Single HSCT

The literature using dose-intensive chemotherapeutic regimens or HSCT consists of case series with small numbers of patients and case reports without direct comparisons between conventional or dose-intensive chemotherapy and HSCT. The evidence compiled for this review includes, for HSCT, 24 case series^353-376 (including two Phase II studies) and six case reports.^377-382 The comparator is conventional chemotherapy and includes seven case series (including one Phase II study).^{116, 376, 383-387} No information on quality of life (QOL) was provided and data on adverse events were sparse and based on small numbers of patients.

The evidence suggests that treatment-related mortality is higher in the patients that underwent HSCT compared to the chemotherapy comparators. The rate of secondary malignancies appeared lower in some reports of dose-intensive chemotherapy compared to HSCT and similar in one report of dose-intensive chemotherapy compared to HSCT.

Tandem Autologous-Autologous HSCT

The literature using tandem HSCT consists of case series with small numbers of patients and a case report.^{355, 380} A direct comparison between tandem HSCT and single HSCT is reported in one case series.³⁵⁴ The evidence compiled for this review includes, for tandem HSCT, two case series and one case report. The comparator is single HSCT and includes 24 case series and six case reports. Data on transplant-related mortality and infectious complications were sparse; data on other adverse effects were not reported.

Overall Survival

Data on overall survival were reported or generated in 20 HSCT studies^{353, 355-358, 360, 362-366, 368-371, 373-376, 389} and four comparator studies (Table 41).^385-388 No direct comparisons can be made from the published data as there are no comparative studies.

Table 41

Overall survival for treatment (single HSCT and tandem auto HSCT) and comparison (conventional chemotherapy +/- radiation) groups.

Event-free Survival

Information on event-free survival can be found in Appendix D.

Adverse Effects

None of the studies evaluated quality of life. Data on treatment-related mortality was reported in 14 HSCT studies^{353, 355 356, 363-365, 367-371, 374, 375 376} and three comparative studies.^{385, 387 388} (Table 42). Eleven HSCT^{353, 355, 356, 359, 360, 364, 370, 372, 374, 375 376} and two comparator studies^{385, 388} reported serious infectious complications. Six HSCT studies^{353, 365, 374, 375, 377 376} and four comparator studies^{383, 384, 386, 388} reported a secondary malignancy. Seven HSCT studies^{356, 359, 361, 381 372, 374, 375} and one comparator study³⁸⁵ reported other long-term complications involving severe organ dysfunction.

Table 42

Adverse effects for single auto HSCT and comparison (conventional chemotherapy +/- radiation) groups.

Overall Survival

Data on overall survival were reported in fifteen studies (Table 47).^{378, 392, 394-398, 400-403, 405-407, 410} No direct comparisons can be made from the published data as there are no comparative studies.

Table 47

Overall survival for treatment (single auto HSCT) and comparison (conventional chemotherapy +/- radiation) groups.

Event-free Survival

Information on event-free survival can be found in Appendix D.

Adverse Effects

None of the studies evaluated quality of life. Data on treatment-related mortality was reported in 10 studies (Table 48).^{378, 392, 394, 395, 397, 398, 400, 402, 403, 406} Two studies reported a case of serious infection leading to death^{394, 403} and one study reported no serious infectious complications.⁴⁰⁷ One study reported a secondary malignancy.⁴⁰³ One study reported a case of mild veno-occlusive disease.⁴⁰⁸ There were no reports of other long-term complications.

Table 48

Adverse effects for single auto HSCT and comparison (conventional chemotherapy +/-radiation) groups.

Overall Survival

Data on overall survival were reported in all but two studies^{420, 422} (Table 52). Survival data is presented (Table 53). Individual studies varied in their method for calculating overall survival. In general studies of patients with metastatic disease used time since diagnosis, where studies with patients of mixed tumor stage used time from treatment. Similar trends were observed in the 1-, 3-, and 5-year OS across studies. While not direct, comparisons with adequate numbers of participants can be made from both the McDowell⁴¹⁵ and Carli⁴¹⁴ studies.

Table 53

Overall survival for treatment (single auto HSCT) and comparison (conventional chemotherapy +/- radiation) groups.

The study published by McDowell and colleagues⁴¹⁵ stratified patients with metastatic rhabdomyosarcoma into two groups, poor risk and standard risk. Poor-risk patients were identified as those 10 years of age or older with bone or bone marrow involvement.⁴¹⁵ These patients were given sequential HDC and HSCT, while the standard-risk patients (younger than 10 years of age and not bone or bone marrow involvement) were treated with conventional chemotherapy. Patients in the standard risk group had 3 year EFS and OS of 54.92 percent and 62.14 percent, respectively, comparable to rates in other studies. While those in the poor-risk group had 3 year EFS and OS of 16.17 percent and 23.17 percent, respectively, statistically worse than those in the standard-risk group in this study and no improvement on prior studies.

Carli et al.⁴¹⁴ published results from the European Collaborative MMT4-91. Fifty-two patients in complete remission after induction were given HDC and stem-cell rescue. Outcomes were then compared to 44 patients also in complete remission after induction, but went onto receive conventional chemotherapy. No differences in OS were observed.

The data from additional case series and case reports appear consistent with these findings.

Event-free Survival

Information on event-free survival can be found in Appendix D.

Adverse Effects

None of the studies evaluated quality of life, and serious adverse events were reported by fifteen studies (Table 52). Data on treatment-related mortality was reported in twelve studies (Table 54).^{357, 363, 365, 387, 414, 415, 419, 423-425, 427, 434} McDowell reported two cases of treatment-related mortality in the comparator group and there were seven serious adverse events in the treatment group with five resulting in death; however it is unclear how many occurred in 100 days of treatment.⁴¹⁵ Toxic death from sepsis was reported in the treatment group in two studies.^{414, 420} Bisogno et al.⁴¹⁹ reported seven of 55 evaluable patients experienced serious infectious complications while Sandler and colleagues⁴²⁷ reported 40 percent of patients experiencing serious infection with seven leading to death. One study reported a secondary malignancy, myelodysplastic syndrome related to alkylating agents.⁴³⁵ No treatment related mortality was observed in 11 studies.^{363, 421, 422, 424, 429-433, 435, 436} Two studies^{416, 426} did not report on adverse events. There were no reports of secondary malignancies, serious hemorrhagic events, irreversible veno-occlusive disease or other long term complications.

Table 54

Adverse effects for single auto HSCT and comparison (conventional chemotherapy +/- radiation) groups.

Overall Survival

Data on overall survival were reported in all 20 studies (Table 58). Survival data are presented stratified by if patients were identified as having metastatic spread to the CNS, then by year (Table 59). A study of trilateral retinoblastoma was also separated into its own category. Ten studies presented data for patients with CNS involvement^{442, 443, 447, 449, 451, 453-457} and the same ten studies plus nine more ^{438-441, 445, 446, 448, 450} presented data on patients without CNS involvement. One study presented data exclusively on trilateral retinoblastoma.⁴⁴⁴ The individual studies either did not define overall survival or used different starting points for this variable (i.e., either years from diagnosis or years from first transplant). No direct comparisons can be made from the published data as there are no comparative studies.

Table 59

Overall survival for treatment (single auto HSCT) and comparison (conventional chemotherapy +/- radiation) groups: Retinoblastoma.

Event-free Survival

Information on event-free survival can be found in Appendix D.

Adverse Effects

No studies evaluated quality of life, and adverse effects were only reported by intervention studies. Data on treatment-related mortality was reported in two intervention studies (Table 60). Two patients died from septicemia and multi-organ failure during induction therapy.^{444, 449} Two studies reported cases of serious infection, both attributed to Candida albicans.^{447, 448} One comparator study⁴⁵¹ reported three secondary malignancies (two osteogenic sarcoma, and one nonlymphocytic leukemia) and one intervention study⁴⁵⁰ reported three secondary malignancies (osteosarcoma, two occurring in irradiated fields). There were no reports of serious hemorrhagic events, irreversible veno-occlusive disease or other long-term complications among patients treated with HSCT or conventional chemotherapy.

Table 60

Adverse effects for single auto HSCT and comparison (conventional chemotherapy +/- radiation) groups: Retinoblastoma.

Overall Survival

Data on OS were reported in seven (of nine) primary studies (Table 64). Six studies presented 3- and/or 5-year rates and the study by George et al.⁴⁵⁹ also presented 7-year rates (Table 65). No significant differences in either the 3-year or 5-year OS between treatment groups were identified in the two comparative studies (Table 65).^{113, 468} Multivariate analysis of EBMT data showed significantly better OS rates in patients younger than 2 years of age at diagnosis (Hazard Ratio [HR], 1.6; 95 percent; Confidence Interval [CI], 1.4-1.9; p<0.0001).¹¹³ It should be noted that the individual studies either did not define OS or used different starting points for this variable (i.e., either years from diagnosis or years from first transplant).

Table 65

Overall survival for treatment (tandem HSCT) and comparison (single HSCT) groups: Neuroblastoma.

Event-free Survival

Information on event-free survival can be found in Appendix D.

Adverse Effects

None of the studies evaluated quality of life (Table 64). Data on treatment-related mortality were reported in six studies (Table 66). There were 20 (of 197) cases in the tandem group and 36 (of 373) cases in the single HSCT group. Secondary malignancies were reported in five studies (Table 66). There were three (of 212) cases in the tandem group (one synovial cell sarcoma, one myelodysplasia with clonal trisomy 8, and one thyroid cancer); two cases were reported in the George et al.⁴⁵⁹ study. The case of thyroid cancer was reported in the 2010 study by Sung et al.⁴⁶⁹, and occurred in a patient receiving only the first HSCT. Three (of 408) cases of secondary malignancies were reported in the single HSCT group (two acute myeloblastic leukemias and one follicular carcinoma of the thyroid).

Table 66

Adverse effects for treatment (tandem HSCT) and comparison (single HSCT) groups: Neuroblastoma.

Infectious complications were reported in four studies (Table 66). Sepsis was more prevalent in the single HSCT group (n=219) compared to the tandem group (n=126) (26 vs. 2 percent). All infectious complications were attributed to sepsis in the single HSCT group. Further serious infections in the tandem group included two cases of viral pneumonia and three cases of Epstein-Barr virus and cytomegalovirus, all resulting in toxicity-related deaths. Other reported serious adverse effects included one case of pulmonary hemorrhage in the tandem group and three cases of bleeding in the single HSCT group.

The frequency of veno-occlusive disease was reported across four studies (Table 66).^{108, 111, 459, 466} There were nine (of 126) cases in the tandem group and two (of 30) cases in the single HSCT group. Only one study (n=13) by Hobbie et al.⁴⁶² reported further long-term complications including developmental delays (i.e., hearing loss, 92 percent), cataracts (54 percent), and growth-hormone deficiency (54 percent) following tandem HSCT.

Overall Survival

Data on OS were reported in all four studies (Table 70). Data were available to compute three-year rates across all studies, and five-year rates for three studies (Table 71). Similar trends were observed between treatment groups in the one-, three-, and five-year OS across studies (Table 71). For the CIBMTR cohort, five-year survival probability was 36 percent (95 percent confidence interval (CI), 10-69 percent) in the tandem group compared to 49 percent (24-68 percent) in the single HSCT group.⁴⁷¹ OS was defined across three studies as the interval between salvage chemotherapy or transplant and death from any cause.

Table 71

Overall survival for tandem HSCT and comparison (single HSCT) groups: Germ cell tumor.

Event-free Survival

Information on event-free survival can be found in Appendix D.

Adverse Effects

None of the studies evaluated quality of life (Table 70). Data on treatment-related mortality was available from three studies (Table 72).^{114, 120, 471} There was no reported cases of treatment-related mortality in the two single HSCT series (N=22). For the CIBMTR cohort, cumulative incidence of treatment-related mortality was 10 percent (2-27 percent) at 5 years for the single HSCT group (n=20); none of the 12 patients in the tandem group had treatment-related mortality (Table 72). Relapse/progression incidence, on the other hand, was 64 percent (30–85 percent) for the tandem group up to five years after transplant compared to 41 percent (20–62 percent) for the single HSCT group.⁴⁷¹ Other adverse events were reported in only two single HSCT studies. There were no secondary malignancies (Table 72). Veno-occlusive disease occurred in two (of 18) patients in the EBMT cohort by De Giorgi et al.¹¹⁴

Table 72

Adverse effects for tandem HSCT and comparison (single HSCT) groups: Germ cell tumor.

Overall Survival

Data on OS were reported in ten (of 12) studies (Table 76). For comparisons between tandem vs. single HSCT, data were available to compute 2-year rates for two studies, 3-year rates for two studies, and 5-year rates for four studies (Table 77). For Sung et al.⁴⁶⁶ (n=14), 2-year survival probability was 82 percent (95 percent confidence interval (CI), 59-100 percent) in the tandem group (MB, n=10; PNET, n=1) compared to 67 percent (13-100 percent) in the single HSCT group (MB, n=1; PNET, n=2). The AT/RT patient reported in Gidwani et al.⁴⁷² has remained disease free for two years following tandem HSCT. OS was defined across studies as the interval between diagnosis to death or last followup.

Table 77

Overall survival for tandem HSCT and comparison (single HSCT) groups: CNS embryonal tumors.

For the conventional-care group of studies, data were available to compute 3-year rates for one study,⁴⁷⁸ and 5-year rates for three studies (Table 78).^{478, 481, 482} There were no comparative studies between single HSCT vs. conventional care. For Geyer et al.⁴⁸¹ on multiple tumor types, five-year survival probability overall was 43 percent (3 percent) for children under three years of age; for MB, PNET and AT/RT, the corresponding rates were 43 percent (5 percent), 31 percent (7 percent), and 29 percent (9 percent), respectively. Similar rates were observed for MB patients with metastatic disease in the multicenter study by Taylor et al.⁴⁷⁸ Packer et al.⁴⁸² reported higher survival rates in their cohort of MB patients without metastasis.

Table 78

Overall survival for single HSCT and comparison (conventional care) groups: CNS embryonal tumors.

Adverse Effects

Only one HSCT study on MB patients evaluated quality of life (Table 76).⁴⁷⁴ Dhall et al.⁴⁷⁴ reported that mean intellectual functioning and QOL for children less than three years of age surviving without radiotherapy (n=4 [of 21]) was within the average range at both followup periods of testing (using the Parent Form of the Child Health Questionnaire [which is a 50-item QOL measure]). Data on treatment-related mortality were reported in 11 studies (Table 79).^{133, 474-479, 481-483} There was one (of 15) case (7 percent) in the tandem group, nine (of 132) cases (8 percent) in the single HSCT group, and 71 (of 663) cases (11 percent) in the conventional care group.

Table 79

Adverse effects for treatment (tandem HSCT) and comparison (single HSCT) groups: CNS embryonal tumors.

Secondary malignancies were reported in three single HSCT studies^{476, 477, 483}and three studies on conventional care (Table 79 and Table 80).^{478, 481, 482} Three (of 69) cases (4 percent) of secondary malignancies were reported in the single HSCT group, and 12 (663) cases (2 percent) in the conventional care group. Other adverse events across studies are reported in Table 79 and Table 80, respectively.

Table 80

Adverse effects for treatment (single HSCT) and comparison (conventional care) groups: CNS embryonal tumors.

High-Grade Glioma: Anaplastic Astrocytoma (AA)/Glioblastoma Multiforme (GBM)

The prognosis for patients diagnosed with high-grade glioma is poor. The median survival is less than 1 year, the majority die within two years despite some exceptional survivors.⁴⁸⁶ Patients with grade II astrocytoma may survive for 5 or more years while patients with AA often die within 2 or 3 years and frequently show progression to GBM with survival times substantially less than 2 years.⁴⁸⁷

Choroid Plexus Carcinomas

Choroid plexus carcinomas are rare typically occurring among children under 12 years of age with the greatest prevalence among children less than 2 years of age. ⁴⁸⁸ Choroid plexus tumors account for 1-4 percent of all childhood brain tumors with 25 percent of these patients developing progressive disease. ⁴⁸⁸ The role of surgery is well established in these tumors. Total resection of the tumor is often limited by tumor vascularity, large tumor size, and the tumor's tendency to invade the brain.⁴⁸⁸ The added benefits of radiation and chemotherapy on overall survival after total resection are unclear.⁴⁸⁸

Ependymomas

Ependymomas are significantly more prevalent in infants and young children, than in adults, and account for 6-10 percent of brain tumors in children.⁴⁸⁹ Sixty percent of ependymal tumors in children are infratentorial with 40 percent supratentorial. With conventional therapy the estimated 5-year OS and PFS are 50-64 percent and 23-45 percent, respectively.⁴⁹⁰ Factors significant in the prognosis of patients are extent of tumor resection and age.⁴⁹⁰ Patients with gross total resection have higher survival rates compared to incompletely resected gliomas (67-80 percent and 22-47 percent 5-year OS, respectively), and younger children tend to have a worse prognosis (more aggressive biological behavior of the tumor, avoidance of irradiation, and unacceptable neurotoxicity).⁴⁹⁰

Overall Survival

Data on overall survival were reported in all but three studies,^{505, 515, 518} and calculated from the raw data from the additional studies (Table 84). Survival data are presented by five histologic categories (Table 85). Individual studies varied in their method for calculating overall survival.

Table 85

Overall survival for single auto HSCT and comparison (conventional chemotherapy +/- radiation) groups: Glial tumors.

Fourteen studies examined overall survival for astrocytic gliomas.^{123, 132, 367, 485, 491, 492, 495, 500-502, 509, 510, 517, 518} Survival data were reported for 20 patients with astrocytic tumors who underwent autologous transplant and 106 conventional therapy patients. Fourteen studies examined overall survival for glioblastoma multiforme.^{123, 132, 367, 485, 491, 492, 495, 498, 500-502, 504, 509, 518} Survival data was reported for 45 patients with glioblastoma multiforme who underwent autologous transplant and 92 conventional therapy patients. Of the noncomparative studies reporting yearly OS, none had HSCT treatment. OS at 5 years ranged from 0 percent in recurrent patients to 25 percent for newly diagnosed patients. One study grouped OS of newly diagnosed AA and GBM patients and stratified by noninfant or infant status. These patients had a 5-year OS of 36±13 for noninfants and 25±15 for infants.

Finlay et al.⁴⁸⁵, compared a historic chemotherapy cohort (CCG-945) to astrocytoma and GBM patients receiving HSCT. This study provided 5-year recurrent HSCT and conventional therapy OS estimates of 40 percent and 4 percent for astrocytoma and 12 percent and 0 percent for glioblastoma multiforme respectively. The OS was statistically significantly better for HSCT compared to chemotherapy at p=0.010 and retained this significance when stratified by tumor histology. The authors also found evidence that degree of surgical debulking impacted survival. OS estimates stratified by treatment and degree of debulking minimized the treatment effect and yielding a nonsignificant survival difference of p=0.39 due to the poor prognosis of patients with bulky tumor in both treatment types. However, when the authors looked at HSCT versus chemotherapy treatment among only surgically debulked patients the HSCT patients had a better survival (p=0.017).

Three noncomparative studies reported yearly GBM OS with a 5-year OS estimate for autologous transplant of newly diagnosed GBM of 0-22 percent and newly diagnosed conventional therapy of 22 percent.^{498, 502, 521} Data comparing HSCT to conventional therapy was provided by Finlay et al.⁴⁸⁵ for recurrent/progressive GBM and AA showed an increase in survival for HSCT. No comparison was made for newly diagnosed AA due to a lack of HSCT studies. Data for newly diagnosed GBM seems to show a similarly poor prognosis for both HSCT and conventional therapy patients.

Seventeen studies examined overall survival for ependymoma^{132, 367, 489, 490, 495, 497, 501, 504, 507-509, 511-514, 516, 520} Survival data was reported for 71 patients with ependymal tumors who underwent transplant and 442 conventional therapy patients. No studies were comparative between HSCT and conventional therapy. Five studies reported overall survival with a 5 year overall survival estimates for autologous transplant of recurrent tumor of 10 percent and newly diagnosed of 38 percent.^{367, 490, 495, 497, 504} Conventional therapy did not include recurrent disease and found estimates of 35.2 percent to 64 percent for newly diagnosed anaplastic ependymoma with newly diagnosed nonanaplastic, mixed or unspecified ependymoma estimates of 52-74 percent.^{489, 508, 511, 513, 514, 516, 520} One study stratified by metastatic/nonmetastatic disease and obtained a 5-year OS of 33 percent and 59 percent respectively.⁵¹² For patients with newly diagnosed ependymoma, patients treated with HSCT appear to have inferior overall survival when compared to those treated with conventional therapy.

Sixty-four patients with choroid plexus carcinoma were in three conventional therapy studies and four patients with HSCT across three studies reported survival.^{488, 499, 504, 513, 522} All HSCT patients died between five and 25 months. A conventional therapy study of 29 patients had survival of 35 percent at last followup (median 25 months, range 3-85 months). Two studies reported 5-year OS of 21.5 and 36 percent.

Event-free Survival

Data on event-free survival can be found in Appendix D.

Adverse Effects

Nine HSCT studies reported adverse events in a patient population of 138 patients composed of 13 anaplastic astrocytoma, three anaplastic glioma, 49 ependymoma, one ganglioma, 30 glioblastoma multiforme, one oligodendroglioma, and 41 pontine tumors (Table 86).^{485, 490, 493, 497, 498, 500, 501, 503, 506} The conventional therapy studies reported adverse events for 113 ependymoma patients, 30 anaplastic astrocytoma patients, 40 glioblastoma multiforme patients, 18 high-grade glioma patients, seven pontine tumor patients and 15 choroid plexus tumor patients.^{508, 512, 513, 521} Overall, the level of adverse event reporting for both HSCT and conventional therapy may be underreported. Many studies included tumor types not relevant to this report in their design, and the authors in most instances did not give data on a tumor group or per patient basis when discussing adverse events.

Table 86

Adverse effects for single auto HSCT and comparison (conventional chemotherapy +/- radiation) group: Glial tumors.

Diseases With Rapid Progression

The overall grade of strength of evidence for overall survival with the use of HSCT for the treatment of inherited metabolic diseases with rapid progression is shown in Table 88.

Table 88

Overall grade of strength of evidence for overall survival with the use of HSCT for the treatment of inherited metabolic diseases with rapid progression.

Diseases With Slow Progression

The overall grade of strength of evidence for stabilization of neurocognitive and neurodevelopmental symptoms with the use of HSCT for the treatment of inherited metabolic diseases with slow progression is shown in Table 89.

Table 89

Overall grade of strength of evidence for stabilization of neurocognitive and neurodevelopmental symptoms with the use of HSCT for the treatment of inherited metabolic diseases with slow progression.

Diseases With Forms That Progress Rapidly and Slowly

The overall grade of strength of evidence for overall survival and stabilization of neurocognitive and neurodevelopmental symptoms with the use of HSCT for the treatment of inherited metabolic diseases with rapid progression and slow progression forms is shown in Table 90.

Table 90

Overall grade of strength of evidence for overall survival and stabilization of neurocognitive and neurodevelopmental symptoms with the use of HSCT for the treatment of inherited metabolic diseases with rapid progression and slow progression form.

Wolman Disease

Wolman disease is a rare autosomal recessive disorder characterized by a deficiency of lysosomal acid lipase which causes an accumulation of cholesterol esters and triglycerides in the spleen, liver, adrenal glands, bone marrow, small intestines, and lymph nodes.²⁶¹ Fewer than 80 cases have been identified. Symptoms appear immediately, within the first week of life, and include failure to thrive, jaundice, anemia, relentless vomiting, abdominal distention, steatorrhea, and hepatosplenomegaly. Because of the failure to absorb nutrients, severe malnutrition occurs and life expectancy is less than 6 months.⁵²⁶ Several patients with Wolman disease have undergone HSCT (Table 92).^527-530

Table 92

Study characteristics and population for Wolman disease.

Refer to Appendix E Table E1 for details of neurocognitive and neurodevelopmental outcomes. In summary, two patients died of treatment-related mortality, one at 2.5 months post-transplant and one at 8 months post-transplant and one died from the natural progression of the disease.⁵²⁷ Three (of 4) patients who survived HSCT are long-term survivors, with followup from 4 to 11 years. They are highly functional in language skills, and social and behavioral skills. One attends regular school and two attend special schools.^{529, 531}

The case report of the patient with Wolman disease who underwent HSCT reported growth in height, weight and head circumference.⁵²⁹ Of the three surviving Wolman disease patients in the case series, one showed improvement in motor skills and another is reported to have average gross motor skills and below average fine motor skills⁵³¹

Evidence for this rapidly progressing disease which has a life expectancy of 6 months, consists of two case reports and two case series. A total of seven patients with Wolman disease have undergone HSCT. Two died from the procedure and 1 died from disease progression. Four have survived and have been followed for 0.3 to 11 years, with normal or near normal functioning. For three patients who have survived long-term followup from 4 to 11 years, HSCT altered the course of Wolman disease.

Gaucher Disease Type II

Gaucher disease is caused by a deficiency in the enzyme glucocerebrosidase, which leads to an accumulation of glucosylceramide in the spleen, liver, lungs, bone marrow, and sometimes the brain.²⁶¹ There are three types of Gaucher disease. Gaucher Type I is discussed in the Narrative Review section of this report. Gaucher Type III is discussed in this Systematic Review section under diseases with slow progression.

Type II is the acute neuronopathic form, exhibiting hepatosplenomegaly as early as three months of age. There is severe central nervous system involvement and death occurs within two years of life. There is no effective treatment for Type II because of the rapid progression of symptoms and neurological involvement. No HSCT and Gaucher Type II studies were found in the literature.

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. Type A occurs most frequently in the Ashkenazi Jewish population (1 in 40,000), while the frequency of Type A and B in the general population is estimated to be 1 in 250,000.⁵³² Type B is discussed in the Narrative Review section of this report. Type C is discussed under the heading “Other Lipidoses” within this Systematic Review.

Type A is the most severe form, occurring in infants and characterized by jaundice, an enlarged liver, and brain damage, with life expectancy of 3 years.²⁶¹ Reports of HSCT on 3 Type A patients have been found in the literature (Table 93).

Table 93

Study characteristics and population for Niemann-Pick Type A.

Refer to Appendix E Table E1 for details of neurocognitive and neurodevelopmental outcomes. In summary, a case report of a patient with Niemann-Pick Type A who underwent HSCT at 3 months of age, showed initial normal neurocognitive and neurodevelopmental progress, followed by brain atrophy at 0.6 years post-transplant, and the onset of seizure disorders and developmental delays by 1.7 years post-transplant.⁵³³ At the time of the report, the patient was alive at 2.7 years' followup. Two patients receiving HSCT continued to decline neurocognitively and neurodevelopmentally, and died 2 years post-transplant, from natural progression of disease.⁵³⁴ Autopsy of one patient showed very little enzyme present in target tissues of brain and liver.⁵³⁴

Evidence for Niemann-Pick Type A, which has a life expectancy of 3 years, consists of 1 case report and 1 case series.^{533, 534} HSCT did not prevent neurocognitive and neurodevelopmental decline in these patients. Based on these reports, HSCT does not show a benefit for Niemann-Pick Type A.

Mucolipidosis II (I-cell Disease)

Mucolipidosis II is an autosomal recessive disorder caused by a defective enzyme, N-acetylglucosamine-1-phosphotransferase, which is instrumental in the transport of enzymes. This defect causes a deficiency of lysosomal enzymes in fibroblasts, and an excess of lysosomal enzymes in tissues and extracellular fluids.⁵³⁵ This is a rare, panethnic disorder with an estimated frequency of 1 in 640,000 live births.⁵²⁴

The skeletal system is most severely affected. Death from progressive psychomotor retardation, pneumonia, or congestive heart failure usually occurs in early childhood. Symptom management of this disease includes antibiotics for respiratory infections and nutritional supplements.

There are reports of four cases of mucolipidosis II undergoing HSCT (Table 94).^536-538 One mucolipidosis II patient was included in the retrospective study of 81 patients in the Japan Marrow Donor Program. The patient failed to engraft and no further information on that case could be separated from the aggregate data in that study.⁵²⁵

Table 94

Study characteristics and population for mucolipidosis II.

Refer to Appendix E Table E1 for details of neurocognitive and neurodevelopmental outcomes. In summary, one patient in a case series of combined diseases, did not have neurocognitive or neurodevelopmental followup, only adverse events reported.⁵³⁶ The patient experienced infectious complications, grade 2 skin aGVHD, and skin cGVHD. The patient was alive at last followup, which had a median of 2 years for the case series.⁵³⁶ One patient with delayed language skills continued to develop neurocognitively after HSCT, although abilities remained below real age. The patient's gross motor skills remained at level of a 1.5 year-old and fine motor skills were slowly developing through 5-years of followup.⁵³⁷ At the time of the report, the patient was alive at 5 years' followup. One patient with severe psychomotor retardation prior to HSCT gained developmental milestones of a 4- to 8-month old. The patient had no change in joint contractures and skeletal symptoms and died of disease progression at 5.6 years post-transplant.⁵³⁸

There was mention in one of the discussion sections⁵³⁷ of a personal communication with another physician who reportedly used HSCT to treat a patient with mucolipidosis II and that at 1 year post-transplant, the patient showed improvement in development and growth retardation. To our knowledge, this case has not been published.

Evidence for this disease which has a life expectancy of less than 1 decade, consists of three case reports. One patient died at 5.6 years post-transplant of disease progression, one is alive at 2 years' followup but with unknown neurological status, and the other patient was reported as showing progress neurocognitively, although below real age levels, and attends a special school. Based on these three patients with differing outcomes, there is uncertainty as to the benefit of HSCT for I-cell disease.

Cystinosis

Cystinosis is a rare autosomal recessive disease caused by a defect in cystinosin, which is needed to transport cystine out of lysosomes, which then results in the accumulation of cystine crystals in most major organs of the body.⁵³⁹ The incidence is estimated at 1 in 100,000-200,000, although the incidence in French Canadians may be higher.⁵⁴⁰ There are three types of cystinosis: classic nephropathic cystinosis, a rare adolescent form, and a mild adult-onset form.

Symptoms in the classic form present in the first year of life. Progressive renal damage and end stage renal failure is the usual cause of death, commonly within the first decade of life.⁵³⁹ The adolescent form of the disease is milder with a slower progression to renal failure. The adult form is benign, with no renal involvement.⁵⁴⁰ Renal transplant, oral cysteamine therapy, cysteamine eyedrops, and dialysis have prolonged survival into adulthood for patients with the nephropathic form.⁵³⁹ No studies of HSCT to treat cystinosis were found in the literature.

Infantile Sialic Acid Storage Disease

Infantile free sialic acid storage disease (ISSD) is a rare autosomal disorder caused by the accumulation of free sialic acid in lysosomes, due to a defect in the lysosomal membrane transport system.⁵⁴¹ More than 27 ISSD cases have been reported. Dysmyelination of the brain occurs in ISSD. Symptoms present at birth and life expectancy is about a year, with cause of death commonly from respiratory infections.⁵⁴² Disease management is symptom specific. No studies of HSCT to treat ISSD were found in the literature.

Hunter Syndrome (Mucopolysaccharidosis Type II)

Hunter Syndrome is a rare X-linked recessive disorder caused by a deficiency of the enzyme iduronate sulfatase, needed to degrade heparin sulfate and dermatan sulfate. The disease is panethnic, with an estimated incidence in Europe between 1 in 110,000–300,000; a higher incidence of 1 in 34,000 has been noted in the Jewish population living in Israel.⁵⁴³

There are two clinical forms of the disease, severe and attenuated. Onset of symptoms in the severe form occur at age 2 to 4 years. Survival can be expected into the second decade of life. Cause of death is usually heart disease, from valvular, myocardial, and ischemic factors.²⁶³ In the attenuated form, symptoms begin later in life, with minimal to no CNS involvement. Survival can extend into the fifth to sixth decade of life.²⁶³

Treatment is symptom specific: developmental, occupational, and physical therapy; shunting for hydrocephalus; tonsillectomy and adenoidectomy; positive pressure ventilation; carpal tunnel release; cardiac valve replacement; inguinal hernia repair; and hip replacement.⁵⁴⁴ HSCT has been attempted in MPS II patients, with both the severe (n=8) and attenuated forms (n=10), in attempts to slow or stop the progression of the disease (Table 95). An enzyme replacement therapy, Elaprase®, was approved by the FDA in 2006 for treatment of MPS II, following clinical trials which proved efficacy in patients with the attenuated form of the disease, aged 5-31 years.

Table 95

Study characteristics and population for mucopolysaccharidosis II (Hunter disease).

Refer to Appendix E Table E2 for details of neurocognitive and neurodevelopmental outcomes. In summary, among 32 patients undergoing HSCT, seven died of the treatment. In eight MPS II patients with the severe form, five showed decreases in neurocognitive scores^545-547 and one showed stable scores.⁵⁴⁸ In 10 MPS II patients with the attenuated form, there are neurocognitive test scores for 6 patients. Four showed stable scores and two showed slight decreases in their neurocognitive scores.^{538, 545, 549, 550} Among the three case series and two case reports that did not specify if patients had the severe or attenuated form, there was neurocognitive information on three patients⁵⁴⁹: two patients showed neurocognitive decline and one patient was stable and attends a special school.

Of 32 MPS II patients undergoing HSCT, there was followup neurodevelopmental information for 19 patients. Improvements in joint stiffness were reported in 14 of the 19 patients,^{538, 545, 548, 551-553} and one patient showed improvement in both fine and gross motor skills.⁵⁴⁸

The two clinical trials of enzyme-replacement therapy for MPS II patients reported pre- and post-treatment measurements for 6-minute walk tests.^{548, 554, 555} The 1-year followup in the Phase II/III trial (N=96) showed improvements in distance walked by the ERT weekly group (p=0.01) and the enzyme-replacement therapy every other week group (p=0.07) compared to the placebo group. The open label extension (n=12) reported that 8 patients improved and 4 experienced no change in walk test results after 1 year of followup.

Evidence for the attenuated form of this disease with a life expectancy into adulthood, consists of three case reports and three case series. HSCT showed stabilization of cognitive skills in four of six patients. Though the numbers are small, HSCT may benefit MPS II patients with the attenuated form.

Evidence for the severe form of this disease with life expectancy into the second decade of life, consists of three case reports and one case series. Neurocognitive decline continued in seven of eight patients. Though the numbers are small, HSCT does not appear to benefit MPS II patients with the severe form.

Sanfilippo Syndrome (Mucopolysaccharidosis Type III)

Sanfilippo Syndrome is an autosomal recessive disorder, with an incidence of 1 in 70,000 births.⁵⁶⁰ There are four types of Sanfilippo Syndrome, differentiated by the specific enzyme deficiency needed to break down heparan sulfate (Type A: heparan sulfate sulfatase, Type B: N-acetyl-o-glucosaminidase, Type C: Acetyl CoA: o-glucosaminide N-acetyltransferase, and Type D: N-acetyl-o-glucosamine-6-sulfate sulfatase).

Type A is the most severe form. Unlike most mucopolysaccharidoses, Sanfilippo disease has milder somatic symptoms, but severe progressive CNS involvement.²⁶³ Initial clinical symptoms occur slowly from 1-6 years of age. Mental deterioration is progressive and severe by ages 6 to 10 years.⁵⁶⁰ Life expectancy is from 12-20 years, with cause of death primarily caused by cardiopulmonary arrest due to airway obstruction and/or pulmonary infection.²⁶³ Symptom management of this disease includes anticonvulsants and sedative medications to improve sleep quality. HSCT has been attempted in several MPS III patients (Table 96).^{553, 561-564}

Table 96

Study characteristics and population for mucopolysaccharidosis III (Sanfilippo disease).

Refer to Appendix E Table E2 for details of neurocognitive and neurodevelopmental outcomes. In summary, one patient died 5 months post-transplant of pneumonia.⁵⁶¹ Of nine MPS III patients undergoing HSCT, there is neurocognitive followup information on six patients. There was a continuing deterioration in six patients^{553, 563, 564} and no significant improvement reported in one patient.⁵⁶²

There is neurodevelopmental information for three of the nine MPS III patients undergoing HSCT.^{563, 564} One patient experienced a slow and continuous decline in skeletal and muscular symptoms and was wheelchair-bound by 7.4 years after the transplant. This patient experienced the same physical deterioration as his untreated sibling.⁵⁶³ Twins experienced less neurodevelopmental decline compared to untreated brothers who were wheelchair-bound by the time they reached the age of the twins.⁵⁶⁴

Evidence for this disease with a life expectancy into the second decade consists of two case reports and two case series.^{553, 561, 562, 564} HSCT did not alter the neurocognitive decline but may have had some effect on the neurodevelopmental decline in two patients. Although the numbers are small, HSCT does not appear to benefit MPS III.

Morquio Syndrome (Mucopolysaccharidosis Type IV)

Morquio Syndrome is an autosomal recessive disorder with an estimated incidence of 1 in 200,000 births.⁵⁶⁵ There are two types, differentiated by which enzyme needed to degrade keratin sulfate is deficient (Type A: N-acetylgalactosamine 6-sulfatase, and Type B: β-galactosidase). Type A is the more severe form. Onset of symptoms occurs around 2 years of age. In most cases, normal intelligence is preserved.²⁶³ Life expectancy can extend into the third or fourth decade of life with the more severe form, while those with the milder form have been reported to live decades longer.²⁶⁴ Common causes of death include myelopathy, restrictive chest wall movement, and valvular heart disease.⁵⁶⁵ Spinal fusion to stabilize the upper cervical spine and prevent irreversible spinal cord injury can be a life-saving treatment for MPS IV patients. HSCT has been attempted on two MPS IV patients (Table 97).^{558, 566}

Table 97

Study characteristics and population for mucopolysaccharidosis IV (Morquio syndrome).

Refer to Appendix E Table E2 for details of neurocognitive and neurodevelopmental outcomes. In summary, one patient was 15 years old at the time of transplant and a pretransplant MRI showed no pathological findings in the brain or spinal cord. The patient had mild bone deformities at the time of transplant, and there was no followup for this patient.⁵⁵⁸ From echocardiograph, aortic stenosis and left ventricular dilatation were detected in one patient prior to HSCT. There was no change in cardiac symptoms after HSCT.⁵⁶⁶

Evidence for this disease with a life expectancy that varies from adolescence into adulthood, is based on two cases of HSCT found in the literature. The reports did not provide any post transplant neurocognitive or neurodevelopmental followup data.

Fabry Disease

Fabry disease is an X-linked recessive disorder characterized by decreased activity of α-galactosidase A. The prevalence is estimated at 1/40,000-60,000 males.⁵²⁶ The onset of symptoms and the severity of the disease vary widely. Males may exhibit symptoms in childhood or adolescence, or remain asymptomatic into adulthood. Female carriers may be asymptomatic or have symptoms as severe as affected males.⁵²⁶ Pain episodes, called Fabry pain crises, consist of burning, tingling, and numbness in the hands and feet, and can last several hours to days.²⁶¹ Decline in kidney function in early adulthood is the main cause of premature death in Fabry disease. Cardiovascular disease is also a cause of premature death, with hypertension, mitral valve prolapse, or congestive heart failure occurring.²⁶¹

Renal transplantation and long-term hemodialysis have prolonged life in Fabry's disease patients, and enzyme-replacement therapy using recombinant alpha-galatosidase has been shown to be safe and effective.²⁶¹

Gaucher Disease Type III

Gaucher disease is caused by a deficiency in the enzyme glucocerebrosidase, which leads to an accumulation of glucosylceramide in the spleen, liver, lungs, bone marrow, and sometimes the brain.²⁶¹ There are three types of Gaucher disease. Gaucher Type I is discussed in the Narrative Review section. Gaucher Type II is discussed in the Systematic Review under diseases with rapid progression.

Gaucher Type III is the subacute neuronopathic form, usually beginning later in childhood or adolescence, with loss of muscle coordination and cognitive deterioration progressing more slowly than in Type II.²⁶¹ Gaucher Type III patients may live into adulthood. Enzyme replacement therapy can be used to alleviate severe visceral symptoms, but is not effective in altering the neurologic progression of the disease.²⁶¹ Combinations of enzyme replacement therapy using recombinant imiglucerase or velaglucerase, substrate reduction therapy using miglustat, and HSCT have been attempted in Type III Gaucher patients (Table 98).

Table 98

Study characteristics and population for Gaucher Type III.

Refer to Appendix E Table E2 for details of neurocognitive and neurodevelopmental outcomes. In summary, among eight patients undergoing HSCT (two case reports and one case series of 6 patients), five showed stable neurocognitive scores.^{561, 569} All eight patients showed improved growth, although skeletal symptoms persisted.^{561, 568, 569} A case series that included two patients that had HSCT followed by enzyme-replacement therapy, report only followup data.⁵⁶⁷ Both patients have borderline mental retardation at last followup, but the mental status prior to HSCT and enzyme-replacement therapy is not specified.

Of 23 Gaucher Type III patients treated with enzyme-replacement therapy, neurocognitive followup is available on nine patients. Seven of the nine patients showed stable neurocognitive function,^{574, 575} one deteriorated clinically,⁵⁷⁴ and one who was showing improvement following enzyme-replacement therapy, deteriorated when therapy was discontinued.⁵⁷² Enzyme-replacement therapy improves growth, but cannot change skeletal deformities. In the enzyme-replacement therapy case series of 11 patients for which grading severity of marrow involvement was provided, one worsened, five remained constant, and five experienced complete improvement.⁵⁷¹ In a 2-year randomized controlled trial of substrate reduction therapy (miglustat) with enzyme-replacement therapy (imiglucerase; n=21) compared to enzyme-replacement therapy alone (n=9), there was no significant difference between study groups using several neurocognitive measurements.⁵⁷⁰

Evidence for HSCT for the treatment of Gaucher Type III which has a life expectancy extending into adulthood, consists of two case reports and two case series. In one case series, HSCT was followed by enzyme-replacement therapy. Among the patients who were treated with HSCT only, five of eight had stable neurocognitive scores at last followup. Among patients treated with enzyme-replacement therapy only, seven of nine had stable neurocognitive scores at last followup. Patients undergoing HSCT and patients treated with enzyme-replacement therapy have shown improved growth, although skeletal symptoms persist. HSCT appears to have a similar benefit compared to enzyme-replacement therapy.

Aspartylglucosaminuria

Aspartylglucosaminuria is a rare autosomal recessive disease characterized by a deficiency in the enzyme aspartylglucosaminidase, leading to an accumulation of glycoproteins in the liver, spleen, and thyroid. There is a higher prevalence of this disease in Finland, where the carrier frequency is estimated to be 1 in 36⁵⁷⁶ and the estimated incidence of the disease is 1 in 35,000. The estimated incidence outside of Finland is 1 in 2,000,000 births.

In the first year of life, recurrent infections, diarrhea, and hernia may occur. During adolescence, the intellectual disabilities worsen. The central nervous system is affected. Survival to mid-adulthood is expected, with most deaths attributed to pneumonia or other pulmonary complications.⁵⁷⁶ Anticonvulsant medications have been used to control seizures. HSCT has been attempted as a potential treatment of this disease (Table 99).

Table 99

Study characteristics and population for aspartylglucosaminuria.

Refer to Appendix E Table E2 for details of neurocognitive and neurodevelopmental outcomes. In summary, there were no reports of treatment-related mortality in the 10 patients undergoing HSCT. Of 10 patients with aspartylglucosaminuria undergoing HSCT, there is neurocognitive followup on nine. Two patients have improved concentration and cooperation.⁵⁷⁹ Two patients have stabilized developmentally at 5 years of age (real ages 15 and 11 years), and can speak in sentences and understand words in two languages.⁵⁷⁷ Five patients had, on average, lower developmental ages compared to 12 untreated patients, but direct comparisons may not be appropriate because the severity of disease differs widely in this disease. Two of the five transplanted patients were more severely retarded than any of the nontransplanted patients, potentially skewing the average age differential higher in the transplanted group.⁵⁷⁸

Evidence for aspartylglucosaminuria which has a life expectancy into mid-adulthood, consists of one case report and three case series, with a total of 10 transplants. Neurocognitive and neurodevelopmental measurements did not show clear improvements following HSCT. Small numbers in studies, and differences in severity of disease make interpretations of results difficult.

ß-Mannosidosis

ß-mannosidosis is a rare autosomal recessive disorder caused by a deficiency in the enzyme ß-mannosidase, resulting in the accumulation of oligosaccarides in lysosomes. Twenty cases have been identified worldwide, but the incidence may be higher because people with milder symptoms may never be diagnosed.

The onset of symptoms varies from infancy to adolescence, and the severity of symptoms varies from relatively mild to moderately severe.⁵⁸¹ Mental retardation is present in all individuals with this disease. There is no cure for ß-mannosidosis and treatment is symptom-specific.

No reports of HSCT for ß-mannosidosis patients have been found.

Mucolipidosis III (Pseudo-Hurler Polydystrophy)

Mucolipidosis III is a rare autosomal recessive disorder caused by a deficiency of the enzyme, N-acetylglucosamine-1-phosphotransferase. A defect of this enzyme affects the function of all lysosomal enzymes, which in turn causes the accumulation of a variety of substrates.⁵³⁵

Symptoms present between the ages of 4 to 5 years and include joint stiffness and short stature. Survival to adulthood is expected. There is no cure and treatment is symptom-specific, and may include: low-impact physical therapy for stiff joints, myringotomy tube placement for recurrent otitis media, tendon release for carpal tunnel syndrome, bilateral hip replacement for older adolescents with milder disease, and monthly bisphosphonate pamidronate IV for bone pain associated with osteoporosis.

No reports of HSCT for mucolipidosis III have been found.

Mucolipidosis IV

Mucolipidosis IV is a rare autosomal recessive disorder caused by a defect in the protein mucolipin-1, which is needed in the transport of lipids and proteins. This defect results in the build-up of lipids and proteins in lysosomes, affecting the development and maintenance of the brain and retinas.⁵⁸² An estimated 1 in 40,000 have mucolipidosis IV, with 70 percent having Ashkenazi Jewish ancestry.

There is a severe and more common form called typical mucolipidosis IV (about 95 percent) and a milder form called atypical mucolipidosis IV. In the severe form, mental and motor developmental delays occur within the first year of life. Most are unable to walk independently. Those with the milder form have less severe psychomotor and ophthalmic symptoms, and may be ambulatory. Life expectancy extends to adulthood, though a shorter life span is expected.⁵⁸²

Treatment is symptom-specific and may include: physical therapy for spasticity and ataxia, antiepileptic drugs, topical lubricating eyedrops, artificial tears, gels, or ointments for ocular irritation, and surgery for strabismus.

There are no reports of HSCT attempted in patients with mucolipidosis IV.

Niemann-Pick Disease C

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. Type A is discussed in the “Sphingolipidoses” section of this Systematic Review and Type B is discussed in the Narrative Review section. The incidence of Type C is estimated to be 1 in 150,000 and is most common in Nova Scotia among those of French-Acadian descent.⁵²³

Prolonged neonatal jaundice may occur, with no other symptoms until 1-2 years later or potentially until teen or adult years, when the disease develops a slow, progressive neurodegenerative course.²⁶¹ Death may occur in the late second or third decade of life, commonly from aspiration pneumonia. Management of this disease is symptom-specific for seizures, dystonia, and cataplexy, and may include chest physical therapy with aggressive bronchodilation and antibiotics for recurrent infections and seizure management. A randomized controlled study using substrate reduction therapy versus standard care has been conducted, and there are two case reports of HSCT to treat this disease (Table 100).

Table 100

Study characteristics and population for Niemann-Pick Type C.

Refer to Appendix E Table E2 for details of neurocognitive and neurodevelopmental outcomes. In summary, results from one case report of a patient with Niemann-Pick Type C undergoing HSCT showed that the transplant did not stop a progressive decline in developmental age, and an MRI confirmed brain atrophy. The patient became bedridden during the conditioning phase of the treatment. She never recovered developmentally following the transplant.⁵⁸⁴ The second case of HSCT showed a resolution of lung disease in the patient, and normal neurocognitive and neurodevelopmental progress, except for delayed speech.⁵⁸³ An abstract referenced in the most recent report of HSCT⁵⁸³ describes the resolution of lung disease in a Niemann-Pick Type C transplanted patient at 2 months post-transplant, but the patient died 3 months post-transplant of an adenovirus pulmonary infection.

Results from the randomized, controlled trial comparing substrate reduction therapy to routine symptom management and the retrospective cohort of substrate reduction therapy for Niemann-Pick Type C combined data for pediatric and adult patients.^{586, 588} The randomized, controlled trial did not find a significant difference in the mini-mental status examination (p=0.165) but found significantly improved ambulatory indexes in the treated group⁵⁸⁸ and the cohort study reported majority stable or improved scores in ambulation.⁵⁸⁶ The open-label extension study, which focused on pediatric patients, reported that eight of ten patients were stable in ambulation.⁵⁸⁵

Evidence for HSCT and Niemann-Pick Type C which has a life expectancy into the second to third decade, consists of two case reports. HSCT for one patient was not successful in stopping the neurocognitive and neurodevelopmental decline. One HSCT patient is developing normally at 1.7 years post-transplant. Based on two case reports, it is unclear if HSCT provides a benefit in the treatment of Niemann-Pick Type C.

Glycogen Storage Disease Type 2 (Pompe Disease)

Pompe disease is an autosomal recessive disorder caused by a deficiency in acid maltase, which results in the accumulation of lysosomal glycogen in tissues and cells. Cardiac, skeletal, and smooth muscle cells are the most seriously affected.⁵⁸⁹ The incidence is estimated at 1 in 40,000 live births. Age of onset and severity of symptoms varies among patients.

In infantile-onset Pompe disease, symptoms begin within the first few months of life and life expectancy is less than one year, with cause of death usually from cardiorespiratory failure or respiratory infection. The juvenile and adult-onset forms of the disease have either no or less severe cardiac involvement. Life expectancy ranges from early childhood to late adulthood, depending on the rate of disease progression. Respiratory failure is the most common cause of death.⁵⁸⁹ Several clinical trials of enzyme-replacement therapy in patients with infantile-onset Pompe disease have shown promising cardiac responses and variable skeletal responses to the treatment.^{590, 591}

There have been no reports of HSCT in the treatment of Pompe disease.

Salla Disease

Salla disease is a type of sialic acid storage disease, which is a rare autosomal disorder caused by the accumulation of free sialic acid in lysosomes, due to a defect in the lysosomal membrane transport system.⁵⁴¹ Salla disease is autosomal recessive. One hundred twenty Salla disease cases have been reported. Patients appear normal at birth, then develop psychomotor delay and ataxia during infancy, as dysmyelination of the brain occurs. Life expectancy is slightly reduced.⁵⁴¹ Disease management is symptom-specific.

There are no reports of HSCT used to treat Salla disease.

Adrenomyeloneuropathy

Adrenomyeloneuropathy is a variant of the X-linked recessive disorder, adrenoleukodystrophy, which is discussed in the Narrative Review section of this report. These disorders are caused by the accumulation of very long chain fatty acids in the brain and adrenal cortex, due to a deficiency in the enzyme that breaks down fatty acids.⁵⁹² About 40 percent of males with adrenoleukodystrophy develop adrenomyeloneuropathy, which presents in their late twenties as a chronic disorder of the spinal cord and peripheral nerves.⁵⁹³ The severity of symptoms varies greatly, even within one family. Depending on the severity of symptoms, life expectancy can reach late adulthood, though ambulation with a cane or walker may be necessary. HSCT has been shown to prevent the progression of symptoms in adrenoleukodystrophy if performed prior to the development of neurological symptoms.

A single case of HSCT for a 39-year-old male with adrenomyeloneuropathy was found in the literature.⁵⁶¹ No pediatric cases treated with HSCT have been reported.

Farber Disease

Farber disease is an autosomal recessive disorder characterized by a deficiency in ceramidase, resulting in the accumulation of ceramide in various tissues, the central nervous system, and most notably the joints. Fifty cases of this disease have been reported in the literature.⁵⁹⁴

Symptoms can begin in the first few weeks of life.²⁶¹ Nodules forming on the vocal cords cause hoarseness and breathing difficulties, which sometimes require the insertion of a breathing tube. Life expectancy in Type 1, the more severe form which has central nervous system involvement, is 2 years of age with progressive neurological deterioration as cause of death. Patients with the milder form, Type 2/3 with either no or mild central nervous system symptoms, can live to their teenage years with chronic respiratory failure as the most common cause of death.⁵⁹⁵

Physical therapy or surgery may provide relief of contractures, and surgery to remove nodules, granulomas, and possibly enlarged lymph nodes may be recommended. Hematopoietic stem-cell transplantation has been attempted in two patients with Type 1 Farber and in five patients with Type 2/3 Farber (Table 101).

Table 101

Study characteristics and population for Farber's disease.

Refer to Appendix E, Table E3 for details of neurocognitive and neurodevelopmental outcomes. In summary, no treatment-related mortality was reported in the seven patients with Farber disease undergoing HSCT. There is neurocognitive followup on the two patients with Type 1 Farber disease with CNS involvement. In one patient at the time of transplant, her developmental age was equivalent to her real age. After 1.4 years followup, at age 2.1 years, her developmental age had deteriorated to 0.6 years.⁵⁹⁸ The second Type I patient had mental regression prior to the transplant, which worsened following the transplant. This patient died 6 months post-transplant of disease progression.⁵⁵³ No neurocognitive followup was provided for the five Farber disease patients who had Type 2 disease, which has little or no CNS involvement.

The five patients reported in the case series on Farber Type 2/3 had nodule and joint inflammation. HSCT was successful in reducing the number of subcutaneous nodules and reducing the number of joints with limited range of motion in five of five patients.^{596, 597}

Evidence for Type 1 Farber disease with CNS involvement and a life expectancy of 2 years, consists of one case report and one case series. HSCT did not stop the neurocognitive deterioration in these patients. Evidence for Type 2 Farber disease without CNS involvement and a life expectancy extending into the second decade, consists of two case series. In all five patients with Farber Type 2/3 undergoing HSCT, both the number of subcutaneous nodules and the number of joints with limited range of motion were reduced. Based on these five patients, HSCT appears to improve the quality of life of patients with Farber Type 2/3.

GM1 Gangliosidosis

GM₁ gangliosidosis is an autosomal recessive disorder caused by a deficiency in ß-galactosidase. There are three subtypes, classified by age at presentation: infantile (type 1), juvenile (type 2), and adult (type 3). Estimated incidence is 1 in 100,000-200,000 live births.⁵⁹⁹ The infantile form, which can present as early as six months, is characterized by overall developmental retardation and generalized seizures. Survival is 2-4 years, with death most commonly due to aspiration pneumonia. Symptoms in the juvenile form begin around 1 year and are primarily neurological. Progression of this form of the disease is slow, and survival through the fourth decade of life is possible. The adult form is a slowly progressive disease characterized by spasticity, ataxia, dysarthria, and loss of cognitive function.⁶⁰⁰

Research in the areas of enzyme replacement therapy and gene therapy for this disease are ongoing, but have not advanced to human trials.⁵⁹⁹ A case report describes the use of HSCT to treat a patient with the juvenile form of the disease (Table 102).

Table 102

Study characteristics and population for GM₁ gangliosidosis.

Refer to Appendix E, Table E3 for details of neurocognitive and neurodevelopmental outcomes. In summary, a case report of a patient with GM₁ gangliosidosis juvenile form describes a slow deterioration in neurocognitive and neurodevelopmental measurements.⁶⁰¹

There have been no reports of HSCT for the infantile form of GM₁ gangliosidosis, which has a life expectancy of 2 to 4 years. Evidence for the juvenile form of GM₁ gangliosidosis, which has a life expectancy extending into the second through fourth decade, consists of 1 case report. Based on this case report, HSCT did not alter the course of the disease.

Tay-Sachs Disease

Tay-Sachs disease is an autosomal recessive disorder caused by a deficiency in the isoenzyme hexosaminidase A, resulting in the accumulation of GM₂ ganglioside in the brain. The Ashkenazi Jewish population is most at risk, with a carrier rate estimated at 1 in 30.⁶⁰⁰ There are infantile-, juvenile-, and adult-onset forms of the disease. In the infantile form, patients have no hexosaminidase A enzyme and in the juvenile and adult forms, patients have low levels of hexosaminidase A enzyme. The infantile form is the most severe, and other than a marked startle reaction to noise, infants appear normal until about 6 months of age when developmental delays begin. Life expectancy is 4 to 5 years, with aspiration or bronchopneumonia the most common causes of death.²⁶¹ The juvenile and adult forms are rare and symptoms are less severe.

Anticonvulsant medication to control seizures, proper hydration to keep airways open, and feeding tubes to provide nutritional supplements have been recommended. HSCT, substrate reduction therapy, and a combination of both, have been attempted on several Tay-Sachs disease patients (Table 103).

Table 103

Study characteristics and population for Tay-Sachs disease.

Refer to Appendix E, Table E3 for details of neurocognitive and neurodevelopmental outcomes. Two case series of HSCT to treat several different diseases included one patient with Tay-Sachs in each series (disease form not specified). One patient died at 4.6 years post-transplant of a possible infection.⁵⁵⁶ The other patient had psychomotor retardation at the time of transplant and further regressed to a vegetative state at 1.7 years' followup.⁵⁵³

The case report⁶⁰² was of a patient with the juvenile form of Tay-Sachs. In the case report, brain MRI, EEG, and neuropsychological tests showed neurological deterioration at 1.5 years post-transplant. At that time, substrate reduction therapy was initiated, but was not successful in stopping the deterioration. Neurodevelopmental followup in this case report showed motor skills deteriorating by 0.5 years post-transplant in this patient; her deterioration was comparable to her untreated sister's.

Among the two patients with the juvenile form who were treated with substrate reduction therapy,⁶⁰³ one who had mild cognitive impairment pretreatment experienced an acute psychotic event at 1.3 years post-treatment, and one who had severe cognitive impairment pretreatment had increased spasticity and seizures post-treatment. The 2 Tay-Sachs disease patients with the juvenile form of the disease who were treated with substrate reduction therapy, continued to have neurodevelopmental decline following the treatment.

Evidence for the juvenile form of Tay-Sachs disease which has a life expectancy of 15 years, consists of one case report. The patient continued to show neurocognitive and neurodevelopmental decline similar to what was experienced in the untreated sibling. Based on this case report, HSCT does not show a benefit in the treatment of the juvenile form of Tay-Sachs disease.

Ceroid Lipofuscinosis

Neuronal ceroid lipofuscinoses are autosomal recessive disorders which are the most common class of neurodegenerative diseases in children.⁶⁰⁰ A defect in the enzyme that degrades fatty acylated proteins causes the storage of autofluorescent lipopigments in lysosomes.⁶⁰⁴ Worldwide incidence of this disease is estimated at 1 in 20,000-100,000, but the incidence is higher in Finland.⁶⁰⁰

Depending on which gene is affected, symptoms may begin during early infancy, late infancy, or during juvenile years. Symptoms develop by the end of age 1 in the early infantile form with life expectancy from 6 to 13 years. In the late infantile form, symptoms begin from 2 to 4 years of age, with a life expectancy extending from 6 to 40 years. In the juvenile form, symptoms begin between 5 to 10 years of age with a life expectancy from teens to thirties.⁶⁰⁰

There is no cure for these disorders and treatment is symptom-specific: antiepileptic drugs and benzodiazepines for seizures, anxiety, and spasticity, gastric tubes for swallowing problems, and antidepressants and antipsychotic agents for patients with the juvenile form. HSCT has been performed in several patients with the early infantile form of the disease (Table 104).

Table 104

Study characteristics and population for ceroid lipofucinosis.

Refer to Appendix E, Table E3 for details of neurocognitive and neurodevelopmental outcomes. Neurocognitive decline continued in three of three patients with ceroid lipofuscinosis with the infantile form undergoing HSCT, as measured by cerebral cortical atrophy and periventricular white matter hyperintensity. HSCT did not prevent the neurodevelopmental decline in the three patients with infantile ceroid lipofuscinosis. By followup of 2 to 4 years, all three were hypotonic and spastic.

Evidence for this disease which has a life expectancy of 6-13 years, consists of one case series of three patients. The procedure was unable to stop the neurocognitive and neurodevelopmental decline in all three patients. Based on this case series, HSCT does not show a benefit of HSCT for the treatment of infantile ceroid lipofuscinosis.

Galactosialidosis

Galactosialidosis is a rare autosomal recessive condition in which there is a deficiency of two lysosomal enzymes, neuraminidase and β-galactosidase. This enzyme deficiency causes the accumulation of oligosaccharides in many tissues such as the liver, bone marrow, and brain.⁵⁷⁶ There are three forms which differ by age of onset of symptoms and symptom severity. One-hundred cases have been reported, with 60 percent of the juvenile/adult forms in patients of Japanese descent.⁶⁰⁶

In the early infantile form, fluid accumulation begins before birth. Life expectancy does not extend beyond late infancy, with kidney failure or cardiomegaly as common causes of death. Symptoms in the late infantile form of the disease are similar to those in the early infantile form, though less severe and the onset is later in the first year of life. Life expectancy can extend into the second decade of life, depending on severity of symptoms. The juvenile/adult form of the disease is least severe, with symptoms first occurring usually in the teen years. There is no cure for galactosialidosis and treatment is symptom specific.

A retrospective study of 81 patients in the Japan Marrow Donor Program who underwent unrelated bone marrow transplantations for immunodeficiency and metabolic diseases reported a single case of galactosialidosis within its study population.⁵²⁵ The form of galactosialidosis was not specified in the report. Outcomes were cumulative overall and event-free survival, and cumulative acute and chronic graft-versus-host disease. Engraftment occurred in the galactosialidosis case, but no other information on that case could be separated from the aggregate data.

Sandhoff's Disease

Sandhoff's disease is caused by a deficiency in both hexosaminidase A and B, resulting in the accumulation of GM₂ ganglioside in lysosomes. Symptoms are similar to those in Tay-Sachs disease, presenting at about 6 months of age. Life expectancy is 3 years of age.⁶⁰⁰ Symptom management includes anticonvulsant medication to control seizures, and proper hydration and nutrition to keep airways open.

A case of a patient with Sandhoff's disease undergoing HSCT is reported in the literature, but the form of the disease is not specified (Table 105). There is also a single arm study reporting the use of substrate reduction therapy in 3 patients with Sandhoff's disease (juvenile form).

Table 105

Study characteristics and population for Sandhoff's disease.

Refer to Appendix E, Table E3 for details of neurocognitive and neurodevelopmental outcomes. In summary, there is no neurocognitive or neurodevelopmental information in the patient with Sandhoff's disease (form unspecified) who underwent HSCT. The three patients with Sandhoff's disease who were treated with substrate reduction therapy experienced stable neurocognitive scores, but neurodevelopmental decline occurred.⁶⁰³ One became wheelchair dependent by 1.8 years post-treatment, and two had gait disturbance.

Evidence for Sandhoff's disease consists of one case report. The report did not specify if the patient had the infantile form or the juvenile form of the disease. No neurocognitive or neurodevelopmental followup information on the single Sandhoff's disease patient was provided; no conclusions on effectiveness can be made.

Adverse Effects

Table 106 summarizes the adverse effects reported in patients undergoing HSCT for inherited metabolic disorders.

Table 106

Adverse effects for treatment (HSCT) in IMD patients.

Rapidly Progressive Diseases

• High strength evidence on overall survival suggests a benefit with single HSCT compared to conventional management for Wolman's disease.
• Low strength evidence on overall survival suggests no benefit with single HSCT compared to symptom management or disease natural history for Niemann-Pick Type A.
• The body of evidence on overall survival with single HSCT compared to symptom management is insufficient to draw conclusions for mucolipidosis II (I-cell disease), Gaucher disease type II, cystinosis and infantile free sialic acid disease.

Slowly Progressive Diseases

• Low strength evidence on neurodevelopmental outcomes suggests a benefit with single HSCT compared to enzyme replacement therapy for the attenuated and severe forms of MPS II (Hunter's disease).
• Low strength evidence on neurocognitive outcomes suggests a benefit with single HSCT compared to enzyme replacement therapy for the attenuated form of MPS II (Hunter's disease).
• Low strength evidence on neurocognitive outcomes suggests no benefit with single HSCT compared to enzyme replacement therapy for the severe form of MPS II (Hunter's disease).
• Low strength evidence on neurocognitive outcomes suggests no benefit with single HSCT compared to enzyme replacement therapy for Gaucher Type III.
• Low strength evidence on neurocognitive or neurodevelopmental outcomes suggests no benefit with single HSCT compared to symptom management, substrate reduction therapy or disease natural history for MPS III (Sanfilippo).
• The body of evidence on neurocognitive or neurodevelopmental outcomes with single HSCT compared to symptom management and/or disease natural history is insufficient to draw conclusions for Niemann-Pick type C, MPS IV (Morquio syndrome), aspartylglucosaminuria, Fabry's disease, β-mannosidosis, mucolipidosis III or IV, glycogen storage disease type II (Pompe disease), Salla disease, and adrenomyeloneuropathy.

Disease With Both Rapidly and Slowly Progressive Forms

• High strength evidence on number of subcutaneous nodules and number of joints with limited range of motion suggests a benefit with single HSCT compared to symptom management or disease natural history for Farber's disease Type 2/3.
• Low strength evidence on neurocognitive outcomes suggests no benefit with single HSCT compared to symptom management or disease natural history for infantile ceroid lipofuscinosis.
• The body of evidence on overall survival and/or neurocognitive and neurodevelopmental outcomes with single HSCT compared to symptom management and or disease natural history is insufficient to draw conclusions for galactosialidosis (type unspecified) and Sandhoff disease (type unspecified), Farber's disease type I, infantile and juvenile forms of GM₁, infantile and juvenile forms of Tay-Sachs, infantile GM₁ gangliosidosis, and juvenile ceroid lipofuscinosis.

Background and Setting

Type 1 diabetes mellitus (DM1) is a T-cell mediated autoimmune disease characterized by selective, relentless and irreversible destruction of insulin-producing pancreatic beta-cells.⁶⁰⁷ DM1 is the most common autoimmune disorder in childhood, with an estimated incidence of 15,000 newly diagnosed cases in the U.S. annually based on 2002-2003 data.⁶⁰⁸ The disease typically is clinically diagnosed after approximately 60 to 80 percent of beta-cell mass has been destroyed.⁶⁰⁹ At this stage of disease, exogenous insulin treatment is required to maintain glucose homeostasis and survival. While DM1 comprises 5-10 percent of all diabetic causes, it is ultimately associated with a high frequency of vascular-related complications, including heart disease, stroke, blindness, and renal disease, with highly compromised quality of life and life expectancy.⁶¹⁰

According to the U.S. Centers for Disease Control and Prevention, diabetes was the seventh leading cause of death listed on U.S. death certificates in 2006. Intensive insulin therapy (IIT) represents the gold standard treatment for DM1, to maintain tight control of blood glucose levels, as reflected by levels of HbA1C. IIT is delivered by multiple daily injections or by continuous subcutaneous infusion. Both methods have been shown to decrease the risk of diabetic retinopathy, nephropathy, and neuropathy by 39 to 90 percent and reduce their rate of progression by 39 to 60 percent when compared to standard insulin therapy with 1 to 2 injections daily.⁶¹¹ However, IIT is complicated by lack of patient acceptance and compliance, cannot fully prevent diabetic complications, and is associated with increased risk of severe hypoglycemia compared to standard therapy.

While DM1 does not typically develop into a fulminant, life-threatening form, it is a relentlessly progressive disorder despite IIT. The natural history may be transiently altered, but not halted, by coadministration of IIT and immune modulating therapies that include cyclosporine, azathioprine, prednisone, etanercept, and antithymocyte globulin (ATG).⁶⁰⁷ These approaches may induce a slower decline or some initial improvement in C-peptide levels, which directly reflect beta-cell mass and endogenous insulin production. However, the majority of patients continue to require increasing amounts of exogenous insulin. Furthermore, the toxic effects of immune suppressants, concerns about potential risks associated with immune suppression, and the need for continuous treatment in an otherwise healthy young population limit the use of these agents in conjunction with IIT.

For these reasons, based on a theory of possible reconstitution of immune tolerance after “immunologic reset,” nonmyeloablative autologous HSCT has been investigated as a way to effect an intense, but brief, immune suppression and preserve islet cell mass in children with newly diagnosed 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 IIT, in the context of adverse events associated with HSCT and IIT.

Evidence Summary

The overall grade of the strength of evidence for insulin independence and the use of HSCT for the treatment of autoimmune type I juvenile diabetes mellitus is shown in Table 107.

Table 107

Overall grade of strength of evidence for insulin independence and the use of HSCT for the treatment of autoimmune Type I diabetes mellitus.

Evidence compiled for this review includes one prospective Phase I/II study of autologous HSCT (n=18 pediatric patients) that reported pre- and post-HSCT data on C-peptide levels and daily insulin use. Comparator data were obtained from the IIT control arms of two studies (total n=35) in newly diagnosed pediatric DM1 patients.

In the HSCT study, among 18 pediatric patients, the majority (89 percent) became free from insulin, either continuously (63 percent) or transiently (37 percent). Insulin independence was maintained for 7 to 52 months at total followup that ranged from 9 to 56 months. Among the 6 patients who resumed insulin, daily doses were lower than prior to HSCT. There was no treatment-related mortality in the HSCT study.

Results

The electronic literature search identified 15 citations relevant to HSCT and DM1, from which seven were retrieved for full-text screening, including those found in examination of the bibliographies of retrieved articles. A total of three reports were included in this review.^612-614

Table 108 shows the criteria that were used to select studies for this section.

Table 108

Study selection criteria: Type I DM.

Table 109 shows the characteristics of one Phase I/II study of HSCT,⁶¹² and the IIT control arms of two randomized trials that compared IIT with IIT plus an immunosuppressant agent.^{613, 614} All three studies included pediatric patients with DM1 who had been clinically diagnosed within 6 weeks prior to study entry.

Table 109

Type 1 juvenile diabetes mellitus study characteristics and population.

In the HSCT study, peripheral blood hematopoietic stem cells were mobilized with cyclophosphamide (2 g/m²) and granulocyte colony-stimulating factor (10 μg/kg daily).⁶¹² Patients were conditioned with a nonmyeloablative regimen comprising cyclophosphamide (50 mg/kg daily for 4 days) and rabbit antithymocyte globulin (0.5 mg/kg daily for 1 day, then 1 mg/kg daily for 4 days) prior to stem cell infusion. The IIT studies utilized 3 to 4 injections of short- or intermediate-acting insulin, with blood glucose levels monitored and maintained as near to normal as possible.^{613, 614}

Table 110 shows the outcomes that were reported across the studies included in this report.

Table 110

Outcomes reported: Type I DM.

Ongoing Research

According to the website ClinicalTrials.gov, five clinical studies are recruiting pediatric patients, as shown in Table 111. None of these originates in the U.S. Of the ongoing trials, only one offers a comparison between autologous mesenchymal stem cells and placebo (NCT01157403).

Table 111

Ongoing clinical trials of HSCT in DM1.

Conclusion

The overall body of evidence is insufficient to draw conclusions on long-term benefits or harms with single autologous HSCT in patients with newly diagnosed type I juvenile diabetes.

Moderate strength evidence suggests that an extended interval of insulin independence can be achieved with single autologous HSCT in patients with newly diagnosed type I juvenile diabetes.

Background and Setting

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is associated with inflammation and eventual organ damage.⁶⁰⁷ It may involve any organ system, with a wide range of disease severity. The exact cause of SLE is unknown. Diagnosis of SLE is the same regardless of age at onset, and is based on a combination of laboratory and clinical criteria. SLE is likely if four of the 11 revised American College of Rheumatology (ACR) criteria are present in a patient simultaneously or over time.⁶¹⁵

SLE is rare in childhood, with an estimated incidence of 10 to 20 per 100,000 children, with some variation depending on ethnicity. Juvenile-onset SLE (prior to age 18 years) accounts for 15 to 20 percent of cases,⁶¹⁶ which in general have a more severe presentation, faster development of organ damage, and a higher disease burden over a lifetime. For all age groups, 5-year survival rates have improved with advances in management of organ damage and complications, from 59 to 93 percent in the 1980s to 94 to 100 percent by the late 1990s.⁶¹⁷ Patients aged younger than 24 years have the highest rate of SLE-related all-cause mortality, about 8-fold greater than the average for all SLE cases.⁶¹⁸

The clinical course of SLE is marked by the alternation of periods of active disease and quiescence. However, children and adolescents with SLE enter adult life with considerable morbidity, secondary to sequelae of disease activity, side effects of medications, and comorbid conditions. The most common symptoms of SLE include fever, rash, fatigue, weight loss, arthritis, and renal disease.⁶¹⁹ Lupus nephritis is one of the main clinical presentations of pediatric SLE, and it determines the course of illness as the major threat to long-term survival. Other major manifestations include neuropsychiatric, cardiac, and lung.

SLE has no known cure. Depending on severity, it is often treated with high-dose corticosteroids and immune suppressants, which are responsible for much of the permanent organ damage observed in these patients. Other treatments include hydroxychloroquine, cyclophosphamide, cyclosporine A, mycophenolate mofetil, azathioprine, nonsteroidal anti-inflammatory drugs (NSAIDs), rituximab, and abatacept.⁶⁰⁷ Only three agents have received U.S. Food and Drug Administration marketing approval for SLE: corticosteroids, hydroxychloroquine, and aspirin.

Autologous HSCT has been used to treat a small number of pediatric SLE cases, all of which have been severe, life-threatening, and refractory to nearly all drug therapies, with a dismal prognosis. Accordingly, this systematic review will present only results from HSCT reports, with the comparison being usual care.

Evidence Summary

The overall grade of strength of evidence for drug-free clinical remission and the use of HSCT for the treatment of severe, refractory systemic lupus erythematosus is shown in Table 112.

Table 112

Overall grade of strength of evidence for drug-free clinical remission and the use of HSCT for the treatment of severe, refractory systemic lupus erythematosus.

Overall, 12 of 17 (71 percent) SLE patients treated with autologous HSCT entered a state of complete drug-free remission, for periods that ranged from about 4 months⁶²⁰ to 66 months.⁶²¹ The former reflects the followup time at preparation of the paper. In the largest series (n=9), patients experienced complete drug-free remission for a median 24 months, and a range of 12 to 66 months.⁶²¹

Three studies reported SLE Disease Activity Index (DAI) score changes pre- and post-HSCT.^621-624 Patients who underwent autologous HSCT and experienced a complete drug-free remission had substantial reduction in their SLEDAI scores. In one study, two of four patients succumbed to treatment-related mortality, one at 63 days from multiorgan failure, the other on day 15 due to multiple causes.⁶²³

Results

A total of seven reports were included in this review. Table 113 shows the criteria that were used to select studies for this section.

Table 113

Study selection criteria: SLE.

Table 114 shows the characteristics of studies of autologous HSCT in 17 patients (16 female) aged 13-21 years with SLE. All had severe, life-threatening SLE that was refractory to most first- and second-line drugs, variously including corticosteroids, pulsed cyclophosphamide, 6-mercaptopurine, azathioprine, plasmapheresis, and hydroxychloroquine. Although rituximab and abatacept have been studied in adults with SLE, we did not identify any studies of those agents in the pediatric setting. Outcomes reported are included in Table 115.

Table 114

Systemic lupus erythematosus study characteristics and population.

Table 115

Outcomes reported: SLE.

Five studies used only peripheral blood stem cells.^{620-622, 625, 626} One used bone marrow cells;⁶²⁴ and, one used both sources.⁶²³ Conditioning regimens typically included cyclophosphamide plus ATG; two studies included total-body irradiation,^{624, 626} and one used modified BEAM regimens with ATG.⁶²³

Complete Drug-Free Remission

Table 116 shows the proportions of patients with severe, refractory SLE who entered a state of complete drug-free remission following intense immune suppression and autologous HSCT. Overall, 12 of 17 (71 percent) entered a state of complete drug-free remission, for periods that ranged from about 4 months⁶²⁰ to 66 months.⁶²¹ The former reflects the followup time at preparation of the paper. In the largest series, patients experienced complete drug-free remission for a median 24 months, and a range of 12 to 66 months.⁶²¹

Table 116

Complete drug-free remission in patients with SLE undergoing autologous HSCT.

Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Score

Three studies reported SLEDAI score changes pre- and post-HSCT,^622-624 as shown in Table 117. In studies that reported this outcome, patients who underwent autologous HSCT and experienced a complete drug-free remission had substantial reduction in their SLEDAI scores.

Table 117

Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Score.

Ongoing Research

According to the Web site ClinicalTrials.gov, two clinical studies are recruiting pediatric patients, as shown in Table 118.

Table 118

Ongoing clinical trials of HSCT in SLE.

Conclusion

The overall body of evidence is insufficient to draw conclusions on long-term benefits or harms with single autologous HSCT for the treatment of severe, refractory SLE in children.

Moderate strength evidence suggests that an extended drug-free clinical remission can be achieved with single autologous HSCT for the treatment of severe, refractory SLE in children.

Background and Setting

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in children, with a prevalence of between 16 and 150 per 100,000.⁶⁰⁷ It is defined as persistent arthritis in one or more joints in a child or adolescent less than 16 years old, after excluding other causes. According to the current International League of Association of Rheumatologists (ILAR) the term JIA refers to seven different disease categories: systemic, persistent oligoarticular, extended oligoarticular, polyarticular rheumatoid factor (RF) negative, polyarticular RF positive, enthesitis-related arthritis, and psoriatic.⁶²⁷

While the cause of JIA is not defined, evidence suggests altered immune system function, particularly T-cell regulation, has a major role in the pathogenesis of joint damage and disease progression.^{628, 629} JIA subtypes vary by the number of joints involved, and by age of onset. The most common form is the early onset (before age 6 years) oligo- or mono-articular JIA, with 1 to 4 asymmetrical joints affected, a high frequency of positive antinuclear antibodies (ANA), and high risk (30 percent) of chronic uveitis. These forms have generally good prognosis, and may be managed with intra-articular steroids and physiotherapy.⁶²⁷

At the other end of the spectrum, systemic-onset JIA is distinct from other JIA subtypes, with a systemic inflammatory component. While about 50 percent of cases will have a waxing and waning course, with favorable long-term prognosis, the other 50 percent will have an unremitting course with polyarthritis; prolongation of active systemic illness past 6 months is a particularly bad prognostic sign.⁶⁰⁷ Despite current treatment that includes methotrexate, corticosteroids, biological response modifiers (blocking agents of TNF-alpha, IL-1, IL-6) or blockers of costimulatory immune cell-surface molecules (e.g., CD28 or CD20),and other immune suppressants, most children with systemic polyarticular JIA do not achieve long-term clinical remission.^{607, 627} More than one-third will have ongoing active disease into adulthood, with sequelae secondary to chronic inflammation. Those who do not respond to early use of antirheumatic agents will experience considerable morbidity from joint damage, osteoporosis, growth retardation, psychosocial morbidity, reduced quality of life and educational and employment disadvantage.⁶²⁷

Autologous HSCT has been used to treat a small number of pediatric JIA cases, all of which have been severe, progressive and refractory to standard drug therapies. Accordingly, this systematic review will present only results from HSCT reports, compared to usual care and the disease course.

Evidence Summary

The overall grade of strength of evidence for drug-free clinical remission and the use of HSCT for the treatment of severe, refractory juvenile idiopathic arthritis is shown in Table 119.

Table 119

Overall grade of strength of evidence for drug-free clinical remission and the use of HSCT for the treatment of severe, refractory juvenile idiopathic arthritis.

Overall the evidence signals that autologous HSCT following chemotherapy-induced immune suppression may be associated with prolonged resolution of JIA into a drug-free, much-improved state. Among all cases reported, 21 of 43 (56 percent) achieved extended drug-free remission for 3 to 60 months. In the largest series, drug-free remission was reported in 53 percent, with a median duration of 29 months. There were four cases of treatment-related mortality, with no other reports of long-term benefits and harms.

Results

A total of four reports were included in this review.^630-633 Table 120 shows the criteria that were used to select studies for this section.

Table 120

Study selection criteria: JIA.

Table 121 presents the study characteristics and populations of 4 reports on the use of autologous HSCT treatment in patients with JIA. All patients had severe, refractory illness, mostly systemic (79 percent) but also polyarticular (21 percent). The largest experience is from the registry of the EBMT, which reports on 34 of 41 total patients who had received autologous HSCT at nine European centers.⁶³⁰ Four cases were treated in Japan^{631, 632} and five were from Italy.⁶³³ Patients ranged in age from 3 to 21 years, with 49 percent females and 51 percent males.

Table 121

Juvenile idiopathic arthritis study characteristics and population.

Among 43 cases, 26 (60 percent) used bone-marrow stem cells, 12 (28 percent) used peripheral-blood stem cells, and the stem-cell source was not identified for five.⁶³³ Various conditioning regimens were reported, typically involving cyclophosphamide and ATG.

Table 122 shows outcomes that were reported in the four studies in this systematic review. Complete drug-free remission is the key outcome, which is generally defined as disappearance of signs and symptoms of JIA and cessation of antirheumatic agents.

Table 122

Outcomes reported: JIA.

Complete Drug-free Remission

Overall, 56 percent of patients in these reports achieved a complete drug-free remission following autologous HSCT (Table 123). In the largest study, a complete drug-free response was achieved in 53 percent of cases, for an average duration of about 2.5 years, although some patients maintained this response for 60 months.⁶³⁰ In the Rabusin series, four of five (80 percent) patients achieved a complete drug-free response at 3 months' followup, with a relapse in one at 6 months, and ultimately relapse in the other three at 8, 12, and 18 months.⁶³³ One patient in the Kishimoto study had disease flares at 11 and 23 months followup, but became medication-free and asymptomatic at 39 months followup.⁶³¹

Table 123

Complete drug-free remission in patients with JIA undergoing autologous HSCT.

Ongoing Research

According to ClinicalTrials.gov, there are no clinical trials of HSCT actively recruiting patients with JIA.

Conclusion

The overall body of evidence is insufficient to draw conclusions on long-term benefits or harms with single autologous HSCT for the treatment of severe, refractory JIA in children.

Moderate strength evidence suggests that an extended drug-free clinical remission can be achieved with single autologous HSCT for the treatment of severe, refractory JIA in children.

Background and Setting

Systemic sclerosis is a generalized, highly heterogeneous autoimmune disorder characterized by diffuse, disabling skin thickening combined with fibrotic changes in many organs, in particular the heart and lung, ultimately resulting in end-stage failure.⁶³⁴

Systemic sclerosis is a rare disease. It is diagnosed in approximately 67 male patients and 265 female patients per 100,000 people each year in the U.S. Systemic sclerosis usually appears in women aged 30 to 40 years, and it occurs in slightly older men. In approximately 85 percent of cases, systemic sclerosis develops in individuals aged 20 to 60 years. Cases also are observed in children and in the elderly population. Immunologic mechanisms and heredity (certain HLA subtypes) play a role in etiology. Systemic sclerosis-like syndromes can result from exposure to vinyl chloride, bleomycin, pentazocine, epoxy and aromatic hydrocarbons, contaminated rapeseed oil, or L-tryptophan.

Systemic sclerosis pathophysiology involves vascular damage and activation of fibroblasts; collagen and other extracellular proteins in various tissues are overproduced. The disease varies in severity and progression, ranging from generalized skin thickening with rapidly progressive and often fatal visceral involvement, primarily end-stage organ failure.^635-637 The course depends on the type of systemic sclerosis but is often unpredictable. Typically, progression is slow. Overall, 5- and 10-year survival is about 20 to 80 percent and 15 to 65 percent, respectively, according to the major organ affected at diagnosis.^638-640 Patients with diffuse skin disease eventually develop visceral complications, which are the usual causes of death. Prognosis is poor if cardiac, pulmonary, or renal manifestations are present early. Heart failure may be intractable. Acute renal insufficiency, if untreated, progresses rapidly and causes death within months.

Results from Phase II open studies suggest intravenous pulse cyclophosphamide therapy may improve skin score and pulmonary function.^641-643 However, no treatment has been shown definitively to halt disease progression. Autologous HSCT has been used to treat a small number of pediatric systemic sclerosis cases, all of which have been severe, progressive and refractory. Accordingly, this systematic review will present only results from HSCT reports, compared to usual care and the disease course.

Evidence Summary

The overall grade of strength of evidence for drug-free clinical remission and the use of HSCT for the treatment of severe, refractory systemic sclerosis is shown in Table 124.

Table 124

Overall grade of strength of evidence for drug-free clinical remission and the use of HSCT for the treatment of severe, refractory systemic sclerosis.

Systemic sclerosis is very rare in children, with one registry report comprising the sole source of published evidence on the use of autologous HSCT in this setting. There are no proven therapies for advanced, progressive systemic sclerosis with visceral involvement, which has a dismal prognosis. In this context, that four of five patients (80 percent) entered a state of complete clinical remission, with the other one in partial remission, signals that autologous HSCT following chemotherapy-induced immune suppression may be associated with these results.

Results

One report was included in this review. Table 125 shows the criteria that were used to select studies for this section.

Table 125

Study selection criteria: Systemic sclerosis.

Table 126 shows the study and patient characteristics of one report on the use of autologous HSCT in pediatric systemic sclerosis patients.⁶⁴⁴ This registry report provides details on 5 children age 9 to 17 years, all of whom had lung disease at inclusion and systemic sclerosis (4 diffuse, 1 limited). Disease had been diagnosed within 62 months (range: 26-85 months) before HSCT. They all received the same mobilization regimen comprising cyclophosphamide and G-CSF plus cell selection before transplantation with either CD34+ selection alone (n=3) or CD34+/4+/8+ (n=2). Different conditioning regimens were used, comprising cyclophosphamide plus antiCD52 (CAMPATH 1) (n=3), cyclophosphamide plus TBI plus ATG (n=1), or cyclophosphamide alone (n=1).

Table 126

Systemic sclerosis study characteristics and population.

Only scant details on pediatric patients are available in the registry report. All five children were reported alive after a median duration of about 38 months (range: 14-68 months). Four (80 percent) entered complete remission, with one partial remission. Disease ultimately progressed in one patient, and one relapsed about 9 months after experiencing a complete remission. One 19-year-old patient, not included in the group of five reported above, succumbed to diffuse alveolar hemorrhage 11 days post-transplant.

Ongoing Research

According to ClinicalTrials.gov, one Phase I/II study in China is actively recruiting individuals with systemic sclerosis to undergo HSCT with allogeneic mesenchymal stem cells (NCT00962923). A pilot study of total body irradiation in combination with cyclophosphamide, antithymocyte globulin, and autologous CD34-selected peripheral blood stem cell transplantation in children with refractory autoimmune disorders is active but not recruiting (NCT00010335).

Conclusion

The overall body of evidence is insufficient to draw conclusions on long-term benefits or harms with single autologous HSCT for the treatment of severe, refractory systemic sclerosis in children.

Moderate strength evidence suggests that an extended drug-free clinical remission can be achieved with single autologous HSCT for the treatment of severe, refractory systemic sclerosis in children.

Background and Setting

Multiple sclerosis (MS) is a CNS demyelinating disease with an autoimmune etiology.⁶⁴⁵ It is characterized by the presence of inflammatory, demyelinating lesions scattered throughout the CNS at different sites and at different times. Clinical features secondary to the CNS lesions include loss of sensation, muscle weakness, visual loss, incoordination, cognitive impairment, fatigue, pain, and bladder and bowel disturbance.⁶⁴⁵

Pediatric MS is diagnosed after two clinical episodes of CNS demyelination that are separated by at least 30 days.⁶⁴⁶ In adults, three of the following four features are required: nine or more white matter lesions or one gadolinium-enhancing lesion; three or more periventricular lesions; one juxtacortical lesion; one infratentorial lesion. These criteria may be applied to identify pediatric cases, but have not been clinically validated in this population.⁶⁴⁷

The worldwide prevalence of pediatric MS is unknown. Data from individual countries or MS centers reported prevalence rates of MS in childhood ranging from 3.1 to 4.4 percent of all MS cases.^648-650 A Canadian study estimated the incidence of initial pediatric demyelinating events (including MS, neuromyelitis optica, acute disseminated encephalomyelitis, complete transverse myelitis, and recurrent optic neuritis) as 0.9 per 100,000 individuals.⁶⁵¹

The natural history of MS is extremely variable, with a waxing and waning pattern that may gradually worsen over time.⁶⁴⁵ Four broad categories are recognized: relapsing remitting MS (RRMS), which accounts for about 85 percent of cases; secondary progressive MS (SPMS), which represents a progression of RRMS with accumulating irreversible neurological deficit and disability; primary progressive MS (PPMS), which is characterized by progressive disease from onset, and accounts for 10 to 15 percent of MS cases; and, progressive relapsing MS (PRMS), defined as progressive disease from onset with superimposed relapses.

Malignant MS is a poorly defined subset of MS that comprises a heterogeneous group of demyelinating disorders that is applied only to cases that succumb within 5 years of onset, accounting for less than 5 percent of all MS subjects.⁶⁵²

The therapeutic approach to MS has evolved over the past two decades. Four first-line disease modifying therapies have received U.S. Food and Drug Administration approval for use in adults with RRMS: glatiramer acetate, intramuscular and subcutaneous interferon-β1a, and subcutaneous interferon-β1b.⁶⁴⁷ Evidence supporting their use in children is very limited.

Most treatment decisions in children with MS are based in part on results achieved in adults. Corticosteroids are used to treat acute, symptomatic relapses, but are associated with serious adverse effects in children.⁶⁴⁵ Second-line agents in children have included cyclophosphamide, mitoxantrone, mycophenolate mofetil, daclizumab, rituximab or natalizumab, primarily described in retrospective case series and reports with limited follow-up.⁶⁴⁷

There is no consensus on how to treat malignant MS. Approaches have included plasmapheresis, aggressive immunosuppression with mitoxantrone, cladribine, and cyclophosphamide, with no documented effect in this setting. Given the extremely poor prognosis of malignant MS, and the lack of effective treatment, autologous HSCT has been used to treat a small number of pediatric malignant MS cases. Accordingly, this systematic review will present only results from HSCT reports compared to usual care and the disease course.

Evidence Summary

The overall grade of strength of evidence for drug-free clinical remission and the use of HSCT for the treatment of severe, refractory malignant multiple sclerosis is shown in Table 127.

Table 127

Overall grade of strength of evidence for drug-free clinical remission and the use of HSCT for the treatment of severe, refractory malignant multiple sclerosis.

Malignant MS is very rare in children, with three reports comprising the sole identified source of published evidence on the use of autologous HSCT in this setting. There are no proven therapies for malignant MS, which has a dismal prognosis. In this context, that five of five patients (100 percent) entered a state of clinical remission, with no relapses at followup, signals that autologous HSCT following chemotherapy-induced immune suppression may be associated with these results.

Results

A total of three reports were included in this review. Table 128 shows the criteria that were used to select studies for this section.

Table 128

Study selection criteria: MS.

Table 129 shows the study and patient characteristics of three reports (total N=5) on the use of autologous HSCT in pediatric patients.^653-655 They ranged in age from 9 to 18 years, with two females and three males.

Table 129

Multiple sclerosis study characteristics and population.

In the first report, peripheral blood stem cells were mobilized using cyclophosphamide and G-CSF.⁶⁵³ One patient underwent conditioning using a BEAM regimen (BCNU, etoposide, cytosine-arabinoside, melphalan), the other (a young male) was conditioned using cyclophosphamide. Total body irradiation was not used in either case. ATG and methylprednisolone were administered 1 and 2 days after stem-cell infusion. In the second report, peripheral blood stem cells were mobilized using cyclophosphamide and G-CSF, and the patient was conditioned with busulfan and ATG.⁶⁵⁴ In the third report, peripheral blood stem cells were mobilized using cyclophosphamide and G-CSF, and conditioned using a BEAM regimen plus cyclophosphamide plus ATG.⁶⁵⁵

In the Fagius study, both patients experienced stabilization of their disease course.⁶⁵³ One was alive at 35 months followup, with expanded disability status scale (EDSS) score reduced from 4.0 at HSCT to 0 at last followup. The second patient in the Fagius study was alive at 28 months, with EDSS score reduced from 8.0 at HSCT to 1.0 at followup. Adverse effects of autologous HSCT were not reported individually, but were as expected with the conditioning regimen, comprising fever, mucositis, and alopecia.

Kimiskidis and colleagues reported their patient showed rapid neurological improvement that was sustained and gradually increased following HSCT.⁶⁵⁴ His EDSS score dropped from 5.0 at HSCT to 1.5 at 66 months' followup. The patient experienced no relapses since HSCT, with no immunomodulatory therapies, and at publication had graduated from college.

Mancardi and colleagues reported results for two pediatric cases.⁶⁵⁵ The first patient was alive at 29 months' followup, with EDSS score reduced from 7.5 to 4.0, the ability to walk 500 meters unaided, independent in activities of daily living, and no relapses. HSCT-related adverse effects were not reported. The second patient was alive at 14 months' followup, with dramatically improved neurological condition and EDSS score reduced from 9.0 to 4.5; information was not provided about the patient's mobility or capability to perform activities of daily living. This patient experienced fever for two weeks post-HSCT, but no pathogen was identified.

In total, five pediatric patients with malignant MS have been reported alive following intense immune suppression and autologous HSCT. All had durable remission of severe, disabling disease and life-threatening disease for 14 to 66 months followup, improved EDSS scores, and improvement in neurological function. Where reported, mobility improved, along with the ability to perform activities of daily living. No patient relapsed in the followup periods reported.

Ongoing Research

According to ClinicalTrials.gov, there are no active clinical studies involving HSCT recruiting patients with any type of multiple sclerosis.

Conclusion

The overall body of evidence is insufficient to draw conclusions on long-term benefits or harms with single autologous HSCT for the treatment of severe, refractory MS in children.

Moderate strength evidence suggests that an extended drug-free clinical remission can be achieved with single autologous HSCT for the treatment of severe, refractory MS in children.

Background and Setting

Crohn's disease is an idiopathic, chronic inflammatory disease of the gastrointestinal tract that primarily affects the small intestine and colon.

There is wide discrepancy in the prevalence and incidence estimates of Crohn's disease in North America.⁶⁵⁶ Prevalence has been estimated between about 44 to nearly 200 per 100,000 persons, perhaps representing the effect of environmental or genetic factors in its development. Similarly, incidence estimates vary considerably, from about 3.1 to about 5 cases per 100,000 person-years; the incidence in children is estimated at about 5 per 100,000. With about 300 million people in the United States, approximately 9,000 to 44,000 cases are diagnosed with Crohn's disease annually.

The natural history of Crohn's disease is characterized by recurring flares with periods of inactive disease and remission.⁶⁵⁷ The waxing and waning nature dictates that patients require medication for a large period of their life, primarily to maintain remission but also to control flares. About 50 percent of cases will remain in a state of remission or mild intermittent disease, but about 5 percent will have severe, drug-refractory disease.⁶⁵⁶ Surgery is required in up to 80 percent of cases at some point.⁶⁵⁷

While Crohn's disease-related mortality is relatively low, the range and severity of symptoms varies from mild to disabling. The most common symptoms of Crohn's disease are abdominal pain, often in the lower right area, and diarrhea. Rectal bleeding, weight loss, arthritis, skin problems, and fever may also occur. Bleeding may be serious and persistent, leading to anemia. Children with Crohn's disease may suffer delayed development and stunted growth. The most common complication is blockage of the intestine. Nutritional complications are common in Crohn's disease, with deficiencies of proteins, calories, and vitamins. These deficiencies may be caused by inadequate dietary intake, intestinal loss of protein, or poor absorption, also referred to as malabsorption. Other complications associated with Crohn's disease include arthritis, skin problems, inflammation in the eyes or mouth, kidney stones, gallstones, or other diseases of the liver and biliary system. Some of these problems resolve during treatment for disease in the digestive system, but some must be treated separately.

Current therapy for Crohn's disease consists of corticosteroids, immunomodulators and biological therapy blocking TNF-alpha (e.g., infliximab).⁶⁵⁷ Corticosteroids efficiently suppress inflammation, but have not been shown definitively to alter the natural course of Crohn's disease. Immunomodulators and biologicals such as azathioprine, 6-mercaptopurine, methotrexate, etanercept, and infliximab can induce and maintain remission, but their overall effect on the long-term course of Crohn's disease and the ultimate need for surgery are not definitively established.⁶⁵⁷ Their postoperative role also is not defined. In general, the optimal timing of therapies relative to disease course is not clear.

Autologous HSCT has been used to treat a small number of pediatric Crohn's disease cases, all of which have been severe, progressive, disabling, and refractory to nearly all drug therapies. Accordingly, this systematic review will present only results from HSCT reports, with the comparison considered usual care and the disease course.

Evidence Summary

The overall grade of strength of evidence for drug-free clinical remission and the use of HSCT for the treatment of severe, refractory Crohn's Disease is shown in Table 130.

Table 130

Overall grade of strength of evidence for drug-free clinical remission and the use of HSCT for the treatment of severe, refractory Crohn's disease.

The evidence signals that autologous HSCT following chemotherapy-induced immune suppression may be associated with prolonged resolution of severe, refractory, disabling Crohn's disease into a drug-free, much-improved state, 3 to 6 months post-HSCT.

Results

Two reports were included in this review. Table 131 shows the criteria that were used to select studies for this section.

Table 131

Crohn's disease study selection criteria.

One pilot study⁶⁵⁸ and one long-term follow-up study⁶⁵⁹ (Table 132) reported results on the use of autologous HSCT utilizing a conditioning regimen of high-dose cyclophosphamide plus equine or rabbit ATG and T-cell depleted CD-34+ enriched peripheral blood stem cells mobilized with cyclophosphamide and G-CSF. Mesna, methylprednisolone, and G-CSF were started in conjunction with the conditioning regimen.

Table 132

Crohn's disease study characteristics and population.

Patients were 5 males, ages 15-21 years, and 2 females, ages 18 and 21 years. Pretransplant CDAI scores averaged 288 ± 37 (range: 101-337), with mean Karnofsky performance score (KPS) of 48 ± 10 (range: 40-60). All were highly symptomatic, completely disabled, with a clinical history and histologic evidence of Crohn's disease, and had failed treatment with corticosteroids, mesalamine, metronidazole, azathioprine, 6-mercaptopurine, and infliximab. Failure was defined as a Crohn's Disease Activity Index (CDAI) of 250-400 despite those therapies. All immunosuppressive and disease-modifying agents were discontinued at stem-cell mobilization, except systemic corticosteroids, which were tapered over 2 to 6 months. The key outcome was clinical remission, defined as CDAI≤150, and freedom from immune suppressant therapy following taper and discontinuation of corticosteroids post-HSCT. Adverse effects of autologous HSCT were also reported.

In the Oyama pilot study, all patients were alive at mean followup of 24 ± 15 months (range: 7-36 months).⁶⁵⁸ They had a rapid and dramatic post-HSCT improvement, discontinued all immunosuppressive therapies, regained normal appetite and oral intake, with cessation of diarrhea and abdominal pain. The mean CDAI score improved by 77 percent, declining from 288 ± 37 (range: 250-337), to 66 ± 13 (range 51-78). The mean Karnofsky Performance Status improved by 92 percent, from 48 ± 10 (range: 40-60) to 92 ± 10 (range: 80-100). Adverse HSCT-related events were not individually documented, but the procedure was reported as well tolerated. One patient (not identified) developed Mallory-Weiss syndrome that responded to intravenous fluids. One patient (unidentified) relapsed at 15 months after achieving remission at 6 months. Among the total patient population (pediatric cases not reported separately), after a median follow-up of 18 months (range 7-37 months) 11 of 12 remained in drug-free clinical remission.

In the second report,⁶⁵⁹ all 3 patients not previously reported in the Oyama paper⁶⁵⁸ were alive at 60 months follow-up, in an immune suppressant drug-free state but still with active Crohn's disease. All had undergone colectomy with or without ileostomy at 18 to 44 months following HSCT.

Ongoing Research

According to ClinicalTrials.gov, two Phase I clinical trials in the U.S. are recruiting pediatric patients with severe Crohn's disease (CDAI>250) for autologous HSCT (NCT00692939, NCT00278577).

Conclusion

The overall body of evidence is insufficient to draw conclusions on long-term benefits and harms with single autologous HSCT in children with severe, refractory, disabling CD.

Moderate strength evidence suggests that an extended clinical remission, free from immune suppressant therapy following taper and discontinuation of corticosteroids 3-6 months post-HSCT, can be achieved with single autologous HSCT in children with severe, refractory, disabling CD.

Background and Setting

Evidence Summary

The overall grade of strength of evidence for drug-free clinical remission and the use of HSCT for the treatment of severe, refractory myasthenia gravis, overlap syndrome, or diffuse calcinosis cutis is shown in Table 133.

Table 133

Overall grade of strength of evidence for drug-free clinical remission and the use of HSCT for the treatment of severe, refractory myasthenia gravis, overlap syndrome, or diffuse calcinosis cutis.

One case report each showed prolonged resolution of myasthenia gravis or overlap syndrome into a drug-free, much-improved state following chemotherapy-induced immunosuppression with allogeneic HSCT. Similarly, immunosuppression and autologous HSCT was followed by complete resolution of disabling diffuse calcinosis cutis in one patient.

Results

A total of three reports for these miscellaneous diseases were included in this review. Table 134 shows the criteria that were used to select studies for this section.

Table 134

Study selection criteria: MG, OS, CC.

As shown in Table 135, three case reports are available, one each on the use of allogeneic HSCT to treat myasthenia gravis⁶⁶⁷ or overlap syndrome,⁶⁶⁸ and one on autologous HSCT to treat calcinosis cutis.⁶⁶⁹

Table 135

Miscellaneous nonhematologic autoimmune disease study characteristics and population.

The myasthenia gravis case report outlined the outcome of reduced-intensity, matched-sibling, peripheral blood allogeneic HSCT using busulfan, fludarabine, and alemtuzumab.⁶⁶⁷ The patient was severely affected 17-year-old male who had failed prior treatment with pyridostigmine, IVIG, corticosteroids, thymectomy, azathioprine, mycophenolate mofetil, plasmapheresis, rituximab, and high-dose cyclophosphamide.

The patient with overlap syndrome was a 15-year-old female with pulmonary vasculitis, severe Cushing's syndrome, stunted growth, profound adrenal steroid dependency, and iatrogenic liver toxicity secondary to failed treatment with methotrexate and cyclophosphamide.⁶⁶⁸ She underwent reduced-intensity allogeneic HSCT using fludarabine, cyclophosphamide, and total body irradiation, followed by infusion of HLA-matched bone marrow stem cells.

The third case report involved a 16-year-old female who had diffuse, severely disabling calcinosis cutis with arthritis, myalgia, anemia, recurrent pulmonary hemorrhage, CNS abnormalities, and painful skin ulcers.⁶⁶⁹ Her condition did not adequately respond to corticosteroids, cyclophosphamide, azathioprine, methotrexate, hydroxychloroquine, and thalidomide. She developed pulmonary hypertension and ischemic digital necrosis, at which time she was referred for high-dose immunosuppression and autologous HSCT. Peripheral blood stem cells were mobilized using cyclophosphamide and G-CSF, and reinfused following a conditioning regimen comprising BCNU, etoposide, cytarabine, and melphalan.

The patient with myasthenia gravis achieved T- and B-cell immune reconstitution within 7 months post-HSCT, and during the next 12 months was weaned off pyridostigmine, developed normal muscle strength and lost 60 pounds of weight.⁶⁶⁷ He experienced mucositis that required total parenteral nutrition and patient-controlled analgesia for 11 days, 1 episode of gram-positive bacteremia that resolved with vancomycin, and CMV reactivation that resolved with ganciclovir. His oropharyngeal muscles and speech normalized, although he still had ophthalmoplegia. At 40 months post-HSCT, despite the presence of elevated acetylcholine receptor antibody levels, he was free of all myasthenia gravis treatments, was able to play basketball, and was reported as completely independent.

The patient with overlap syndrome achieved greater than 90 percent donor chimerism at 12 months post-HSCT.⁶⁶⁸ She was weaned off methylprednisolone, IVIG, and asthma medications over the next year, her cushingoid features resolved, she grew approximately 7 inches over 3 years' followup and became a full-time student in a regular classroom. She had no evidence of clinical graft-versus-host disease or systemic infection over 36 months' followup, but continued to have occasional periods of fatigue and mild Gottron-like rash, which was reported to decrease in frequency at followup.

The patient with calcinosis cutis engrafted promptly, with no significant HSCT-related complications reported.⁶⁶⁹ She regained mobility and ability to perform unaided activities of daily living, such as sitting, standing, and walking. At 6 weeks post-HSCT, the subcutaneous calcinosis nodules began to liquefy and calcium salts extruded through her skin. Deep calcinosis plaques disappeared, all skin ulcers healed completely, and her pulmonary blood pressure normalized. At 24 months' followup, the patient was free from clinical and laboratory evidence of disease activity.

Ongoing Research

According to ClinicalTrials.gov, one Phase I study is recruiting patients with severe, refractory myasthenia gravis for autologous HSCT (NCT00424489). A Phase I study is recruiting patients with severe, refractory systemic vasculitis and overlap syndrome for autologous HSCT (NCT00278512). No studies are recruiting for HSCT in patients with calcinosis cutis.

Conclusion

The overall body of evidence is insufficient to draw conclusions on benefits and harms with allogeneic HSCT to treat severe, refractory MG or OS, and autologous HSCT for the treatment of severe, refractory CC is insufficient to draw conclusions.

The overall body of evidence is insufficient to demonstrate that an extended drug-free remission can be achieved with allogeneic HSCT to treat severe, refractory MG or OS, and autologous HSCT for the treatment of severe, refractory CC.

Background and Setting

Evidence Summary

The overall grade of strength of evidence for drug-free clinical remission and the use of HSCT for the treatment of severe, refractory Evans syndrome, autoimmune hemolytic anemia, or autoimmune thrombocytopenia is shown in Table 136.

Table 136

Overall grade of strength of evidence for drug-free clinical remission and the use of HSCT for the treatment of severe, refractory Evans syndrome, autoimmune hemolytic anemia, or autoimmune thrombocytopenia.

One case report each showed resolution of Evans syndrome or autoimmune hemolytic anemia into a drug-free, much-improved state following chemotherapy-induced immune suppression with allogeneic HSCT. Similarly, one case report showed resolution of severe, refractory autoimmune hemolytic anemia following autologous HSCT. The single case report of autologous HSCT for autoimmune thrombocytopenia showed no response to the procedure.

Results

A total of seven publications comprising eight studies (six case reports and two case series) on autoimmune hematologic conditions were included in this review. Table 137 shows the criteria that were used to select studies for this section.

Table 137

Study selection criteria: Refractory Evans syndrome, autoimmune hemolytic anemia, or autoimmune thrombocytopenia.

Evans Syndrome

Four studies (three case reports and one case series) described results of allogeneic HSCT in eight patients with severe, refractory Evans syndrome (Table 138).

Table 138

Evans syndrome, autoimmune hemolytic anemia, and autoimmune thrombocytopenia study characteristics and population.

The case series described 5 cases of Evans syndrome reported to the European Group for Blood and Marrow Transplantation (EBMT) registry between 1984 and 2007⁶⁷⁹. After receiving unspecified standard therapy, patients (100% male, age range 2-21) were referred for allogeneic HSCT (3 bone marrow, 1 peripheral blood, and 1 cord blood) with various combination conditioning regimens including cyclophosphamide, fludarabine, busulfan, thiotepa, ATG, TBI and received immunosuppressive cyclosporine A with either methotrexate or mycophenolate mofetil therapy for GVHD. Three patients were alive at 36, 85 and 113 months following allogeneic HSCT; one was dead from disease at 59 months and one was dead from interstitial pneumonitis at 6 months following allogeneic HSCT.⁶⁷⁹ All five patients were reported to have aGVHD (grade 1 n=1, grade 2 n=1, grade 3 n=1, NR n=2) and cGVHD (extensive: n=1, limited: n=1, NR: n=3), but no other HSCT-related adverse events were reported.

In the Connor et al. report, the female subject presented at age 6 months with Evans syndrome.⁶⁸⁰ Over the next several years, she was treated with corticosteroids, IVIG, cyclosporine A, mycophenolate mofetil, rituximab alone and with other drugs, and underwent a splenectomy, without experiencing durable remission. Her condition worsened, she developed pulmonary hypertension with dilated right ventricle and tricuspid regurgitation. She was referred for an unrelated, single-antigen mismatched allogeneic HSCT, using a conditioning regimen of alemtuzumab, fludarabine, and melphalan, with cyclosporine A and mycophenolate mofetil as graft-versus-host disease prophylaxis. The patient developed full donor chimerism, was weaned off all immunosuppressants, developed normalized pulmonary pressures, and exhibited normal right ventricular size and function at 10 months following allogeneic HSCT.⁶⁸⁰ No HSCT-related adverse events were reported.

A second case report describes the results achieved with an unrelated cord blood HSCT in a 7-year old boy with severe, refractory Evans syndrome who failed a previous double autologous HSCT.⁶⁸¹ His disease was poorly responsive to previous therapy, including corticosteroids, IVIG, cyclosporine A, mycophenolate mofetil, vincristine, vinblastine, cyclophosphamide, rituximab, and danazol. He became pancytopenic, with disfiguring hypercorticism and polyneuropathy, and underwent double high-dose chemotherapy with autologous HSCT, with temporary improvement. After suffering a massive intracranial bleed, he received a 7/10 HLA-matched female cord blood HSCT, with a conditioning regimen comprising busulfan, ATG, thiotepa and etoposide. The patient developed graft-versus-host disease with grade II skin, liver, and mucosa involvement that resolved after a short course of prednisone and cyclosporine A.⁶⁸¹ At 1.5 years' followup, he was reported with 100 percent donor chimerism, normal blood counts, in good clinical condition, free of graft-versus-host disease and the need for immunosuppressant drugs.

The third case involved a nearly 5-year-old boy who presented with Evans syndrome at age 5 months.⁶⁸² His disease responded poorly to courses of therapy with corticosteroids, IVIG, 6-mercaptopurine, danazol, cyclosporine, azathioprine, vincristine, and anti-D, with increasingly worse mucosal bleeding and intracranial hemorrhage. He was referred for a matched-sibling cord blood allogeneic HSCT, with a myeloablative conditioning regimen consisting of total body irradiation, followed by cyclophosphamide, and cyclosporine-A graft-versus-host disease prophylaxis. The patient engrafted with adequate absolute neutrophil count by day 16 post-HSCT.⁶⁸² However, he developed graft-versus-host disease with severe pulmonary insufficiency that resolved promptly following high-dose corticosteroid treatment. He ultimately experienced fulminant hepatic failure of unknown origin 286 days after transplant, and died on day 289.

Ongoing Research

According to ClinicalTrials.gov, no clinical trials of HSCT are recruiting patients with severe, refractory Evans syndrome, autoimmune hemolytic anemia, or autoimmune thrombocytopenia.

Conclusion

The overall body of evidence is insufficient to draw conclusions about the comparative benefits or harms of single autologous or allogeneic HSCT compared to conventional therapy or disease natural history pediatric patients with severe, refractory ES, AIHA, or AITP.

The overall body of evidence is insufficient to conclude that an extended drug-free clinical remission can be achieved with allogeneic HSCT for severe, refractory ES or AIHA and autologous HSCT for severe, refractory AIHA.