Comparative Effectiveness Review Number 48 Effective Health Care Program Hematopoietic Stem-Cell Transplantation in the Pediatric Population Executive Summary Background Effective Health Care Program Hematopoietic stem-cell transplantation The Effective Health Care Program (HSCT) refers to a procedure in which was initiated in 2005 to provide hematopoietic progenitor cells, including valid evidence about the comparative repopulating stem cells, are infused effectiveness of different medical to restore bone marrow function in interventions. The object is to help patients.1,2,3 HSCT is categorized by the consumers, health care providers, source of the stem cells, with its role in and others in making informed pediatric diseases dependent in part on choices among treatment alternatives. the indication for which it is being used.4 Through its Comparative Effectiveness Autologous transplants involve harvesting Reviews, the program supports the patient’s own blood stem cells and then systematic appraisals of existing returning them, typically after the patient scientific evidence regarding has received doses of chemotherapy that treatments for high-priority health are myeloablative.1,2 Allogeneic HSCT conditions. It also promotes and uses stem cells from a donor who is generates new scientific evidence by either matched or unmatched on human identifying gaps in existing scientific leukocyte antigen (HLA) and either evidence and supporting new research. related or unrelated; in malignant diseases, The program puts special emphasis it exploits a graft-versus-tumor effect.5,6 on translating findings into a variety In the pediatric population, HSCT is of useful formats for different used to treat a wide variety of diseases, stakeholders, including consumers. both malignant and nonmalignant.7 For The full report and this summary are many of these diseases, HSCT is a well- available at www.effectivehealthcare. established treatment. For example, ahrq.gov/reports/final.cfm. the literature on the use of HSCT in hematologic malignancies is robust, including randomized controlled trials that date back 20 years, and its practice is supported by evidence-based guidelines. evidence consists of case series and case For many less common diseases—for reports, it is sufficient to demonstrate example, the primary immunodeficiencies improved outcomes, supporting use of and hemoglobinopathies—although the HSCT. Effective Health Care 1 The success of treating many of the pediatric diseases Key Question 3. For pediatric patients with inherited with HSCT has resulted in an increased number of metabolic diseases, what is the comparative effectiveness long-term survivors. As improvements in survival have of HSCT, enzyme-replacement therapy (ERT), and been achieved, there is greater concern about long- substrate reduction with iminosugars regarding overall term effects and how adverse effects (e.g., graft-vs.- survival, cure, long-term consequences of HSCT, and host disease, opportunistic infections, future infertility, quality of life? developmental delay, and secondary malignancies) might 7,8,9,10 Key Question 4. For pediatric patients with inherited be mitigated. The Key Questions for this review metabolic diseases, what are the comparative harms of compared benefits and harms of HSCT and conventional HSCT, ERT, and substrate reduction with iminosugars therapy for pediatric diseases. regarding adverse effects of treatment, long-term consequences of HSCT, and impaired quality of life? Objectives Key Question 5. For pediatric patients with autoimmune Key Questions addressed in this report are split into diseases, what is the comparative effectiveness of HSCT, three groups of two questions each. They pertain to immunosuppressants, targeted biologic therapies, and low- malignant solid tumors, inherited metabolic diseases, and dose chemotherapy regarding overall survival, cure, and autoimmune diseases. remission? Key Question 1. For pediatric patients with malignant Key Question 6. For pediatric patients with autoimmune solid tumors, what is the comparative effectiveness of diseases, what are the comparative harms of HSCT, HSCT and conventional chemotherapy regarding overall immunosuppressants, targeted biologic therapies, and low- survival, long-term consequences of HSCT, and quality of dose chemotherapy regarding adverse effects of treatment, life? long-term consequences of HSCT, and impaired quality of Key Question 2. For pediatric patients with malignant life? solid tumors, what are the comparative harms of HSCT and conventional chemotherapy regarding adverse effects Analytic Framework of treatment, long-term consequences of HSCT, and Analytic frameworks are detailed in Figures A, B, and C. impaired quality of life? Figure A. Analytic framework for HSCT for pediatric malignant solid tumors KQ 1 Treatment, therapy, or intervention -HSCT Final health outcomes Intermediate Outcomes Pediatric KQ 1 KQ 1 • Overall survival malignant solid • Recurrence-free survival • Long-term tumors • Progression-free survival consequences of HSCT • QOL KQ 2 Adverse effects of treatment • Immunosuppression (e.g., opportunistic infection) • Specific organ injury HSCT = hematopoietic stem-cell transplantation; KQ = Key Question; QOL = quality of life 2 Figure B. Analytic framework for HSCT for pediatric inherited metabolic diseases KQ 3 Treatment, therapy, or intervention -HSCT Intermediate Outcomes Final health outcomes Pediatric KQ 3 • Stable source of endogenous KQ 3 • Survival inherited metabolic enzyme • Cure • Long-term diseases • Stabilization or slowed progression of neurocognitive consequences of decline HSCT KQ 4 • QOL Adverse effects of treatment • GVHD • Immunosuppression (e.g., opportunistic infection) • Specific organ injury GVHD = graft-versus-host disease; HSCT = hematopoietic stem-cell transplantation; KQ = Key Question; QOL = quality of life Figure C. Analytic framework for HSCT for pediatric autoimmune diseases KQ 5 Treatment, therapy, or intervention -HSCT Final health outcomes Intermediate Outcomes • Remission Pediatric KQ 5 Slowing of the progression of or KQ 5 inherited metabolic • Overall survival improvement in organ damage • Cure diseases secondary to the autoimmune • Long-term disease consequences of HSCT KQ 6 • QOL Adverse effects of treatment • GVHD • Immunosuppression (e.g., opportunistic infection) • Specific organ injury GVHD = graft-versus-host disease; HSCT = hematopoietic stem-cell transplantation; KQ = Key Question; QOL = quality of life 3 Methods clinical practice was less established, so that systematic review of the literature would be more likely to provide Topic Refinement new insight to inform the field (Table B). This report comprises a set of narrative reviews and The final categorization of indications for the narrative systematic reviews that were defined during the topic reviews was determined in an iterative process. refinement phase of the project. Topic refinement Information sources for the narrative reviews were not also outlined the frameworks and PICOTS (patients, identified by a systematic search of the literature. Rather, interventions, comparator, outcome, timing, setting) that the EPC relied on recently published reviews of pediatric were posted for public comments and incorporated into the transplantation studies and publicly available sources, such final version. Following completion of the topic refinement as the National Guidelines Clearinghouse and the National phase, a Technical Expert Panel (TEP) was formed. The Cancer Institute Physicians Data Query (PDQ) Web site, TEP included original Key Informant (KI) panel members to develop an initial list of diseases for discussion with the and clinical experts not previously involved. The TEP KI panel. The EPC subsequently reexamined the lists and provided consultation on the development of the protocol compared them with existing evidence in the context of and evidence tables for the review. In particular, the TEP the KI discussions. A final list of indications for narrative provided advice on appropriate clinical outcome data reviews compiled by the EPC was posted for public to compile for both benefits and harms. Ad hoc clinical comment. Neuroblastoma, germ cell tumors, and central questions were also addressed to the TEP. nervous system embryonal tumors are covered in both narrative and systematic reviews. They are distinguished Narrative Reviews in each by the specific indication and the type of transplant The narrative review approach to the conditions presented procedure, as shown in Tables A and B. in Table A was based on the recognition that there exists Systematic Reviews a substantial body of evidence from 20 years or more of transplantation research and experience that has been Table B shows the indications that were systematically codified into published guidelines and reviews. Thus, reviewed. Neuroblastoma, germ cell tumors, and central systematic review of the evidence for these diseases would nervous system embryonal tumors are covered in both not be expected to offer new insights or information. narrative and systematic reviews. They are distinguished In contrast, the Evidence-based Practice Center (EPC) in each by the specific indication and the type of transplant recognized that there were a number of diseases for which procedure, as shown in Tables A and B. evidence of benefits and harms was less clear or for which Table A. Pediatric HSCT indications to be addressed with narrative review Type Disease Indication(s) Transplant Type MH Acute lymphoblastic