what is the expected clinical outcome after bmt
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What is the Expected Clinical Outcome after BMT. ?. Blood Counts for BMT Recipients Surviving more than 15 Years. Clonogenic Progenitors in the Graft and the Recipient post BMT. 1.0. 0.8. 0.6. 0.4. 0.2. 0.0. 0. 2000. 4000. 6000. 8000. 10000. - PowerPoint PPT PresentationTRANSCRIPT
What is the Expected Clinical Outcome
after BMT
?
Blood Counts for BMT Recipients Surviving more than 15 Years
Parameters Mean SDHemoglobin 138.9 16.4Platelets 243.1 65.1WBC 6.6 1.7Neutrophils 4.6 3.4Lymphocytes 1.9 0.7
Donor1 Month
6 Months1 Year
2 Years6 Years
8 Years 10 Years
0
50
100
150
200
250
BFU-ECFU-GMCFU-MEGCFU-GEMM
Clonogenic progenitors in the Graft and Recipient post BMTOverlapping Column Chart
Clonogenic Progenitors in the Graft and the Recipient post BMT
Overall Survival of all Patients Receiving an Allogeneic BMT at PMH
Days after BMT
Sur
viva
l
0 2000 4000 6000 8000 10000
0.00.2
0.40.6
0.81.0
Outcome by Disease Status at BMT in Recipients Transplanted since 1986
Status at BMT when BMT After 9/10/1986
Days After BMT
Pro
porti
on S
urvi
ving
0 1000 2000 3000 4000 5000
0.0
0.2
0.4
0.6
0.8
1.0
1st remission/phaseOther
Days after BMT
Sur
viva
l
CR1 / CP1 -----Other ___
Long-term Survival of Patients alive 6 Years by Disease Status at BMT
Status at BMT when BMT After 9/10/1986
Days After BMT
Pro
porti
on S
urvi
ving
0 1000 2000 3000 4000 5000
0.0
0.2
0.4
0.6
0.8
1.0
1st remission/phaseOther
Days after BMT
Sur
viva
l
AML/CML CR1/CP1 ------AML/CML other - - - -
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150.1
1
10
100
1000
Expected
Observed over Expected Survival after BMTCompared to Survival Expectedfor the Normativer Population
Years after BMT
Obs
erve
d / E
xpec
ted
#of
Dea
ths
The Probability of Survival Remains lower than that of the Normative
Population even more than a Decade after BMT
Lessons learned for Allogeneic Transplants
• High transplant related morbidity and mortality
• Low relapse rate• Disease control predominantly related
to anti-tumor effects by donor derived cells of the immune system
Evidence for Graft vs Malignancy Effects (GvM)
• High relapse rate in syngeneic transplants.• Increased relapse rate in T cell depleted
transplants in some diseases• Lower relapse rate in patients with GvHD
compared to patients without • Leukocyte Infusions (DLI) in recipients
relapsing after a transplant may result in remissions and long-term disease control
Strategies to provide treatment for more patients in need of a
transplant
Matched Unrelated Donors
Cord Blood Transplants
Haplo-identical Donors
Reduced IntensityTransplants
Unrelated donor registries
Matched unrelated donors
• 13 million donors worldwide• Improved donor recruitment• Improved HLA-typing• Outstanding international cooperation• International standards• Outcomes similar to those achieved with
related donors
Donor availability for allogeneic transplants
(O’Brien TA et al MJA 2006; 184: 407 – 410)
Cord Blood Transplants
Principles:
• Utilization of a waste product• High proportion of primitive progenitors• Presence of mainly naïve T cells• Product readily available
Outcome of CBT from related donors by diagnosis
Months
Surv
ival
(Rocha V et al EUROCORD)
Lessons learned• Cord blood cells are a viable alternative source
of hemopoietic progenitor cells• In the pediatric age group CBT may be
preferable because of decreased acute and chronic GvHD and the requirement for a lesser degree of HLA matching
• The outcome of mismatched transplants can be overcome by higher cell doses
• Cell dose remains a limiting problem particularly for adults. This problem is being addressed by the use of double cords.
Transplants from Haplo-identical Donors
Principles:
• Intensive preparation• High stem cell numbers• Extensive T cell depletion• Preparation with regimens that maintain regulatory T cell populations • Availability of donors for nearly everyone
Aversa et al Rev Clin Hematol
Event-free Survival by Disease Status
Non-myeloablative Transplants
Principles:
• Immune suppression with purine analog based regimens of low intensity• Slow replacement of recipient marrow by donor cells• Engraftment fostered by decreasing immune suppression and administration of DLI• Reduction of early transplant related toxicity• Reliance on a GvM effect as mechanism of disease control
Engraftment Process afterNon-myeloablative Allografting
Recipient
Donor
MixedChimera
FullChimera
Immune- suppression
DLI
Non-myeloablative Transplants
Non-myeloablative Transplants
• Decrease of early transplant related toxicity
• Broadened eligibility to include patients with otherwise non-permissive co-morbidities
• Inclusion of patients with chronic non life threatening diseases
• Reliance on a GvM effect for disease control in patients with malignancies
Disease-free Survival of Patients with AML/MDS by Disease Status
Giralt In: NST, 2000
Novel Strategies for Allogeneic BMT
Objectives
Reduction of
other TRM
Avoidance of
GvHD
DiseaseElimination
Risk factors for Transplantation
Recipient
Donor
Graft
TransplantProcedure
Risk factors for Transplantation
Recipient
Donor
Graft
TransplantProcedure
AgeDisease (AA, CML)HLA compatibilityMinor histocompatibility antigensNon-HLA immunogenic polymorphismsGenderImmune status
PBSCCord bloodCell countT cell depletionTregs
AgeHLA compatibilityGender (F M)Unrelated donor
Preparative Regimen
GvHD Prophylaxis andManagement
Malignant stem cells and their protective microenvironment
Mobilization
Reestablishment of potential to undergo apoptosis
Myeloablative therapy and transplant
Events during mobilization(Winkler I, Levesque JP Exp Hematol 2006; 34: 996 – 1009)
Steady state Mobilization with G-CSF
LSC LSC
Allogeneic transplants:A platform for Cell therapy
Donor derived Cells after BMT can be found in strange places
• Myelopoiesis• Lymphopoiesis• von Kupffer cells• Pulmonary alveolar macrophages• Langerhans cells • Osteoclasts• Macro and Microglia• Hepatocytes
Male recipient cellsin female cardiac allografts
(Schwartz and CurfmanNEJM 2002; 346: 2 – 4)
Intracoronary Mononuclear Marrow Cell TransplantationStrauer BE et al Circulation 106: 1913 – 1918, 2002
Intracoronary injection of BM cells in acute myocardial infarction
• Lunde K et al (NEJM 2006; 355: 1199 – 1209) 100 patients randomized to marrow cell injections or no intervention
NO differences in global left ventricular function
• Schachinger V et al (NEJM 2006; 355: 1210 – 1221)204 patients randomized to marrow cell injections or placeboImproved recovery of left ventricular contractility after marrow cell infusion
• Assmus B et al (NEJM 2006; 355: 1222 – 1232)75 patients randomized to circulating blood cells, marrow, or no cellsModerate but significant improvement of left ventricular ejection fraction after marrow cell infusion
Stem cell recruitment to ischemic infarcts(Kim DE et al Stroke 2004; 35: 952 – 957)
Cells positive for neuronal markerNeuN
Neurogenic Regions in the Mouse
Subventricular zone Dentate gyrus (DG)
(Seaberg R, van der Kooy D J.Neurosci 2002; 22: 1784 – 1793)
Newly generated cells in the subventricular zone with EGF or EGF plus EPO
a
BrdU
LV Str
BrdU
LV Str
EGF EGF + EPO
Courtesy Sam Weiss, Calgary
Histological analyses reveal new tissue in the lesion cavity of rats that received EGF+EPO infusions
No Lesion Lesion + EGF/EPO
Lesion
Courtesy Sam Weiss, Calgary
Embryonal Stem Cells
(Langston JW J Clin Invest 2005; 115: 23 – 25)
The promise of stem cellresearch
Conclusions (I)• Stem cell transplants are a major treatment
modality for patients with marrow failure, hemopoietic malignancies and diseases with immune dysfunction
• Stem cell sources include marrow, peripheral blood and cord blood
• Stem cells can be derived from autologous and allogeneic sources
• Currently available strategies facilitate their use for patients with more advanced age
Conclusions (II)
• Advances are being made to test whether or not stem cells may facilitate repair of defective organs in general
BM
PBSC
Months post Transplant
P=0.036
Probability of Survival
BM
PBSC
Months post Transplant
Survival of Patients with moreAdvanced Disease