Comparative Effectiveness of Hematopoietic Stem-Cell Transplants in the Pediatric Population /Comment Key Questions-AHRQ Effective Health Care Program

Comparative Effectiveness of Hematopoietic Stem-Cell Transplants in the Pediatric Population
Open for comment until Jan. 14, 2010 .

Figures 1-3. Proposed Analytic Frameworks
hacer doble click en las imágenes para ampliarlas










Background
Hematopoietic stem-cell transplantation (HSCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in patients, and is categorized by the source of the stem cells. Autologous transplants involve returning the patient’s own stem cells, typically after the patient has received doses of chemotherapy that are myeloablative. Allogeneic HSCT uses stem cells from an HLA-matched donor, either related or unrelated, and, in malignant diseases, exploits a graft-versus-tumor effect. In many of the nonmalignant diseases, donor hematopoietic stem cells are used to “replace” the patient’s abnormal bone marrow with a donor’s normal one. The third source of hematopoietic stem cells is from the umbilical cord and placenta.

In the pediatric population, HSCT is used to treat a wide variety of diseases, both malignant and nonmalignant. Malignant diseases in the pediatric population include hematologic (leukemias and lymphomas) and nonhematologic (or solid) including primary brain tumors, those derived from the peripheral nervous system (neuroblastoma), soft tissues or bone (Ewing’s sarcoma, rhabdomyosarcoma), kidney (Wilms tumor), and eye (retinoblastoma). A wide variety of nonmalignant conditions may also be treated with HSCT, and in the pediatric population include hemoglobinopathies, bone marrow failure (BMF) syndromes, primary immune deficiencies (PID), autoimmune diseases, and inherited metabolic diseases (IMD).

Treating many of the pediatric diseases with HSCT has resulted in an increased number of long-term survivors. However, HSCT may be associated with morbidity and mortality, including graft-versus-host disease and other transplant-related complications like opportunistic infections. There are also concerns of the long-term effects HSCT, including its impact on growth and development, cognitive ability, future fertility, and secondary malignancies. The comparative benefits and harms of HSCT versus other therapies in the pediatric population for these various diseases form the basis for the key questions developed for this topic.

For many of these diseases, HSCT is a well-established treatment. For example, the literature for the use of HSCT in the hematologic malignancies is relatively robust, including randomized, controlled trials that date back 10 to 15 years, and it has become common and accepted medical practice. For other less-common diseases, for example, the primary immunodeficiencies and hemoglobinopathies, the evidence consists of case series and case reports, but the results after HSCT have shown improved outcomes and/or cure. In other pediatric diseases, HSCT is not well established, is evolving, or has been shown not to be beneficial. For those diseases in which HSCT in pediatric patients is a well-established treatment option (e.g., hematologic malignancies), the report will include a narrative review of the evidence relying on focused searches of the literature to identify existing reviews and key studies. The remainder of the diseases, including solid malignant tumors, inherited metabolic syndromes, and autoimmune diseases will be approached as a systematic comparative effectiveness review to guide decision makers as to appropriate indications for HSCT.

While the intervention (i.e., autologous, allogeneic, umbilical cord/placenta HSCT) does not differ within each disease category, the therapeutic intent will vary, involving not only hematopoietic rescue following administration of myelotoxic agents, but may also aim to reconstitute normal immune or biochemical functionality necessary to correct immune dysfunction or inborn metabolic disorders, respectively. Given the number and variety of diseases covered, the report will consider disparate populations, comparators, and outcomes. The proposed six Key Questions and three analytic frameworks attempt capture the relevant clinical issues for each disease category.

Population(s)
Pediatric population may vary somewhat from disease to disease, but in general will include birth to 18 years of age, although, for example, the autoimmune diseases may include up to 21 years of age.

Interventions
Hematopoietic stem-cell transplantation (autologous or allogeneic or cord blood/placenta)

Comparator(s)
Comparators will vary for each condition. For malignant solid tumors, HSCT will be compared to conventional chemotherapy. For the inherited metabolic diseases, HSCT will be compared to enzyme-replacement therapy (ERT) or substrate reduction with iminosugars/chapperones. For autoimmune diseases, HSCT will be compared to immunosuppressant therapy, targeted biologic therapies, or low-dose chemotherapy.

Outcomes
Malignant solid tumorsPrimary outcomes:

Survival,
Harms/Adverse events:

adverse effects of treatment, long-term consequences of HSCT (e.g., growth and development, future fertility, secondary malignancies), and may include impaired quality of life.
Inherited metabolic diseases
Primary outcomes:

survival and cure
Harms/Adverse events:

adverse effects of treatment, long-term consequences of HSCT (e.g., growth and development, future fertility, secondary malignancies), and may include impaired quality of life.

Autoimmune diseases
Primary outcomes:

remission, survival, cure

Harms/Adverse events:

adverse effects of treatment, long-term consequences of HSCT (e.g., growth and development, future fertility, secondary malignancies), and may include impaired quality of life.
Timing
Will vary from disease to disease.
Setting
Upfront (initial therapy)
Relapsed/refractory

Definition of Terms
Hematopoietic stem-cell transplantation (HSCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in patients, and is categorized by the source of the stem cells.
Autologous transplants involve collecting and returning the patient’s own stem cells.
Allogeneic transplants use stem cells from an HLA-matched donor, either related or unrelated, and may also include those derived from umbilical cord blood.

References
-Alonzo TA, Wells RJ, Woods WG, et al. Postremission therapy for children with acute myeloid leukemia: the children’s cancer group experience in the transplant era. Leukemia 2005; 19:965-70.
-Amadori S, Testi AM, Arico M, et al. Prospective comparative study of bone marrow transplantation and postremission chemotherapy for childhood acute myelogenous leukemia. The Associazione Italiana Ematologia ed Oncologia Pediatrica Cooperative Group. J Clin Oncol 1993;11:1046-1054.
-Baldissera RC, Nucci M, Vigorito AC, et al. Frontline therapy with early intensification and autologous stem cell transplantation versus conventional chemotherapy in unselected high-risk, aggressive non-Hodgkin's lymphoma patients: a prospective randomized GEMOH report. Acta Haematol 2006; 115(1-2):15-21.
-Bernaudin F, Socie G, Kuentz M, et al. Long-term results of related, myeloablative stem cell transplantation to cure sickle cell disease. Blood 2007; 110(7):2749-56.
-Berthold F, Boos J, Burdach S, et al. Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomized controlled trial. Lancet Oncol 2005; 6(9):649-58.
-Betticher DC, Martinelli G, Radford JA, et al. Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL). Ann Oncol 2006; 17(10):1546-52.
-Bhatia M, Walters MC. Hematopoietic cell transplantation for thalassemia and sickle cell disease: past, present and future. Bone Marrow Transplant 2008; 41:109-17.
-Bleakley M, Lau L, Shaw PJ, et al. Bone marrow transplantation for paediatric AML in first remission: a systematic review and meta-analysis. Bone Marrow Transplantation 2002; 29(10):843-852.
-Connock M, Juarez-Garcia A, Frew E, et al. A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry’s disease and mucopolysaccharidosis type 1. Health Technol Assess 2006; 10(20):iii-iv, ix-113.
-Fish JD, Grupp SA. Stem cell transplantation for neuroblastoma. Bone Marrow Transplant 2008; 41(2):159-65.
-Greb A, Bohlius J, Schiefer D, et al. High-dose chemotherapy with autologous stem cell transplantation in the first line treatment of aggressive non-Hodgkin lymphoma (NHL) in adults. Cochrane Database Syst Rev. 2008 Jan 23; (1):CD004024.
-Hahn T, Wall D, Camitta B, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based review. Biol Blood Marrow Transplant 2005 Nov; 11(11):823-61.
-Hahn T, Wolff SN, Czuczman M, et al.; ASBMT Expert Panel. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of diffuse large cell B-cell non-Hodgkin's lymphoma: an evidence-based review. Biol Blood Marrow Transplant 2001; 7(6):308-31.
-Haioun C, Lepage E, Gisselbrecht C, et al. Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 1997; 15(3):1131-7.
-Hale GA. Autologous hematopoietic stem cell transplantation for pediatric solid tumors. Expert Rev Anticancer Ther 2005; 5(5), 835-46.
-Harrison G, Richards S, Lawson S, et al. Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. Ann Oncol 2000; 11(8):999-1006.
-Hehlmann R, Berger U, Pfirrmann M, et al. Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood 2007 Jun 1; 109(11):4686-92. Epub 2007 Feb 22.
-Kaiser U, Uebelacker I, Abel U, et al. Randomized study to evaluate the use of high-dose therapy as part of primary treatment for "aggressive" lymphoma. J Clin Oncol 2002; 20(22):4413-9.
-Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al. Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study. J Natl Cancer Inst 2001; 93(1):22-30.
-Kruse EB, Naumann F, Schwarzer G, et al. First-line stem cell transplantation from related donors compared to immunosuppressive treatment for acquired severe aplastic anaemia. (Protocol) Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD006407. DOI: 10.1002/14651858.CD006407.
-Lawson SE, Harrison G, Richards S, et al. The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the Medical Research Council UK ALLR1 study. Br J Haematol 2000; 108(3):531-43.
-Linch DC, Winfield D, Goldstone AH, et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomized trial. Lancet 1993; 341(8852):1051-4.
-Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med 1999; 341(16):1165-73.
-Meyers PA. High-dose therapy with autologous stem cell rescue for pediatric sarcomas. Curr Opin Oncol 2004; 16(2):120-5.
-Motzer RJ, Nichols CJ, Margolin KA, et al. Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol 2007; 25(3):247-56.
-Oliansky DM, Antin JH, Bennett JM, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes: an evidence-based review. Biol Blood Marrow Transplant 2009 Feb; 15(2):137-72.
-Oliansky DM, Rizzo JD, Aplan PD, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: an evidence-based review. Biol Blood Marrow Transplant 2007 Jan; 13(1):1-25.
-Olivieri A, Santini G, Patti C, et al. Upfront high-dose sequential therapy (HDS) versus VACOP-B with or without HDS in aggressive non-Hodgkin's lymphoma: long-term results by the NHLCSG. Ann Oncol 2005; 16(12):1941-8.
-Olsson-Strömberg U, Simonsson B, Ahlgren T, et al. Comparison of busulphan, hydroxyurea and allogeneic bone marrow transplantation (BMT) in chronic myeloid leukaemia: BMT prolongs survival. Hematol J 2004;5(6):462-6.
-Oringanje C, Nemecek E, Oniyangi O. Hematopoietic stem cell transplantation for children with sickle cell disease. (Protocol) Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD007001. DOI: 10.1002/14651858.CD007001.
-Pession A, Rondelli R, Basso G, et al. Treatment and long-term results in children with acute myeloid leukaemia treated according to the AIEOP AML protocols. Leukemia 2005; 19:2043-2053.
-Peters C, Steward CG. Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines. Bone Marrow Transplant 2003; 31:229-39.
-Pico JL, Rosti G, Kramar A, et al. A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours. Ann Oncol 2005; 16(7):1152-9.
-Pritchard J, Cotterill SJ, Germond SM, et al. High dose melphalan in the treatment of advanced neuroblastoma: results of a randomized trial (ENSG-1) by the European Neuroblastoma Study Group. Pediatr Blood Cancer 2005; 44(4):348-57.
-Ravindranath Y, Yeager AM, Chang MN, et al. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. Pediatric Oncology Group. N Engl J Med 1996; 334:1428-1434.
-Ribera JM, Ortega JJ, Oriol A, et al. Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 trial. J Clin Oncol 2007; 25(1):16-24.
-Schmitz N, Pfistner B, Sextro M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: a randomized trial. Lancet 2002; 359(9323):2065-71.
-Somaraju UR, Tadepalli K. Hematopoietic stem cell transplantation for Gaucher disease. (Protocol) Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD006974. DOI: 10.1002/14651858.CD006974
-Stevens RF, Hann IM, Wheatley K, et al. Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: results of the United Kingdom Medical Research Council’s 10th AML trial. MRC Childhood Leukaemia Working Party. Br J Haematol 1998; 101:130-140.
-Sweetenham JW, Santini G, Qian W, et al. High-dose therapy and autologous stem-cell transplantation versus conventional-dose consolidation/maintenance therapy as postremission therapy for adult patients with lymphoblastic lymphoma: results of a randomized trial of the European Group for Blood and Marrow Transplantation and the United Kingdom Lymphoma Group. J Clin Oncol 2001; 19(11):2927-36.
-Wheeler KA, Richards SM, Bailey CC, et al. Bone marrow transplantation versus chemotherapy in the treatment of very high-risk childhood acute lymphoblastic leukemia in first remission: results from Medical Research Council UKALL X and XI. Blood 2000; 96(7):2412-8.
-Woods WG, Neudorf S, Gold S, et al. A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 2001; 97:56-62.
-Yalçyn B, van Dalen EC, Caron HN, et al. High dose chemotherapy and autologous stem cell rescue for children with high risk neuroblastoma. (Protocol) Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD006301. DOI: 10.1002/14651858.CD006301

abrir aquí para acceder al documento AHRQ completo con sus vínculos y accesos:
Comment Key Questions - AHRQ Effective Health Care Program