A prospective randomized trial comparing

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Aug 4, 2016 - by Johan Törlén, Olle Ringdén, Karin Garming-Legert, Per ... Citation: Törlén J, Ringdén O, Garming-Legert K, Ljungman P, Winiarski J, Remes ...
Published Ahead of Print on August 4, 2016, as doi:10.3324/haematol.2016.149294. Copyright 2016 Ferrata Storti Foundation.

A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation by Johan Törlén, Olle Ringdén, Karin Garming-Legert, Per Ljungman, Jacek Winiarski, Kari Remes, Maija Itälä-Remes, Mats Remberger, and Jonas Mattsson Haematologica 2016 [Epub ahead of print] Citation: Törlén J, Ringdén O, Garming-Legert K, Ljungman P, Winiarski J, Remes K, Itälä-Remes M, Remberger M, and Mattsson J. A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation. Haematologica. 2016; 101:xxx doi:10.3324/haematol.2016.149294 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.

TITLE PAGE Article title:

A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation Short/Running title:

CsA/Mtx vs. Tac/Sir as GVHD prophylaxis in HSCT Authors and affiliations:

Johan Törlén1,2, Olle Ringdén1, Karin Garming-Legert3, Per Ljungman1,4, Jacek Winiarski5, Kari Remes6,7, Maija Itälä-Remes6, Mats Remberger1,2, and Jonas Mattsson1,2 Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden Division of Oral and Maxillofacial Surgery, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden Department of Hematology, Karolinska University Hospital and Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden Department of Internal Medicine, Turku University Hospital, Turku, Finland Turku University, Turku, Finland 1

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Corresponding author: Johan Törlén, MD Center for Allogeneic Stem Cell Transplantation (CAST) M72-74 Karolinska University Hospital, Huddinge SE-141 86 Stockholm Sweden

E-mail: [email protected] Phone: +46 705 69 38 99 Fax: +46 8 585 878 70 Trial registration: clinicaltrials.gov identifier: NCT00993343 Word counts (Article): Title: 172 (≤ 200 characters, excl. spaces) Running head/title: 47 characters (≤ 50 characters, incl. spaces) Abstract: 247 (≤ 250 words) Text: 3,991 (≤ 4,000 words, incl. introduction + methods + results + discussion) Table count: 2 (excl. supplemental data) Figure count: 4 (excl. supplemental data) Supplemental files: 1 pdf-file (uploaded as requested, “torlen_sup.pdf”) Reference count: 50 (≤ 50)

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ABSTRACT

Improvement of graft-versus-host disease prophylaxis remains an important goal in allogeneic hematopoietic stem cell transplantation. Based on reports of possibly preferential properties of sirolimus, we compared the standard regimen of cyclosporine and methotrexate (n=106) with a combination of tacrolimus and sirolimus (n=103) as graft-versus host disease prophylaxis after allogeneic hematopoietic stem cell transplantation in a prospective, open, randomized trial. The hypothesis was that the tacrolimus/sirolimus regimen would lead to less acute graft-versus-host disease and reduced transplant-related mortality. There was no significant difference in the cumulative incidence of acute graft-versus-host disease of grades IIJIV (41% vs. 51%; p=0.19) or grades III-IV (13% vs. 7%; p=0.09) between the groups. Time to neutrophil engraftment (18 days vs. 17 days; p=0.24) was similar, but time to platelet engraftment was longer in cyclosporine/methotrexate patients (14 vs. 12 days; p20 ×10 /l without 9

transfusions. Oropharyngeal mucositis was assessed three times a week, and graded according to the International Classification of Diseases from the WHO (39) until day +24 or until hospital discharge. Cytomegalovirus (CMV) infection was defined as detection of CMV DNA in whole blood by real-time PCR. A PCR result of >1,000 CMV DNA copies/ml (changed to >2,000 CMV DNA copies/ml in 2009) was considered to be a clinically relevant CMV-viremia, and initiation of preemptive CMV therapy was used as a basis for analysis between the groups. Patients were monitored with CMV-PCR once a week for 3 months after HSCT. Subsequent monitoring was individually prescribed for each patient at the discretion of the treating physician, according to standard operating protocols. Chimerism analyses of peripheral blood and/or bone marrow were performed on all patients at regular intervals after HSCT, according to standard operating protocols, or at the discretion of the treating physician. The cell lineages analyzed were T-lymphocytes (CD3), Blymphocytes (CD19), myeloid cells (CD33), and hematopoietic precursors (CD34; applicable to bone marrow samples). Analyses were done with real-time PCR based on single nucleotide polymorphisms 7

(40). Full donor chimerism was defined as >95% donor-derived cells in all lineages, and mixed chimerism was assumed when >5% but