Improved overall survival for pediatric patients undergoing allogeneic hematopoietic stem cell transplantation – A comparison of the last two decades
Corresponding Author
Petter Svenberg
Oncology/Coagulation Section, Karolinska University Hospital, Stockholm, Sweden
Petter Svenberg, MD, Department of Pediatric Oncology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm 171 76, Sweden
Tel.: +46851770182
Fax: +46851773283
E-mail: [email protected]
Search for more papers by this authorMats Remberger
Department of Oncology/Pathology, Karolinska Institute, Stockholm, Sweden
Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorMehmet Uzunel
Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
Search for more papers by this authorJonas Mattsson
Department of Oncology/Pathology, Karolinska Institute, Stockholm, Sweden
Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorBritt Gustafsson
Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden
Search for more papers by this authorGustav Fjaertoft
Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorMikael Sundin
Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden
Hematology/Immunology Section, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorJacek Winiarski
Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden
Hematology/Immunology Section, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorOlle Ringdén
Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
Search for more papers by this authorCorresponding Author
Petter Svenberg
Oncology/Coagulation Section, Karolinska University Hospital, Stockholm, Sweden
Petter Svenberg, MD, Department of Pediatric Oncology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm 171 76, Sweden
Tel.: +46851770182
Fax: +46851773283
E-mail: [email protected]
Search for more papers by this authorMats Remberger
Department of Oncology/Pathology, Karolinska Institute, Stockholm, Sweden
Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorMehmet Uzunel
Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
Search for more papers by this authorJonas Mattsson
Department of Oncology/Pathology, Karolinska Institute, Stockholm, Sweden
Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorBritt Gustafsson
Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden
Search for more papers by this authorGustav Fjaertoft
Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorMikael Sundin
Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden
Hematology/Immunology Section, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorJacek Winiarski
Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden
Hematology/Immunology Section, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorOlle Ringdén
Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
Search for more papers by this authorAbstract
Pediatric protocols for allogeneic hematopoietic SCT have been altered during the last two decades. To compare the outcomes in children (<18 yr old), who underwent SCT at our center during 1992–2002 (P1) and 2003–2013 (P2). We retrospectively analyzed 188 patients in P1 and 201 patients in P2. The most significant protocol changes during P2 compared with P1 were a decrease in MAC protocols, particularly those containing TBI, an increase in RIC protocols, and altered GvHD prophylaxis. In addition, P2 had more patients with nonmalignant diagnoses (p = 0.002), more mismatched (MM) donors (p = 0.01), and more umbilical CB grafts (p = 0.03). Mesenchymal or DSCs were used for severe acute GvHD during P2. Three-yr OS in P1 was 58%, and in P2, it was 78% (p < 0.001). Improved OS was seen in both malignant disorders (51% vs. 68%; p = 0.05) and nonmalignant disorders (77% vs. 87%; p = 0.04). Multivariate analysis showed that SCT during P2 was associated with reduced mortality (HR = 0.57; p = 0.005), reduced TRM (HR = 0.57; p = 0.03), unchanged relapse rate, similar rate of GF, less chronic GvHD (HR = 0.49; p = 0.01), and more acute GvHD (HR = 1.77, p = 0.007). During recent years, OS has improved at our center, possibly reflecting the introduction of less toxic conditioning regimens and a number of other methodological developments in SCT.
References
- 1Miano M, Labopin M, Hartmann O, et al. Haematopoietic stem cell transplantation trends in children over the last three decades: A survey by the pediatric diseases working party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2007: 39: 88–89.
- 2Remberger M, Ackefors M, Berglund S, et al. Improved survival after allogeneic hematopoietic stem cell transplantation in recent years: A single-center study. Biol Blood Marrow Transplant 2011: 17: 1688–1697.
- 3Eapen M, Horowitz MM, Klein JP, et al. Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: The Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. J Clin Oncol 2004: 22: 4872–4880.
- 4Shaw PJ, Kan F, Woo Ahn K, et al. Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors. Blood 2010: 116: 4007–4015.
- 5Ringden O, Remberger M, Svahn BM, et al. Allogeneic hematopoietic stem cell transplantation for inherited disorders: Experience in a single center. Transplantation 2006: 81: 718–725.
- 6Boelens JJ, Prasad V, Tolar J, et al. Current international perspectives on hematopoietic stem cell transplantation for inherited metabolic disorders. Pediatr Clin North Am 2010: 57: 123–145.
- 7Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: The first 25 years and beyond. Blood 2013: 122: 491–498.
- 8Eapen M, Rubinstein P, Zhang MJ, et al. Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: A comparison study. Lancet 2007: 369: 1947–1954.
- 9Oeverman L, Handgretinger R. New strategies for haploidentical transplantation. Pediatr Res 2012: 71: 418–426.
- 10Schaffer M, Aldener-Cannava A, Remberger M, et al. Roles of HLA-B, HLA-C and HLA-DPA1 incompatibilities in the outcome of unrelated stem-cell transplantation. Tissue Antigens 2003: 62: 243–250.
- 11Satwani P, Morris E, Bradley B, et al. Reduced intensity and non-myeloablative allogeneic stem cell transplantation in children and adolescents with malignant and non-malignant diseases. Pediatr Blood Cancer 2008: 50: 1–8.
- 12Lawitschka A, Faraci M, Yaniv I, et al. Pediatric reduced intensity conditioning: Analysis of centre strategies on regimens and definitions by the EBMT Pediatric Diseases and Complications and Quality of Life WP. Bone Marrow Transplant 2015: 50: 592–597.
- 13Bontant T, Sedlaçek P, Balduzzi A, et al. Survey of CMV management in pediatric allogeneic HSCT programs, on behalf of the inborn errors, infectious diseases and pediatric diseases working parties of EBMT. Bone Marrow Transplant 2014: 49: 276–279.
- 14Groll AH, Castagnola E, Cesaro S, et al. Fourth European Conference on Infections in Leukaemia, Infectious Diseases Working Party of the European Group for Blood Marrow Transplantation (EMBT-IDWP), Infectious Diseases Group of the European Organisation for Research and Treatment of Cancer (EORIC-IDG), International Immunocompromised Host Society (ICHS), European Leukaemia Net (ELN). Fourth European Conference on Infections in Leukaemia (ECIL-4): Guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in pediatric patients with cancer or allogeneic hematopoietic stem-cell transplantation. Lancet Oncol 2014: 15: e327–e340.
- 15Mattsson J, Uzunel M, Remberger M, Ringden O. T cell mixed chimerism is significantly correlated to a decreased risk of acute graft-versus-host disease after allogeneic stem cell transplantation. Transplantation 2001: 71: 433–439.
- 16Lion T, Watzinger F, Preuner S, et al. The EuroChimerism concept for a standardized approach to chimerism analysis after allogeneic stem cell transplantation. Leukemia 2012: 26: 1821–1828.
- 17Vrijmoet-Wiersma CM, Kolk AM, Grootenhuis MA, et al. Child and parental adaptation to pediatric stem cell transplantation. Support Care Cancer 2009: 17: 707–714.
- 18Le Blanc K, Rassmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004: 363: 1439–1441.
- 19Ringdén O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 2006: 81: 1390–1397.
- 20Ringdén O, Erkers T, Nava S, et al. Fetal membrane cells for treatment of steroid-refractory acute graft-versus-host disease. Stem Cells 2013: 31: 592–601.
- 21Schaffer M, Aldener-Cannavá A, Remberger M, et al. Roles of HLA-B, HLA-C and HLA-DPA1 incompatibilities in the outcome of unrelated stem-cell transplantation. Tissue Antigens 2003: 62: 243–250.
- 22Ringdén O, Lönnqvist B, Hägglund H, et al. Transplantation with peripheral blood stem cells from unrelated donors without serious graft-versus-host disease. Bone Marrow Transplant 1995: 16: 856–857.
- 23Remberger M, Swahn BM, Mattsson J, Ringden O. Dose study of thymoglobulin during conditioning for unrelated donor allogeneic stem cell-cell transplantation. Transplantation 2004: 78: 122–127.
- 24Storb R, Deeg HJ, Pepe M, et al. Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: Long-term follow-up of a controlled trial. Blood 1989: 73: 1729–1734.
- 25Cutler C, Logan B, Nakamura R, et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic SCT. Blood 2014: 124: 1372–1377.
- 26Ringdén O, Pihlstedt P, Markling L, et al. Prevention of graft-versus-host disease with T cell depletion or cyclosporin and methotrexate. A randomized trial in adult leukemic marrow recipients. Bone Marrow Transplant 1991: 7: 221–226.
- 27Ljungman P, Lore K, Aschan J, et al. Use of a semi-quantitative-PCR for cytomegalovirus DNA as a basis for pre-emptive antiviral therapy in allogeneic bone marrow transplant patients. Bone Marrow Transplant 1996: 17: 583–587.
- 28Svahn BM, Remberger M, Myrback KE, et al. Home care during the pancytopenic phase after allogeneic hematopoietic stem cell transplantation is advantageous compared with hospital care. Blood 2002: 100: 4317–4324.
- 29Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995: 15: 825–828. Review.
- 30Sk Lee, Cook EF, Soiffer R, et al. Development and validation of a scale to measure symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2002: 8: 444–452.
- 31Ringdén O, Remberger M, Persson U, et al. Similar incidence of graft-versus-host disease using HLA-A,-B and –DR identical unrelated bone marrow donors as with HLA-identical siblings. Bone Marrow Transplant 1995: 15: 619–625.
- 32Remberger M, Aschan J, Barkholt L, et al. Treatment of severe acute graft-versus-host disease with anti-thymocyte globulin. Clin Transplant 2001: 15: 147–153. Review.
- 33Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958: 53: 457–481.
- 34Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999: 1999: 496–509.
- 35Passweg JR, Baldomero H, Peters C, et al. Hematopoietic SCT in Europe: Data and trends in 2012 with special consideration of pediatric transplantation. Bone Marrow Transplant 2014: 49: 744–750.
- 36Remberger M, Törlén J, Ringdén O, et al. Effect of total nucleated and CD34(+) cell dose on outcome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2015: 21: 889–893.
- 37Mateos MK, O'Brien TA, Oswald C, et al. Transplant-related mortality following allogeneic hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia: 25-year retrospective review. Pediatr Blood Cancer 2013: 60: 1520–1527.
- 38Satwani P, Jin Z, Duffy D, et al. Transplantation-related mortality, graft failure and survival after reduced-toxicity conditioning and allogeneic stem cell transplantation in 100 consecutive pediatric recipients. Biol Blood Marrow Transplant 2013: 19: 552–561.
- 39Leblanc K, et al. Mesenchymal stromal cells ha a trend to be more effective in children compared to adults. Lancet 2008: 372: 715–716.
- 40Kanada Y, Kobayaashi T, Mori T, et al. A randomized controlled trial of cyclosporine and tacrolimus with strict control of blood concentrations after unrelated bone marrow transplantation. Bone Marrow Transplant 2016: 51: 103–109.
- 41Malard F, Chevallier P, Guillaume T, et al. Continuous reduced nonrelapse mortality after allogeneic hematopoietic stem cell transplantation: A single-institution's three decade experience. Biol Blood Marrow Transplant 2014: 20: 1217–1223.
- 42Dhir S, Slatter M, Skinner R. Recent advances in the management of graft-versus-host disease. Arch Dis Child 2014: 99: 1150–1157.
- 43Azik FM, Tezer H, Parlakay AO, et al. Secondary antifungal prophylaxis in pediatric hematopoietic stem cell transplants. J Pediatr Hematol Oncol 2015: 37: e19–e22.
- 44Arai S, Arora M, Wang T, et al. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: A report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant 2015: 21: 266–274.
- 45Strob R, Prentice RL, Sullivan KL, et al. Predictive factors in chronic graft-versus-host disease in patients with aplastic anemia treated by marrow transplantation from HLA-identical siblings. Ann Intern Med 1983: 98: 461–466.
- 46Storek J, Gooley T, Siadak M, et al. Allogeneic peripheral blood stem cell transplantation may be associated with a high risk of chronic graft-versus-host disease. Blood 1997: 90: 4705–4709.
- 47Stikvoort A, Gertow J, Sundin M, et al. Chimerism patterns of long-term stable mixed chimeras post hematopoietic stem cell transplantation in patients with nonmalignant diseases: Follow-up of long term stable mixed chimerism patients. Biol Blood Marrow Transplant 2013: 19: 828–844.
- 48Gustafsson-Jernberg Å, Remberger M, Ringden O, Winiarski J. Graft-versus-leukaemia effect in children: Chronic GVHD has a significant impact on relapse and survival. Bone Marrow Transplant 2003: 31: 175–181.
- 49Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990: 75: 555–562.
- 50Ringdén O, Labopin M, et al. Graft-versus-leukemia effect in allogeneic marrow transplant recipients with acute leukemia is maintained using cyclosporine A combined with methotrexate as prophylaxis. Bone Marrow Transplant 1996: 18: 921–929.
- 51Boyiadzis M, Arora M, Klein J, et al. Impact of chronic graft-versus-host disease on late relapse and survival on 7489 patients after myeloablative allogeneic hematopoietic cell transplantation for leukemia. Clin Cancer Res 2015: 21: 2020–2028.
- 52Mallhi K, Lum LG, Schultz KR, Yankelevich M. Hematopoietic cell transplantation and cellular therapeutics in the treatment of childhood malignancies. Pediatr Clin North Am 2015: 62: 257–273.
- 53Angelucci E, Matthes-Martin S, Baronciani D, et al. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: Indications and management recommendations from an international expert panel. Hematologica 2014: 99: 811–820.
Citing Literature
