the impact of the source of stem cells: … · the impact of the source of stem cells:...

The impact of the source of stem cells:

Bone marrow versus Peripheral Blood

NC Gorin

EBMT 2011

0

20

40

60

80

100

90 92 94 96 98 00 02 04 06 08

%

auto PB

allo PB

cord

EBMT Activity Survey on HSCT 1990-2008

changes in stem cell source

2008: final data

BM vs PB: A simple question

Numerous complex answers

• Many factors matter:

• The patient age and physical condition

• The disease and its status (AML….CML…)

• The pre transplant regimen (MA, RIC)

• The dose of stem cells

• The donor HLA compatibility

• The donor opinion

• The medical team politics, research and belief.

Allogeneic stem cell transplantation

HLA identical siblings

• 1-Randomized studies

• 2-Retrospective studies: yes they are useful

Is mobilized peripheral blood comparable with bone marrow as a

source of hematopoietic stem cells for allogeneic transplantation

from HLA-identical sibling donors? A case-control study

David Gallardo, E Carreras

GvHD/Immunotherapy Committee of the Spanish Group of Hematopoietic Stem Cell Transplantation (GETH: Grupo Español

de Trasplante Hemopoyético)

Haematologica 2009

Overall survival

QUALITY OF LIFE

Function

score

BM PB P

Physical

function

92.7 88.1 0.078

Role function 92.5 80.3 0.002

Social

function

87.7 76.6 0.019

Financial

difficulties

11.8 32 <0.001

David Gallardo et al 2009

Conclusion

• Patients receiving PBSC have a higher incidence of

acute and chronic GvHD and worse social and role

functioning indicators after quality of life

assessment.

• Peripheral blood can not be considered equal to

or better than bone marrow for an important

proportion of patients.

D Gallardo GETH Haematologica 2009

Stem Cell Trialists' Collaborative Group, JCO 2010:23, 5074-5087

Summary of Randomized Clinical Trials

Principal Investigator No. Patient characteristics

Schmitz et al, 2002 350 AML or ALL (1st or 2nd remission, incipient relapse),

CML (chronic or accelerate phase),

MDS (no RAEBT)

Couban et al, 2002 228 CML (chronic or accelerate phase),

AML (remission) or MDS

Bensinger et al, 2003 176 Various hematologic malignances

Blaise et al, 2000 101 ALL, AML and CML (1st chronic phase)

Further studies

Saudi Arabia (unpublished) 83

Heldal et al, 2000 61

Morton et al, 2001 57

Vigorito et al, 1998 56

Powels et al, 2000 39

Mahmoud et al, 1999 30

Allogeneic peripheral blood stem cell vs. bone

marrow transplantation in the management of

hematological malignancies:

an individual patient data meta-analysis

of 9 randomized trials and 1,111 patients

Stem Cell Trialists' Collaborative Group

J Clin Oncol 2005; 23: 5074-87

Effect on acute GVHD

Chi2 Statistic: 1.60P = 0.20590Abs Diff at100 days = 3.21%

36.41%

39.8%

38.33%

41.55%

100

90

80

70

60

50

40

30

20

10

0Proportion of patients that developed acute GVHD (%)

0 20 40 60 80 100Days

PBSCT

BMT__

Time to acute GVHD (grade II-IV)

Individual patient-data meta-analysis of allogeneic PBSCT vs. BMT transplant

Events/Person-days:PBSCT : 10/4150 49/3844 60/3216 39/2631 20/2240 12/2065BMT__ : 8/4320 34/4064 56/3418 35/2800 29/2388 12/2183

Effect on chronic GVHD

Chi2 Statistic: 23.34P = 0.00000Abs Diff at5 yrs = 14.92%

35.69%

50.61%

39.96%

58.79%

100

90

80

70

60

50

40

30

20

10

0Proportion developing chronic GVHD (%)

0 1 2 3 4 5 6Years

PBSCT

BMT__

Time to chronic GVHD (extensive stage)


Events/Person-years:PBSCT : 159/325.72 12/126.20 5/99.81 5/63.48 0/40.63 4/23.19BMT__ : 101/344.25 9/171.96 5/142.56 1/76.68 2/40.85 2/25.46

From day +100

Relapse in “unfavorable” prognostic category


43.51%

57.63%

43.51%

57.63%

100

90

80

70

60

50

40

30

20

10

0Proportion of patients suffering from relapse (%)

0 1 2 3 4 5 6Years

PBSCT

BMT__

Probability of relapse ('poor' prognosis)


Relapse/Person-years:PBSCT : 29/99.22 6/67.85 2/55.08 3/36.00 2/25.34 0/13.32BMT__ : 37/81.37 6/44.72 5/33.56 1/20.19 1/8.81 0/3.45

Survival in “favorable” prognostic category


65.26%

63.88%

63.82%

61.59%

0102030405060708090100

Survival (%

)

0 1 2 3 4 5 6Years

PBSCT

BMT__

Survival in patients with 'good' prognosis


Deaths/Person-years:PBSCT : 84/344.60 30/276.88 9/232.87 2/133.45 3/74.56 0/35.23BMT__ : 91/354.93 29/283.69 7/240.85 3/122.86 1/64.77 2/33.85

Think of the QOL

Prefer BM?

Survival in “unfavorable” prognostic category


39.45%

29.29%

39.45%

29.29%

0102030405060708090100

Survival (%

)

0 1 2 3 4 5 6Years

PBSCT

BMT__

Survival in patients with 'poor' prognosis


Deaths/Person-years:PBSCT : 55/106.35 12/72.56 4/59.60 3/42.39 2/28.24 0/13.48BMT__ : 74/91.79 16/50.53 3/37.88 0/21.98 1/13.04 0/5.63

Prefer PB

A Phase III, Randomised, Multicentre Trial Comparing

Allogeneic Filgrastim-Mobilised Peripheral Blood Progenitor Cell

Transplantation (PBPCT) with

Allogeneic Bone Marrow Transplantation (BMT) in Patients with Acute

Leukaemia, Chronic Myelogenous Leukaemia or Myelodysplastic

Syndrome

Norbert Schmitz, Meral Beksac, Dirk Hasenclever, Andrea Bacigalupo, Tapani Ruutu, Arnon

Nagler, Eliane Gluckman, Nigel Russell, Jane F. Apperley, Norbert C. Gorin, Jeff Szer, Ken

Bradstock, Agnes Buzyn, Peter Clark, Keith Borkett, and Alois Gratwohl

Blood 2002; 100: 761 - 767

Study Schema - Donor

Filgrastim 10µg/kg/day

Leukapheresis D5 (6, 7)

Bone-marrow

HLA-Identical Sibling Donor

Age 16-60 PBPC

Harvest

R

Patient Flow

PatientsRandomised

350BMT PBPCT

Donor

Harvest RECIPIENT

Conditioning

Transplanted

Alive End of Study

Alive Last Follow-up

176

Donor

Harvest

174

166

166

149

119

163

163

140

113

Recipient Characteristics

BMT PBPCT

N 166 163

Age (Median, years) 37 39

ALL 31 (19%) 24 (15%)

AML 56 (34%) 61 (37%)

CML 74 (44%) 73 (45%)

MDS 5 (3%) 5 (3%)

Maximum Acute GvHD

0

5

10

15

20

25

30

35

40

Percentage of Patients

0 I II III IV

Max acute GvHD

BMT

PBPCT

p = 0.009

Overall Chronic GvHD

0

10

20

30

40

50

60

Percentage of Patients

6 9 12 24 36

Months Since Transplant

BMT

PBPCT

Overall Survival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36Months since transplant

Probability of survival

BMT

PBPCT

HR = 1.15 P = 0.47

Long-term outcome and late effects in patients transplanted

with mobilised blood or bone marrow: a randomised trial

B Friedrichs, N Schmitz et al.

Lancet Oncol 2010; 11: 331–38

8 YEARS LATER !!!

GvHD and Immunosuppression

p = 0.035

BMT PBPCT

Proportion of patients with GvHD

Hazard Ratio 1.40

95% CI 1.07-1.8

0 2 4 6 8 10 12

Years post TX

* Other than CSA

total p-value

Information available 75 68 142 n.s.

Patients with cGvHD 52.7% 71.2% 61.6% 0.03

Extensive cGvHD 30.4% 56.3% 0.002

Patients with additional IS* 8.0% (6/75) 17.8% (13/68) 14.1% (19/142) 0.09

Patients on IS 5 yrs. post TX 10.6% (10/75) 29.4% (20/68) 21.1% (30/142) 0.01

BMT

PBPCT

Survival

10-year estimate

56.5% BMT

49.1% PBPCT

p log rank = 0.27

(HR 0.83; CI 95% 0.60-1.15 )

Overall survival Leukemia-free survival

BMT n = 166

PBPCT n = 163

10-year estimate

45.8% BMT

42.3% PBPCT

p log rank = 0.4

(HR 0.88; CI 95% 0.65-1.12 )

LFS - subgroup analysis

10-year LFS estimate

BM 28.1%

PB 13.0%

(p = 0.13)


BM 62.3%

PB 47.1%

(p = 0.16)


BM 40.8%

PB 47.5 %

(p = 0.6)

Remaining issues

All randomized studies have been done in HLA

identical siblings transplants

What about:

younger adults

Aplastic anemias

The doses of cells infused

Unrelated donors

RIC transplants

Eapen et al., JCO 2004; 22:4872

Overall survival after alloBMT vs PBSCT

in children and adolescents

Schrezenmeier et al., Blood 2007 110: 1397-1400

Severe aplastic anemia after PBPC and BM Transplantation

Overall Survival

Marrow versus peripheral blood for geno identical allogeneic stem cell

transplantation in acute myelocytic leukaemia: influence of the dose and the

source of stem cells: better outcome with rich marrow

EBMT retrospective study

NC Gorin, M Labopin, P Zikos, W Arcese, M Beksac, E

Gluckman, O Ringden, T Ruutu, J Reiffers, G Bandini,

M Falda, R Willemze, V Rocha, F Frassoni

Blood 2003

Outcome: BM vs PB

Outcome (%) BM PB

TRM 22 ± 2 22 ± 2

RI 19 ± 2 22 ± 3

LFS 63 ± 2 61 ± 3

OS 66 ± 2 66 ± 3

Copyright ©2003 American Society of Hematology. Copyright restrictions may apply.

Gorin, N. C. et al. Blood 2003;102:3043-3051

Figure 3. RI of patients receiving transplants with high-dose BM, low-dose BM, or PB



Figure 1. LFS of patients receiving transplants with high-dose BM, low-dose BM, or PB



Figure 4. OS of patients receiving transplants with high-dose BM, low-dose BM, or PB

96847260483624120

1.0

.8

.6

.4

.2

0.0

<1.62 x 108/kg 41±5%

1.63-2.4 x 108/kg

months

P (log rank) <0.0001

Leukemia Free Survival according to bone marrow cell dose

2.41-2.93 x 108/kg 59±5%

>3.93 x 108/kg 67±3%

50±5%

V Rocha, M labopin et al EBMT)

CONCLUSION

2003:

Patients with AML allografted in first

remission, have a better outcome with

marrow as compared to PB, when the dose of

marrow infused is rich.

2011:

Nobody really cares

Extensive chronic GvHD after allogeneic transplantation

from unrelated donors

Remberger M , Ringden O et al., BLOOD 2005; 105:548

EXTENSIVE cGVHD

REDUCED INTENSITY

CONDITIONING

The European Group for Blood and Marrow Transplantation

Mobilized Peripheral Blood Stem Cells (PBSC)

Compared with Bone Marrow (BM) as the Stem cell

Source for HLA Identical Sibling Allogeneic

Transplantation with Reduced Intensity Conditioning

(RIC-alloSCT) in Patients with Acute Myeloid Leukemia

(AML) in Complete Remission:

A Retrospective Analysis From the ALWP of EBMT

A. Nagler, M. Labopin, A. Shimoni, G. Mufti, J.J. Cornelissen, D. Blaise, J.J.W.M. Janssen, N. Milpied, L. Vindelov, E. Petersen, J. Gribben, A. Bacigalupo, C. Malm, D. Niederwieser, G. Socie, R. Arnold, P. Brown,

H. Goker, M. Mohty, V. Rocha

On behalf of the Acute Leukemia Working Party EBMT


0 1 2 3 4 5

0.0

0.2

0.4

0.6

0.8

1.0

RIC in sib. SCT for AML in remission:

Cumulative Incidence of relapse

years

32 ± 1%

38± 6%

PB n=1430

BM n=107

P Gray=0.66


RIC in sib. SCT for AML in remission:

Leukemia Free Survival

years

51 ± 2%

50 ± 6%

PB n=1430

BM n=107

P Gray=0.86


A first rapid (and yet incomplete)

conclusion

� BM and PB give equivalent outcomes

� PB is easier to collect and kinetics of

engraftment are more rapid

� We adressed the question of the graft

compositionIIIIII..

RESULTS OF GENOIDENTICAL HEMOPOIETIC STEM CELL

TRANSPLANTATION WITH REDUCED INTENSITY CONDITIONING

FOR ACUTE MYELOCYTIC LEUKEMIA. higher doses of stem cells

infused benefit patients transplanted in CR2 or beyond. A report from the

Acute Leukemia Working Party (ALWP) of the European Group for Blood and

Marrow Transplantation (EBMT).

NC Gorin, M Labopin, JM Boiron, N Theorin, T Littlewood , S Slavin, H

Greinix, JY Cahn , E.P. Alessandrino, A Rambaldi, A Nagler, E Polge

and Vanderson Rocha

A report from the Acute Leukemia Working Party (ALWP) of the

European Group for Blood and Marrow Transplantation (EBMT).

2006;24(24):3959

0 200 400 600

0.0

0.2

0.4

0.6

0.8

1.0

30 ± 4%

56 ±5%

RIC from an HLA identical donor

in adult AML

Cumulative Incidence: chronic GVHD

days

Nucleated cells < median

Nucleated cells>median

P=0.003

3210

1.0

.8

.6

.4

.2

0.0

Figure 3: LFS according to the nucleated cell dose infused

Below the median

Above the median

years

P=0.03

Higher doses

Lower doses

NC Gorin et al JCO 2006 Aug 20;24(24):3959

NO INFLUENCE OF THE DOSE

OF CELLS INFUSED IN CR1Dose LFS RI TRM aGVHD

≥2

cGVHD

<median 54+/-7 30+/-7 16+/-5 21+/-5 48+/-7

>median 45+/-7 42+/-7 13+/-4 17+/-5 56+/-7

p 0.8 0.53 0.58 0.49 0.29

INFLUENCE OF THE DOSE OF

CELLS INFUSED IN CR2

Dose LFS RI TRM aGVHD

≥2

cGVHD

<median 20+/-8 65+/-7 16+/-5 21+/-5 31+/-8

>median 47+/-8 44+/-8 10+/-4 22+/-6 62+/-9

p 0.0025 0.01 0.45 0.65 0.006

RIC transplants AML Conclusion :

Nucleated cell dose infused

� LFS: Better with higher NC dose infused: In CR2 , not in CR1.

� RI: Lower with higher NC dose infused

� The role of CD8+ T cells is possible

3210

1.0

.8

.6

.4

.2

0.0

Figure 5: LFS according to the CD34 cells dose infused

years

Below the median

Above the medianP=0.82

Higher doses

Lower doses

NC Gorin et al JCO 2006 Aug 20;24(24):3959-66.

Engraftment and survival following

RIC allogeneic PBSC transplants: CD8 T cell doseTM Cao, et al Stanford, Blood March 15 2005

Conclusion

• Higher cell doses exclusively benefitted patients

transplanted in second remission (CR2) or beyond .

• 2006

We paid attention

• 2011

Reinfusion of larger doses of PB nucleated cells is usually

recommended in higher risk patientsI.

Autologous stem cell transplantation

for AML

IS BONE MARROW BETTER?

543210

1,0

0,8

0,6

0,4

0,2

0,0

Pro

ba

bil

ity

(%

)

years

47 ± 1%

50 ± 1%

P=0.01

Estimated Leukemia-Free Survival (LFS) in patients receiving autogolous transplantation before 1994 (_______)

or after1994 (-------)

Cumulative incidence of relapse in patients receiving bone marrow (BM), peripheral blood (PB) more than 80 days after the first complete remission (PB late), or PB 80 days or less after the first complete

remission (PB early).

Gorin N et al. JCO 2009;27:3987-3993

©2009 by American Society of Clinical Oncology

Estimated leukemia-free survival in patients receiving bone marrow (BM), peripheral blood (PB) more than 80 days after the first complete remission (PB late), or PB 80 days or less after the first complete

remission (PB early).

Gorin N et al. JCO 2009;27:3987-3993

©2009 by American Society of Clinical Oncology


Gorin, N.-C. et al. Blood 2010;116:3157-3162

Figure 1 Cumulative incidence of relapse

Dose of infused CD34+ cells > 7.16 x 106 cells/kg.


Gorin, N.-C. et al. Blood 2010;116:3157-3162

Figure 2 Probability of LFS

Dose of infused CD34+ cells > 7.16 x 106 cells/kg.

Patients with AML in CR with insufficient mobilization of CD34+ cells with G-SCF and/or Cytoxan:

G-SCF: 10µµµµg/kg QD x 7-8 days;

AMD3100: 240 µµµµg/kg QD starting Day 4 x 3-4 days

Mobilization of AML progenitor cells with G-CSF+Plerixafor

in patients with AML in CR

Courtesy: M Andreef MDA Houston

Increase in circulating clonal cells during apheresis

following G-CSF and AMD3100

G-SCF

AMD-3100

GENERAL CONCLUSION

ASCT in AML

• BM superior to PB

• PB better if more in vivo purging (CR to

ASCT > 80 days)

• PB better if CD34+ Cell dose not too high

• Can we compare BM to Good PB ?

LFS after autograft for AML CR1

1994-2008

Optimal PB identical to BM

BM n=1028

PB* n=672

50 ± 2%

48 ± 2%

years

P=0.95 * interval CR1 to transplant>80 days and CD34 <7.16 106/Kg

BM VERSUS PB

CONCLUSIONS

Peripheral Blood vs Marrow

Allogeneic

• First period: 1993-1999: Discovery of PB and enthusiasm

• Second period: 2000-2007: PB is the Golden standard «

eyes shot »

• Third period: 2008 - 2010 :Concerns and reasonable doubt

« eyes open »: Quality of life assesment

• Today: tailored grafts: source and dose……

Good riskpatient

Standard risk disease

RICH MARROW

Good riskpatient

High risk disease

RICH PB

High riskpatient

Standard risk disease

RICH MARROW OF

COURSE

High riskpatient

High risk disease

PB for the disease

Very rich for the patient

NO TRANSPLANT

or

VERY RICH PB OF

COURSE

Peripheral Blood vs Marrow

Autologous AML

• 1977- 1985: Marrow and in vitro purged marrow

• 1987-1995: Enthusiam for PB giving more rapid engraftment;

concerns on early unexpected relapses in AML…… (JP laporte, J

Mehta…)

Mobilisation of tumor cells

Eyes shot

• Second period 1995-2005: The concept of in vivo purging ( NHL,

Acute Leukemias, ..)

• An old newcomer: Monitoring of Minimal Residual disease.

MARROW MINER TWO

First presented at the EBMT 2008 Meeting

In Florence Italy


Acknowledgments

• All participating EBMT participating centers and

investigators

• National registries

• Local and national data managers

• Norbert Schmitz

• Myriam Labopin

• Arnon Nagler

• Didier Blaise

• Vanderson Rocha

• Mohamad Mohty

the impact of the source of stem cells: … · the impact of the source of stem cells:...

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