Accepted Manuscript

Influence of previous inflammatory bowel disease on the outcome of allogeneic

hematopoietic stem cell transplantation: a matched-pair analysis
Florence Rabian, Raphael Porcher, Flore Sicre de Fontbrune, Bruno Lioure, Anne
Laplace, Stephanie Nguyen, Reza Tabrizi, Stephane Vigouroux, Ccile Tomowiak,
Nathalie Maillard, Felipe Suarez, Jeremy Delage, Rgis Peffault de Latour, Grard
Soci
PII:

S1083-8791(16)30114-8

DOI:

10.1016/j.bbmt.2016.05.022

Reference:

YBBMT 54295

To appear in:

Biology of Blood and Marrow Transplantation

Received Date: 24 March 2016

Accepted Date: 8 May 2016

Please cite this article as: Rabian F, Porcher R, de Fontbrune FS, Lioure B, Laplace A, Nguyen S,
Tabrizi R, Vigouroux S, Tomowiak C, Maillard N, Suarez F, Delage J, Peffault de Latour R, Soci
G, on behalf of the SFGM-TC, Influence of previous inflammatory bowel disease on the outcome of
allogeneic hematopoietic stem cell transplantation: a matched-pair analysis, Biology of Blood and
Marrow Transplantation (2016), doi: 10.1016/j.bbmt.2016.05.022.
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ACCEPTED MANUSCRIPT

Influence of previous inflammatory bowel disease on the outcome of

allogeneic hematopoietic stem cell transplantation: a matched-pair analysis
Florence Rabian1, Raphael Porcher2, Flore Sicre de Fontbrune1, Bruno Lioure3, Anne Laplace3,
Stephanie Nguyen4, Reza Tabrizi5, Stephane Vigouroux5, Ccile Tomowiak6, Nathalie
Maillard6, Felipe Suarez7,8, Jeremy Delage9, Rgis Peffault de Latour1, and Grard Soci1, 10, 11
on behalf of the SFGM-TC

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1; APHP, Hematology Transplantation, St Louis Hospital, Paris, France

2; APHP, Center for Clinical Epidemiology, Htel-Dieu Hospital, Paris, France
3; CHRU de Strasbourg, Hematology, Hopital de Hautepierre, Strasbourg, France
4; APHP, Hematology, Piti Salptrire Hospital, Paris, France
5; CHU Bordeaux, Hematology, Hopital Haut-Leveque, Pessac, France
6; Poitiers University Hospital, Department of Oncology Haematology and Cell Therapy,
Poitiers, France
7; APHP, Hematology Adult Unit, Necker Hospital, Paris, France
8; Paris Descartes University, France
9; CHU Montpellier, Hematology, St Eloi Hospital, Montpelier, France
10; Inserm UMR 1160, France
11; University Paris 7, France

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Reprint request and correspondence;

G Soci, MD,PhD
APHP, Hematology Transplantation, Hospital St Louis
1 Avenue C Vellefaux, 75010, Paris
France
E.mail; gerard.socie@aphp.fr

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Abstract

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Crohns disease (CD) and ulcerative colitis (UC), idiopathic inflammatory bowel diseases
(IBDs) are associated with increased risk of hematological malignancies. Allogeneic
transplantation could be a curative strategy in this setting but has been thought to be
associated with increased non relapse mortality (NRM).
We conduct a national French retrospective analysis of IBD patients transplanted for
hematological malignancies and were matched with 3 controls according to recipient, donor
and transplant characteristics.
Between 2004 and 2015, 18 IBD patients were transplanted. With a median follow-up of 33
months for IBD patients and 57 months for controls, the cumulative incidence of grade 2-4
acute GVHD was 39% for IBD patients and 40% for controls. (HR 1.10, P=0.82). The
cumulative incidence of chronic GVHD at 48 months was 52% for IBD patients and 43% for
controls (HR 0.92, P=0.89). Non-relapse mortality at 48 months was 19% for IBD patients and
11% for controls (HR 4.93, P=0.067). Overall survival at 48 months was 59% for IBD patients
and 60% for matched controls (HR 1.35, P=0.56). In conclusion IBD should not be considered
as contraindication for transplantation and its impact on comorbidity indexes should be
reduced.
Introduction

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Crohns disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBDs) with
an incidence and prevalence rate of 8 14 per 100,000 persons and 120 200 per 100,000
persons, respectively for CD in western countries (similar to what are incidence and
prevalence for UC; 6 15 per 100,000 and 50 200 per 100,000 persons)1. CD is characterized
by ulcerative bowel lesions that can occur in the entire gut tract with interspace of normal
mucosa between the ulcerations whereas in UC, ulcerations are continuous and can only
affect the colon. Dysregulation of the immune response favored by genetic predispositions
and environmental factors are implicated in IBD pathogenesis. IBD therapies as, non-steroid
anti-inflammatory drugs, glucocorticoids, anti-tumor necrosis factor (TNF) or azathioprine
aim to decrease inflammation flares and disease evolution by modulating the immune
system but are not curative. In severe cases autologous stem cell transplantation has been
advocated2.

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Inflammatory bowel diseases have been shown to be associated with an increased risk of
intestinal cancers and hematologic malignancies 3 . These later malignancies including
lymphoma or leukemia can be triggered by chronic inflammation or be induced by IBD
treatment. These secondary hematological malignancies are associated with a dismal
prognosis, and allogeneic hematopoietic stem cell transplantation (HSCT) is often considered
as a therapeutic option.
However IBDs are thought to increase the risk and the severity of graft versus host disease
(GVHD) after allogeneic HSCT, resulting in increased non-relapse mortality (NRM). Thus IBDs
before allogeneic HSCT have been considered to increase comorbidity risk scores such as the
HSCT comorbidity index described by Sorror and coworkers4. To assess the outcome of
patients with IBDs after allogeneic HSCT, we design a nation-wide French retrospective casecontrolled analysis. The aims were to compare the incidence of GVHD, NRM and the overall
survival in the two groups of patients.

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Materials and Methods

Study Population

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All French transplant centers were asked though the SFGM-TC (Socit Francophone de
Greffe de Moelle et de Thrapie Cellulaire) for patients 18 years old with previous IBD (CD
or UC) who underwent an allogeneic HSCT between January 2004 and December 2015 for an
hematological malignancy. Patients clinical and biological data were abstracted from the
prospective ProMISE database and additional data were collected through a special
questionnaire. Every IBD patient was paired with 3 controls matched for the following
factors: center, gender, age at transplant, disease, intensity of conditioning, HLA disparity
between donor and recipient, donor type (related or unrelated), stem cells source, and
period of transplant. The incidence of GVHD and non-relapse mortality and overall survival
were compared between the two groups.

Acute GVHD was diagnosed and scored according to the IBMTR and Glucksberg criteria.
Patients who developed acute GVHD where treated by methylprednisolone (1-2mg/kg/day).
Chronic GVHD was staged according to the NIH criteria. Non-relapse mortality (NRM) was
dened as any death during continuous complete remission.

Statistical Analysis

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All time-to-event outcomes were counted from the date of transplant to the date of event or
date of last follow-up except acute GVHD that was arbitrarily censored at 100 days. Nonrelapse mortality (NRM) was considered as death by any cause occurring before disease
relapse/progression. Death was considered as a competing event for GVHD and NRM and
relapse/progression were considered to be mutually competing risks. Overall survival curves
were estimated using Kaplan-Meier product-limit estimator. For competing risks analyses,
cumulative incidence functions were estimated using usual methodology. Group comparison
relied on stratified Cox proportional hazard models for overall survival and stratified causespecific proportional hazards models for NRM and chronic GVHD. For acute GVHD, a
stratified proportional subdistribution hazard was used5. All tests were stratified on the
matched set (1 IBD patient matched with 1 to 3 controls). P-values <0.05 was considered as
statistically significant. All statistical analyses were performed using the R statistical software
(The R Foundation for Statistical Computing, Vienna, Austria).

Results

Patient characteristics

Between 2004 and 2015, 18 patients with IBD (13 CD and 5 UC) underwent an allogeneic
HSCT for a hematologic malignancy (Table 1). There were 6 females and 12 males with a

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median age of 49 years (38-55) at the time of transplantation. 8 IBDs patients (44%) were
transplanted between 2006 and 2010 and 10 (56%) patients matched were transplanted
between 2011 and 2015. The most frequent malignancies in the IBD group was acute
leukemia (n= 9 patients (50%), and myelodysplastic/myeloproliferative neoplasm (n= 7). The
donor was an identical sibling for 10 IBD patients (56%), a matched unrelated donor for 6
patients (33%). Eleven patients received a reduced intensity and 7 a myeloablative
conditioning. There was no difference in antimicrobial prophylaxis, GVHD prophylaxis and
supportive measures between the 2 groups. There was no statistical difference between
IBDs and control patients at baseline (Table 1).

Treatment outcome

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Discussion

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Median follow-up was 33 months for IBD patients and 57 months for controls. Acute GVHD
grade 2-4 occurred for 7 IBD patients (6 skin, 3 gut, 2 liver grade 2-4 aGVHD) and 20 controls
(15 skin, 2 gut, 0 liver grade 2-4 aGVHD). The cumulative incidence of acute GVHD 2-4 at 48
months was 39% (95% CI 17 to 61) for IBD patients and 40% (26 to 53) for controls (subdistribution hazard ratio (HR) for IBD vs controls 1.10, 95% CI 0.50 to 2.40, P=0.82; Figure
1a). Chronic GVHD occurred for 8 IBD patients and 19 controls. The cumulative incidence of
chronic GVHD at 48 months was 52% (95% CI 23 to 75) for IBD patients and 43% (28 to 58)
for controls (HR 0.92, 95% CI 0.31 to 2.79, P=0.89, Figure 1b). IBD comorbidity therefore
doesnt increase the risk of acute GVHD or chronic GVHD after allogeneic transplantation.
Non-relapse death occurred in 4 IBD patients and 5 patients relapse, while 5 controls died
without and 17 of relapse. Overall, there were 7 deaths in IBD patients and 19 deaths in the
control group. Non-relapse mortality at 48 months was 19% (4 to 42) for IBD patients and
11% (4 to 23) for controls (HR 4.93, 95% CI 0.90 to 27.1, P=0.067) (Figure 1c), and the
cumulative incidence of relapse was 33% (10 to 59) and 43% (26 to 58), in both groups,
respectively (HR 1.08, 95% CI 0.37 to 3.16, P=0.89). Overall survival at 48 months was 59%
(45 to 77) for IBD patients and 60% (39 to 93%) for matched controls (HR 1.35, 95% CI 0.49
to 3.69, P=0.56).

The number of allogeneic HSCT have increased during the last decades with the use of
reduced intensity conditioning (RIC), use of different stem cell sources and donor origin.
Furthermore the upper limit for recipient age has steadily increased with HSCT now being
proposed to patients more than 70 years of age. However, NRM mainly associated with
GVHD remains a major limitation for HSCT. The use of indexes and scores that may predict
NRM has thus came into clinical practice as an aid to treatment decision for physicians and
for patients counseling.
While previously not considered in the HCTCI scoring system, previous IBD has been
introduced into Sorrors severity index based on limited literature reports. Sorror and
colleagues isolated IBD as strongly associated with grade 3 to 4 GVHD (HR=1,606) in a new
Cox regression risk model for time-to-event grades 3 to 4 GVHD among 9 comorbidities6.

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Mechanisms that could lead to increased GVHD risk in patients with IBD are not well
understood. NOD2/CARD15 single nucleotide polymorphism (SNPs) that is associated with
NfkB response to bacterial cell wall products have been associated with an increased
susceptibility to develop Crohn disease and been associated in some studies (but not all)
with GVHD and NRM7. Nalle and Turner8 recently reviewed data on intestinal barrier loss as
a critical pathogenic link between IBD and GVHD. Intestinal barrier dysfunction contributes
to IBD and GVHD pathogenesis by allowing microbes or their products to cross the barrier
leading to pattern recognition receptors (PPRs) engagement. They emphasize that IBD and
GVHD share genetic association at microbial sensing loci as NOD-2, TLR-4, TLR-5 and TLR-9
polymorphisms that have all been linked to GVHD, CD and some of UC.

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However, to the best of our knowledge, no formal analysis of GVHD risk and NRM in patients
with IBD, as compared to matched control, has ever been performed. Contrary to our
expectation to quantify an increase of severe GVHD and subsequent NRM this study failed to
show any significant difference between IBD patients as compared with controls. Although
limited by numbers of patients with this are condition, our results do suggest that HSCT
should not be contraindicated if IBD alone is considered as comorbidity. Furthermore it
should be reminded that that the overall prognosis of these patients with secondary
MDS/AML remains dismal in the absence of allogeneic HSCT that could eventually also cure
IBD 9,10.

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Autologous hematopoietic stem cell transplantation is currently proposed in patients with

severe inflammatory bowel disease resistant to other treatments with the aim to reset
immune system and to generate new self-tolerant lymphocytes. In a phase 1 study11 in 12
patients with refractory CD, 11 had sustained remission after a median follow up of 18.5
months. In another study involving 24 patients 12 who underwent autologous nonmyeloablative hematopoietic HSCT for anti-TNF refractory CD the relapse free survival was
91% at 1 year, but only 19% at 5 years.

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Allogeneic has also been proposed in treatment-refractory CD in a limited number of

patients13 14 with promising results (10 of 11 patients transplanted free of disease with a
median follow up of 34 months) with no severe GVHD. In our study, only 2 of the 18 patients
of the IBD group relapsed of their IBD but NRM remains significant (20%) although in the
setting of hematological malignancy.

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All tests were stratified on the matched set (1 IBD patient matched with 1 to 3 controls).
Table 1. Characteristics of patients at baseline
Variable

IBD
N=18

Control
N=50

Gender - no. (%)

.89
6 (33)

18 (36)

Male

12 (67)

32 (64)

49 (38 to 55)

49 (37 to 54)

Age at transplant (years) - median (IQR)

Disease - no. (%)

.62

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Female

>.99

AL

9 (50)

30 (60)

MDS/MPN

7 (39)

14 (28)

NHL

1 (6)

3 (6)

MM

1 (6)

2006-2010

8 (44)

2011-2015

10 (56)

Identical sibling
Matched unrelated
Mismatched relative
Mismatched unrelated
Stem cell source - no. (%)
PB
CB
Conditioning - no. (%)
RIC
MAC
TBI > 2 Gy - no. (%)

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.88

24 (48)

26 (52)

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Donor - no. (%)

3 (6)

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Period - no. (%)

**

10 (56)

30 (60)

6 (33)

14 (28)

1 (6)

3 (6)

1 (6)

3 (6)

15 (83)

42 (84)

2 (11)

5 (10)

1 (6)

3 (6)

11 (61)

31 (62)

7 (39)

19 (38)

3 (17)

11 (22)

.44

>.99

**

9 (50)

21 (42)

.45

5.5 (2.7 to 8.2)

5.1 (4.0 to 8.0)

.85

43 (33 to 49)

41 (28 to 53)

Female/Female

2 (11)

9 (18)

Female/Male

4 (22)

12 (24)

Male/Female

4 (22)

9 (18)

Male/Male

8 (44)

20 (40)

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ATG - no. (%)

CD34 cells in graft (x 106/kg) - median (IQR)

No. missing

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Donor age (years) - median (IQR)

Donor/recipient gender - no. (%)

.48
.92

Donor/recipient CMV status - no. (%)

.42

Negative/Negative

9 (50)

17 (35)

Negative/Positive

3 (17)

7 (14)

Positive/Negative

3 (17)

9 (18)

Positive/Positive

3 (17)

16 (33)

No. missing
0
1
* Each case was matched to 3 controls, except 2 cases for whom only 1 match was found. Percentages may
thus appear different even in case of perfect matching. ** Exact matching

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Figure 1a. Cumulative incidence of acute GVHD grade 2-4

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Figure 1b. Cumulative incidence of chronic GVHD

Figure 1c. Non-relapse mortality

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- The outcome of the IBD cohort was not significantly different to matched controls with
respect to NRM and OS at 48 months as well as cumulative incidence of acute and
chronic GvHD.
- Non-relapse mortality at 48 months was 19% for IBD patients and 11% for controls
(HR 4.93, P=0.067).
- Overall survival at 48 months was 59% for IBD patients and 60% for matched controls
(HR 1.35, P=0.56).
- IBD should not be considered as contraindication for transplantation.