Management of Problems with Stem
Cell Mobilization
International Myeloma Working Group (IMWG) Consensus Statement
and Guidelines on Collection of Stem Cells prior to High Dose Therapy
in Patients with Multiple Myeloma undergoing Initial Therapy with a
Th lid
a
id
om e, Lenalidomide or Bortezomib Based Regimen
Atl
Autologous St
Stem Cellll
Transplantation for Multiple Myeloma
· Majority of randomized clinical trials
demonstrate superior
superior progression
progression free and
overall survival among patients receiving ASCT
· Lack of long-term followup in terms of durability
of response and long term adverse effects in
patients treated with only
py new agents
· ASCT continues to be an important part of
myelt
loma h
therapy
Induction Therapy
·
Traditional approaches to patients with newly
diagnosed multiple myeloma and candidates for
for ASCT:
4 to 6 cycles of a non-alkylator containing regimen
·
Alkylating agents such
such as
as melphalan
melphalan or bendamustine
should be avoided
potentially affect stem cell pool
interfere with
with the
the ability to
to collect
collect adequate stem
stem cells
cells
·
Target for single ASCT: 4-6x106 CD34+ cells/kg
·
Engraftment decreases if the number falls below 2x106
CD34+ cells/kg
Mobilization Regimens
Regimens
· G-CSF dosage 10 mcg/kg/day
· AMD3100 (Plerixafor):
reversible chemokine receptor (CXCR4) inhibitor of the binding
of stromal cell
cell derived factor-1
1 (SDF-
(SDF 1
1 )
towards
towards CXCR4
induces leukocytosis and elevations in circulating hematopoietic
progenitor
pg
cell levels
AMD3100 and G-CSF combined have an additive effect on the
number of circulating hematopoietic stem cells
Randomized trials testing AMD3100 plus G-CSF vs. placebo
plus G-CSF showed a faster mobilization of CD34+ cells
Donzella et al, Nature Med, 1998;
Liles et al, Blood, 2003
Devine et al, JCO, 2004;
DiPersio et al, Annual ASH Meeting, 2007
Effects of Induction Therapy on Mobilization of
Ht
Hemat
i
opo eti
tic St
Stem Celllls: Thalidomide
· Thalidomide: contradictory data
· Several trials showed a decrease of collected stem cells after
thalidomide containing regimens
· GMMG: TAD median 9.8x106 CD34+cells/kg, range
g 2.0-33.6; VAD
median 10.9x106 cells/kg, range 3.0-36.0; p =0.02
· HOVON: TAD median 7.4x106 CD34+cells/kg, range 2.0-33.0; VAD
median 9.4x106 cells/kg, range 0.0-48.7; p =0.009
· Cavo et al, 2005: Thal-Dex median 7.85x106 CD34+ cells/kg
compared to 10.5x106 cells/kg in VAD group; no significant
difference
· Rajkumar et al, 2006 phase III trial comparing TD vs. D with 90%
successful collection in both groups
Breitkreutz et al, Leukemia, 2007
Cavo et al, Blood, 2005
Rajkumar et al, JCO 2006
Effects of Induction Therapy on Mobilization of
Ht
Hemat
i
opo eti
tic St
Stem Celllls: Bt
Bortezomib
ib
· No apparent effect on mobilization and harvest of stem
ll
ce s
· IFM 2005/01
trend towards lower CD34+ numbers among those receiving
bortezomib, dexamethasone with a median CD34+ cell collection
being 6.8x106 CD34+ cells/kg compared to 8.4x106 cells/kg with
VAD
·Besinger
g
et al
100% success with stem cell harvest among patients treated
with bortezomib, cyclophosphamide, thalidomide, and
dexamethasone as a first line of therapy
Harousseau et al, JCO Meeting Abstracts, 2008
Besinger et al, ASH Annual Meeting, 2008
Effects of Induction Therapy on Mobilization of
Ht
Hemat
i
opo eti
tic St
Stem Celllls: Lenalidomide
· Kumar et al, 2007: lenalidomide vs. dexamethasone, thalidomide or
VAD
Significant decrease in CD34+ cells if mobilized with G-CSF alone
(10 vs. 7.86x106 CD34+cells/kg, p0.001);
significant decrease average daily collection (3.5 vs. 1.96x106 CD34+ cells
/kg, (p0.001)
increase in the number of aphereses (4.9 vs 3.09, p=0.006)
· Mazumdar et al, 2008: experience from 3 different centers
lenalidomide
found a 43% rate of mobilization failure (2x106 CD34+ cells /kg) among 28
patients who
who had received lenalidomide
· Paripati et al, 2008: lenalidomide
45% failure rate among 20 patients receiving initial therapy with lenalidomide
usil
ing only G-CSF
Kumar et al, Leukemia, 2007
Mazumder et al, Leukemia, 2008
Paripati et al, Leukemia, 2008
Effects of Induction Therapy on Mobilization of
Hematopoietic Stem Cells: Lenalidomide
· Mark et al, 2008
sufficient stem cells for 2 ASCTs were collected from all patients (100%)
mobilized with G-CSF and Cyclophosphamide vs. 33% mobilized with
G-CSF alone (p0.0001)
· Cyclophosphamide plus G-CSF combined treatment
overcomes the impairment in stem cell mobilization associated
with lenalidomide
Mark et al, Biol Blood Marrow Transplant, 2008
Kumar et al, ASH Annual Meeting, 2008
Mechanism of the Impact of
Lenalidomide Treatment on Stem
Cell Collection
IMiDs induce myeloid progenitors at the
expense of erythroid progenitors in
colony formation assays
*
*
*
*
*
*
*
CFU-G, CFU-GM and CFU-GEMM
CD34+ cells were cultured in methylcellulose medium (Methocult GF H4434, Stem Cell Technology,
Vancouver, Canada) in increasing concentrations of thalidomide, pomalidomide or lenalidomide. 0.1%
DMSO was us d
e as
hi
ve clecontl
trol. CFUs were evalt
luat d
e at day 14. Significant change *(p 0.05)
05 from
control was calculated using Student's t-test
Lenalidomide induces a myeloid maturation arrest with
concomitant peripheral
peripheral neutropenia
neutropenia
pretreatment
WBC nadir
PreTreatment
Cytopenia Nadir
M:E Ratio
Cellularity
M:E Ratio
Cellularity
150
2
60
1.2
70
40
50
1
80
25
2.5
75
0.5
100
1
80
550
2
25
3
40
7.5
70
Mean
2.0
65
9.2
60
Median
1.1
60
2.3
65
S.D.
1.7
22.6
15.3
20.2
Bone marrow aspirate obtained pre-treatment and at the time of WBC nadir (Wright Giemsa,100 x magnification)
1000
900
DMSO
lenalidomide
800
700
600
ng/mLin 500
400
G-CSF 300
200
100
0
day 1
day 3
day6
Day 6
Day 8
DMSO
Pomalidomide
DMSO
Pomalidomide
0.1%
10M
100M
0.1%
10M
100M
G-CSFR
G-CSFR
-actin
-actin
Day 6
Day 8
DMSO
Lenalidomide
DMSO
Lenalidomide
01
0. %
1%
10
10 M
100
100 M
01
0. %
1%
10
10 M
100
100 M
G-CSFR
G-CSFR
-actin
-actin
Recommendations for Stem Cell Collection in
Patients Undergoing Initial Therapy with
with Novel
Novel
Agents First Attempt
· Induction with thalidomide or bortezomib in combination with
dexamethasone G-CSF
· 4 cycles of lenalidomide and are younger than 65, G-CSF
· >4 cycles of lenalidomide therapy, cyclophosphamide plus G-
CSF
· 65 years, reduced-dose cyclophosphamide with G-CSF or G-
CSF with
with addition of AMD-
AMD 3100 before second
second leukapheresis if the
first leukapheresis results in less than million CD34+ cells/kg
· Not recommended: a minimum period that patients have to be off
l
lid
ena omide prior to startiting G-CSF for mobilization
Recommendations for Stem Cell Collection in
Patients Undergoing Initial Therapy with Novel
Agents
g
Failed Stem Cell Collection
·Cyclop
yphosphamide plus G-CSF
· AMD3100 in combination with
with G-
G CSF
· G-
G CSF and GM-
GM CSF
(GM-CSF 10 mcg/kg/day subcutaneously for 2 days,
followed by G-CSF 16 mcg/kg/day subcutaneously
until stem cell collection is complete
Upfront Use of Pl
Pl i
er xafor (AMD3100)
(AMD3100)
· Due to the lack of clinical trials addressing the use in
patients post lenalidomide with no recommendation for
routine use of Plerixafor