An analysis of the effect of chronic GvHD on relapse and survival following allogeneic PBSC transplantation

doi:10.1080/146532400539369

Cytotherapy

Volume 2, Issue 6, June 2000, Pages 423-428

https://doi.org/10.1080/146532400539369 Get rights and content

Background

PBSC are increasingly being used as the source of stem cells in allogeneic transplantation. An increased incidence of chronic GvHD has been suggested following unmanipulated allogeneic PBSC transplantation (PBSCT), however, how this affects overall survival is not yet clear. Our aim was to study the impact of chronic GvHD on survival and relapse following allogeneic PBSCT.

Methods

We have analyzed data from 73 patients undergoing HLA-matched allogeneic PBSCT. GvHD prophylaxis was with CYA and MTX in 97% of patients. We have studied the incidence of chronic GvHD and its affect on relapse and survival in these patients. All patients were at least 100 days post-transplant at the time of analysis.

Results

Seventy-three patients were evaluable for analysis of chronic GvHD. The overall incidence of chronic GvHD was 55% (limited in 18% and extensive in 37%). Overall median survival was 991 days, with a 4 year survival rate of 48%. Twelve patients relapsed. Patients with chronic GvHDhadasignificantly lowerincidence of disease relapse (p = 0.005) with a relapse probability of 8% at 3 years, compared with 40% in patients with no chronicGvHD. Inaddition, the extent of chronicGvHD had a marked effect on survival, patients with limited chronicGvHDhad a 4 year survival rate of 83%, compared with 45% in patients with extensive chronic GvHD and 38% in patients with no chronic GvHD. This differencewas primarily due to the lowincidence of relapse and low mortality seen in patients with limited chronic GvHD.

Discussion

The presence and extent of chronic GvHD is an important predictor of outcome following allogeneic PBSCT, in that patients who developed either limited or extensive chronic GvHD had a low risk of disease relapse.

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Superior Survival of Black Versus White Patients Following Post-Transplant Cyclophosphamide-Based Haploidentical Transplantation for Adults with Hematologic Malignancy
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Chronic GVHD has been shown in multiple publications to reduce the risk of disease relapse. However, given reciprocal increases in NRM with more extensive chronic GVHD, only milder expressions of chronic GVHD has been reproducibly associated with improved survival [19-22]. The etiology of this increased chronic GVHD incidence in black patients remains unclear and should be a focus of future study.
Available evidence from large registry studies has shown inferior survival for black adult patients following both unrelated donor and cord blood transplantation. Post-transplant cyclophosphamide (PTCy)–based haploidentical donor transplantation (HIDT) is being increasingly used in ethnic minorities. However, no studies of the impact of race on outcomes following HIDT have been reported. We analyzed 203 consecutive patients (123 white, 80 black) who underwent first HIDT using PTCy for hematologic malignancy at a single institution. Median recipient age was 53 (range, 19-75) years. Peripheral blood stem cells (PBSCs) were used as the stem cell source in 66% of patients, and conditioning intensity was myeloablative (MA) in 41%. After a median follow-up of 36 months, the estimated 3-year overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR) were significantly better in black patients, compared with white patients (72% [95% confidence interval (CI), 60% to 81%], 65% [95% CI, 52% to 75%], and 25% [95% CI, 16% to 35] versus 50% [95% CI, 40% to 59%], 45% [95% CI, 36% to 54%], and 39% [95% CI, 31% to 47%], respectively; P < .001 for OS and DFS, P = .015 for CIR). In contrast, 3-year nonrelapse mortality was similar between black (11%) and white (16%) patients, as were the incidences of acute graft-versus-host disease (GVHD) and moderate-to-severe chronic GVHD. Improved survival was noted in all subgroups of black patients—younger versus older, male versus female, lower versus higher disease risk index, MA versus non-MA conditioning, or PBSC versus marrow stem cell source. In multivariate analysis, black race was independently associated with better OS (hazard ratio [HR], .47; P = .003), DFS (HR, .49; P = .003), and relapse (HR, .49; P = .01). Black patients achieve superior outcomes to their white counterparts following PTCy-based HIDT due to a decreased incidence of disease relapse.
Efficacy of Bone Marrow-Derived Mesenchymal Stem Cells in the Treatment of Sclerodermatous Chronic Graft-versus-Host Disease: Clinical Report
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Previous studies have shown that MSC transplantation can increase the risk of leukemia recurrence [35]. Some studies have claimed that AHCT recipients who develop GVHD experience fewer leukemia recurrences and have a longer life span compared with those who do not develop GVHD; these positive effects are achieved via the graft-versus-leukemia (GVL) reaction [36]. GVHD and GVL are usually concomitant; that is, the GVL effect is subdued when GVHD is attenuated, leading to leukemia relapse.
The success of treatment for sclerodermatous chronic graft-versus-host disease (ScGVHD) remains disappointing. The immunomodulatory ability of bone marrow (BM)–derived mesenchymal stem cells (MSCs) shows promise in treating GVHD, especially given its previous success in treating patients with acute GVHD (aGVHD). The potential efficacy and safety issues for treating cGVHD, particularly ScGVHD, remain to be clarified, however. Here, we report 4 patients with ScGVHD who received MSCs expanded ex vivo from unrelated donors by intra-BM injection. After MSC infusion, the ratio of helper T lymphocyte (Th) 1 cells to Th2 cells was dramatically reversed, with an increase in Th1 and a decrease in Th2 achieving a new balance. Correspondingly, symptoms gradually improved in all 4 patients. During the course of MSC treatment, the patients' vital signs and laboratory results remained normal. At the time of this report, none of the 4 patients had experienced recurrence of leukemia. Although this study alone cannot guarantee the application of MSCs in ScGVHD, our findings strongly suggest that this treatment is therapeutically practicable, with no detectable side effects. This approach may provide new insight into the clinical treatment of ScGVHD, with the aim of greatly increasing the survival rate in patients with leukemia who undergo allogeneic BM transplantation (BMT).
Chronic graft-versus-host disease after allogeneic blood stem cell transplantation
2001, Blood
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Several reports have suggested that the graft-vs-leukemia (GVL) effect is increased with use of blood stem cells in place of marrow for allogeneic transplantation.15,16,39 Others have noted specifically that fewer relapses occurred in patients with chronic GVHD after allogeneic blood stem cell transplantation.19,40,41 In the current analysis, using chronic GVHD entered as a time-dependent covariate, chronic GVHD did not have a significant effect on the risk of relapse.
The incidence, characteristics, risk factors for, and impact of chronic graft-vs-host disease (GVHD) were evaluated in a consecutive series of 116 evaluable HLA-identical blood stem cell transplant recipients. Minimum follow-up was 18 months. Limited chronic GVHD occurred in 6% (95% confidence interval [CI], 0%-13%), and clinical extensive chronic GVHD in 71% (95% CI, 61%-80%). The cumulative incidence was 57% (95% CI, 48%-66%). In univariate analyses, GVHD prophylaxis other than tacrolimus and methotrexate, prior grades 2 to 4 acute GVHD, use of corticosteroids on day 100, and total nucleated cell dose were significant risk factors for clinical extensive chronic GVHD. On multivariate analysis, GVHD prophylaxis with tacrolimus and methotrexate was associated with a reduced risk of chronic GVHD (hazard ratio [HR], 0.35; P = .001), whereas the risk was increased with prior acute GVHD (HR, 1.67;P = .046). When adjusted for disease status at the time of transplantation, high-risk chronic GVHD had an adverse impact on overall mortality (HR, 6.6; P < .001) and treatment failure (HR, 5.2; P < .001) at 18 months. It was concluded that there is a substantial rate of chronic GVHD after HLA-identical allogeneic blood stem cell transplantation, that clinical factors may alter the risk of chronic GVHD, and that high-risk chronic GVHD adversely affects outcome.
Allogeneic transplantation using peripheral blood stem cells
2001, Best Practice and Research: Clinical Haematology
Over the past 9 years there has been a remarkable increase in the use of peripheral blood stem cells (PBSC) for allogeneic transplantation, primarily for matched sibling transplants but also increasingly for unrelated donor transplantation. In 1999 over 50% of all sibling transplants and over 25% of unrelated donor transplants reported to the European Group for Blood and Marrow Transplantation (EBMT) used PBSC. The major reason for this increasing use of PBSC relates to the rapid haemopoietic recovery seen which mirrors the advantages of using PBSC in autologous transplantation. This improvement in engraftment is a consequence of the larger number of stem cells that can be collected from G-CSF-mobilized peripheral blood compared to bone marrow. Evidence from randomized trials now shows a survival advantage for the use of PBSC in patients with advanced leukaemia. The reason for this improved survival appears primarily to relate to a reduced risk of transplant-related mortality and, possibly, a reduced risk of relapse, However, these randomized studies have also confirmed that there is an increased risk of chronic graft-versus-host disease associated with PBSC transplantation and further follow-up is required to determine the long-term impact on outcome.
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An analysis of the effect of chronic GvHD on relapse and survival following allogeneic PBSC transplantation

Background

Methods

Results

Discussion

Blood

Blood

Blood

Blood

Blood

Blood

Blood and marrow transplantation activity in Europe in 1996

Bone Marrow Transplant

Collection of progenitor cells for allogeneic transplantation from peripheral blood of normal donors

Bone Marrow Transplant

Peripheral blood progenitor cell (PBPC) versus bone marrow (BM) transplants from HLA-identical donors — a joint analysis of the International Bone Marrow Transplant Registry (IBMTR) and the European Group for Blood and Marrow Transplantation (EBMT)

Bone Marrow Transplant

Allogeneic blood cell transplants for haematological malignancy: preliminary comparison of outcomes with bone marrow transplantation

Bone Marrow Transplant

Allogeneic peripheral blood progenitor cell transplantation: analysis of short term engraftment and acute GVHD incidence in 33 cases

Bone Marrow Transplant