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Autologous Hematopoietic Stem Cell Transplantation
in Patients With Refractory Crohn’s Disease
Divisions of Immunotherapy and Gastroenterology, Department of Medicine,
Department of Surgery, and Department of Pediatrics,
Northwestern University Medical Center, Chicago, IL, USA
Gastroenterology 2005; 128: 552–563
BACKGROUND
Hansoo Kim, M.D.
Introduction
Crohn’s disease (CD)

immunologically mediated inflammatory disease of GI tract

variable course

etiology: unknown


exposure to antigens
excessive Th1-mediated chronic inflammations?
treatment

anti-inflammatory agents, antibiotics

immunosuppressive agents
Hansoo Kim, M.D.
Introduction
Molecular etiology of CD

cellular interaction w/ bacterial pathogens?

dendritic cell


antigen-presenting cell (APC)

toll-like receptor family required for signal transmission
excessive T-cell mediated Th1 inflammation response
chronic inflammation in GI tract?

genetic & pathogenic factors dysregulating immune response
Hansoo Kim, M.D.
Pathogen
Dendritic cell
Pathogen
cytokines
antigen
Th1 cell
Hansoo Kim, M.D.
Introduction
Crohn’s disease (CD)


conflicts in treatment

no cure regimens

high incidence of recurrence and non-responders

high mortality, high morbidity in refractory cases

frequent complications
new treatment approach needed for therapy-refractory cases
Hansoo Kim, M.D.
Introduction
Autologous hematopoietic stem cell transplantation (HSCT)

maximizing immune suppression to point of immune ablation

in theory

conditioning regimen: ablates disease-causing immune cells

HSCT: regenerates new & antigen-naïve immune system
Hansoo Kim, M.D.
PBSCT
subject
Mobilization
• Cyclophosphamide
Conditioning
• GCSF
• Cyclophosphamide
• ATG
Leukapheresis
Stem cells
Hansoo Kim, M.D.
Objectives
Can maximum immune ablation by autologous
hematopoietic stem cell transplantation (HSCT) induce
a remission in patients w/ therapy-refractory CD ?
Hansoo Kim, M.D.
MATERIALS and METHODS
Hansoo Kim, M.D.
Study Design
Study design

pilot study

investigate safety & efficacy of HSCT

primary end point: treatment-related toxicity and engraftment

2ndary end point: HSC mobilization and disease response
Hansoo Kim, M.D.
Patient Selection
Patient selection
treatment failure: CDAI of 250-400 despite treatment


inclusion criteria

clinical, histologic evidence of CD, < 60Y

treatment failure w/ CS, mesalazine, metronidazole, azathioprine, infliximab
exclusion criteria

IHD, CHF, EF < 40 %

FEV1/ FVC < 50 %, diffusing capacity for CO < 50 %

bilirubin > 2.0 mg/dL, creatinine > 2.0 mg/dL, PLT < 105/ μL, ANC < 1500/ μL

active infection, toxic megacolon, intestinal perforation
Hansoo Kim, M.D.
HSC Procurement
HSCT



mobilization:

cyclophosphamide 2 g/ m2

GCSF 10 μg/ kg/ day beginning 72H after completion of cyclophosphamide
leukapheresis:

initiated when WBC > 1000/ μL

continued daily until CD34+ cell 2.0 X 106/ kg achieved
T-cell depletion


enrichment of CD34+ cells using Isolex 300i magnetic immunoselection
HSC graft cryopreserved for reinfusion
Hansoo Kim, M.D.
Conditioning Regimen
Regimen


cyclophosphamide

50 mg/ kg/ day on D -5, -4, -3, -2 (totally 2000 mg/ kg)

mesna co-administered
antithymocyte globulin

30 mg/ kg/ day on D -4, -3, -2 (totally 90 mg/ kg)

MPD 1.0 g/day

GCSF: 5 μg/ kg/ day from D 0 until ANC > 500/ μL

HSC reinfusion IV on D 0
Hansoo Kim, M.D.
Supportive Care
General conditions

HEPA (high efficiency particulate air)-filtered medical floor

medications

ciprofloxacin 500 mg BID, fluconazole 400 mg QD, metronidazole 500 mg TID

valacyclovir 500 mg TID, pentamidine 300 mg

Bactrim® DS 3 tomes weekly from engraftment for 6 M post-HSCT

hemoglobin > 8 g/dl, platelet 2X105/ μL maintained

TPN considered
Hansoo Kim, M.D.
CCSI
Assessment of Outcomes
Assessment

neutrophil engraft: ANC ≥ 500/ μL in 3 consecutive days

platelet engraftment: ≥ 2 X 104/ μL in 3 consecutive days w/ no transfusion

follow-up: post-HSCT 6M, 12M, then yearly

clinical remission: CDAI ≤ 150

evaluation criteria

PE, ROS, infection, CDAI, Craig Crohn’s Severity Index (CCSI)

ESR, CRP, hemoglobin, albumin, BMI

colonoscopy, SI series, EGD
Hansoo Kim, M.D.
RESULTS
Hansoo Kim, M.D.
Patient Demographics
Characteristics

12 white: 6 male & 6 female

median age: 27Y (range 15 – 38Y)

median disease duration: 10Y (range 1.5 - 20Y)

median CDAI: 291 (range 250 - 358)

median CCSI: 27.5 (range 20 - 33)

complications from immunosuppressive therapy: 5

4: anaphylaxis from infliximab

1: pancreatitis from 6-mercaptopurine

1: cytopenia d/t BM suppression
Hansoo Kim, M.D.
Mobilization, Engraftment, and Discharge Day
Outcomes
disease improvement in most patients

no mobilization-related disease flares or infection

median number of leukapheresis : 2 (range 1 - 4)

median CD 34+: preselection 7.69 X 106/kg (range 3.05 – 17.5 X 106/kg)
postselection 5.64 X 106/kg (range 1.73 – 9.93 X 106/kg)

median CD 3+: preselection 1.51 X 108/kg (range 0.6 – 5.33 X 106/kg)
postselection 0.59 X 104/kg (range 0.3 – 3.09 X 106/kg)

median days of neutrophil/ platelet engraftment: 9.5/ 9

median day of discharge: 11 (range 10 - 17)
Hansoo Kim, M.D.
Toxicity & Survival
Complications related with HSCT
Survival

well tolerated
median
follow-up:
without
18.5M
a documented
(range 7 – 37M)
infection

in patient
1
hospitaldied d/t an accidental cause


1: hematemesis d/t Mallory-Weiss syndrome

2: CD-related fever, subsided
after discharge

1: central line-related bacteremia 15M post-HSCT

1: small bowel narrowing d/t scaring 5M post-HSCT

1: viral gastroenteritis 8W post-HSCT
Hansoo Kim, M.D.
Disease Response
CDAI ( Crohn’s Disease Activity Index)


generally:

diarrhea, abdominal pain stopped before discharge

immunosuppressive therapy discontinued, appetite/ oral intake regained

remained in remission (CDAI ≤ 150) during follow-up

gradual improvements in imaging studies
diarrhea in 2 patients

C.difficile colitis 14M post-HSCT: treated w/ oral vancomycin

recurrence of active CD 15M post-HSCT d/t smoking?
Hansoo Kim, M.D.
Disease Response
CCSI ( Craig’s Crohn’s Severity Index)


CCSI correlated w/ CDAI

average ESR: 33 mm/h (pre-HSCT), 22.2 mm/h (12 M post-HSCT)

average hemoglobin: 10.9 g/dL (pre-HSCT), 12.1 g/dL (12 M post-HSCT)
CRP

not parallel w/ improvement of CDAI

average CRP: 2.9 mg/L (pre-HSCT), 2.9 mg/L (12 M post-HSCT)
Hansoo Kim, M.D.
CDAI
Recurrence
CCSI
Recurrence
Colonoscopy Findings
Pre-transplant
Hansoo Kim, M.D.
Colonoscopy Findings
Post-transplant
Hansoo Kim, M.D.
Conclusions
• autologous HSCT can be performed safely and has a marked
salutary effect on CD activity
• randomized study and longer follow-up will be needed
to confirm efficacy
Hansoo Kim, M.D.
DISCUSSION
Hansoo Kim, M.D.
Etiology of CD
Molecular views

unknown etiology: no intestinal self-antigen identified

deficiency of multiple Th2 cytokines cause colitis


acute & chronic colitis in IL-10-deficient mice

colitis in IL-2-, IL-4-, TGF-β-deficient mice
disease free in germ-free environment
cytokine imbalance & gut bacterial flora as disease triggers
Hansoo Kim, M.D.
Conundrum
CDAI


drawbacks

favor predominantly colonic disease: less score for UGI, SI diseases

subjective state of patient

equal weight to anal fissure & fistulae

unnecessarily high score for abdominal pain/ anemia

no objective values: endoscopy, ESR, CRP, albumin

no consideration in current therapy
CCSI

new comprehensive grading scale: against CDAI
Hansoo Kim, M.D.
Conundrum
Post-HSCT follow-up

in most patient,

still showed improving histologic/ radiologic evidence of CD

nonsymptomatic, in clinical remission

significance of this finding?

clinical recurrence 15M post-HSCT in 1 patient

clinical, drug-free remission in others
Hansoo Kim, M.D.
HSCT in Refractory CD
HSCT

ultimate effect: immunosuppressive/ cytoreductive of conditioning regimen

autologous HSCT: not alter genetic tendency


reset immune system to predisease status?


higher risk of recurrence / lower morbidity & mortality
treatment-free remission (≥ 3Y) w/ no active therapy
safety

minor regimen-related toxicity

prompt & durable engraftment, easy mobilization
Justified risk-benefit ratio!
Hansoo Kim, M.D.