Comparison of bone marrow versus peripheral blood allogeneic hematopoietic stem cell transplantation for hematological malignancies in adults—a systematic review and meta-analysis

https://doi.org/10.1016/j.critrevonc.2014.12.007Get rights and content

Highlights

  • Peripheral blood stem cells have replaced bone marrow as main stem cell source in the last two decades.

  • Transplant indications, conditioning regimens and donor selection criteria have clearly changed in the last 10–15 years.

  • It is under debate, whether transplant outcomes might be influenced by the choice of the stem cell source against the background of current transplant settings.

  • This systematic review demonstrates that the current clinical standard to use peripheral blood stem cells instead of bone marrow for allo-SCT is not inferior with regard to the primary outcome overall survival although graft-versus-host disease is increased.

  • Data must be collected analysing more recently treated patients with regard to reduced-intensity and mismatch transplants as well as transplants of elderly patients.

Abstract

It is still under debate whether bone marrow (BM) or peripheral blood (PB) should be the preferred stem cell source in adult patients undergoing allogeneic stem cell transplantation for hematological malignancies. After systematic literature search we identified nine randomised controlled trials comparing BM and PB as stem cell source from 2341 total hits. Meta-analysis involving 1521 patients showed a statistically significant reduction in overall and extensive chronic GvHD for patients transplanted with BM (HR 0.72; 95% CI 0.61 to 0.85 and HR 0.69; 95% CI 0.54 to 0.9), but no difference in overall and disease-free survival. In the related donor setting, data from two of eight studies demonstrated a significant increase of relapse incidence for BM (HR 2.73; 95% CI 1.47 to 5.08). This systematic review demonstrates that the current clinical standard to use peripheral blood stem cells instead of bone marrow for allo-SCT is not inferior with regard to the primary outcome overall survival.

Introduction

The use of peripheral blood stem cells (PBSC) has largely replaced bone marrow (BM) as main stem cell source for allogeneic hematopoietic stem cell transplantation (allo-SCT) in adults with hematological malignancies [1]. On the one hand, donor convenience and safety as well as logistic reasons favor peripheral blood stem cell donation and boosted the use of this stem cell source. On the other hand, case-control, cohort or randomized studies indicated that PBSC transplants are characterized by faster engraftment, immune reconstitution and a higher risk for graft-versus-host disease most likely due to the higher T-cell content of the graft [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. A difference with regard to overall or disease-free survival and non-relapse mortality could not be detected by two previous meta-analyzes [27], [28]. Both these meta-analyzes included data of patients treated from 1990 to 2002. In this cohort, 75% of the data were documented in patients with early disease (chronic myeloid leukemia in chronic phase, acute myeloid leukemia, acute lymphoblastic leukemia in first complete remission and early myelodysplastic syndrome) and chronic myeloid leukemia was the most frequent diagnosis (40% of all patients treated). Indications for allo-SCT have shifted significantly [29]. In 2007, nearly 45% of the patients who received an allo-SCT in Europe were suffering from acute lymphoid or myeloid leukemia and only approximately 5% had chronic myeloid leukemia [30]. Furthermore, patients with co-morbidities and patients up to 70 years of age and older are now eligible to receive an allo-SCT after the introduction of reduced intensity or non-myeloablative conditioning regimens which led to decreased regimen-related morbidity and mortality. Due to laboratory improvements such as more precise HLA-typing and improvements in patient care, the usage of unrelated donors and HLA-mismatched HSCT increased as well. From 2006, when about one-third of allogeneic transplants performed worldwide used unrelated donors [30], the number has now further increased to more than 50% of the transplants [29], [31]. These recent developments require an updated review of the clinical data to assess the impact of either stem cell source on survival, relapse and GvHD under current clinical conditions. Controversy remains on the appropriate stem cell source [32], [33] as bone marrow transplantation in some studies led to lower acute and chronic GvHD rates potentially translating into improved overall survival. With this meta-analysis we attempt to consider more recent clinical trials reflecting current transplant practice.

Section snippets

Inclusion criteria

Randomized controlled studies comparing PBSCT and BMT in adult patients treated for hematological malignancies were included in this analysis.

Literature search

Trials were identified by searching the Cochrane Central Register of Controlled trials register (CENTRAL) and MEDLINE databases (January 1948 to February 2014). Full text, abstract publications and unpublished data, were considered if sufficient information was available. Furthermore, abstracts from the annual conference proceedings of the following

Results

We included nine randomized controlled trials which met the pre-defined selection criteria, involving a total of 1521 participants treated from 1994 to 2009. Demographics, conditioning regimens and graft characteristics of the nine studies are summarized in Table 1. Quality of data reporting was heterogeneous among these studies but overall risk of bias was judged to be moderate (Fig. 2).

Discussion

Overall survival as most important outcome read-out after allogeneic stem cell transplantation is influenced by several factors. At first, direct conditioning and treatment related toxicity affects this endpoint. Furthermore, the balance between beneficial immune responses directed against infection and tumor (engraftment, immune recovery and graft-versus-tumor effect) and detrimental immune responses towards recipients’ healthy tissues (i.e. GvHD) is crucial [36]. Besides infections, acute and

Conflict of Interest

The authors have nothing to disclose in relation to the manuscript submitted.

Reviewers

Professor Matthew Collin

Institute of Cellular Medicine, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom

Dr Tobias Gedde-Dahl, M.D, Ph.D

Head stem cell transplantation, Oslo University Hospital, Hematology, Songsvannsveien 20, N-0027 Oslo, Norway

Udo Holtick is resident physician in the Department I of Internal Medicine (Hematology/ Oncology) at the University of Cologne. After receiving his MD and a PhD in transplantation immunology he completed his training in internal medicine and hematology, oncology in 2011. Dr Holtick's main clinical and scientific focus is allogeneic hematopoietic stem cell transplantation and mechanisms and treatment of graft-versus-host disease.

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  • Cited by (0)

    Udo Holtick is resident physician in the Department I of Internal Medicine (Hematology/ Oncology) at the University of Cologne. After receiving his MD and a PhD in transplantation immunology he completed his training in internal medicine and hematology, oncology in 2011. Dr Holtick's main clinical and scientific focus is allogeneic hematopoietic stem cell transplantation and mechanisms and treatment of graft-versus-host disease.

    Melanie Albrecht is a medical student at the University of Cologne and performed this study as part of her doctoral thesis.

    Jens Chemnitz is attending physician at the Department I of Internal Medicine (Hematology/ Oncology) at the University of Cologne, Germany. His clinical work is focused on the treatment of patients undergoing hematopoietic stem cell transplantation.

    Sebastian Theurich studied medicine in Lübeck and Berlin (Germany), Umea (Sweden) and New York (USA) and graduated from medical school at Charité, University Hospital of Berlin, Germany, in 2004. His doctoral thesis on the molecular pathology of Hodgkin Lymphoma performed at the Max-Delbrück-Center for Molecular Medicine and the Humboldt-University of Berlin was awarded with summa cum laude in 2006. Completing his clinical training at the University Hospital of Cologne, Dr. Theurich was board certified for internal medicine and hematology, oncology in 2012 and his clinical and scientific work focus on tumor immunology and allogeneic stem cell transplantation. On these topics he has authored various peer-reviewed articles and is an invited reviewer for several scientific journals. Since 2013 he joined the editorial board of the Cochrane Haematological Malignancies Group and started a research fellowship at the Max-Planck-Institute for Metabolism Research, Cologne, Germany.

    Alexander Shimabukuro-Vornhagen received his medical degree in 2002 form the Johannes Gutenberg University, School of Medicine in Mainz, Germany. He is a physician and translational researcher in the Department of Internal Medicine of the University Hospital of Cologne, Germany. His main research interests include tumor immunology, medical data science, and critical care.

    Nicole Skoetz is co-ordinating Editor of the Cochrane Haematological Malignancies Group. From 1989 to 1993 Dr. med. Skoetz worked as a computer scientist for a pharmaceutical company. Thereafter she studied medicine and received her medical degree in 2002 from the University of Cologne. From 2002 to 2005, she was the consumer co-ordinator for the CHMG. Afterwards she worked as project manager in a university-based contract research organization, planning, conducting and analyzing clinical trials. In January 2008 she rejoined the CHMG as Managing Editor, she became Co-ordinating Editor in 2011 and is working in this leading position to date. Dr Skoetz leads the development of evidence-based guidelines on Hodgkin lymphoma and chronic lymphocytic leukaemia and is expert for evidence-based breast-cancer guideline.

    Christof Scheid is attending physician at the Department I of Internal Medicine and the head of the stem cell transplantation program at the University of Cologne, Germany. His clinical work is focused on the treatment of patients with myeloproliferative diseases, multiple myeloma and patients undergoing hematopoietic stem cell transplantation.

    Michael von Bergwelt-Baildon is the deputy medical director of the Department I of Internal Medicine at the University of Cologne. After receiving his MD and a PhD in immunology he completed his training in internal medicine, hematology, oncology, infectious diseases, intensive and emergency medicine. Dr von Bergwelt's focus is the science-driven development of B cell based immunotherapies in the context of allogeneic stem cell transplantation and in solid tumors. This work was recognized by numerous scientific honors including a Basic Science Award of the EBMT.

    1

    UH/MA and CS/MBB contributed equally to the manuscript

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