what is the expected clinical outcome after bmt ?

What is the Expected Clinical Outcome

after BMT

?

Blood Counts for BMT Recipients Surviving more than 15 Years

Parameters Mean SDHemoglobin 138.9 16.4

Platelets 243.1 65.1

WBC 6.6 1.7

Neutrophils 4.6 3.4

Lymphocytes 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

0.0

0.2

0.4

0.6

0.8

1.0

Outcome by Disease Status at BMT in Recipients Transplanted since 1986

Status at BMT when BMT After 9/10/1986

Days After BMT

Pro

port

ion

Sur

vivi

ng

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

port

ion

Sur

vivi

ng

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

Ob

serv

ed /

Exp

ecte

d #

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

Su

rviv

al(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

LSCLSC

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 Transplantation

Strauer 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