL-7 levels might be associated with the development of aGVHD in patients (pts) undergoing allogeneic HSCT, and evaluated this using serum samples obtained for this purpose in a prospective clinical trial. METHODS: Thirty-one pts underwent allogeneic HSCT from HLA-identical siblings. Pts received 1 to 3 pre-transplant chemotherapy cycles to induce profound, uniform host lymphopenia (CD4<100), followed by fludarabine-based reduced-intensity conditioning. GVHD prophylaxis was cyclosporine & methotrexate. Serum IL-7 was measured by ELISA at baseline and multiple time points from the day of transplant through 1 year after allogeneic HSCT. IL-7 levels were evaluated for associations with blood lymphocyte counts, aGVHD, and survival. Other variables examined for association with aGVHD were pt and donor age; CD3+ and CD34+ cell doses; donor gender; donor-recipient gender mismatch; donor or recipient CMV status, prior rituximab therapy; donor lymphoid or myeloid chimerism >95% at day +14; serum IL-15 levels; and levels of soluble tumor necrosis factor-α receptors 1 and 2 (sTNFR1 and sTNFR2). RESULTS: Grades I, II, and III aGVHD occurred in 3%, 23%, and 19%, respectively; none had grade IV. Median (range) IL-7 levels rose from baseline 12.1 (0–46.9) pg/ml to 37 (13.3–79.2) pg/ml on day 0 before allografting, then fell to 12.0 (1.3–74.7) pg/ml by day +14; these changes were inversely correlated with absolute lymphocyte counts, CD3, CD4, and CD8 counts at baseline and day +7. The development of aGVHD was associated with IL-7 levels at day +7 (p=0.01) and day +14 (p=0.000033) post-transplant (Figure), along with the allograft CD34+ cell dose (p=0.012). Higher IL-7 levels at day +14 corresponded to more severe grades of aGVHD (p<0.0001). Figure Figure In logistic regression models, these factors jointly classified pts according to development or avoidance of aGVHD with a maximum sensitivity of 86% and a specificity of 100%. IL-7 levels were more strongly associated with aGVHD than were sTNFR levels or other parameters. CONCLUSIONS: Determination of serum IL-7 levels in the early post-transplant period accurately predicted the risk of developing aGVHD after allogeneic HSCT and holds promise as a simple, reproducible test to select pts for pre-emptive therapy. These data support preclinical observations that demonstrate a critical role for IL-7 in inducing aGVHD and provide a rational basis for novel approaches to GVHD prophylaxis through modulation of the IL-7 homeostatic pathway.

Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti–T-cell globulin ATG-Fresenius

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6375-6382 ◽  
Author(s):  
Gérard Socié ◽  
Claudia Schmoor ◽  
Wolfgang A. Bethge ◽  
Hellmut D. Ottinger ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Group Versus ◽  
Long Term Results ◽  
Control Group ◽  
Host Disease ◽  
Graft Versus Host ◽  
Probability Of Survival ◽  
Gvhd Prophylaxis

Abstract Previous randomized graft-versus-host disease (GVHD)-prophylaxis trials have failed to demonstrate reduced incidence and severity of chronic GVHD (cGVHD). Here we reanalyzed and updated a randomized phase 3 trial comparing standard GVHD prophylaxis with or without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before transplantation from unrelated donors. The cumulative incidence of extensive cGVHD after 3 years was 12.2% in the ATG-F group versus 45.0% in the control group (P < .0001). The 3-year cumulative incidence of relapse and of nonrelapse mortality was 32.6% and 19.4% in the ATG-F group and 28.2% and 33.5% in the control group (hazard ratio [HR] = 1.21, P = .47, and HR = 0.68, P = .18), respectively. This nonsignificant reduction in nonrelapse mortality without increased relapse risk led to an overall survival rate after 3 years of 55.2% in the ATG-F group and 43.3% in the control group (HR = 0.84, P = .39, nonsignificant). The HR for receiving immunosuppressive therapy (IST) was 0.31 after ATG-F (P < .0001), and the 3-year probability of survival free of IST was 52.9% and 16.9% in the ATG-F versus control, respectively. The addition of ATG-F to standard cyclosporine, methotrexate GVHD prophylaxis lowers the incidence and severity of cGVHD, and the risk of receiving IST without raising the relapse rate. ATG-F prophylaxis reduces cGVHD morbidity.

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