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.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.

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 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. 2010;63:513-23. 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.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.

7. Rare Pediatric Malignant Solid Tumors Included in the Systematic Review • Ewing’s 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:adrenomyeloneuropathy 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 Crohn’s 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.ahrq.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 Ewing’s 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. • 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. 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. • 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. • 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: Ewing’s Sarcoma Family of Tumors • Ewing’s 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 Ewing’s Sarcoma Family of Tumors • Patients with any type of Ewing’s 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 <35 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 Ewing’s 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. • 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 (<6 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. 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-children.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 (4–11 years of followup) and are highly functional. • 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. 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. 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. 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. 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. 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.ahrq.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 • Crohn’s 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-cell–mediated 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%). 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. Background:Treatments 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. 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. 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.