tacrolimus and Lymphoma--Non-Hodgkin

Pediatric heart transplantation is a surgical therapy for dilated cardiomyopathy and for complex congenital heart defects with low pulmonary artery resistance. However, it is still discussed as controversial because of uncertain long-term results. We report our experience with pediatric heart transplantation in a heterogeneous population.. Since 1988, 50 heart transplants were performed in 47 patients (30 with dilated cardiomyopathy, 17 with congenital heart disease). Mean age was 9.4 +/- 6.9 years (range, 4 days to 17.9 years). Twenty-three patients had a total of 36 previous operations. Clinical outcome was evaluated retrospectively.. Perioperative mortality was 6% due to primary graft failure. Late mortality (12%) was caused by acute rejection (n = 2), pneumonia (n = 2), intracranial hemorrhage (n = 1), and suicide (n = 1). Mean follow-up was 5.24 +/- 3.6 years. Actuarial 1, 5, and 10 year survival was 86%, 86%, and 80% and improved significantly after 1995 (92% [1 year]; 92% [5 years]). There was no significant difference between patients with dilated or congenital heart disease (1 year: 86% vs 82%; 5 years: 83% vs 74%; 10 years 83% vs 74%; p = 0.62). Three patients with therapy resistant acute or chronic rejection and assisted circulation underwent retransplantation and are alive. Freedom from acute rejection after 5 years was 40% with primary cyclosporine immunosuppression regime and 56% with tacrolimus. Since the introduction of mycophenolate mofetil, freedom from acute rejection increased to 62%. All survivors are at home and in good cardiac condition.. Pediatric heart transplantation is the treatment of choice for end-stage dilated cardiomyopathy as for congenital heart disease with excellent clinical midterm results. It is a valid alternative to reconstructive surgery in borderline patients. However, further follow-up is necessary to evaluate the long-term side effects of immunosuppressants.

Topics: Adolescent; Antiviral Agents; Bacterial Infections; Cardiomyopathy, Dilated; Child; Child, Preschool; Cyclosporine; Cytomegalovirus Infections; Extracorporeal Membrane Oxygenation; Female; Follow-Up Studies; Ganciclovir; Germany; Graft Rejection; Heart Defects, Congenital; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Immunosuppressive Agents; Life Tables; Lymphoma, Non-Hodgkin; Male; Mycophenolic Acid; Pneumonia, Pneumocystis; Postoperative Complications; Reoperation; Retrospective Studies; Survival Analysis; Survival Rate; Tacrolimus; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Vascular Resistance; Virus Diseases

A once-daily modified release formulation of oral tacrolimus (Tac QD) has been developed in response to the problem of nonadherence. However, there have been no data available about the efficacy of Tac QD conversion from intravenous Tac (Tac i.v.) in allogeneic hematopoietic stem cell transplantation (allo-SCT). We analyzed the pharmacokinetics (PK) of Tac QD in allo-SCT recipients. A total of 10 patients with hematological malignancies who received allo-SCT from unrelated donors were enrolled. Patients received Tac i.v. at 0.03 mg/kg a day before transplantation. Administration of Tac i.v. was converted to Tac QD at a 1:4 ratio when the patients had recovered from regimen-related gastrointestinal toxicity and could tolerate oral medication. After conversion, six out of 10 patients (60 %) showed a sustained decrease in Tac exposure and required dose adjustment. The conversion from Tac i.v. to Tac QD should be performed under close medical supervision. Area under the curve (AUC) and the trough of Tac QD showed a correlation, and the trough should be maintained above 7.5 ng/ml to provide an adequate AUC. Although four patients received bone marrow from an HLA DRB1 1 antigen-mismatched unrelated donor, no patients developed grade III-IV acute graft-versus-host disease (GVHD). The modification of Tac QD to maintain a whole-blood trough concentration above 7.5 ng/ml may be as effective as Tac BID.

Topics: Adult; Aged; Delayed-Action Preparations; Drug Administration Schedule; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia; Lymphoma, Non-Hodgkin; Male; Middle Aged; Myelodysplastic Syndromes; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Unrelated Donors; Young Adult

A high incidence of nonrelapse mortality (NRM) has limited the use of allogeneic transplantation for poor prognosis non-Hodgkin's lymphoma (NHL). We sought to improve the outcome of allografting by utilizing Filgrastim-mobilized peripheral blood stem cells (PBSC) in combination with either standard ablative or reduced-intensity conditioning. A total of 21 patients with intermediate/high-grade lymphoma and seven patients with low-grade histology were enrolled on protocols using PBSC. All patients were considered high risk for recurrence and/or NRM because of age >50 (n=16), refractory disease (n=17), failed autologous transplant (n=11) and abnormal organ function (n=2). In all, 17 patients received ablative regimens and 11 received modified conditioning including fludarabine, intravenous busulfan and ATG. Tacrolimus and mini-dose methotrexate were used for graft-versus-host-disease (GVHD) prophylaxis. Median follow-up was 38 months. Disease-free and overall survival were 57 and 58%. Seven of the 11 patients who relapsed after a previous transplant remain disease free. Four of the 10 patients with recurrent/persistent disease post transplant responded to additional therapy including withdrawal of immunosuppression+/-DLI. These results support a potent graft-versus-lymphoma effect and suggest that patients who relapse after an autologous transplant can be salvaged with an allogeneic transplant.

Topics: Adult; Disease-Free Survival; Drug Therapy, Combination; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Recurrence; Risk Factors; Survival Rate; Tacrolimus; Transplantation, Homologous

Mortality associated with allogeneic hematopoietic cell transplantation (allo-HCT) has limited its broader application in patients with non-Hodgkin lymphoma (NHL). Pharmacokinetic treatment with targeted intravenous busulfan combined with fludarabine (BuFlu) was developed as a preparative regimen for acute leukemia and myelodysplasia. Data from this regimen in lymphoid malignancies are limited.. We assessed outcomes in 60 consecutive patients with various subtypes of NHL and a median age of 54 years (range, 27-68 years) who received allo-HCT with targeted intravenous BuFlu between December 2004 and August 2010. The median number of previous therapies was 3 (range, 1-8) and median time from diagnosis to HCT was 32 months (range, 4.5-177.5 months).. At conditioning, 28 (47%) patients had a complete response (CR). Graft versus host disease (GVHD) prophylaxis consisted of tacrolimus plus methotrexate in 65% of cases. Donors were matched/related (n = 32 [53%]), matched/unrelated (n = 21 [35%]), or mismatched/unrelated (n = 7 [12%]). All patients underwent grafting. The cumulative incidence of grade II/IV acute GVHD was 74% (grade III/IV was 20%). The 2-year cumulative incidence of moderate to severe chronic GVHD was 62%. Nonrelapse mortality (NRM) at 100 days and 3 years was 10% and 25%, respectively. The cumulative incidence of relapse was 27%. Three-year progression-free and overall survival for all patients was 47.8% and 55%, respectively.. Targeted intravenous BuFlu is a relatively well tolerated regimen and offers an alternative option when myeloablation is deemed necessary in patients with NHL.

Topics: Administration, Intravenous; Adult; Aged; Antineoplastic Agents; Busulfan; Disease-Free Survival; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Myeloablative Agonists; Recurrence; Retrospective Studies; Survival Rate; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Topics: Adult; Carotid Stenosis; Cord Blood Stem Cell Transplantation; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Magnetic Resonance Imaging; Myelodysplastic Syndromes; Neutrophils; Tacrolimus; Takayasu Arteritis; Time Factors; Tomography, X-Ray Computed; Transplantation, Homologous; Treatment Outcome

Adoptive transfer of autologous Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs) to solid organ transplant (SOT) recipients has been shown safe and effective for the treatment of EBV-associated posttransplantation lymphoproliferative disorders (PTLDs). SOT recipients, however, require the continuous administration of immunosuppressive drugs to prevent graft rejection, and these agents may significantly limit the long-term persistence of transferred EBV-CTLs, precluding their use as prophylaxis. Tacrolimus (FK506) is one of the most widely used immunosuppressive agents in SOT recipients, and its immunosuppressive effects are largely dependent on its interaction with the 12-kDa FK506-binding protein (FKBP12). We have knocked down the expression of FKBP12 in EBV-CTLs using a specific small interfering RNA (siRNA) stably expressed from a retroviral vector and found that FKBP12-silenced EBV-CTLs are FK506 resistant. These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity. We confirmed their FK506 resistance and anti-PTLD activity in vivo using a xenogenic mouse model, suggesting that the proposed strategy may be of value to enhance EBV-specific immune surveillance in patients at high risk of PTLD after transplantation.

Topics: Adoptive Transfer; Animals; Antigens, Viral; Cells, Cultured; Cytotoxicity, Immunologic; Drug Resistance; Gene Knockdown Techniques; Genetic Vectors; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Mice; Mice, SCID; Protein Processing, Post-Translational; Recombinant Fusion Proteins; Retroviridae; Ribosomal Protein S6 Kinases; RNA, Messenger; RNA, Small Interfering; T-Lymphocytes, Cytotoxic; Tacrolimus; Tacrolimus Binding Protein 1A; Xenograft Model Antitumor Assays

Topics: Acute Kidney Injury; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Busulfan; Carmustine; Combined Modality Therapy; Cyclophosphamide; Cytomegalovirus Infections; Etoposide; Glomerulonephritis, Membranous; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Male; Methotrexate; Middle Aged; Multiple Myeloma; Nephrotic Syndrome; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Prednisone; Rituximab; Sepsis; Staphylococcal Infections; Tacrolimus; Transplantation Conditioning