Post-transplant cyclophosphamide as graft-versus-host disease prophylaxis in HLA matched sibling donor stem cell transplantation for patients with acute leukemia.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e19523-e19523
Author(s):  
Alaa Nabil Elshamy ◽  
Essam Ali Abdelmohsen ◽  
Mai Denewer ◽  
Mohamed Nasr Mabed
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Graft Versus Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Matched Sibling ◽  
Group 2 ◽  
Related Mortality ◽  
Group 1

e19523 Background: Graft-versus-host disease (GVHD) is a life-threatening complication of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT). Calcineurin inhibitor (CNI) and methotrexate (MTX) have been used as the standard GVHD prophylaxis in HLA-matched HSCT. Promising clinical trial data using high dose post-transplant Cyclophosphamide (PT-Cy) with or without additional immunosuppressive agents (IS) have shown that it’s an effective, well tolerated alternative. However, experiences are limited with controversial results. Methods: We analyzed 62 patients with Acute Leukemia (39 males, 23 females) with age ranges from 18 to 60 years underwent allogeneic HSCT from matched sibling donors (MSD) using reduced intensity chemotherapy at Maadi Armed Forces Medical Hospital after informed consent. They were randomized into 2 groups according to GVHD prophylaxis regimen. The 1st group (40 patients) received MTX in the following doses; day+2 (15mg), day +4 (10 mg), day +6 (10 mg) with Cyclosporine (5mg/kg) from day -3 till day +90 and Mycophenolate (MMF) (2 -3gm/day) from day +1 till day +30. The 2nd group(22 patients) received PT-Cy (45 mg/kg/day) on days +3 and +4 with Cyclosporine (5mg/kg) from day +5 till day +30 & MMF:(2-3gm /day) from day +5 till +30. Results: At median 1 year Post Allo, PT-Cy was associated with statistically significant lowering of chronic GVHD (cGVHD) incidence compared to MTX group (22.7%, 56.4%) respectively (P = 0.011). Incidence of acute GVHD (aGVHD) at day +100 was (40%, 22.7%) in group 1, 2 respectively (P = 0.169). 92% of patients in group 1 and 86.4 % of patients in group 2 were engrafted with full donor chimerism on day +30 (P = 0.659). The cumulative incidence of relapse at 4 years after transplantation was 17.9 % for group 1 and 36.4 % for group 2 (P > 0.05). Relapse related mortality were 16.2% among MTX group while 27.3% in PT-Cy group (P = 0.10). Transplant related mortality (TRM) in MTX group were; Severe aGVHD (8%), cGVHD (10%), Hepatic Toxicity (8%), Nephrotoxicity (2.7%) & ARDS (5.4%). In PT-Cy group TRM were; septicemia (18%), severe aGVHD (4.5%) & ARDS (4.5%). Cumulative 4 years Disease Free Survival (DFS) & Overall survival (OS) in PT-Cy group were (51.8 %, 46.4%) respectively while (69.3%, 39%) in MTX group which is statistically non-significant (P > 0.05). Conclusions: For GVHD prophylaxis in MSD, PT-Cy is a safe alternative that reduces the risk of cGVHD in comparison with MTx based regimen without affecting Relapse rate, DFS or OS.

scholarly journals Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell–depleted stem cell transplantation

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2240-2245 ◽  
Author(s):  
Annoek E. C. Broers ◽  
Ron van der Holt ◽  
Joost W. J. van Esser ◽  
Jan-Willem Gratama ◽  
Sonja Henzen-Logmans ◽  
...  
Keyword(s):  
Overall Survival ◽  
Risk Factor ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Graft Versus Host ◽  
Cmv Disease ◽  
Treatment Related Mortality ◽  
Related Mortality ◽  
Acute Graft

We evaluated the efficacy, toxicity, and outcome of preemptive ganciclovir (GCV) therapy in 80 cytomegalovirus (CMV)-seropositive patients allografted between 1991 and 1996 and compared their outcome to 35 seronegative patients allografted during the same period. Both cohorts were comparable with respect to diagnosis and distribution of high- versus standard-risk patients. All patients received a stem cell graft from an HLA-identical sibling donor, and grafts were partially depleted of T cells in 109 patients. Patients were monitored for CMV antigenemia by leukocyte expression of the CMV-pp65 antigen. Fifty-two periods of CMV reactivation occurring in 30 patients were treated preemptively with GCV. A favorable response was observed in 48 of 50 periods, and only 2 patients developed CMV disease: 1 with esophagitis and 1 with pneumonia. Ten of 30 treated patients developed GCV-related neutropenia (less than 0.5 × 109/L), which was associated with a high bilirubin at the start of GCV therapy. Overall survival at 5 years was 64% in the CMV-seronegative cohort and 40% in the CMV-seropositive cohort (P = .01). Increased treatment-related mortality accounted for inferior survival. CMV seropositivity proved an independent risk factor for developing acute graft-versus-host disease, and acute graft-versus-host disease predicted for higher treatment-related mortality and worse overall survival in a time-dependent analysis. We conclude that, although CMV disease can effectively be prevented by preemptive GCV therapy, CMV seropositivity remains a strong adverse risk factor for survival following partial T-cell–depleted allogeneic stem cell transplantation.

scholarly journals Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell–depleted stem cell transplantation

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2240-2245 ◽  
Author(s):  
Annoek E. C. Broers ◽  
Ron van der Holt ◽  
Joost W. J. van Esser ◽  
Jan-Willem Gratama ◽  
Sonja Henzen-Logmans ◽  
...  
Keyword(s):  
Overall Survival ◽  
Risk Factor ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Graft Versus Host ◽  
Cmv Disease ◽  
Treatment Related Mortality ◽  
Related Mortality ◽  
Acute Graft

Abstract We evaluated the efficacy, toxicity, and outcome of preemptive ganciclovir (GCV) therapy in 80 cytomegalovirus (CMV)-seropositive patients allografted between 1991 and 1996 and compared their outcome to 35 seronegative patients allografted during the same period. Both cohorts were comparable with respect to diagnosis and distribution of high- versus standard-risk patients. All patients received a stem cell graft from an HLA-identical sibling donor, and grafts were partially depleted of T cells in 109 patients. Patients were monitored for CMV antigenemia by leukocyte expression of the CMV-pp65 antigen. Fifty-two periods of CMV reactivation occurring in 30 patients were treated preemptively with GCV. A favorable response was observed in 48 of 50 periods, and only 2 patients developed CMV disease: 1 with esophagitis and 1 with pneumonia. Ten of 30 treated patients developed GCV-related neutropenia (less than 0.5 × 109/L), which was associated with a high bilirubin at the start of GCV therapy. Overall survival at 5 years was 64% in the CMV-seronegative cohort and 40% in the CMV-seropositive cohort (P = .01). Increased treatment-related mortality accounted for inferior survival. CMV seropositivity proved an independent risk factor for developing acute graft-versus-host disease, and acute graft-versus-host disease predicted for higher treatment-related mortality and worse overall survival in a time-dependent analysis. We conclude that, although CMV disease can effectively be prevented by preemptive GCV therapy, CMV seropositivity remains a strong adverse risk factor for survival following partial T-cell–depleted allogeneic stem cell transplantation.

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

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

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

A Pilot Study of Mycophenolate Mofetil for the Prophylaxis and Treatment of Graft-Versus-Host Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4969-4969
Author(s):  
Chengwei Luo ◽  
Xin Du ◽  
Jianyu Weng ◽  
Rong Guo ◽  
Zesheng Lu
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Peripheral Blood Stem Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis

Abstract Graft-versus-host disease (GVHD) is a serious complication of allogeneic peripheral blood stem cell transplantation (PBSCT), which contribute to morbidity and mortality after transplantation. Approximately half of the patients that undergo allogeneic stem cell transplantation develop severe acute or chronic graft-versus-host disease [Shulman HM et al. Am J Med, 1980], which varies with the degree of histoincompatibility, the recipient and donor ages, the source and quality of donor T lymphocytes, the incidence of cytomegalovirus infection,and type of GVHD prophylaxis strategy. The combination of immunosuppressive drugs, CsA and short-course MTX is a standard regiment for prevention of GVHD after BMT [Nademanee A et al. Blood, 1995], and have been shown in randomize trials to be superior to either drug alone in preventing severe GVHD [Storb R N Engl J Med.1986]. Although the efficacy of the regimens in preventing GVHD, the incidence reported for GVHD after transplantation is 38–68%. Each of these agents is also associated with significant organ toxicity. MMF is an new immunosuppressive drug, which selectively inhibits proliferation of T and B lymphocytes, formation of antibodies, and glycosylation of adhesion molecules by inhibition purine nucleotide synthesis and depleting the lymphocytes and monocytes of guanosine triphosphate. In patients undergoing renal and heart transplantation, it has been successfully used to prevent graft rejection [Lang P et al.Transplantation, 2005]. We compared the effects of MMF+ CsA+ MTX as GVHD prophylaxis vs CsA + MTX in patients undergoing allogeneic peripheral blood stem cell transplantation. In all, 33 patients were enrolled in this study. The first group, of 16 patients, received CsA at 3mg/kg i.v. from day −1 to +30 day and MTX was on 15mg/m2 day +1 and 10mg/m2 day +3, +6, +11. The other group, of 17 patients received MMF 1g/d day −7 until day 0 and CsA + MTX. Here we used flow cytometric analysis technique to measure the changes of T cell subsets before and after treatment of MMF and CsA. Our study showed the incident of aGVHD is 25% when we combined standard GVHD proplylaxis with MMF after PBSCT, Which significantly reduce the risk of aGVHD than the combination of CsA and MTX (58.8%). Therefore, MMF is an effective drug in prophylaxis of aGVHD. Chronic GVHD is a late complication of PBSCT, Which develops approximately 30% in related donor HLA-matched allografts, and 60–70% in HLA-unmatched. The incident is not reduce with the development of aGVHD prophylaxis, Our result showed that the incident of cGVHD in research group (25%) is the same as the control group (23.5%). It seems that MMF is not reduce the incident of cGVHD, which may be different frome aGVHD. Our conclude that the number of CD3+ CD4+T cells decreased after the treatment of MMF, and those of CD3+ CD8+T cells increased,with reduction of the CD4+/CD8+ ratio. the number of CD25+ CD4+ and CD69+ CD8+ T cells were all increase. It seems that MMF may preferably effect on the CD3+CD4+T cells and the combination of MMF with CSA and MTX can significantly reduce the incidence of acute graft-vost-host diease, It appears to have a synergic action with CSA for the treatment of aGVHD.

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

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

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

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