Successful Hematopoietic Stem Cell Transplantation for Niemann-Pick Disease Type B

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EXPERIENCE AND REASON—Briefly Recorded

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Successful Hematopoietic Stem Cell Transplantation for

Niemann-Pick Disease Type B

Ami J. Shah, MD‡§; Neena Kapoor, MD‡§; Gay M. Crooks, MD‡§; Robertson Parkman, MD‡§;

Kenneth I. Weinberg, MD*‡§

㛳

; Kathy Wilson, RN‡; and Donald B. Kohn, MD*‡§

ABSTRACT. Histocompatible hematopoietic stem cell transplantation (HSCT) was conducted on a 4.5-year-old girl with Niemann-Pick disease type B. The donor was her unaffected brother. At the time of transplantation, she had severe pulmonary disease. After her first HSCT, she developed graft failure. Five years after her second HSCT, her sphingomyelinase levels are within normal levels, she has no pulmonary symptoms, and aside from persistent graft versus host disease, she is doing well.

Pediatrics 2005;116:1022–1025; hematopoietic stem cell transplantation, Niemann-Pick disease.

ABBREVIATIONS. NPD, Niemann-Pick disease; ASM, acid sphin-gomyelinase; HSCT, hematopoietic stem cell transplantation; CT, computed tomography; ATG, antithymocyte globulin; GVHD, graft-versus-host disease; MMF, mycophenolate mofetil; CSA, cy-closporin A.

N

iemann-Pick disease (NPD) type B is a

lyso-somal storage disorder characterized by a

deficiency of acid sphingomyelinase (ASM)

resulting in the accumulation of sphingomyelin in

tissues such as the bone marrow, liver, spleen, and

lungs.

1

_{Unlike NPD type C, type B has little or no}

neurologic symptoms. We report a patient with NPD

type B who was treated with hematopoietic stem cell

transplantation (HSCT) with stable mixed chimerism

5 years post-HSCT.

CASE REPORT

A 15-month-old Hispanic female was diagnosed as having NPD after having an initial presentation of hepatosplenomegaly. The diagnostic work-up included a sphingomyelinase activity level of ⬍20 pmol/minute per mg of protein (normal: 30 –120 pmol/minute per mg of protein). The absence of any obvious neurologic impairment placed her in the type B category.

Muta-tion analysis revealed a A452V/L476P mutaMuta-tion. She developed rapid pulmonary complications with diffuse interstitial lung dis-ease, as shown on a computed tomography (CT) scan, and ob-structive sleep apnea. Her obob-structive sleep apnea improved with a tonsillectomy and adenoidectomy, but she remained hypoxemic during sleep because of her interstitial lung disease. At the time that she was referred for transplantation, her liver span was 15 cm in length and spleen span was 18 cm as measured by a CT scan. The patient’s mother delivered a healthy infant boy. At the age of 4.5 years, the patient received a histocompatible HSCT using the cord blood and additional bone marrow harvested from this brother. Before HSCT, the parents signed institutional review board–approved informed-consent forms for the transplant and the long-term evaluations for engraftment and late effects. Her conditioning regimen consisted of oral busulfan (16 mg/kg)/ Cytoxan (200 mg/kg) and antithymocyte globulin (ATG). Her busulfan dose yielded a steady-state concentration of only 277 ng/mL (target level: 750 –950 ng/mL). The busulfan dose was increased, and a repeat steady-state concentration was 472 ng/mL. Four additional doses of busulfan at a higher dose were given to compensate for the low levels. The patient received 1 dose of ATG with significant complications; however, additional doses could not be given because of hypoxia and pulmonary edema. These symptoms resolved after the ATG was discontinued. She received a total of 2.3⫻108_{total nucleated bone marrow cells per kg and}

1.3⫻107_{total nucleated cord blood cells per kg. The total number}

of CD34⫹_{cells infused was 8}_⫻₁₀6_{cells per kg. Graft-versus-host}

disease (GVHD) prophylaxis consisted of methotrexate 10 mg/m2

on days 3, 6, 11, and 18. Her transplant complications included veno-occlusive disease and mild to moderate respiratory distress. After an initial engraftment that showed mixed chimerism (85% donor/15% recipient), she began losing her graft. Additional im-munosuppression was instituted with mycophenolate mofetil (MMF) and cyclosporin A (CSA). The graft improved for a short time, but as the immunosuppressive agents were tapered because of the adverse effects, she subsequently began to reject her graft, with peripheral blood chimerism studies showing 5% donor/95% recipient.

At the time of her graft failure, her liver and spleen sizes increased, and she became pancytopenic. Before initiating a sec-ond HSCT, she underwent a splenectomy. Her pancytopenia re-solved, but her engraftment status remained at 95% recipient cells. Her pulmonary status at this time showed worsening interstitial lung disease by CT scan and moderate hypoxemia.

A second HSCT from her sibling was performed 19 months after the first transplant. She received a conditioning regimen of CamPath 1H (92 mg/m2_{) and total body irradiation of 200 cGy as}

a single fraction. GVHD prophylaxis consisted of CSA and MMF. The second transplant was complicated by enteroviral meningitis, acute pancreatitis, a Mallory Weiss esophageal tear resulting from the MMF, and renal tubular acidosis resulting from the CSA. Both the MMF and CSA were stopped, and tacrolimus was begun for GVHD prophylaxis.

At the time of this writing, she is 10 years old and it is 5.5 years after her second HSCT. She developed significant chronic GVHD From the *Division of Research Immunology/Bone Marrow

Transplanta-tion, ‡Department of Pediatrics, Keck School of Medicine, §Saban Research Institute, and㛳General Clinical Research Center, Childrens Hospital Los Angeles, Los Angeles, California.

Accepted for publication May 20, 2005. doi:10.1542/peds.2005-0867

No conflict of interest declared.

Reprint requests to (A.J.S.) Division of Research Immunology/Bone Mar-row Transplantation, Childrens Hospital Los Angeles, 4650 Sunset Blvd, MS #62, Los Angeles, CA 90027. E-mail: ashah@chla.usc.edu

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of her skin only and has required ongoing therapy with tacroli-mus, Rapamune, and daclizumab.

Engraftment

Since her second HSCT, she has remained stable with⬃95% donor cell engraftment and 5% recipient cells.

Her sphingomyelinase level 5 years post-HSCT is 76 pmol/ minute per mg of protein (normal: 30 –120 pmol/minute per mg of protein).

Pulmonary

A pre-HSCT CT scan of the patient’s chest is shown in Fig 1A, and a CT scan performed 4 years post-HSCT is shown for com-parison in Fig 1B. Her initial CT scan showed significant intersti-tial lung disease. Four years post-HSCT, her CT scan showed no evidence of interstitial lung disease. Her pulmonary-function test-ing revealed very mild restrictive lung disease, which was felt to be caused by low lung volumes from her hepatomegaly. She no longer needs oxygen and is not on any pulmonary medications.

Cardiac

The patient developed a mitral regurgitation and a mild mitral valve prolapse that was revealed on echocardiogram. She clini-cally does not have any cardiac symptoms at this time. Five years post-HSCT, the patient had a lipid profile that showed a triglyc-eride level of 305 mg/dL (normal: 35–135 mg/dL), total choles-terol of 690 mg/dL (normal: 65–175 mg/dL), high-density li-poprotein of 45 mg/dL (normal: 35–70 mg/dL), and low-density lipoprotein of 584 mg/dL (normal: 60 –115 mg/dL). There were no pretransplant lipid panels performed to determine if these values have increased or decreased. Therefore, we do not know whether the HSCTs had an effect on her lipid profile.

Hepatic

The patient’s most recent CT scan shows that her liver span is now 9 cm (her spleen was removed previously). Her transaminase levels remain elevated, with an aspartate aminotransferase level of 283 U/L (normal: 15– 46 U/L) and alanine aminotransferase level of 305 U/L (normal: 3–35 U/L). The transaminase levels have remained stable for the past 3 years, with no significant change in values.

Neurologic

Long-term follow-up studies reveal that although she had a decline in her neurocognitive function 3 years post-HSCT, she has improved by 5 years post-transplant. She now remains stable to improved in all areas of neurocognitive function except in the areas of visual motor development and memory (Fig 2). Tests for expressive vocabulary and memory tests could not be performed pretransplant because of her young age. Her ophthalmologic eval-uation is normal, with no evidence of cherry-red spots.

Endocrine

Endocrine evaluations revealed that she is below the 5th per-centile for height and weight and 50th perper-centile for a 5-year-old. Glucagon stimulation testing shows normal growth-hormone lev-els despite not growing. Her bone age is 2 standard deviations below her chronological age. Her thyroid function remains nor-mal. Her pubertal development is delayed, and she has prepuber-tal gonadotropic hormone levels. She remains Tanner stage 1 for both breast development and genitalia.

DISCUSSION

NPD type B is a lysosomal-storage disorder

result-ing from the loss of ASM activity. There is marked

hepatosplenomegaly and the presence of foam cells

in the bone marrow; however, there is minimal to no

neurologic impairment. Children who present with

NPD type B have a pronounced hepatic impairment,

often leading to death in those patients who present

early. There are several patients with NPD type B

who have a phenotype that includes

neurodegenera-tion.

2,3

_{This disorder is autosomal recessive and}

pan-ethnic. The natural history of these patients includes

worsening hematologic, lipid, pulmonary, and

he-patic symptoms over time. The majority of patients

have an atherogenic lipid profile (low high-density

lipoprotein cholesterol, high low-density lipoprotein

cholesterol, and high triglycerides), restrictive lung

disease with abnormal diffusion lung capacity, and

hepatic dysfunction, with some patients developing

liver failure.

4

_{Long-term follow-up studies on}

tients with NPD type B have shown that these

pa-tients have short stature, delayed bone age, and low

insulin-like growth factor I levels.

5

_{It is unclear at this}

time whether an HSCT would reverse these

under-lying problems.

There have been very few therapeutic options

available to patients with NPD type B. To date there

have been 2 reported cases of successful

transplan-Fig 1. A, High-resolution CT scan of the chest performed before

HSCT. The lungs show significant bilateral interstitial lung disease in the bases. B, High-resolution CT scan of the chest performed 4 years post-HSCT. There is complete resolution of the interstitial lung disease.

EXPERIENCE AND REASON 1023

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tation of this disorder. One patient had resolution of

her pulmonary symptoms; however, neurologic

symptoms occurred with the presence of cherry-red

spots. Her neurologic symptoms led to a respiratory

arrest. This patient is now 16 years post-HSCT but

has severe physical and mental disabilities.

6,7

_The

second patient has not been described in any

publi-cations but is reportedly stable (Morris Kletzel, MD,

Northwestern University, personal communication,

2005.

The mutations in our patient, A452V/L476P, are

private mutations and have not been well

character-ized phenotypically. Therefore, we do not know the

severity of the symptoms that patients with this

mu-tation might expect. Because of the severe hepatic

and pulmonary impairment that this child had, one

would expect that this type of mutation would result

in patients with severe symptoms. Over the past 5

years posttransplant, our patient has had resolution

of her pulmonary symptoms. Although her liver has

decreased in size clinically, it remains enlarged with

elevated transaminase levels. She continues to have

elevated triglyceride and low-density lipoprotein

cholesterol levels. There has not been any long-term

neurologic impairment to date in our patient. It is

concerning that her neurocognitive studies show a

deterioration in her visual motor development and

her memory scores. It has been shown that long-term

effects of HSCT can result in deficits of visual motor

development and memory.

8,9

_{It is unclear whether}

these are manifestations of her underlying disease,

her transplant, or complications from having GVHD.

Gene therapy has been used in murine models

with partial correction of NPD. Miranda et al

10

_have

performed stem cell gene therapy in ASM-knockout

mice. The results of these studies showed high levels

of ASM (fivefold over normal), and engrafted

ani-mals had increased life spans from 5 to 9 months.

ASM activities were increased, and sphingomyelin

storage was reduced in the spleen, liver, and lungs of

the treated mice. However, all transplanted animals

developed ataxia and died earlier than normal mice.

CONCLUSIONS

This case represents a successful HSCT for NPD

type B, which has improved the patient’s pulmonary

symptoms. However, the complications of her

trans-plant are still present (GVHD, renal tubular

dysfunc-tion). Early diagnosis of this disease is imperative

for this and other metabolic disorders for HSCT to

offer a curative potential. Transplantation should be

considered for those with severe disease, especially

those with pulmonary symptoms. Unfortunately,

the likelihood of finding an unaffected

HLA-matched sibling donor is small. For those who do

not have a sibling donor, an unrelated transplant

is a possible option. Future directions should be

di-rected toward enzyme-replacement or gene therapy,

which would solve the problem of not finding a

suitable donor and reduce the complications of

trans-plant.

ACKNOWLEDGMENTS

This work was supported in part by National Institute of Health NCRR General Clinical Research Center (GCRC) grant MO1 RR00043 and was performed at the GCRC at Childrens Hospital Los Angeles. Computational assistance was provided by National institutes of Health NCRR GCRC grant MO1 RR00043, CDMAS Project, and performed at the GCRC at Childrens Hos-pital Los Angeles.

REFERENCES

1. Schuchman EH, Desnick RJ. Niemann Pick disease type A and B: acid sphyngomyelinase deficiencies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds.The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001

2. Elleder M, Cihula J. Niemann-Pick disease (variation in the sphingo-myelinase deficient group). Neurovisceral phenotype (A) with an ab-normally protracted clinical course and variable expression of neuro-logical symptomatology in three siblings.Eur J Pediatr.1983;140:323–328 3. Elleder M, Nevoral J, Spicakova V, et al. A new variant of sphingomy-elinase deficiency (Niemann-Pick): visceromegaly, minimal neurologi-cal lesions and low in vivo degradation rate of sphingomyelin.J Inherit Metab Dis.1986;9:357–366

4. Wasserstein MP, Desnick RJ, Schuchman EH, et al. The natural history of type B Niemann-Pick disease: results from a 10-year longitudinal study. Pediatrics.2004;114(6). Available at: www.pediatrics.org/cgi/ content/full/114/6/e672

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5. Wasserstein MP, Larkin AE, Glass RB, Schuchman EH, Desnick RJ, McGovern MM. Growth restriction in children with type B Niemann-Pick disease.J Pediatr.2003;142:424 – 428

6. Vellodi A, Hobbs JR, O’Donnell NM, Coulter BS, Hugh-Jones K. Treat-ment of Niemann-Pick disease type B by allogeneic bone marrow trans-plantation.Br Med J (Clin Res Ed).1987;295:1375–1376

7. Victor S, Coulter JBS, Besley GTN, et al. Niemann-Pick disease: sixteen-year follow-up of allogeneic bone marrow transplantation in a type B variant.J Inherit Metab Dis.2003;26:775–785

8. Cool VA. Long-term neuropsychological risks in pediatric bone marrow

transplant: what do we know?Bone Marrow Transplant.1986;18(suppl 3):S45–S49

9. Smedler AC, Ringden K, Bergman H, Bolme P. Sensory-motor and cognitive functioning in children who have undergone bone marrow transplantation.Acta Paediatr Scand.1990;79:613– 621

10. Miranda SR, Erlich S, Friedrich VL, Gatt S, Schuchman EH. Hemato-poietic stem cell gene therapy leads to marked visceral organ improve-ments and a delayed onset of neurological abnormalities in the acid sphingomyelinase deficient mouse model of Niemann-Pick disease.

Gene Ther.2000;7:1768 –1776

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Noted by JFL, MD

EXPERIENCE AND REASON 1025

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DOI: 10.1542/peds.2005-0867

2005;116;1022

Pediatrics

Weinberg, Kathy Wilson and Donald B. Kohn

Ami J. Shah, Neena Kapoor, Gay M. Crooks, Robertson Parkman, Kenneth I.

Type B