Allogeneic Mini Transplantation

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Allogeneic Mini Transplantation

• Mark B. Juckett M.D.
• June 4, 2004

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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

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100-DAY MORTALITY AFTER HLA-IDENTICAL SIBLING
TRANSPLANTS 1999-2000
100
CR1 CR2 Other
CP AP BP
80
60
MORTALITY,
173
40
464
67
437
212
20
258
359
386
952
433
1,267
90
0
AML
ALL
CML
MDS
AplasticAnemia
ImmuneDeficiency
Numbers on bars numbers of patients evaluable
SUM02_39.ppt
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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.

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Pathogenesis of GVHD
Present self Ags to Donor
React to Recipient Ags
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Why Does allogeneic BMT Work?

• Roundup theory eradicate all hematopoeitic
  tissue

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Why Does allogeneic BMT Work?

• Rescue patient with healthy stem cells

• Graft vs. Host reactions a nuisance

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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

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Intensified Regimen
Randomized trial of 12.0 Gy vs. 15.75 Gy Total
Body Irradiation cyclophosphamide
Clift, Blood, 76, 1867,1990

• Lower risk of relapse

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BUT
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GVHD Prophylaxis - How much?

• Aggressive Prophylaxis
• LESS GVHD
• MORE infection
• MORE relapse

• Minimal Prophylaxis
• MORE GVHD
• LESS infection
• LESS relapse

SURVIVAL
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Non-selective T cell depletion
Champlin, Blood, 95, 3996, 2000
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Twin Best Donor?
Gale, Ann Intern Med 120646, 1994
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Chronic GVHD marks long-term disease control
Overall survival best with mild cGVHD
Horowitz, Blood 75555, 1990
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Donor Lymphocyte Infusion for relapse after
allogeneic BMT
Patient relapsing after allogeneic BMT for
CML received donor lymphocyte infusions
Porter, NEJM 330100, 1994
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DLI for relapse after allogeneic BMT
Porter, BBMT 5253, 1999
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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

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New Paradigm

• Hematopoeitic stem cell transplantation succeeds
  when a chronic alloimmune 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.

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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

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Spectrum of Preparative Regimens
Cy/12Gy TBI
Bu/F/ATG
2Gy TBI/Flu
Bu/Cy
Immunosuppresion
MF
FC
Human LD50 4Gy
2Gy TBI
Flag
Myeloablative dose 8Gy
Myelosuppression
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Non-myeloablative TransplantionSeattle Study
Mini-transplant
Chimerism Analyses DNA fingerprinting
McSweeney, Blood 973390, 2001
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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 973390, 2001
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Neutrophil/Platelet changes after transplant
McSweeney, Blood 973390, 2001
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Graft vs. Host Disease

• Lower risk of severe aGVHD
• Delayed onset

• Similar risk of cGVHD

McSweeney, Blood 973390, 2001
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Survival after Non-myeloablative Stem cell
Transplant
McSweeney, Blood 973390
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Grade 3-5 toxicity by day 100
Diaconescu, Blood, 102261a, 2003
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Non-myeloablative transplant for Chronic Myeloid
Leukemia
N 24
Disease Free Survival
Chronic GVHD
Or, Blood 101441, 2003
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Non-myeloablative transplant for Myelodysplastic
Syndrome
N 16
Overall and EFS
Chronic GVHD
Taussig, JCO 213060, 2003
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Non-myeloablative transplant for Renal Cell Cancer
N 19
Time to response
Overall Survival
Childs, NEJM 343750, 2000
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Problem Early Disease Control Patient GN - IgA
myeloma
2Gy TBI PBSCT
CSA
IgA
DLI
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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

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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

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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

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Auto/Allo strategyfor Myeloma
60 90 days
BMT CTN 0102
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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 981822a
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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

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BMT CTN Protocol 0102Myeloma
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BMT CTN Protocol 0202Follicular Lymphoma
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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.