Alexandra Laberko1, Vasiliy Burlakov2, Sarah Maier3, Mario Abinun4, Roderick Skinner4, Anna Kozlova2, Deepti Suri5, Kai Lehmberg3, Ingo Müller3, Dmitry Balashov6, Galina Novichkova7, Dirk Holzinger8, Andrew R Gennery4, Anna Shcherbina2. 1. Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom. Electronic address: alexandra.laberko@gmail.com. 2. Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia. 3. Division of Pediatric Stem Cell Transplantation and Immunology, Department of Pediatric Hematology and Oncology, University Medical Center Eppendorf, Hamburg, Germany. 4. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; Great North Children's Hospital, Newcastle University, Newcastle upon Tyne, United Kingdom. 5. Great North Children's Hospital, Newcastle University, Newcastle upon Tyne, United Kingdom. 6. Department of Hematopoietic Stem Cell Transplantation, Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia. 7. Department of Hematology, Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia. 8. Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany.
Abstract
BACKGROUND: Proline-serine-threonine phosphatase-interacting protein 1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a novel genetic disorder, causing hypercalprotectinemia and hyperzincemia with inflammatory complications accompanied by cytopenia. Immunosuppressive and/or anticytokine therapy is of limited effect. OBJECTIVES: Because of cytokine production in nonhematopoietic tissues, the potential therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) in autoinflammatory disorders, including PAMI syndrome, has remained uncertain. METHODS: Five patients with PAMI syndrome underwent allogeneic HSCT with myeloablative (4) or reduced-intensity (1) conditioning regimens. Lack of PAMI disease control served as indication for the HSCT in 4 patients and myelodysplastic syndrome development in 1. RESULTS: All 5 patients engrafted; however, 1 patient at day +13 developed hemophagocytic syndrome, followed by graft rejection at day +17. After 5.5 months, a second HSCT was performed from an alternative donor. A further patient at day +116 developed an intense inflammatory syndrome with significant serositis and severe mitral and aortic valve regurgitation, controlled with adalimumab, tacrolimus, and prednisone. No other noninfectious inflammatory episodes, or acute or chronic graft-versus-host disease, occurred in any patient. At the last follow-up (median, 2.2 years), all 5 patients have predominantly or complete donor chimerism and adequate immune recovery and are free of any PAMI symptoms. CONCLUSIONS: Allogeneic HSCT seems to be an effective option to cure cytopenia and severe autoinflammation in PAMI syndrome and may be a curative option for other proline-serine-threonine phosphatase-interacting protein 1-associated inflammatory disorders with poor therapeutic control.
BACKGROUND: Proline-serine-threonine phosphatase-interacting protein 1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a novel genetic disorder, causing hypercalprotectinemia and hyperzincemia with inflammatory complications accompanied by cytopenia. Immunosuppressive and/or anticytokine therapy is of limited effect. OBJECTIVES: Because of cytokine production in nonhematopoietic tissues, the potential therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) in autoinflammatory disorders, including PAMI syndrome, has remained uncertain. METHODS: Five patients with PAMI syndrome underwent allogeneic HSCT with myeloablative (4) or reduced-intensity (1) conditioning regimens. Lack of PAMI disease control served as indication for the HSCT in 4 patients and myelodysplastic syndrome development in 1. RESULTS: All 5 patients engrafted; however, 1 patient at day +13 developed hemophagocytic syndrome, followed by graft rejection at day +17. After 5.5 months, a second HSCT was performed from an alternative donor. A further patient at day +116 developed an intense inflammatory syndrome with significant serositis and severe mitral and aortic valve regurgitation, controlled with adalimumab, tacrolimus, and prednisone. No other noninfectious inflammatory episodes, or acute or chronic graft-versus-host disease, occurred in any patient. At the last follow-up (median, 2.2 years), all 5 patients have predominantly or complete donor chimerism and adequate immune recovery and are free of any PAMI symptoms. CONCLUSIONS: Allogeneic HSCT seems to be an effective option to cure cytopenia and severe autoinflammation in PAMI syndrome and may be a curative option for other proline-serine-threonine phosphatase-interacting protein 1-associated inflammatory disorders with poor therapeutic control.
Authors: Deborah L Stone; Amanda Ombrello; Juan I Arostegui; Corinne Schneider; Vinh Dang; Adriana de Jesus; Charlotte Girard-Guyonvarc'h; Cem Gabay; Wonyong Lee; Jae Jin Chae; Ivona Aksentijevich; Raphaela T Goldbach-Mansky; Daniel L Kastner; Scott W Canna Journal: Arthritis Rheumatol Date: 2022-01-03 Impact factor: 10.995