www.nature.com/bmt. Case report. Acute pancreatitis during immunosuppression with tacrolimus following an allogeneic umbilical cord blood transplantation.
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 pancreatitis 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 1
University of Colorado Bone Marrow Transplant Program, 2Radiology and 3Gastroenterology Departments, Denver, CO, USA
Summary:
Case report
Tacrolimus is increasingly used for graft-versus-host disease (GVHD) prophylaxis and therapy in the allogeneic stem cell transplant (allo-SCT) setting. Pancreatitis, previously described as a side-effect of cyclosporine, has not been reported in allo-SCT recipients receiving tacrolimus. We present here a case of acute pancreatitis in a 28-year-old patient with chronic myelogenous leukemia (CML) who received an unrelated umbilical cord blood transplant (UCBT) and tacrolimus for GVHD prophylaxis. On day +31 post-transplant, she developed severe acute pancreatitis with multiorgan failure, from which she recovered completely. Tacrolimus was the probable cause of pancreatitis in this patient. Bone Marrow Transplantation (2000) 26, 109– 111. Keywords: tacrolimus; FK506; pancreatitis; cord blood transplant
The patient was a 28-year-old female with chronic myelogenous leukemia (CML), diagnosed in 1996. She was treated with ␣-interferon plus hydroxyurea, and never achieved a complete cytogenetic remission. She had no HLAmatched sibling donors, nor an unrelated donor in any of the bone marrow registries. An unrelated 5/6 cord unit, HLA-mismatched for the DR locus, was identified at the University of Colorado Umbilical Cord Blood Bank. She consented to participate in a clinical trial of ex vivo expanded UCBT for adult patients. Conditioning therapy consisted of fractionated TBI at 12 Gy, melphalan at 140 mg/m2 i.v., and antithymocyte globulin at 30 mg/kg × 3 days. On day 0, cord blood cells, a fraction of which (40%) were expanded ex vivo, were infused. Supportive care included standard antimicrobials, and GVHD prophylaxis with cyclosporine at a dose of 4 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 +5 to +20, and in a tapering schedule thereafter. On day +16 posttransplant, tacrolimus was substituted for cyclosporine because of the patient’s complaints of severe headache and visual disturbances, with white matter changes on the brain MRI. Tacrolimus dose was 0.04 mg/kg/day, adjusted to a target blood level of 10–20 ng/ml. On day +20, inhaled pentamidine was started for Pneumocystis carinii prophylaxis. On day +31 (day +15 of tacrolimus treatment), she presented with acute complications of stabbing abdominal pain in the epigastrium, tachypnea, hypoxia, and oliguria. On physical examination, her abdomen was distended and tender, with diminished bowel sounds. Laboratory analyses showed 500 WBC/l, with no neutrophils, hemoglobin 10, hematocrit 28.6, 78 000 platelets, creatinine 1.8 mg/dl, blood urea nitrogen (BUN) 50 mg/dl, CO2 11 mEq/l, chloride 107 mEq/l, sodium 132 mEq/l, potassium 3 mEq/l, calcium 5.7 mg/dl, magnesium 1.6 mg/dl, glucose 230 mg/dl, albumin 1.2 g/l, total bilirubin 4.3 mg/dl, AST 17 U/l, ALT 23 U/l, amylase 369 U/l (normal ⬍ 100), lipase 475 U/l (normal ⬍ 100), LDH 252 U/l. Arterial blood gas analysis: pH 7.34, pO2 76, pCO2 25, and base deficit 12. Urine electrolytes, creatinine and sediment were consistent with acute tubular necrosis. The blood level of tacrolimus measured the day before was 17.6 ng/ml, within its target range. An abdominal CT scan revealed an enlarged and edematous
Tacrolimus is a new immunosuppressive agent with an emerging role in allo-SCT. While its chemical structure is different from that of cyclosporine, both drugs share a similar mechanism of action, inhibiting signaling initiated by the T cell receptor that stimulates production of interleukin2.1 A recent randomized phase III trial comparing both agents for GVHD prophylaxis in the unrelated marrow transplant setting, showed that patients receiving tacrolimus had a significantly lower incidence of acute GVHD, and similar rates of chronic GVHD, relapse, and overall survival.2 The toxic profile of tacrolimus, compared to that of cyclosporine, includes similar nephrotoxicity, hepatotoxicity, neurologic complications, hypomagnesemia, and immunosuppression-related infections. There appears to be less hypertension, hypertrichosis, and gingival hyperplasia, and more hyperkalemia and hyperglycemia with tacrolimus.3,4 To our knowledge, pancreatitis has not been described in association to tacrolimus in the allo-SCT setting. Correspondence: Dr Y Nieto, University of Colorado Bone Marrow Transplant Program, B#190, 4200 East 9th Avenue, Denver, CO 80262, USA Received 11 November 1999; accepted 11 February 2000
Acute pancreatitis probably caused by tacrolimus Y Nieto et al
110
pancreas, consistent with pancreatic and peripancreatic inflammation (Figure 1). The degree of necrosis could not be determined, as no i.v. contrast was given because of her renal dysfunction. Tacrolimus was discontinued, and other supportive measures included i.v. fluids and imipenem. The patient’s condition worsened substantially over the subsequent 48 h, with development of acute respiratory distress requiring intubation, and anuria requiring hemodialysis. Over the next several days, her condition improved and all her laboratory parameters normalized. The patient was extubated 4 days later and hemodialysis was discontinued on day 12 after the onset of symptoms. The patient died on day +85 of acute brain hemorrhage, deemed unrelated to her prior episode of pancreatitis. On post-mortem examination, the pancreas did not have any residual acinar glandular atrophy, fibrosis or inflammation, and islets had normal appearance. Discussion Immunosuppressive drugs have been associated with acute pancreatitis after solid organ transplantation and allo-SCT.5 In an autopsy series of allo-SCT patients from Seattle, signs of pancreatitis were found in 28% of allo-SCT recipients, although a premortem clinical diagnosis was made in only 10% of those patients.6 Two cases of pancreatitis apparently related to tacrolimus have been reported after liver transplantation.7,8 However, to the authors’ knowledge, tacrolimus-associated pancreatitis has not been reported yet in allo-SCT recipients. Of all the drugs this patient was receiving at the time of onset of pancreatitis, only two of them, pentamidine and methylprednisolone, have been described as causes of pancreatitis.6 Although pancreatitis seems much more common after intravenous pentamidine, a few cases of aerosolized pentamidine-related pancreatitis have been reported.9,10 Intravenous pentamidine-associated pancreatitis appears to
Figure 1 Abdominal CT scan showing enlarged and edematous pancreas (large white arrows). Inflammatory exudate extends from the body and tail of the pancreas into the left anterior pararenal space and left paracolic gutter (small white arrows). Note the distended contrast-filled stomach(s) with nasogastric tube (black arrowhead). Bone Marrow Transplantation
develop after an accumulated dose of more than 1 g, whereas this patient had received a cumulative dose of 300 mg of inhaled drug at the time of symptom onset. Importantly, pancreatitis did not recur when pentamidine was readministered. Corticosteroids are considered probable causes of pancreatitis, with a length of treatment ranging from 1 week to several years, and cumulative doses ranging from 8 to 200 mg/day of prednisone prior to start of pancreatitis.5 However, pancreatitis resolved without discontinuation of steroids, and did not reappear when its dose was later increased for treatment of liver GVHD. Therefore, in this case, both pentamidine and methylprednisolone can be reasonably excluded as potential causes of her pancreatitis. Other possible etiologies of acute pancreatitis can be also excluded, including: (1) extrahepatic biliary obstruction, as no bile duct dilatation was observed on the CT scan; (2) hypercalcemia or hyperlipidemia, none of which was present in this patient; (3) total parenteral nutrition, which was restarted upon resolution of pancreatitis, without recurrence; (4) drugs with a definitive association with pancreatitis, including sulfonamides, furosemide, thiazides, valproic acid, tetracyclines, salicylates, estrogens, azathioprine, or l-asparaginase, none of which was given to the patient at the time of symptoms. Pancreatic infections with CMV, zoster, or adenovirus are usually a manifestation of disseminated viral disease, which was not present. Other infectious agents, such as mumps, viral hepatitis, or mycoplasma, can also be reasonably excluded. An infection from coxsackie or echovirus seems more difficult to rule out; however, this patient did not present any of the syndromes usually caused by these enteroviruses, such as aseptic meningitis, myocarditis, pericarditis, exanthems/enanthems, or pleuritis, which would argue against a possible enterovirus etiology. While involvement of the epithelium of the pancreatic duct, but not of the acinar tissue, with acute GVHD has been reported,11,12 the patient did not have other clinical signs of GVHD in her skin, liver or gut, which makes this hypothesis 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 pancreatitis, 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 tacrolimusinduced pancreatitis, impairment of pancreatic endocrine function has been shown in rats treated with tacrolimus.14 Experiments in a murine model of acute pancreatitis suggest 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 number of Ranson’s criteria,16 which include signs at diagnosis (age over 55 years, WBC ⬎ 16 000/mm3, glucose ⬎ 200 mg/dl, LDH ⬎ 350 IU/l, and GOT ⬎ 250 IU/l) and during the initial 48 h (hematocrit drop greater than 10 percentage
Acute pancreatitis probably caused by tacrolimus Y Nieto et al
points, BUN rise ⬎5 mg/dl, calcium ⬍8 mg/dl, arterial PO2 ⬍60 mm Hg, base deficit ⬎4 mEq/l, and estimated liquid sequestration ⬎6 l). The patient described above met five criteria (hyperglycemia, uremia, hypocalcemia, hypoxemia, metabolic acidosis, and liquid sequestration), which is associated with a 40% risk of death. The optimal dose of tacrolimus for GVHD prophylaxis is not known yet. Przepiorka et al17 reported a lack of correlation between the levels of tacrolimus and risk of acute GVHD within a concentration range of 5–40 ng/ml, but a significant increase in the risk of nephrotoxicity above levels ⬎20 ng/ml. It is noticeable that the blood level of tacrolimus in this patient, measured the day before the start of pancreatitis, was within the target range of 10–20 ng/ml. Since tacrolimus will likely be increasingly administered in allo-SCT in the future, we wish to alert clinicians involved in the care of these patients to the possibility of tacrolimus-related acute pancreatitis, an uncommon but potentially fatal complication. References 1 Chao NJ. Pharmacology and use of immunosuppressive agents after hematopoietic cell transplantation. In: Thomas ED, Blume KG, Forman SJ (eds). Hematopoietic Cell Transplantation. Blackwell Science: Malden, MA, 1999, pp 176–185. 2 Antin J, Nash R, Karanes C et al. Two-year results of a phase III study comparing tacrolimus and cyclosporine for GVHD prophylaxis in unrelated donor bone marrow transplantation. Biol Blood Marrow Transplant 1999; 5: 98a. 3 Woo M, Przepiorka D, Ippoliti C et al. Toxicities of tacrolimus and cyclosporin A after allogeneic blood stem cell transplantation. Bone Marrow Transplant 1997; 20: 1095–1098. 4 Mihatsch MJ, Kyo M, Morozumi K et al. The side-effects of cyclosporine-A and tacrolimus. Clin Nephrol 1998; 49: 356– 363.
5 Ru¨nzi M, Layer P. Drug-associated pancreatitis: facts and fiction. Pancreas 1996; 13: 100–109. 6 Ko CW, Gooley T, Schoch HG et al. Acute pancreatitis in marrow transplant patients: prevalence at autopsy and risk factor analysis. Bone Marrow Transplant 1997; 20: 1081–1086. 7 McDiarmid SV, Klintmalm G, Busuttil RW. FK506 rescue therapy in liver transplantation: outcome and complications. Transplant Proc 1991; 23: 1996–1999. 8 Uemoto S, Tanaka K, Honda K et al. Experience with FK506 in living-related liver transplantation. Transplantation 1993; 55: 288–292. 9 Murphy RL, Noskin GA, Ehrenpreis ED. Acute pancreatitis associated with aerosolized pentamidine. Am J Med 1990; 88: 53N–56N. 10 Hart CC. Aerosolized pentamidine and pancreatitis (letter). Ann Intern Med 1989; 111: 691. 11 Foulis AK, Farquharson MA, Sale GE. The pancreas in acute graft-versus-host disease in man. Histopathology 1989; 14: A48. 12 Washington K, Gossage DL, Gottfired MR. Pathology of the pancreas in severe combined immunodeficiency and DiGeorge syndrome: acute graft-versus-host disease and unusual viral infections. Hum Pathol 1994; 25: 908–914. 13 Mallory A, Kern Jr F. Drug-induced pancreatitis: a critical review. Gastroenterology 1980; 78: 813–820. 14 Mu¨ller MK, Wojcik M, Coone H, Singer MV. Inhibition of insulin release by FK506 and its prevention by rioprostil, a stable prostaglandin E1 analogue. Transplant Proc 1991; 23: 2812–2813. 15 Echigo Y, Inoue K, Kogire M et al. Effects of cyclosporine and tacrolimus (FK506) on acute pancreatitis in mice. Arch Surg 1995; 130: 64–68. 16 Ranson JHC, Pasternack BS. Statistical methods for quantifying the severity of clinical acute pancreatitis. J Surg Res 1997; 22: 79–91. 17 Przepiorka D, Nash RA, Wingard JR et al. Relationship of tacrolimus whole blood levels to efficacy and safety outcomes after unrelated donor marrow transplantation. Biol Blood Marrow Transplant 1999; 5: 94–97.
111
Bone Marrow Transplantation
