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.