© 2014 sanofi-aventis u.s. llc, a sanofi company all rights reserved us.ple.14.09.022 brief...

© 2014 sanofi-aventis U.S. LLC, A SANOFI COMPANY All rights reserved US.PLE.14.09.022


Brief Overview of Hematopoietic Cell

Transplantation (HCT) Use


History of Early Peripheral Blood Stem Cell Transplant (PBSCT) Use

1. Goodman JW, et al. Blood. 1962;19:702-714. 2. Motabi IH, et al. Blood Rev. 2012;26(6): 267-278.3. Kessinger A, et al. Blood. 1989;74(4):1260-1265.4. Damon LE, et al. Expert Rev Hematol. 2009;2(6):717-733.5. Weaver CH, et al. Blood. 1995;86:3961-3969.

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1962 1980s 1990sand later

Hematopoietic stem cells (HSC) identified in peripheral blood1

Peripheral blood stem cells (PBSCs) facilitate recovery of hematopoietic system after myeloablation2

PBSC transplantationused for patients unableto undergo bone marrow transplantation (BMT)3

Collection of PBSCs using mobilization more efficient than not using mobilization4

Validation of CD34+ cells as a surrogate for hematopoietic potential5


Distinct Goals of Autologous HCT Therapy

Goals of therapy• Regenerate hematopoietic cell system after myeloablative therapy• Sustained engraftment of the infused cells

Benn H, et al. In: Hillyer CD, et al., eds. Blood Banking and Transfusion Medicine: Basic Principles and Practice. 2nd ed. Philadelphia, PA: Churchill Livingstone; 2006.

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Advantages of Peripheral Blood vs Bone Marrow as Stem Cell Source

• Collection in outpatient setting1

• Avoidance of general anesthesia1

• Accelerated engraftment1

• Shorter duration of hospitalization2

• Improved effectiveness1

1. Vose JM, et al. J Clin Oncol. 2002;20(9):2344-2352.2. Schmitz N, et al. Lancet. 1996; 347:353-357.3. Laird DJ, et al. Cell. 2008;132:612-630.4. Benn H, et al. In: Hillyer CD, et al., eds. Blood Banking and Transfusion Medicine: Basic Principles and Practice.

2nd ed. Philadelphia, PA: Churchill Livingstone; 2006.

Migrates out ofthe bone to theperipheral organs

Physiologic circulation of stem cells

Stomach

Liver

Stem Cell Migration3

Returns to thebone marrowfrom the blood Liver

Heart

Given these advantages, peripheral blood has mostly replaced bone marrow as the source for autologous HCT4

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Mobilization StrategiesCytokines and Chemomobilization

5


Chemotherapy• Prior to cytokines becoming widely available, only chemotherapy was in use to

mobilize stem cells1

• Chemotherapy choice depends on patient treatment needs2

• Although several regimens have been used for mobilization,2 cyclophosphamide is the most commonly used agent3

1. Motabi IH, et al. Blood Rev. 2012;26(6): 267-278.2. Rowley SD, et al. In: Hoffman R, et al., eds. Hematology: Basic Principles and Practice. 6th ed. Philadelphia,

PA Elsevier Saunders; 2013:1472-1485.3. Damon LE, et al. Expert Rev Hematol. 2012;2(6):717-733.

Early Use of Chemotherapy to Mobilize Stem Cells

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Mechanism of Action of Cytokine-Mediated Mobilization

1.Damon LE, et al. Expert Rev Hematol. 2009;2(6):717-733.2.Lataillade JJ, et al. Eur Cytokine Netw. 2004;15(3):177-188.

Leukocytes

Stromal cells

Degradationof the ECM

CXCR-4

SDF-1

HSCHPC

G-CSF

MMPelastases

cathepsin G

Loss of attachment to stromal cellsand the ECM

EC

Cytokine Mechanisms2

• Cytokines induce granulocytes, trigger the proliferation and elaboration of proteases that mediate mobilization, stimulate osteoclast activity, and down-regulate SDF 11

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Mobilization of HSCs With CombinedChemotherapy and Cytokine Therapy

1. Koc ON, et al. J Clin Oncol. 2000;18:1824-1830.2. Karanth M, et al. Bone Marrow Transplant. 2004;34:399-403.3. Gertz MA, et al. Bone Marrow Transplant. 2009;43:619-625..4. Sung AD, et al. Bone Marrow Transplant. 2013;48:1444-1449.

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aMean CD34+ counts shown; bMedian CD34+ counts shown. CLL, chronic lymphocytic leukemia; HL, Hodgkin lymphoma; NHL, non-Hodgkin lymphoma.

Results without P valueNot significant

Study Patient PopulationMobilization Regimen

CSF = Colony Stimulating Factor

CD34+ Cells Collected, cells/kg

Chemotherapy + Cytokines

Cytokines Alone

Koc et al1,a N=29; 12 with lymphoma, 8 with MM, 9 with solid tumors

Cyclophosphamide (CY) 4 g/m2 on day 1 + CSF (36-48 h later) vs CSF (days 1-12)

3.36 × 106

(P=0.0075)1.36 × 106

(P=0.0075)

Karanth et al2,b

N=79; 22 with CLL, 35 with MM, 16 with NHL, and 6 with HL

CY 2 g/m2 on day 1 + CSF (day 5 until collection) vs CSF (days 1-5 or until collection completed)

2.2 × 106 2.3 × 106

Gertz et al3 N=716 patients with MM

CY 1.5 g/m2 on days 1 and 2 + CSF(day 3 through collection) vs CSF(days 1 through collection; dose increases permitted)

10.3 × 106

(P=0.01)9.9 × 106

(P=0.01)

Sung et al4,b N=226 patients162 MM (M)64 Lymphoma (L)

Various chemotherapies – Majority CY 3 g/m2

(97% L and 83% M) + CSF (3 days after chemotherapy for L and 4 days for M) vs. CSF (median of 10 days with CY arms and 6 days with CSF alone arms)

M 13.8 × 106

(P<0.001)

L 6.6 × 106

M 6.8 × 106

(P<0.001)

L 5.5 × 106


*Progression: Positive immunofixation in patients who previously had a complete response after autologous SCT or 50% increase in serum or urine monoclonal protein in patients who previously had a partial response.

Dingli D, et al. Clin Lymphoma Myeloma. 2006;6(5):384-388.

When Used for Mobilization, Cyclophosphamide Did Not Alter

Multiple Myeloma Disease Control

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P=0.61


When Used for Mobilization, Cyclophosphamide Did Not Alter

MM Disease Control

Bacon et al• Retrospective analysis (N=186)

of patients with MM showed that, compared with cytokines alone, cytokines + high-dose cyclophosphamide was associated with

– No significant differences in posttransplant efficacy outcomes

– Significantly increased toxicity

Bacon WA, et al. [ASH abstract 4127]. Blood. 2011;118.

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Overall Survival

Event-free Survival


Cytokines Alone Elicit Engraftment Kinetics Similar to

That of Cytokines + Cyclophosphamide

Desikan KR, et al. J Clin Oncol. 1998;16(4):1547-1553.

Engraftment• Outcome with cytokines alone compared with that achieved

with cytokines + cyclophosphamide (CTX)

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Event-free Survival


Limitations of Using Cytokines Alone

Limitations: Inadequate PBSC collection in some patients• Lacativa et al1 (MM)

Patient Characteristics EvaluatedPBSC Failure

(<4 × 106 cells/kg) (n=62)PBSC Success

(≥4 × 106 cells/kg) (n=92) P

Age, median years (range) 60 (29-70) 54 (33-67) <0.001

PBSC count before collection, median cells/kg (range)

11.5 (0-43) 27 (6.9-209) <0.001

Number of sessions, n (%)*0123

6 (11)10 (18)37 (66)3 (5)

046 (50)37 (40)9 (10)

<0.001

• Micallef et al2 (NHL)

Bone Marrow Infiltration (n=19) (n=33) P

Any time 16 20 0.02

At diagnosis 16 13 0.002

At mobilization 3 6 0.83

1. Lacativa CP, et al. Transfus Apher Sci. 2012; 47(3):331-335.2. Micallef IN, et al. Hematol J. 2000;1(6):367-373.

*Data not available in 6 patients in the failure group.

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Limitations in Cytokine Mobilization in Patients Treated With Certain Agents

Certain treatments linked to collection failure

•Radiation therapy1

•Radioimmunoconjugate2

•Melphalan3

•Fludarabine4

•Lenalidomide5

1. Rowley SD, et al. In: Hoffman R, et al., eds. Hematology: Basic Principles and Practice. 6th ed. Philadelphia, PA Elsevier Saunders; 2013:1472-1485.

2. Richman CM, et al. Cancer. 1997;80(12 suppl): 2728-2732.3. Moskowitz CH, et al. Clin Cancer Res. 1998;4(2):311-316.4. Micallef IN, et al. Hematol J. 2000;1(6):367-373.5. Kumar S, et al. Leukemia. 2007;21(9):2035-2042.

Dex, dexamethasone; VAD, vincristine-adriamycin-dexamethasone; Thal Dex, thalidomide-dexamethasone; Len Dex, lenalidomide-dexamethasone.

Effect of Lenalidomide on Mobilization5

CD

34/k

g, m

illio

n

Total Collection

Dex VAD Thal Dex Len Dex

P<0.00112.00

10.00

8.00

6.00

4.00

2.00

0.00

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Summary

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• PBSCT has mostly replaced BMT for patients undergoing autologous HCT

• Mobilization strategies emerged to overcome early limitations of collecting PBSCs

• Using chemotherapy + cytokines for mobilization is effective but is not associated with improved outcomes versus cytokines alone

© 2014 sanofi-aventis u.s. llc, a sanofi company all rights reserved us.ple.14.09.022 brief...

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