Transcript Problems with BMT - UW Hematology Protocols

Allogeneic “Mini” Transplantation
Mark B. Juckett M.D.
June 4, 2004
Problems with BMT
• Relapse
– CML chronic phase – 10%
– High risk AML/ALL – 50%
• Toxicity
– Non-relapse mortality of 10 – 40%
– Graft vs. Host disease (GVHD) of 40 – 60%
• Cost
100-DAY MORTALITY AFTER
HLA-IDENTICAL SIBLING TRANSPLANTS
1999-2000
100
CR1
CR2+
Other
MORTALITY, %
80
CP
AP
BP
60
173
464
40
67
20
952
258
386 359
1,267
212
437
433
90
0
AML
ALL
CML
MDS
Aplastic Immune
Anemia Deficiency
Numbers on bars = numbers of patients evaluable
SUM02_39.ppt
What is GVHD?
• An cell mediated reaction of donor origin
against recipient tissues
• It requires:
– a donor graft with immunologically competent
cells
– a recipient unable to mount immune response
– recipient expresses tissue antigens that are not
present in the donor.
Pathogenesis of GVHD
Present
self Ags
to Donor
React to
Recipient
Ags
Recipient APC
Recipient
Donor
T cells
Donor
Why Does allogeneic BMT
Work?
• “Roundup” theory – eradicate all hematopoeitic
tissue
Why Does allogeneic BMT
Work?
• Rescue patient with healthy stem cells
•Graft vs. Host reactions a nuisance
Past Approaches used to
Improve Outcome
• Intensify regimen (More Roundup)
• Better matching (twin donor best?)
• Improve immune suppression
– i.e. “GVHD prophylaxis”
• Remove immune cells capable of GVHD
– “T cell depletion” started at UW
Intensified Regimen
Randomized trial of
12.0 Gy vs. 15.75 Gy
Total Body Irradiation
& cyclophosphamide
12.0 Gy vs. 15.75 Gy
Clift, Blood, 76, 1867,1990
•Lower risk of relapse…
12.0 Gy vs. 15.75 Gy
•Higher rate of aGVHD
…BUT
•Higher non-relapse mortality
12.0 Gy vs. 15.75 Gy
GVHD Prophylaxis - How much?
Aggressive Prophylaxis
Minimal Prophylaxis
•LESS GVHD
•MORE infection
•MORE relapse
•MORE GVHD
•LESS infection
•LESS relapse
SURVIVAL
Non-selective T cell depletion
Relative Risk
Grade 2-4 AGVHD
0.50
Graft Rejection
3.37
Relapse (5yr)
1.87
Transplant Mortality
1.60
Champlin, Blood, 95, 3996, 2000
Twin – Best Donor?
Gale, Ann Intern Med 120:646, 1994
Chronic GVHD marks long-term
disease control
Overall survival best with mild cGVHD
Horowitz, Blood 75:555, 1990
Donor Lymphocyte Infusion for
relapse after allogeneic BMT
Patient relapsing after
allogeneic BMT for CML
received donor lymphocyte
infusions
Porter, NEJM 330:100, 1994
DLI for relapse after allogeneic
BMT
Porter, BBMT 5:253, 1999
Learning Points
• Preparative regimen provides short-term disease
control – not cure.
• Preparative regimen toxicity increases risk of
acute GVHD (“cytokine storm”)
• A “graft vs. disease” response exists
– Varies with respect to disease
• Long term disease control related to
immunological effects from the donor
– Correlates with chronic GVHD
New Paradigm
•
•
Hematopoeitic stem cell transplantation succeeds
when a chronic “allo”immune process is created
that is specific to the disease/diseased tissue.
The “preparative regimen” is necessary to
provide:
– Sufficient immune suppression for donor engraftment
And
–
Short-term disease control sufficient to allow the
autoimmune process to develop.
Strategies for Improvement
• Reduce the intensity of the preparative
regimen
– Use agents specific to the disease &
immunosuppressive
• Speed neutrophil engraftment
– Peripheral blood stem cell collection
• Improve lymphoid immune reconstitution
– Donor lymphocyte infusion
Spectrum of Preparative
Regimens
Immunosuppresion
Cy/12Gy TBI
Bu/F/ATG
2Gy TBI/Flu
Bu/Cy
MF
FC
2Gy TBI
Flag
Myelosuppression
Human LD50 = 4Gy
Myeloablative dose = 8Gy
Non-myeloablative Transplantion
Seattle Study
“Mini-transplant”
Chimerism Analyses = “DNA fingerprinting”
McSweeney, Blood 97:3390, 2001
Patients – Seattle Study
•
•
•
•
•
•
•
•
MM
MDS
CLL
CML
AML
NHL
HD
Other
41
26
19
17
17
19
12
5
• Eligibility
– Age greater than 50
• Or
– Ineligible for
Conventional BMT
• Aspergillis infection
• Liver/cardiac/pulm
disease
• Previous BMT
McSweeney, Blood 97:3390, 2001
Neutrophil/Platelet changes
after transplant
McSweeney, Blood 97:3390, 2001
Graft vs. Host Disease
•Lower risk of severe aGVHD
•Delayed onset
•Similar risk of cGVHD
McSweeney, Blood 97:3390, 2001
Survival after Non-myeloablative
Stem cell Transplant
McSweeney, Blood 97:3390
Grade 3-5 toxicity by day 100
Organ system
Nonmyeloablative
Myeloablative
Cardiovascular
47%
74%
Gastrointenstinal
12%
76%
Hepatic
37%
57%
Infection
56%
84%
Pulmonary
6%
21%
Diaconescu, Blood, 102:261a, 2003
Non-myeloablative transplant for
Chronic Myeloid Leukemia
N = 24
Disease Free Survival
Chronic GVHD
Or, Blood 101:441, 2003
Non-myeloablative transplant for
Myelodysplastic Syndrome
N = 16
Overall and EFS
Chronic GVHD
Taussig, JCO 21:3060, 2003
Non-myeloablative transplant for
Renal Cell Cancer
N = 19
Time to response
Overall Survival
Childs, NEJM 343:750, 2000
Problem: Early Disease Control
Patient GN - IgA myeloma
IgA
2Gy TBI
PBSCT
CSA
DLI
Findings from NST trials
• Early toxicity reduced
– Heme toxicity much shortened
• Outpatient management feasible
• Engraftment successful
– with fludarabine added to regimen
• Risk of aGVHD reduced and delayed
• Risk of cGVHD unchanged but delayed
• Early disease progression common
Disease Sensitivity to
“Graft vs. Malignancy”
• Sensitive
–
–
–
–
CML
Follicular lymphoma
Mantle cell lymphoma
CLL
• Insensitive
– ALL
– High-grade NHL
• Intermediate
–
–
–
–
–
–
AML
Diffuse large NHL
Multiple myeloma
Hodgkin disease
Renal cell
Breast cancer
Strategies to Improve NST
• Treat to remission prior to transplant
• Use disease specific chemotherapy in
regimen
• Incorporate monoclonal antibodies
• Infuse engineered lymphocytes
• Use Auto followed by Allo strategy
– Allow recovery/healing prior to allo transplant
“Auto/Allo” strategy
for Myeloma
Auto PBSCT
Allogeneic PBSCT
Recovery
60 – 90 days
High dose
Melphalan
Immune suppression
2 Gy TBI
BMT CTN 0102
“Auto/Allo” - Results
•
•
•
•
•
54 patients (median age 52)
Overall 1-year survival 78% at 18 months
Event Free Survival 2-year 55%
Day-200 mortality 7%
GVHD
– Acute 39%
– Chronic 46%
• Response Rate 81% (CR 52%, PR 29%)
Maloney, Blood 98:1822a
Problem: Need for phase III trials!
• Blood and Marrow Transplant Clinical
Trials Network (BMT CTN)
– NCI sponsored cooperative trials group
– Composed of 14 Core Transplant Centers
– Goal to complete high-quality clinical trials in
BMT
BMT CTN Protocol 0102
Myeloma
Melphalan
PBSCT
HLA Match
No HLA Match
Non-ablative
Allogeneic Transplant
(2 Gy, MMF/CSA)
Mel 200
AutologousTransplant
Observation
Thalidomide 200
Dexamethasone 40 x 4
monthly one year
BMT CTN Protocol 0202
Follicular Lymphoma
Cyclophosphamide
Rituximab
HLA Matched Sib
No Donor
Rituximab
Fludarabine
Cyclophosphamide
Non-ablative Allo Transplant
Cyclophosphamide
BCNU
Etoposide
Autologous Transplant
Withdraw
Immunesuppression
Mainenance
Rituximab
Conclusions
• Allogeneic transplantation works due to a
“Graft vs. Malignancy” immune response.
• NST approaches have improved the safety
of transplantation.
• NST allows transplantation of patients not
eligible for standard approaches.
• Phase III studies are need to determine
place in therapy.