tacrolimus and Lymphoma

The topical calcineurin inhibitors (TCIs) tacrolimus and pimecrolimus have been used widely as corticosteroid-sparing agents in treating various cutaneous diseases. However, the association between TCIs and risk of malignancy remains controversial. By systematic review and meta-analysis, we aimed to investigate the association between TCIs and lymphoma. Eligible studies in online databases were identified from the date of inception to August 30, 2020. To assess the outcome of TCI-related risk of lymphoma, analysis of cohort studies comparing the incidence of lymphoma with and without treatment with TCIs was performed. Furthermore, the subgroup analyses of Hodgkin lymphoma and non-Hodgkin lymphoma were also conducted. The pooled results revealed that using topical tacrolimus (RR 1.68, 95 % CI 1.39-2.04) or pimecrolimus (RR 1.40, 95 % CI 1.13-1.74) significantly increased the risk of lymphoma. TCI users also showed higher incidence of lymphoma in the range of 0.02-0.09 %, compared to that of 0.02-0.06 % in the control group. Additionally, subgroup analyses showed both tacrolimus (RR 1.89; 95 % CI 1.53-2.32) and pimecrolimus (RR 1.38; 95 % CI 1.09-1.74) had significantly higher risk of non-Hodgkin lymphoma, but no increased risk of Hodgkin lymphoma. In conclusion, TCI-exposed patients have a significantly increased risk of lymphoma, especially non-Hodgkin lymphoma.

Topics: Administration, Topical; Calcineurin Inhibitors; Dermatitis, Atopic; Hodgkin Disease; Humans; Lymphoma; Tacrolimus

Topical calcineurin inhibitors (TCIs), commercially available since 2000-2001, are the first and only topical medications approved for chronic treatment of atopic dermatitis (AD) in pediatric patients and remain a welcomed alternative to topical corticosteroids. In January 2006, the US Food and Drug Administration (FDA) issued a boxed warning requirement based on a theoretical risk of malignancy (including lymphoma) with TCI use. However, in the years since, analyses of epidemiologic and clinical data have failed to demonstrate a causal relationship between TCI use and malignancy or lymphoma risk, especially for pimecrolimus cream. In fact, the observed number of malignancies and lymphomas observed both in post-marketing surveillance and reported to the FDA using its adverse events reporting system is much lower among TCI-exposed patients than the expected number for the general population. Furthermore, among children enrolled in post-marketing pediatric registry studies for both tacrolimus and pimecrolimus followed for up to 5.5 years [10,724 patient-years (PY)] or 6.5 years (16,219 PY), respectively, the observed number of malignancies and lymphomas is very low and similar to the number expected for a sample of similar size in the general population. In addition to reporting these comparative malignancy and lymphoma data, this article provides a historical overview of the boxed warning requirement and critically evaluates the preclinical, clinical, and epidemiological evidence that has thus far failed to substantiate a relationship between TCI use and malignancy. The authors also provide practical clinical advice for optimizing AD management and patient care in the context of the boxed warning.

Topics: Advertising; Animals; Calcineurin Inhibitors; Dermatitis, Atopic; Drug Labeling; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Lymphoma; Risk Factors; Tacrolimus; United States; United States Food and Drug Administration

Cases of lymphoma or cutaneous cancer have been observed following use of topical calcineurin inhibitors (TCIs), but it is unclear whether TCI use increases cancer risk. We used published literature to assess the extent to which atopic dermatitis (AD) or TCI use is associated with lymphoma, melanoma, basal cell carcinoma and squamous cell carcinoma. We searched the literature and summarized the results of all studies that provided data on the absolute or relative frequency of any malignancy among patients with AD or eczema or among patients using TCIs. The relative risk for all lymphoma in broad populations of AD or eczema ranged from 0·7 to 1·8. Available data on lymphoma following TCI use were inconsistent and insufficient to draw a conclusion about the causal role of TCIs. We found no evidence indicating that melanoma or nonmelanoma skin cancer is associated with TCI use. A bias analysis showed that cutaneous T-cell lymphomas initially misdiagnosed and treated as AD would lead to overestimation of the association between TCI use and lymphoma. However, there are only sparse data on specific malignancies among TCI-treated patients. The short duration of typical TCI exposure hinders conclusions about longer exposure. There is insufficient evidence in the epidemiological literature to infer whether TCIs do or do not cause malignancy.

Topics: Administration, Topical; Calcineurin Inhibitors; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Dermatitis, Atopic; Dermatologic Agents; Humans; Lymphoma; Melanoma; Risk Factors; Skin Neoplasms; Tacrolimus

This article reviews if local immunosuppression of atopic dermatitis is associated with an increased risk of cancer - as implicated by a warning issued by the FDA and EMEA health authorities because systemic immunosuppression of transplanted patients leads to a significant increase of non-melanoma skin cancer and lymphoma. So far, no studies support that the use of topical immunosuppression increases the risk of local or systemic cancer.

Topics: Administration, Topical; Adult; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Lymphoma; Risk Factors; Skin Neoplasms; Tacrolimus

More than five years have passed since tacrolimus (Protopic) has been put on the market in Spain. This is sufficient time to reevaluate the successes and failures that this product has had after the great expectations created prior to the time when it was put on the market based on its extensive experimentation in clinical trials and very encouraging results. It is also time to reconsider the future of the indications and uses of tacrolimus, to reconsider our personal experiences with it and to offer answers to the new questions that have arisen after five years of using the product. Tacrolimus was sold for topical use in the treatment of atopic dermatitis. Since atopic dermatitis (AD) is a disease that affects children more frequently, tacrolimus is a product oriented directly toward use in children. This entails some added concerns. In this article, we review the most relevant findings that have arisen in the last five years in regards to the treatment of AD with tacrolimus in children.

Topics: Adolescent; Adrenal Cortex Hormones; Age Factors; Calcineurin Inhibitors; Child; Child, Preschool; Clinical Trials as Topic; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Infant; Lymphoma; Retrospective Studies; Skin Neoplasms; Spain; Tacrolimus

Tacrolimus ointment is a nonsteroid treatment for atopic dermatitis which is both effective and has a minimal side-effect profile. However, some clinicians may be reluctant to use tacrolimus ointment due to the "unknown risks", meaning those that have not been uncovered in human studies conducted thus far. Therefore, the available animal data regarding the "unknown risks" of topical tacrolimus therapy are reviewed, and a discussion of the interpretation of this available but limited data is presented.. Some of the fear on the part of clinicians regarding the use of topical tacrolimus may come from the results of animal studies which showed an increase in lymphoma and UV-induced skin cancer after treatment with topical tacrolimus in animal models of carcinogenesis. However, rigorous assessment of these studies suggest that it is somewhat likely that these represent a species-specific response to tacrolimus in an animal already predisposed to tumor formation, and therefore may not be relevant in assessing the possibility of an increased human health risk.. Animal and human studies suggest that topical tacrolimus is a safe alternative to topical steroids, with the major known adverse effect being a transient burning sensation, compared with the known adverse effects of topical steroids, including long-lasting ones. Therefore, in the opinion of the authors, currently available data, including animal studies, does not suggest that "unknown risks" of topical tacrolimus need be any more concerning than the known side-effects of the topical steroids.

Topics: Administration, Topical; Animals; Dermatitis, Atopic; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Lymphoma; Skin Absorption; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Atopic dermatitis is a chronic, highly pruritic, and frequently recurring inflammatory skin disease that can be burdensome to affected individuals as well as to their family members, the health care system, and society as a whole. Immunomodulatory agents, such as topical corticosteroids and topical calcineurin inhibitors (TCIs), target the underlying immunopathology of atopic dermatitis and are the foundation of pharmacologic treatment for disease exacerbations. Recent recommendations from the United States Food and Drug Administration prompted the addition of a black-box warning and medication guide for tacrolimus ointment and pimecrolimus cream (both TCIs). The recommendations were based on a theoretical risk of malignancy derived from safety profiles, animal data, and reported cases of malignancy from clinical trials and postmarketing safety surveillance of oral calcineurin inhibitors. We know of no data that suggest that TCI use increases the risk of malignancy. Several dermatologic associations have issued statements supporting the safety of TCIs, and independent oncology experts have concluded that reported lymphomas were not related to TCI use. The black-box warning added to the TCI prescribing information also states that no causal link has been established. Effective treatment of atopic dermatitis can help alleviate the burden this disease imposes, and TCIs remain important treatment options.

Topics: Animals; Calcineurin Inhibitors; Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Lymphoma; Product Surveillance, Postmarketing; Tacrolimus

The topical immunomodulators tacrolimus and pimecrolimus were approved for the treatment of atopic dermatitis in 2000 and 2001, respectively. However, on 20 January 2006, the US FDA approved a 'black box' warning for these agents because of concerns regarding a possible link to development of malignancy. These concerns were based upon the known mechanism of action of this drug class, the results of animal studies, and case reports. This article provides an overview of the data that led to the approval by the FDA of a 'black box' warning and concludes that physicians, patients, and caregivers should feel confident about using tacrolimus and pimecrolimus for atopic dermatitis so long as they follow the FDA guidelines.

Topics: Administration, Topical; Animals; Carcinogenicity Tests; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Lymphoma; Models, Animal; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Atopic eczema is a chronic inflammatory skin disorder with a relapsing and remitting course. For many decades,topical corticosteroids have been the mainstay therapy for atopic dermatitis. After the introduction of calcineurin inhibitors as a corticosteroid-free alternative, there were high expectations. After the black box warning from the FDA regarding the potential theoretical risk for developing neoplasia under treatment with calcineurin inhibitors, patients and physicians became uncertain about its safety, regardless of the fact that current scientific data do not support increased concern for risk of malignancy.

Topics: Administration, Topical; Adult; Animals; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Infant; Lymphoma; Product Surveillance, Postmarketing; Skin Neoplasms; Tacrolimus

Topics: Administration, Topical; Adult; Adverse Drug Reaction Reporting Systems; Allergy and Immunology; Attitude of Health Personnel; Attitude to Health; Causality; Child; Dermatitis, Atopic; Drug Labeling; Fear; Humans; Lymphoma; Lymphoproliferative Disorders; Neoplasms; Patient Acceptance of Health Care; Patients; Physicians; Quality of Life; Skin Neoplasms; Societies, Medical; Tacrolimus

Extracorporeal photopheresis (ECP) is an immunomodulatory cellular therapy which has been shown to induce a tolerogenic state in patients with acute and chronic graft-vs-host disease. ECOG-ACRIN explored the activity of ECP as a part of a reduced intensity conditioning regimen in two multicenter trials in patients with MDS (E1902) and lymphomas (E1402). While both studies closed before completing accrual, we report results in 23 patients (17 MDS and 6 lymphoma).. Patients received 2 days of ECP followed by pentostatin 4 mg/m2 /day for two consecutive days, followed by 600 cGy of total body irradiation prior to stem cell infusion. Immunosuppression for aGVHD was infusional cyclosporine A or tacrolimus and methotrexate on day +1, +3, with mycophenolate mofetil starting on day 100 for chronic GVHD prophylaxis.. All patients engrafted, with median time to neutrophil and platelet engraftment of 15-18 days and 10-18 days respectively. Grade 3 or 4 aGVHD occurred in 13% and chronic extensive GVHD in 30%.. These studies demonstrate that ECP/pentostatin/TBI is well tolerated and associated with adequate engraftment of neutrophils and platelets in patients with lymphomas and MDS.

Topics: Adult; Allografts; Cyclosporine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Methotrexate; Middle Aged; Myelodysplastic Syndromes; Pentostatin; Photopheresis; Tacrolimus; Transplantation Conditioning; Whole-Body Irradiation

The current standard of care for patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is high-dose conditioning followed by autologous stem cell transplantation (ASCT). For some patients (ie, those with highest-risk disease, insufficient stem cell numbers after mobilization, or bone marrow involvement) allogeneic hematopoietic cell transplantation (alloHCT) offers the potential for cure. However, the majority of patients undergoing alloHCT receive reduced-intensity conditioning as a preparative regimen, and studies assessing outcomes of patients after alloHCT with myeloablative conditioning are limited. In this retrospective study, we reviewed outcomes of 22 patients with recurrent and refractory NHL who underwent alloHCT with myeloablative BEAM conditioning and received tacrolimus/sirolimus as graft-versus-host disease (GVHD) prophylaxis at City of Hope between 2005 and 2018. With a median follow-up of 2.6 years (range, 1.0 to 11.2 years), the probabilities of 2-year overall survival and event-free survival were 58.3% (95% confidence interval [CI], 35.0% to 75.8%) and 45.5% (95% CI, 24.4% to 64.3%), respectively. The cumulative incidence of grade II to IV acute GVHD was 45.5% (95% CI, 23.8% to 64.9%), with only 1 patient developing grade IV acute GVHD. However, chronic GVHD was seen in 55% of the patients (n = 12). Of the 22 eligible patients, 2 had undergone previous ASCT and 2 had undergone previous alloHCT. Both patients with previous ASCT developed severe regimen-related toxicity. Patients who underwent alloHCT with chemorefractory disease had lower survival rates, with 1-year OS and EFS of 44.4% and 33.0%, respectively. In conclusion, alloHCT with a BEAM preparative regimen and tacrolimus/sirolimus-based GVHD should be considered as an alternative option for patients with highest-risk lymphoma whose outcomes are expectedly poor after ASCT.

Topics: Adolescent; Adult; Allografts; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Lymphoma; Male; Melphalan; Middle Aged; Podophyllotoxin; Sirolimus; Survival Rate; Tacrolimus; Transplantation Conditioning

Inhibition of the mechanistic target of rapamycin (mTOR) pathway has clinical activity in lymphoma. The mTOR inhibitor sirolimus has been used in the prevention and treatment of graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (HSCT). A retrospective study suggested that patients with lymphoma undergoing reduced intensity conditioning (RIC) HSCT who received sirolimus as part of their GVHD prophylaxis regimen had a lower rate of relapse. We therefore performed a multicentre randomized trial comparing tacrolimus, sirolimus and methotrexate to standard regimens in adult patients undergoing RIC HSCT for lymphoma in order to assess the possible benefit of sirolimus on HSCT outcome. 139 patients were randomized. There was no difference overall in 2-year overall survival, progression-free survival, relapse, non-relapse mortality or chronic GVHD. However, the sirolimus-containing arm had a significantly lower incidence of grade II-IV acute GVHD (9% vs. 25%, P = 0·015), which was more marked for unrelated donor grafts. In conclusion, the addition of sirolimus for GVHD prophylaxis in RIC HSCT is associated with no increased overall toxicity and a lower risk of acute GVHD, although it does not improve survival; this regimen is an acceptable option for GVHD prevention in RIC HSCT. This trial is registered at clinicaltrials.gov (NCT00928018).

Topics: Adolescent; Adult; Aged; Allografts; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Methotrexate; Middle Aged; Sirolimus; Tacrolimus; Transplantation Conditioning

Many patients with lymphoma relapse after autologous stem cell transplantation (AutoSCT). These patients are often considered for allogeneic stem cell transplantation (AlloSCT) if remission can be achieved. If a tandem approach was organized, some cases of relapse might be prevented. We conducted a phase II trial of tandem AutoSCT followed by reduced-intensity conditioning (RIC) AlloSCT for patients with high-risk lymphoma. High-dose chemotherapy was given with busulfan, cyclophosphamide, and etoposide. AlloSCT was composed of RIC with busulfan/fludarabine and tacrolimus, sirolimus, and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Donors were fully matched related or unrelated donors. AlloSCT was performed any time between 40 days and 6 months after AutoSCT. Forty-two patients were enrolled, and all patients underwent AutoSCT. RIC AlloSCT was performed in 29 patients. In the 29 patients who underwent tandem transplant, median time from AutoSCT to AlloSCT was 96 days (range, 48 to 169). The 6-month cumulative incidence of grades II to IV acute GVHD was 13.8% (90% confidence interval [CI], 5.3% to 26.3%). Cumulative incidence of chronic GVHD at 1 year was 37.9% (90% CI, 23.1% to 52.7%). Nonrelapse mortality at 2 years after AlloSCT was 11.1% (90% CI, 3.5% to 23.6%). At a median follow-up of 30 months (range, 17.1 to 51.5) for the entire group, the 2-year progression-free survival rate was 64% (90% CI, 50% to 75%) and the 2-year overall survival rate was 69% (90% CI, 43% to 85%). For the 29 patients who underwent tandem SCT, the 2-year progression-free survival rate was 72% (90% CI, 55% to 83%) and the 2-year OS rate was 89% (90% CI, 74% to 96%). Tandem AutoSCT-RIC AlloSCT appears to be safe and effective in patients with high-risk lymphoma. Prospective trials using such an approach in specific lymphoma subtypes are warranted.

Topics: Adult; Aged; Allografts; Antineoplastic Combined Chemotherapy Protocols; Autografts; Busulfan; Disease-Free Survival; Female; Follow-Up Studies; Graft vs Host Disease; Humans; Lymphoma; Male; Methotrexate; Middle Aged; Sirolimus; Stem Cell Transplantation; Survival Rate; Tacrolimus; Vidarabine

The study is a randomized phase II trial investigating graft-versus-host disease prophylaxis after non-myeloablative (90 mg/m(2) fludarabine and 2 Gy total body irradiation) human leukocyte antigen matched unrelated donor transplantation. Patients were randomized as follows: arm 1 - tacrolimus 180 days and mycophenolate mofetil 95 days (n=69); arm 2 - tacrolimus 150 days and mycophenolate mofetil 180 days (n=71); arm 3 - tacrolimus 150 days, mycophenolate mofetil 180 days and sirolimus 80 days (n=68). All patients had sustained engraftment. Grade II-IV acute graft-versus-host disease rates in the 3 arms were 64%, 48% and 47% at Day 150, respectively (arm 3 vs. arm 1 (hazard ratio 0.62; P=0.04). Owing to the decreased incidence of acute graft-versus-host disease, systemic steroid use was lower at Day 150 in arm 3 (32% vs. 55% in arm 1 and 49% in arm 2; overall P=0.009 by hazard ratio analysis). The Day 150 incidence of cytomegalovirus reactivation was lower in arm 3 (arm 1, 54%; arm 2, 47%; arm 3, 22%; overall P=0.002 by hazard ratio analysis). Non-relapse mortality was comparable in the three arms at two years (arm 1, 26%; arm 2, 23%; arm 3, 18%). Toxicity rates and other outcome measures were similar between the three arms. The addition of sirolimus to tacrolimus and mycophenolate mofetil is safe and associated with lower incidence of acute graft-versus-host disease and cytomegalovirus reactivation. (clinicaltrials.gov identifier: 00105001).

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Graft Rejection; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Leukemia; Lymphoma; Male; Middle Aged; Mycophenolic Acid; Recurrence; Sirolimus; Tacrolimus; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Unrelated Donors; Young Adult

Antifungal prophylaxis is shown to decrease the risk of invasive fungal infection (IFI) after hematopoietic stem-cell transplantation (HSCT). Posaconazole has been approved for prophylaxis in HSCT. However, it is only available orally given three times per day. We evaluated once weekly intravenous amphotericin B lipid complex (ABLC), given its broad-spectrum antifungal activity and prolonged half-life (172 hr), as an alternative prophylaxis in HSCT.. We prospectively randomized allogeneic HSCT patients to receive 7.5 mg/kg of intravenous ABLC weekly or 200 mg of posaconazole orally three times per day as prophylaxis for up to 6 weeks. Endpoints were the incidence of IFI and drug-related toxicities. ABLC was discontinued if creatinine level increased to two times the baseline or greater.. A total of 46 patients were randomized; 40 received at least one dose of the drug and were included in the analysis: 19 received ABLC and 21 received posaconazole. All patients received tacrolimus. Apache II score, neutropenia, and creatinine, bilirubin, and alanine aminotransferase levels were similar in both groups at baseline. One patient in the ABLC arm and none in posaconazole arm developed IFI (5% vs. 0%, P=0.48). More patients in the ABLC arm doubled their serum creatinine (53% vs. 5%, P=0.001) necessitating discontinuation of the study drug.. High-dose prophylactic ABLC in HSCT was associated with nephrotoxicity that could be aggravated by the concomitant use of other nephrotoxic agents. Further studies are needed to evaluate the role of weekly high-dose ABLC as antifungal prophylaxis in patients at lower risk for nephrotoxicity.

Topics: Administration, Oral; Adult; Aged; Amphotericin B; Antifungal Agents; Female; Hematopoietic Stem Cell Transplantation; Humans; Infusions, Intravenous; Leukemia; Lipids; Lymphoma; Male; Middle Aged; Mycoses; Prospective Studies; Risk; Tacrolimus; Time Factors; Transplantation, Homologous; Triazoles

A phase HI comparative trial of tacrolimus- vs. cyclosporine-based graft-vs.-host disease (GVHD) prophylaxis for human leukocyte antigen (HLA)-identical sibling bone marrow transplantation showed less GVHD but poorer survival in the tacrolimus arm. To test the comparability of the two treatment arms with respect to baseline survival prognosis, a matched control study using exclusively cyclosporine-treated patients from the International Bone Marrow Transplant Registry (IBMTR) database was performed. Controls were matched (2:1) based on age (within 5 years), disease, and pretransplant disease status. Two-year survival for tacrolimus-treated clinical trial patients was similar to that of their cyclosporine-treated matched controls (27 and 24%, respectively), and 2-year survival of the cyclosporine-treated clinical trial patients was similar to that of their cyclosporine-treated matched IBMTR controls (42 and 45%, respectively). Consistent with the clinical trial results, the cyclosporine-treated IBMTR controls matched to the tacrolimus group had significantly poorer 2-year survival than the cyclosporine-treated IBMTR controls matched to the cyclosporine group (24 and 45%, respectively; p < 0.01). No significant difference was seen in GVHD between the cyclosporine-treated clinical trial patients and their matched controls; however, the tacrolimus-treated clinical trial patients had significantly less GVHD than their cyclosporine-treated IBMTR controls (p < 0.01). These results support the hypothesis that the survival difference in the phase III trial resulted from an imbalance in the underlying risk factors for death in the two groups rather than from the randomized immunosuppressive regimen.

Topics: Adolescent; Adult; Bone Marrow Transplantation; Case-Control Studies; Cyclosporine; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia; Lymphoma; Male; Middle Aged; Multiple Myeloma; Prospective Studies; Survival; Tacrolimus

This follow-up multicenter analysis is based on 362 pancreas allograft recipients at 14 institutions who were given tacrolimus between 1 May 1994 and 15 November 1995. Three groups were studied: (1) recipients given tacrolimus initially for induction and maintenance therapy (n = 250; 215 without, 35 with, a concurrent bone marrow transplant), (2) recipients who converted to tacrolimus for rescue or rejection therapy (n = 89), and (3) recipients who converted to tacrolimus for other reasons (n = 23). Of 215 recipients without a bone marrow transplant in the induction group, 166 (77%) underwent a simultaneous pancreas-kidney transplant (SPK), 29 (14%) a pancreas transplant alone (PTA), and 20 (9%) a pancreas after previous kidney transplant (PAK). Initial antibody therapy was given to 185 (86%) recipients. All 215 received tacrolimus and prednisone; 202 (94%) also received azathioprine (AZA) and 11 (5%) mycophenolate mofetil (MMF). The most common side effects of tacrolimus were neurotoxicity in 21%, nephrotoxicity in 21%, gastrointestinal (GI) toxicity in 13%, and diabetogenicity in 13% of these recipients. No recipient in this group developed new-onset insulin-dependent diabetes mellitus. Of 89 recipients in the rescue group, 71 (79%) had an SPK, 11 (13%) a PTA, and 7 (8%) a PAK. Before conversion, all had been on cyclosporine (CsA)-based immunosuppression; 74% of them had 2 or more rejection episodes previously. The most common side effects were nephrotoxicity in 27%, neurotoxicity in 26%, GI toxicity in 18%, and diabetogenicity in 8% of these recipients. No recipient in this group developed new-onset insulin-dependent diabetes mellitus. In the induction group patient survival at 1 yr was 98% for SPK, 79% for PTA, and 100% for PAK recipients. According to a matched-pair analysis, pancreas graft survival for SPK recipients at 1 yr was 88% with tacrolimus vs. 73% with CsA (p = 0.002); for PTA recipients, 68% vs. 70% (p > 0.35); and for PAK recipients, 85% vs. 65% (p = 0.13). Graft loss from rejection was not different with tacrolimus vs. CsA in all 3 pancreas recipient categories. At 1 yr, 17% of recipients had converted from tacrolimus to CsA for diabetogenicity, nephrotoxicity, or rejection; 23% had converted from AZA to MMF. The incidence of post-transplant lymphoma was < 2%. In the rescue group, patient survival rates at 1 yr were 96% for SPK, 100% for PTA, and 86% for PAK recipients (p < 0.08). Pancreas graft survival at 1 yr was 89% for SPK, 58% for

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Bone Marrow Transplantation; Case-Control Studies; Cyclosporine; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Gastrointestinal Diseases; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Diseases; Kidney Transplantation; Lymphoma; Male; Muromonab-CD3; Mycophenolic Acid; Nervous System Diseases; Pancreas Transplantation; Prednisone; Prospective Studies; Randomized Controlled Trials as Topic; Survival Rate; Tacrolimus; Transplantation, Homologous

Although conventional immunosuppression after liver transplantation consists of cyclosporine A (CsA), steroids, and azathioprine, recently introduced protocols entail CsA-based quadruple induction protocols or tacrolimus-based combinations. These protocols aim to reduce the rejection rate and the considerable morbidity related to the side effects of additional immunosuppressive treatment, but have not yet been analyzed regarding their long term de novo neoplastic risk.. From September 1988 to May 1994, 500 liver transplantations were performed in 458 patients. The median follow-up was 50 months (range, 0.3-97 months) for all patients. Conventional triple therapy was implemented in 25 patients, CsA-based quadruple induction therapy using an antilymphocyte globulin preparation (ATG) in 190 patients, an interleukin-2 receptor antibody (BT563) in 141 patients, and tacrolimus-based dual or triple immunosuppression in 102 patients. The different protocols were evaluated in four randomized and two nonrandomized prospective trials.. De novo neoplasias were detected in 33 patients (7.2%) and were comprised of lymphomas (n = 7), skin malignancies (n = 8 lesions in 7 patients), intraepithelial neoplasias of the cervix uteri (n = 7), breast carcinoma (n = 3), lung carcinoma (n = 3), and other malignancies (n = 6). The incidence of de novo neoplasias did not differ in the different trial arms. Only a positive T-crossmatch and a low CD4+/CD8+ ratio in patients receiving CsA-based immunosuppression demonstrated a significant correlation with the development of a de novo tumor in a multivariant logistic regression analysis.. The development of de novo neoplastic diseases after liver transplantation with the use of CsA-based quadruple induction protocols or tacrolimus-based regimens for immunosuppresion was assessed over the long term. Recently introduced immunosuppressive protocols did not alter the posttransplant de novo tumor rate. Patients with a low CD4+/CD8+ ratio during CsA-based therapy or a positive T-crossmatch were identified to be at an increased risk for the development of a de novo malignancy.

Topics: Antibodies, Monoclonal; Antilymphocyte Serum; Clinical Trials as Topic; Cyclosporine; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoma; Neoplasms, Second Primary; Prospective Studies; Randomized Controlled Trials as Topic; Receptors, Interleukin-2; Skin Neoplasms; Tacrolimus; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Thirty adults with leukemia or lymphoma undergoing marrow transplantation from HLA-compatible unrelated donors received tacrolimus (FK506), a new immunosuppressive macrolide lactone, and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 36 years (range 21 to 49 years). Twenty-four patients had advanced disease, and 11 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/d intravenously (i.v.) by continuous infusion from day -2, converted to oral at four times the i.v. dose following engraftment, and continued through day 180 posttransplant. Methotrexate 5 mg/m2 was given i.v. on days 1, 3, 6, and 11. All patients engrafted. Grades 2-4 GVHD occurred in 34% (95% CI, 17% to 52%), and grades 3-4 GVHD in 17% (95% CI, 3% to 31%). Mild renal toxicity was common before day 100; 63% of patients had a doubling of creatinine, and 52% had a peak creatinine greater than 2 mg/dL, but only one patient was dialyzed. The median last i.v. dose of tacrolimus was 53% of the scheduled dose, and the median oral dose on day 100 was 41% of that scheduled. Overall survival at 1 year was 47% (95% CI, 27% to 66%). We conclude that tacrolimus can be combined safely with minidose methotrexate, and the combination has substantial activity in preventing acute GVHD after unrelated donor marrow transplantation.

Topics: Actuarial Analysis; Administration, Oral; Adult; Anemia, Refractory, with Excess of Blasts; Bone Marrow Transplantation; Creatinine; Disease-Free Survival; Drug Administration Schedule; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney Diseases; Leukemia; Lymphoma; Male; Methotrexate; Middle Aged; Salvage Therapy; Survival Analysis; Tacrolimus; Transplantation Conditioning

The cancer risks associated with treatment with topical calcineurin inhibitors (TCIs) in patients with atopic dermatitis (AD) remain controversial, and limited evidence exists regarding the cancer risks among patients with AD treated with TCIs in Asian populations.. This study identified the association between TCI use and the risks of developing all cancers, lymphoma, skin cancers, and other cancers.. This study was a nationwide, population-based, retrospective cohort study.. Taiwan's National Health Insurance Research Database.. Patients diagnosed at least twice with ICD-9 code 691 or at least one time with ICD-9 codes 691 or 692.9 within 1 year between 1 January 2003 and 31 December 2010 were included and followed until 31 December 2018. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using the Cox proportional hazard ratio model.. Patients using tacrolimus or pimecrolimus were identified in the National Health Insurance Research Database and compared with patients using topical corticosteroids (TCSs).. The main outcomes were hazard ratios (HRs) of cancer diagnoses and associated outcomes obtained from the Taiwan Cancer Registry database.. After propensity score (PS) matching, the final cohort included 195,925 patients with AD, including 39,185 who were initial TCI users and 156,740 who were TCS users. Propensity score matching was performed according to age, sex, index year, and Charlson Comorbidity Index using a ratio of 1:4. Except for leukemia, HR and 95% CI showed no significant associations between TCI use and the risk of developing all cancer, lymphoma, skin cancers, and other cancers. Sensitivity analysis showed that the lag time HRs for every cancer subtype continued to show no significant association between TCI use and cancer risk, except for leukemia.. Our study found no evidence to support an association between TCI use and the risks of almost all cancers compared with TCS use in patients with AD, but physicians should be aware of potentially higher risks of leukemia with TCI use. This study represents the first population-based study focused on the cancer risk of TCI use among patients with AD in an Asian population.

Topics: Calcineurin Inhibitors; Dermatitis, Atopic; Humans; Leukemia; Lymphoma; Retrospective Studies; Skin Neoplasms; Tacrolimus

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) occur in patients receiving immunosuppressive drugs for autoimmune diseases; however, their clinicopathological and genetic features remain unknown. In the present study, we analysed 67 patients with OIIA-LPDs, including 36 with diffuse large B-cell lymphoma (DLBCL)-type and 19 with Hodgkin lymphoma (HL)-type. After discontinuation of immunosuppressive drugs, regression without relapse was achieved in 22 of 58 patients. Spontaneous regression was associated with Epstein-Barr virus positivity in DLBCL-type (P = 0·013). The 2-year overall survival and progression-free survival (PFS) at a median follow-up of 32·4 months were 92·7% and 72·1% respectively. Furthermore, a significant difference in the 2-year PFS was seen between patients with DLBCL-type and HL-type OIIA-LPDs (81·0% vs. 40·9% respectively, P = 0·021). In targeted sequencing of 47 genes in tumour-derived DNA from 20 DLBCL-type OIIA-LPD samples, histone-lysine N-methyltransferase 2D (KMT2D; eight, 40%) and tumour necrosis factor receptor superfamily member 14 (TNFRSF14; six, 30%) were the most frequently mutated genes. TNF alpha-induced protein 3 (TNFAIP3) mutations were present in four patients (20%) with DLBCL-type OIIA-LPD. Cases with DLBCL-type OIIA-LPD harbouring TNFAIP3 mutations had shorter PFS and required early initiation of first chemotherapy. There were no significant factors for spontaneous regression or response rates according to the presence of mutations. Overall, OIIA-LPDs, especially DLBCL-types, showed favourable prognoses.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Histone-Lysine N-Methyltransferase; Hodgkin Disease; Humans; Iatrogenic Disease; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Kaplan-Meier Estimate; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Myeloid-Lymphoid Leukemia Protein; Prognosis; Progression-Free Survival; Proportional Hazards Models; Receptors, Tumor Necrosis Factor, Member 14; Retrospective Studies; Rheumatic Diseases; Tacrolimus; Tumor Necrosis Factor alpha-Induced Protein 3

Posttransplant lymphoproliferative disorder (PTLD) occurs in 1% to 3% of adult renal transplant recipients (RTRs). PTLD has a heterogeneous presentation and is often associated with Epstein-Barr virus (EBV) and immunosuppression. We present a descriptive case series of 16 RTRs who demonstrate a variety of PTLD manifestations. Fifty-six percent received rabbit antithymocyte globulin induction, and 37.5% received basiliximab. Maintenance immunosuppression included glucocorticoids, tacrolimus, and mycophenolate mofetil. Median time from transplantation to PTLD diagnosis was 96.5 months. PTLD involved a single site in 44% of RTRs and multiple sites in 56%. PTLD was localized to the gastrointestinal tract in 9 RTRs, in lymph nodes in 9, central nervous system in 4, bone marrow in 3, skin in 3, lungs in 2, perinephric space in 2, mediastinum in 1, and native kidney in 1. PTLD was EBV positive in 8 RTRs, monomorphic/monoclonal in 14, and of B-cell lineage in 13. Three RTRs had T-cell PTLD. Immunosuppressive agents, except glucocorticoids, were discontinued at diagnosis. Treatment was chemotherapy either alone (in 14 RTRs) or in combination with radiation. Complete remission was achieved in 62.5% of RTRs. Renal dysfunction developed in 62.5% of RTRs, and 4 received dialysis. The overall mortality rate was 62.5%, with median time of death 6.5 months after diagnosis. PTLD that was EBV negative and had T-cell involvement presented with aggressive disease and a higher mortality. Clinicians should be aware of the various PTLD manifestations. Early diagnosis and a multidisciplinary approach to treatment is crucial for improved patient outcomes.

Topics: Adult; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lymphoma; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Postoperative Complications; Renal Dialysis; Tacrolimus; Treatment Outcome

Heart transplantation has been an option for children in Sweden since 1989. As our unit faced an increased rate of post-transplant lymphoproliferative disorder, the objective of the study was to identify possible risk factors.. This is a retrospective study of all children aged 0-18 years who underwent heart transplantation in Gothenburg from 1989 to 2014.. A total of 71 children underwent heart transplantation. The overall incidence of post-transplant lymphoproliferative disorder was 14% (10/71); however, 17% (6/36) of those undergoing transplantation after 2007 developed lymphoma, compared with only 10% (4/35) of transplantation cases before 2007 (p=0.85). The mean age at transplantation was 9 years (0-17). The mean post-transplant follow-up time was 5.5 years (0.5-21.9) in the group that developed post-transplant lymphoproliferative disorder, compared with 10.2 years (0.02-25.2) in those who did not. In our study group, risk factors for post-transplant lymphoproliferative disorder were surgically palliated CHD (p=0.0005), sternotomy during infancy (p⩽0.0001), hypoplastic left ventricle (p=0.0001), number of surgical events (p=0.0022), mismatch concerning Epstein-Barr virus infection - that is, a positive donor-negative recipient (p⩽0.0001) - and immunosuppressive treatment with tacrolimus compared with ciclosporine (p=0.028). Discussion This study has three major findings. First, post-transplant lymphoproliferative disorder only developed in subjects born with CHD. Second, the vast majority (9/10) of the subjects developing the disorder had undergone sternotomy as infants. Third, the number of surgical events correlated with a higher risk for developing post-transplant lymphoproliferative disorder.

Topics: Adolescent; Child; Child, Preschool; Female; Heart Defects, Congenital; Heart Transplantation; Heart Ventricles; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Lymphoma; Lymphoproliferative Disorders; Male; Postoperative Complications; Proportional Hazards Models; Retrospective Studies; Risk Factors; Sternotomy; Sweden; Tacrolimus

Recently, haploidentical transplantations have been performed with unmanipulated BM or PBSC. This approach is becoming more widely adopted with the use of PTCY. However, there is limited evidence about this approach in children. We present 15 children who received 16 haploidentical HSCT with unmanipulated BM or PBSC using PTCY for GVHD prophylaxis. Post-transplant CY(50 mg/kg IV) was given on the third and fifth day, and CsA or tacrolimus with MMF or MP was also used for GVHD prophylaxis. All patients engrafted at a median of 16 and 18 days for neutrophil and thrombocyte recovery, respectively. Grades II-III acute GVHD developed in seven patients, and mild chronic GVHD was found in two patients. Two patients died within the first 100 days due to sepsis (TRM 12.5%). Eleven patients are currently alive, with a median follow-up of 12 months (range 6-22 months). The 12-month OS and DFS were 75 ± 10.8% and 68.8 ± 11.6%, respectively. Our results with these high-risk patients are encouraging for haploidentical HSCT in pediatric patients. Future studies should continue to assess haploidentical HSCT, including comparison of other modalities, in a primary pediatric population.

Topics: Adolescent; Blood Platelets; Child; Child, Preschool; Cyclophosphamide; Cyclosporine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Lymphoma; Male; Methylprednisolone; Mycophenolic Acid; Neutrophils; Retrospective Studies; Risk; Sepsis; Tacrolimus; Tissue Donors; Transplantation Conditioning

Topics: Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Humans; Immunosuppressive Agents; Infant; Lymphoma; Skin Neoplasms; Sunlight; Tacrolimus

Epstein-Barr virus (EBV)-associated posttransplant lymphoma (PTLD) is a major cause of morbidity/mortality after hematopoietic stem cell (SCT) or solid organ (SOT) transplant. Adoptive immunotherapy with EBV-specific cytotoxic lymphocytes (CTLs), although effective in SCT, is less successful after SOT where lifelong immunosuppression therapy is necessary. We have genetically engineered EBV-CTLs to render them resistant to calcineurin (CN) inhibitor FK506 through retroviral transfer of a calcineurin A mutant (CNA12). Here we examined whether or not FK506-resistant EBV-CTLs control EBV-driven tumor progression in the presence of immunosuppression in a xenogeneic mouse model. NOD/SCID/IL2rγ(null) mice bearing human B-cell lymphoma were injected with autologous CTLs transduced with either CNA12 or eGFP in the presence/absence of FK506. Adoptive transfer of autologous CNA12-CTLs induced dramatic lymphoma regression despite the presence of FK506, whereas eGFP-CTLs did not. CNA12-CTLs persisted longer, homed to the tumor, and expanded more than eGFP-CTLs in mice treated with FK506. Mice receiving CNA12-CTLs and treated with FK506 survived significantly longer than control-treated animals. Our results demonstrate that CNA12-CTL induce regression of EBV-associated tumors in vivo despite ongoing immunosuppression. Clinical application of this novel approach may enhance the efficacy of adoptive transfer of EBV-CTL in SOT patients developing PTLD without the need for reduction in immunosuppressive therapy.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Drug Resistance; Epstein-Barr Virus Infections; Genetic Engineering; Genetic Therapy; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Immunotherapy, Adoptive; Lymphoma; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; T-Lymphocytes, Cytotoxic; Tacrolimus; Transduction, Genetic

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (PTLD) remains a major cause of morbidity and mortality after hematopoietic stem cell (HSCT) or solid organ transplant (SOT). Strategies to reconstitute immunity by adoptive transfer of EBV-specific cytotoxic T lymphocyte (CTL) therapy while highly effective in the HSCT setting where immunosuppression can be withdrawn have been less successful in the SOT setting where continued immunosuppression therapy is necessary. Additionally, the complexity and time taken to generate EBV-CTLs for adoptive transfer limit the clinical applicability. We have developed a system for the rapid generation of EBV-CTLs resistant to immunosuppression based on selection of interferon-gamma (IFN-γ) secreting EBV-CTLs and retroviral transduction with a calcineurin B mutant. With this methodology, EBV-CTLs resistant to the calcineurin inhibitor Tacrolimus (TAC) can be produced in 14 days. These CTLs show high specificity for EBV with negligible alloreactivity in both proliferation and cytotoxicity assays and are able to proliferate and secrete IFN-γ in response to antigen stimulation in the presence of therapeutic doses of TAC. This strategy will substantially facilitate clinical application of this approach for the treatment of PTLD in SOT recipients.

Topics: Antigens; Calcineurin; Calcineurin Inhibitors; Cell Proliferation; Epstein-Barr Virus Infections; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Humans; Immunologic Memory; Immunosuppression Therapy; Immunotherapy, Adoptive; Interferon-gamma; Leukocytes, Mononuclear; Lymphoma; Mutation; Organ Transplantation; Phenotype; Postoperative Complications; Retroviridae; T-Lymphocytes; T-Lymphocytes, Cytotoxic; Tacrolimus

Post-transplantation lymphoproliferative disorders (PTLD) are a spectrum of diseases defined as polyclonal or monoclonal proliferations of lymphocytes which occur after solid organ transplants. In this study, we report our first experiences with PTLD following liver transplantation in Iran.. We retrospectively analyzed five cases of PTLD which followed liver transplantation among more than 550 liver transplants in our center. Of these, three were pediatric cases and two were adults. The underlying causes were tyrosinemia, autoimmune hepatitis, and progressive familial intrahepatic cholestasis (PFIC) in the three pediatric cases. HCV hepatitis was the primary cause for cirrhosis in one of the adults and the other adult was labeled as cryptogenic cirrhosis. All cases, except for one, developed PTLD during the first year following liver transplantation.. Patients were diagnosed as PTLD, B-cell, MALT and Hodgkin-like (according to the WHO classification of PTLD). The three pediatric patients died despite discontinuation of immunosuppressive drugs and chemotherapy. Fortunately both adult patients, until now, are still alive.. The incidence of PTLD in our center is lower than previous reports from other centers (0.9%), with a 60% mortality rate and worse prognosis in the pediatric age group.

Topics: Adolescent; Adult; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Child, Preschool; Cyclophosphamide; Cyclosporine; Fatal Outcome; Female; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Infant; Iran; Liver Transplantation; Lymphoma; Male; Mycophenolic Acid; Prednisolone; Tacrolimus; Vincristine

A potential risk of lymphoma associated with the use of topical calcineurin inhibitors is debated. We assessed the risk of lymphoma among patients treated with topical pimecrolimus, tacrolimus or corticosteroids.. We conducted a cohort study using health insurance claims data. Cohorts of initiators of topical pimecrolimus, tacrolimus and corticosteroids, along with cohorts of persons with untreated dermatitis and randomly sampled enrollees were identified from January 2002 to June 2006. Lymphomas were identified using insurance claims and adjudicated by medical records review. We adjusted for confounders by propensity score matching.. Among 92,585 pimecrolimus initiators contributing 121,289 person-years of follow-up, we identified 26 lymphomas yielding an incidence of 21/100,000 person-years. This incidence of lymphoma was similar to that among tacrolimus users (rate ratio, RR = 1.16; 95% confidence interval, CI = 0.74-1.82) as well as corticosteroid users (RR = 1.15; 95% CI = 0.49-2.72). All three topical treatments were associated with an increased risk of lymphoma compared with the general population (RR(Pim) = 2.89; RR(Tac) = 2.82; RR(Cort) = 2.10) suggesting increased detection of preexisting lymphomas.. This study did not find an increased risk of lymphoma among initiators of topical pimecrolimus relative to other topical agents during an average follow-up of 1.3 years. Longer-term studies may be needed.

Topics: Administration, Topical; Adolescent; Adult; Aged; Calcineurin Inhibitors; Child; Child, Preschool; Dermatitis, Atopic; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Infant; Lymphoma; Male; Middle Aged; Risk Factors; Tacrolimus; Young Adult

We studied the incidence, risk factors, treatment, and outcomes of post-transplantation lymphoproliferative disorder (PTLD) that occurred at the University of Michigan since 1964.. We identified 7,040 patients who received solid organ transplantation (SOT) and post-transplantation immunosuppressive therapy. Seventy-eight patients developed PTLD.. Diffuse large B-cell lymphoma (n = 43), polymorphic PTLD (n = 10), Hodgkin's lymphoma (n = 7), Burkitts lymphoma (n = 6), plasmacytoma (n = 5), and mucosa-associated lymphoid tissue lymphoma (n = 3) were all over-represented in the SOT population compared with a population sample from the Surveillance, Epidemiology, and End Results (SEER) database; follicular lymphoma (n = 0) was underrepresented. Negative pretransplantation Epstein-Barr virus (EBV) serology was a risk factor for PTLD. Available histologic analysis of tumor tissue showed that 75% were CD20 positive and that 62% were EBV positive; EBV-positive tumors occurred sooner after SOT than EBV-negative tumors (mean, 29 v 66 months). Extralymphatic disease (79%), poor performance status (68%), elevated lactate dehydrogenase (LDH; 71%), and advanced stage (68%) disease were all common at the time of lymphoma diagnosis. Two thirds of patients had a complete response when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone-like chemotherapy (either with or without rituximab). Median overall survival in all patients with PTLD was 8.23 years (95% CI, 2.28 to 30.0 years).. EBV-naïve patients who receive a donor organ from an EBV-infected donor are in the highest-risk situation for PTLD development. Most of these lymphomas are CD20 positive. Follicular lymphoma is unusual. With treatment, survival of patients with PTLD was indistinguishable from that of the SEER population sample.

Topics: Adolescent; Adult; Aged; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunohistochemistry; Immunosuppressive Agents; In Situ Hybridization; Kaplan-Meier Estimate; Lymphoma; Lymphoproliferative Disorders; Male; Michigan; Middle Aged; Organ Transplantation; Risk Factors; RNA, Viral; Tacrolimus; Treatment Outcome; Viral Matrix Proteins

We investigated the pharmacokinetics of oral tacrolimus in 31 hematopoietic cell transplant recipients, identifying 2 subgroups based on the differences between C(0) (trough) and C(max) (maximal) levels: group A (n = 21; 68%) with a C(max)-C(0) value of <10 ng/mL, and group B (n = 10; 32%) with a C(max)-C(0) value of >or=10 ng/mL. Although the C(0) and C(12) values were not significantly different between the 2 groups, the mean area under the concentration curve for 12 hours (AUC(0-12)) was significantly greater in group B than group A (200.9 +/- 36.3 vs 155.1 +/- 43.1 ng.h/mL; P < .05), and the mean half-life was significantly shorter in group B than group A (13.55 +/- 6.70 vs 18.17 +/- 6.30 hours; P < .05). Thus after the oral administration of tacrolimus, we observed a notably high AUC due to high peak level, which we were unable to predict simply by measuring the trough level. A pharmacokinetic analysis of each patient was essential to optimize the oral tacrolimus dose.

Topics: Administration, Oral; Adolescent; Adult; Area Under Curve; Body Weight; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia; Lymphoma; Male; Middle Aged; Multiple Myeloma; Tacrolimus; Young Adult

We analyzed the kinetics of CD3 chimerism in 120 consecutive allogeneic hematopoietic cell transplantation (HCT) recipients receiving alemtuzumab-based conditioning. Fifty-two received fludarabine/melphalan, 44 received fludarabine/busulfan, and 24 received clofarabine/melphalan in addition to alemtuzumab. Post-transplant GVHD prophylaxis consisted of tacrolimus. No prophylactic donor lymphocyte infusion or other interventions were used for mixed donor chimerism (MDC). Bone marrow (BM) and/or peripheral blood (PB) samples were obtained at 30 days, 100 days, 180 days, and 1 year following HCT. On Day 30, 15% of assessable patients had MDC in the CD3 compartment. This had increased to 50% by Day 100, and to 63% by Day 180. MDC predicted for a lower risk of acute (p = 0.08) and particularly of chronic GVHD (p = 0.01). MDC was not associated with subsequent relapse or TRM (p = 0.67 and 0.72, respectively). A decline of more than 15% in CD3 chimerism between Day 30 and Day 180 predicted for a 40% risk of subsequent disease recurrence. The observation of MDC after alemtuzumab conditioning does not by itself constitute a risk factor for relapse and should not be used to guide therapeutic intervention. By contrast, declining donor chimerism between Day 30 and Day 180 is associated with a somewhat increased risk of disease recurrence. The high incidence of MDC after alemtuzumab containing conditioning contributes to the low risk of acute and chronic GVHD.

Topics: Adolescent; Adult; Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; CD3 Complex; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Lymphoma; Middle Aged; Tacrolimus; Time Factors; Transplantation Chimera; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Young Adult

In order to exert their activity, transcription factors must be transported to the nucleus. Certain transcription factors have also been found on mitochondria. Here, the localization of RelB and NFATx in the mitochondrial fractions of normal thymocytes and thymic lymphoma cells is shown for the first time. CREB was only found in the nucleus, while p50 (NFkappaB) was found in both the nucleus and the cytoplasm, but outside the mitochondria. The translocation of transcription factors to the mitochondria is differentially regulated. Unlike RelB, which is always present in the mitochondrial fraction, NFATx appeared on the mitochondria in cells treated with ionomycin together with an immunosuppressant and inhibitor of calcineurin (FK506). This data reveals that the mitochondrial localization of some transcription factors is precisely controlled by a calcium signal sensitive to FK506 in T cells.

Topics: Animals; Cell Line; Cyclic AMP Response Element-Binding Protein; Immunosuppressive Agents; Ionomycin; Ionophores; Lymphoma; Mice; Mice, Transgenic; Mitochondria; NF-kappa B p50 Subunit; NFATC Transcription Factors; T-Lymphocytes; Tacrolimus; Thymus Gland; Transcription Factor RelB

Systemic use of immunosuppressant agents increases the risk of lymphoma in transplantation. We performed a nested case-control study in the PharMetrics database to evaluate the association between topical immunosuppressants and lymphoma in a cohort of patients with atopic dermatitis. We identified cases of lymphoma and randomly selected four controls for each case, matched by length of follow-up. We used conditional logistic regression to calculate odds ratio (OR) and 95% confidence intervals (CIs) of the association between topical immunosuppressants and lymphoma. Two hundred and ninety-four cases of lymphoma occurred in 293,253 patients, 81 in patients younger than 20 years. The adjusted analysis yielded the following OR (95%CI) for: severity (OR 2.4; 95% CI 1.5-3.8), oral steroids 1.5 (1.0-2.4), "super potent" topical steroids 1.2 (0.8-1.8) , "low potency" topical steroids OR 1.1 (0.7-1.6); pimecrolimus 0.8(0.4-1.6), tacrolimus OR 0.8 (0.4-1.7), and concomitant topical steroids, pimecrolimus, and tacrolimus 1.0 (0.3-4.1). We did not find an increased risk of lymphoma in patients treated with topical calcineurin inhibitors. It is difficult to disentangle the effects of severity of disease on outcome versus the true effects of drugs. However, in the adjusted analysis, severity of AD was the main factor associated with an increased risk of lymphoma.

Topics: Administration, Topical; Adolescent; Adult; Calcineurin Inhibitors; Case-Control Studies; Child; Child, Preschool; Cohort Studies; Databases, Factual; Dermatitis, Atopic; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Lymphoma; Male; Middle Aged; Risk Assessment; Severity of Illness Index; Steroids; Tacrolimus

Topics: Animals; Antineoplastic Agents; Graft vs Host Disease; Hematology; Humans; Immunosuppressive Agents; Interleukin-2 Receptor alpha Subunit; Leukemia; Leukemia, Myeloid; Lymphoma; Porifera; Sirolimus; Stem Cell Transplantation; Stem Cells; Tacrolimus

Eighteen patients with hematologic malignancies underwent cord blood transplantation (CBT) from unrelated donors after being conditioned with myeloablative or reduced-intensity regimens, and received tacrolimus and methotrexate (15 mg/m(2) on day 1, 10 mg/m(2) on days 3 and 6) as graft-versus-host disease (GVHD) prophylaxis. The median number of nucleated cells in infused cord blood was 2.66 x 10(7)/kg (range 1.90 to 4.15 x 10(7)/kg). Engraftment was achieved in 16 of 18 patients. The median time to absolute neutrophil count >0.5 x 10(9)/L was 21.5 days (range 17 to 32), and the median time to platelet count >2.0 x 10(9)/L was 36 days (range 26 to 57). Of the 16 evaluable patients, five and eight had grades I and II acute GVHD, respectively, and none had grades III/IV acute GVHD. The cumulative incidence of grade II acute GVHD was 44.4%. Chronic GVHD occurred in 7 of 15 evaluable patients: limited type in three patients, extensive type in four patients. Of the 18 patients, 14 were alive and disease-free between 173 and 1514 days after CBT (median 746 days). The probability of disease-free survival at 2 years was 79.1%. These results, although in a retrospective study, suggested that tacrolimus and short-term methotrexate effectively prevented the occurrence of severe acute GVHD after unrelated CBT, and may contribute to a high survival rate.

Topics: Adult; Cord Blood Stem Cell Transplantation; Disease-Free Survival; Female; Graft vs Host Disease; Hematologic Neoplasms; Humans; Immunosuppressive Agents; Leukemia; Leukocyte Count; Lymphoma; Male; Methotrexate; Middle Aged; Myelodysplastic Syndromes; Neutrophils; Probability; Tacrolimus; Transplantation Conditioning

Nur77 is reported to undergo translocation to mitochondria in response to apoptotic signaling in a variety of cancer cell lines. It was shown that on the mitochondrial membrane, Nur77 interacts with Bcl-2, leading to the conversion of this protein from a protector to a killer with subsequent release of cytochrome c to the cytosol. Here it is shown that in thymic lymphoma cells resistant to calcium-mediated apoptosis, cytochrome c release is abolished despite of Nur77 mitochondrial targeting. However, cytochrome c release and apoptosis can be restored by treatment with FK506. Hence, the molecular target regulation of the sensitivity of lymphoma cells to calcium signaling is associated with cytochrome c release and is FK506 sensitive. These results provide new insight into the role of FK506-sensitive factors as a critical link between calcium signaling and resistance of lymphoma cells to death.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Nucleus; Cytochromes c; Cytoplasm; DNA-Binding Proteins; Immunosuppressive Agents; Lymphoma; Mice; Mitochondria; Nuclear Receptor Subfamily 4, Group A, Member 1; Proto-Oncogene Proteins c-bcl-2; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Signal Transduction; Tacrolimus; Transcription Factors

Topics: Adult; Animals; Child; Child, Preschool; Dermatitis, Atopic; Dermatologic Agents; Eczema; Humans; Immunosuppressive Agents; Lymphoma; Skin Neoplasms; Tacrolimus

Topics: Animals; Child; Dermatitis, Atopic; Dermatologic Agents; Eczema; Haplorhini; Humans; Leukemia; Lymphoma; Mice; Skin Neoplasms; Tacrolimus

Topics: Administration, Topical; Adolescent; Adult; Age Factors; Animals; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Lymphoma; Mice; Neoplasms; Neoplasms, Experimental; Product Surveillance, Postmarketing; Tacrolimus

The development of Epstein-Barr virus (EBV) associated lymphoproliferative disorder (PTLD) is related to EBV genome numbers in serum or plasma and B-cells, and the level of immunosuppression. EBV DNA viremia, defined as presence of EBV genomes in serum or plasma, is common in immunodeficiency. This survey of EBV viremia was performed by real-time polymerase chain reaction (PCR) on consecutive serum samples of 21 patients with acute (n = 3) or chronic liver disease (n = 18) during the first year after liver transplantation (LTX). Cytomegalovirus (CMV) DNA was analyzed with PCR in serum or leukocytes. The levels of EBV and CMV viremia were related to PTLD and the effect of different anti-rejection regimens. All patients were EBV-seropositive pre-LTX. In total, 24 of 152 (16%) samples from 10 of 21 (48%) individuals were EBV positive [five of 11 cyclosporin A (CsA); five of 10 tacrolimus treated cases]. EBV viremia was demonstrated in five of seven patients with OKT3 therapy. The number of EBV DNA positive samples was highest (26%) at 14 days after LTX. In the OKT3 treated groups, the medians of EBV DNA copy numbers were 1600/ml (range 230-7200) and 380/ml (range 120-860) in the CsA and tacrolimus patients, respectively (P < 0.02). One patient developed EBV lymphoma and another one EBV hepatitis 13 months and 24 days post-LTX, respectively. Both patients had received OKT3. Their EBV genome load was not significantly different from what was found in other patients. After ganciclovir therapy, EBV DNA was eradicated from serum in four of five patients for several months. EBV DNA load was not affected by CMV infection or disease. We conclude that presence of EBV in serum is a possible marker of an active infection and an early ganciclovir therapy may be beneficial. Quantification of EBV load offers the potential to implement pre-emptive interventions.

Topics: Adult; Antiviral Agents; Cytomegalovirus; DNA, Viral; Epstein-Barr Virus Infections; Female; Ganciclovir; Gene Dosage; Genome, Viral; Hepatitis, Viral, Human; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoma; Male; Middle Aged; Muromonab-CD3; Postoperative Period; Tacrolimus; Viral Load; Viremia

Thymic lymphoma cells restore their sensitivity to ionomycin-induced apoptosis when treated with FK506 or HA1004. In apoptosis-resistant cells, ionomycin-induced Nur77 strongly binds DNA during the first 2 h of response, in contrast to lymphoma cells treated with ionomycin together with FK506 or HA1004, which undergo massive apoptosis. We show that Nur77 could discriminate between calcium signals sensitive to FK506 and those sensitive to HA1004, as the inhibitors differentially regulate the kinetics of Nur77 nuclear import, and FK506, unlike HA1004, inhibits Nur77 DNA-binding activity. In the presence of HA1004, NBRE binding by Nur77 protein increases with time (6 h vs 2 h), whereas the final outcome of both inhibitors is apoptosis of thymic lymphoma cells.

Topics: Active Transport, Cell Nucleus; Animals; Cell Line, Tumor; Cell Nucleus; DNA-Binding Proteins; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Isoquinolines; Lymphoma; Mice; Nuclear Receptor Subfamily 4, Group A, Member 1; Oligonucleotides; Protein Binding; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Sulfonamides; Tacrolimus; Thymus Neoplasms; Transcription Factors

Topics: Administration, Cutaneous; Diagnosis, Differential; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lymphoma; Middle Aged; Scalp Dermatoses; Severity of Illness Index; Stem Cell Transplantation; Tacrolimus

Transplantation conditioning regimens have been shown to affect the brain imaging appearance in patients with cyclosporine or FK-506 neurotoxicity. We assessed whether the occurrence of neurotoxicity was affected by the choice of conditioning regimen used before allogeneic bone marrow transplantation (allo-BMT).. An allo-BMT was performed in 290 patients conditioned before transplantation with myeloablative therapy. Neurotoxicity from cyclosporine or FK-506 developed in 21 (7.2%) of these patients, as confirmed with CT or MR imaging. Two hundred seventy-four (94%) of these 290 patients were conditioned with minor variations of one of five fundamental regimens: cyclophosphamide (Cy)/busulfan (n = 97), Cy/total body irradiation (TBI) (n = 122), Cy/thiotepa/TBI (n = 40), bischloroethylnitrosourea/etoposide/cytarabine/melphalan, or BEAM (n = 10), and Cy/thiotepa/busulfan (n = 5). The remaining 16 patients were prepared with variable regimens. The rates of occurrence of cyclosporine or FK-506 neurotoxicity relative to these conditioning regimens were compared.. The lowest rate of cyclosporine or FK-506 neurotoxicity was found in those patients conditioned with Cy (2 days)/busulfan (4 days) (5.1%) or Cy (2 days)/TBI (4 days) (5.9%). Rate of neurotoxicity increased with lengthier conditioning regimens. A high rate of neurotoxicity was present in those patients conditioned with Cy (4 days)/TBI (4 days) (13.7%), and this was statistically significant (P <.05) when compared with Cy (2 days)/busulfan (4 days).. The rate of occurrence of cyclosporine or FK-506 neurotoxicity varies with the conditioning regimen used, with lengthier regimens associated with a higher rate of neurotoxicity. As the length of the conditioning regimen equates to the total dose of chemotherapy administered, it suggests that the intensity of the regimen is correlated to the predisposition to neurotoxicity from cyclosporine or FK-506.

Topics: Adolescent; Adult; Aged; Bone Marrow Transplantation; Cerebral Cortex; Cyclosporine; Female; Humans; Immunosuppressive Agents; Leukemia; Lymphoma; Magnetic Resonance Imaging; Male; Middle Aged; Myelodysplastic Syndromes; Neurotoxicity Syndromes; Retrospective Studies; Survival Rate; Tacrolimus; Tomography, X-Ray Computed; Transplantation Conditioning; Whole-Body Irradiation

We report our experience with the combination of anti-thymocyte globulin (ATGAM) and tacrolimus in the treatment of 20 patients with steroid refractory and dependent acute graft-versus-host disease (GVHD) transplanted between August 1996 and February 2000. All patients received cyclosporine-based GVHD prophylaxis. Thirteen patients developed a maximum of grade IV, five grade III and two grade II acute GVHD, with 15 patients being refractory to steroids and five dependent on steroids. Patients were treated with ATGAM (15 mg/kg for 5 d) and tacrolimus (0.025--0.1 mg/kg/d) in addition to continuation of their high-dose steroids and cessation of their cyclosporine. Within 28 d of treatment, we observed eight complete responses (CR), six partial responses (PR) and six with no response. Overall response (CR + PR) was predicted by GVHD severity. Infectious complications occurred in 80% of patients. The median survival was 86.5 d (range, 21--1081 d) with 35% of patients remaining alive. Survival following combination therapy was significantly more likely in men (P < 0.001), skin-only GVHD (P = 0.027), less severe GVHD (P = 0.048), and in responders to tacrolimus and ATGAM (P < 0.001). In conclusion, concurrent introduction of ATGAM and tacrolimus is a promising therapeutic combination for GVHD refractory to steroids and cyclosporine.

Topics: Acute Disease; Adult; Cyclosporine; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Isoantibodies; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoma; Male; Methotrexate; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Tacrolimus; Transplantation, Homologous

Autologous graft-versus-host disease has been reported after the administration of cyclosporine in patients who have received autologous bone marrow transplantation.. The purpose of this study was to determine whether autologous graft-versus-host disease could be induced in recipients of autologous peripheral blood stem cell transplantation and whether tacrolimus induced the disease instead of cyclosporine.. Twelve patients with acute leukemia and 5 patients with malignant lymphoma received either cyclosporine (1 mg/kg/day) or tacrolimus (0. 05 mg/kg/day) orally after autologous bone marrow or peripheral blood stem cell transplantation.. Autologous graft-versus-host disease of the skin, confirmed by histopathologic criteria, occurred in 40% of the patients at 8 to 25 days after transplantation and lasted 3 to 15 days. The frequency of autologous graft-versus-host disease was approximately the same (40%) irrespective of the source of the graft (bone marrow cells or peripheral blood stem cells) and the drug used for induction (cyclosporine or tacrolimus).. This pilot study suggests that autologous graft-versus-host disease can be induced in recipients of autologous peripheral blood stem cell transplantation by cyclosporine or tacrolimus.

Topics: Acute Disease; Adult; Biopsy; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Lymphoma; Male; Skin; Tacrolimus; Transplantation, Autologous; Treatment Outcome

Although the kidney transplant program at this center has been active for the past 18 yr, five out of the seven cases of post-transplant lymphoma in kidney transplant patients were observed over the past 2 yr. During this period, we have shifted from cyclosporine to tacrolimus (FK506 or prograf) for maintenance immunosuppression and for rescue therapy. We have also introduced mycophenolate (RS-61443) and have continued an antibody induction regimen in the immediate postoperative period. FK506 is 50-100 times more potent than cyclosporine. We have reported a decreased incidence of rejection, improved graft survival, and a general optimalization of patient survival with these newer regimens. Nonetheless, five cases of post-transplant lymphoma out of 233 kidney transplants (2.1%) performed during this time period (December 1993 to December 1995) occurred between 3 months to 1 yr after the transplant. Four of the five patients are still alive between 12 and 24 months after the diagnosis of lymphoma was made. All were without evidence of ongoing disease. Three of the five have grafts with excellent function for longer than 18 months after transplantation, while one is marginal and one patient expired on dialysis. The third and fourth patients had severe rejection before the diagnosis of PTLD was made. While the occurrence of five cases of post-transplant lymphoma over a 2 yr period is alarming, this is still within the 2-4% incidence of post-transplant lymphoma that has been reported in the literature in kidney transplant patients. Our results probably reflect the increasing potency of our immunosuppressive protocols but do not show any increase in the aggressiveness of this entity of post-transplant lymphoma during the continued follow up.

Topics: Adolescent; Adult; Antibody Formation; Cause of Death; Child; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Incidence; Kidney Transplantation; Lymphoma; Male; Mycophenolic Acid; Prodrugs; Renal Dialysis; Survival Rate; Tacrolimus

Topics: Carcinoma, Hepatocellular; Cyclosporine; Follow-Up Studies; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Lymphoma; Neoplasms; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Topics: Anti-Bacterial Agents; Child; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoma; Male; Neoplasms, Multiple Primary; Tacrolimus

The new immunosuppressive drug FK 506 was used from the outset with low doses of prednisone to treat 120 recipients of primary liver grafts and 20 more patients undergoing liver retransplantation. The patient survival rate after 2 to 8 months in the primary liver transplantation series is 93.3%, with original graft survival of 87.5%. Of the 20 patients in the hepatic retransplant series, 17 (85%) are living. Almost all of the surviving patients have good liver function. In addition 11 hearts, 2 double lungs, and a heart-lung have been transplanted under FK 506, with survival of all 14 patients. With all of the organ systems so far tested, including the kidney (which has been reported elsewhere), rejection usually has been controlled without additional drugs and with lower average steroid doses than in the past. Nephrotoxicity has been observed, but not to an alarming degree, and there has been a notable absence of hypertension. There is a suggestion that serum cholesterol may be lowered by FK 506, but this is unproved. Although the adverse reactions of FK 506 and the immunosuppressive mechanisms resemble those of cyclosporine, our preliminary observations suggest that FK 506 may have a more advantageous therapeutic index.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Cause of Death; Child; Child, Preschool; Female; Graft Rejection; Graft Survival; Heart Transplantation; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Incidence; Infant; Infections; Kidney Transplantation; Liver Transplantation; Lymphoma; Male; Middle Aged; Reoperation; Tacrolimus; Transplantation