Bierings, M.

Boelens, J.J.

Lindemans, C.

Terhegge-Lagro, S.

Versluys, B.

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Standardized Early Initiation of a “High Dose Steroid (HDS)” Treatment Protocol for Allo-Immune Lung Syndromes is Associated With Improved Survival Despite the Presence of High Viral Loads of “Common Cold Viruses” 

Poster Session II S329to support one over the others.We historically usedCSA/MTX (n5
187pts).Over the last 3 yearswe usedCSA/MMF(n592).Medianpt
age was 52 years (18-73). Diagnoses included AML/MDS (n5 152),
ALL (n5 30),CML (n5 12),myeloma (n5 24), lymphoma (n5 40),
others (n5 21).The donorwas 10/10 (n5 191), 9/10 (n554) or# 8/
10 match (n 5 34). Conditioning was myeloablative (n 5 58) or
reduced intensity/toxicity (RIC, n 5 221). Non-relapse mortality
(NRM) is dependant on regimen toxicity and GVHD. CSA/MMF
was less toxic than CSA/MTX. It allowed faster engraftment, day
+11 and +14, respectively (p\ 0.001). Day30 mortality was 2.2%
and 10.7%, respectively (p 5 0.04). Multivariate analysis (MVA)
identified high comorbidity index (HR 2.5, p 5 0.05), advanced
disease (HR 6.2, p 5 0.005), mismatched donor (HR 2.4, p 5 0.03)
and lymphoid malignancies (HR 2.8, p 5 0.03) as adverse factors
for regimen-related mortality. CSA/MMF was protective (HR 0.4,
p50.02).However,CSA/MMFwas less effective inpreventinggrade
III-IV acute GVHD; cumulative incidence 29% and 18%, respec-
tively (p 5 0.005). MVA identified mismatched donor (HR 3.4, p 5
0.001) and CSA/MMF (HR 2.4, p5 0.004) as adverse factors, while
RICwas protective (HR 0.4, p5 0.01). The net effect was that NRM
was equivalent with both regimens. GVHD regimen had major im-
pact on overall survival (OS) when pts were stratified based on disease
status. In early stage disease, OSwas 65% and 42%, after CSA/MTX
and CSA/MMF, respectively (HR 1.9, p5 0.05), predominantly due
to excess GVHDdeaths in theMMF group. In advanced disease, OS
was betterwithCSA/MMF; 20%and 12%, respectively (HR0.5, p5
0.04), predominantly due to less relapses. In conclusion, GVHDpre-
vention regimen has major impact on outcome after MUD SCT.
CSA/MMF is a less toxic regimen and allows prompt engraftment,
but is less effective in preventing GVHD. In early stage disease, out-
come is dominated by NRM and more effective GVHD prevention
regimen such as CSA/MTX is needed. In advanced disease both tox-
icity and relapse increase. A less intensive regimen, that also better
preserves GVL, such as CSA/MMF, may be associated with better
outcome. The GVHD prevention regimen selected may need to be
tailored to pt and disease characteristics.489
RITUXIMAB TREATMENT IN CHRONIC GVHD: CLINICAL EFFICACY ASSO-
CIATES WITH RESTORING A PHYSIOLOGICAL B-CELL BALANCE
van Dorp, S.1, Resemann, H.K.2, te Boome, L.C.J.2, Lokhosrt, H.M.2,
Petersen, E.J.2, Minnema, M.C.2, Ebeling, S.B.1, de Weger, R.A.3, van
Dijk, M.R.3, Meijer, E.2, Kuball, J.H.E.1,2 1UMCU, Utrecht, Utrecht,
Netherlands; 2UMCU, Utrecht, Utrecht, Netherlands; 3UMCU,
Utrecht, Utrecht, Netherlands
Introduction:Chronic graft-versus-host disease (cGVHD) is thema-
jor long termcomplicationof allogeneic stemcell transplantation (allo-
SCT). Although the contribution of donor T cells in the development
ofGVHDisbeyonddoubt, the role of B cells is less defined.Promising
results of B-cell depleting therapy with rituximab (RTX), suggest that
B cells do contribute to cGVHD. However, there is no consensus on
the exact mechanism by which B cells can cause allo-reactivity.
Objective: In order to elucidate efficacy in a prospective clinical trial
and elucidate the potential role of B cells in allo-reactivity and how
B-cell depletion results in amelioration of steroid refractory exten-
sive cGVHD, T- and B-cell subsets were studied before and after
RTX treatment.
Methods: In a prospectivephase I/II study 20patientswith steroid-re-
fractory extensive cGVHD were treated with RTX (4 x 375 mg/m2).
Clinical responses were monitored monthly for 1 year according to
the NIH criteria. T-cell and B-cell subsets and phenotypes were ana-
lyzed before and after treatment in responders andnon-responders and
compared to time matched no GVHD controls (no GVHD) and
healthy donors (HD) by FACS analysis. (EudraCT 2008-004125-42).
Results: A total of 80 RTX infusions were administered to 20 pa-
tients. Toxicity was limited to one infectious event and one allergic
reaction. Median follow-up was 6.5 months (range 1-13). Overall
response rate was 62%. Best clinical responses were observed in
patients with deep sclerosis of the skin (80%). Before treatment
absolute numbers of B cells were increased in responders compared
to non-responders, no GVHD and HD. Moreover, selectively in re-
sponders also the balance within B-cell subsets was disturbed. One
year after RTX treatment B-cells could be detected and responders
had a restored physiological B-cell phenotype.Conclusion: RTX treatment is a feasible and effective treatment in
patients with steroid refractory cGVHD. Sclerotic lesions of the skin
are most susceptible to treatment. In responders the increase in B
cells before treatment and the disturbed phenotype suggest that a dis-
balance in B cells is involved in inducing cGVHD. This allows to
speculate that cGVHD is heterogenous and can be either B-cell or
rather T-cell mediated. Analyzing B-cell numbers and phenotype
in patients with cGVHD might be useful in upfront identification
of patients which will benefit from RTX treatment and include
patients which will not in alternative clinical trials.490
STANDARDIZED EARLY INITIATION OF A ‘‘HIGH DOSE STEROID (HDS)’’
TREATMENT PROTOCOL FOR ALLO-IMMUNE LUNG SYNDROMES IS
ASSOCIATED WITH IMPROVED SURVIVAL DESPITE THE PRESENCE OF
HIGH VIRAL LOADS OF ‘‘COMMON COLD VIRUSES’’
Boelens, J.J.1, Versluys, B.1, Lindemans, C.1, Terhegge-Lagro, S.2,
Bierings, M.1 1UMC Utrecht, Utrecht, Netherlands; 2UMC Utrecht,
Utrecht, Netherlands
Background: Alloimmune lung syndromes (allo-LS), including Id-
iopathic Pneumonia Syndrome (IPS) and Bronchiolitis Obliterans
(BOS), are severe life-treatening complications after HSCT.We re-
cently found that a ‘‘common cold’’ respiratory viral (RV) infection
early after HSCT is an important predictor for the development of
allo-LS and that prolonged administration of immunosuppression,
in patients with a RV infection, because of aGVHD, paradoxically
had a protective effect on the development of allo-LS (BBMT
2010). We therefore hypothesised that despite presence of a RV,
alloLD should be treated with ‘high dose steroids (HDS)’’. We pro-
spectively studied the outcomes of the treatment of allo-immune
lungsyndromes (alloLS) with a standard HDS-protocol’’ and com-
pared this with our historical cohort.
Methods: All patients transplanted between January 2004 and July
2010, within our pediatric transplant program were included. All pa-
tients were tested for the presence of a RV using qPCR prior to
HSCT and subsequently weekly till discharge. After discharge
only when having symptoms. Allo-LS (IPS or BOS) was diagnosed
according international criteria, excluding infection (except presence
of a RV). In 2006 the HDS treatment protocol was introduced when
allo-LS was suspected: MP-pulse (10mg/kg: 3 days), followed by
2mg/kg/d prednisone, tapered 25% per week till 0.5mg/kg. After 4
weeks the MP-pulse was repeated, followed by 0.5mg/kg/d for at
least 1 months. In case there was still suspicion of disease the MP-
pulse was repeated (max. 6times). Ciclosporine tough levels were
maintained between 150 and 250 ug/L. In the old treatment guide-
lines we were reluctant giving HDS because of the presence of a RV.
Results: 182 patients were included of whom 38 (21%; 15% IPS and
6%BO) developed an allo-LS. 35/38 of the patients with an alloLS
had a proven RV. Follow up: 36mths (1–76 mths). The overall
survival was 63% (73% without alloLS, 43% with alloLS). Cause
of death in the alloLS group was 90% TRM and 10% relapse. 10
pts were treated according to old treatment guidelines, while 28
were included in the HDS protocol. The probability of OS was
20% for the ‘‘old treatment group’’ while 54% of the patients within
the HDS group survived (p 5 0.041). The viral load of the RV,
expressed as CT-values, remained stable (median value 20: range
17 – 24) during the treatment with HDS.
In summary: Early initiation of HDS in alloLS improved survival,
despite the presence of a RV (infection).491
DISTINCT OLIGOCLONAL T CELLS ARE ASSOCIATED WITH GVHD OR
GVHD-FREE RESPONSES IN PATIENTS WITH HEMATOLOGIC MALIGNAN-
CIES FOLLOWING STEM CELL TRANSPLANTATION
Toor, A.A.1, Kmieciak,M.2, Berrie, J.L.2, Mallory, K.L.2, Roberts, C.H.1,
Sabo, R.1, Idowu, M.1, Chung, H.M.1, Veronica, B.1, Clark, W.B.1,
McCarty, J.M.1, Detwiler, M.3, Kazim, L.3, Manjili, M.H.2 1Virginia
Commonwealth University, Richmond, VA; 2Virginia Commonwealth
University, Richmond, VA; 3Roswell Park Cancer Institute, Buffalo, NY
Graft-versus-host disease (GVHD) and graft-versus-tumor
(GVT) effects observed following allogeneic stem cell transplanta-
tion may be associated with unique clonal T cell expansion. To


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Standardized Early Initiation of a “High Dose Steroid (HDS)” Treatment Protocol for Allo-Immune Lung Syndromes is Associated With Improved Survival Despite the Presence of High Viral Loads of “Common Cold Viruses”

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