Long-term outcome and late effects in patients transplanted with mobilised blood or bone marrow: a randomised trial

doi:10.1016/S1470-2045(09)70352-3

The Lancet Oncology

Volume 11, Issue 4, April 2010, Pages 331-338

https://doi.org/10.1016/S1470-2045(09)70352-3 Get rights and content

Summary

Background

Most allogeneic haematopoietic stem cell transplants now use peripheral blood progenitor cell transplantation (PBPCT) instead of bone-marrow transplantation (BMT). Long-term data on outcome and late effects of PBPCT compared with BMT are scarce. Here we present long-term data from a randomised study comparing PBPCT with BMT.

Methods

Between February, 1995, and September, 1999, 329 patients with leukaemia received either PBPCT (n=163) or BMT (n=166) from HLA-identical sibling donors after central randomisation accounting for stratification criteria. Follow-up data were collected via questionnaires from 87% (176 of 202; 84 PBPCT, 92 BMT) patients who survived for more than 3 years (median of 9·3 years) after transplantation. Efficacy analyses included all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01020175.

Findings

10-year overall survival was 49·1% for patients who underwent PBPCT and 56·5% for patients who underwent BMT (HR 0·83, 95% CI 0·60–1·15; p=0·27). Leukaemia-free survival was 28·3% with BMT versus 13·0% with PBPCT (0·61, CI 0·32–1·16; p=0·12) for acute lymphoblastic leukaemia; 62·3% with BMT versus 47·1% with PBPCT for acute myeloid leukaemia (0·67, 0·39–1·16; p=0·16); and 40·2% with BMT versus 48·5% with PBPCT for chronic myeloid leukaemia (1·12, 0·73–1·74; p=0·60). More patients developed chronic graft-versus-host disease after PBPCT (n=56, 73%) than after BMT (n=46, 56%; p=0·021), with more frequent involvement of skin, liver, and oral mucosa, and more patients who underwent PBPCT needed immunosuppressive treatment 5 years after transplantation (n=20, 26%) than patients who had BMT (n=10, 12%; p=0·024). Nonetheless, there was no difference in performance status, return to work, incidence of bronchiolitis obliterans, and haematopoietic function between the two groups. 14 cases of secondary malignancies occurred (five after BMT, nine after PBPCT), resulting in a cumulative incidence of 3% and 7% after BMT and PBPCT (p=0·17), respectively.

Interpretation

More than 9 years after transplantation, overall and leukaemia-free survival remain similar in patients who underwent BMT and PBPCT. Differences in the incidence of chronic graft-versus-host disease and the duration of immunosuppression exist, but do not affect survival, general health status, or late events.

Funding

No external funding was received.

Introduction

In 2008, most allogeneic stem cell transplantations used granulocyte-colony-stimulating factor (GCSF)-mobilised peripheral blood as the source of haematopoietic stem cells (HSC).¹ Compared with bone marrow, peripheral blood results in faster haematopoietic recovery, but the relative effect of both sources of HSCs on other endpoints of allogeneic stem-cell transplantations, including acute and chronic graft-versus-host disease (GvHD), relapse rates, leukaemia-free survival, and overall survival remain controversial.² Short-term results of randomised studies have been reported,3, 4, 5, 6, 7, 8 and two meta-analyses comparing peripheral blood with bone marrow grafts have been published.9, 10 Cutler and colleagues⁹ found that acute and chronic GvHD were more common after peripheral blood stem cell transplantation (PBSCT) than bone-marrow transplantation (BMT), and that PBSCT was associated with a trend toward lower rates of malignant relapse. One of the major findings of the recent meta-analysis by the Stem Cell Trialists' Collaborative Group¹⁰ was that PBSCT was associated with a decreased relapse rate in haematological malignancies, and improved survival in patients with late-stage disease and a significant risk of extensive chronic GvHD.¹⁰ The follow-up reports of these trials focused on chronic GvHD; however, the median follow-up of 41 months,¹¹ 45 months,¹² and 36 months¹³ was still relatively short.

We aimed to collect information on the long-term outcome of patients treated in, to our knowledge, the largest randomised trial to compare peripheral blood with bone marrow grafts. We paid particular attention to chronic GvHD and late effects, including secondary malignancies.

Section snippets

Patients

This was a multicentre, prospective, randomised trial initiated by the European Group for Blood and Marrow Transplantation.⁸ Patients aged 18–55 years were eligible if diagnosed with de-novo acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL) in first or second remission, chronic myeloid leukaemia (CML) in first chronic or accelerated phase, or myelodysplastic syndrome (MDS). Patient accrual took place between February, 1995, and September, 1999. The study was approved by the

Results

350 patients from 42 transplantation centres (webappendix) in 13 European countries, Israel, and Australia were randomly assigned to receive either peripheral blood or bone marrow from their HLA-identical sibling donor. 329 patients were eligible for transplantation (figure 1). Completed questionnaires collected at a median of 9·3 years (range 3·0–12·1) after transplantation were available for 176 patients; 87% of all patients reported to be alive 3 years or more after transplantation (92 [52%]

Discussion

This study reports long-term follow-up data of patients treated within the largest randomised study comparing allogeneic PBPCT with BMT. Earlier studies with median follow-up of 3–4 years had repeatedly shown that patients transplanted with peripheral blood experienced more severe chronic GvHD more often than patients who underwent BMT.9, 10, 11, 14 Furthermore, the study by Flowers and colleagues¹¹ indicated that patients who underwent PBPCT experienced protracted courses of GvHD and needed

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Hitherto, the optimal timing of rabbit anti-thymocyte globulin (rATG) in matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT) remains to be elucidated. We wanted to evaluate the effect of a new timing strategy of rATG in MSD-PBSCT patients on transplantation outcomes. In this prospective single-arm phase 2 clinical trial, 45 consecutive MSD-PBSCT patients were enrolled from February 1, 2019, to January 31, 2021. The rATG was administered intravenously at a total dose of 5 mg/kg from day −5 to day −2 before graft infusion (4d-ATG group). Thirty-seven MSD-PBSCT patients receiving rATG at the same total dose of 5 mg/kg from day −5 to day −4 before graft infusion from December 1, 2014, to January 31, 2019 served as historical control (2d-ATG group). No graft failure occurred in either group. In the 4d-ATG group, median timing to neutrophil and platelet engraftment was 12 days. The cumulative incidences (CI) of grade 2-4 and grade 3-4 acute graft-versus-host disease (GVHD) at day 100 were 37.8% and 4.4%. The 2-year CIs of severe chronic GVHD and extensive chronic GVHD were 2.2% and 9.6%. The rates of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation at day 180 were 24.4% and 37.8%, respectively. No patients died of non-relapse causes. Twenty-one patients relapsed at a median of 203 days after transplantation, and the 2-year cumulative incidence of relapse (CIR) was 51.4%. The 2-year probabilities of overall survival (OS), disease-free survival (DFS), and GVHD-free and relapse-free survival (GRFS) were 72.4%, 48.6%, and 40.8%, respectively. There were no significant differences between the 4d-ATG group and 2d-ATG group with regard to timing of neutrophil and platelet engraftment, incidences of CMV reactivation, EBV reactivation, acute GVHD, chronic GVHD, probabilities of OS, and GRFS. The 2-year CIR was significantly increased, and the 2-year DFS was significantly reduced in 4d-ATG group compared with the control group (CIR: 51.4% versus 13.5%, P < .001; DFS: 48.6% versus 75.7%, P = .014). High CIR and worse DFS were noted in MSD-PBSCT receiving 4d-ATG regimen compared with historical control (2d-ATG regimen). Inappropriate rATG timing may increase the risk of relapse after MSD-PBSCT in patients with hematologic malignancies.
© 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Citation Excerpt :
Female patients may face a heightened risk of ocular GVHD due to the effects of sex on the prevalence of dry eye disease.31 Recently, the use of PBSC has greatly increased due to its advantages over BM including faster engraftment and ease of collection.32 However, the use of PBSC is a recognized risk factor for developing chronic GVHD.22,23,33
The purpose of this research was to evaluate the incidence, risk factors, and complications of ocular graft-versus-host disease (GVHD) in a large single-center study.
Retrospective observational case series.
This study included 283 patients who underwent hematopoietic stem cell transplantation (HSCT) between 2005 and 2020. Ocular GVHD was diagnosed according to International Chronic Ocular GVHD Consensus Group criteria. Potential risk factors for ocular GVHD were evaluated using the Cox proportional hazards model.
The cumulative incidence of ocular GVHD was 19.7% at 1 year, 29.3% at 2 years, 40.7% at 3 years, 47.2% at 4 years, and 49.7% at 5 years. Ocular GVHD was significantly associated with recipient age (hazard ratio [HR]: 1.228; 95% confidence interval [CI]: 1.033–1.459; P = .020); female sex (HR: 1.797; 95% CI: 1.195–2.703; P = .005); peripheral blood stem cell use (PBSC) (HR: 2.079; 95% CI: 1.268–3.411; P = .004); and previous acute GVHD (HR: 1.276; 95% CI: 1.073–1.518; P = .006). Ocular complications after HSCT included cataract, corneal ulcer, corneal perforation, lacrimal obstruction, herpetic keratitis, and cytomegalovirus retinitis.
Half of patients developed ocular GVHD in the 5 years following HSCT. Older age, female sex, use of PBSC, and acute GVHD disease were significant predictors of ocular GVHD. Hematologists and ophthalmologists should be aware of its vision threating complications.
Time-Varying Effects of Graft Type on Outcomes for Patients with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation
2020, Biology of Blood and Marrow Transplantation
This study aimed to investigate time-varying effects of graft type on outcomes for patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplant. For this purpose we analyzed 3952 patients, 720 of whom underwent matched related bone marrow transplantation (BMT), 1004 matched related peripheral blood stem cell transplantation (PBSCT), 856 matched unrelated BMT, and 1372 umbilical cord blood transplantation (UCBT) during complete remission. The 4-year relapse-free survival (RFS) rates were 59.1%, 52.8%, 59.5%, and 50.6%, respectively. Compared with related BMT, related PBSCT, unrelated BMT, and UCBT were associated with higher risk of nonrelapse mortality and unrelated BMT and UCBT with lower risk of relapse. As a result, both RFS and overall survival were comparable between related BMT and unrelated BMT but were worse for related PBSCT and UCBT than for related BMT. Adverse impact of UCBT was observed only during the early phase of transplant, whereas that of related PBSCT continued even after 2 years post-transplant. Our findings raise concerns about the increased risk of late nonrelapse mortality with the use of PBSC grafts and suggest that related BMT is preferable to related PBSCT; matched unrelated BMT is the next choice in the absence of a matched related donor.
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The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consisting of both transplant and nontransplant experts, was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by the American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate- and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed.

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Fast track — ArticlesLong-term outcome and late effects in patients transplanted with mobilised blood or bone marrow: a randomised trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Patients

Results

Discussion

Lancet

Blood

Blood

Blood

Blood

Blood

Blood

Lancet Oncol

Blood

Blood

Blood

Blood

Blood

Blood

Int J Radiat Oncol Biol Phys

Fast track — Articles
Long-term outcome and late effects in patients transplanted with mobilised blood or bone marrow: a randomised trial