tacrolimus and Intussusception

We describe the case of a boy who presented with abdominal Burkitt lymphoma; he had been regularly using tacrolimus ointment 0.1% for severe recurrent atopic dermatitis for 7 years immediately prior to developing cancer. We present his medical history and review the current knowledge regarding a link between topical tacrolimus and malignancy risk.

Topics: Administration, Cutaneous; Burkitt Lymphoma; Child; Dermatitis, Atopic; Diagnosis, Differential; Humans; Ileal Diseases; Ileal Neoplasms; Ileocecal Valve; Immunosuppressive Agents; Intussusception; Male; Tacrolimus; Tomography, X-Ray Computed

We previously reported an synergism between methotrexate and tacrolimus (FK506) in preventing graft-versus-host disease (GVHD) in dogs given DLA-nonidentical unrelated marrow grafts after 9.2 Gy of total body irradiation (TBI). Methotrexate was given at 0.4 mg/kg i.v. on days 1, 3, 6 and 11 and FK506 at 0.15 mg/kg/day i.m. on days 0-8 and 0.5 mg/kg/day orally on days 9-90. Half of the dogs became long-term survivors. A major toxicity was gastrointestinal, and 25% of dogs died with intussusception. The current study addresses the problem of intussusception by making changes in drug doses used. In one group of dogs, FK506 was reduced to 0.075 mg/kg i.m. on days 1-8, while methotrexate was administered per original schedule. In a second group, methotrexate was reduced to a single dose on day 7, while FK506 was either administered per the original or reduced-dose schedule. None of the 17 current dogs developed intussusception, however, all but two dogs died with GVHD (n = 12) or graft failure (n = 3). Only two dogs survived after transient GVHD. Results show that there is little room for maneuvering FK506 or methotrexate doses, and hopes of reducing gastrointestinal toxicity by dose modifications while retaining the ability to prevent GVHD were not fulfilled.

Topics: Animals; Bone Marrow Transplantation; Dogs; Drug Synergism; Graft Rejection; Graft vs Host Disease; Histocompatibility; Histocompatibility Antigens; Immunosuppressive Agents; Intussusception; Methotrexate; Radiation Chimera; Tacrolimus; Transplantation Conditioning

The immunosuppressive activities of a newly discovered macrolide extracted from Streptomyces tsukubaensis, FK506, were examined using 38 renal allografts in the beagle dog. The median survival time was 15.5 days in dogs without treatment, 61 days with a dose of 0.08 mg/kg/day and 176 days with a dose of 0.16 mg/kg/day of intramuscularly administered FK506. Prolongation of survival was statistically significant when compared with controls (P = 0.02, 0.0044, respectively). None of 6 recipient dogs receiving the agent at a dose of 0.16 mg/kg/day encountered rejection during the treatment course. Three of them survived over 200 days. Oral administration of FK506 at a dose of 0.32 mg/kg/day did not prolong the median survival time (20.5 days) compared with the placebo treated control (16.5 days), but oral treatment with 1.0 mg/kg/day resulted in all of the recipient dogs surviving over 130 days. Histological studies of 7 kidney graft biopsy specimens of the dogs surviving over 3 months revealed no cell infiltration or only some degree of reversible interstitial cell infiltration, but vascular and glomerular changes were not observed in any of the specimens. Irregularity of nuclear shape and cytoplasmic vacuolation of the pars recta of the proximal tubules were observed in one dog each. Liver biopsy specimens showed no consistent evidence of hepatocellular damage. Three dogs died of intussusception 2-3 weeks posttransplant. The dogs treated intramuscularly with 0.32 mg/kg/day suffered from anorexia. Two dogs receiving oral treatment at a dose of 1.0 mg/kg developed papilloma of the skin around day 60, but the tumors disappeared by day 120. We conclude that FK506 is a powerful immunosuppressant in the dog with tolerable side effects.

Topics: Administration, Oral; Animals; Anorexia; Dogs; Drug Evaluation, Preclinical; Female; Graft Survival; Immunosuppressive Agents; Injections, Intramuscular; Intussusception; Kidney; Kidney Transplantation; Liver; Postoperative Complications; Pyridines; Tacrolimus; Transplantation, Homologous