Adult Recipients of Matched Related Donor Blood Cell Transplants (BCT) Given Pretransplant Low-Dose Antithymocyte Globulin (ATG) Have Less Chronic Graft-Versus-Host Disease (cGVHD) and Transplant-Related Mortality (TRM): A Matched Pair Analysis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2250-2250
Author(s):  
James A. Russell ◽  
A. Robert Turner ◽  
Loree Larratt ◽  
Ahsan M. Chaudhry ◽  
Oluyeme Jeje ◽  
...  
Keyword(s):  
Blood Cell ◽  
Graft Versus Host Disease ◽  
Antithymocyte Globulin ◽  
Progression Free Survival ◽  
Not Given ◽  
Free Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Related Donor ◽  
Related Mortality

Abstract Because pretransplant antithymocyte globulin (ATG) seems to reduce graft-versus-host disease (GVHD) and transplant-related mortality (TRM) after unrelated donor bone marrow transplant (BMT) we have investigated this agent in matched related donor (MRD) blood cell transplant (BCT). Of 82 adults receiving myeloablative conditioning and first MRD BCT between 01/99 and 05/02, 54 were matched for disease and stage with 54 patients (pts) not given ATG between 12/94 and 11/98. Median age was 42 (range 18 – 63) for ATG pts and 41 (range 22 – 54) for controls. Included in each group were 22 standard-risk pts (16 AML CR1, 6 ALL CR1), and 14 with high-risk acute leukemia of whom 12 had active AML (7 arising from MDS, 3 induction failures, 1 refractory, 1 relapse), and 2 ALL (1 refractory, 1 relapse). An additional 18 pts included 2 AML CR2, 1 ALL CR2, 2 CML AP/CP2, 2 MM, 8 relapsed/refractory NHL (2 mantle cell, 4 low, 1 intermediate, 1 high-grade) and 3 relapsed/refractory CLL. More control pts had conditioning incorporating TBI (32 vs 11, p<0.0001). All pts were given cyclosporine A and “short course” methotrexate with folinic acid. The study group received Thymoglobulin (Genzyme) (ATG) 4.5 mg/kg in divided doses over 3 consecutive days pretransplant finishing D0. ATG recipients were followed for 22 to 62 months (median 46) and control patients for 65–112 months (median 84). The actuarial incidence of acute GVHD grades II – IV was 25±6% in ATG recipients compared with 37±7% in the controls (p = ns). The figures for grade III – IV disease were 13±5% and 20±7% respectively (p = ns). Incidence of cGVHD at two years was 40±7% with ATG vs 97±3% without ATG (p < 0.0001), figures for extensive disease were 32±7% and 94±3% respectively (p < 0.0001). Sites of involvement by cGVHD were similar apart from gastrointestinal disease which was relatively more frequent in those ATG recipients who developed cGVHD (26% vs 5%, p = 0.03). Non-relapse mortality with and without ATG respectively was 4±3% vs 17±5% at 100 days and 9±4% vs 32±7% at 2 years (p = 0.004). Deaths were GVHD related in 3 ATG treated patients vs 13 controls (p=0.01). In the control group 2 year TRM was 26±8% in 32 TBI recipients compared with 42±11% in 22 patients not given TBI (p = ns). Relapse rate at 2 years was 36±7% for ATG recipients and 23±7% in controls (p = 0.06). Six of 21 relapsing patients in the ATG group survive having achieved another remission (4) or disease stabilization (2) after more treatment. One of 12 control patients who relapsed is currently alive in remission after a second BCT. Survival at 2 years was 70±6% in the patients given ATG vs. 54±7% in the controls (p=0.08) and progression-free survival was 57±7% vs 52±7% respectively. This study indicates that MRD BCT recipients given pretransplant ATG experience less cGVHD, less overall TRM and lower mortality related to both acute and chronic GVHD. These findings are not due to more control pts receiving TBI. Despite a trend to more relapse progression-free survival is unaffected, there is a trend to improved survival and presumably quality of life is generally better in ATG recipients because fewer of them have cGVHD.

High Levels of Donor Chimerism Early after Non-Myeloablative Transplantation Predictive of Overall and Progression Free Survival but Not Risk of Acute Graft Versus Host Disease for Patients with AML or MDS.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 185-185
Author(s):  
Edwin P. Alyea ◽  
Shuli Li ◽  
Haesook Kim ◽  
Vincent T. Ho ◽  
Corey Cutler ◽  
...  
Keyword(s):  
Overall Survival ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Early Stage ◽  
Progression Free Survival ◽  
Free Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor Chimerism ◽  
The Impact

Abstract Non-myeloablative (NST) transplantation is increasingly used in the treatment of patients with AML and MDS who are not candidates for myeloblative transplant. Relapse of disease remains a major cause of treatment failure after NST. Predictive factors to identify patients at high risk of relapse are needed to identify patients who would benefit from additional interventions. Attainment of a high degree of donor engraftment achieved early after transplantation may indicate the presence of a more significant allo-immune effect. We have performed a retrospective analysis of 64 patients with AML and MDS receiving NST, assessing the impact of donor chimerism when measured early after transplantation on outcome. Overall survival (OS), progression free survival (PFS) and risk of graft versus host disease (GVHD) were compared for patients achieving ≥90 % or <90% donor derived hematopoiesis when measured 1 month after transplant. All patients received fludarabine 30 mg/m2/day x 4 days and intravenous busulfan (Busulfex)0.8 mg/kg/day x 4 days for conditioning. All patients received calcineurin-inhibitor based GVHD prophylaxis. All patients received PBSC with G-CSF at 5 mcg/kg beginning day 1 after transplantation. Chimerism was measured using FISH for sex mismatched patient donor pairs or by STR analysis. 37 patients had ≥90% donor derived hematopoiesis, 27 patients had <90% donor derived hematopoiesis after transplantation. The two groups had similar characteristics with a median age of 57 yrs (range 21–70) for patients ≥90% and 58 yrs (range 32–69) for patients <90%. Of patients achieving ≥90%, 23 patients had AML and 14 MDS. Of patients <90%, 13 had AML and 14 with MDS. 7 of 16 (44%) patients with early stage disease(AML in CR1 or early stage MDS) achieved ≥90% donor hematopoiesis, while 30 of 48 (63%) patients with advanced disease achieved ≥90%. 17 of 29 (59%) patients with unrelated donors achieved ≥90% donor derived hematopoiesis, while 20 of 33 (61%) patients with matched related donors achieved ≥90% donor derived hematopoiesis. 21 of 32 (66%) patients with donor-recipeint sex mismatch achieved ≥90% while 16 of 32 (50%) patients with same sex donors were ≥90%. The median follow-up for surviving patients achieving ≥90% donor chimerism was 12 months and 15 months for those <90%. Patients achieving ≥90% donor chimerism had a significantly improved 1-year (71% versus 41%) and 2-year (39% versus 19%) OS (p=0.05). Similarly, for patients achieving ≥90% donor chimerism, there was a trend toward an improved PFS at 1-year (49% versus 30%) and 2-years (32% versus 19%) (p=0.08). There was no difference in the risk of developing stage 2–4 acute GVHD, 19% for both patients above and below 90%. Achieving high levels of donor chimerism when measured early after NST predicts for an improved overall survival and there is a trend toward an improved progression free survival. This may represent the presence of an enhanced graft versus leukemia effect in these patients. The degree of donor chimerism does not predict the development of acute GVHD. These results suggest that patients with <90% donor derived hematopoiesis may be candidates for strategies to enhance donor chimerism.

Long-Term Outcomes of Myeloablative Conditioning and Matched-Related Donor Hematopoietic Cell Transplantation for Patients with High-Risk and Advanced-Stage Hematolymphoid Malignancies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4383-4383
Author(s):  
Jonathan E. Benjamin ◽  
Ginna G. Laport ◽  
Laura J. Johnston ◽  
Sally Arai ◽  
Wen-Kai Weng ◽  
...  
Keyword(s):  
High Risk ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
Free Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Related Donor

Abstract Patients with high-risk hematolymphoid malignancies who relapse or who do not achieve a complete remission to induction chemotherapy generally do not achieve long-term survival when treated with the best available non-transplant therapies. The benefit of allogeneic hematopoietic cell transplantation has been well described for patients in first complete remission, but less so for patients with advanced disease. We report the long-term follow-up of 131 patients with leukemia or lymphoma who received an HLA-matched related donor transplant following myeloablative conditioning with fractionated total body irradiation (1320cGy), etoposide (60mg/kg), and cyclophosphamide (60mg/kg). Eligibility for transplantation under this protocol included induction failure or high-risk disease that was beyond first remission. All patients were treated at a single institution. Diagnosis at the time of transplantation included ALL (n=57), AML (n=38), NHL (n=20), CML (n=10), MDS (4), JMML (n=2). Of the 95 patients with acute leukemia, 62 (65%) were not in remission at the commencement of the conditioning regimen. The median age at transplantation was 29 years (range 2–55). Seventy-four (56%) patients received unmanipulated bone marrow and the remainder received filgrastim-mobilized peripheral blood. Median follow-up of surviving patients was 8 years (range 0.3–17). The estimated five-year overall survival and event-free survival were 34% (95% confidence interval: 22–42%) and 32% (95% confidence interval: 24–39%), respectively. Leading causes of death included relapse (n=43), infection (n=11), acute graft-versus-host disease (n=8), respiratory failure (n=5) and hepatic veno-occlusive disease (n=4). Grade II–IV acute graft-versus-host disease occurred in 26% of patients. The cumulative incidence of extensive chronic graft-versus-host disease among those patients who survived beyond day 100 was 32%. These results indicate that patients with high-risk or advanced disease can experience long-term disease-free survival following an aggressive conditioning regimen that combines radiotherapy, etoposide, and cyclophosphamide. Relapse remains the most significant cause of mortality, and future efforts should focus on augmenting the graft-versus-malignancy effect.

Administration of cyclosporine for 24 months compared with 6 months for prevention of chronic graft-versus-host disease: a prospective randomized clinical trial

Blood ◽  
2001 ◽  
Vol 98 (13) ◽  
pp. 3868-3870 ◽  
Author(s):  
Emin Kansu ◽  
Ted Gooley ◽  
Mary E. D. Flowers ◽  
Claudio Anasetti ◽  
H. Joachim Deeg ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Clinical Manifestations ◽  
Disease Free Survival ◽  
Free Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Alternative Donor ◽  
To Receive ◽  
Related Mortality

Abstract This study compared the incidence of clinical extensive chronic graft-versus-host disease (GVHD), transplantation-related mortality, survival, and relapse-free survival among recipients randomly assigned to receive a 24-month or a 6-month course of cyclosporine prophylaxis after transplantation of allogeneic marrow from an HLA-identical sibling or alternative donor. Patients who did not have clinical manifestations of chronic GVHD on day 80 after transplantation were eligible for the study if they previously had acute GVHD or if a skin biopsy showed histologic evidence of chronic GVHD. Clinical extensive chronic GVHD developed in 35 of the 89 patients (39%) in the 24-month group and 37 of the 73 patients (51%) in the 6-month group. The hazard of developing chronic GVHD was not significantly different in the 2 groups (hazard ratio = 0.76; 95% confidence interval, 0.48-1.21; P = .25). In addition, there were no significant differences between the 2 groups in transplantation-related mortality, survival, or disease-free survival.

High Progression-Free Survival At 10 Years After Tandem Autologous/Nonmyeloablative Allogeneic Transplants For Multiple Myeloma In a Cohort Of 93 Patients: Impact Of Disease Remission Status At Transplant and Chronic Graft-Versus-Host Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3353-3353
Author(s):  
Imran Ahmad ◽  
Sandra Cohen ◽  
Silvy Lachance ◽  
Guy Sauvageau ◽  
Thomas Kiss ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Induction Therapy ◽  
Graft Versus Host Disease ◽  
Protective Factor ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Free Survival ◽  
Host Disease ◽  
Graft Versus Host ◽  
Sibling Donor

Abstract Introduction Despite improved survival with new molecules, allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative option for multiple myeloma (MM). Myeloablation with autologous HSCT (autoHSCT) followed by nonmyeloablative (NMA) alloHSCT has reduced the high nonrelapse mortality (NRM) rates associated with myeloablative alloHSCT, but randomized trials comparing NMA alloHSCT with standard therapy have yielded conflicting results. Factors affecting long-term outcomes have not been clearly defined. We sought to identify factors associated with outcomes in a large single-center cohort of 93 tandem transplant recipients. Methods We conducted a prospective phase II trial in Durie-Salmon (DS) stage II/III newly diagnosed MM patients <65 years with a 6/6 sibling donor, characterized by outpatient alloHSCT and complete immunosuppression withdrawal by day +100. Following induction therapy, patients received autoHSCT followed 3 months later by an outpatient NMA alloHSCT. Conditioning regimen consisted of fludarabine (30 mg/m2 x 5 days) and cyclophosphamide (300 mg/m2 x 5 days), followed by donor G-CSF mobilized stem cells (target dose: ≥4 x 10^6 CD34+/kg). GVHD prophylaxis included tacrolimus (day -10 to +50, taper by +100) and mycophenolate mofetil 1000 mg BID (day +1 to +50). Probabilities of overall and progression-free survival (OS and PFS), relapse, NRM and graft-versus-host disease (GVHD) incidences were estimated taking competing risks into account when appropriate. Regression analysis using Cox and Fine & Gray models were used to determine factors influencing outcomes. Severity of chronic GVHD was assessed by the proportion of alive patients on systemic immunosuppression. Results From 2001 to 2010, 93 patients received tandem HSCT from a matched sibling donor; median age was 52 years (range 39-64) and DS stage III present in 76%. All but 6 patients received a single line of induction therapy. Median time from diagnosis to autoHSCT and from auto- to alloHSCT were 7 (range 3-57) and 4 (range 2-13) months, respectively. At least partial remission (PR) status was obtained in 84% patients before tandem HSCT. After a median follow-up of 7 years, cumulative incidences of grade II-IV acute and extensive chronic GVHD were 9% (95%CI: 4-15) and 85% (75-91) respectively. Cumulative incidences of NRM and progression were 10% (95%CI: 3-22) and 47% (37-58; Fig. 1). Probability of 10-year OS and PFS were 64% (50-74; Fig. 2) and 44% (31-56; Fig. 1) respectively. In multivariate analysis, at least stable disease (SD) status before alloHSCT was a significant protective factor for progression incidence and PFS (respectively, HR 0.18, CI: 0.05-0.64, and HR 0.12, CI: 0.04-0.36). Extensive chronic GVHD as time-dependent variable was also protective for PFS (HR 0.39, CI: 0.19-0.80). The most significant protective factor for OS was at least SD status before alloHSCT (HR 0.15, CI: 0.04-0.56). The association between chronic GVHD and OS did not reach statistical significance. In survivors, the probability of being on systemic immunosuppressive treatment for GVHD was 39% (CI: 27-52) at 5 years and 15% (CI: 4-42) at 10 years. Conclusions We report a very high PFS of 44% at 10 years in a large cohort of 93 NMA alloHSCT recipients. Despite the high incidence of chronic GVHD, we observed a low NRM of 10% and an acceptable prevalence of immunosuppressive therapy of 15% at 10 years. Chronic extensive GVHD and achievement of disease control before HSCT were both associated with better PFS. Patients with progressive disease do not seem to benefit from NMA alloHSCT and efforts to reduce chronic Disclosures: No relevant conflicts of interest to declare.

scholarly journals Incidence and Pattern of Graft-versus-Host Disease in Patients Undergoing Allogeneic Transplantation after Nonmyeloablative Conditioning with Total Lymphoid Irradiation and Antithymocyte Globulin

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Lauren Veltri ◽  
Michael Regier ◽  
Aaron Cumpston ◽  
Sonia Leadmon ◽  
William Tse ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Antithymocyte Globulin ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Progression Free Survival ◽  
Allogeneic Transplantation ◽  
Host Disease ◽  
Total Lymphoid Irradiation ◽  
Graft Versus Host ◽  
Institutional Experience

Nonmyeloablative (NMA) conditioning with total lymphoid irradiation and antithymocyte globulin (TLI/ATG) has been shown to protect against acute graft-versus-host disease (GVHD). We report here our institutional experience with allogeneic transplantation following NMA conditioning with TLI/ATG (). GVHD prophylaxis consisted of a combination of a calcineurin inhibitor and mycophenolate mofetil. Median patient age was 59 years. The median followup of surviving patients is 545 days. One patient experienced primary graft rejection. The median time to neutrophil engraftment was 18 days and platelet engraftment was 9.5 days. The cumulative incidence (CI) of grade II–IV acute GVHD at day +100 was 28.6% and 38.1% at day +180. The CI for grade III-IV acute GVHD was 28.6% at day +180. CI of chronic GVHD was 45.2% at 1 year. The CI of disease relapse was 9.5% at 1 year. The rate of nonrelapse mortality (NRM) was 0% at day +100 and only 9.5% at 1 year. The overall and progression free survival at 1 year was 81% and 80.4%, respectively. Our limited, retrospective data show encouraging relapse and NRM rates with TLI/ATG-based NMA conditioning, but with higher than previously reported rates of acute and chronic GVHD, underscoring the need for novel strategies designed to effectively prevent GVHD.

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