Graft vs Host Disease

• Remains the major cause of treatment related morbidity and mortality in allogeneic HCT.

• Caused by donor derived alloreactive T cells.• B cells may also play a critical role in GVHD

pathophysiology.• Chronic GVHD linked most closely with the

beneficial GVT response.

Approaches to the Prevention of GVHD

• Pharmacologic– CNI/MTX– CNI/MTX vs Rapa/CNI – RAPA/MMF– Post transplant cyclophosphamide

• Graft source– BM, PBPC, UCB

• T Cell depletion– CD34 Selection– ATG, Campath

• Immune regulatory mechanisms– Treg – NK-T – MSCs

BMT CTN 0402:Phase 3 Randomized Multicenter Trial comparing Sirolimus/tacrolimus vs

Tacrolimus/MTX for Acute GVHD Prophylaxis

• Primary Objective• Compare rates of acute grade 2-4 GVHD survival after HLA-

matched sibling allogneic HCT

• Secondary Objectives• 1 year relapse-free and overall survival• Incidence of grade 3-4 acute GVHD• Incidence of chronic GVHD• Neutrophil and platelet engraftment• Infection incidence• VOD incidence

BMT CTN 0402:Tac/Sir vs Tac/MTX for aGVHD Prophylaxis

Accrual completed Oct, 2011

• Age 2 – 60 yo• Diagnoses:

• Low risk: AML,ALL CML, MDS• HLA matched sibling

RANDOMIZE

Tacrolimus/Sirolimus

n= 156

Tacrolimus/ MTX

n= 156

Prep regimens allowed:- TBI/VP16 or TBI/Cy

HCT

Acute GVHD

Chronic GVHD

Randomized Trial Incorporating F-ATG in URD Allogeneic Transplants

Finke et al. Lancet Oncology 10:855, 2009

Cumulative incidence of extensive chronic GVHD by treatment groups overall and by prognostic subgroups.

Socié G et al. Blood 2011;117:6375-6382

©2011 by American Society of Hematology

TLI/ATG Reduced Intensity Conditioning

• Animal studies have demonstrated that novel conditioning with TLI/ATS results in protection from GVHD

• Pillai et al. J Immunol 178:6241, 2007 • Pillai et al. Blood 113:4458, 2009

• Translation to the clinic demonstrating low acute GVHD incidence and severity and low TRM

• Lowsky et al. N. Engl. J Med 353:1321, 2005• Kohrt et al. Blood 114:1099, 2009

Host NK T cells

Host T cell

TLI +

ATG

CD1d

InvariantTCR

APC

IL-4

Naïve donor CD4 and CD8 T cells

CD4+CD25+ donor Treg

Polarized donor Th2 cell

IL-4

GVHD

Donor HSC

HOST CELLS DONOR GRAFT

+

+

TLI and ATG Conditioning

ATG 1.5 mg/kg/day

Day 0

Day 180

Days -11 to -7

CSA

MMF

TLI 800 cGy over 10 fractionsDays -4 to -1Days -11 to -7

Infection ProphylaxisHSV: if +ve acyclovir 400 mg BIDCMV: blood PCR weeklyEBV: blood PCR every 2 weeksPCP: Septra DS BID weekends D+42Fungus: if prior infection or URD

Related Donors Unrelated Donors

1.5%

11%

Kohrt et al. Blood 2009

Incidence of Acute GVHD (II-IV)

CD4+CD25+ Regulatory T Cells• Major population of cells which regulate immune

reactions

• Express transcription factor FoxP3

• Deficiency or mutation of FoxP3 has autoimmune consequences in animal models and humans

• Cell contact-dependent suppression of alloreactive responses in mixed lymphocyte reactions (MLR)

• Prevent organ specific autoimmune diseases in animal models (e.g. IBD, diabetes)

Selection of CD4+CD25+ Regulatory T Cells (U. Perugia)

Cells (x109) 1060 (540-1370) 280 (202- 390)

%CD4CD25 3.0 (1.5-7.45) 92.4 (90-97.1)N° cells (x 106) 330 (221-1020) 256 (185.6-365.4)

%CD4CD25high 0.3 (0.12- 0.89) 33.6 (14.4-39.6)N° cells (x 106) 36.12 (19.98 - 84) 68.6 (20.9-143)

Starting fraction Final fraction

CD

25

CD127

CD4

FoxP3

Gate on CD4CD25+high

Gate on CD4CD25+

Fox P3+ cells 71.9 ± 15 %

ImmunomagneticSelection of

CD4+CD25+Cells

1st step:Depletion of CD8+/CD19+cells

2ndstep:Enrichment of CD25+ cells

TBI CD34+

Fludarabine

T regs

Tcons

days

Treg Haploidentical Protocol – Unversity of Perugia

CytoxanTT

8 Gy TBI in a single fraction at 16 cGy/m Thiotepa 4 mg/kg/dayCytoxan 35 mg/kg/dayFludarabine 40 mg/sqm/day

D’Ianni et al. Blood 2011

Evaluable Patients

Patients with CMV reactivation

0-30 31-60 61-90 91-120 121-150 151-180 181-365 >3650

10

20

30

40

50

60

70

80

90

100100

96

8275

67

5648

2928

50

34

22

9 91 1

0-30 31-60 61-90 91-120 121-150 151-180 181-365 >3650

5

10

15

20

25

30 27

21

16

109

5

212

5

1 0 0 0 0 0

Days after transplant

Days after transplant

CMV reactivation episodes

Tregs Group

Control Group

p<0.05

Outcomes – U. of Perugia

Event-Free Survival 12/26 (46%)

• Regimen Related Toxicities:– Veno-occlusive disease (3)– Multi-organ failure (1)

• Acute GVHD grade III-IV (2)• Serious infections (7)

• Relapse (AML 1)

Median follow-up 18.5 months (range 16.1-27.6)

D’Ianni et al. Blood 2011

Ex Vivo Expanded UCB Treg

Brunstein C G et al. Blood 2011;117:1061-1070

Treatment plans

Brunstein C G et al. Blood 2011;118:282-288

Risk of GVHD following Double UCB and Haploidentical BMT with post-transplant Cy

Brunstein C G et al. Blood 2011;118:282-288

Treatment for Acute GVHD

• Corticosteroids the mainstay of therapy• Many phase II studies showing a variety of

agents may have biological impact• Day 28 response most predictive of long term

outcome

Etanercept (N=46)

MMF (N=45)

Denil(N=47)

Pentostatin (N=42)

Complete Response

44% 73% 55% 62%

Complete Response(Excl. prior MMF)

53% 73% 61% 64%

Treatment Failure *

24% 9% 26% 29%

BMT CTN Phase II Pick the Winner Strategy

* Treatment Failure = no response, progression, or addition of another immunosuppressive agents by day 56.

Alousi et al, Blood, 2009

Where now for treatment of Acute GVHD?

• Phase III MMF vs Placebo CTN study halted for futility

• New phase II trial with other agents?– ATG, Campath– ECP– MSCs– Rapamycin– Cytokines

Chronic GVHD

• Major source of morbidity and some mortality • Immunosuppression with PSA and CNI remains the

mainstay of treatment• Alternative approaches

– Rapamycin– ECP– Rituximab– TKIs– MSCs– Cytokines

Ratio of Treg:Tcon post IL-2

Koreth et al. NEJM, 2011

Long term administration of IL-2 for cGVHD

Koreth et al. NEJM 2011

Future Risk Adapted Strategies

• Genetics of donor – recipient pairs• Treatment of the donor

– Statins• Earlier detection

– Biomarkers– Imaging