Stem Cell Mobilization Standards of Care for HSCT Novel Applications
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Transcript of Stem Cell Mobilization Standards of Care for HSCT Novel Applications
Stem Cell MobilizationStandards of Care for HSCT
Novel ApplicationsRichard Champlin, M.D.
Why is the bone marrow in the bone marrow?
Hematopoietic stem cells home to a “niche” in the marrow
Marrow microenvironment provides critical interactions controlling the growth and differentiation of hematopoietic cells
Maturing cells naturally egress the bone marrow into the blood and later into the tissues
Stem cells traffic into and out of the bone marrow physiologically
HSC
Stem Cell Niche
VLA-4VCAM-1
Bone Marrow Stromal Microenvironment
CXCR4
Osteoblasts
SDF1
Pamela S, et al. ASH 2008. Abstract #: 858;
Shivtiel et al. J Exp Med. 2008;205:2381.
Mechanisms Governing Stem Cell Mobilization with G-CSF
Adhesive Adhesive interactions interactions between HSC and between HSC and matrix components matrix components in the BMin the BM
G-CSF MobilizationG-CSF Mobilization
Cathepsin G (CG), chemokine receptor-4 (CXCR4), hematopoieic stem cell (HSC), hyaluronic acid (HA), interleukin 8 (IL-8), kit ligand (KL), matrix metalloproteinase-9 (MMP-9), neutrophil elastase (NE), stromal cell derived factor-1 (SDF-1), vascular cell adhesion molecule-1 (VCAM-1), very lateantigen-4 (VLA-4), P-selectin glycoprotein ligand-1 (PSGL). Source: Nervi B, et al. J Cell Biochem. 2006;99:690-705
Considerations for Mobilization Regimen
• Reliable• Collect sufficient number of HSCs and progenitors
• Predictable• Able to predict day of collection
• Low failure rate
• Limited toxicity
• Cost Effective • Limited number of days of apheresis required• Low resource utilization
• Low tumor contamination
HSC
Agents for Stem Cell Mobilization
VLA-4VCAM-1
G-CSFG-CSF
SDF1
Bone Marrow Stromal Microenvironment
Fibronectin
CXCR4
Osteoblasts
D11-5908
Plerixafor
SDF1
MM9
G-CSFG-CSF
Scr kinase
PP2 scr inhibitor
Pamela S, et al. ASH 2008. Abstract #: 858;
Shivtiel et al. J Exp Med. 2008;205:2381.
CD34+ Cells Are Heterogenous
CD34CD34++
CD34+/CD38-
CD34CD34++//CD133CD133++
CD34CD34++//CD133CD133--
CD34CD34++/HLA-/HLA-DRDR++
CD34CD34++/HLA-/HLA-DRDR--
CD34+/CD61-
CD34+/CD61+
CD34CD34++/CD38/CD38- - = Most Primitive Stem Cells= Most Primitive Stem CellsHock H. J Exp Med. 2010;207:1127-1130
When to Collect?
Armitage S, et al. Bone Marrow Transplant. 1997;20:587-591.
Correlation between PB CD34+ cells/Correlation between PB CD34+ cells/µLµL and CD34+ cells/kg and CD34+ cells/kg collectioncollection
How Many HSCT do you need for AutoSCT?Richard Champlin, MD
Platelet Engraftment Kinetics As A Function Of CD34+ Cell Dose
Glaspy JA, et al. Blood. 1997;90(8):2939-2951.
CD34+ Cells x 106/kg
1.02.05.010.0
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Importance of CD34+ Cell Dose
Stiff PJ, et al. Blood. 2008;112:758-759. Abstract 2175.
Percent Patient Platelet Count > 150,000/L
Defining a Target?
Generally accepted that ≥ 2 x 106 CD34+ cells/kg is ensures a threshold effect for a rapid hematopoietic engraftment1-2
95% of patients receiving > 2.5 x 106 CD34+ cells/kg experience durable neutrophil engraftment by day 18
5 x 106/kg may be threshold for rapid platelet engraftment3-4
Unclear if > 5 x 106/kg will result in any better engraftment, may be associated with improved outcome5
1To LB, et al. Blood. 1997;89:2233-58; 2Schiller G, et al. Blood. 1995;86:390-7; 3Kiss JE, et al. Bone Marrow Transplant. 1997;19:303–10;4Weaver CH, et al. Blood 1995;86:3961–9; 5Dercksen MW, et al. J Clin Oncol. 1995;13:1922–32.
Higher Cell Dose: Impact on Cost
Costs of transplant-related care in patients who experience “good” versus “poor” mobilization Retrospective analysis of 172 NHL patients treated
with HDT and autologous PBSC transplantation Mobilizations categorized as “poor” (<2 ×106 CD34+
cells/kg) or “good” (≥2 ×106 CD34+ cells/kg) Cyclophosphamide + G-CSF used for mobilization Cost data in a subset of patients (n=57)
Stockerl-Goldstein KE, et al. Biol Blood Marrow Transplant. 2000;6(5):506-512.a Includes cost of apheresis and bone marrow harvest, if performed.
How to collect HSCT
Chemo-Mobilization Integrates collection
into disease management
Improves CD34 yield
Cost, complications, can’t predict date of collection
We use this for aggressive lymphoma
Growth Factor Mobilization Simple Efficient, can schedule Provides adequate
CD34 yield in many categories of patients
Less Costly, few complications, can predict date of collection
May interrupt/delay chemotherapy
We use this for myeloma
Factors Affecting CD34+ Cell Yield
Patient-related Age
Mobilization regimen chosen Generally higher CD34 yields with chemo-
based mobilization
Amount and type of prior therapy Alkylators, lenalidomide, radiation
Platelet count at the time of mobilization
G-CSF vs Chemotherapy + G-CSF
Chemo = various chemotherapeutic agents; Cy = cyclophosphamide; HD = Hodgkin's disease; MM = multiple myeloma; NHL = non-Hodgkin's lymphoma; NR = not reported.
1Alegre A, et al. Bone Marrow Transplant. 1997;20:211–217; 2Desikan KR, et al. J Clin Oncol. 1998;16:1547–1553; 3Dazzi C, et al. Leuk Lymphoma. 2000;39:301–310; 4Narayanasami U, et al. Blood. 2001;98:2059–2064; 5Pusic I, et al. Biol Blood Marrow Transplant 2008;14:1045–1056.
Rituximab and HSC Mobilization- MDACC Experience
Rituximab reduces circulating lymphoma cells
No impact on HSC mobilization, particularly with chemomobilization
Improvement in results of autoSCT using Rituximab in mobilization and transplant.
ASCT for Aggressive NHLImpact of Rituximab on DFS
0 3 6 9 12 15 18 21 24 27 30
Months Post Transplant
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No Rituximab (N=30)
p = 0.004
Adhesion Molecules And HSC Mobilization
NatalizumabBIO5192
Plerixafor
MobilizationMobilization
Nervi B, et al. J Cell Biochem. 2006;99:690-705.
20
Plerixafor
A sustained elevation of peripheral blood CD34+ cell levels was noted between 4 and 18 hours1
G-CSF, granulocyte-colony stimulating factor.1. Mozobil™ [prescribing information]. Cambridge, MA: Genzyme Corp; 2008. 2. Adapted from Liles WC, et al. Transfusion. 2005;45:295-300.
250
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Time (hours) calculated after 4 days of G-CSF therapy and addition of G-CSF + Mozobil™ (plerixafor injection) on day 5
Mobilization Using G-CSF With Plerixafor
Efficacy as single agent
Synergistic with G-CSF
Increases likelihood of successful CD34+ cell mobilization
QUESTIONS: Are there important functional differences in the grafts
collected? Are the improvements in CD34 yield worth the added
cost? Effect on mobilization of malignant cells?
Gene Expression of Mobilized CD34+ Cells and Leukocytes
Donahue RE, et al. Blood. 2009;114:2530-2541.
Gene expression differs among CD34 cells mobilized plerixafor, G-CSF, and plerixafor + G-CSF1. Composition of mobilized
CD34+ cells is dependent on the mobilization protocol
2. Composition of CD34+ cells mobilized by the combination is not simply a mixture of cells mobilized by each agent separately
Functional Differences Noted With Plerixafor vs G-CSF-Mobilized HSPCs
Higher proportion of cells in G1 phase of the cell cycle
Higher proportion of more ‘primitive’ CD34+CD38- cells
More cells expressing CXCR4 and VLA-4 on the cell surface
Grafts contain more T, B and NK cells
Larochelle A, et al. Blood. 2006; 107:3772–3778; Hess DA, et al. Biol Blood Marrow Transplant. 2007; 13:398–411;Fruehauf S, et al. Cytotherapy. 2009; 11:992–1001; Donahue RE, et al. Blood. 2009; 114:2530–2541;
Plerixafor vs G-CSF-Based Stem Cell Mobilization in HLA-Identical Donors: Allograft Composition
*Mean.†Median.‡Includes 8 donors mobilized by both plerixafor and G-CSF.
Devine S, et al. Blood. 2008;112(4):990-998.
Cancer Cell Mobilization in Autologous Donors???
CXCR4 / SDF-1
? Release of Tumor Cells
CXCR4 CXCR4 AntagonistAntagonist
Gazitt Y. Leukemia. 2004;18;1-10.
Apheresis Costs
Treatment Phase Cost
Pre-apheresis Clinic visit
Lab evaluation
Insertion of CVC
Chest –x-ray
$1,800
Apheresis Apheresis procedure (2)
G-CSF treatment (2)
CD34+ analysis
$5,161
($2,580.7 per day)
Post-apheresis Cryopreservation
Supplies
Storage
Sterility testing
$2,493
($1,246 per bag)
Total Cost* $9,454
Cost Savings of Eliminating One Day of Apheresis*,#
$3,826
Hosing et al
MDACC Policy PBPC Collection
For autos and allos- goal 5 million, accept minimum 2 million CD34/kg,
Day 1 or 2 stop >4M
Day 3 stop >3M
Day >4 stop >2M
Collect If CD34 > 10/mcl
If collection is ≤ 0.3 million/kg/d x 2 consecutive days despite use of plerixafor or stop apheresis
Myeloma- plan for 2 transplants
Target doses: Goal 6-8 million/kg for 2 transplants (minimum acceptable 4 million/kg)
If after 1 or 2 collections CD34 collected is > 8 million/kg stop
If after 3 collections CD34 collected is > 6 million/kg stop
If after 4 collections CD34 collected > 4 million/kg stop
If after 5 collections CD34 collected > 2 million/kg stop, do one transplant
Just In Time Strategy for Cost Effectiveness
G-CSF alone successfully mobilizes many patients
Plerixafor is synergistic with G-CSF for stem cell mobilization
An approach to improving cost effectiveness is reserving plerixafor for patients with suboptimal mobilization
Use circulating CD34 on day 4 or first day’s collection to determine who needs addition of plerixafor.
Factors Associated With Poor Mobilization
Increasing cycles / duration of prior chemotherapy
Female gender
Prior radiation to bone marrow
Low pre-mobilization platelet count
Bone marrow positivity
Indolent lymphoma histology
Exposure to fludarabine, platinum-based chemotherapy, alkylating agents, lenalidomide
Low PB CD34 count during mobilization
Outcome of Mobilization by Disease
2727%%
3333%%
1414%%
Gertz M, et al. Bone Marrow Transplant. 2010 Jan 11. epub.
Percent ≥ 2 Million CD34+ Cells/kg
Phase III NHL Study
Plerixafor +G-CSFPlerixafor +G-CSF
Placebo + G-CSFPlacebo + G-CSF
HR=2.50, 95%CI (1.86, 3.36), p<0.0001 HR=2.50, 95%CI (1.86, 3.36), p<0.0001
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DiPersio JF, et al. J Clin Oncol. 2009;27:4767-4773.
Conclusions
Hematopoietic stem and progenitor cells are mobilized by G-CSF and plerixafor a CXCR4 inhibitor
Plerixafor mobilizes PBPC by inhibition of SDF-1 and CXCR4 interaction
Plerixafor and G-CSF are synergistic
The combination of Plerixafor and G-CSF will reduce the number of aphereses required for PBPC collection and enhance to ability to perform autologous HSCT in “hard to mobilize” patients
Chemotherapy plus growth factor enhances mobilization and is warranted when the chemotherapy is indicated for treatment of the malignancy