PEDIATRICS (doi:10.1542/peds.2006-3397)
EXPERIENCE & REASON |
Correction of Celiac Disease After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia
a Pediatric Division, Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada
b Department of Pediatrics, University of Nevada School of Medicine, Las Vegas, Nevada
c Department of Clinical Education, Touro University Nevada College of Osteopathic Medicine, Henderson, Nevada
d Division of Oncology, Children's Hospital of Orange County, Orange, California
e Department of Pediatrics, University of California-Irvine, Irvine, California
f Pediatric Gastroenterology and Nutrition Associates, Las Vegas, Nevada
ABSTRACT
Allogeneic hematopoietic stem cell transplantation has been shown to correct or improve a variety of autoimmune disorders. This has not been reported for celiac disease, but transmission to a hematopoietic stem cell transplantation recipient from a donor with celiac disease has been reported. We report a 12-year-old girl with celiac disease who was diagnosed with acute leukemia and received an allogeneic hematopoietic stem cell transplant. Her celiac disease resolved after the hematopoietic stem cell transplant.
Key Words: celiac disease • hematopoietic stem cell transplantation • autoimmune disease
Abbreviations: CD, celiac disease • Ig, immunoglobulin • HSCT, hematopoietic stem cell transplantation • GvHD, graft-versus-host disease
Celiac disease (CD) is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. It occurs in symptomatic people with gastrointestinal and nongastrointestinal symptoms and in some asymptomatic people with type 1 diabetes, Down syndrome, Turner syndrome, Williams syndrome, selective immunoglobulin A (IgA) deficiency, and first-degree relatives of people with CD.1 The prevalence of CD in children between 2 1/2 and 15 years of age in the general population is 3 to 13 per 1000 children (
1:300 to 1:80 children).2
The improvement or stabilization of a number of autoimmune diseases by allogeneic hematopoietic stem cell transplantation (HSCT) has been reported, including systemic lupus erythematosus,3 rheumatoid arthritis,4 multiple sclerosis,5 and Crohn disease.6 The principles that apply to the correction of autoimmune phenomena in these diseases are also applicable, theoretically, to other autoimmune diseases as well. However, because clinical experience with allogeneic HSCT for autoimmune diseases is limited, we believe that it is important to demonstrate for each specific autoimmune disease its response to transplant.
Here we report the case of an adolescent girl with a diagnosis of CD who subsequently developed acute myelogenous leukemia. She underwent HLA-identical matched-sibling transplantation for her leukemia, which also successfully treated her CD. To our knowledge, a cure of CD by HSCT has not been reported previously, although its converse, the transfer of CD from donor to host, has been reported.7
CASE REPORT
The patient originally presented at 2 years of age with complaints of chronic diarrhea and vomiting. She was originally thought by her parent to have a milk protein allergy as an infant and was given goat's milk instead of formula. Immediately before presentation, she had an accelerating course of foul-smelling, diarrheal stools without visible blood or mucus. She had also been vomiting and had significant abdominal bloating. She had lost a small amount of weight but, more significantly, had not gained any weight for several months before presentation to the gastroenterologist. Because of a family history of CD in a maternal aunt and grandmother, the mother had independently researched Celiac sprue and began limiting wheat products in her daughter's diet 10 days before presentation, with complete resolution of diarrhea. The initial examination was significant for weight at the 25th percentile and height at 75th percentile, a bloated-appearing abdomen, and wasting of the buttocks. The family was instructed to allow wheat in the child's diet, and laboratory evaluation only 1 week later revealed an indeterminate titer of antigliadin IgG and IgA. Antiendomysial antibody titers were ordered but not completed. Because of a high degree of clinical suspicion, however, endoscopic biopsies were obtained from multiple areas of her duodenal mucosa. These revealed uniform flattening of the villi, crypt hyperplasia with a crypt-to-villus ratio of 3:1, and a mixed chronic inflammatory cellular infiltrate in the lamina propria with abundant intraepithelial lymphocytes and mitotic figures, typical of gluten-sensitive enteropathy. The child and family were instructed on a gluten-free diet, having reintroduced gluten 2 weeks before obtaining the biopsies after being off all gluten for only 10 days before the serologic testing. Subsequent visits demonstrated accelerated growth with cessation of gastrointestinal symptoms, which recurred only with identified gluten exposure in the diet. She demonstrated continued clinical improvement, as well as negative antigliadin and antiendomysial antibody titers and normal results from a complete blood count, and her electrolyte, iron-panel, vitamin B12, and folic acid levels were within reference ranges. Because of suspicion of noncompliance with the gluten-free diet despite negative serologic testing (antigliadin IgG, IgA, tissue transglutaminase IgA, and total serum IgA levels within reference ranges), an endoscopy was performed 6 years after the original diagnosis was made. At that time, there was no villus blunting or crypt hyperplasia and no intraepithelial lymphocytes, which indicated reversal of the original pathognomonic histologic findings on a gluten-free diet. The patient was growing just above the 95th percentile for both height and weight. She was subsequently lost to follow-up until her presentation to the pediatric oncology service 3 years later.
The patient presented to the pediatric oncology service in December 2002 with progressive thrombocytopenia and anemia. Bone marrow examination showed 51% blasts that were positive by flow cytometry for CD7, CD13 (subpopulation), CD33, CD34, CD38, CD45, CD117, and HLA-DR. They were positive for myeloperoxidase and negative for terminal deoxynucleotidyl transferase, and the patient was classified as having acute myelogenous leukemia with an M1 subtype. She was treated according to the Children's Cancer Group 2961 protocol with 4 courses of cytosine arabinoside, dexamethasone, 6-thioguanine, etoposide, and daunomycin and went into remission. HLA typing of her family showed that her brother was a fully matched donor, and the patient subsequently underwent allogeneic HSCT after conditioning with busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg). The patient also received 4 doses of methotrexate and cyclosporine for graft-versus-host disease (GvHD) prophylaxis. The patient's transplant course was uneventful, and she showed no evidence of acute or chronic GvHD. HLA typing also showed that the patient was homozygous for the presence of HLA-DQ2; the HLA-DQ2 or DQ8 allele is seen in 95% of those with CD.8
Three months after her transplant, the patient began eating a regular diet after having eaten a gluten-free diet for the previous 9 years since her diagnosis of CD. She has tolerated this diet well without abdominal pain, nausea, vomiting, or diarrhea and continues to tolerate a regular diet at the time of this report. Follow-up studies 5 months after the transplant, at a time when the patient was on tapering doses of cyclosporine, showed no serologic evidence of CD as evidenced by negative antigliadin, tissue transglutaminase, and reticulin antibodies at a time when the patient's humoral immune system was quantitatively intact as demonstrated by normal quantitative Ig levels (including IgA) without Ig support. Follow-up studies 3 1/2 years after the transplant continued to show no serologic evidence of CD (negative antigliadin and tissue transglutaminase antibodies with a normal serum IgA level). The patient has not been on any immunosuppressive medications in >2 years, has had no evidence of GvHD, and has had demonstrable serologic responses to immunizations while also eating an unrestricted diet.
Engraftment studies continued to show complete donor chimerism 3 years after transplant. The patient developed thrombocytopenia 16 months after the transplant. Bone marrow aspiration and biopsy showed increased megakaryocytes consistent with a platelet-destructive process, and the patient was diagnosed with posttransplant idiopathic thrombocytopenic purpura.9–11 She was treated on 1 occasion with anti-D antibody (WinRho; Baxter Healthcare, Deerfield, IL) and on 1 occasion with intravenous Ig, in each case with a good response. She continues to have mild-to-moderate thrombocytopenia but has not been treated further, with her single dose of intravenous Ig having been given 7 months before her most recent serologic studies for CD.
DISCUSSION
Although the cure of autoimmune disease by allogeneic HSCT has been demonstrated for a variety of different diseases, this has not been the case for all of these diseases. Even when cure can be obtained with HSCT, the stage or severity of the disease can have an impact on the resolution of the disease.12 Therefore, we believe that it is important to report that allogeneic HSCT is effective in curing CD.
This patient had a definitive diagnosis of CD for 9 years before her transplant, with 2 sets of endoscopic biopsies separated by 6 years confirming this diagnosis (the first endoscopy demonstrated findings pathognomonic of CD, whereas the second set showed resolution of these findings on a gluten-free diet). Furthermore, on occasions when the patient would stray from her gluten-free diet, her gastrointestinal symptoms would recur, which clinically reconfirmed the diagnosis of CD. HLA typing that was performed before HSCT showed the patient to be homozygous for the HLA-DQ2 allele, which is consistent with a diagnosis of CD. Within 3 months of her transplant, the patient was eating an unrestricted diet without any gastrointestinal symptoms and has continued to do so 4 years after transplant. Because there have been no clinical indications for endoscopy after the transplant, the family has refused follow-up biopsies. However, the patient's antigliadin, tissue transglutaminase, and antireticulin antibodies were negative 5 months and 3 1/2 years after the transplant, at times when the patient's immune system was intact and should have been able to generate antibodies if the correct antigenic stimulus (in the context of host presentation of antigens) was present.
This patient's clinical improvement is consistent with the encouraging results reported by Oyama et al,13 who used autologous transplant for inflammatory bowel disease, and Lopez-Cubero et al,6 who used allogeneic transplantation for Crohn disease. Although inflammatory bowel disease and CD are different autoimmune diseases, they are both enteropathies with an autoimmune process that affects the gastrointestinal mucosa. We have been unable to find any reports of autologous HSCT for CD in children, although autologous HSCT was reported recently in a series of 7 adults with refractory CD with aberrant T cells.14
CONCLUSIONS
Although we do not, at this time, advocate allogeneic HSCT as the definitive treatment of CD, the decreased morbidity and mortality associated with the use of reduced-intensity stem cell transplants may someday allow HSCT to be an acceptable alternative to a lifelong gluten-restricted diet, which, at best, is extremely difficult to remain adherent to for life. Whether HSCT will reduce the purportedly increased risk of enteric malignancy in this population remains unclear.15
FOOTNOTES
Accepted Feb 6, 2007.
Address correspondence to Ronald M. Kline, MD, Comprehensive Cancer Centers of Nevada, Pediatric Division, 3196 S Maryland Pkwy, Suite 400, Las Vegas, NV 89109. E-mail: ronald.kline{at}usoncology.com
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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