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

Hematopoietic Stem-Cell Transplantation for Rare Diseases in the Pediatric

PopulationPrepared for:

Agency for Healthcare Research and Quality (AHRQ)

www.ahrq.gov

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.

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

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

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

Outline of Material


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.

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


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

Strength-of-Evidence Ratings

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.

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.

Clinical Questions Addressed in the Comparative Effectiveness 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

Rare Pediatric Malignant Solid Tumors 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

Rare Pediatric Inherited Metabolic Disorders 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.

Rare Pediatric Autoimmune Diseases Included in the Systematic Review


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

Outcomes of Interest


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

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


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

Background: Glial Tumors


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).

Background: Included Glial Tumor Studies


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

Outcome ResultsStrength of Evidence

Overall survival

Improves 5-year overall survival (40%, n = 10) when compared with patients who receive conventional therapy (0%, n = 71).

Low

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.


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

Outcome

Results

Strength of

Evidence

Overall survival

Associated with higher treatment-related mortality than conventional therapy and leads to shorter overall survival

Low

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.


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.

Background: Rhabdomyosarcoma


Evidence for Using Autologous HSCT To Treat Patients With Metastatic Rhabdomyosarcoma

Outcome Results

Strength of

Evidence

Overall survival

No benefit with a single HSCT when compared with conventional therapy.

Moderate

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.


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.

Background: Retinoblastoma


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

Outcome Results

Strength of

Evidence

Overall survival


Low

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.


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.

Background: 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.

Background: High-Risk Tumors in the Ewing’s Sarcoma Family of Tumors


Evidence for Using Autologous HSCT To Treat Patients With High-Risk Tumors in the Ewing’s Sarcoma Family of Tumors

Outcome Results

Strength of

Evidence

Overall survival


Low

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.


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.

Background: Wilms’ Tumor


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


Overall survival

No benefit with a single autologous HSCT when compared with conventional therapy.

Low

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.


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

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


* 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.

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.

Background: Wolman Disease


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.



Overall survival

Significant benefit with a single HSCT when compared with conventional therapy.

High

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.

Background: 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.

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


Outcome

Results

Strength of

Evidence

Overall survival

No benefit was conferred with a single hematopoietic stem-cell transplantation when compared with conventional therapy.

Low

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.

Background: Mucopolysaccharidosis Type 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.

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


OutcomeResults 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

No benefit for the severe form Low

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

Background: 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.

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


OutcomeResults for a Single Allogeneic HSCT Compared With Symptom

Management

Strength of

Evidence

Neurodevelopmental

No benefit from HSCT Low

Neurocognitive No benefit from HSCT Low

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.

Background: Gaucher Disease


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.

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


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

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.

Background: Farber Disease


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.

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


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

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.

Background: 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

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


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

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


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.

Background: Newly Diagnosed Juvenile Type-1 Diabetes Mellitus


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.

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


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.

Background: Rationale for Using 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%).

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


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

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.

Background: 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.

Background:Treatments for 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.

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


OutcomeResults 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

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.

Background: 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.

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

OutcomeResults for Autologous HSCT Compared

With Usual Care

Strength of

Evidence


__ Insufficient


An extended drug-free clinical remission can be achieved after immune suppression and autologous HSCT.

Moderate


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.

Background: 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.

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


Outcome

Results for Autologous HSCT Compared

With Usual Care

Strength of

Evidence


__ Insufficient



Moderate

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 < 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

Background: 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.

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


OutcomeResults for Autologous HSCT

ComparedWith Usual Care

Strength of

Evidence


__ Insufficient



Moderate

Crohn’s 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 Crohn’s 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.

Background: Pediatric Crohn’s 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.

Evidence for Using Autologous HSCT To Treat Severe, Progressive, Refractory, and Disabling Pediatric Crohn’s Disease


OutcomeResults for Autologous HSCT Compared With Usual Care

Strength of Evidence


__ Insufficient



Moderate

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

Adverse Effects


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.

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


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.

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


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 Crohn’s disease

Conclusions: Using Autologous HSCT To Treat Severe, Refractory 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.

Conclusions: Using Autologous HSCT To Treat Other Pediatric Autoimmune Disorders


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.

Conclusions: Adverse Effects


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.

Gaps in Knowledge


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

Shared Decisionmaking: What To Discuss With Your Patients’ Parents and Caregivers


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

Ongoing Clinical Trials Available for Pediatric Patients With Some of These Rare Diseases


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


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


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

Documents

Transcript of Hematopoietic Stem-Cell Transplantation for Rare Diseases in the Pediatric Population Prepared for:...