Beelen, Dietrich W.

Ehninger, Gerhard

Finke, Jürgen

Floisand, Yngvar

Ganser, Arnold

Ghavamzadeh, Ardeshir

Giebel, Sebastian

Labopin, Myriam

Mailhol, Audry

Nagler, Arnon

Ringden, Olle

Sadeghi, Behnam

Schmid, Christoph

Volin, Liisa

English

OPUS Augsburg

were treated from day 14 to day 28. Animals were assessedfor acute GVHD clinically and by organ pathology. Curcumineffects on in vitro T cell proliferation and cytokine produc-tion were assessed uin vitroT cell activation assay using CD3/CD28 stimulation and in mixed lymphocyte reaction (MLR).Results: Both preventive and therapeutic administration ofcurcumin resulted in improved survival on day +100 afteralloHCT (50.5% vs 20% and 45% vs 20%, respectively). Curcuminattenuated GVHD by significantly suppressing serum levelsof IL-6 and TNF-α along with significant reduction in gut pa-thology and concurrent induction of splenic Tregs on day +7after alloHCT. T cell proliferative responses were suppressedin the presence of curcumin and a significant reduction incytokine concentration, pSTAT3 and NFkB in the superna-tant was observed.Conclusions:Our data supports a beneficial effect of curcuminin the multifactorial pathogenesis of GVHD. Preventivecurcumin treatment improved GI tract and clinical GVHD andsurvival, as well as therapeutic curcumin improved clinicalGVHD and survival. Clinical relevance of curcumin is com-monly questioned, as curcumin is known for oftenunsatisfactory bioavailability due to fast metabolism and deg-radation, as well as it has a multitude of effects. Nevertheless,it’s positive safety profile and low toxicity risk make curcuminan attractivemother compound to prevent or treat GVHD, andits application in this field may be optimized by discoveryof novel derivatives interfering with individual specific targetsand improvement of pharmacokinetic properties, both ofwhich are currently being tested in our lab.452What Is the Outcome of Patients with Acute LeukemiaWho Survive Severe Acute Graft-Versus-Host Disease?Olle Ringden 1, Myriam Labopin 2, Audry Mailhol 3,Dietrich W. Beelen 4, Behnam Sadeghi 5, Yngvar Floisand 6,Ardeshir Ghavamzadeh 7, Jürgen Finke 8, Gerhard Ehninger 9,Liisa Volin 10, Arnold Ganser 11, Christoph Schmid 12,Sebastian Giebel 13, Arnon Nagler 14. 1 Division of TherapeuticImmunology, Department of Laboratory Medicine, KarolinskaInstitutet, Stockholm, Sweden; 2 Hopital Saint-Antoine, Paris,France; 3 Acute leukemia working party of EBMT, Paris,France; 4 University Hospital of Essen, Essen, Germany;5 Division of Therapeutic Immunology, F79, KarolinskaInstitutet, Stockholm, Sweden; 6 Hematol, Oslo, Norway;7 Hematology, Oncology and Stem Cell TransplantationResearch Center, Tehran University of Medical Sciences,Tehran, Iran (Islamic Republic of); 8 Department of Medicine,Haematology & Oncology, Freiburg University Medical Center,Freiburg, Germany; 9 Universitaetsklinikum Dresden, Dresden,Germany; 10 Third Department of Medicine, Stem CellTransplantation Unit, HUCH Comprehensive Cancer Center,Helsinki, Finland; 11 Department of Hematology/Oncology,Medizinische Hochschule Hannover, Hannover, Germany;12 Department of Hematology and Oncology, KlinikumAugsburg, Ludwig-Maximilians-University, Munich, Germany;13 Department of Bone Marrow Transplantation andOncohematology, Maria Sklodowska-Curie Memorial CancerCenter and Institute of Oncology, Gliwice Branch, Gliwice,Poland; 14 The Bone Marrow Transplantation Department,Division of Internal Medicine, The Chaim Sheba MedicalCenter, Tel-Hashomer, IsraelAcute graft-versus-host disease (GVHD) is a major compli-cation of allogeneic hematopoietic stem cell transplantation(HSCT). With new promising therapies, survival may improvein patients with severe acute GVHD. We wanted to analyzethe long-term outcome among patients who survive severeacute GVHD.Patients and Methods: This is a landmark analysis of 23,567patients with acute leukemia who survived >6 months afterHSCT during 2002-2014. Patients with severe acute GVHD(n = 1,738) were compared to controls.Results: Patients with severe acute GVHD had a higher non-relapse mortality (NRM) and chronic GVHD compared tocontrols (p < 10−5). Extensive chronic GVHDwas 26.9% before6 months and 27.2% after 6 months in the severe acute GVHDgroup (p < 10−5). The probability of relapse was significantlylower in the severe acute GVHD group, and leukemia-free sur-vival (LFS) and survival was significantly lower than for thecontrols (p < 10−5). Five-year LFS in patients who survivedsevere acute GVHD was 49% as opposed to 61% in controlswith no or mild, and 59% in patients with moderate GVHD.Conclusion: HSCT patients who survive severe acute GVHDhave a high risk of extensive chronic GVHD, a higher NRM,a lower relapse probability and lower LFS, compared to otherHSCT patients.453Selective Alloreactive Depletion Is Not a MechanismUnderlying the Efficacy of Post-TransplantationCyclophosphamide in a Murine HaploidenticalTransplantation ModelLucas P. Wachsmuth 1, Michael Eckhaus 2, Ehydel Castro 1,Ronald E. Gress 1, Christopher G. Kanakry 1. 1 ExperimentalTransplantation and Immunology Branch, National CancerInstitute, National Institutes of Health, Bethesda, MD;2 Division of Veterinary Resources, Office of Research Services,Office of the Director, National Institutes of Health, Bethesda,MDDespite its clinical efficacy, the mechanisms by which post-transplantation cyclophosphamide (PTCy) prevents graft-versus-host disease (GVHD) remain poorly understood. Theprevailing theory, extrapolated from murine skin allograft-ing models, posits that PTCy preferentially eliminatesalloreactive T cells, which may selectively proliferate earlypost-transplant. Those studies, which exploited strain-specific differential expression of certain T-cell receptor (TCR)Vβs as markers of alloreactive cells, also proposed two othermechanisms underlying PTCy’s efficacy: intrathymic clonaldeletion of alloreactive T cells and generation of suppressorT cells.To test the hypothesis that PTCy works via preferentialelimination of alloreactive T cells and investigate the biologyof PTCy, we developed a murine model of haploidenticaltransplantation that more directly parallels clinical prac-tice. In this model (B6C3F1→B6D2F1), the administrationof 40 × 106 splenocytes and 10 × 106T-cell-depleted bonemarrow cells following 10.5 Gy irradiation induces univer-sally fatal GVHD, with the Vβ6 TCR serving as a marker ofalloreactive T cells. Administration of PTCy on days +3 and+4 at doses ranging from 10 to 50 mg/kg effectively pre-vented lethal GVHD.In untreated mice at day +7, the majority of T cells wereproliferating as measured by Ki-67, consistent with recenthuman data. Mice treatedwith PTCy at ≥10mg/kg hadmarkedglobal reductions in Ki-67 + T cells, but this effect appearednon-selective. Indeed, Vβ6+ T cells (~6-12% of B6C3F1 Tcells) persisted at normal frequencies at early (day +7 and+21) and late (day +200) timepoints post-transplant, incon-sistent with selective alloreactive T-cell elimination orintrathymic clonal deletion. The latter was confirmed usingthymectomized recipients, for which PTCy remained effec-S327Abstracts / Biol Blood Marrow Transplant 23 (2017) S18–S391

What is the outcome of patients with acute leukemia who survive severe acute graft-versus-host disease?

https://opus.bibliothek.uni-augsburg.de/opus4/files/98616/1-s2.0-S1083879116308758-main.pdf

What is the outcome of patients with acute leukemia who survive severe acute graft-versus-host disease?

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