Bone Marrow Transplantation (2000) 26, 109–111  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Case report Acute during immunosuppression with tacrolimus following an allogeneic umbilical cord blood transplantation

Y Nieto1, P Russ2, G Everson3, SI Bearman1, PJ Cagnoni1, RB Jones1 and EJ Shpall1

1University of Colorado Bone Marrow Transplant Program, 2Radiology and 3Gastroenterology Departments, Denver, CO, USA

Summary: Case report

Tacrolimus is increasingly used for graft-versus-host The patient was a 28-year-old female with chronic myelo- disease (GVHD) prophylaxis and therapy in the allo- genous leukemia (CML), diagnosed in 1996. She was geneic stem cell transplant (allo-SCT) setting. Pancrea- treated with ␣-interferon plus hydroxyurea, and never achi- titis, previously described as a side-effect of cyclospor- eved a complete cytogenetic remission. She had no HLA- ine, has not been reported in allo-SCT recipients matched sibling donors, nor an unrelated donor in any of receiving tacrolimus. We present here a case of acute the bone marrow registries. An unrelated 5/6 cord unit, pancreatitis in a 28-year-old patient with chronic mye- HLA-mismatched for the DR locus, was identified at the logenous leukemia (CML) who received an unrelated University of Colorado Umbilical Cord Blood Bank. She umbilical cord blood transplant (UCBT) and tacrolimus consented to participate in a clinical trial of ex vivo for GVHD prophylaxis. On day +31 post-transplant, she expanded UCBT for adult patients. developed severe with multiorgan Conditioning therapy consisted of fractionated TBI at 12 failure, from which she recovered completely. Tacro- Gy, melphalan at 140 mg/m2 i.v., and antithymocyte globu- limus was the probable cause of pancreatitis in this lin at 30 mg/kg × 3 days. On day 0, cord blood cells, a patient. Bone Marrow Transplantation (2000) 26, 109– fraction of which (40%) were expanded ex vivo, were 111. infused. Supportive care included standard antimicrobials, Keywords: tacrolimus; FK506; pancreatitis; cord blood and GVHD prophylaxis with cyclosporine at a dose of 4 transplant mg/kg/day, adjusted to a whole blood level of 350–450 ng/ml, and methylprednisolone at 0.2 mg/kg twice a day from day 0 to +4, 0.5 mg/kg twice a day from day +5to +20, and in a tapering schedule thereafter. On day +16 post- Tacrolimus is a new immunosuppressive agent with an transplant, tacrolimus was substituted for cyclosporine emerging role in allo-SCT. While its chemical structure is because of the patient’s complaints of severe headache and different from that of cyclosporine, both drugs share a simi- visual disturbances, with white matter changes on the brain lar mechanism of action, inhibiting signaling initiated by MRI. Tacrolimus dose was 0.04 mg/kg/day, adjusted to a the T cell receptor that stimulates production of interleukin- target blood level of 10–20 ng/ml. On day +20, inhaled 1 2. A recent randomized phase III trial comparing both pentamidine was started for Pneumocystis carinii prophy- agents for GVHD prophylaxis in the unrelated marrow laxis. On day +31 (day +15 of tacrolimus treatment), she transplant setting, showed that patients receiving tacrolimus presented with acute complications of stabbing abdominal had a significantly lower incidence of acute GVHD, and pain in the epigastrium, tachypnea, hypoxia, and oliguria. similar rates of chronic GVHD, relapse, and overall On physical examination, her abdomen was distended and 2 survival. tender, with diminished bowel sounds. Laboratory analyses The toxic profile of tacrolimus, compared to that of showed 500 WBC/␮l, with no neutrophils, hemoglobin 10, cyclosporine, includes similar nephrotoxicity, hepatotoxi- hematocrit 28.6, 78000 platelets, creatinine 1.8 mg/dl, city, neurologic complications, hypomagnesemia, and blood urea nitrogen (BUN) 50 mg/dl, CO2 11 mEq/l, chlor- immunosuppression-related infections. There appears to be ide 107 mEq/l, sodium 132 mEq/l, potassium 3 mEq/l, cal- less hypertension, hypertrichosis, and gingival hyperplasia, cium 5.7 mg/dl, magnesium 1.6 mg/dl, glucose 230 mg/dl, and more hyperkalemia and hyperglycemia with tacro- albumin 1.2 g/l, total bilirubin 4.3 mg/dl, AST 17 U/l, ALT 3,4 limus. To our knowledge, pancreatitis has not been 23 U/l, amylase 369 U/l (normal Ͻ 100), lipase 475 U/l described in association to tacrolimus in the allo-SCT (normal Ͻ 100), LDH 252 U/l. Arterial blood gas analysis: setting. pH 7.34, pO2 76, pCO2 25, and base deficit 12. Urine elec- trolytes, creatinine and sediment were consistent with acute Correspondence: Dr Y Nieto, University of Colorado Bone Marrow Trans- tubular necrosis. The blood level of tacrolimus measured plant Program, B#190, 4200 East 9th Avenue, Denver, CO 80262, USA the day before was 17.6 ng/ml, within its target range. An Received 11 November 1999; accepted 11 February 2000 abdominal CT scan revealed an enlarged and edematous Acute pancreatitis probably caused by tacrolimus Y Nieto et al 110 , consistent with pancreatic and peripancreatic develop after an accumulated dose of more than 1 g, inflammation (Figure 1). The degree of necrosis could not whereas this patient had received a cumulative dose of 300 be determined, as no i.v. contrast was given because of her mg of inhaled drug at the time of symptom onset. renal dysfunction. Tacrolimus was discontinued, and other Importantly, pancreatitis did not recur when pentamidine supportive measures included i.v. fluids and imipenem. The was readministered. patient’s condition worsened substantially over the sub- Corticosteroids are considered probable causes of pan- sequent 48 h, with development of acute respiratory distress creatitis, with a length of treatment ranging from 1 week requiring intubation, and anuria requiring hemodialysis. to several years, and cumulative doses ranging from 8 to Over the next several days, her condition improved and 200 mg/day of prednisone prior to start of pancreatitis.5 all her laboratory parameters normalized. The patient was However, pancreatitis resolved without discontinuation of extubated 4 days later and hemodialysis was discontinued steroids, and did not reappear when its dose was later on day 12 after the onset of symptoms. increased for treatment of GVHD. Therefore, in this The patient died on day +85 of acute brain hemorrhage, case, both pentamidine and methylprednisolone can be deemed unrelated to her prior episode of pancreatitis. On reasonably excluded as potential causes of her pancreatitis. post-mortem examination, the pancreas did not have any Other possible etiologies of acute pancreatitis can be also residual acinar glandular atrophy, fibrosis or inflammation, excluded, including: (1) extrahepatic biliary obstruction, as and islets had normal appearance. no dilatation was observed on the CT scan; (2) hypercalcemia or hyperlipidemia, none of which was present in this patient; (3) total parenteral nutrition, which Discussion was restarted upon resolution of pancreatitis, without recur- rence; (4) drugs with a definitive association with pancrea- Immunosuppressive drugs have been associated with acute titis, including sulfonamides, furosemide, thiazides, valp- pancreatitis after solid organ transplantation and allo-SCT.5 roic acid, tetracyclines, salicylates, estrogens, azathioprine, In an autopsy series of allo-SCT patients from Seattle, signs or l-asparaginase, none of which was given to the patient of pancreatitis were found in 28% of allo-SCT recipients, at the time of symptoms. Pancreatic infections with CMV, although a premortem clinical diagnosis was made in only zoster, or adenovirus are usually a manifestation of dissemi- 10% of those patients.6 Two cases of pancreatitis apparently nated viral disease, which was not present. Other infectious related to tacrolimus have been reported after liver trans- agents, such as mumps, viral hepatitis, or mycoplasma, can plantation.7,8 However, to the authors’ knowledge, tacrol- also be reasonably excluded. An infection from coxsackie imus-associated pancreatitis has not been reported yet in or echovirus seems more difficult to rule out; however, this allo-SCT recipients. patient did not present any of the syndromes usually caused Of all the drugs this patient was receiving at the time of by these enteroviruses, such as aseptic meningitis, myocar- onset of pancreatitis, only two of them, pentamidine and ditis, pericarditis, exanthems/enanthems, or pleuritis, which methylprednisolone, have been described as causes of pan- would argue against a possible enterovirus etiology. While creatitis.6 Although pancreatitis seems much more common involvement of the epithelium of the pancreatic duct, but after intravenous pentamidine, a few cases of aerosolized not of the acinar tissue, with acute GVHD has been pentamidine-related pancreatitis have been reported.9,10 reported,11,12 the patient did not have other clinical signs of Intravenous pentamidine-associated pancreatitis appears to GVHD in her skin, liver or gut, which makes this hypoth- esis unlikely. Criteria established by Mallory and Kern13 for a definite association of any drug with pancreatitis include: (1) appearance of this complication during treatment with the drug; (2) disappearance upon withdrawal of the drug; (3) exclusion of other causes; and (4) relapse upon rechallenge. This case meets the first three criteria. Since tacrolimus was never readministered to the patient after recovery of pan- creatitis, the fourth criterion was not present. Therefore, this should be considered a case of probable, not definite, association between tacrolimus and pancreatitis. While there are no preclinical reports of tacrolimus- induced pancreatitis, impairment of pancreatic endocrine function has been shown in rats treated with tacrolimus.14 Experiments in a murine model of acute pancreatitis sug- gest that tacrolimus also damages the exocrine portion of the gland, although its deteriorating effect seems less potent than that of cyclosporine.15 Mortality from acute pancreatitis correlates with a num- Figure 1 Abdominal CT scan showing enlarged and edematous pancreas ber of Ranson’s criteria,16 which include signs at diagnosis (large white arrows). Inflammatory exudate extends from the body and Ͼ 3 Ͼ tail of the pancreas into the left anterior pararenal space and left paracolic (age over 55 years, WBC 16000/mm , glucose 200 gutter (small white arrows). Note the distended contrast-filled (s) mg/dl, LDH Ͼ 350 IU/l, and GOT Ͼ 250 IU/l) and during with nasogastric tube (black arrowhead). the initial 48 h (hematocrit drop greater than 10 percentage

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