Table Of ContentNovel Developments in Stem Cell Mobilization
Stefan Fruehauf W. Jens Zeller Gary Calandra
● ●
Editors
Novel Developments in Stem
Cell Mobilization
Focus on CXCR4
Editors
Stefan Fruehauf W. Jens Zeller
Center for Tumor Diagnostics and Therapy German Cancer Research Center
Paracelsus Klinik Heidelberg, Germany
Osnabrueck, Germany [email protected]
[email protected]
Gary Calandra, MD, PhD
Private Consultant, Cresco, PA, USA
[email protected]
ISBN 978-1-4614-1959-4 e-ISBN 978-1-4614-1960-0
DOI 10.1007/978-1-4614-1960-0
Springer New York Dordrecht Heidelberg London
Library of Congress Control Number: 2011945168
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Preface
Systemic cancer treatment led to increasing survival rates and even cures in an impres-
sive number of tumor types within the last fi ve decades, especially in patients with
high-growth-fraction tumors benefi tted from this development.
Autologous transplantation of bone marrow or peripheral blood hematopoietic
stem and progenitor cells (PB HSC/HPC) following high-dose chemotherapy
allowed an up to sixfold increase in dose intensity and was a further milestone
enabling cure or long-term disease control in lymphoma, myeloma, and solid
tumors. Introduction of cytokines (e.g., G-CSF) in the 1980s signifi cantly improved
PB HSC/HPC collection for blood stem cell transplantation. Since then, no signifi -
cant progress beyond chemotherapy-supported and cytokine-based HSC/HPC
mobilization had been made.
In the early 1990s, AMD3100, now plerixafor—chemically a bicyclam—was
originally developed as an anti-HIV drug; the chemokine receptor CXCR4 was
identifi ed as the target for plerixafor. In the late 1990s, CXCR4 was discovered as a
crucial factor for HSC/HPC retention in the bone marrow. As with a considerable
number of drugs, serendipity played a decisive role in elucidating the potency of
plerixafor for HSC/HPC mobilization: in HIV-infected patients plerixafor induced
an unexpected dose-dependent leukocytosis and in healthy volunteers it was found
that these increased peripheral blood mononuclear cells were enriched by CD34+
HSC/HPC. Subsequently, it became clear that the number of patients who can profi t
from PB HSC/HPC transplantation could be increased since older patients and poor
mobilizers following standard mobilization strategies (G-CSF, chemotherapy) also
showed increased numbers of circulating CD34+ HSC/HPC after addition of plerix-
afor. This action and the synergism of plerixafor with G-CSF led to the clinical
approval of plerixafor as a fi rst in class compound for mobilization of HSC/HPC.
The amount of HSC/HPC mobilization and the rapid kinetics compare favorably
with classical mobilization protocols and are a quantum leap for hard-to-mobilize
patients who now become eligible for potentially curative treatment.
v
vi Preface
Increased HSC/HPC mobilization by compounds interacting with their adhesion
in bone marrow niches is a substantial step toward improvement of PB HSC/HPC
transplantation, so that meanwhile, further compounds with potent mobilizing
capacity were developed and are presently in clinical phase I and II trials.
An exciting new role for CXCR4 inhibitors emerged by the discovery that cells
of different tumor types—leukemias and solid tumors—express CXCR4 as well
and that SDF-1–CXCR4 interaction is involved in adhesion and movement of can-
cer cells. Although there are concerns regarding side effects to normal cells, it is a
fascinating idea for oncologists that mobilization of tumor cells (e.g., by interrup-
tion of the SDF-1–CXCR4 axis) could someday eliminate the threat of minimal
residual disease, since mobilization of MRD cells from protective niches to the
blood might increase their chemotherapeutic sensitivity.
Last but not least, use of CXCR4 antagonists in tissue repair and in infl ammatory
diseases has led to exciting new approaches that will be reviewed in this book, too.
Finally, we would like to express our thanks to all contributors, who facilitated a
timely publication of this book and we are greatly obliged to Springer for their
competent support.
Osnabrueck, Germany Stefan Fruehauf
Heidelberg, Germany W. Jens Zeller
Cresco, PA, USA Gary Calandra
Contents
Part I Basic Science and Experimental Studies
on Stem Cell Mobilization
1 Preclinical Experience with AMD3100 for Mobilization
of Hematopoietic Stem and Progenitor Cells ...................................... 3
Hal E. Broxmeyer
2 Molecular Pharmacology of CXCR4 Inhibition ................................. 23
Anne Steen and Mette Marie Rosenkilde
3 Combination Strategies for Stem Cell Mobilization
Targeting CXCR4 and S1P Receptors ................................................. 37
Nadia Harun, Kenneth Bradstock, and Linda J. Bendall
4 Should We Stay or Should We Go Now?
Cell Adhesion and Mobilization Pathways
of Hematopoietic Cells ............................................................................ 55
Eike C. Buss and Anthony D. Ho
5 Role of the CXCR4/CXCL12 Axis in Hematopoietic
Stem Cell Traffi cking ............................................................................. 71
Amnon Peled and Arnon Nagler
Part II Clinical Studies on Stem Cell Mobilization
6 Early Studies of AMD3100/Plerixafor in Healthy Volunteers ........... 89
David C. Dale and W. Conrad Liles
7 The Current Role of Plerixafor in Stem Cell Mobilization
for Hematopoietic Stem Cell Transplantation ..................................... 103
Amy R. MacKenzie, Matias E. Valsecchi, and Neal Flomenberg
vii
viii Contents
8 Experience with Apheresis Procedures After
Plerixafor Mobilisation .......................................................................... 133
Kenneth Douglas
9 Infl uence of Different Stem Cell Mobilization Strategies
on Graft Composition and Outcome of Autologous
or Allogeneic Transplantation............................................................... 165
Stefan Fruehauf and Guido Tricot
10 Relevance and Clinical Implications of Tumor Cell
Mobilization in Autologous Transplantation of Multiple
Myeloma and Non-Hodgkin’s Lymphoma .......................................... 201
Stefan Fruehauf, Anthony D. Ho, Jessie Hanrahan,
Frank J. Hsu, and John F. DiPersio
11 Plerixafor: Data from the Compassionate Use Program .................... 221
Maximilian M. Fresen and Kai Hübel
12 Stem Cell Mobilization with Chemomobilization Plus
Plerixafor in Hard-to-Mobilize Patients: The Experience
at Kuopio University Hospital, Finland ............................................... 235
Esa Jantunen and Tapio Nousiainen
13 Blood Stem Cell Mobilization in Solid Tumors:
Experience with Plerixafor and Alternative Ways
of Hematopoietic Stem Cell Mobilization ............................................ 247
Guido Kobbe and Rainer Haas
14 Mobilization with Chemotherapy + G-CSF + Plerixafor
in Europe: The Italian Experience ....................................................... 263
Roberto M. Lemoli and Alessandra D’ Addio
15 Experience with Plerixafor in Poor Mobilizers ................................... 277
Catherine H. Roberts and John M. McCarty
16 CXCR4 Antagonists ............................................................................... 303
Klaus Dembowsky, Barbara Romagnoli, Johann Zimmermann,
Eric Chevalier, Christian Ludin, and Daniel Obrecht
Part III CXCR4 Antagonists for Treatment of Leukemias
and Solid Tumors
17 Application of CXCR4 Inhibitors in Leukemia .................................. 335
George Ansstas, Fazia Mir, Michael P. Rettig,
Mark Schroeder, Linda Eissenberg, and John F. DiPersio
18 CXCR4 Antagonists for the Treatment of CML ................................. 351
Anupriya Agarwal, Thomas O’Hare, and Michael Deininger
Contents ix
19 Targeting CXCR4 in Chronic Lymphocytic Leukemia:
Preclinical Rationale and Early Clinical Experience.......................... 369
Jan A. Burger
20 CXCR4-Blockade for Treatment of Breast Cancer ............................ 387
Patricia A. Cronin and H. Paul Redmond
21 Molecular Imaging of CXCR4 Receptor
Expression in Tumors ............................................................................ 399
Lauren E. Woodard and Sridhar Nimmagadda
Part IV Novel Applications
22 Potential Use of CXCR4 Antagonists to Mobilize
Endothelial and Mesenchymal Stem Cells ........................................... 423
Sara M. Rankin
23 Strategies to Enhance Hematopoietic Stem Cell
Engraftment Following Transplantation ............................................. 439
Yubin Kang and Nelson J. Chao
24 Mobilization for Gene Therapy ............................................................ 457
Andre Larochelle and Cynthia E. Dunbar
Index ................................................................................................................ 487
