Steroid Refractory Acute GVHD

Mark A. Schroeder, MD

Hematology/Oncology Grand Rounds

2/16/2007

Outline and Objectives

• Case Presentation

• Epidemiology of GVHD

• Staging and grading GVHD

• Pathophysiology

• Primary treatment

• Secondary treatment

• Novel treatments and future directions

The Case of KH64 yo WM

MDS with nl cytogentics dx 4/04 progressing to AML status post MUD.

Day 45 with 100% engraftment and acute abdominal pain, nausea, bilious emesis and voluminous watery diarrhea.

No rash, no melana/BRBPR, +30 pound wt loss since initiating treatment. No fevers, sweats, chills.

Recently completed course of Flagyl for C-diff colitis on October 25 and has had history of recurrent C.dif.

PMHMDS nl cytogenetics (IPSS 1) progressing to AML

dx 4/04 with fatigue and shortness of breath and found to be anemic. BMBx showed 6% blasts and 85 to 90% cellularity c/w MDS, INT-1. Azacytidine x 18 months with CR until 3/06. BMBx with 16% blasts. SAHA (HDAC) study 6/06 but progression (circulating blasts = 87%). 6/06 standard induction with 7+3 c/b neutropenic fever and C-diff. Persistent disease on BMBx and 10% cellularity. Delayed count recovery and f/u BMBx on Day +48 showed persistent AML, 83% blasts. He was treated with five days of Decitabine at 20 mg/m2. He was readmitted 9/06 for MUD 10/10 HLA matched PBSC transplant. Conditioned with Busulfan + Cyclophosphamide transplanted on September 23 with MTX+Tacro + MMF GVHD prophylaxis. His hospital course at that time was complicated by acute renal failure and recurrent C-diff colitis. Post transplant BMBx at count recovery was normal cellular without AML and VNTR was 100% donor

HTN

The Case of KHMEDS:1. Tacrolimus 0.5 mg PO Q day.2. Valtrex 500 mg PO Q day.3. Voriconazole 200 mg PO Q day.4. Recent course of Flagyl completed on October 25.5. Prednisone 5 mg PO Q day for appetite.ALLERGIES:No known drug allergies.FAMILY HISTORY: sister with CMLSOCIAL HISTORY: no bad habitsPHYSICAL EXAMINATION:Afebrile, Normotensivemild distress from pain.anicteric sclera. Oropharynx was clear.NECK: No lymphadenopathy. Normal thyroid.LUNGS: CTACARDIOVASCULAR: RRR no murmurABDOMEN: soft, diffusely tender; no guarding or rebound; no HSM. Decreased

bowel soundsEXTREMITIES: no C/C/ESKIN: no rash

The Case of KH

CT Abd/Pelvis:moderate bowel wall thickening involving the entire small bowel with marked

enhancement of the mucosa highly suspicious for graft versus host disease. Mild mucosal enhancement of the colon is also noted. NL liver, spleen, bilateral kidneys, pancreas and gallbladder. No LAD.

129 58

1.519 Gap 18236

WBC 6.7H/H 15/45Plts 230LDH 136alkaline phos 136AST 17ALT 24,bilirubin 1.3albumin 2.7total protein 6.2

Surgical Pathology:LARGE INTESTINE: ACUTE GRAFT-VERSUS-HOST DISEASE, GRADE 3 SMALL INTESTINE: ACUTE GRAFT-VERSUS-HOST DISEASE, GRADE 4. Negative staining for CMV

Epidemiology of GVHD

• Major cause of morbidity and mortality in the HSCT setting

• IBMTR retrospective review– 2416 patients from 1995-2002 receiving

CSA+MTX with (15%) or without (85%) other prophylactic agents

– 31% developed grade II-IV GVHD

• 50-75% of patients will have a clinical response to steroids (most are grade II)

• Steroid refractory aGVHD carries a high morbidity and mortality (>50%)

Couriel, D, Caldera, H, Champlin, R, Komanduri, K. Acute graft-versus-host disease: pathophysiology, clini cal manifestations, and management. Cancer 2004; 101:193 6.

Predictors of acute GVHD• HLA disparities• Increasing age (>40)• Gender mismatch / parity of donor• Minor histocompatibility antigens• CD34 dose• Intensity of preparative regimen and XRT• GVHD prophylaxis (dose and type)• T-cell depletion in graft• Advanced disease status• SibAllo<<UCT<MUD• Eosinophilia is protective

Couriel et al. Cancer. 2004. 101(9):1936-1946ASBMT 2007 Abstract #25 Blood Eosinophilia as a Marker of Favorable Outcome after Allogeneic Stem Cell TransplantationAisa, Y., Mori, T., Nakazato, T., Shimizu, T., Yamazaki, R., Ikeda, Y., Okamoto, S.. Keio University Hospital, Tokyo, Japan

A balance of GVHand GVL

Gratwohl, A. et al. Blood 2002;100:3877-3886

• 4174 HLA-identical sibling transplants for chronic myelogenous leukemia in first chronic phase

• TRM increased with increasing grades of aGVHD

• Increasing degrees of aGVHD reduced the risk of relapse

OS

TRM

Relapse Incidence

Pathophysiology• Donor T-cells recognizing host major and

minor histocompatability complexes are the major mediators of GVHD

• Triad of etiologic factors– Inflammatory milieu (IL-1, TNF, INF) /

Conditioning– Activation phase (APCs and cytokines trigger

expansion of donor T-cells to effector cells)• Minor histocompatibility antigens• IL-2, IFN = Th1 phenotype potentiates acute GVHD

– Effector phase• Fas-Fas ligand interactions, perforin-granzyme B, and

cytokine production (TNF)Couriel et al. Cancer. 2004. 101(9):1936-1946Antin, JH, Ferrara, JL. Cytokine dysregulation and acute graft-versus-host disease. Blood 1992; 80:2964.Ferrara, JL, Deeg, HJ. Graft-versus-host disease. N Engl J Med 1991; 324:667.

Phase I (Initiation) Phase II (Activation) Phase III (Effector)

Conditioning

Tissue DamageGI

Skin

Endotoxin (LPS) andcytokine release (TNFa, IL-1, IL-6)

M0 and Monocytes

DonorTcell

HostAPC

IL-2IFNg

CTL

NK

Treg

Cell Death

IL-12

DonorAPC

MLR

MiHC

Other T-cell subsets mediating GVHD

• CD4+ T cells are crucial for sustaining the secondary expansion of CD8+ T cells

• CD4+/CD25+/FoxP3+ regulatory T-cells suppress allo reactivity in murine and human allogeneic transplantation– Contact-dependent– IL-10, TGF-

Clinical Manifestations• Skin

– Most often involved– Maculopapular rash

• Palms and soles initially

• Liver– Hyperbili and increased alk phos

• GI– Manifests as diarrhea– Upper GI symptoms - nausea, anorexia– Severe cases - ileus, cramping pain, bleeding

• Upper GI tract / oral mucosa• Renal (rarely)• Eye

Skin Biopsy in Acute GVHD

UpToDate.comCancer. 2004;101:1936

Rectal biopsy

Stage and Grading of GVHD

Przepiorka, D, Weisdorf, D, Martin, P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15:8 25.

Treatment

• Once established acute GVHD is difficult to treat

• The best primary treatments have a 50% response

• Once steroid refractory the chance of survival is slim and chronic GVHD is the rule

An Ounce of Prevention

• Most common regimen of MTX + CSA, reduced incidence of GVH from 55% to 30%

• A prospective RCT comparing the addition of steroids to the standard regimen of CSA and MTX did not demonstrate an improvement in the prevention of acute GVHD in patients with more advanced disease

• A large phase III study in patients with matched related allo, MTX+FK506 results in a lower incidence of acute GVHD compared to MTX+CSA (32% vs 44%)

• Current Phase III trial CTN 0402 at Wash U comparing Tacro/MTX vs Sirolimus/tacrolimus in matched related PBSC transplantation

Chao, N et al. BBMT 2000;6:28Ratanatharathom V. et al. Blood. 1998;92:2303Storb R et al. NEJM. 1986;314:729

Primary Treatment• Disrupt the triad• Non-specific Immunosuppressives

– methylpred 2mg/kg/day– Steroid + calcineurin inhibitor (CSA, tacro)

• ~40% of sib transplants and 24% of MUDs will respond to steroids– Response is worse with liver involvement and

with higher grade

• Current phase II (CTN 0302) protocol underway at Wash U– Etanercept vs MMF vs Pentostatin vs Denileukin

diftitox in addition to steroidsAntin J et al. BBMT. 2004;10:655Weisdorf D et al. Blood. 1990;75:1024Roy J et al. BMT. 1992;10:77Martin PJ et al. Blood. 1991;77:1821

Secondary Therapies

• Defined as no response to steroid for 1 wk or progressive disease after 72hrs

• No consensus and uniformly poor outcomes (mostly phase I and II trials)

• ATG– Variations in product and dosing– 19-56% OR (59-79% in skin) without affect on OS

and 90% 1 yr mortality– Wash U experience Khoury et al.

• 58pts failing steroids treated with ATG (dif. dose schedules)

• 90% died at 40 days, mainly from infections– Hopkins experience

• 4/69 patients survived

BMT. 2001;27:1059-1064

Antin J et al. BBMT. 2004;10:655

Target Therapy At Activation Phase

CSA

Tacro

RapamycinCorticosteroid

Uptodate.com

Secondary Therapies: Targeting the IL2-receptor

• Denileukin Diftitox, Inolimomab, Basiliximab, Daclizumab

• Daclizumab – humanized IgG1 anti-CD25, competative inhibition

of IL-2R alpha– 43 patients– CR 47% (majority in GVH isolated to skin)– OS 53% at 4 months (major cause of death GVH

and infection)

• Daclizumab+steroid as primary treatment of GVH lead to decreased OS at day 100 (77% vs 94%) and 1yr OS 29% vs 60%– Mortality related to GVH and recurrence

Przepiorka et al. Blood. 2000;95:83Lee SJ et al. Blood. 2004;104:1559

Secondary Therapy

• Denileukin Diftitox (Ontak)– Recombinant fusion protein with diphteria

toxin fusion selective for IL2-R– N=24, OR 69% with 46% CR– Response greatest in skin and GI– 10 pts previously treated with Daclizumab

and 8 patients had response– Infection was leading cause of mortality– If CR was obtained OS was 58% at 7.2

months, compared with <10% if PR

Ho V et al. Blood. 2004;104:1224

Secondary Therapies

• MMF– Response rates of 29-67%– Better results in skin GVH– OS at 2 yrs 16%

• Pentostatin– Neucleoside analog that inhibits adenosine

deaminase, resulting in diminished T-cell fxn and lymphocyte apoptosis

– OR of 71% (64% CR) – Median survival 91 days– Highest response in skin and gut

Antin J et al. BBMT.2004;10:655

BMT. 2001;27:1059-1064

Secondary Therapy• Infliximab

– Humanized monoclonal Ab binding TNF (membrane bound and soluble)

– RR 65% and OS 31% reported by MDACC– Substantial increased risk of infections (fungal)

• Visiluzumab– Anti-CD3 humanized monoclonal antibody– Induces apoptosis of activated T-cells– Fred Hutch experience

• 6/17 patients achieved CR• Median survival not met at 1yr

Antin J et al. BBMT.2004;10:655Couriel et al. Blood. 2004;104:649Ho et al. Blood. 2004;104:1224

Antin J et al. Blood. 2004.BBMT;10:665

Summary

•Higher grade GVHD does worse•Nearly all survivors of acute GVHD go on to develop cGVHD

Secondary Therapy

• No secondary therapy to date provides an improved OS in steroid refractory aGVHD

• Focus remains on prevention and prediction

Novel Approaches

• Graft Engineering

• ECP

• Target multiple pathways

• MSCs

Phase I (Initiation) Phase II (Activation) Phase III (Effector)

Conditioning

Tissue DamageGI

Skin

Endotoxin (LPS) andcytokine release (TNFa, IL-1, IL-6)

M0 and Monocytes

DonorTcell

HostAPC

IL-2IFNg

CTL

NK

Treg

Cell Death

IL-12

DonorAPC

MLR

MiHC

Graft engineering• T-cells are required to develop GVH but without them

engraftment fails, immune recovery is slow, and GVL is reduced

• T cell depleted grafts– ex vivo depletion using mAbs (CD-2, CD-5/6/7, CD-

4/8, CD25)• Incidence of GVH ranged 5-28%• Graft failure 3-60%

– Cell sort depletion of allo-reactive CD4 cells– Ex vivo expansion of T regs (Rapamycin?)– Deplete naïve T cells (murine model)

• Mesenchymal stromal cell therapy• T-cell deplete graft followed by DLI after non-

myeloablative conditioning• T-cell Suicide gene therapy

ECP

• Photoactivated 8-Methoxsalen damages cell membrane and DNA and is taken up by activated lymphocytes – Expose PBMCs to 8-MOP expose to

UVA and re-infuse• More experience in cGVHD• Single institution study of 21 pts

– 60% CR (100% CR in grade II GVH)– OS 57% at 25 months for responders

Extracorporeal Photopheresis for Acute and Chronic Graft-versus-Host Disease: Does It Work?. Blood. 2006;12(1)Sup2:37 

Update from ASBMT/CIBMTR

• [34] Preserved Anti-Viral Responses and Improved Survival in Steroid Refractory GVHD Using a Combination of Daclizumab and Infliximab. Rao, K. et al. London, United Kingdom– Daclizumab (1mg/kg, days 1,4,8,15,22) + Infliximab

(10mg/kg, days 1,8,15,22), with rapid reduction of steroid dosage to ≤ 1mg/kg

– N=15 children, grade 3 (n=5) or 4 (n=10) GVHD– All had improvement – median follow-up of 30 months and 10/15 (66%)

children are alive

Update from ASBMT/CIBMTR

• EBMT MSC Expansion Consortium– Used MSCs to treat grade III-IV second line

refractory GVHD– N=40, 1-5 doses given– 19 CRs (48%), 7 PRs (18%) – 21 pts alive at 6wks – 3.5 yrs

Update from ASBMT/CIBMTR

• [306] Successful Phase II Trial Using Mesenchymal Stem Cells (MSC) in Combination with Steroid Therapy for the Primary Treatment of Acute Graft-vs-Host Disease (aGVHD). Kebriaei, P.,et al.– N=32, 66% had grade II GVHD– 90% initially responded to aGVHD treatment

• 21 CRs with no evidence of GVHD• 7 PRs with a reduction in 1 organ stage• 100% with skin GVHD responded• 83% with GI or single organ GVHD responded• 9 pts (31%) eventually required a second line

agent to control aGVHD

Update from ASBMT/CIBMTR

• [308] Treatment of Steroid Refractory, Severe Acute Graft Versus Host Disease with Expanded Mesenchymal Stem Cells in Children Having Undergone Allogeneic Stem Cell Transplantation: A Single Center Experience. Ball, L.M. et al. Netherlands

– N=8, 100% had grade 4 GVHD– 5/8 (63%) had CR, 1 PR– OS 4/8 (50%), deaths secondary to

infection

Back to the Case of KH• Started on methylpred 2mg/kg/day• Did not enroll into CTN study• Developed diffuse macular rash (Grade II)• Persistent profuse diarrhea up to 5L/day

(Grade IV)• Persistent crampy abdominal pain with ileus

(Grade IV)• Started on Daclizumab (1mg/kg, days

1,4,8,15,22)• Worsening liver failure and renal failure• Mental status worsened• Died 12/1/06, 25 days into hospitalization,

multisystem organ failure

Conclusions• GVHD is the major barrier to successful

allogeneic stem cell transplantation

• Steroid refractory acute GVHD remains a major cause of early morbidity and mortality in the transplant setting and current approaches do little to affect OS

• Novel approaches to its prevention and treatment are needed

• Graft engineering remains a tantalizing option to prevent acute GVHD