From www.bloodjournal.org at Mayo Clinic Libraries on June 29, 2009. For personal use only.
Prepublished online Jun 26, 2009;
doi:10.1182/blood-2009-04-205013
Mobilization in myeloma revisited: IMWG consensus perspectives on stem
cell collection following initial therapy with thalidomide, lenalidomide or
bortezomib- containing regimens
Shaji Kumar, Sergio Giralt, Edward A. Stadtmauer, Jean L. Harousseau, Antonio Palumbo, William
Bensinger, Raymond L. Comenzo, Suzanne Lentzsch, Nikhil Munshi, Ruben Niesvizky, Jesus San
Miguel, Heinz Ludwig, Leif Bergsagel, Joan Blade, Sagar Lonial, Kenneth C. Anderson, Patrizia Tosi,
Pieter Sonneveld, Orhan Sezer, David Vesole, Michele Cavo, Hermann Einsele, Paul G. Richardson,
Brian G.M. Durie and S. Vincent Rajkumar
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Blood First Edition Paper, prepublished online June 26, 2009; DOI 10.1182/blood-2009-04-205013
From www.bloodjournal.org at Mayo Clinic Libraries on June 29, 2009. For personal use only.
Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell
collection following initial therapy with thalidomide, lenalidomide or bortezomib
containing regimens
Shaji Kumar, MD1; Sergio Giralt, MD2; Edward A. Stadtmauer, MD3; Jean L.
Harousseau, MD4; Antonio Palumbo, MD5; William Bensinger, MD6; Raymond L.
Comenzo, MD7; Suzanne Lentzsch, MD8; Nikhil Munshi, MD9; Ruben Niesvizky, MD10;
Jesus San Miguel, MD11; Heinz Ludwig, MD12; Leif Bergsagel, MD1; Joan Blade, MD13;
Sagar Lonial, MD14; Kenneth C. Anderson, MD9; Patrizia Tosi, MD15; Pieter Sonneveld,
MD16; Orhan Sezer, MD17; David Vesole, MD18; Michele Cavo, MD19; Hermann
Einsele, MD20; Paul G. Richardson, MD9; Brian G.M. Durie, MD21; S. Vincent Rajkumar,
MD1; On behalf of the IMWG*
1Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA; 2Department
of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D.
Anderson Cancer Center, Houston, Texas, USA; 3Bone Marrow and Stem Cell
Transplant Program, University of Pennsylvania Abramson Cancer Center,
Philadelphia, Pennsylvania, USA; 4Department of Hematology, Institute de Biologie,
Nantes. France; 5Divisione di Ematologia dell Universita di Torino, Azienda Ospedaliera
S. Giovanni Battista, Ospedale Molinette Torino, Italy; 6Clinical Research Division, Fred
Hutchinson Cancer Research Center, Seattle, Washington, USA; 7Department of
Clinical Laboratories, Memorial Sloan-Kettering Cancer Center, New York, NY, USA;
8Division of Hematology/Oncology University of Pittsburgh UMPC Cancer Pavilion,
1
Copyright © 2009 American Society of Hematology
From www.bloodjournal.org at Mayo Clinic Libraries on June 29, 2009. For personal use only.
Pittsburgh, PA, 9Department of Medical Oncology, Division of Hematologic
Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; 10Weill
Cornell Medical College, New York, NY, USA,11Department of Hematology, Servicio de
Hepatología, Hospital Universitario de Salamanca. CIC, IBMCC (USAL-CSIC). Spain;
121st Medical Department, Center for Oncology and Hematology, Wilhelminenspital,
Wien, Vienna, Austria; 13Department of Hematology, Hospital Clinic, IDIBAPS,
Barcelona, Spain; 14Department of Hematology & Medical Oncology, Emory University,
Atlanta, Georgia, USA; 15Institute of Hematology and Medical Oncology, University of
Bologna, Bologna, Italy; 16Erasmus MC, Department of Hematology, Rotterdam, The
Netherlands; 17Department of Hematology/Oncology, University of Berlin, Germany;
18David Vesole, Division of Hematology/Oncology, Loyola University, Chicago, Illinois,
USA; 19Institute of Hematology and Medical Oncology Seragnoli, Bologna, Italy; 20
Department of Internal Medicine University of Wurzburg, Wurzburg, Germany; 21Aptium
Oncology, Inc., Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin
Comprehensive Cancer Institute, Los Angeles, California, USA,
Corresponding Author: Dr. Shaji Kumar, M.D., Associate Professor of Medicine,
Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55906
Phone: (507) 266-0523; Fax: (507) 284-4972; kumar.shaji@mayo.edu
For a complete list of IMWG participants, see the Supplemental Appendix.
2
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ABSTRACT
The past decade has witnessed a paradigm shift in the initial treatment of multiple
myeloma with the introduction of novel agents such as thalidomide, lenalidomide and
bortezomib, leading to improved outcomes. High dose therapy and autologous stem cell
transplantation remains an important therapeutic option for patients with multiple
myeloma eligible for the procedure. Prior to the advent of the novel agents, patients
underwent stem cell collection prior to significant alkylating agent exposure, given their
potential deleterious effect on stem cell collection. With increasing use of the novel
agents in the upfront setting, several reports have emerged raising concerns about their
impact on the ability to collect stem cells. An expert panel of the International Myeloma
Working Group was convened to examine the implications of these therapies on stem
collection in patients with myeloma and to develop recommendations for addressing
these issues. Here we summarize the currently available data and present our
perspective on the problem and potential options to overcome this problem. Specifically,
we recommend early mobilization of stem cells, preferably with in the first 4 cycles of
initial therapy, in patients treated with novel agents and encourage participation in
clinical trials evaluating novel approaches to stem cell mobilization.
3
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High Dose Therapy and Autologous Stem Cell Transplantation for multiple
myeloma (MM)
High Dose Therapy and autologous stem cell transplantation (ASCT) remains an
integral component of the myeloma treatment algorithm for patients considered eligible
for the procedure. The majority of the randomized clinical trials have demonstrated a
superior progression free survival among patients receiving ASCT compared to those
treated with only conventional therapies and ASCT was associated with superior overall
survival in three of those.1-7 Subsequent randomized trials have further defined the role
of ASCT by demonstrating equivalent overall survival for delayed transplant compared
to upfront ASCT, albeit with some compromise in the quality of life parameters.8
Introduction of novel agents such as thalidomide, lenalidomide and bortezomib have
resulted in a paradigm change in the therapy of myeloma.9-14 The high response rates
with these agents, hitherto seen only in the context of high dose therapy, have once
again raised questions regarding the utility of ASCT in the setting of myeloma. Given
the lack of long term follow up of patients treated with these new agents, the durability
of these responses as well as their potential long term adverse effects remain unknown
and ASCT continues to be an important part of myeloma therapy.
Despite the increased use of the newer drugs for the initial treatment of myeloma, there
is a continuous increase in the number of ASCTs reported to the Center for International
Blood and Marrow Transplant Research (CIBMTR), highlighting its continued important
role. Currently, the novel agents appear best suited to be employed as first line therapy
enhancing the quality of responses prior to proceeding to ASCT and diminishing early
4
From www.bloodjournal.org at Mayo Clinic Libraries on June 29, 2009. For personal use only.
mortality from the disease, or in selected patients as primary therapy moving ASCT to a
second line position or as adjuncts to transplant conditioning regimens or as
maintenance therapy in patients undergoing ASCT.15-23 Furthermore, in a randomized
trial evaluating single versus double ASCT a survival advantage with tandem ASCT was
demonstrated in an unplanned subset analysis for those patients not obtaining at least a
very good partial response (VGPR) after the first ASCT. This observation has increased
the number of ASCT being performed for patients not achieving VGPR after the first
ASCT.24 In addition, ASCT can also be employed as part of second-line therapy after
relapse especially among patients who achieved a durable response after the first
ASCT.6,23
The traditional approach to patients with newly diagnosed myeloma, considered to be a
candidate for ASCT, has been to provide initial therapy with 4-6 cycles of a non-
alkylator containing regimen followed by collection of stem cells and high dose therapy.
The initial therapy for the disease allows time to obtain necessary insurance approvals
as well as control disease related symptoms, simultaneously controlling toxicity by
limiting the number of cycles. In addition, adequate disease control provides an
opportunity to reverse disease related complications where feasible, and generally
improve the functional status of the patient, allowing for a safer transplant. Until the
advent of the novel agents, the initial therapy regimens commonly used were VAD or
single agent dexamethasone, both of which shared the advantage of having little impact
stem cell mobilization and collection. Previous studies had shown that alkylating agents
5
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can potentially affect the stem cell pool and thus interfere with the ability to collect
adequate numbers of stem cells.25-28
The number of CD34+ cells collected for ASCT is dependent on a number of factors,
most importantly the number of intended transplants. The cell collection target usually
depends on patient age, upfront vs. delayed ASCT, patient preference, patient
performance status and presence of co-morbidities among others. Traditionally, the
target for CD34 cell collection for a single ASCT has been 4-6x106 CD34+ /kg with
studies showing a deleterious impact on engraftment characteristics once the number
falls below 2x106 CD34+ /kg.29,30 Use of more CD34 cells has not been consistently
associated with any significant benefit in the parameters studied. Patient age is an
important factor form several perspectives. Clearly there is decreasing use of SCT with
increasing patient age, although selected patients with good performance status may be
transplanted into their mid-seventies. The target for stem cell collection is usually based
on single transplantation in the United States, since Medicare reimburses only single
SCT for myeloma. Finally, there is a clear impact of age on the ability to collect stem
cells with decreasing yield with advancing age.31 In the majority of patients undergoing
an ASCT for myeloma, stem cells are collected from the peripheral blood following
mobilization
using
growth
factor
administration
with
or
with
out
preceding
chemotherapy. A minority of patients undergoes ASCT with stem cells collected through
a bone marrow harvest. Use of cyclophosphamide or other chemotherapy regimens for
myelosuppression to achieve rebound CD34+ cell spillover into the blood with enhanced
effects of myeloid growth factors during the recovery phase of peripheral blood counts
6
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allows for a more rapid stem cell collection and higher numbers of collected CD34+ cells
compared to myeloid growth factor alone.32-35 Institutions differ in their standard
approach for collecting stem cells, there being pros and cons to either approach. Use of
cyclophosphamide, while allowing better stem cell collection and less likelihood of a
collection failure (less than the 2x106 CD34+ /kg), prolongs the collection process while
awaiting count recovery and increases the risk of febrile neutropenia and other
infectious complications.
One of the recent advances in the field of stem cell mobilization strategies has been the
introduction of AMD3100 (Plerixafor®), a receptor chemokine receptor 4 (CXCR4)
inhibitor. Previous studies have highlighted the role of CXCR4 in the stem cell
mobilization induced by G-CSF and cyclophosphamide. Levesque et al showed that
mobilization of stem cells by GCSF coincides in vivo with the cleavage of the N-
terminus of the chemokine receptor CXCR4 on the stem cells in the BM, leading to loss
of chemotaxis in response to the CXCR4 ligand, the chemokine stromal cellderived
factor-1 (SDF-1/CXCL12).36 In addition, accumulation of serine proteases led to
cleavage and inactivation of SDF-1. Originally developed as an anti-HIV drug, the ability
of this drug to enhance peripheral mobilization of CD34+ cells was subsequently
recognized. AMD3100, a reversible inhibitor of the binding of stromal cell derived factor
- 1 (SDF-1, also known as CXCL12) to its cognate CXCR4, has been shown to
increase the number of circulating CD34+ cells in healthy volunteers when administered
alone or with G-CSF prior to treatment. 37-39 Stem cells express CXCR4 and are known
to migrate to the bone marrow through a chemo-attractant effect of SDF-1 that is
7
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produced locally by bone marrow stromal cells. Once in the marrow, it is also believed
that stem cell CXCR4 can act to help "anchor" these cells to stromal cell surface SDF-
1. AMD3100-induced leukocytosis and elevations in circulating hematopoietic
progenitor cell levels are thought to result from a disruption of the CXCR4/CXCL12
interaction and cell adhesion effects, resulting in the appearance of both mature and
pluripotent cells in the systemic circulation.
AMD3100 has been shown to exert an
additive effect on the number of circulating hematopoietic stem and progenitor cells
when administered with G-CSF. AMD3100-3102 was a multi-center randomized,
double-blind, placebo-controlled comparative trials designed to examine the ability of
240 µg/kg AMD3100 plus G-CSF vs. placebo plus G-CSF to mobilize CD34+ stem cells
in patients with MM, who had not previously failed stem cell collections and had not
received prior stem cell transplant. The primary endpoint, the percentage of patients
who achieved 6 x 106 CD34+ cells/kg in 2 or less apheresis days, was met in 106/128
(72%) patients in the AMD plus G-CSF group and 53/154 (34%) patients in the placebo
plus G-CSF group, p<0.0001. Fifty four percent of study patients reached target after 1
day of apheresis in the AMD + GCSF group compared to 17.3% in the placebo plus G-
CSF group. After 4 days of apheresis, these numbers were 86.8% and 56%
respectively. 40
Thalidomide, lenalidomide or bortezomib based regimens as initial therapy for
multiple myeloma
Introduction of thalidomide represented the first major therapeutic advance in myeloma
in several decades. Following the initial trials in relapsed myeloma, several randomized
8
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phase III trials of thalidomide and dexamethasone in patients with previously untreated
myeloma were performed.15,18,41,42 Thalidomide combinations were associated with
superior response rates and improved response duration with no definite impact on the
overall survival compared to dexamethasone alone or VAD. This was followed by
introduction of the thalidomide analogue, lenalidomide, that in phase II trials resulted in
very high response rates as well as deeper responses than were seen with previous
approaches. 11,43 Subsequent phase III trials of lenalidomide and dexamethasone
demonstrated its superiority compared to dexamethasone alone as well as its ability to
spare high doses of steroids and simultaneously improving survival.12,19 More recent
clinical trials have examined the efficacy and tolerability of lenalidomide combined with
cyclophosphamide
(CTX),
bortezomib,
and
clarithromycin,
as
well
as
other
combinations.44-46 Another major advance in the field had been the introduction of the
proteasome inhibitor bortezomib, which along with dexamethasone or in combination
with conventional chemotherapy agents is increasingly being used in the setting of
newly diagnosed disease with high efficacy. Phase III trials of bortezomib in
combination with dexamethasone with or with out doxorubicin has shown excellent
tolerability and improved response rates and progression free survival when compared
to traditional VAD in the setting of initial therapy prior to SCT.17,20,47 Both lenalidomide
and bortezomib have been combined with cyclophosphamide in the setting of transplant
eligible patients in phase II studies with excellent response rates.48,49 Recently reported
phase II trials have examined the efficacy of combining bortezomib with lenalidomide or
thalidomide with or without cyclophosphamide in the setting of newly diagnosed MM.50-
53 These combinations have led to very high complete and very good partial response
9
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rates and will undoubtedly become integral components of the initial treatment choices
in the future. This in turn has led to renewed interest in the potential impact of initial
therapy on the ability to collect adequate numbers of stem cells for one or more
transplants.
Impact of thalidomide, lenalidomide and bortezomib on peripheral blood stem cell
collection
A large volume of data, albeit limited to single institution reports and less detailed data
from phase III trials, have appeared in the past few years evaluating the effect of these
new drugs on the stem cell collection process (Table 1). While there is contradictory
data on the impact of thalidomide on stem cell mobilization and collection, the effect if
any appears to be relatively small with limited impact on the ability to proceed with
SCT.15,18,33,54 In addition, there is no evidence to suggest that initial therapy with
thalidomide containing regimens prior to stem cell collection adversely impacts the
engraftment potential of the collected stem cells.
In contrast to thalidomide, one of the common adverse effects of lenalidomide has been
hematological toxicity, especially myelosuppression. This finding raised concern that
use of lenalidomide could adversely affect the ability to mobilize and collect adequate
numbers of CD34+ cells for ASCT. In two large studies form Mayo Clinic and MD
Anderson, the most significant factor influencing the ability to collect adequate numbers
of stem cells appeared to be initial therapy with lenalidomide (Table 1).33,55 In addition
to lenalidomide therapy, other important factors impacting the stem cell collection
10
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appeared to be the patient age and the duration of lenalidomide therapy. 33,55 The failure
rate of mobilization following lenalidomide therapy has varied significantly between the
different studies, likely a reflection of the lenalidomide treatment duration, age of the
patient population undergoing stem cell collection, mobilization regimens and collection
targets employed. However, data so far do not indicate any impact on the quality of
stem cells collected, as reflected in the engraftment kinetics as well as success. 12,56,57
The effect of bortezomib on the ability to collect stem cells has also been examined in
the context of phase II and III trials examining the combinations (Table 1).17,21,49,58 While
no definite impact of initial therapy on stem cell harvest was demonstrated in the smaller
phase II studies of bortezomib and dexamethasone,21 in the IFM 2005/01 trial
comparing bortezomib/ dexamethasone to VAD there was a trend towards lower CD34
numbers among those receiving bortezomib.17 In contrast, in the HOVON-65/GMMG-
HD4 randomized phase III trial comparing Bortezomib, Adriamycin, Dexamethasone
(PAD) vs. VAD as induction treatment, no impact of the regimen was seen on the ability
to collect stem cells.59 No significant impact of initial therapy has been seen in other
trials that have combined the novel agents, bortezomib in combination with either
lenalidomide or thalidomide.51,60 Addition of alkylating agents to the initial therapy,
especially in combination may increase the risk of collection failures, but no comparative
data is available.48,49 In a phase II study looking at the combination of lenalidomide with
cytoxan and dexamethasone for newly diagnosed myeloma, we observed 8/30 failures
at mobilization.48 In contrast, in a phase II study of cytoxan, bortezomib, and
11
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dexamethasone by Reeder et al, all patients who attempted stem cell collection were
able to get enough cells for at least one transplant.49
While there has been a wide spectrum of reported data on the initial therapy with a
novel agent and the ability to collect stem cells, some common themes have emerged.
In the two larger experiences published to date of lenalidomide therapy prior to harvest,
the number of cycles of therapy appear to be important.33,55 While none of the patients
with less than 6 cycles of lenalidomide failed to collect stem cells in the Mayo Clinic
series, more than 3 cycles of lenalidomide was associated with a higher risk in the MD
Anderson series. While the smaller studies have not demonstrated such a relationship,
and in the absence of detailed data from the larger prospective studies, it would be
reasonable to assume that longer duration of therapy will increase the risk of failure.
Another common finding has been the age of the patients, with more than one study
demonstrating increased likelihood of failure in the older patients. 33,55 In these two
studies no relationship was noted between the time off lenalidomide prior to stem cell
harvest. Another important finding across the studies has been the low incidence of
collection
failure
among
patients
mobilized
with
chemotherapy,
typically
cyclophosphamide, and G-CSF.61,62 Among 28 treatment-naive patients treated with the
combination of clarithromycin, lenalidomide, and dexamethasone (BiRD) reported by
Mark et al, sufficient stem cells for 2 autologous stem cell transplants were collected
from all patients mobilized with CTX plus G-CSF, versus 33% mobilized with G-CSF
alone demonstrating that this approach can potentially overcome the impairment in
stem cell mobilization associated with lenalidomide.61 For patients failing initial attempts
12
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at stem cell mobilization with G-CSF alone, chemotherapy + G-CSF approach appears
to have a reasonable efficacy. Five of seven patients failing G-CSF alone was
successfully mobilized with CTX + G-CSF in one study63 and 18/21 patients were
remobilized successfully with a chemotherapy + G-CSF approach in another study.55
Mazumder et al also reported three patients who failed to collect successfully despite
undergoing mobilization with the CXCR4 inhibitor Plerixafor, but were subsequently
collected using a combination of cyclophosphamide and G-CSF.56
Potential mechanisms of the impact of lenalidomide treatment on stem cell
collection
The exact mechanism why lenalidomide inhibits stem cell mobilization is not clear.
Lentzsch et al. investigated the effects of lenalidomide, pomalidomide (CC4047) (IMiDs)
and thalidomide on CD34+ hematopoietic progenitors. They showed in human Colony
Formation Assays and Long-Term Culture-Initiating Cell tests (LTC-CIs) that IMiDs and
thalidomide are not toxic to hematopoietic stem cells and do not inhibit self renewal
capacity of stem cells.64 This makes it less likely that a direct toxic effect of lenalidomide
on hematopoietic progenitors explains the limitation in stem cell collection. The group
further showed that IMiDs promote myelopoiesis with a concomitant maturation stop of
neutrophil granulocytes by down regulation of critical transcription factors such as PU.1.
This leads to an accumulation of immature granulocytes within the bone marrow
compartment and neutropenia in the peripheral blood.65 Interestingly the group also
observed that the G-CSF secretion is highly up-regulated in cultures of hematopoietic
progenitors treated with IMiDs (day 3 of treatment: control 140 pg/mL, Lenalidomide
13
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800 pg/ml, CC4047 1500pg/mL).64 (personal communication, S.Lentzsch) The biological
reason for the strong up-regulation of G-CSF is unknown. It is likely that self-regulatory
mechanisms up regulate G-CSF in order to overcome the maturation stop of
granulocytes. Higher levels of G-CSF might lead to a tachyphylactic response resulting
in resistance to G-CSF mobilization. These findings are also supported by our
observation that all other "non-G-CSF based" mobilization approaches such as CTX
and AMD3100 are successful in mobilizing a sufficient CD34+ cell number.
Suggested approach to stem cell collection in patients undergoing initial therapy
with novel agents
In June, 2008 a panel of experts was convened by the International Myeloma
Foundation
to
address
issues
regarding
stem
cell
collection
for
autologous
transplantation in patients receiving therapy with lenalidomide. The following statements
reflect the considerations of the panel and the consensus recommendations formulated
by the panel. The recommendations take into account the existing data suggesting
compromised collection with the newer agents in some of the patients as well as the
data, although limited, examining alternate approaches to stem cell mobilization. These
recommendations will be revised when additional data becomes available enabling us
to make more specific recommendations.
First attempt: Given the potential for the novel agents to impact the ability of the stem
cell collection, we recommend early stem cell mobilization when SCT is being
contemplated immediately or later in the course of disease. Such an approach, after 3-4
14
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cycles of initial therapy is quite feasible given the rapid response seen with the new
combinations. However, there exists considerable confusion at this point in terms of the
mechanisms mediating the decreased collection as well as the best approaches to
prevent this problem and every effort should be made to enroll these patients in clinical
trials evaluating these questions.
Among patients undergoing initial therapy with thalidomide or bortezomib in combination
with dexamethasone or among those treated with lenalidomide and dexamethasone
who have received < 4 cycles of therapy and are younger than 65 years, G-CSF alone
is considered adequate for the initial attempt at mobilizing stem cells although many
centers will continue to use cyclophosphamide and G-CSF as their standard protocol.
Among those who have received > 4 cycles of lenalidomide therapy, one should
consider the initial use of cyclophosphamide and G-CSF for mobilization. This
suggestion is based on the findings of increased failure risk in this population as well as
the reduced risk of failure associated with the use of cyclophosphamide and G-CSF.
While the use of cyclophosphamide in all patients is likely to decrease the risk of failure
at first attempt, the recommendation to use G-CSF alone in the former group is driven
by the low risk of failure in that group, the increased risks and delay associated with use
of
cyclophosphamide
and
finally
the
ability
to
successfully
collect
with
cyclophosphamide and G-CSF in the few patients who fail the initial attempt with G-CSF
alone. In patients > 65 years old we recommend consideration of reduced-dose Cy with
G-CSF or G-CSF alone with addition of AMD-3100 before the second leukapheresis if
the first leukapheresis results in less than 2 million CD34+ cells/kg. In patients receiving
15
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other myelosuppressive drugs in combination with lenalidomide, cyclophosphamide and
G-CSF should be considered for the initial attempt as the rate of failure increases in
these situations. There is no data supporting additional time off therapy prior to
mobilization enhancing the likelihood of a successful mobilization. We do not
recommend a minimum period that patients have to be off lenalidomide prior to starting
G-CSF for mobilization.
Failed stem cell collection: Among patients receiving initial therapy with lenalidomide
containing regimens failing to collect with G-CSF alone, there are three options for the
subsequent
attempt.
The
majority
of
the
patients
can
be
collected
with
cyclophosphamide priming and G-CSF. These patients will be candidates for use of
AMD3100, which in combination with G-CSF has been very successful in mobilizing
stem cells. Another approach includes the use of a combination of G-CSF and GMCSF
(GM-CSF 10 mcg/kg/day SC for 2 days, followed by G-CSF 16 mcg/k/g/day SC until
stem cell collection is complete).
Upfront use of Plerixafor (AMD3100) in lenalidomide treated patients: The panel
discussed the question of routine use of Plerixafor for mobilization in this patient group.
It was felt that at this time, without a detailed cost benefit analysis such a
recommendation cannot be made and additional clinical trials specifically addressing its
use in these patients will allow us to answer this question. Prospective trials should be
conducted to study the use of plerixafor in patients failing to reach certain thresholds for
peripheral blood CD34 counts.
16
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Author Contributions
Kenneth Anderson attended Ad Board, Collected Data, and wrote paper. Paul
Richardson attended Ad Board, collected data, and wrote paper. Ruben Niesvizky
attended Ad Board, collected data, and wrote paper. Shaji Kumar attended Ad Board,
wrote paper (Lead Author), and revised paper. Antonio Palumbo attended Ad Board,
Collected Data, and Wrote Paper. Edward Stadtmauer attended Ad Board, Collected
Data, and Wrote Paper. P. Leif Bergsager attended Ad Board, Collected Data, and
Wrote Paper. Sagar Lonial attended Ad Board, Collected Data, and Wrote Paper. Nikhil
Munshi attended Ad Board, Collected Data, and Wrote Paper. Brian Durie attended Ad
Board, Collected Data, and Wrote Paper. Vincent Rajkumar attended Ad Board,
Collected Data, and Wrote Paper. Sergio Giralt Contributed Comments and Edited
Paper. Jean Luc Harousseau contributed Comments and Edited Paper. William
Bensinger contributed Comments and Edited Paper. Ray Comenzo contributed
Comments and Edited Paper. Suzanne Lentzsch contributed Comments and Edited
Paper. Jesus San Miguel contributed Comments and Edited Paper. Heinz Ludwig
contributed Comments and Edited Paper. Joan Blade contributed Comments and
Edited Paper. Patrizia Tosi contributed Comments and Edited Paper. Pieter Sonneveld
contributed Comments and Edited Paper. Orhan Sezer contributed Comments
and Edited Paper. David Vesole contributed Comments and Edited Paper. Michele
Cavo contributed Comments and Edited Paper. Hermann Einsele contributed
Comments and Edited Paper.
17
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Conflict of Interest Disclosure
S. Giralt: Advisory Board for Celgene, Millennium, Novartis, and Genzyme; E.
Stadtmauer: Advisory Board for Genzyme; J. Harousseau: Received Honoraria from
Genzyme and Amgen, Advisory Board for Celgene and Janssen-Cilag; A. Palumbo:
Advisory Board for Ortho Biotech and Celgene; W. Bensinger: Advisory Board for
Celgene and Millennium, Research funding from Genzyme, Millennium, Celgene,
AstraZeneca and Novartis; R. Comenzo: Advisory Board for Millennium and Ortho
Biotech; S. Kumar: Clinical trial funding from Celgene, Millennium, Genzyme; N.
Munshi: Advisory Board for Celgene; R. Niesvizky: Clinical trial funding from Celgene; J.
San Miguel: Advisory Board for Millennium, Janssen-Cilag, and Celgene; H. Ludwig:
Clinical trial funding from Schering-Plough, Janssen-Cilag, and participation in
Speaker's Bureau for Amgen, Roche, Janssen-Cilag; J. Blade: Honorarium for lectures
and Advisory Board for Celgene, Janssen-Cilag. Research grant from Celgene; S.
Lonial: Consultant for Millennium, Celgene, Novartis, and BMS; H. Einsele: Advisory
Board for Celgene and Ortho Biotech; P. Tosi: No disclosures; P. Sonneveld: Advisory
Board for Ortho Biotech and Celege; O. Sezer: Clinical trial/ research funding from
Janssen-Cilag, Merck, and Novartis. Speaker's Bureau for Amgen, Celgene, Merck,
Novartis, Ortho Biotech, Pharmion, and Roche; M. Cavo: No disclosures; P.
Richardson: Advisory Board for Celgene and Millennium; SV. Rajkumar: No disclosures;
B. Durie: Advisory Board for Celgene and Millennium
18
From www.bloodjournal.org at Mayo Clinic Libraries on June 29, 2009. For personal use only.
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27
Table 1. Studies of novel agents with data available for success of stem cell collection
Reference
Treatment
N
Clinical Trial
Mobilization
CD34 yield
P
Days of
Failed collection %
Regimen
Regimen
(x 10(6)/kg)
Leukaphere
(Definition)
sis
From
Breitkrutz54
TAD
93
Phase III
CAD
9.8 (2-33.6)
0.02
1 (1-6)
4 (<2.5 x 106/kg)
VAD
105
(GMMG-HD3)
10.9 (3-36)
1 (1-7)
7
www.bloodjournal.org
Breitkrutz54
TAD
100
Phase III
CAD
7.4 (2-33)
0.009
1 (1-4)
3 (<2.5 x 106/kg)
VAD
100
(HOVON-50)
9.4 (0-48.7)
1 (1-4)
5
1Rajkumar15
TD
99
Phase III
Various
NA
NA
NA
10 (NA)
D
100
(E1A00)
NA
10
Cavo18
TD
100
Matched pair
CTX + G-CSF
7.85
0.4
2
17 (< 4 x 106/kg)
VAD
100
analysis
10.5
2
12
Kumar33
Dex
78
Retrospective
GCSF
9.6 (118)
3 (110)
1 (<2.5 x 106/kg)
at
VAD
22
9.8 (2.116.2)
< 0.01
4 (210)
1
Mayo
TD
99
10.0 (3.530.1)
4 (110)
0
LD
43
7.9 (015.6)
5 (112)
3
Clinic
Mazumder56
LD
28
Retrospective
G-CSF
5.4 (0-17.5)
NA
NA
43 (< 2x106/kg)
Paripati57
Other
41
Retrospective
G-CSF
7.4
0.003
7.3 (< 2x106/kg)
Libraries
LD
20
5.1
45
2Rajkumar12
LD
223
Phase III
Various
NA
NA
3 (NA)
Ld
220
(E4A03)
3 (NA)
on
Kumar63
LD/Ld
92
Retrospective
G-CSF
7.9 (0-16)
NA
11 (<2.5 x 106/kg)
June
11
CTX + G-CSF
8.6 (0-21)
Mark61
BiRD
9
Retrospective
G-CSF
3.1 (0.2-8.6)
< 0.01
3 (< 4 x 106/kg)
29,
19
CTX + G-CSF
14.2 (4.9-236)
0
2009.
Cook62
LD
21
Retrospective
CTX + G-CSF (4
6.3 (2.4-19.7)
3 (1-8)
9 (<2.5 x 106/kg)
137
with G-CSF+/-
7.3 (2.4-72.5)
2 (1-11)
1.5
For
AMD3100)
personal
Popat55
LD
64
Retrospective
G-CSF
NA
25 (< 2x106/kg in 4 days)
Other
238
4
Jagannath21
BD
8
13·20 (7·2
2 (2-3)
0
16·1
use
Harousseau17
BD
240
Phase III (IFM
G-CSF
6.8
2.0 (mean)
4 (< 2x106/kg)
only.
VAD
242
2005-01)
8.4
1.6 (mean)
2
Sonneveld20
BAD
150
HOVON-65
CTX + G-CSF
10.48 (4-37)
1 (1-5)
VAD
150
9.26 (4.1-37.6)
1 (1-4)
Richardson51
VRD
23
Phase II
GCSF
6.2
8.7
28
VAD: vincristine, doxorubicin and dexamethasone; TAD: Thal, doxorubicin and dexamethasone ; CAD: cyclophosphamide 1 g/m2/day, i.v., on day
1; doxorubicin 15 mg/m2/day, i.v., on days 14; dexamethasone 40 mg orally, days 14) and granulocyte colony-stimulating factor (G-CSF); CTX:
From
cyclophosphamide; TD: Thalidomide, dexamethasone; LD: Lenalidomide, dexamethasone; Ld: Lenalidomide and weekly dexamethasone, BD:
Bortezomib and Dexamethasone; NA: not available
www.bloodjournal.org
1 Information on whether a stem cell harvest was attempted was available only for 79% of patients among whom 37% attempted stem cell harvest.
Collection details were not available.
2 Details of stem cell collection regarding cell counts and definition of failure not available and likely to represent a mix of practices given the
multicenter nature of trial.
at
Mayo
Clinic
Libraries
on
June
29,
2009.
For
personal
use
only.
29