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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.

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Allogeneic mini transplantation

Allogeneic “Mini” Transplantation

Mark B. Juckett M.D.

June 4, 2004


Problems with bmt
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

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


What is gvhd
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 APC

Recipient

Donor T cells

Donor

Pathogenesis of GVHD

Present self Ags to Donor

React to Recipient Ags


Why does allogeneic bmt work
Why Does allogeneic BMT Work?

  • “Roundup” theory – eradicate all hematopoeitic tissue


Why does allogeneic bmt work1
Why Does allogeneic BMT Work?

  • Rescue patient with healthy stem cells

  • Graft vs. Host reactions a nuisance


Past approaches used to improve outcome
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

12.0 Gy vs. 15.75 Gy

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…


12.0 Gy vs. 15.75 Gy

  • Higher non-relapse mortality

  • Higher rate of aGVHD

12.0 Gy vs. 15.75 Gy

…BUT


Gvhd prophylaxis how much
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
Non-selective T cell depletion

Champlin, Blood, 95, 3996, 2000


Twin best donor
Twin – Best Donor?

Gale, Ann Intern Med 120:646, 1994


Chronic gvhd marks long term disease control
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
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
DLI for relapse after allogeneic BMT

Porter, BBMT 5:253, 1999


Learning points
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
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
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
Spectrum of Preparative Regimens

Cy/12Gy TBI

Bu/F/ATG

2Gy TBI/Flu

Bu/Cy

MF

Immunosuppresion

FC

Human LD50 = 4Gy

2Gy TBI

Flag

Myeloablative dose = 8Gy

Myelosuppression


Non myeloablative transplantion seattle study
Non-myeloablative TransplantionSeattle Study

“Mini-transplant”

Chimerism Analyses = “DNA fingerprinting”

McSweeney, Blood 97:3390, 2001


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

Patients – Seattle Study

McSweeney, Blood 97:3390, 2001


Neutrophil platelet changes after transplant
Neutrophil/Platelet changes after transplant

McSweeney, Blood 97:3390, 2001


Graft vs host disease
Graft vs. Host Disease

  • Lower risk of severe aGVHD

  • Delayed onset

  • Similar risk of cGVHD

McSweeney, Blood 97:3390, 2001



Grade 3 5 toxicity by day 100
Grade 3-5 toxicity by day 100

Diaconescu, Blood, 102:261a, 2003


Non myeloablative transplant for chronic myeloid leukemia
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
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
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
Problem: Early Disease Control Patient GN - IgA myeloma

2Gy TBI

PBSCT

CSA

IgA

DLI


Findings from nst trials
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

Disease Sensitivity to “Graft vs. Malignancy”


Strategies to improve nst
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

Allogeneic PBSCT

Auto PBSCT

Recovery

Immune suppression

2 Gy TBI

High dose

Melphalan

“Auto/Allo” strategyfor Myeloma

60 – 90 days

BMT CTN 0102


Auto allo results
“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
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 0202Follicular Lymphoma


Conclusions
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.


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