Evolution of disease activity and biomarkers on and off rapamycin in 28 patients with autoimmune lymphoproliferative syndrome

doi:10.3324/haematol.2016.153411

Multicenter Study

. 2017 Feb;102(2):e52-e56.

doi: 10.3324/haematol.2016.153411. Epub 2016 Oct 27.

Evolution of disease activity and biomarkers on and off rapamycin in 28 patients with autoimmune lymphoproliferative syndrome

Christian Klemann^{1

2}, Myrian Esquivel^{3

4}, Aude Magerus-Chatinet^{3

5}, Myriam R Lorenz^{6

7}, Ilka Fuchs¹, Nathalie Neveux⁸, Martin Castelle⁴, Jan Rohr^{1

2}, Claudia Bettoni da Cunha⁹, Martin Ebinger¹⁰, Robin Kobbe¹¹, Bernhard Kremens¹², Florian Kollert¹³, Eleonora Gambineri¹⁴, Kai Lehmberg¹⁵, Markus G Seidel¹⁶, Kathrin Siepermann¹⁷, Thomas Voelker¹⁸, Volker Schuster¹⁹, Sigune Goldacker¹, Klaus Schwarz^{6

7}, Carsten Speckmann^{1

2}, Capucine Picard^{3

4

20}, Alain Fischer^{3

4

21}, Frederic Rieux-Laucat^{3

5}, Stephan Ehl^{1

2}, Anne Rensing-Ehl²², Benedicte Neven²³

Affiliations

¹ Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Germany.
² Center for Pediatrics, Department of Pediatric Hematology and Oncology, University Medical Center, Faculty of Medicine, University of Freiburg, Germany.
³ INSERM UMR 1163, Laboratory of the immunogenetics of Pediatric Autoimmune Diseases, Paris, France.
⁴ Unite d'Immuno Hematologie Pediatrique, Hopital Necker-Enfants Malades, Assistance Publique des Hopitaux de Paris, France.
⁵ Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, France.
⁶ Institute for Transfusion Medicine, University of Ulm, Germany.
⁷ Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Germany.
⁸ Service de Biochimie, Hopital Cochin, Assistance Publique Hopitaux de Paris, France.
⁹ Department of Pediatric Hematology and Oncology, Hannover Medical School, Germany.
¹⁰ University Children's Hospital Tübingen, Germany.
¹¹ Department of Pediatrics, Infectious Diseases and Immunity, University Medical Centre Hamburg-Eppendorf, Germany.
¹² Department of Rheumatology and Clinical Immunology, University Medical Centre Freiburg, Germany.
¹³ University Hospital Essen, Department of Paediatrics III, University of Duisburg-Essen, Germany.
¹⁴ Department of "NEUROFARBA": Section of Child's Health, University of Florence, Department of Haematology-Oncology: BMT Unit, Department of Fetal and Neonatal Medicine: Rare Diseases, "Anna Meyer" Children's Hospital, Florence, Italy.
¹⁵ Department of Pediatric Haematology/Oncology, University Medical Centre Hamburg, Germany.
¹⁶ Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Austria.
¹⁷ Department of Pediatric and Adolescent Medicine, HELIOS Klinikum Krefeld, Germany.
¹⁸ Hospital for Pediatric Haematology and Oncology, Medical Center Kassel GmbH, Germany.
¹⁹ Hospital for Children and Adolescents, University of Leipzig, Germany.
²⁰ Centre d'Etude des Deficits Immunitaires, Hopital Necker-Enfants Malades, Assistance Publique des Hopitaux de Paris, France.
²¹ College de France, Paris, France.
²² Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Germany benedicte.neven@aphp.fr anne.rensing-ehl@uniklinik-freiburg.de.
²³ Unite d'Immuno Hematologie Pediatrique, Hopital Necker-Enfants Malades, Assistance Publique des Hopitaux de Paris, France benedicte.neven@aphp.fr anne.rensing-ehl@uniklinik-freiburg.de.

PMID: 27789675
PMCID: PMC5286954
DOI: 10.3324/haematol.2016.153411

Multicenter Study

Evolution of disease activity and biomarkers on and off rapamycin in 28 patients with autoimmune lymphoproliferative syndrome

Christian Klemann et al. Haematologica. 2017 Feb.

. 2017 Feb;102(2):e52-e56.

doi: 10.3324/haematol.2016.153411. Epub 2016 Oct 27.

Authors

Affiliations

¹ Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Germany.
² Center for Pediatrics, Department of Pediatric Hematology and Oncology, University Medical Center, Faculty of Medicine, University of Freiburg, Germany.
³ INSERM UMR 1163, Laboratory of the immunogenetics of Pediatric Autoimmune Diseases, Paris, France.
⁴ Unite d'Immuno Hematologie Pediatrique, Hopital Necker-Enfants Malades, Assistance Publique des Hopitaux de Paris, France.
⁵ Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, France.
⁶ Institute for Transfusion Medicine, University of Ulm, Germany.
⁷ Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Germany.
⁸ Service de Biochimie, Hopital Cochin, Assistance Publique Hopitaux de Paris, France.
⁹ Department of Pediatric Hematology and Oncology, Hannover Medical School, Germany.
¹⁰ University Children's Hospital Tübingen, Germany.
¹¹ Department of Pediatrics, Infectious Diseases and Immunity, University Medical Centre Hamburg-Eppendorf, Germany.
¹² Department of Rheumatology and Clinical Immunology, University Medical Centre Freiburg, Germany.
¹³ University Hospital Essen, Department of Paediatrics III, University of Duisburg-Essen, Germany.
¹⁴ Department of "NEUROFARBA": Section of Child's Health, University of Florence, Department of Haematology-Oncology: BMT Unit, Department of Fetal and Neonatal Medicine: Rare Diseases, "Anna Meyer" Children's Hospital, Florence, Italy.
¹⁵ Department of Pediatric Haematology/Oncology, University Medical Centre Hamburg, Germany.
¹⁶ Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Austria.
¹⁷ Department of Pediatric and Adolescent Medicine, HELIOS Klinikum Krefeld, Germany.
¹⁸ Hospital for Pediatric Haematology and Oncology, Medical Center Kassel GmbH, Germany.
¹⁹ Hospital for Children and Adolescents, University of Leipzig, Germany.
²⁰ Centre d'Etude des Deficits Immunitaires, Hopital Necker-Enfants Malades, Assistance Publique des Hopitaux de Paris, France.
²¹ College de France, Paris, France.
²² Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, University of Freiburg, Germany benedicte.neven@aphp.fr anne.rensing-ehl@uniklinik-freiburg.de.
²³ Unite d'Immuno Hematologie Pediatrique, Hopital Necker-Enfants Malades, Assistance Publique des Hopitaux de Paris, France benedicte.neven@aphp.fr anne.rensing-ehl@uniklinik-freiburg.de.

PMID: 27789675
PMCID: PMC5286954
DOI: 10.3324/haematol.2016.153411

No abstract available

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Figures

**Figure 1.**
Biomarker responses at six months in patients receiving rapamycin as first-line or second-line treatment. The percentage of DNT cells among CD3⁺TCRαβ⁺ lymphocytes (A), the serum levels of VitB12 (B), IL-10 (C) and sFASL (D) were determined before rapamycin therapy and 6–8 months after initiation of treatment in patients who received rapamycin as first-line therapy (left panels) or after prior immunosuppressive treatment (right panels). Patients with complete remission are depicted in black, partial remissions are indicated by open gray circles. Analyses were performed using PRISM-software (GraphPad software, San Diego, USA). Populations were compared using the Wilcoxon matched-pairs signed rank t-test. P<0.05 was considered significant. ^*P<0.05; ^***P<0.001.

**Figure 2.**
Effect of treatment discontinuation. Summary of observations in 6 patients who discontinued rapamycin treatment. (A) Status of rapamycin treatment is indicated by [−]/[+]. The spleen size is indicated as follows: − not palpable; + palpable but <5 cm; ++ >10 cm or up to umbilicus. °Additional lymphadenopathy. ^*Cytopenia. (B) Percentages of DNT cells (left y-axis, black circles) and sFASL levels (right y-axis, open boxes/broken lines) at different stages of therapy.

See this image and copyright information in PMC

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References

1. Fisher GH, Rosenberg FJ, Straus SE, et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995;81(6):935–946. - PubMed
1. Rieux-Laucat F, Le Deist F, Hivroz C, et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science. 1995;268(5215):1347–1349. - PubMed
1. Teachey DT, Greiner R, Seif A, et al. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br J Haematol. 2009;145(1):101–106. - PMC - PubMed
1. Bride KL, Vincent T, Smith-Whitley K, et al. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood. 2016;127(1):17–28. - PMC - PubMed
1. Oliveira JB, Bleesing JJ, Dianzani U, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010;116(14):e35–40. - PMC - PubMed

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[1] Fisher GH, Rosenberg FJ, Straus SE, et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995;81(6):935–946. - PubMed

[2] Fisher GH, Rosenberg FJ, Straus SE, et al. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995;81(6):935–946. - PubMed

[3] Rieux-Laucat F, Le Deist F, Hivroz C, et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science. 1995;268(5215):1347–1349. - PubMed

[4] Rieux-Laucat F, Le Deist F, Hivroz C, et al. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science. 1995;268(5215):1347–1349. - PubMed

[5] Teachey DT, Greiner R, Seif A, et al. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br J Haematol. 2009;145(1):101–106. - PMC - PubMed

[6] Teachey DT, Greiner R, Seif A, et al. Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. Br J Haematol. 2009;145(1):101–106. - PMC - PubMed

[7] Bride KL, Vincent T, Smith-Whitley K, et al. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood. 2016;127(1):17–28. - PMC - PubMed

[8] Bride KL, Vincent T, Smith-Whitley K, et al. Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial. Blood. 2016;127(1):17–28. - PMC - PubMed

[9] Oliveira JB, Bleesing JJ, Dianzani U, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010;116(14):e35–40. - PMC - PubMed

[10] Oliveira JB, Bleesing JJ, Dianzani U, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010;116(14):e35–40. - PMC - PubMed

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Evolution of disease activity and biomarkers on and off rapamycin in 28 patients with autoimmune lymphoproliferative syndrome

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Evolution of disease activity and biomarkers on and off rapamycin in 28 patients with autoimmune lymphoproliferative syndrome

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