Hematopoietic Stem-Cell Transplantation for Rare Diseases in the Pediatric Population

1
Hematopoietic Stem-Cell Transplantation for
Rare Diseases in the Pediatric Population

• Prepared for
• Agency for Healthcare Research and Quality (AHRQ)
• www.ahrq.gov

2
Rationale for a Systematic Review on
Hematopoietic Stem-Cell Transplantation for Rare
Diseases in the Pediatric Population

• Hematopoietic stem-cell transplantation (HSCT) is
  usually reserved for patients or for subgroups of
  patients who have diseases with a very poor
  prognosis that are often refractory to the best
  available treatments.
• This summary of a review of HSCT in the pediatric
  population addresses indications for which there
  is uncertainty or evolving evidence, often
  comprising uncontrolled single-arm studies and
  case reports.
• Randomized controlled trials were rare for any of
  the indications included.
• A narrative review of pediatric diseases for
  which a larger evidence base and/or guidelines
  are available for the use of allogeneic or
  autologous HSCT is presented in detail in the
  complete report available at www.effectivehealthca
  re.ahrq.gov/stem-cell-children.cfm.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

3
Outline of Material

• Agency for Healthcare Research and Quality (AHRQ)
  Comparative Effectiveness Review (CER) Process
• Clinical Questions Addressed in the CER
• Lists of rare pediatric diseases contained in the
  systematic review are included here.
• Summary of CER Results
• For each disease where there are results with a
  strength-of-evidence rating, brief background
  information is given and followed by the specific
  results.
• Summary of Conclusions
• Gaps in Knowledge
• Resources for Shared Decisionmaking

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

4
Agency for Healthcare Research and Quality (AHRQ)
Comparative Effectiveness Review (CER) Development

• Topics are nominated through a public process,
  which includes submissions from health care
  professionals, professional organizations, the
  private sector, policymakers, the public, and
  others.
• A systematic review of all relevant clinical
  studies is conducted by independent researchers,
  funded by AHRQ, to synthesize the evidence in a
  report summarizing what is known and not known
  about the select clinical issue. The research
  questions and the results of the report are
  subject to expert input, peer review, and public
  comment.
• The results of these reviews are summarized into
  a Clinician Research Summary and a Consumer
  Research Summary for use in decisionmaking and in
  discussions with patients.
• The Research Summaries and the full report are
  available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

5
Strength-of-Evidence Ratings

• The strength-of-evidence ratings are classified
  into four broad categories

High Further research is very unlikely to change the confidence in the estimate of effect.
Moderate Further research may change the confidence in the estimate of effect and may change the estimate.
Low Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.
Insufficient Evidence either is unavailable or does not permit a conclusion.

• Agency for Healthcare Research and Quality.
  Methods Guide for Effectiveness and Comparative
  Effectiveness Reviews. Chapters available at
  www.effectivehealthcare.ahrq.gov/methodsguide.cfm.
  Owens DK, Lohr KN, Atkins D, et al. J Clin
  Epidemiol. 201063513-23. PMID 19595577.
• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

6
Clinical Questions Addressed in the Comparative
Effectiveness Review

• What are the comparative effectiveness and
  adverse effects of hematopoietic stem-cell
  transplantation (HSCT) versus usual care in the
  pediatric population (aged 21 years) for rare
  pediatric diseases including
• Malignant solid tumors
• Inherited metabolic disorders
• Autoimmune diseases (mostly severe, refractory,
  and/or progressive)
• A narrative review of pediatric diseases for
  which a larger evidence base and/or guidelines
  are available for the use of allogeneic or
  autologous HSCT is presented in detail in the
  complete report available at www.effectivehealthca
  re.ahrq. gov/stem-cell-children.cfm.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

7
Rare Pediatric Malignant Solid Tumors Included in
the Systematic Review

• Ewings sarcoma family of tumors
• Wilms tumors
• Rhabdomyosarcoma
• Retinoblastoma
• Neuroblastoma
• Germ cell tumor
• Central nervous system embryonal tumors
• Central nervous system glial tumors

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

8
Rare Pediatric Inherited Metabolic Disorders
Included in the Systematic Review

• Mucopolysaccharidosis MPS II (Hunter syndrome),
  MPS III (Sanfilippo syndrome), and MPS IV
  (Morquio syndrome)
• Sphingolipidosis Fabry disease, Farber disease,
  Gaucher disease types II and III, GM1
  gangliosidosis, Niemann-Pick disease type A,
  Tay-Sachs disease, and Sandhoff disease
• Glycoproteinosis aspartylglucosaminuria,
  beta-mannosidosis, and mucolipidosis types III
  and IV
• Other lipidoses Niemann-Pick disease type C,
  Wolman disease, and neuronal ceroid
  lipofuscinosis
• Glycogen storage disease GSD type II
• Multiple enzyme deficiency galactosialidosis and
  mucolipidosis type II
• Lysosomal transport defects cystinosis, sialic
  acid storage disease, and Salla disease
• Peroxisomal storage disorders adrenomyeloneuropat
  hy

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

9
Rare Pediatric Autoimmune Diseases Included in
the Systematic Review

• Systemic lupus erythematosus
• Severe, refractory, juvenile idiopathic arthritis
• Severe, refractory, systemic sclerosis
• Severe, refractory, malignant multiple sclerosis
• Severe, refractory, disabling Crohns disease
• Newly diagnosed juvenile type-1 diabetes (DM1)
• DM1 is included here not because it is rare, but
  because the use of autologous hematopoietic
  stem-cell transplantation in this pediatric
  population is rare.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

10
Outcomes of Interest

• Pediatric malignancies
• Overall survival
• Treatment-related mortality
• Other severe adverse events
• Inherited metabolic diseases
• Overall survival
• Neurocognitive and neurodevelopmental measures
• Treatment-related mortality
• Other severe adverse events
• Autoimmune diseases
• Drug-free clinical remission
• Treatment-related mortality
• Other severe adverse events

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

11
Evidence for Autologous HSCT for Pediatric
Malignant Solid Tumors Included in the Systematic
Review

• A narrative review of pediatric malignant solid
  tumors (e.g., neuroblastoma, germ cell tumors,
  and central nervous system embryonal tumors) for
  which a larger evidence base and/or guidelines
  are available for the use of autologous
  hematopoietic stem-cell transplantation (HSCT) is
  presented in detail in the narrative section of
  the report available at www.effectivehealthcare.ah
  rq.gov/stem-cell-children.cfm.
• In the systematic review, the authors focused on
  the evidence for using autologous HSCT for those
  pediatric solid tumors for which evidence is less
  certain.
• The authors of the systematic review included
  evidence on a single versus conventional therapy
  for
• Glial tumors
• High-risk, recurrent, or progressive anaplastic
  astrocytoma
• Nonanaplastic, mixed, or unspecified ependymoma
• Metastatic rhabdomyosarcoma
• Extraocular retinoblastoma with central nervous
  system involvement
• High-risk Ewings sarcoma family of tumors
• High-risk, relapsed Wilms tumor

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

12
Background Glial Tumors

• Glial tumors are the largest group of primary
  brain tumors in children and adolescents and
  contribute significant morbidity and mortality.
• Glial tumors are classified into four major
  categories
• Astrocytic
• Ependymal
• Oligodendroglial or mixed gliomas
• Choroid plexus tumors
• According to SEER data, the pediatric
  age-adjusted incidence rates of primary central
  nervous system glial tumors per 100,000 people
  are
• Astrocytoma (excluding pilocytic) 0.411
• Glioblastoma 0.138
• Ependymoma/anaplastic ependymoma 0.226
• Choroid plexus tumor 0.025
• Oligodendroglioma 0.083
• Brain and other nervous system tumors 0.65

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

13
Background Included Glial Tumor Studies

• Data are primarily from case series and case
  reports.
• Overall survival outcomes are difficult to
  interpret due to differences in patient
  selection, small numbers of patients, patient
  data not stratified by tumor type, and
  differences in conditioning regimens.
• Patients were classified as newly diagnosed or as
  having recurrent/progressive disease.
• Evidence includes 1 comparative cohort study of
  hematopoietic stem-cell transplantation (HSCT)
  versus conventional therapy, 1 noncomparative
  cohort study, 4 randomized clinical trials, 3
  phase II trials, and 30 case series (total
  patients N 1,012 215 received HSCT and 797
  received conventional therapy).

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

14
Evidence for Using Autologous HSCT To Treat
Patients With High-Risk, Recurrent, or
Progressive Anaplastic Astrocytoma

• The prognosis for patients with high-grade glioma
  is poor.
• The median survival is less than 1 year, and the
  majority of patients die within 2 years.
• Patients with grade II astrocytoma may survive
  for 5 or more years, while patients with
  anaplastic astrocytoma often die within 2 or 3
  years their tumor frequently shows signs of
  progression to glioblastoma multiforme, with
  survival times substantially less than 2 years.

Outcome Results Strength of Evidence
Overall survival Improves 5-year overall survival (40, n 10) when compared with patients who receive conventional therapy (0, n 71). Low

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

15
Evidence for Using Autologous HSCT To Treat
Patients With Nonanaplastic, Mixed, or
Unspecified Ependymoma

• Ependymomas account for 6 to 10 percent of brain
  tumors in children.
• Conventional therapy has an estimated 5-year
  overall survival of 50 to 64 percent and a
  progression-free survival of 23 to 45 percent.
• Significant prognostic factors are the extent of
  tumor resection and age.

Outcome Results Strength of Evidence
Overall survival Associated with higher treatment-related mortality than conventional therapy and leads to shorter overall survival Low

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

16
Background Rhabdomyosarcoma

• The incidence of rhabdomyosarcoma is 4 to 7 cases
  per 1 million children aged 15 years or younger.
• Approximately 350 new cases are diagnosed each
  year in the United States.
• A majority of children have an initial
  presentation of nonmetastatic disease and have a
  60- to 70-percent chance of cure.
• Metastatic rhabdomyosarcoma is generally a lethal
  disease less than 20 percent of patients are
  cured.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

17
Evidence for Using Autologous HSCT To Treat
Patients With Metastatic Rhabdomyosarcoma

• Twenty-six studies with 887 patients were
  included.
• Treatment consisted of hematopoietic stem-cell
  transplantation (HSCT) for 340 patients and
  conventional chemotherapy for 547 patients.
• No information on quality of life was provided,
  and data on adverse events were sparse and,
  therefore, insufficient to permit conclusions.

Outcome Results Strength of Evidence
Overall survival No benefit with a single HSCT when compared with conventional therapy. Moderate

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

18
Background Retinoblastoma

• Retinoblastoma is the most common primary
  intraocular tumor in children.
• It has an incidence of 1 in 15,000 births.
• It accounts for 4 percent of all childhood
  cancerous tumors.
• The most affected children present with
  intraocular disease, and conventional treatments
  offer at least a 90-percent chance of cure.
• Trilateral, extraocular, and metastatic
  retinoblastoma are generally lethal, specifically
  when the disease has reached the central nervous
  system.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

19
Evidence for Using Autologous HSCT To Treat
Patients With Extraocular Retinoblastoma With CNS
Involvement

• Twenty reports were included, with a total number
  of patients of 267.
• With regard to treatment, 91 patients in 15
  studies received hematopoietic stem-cell
  transplantation (HSCT), whereas 176 patients in 7
  studies received conventional chemotherapy.
• Other than the patients with trilateral
  retinoblastoma, all patients had metastatic
  disease before HSCT.
• A study of trilateral retinoblastoma was also
  separated into its own category.
• Ten studies reported on patients with central
  nervous system (CNS) involvement.

Outcome Results Strength of Evidence
Overall survival No benefit with a single HSCT when compared with conventional therapy. Low

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

20
Background Ewings Sarcoma Family of Tumors

• Ewings sarcoma is the second most common primary
  malignant bone tumor in children, adolescents,
  and young adults.
• The incidence in the United States is 1 per
  1,000,000 in the population, and 25 percent of
  cases will have metastatic disease at diagnosis.
• Conventional treatment is systemic chemotherapy
  in conjunction with either surgery or radiation
  or both for local tumor control.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

21
Background High-Risk Tumors in the Ewings
Sarcoma Family of Tumors

• Patients with any type of Ewings sarcoma who
  have the following characteristics are considered
  at high risk
• Relapsed or resistant disease
• Primary tumor site in the axial skeleton
  including the pelvis
• Large tumor volume
• Presence of metastatic disease
• The prognosis for patients with high-risk tumors
  treated with conventional chemotherapy,
  radiation, and surgery remains poor.
• Long-term survival for patients with metastatic
  disease is lt35 percent.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

22
Evidence for Using Autologous HSCT To Treat
Patients With High-Risk Tumors in the Ewings
Sarcoma Family of Tumors

• Evidence regarding a single autologous
  hematopoietic stem-cell transplantation (HSCT)
  comes from 24 case series and 6 case reports and
  includes 446 patients.
• Comparator evidence is from 7 case series
  including 283 patients who received conventional
  chemotherapy.

Outcome Results Strength of Evidence
Overall survival No benefit with a single HSCT when compared with conventional therapy. Low

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

23
Background Wilms Tumor

• Wilms tumor is the fifth most common pediatric
  malignancy and the most common renal tumor in
  children.
• Its incidence is about 0.8 cases per 100,000
  people.
• There are 500 new cases diagnosed each year in
  the United States.
• Wilms tumor is diagnosed at a mean age of 3.5
  years.
• Overall survival rates are about 90 percent with
  first-line therapy (surgery, chemotherapy, and
  possibly radiation).
• Recurrence occurs in 15 percent of nonanaplastic
  cases and 50 percent of anaplastic cases.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

24
Evidence for Using Autologous HSCT To Treat
Patients With High-Risk, Relapsed Wilms Tumor

• Patients with relapsed Wilms tumor and adverse
  prognostic factors are in the high-risk relapse
  category.
• Adverse prognostic factors include
• Initial advanced tumor stage
• Anaplastic histology
• Early recurrence (lt6 months after diagnosis)
• Recurrence in multiple organs or a previously
  irradiated field
• Initial chemotherapy regimen that includes
  doxorubicin (VAD)
• Twenty reports with 202 patients were included
  114 patients had hematopoietic stem-cell
  transplantation (HSCT), and 88 had chemotherapy.

Outcome Results Strength of Evidence
Overall survival No benefit with a single autologous HSCT when compared with conventional therapy. Low

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

25
Evidence for the Use of Allogeneic HSCT for
Pediatric Inherited Metabolic Diseases Included
in the Systematic Review

• A narrative review of pediatric inherited
  metabolic diseases (e.g., Hurler disease,
  Maroteaux-Lamy syndrome, Sly syndrome, Gaucher
  disease type I, among others) for which a larger
  evidence base and/or guidelines are available for
  the use of allogeneic hematopoietic stem-cell
  transplantation (HSCT) is presented in detail in
  the narrative section of the report available at
  www.effectivehealthcare.ahrq.gov/stem-cell-childre
  n.cfm.
• In the systematic review, results are reported
  for a single allogeneic HSCT versus conventional
  therapy for
• Diseases with rapid progression Wolman disease
  and Niemann-Pick disease type A
• Diseases with slow progression
  mucopolysaccharidosis type II (Hunter syndrome),
  mucopolysaccharidosis type III (Sanfilippo
  syndrome), and Gaucher disease type III
• Diseases with both rapid and slow progression
  forms Farber disease (slow-progression type 2/3)
  and neuronal ceroid lipofuscinosis

For Wolman disease, no head-to-head comparative
studies were available the disease is uniformly
fatal without HSCT, so the natural history of the
disease was considered an indirect comparator.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

26
Background Wolman Disease

• Wolman disease is a rare autosomal recessive
  disorder characterized by a deficiency of
  lysosomal acid lipase.
• Cholesterol esters and triglycerides accumulate
  in the spleen, liver, adrenal glands, bone
  marrow, small intestine, and lymph nodes.
• Fewer than 80 cases have been identified.
• Symptoms occur within the first week of life and
  include failure to thrive, jaundice, anemia,
  relentless vomiting, abdominal distention,
  steatorrhea, and hepatosplenomegaly.
• Life expectancy is about 6 months or less.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

27
Evidence for Using Allogeneic HSCT To Treat
Patients With Wolman Disease

• Evidence includes two case reports and two case
  series.
• Seven patients were treated with allogeneic
  hematopoietic stem-cell transplantation (HSCT).
• Two patients died of treatment-related mortality
  and one from disease progression.
• Four patients survived treatment three were
  long-term survivors (411 years of followup) and
  are highly functional.

Outcome Results Strength of Evidence
Overall survival Significant benefit with a single HSCT when compared with conventional therapy. High

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

28
Background Niemann-Pick Disease Type A

• Niemann-Pick disease is characterized by the
  accumulation of lipids in the spleen, liver,
  lungs, bone marrow, and the brain.
• There are three types of this disease A, B, and
  C.
• Type A occurs in 1 in 40,000 of Ashkenazi Jewish
  people.
• The frequency of types A and B in the general
  population is 1 in 250,000.
• Type A is the most severe form.
• It occurs in infants and is characterized by
  jaundice, an enlarged liver, and brain damage.
• Life expectancy is about 3 years.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

29
Evidence for Using Allogeneic HSCT To Treat
Patients With Niemann-Pick Disease Type A

• Evidence is from one case report and one case
  series (N 3 patients).
• Two patients died of disease progression at 2
  years of followup.
• One patient was alive at 2.7 years of followup
  but with neurocognitive and neurodevelopmental
  decline.

Outcome Results Strength of Evidence
Overall survival No benefit was conferred with a single hematopoietic stem-cell transplantation when compared with conventional therapy. Low

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

30
Background Mucopolysaccharidosis Type II (Hunter
Syndrome)

• Hunter syndrome is a rare X-linked recessive
  disorder caused by a deficiency in the iduronate
  2-sulfatase enzyme.
• The estimated incidence in Europe is between 1 in
  110,000 to 300,000 a higher incidence of 1 in
  34,000 has been noted in the Israeli Jewish
  population.
• In the attenuated form, there is minimal central
  nervous system involvement survival extends into
  the 5th and 6th decade.
• In the severe form, onset can occur at age 2 to 4
  years, with survival into only the 2nd decade of
  life. The cause of death is usually heart disease.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

31
Evidence for Using Allogeneic HSCT To Treat
Patients With Attenuated or Severe MPS II (Hunter
Syndrome)

• Evidence from three case reports and three case
  series included six patients with the attenuated
  form of mucopolysaccharidosis type II (MPS II)
  who were treated with hematopoietic stem-cell
  transplantation (HSCT)
• Four patients showed stabilization of cognitive
  skills.
• Evidence from three case reports and one case
  series included eight patients with the severe
  form of MPS II who were treated with HSCT
• Neurocognitive decline continued in seven of the
  eight patients.

Outcome Results for a Single HSCT Compared With Enzyme-Replacement Therapy Strength of Evidence
Neurodevelopmental Benefit for both the attenuated and severe forms Low
Neurocognitive Benefit for the attenuated form Low
Neurocognitive No benefit for the severe form Low

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

32
Background Mucopolysaccharidosis Type III
(Sanfilippo Syndrome)

• Mucopolysaccharidosis type III is an autosomal
  recessive disorder defined by specific enzyme
  deficiencies related to the breakdown of heparin
  sulfate
• Type A heparan sulfate sulfatase
• Type B N-acetyl-?-glucosaminidase
• Type C acetyl-CoA?-glucosaminide
  N-acetyltransferase
• Type D N-acetyl-?-glucosamine-6-sulfate
  sulfatase
• Type A is the most severe form of the disease
• Severe progressive central nervous system
  involvement
• Initial symptom onset from 1 to 6 years of age
• Progressive mental deterioration reaching
  severity by ages 6 to 10 years
• Life expectancy of 12 to 20 years
• Death primarily caused by cardiopulmonary arrest

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

33
Evidence for Using Allogeneic HSCT To Treat
Patients With Mucopolysaccharidosis Type III
(Sanfilippo Syndrome)

• Evidence regarding allogeneic hematopoietic
  stem-cell transplantation (HSCT) in patients with
  mucopolysaccharidosis type III comes from two
  case reports and two case series.
• Continuing neurocognitive deterioration occurred
  in all six patients for whom there were followup
  data.
• Two out of three treated patients had less
  neurodevelopmental decline when compared with
  untreated patients.

Outcome Results for a Single Allogeneic HSCT Compared With Symptom Management Strength of Evidence
Neurodevelopmental No benefit from HSCT Low
Neurocognitive No benefit from HSCT Low

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

34
Background Gaucher Disease

• Gaucher disease is caused by a deficiency in the
  enzyme glucocerebrosidase, which leads to
  accumulation of glucosylceramide in the spleen,
  liver, lungs, and bone marrow and sometimes in
  the brain.
• There are three types of Gaucher disease I, II,
  and III.
• Gaucher disease type III is the subacute
  neuronopathic form.
• It usually begins later in childhood or
  adolescence, with loss of muscle coordination and
  cognitive deterioration progressing more slowly
  than with type II.
• Patients may live into adulthood.
• Enzyme-replacement therapy can help severe
  visceral symptoms but not the neurologic
  progression of the disease.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

35
Evidence for Using Allogeneic HSCT To Treat
Patients With Gaucher Disease Type III

• Evidence comes from two case reports and two case
  series that include eight patients treated with
  hematopoietic stem-cell transplantation (HSCT),
  one patient treated with HSCT followed by
  enzyme-replacement therapy (ERT), and nine
  patients treated with ERT only.
• Patients undergoing HSCT and patients treated
  with ERT have shown improved growth, although
  their skeletal symptoms persist.

Outcome Results for a Single Allogeneic HSCT Compared With Enzyme-Replacement Therapy Strength of Evidence
Neurodevelopmental No benefit from HSCT Low
Neurocognitive No benefit from HSCT Low

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

36
Background Farber Disease

• Farber disease is an autosomal recessive disorder
  characterized by a deficiency in ceramidase.
• This deficiency results in the accumulation of
  ceramide in various tissues, the central nervous
  system (CNS), and most notably the joints.
• Symptoms can begin in the first few weeks of
  life.
• Type 1 is the severe form.
• It has CNS involvement.
• It has a life expectancy of 2 years.
• Type 2/3 is the milder form.
• It has mild or no CNS involvement.
• Patients can live into their teenage years.
• Chronic respiratory failure is the most common
  cause of death.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

37
Evidence for Using Allogeneic HSCT To Treat
Patients With Farber Disease Type 2/3

• Evidence from two case series included five
  patients with Farber disease type 2/3 undergoing
  hematopoietic stem-cell transplantation (HSCT).
• The number of subcutaneous nodules and the number
  of joints with limited range of motion were
  reduced.

Outcome Results for a Single Allogeneic HSCT Compared With Symptom Management or Natural History of Farber Disease Strength of Evidence
Subcutaneous nodules and joints with limited range of motion Reduced number of subcutaneous nodules and joints with limited range of motion at 0.7 to 1.3 years of followup. High

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

38
Background Neuronal Ceroid Lipofuscinosis

• Neuronal ceroid lipofuscinoses are autosomal
  recessive disorders that are the most common
  class of neurodegenerative diseases in children.
• A defect in the enzyme that degrades fatty
  acylated proteins causes the storage of
  autofluorescent lipopigments in lysosomes.
• Depending on which gene is affected, symptoms may
  begin during early infancy, late infancy, or the
  juvenile years.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

39
Evidence for Using Allogeneic HSCT To Treat
Patients With Infantile Neuronal Ceroid
Lipofuscinosis

• Evidence from one case series includes three
  patients.
• Neurocognitive decline continued in all three
  patients.
• Hematopoietic stem-cell transplantation (HSCT)
  does not show a benefit when used to treat
  infantile ceroid lipofuscinosis.
• Strength of Evidence Low

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

40
Evidence for the Role of Autologous HSCT for
Select Pediatric Autoimmune Diseases Included in
the Systematic Review

• A narrative review of pediatric autoimmune
  diseases (e.g., primary immunodeficiencies) for
  which a larger evidence base and/or guidelines
  are available for the use of autologous
  hematopoietic stem-cell transplantation (HSCT) is
  presented in detail in the narrative section of
  the report available at www.effectivehealthcare.ah
  rq.gov/stem-cell-children.cfm.
• The autoimmune diseases for which there was
  evidence are
• Newly diagnosed juvenile type-1 diabetes
• Systemic lupus erythematosus
• Severe, refractory juvenile idiopathic arthritis
• Severe, refractory systemic sclerosis
• Severe, refractory malignant multiple sclerosis
• Crohns disease

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

41
Background Newly Diagnosed Juvenile Type-1
Diabetes Mellitus

• Juvenile type-1 diabetes is a T-cellmediated
  autoimmune disease that is characterized by
  selective, relentless, and irreversible
  destruction of insulin-producing pancreatic
  beta-cells.
• Typically, 60 to 80 percent of beta-cells have
  been destroyed by the time of diagnosis.
• It is the most common childhood autoimmune
  disorder ,with 15,000 newly diagnosed cases in
  the United States annually.
• It does not usually develop into a fulminant,
  life-threatening form, but it is a relentlessly
  progressive disorder despite standard therapy,
  which includes either standard or intensive
  insulin therapy.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

42
Background Intensive Insulin Therapy and Immune
Modulation Therapy for Newly Diagnosed Juvenile
DM1

• In patients with juvenile type-1 diabetes
  mellitus (DM1), intensive insulin therapy (IIT)
  decreases the risk of diabetic retinopathy,
  nephropathy, and neuropathy by 39 to 90 percent
  and reduces the rate of progression by 39 to 60
  percent when compared with standard insulin
  therapy.
• IIT treatment is complicated by
• Lack of patient acceptance and compliance
• Deficiency in fully preventing diabetic
  complications
• Its association with an increased risk of severe
  hypoglycemia versus standard therapy
• Immune modulation therapy can be used in addition
  to IIT but
• It may induce slower decline or initial
  improvement of C-peptide levels.
• Most patients will still rely on increasing doses
  of exogenous insulin.
• Concerns exist with regard to the toxic effects
  of immune suppression.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

43
Background Rationale for Using HSCT To Treat
Newly Diagnosed Juvenile Type-1 Diabetes Mellitus

• To possibly reconstitute immune tolerance after
  immunologic reset, nonmyeloablative autologous
  hematopoietic stem-cell transplantation (HSCT)
  has been investigated as a way to effect intense,
  but brief, immune suppression and preserve islet
  cell mass in children with newly diagnosed type-1
  diabetes mellitus (DM1).
• It is hypothesized that early intervention with
  HSCT will prevent the development of
  DM1-associated complications, improve quality of
  life, and ultimately increase life expectancy in
  this population.
• The effects of HSCT on insulin use and C-peptide
  levels will be compared to those parameters in
  children treated with intensive insulin therapy
  (IIT), in the context of the adverse events
  associated with HSCT and IIT.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

44
Evidence for Using Nonmyeloablative Autologous
HSCT To Treat Newly Diagnosed Juvenile Type-1
Diabetes Mellitus

• The evidence comes from one prospective phase
  I/II study of patients who were treated with
  nonmyeloablative autologous hematopoietic
  stem-cell transplantation (HSCT n 18) versus
  intensive insulin therapy in the control arms of
  two studies (n 35).
• Among patients who received HSCT, 89 percent
  became insulin free either continuously (63) or
  transiently (37).

Outcome Results for Nonmyeloablative Autologous HSCT Compared With Intensive Insulin Therapy Strength of Evidence
Long-term benefits and/or adverse effects __ Insufficient
Insulin independence Extended interval of insulin independence with a single autologous nonmyeloablative HSCT Moderate

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

45
Background Systemic Lupus Erythematosus

• Systemic lupus erythematosus (SLE) is a chronic
  autoimmune disease that is associated with
  inflammation and eventual organ damage.
• SLE has no known cure.
• Juvenile-onset SLE (prior to age 18 years)
  accounts for 15 to 20 percent of cases of the
  estimated 10 to 20 cases per 100,000 children.
• Juvenile-onset SLE has a more severe
  presentation, faster development of organ damage,
  and a higher disease burden over a lifetime.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

46
BackgroundTreatments for Systemic Lupus
Erythematosus

• Depending on severity, treatments often include
  high-dose corticosteroids and immune
  suppressants.
• Other treatments include hydroxychloroquine,
  cyclophosphamide, cyclosporine A, mycophenolate
  mofetil, azathioprine, nonsteroidal
  anti-inflammatory drugs, rituximab, and
  abatacept.
• The U.S. Food and Drug Administration has
  approved only corticosteroids, hydroxychloroquine,
  and aspirin.
• Autologous hematopoietic stem-cell
  transplantation (HSCT) has been used to treat a
  small number of severe, life-threatening, and
  refractory cases of pediatric SLE. Accordingly,
  this systematic review presented only results
  from HSCT reports, with the comparison being
  usual care.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

47
Evidence for Using Autologous HSCT To Treat
Patients With Systemic Lupus Erythematosus

• Overall, 12 of 17 (71) SLE patients treated with
  intense immune suppression and autologous
  hematopoietic stem-cell transplantation (HSCT)
  entered a state of complete drug-free remission
  for periods that ranged from about 4 to 66
  months.

Outcome Results for Autologous HSCT Compared With Usual Care Strength of Evidence
Long-term benefits or adverse effects __ Insufficient
Extended drug-free clinical remission An extended drug-free clinical remission can be achieved after intense immune suppression and autologous HSCT. Moderate

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

48
Background Juvenile Idiopathic Arthritis

• Juvenile idiopathic arthritis (JIA) is the most
  common chronic rheumatic condition in children,
  with a prevalence between 16 and 150 per 100,000.
• Altered immune system function, particularly
  T-cell regulation, has a major role in the
  pathogenesis of joint damage and disease
  progression.
• JIA subtypes vary, depending on the joints
  involved and the age of onset.
• Systemic onset JIA has a systemic inflammatory
  component.
• Of children affected, 50 percent will have an
  unremitting course with polyarthritis.
• Prolongation of active systemic illness past 6
  months is a particularly poor prognostic sign.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

49
Evidence for Using Autologous HSCT To Treat
Patients With Severe, Refractory Juvenile
Idiopathic Arthritis

• Autologous hematopoietic stem-cell
  transplantation (HSCT) following
  chemotherapy-induced immune suppression may be
  associated with prolonged resolution of juvenile
  idiopathic arthritis into a drug-free,
  much-improved state.
• Among all cases reported, 21 of 43 (56) patients
  achieved extended drug-free remission for 3 to 60
  months.
• There were four cases of treatment-related
  mortality, with no other reports of long-term
  benefits and adverse effects.

Outcome Results for Autologous HSCT Compared With Usual Care Strength of Evidence
Long-term benefits or adverse effects __ Insufficient
Extended drug-free clinical remission An extended drug-free clinical remission can be achieved after immune suppression and autologous HSCT. Moderate

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

50
Background Systemic Sclerosis

• Systemic sclerosis is a highly heterogeneous
  autoimmune disorder characterized by diffuse,
  disabling skin thickening combined with fibrotic
  changes in many organs, particularly the heart
  and lungs, which ultimately result in end-stage
  organ failure.
• Prognosis is related to the major organ affected
  at diagnosis and is poor if cardiac, pulmonary,
  or renal manifestations are present early.
• No treatment has been shown to halt disease
  progression.
• Autologous hematopoietic stem-cell
  transplantation has been used to treat severe,
  progressive, and refractory pediatric systemic
  sclerosis.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

51
Evidence for Using Autologous HSCT To Treat
Severe, Refractory Pediatric Systemic Sclerosis

• Evidence from one registry report included five
  patients treated with autologous hematopoietic
  stem-cell transplantation for severe, refractory
  systemic sclerosis.
• Complete clinical remission was achieved in four
  of five patients, with the remaining patient in
  partial remission.

Outcome Results for Autologous HSCT Compared With Usual Care Strength of Evidence
Long-term benefits or adverse effects __ Insufficient
Extended drug-free clinical remission An extended drug-free clinical remission can be achieved after immune suppression and autologous HSCT. Moderate

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

52
Background Severe, Refractory, Malignant
Multiple Sclerosis

• Multiple sclerosis (MS) is a demyelinating
  disease of the central nervous system that has an
  autoimmune etiology.
• Malignant MS
• Is a poorly defined subset of MS that comprises a
  heterogeneous group of demyelinating disorders
• Applies to cases that succumb to the disease
  within 5 years of onset
• Accounts for lt 5 percent of all MS subjects
• There is no consensus about how to treat
  malignant MS. Approaches have included
• Plasmapheresis
• Aggressive immunosuppression with mitoxantrone
• Cladribine
• Cyclophosphamide
• Autologous hematopoietic stem-cell
  transplantation used in only a few pediatric cases

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

53
Evidence for Using Autologous HSCT To Treat
Severe, Refractory, Malignant Multiple Sclerosis

• Evidence is from three reports that included five
  patients.
• Clinical remission was achieved in all five
  patients treated with an autologous hematopoietic
  stem-cell transplantation (HSCT) with no relapse
  at followup ranging from 14 to 66 months.

Outcome Results for Autologous HSCT Compared With Usual Care Strength of Evidence
Long-term benefits or adverse effects __ Insufficient
Extended drug-free clinical remission An extended drug-free clinical remission can be achieved after immune suppression and autologous HSCT. Moderate

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

54
Background Pediatric Crohns Disease

• Crohns disease is an idiopathic, chronic
  inflammatory disease of the gastrointestinal
  tract that primarily affects the small intestine
  and colon.
• Symptoms range in severity from mild to
  disabling.
• Children may suffer delayed development, stunted
  growth, and nutritional complications.
• Current therapy for Crohns disease consists of
  corticosteroids, immunomodulators, biologicals
  that block tumor necrosis factor-alpha, and often
  surgery.
• Autologous hematopoietic stem-cell
  transplantation has been used in a few pediatric
  cases that all were severe, progressive,
  disabling, and refractory to nearly all drug
  therapies.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

55
Evidence for Using Autologous HSCT To Treat
Severe, Progressive, Refractory, and Disabling
Pediatric Crohns Disease

• Evidence from one case series and one long-term
  followup study includes seven pediatric patients.
• All seven patients achieved clinical remission
  after hematopoietic stem-cell transplantation
  (HSCT) for a period ranging from 7 to 60 months
  and after being free from immune-suppressant
  corticosteroid therapy within 3 to 6 months
  post-HSCT.

Outcome Results for Autologous HSCT Compared With Usual Care Strength of Evidence
Long-term benefits or adverse effects __ Insufficient
Extended drug-free clinical remission An extended drug-free clinical remission can be achieved after immune suppression and autologous HSCT. Moderate

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

56
Adverse Effects

• A meta-analysis with evidence grading was not
  performed for adverse effects related to
  hematopoietic stem-cell transplantation (HSCT)
  for the pediatric diseases covered in the
  systematic review.
• However, in all applications of HSCT,
  chemotherapy radiation is used for
  immunosuppression or to eliminate diseased cells
  in preparation for the transplant.
• HSCT-related adverse effects can include
• Cytotoxicity
• Pancytopenia
• Opportunistic infections (bacterial, viral, and
  fungal rapid and later onset)
• Graft-versus-host disease (acute and chronic
  only for allogeneic HSCT)
• Risk of secondary malignancies
• Treatment-related mortality

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

57
Conclusions Using Allogeneic HSCT To Treat Rare
Pediatric Inherited Metabolic Disorders

• Allogeneic hematopoietic stem-cell
  transplantation (HSCT) may improve overall
  survival rates for patients with Wolman disease
  and may improve neurodevelopment-related outcomes
  for patients with Farber disease.
• Low-strength evidence suggests that allogeneic
  HSCT may help prevent neurocognitive decline and
  may have improved neurodevelopmental outcomes
  versus standard care for patients with the
  attenuated form of mucopolysaccharidosis type II
  (Hunter syndrome).
• HSCT did not have improved outcomes versus usual
  care for patients with mucopolysaccharidosis type
  III, Niemann-Pick disease type A, or Gaucher
  disease type III.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

58
Conclusions Using Autologous HSCT To Treat Rare
Pediatric Malignant Solid Tumors

• Patients with high-risk, recurrent, or
  progressive anaplastic astrocytoma had improved
  5-year survival rates with hematopoietic
  stem-cell transplantation (HSCT) versus usual
  care.
• There is low-strength evidence that patients with
  other malignant solid tumors included in this
  analysis may not benefit from HSCT versus usual
  care.
• In fact, there is low-strength evidence that
  patients with nonanaplastic, mixed, or
  unspecified ependymoma had higher HSCT-related
  mortality rates than patients treated with
  conventional therapy.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

59
Conclusions Using Autologous HSCT To Treat
Severe, Refractory Pediatric Autoimmune Disorders

• While most of the evidence is from smaller case
  studies, case series, and case reports, there is
  moderate-strength evidence that extended periods
  of drug-free remission can be achieved in
  patients with
• Severe, refractory juvenile idiopathic arthritis
• Systemic lupus erythematosus
• Severe, refractory systemic sclerosis
• Severe, refractory, malignant multiple sclerosis
• Severe, refractory, disabling Crohns disease

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

60
Conclusions Using Autologous HSCT To Treat Other
Pediatric Autoimmune Disorders

• Autoimmune type-1 juvenile diabetes can be
  managed satisfactorily over the long term, at
  relatively low risk, in a large proportion of
  children with intensive insulin therapy (IIT) and
  lifestyle modifications.
• The risk-benefit ratio for hematopoietic
  stem-cell transplantation (HSCT), when compared
  with IIT, must take into account contextual
  factors including potential long-term benefits
  (cure) and adverse effects, particularly those
  secondary to cytotoxic chemotherapy.
• The decision to apply a high-risk procedure such
  as HSCT to this population is not clear cut.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

61
Conclusions Adverse Effects

• For most of the pediatric metabolic disorders,
  malignant solid tumors, and autoimmune disorders
  covered in the systematic review, there is not
  enough evidence to permit conclusions about the
  relative balance of benefits and adverse effects.
• Without a clear benefit for overall survival
  (e.g., Wolman disease) or neurological
  development (e.g., Farber disease), the risk of
  adverse effects (especially severe adverse
  effects) may be a determining factor in the
  decision to perform autologous or allogeneic
  hematopoietic stem-cell transplantation versus
  standard therapy in these pediatric populations.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

62
Gaps in Knowledge

• Because of the rarity of many of the diseases
  examined in this report, studies that assess the
  comparative effectiveness of hematopoietic
  stem-cell transplantation versus conventional
  therapy in pediatric patients mostly consist of
  small case series and case reports.
• Controlled trials with sufficient followup are
  needed to evaluate the long-term balance of
  benefits with adverse effects.

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

63
Shared Decisionmaking What To Discuss With Your
Patients Parents and Caregivers

• The difficulties and dilemmas of treating rare
  pediatric disorders
• Appropriate therapeutic interventions to treat a
  specific disorder
• Realistic outcomes to expect from each
  therapeutic option
• The trade-offs between benefits and adverse
  effects of possible therapeutic interventions
• Overview of relevant clinical trials enrolling
  patients
• Referrals to institutions with expertise in
  treating a particular disorder
• How treatment decisions will affect quality of
  life for patients and their families

Ratko TA, Belinson SE, Brown HM, et al. AHRQ
Comparative Effectiveness Review No. 48.
Available at www.effectivehealthcare.ahrq.gov/stem
-cell-children.cfm.
64
Ongoing Clinical Trials Available for Pediatric
Patients With Some of These Rare Diseases

• Several clinical trials are currently recruiting
  patients for studies examining treatments for
  pediatric patients with some of these rare
  diseases.
• Resources that may be helpful
• www.clinicaltrials.gov
• www.childrensoncologygroup.org

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

65
Resources for Parents and Caregivers (1 of 2)

• Bone Marrow or Blood Stem Cell Transplants in
  Children With Certain Rare Inherited Metabolic
  Diseases, A Review of the Research for Parents
  and Caregivers is a free companion to
  presentation. It can help parents and caregivers
  talk with their health care professionals about
• Information on Wolman disease, Farber disease,
  Niemann-Pick disease, Gaucher disease, infantile
  neuronal ceroid lipofuscinosis, Hunter syndrome,
  and Sanfilippo syndrome
• What an allogeneic hematopoietic stem-cell
  transplantation (HSCT) is and how it is done
• What researchers have found about treating
  children who have one of these illnesses with an
  allogeneic HSCT
• Possible risks of an allogeneic HSCT

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.

66
Resources for Parents and Caregivers (2 of 2)

• Bone Marrow or Blood Stem Cell Transplants in
  Children With Severe Forms of Autoimmune
  Disorders or Certain Types of Cancer, A Review of
  the Research for Parents and Caregivers is a free
  companion to this presentation. It can help
  parents and caregivers talk with their health
  care professionals about
• Information on severe autoimmune diseases and
  certain types of cancer
• What an autologous hematopoietic stem-cell
  transplantation (HSCT) is and how it is done
• What researchers have found about children with
  one of these illnesses who received an HSCT using
  their own stem cells

• Ratko TA, Belinson SE, Brown HM, et al. AHRQ
  Comparative Effectiveness Review No. 48.
  Available at www.effectivehealthcare.ahrq.gov/stem
  -cell-children.cfm.