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Ratko TA, Belinson SE, Brown HM, et al. Hematopoietic Stem-Cell Transplantation in the Pediatric Population [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Feb. (Comparative Effectiveness Reviews, No. 48.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Introduction

Background

Hematopoietic stem-cell transplantation (HSCT) involves the infusion of pluripotent hematopoietic progenitor cells to an individual in the course of treatment of a variety of conditions, including certain malignancies, autoimmune diseases, anemias, immunodeficiencies and inborn metabolic disease.1-3 While the term HSCT is used throughout this report, it is important to note that graft preparations actually contain a mixture of hematopoietic progenitor cells at different stages of maturity, including cells with self-renewal capability (stem cells).4

Hematopoietic progenitor cells arise in the bone marrow. These cells may be isolated from marrow that is aspirated from long bones or the pelvis; alternatively, they can be obtained from the blood by apheresis, and are termed peripheral blood stem cells (PBSC). The proportion of PBSCs circulating in the blood is normally very low, but can be significantly increased by the administration of cyclophosphamide, growth factors such as G-CSF, antibodies (e.g., anti-VLA-4), polyanions (e.g., fucoidan), chemokines (e.g., GROβ), and some signaling pathway inhibitors (e.g., AMD3100).4 Target yields of PBSCs sufficient for transplantation (i.e., more than 2 × 106 CD34+ cells/kg) are usually obtained with one to three aphereses, although this may vary in patients with different malignancies or other conditions (e.g., Fanconi's anemia). PBSCs generally result in faster hematopoietic reconstitution than progenitor cell concentrates isolated from aspirated bone marrow, and are the preferred preparation for autologous transplantation in modern clinical practice.4

Two fundamentally different types of HSCT are in clinical use, depending on the indication and the patient.1, 2 The first, autologous HSCT, involves infusion of hematopoietic progenitor cells obtained from the patient, with the sole intent to restore hematopoietic function following the administration of bone marrow ablative doses of cytotoxic agents. The effectiveness of autologous HSCT is derived entirely from the high-dose cytotoxic conditioning regimen, particularly for treatment of aggressive but chemosensitive malignancies, such as some Hodgkin's and non-Hodgkin's lymphomas. Tandem autologous HSCT refers to a planned treatment that involves administration of two cycles of myeloablative therapy, each followed by infusion of autologous HSCT.

The second type of HSCT, allogeneic HSCT, refers to the infusion of hematopoietic progenitor cells obtained from a donor, but has two purposes. It recreates a new immunohematopoietic system in patients who receive marrow ablative doses of cytotoxic agents. In addition, the nonself allogeneic immune effector cells contained in a donor stem cell preparation exert a therapeutic graft-versus-malignancy (GVM) effect, and in the case of autoimmune diseases, a possible graft-versus-autoimmune disease effect.

Allogeneic HSCT may involve the use of a fully marrow ablative, high-dose conditioning regimen, with accompanying tumor cytoreduction, or a nonmyeloablative regimen, that is referred to as reduced-intensity conditioning, with clinical benefit primarily secondary to the GVM effect.5, 6 Reduced-intensity conditioning regimens have been designed to extend the potential benefits of allogeneic HSCT to patients who for reasons of age, disease, or underlying comorbidities, would not be considered candidates for a high-dose, myeloablative procedure. In essence, autologous HSCT is a lifesaving rescue procedure to restore bone marrow function, whereas allogeneic HSCT may be both a rescue and therapeutic procedure.

Umbilical cord blood (UCB) also is a source of hematopoietic stem cells for transplantation.1 UCB is technically an allogeneic source of hematopoietic progenitor cells; it is hypothesized, however, that cord blood cells are more immunologically naïve than bone-marrow-derived progenitor cells. As a consequence, the incidence of acute and chronic graft-versus-host disease (GVHD) is lower with the use of UCB transplantation than with bone marrow-derived cell preparations. Human leukocyte antigen (HLA) matching requirements are thus less stringent than with marrow-derived progenitor cell preparations. However, the total number of progenitor cells that can be obtained from a single umbilical cord is relatively low, which has hampered the application of UCB transplantation in adults, even though outcomes are similar to those achieved with matched unrelated bone-marrow-derived cell preparations.1

HSCT of any type is associated with a number of adverse events, regardless of the conditioning regimen and type of transplant. Acute and chronic GVHD can be highly problematic in patients who undergo an allogeneic HSCT, and represent the major limitation to use of this procedure in older or otherwise debilitated patients.5 Short term (i.e., days 0-100 post-transplant) complications of HSCT of either type include mucositis, hemorrhage, infections (e.g., bacterial, fungal, viral), veno-occlusive disease of the liver, and pulmonary complications. Long-term complications include infertility, impaired growth and cognitive development, and secondary malignancies. The long-term complications assume greater importance in pediatric patients than in older recipients, in particular as post-HSCT survival rates have increased and treatment-related mortality has decreased with improved life support and management.7-10 Additional background information is presented in the discussion of each condition.

Scope and Key Questions

This comparative effectiveness review consists of two major sections, which were determined through the Agency for Healthcare Research and Quality (AHRQ) topic refinement process with input from Key Informants and AHRQ personnel (see Methods chapter). The first section comprises a set of narrative reviews on the use of HSCT in pediatric malignant and nonmalignant diseases for which HSCT is considered a well-established treatment option. The second section contains a set of systematic reviews of the use of HSCT in malignant and nonmalignant diseases, including solid tumors, inherited metabolic diseases, and autoimmune diseases. The indications systematically reviewed were those for which the therapeutic role of HSCT has not been established by clinical study. Specific settings are outlined in the Methods chapter. For pediatric malignancies, key outcomes of interest included overall survival, treatment-related mortality, and other severe adverse events.

For the inherited metabolic diseases, outcomes of interest were overall survival, neurocognitive and neurodevelopmental measures, treatment-related mortality, and other severe adverse events. For the autoimmune diseases, the key outcomes were drug-free clinical remission, as well as treatment-related mortality and other severe adverse events. No effort was made to systematically review outcomes in the context of different induction chemotherapy or consolidation conditioning regimens, supportive care, or stem-cell preparations. Rather, the document is intended to show the level of evidence in the literature on the use of HSCT for each indication, supposing that treatment will be delivered according to protocols in place at individual clinical institutions. The EPC Methods Guide process was used to provide an overall evaluation of the strength of evidence for each key outcome and for the overall body of evidence for each indication.

Table 1 displays the indications to be approached as a narrative review, while Table 2 displays the indications to be addressed in the systematic review. It is important to note that neuroblastoma, germ cell tumors, and central nervous system embryonal tumors are covered in both the narrative and systematic reviews; however, they are distinguished in each by the specific indication and the type of transplant procedure.

Table 1. Pediatric HSCT indications to be addressed with narrative review.

Table 1

Pediatric HSCT indications to be addressed with narrative review.

Table 2. Pediatric HSCT indications to be addressed with systematic review.

Table 2

Pediatric HSCT indications to be addressed with systematic review.

Systematic Review Key Questions

  • Key Question 1. For pediatric patients with malignant solid tumors, what is the comparative effectiveness of HSCT and conventional chemotherapy regarding overall survival, long-term consequences of HSCT, and quality of life?
  • Key Question 2. For pediatric patients with malignant solid tumors, what are the comparative harms of HSCT and conventional chemotherapy regarding adverse effects of treatment, long-term consequences of HSCT, and impaired quality of life?
  • Key Question 3. For pediatric patients with inherited metabolic diseases, what is the comparative effectiveness of HSCT, enzyme-replacement therapy (ERT), and substrate reduction with iminosugars regarding overall survival, cure, long-term consequences of HSCT, and quality of life?
  • Key Question 4. For pediatric patients with inherited metabolic diseases, what are the comparative harms of HSCT, enzyme-replacement therapy (ERT), and substrate reduction with iminosugars regarding adverse effects of treatment, long-term consequences of HSCT, and impaired quality of life?
  • Key Question 5. For pediatric patients with autoimmune diseases, what is the comparative effectiveness of HSCT, immunosuppressants, target biologic therapies, and low-dose chemotherapy regarding overall survival, cure, and remission?
  • Key Question 6. For pediatric patients with autoimmune diseases, what are the comparative harms of HSCT, immunosuppressants, target biologic therapies, and low dose chemotherapy regarding adverse effects of treatment, long-term consequences of HSCT, and impaired quality of life?

The PICOTS (Patient, Intervention, Comparator, Outcome, Timing, and Setting) for the three indications addressed in the systematic review follow.

Indication 1. Malignant Solid Tumors (Key Questions 1 and 2)

P:Pediatric patients with malignant solid tumors including rhabdomyosarcoma and retinoblastoma
I:Hematopoietic stem-cell transplantation (HSCT)
C:Conventional chemotherapy
O:Overall survival (OS); long-term consequences of HSCT; quality of life (QOL)
T:All durations of followup will be included
S:Inpatient

Indication 2. Inherited Metabolic Disease (Key Questions 3 and 4)

P:Pediatric patients with inherited metabolic diseases
I:Hematopoietic stem-cell transplantation (HSCT)
C:Enzyme-replacement therapy (ERT) for IMDs with products approved by the U.S. Food and Drug Administration (FDA), substrate reduction with iminosugars disease natural history
O:OS; cure; long-term consequences of HSCT; QOL
T:All durations of followup will be included
S:Inpatient

Indication 3. Autoimmune Disease (Key Questions 5 and 6)

P:Pediatric patients with autoimmune diseases
I:Hematopoietic stem-cell transplantation (HSCT)
C:Immunosuppressants, targeted biologic therapies, low-dose chemotherapy
O:Remission, survival, cure
T:All durations of followup will be included
S:Inpatient

Analytic frameworks are detailed in Figure 1, Figure 2, and Figure 3.

Figure 1 shows an analytic framework, i.e., a graph that depicts key questions one and two. Briefly, patients with pediatric malignant solid tumor can be treated with HSCT or other therapies. The short term effectiveness and safety of the interventions is measured by intermediate outcomes (recurrence free survival and progression free survival) and adverse event data. The long term effectiveness and safety of the interventions is measured overall survival, long term consequences of HSCT, and quality of life.

Figure 1

Analytic framework for HSCT for pediatric malignant solid tumors. HSCT = hematopoietic stem-cell transplantation; KQ = Key Question; QOL = quality of life

Figure 2 shows an analytic framework, i.e., a graph that depicts key questions three and four. Briefly, patients with pediatric inherited metabolic disease can be treated with HSCT or other therapies. The short term effectiveness and safety of the interventions is measured by intermediate outcomes stable source of endogenous enzyme, stabilization or slowed progression of neurocognitive decline) and adverse event data. The long term effectiveness and safety of the interventions is measured overall survival, cure, long term consequences of HSCT, and quality of life.

Figure 2

Analytic framework for HSCT for pediatric inherited metabolic diseases. GVHD = graft-versus-host disease; HSCT = hematopoietic stem-cell transplantation; KQ = Key Question; QOL = quality of life

Figure 3 shows an analytic framework, i.e., a graph that depicts key questions five and six. Briefly, patients with pediatric inherited metabolic disease can be treated with HSCT or other therapies. The short term effectiveness and safety of the interventions is measured by intermediate outcomes (slowed progression or improvement in organ damage secondary to the autoimmune disease) and adverse event data. The long term effectiveness and safety of the interventions is measured by remission, overall survival, cure, long term consequences of HSCT, and quality of life.

Figure 3

Analytic framework for HSCT for pediatric autoimmune diseases. GVHD = graft-versus-host disease; HSCT = hematopoietic stem-cell transplantation; KQ = Key Question; QOL = quality of life

Cover of Hematopoietic Stem-Cell Transplantation in the Pediatric Population
Hematopoietic Stem-Cell Transplantation in the Pediatric Population [Internet].
Comparative Effectiveness Reviews, No. 48.
Ratko TA, Belinson SE, Brown HM, et al.

AHRQ (US Agency for Healthcare Research and Quality)

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