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How to Find the Optimal Mobilisation Strategy – Impact, Challenges and Solutions

European Oncology & Haematology, 2016;12(2):87–92 DOI: https://doi.org/10.17925/EOH.2016.12.02.87

Abstract:

Autologous haematopoietic stem-cell transplantation (HSCT) is the standard treatment for a number of haematological malignancies. Achieving sufficient haematopoietic stem cell mobilisation is a prerequisite, but exactly how to define and achieve this goal remains a subject of debate. Key questions include which pharmacological agents to use, timing of treatments and mobilisation, and, in particular, target numbers of stem cells. Clinicians from Europe, North America and Asia compared their experiences and discussed these issues at a satellite workshop during the 3rd International Congress on Controversies in Stem Cell Transplantation and Cellular Therapies (COSTEM 2015). This review discusses the challenges of optimising leukapheresis in the context of these discussions. Although several studies suggest that the cell dose influences transplant outcomes in HSCT, other studies have not reached this conclusion. Recent data indicate that the graft composition also plays a role. More prospective study data are needed for a fuller understanding of engraftment outcomes using different mobilisation protocols.
Keywords: Autologous haematopoietic stem-cell transplantation, leukapheresis, stem cell mobilisation
Disclosure: Patrick Wuchter is an Advisory Board member and has received honoraria from Sanofi-Aventis. He is an Advisory Board member and has received travel grants from Hexal AG. Kai Hubel is an Advisory Board member and received honoraria from Sanofi-Aventis, Roche, Gilead, Teva, Hexal, Celgene and Amgen.
Acknowledgments: Medical writing assistance was provided by Katrina Mountfort at Touch Medical Media, supported by Sanofi-Genzyme.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
Received: June 23, 2016 Accepted: August 25, 2016
Correspondence: Patrick Wuchter, Institute of Transfusion Medicine and Immunology, German Red Cross Blood Donor Service Baden-Württemberg-Hessen, Medical Faculty Mannheim, Heidelberg University, Friedrich-Ebert- Str. 107, D- 68167 Mannheim, Germany. E: Patrick.Wuchter@medma.uni-heidelberg.de; Kai Hübel, Clinic I of Internal Medicine, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany. E: kai.huebel@uk-koeln.de
Support: This review article was developed following a satellite workshop presented at the 3rd International Congress on Controversies in Stem Cell Transplantation and Cellular Therapies, which was organised by Sanofi- Genzyme. The publication of this article was supported by Sanofi-Genzyme, who were given the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the author’s discretion.

Autologous haematopoietic stem-cell transplantation (HSCT) is widely employed in haematological malignancies including multiple myeloma (MM),1 Hodgkin and non-Hodgkin lymphoma (HL and NHL)2–5 and acute myeloid leukaemia (AML).6,7 High-dose chemotherapy is an effective treatment strategy in numerous malignant conditions, however, it requires the subsequent use of autologous HSCT in order to restore bone marrow function, mostly using HSCs from the patient’s peripheral blood.8 Rates of autologous HSCT have increased steadily during the past 2 decades.9–12 In 2014, more than 40,000 HSCT (57% autologous) were performed in Europe.13 The main indications for HSCT were leukaemias (33%; 4% autologous); lymphoid neoplasias (57%; 89% autologous); solid tumours; (4%; 97% autologous) and non-malignant disorders; (6%; 12% autologous).13 Recent trends in transplant activity include increased use of allogeneic HSCT for AML in first complete remission, myeloproliferative neoplasm (MPN) and aplastic anaemia with decreasing use in chronic lymphocytic leukaemia (CLL); and increased autologous HSCT for plasma cell disorders.13 The ability to improve patient outcomes with autologous HSCT is directly dependent, however, on successful mobilisation and collection of stem cells.

Various advances in HSCT over the past decade, including new stem cell mobilisation techniques, have led to the need to reassess strategies to optimise outcomes. In October 2015, clinicians from Europe, North America and Asia compared their experiences and discussed these issues at a Sanofi-sponsored satellite workshop at the 3rd International Congress on Controversies in Stem Cell Transplantation and Cellular Therapies (COSTEM 2015). This review aims to discuss the challenges of finding the optimal mobilisation strategy in the context of these discussions.

Key stages of haematopoietic stem-cell transplantation The HSCT process can be summarised as follows: administration of mobilisation agents, mobilisation, collection by leukapheresis, preparation of product for storage, cryopreservation, administration of high-dose chemotherapy, stem cell transplantation, and engraftment and recovery.14 HSCs usually circulate in small numbers in peripheral blood, therefore, their mobilisation from bone marrow into peripheral blood following treatment with chemotherapy and/or cytokines is an essential part of HSCT, and is one of the major challenges of the process.15

Progenitor stem cells express the cell surface marker antigen CD34, which is used in clinical practice to determine the extent and efficiency of peripheral blood stem cell collection.16 The number of peripheral blood CD34+ cells is used to monitor the timing of leukapheresis for autologous transplantation.17 Before collection, the number of CD34+ cells should ideally exceed 10-20/μl in peripheral blood.18

In terms of transplantation, a number of Phase II studies have established a correlation between CD34+ dose and outcome in terms of progressionfree survival (PFS) and overall survival (OS).19 Most clinical centres regard 2.5–4 x 106 CD34+ cells/kg body weight as an adequate cell number for autologous HSCT and 2.0 x 106 CD34+ cells/kg as the absolute minimum; this is based on a substantial body of clinical data.18,20–24 However, a minority of experts recommend increasing this threshold. Some studies suggest that doses exceeding 5 x 106 cells/kg are necessary for optimal engraftment23,25 and to reduce febrile complications and antibiotic use after transplantation.26 A 2000 literature review concluded that a of ≥8 x 106 CD34+ cells/kg is optimal, and correlated cell dose to platelet recovery,25 but this has been disputed. In addition, high levels of circulating CD34+ cells have been associated with better outcomes in MM27 and NHL.28 The reported improvement in outcomes may be due to decreases in non-relapse mortality from improved haematologic reconstitution and lower rates of infection.

Conversely, some studies have concluded that high cell doses are not correlated with improved outcomes. A study of patients with MM and NHL found that cell dose did not affect OS at one year.29 A cohort study (n=80) demonstrated that high dose CD34+ cells were not associated with lower blood component consumption after HSCT.30 In a retrospective study, patients (n=350) who mobilised high numbers of CD34+ cells (so-called supermobilisers) had improved outcomes in autologous HSCT for NHL and HL (see Figure 1).31 However, a similar study design (n=39) of patients with MM or Waldenström macroglobulinemia (WM) found no correlation between survival and number of mobilised CD34+ cells.32

In summary, there are insufficient data to conclude that high cell numbers are necessary in autologous HSCT. The optimum dose has not been comprehensively evaluated in prospective studies, most of which are registry-based and retrospective.

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Keywords: Autologous haematopoietic stem-cell transplantation, leukapheresis, stem cell mobilisation