Transcript Alan Teh • Early bone marrow transplants in 1950's. • 1960's HLA compatibility to perform transplants between siblings. • In 1973 a team.

Alan Teh
2009
• Early bone marrow transplants in 1950's.
• 1960's HLA compatibility to perform transplants
between siblings.
• In 1973 a team of physicians performed the first
unrelated bone marrow transplant.
The Nobel Prize, 1990
E. Donnall Thomas
first succsessful HSCT in treatment of acute leukemias
Thomas ED, Lochte HL, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in
patients receiving radiation and chemotherapy. N. Engl. J. Med. 1957; 257: 491.
Conditioning regimen in HSCT
Goals of Conditioning
– Space-making (controversial)
speed of engraftment
– Immunosuppression
– Disease eradication
dose limiting toxicity
Myeloablative Conditioning
•Busulphan + Cyclophosphamide (Santos,
Tuschka)
•Cyclophosphamide + TBI
• Regimen Related Toxicity
- Mucositis
- VOD
- IP
- Infections
• GVHD
• Relapse
Current Challenges
• Reducing Regimen Related Toxicity
• Reducing Risk of GVHD and Rejection
• Expanding Options for older, “high risk”
patients
• Expanding Options for Patients Without
Matched Sibling Donors
• Refining Criteria for transplantation
Nomenclature
• Reduced Intensity Conditioning
Transplants
• Non-Myeloablative Transplants
• Mini-Transplants
• Transplant-lite
• Demonstration of DLI effect:
• Kolb - DLI restored remission in CML patients
relapsing after allogeneic BMT (Blood 1990)
• Porter – NEJM (1994)
• However immunosuppression still required for
engraftment
Reduced intensity conditioning SCT
OBJECTIVES:
-> Reduce the early toxicity of allogeneic SCT
-> Keep the Graft-versus-leukemia effect

Mainly proposed to:
- older patients (> 55 y)
- patients with comorbidity

Reduces the duration of neutropenia

Reduces mucosal and liver toxicity

But GVHD, Relapse still problems
10
Example of a RIC / non myelo-ablative regimen
Immunesuppression vs Myelosuppression
TBI 2 Gy
PB SCT
Chimerism Analyses
-4 -3 -2 -1 0
28
56
84
Fludarabine: 30 mg/sq./d
Cyclosporine
Mycophenolate Mofetil
From Niederwieser et al. 2003
11
RIC conditioning - variations
• Varying intensity and effects on
lymphohaemopoietic system
• Low intensity
e.g. Flu Cyclo, Flu + low dose TBI
• Moderate intensity
e.g. FluBu, FluBuATG
RIC: Different preparative regimens
from Kassim AA et al. BMT 2005
MyeloAblative
MOderate
intensity
MInimal
intensity
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RIC transplants – reducing RRT
Reduction in
•Cytopaenias
•Transfusion requirements
Recovery after RIC Neutropenia
After Fluda-TBI 2Gy in AML (Hegenbart JCO 2006):
No neutropenia at all (PMN > 500/µL):
27%
Median nadir of PMN:
216/µL
Median No. Days with PMN<500/µL:
6 days
Other RIC regimens:
Variable
Never as deep and long as in MA regimens
16
Decreased transfusion requirements for patients receiving nonmyeloablative
compared with conventional peripheral blood stem cell transplants
from HLA-identical siblings
Florian Weissinger, Brenda M. Sandmaier, David G. Maloney, William I. Bensinger, Ted Gooley, and Rainer Storb
(Blood Dec 2001)
Non-Myeloablative Transplants
•
•
•
N=40 (median age 51 yrs)
Conditioning: 2 Gy TBI
2 Gy TBI + Flu
GVHD prophylaxis: MMF + CSA
Controls
•
•
•
N=67 (median age 46 yrs)
Conditioning: 12-14.4 Gy TBI+ Bu
12-14.4 Gy TBI+ Cy
BuCy
GVHD prophylaxis: CSA + Mtx
RIC Transplants – reducing RRT
•Mucositis
- mild/absent
- no TPN
•VOD
- virtually Nil
RIC transplants – infections
• No prospective comparative studies so far
• A clear trend for less early bacterial infections
• Comparable incidences of IFI, a trend for less
in RIC
• A likely protective effect of RIC in case of
previous IA
• Comparable incidences of CMV infection and
disease
• Delayed occurrence of fungal and viral
infections
RIC Transplants - GVHD
• Risk of aGVHD cGVHD similar to MAST
• May be less in MIST compared with
MOST
• Pattern of onset different
- aGVHD may be delayed
RIC Transplants - Relapse
• Cytoreduction MIST < MOST < MAST
• Relapse a major problem in RIC Tx
• Determinants of success
- stage of disease (cr vs not in cr)
- GVL / degree of co-stimulatory signals
e.g. CML, CLL, low grade lymphomas
- disease itself – “indolent” vs proliferative
less likely to succeed in “aggressive
disease”
Indications for Reduced Intensity
Transplantation
• Older patients /co-morbidities with
myeloid neoplasms – AML, MDS, CML
• 2nd transplant after prior autologous or
allogeneic transplant
• Low grade lymphoproliferative disorders
• ?As part of tandem auto-allogeneic
approach for myeloma and aggressive
lymphoid neoplasms.
• Non-malignant disorders – SAA,
congenital disorders
RIC Case Example 1
•
•
•
•
•
•
•
54 yr old F
Breast Ca 2004 : mastectomy & chemo
09/2007: fever, pancytopaenia
AML M4, normal cytogenetics
3+7 Induction: stormy, heart failure, ccu
CR
Post-remission chemo, non-anthracycline
RIC Case Example 1
• 05/2008
RIC sibling allogeneic transplant
• VNTR:
+30 – mixed (>70%)
+60, +90, +1 yr - 100% donor chimerism
CYK: Post transplant T3
Gel image
Donor
Patient pretransplant
Patient post-transplant T3
Electropherogram view of results: Standards
100% donor DNA, 0% patient (pre-transplant)
DNA
Donorspecific
allele
Corresponding
gel image
RIC Case example 2
•
•
•
•
•
•
19 yr old Indonesian F
Feb 2003 AML M4, normal cytogenetics
Induction, post-remission chemo
August 2003 MAST sibling donor
Engrafted, No gvhd
December 2006 : hematological relapse
RIC Case example 2
•
•
•
•
•
•
Salvage chemo: FLAG-Ida + DLI
2nd CR (cyto?)
Feb 2007 : MOST
Further DLI q 3 monthly x 3
Mild chronic GHVD
Remains in CCR
Long-term follow-up of allogeneic hematopoietic stemcell transplantation with reduced-intensity conditioning
for patients with chronic myeloid leukemia
Partow Kebriaei et al Blood November 2007, Vol. 110,
No. 9, pp. 3456-3462.
N – 64
Med f/u 7
yrs
Med age 52
OS
GVHD 30%
Prolonged survival in adults with acute lymphoblastic leukemia after
reduced-intensity conditioning with cord blood or sibling donor
transplantation
Veronika Bachanova et al Blood, 26 March 2009, Vol. 113, No. 13, pp.
2902-2905
N = 22
Med age 49
Probability of Survival after Allotransplants for
Advanced MDS, Age >50 Years, 1998-2004
- by Conditioning Regimen and Donor Type 100
Probability, %
80
Myeloablative, HLA-id sib (N=249)
60
Myeloablative, unrelated (N=163)
RIC, HLA-id sib (N=135)
40
20
RIC, unrelated (N=93)
P < 0.001
0
0
1
2
RIC = Reduced Intensity
Conditioning
3
Years
4
5
6
Probability of Survival after HLA-identical Sibling
Transplants for Diffuse Large Cell Lymphoma,
1998-2004
- by Disease Status and Conditioning Regimen 100
Probability, %
80
Chemo-sensitive, RIC (N=56)
Chemo-sensitive, Myeloablative (N=214)
60
Chemo-resistant, Myeloablative (N=75)
Chemo-resistant, RIC (N=26)
40
20
P = 0.011
0
0
1
2
RIC = Reduced Intensity
Conditioning
3
Years
4
5
6
Summary
• Increasing number of RIC transplants
• Expands transplant opportunity – older
patients, co-morbidities
• Early RRT is reduced
• Still carry risk of Opp infection and GVHD
• Relapse if disease not controlled pre-Tx,
no GVL
Summary
• Studies largely small patient sets,
retrospective comparisons
• Efficacy of RIC to be further defined for
individual diseases
Thank you