Influence of the Intensity of the Conditioning Regimen on the Characteristics of Acute and Chronic Graft Versus Host Disease after Allogeneic Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5157-5157
Author(s):  
Maria Diez-Campelo ◽  
Jose A. Perez-Simon ◽  
Rodrigo Martino ◽  
Daniel Valcarce ◽  
Alvaro Urbano ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Allogeneic Transplantation ◽  
Response To Treatment ◽  
Host Disease ◽  
Graft Versus Host ◽  
Conditioning Regimens ◽  
Reduced Intensity

Abstract Although increasing numbers of allogeneic stem cell transplants are being performed worldwide using reduced intensity conditionings (allo-RIC), most of the current experience and knowledge on the characteristics of graft-versus-host disease (GVHD), especially chronic GVHD (cGVHD), comes from the use of myeloablative conditioning regimens (MCR). We have analyzed the incidence and characteristics of GVHD among 150 consecutive patients undergoing allo-RIC as compared to 88 concomitant patients undergoing MCR. All patients analized received peripheral blood stem cells (PBSC) from an HLA identical sibling and the same GVHD prophylaxis (cyclosporine and methotrexate). Incidences of acute GVHD (aGVHD) were 69% and 47% among MCR and allo-RIC, respectively (p<0.001). Incidences of grades 2–4 aGVHD were 51% vs 33%, respectively (p=0.0009). Regarding organ involvement, no signifficant differences were observed between either subgroups. Skin was the organ most frecuently involved in both subgroups (83 % vs 75.3% cases among MCR and allo-RIC patients, respectively; p=0.08). Regarding response to treatment, no significant differences were observed between both subgroups, with 66.1% vs 52.2% of patients reaching complete remission (CR) after first line therapy. Interestingly, gastrointestinal tract was the organ most frequently involved in treatment failure in both subgroups: 16 (66.6%) and 20 (80%) of MCR and allo-RIC patients (p=0.21) had gut GVHD relapse/progression/no response with or without other organs involvement. Liver was involved in treatment failure in 6 (25%) vs 12 (48%) patients undergoing MCR vs allo-RIC, respectively (p=0.02). In multivariate analysis, only type of conditioning (MCR vs RIC) significantly influenced the incidence of overall aGVHD: HR= 2.16 (95 % CI: 1.52–3.07), p<0.0001. Incidences of chronic GVHD (cGVHD) were 68% and 76% among MCR and allo-RIC patients, respectively (p=0.03), although patients who developed cGVHD, incidence of extensive cGVHD was higher in the MCR group as compared to allo-RIC (88 vs 64%, p=0.01). A higher incidence of severe skin cGVHD involvement was observed among MCR recipients (39.4% vs 9.6%, respectively; p=0.008). As far as response to immunosupressive treatment 41.4% of MCR vs 58.2% of allo-RIC patients reached CR (p=0.43). Among patients who reached CR of cGVHD, a high incidence of cGVHD relapse was observed in both subgroups (58.3% vs 50% among MCR vs allo-RIC patients), with most relapses occurring in the first year after inmunosuppression was stopped. Among patients who developed extensive cGVHD, 83.3% vs 37.9% of patients undergoing MCR vs allo-RIC required systemic immmunosupression 3 years after allogeneic PBSC transplantation (p=0.009). Thus, overall, duration of immunosupression was shorter among allo-RIC patients, since 36 months after transplant 68.8% vs 35.5% of patients receiving MCR vs RIC required systemic immunosupression (p=0.028). In conclusion, the use of reduced intensity conditioning regimens decreases the incidence of both acute and extensive cGVHD after PBSC allogeneic transplantation, thus reducing the immunosupression requirements at the long term follow up.

scholarly journals Final Results of a Multicenter Prospective Phase II Trial of Allogeneic Transplantation for Relapsed/Refractory CD20+ B-Cell Lymphomas: Effect of Rituximab on Graft-Versus-Host Disease-Free/Relapse-Free Survival (GRFS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3473-3473
Author(s):  
Anna Dodero ◽  
Francesca Patriarca ◽  
Giuseppe Milone ◽  
Barbara Sarina ◽  
Rosalba Miceli ◽  
...  
Keyword(s):  
B Cell ◽  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
High Dose ◽  
B Cell Lymphomas ◽  
Host Disease ◽  
Graft Versus Host ◽  
Prospective Phase ◽  
Unrelated Donors

Abstract Introduction: Patients with refractory and relapsed B-cell lymphomas have few curative options. Despite novel target therapies, only patients receiving allogeneic stem cell transplantation (alloSCT) can achieve a long-term disease control. A lot of effort has been done over the last years to produce strategies reducing non-relapse mortality (NRM) without damaging the graft-versus-lymphoma effect. We conducted a multicenter prospective phase II trial to evaluate the benefit of high-dose Rituximab (R) in the conditioning regimen before alloSCT. The primary end-point of the study was progression-free (PFS) survival. We evaluated also the long-term outcome with the novel composite end-point of graft-versus-host disease-free/relapse-free survival (GRFS). Methods:The study enrolled 121 adult patients who received alloSCT for relapsed/refractory B-cell lymphomas [n=35 (28%) follicular lymphomas; n=29 (24%) chronic-lymphocytic leukemia; n=35 (28%) diffuse large B-cell lymphomas; n= 22 (18%) mantle cell lymphomas]. The median age was 52 years (range, 23-65). Seventy-four pts (61%) failed a previous autograft. The conditioning regimen consisted of thiotepa (12 mg/kg), cyclophosphamide (60 mg/kg) and fludarabine (60 mg/m2) and high-dose of rituximab (500 mg/m2 on day-6),. Graft-versus-host disease (GVHD) prophylaxis was based on cyclosporine and mini-methotrexate; ATG (7 mg/kg) was given to the patients allografted from unrelated donors. Sixty-seven (55%) and fifty-four (45%) patients received grafts from related and unrelated donors, respectively. Results: At a median follow-up of 41 months (range 6-95 months), the estimated 3-years PFS and overall survival (OS) were 50% (95%CI, 41%-61%) and 61% (95%CI, 51%-71%), respectively. The 1 and 3-years GRFS were 40% (95%CI, 32%-50%) and 34% (95%CI, 26%-44%), respectively. The GRFS was significantly better in patients affected by indolent disease (43% versus 22%, long-rank test, p=0.02); in addition there was a tendency for better GRFS for those transplanted from unrelated donors (41% versus 27%, p=0.096). The 3-years GRFS were 41% and 30% in patients with complete remission (CR) and partial remission (PR) at the time of transplant, respectively (p=0.185). The multivariate analysis showed that patients affected by aggressive histotype and with bone marrow (BM) infiltration at time of transplant had a poor outcome in terms of PFS, OS and GRFS [hystotype: PFS, HR 3.30 (p=0.003); OS, HR 3.73 (p=0.007); GRFS, HR 2.02 (p=0.026); BM infiltration: PFS, HR 4.79 (p<0.001); OS, HR 6.00 (p<0.001); GRFS, HR 2.7 (p=0.004)]. The crude cumulative incidence (CCI) of NRM was 21% (95%CI, 14%-30%) at 3-years whereas the CCI of acute GVHD grade II-IV was 22% (95%CI,15%-30%). The CCI of acute GVHD was not statistically significant different in matched sibling donors and unrelated donors (21% versus 22%, respectively p=0.717). According to the modified Seattle criteria, the CCI of extensive GVHD was 17% (95%CI, 11%-27%) whereas the limited form was 27% (95%CI, 19%-39%). In the univariable Fine and Gray model, the only factor that was protective against the occurrence of chronic GVHD was the transplant from unrelated donors when R and ATG were combined together [HR 0.50 (95%CI, 0.25-0.99), p=0.05]. In fact, the CCI of chronic GVHD at 3-years from matched sibling donors was 54% (95%CI,42%-71%) as opposed to 31% from unrelated donors (95%CI, 19%-49%) (p=0.04). Conclusions: Our trial showed:1) R did not improve PFS as compared with our historical control; 2) the combination of R and ATG is synergistic and resulted protective against chronic GVHD; 3) GRFS analysis showed that 34% of the patients are alive without any complications at 3-years after allograft and this should be the standard to compare novel drug results. Future protocols should consider the use of GRFS as endpoint and inclusion of ATG also for those receiving sibling grafts. Disclosures Cascavilla: Janssen-Cilag: Honoraria.

Use of Peripheral Blood Grafts Is Associated with Increased Acute and Chronic Graft-Versus-Host Disease without Improved Survival after Unrelated Donor Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 443-443 ◽  
Author(s):  
Mary Eapen ◽  
Michael Haagenson ◽  
Brent Logan ◽  
Dennis Confer ◽  
Mary Horowitz ◽  
...  
Keyword(s):  
Stem Cell ◽  
Treatment Failure ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Chronic Gvhd ◽  
Single Locus ◽  
Unrelated Donor ◽  
Host Disease ◽  
Graft Versus Host

Abstract Data from the CIBMTR indicate that approximately 70% of unrelated donor hematopoietic stem cell transplants (HCT) in the U.S. utilize peripheral blood (PB) rather than bone marrow (BM) as a graft source. Comparative studies verifying its benefit, however, are lacking. We, therefore, performed a retrospective analysis comparing the results of 275 unrelated PB and 620 unrelated BM transplants in adults 18–60 years of age with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or chronic myeloid leukemia (CML), transplanted in 2000–2002. 73% of PB grafts were matched at HLA A, B, C (low resolution) and DRB1, 21% were mismatched at a single locus and 6% were mismatched at ≥ 2 loci. 69% of BM grafts were matched, 26% were mismatched at a single locus and 5% were mismatched at ≥ 2 loci. Median follow-up was 24 (range, 6–48) and 34 (range, 6–54) months for PB and BM recipients, respectively. Groups were similar except PB recipients were less likely to have CML, were more likely to have MDS and were transplanted more recently. Incidences of neutrophil recovery (95% vs. 90% at day 100, p=0.01) and platelets ≥20,000/ul (81% vs. 66%, at 1-year, p <0.0001) were significantly higher after PB than BM transplants. Incidences of grades 2–4 but not grades 3–4 acute graft-versus-host disease (GVHD) were significantly higher after PB than BM transplants (56% vs.45%, at day 100, p=0.003). Chronic GVHD was also significantly higher after PB transplants (54% vs. 39%, at 3 years, p<0.0001). Despite higher rates of grade 2–4 acute and chronic GVHD after PB transplantation, incidence of relapse was similar in the two groups for both early and advanced leukemia. In multivariate analysis, risks of treatment-related mortality (TRM), treatment failure (relapse or death) and overall mortality during the first 9 months after transplantation were similar. However, among patients surviving the first 9 months, subsequent risks of TRM (relative risk [RR] 1.90, 95% confidence interval [CI], 1.14–3.17, p=0.01) and treatment failure (RR 1.60, 95% CI 1.06–2.44, p=0.03) were significantly higher in the PB cohort. Three-year adjusted (from multivariate models) probabilities of leukemia-free survival were 29% and 31%, p=0.5, after PB and BM transplantation, respectively; corresponding probabilities of overall survival were 31% and 32%, p=0.8. While these data do not indicate a survival advantage with either stem cell source by disease or risk group, PB is associated with earlier engraftment. This advantage is offset by higher rates of grades 2–4 acute and chronic GVHD, leading to a higher risk of late adverse events. Randomized clinical trials are necessary to better define the relative risks and benefits of PB in the setting of unrelated donor HCT.

Single Nucleotide Polymorphism of CC Chemokine Ligand 5 Promoter Gene in Recipient May Affect on the Development of Chronic Graft-Versus-Host Disease and Its Severity after Allogeneic Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2878-2878
Author(s):  
Dong Hwan Kim ◽  
Sang Kyun Sohn ◽  
John Kuruvilla ◽  
Vikas Gupta ◽  
Jeffrey Lipton ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Allogeneic Transplantation ◽  
Rank Test ◽  
Leukocyte Trafficking ◽  
Single Nucleotide ◽  
Host Disease ◽  
Graft Versus Host ◽  
Promoter Gene ◽  
Severe Grade

Background: The leukocyte trafficking, which is critically regulated by chemokine ligands and their receptors, has been known to be involved in the pathogenesis of graft-versus-host disease (GVHD). CC ligand 5 (CCL5; previously called as RANTES) is expressed on antigen-presenting cells, endothelium, and epithelium, while CC receptor 5 (CCR5) is expressed on type 1 T-cells. The current study analyzed the association of CCR5/CCL5 gene single nucleotide polymorphisms (SNPs) on both side of recipients and donors with acute or chronic GVHD (cGVHD) after allogeneic transplantation. Methods and patients: We evaluated the SNPs of CCL5 promoter gene at loci −28/−403 and CCR5 gene at 59029 in 72 recipients and 107 donors using PCR/RFLP methods with genomic DNAs. The associations of acute/cGVHD and its severity with CCL5/CCR5 SNPs of recipients/donors were examined using chi-square test, while the incidences of acute/cGVHD were also compared by Log-rank test. Results: With a median follow up of 924 days for survivors (range 48~2,360 days), the CG genotype of CCL5 gene −28 loci of recipients was significantly associated with a higher incidence of overall cGVHD (p=0.004), extensive cGVHD (p=0.038 by Seattle criteria) and severe grade of cGVHD at presentation compared to CC genotype (p=0.017 by prognostic grading by Apkek et al). The patients with AG haplotype of CCL5 SNP of recipients also showed a higher incidence of overall cGVHD (p=0.003), extensive cGVHD (p=0.023), and more severe grade of cGVHD (p=0.020). However, the CG genotype at CCL5, −28 and AG haplotype did not correlate with the clinical course of cGVHD in terms of GVHD-specific survival or the duration of systemic immunosuppressive therapy. In addition, an association of CCL5/CCR5 SNPs with acute GVHD was not noted. The SNP of CCL5/CCR5 of donors did not influence the occurrence of cGVHD. Conclusion: The CCL5 promoter gene polymorphism of recipients may be associated with the development of cGVHD and its severity. The current study suggested an involvement of CCL5 in leukocyte trafficking for the development of cGVHD.

scholarly journals Recovery of antibody production in human allogeneic marrow graft recipients: influence of time posttransplantation, the presence or absence of chronic graft-versus-host disease, and antithymocyte globulin treatment

Blood ◽  
1981 ◽  
Vol 58 (2) ◽  
pp. 360-368 ◽  
Author(s):  
RP Witherspoon ◽  
R Storb ◽  
HD Ochs ◽  
N Fluornoy ◽  
KJ Kopecky ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Antithymocyte Globulin ◽  
Hematologic Malignancy ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Antibody Responses ◽  
Secondary Response ◽  
Significant Information ◽  
Host Disease ◽  
Graft Versus Host

Abstract One-hundred fifty-three recipients of HLA-identical sibling marrow transplants for aplastic anemia or hematologic malignancy were injected with bacteriophage phi X174 (phage), pneumococcal polysaccharide antigen (PPA), or keyhole limpet hemocyanin (KLH). Antibody levels were determined several times in the 6 wk after injection. Multiple regression techniques were used to determine what factors played significant roles in the antibody response. The most significant factors were the time elapsed from transplantation, chronic graft- versus-host disease (GVHD), and antithymocyte globulin (ATG) treatment. All patients had low antibody responses to all antigens in the first 180 days from transplant. Beyond 180 days patients without chronic GVHD showed antibody responses indistinguishable from those of normal donors. However, patients with chronic GVHD had the following impairments: (1) primary response to phage, (2) conversion from IgM to IgG in secondary response to phage, (3) secondary response to KLH, and (4) response to PPA. ATG treatment given to patients either prophylactically or therapeutically for acute GVHD was followed by lower primary responses to phage in the first 180 days and poor ability to switch from IgM to IgG antibody in the secondary response beyond 180 days postgrafting. Other factors did not yield additional significant information about ability to predict antibody responses including diagnosis, conditioning regimen, treatment in or out of laminar air flow rooms, transplantation, pretransplant refractoriness of the recipient to platelet transfusions from random donors, donor age or donor sex, and steroid administration for treatment for prevention of GVHD. The data indicate that, given enough time after transplantation, the ability to produce normal antibody function recovers except in those patients experiencing chronic GVHD.

Pericapillary hemorrhage as criterion of severe human digestive graft-versus-host disease

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4681-4684 ◽  
Author(s):  
Marjan Ertault-Daneshpouy ◽  
Christophe Leboeuf ◽  
Marc Lemann ◽  
Fatiha Bouhidel ◽  
Lionel Ades ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Conditioning Regimen ◽  
Basal Membrane ◽  
Allogeneic Transplantation ◽  
Host Disease ◽  
Graft Versus Host ◽  
Pathologic Lesions ◽  
Cell Alterations ◽  
Highly Correlated ◽  
Separate Cohort

Abstract In an experimental model we demonstrated that endothelial cells of all organs are targets of the alloimmune reaction. Here, in 68 digestive biopsies, we found endothelial lesions by immunohistochemistry and ultrastructure in patients with severe acute graft-versus-host disease (GVHD). In contrast, no such endothelial cell alterations were found either in patients without GVHD or in nongrafted controls. In the biopsies with severe GVHD lesions, ultrastructure showed rupture of the capillary basal membrane and extravased red blood cells. These pericapillary hemorrhages were highly correlated with GVHD severity. In a separate cohort of 39 patients who underwent an allogeneic transplantation after a nonmyeloablative conditioning, 8 patients had intestinal biopsies. Three of these latter patients had both severe pathologic lesions of GVHD and similar endothelial lesions, thus, strengthening the concept that endothelial lesions are linked to GVHD severity and not to the intensity of the conditioning regimen. (Blood. 2004;103:4681-4684)

Graft Versus Host Disease Correlates with Increased Survival After Allogeneic Stem Cell Transplant for Mature T-Cell Lymphomas: Evidence of Graft Versus T-Cell Lymphoma Effect.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3367-3367
Author(s):  
Maria L Delioukina ◽  
Joycelynne Palmer ◽  
Jasmine M. Zain ◽  
NC Tsai ◽  
Auayporn P. Nademanee ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Disease Control ◽  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Host Disease ◽  
Graft Versus Host ◽  
T Cell Lymphomas ◽  
Reduced Intensity

Abstract Abstract 3367 Poster Board III-255 Background: For aggressive lymphomas a T-cell phenotype confers a poor prognosis. Current therapeutic strategies for T-cell non-Hodgkin lymphoma (NHL) are poorly defined and are associated with a high rate of chemorefractory disease and relapse following chemotherapy +/- autologous stem cell rescue. Allogeneic related and unrelated stem cell transplantation (Allo-HCT) is a potentially curative option, with graft-versus-lymphoma effect as the suggested mechanism for long-term disease control. We report the results of patients with T-cell and NK/T-cell NHL who underwent Allo-HCT at City of Hope National Medical Center. Methods: A consecutive case-series of 38 patients with mature T-cell NHL who underwent Allo-HCT between 2000 and 2007 were included in this analysis. Histologies included: PTCL NOS (n=9); AILD (n=4); ALCL (n=7; four were alk+ and three were alk-); rare histologies (n=6) (NK/T cell nasal and extranasal, enteropathy type, hepatosplenic); and cutaneous T-cell (mycosis fungoides/Sezary syndrome) (n=12). Most patients (n=26, 68%) had advanced disease at the time of transplant. Disease status at transplant: CR1=3, CR2=4, PR after relapse=5, relapse or primary induction failure n=24 and progressive disease at the time of transplant =2. Conditioning regimens consisted of fully ablative regimens (TBI and non-TBI based) in 14 (37%), and reduced intensity (fludarabine/melphalan) in 24 (63%). Results: The median age at transplant was 43 years (range: 7-74), 74% were male (n=28). The stem cell sources were matched sibling (n=27, 71%) and unrelated donor 39%. The median number of prior regimens was 3 (range: 1-6); 1 patient had a prior autologous transplant. The median follow-up for the 20 (53%) surviving patients is 64 months (range: 16-100). Day 100 mortality was 18%. There were 18 deaths; 5 from disease progression and 13 from transplant-related mortality. A total of 29 patients (78%) developed graft versus host disease (GVHD); six developed only acute GVHD, 10 developed only chronic GVHD and the remaining 13 developed both acute and chronic. The 5-year probabilities of overall (OS) and disease-free (DFS) survival were 51% (95%CI: 42-59%) and 46% (95%CI: 38-53%), respectively. The relapse/progression and non-relapse mortality (NRM) rates at 5 years were 35% (95%CI: 25-48%) and 29% (95%CI: 20-42%) respectively. Analysis for prognostic factors considered predictive for survival showed that the presence or absence of any form of GVHD (either acute grade I-IV or chronic) significantly affected the outcome. The presence of GVHD was significantly associated with improved OS; the estimate OS at 5 years for those with GVHD was 59% (95% CI: 47-69%) versus 25% (95%CI: 18-33%) for those who did not develop acute or chronic GVHD, P=0.007. DFS showed a similar trend, the 5 year survival estimate was 52% (95%CI: 42-62%) for those with GVHD compared to 25% (95%CI: 18-33%) for those without GVHD, P=0.009. As expected the relapse/progression rate among those patients who did not develop acute or chronic GVHD was significantly higher (5 year estimate: 64%, 95%CI: 51-78%) than those who did develop acute and/or chronic GVHD (5 year estimate: 30%, 95%CI: 19-46%), P=0.01.There was no statistically significant difference between OS or DFS for patients who received a fully ablative or reduced intensity conditioning regimen. Conclusion: In this analysis, the presence of GVHD either acute or chronic was the most important prognostic factor for survival thus strongly supporting a graft-versus-lymphoma effect for T-cell lymphomas. Allo-HCT can confer long-term disease control even in advanced stage patients. Disclosures: No relevant conflicts of interest to declare.

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