12th Congress of the European Hematology ... - Haematologica

Basic disease was AML (n=5), ALL (n=3), NHL (n=1), hemophagocytosis
(n=1) and malignant melanoma (n=1). Seven patients were
transplanted from HLA-A, B, C and high resolution DR fully matched
family members (siblings=6, father=1); 2 patients received stem cell
graft from fully matched unrelated donor (MUD) non-reactive in
mixed lymphocyte culture; 2 from mismatched family members and
1 from a matched unrelated cord blood unit. All patients had an extensive
cGVHD.Alefacept dose for children was 15 mg given intramuscularly
(IM) once weekly. The dose for adults was 30 mg IM once
weekly. Results. a median of 9 (range 1-25 injections were given to the
patients. Eight out of 12 patients (9/13 episodes) showed response.
The median time to initial response was 2.25 weeks (range 1-8). The
response was either marked (n=3), moderate (n=2) or minimal (n=4).
One patient with pulmonary GVHD had a consistent improvement
(Figure 1). In 2 responding patients, the response was only temporary.
Treatment complications included infection (n=3), pericarditis (n=1)
and squamous cell carcinoma of the lip (n=1). All these events may be
related to other drugs given simultaneously. Currently, 7/12 patients
are alive all with stable or improved cGVHD. Five patients died due
to GVHD progression. Conclusions. Alefacept is effective for the treatment
of cGVHD, dose and treatment's time intervals should be
explored.
0582
EPIGENETIC REGULATION OF ADHESION IN HEMATOPOIETIC AND LEUKEMIC STEM
CELLS
U. Mahlknecht, U. Mahlknecht, Ch. Schönbein
University of Heidelberg, HEIDELBERG, Germany
The α 4 β 1 integrin very late activation antigen-4 (VLA-4) plays a key
role in the adhesion of both hematopoietic progenitor cells and leukemic
blast cells to bone marrow stromal cells expressing the vascular cell adhesion
molecule-1 (VCAM-1). VLA-4 is an a4 (CD49d)/b1 (CD29) heterodimer
and its expression on leukemic cells has been associated with
bone-marrow minimal residual disease (MRD). Conversely, the absence
of VLA-4 reduces bone marrow retention of both hematopoietic progenitor
and leukemic blast cells. In this study, we have demonstrated a
downregulation of VLA-4/CD49d on various AML cells lines, on primary
cells from AML patients and on hematopoietic stem cells and
peripheral blood mononuclear cells from healthy donors upon treatment
with the histone deacetylase inhibitors suberoylanilide hydroxamic acid
(SAHA) and valproic acid (VPA). This was also functionally associated
with decreased adhesion to mesenchymal stromal cells. These findings
suggest that HDAC-inhibitor treatment might impair homing of both
normal and leukemic progenitors to the bone marrow. On the other
hand it might also facilitate the mobilization of hematopoietic progenitors.
0583
CLINICAL BENEFIT OF TREATMENT WITH SYNTHETIC PGI-2 IN PATIENTS SUFFERING
FROM RESISTANT SCLERODERMIC CHRONIC GVHD AFTER
ALLOGENEIC HEMOPOIETIC STEM CELL TRANSPLANTATION
M. Sorio, A. Andreini, D. De Sabata, R. Di Bella, S. Ledro, G. Ruggeri,
C. Tecchio, M. Tinelli, F. Benedetti
BMT unit, VERONA, Italy
Background. Scleroderma is a late manifestation of cGVHD, presenting
as progressive tightness of the skin and hampering patients’ quality
of life. In recent times Iloprost, a synthetic PGI-2, has been proving effective
in the therapy of idiopathic systemic sclerosis, which has a similar
pathogenesis to sclerodermic cGVHD. Patients and Methods. From 2001
to 2006 we observed 9 pts. affected by diffuse or limited sclerodermic
cGVHD. The patients (8 affected by acute leukemia, 1 by NHL) were
transplanted with classical conditioning regimen (FTBI 1200 cGy plus
Cytoxan 120 mg/Kg) from their sibling donors. The source of stem cells
was bone marrow in 3/9 cases and peripheral blood in 6/9 cases. Chronic
GVHD was observed at a median of 20 months from HSCT (range 11-
36), presenting as diffuse skin changes (tightness and thickening of the
face, neck, hands, thorax and abdomen), cutaneous dyschromia, digital
pitting scars and functional joint impairment. In two patients these alterations
were linked with itching and pain. In all cases cGVHD severely
affected quality of life. It was limited to the skin in 8/9 cases, and
involved internal organs in the other one (liver and lungs); in two cases
diffuse scleroderma was associated with severe discomfort in tendons
or muscles. In seven cases it presented as de novo cGVHD. All pts had
already been treated with various regimens including CSA, azathioprine,
12 th Congress of the European Hematology Association
mofetil mycophenilate, steroids, repeated cycles of PUVA with little or
no effect on the skin. Iloprost, 50 microgram a day over 8 hours IV continuous
infusion for 5 days every month, was started after a median of
8 months from the appearance of cGVHD (range 1-64). Results. The drug
was well-tolerated with little or no severe side effects: the most frequent
side effect was mild hypotension. No other major side effects were
observed. In 8/9 cases we saw a significant clinical benefit after a median
of 5 cycles (range 3-12). Further improvement was observed over the
subsequent courses. Iloprost courses were given in Outpatient Department
for at least 8-10 courses every month until a satisfactory clinical
response that was obtained after a median of 5 courses. In all cases the
patients received a maintenance therapy with 3-4 treatments a year. At
present, one patient has died because of relapse of acute leukaemia, 7 out
of the 8 remaining pts are alive and well, with satisfactory improvement
of quality of life. One patient, poor responder, is still on Iloprost, with
stable severe skin Scleroderma after 14 cycles. Conclusions. In our study
Iloprost seems to be one of the most effective drugs in reverting sclerodermic
diffuse cGVHD and in reducing the extension of the skin lesions.
Skin tenderness and disappearance of pain were reached after less than
6 months from the beginning of symptoms. The quality of life has
improved dramatically in all but one case.
0584
ANALYSIS OF BONE MARROW-RESIDING CD4+CD25+FOXP3+ T REGULATORY CELLS IN
PATIENTS WITH MULTIPLE MYELOMA TREATED WITH ALLOGENEIC STEM CELL
TRANSPLANTATION
D. Atanackovic, Y. Cao, T. Luetkens, C. Faltz, K. Bartels, C. Wolschke,
A.R. Zander, C. Bokemeyer, N. Kröger
University Medical Center Hamburg, HAMBURG, Germany
Introduction. Peripheral tolerance is largely maintained by immunosuppressive
regulatory T cells (Treg), such as CD4 + CD25 + T cells co-expressing
transcription factor forkhead box P3 (FOXP3) and it has been sugegested
that Treg contribute to the prevention of graft-versus-host disease
(GVHD) following allogeneic stem cell transplantation (alloSCT).
Unfortunately, Treg also represent a main obstacle of an effective antitumor
T cell response and depletion of CD4 + CD25 + FOXP3 + Treg seems
to enhance anti-tumor immunity. It is unclear, however, whether a
reduced number or function of Treg might play a role in the induction
of graft-versus-myeloma (GVM) effects in multiple myeloma (MM)
patients post alloSCT and very little is known about Treg residing in the
bone marrow (BM) of these patients. Aims and Methods. We performed
the first systematic analysis of Treg numbers and function in the BM and
in the peripheral blood (PB) of MM patients treated with alloSCT (N=40),
newly diagnosed MM patients (N=17), and healthy BM donors (N=20)
using flow cytometry and functional assays. Mechanisms which might
serve as potential mediators of the immunosuppressive function of BM
Treg were investigated using real-time PCR. Results. Following alloSCT,
donor-derived CD4 + CD25 + FOXP3 + Treg expanded faster than conventional
CD4 + T cells, leading to an accumulation of Treg in the BM of
transplanted patients. Since patients post alloSCT are devoid of a relevant
thymic function, Treg reconstitution was most likely based on
peripheral expansion. This idea was supported by the fact that reconstituted
BM CD4 + CD25 + FOXP3 + Treg of MM patients post alloSCT consisted
preferably of CD45RA-CCR7- memory T cells. BM-residing Treg
of newly diagnosed and MM patients post alloSCT showed a strong
inhibitory function and transforming growth factor (TGF)-β1 seemed to
represent an important mediator of Treg function in the BM of MM
patients post alloSCT and might also be involved in the expansion of
BM-residing CD4 + CD25 + FOXP3 + Treg. Conclusions. Our study demonstrates
for the first time that BM-residing Treg expand outside the thymus
and accumulate in the BM of MM patients post alloSCT. These
Treg, which are donor-derived and lead to an efficient replenishment of
Treg in the periphery, might be necessary for the prevention of GVHD.
However, BM Treg might also contribute to the failure of an effective
GVM effect in these patients.
0585
IS THERE A DIFFERENCE IN OUTCOME AND INCIDENCE OF ACUTE/CHRONIC GVHD IN
PEDIATRIC PATIENTS UNDERGOING UNMANIPULATED MUD-PBSCT VS MUD-BMT?
SINGLE LARGE CENTER EXPERIENCE
K. Kalwak, E. Gorczynska, M. Ussowicz, J. Owoc-Lempach,
D. Wójcik, M. Slociak, A. Dyla, A. Chybicka
Wroclaw Medical University, WROCLAW, Poland
There is an unresolved question whether unmanipulated matched
haematologica/the hematology journal | 2007; 92(s1) | 217