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Stem Cell Mobilization Standards of Care for HSCT Novel Applications

Stem Cell Mobilization Standards of Care for HSCT Novel Applications. Richard Champlin, M.D. Why is the bone marrow in the bone marrow?. Hematopoietic stem cells home to a “ niche ” in the marrow

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Stem Cell Mobilization Standards of Care for HSCT Novel Applications

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  1. Stem Cell MobilizationStandards of Care for HSCTNovel Applications Richard Champlin, M.D.

  2. 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

  3. Stem Cell Niche Bone Marrow Stromal Microenvironment HSC SDF1 CXCR4 VLA-4 VCAM-1 Osteoblasts Pamela S, et al. ASH 2008. Abstract #: 858; Shivtiel et al. J Exp Med. 2008;205:2381.

  4. Mechanisms Governing Stem Cell Mobilization with G-CSF Adhesive interactions between HSC and matrix components in the BM G-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 late antigen-4 (VLA-4), P-selectin glycoprotein ligand-1 (PSGL). Source: Nervi B, et al. J Cell Biochem. 2006;99:690-705

  5. 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

  6. Agents for Stem Cell Mobilization Plerixafor G-CSF Bone Marrow Stromal Microenvironment SDF1 D11-5908 HSC SDF1 CXCR4 PP2 scr inhibitor VLA-4 VCAM-1 Osteoblasts MM9 Fibronectin Scr kinase G-CSF Pamela S, et al. ASH 2008. Abstract #: 858; Shivtiel et al. J Exp Med. 2008;205:2381.

  7. CD34+ Cells Are Heterogenous CD34+ CD34+/CD61+ CD34+/CD38- CD34+/CD61- CD34+/CD133+ CD34+/HLA-DR+ CD34+/HLA-DR- CD34+/CD133- CD34+/CD38- = Most Primitive Stem Cells Hock H. J Exp Med. 2010;207:1127-1130

  8. When to Collect? Correlation between PB CD34+ cells/µL and CD34+ cells/kg collection Armitage S, et al. Bone Marrow Transplant. 1997;20:587-591.

  9. How Many HSCT do you need for AutoSCT? Richard Champlin, MD

  10. Platelet Engraftment Kinetics As A Function Of CD34+ Cell Dose Probability of Engraftment of Platelets ≥ 20 x 109/L 1.0 N = 212 0.9 0.8 0.7 0.6 0.5 0.4 CD34+ Cells x 106/kg 0.3 1.0 2.0 0.2 5.0 10.0 0.1 0.0 7 14 28 28 Days Glaspy JA, et al. Blood. 1997;90(8):2939-2951.

  11. Importance of CD34+Cell Dose Percent Patient Platelet Count > 150,000/L Stiff PJ, et al. Blood. 2008;112:758-759. Abstract 2175.

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. 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.

  18. ASCT for Aggressive NHL Impact of Rituximab on DFS 1.0 p = 0.004 0.9 Rituximab (N=67) 0.8 0.7 0.6 Cumulative Proportion Surviving 0.5 No Rituximab (N=30) 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 Months Post Transplant

  19. Adhesion Molecules And HSC Mobilization Mobilization Plerixafor Natalizumab BIO5192 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 250 200 150 100 50 n = 3 healthy volunteers 0 0 5 10 15 20 Time (hours) calculated after 4 days of G-CSF therapy and addition of G-CSF + Mozobil™ (plerixafor injection) on day 5 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. 20

  21. 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?

  22. Gene Expression of Mobilized CD34+ Cells and Leukocytes Gene expression differs among CD34 cells mobilized plerixafor, G-CSF, and plerixafor + G-CSF Composition of mobilized CD34+ cells is dependent on the mobilization protocol Composition of CD34+ cells mobilized by the combination is not simply a mixture of cells mobilized by each agent separately Donahue RE, et al. Blood. 2009;114:2530-2541.

  23. Functional Differences Noted With Plerixafor vs G-CSF-Mobilized HSPCs 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; 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

  24. 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.

  25. Cancer Cell Mobilization in Autologous Donors??? CXCR4 Antagonist CXCR4 / SDF-1 ? Release of Tumor Cells Gazitt Y. Leukemia. 2004;18;1-10.

  26. Apheresis Costs

  27. 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

  28. 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

  29. 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.

  30. 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

  31. Outcome of Mobilization by Disease 27% 33% 14% Gertz M, et al. Bone Marrow Transplant. 2010 Jan 11. epub.

  32. Percent ≥ 2 Million CD34+ Cells/kgPhase III NHL Study HR=2.50, 95%CI (1.86, 3.36), p<0.0001 Plerixafor +G-CSF Kaplan-Meier estimate of proportion of patients reaching ≥ 2 x 106 CD34+ cells/kg Placebo + G-CSF DiPersio JF, et al. J Clin Oncol. 2009;27:4767-4773.

  33. 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

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