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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
SUM02_39.ppt
MO
RT
AL
ITY
, %
100
0
20
40
60
80
464
3591,267
90
67
952
AML ALL CML MDS AplasticAnemia
ImmuneDeficiency
Numbers on bars = numbers of patients evaluable
CR1CR2+Other
386
173
212433
437258
CPAPBP
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
Recipient DonorDonor T cells
Recipient APC
Present self Ags to Donor
React to Recipient
Ags
Why Does allogeneic BMT Work?
• “Roundup” theory – eradicate all hematopoeitic tissue
• Rescue patient with healthy stem cells
•Graft vs. Host reactions a nuisance
Why Does allogeneic BMT Work?
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
Clift, Blood, 76, 1867,1990
Intensified Regimen
Randomized trial of 12.0 Gy vs. 15.75 GyTotal Body Irradiation & cyclophosphamide
•Lower risk of relapse…
12.0 Gy vs. 15.75 Gy
…BUT
•Higher rate of aGVHD
12.0 Gy vs. 15.75 Gy
•Higher non-relapse mortality
12.0 Gy vs. 15.75 Gy
GVHD Prophylaxis - How much?
Aggressive Prophylaxis•LESS GVHD
•MORE infection•MORE relapse
Minimal Prophylaxis•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
Gale, Ann Intern Med 120:646, 1994
Twin – Best Donor?
Chronic GVHD marks long-term disease control
Overall survival best with mild cGVHD
Horowitz, Blood 75:555, 1990
Porter, NEJM 330:100, 1994
Donor Lymphocyte Infusion for relapse after allogeneic BMT
Patient relapsing afterallogeneic BMT for CMLreceived donor lymphocyteinfusions
Porter, BBMT 5:253, 1999
DLI for relapse after allogeneic BMT
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
Imm
unos
uppr
esio
n
Myelosuppression
2Gy TBI
FC
Flag
2Gy TBI/Flu
Cy/12Gy TBI
MF
Bu/CyBu/F/ATG
Human LD50 = 4GyMyeloablative dose = 8Gy
Non-myeloablative TransplantionSeattle Study
McSweeney, Blood 97:3390, 2001
Chimerism Analyses = “DNA fingerprinting”
“Mini-transplant”
Patients – Seattle Study
• MM 41
• MDS 26
• CLL 19
• CML 17
• AML 17
• NHL 19
• HD 12
• Other 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
McSweeney, Blood 97:3390, 2001
•Lower risk of severe aGVHD•Delayed onset
•Similar risk of cGVHD
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
Disease Free Survival Chronic GVHD
Or, Blood 101:441, 2003
N = 24
Overall and EFS Chronic GVHD
Non-myeloablative transplant for Myelodysplastic Syndrome
N = 16
Taussig, JCO 21:3060, 2003
Non-myeloablative transplant for Renal Cell Cancer
Childs, NEJM 343:750, 2000
Time to response Overall Survival
N = 19
Problem: Early Disease Control Patient GN - IgA myeloma
2Gy TBIPBSCT
DLI
IgA CSA
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” strategyfor Myeloma
High doseMelphalan
Auto PBSCT
Recovery
2 Gy TBI
Allogeneic PBSCT
Immune suppression
BMT CTN 0102
60 – 90 days
“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 0102Myeloma
N on -a b la tiveA llog en e ic T ra n sp la n t
(2 G y , M M F /C S A )
H L A M a tch
O bse rv a tion T ha lid om ide 200D e xa m eth aso ne 40 x 4
m on th ly o ne ye ar
M e l 200A uto log ou sT ra n sp la n t
N o H L A M a tch
M elph a lanP B S C T
BMT CTN Protocol 0202Follicular Lymphoma
W ith drawIm m un e su pp re ssion
R itux im abF luda rab ine
C yclo ph osp ha m ideN on -ab la tiv e A llo T ran sp la n t
H L A M a tch e d S ib
M a in en an ceR itux im ab
C yclo ph osp ha m ideB C N U
E top os ideA uto log ou s T ra nsp la n t
N o D o n or
C yclo ph osp ha m ideR itux im ab
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.