Title: Presentazione di PowerPoint
1University of Milano Department of Hematology
Evolving Strategies and New Indications of
Hemopoietic Stem Cell Transplantation
Giorgio Lambertenghi Deliliers XXIII IATMO
Conference Trieste, October 19-21 2007
2HEMOPOIETIC STEM CELL TRANSPLANTATION AT 50
September 12, 2007, marked the 50th anniversary
of E. Donnall Thomass initial report of a
radical new approch to cancer treatment
radiation and chemotherapy followed by the
intravenous infusion of bone marrow. This new
form of therapy was used to treat approximately
50,000 people worldwide between 1957 and 2006.
3EVOLVING SRATEGIES IN HSCT
Increasing use of cord blood and haploidentical
stem cells
Shift burden of tumor cell kill from cytotoxic
chemoradiotherapy to donor T cells
Incorporation of new agents in transplant
strategies
Recognition of new indications
4DONOR AVAILABILITY IS A PROBLEM !!!
5(No Transcript)
6CORD BLOOD HSCT
7ADVANTAGES OF CORD BLOOD
Low number of CD34 cells, but high
proliferative potential of hematopoietic
progenitors Immaturity of lymphocytes Low viral
contamination Donor availability is lt 1 month
8UCBT MALIGNANT DISORDERS (N929) Disease-free
survival according to number of HLA
1.0
0.8
0.6
Event-Free Survival
3-4 differences
0.4
2 differences
0-1 difference
0.2
P0.99
0.0
0
20
40
60
80
100
Months
9UCBT MALIGNANT DISORDERS (N929)
Neutrophils recovery according to number of
nucleated cells (107/kg)
Cells collected
Cells infused
1.0
1.0
gt7.2
gt5.0
4.4 -7.2
2.1 - 3.1
0.8
0.8
3.0 - 4.4
3.1 -5.0
lt 3.0
lt 2.1
0.6
0.6
Cumulative incidence
0.4
0.4
P0.0012
Plt 0.0001
0.2
0.2
0.0
0.0
0
20
40
60
80
100
0
20
40
60
80
100
Days
Days
10UCBT MALIGNANT DISORDERS (N929)Neutrophils
recovery according to number of HLA
1.0
0-1 difference
0.8
2 differences
3-4 differences
0.6
Cumulative incidence
- 0-1 447 patients, 360 engraftments
- 357 patients, 269 engraftments
- 3-4 79 patients, 52 engraftments
0.4
0.2
P0.037
0.0
0
20
40
60
80
100
Days
11OSPEDALE MAGGIORE POLICLINICO, MANGIAGALLI E
REGINA ELENA MILAN, ITALY
Milano Cord Blood Bank
12MILANO CBB - EUROCORD
Malignancies n152 Acute leukemia 103
ALL 70 AML 25
Sec. AL 8 (CR1 19 CR2 47
advanced 34 missing n 3) CML
15 Lymphoma (NHL/HD) 9 MDS
17 Histiocytosis 8
13SURVIVAL ACCORDING TO DIAGNOSIS
1,0
,9
,8
,7
Other diagn 59 11
,6
,5
,4
Malignancies 39 4
,3
,2
,1
p0.15
36
30
24
18
12
6
0
Months
14EVENT FREE SURVIVAL IN PATIENTS WITH
MALIGNANCIES ACCORDING TO DISEASE STATUS AT
TRANSPLANT
1,0
,8
,6
Early 52 13
Intermediate 33 6
,4
,2
Advanced 25 6
p0.12
0,0
36
30
24
18
12
6
0
Months
15SURVIVAL ACCORDING
TO THE NUMBER TO NUCLEATED CELLS INFUSED
1,0
,9
,8
,7
,6
gt4x107/kg 44 6
,5
,4
lt4x107/kg 41 6
,3
,2
,1
p0.48
36
30
24
18
12
6
0
Months
16 CUMULATIVE INCIDENCE OF TRANSPLANT RELATED
MORTALITY
1.0
0.8
0.6
0.4
26 3
0.2
0.0
0
20
40
60
80
100
Days
17MILANO CBB - EUROCORD
Unrelated Cord Blood Transplants n175
Acute GvHD gt II n54
Grade IV n12
Grade III n9
7
5
No GvHD n78
Grade II n33
45
19
Grade I n41
24
Chronic GvHD 26/123 (CI17/-3)
18NEW STRATEGY TO IMPROVE ENGRAFTMENT IN CORD BLOOD
TRANSPLANT
4-6/6
4-6/6
4-6/6
19SUSTAINED NEUTROPHIL ENGRAFTMENT
Double
1.0
Single
0.8
0.6
Incidence
0.4
0.2
0.0
0
7
14
21
28
35
42
Days
20OVERALL SURVIVAL Acute Leukemia in CR1 CR2
1.0
0.8
Double
I
I
72
0.6
Single
Probability
I
I
I
I
I
I
I
I
47
0.4
0.2
p .16
0.0
0
1
2
3
Years
21INCIDENCE of RELAPSE Acute leukemia in CR1 CR2
1.0
0.8
p .05
0.6
Incidence
0.4
Single
0.2
30
Double
9
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
Months
22DONOR AVAILABILITY IS NOT A PROBLEM ANYMORE
No suitable donor/not available in time
Sibling donor
20 find a compatible sibling donor
Unrelated donor
35 Receive BMT via Registry Match
23EVENT FREE SURVIVAL AND NK ALLOREACTIVITY IN AML
Chemoresistant relapse
Any remission
1.0
1.0
0.8
0.8
NK alloreactive (n30)
0.6
0.6
Survival
NK alloreactive (n21)
0.4
0.4
P 0.02
0.2
0.2
P 0.04
Non -NK alloreactive (n31)
Non -NK alloreactive (n30)
0.0
0.0
0.0
0.0
0
2
4
6
8
10
0
2
4
6
8
10
Years
Years
Ruggeri et al, Blood 2007
24ENGRAFTMENT and GVHD in 255 PATIENTS WITH ACUTE
LEUKEMIA
Primary Engrafment
Acute GVHD grade II
96
1.0
0.5
95
Probability
0.8
0.4
84
0.6
0.3
1993-1995
17
0.4
0.2
6
0.2
SBA n36
0.1
1999-2005
Cellpro n44
0
Clinimacs n175
1995-1998
0.0
0.0
5
10
15
20
25
30
0
20
40
60
80
100
Days to engraft (gt500 N)
Days after transplantation
Overall Engraftment 98
HSCT Program University of Perugia
25EVENT FREE SURVIVAL
ALL (n108)
AML (n147)
1,0
0,8
0,6
Probability
0.50 0.09
CR 1 (n34)
CR 2 (n49)
0.35 0.07
0,4
CR 2 (n39)
0.27 0.10
Relapse (n64)
0.14 0.04
0,2
CR 1 (n23)
0.25 0.08
0.05 0.04
Relapse (n46)
0,0
P0.0003
P0.0006
0
20
40
60
80
100
120
140
Months
Months
HSCT Program University of Perugia
26RATIONAL OF ALLOGENEIC HSCT
Hematological rescue allows administration of
high dose chemo-radiotherapy to kill neoplastic
cells
Donor T cell reaction allows an adoptive
immunotheraphy to eradicate minimal residual
disease
27EVOLVING SRATEGIES IN HSCT
Increasing use of cord blood and haploidentical
stem cells
Shift burden of tumor cell kill from cytotoxic
chemoradiotherapy to donor T cells
Incorporation of new agents in transplant
strategies
Recognition of new indications
28RATIONAL OF REDUCED INTENSITY REGIMENS
Avoid the excessive regimen related toxicity
Its benefit can be extended to patients not be
considered candidates for conventional
myeloablative transplant (age, concurrent medical
conditions)
Immunosuppress the host sufficiently to allow
donor engraftment
Cure the disease by through the GVL effect,
eventually potentiated by DLI
29AGE RELATED INCIDENCE OF HEMATOLOGICAL
MALIGNANCIES
500
400
CLL
300
Number of Cases
AML/MDS
200
MM
100
ALL
0
0
10
20
30
40
50
60
70
80
Age (years)
30REDUCED INTENSITY ALLOGENEIC HSCT FOR HIGH RISK
CLL
Related Recipients
Unrelated Recipients
100
100
80
80
OS
DFS
Percentage
60
60
OS
Percentage
40
40
DFS
NRM
NRM
20
20
Relapse-Related Mortality
Relapse-Related Mortality
0
0
0
6
12
18
24
30
36
42
48
0
6
12
18
24
30
36
42
48
Months after HCT
Months after HCT
Sorror, J. Clin Oncol 2005
31100
Ms 293 months
50
Surviving
plt0.0001
IgVH Mutated
Ms 97 months
IgVH Unmutated
0
0
100
200
300
400
Months
ASH, 2002
32AUTO and RIC-ALLO HSCT in Ig-VH UNMUTATED CLL
Autologous
Allogeneic
100
100
10-1
10-1
MRD level
10-2
10-2
10-3
10-3
10-4
10-4
10-5
10-5
100
200
360
720
gt720
Days
100
200
360
720
gt720
Days
Ritgen, Blood 2004
33REDUCED INTENSITY ALLOGENEIC HSCT FOR
AML/MDS Rationale
Median age of presentation is between 65 and 70
years for AML and 70 years for MDS
In conventional HSCT NRM is a persistent problem
mainly because toxicity induced by conditioning,
acute and chronic GVHD, and concomitant medical
diseases
Therefore most AML and MDS patients are not
eligible for conventional transplant procedures.
Arbitrary age limit is 50-55 years
34REDUCED INTENSITY ALLOGENEIC HSCT FOR AML/MDS
Some promise in patients ineligible for standard
transplantation. Lower transplant related
mortality
Less toxicities and less GVHD related
complications
Clinical outcome in elderly patients are superior
than conventional chemotherapy
Higher incidence of relapse!! Longer follow-up
and great numbers of patients are required for
delineate the real therapeutic efficacy of the
procedure
35AUTOGRAFT vs ABLATIVE ALLOGRAFT IN MULTIPLE
MYELOMA
SWOG 9321
Autologous SCT and conventional CT
Myeloablative allogeneic SCT
Overall survival
Overall survival
100
100
80
80
60
60
40
40
20
20
0
0
0
3
6
9
12
2
4
6
8
10
0
Years from randomization
Years fram
Barlogie, JCO, 2006
36TANDEM AUTO-REDUCED INTENSITY ALLO HSCT FOR
MULTIPLE MYELOMA
Diagnosis
1.8
1.6
1.4
1.2
RICAllo
Serum Paraprotein (gm/L)
Poliche
1
DLI
0.8
Auto
0.6
0.4
0.2
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Months
37ESTIMATES OF SURVIVALS IN MM
NEJM 2007
38EVOLVING SRATEGIES IN HSCT
Increasing use of cord blood and haploidentical
stem cells
Shift burden of tumor cell kill from cytotoxic
chemoradiotherapy to donor T cells
Incorporation of new agents in transplant
strategies
Recognition of new indications
39INCORPORATION OF NEW AGENTS IN TRANSPLANT
STRATEGIES
Maximize the chance of response
(overall and CR) Accelerate tumor mass
reduction Overcome chemoresistance related to
cytogenetic abnormalities Reduce the risk of
relapse and extend EFS and OS, particularly in
high-risk patients
40RITUXIMAB IN HSCT FOR MALIGNANT LYMPHOMAS
In conditionig regimens increases the quality of
response. It is the main prognostic factor before
transplant In autologous transplant alone or with
chemotherapy allows in vivo purging. Easy and
efficient. Does not impair stem cell
collection Increases DFS in RIC regimens Is a
useful adjuvant in post transplant
41RITUXIMAB IN AUTOLOGOUS HSCT FOR
MALIGNANT LYMPHOMAS
Preparative Regimen
Rituximab1000 mg/m2
Rituximab1000 mg/m2
High-Dose Chemotherapy
-6
-5
-4
-3
-2
-1
0
1
8
Days
Transplant on day 0
Kouri, JCO 2005
42AUTOLOGOUS HSCT FOR AGGRESSIVE NHL Impact of
Rituximab on DFS
1.0
Rituximab
0.9
0.8
0.7
0.6
Cumulative Proportion Surviving
0.5
0.4
No Rituximab
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
27
30
Months post transplant
43REDUCED CONDITIONING REGIMENS FOR ALLOGENEIC
HSCT IN CLL Impact of Rituximab on DFS
1.0
R-FC
0.8
0.6
Probability
FC
0.4
0.2
P 0.01
0.0
0
3
15
21
6
9
12
18
24
Months post transplant
44REDUCED CONDITIONING REGIMENS FOR ALLOGENEIC
HSCT IN CLL
Impact of Rituximab on GVHD
FC
FCR
Regimen
cGVHD
81
36
Ac II-IV GVHD
43
20
Kouri et al, 2004
45POTENTIAL ADVANTAGES OF RADIOIMMUNOTHARAPY
Radioimmuno- conjugate
- Lymphoma cells are inherently sensitive to
radiation - RIT delivers continuous low-dose radiation to
CD20 cells - Targeted radiation also destroys tumour cells by
a cross-fire effect (bulky tumor, CD20 low
expression)
90Y
90Y
CD20
Lymphoma cells
90Y
46OVERALL SURVIVAL BY TREATMENTZ-ASCT (N 62) vs
TBI-ASCT (N 125)
1.0
Z-ASCT
0.8
0.6
Survival probability
TBI-ASCT
0.4
0.2
p 0.0229
0.0
0
6
24
36
48
60
72
84
Months from date of transplant
AP Nademanee, et al., Blood, 108 (11) abs, 2006
47ALENTUZUMAB IN ALLOGENEIC HSCT
- Has a long history of T cell depletion
- In pretransplant conditioning allows
- Tumor reduction in vivo
- T cell depletion of donor T cells
- Reduction of GVHD
- Allows transplantation of HLA mismatched cells
48ALEMTUZUMAB IN RIC-HSCT FOR RELAPSED AND
REFRACTORY NHL
100
90
80
70
Low Grade
3-year Current PFS ()
60
65
50
MCL
40
50
30
34
20
High Grade
10
0
0
12
24
36
48
60
Time after Transplantation (months)
Morris et al, Blood 2004
49- The landscape of myeloma treatment has changed
substantially over the past few years. - Currently, the main clinical challenge is
determining whether new agents should be given
sequentially or in combination, and how they
should be integrated with old therapies. - Two treatment strategies are being explored. The
first aims to eradicate the tumor with the use of
a combination of all the available agents with
stem-cell transplantation. The second approach is
to reserve the use of new agents for the
sequential treatment of relapses.
50DOUBLE ASCT vs DOUBLE ASCT THALIDOMIDE
? VERY GOOD PARTIAL RESPONSE
EVENT-FREE SURVIVAL
THAL52
NO THAL33
median (mos)
P.002
P.003
Plt.001
P.001
NO THAL
THAL
45
25
P.01
months
OVERALL SURVIVAL
SURVIVAL AFTER RELAPSE
THAL26
NO THAL23
median (mos)
69
54
THAL68
NO THALnot reach.
median (mos)
P.47
P.23
months
months
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52SURVIVAL FOLLOWING ALLOGENEIC HSCT IN CML (1992
2004)
1.0
Chronic phase (n303)
0.8
0.6
Accelerated phase/blast crisis remission (n359)
Probability of Survival
0.4
0.2
Blast crisis (n20)
0.0
0
2
4
6
8
10
Years after transplant
53IMATINIB (GLIVEC, STI571) IS THE STANDARD
TREATMENT of Ph LEUKEMIA
Savage and Antman NEJM 2002
54EBMT ACTIVITY SURVEY ON HSCT
1990 - 2005 CHANGES IN CML
1200
1000
HSCT
CML 1st cP allo
800
600
CML Not 1st cP allo
400
CML 1st cP auto
200
CML Not 1st cP auto
0
1990
1992
1994
1996
1998
2000
2002
2004
55IMATINIB IN EARLY CHRONIC PHASE CML SUSTAINED
RESPONSES
56NOVEL TYROSINE KINASE INHIBITORS FOR CML
NILOTINIB
20
-
to 50
-
fold more potent than imatinib
DASATINIB
300 times more potent than imatinib
Sources Weisberg.
Cancer Cell.
20057129
-
141.
Golemovic
.
Clin
Cancer Res.
2005114941. OHare T.
Cancer Res.
2005654500
-
4505.
57PROGRESSION-FREE SURVIVAL
Dasatinib 70 mg BID in CP-CML
START-C EHA 2007
58WHEN ALLOGENEIC HSCT IS TODAY RECOMMENDED FOR CML?
In high risk patients according to Sokal and Euro
scores
After failure with Imatinib or second generation
TK inhibitors
In all patients responding to high dose Imatinib
or second generation TK inhibitors (not durable
response)
Novel TK inhibitors can be used for reducing the
tumor burden before performing transplant
59EVOLVING SRATEGIES IN HSCT
Increasing use of cord blood and haploidentical
stem cells
Shift burden of tumor cell kill from cytotoxic
chemoradiotherapy to donor T cells
Incorporation of new agents in transplant
strategies
Recognition of new indications
60THE EXPANDING APPLICATION OF HEMOPOIETIC STEM
CELL TRANSPLANTATION
Thalassemia
Sickle cell anemia
Paroxysmal nocturnal hemoglobinuria
Hemolytic anemia due to enzymatic effect
Congenital T cell immunodeficiency
Autoimmune diseases
61AUTOLOGOUS HSCT IN AUTOIMMUNE DISORDERS
From suppression of the immune system
to a reset of the autoreactive immune system and
reconstruction of a tolerant immune system
62DISEASE BREAKDOWN 1999/2004-2005
Transplants in 1999
Transplants in 2004-2005
Unknown 7
Unknown 2
IBD1
Wegener 1
Vasculitis 1
MS 37
RA 28
ITP 2
Wegener 2
RA 2
AIHA 3
JCA 2
ITP 2
PM_DM 3
IBD 2
Vasculitis 3
SSc 7
Evan's 3
JCA 9
SLE 9
MS 25
SSc 24
SLE 9
63CONDITIONING REGIMEN FOR AUTOLOGOUS HSCT IN AD
Autologous CD34 infusion
CTX 50 mg/kg/die
-5
-4
-3
-2
-1
0
1
2
10
11
12
13
ATG 2,5 mg/kg/die
64SURVIVAL AFTER AUTOLOGOUS HSCT IN AD
Gratwohl A, BMT 2005 35, 869 - 879.
65TRM AFTER AUTOLOGOUS HSCT IN AD
Gratwohl A, BMT 2005 35, 869 - 879.
66AUTOLOGOUS HSCT FOR SYSTEMIC SCLEROSIS
1.0
0.8
0.6
Probability
0.4
Overall Survival
0.2
Progression-free Survival
0.0
0
1
2
3
4
5
6
7
8
Years after transplant
Nash, Blood 2007
67EVOLVING STRATEGIES OF HSCTconclusions
Still is considered the best chance of cure for
many hematological diseases malignant or not
Outcomes vary according to many factors type ad
stages of the diseases, age of the patients,
source of stem cells, degree of HLA mismatch
Proper time to perform transplant is difficult to
establish (prognostic factors)
Benefit must be balanced against its risks and
versus the availability of novel targeted agents
that have the potential to eradicate the
neoplastic clone
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