Stem Cell Mobilization - CBMTG

Stem Cell Mobilization:
Patient Specific Adapted
Approaches with Plerixafor
(Mozobil)
Robert K. Stuart, MD

DISCLOSURES
• This presentation is sponsored by Genzyme Corporation.
– Honorarium Yes
– Employment No
– Stock No
– Stock options No
– Coercion No
– Bribes No

SDF-1 CXCR4 Interaction

Plerixafor Mechanism of Action

Plerixafor
• US FDA approval Dec. 15, 2008
– “for use in combination with G-CSF to mobilize hematopoietic stem
cells to the peripheral blood for collection and subsequent
autologous transplantation in patients with non-Hodgkin lymphoma
(NHL) and multiple myeloma (MM).”
• Study 1:
– 298 patients with NHL: goal 5x10 6 CD34+ cells/kg in < 5 sessions
– Plerixafor + G-CSF: 59% median 3 sessions
– Placebo + G-CSF: 20% n/a
• Study 2:
– 302 patients with MM: goal 6x1010 6 CD34+ cells/kg in < 3 sessions
– Plerixafor + G-CSF: 72% median 1 session
– Placebo + G-CSF: 34% median 4 sessions

Cost Effective Use of Plerixafor
• Maximize likelihood of
successful mobilization
• Minimize total costs of
mobilization

QUESTIONS
• Can plerixafor use be adapted to use it only in patients
who need it for stem cell mobilization?
• Can patients who need G only vs P+G be identified?
• Is patient adapted plerixafor + growth factors (P+G) as
effective as chemotherapy + growth factors (C+G)?
• What is the quality of the stem cell graft mobilized by
P+G vs C+G?
• Does C+G mobilization add antineoplastic value?

Strategy 1 : Plerixafor for Mobilization failures
Advantages
Lowest use of plerixafor
(~20%)
Disadvantages
Longer “wait” for transplant
Higher growth factor cost
Higher apheresis cost
Unpredictability
Disruption of “flow” through the
transplant center
8

Strategy 2 : Plerixafor for patients “at risk” for
mobilization failure
Advantages
Intermediate rate of use of
plerixafor (~30-40%)
Reduced need for re-mobilization
Greater predictability
Disadvantages
Models for prediction of
mobilization failure are
imperfect
Does not correct “slow” and
“inadequate” collections
High cost of plerixafor
9

Strategy 3 : Plerixafor decision based on actual
mobilization of CD34+ cells after 4 days of G-CSF
Advantages
Disadvantages
Reduced need for
remobilization
Lower number of apheresis
sessions
High rate of plerixafor utilization
(~40-70%)
Need for stat CD34+ count
Avoid unnecessary use of
plerixafor in patients with
adequate G-CSF mobilization
Lower growth-factor,
apheresis and
cryopreservation costs
Improved transplant center
“flow” (predictability)
10

Decision based on actual mobilization results
– CD34+ enumeration on Day 4 of G-CSF
Intermediate CD34
Cut-off CD34+ count determined by:
-Mobilization target
-Cost
•
Extremely low CD34
Destined to fail –
Plerixafor necessary
CD34+
Extremely high CD34
Destined to succeed –
Plerixafor unnecessary
11

Decision based on actual mobilization capacity – What
threshold to use? What about CD34=10/μL?
PB CD34+ /μL
≤ 10
PB CD34+ /μL > 10
Median (range) cumulative CD34+ cells/kg
x 10 6 after 2 apheresis days
Median (range) cumulative CD34+ cells/kg
x 10 6 after 4 apheresis days
0.97 (0.06 - 9.16) 3.30 (0.46 - 12.00)
1.31 (0.06 - 10.58) 4.52 (0.46 - 15.00)
20.4% of patients did not
collect ≥ 2 x 10 6 after 4
aphaeresis sessions
% Patients achieving ≥2 x 10 6 CD34+
Cells/kg in 2 days
22.7 65.3
% Patients achieving ≥2 x 10 6 CD34+
Cells/kg in 4 days
% Patients achieving ≥5 x 10 6 CD34+
Cells/kg in 2 days
34.7 79.6
5.3 30.6
59.2% did not collect the
target number of cells (≥ 5 x
10 6 ) even after 4 apheresis
sessions
% Patients achieving ≥5 x 10 6 CD34+
Cells/kg in 4 days
10.7 40.8
DiPersio J, et al. Biol Blood Marrow Transplant. 2010;16 (Suppl):S201. Abstract 115.
12

Cost-Effective Use of Plerixafor for
Hematopoietic Stem Cells mobilization:
Development and Validation of a
Decision-Making Algorithm
Costa LJ, Alexander ET, Hogan KR, Schaub C, Fouts TV, and Stuart RK
Division of Hematology/Oncology
Medical University of South Carolina, Charleston, SC
Costa LJ, et al. Bone Marrow Transplant. 2011 Jan;46(1):64-9. 13

MUSC - Historical Linear Correlation
Between Peripheral Blood CD34+ and
Apheresis Product CD34+
Assumption that
Plerixafor will lead to a
3 fold increment in
CD34+ count in the
apheresis product
Costa LJ, et al. Bone Marrow Transplant. 2011 Jan;46(1):64-9. 14

Projected number of daily apheresis
sessions
Projected number of daily apheresis
sessions
10
9
8
target 3 x 10e6/Kg
target 6 x 10e6/Kg
target 9 x 10e6/Kg
7
N G
6
5
G-CSF
approach
Cost= (3+N G )x F + N G xA
4
3
2
1
0
0 10 20 30 40 50 60
10
peripheral blood CD34+ cells
target 3 x 10e6/Kg
9
target 6 x 10e6/Kg
8
target 9 x 10e6/Kg
Proceed with the approach with
the lowest estimated cost
7
N G+P
6
5
4
G-CSF + Plerixafor
approach
Cost= (4+N G+P )x F + N G+P xA + N G+P xP
3
2
1
0
0 10 20 30 40 50 60
peripheral blood CD34+ cells
N = number of days of collection.
F = cost of filgrastim.
A = cost of apheresis.
P = cost of plerixafor.
Costa LJ, et al. Bone Marrow Transplant. 2010. 2011 Jan;46(1):64-9.

PB CD34+ on day 4 of mobilization (cells/mm3)
50
50
45
45
40
40
35
35
30
30
25
G approach favored
X=24
29
33
37
25
20
25
20
15
15
10
10
5
10
X=13
14
18
21
G+P approach favored
5
0
0
0 1 2 3 4 5 6 7 8 9 10
0 1 2 3 4 5 6 7 8 9 10
Target collection (x 10e6 CD34+ cells/kg)
Costa LJ, et al. Bone Marrow Transplant. 2011 Jan;46(1):64-9.
16

MUSC Algorithm
Yes- end of
collection
G-CSF
(G-approach)
Same day
Apheresis
CD34+ > X
Target met?
No
Next day G-CSF
+ Apheresis
Peripheral blood
CD34+ cell count
Daily G-CSF x 3
Day 4 G-CSF dose
G-CSF + plerixafor
(G+P approach)
CD34+ ≤ X
Same day (PM)
Plerixafor dose
Next day G-CSF
+ Apheresis
Same day (PM)
Plerixafor dose
No
Target met?
Yes- end of
collection
Costa LJ, et al. Bone Marrow Transplant. 2011 Jan;46(1):64-9.
17

Algorithm Validation
Characteristic Number of patients %
Total 34 100
MM 24 71
Lymphoma 10 29
≤ 60 years 21 62
> 60 years 13 38
Gender
Male 13 38
Prior radiation 13 38
Prior lines of therapy – lymphomas
1 1 10
> 1 9 90
Prior line of therapy – MM
1 11 46
>1 13 54
Prior lenalidomide 14 58
Costa LJ, et al. Bone Marrow Transplant. 2011 Jan;46(1):64-9. 18

Algorithm Effectively Guides
Plerixafor Use
• 11 patients (32%) collected via the G approach
• 23 patients (68%) collected via the G+P approach
• With the G approach median CD34+/kg was 129% of
T-CD34+
• With the G+P approach median CD34+/kg was 166% of
T-CD34+ (P = .22)
• Overall, 97% of patients met their mobilization target and
94% (81.9% for G and 95.7% for G+P, P = .18)
completed collection within the predicted number of
apheresis sessions
Costa LJ, et al. Bone Marrow Transplant. 2011 Jan;46(1):64-9. 19

Growth Factor and Patient-Adapted Use of
Plerixafor is Superior to CY and Growth
Factor for Autologous Hematopoietic
Stem Cell mobilization
Costa LJ, Miller AN, Alexander ET, Hogan KR, Shabbir M,
Schaub C and Stuart RK
Medical University of South Carolina, Charleston, SC
Costa LJ, et al. Bone Marrow Transplant. 2011 Apr;46(4):523-8. Epub 2010 Jul 12.
20

Comparison Between MUSC Algorithm
(MA) and Cyclophosphamide +
G/GM-CSF mobilization (CY)
• CY cohort: patients mobilized prior to 11/2008
– Cyclophosphamide 2,000 mg/m 2
– G-CSF 5 mcg/kg/day + GM-CSF 5 mcg/kg/day
– Apheresis starting when PB CD34+ count ≥ 10 cells/m 3
• MA cohort: Patients mobilized after 11/2008 utilizing
previously described algorithm
• Cohorts compared in terms of success rate, complications,
CD34+ yield, estimated cost, graft content, and engraftment
Costa LJ, et al. Bone Marrow Transplant. 2011 Apr;46(4):523-8. Epub 2010 Jul 12. 21

Patient Characteristics in MA and CY
Characteristic, n (%) MA (n=50) CY (n=81) P value
Diagnosis
Multiple Myeloma 32 (64%) 33 (41%) .01
Lymphoma 18 (36%) 48 (59%)
Age
≤ 60 years 28 (56%) 49 (60%) .6
> 60 years 22 (44%) 32 (40%)
Gender
Male 24 (48%) 42 (52%) .7
Female 26 (52%) 39 (48%)
Prior lines of therapy - LY
≤ 2 16 (89%) 40 (83%) .3
>2 2 (11%) 8 (17%)
Prior line of therapy – MM
1 17 (53%) 13 (39%) .3
>1 15 (47%) 20 (61%)
Prior lenalidomide 19 (59%) 7 (21%) .02
Costa LJ, et al. Bone Marrow Transplant. 2011 Apr;46(4):523-8. Epub 2010 Jul 12. 22

MUSC Algorithm (MA) vs
CY Mobilization
MUSC Algorithm (N=50)
CY Mobilization (N=81)
Goal Met Apheresis Session No. Goal Met
27 (54%) 1 36 (44%)
15 (30%) 2 16 (22%)
7 (14%) 3 6 (7%)
--- 4 3 (4%)
--- 5 2 (2%)
49 (98%) Total 63 (78%) p

Median yield of CD34+/kg:
MA: 7 x 10 6 (IQR 4.2-9.9)
CY: 7.74 x 10 6 (IQR 5-12.7) (P = .08).
P

Median time from mobilization to transplant :
14 days (MA) vs. 43 (CY) days (P < .01)
p=

Comparison Between MUSC Algorithm
(MA) and Cyclophosphamide +
G/GM-CSF mobilization (CY)
• All but one patient in MA (98%) successfully completed mobilization
and stem cell collection vs. 78% in the CY group (P< .01).
• Of the 18 patients who failed mobilization in CY, 10 completed
collection in a subsequent mobilization attempt and 8 (10%)failed a
second mobilization attempt and did not undergo autologous HSCT.
• Only one patient (2%) in MA and 24 (30%) patients in CY had
complications requiring hospitalization during mobilization (P

Summary
• The MUSC Algorithm (MA) results in 98% mobilization success rate.
• Compared to CY mobilization, MA
– decreases time from mobilization to transplant
– eases scheduling of apheresis and transplant
– improves utilization of resources
– increases patient satisfaction
– reduces hospitalization rate
– costs less
• MA is more predictable, safer and less expensive than CY
mobilization
27

Beyond CD34+ cell dose: impact of method of
peripheral blood hematopoietic stem cell
mobilization (G-CSF, G-CSF + plerixafor, or
cyclophosphamide + G/GM-CSF) on number of
colony-forming unit-GM, engraftment, and day
+100 hematopoietic graft function
Alexander ET , Towery JA, Miller AN, Kramer C, Hogan KR, Squires JR,
Stuart RK, Costa LJ
Medical University of South Carolina, Charleston, SC
Alexander ET, et al. Transfusion. 2011 Sep;51(9):1995-2000. Epub 2011 Mar 10.
28

Hematopoietic Graft Composition According to
Mobilization Method: G vs G+P vs Cy+G
Mobilization Methods
G (n=26) G+P (n=32) Cy+G (n=38)
P value
CD 34+ dose (x 10 6 /kg) 4.21 (3.35-4.81) 4.11 (3.41-6.36) 4.67(4.17-5.34) 0.433
Total Mononuclear Cell
dose (x10 8 /kg)
5.62 (4.08-7.65) 6.54 (5.11-10.01 3.55 (1.76-6.65)

x 10e3 /mm3
x 10e3 /mm3
x 10e3/mm3
Hematopoietic Graft Function According to
Mobilization Method: G vs G+P vs Cy+G
Day 100 Blood Counts (mean + SE
8
7
WBC ANC Platelet
P=0.172 P=0.117 P=0.947
8
200
7
6
5
6
5
150
4
3
4
3
100
2
2
50
1
1
0
G G+P Cy+G
0
G G+P Cy+G
0
G G+P Cy+G

Future Questions
• Is peg-filgrastim (Neulasta) as effective as repeated
doses of filgrastim (Neupogen)?
• Does chemotherapy mobilization add to the anti-tumor
effect of ASCT?

ACKNOWLEDGMENTS
• Physicians:
– Luciano J. Costa, MD, PhD (PI)
– Yubin Kang, MD (BMT)
– Jerry Squires, MD (Blood Bank)
– Erin Alexander, MD (PGY4)
– Munira Shabbir, MD (PGY6)
• Nurse Practitioners:
– Christine Schaub, ANP
– Ashley Miller, ANP
• Others:
– Jeanne Towery, CMT (Cryopreservation)
– Sally Potts, RN (Apheresis)
– Cindy Kramer, RN (BMT Coordinator)
– Theo Fouts, RN (BMT Coordinator)
– Kathy Hogan, PharmD (Pharmacy)

Stem Cell Mobilization:
Patient Specific Adapted
Approaches with Plerixafor
(Mozobil)
QUESTIONS?

Li, J, et al. 2010 ASH Annual Meeting, abstract #2246