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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

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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

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?

  • 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.


Recipient APC

Recipient

Donor T cells

Donor

Pathogenesis of GVHD

Present self Ags to Donor

React to Recipient Ags


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


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?

  • Aggressive Prophylaxis

  • LESS GVHD

  • MORE infection

  • MORE relapse

  • Minimal Prophylaxis

  • MORE GVHD

  • LESS infection

  • LESS relapse

SURVIVAL


Non-selective T cell depletion

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

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 TransplantionSeattle Study

“Mini-transplant”

Chimerism Analyses = “DNA fingerprinting”

McSweeney, Blood 97:3390, 2001


MM41

MDS26

CLL19

CML17

AML17

NHL19

HD12

Other5

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

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

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

2Gy TBI

PBSCT

CSA

IgA

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


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

  • 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


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

  • 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


BMT CTN Protocol 0202Follicular Lymphoma


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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