Severe oesophagitis after allogeneic bone marrow ... - Nature

Bone Marrow Transplantation (2000) 26, 215–218  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt

Severe oesophagitis after allogeneic bone marrow transplantation for Fanconi’s anemia I Yakoub-Agha1, G Damaj1, L Garderet1, J Bonnet2, A Devergie1, H Esperou1, P Ribaud1, G Socie1 and E Gluckman1 1

Hematology Bone Marrow Transplant and 2Gastroenterology Department AP/HP, Hoˆpital Saint-Louis, Paris, France

Summary: Allogeneic bone marrow transplantation (BMT) is an effective treatment for Fanconi’s anemia (FA) but it requires a dose reduction of alkylating agents used for conditioning because of the increased sensitivity of FA cells to DNA cross-linking agents. Oesophageal damage has not previously been described as a complication after allogeneic BMT for this indication. We report five cases of severe oesophagitis with stenosis in patients transplanted for FA. It occurred either early, or more surprisingly, several years after BMT and could have easily been misdiagnosed. It could be explained by hypersensitivity of the FA mucosal cells to cytotoxic agents despite the reduced doses of cyclophosphamide and irradiation or to non diagnosed congenital abnormalities of the oesophagogastric junction. However, the evolution of the oesophageal disease was favorable in all, and none of the patients developed secondary cancer. Awareness of this complication will lead to earlier diagnosis and treatment of oesophageal stenosis and related malnutrition. Bone Marrow Transplantation (2000) 26, 215–218. Keywords: Fanconi’s anemia; allogeneic bone marrow transplantation; oesophageal stenosis

Fanconi anemia (FA) is an autosomal recessive disorder belonging to the group of chromosomal instability syndromes.1 Skeletal and urogenital malformations, skin hyperpigmentation and pancytopenia are the classical hallmarks of the disease.2 However, atypical presentations with patients more than 20 years of age and no morphological abnormalities are frequently reported.3 The diagnosis is usually confirmed by increased chromosomal breakage in FA cells following exposure to DNA cross-linking agents such as mitomycin C and diepoxybutane, or less frequently by a cell cycle study displaying an arrest of the cells in G2/M phase.4–7 The natural history of FA is to evolve towards progressive bone marrow failure, which is, without treatment, most often lethal before the end of the second decade of life. Bone marrow transplantation (BMT) is still Correspondence: Pr E Gluckman, Hematology Bone Marrow Transplantation Department, Hoˆpital Saint Louis, 1 Ave Claude Vellefaux, F-75475 Paris Cedex 10, France Received 21 January 2000; accepted 6 April 2000

the treatment of choice when patients develop cytopenia or leukemia. However, the hypersensitivity to DNA crosslinking agents of Fanconi’s anemia cells is associated with a poor tolerance to cyclophosphamide and irradiation used in conditioning regimens. Reduction of the dose of cyclophosphamide and irradiation has been shown to decrease the post-transplant morbidity and mortality.8–12 We describe here five cases of severe oesophageal damage following allogeneic BMT for Fanconi’s anemia despite the use of reduced dose conditioning regimens. Patients and methods Among 50 patients transplanted for Fanconi anemia with an HLA-identical sibling and 20 transplanted with an unrelated donor, five developed severe oesophageal damage after BMT. FA diagnosis was confirmed by spontaneous and induced chromosome breaks in all patients using previously described methods.4,5 Patients with dyskeratosis congenita were excluded. Initial characteristics of the five patients are summarised in Table 1. Conditioning regimens included low-dose cyclophosphamide 5 mg/kg i.v., once daily for 4 days (total dose 20 mg/kg) and thoraco-abdominal irradiation (dose 4.5 Gy) in HLA-identical sibling BMT and in one unrelated BMT (patient 4). Patient 5 received an unrelated BMT; he was conditioned with 40 mg/kg cyclophosphamide, 4.5 Gy total body irradiation and antithymocyte globulin (5 days). The bone marrow was T celldepleted by CD34+ selection (Isolex, Baxter, Deerfield, IL, USA). Cyclosporin A alone was used for graft-versus-host disease (GVHD) prophylaxis. Infection prophylaxis was given from day 9 before BMT and consisted of ketoconazole or fluconazole and broad spectrum, non-absorbable antibiotics. In addition, patients 1, 3, 4 and 5 received oral acyclovir and patients 1, 2 and 4 received, an H2-receptor antagonist (cimetidine). Results Donor–recipient HLA-compatibility, occurrence of GVHD and main complications observed after BMT are listed in Table 2. None of the patients developed chronic GVHD. Oesophageal damage and outcome after BMT Patient 1: On day 12 after BMT, he had unexplained gastrointestinal bleeding which was treated with high-dose

Oesophageal complications after BMT for Fanconi’s anemia I Yakoub-Agha et al

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Table 1 Patient

Initial clinical characteristics of the five patients with FA Age (years) at diagnosis

Gender

Main clinical features

History of oesophageal symptoms before BMT

Prior treatment/complications

1

7

Male

Microcephaly Poor growth Bifid thumbs Skin pigmentation Renal malformation Hypertension

No

Androgens/hepatic adenomas

2

7

Female

Lack of thumbs Microcephaly Skin pigmentation Deafness

No

Androgens/hepatic adenomas

3

7

Male

Cafe´ aut lait spots

Reflux symptoms

Androgens

4

6

Female

Cafe´ au lait spots Renal malformation

No

Blood transfusions

5

4

Male

Renal malformation Cafe´ au lait spots

No

Blood transfusions Androgens

Table 2

Clinical characteristics and post-transplant complications of the five patients transplanted for FA

Patient

Age/year of BMT

Donor

Acute GVHD/treatment

Main post-transplant complications

Outcome

1

15/1981

HLA-matched sibling

Grade I no treatment

Gastrointestinal bleeding

Died 15 years Hepatocarcinoma

2

11/1982

HLA-matched sibling

Grade II skin, GI and liver Steroids and ATG

Encephalitis, hepatitis B

Died 5 years liver cirrhosis

3

19/1984

HLA-matched sibling

No

Hypertension

Died 14 years Tongue carcinoma

4

8/1988

HLA-matched unrelated donor

Grade II skin and GI Steroids

None

Alive ⬎11 years

5

11/1997

HLA-matched unrelated donor

No

None

Alive ⬍2. years

cimetidine (Tagemet; Beecham), anti-acid (Omeprezole; Astra, France) and platelet transfusions. On day 47, grade I acute skin GVHD was diagnosed and improved without any specific treatment. On day 60, the patient complained of anorexia, dysphagia and weight loss. An oesophago-gastroscopy revealed peptic oesophagitis with circular ulcer and severe stenosis in the distal oesophagus. Biopsies showed non-specific inflammation without signs of GVHD or infection. He was treated with high doses of antisecretory agents and a semi-liquid oral diet. Three months later, he felt better but dysphagia with solid foods persisted. Endoscopy showed severe stenosis with normal oesophageal mucosa with sclerotic tissue on biopsy. Oesophageal barium meal confirmed the stricture and revealed a hiatus hernia with reflux. He underwent successfully multiple oesophageal instrumental dilatation. Thereafter, the outcome of the BMT was favorable with improvement of oesophageal symptoms and weight gain. In 1996, 15 years after BMT, the patient was admitted for dysphagia and retrosternal pain. Endoscopy showed relapse of the ulcer and oesophageal stenosis. He received medical therapy (omeprazole and liquid oral intake) with improvement in Bone Marrow Transplantation

the symptoms. Unfortunately, he died a few months later of hepatocarcinoma following viral hepatitis-C infection. Patient 2: On day 8 after BMT, she developed grade III acute GVHD (skin, gut and liver) successfully treated with steroids and antithymocyte globulin (ATG). On day 19 after BMT, she presented with an encephalitis of unknown origin and received intravenous acyclovir with improvement of symptoms. On day 40 after BMT, she complained of anorexia, retrosternal pain and dysphagia. Endoscopy revealed a peptic oesophagitis and biopsies showed inflammatory tissue. Treatment consisted of high doses of antisecretory agents. A second endoscopy, performed on day 70 after BMT because of persisting dysphagia, showed severe stenosis of the oesophagus with normal oesophageal mucosa. No signs of GVHD or infection were found on biopsy. Oesophageal barium studies showed a stricture of the medium third of oesophagus with reflux. An instrumental dilatation of the oesophagus was successfully performed with improvement in symptoms. Five years later, she died of liver cirrhosis following prior hepatitis-B infection.


Patient 3: Because of reflux symptoms just before BMT, an endoscopy was performed but no oesophageal abnormality was observed. Transplant outcome was uneventful. Antifungal prophylaxis and acyclovir were stopped on day 75 after BMT. On day 100, he developed mucositis, pharyngeal ulcers, dysphagia and retrosternal pain. Treatment with oral acyclovir, cimetidine and liquid oral intake was prescribed without improvement in symptoms. Gastroscopy was performed on day 128 and showed severe peptic-type oesophagitis. Biopsies revealed herpetic inclusions in epithelial cells with detachment of the epithelium. Treatment was with acyclovir for 20 additional days and cimetidine. Improvement in symptoms occurred and cimetidine was stopped 2 months later. A further endoscopy was performed 2 years later because of the persistence of intermittent reflux symptoms and did not show any abnormality. The patient was admitted 14 years after BMT for tongue carcinoma. He died a few months later. Patient 4: This patient received an unrelated bone marrow transplant. On day 8 after BMT, she presented acute grade II skin and gut GVHD. Cyclosporin A and steroids were given with improvement in the lesions. She had no chronic GVHD and treatment was stopped 1 year after BMT. Nine years after transplantation, the patient complained of progressive dysphagia with solid foods and weight loss. Endoscopy showed severe short diaphragmatic-type stenosis of the upper oesophagus with no other abnormalities. No signs of GVHD, infection or neoplasm were found on biopsy. She underwent multiple instrumental dilatation with improvement of symptoms. She is alive but still complaining of mild dysphagia. Patient 5: This patient has received an unrelated bone marrow transplant. He had good engraftment and no GVHD. Two years after transplant, he developed dysphagia with frequent vomiting. Oesophagoscopy showed a brachy endooesophagitis which was successfully treated with omeprazole and cisapride.

conditioning regimen because these two patients did not have any oesophageal symptoms before BMT and no infectious agent was found on biopsy. However, they probably had oesophageal reflux before BMT, as suggested by the results of a barium meal performed after BMT in both patients. Severity of the symptoms and development of oesophageal stenosis can probably be explained by the hypersensitivity of the FA epithelial cells to cytotoxic agents despite the reduced doses of cyclophosphamide and irradiation. The third patient developed herpetic oesophagitis. This infection, after BMT, usually occurs during the period of maximum suppression of specific antiviral cellular immune responses.18 In this patient, mucosal damage from radiation and chemotherapy and immune suppression, probably contributed to the severity of the infection. In the last two observations, the oesophageal stricture seemed to be different from that of the first cases and could probably be considered as a late complication of BMT due to hypersensitivity of FA mucosal cells to cytotoxic agents, or more probably to non-diagnosed malformations of the oesophagogastric junction leading to abnormal reflux. BMT remains the only curative therapy for FA associated with aplastic anemia or leukemia. Oesophageal stenosis, in the absence of previously known malformation, is a possible complication after bone marrow transplantation in patients with FA. Preventive antisecretory treatment is therefore strongly recommended in patients with FA undergoing allogeneic BMT. Endoscopy should be performed whenever oesophageal symptoms occur in these patients. Furthermore, use of omeprazole instead of H2receptor antagonists may be useful.19 In our experience, this complication remains apparently without consequence for the outcome of BMT as long as the diagnosis is made early enough before severe malnutrition occurs. Despite the high probability of these patients developing secondary carcinoma of the oral and pharyngeal mucosa after BMT,20 none of the lesions we observed showed signs of malignant transformation but this stresses the importance of careful longterm follow-up of these patients and the advisability of performing endoscopies and biopsies as soon as symptoms occur.

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Discussion Oesophageal atresia has been observed in FA in 1.5% and tracheo-oesophageal fistula in 3.5% of patients. This contrasts with the frequency of 1/4000 or 1/3000 for this type of malformation in the general population. This is a component of the VACTERL-hydrocephalus picture which associates vertebral defects, anal atresia, tracheo-oesophageal fistula with oesophageal atresia and renal defects.13,14 In our patients, none had been diagnosed with oesophageal atresia before BMT but clinical manifestations can be so mild that they remain undetected unless additional damage occurs. This secondary insult can be either the conditioning regimen, infectious complications including herpes virus infection, candidiasis or manifestations of acute or chronic GVHD.15,16 Two cases of autologous BMT complicated by oesophageal stricture have been described and seemed to be related to the toxicity of agents including etoposide used for conditioning.17 We feel that oesophageal stenosis, in our first two cases, could have been due to toxicity of the

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