Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FK506 is an important immunosuppressant that has shown great promise in the treatment of autoimmune diseases. Approximately 5% of patients receiving FK506 develop major central nervous system toxicity, but the peripheral nerves are usually spared. During 1990-1991, some 1000 patients received liver transplants under FK506 immunosuppression. Of these, 3 patients developed severe multifocal demyelinating sensorimotor polyneuropathy 2-10 weeks after initiation of FK506 therapy. Improvement followed plasmapheresis or intravenous immunoglobulin (IVIG), suggesting an immune-mediated cause. Although autoimmune neuropathy has been previously reported in immune-deficient states such as Hodgkin's disease and AIDS, it is not an expected complication of immunosuppressive therapy. However, others have shown that this phenomenon can be produced in rats with cyclosporine A (CsA), whose effects on T-cell subsets are similar to those seen with FK506. These T-cell subset changes may have precipitated this dysimmune neuropathy in our patients.
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PMID:Sensorimotor neuropathy resembling CIDP in patients receiving FK506. 751 91

Posttransplant lymphoproliferative disorders are typically of B cell origin, whereas T cell lymphomas have been rarely documented. We present a case of a non-Hodgkin's T cell lymphoma involving the intestinal graft of a multivisceral transplant patient. The patient was a 7-year-old girl who underwent at age 5 a multivisceral transplant secondary to short gut syndrome. Baseline immunosuppressive therapy consisted of FK506, methylprednisone, and mycophenolate mofetil. At 2 years posttransplant she presented with fever, diarrhea, nausea, and vomiting. Multiple endoscopic biopsies revealed a severe intensity, diffuse and focally nodular lymphocytic infiltrate composed predominantly of small, monomorphic lymphoid cells with scattered plasma cells and abundant eosinophils. Immunohistochemically, the majority of the lymphoid cells expressed the pan T cell marker CD3. Southern blot analysis revealed rearrangement of the T cell receptor beta chain gene, with germline configuration of the heavy immunoglobulin chain gene, confirming a clonal T cell genotype. In situ hybridization for Epstein Barr virus revealed rare positive lymphoid cells, that were negative with CD3 by immunohistochemical staining. A detailed clinico-radiological work-up revealed no other sites of involvement by the lymphomatous process. After the diagnosis of posttransplant lymphoproliferative disorder, immunosuppression was reduced with a subsequent partial improvement in the endoscopic appearance of the graft and a focal decrease in the lymphocytic infiltrate seen in the follow-up biopsies. Repeat gene rearrangement studies demonstrated germline configuration of both the T cell receptor beta chain gene and the heavy chain immunoglobulin. gene. To our knowledge, this represents the first description of a T cell lymphoma affecting the intestinal allograft of a multivisceral transplant patient.
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PMID:T cell lymphoma involving the graft of a multivisceral organ recipient. 1055 42

Tacrolimus (FK506)/mycophenolate mofetil (MMF) has been demonstrated to be an effective salvage therapy for steroid-resistant chronic graft-versus-host disease (GVHD), but its effectiveness as prophylaxis for acute GVHD (aGVHD) is unknown. We investigated the safety and efficacy of FK506/MMF in preventing aGVHD and sparing the use of methotrexate and methylprednisolone in childhood and adolescent allogeneic stem cell transplant (AlloSCT) recipients. Thirty-four childhood and adolescent patients (median age, 7 years; range, 0.5-21 years; 24 males and 10 females) undergoing 37 AlloSCTs for malignant (n = 22) and nonmalignant (n = 12) disorders received FK506 (0.03 mg/kg/d by continuous intravenous infusion) and MMF (15 mg/kg per dose orally or intravenously twice daily). Stem cell sources included 22 umbilical cord blood donors (21 unrelated and 1 related), 6 related bone marrow donors, and 9 related peripheral blood donors. Malignant diagnoses included 7 acute lymphoblastic leukemias, 3 acute myeloid leukemias, 1 acute promyelocytic leukemia, 2 non-Hodgkin lymphomas, 4 Hodgkin diseases, 3 chronic myeloid leukemias, and 2 neuroblastomas; nonmalignant diagnoses included 2 beta-thalassemias, 1 sickle cell disease, 4 aplastic anemias, 1 Wiskott-Aldrich syndrome, 1 Hurler syndrome, 2 hemophagocytic lymphohistiocytoses, and 1 myelodysplastic syndrome. The probability of developing grade > or =II aGVHD was 45.4% +/- 9.7% (7 related bone marrow/related peripheral blood; 5 umbilical cord blood), and for chronic GVHD it was 38.1% +/- 19.7%. FK506/MMF was well tolerated. Three patients had grade III to IV neurotoxicity (disorientation and leukoencephalopathy); 4 patients developed grade III to IV nephrotoxicity (all received concomitant nephrotoxins). Patients who achieved target mycophenolic acid levels (1.0-3.5 microg/mL) before day +30 had a significantly reduced incidence of developing grade >/=II aGVHD (16.7% +/- 15.2% versus 100%; P <.02). These results suggest that FK506/MMF is well tolerated and may be a safe and effective methotrexate- and methylprednisolone-sparing alternative GVHD prophylaxis regimen after AlloSCT. Further pharmacokinetic and pharmacodynamic studies are ongoing in pediatric and adolescent AlloSCT recipients to define optimal MMF dosing.
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PMID:A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients. 1507 23

A 46-year-old woman with Hodgkin's disease who underwent nonmyeloablative allogeneic stem cell transplantation developed cortical blindness, seizures, and left hemiparesis on day 100 while receiving tacrolimus (FK506) and prednisone for the treatment of graft-versus-host disease (GVHD). Magnetic resonance imaging revealed multiple changes, mainly in the bilateral occipital lobes, suggesting FK506-related leukoencephalopathy. These abnormalities improved after discontinuation of FK506. However, 3 days after the episode, cerebral hemorrhage in the left occipital lobe with perforation to the left subdural space occurred. Although FK506-induced leukoencephalopathy with cerebral hemorrhage is considered the more severe form of such leukoencephalopathy, the patient's neurological symptoms almost completely resolved and radiographic findings improved after discontinuation of FK506, tapering of methylprednisolone, and initiation of mycophenolate mofetil. FK506-related leukoencephalopathy is a rare complication after allogeneic stem cell transplantation. Although the symptoms usually subside after discontinuation of FK506, therapeutic intervention in many cases may result in severe complications, including GVHD and vascular disease. We consider it important to use immunosuppressive agents without vascular endothelial toxicity for preventing the development of fatal GVHD after discontinuation of FK506.
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PMID:Successful treatment of tacrolimus (FK506)-related leukoencephalopathy with cerebral hemorrhage in a patient who underwent nonmyeloablative stem cell transplantation. 1554 Sep 7

Incidence of grade II-IV acute graft-versus-host disease (aGVHD) in nonmyeloablative (NMA) transplant recipients remains high. To date, the ideal prophylaxis regimen, which minimizes aGVHD and chronic GVHD (cGVHD), but does not abrogate graft-versus-tumor (GVT) response, has not been described. Because tacrolimus is more potent than cyclosporine (CSA), and because mycophenolate mofetil (MMF) is an effective immunosuppressant that does not lead to mucositis, we hypothesized that a combination of these 2 oral agents may be an effective GVHD prophylactic strategy. We, therefore, designed an outpatient prospective cohort study with a conditioning regimen consisting of fludarabine (Flu) 30 mg/m2 daily and cyclophosphamide (Cy) 300 mg/m2 daily for 5 days followed by infusion of blood stem cells. Tacrolimus 3mg twice a day was started on day (D) -8, adjusted to achieve levels 10-15 nmol/L, continued until D +50 and then tapered by D +100 or +180 according to estimated risk of relapse. MMF 1000 mg twice a day was started on D +1 and discontinued on D +50. To date, 131 patients (males/females: 75/56) with a median age of 54 years have received a 6/6 matched sibling transplant using this protocol. Indication for NMA transplant included age >55 years (24%), expected increased risk of toxicity (28%), or participation in a multiple myeloma (MM) sequential protocol (48%). Most common diagnoses included MM (N = 62), non-Hodgkin lymphoma (NHL, N = 46), and acute leukemia (N = 10). Following infusion of 6.8 x 10(6) CD34+ cells/kg (range: 0.30-22.3), neutrophil and lymphocyte engraftment occurred in 95% of patients by D +180. The estimated cumulative incidence of classical grade I-IV aGVHD by D +120 was 11.6% (95% confidence interval [CI]: 7.1-18.5). No grade IV aGVHD was observed. In addition, 15 patients (12%: CI: 7.4-19.2; median D +140) developed an overlap syndrome consisting of clinical and histologic features of both aGVHD and cGVHD simultaneously. The estimated cumulative incidence of extensive cGVHD was 76.1% (95% CI: 67.4-83.9) at 2 years, with clinical features at presentation similar to other reported series. In patients developing extensive cGVHD, the probability of remaining on immunosuppression at 5 years was 34.8% (95% CI: 16.4-57.3). With a median follow-up of 982 days, the estimated probabilities of nonrelapse mortality (NRM) and overall survival (OS) were 15.5% (95% CI: 9.0-26.1) and 62.7% (95% CI: 51.4-72.1). The cumulative incidence of relapse was 30% at 7 years. Following NMA transplant, disease-free survival (DFS) was highest in recipients with follicular NHL (79.8%: 95% CI: 57.6-91.2) and lowest in large cell NHLs (34.3%: 95% CI: 1.6-75.9). From this large group of patients treated with a uniform conditioning and GVHD prophylaxis regimen, we conclude that aGVHD prophylaxis with early use of tacrolimus and MMF is safe, effective, and associated with low NRM. Future strategies will need to focus on decreasing the incidence of extensive cGVHD without increasing the risk of relapse.
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PMID:Graft-versus-host disease prophylaxis with tacrolimus and mycophenolate mofetil in HLA-matched nonmyeloablative transplant recipients is associated with very low incidence of GVHD and nonrelapse mortality. 1958 81

Cryptogenic organizing pneumonia (COP, formerly bronchiolitis obliterans organizing pneumonia) is rare in children. We describe an 11-year-old girl with Epstein-Barr virus (EBV) reactivation/presumed post-transplant lymphoproliferative disease (PTLD) 15 months after undergoing a deceased donor kidney transplantation. Treatment with reduced immunosuppression, ganciclovir, and cytomegalovirus immunoglobulin was complicated by severe graft rejection, prompting therapy with methylprednisolone, anti-thymocyte globulin and four weekly doses of rituximab (total 1500 mg/m(2)). Tacrolimus- and prednisone-based anti-rejection prophylaxis was complemented with low-dose sirolimus. When the lactate dehydrogenase and uric acid levels rose 10 weeks after the first rituximab infusion and bilateral pulmonary nodules were detected by computerized tomography, recurrence of PTLD was suspected. Open lung biopsy of the clinically asymptomatic patient identified the nodules as COP, characterized by abundant CD3(+) T-cells, few B-cells, and the absence of EBV, cytomegalovirus, or adenovirus antigens. With normalization of the peripheral B-cell count, EB viremia reappeared and persisted, despite minimal immunosuppression. Four years later, the patient was diagnosed with classical Hodgkin lymphoma-type PTLD with multiple pulmonary and abdominal nodes. This first report of rituximab-associated, pediatric COP highlights the risk of pulmonary complications after treatment with B-cell depleting agents in solid organ transplant recipients, and the importance of a histopathologic diagnosis and vigilant follow-up of such lesions.
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PMID:Cryptogenic organizing pneumonia after rituximab therapy for presumed post-kidney transplant lymphoproliferative disease. 2014 Apr 60