sirolimus and Hematologic-Diseases

We performed a systematic review and meta-analysis of hematologic toxicities associated with everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor. Eligible studies included phase II and III trials of patients with solid tumors on 10mg of everolimus daily describing events of neutropenia, thrombocytopenia, anemia or lymphopenia. The incidence of everolimus-associated all-grade and high-grade (Grade 3-4) hematologic toxicities were, respectively: neutropenia: 21.7% and 3.6%; thrombocytopenia: 36.0% and 4.7%; anemia: 61.2% and 8.4% and lymphopenia: 40.9% and 14.9%. Everolimus was associated with an increased risk of all-grade neutropenia (RR=2.24, [95% CI 1.51-3.32]), all-grade (RR=9.19, [95% CI 4.51-18.70]) and high-grade (RR=7.46, [95% CI 2.58-21.61]) thrombocytopenia, all-grade (RR=1.58, [95% CI 1.25-1.99]) and high-grade (RR=3.92, [95% CI 1.46-10.52]) anemia and all-grade (RR=1.72, [95% CI 1.50-1.97]) and high-grade (RR=2.70, [95% CI 1.86-3.93]) lymphopenia.

Topics: Antineoplastic Agents; Everolimus; Hematologic Diseases; Humans; Incidence; Neoplasms; Odds Ratio; Publication Bias; Risk; Sirolimus

Pancreas-kidney transplant is an effective treatment for patients with insulin-dependent dabetes and chronic renal failure. Reduction in technical failure loss and early acute rejection rates contributed to prolong pancreas graft survival. However, drug toxicity affects negatively both short- and long-term follow-ups.. This article reviews the existing literature and knowledge of the immunosuppressive drugs that are frequently used in pancreas transplant, including calcineurin inhibitors, sirolimus, corticosteroids, and mycophenolate. The article also discusses the short- and long-term adverse effects of these drugs. The article also reports and discusses the most relevant in vitro studies, providing additional information to in vivo findings. Some clinically relevant drug interactions with immunosuppressive drugs are also highlighted. Over- and underimmunosuppression effects will not be addressed.. Immunosuppressive regimen after pancreas transplant is very effective and contributed to pancreas allograft survival. However, they present several side effects that are potentiated when drugs are combined. Modifiable and non-modifiable risk factors can aggravate metabolic and toxicological effects of immunosuppressive drugs. It is important to critically analyze the results of clinical studies and investigate new immunosuppressive drugs and/or novel drug combinations. It is equally important to comprehend and interpret experimental data. Therefore, minimization of side effects, based on safe approaches, can prolong pancreas allograft survival.

Topics: Adrenal Cortex Hormones; Bone Diseases; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Gastrointestinal Diseases; Graft Rejection; Graft Survival; Hematologic Diseases; Humans; Hyperkalemia; Hyperuricemia; Immunosuppressive Agents; Mycophenolic Acid; Nervous System Diseases; Pancreas Transplantation; Pneumonia; Renal Insufficiency, Chronic; Sirolimus

First-line therapies available for metastatic renal cell carcinoma (RCC) have increased rapidly with the recent introduction of three novel agents: sunitinib, temsirolimus and bevacizumab (in combination with interferon [IFN]). This expansion means that the selection of the optimal therapy for individual patients has become more difficult and increasingly important. A treatment algorithm based on tumour histology and patient risk status is currently used to guide clinical practice, but does not always allow specific treatment for individual patients to be identified. This is particularly true for the largest group of patients, who have favourable or intermediate risk clear cell RCC. Considerations guiding treatment selection for these patients include: potential for cure; and optimal progression-free survival (PFS) with good tolerability and quality of life. In patients who have a realistic opportunity for cure, bevacizumab combined with IFN might be the treatment of choice. However, sunitinib and bevacizumab combined with IFN produce similar PFS. Thus, if optimal PFS is the treatment goal, other factors must be considered. These include patient-related factors such as the needs, circumstances and comorbidities of individual patients and the associated side effects of bevacizumab combined with IFN and sunitinib. More data are currently available to support treatment decisions based on the latter and these are considered in detail, highlighting factors that may lead to selection of bevacizumab combined with IFN or sunitinib in individual patients.

Topics: Algorithms; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Double-Blind Method; Drug Approval; Drug Design; Europe; Gastrointestinal Diseases; Hematologic Diseases; Humans; Indoles; Interferons; Kidney Neoplasms; Palliative Care; Patient Selection; Pyrroles; Quality of Life; Randomized Controlled Trials as Topic; Sirolimus; Sunitinib; United States

The treatment options for metastatic renal cell carcinoma have expanded rapidly over the past 3 years, with four new agents available and others in late-stage development. This has resulted in a change of the standard of first-line care, with sunitinib or bevacizumab plus interferon the treatments of choice for patients with good or intermediate-risk renal cell carcinoma and temsirolimus treatment of choice for poor-risk disease. Sunitinib and bevacizumab plus interferon have similar efficacy, meaning that treatment choice is influenced by other factors: disease-related factors such as clear cell versus non-clear cell histology; patient factors such as co-morbidities, Memorial Sloan-Kettering Cancer Center risk and patient preference; and drug-related factors such as tolerability profile. The aim of this review is to describe the tolerability of the first-line treatment options for clear cell renal cell carcinoma, giving consideration to how tolerability profiles relate to drug mechanism of action. Thus, the incidence and aetiology of side effects related to vascular endothelial growth factor and vascular endothelial growth factor receptor inhibition using sunitinib and bevacizumab, as well as those of the non-specific side effects observed with sunitinib, are described. In addition, the potential patient impact and management of these side effects, as well as those of interferon and temsirolimus, are considered. Finally, the implications of the tolerability profiles of these agents for combination therapy and use in broader populations than those enrolled in trials are assessed.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Blood Coagulation Disorders; Carcinoma, Renal Cell; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Disease-Free Survival; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hypothyroidism; Indoles; Interferons; Kidney Neoplasms; Multicenter Studies as Topic; Neoplasm Proteins; Pyrroles; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sunitinib; Wound Healing

To improve the outcome of relapsed/refractory acute myeloid leukemia (AML), a randomized phase II trial of three novel regimens was conducted. Ninety patients were enrolled and were in first relapse or were refractory to induction/re-induction chemotherapy. They were randomized to the following regimens: carboplatin-topotecan (CT), each by continuous infusion for 5 days; alvocidib (formerly flavopiridol), cytarabine, and mitoxantrone (FLAM) in a timed sequential regimen; or sirolimus combined with mitoxantrone, etoposide, and cytarabine (S-MEC). The primary objective was attainment of a complete remission (CR). A Simon two-stage design was used for each of the three arms. The median age of the patients in the FLAM arm was older at 62 years compared with 55 years for the CT arm and the S-MEC arm. The overall response was 14% in the CT arm (5/35, 90% CI 7%-35%), 28% in the FLAM arm (10/36, 90% CI, 16%-43%), and 16% in the S-MEC arm (3/19, 90% CI, 4%-36%). There were nine treatment-related deaths, seven of which occurred in the FLAM arm with four of these in elderly patients. We conclude that the FLAM regimen had an encouraging response rate and should be considered for further clinical development but should be used with caution in elderly patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cytarabine; Disease-Free Survival; Etoposide; Female; Flavonoids; Follow-Up Studies; Gastrointestinal Diseases; Hematologic Diseases; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mitoxantrone; Piperidines; Recurrence; Remission Induction; Salvage Therapy; Sirolimus; Topotecan; Tumor Lysis Syndrome

Everolimus, which inhibits the mammalian target of rapamycin (mTOR), is increasingly used in breast cancer and familiarity with its full range of toxicity is critical for practicing oncologists.. We studied hematologic changes in 31 patients with metastatic breast cancer treated in a phase II clinical trial using everolimus. Complete blood counts were collected at baseline, 2 weeks, 4 weeks, every 4 weeks during treatment, and 1 month after discontinuation. Adverse events were defined using Common Toxicity Criteria version 3. Linear mixed models with fixed effects of time and random intercepts and slopes were used to study trends and comparisons were conducted using paired t tests.. Anemia was reported in 22 patients (71%), thrombocytopenia in 17 (55%), and leukopenia in 14 (45%). These were predominantly grade 1 or 2 and did not require dose modification. Red blood cell mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) both decreased significantly over time (P < .0001) starting at 2 weeks with no significant change in mean corpuscular hemoglobin concentration (MCHC) (P = .104). Both MCV and MCH increased 1 month after treatment discontinuation (P values < .0001 and .0003, respectively) indicating reversibility of this effect. Although total leukocyte counts remained largely stable, lymphocyte percentage progressively decreased over time with a trend for increased neutrophils.. In addition to anemia, leukopenia, and thrombocytopenia, everolimus consistently induces red cell microcytosis and reduced hemoglobin content. Lymphopenia may contribute to immune suppression and increased risk of infection. Familiarity with these hematologic changes is prudent as more patients are treated with this class of drugs.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Erythrocyte Count; Erythrocyte Indices; Estradiol; Everolimus; Female; Fulvestrant; Hematologic Diseases; Humans; Leukocyte Count; Leukopenia; Neoplasm Metastasis; Sirolimus; Thrombocytopenia

The multicentre, open-label, two-stage, single-arm, phase 2, PILLAR (PIvotaL Lymphoma triAls of RAD001)-1 study (NCT00702052) assessed the efficacy and safety of everolimus 10 mg/d in adults with confirmed mantle cell lymphoma (MCL) refractory to or intolerant of bortezomib who received ≥1 other antineoplastic agent, either separately or in combination with bortezomib. Primary endpoint was overall response rate (ORR) per investigator review according to the response criteria for malignant lymphoma. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Fifty-eight patients were enrolled from August 2008-January 2011. Five partial responses were observed (ORR 8·6%; 90% confidence interval [CI] 3·5-17·3%); the study did not meet the prespecified objective of ≥8 objective responses among 57 patients. Median PFS and OS were 4·4 months (95% CI 3·5-6·1) and 16·9 months (95% CI 14·4-29·9), respectively. Grade 3/4 non-haematological toxicities occurred in 70·7% of patients. Based on laboratory values, grade 3/4 thrombocytopenia, neutropenia and anaemia occurred in 13·8%, 13·8% and 8·6% of patients, respectively. Everolimus demonstrated modest activity and acceptable tolerability in heavily pretreated patients with MCL refractory to or intolerant of bortezomib. Future studies evaluating everolimus in a less refractory population or in combination with other targeted therapies in refractory MCL are warranted.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Combined Modality Therapy; Disease-Free Survival; Drug Resistance, Neoplasm; Everolimus; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Kaplan-Meier Estimate; Lymphoma, Mantle-Cell; Male; Middle Aged; Pain; Pneumonia; Pyrazines; Salvage Therapy; Sirolimus; Treatment Outcome

The International Extranodal Lymphoma Study Group coordinated a phase II trial to evaluate the activity and safety of everolimus in marginal zone lymphomas (MZLs). Thirty patients with relapsed/refractory MZLs received everolimus for six cycles or until dose-limiting toxicity or progression. Median age was 71 years (range, 51-88 years). Twenty patients had extranodal, six splenic, four nodal MZL. Twenty-four patients had stage III-IV. Median number of prior therapies was two (range 1-5). Seventeen patients had early treatment discontinuation, in most cases due to toxicity. Median number of cycles was 4.5 (range, 1-16). Among the 24 assessable patients, the overall response rate (ORR) was 25% (95% confidence interval: 10-47). Grade 3-4 adverse events were neutropenia and thrombocytopenia (17% of patients, each), infections (17%), mucositis and odontogenic infections (13%) and lung toxicity (3%). The median response duration was 6.8 months (range, 1.4-11.1+). After a median follow-up of 14.5 months, five deaths were reported: four deaths were due to lymphoma, one was due to toxicity. In an intent-to-treat analysis, the projected median progression-free survival was 14 months. The moderate antitumour activity of everolimus in relapsed/refractory MZLs and the observed toxicity limit its therapeutical applicability in these indolent entities. Lower doses of the drug and, perhaps, different strategies including combination with additional agents need to be explored.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Drug Administration Schedule; Everolimus; Female; Hematologic Diseases; Humans; Lymphoma, B-Cell, Marginal Zone; Male; Middle Aged; Neoplasm Staging; Prognosis; Recurrence; Remission Induction; Sirolimus; Survival Analysis; Treatment Outcome

Everolimus is an oral raptor mTOR inhibitor and has shown activity in patients with Waldenstrom's macroglobulinemia (WM). This study examines a large cohort of patients with relapsed/refractory WM with long-term follow up for survival. Patients were eligible if they had measurable disease, a platelet count >75,000 x 10(6)/L, an absolute neutrophil count >1,000 x 10(6)/L. Patients received everolimus 10 mg PO daily and were evaluated monthly. A success was defined as a complete or partial response (PR); minor responses (MR) were recorded and considered to be of clinical benefit. Sixty patients were enrolled and treated. The overall response rate (ORR) was 50% (all PR); the clinical benefit rate including MR or better was 73% (95% CI: 60-84%) with 23% MR. The median time to response for patients who achieved PR was 2 months (range, 1-26). The median duration of response has not been reached and median progression-free survival (PFS) was 21 months. Grade 3 or higher toxicities (at least possibly related to everolimus) were observed in 67% of patients. The most common grade 3 or 4 toxicities were anemia (27%), leukopenia (22%), and thrombocytopenia (20%). Other nonhematological toxicities were diarrhea (5%), fatigue (8%), stomatitis (8%) and pulmonary toxicity (5%). Everolimus has a high single-agent activity of 73% including MR, with a progression free survival of 21 months, indicating that this agent is active in relapsed/refractory WM.

Topics: Adult; Aged; Aged, 80 and over; Alkylating Agents; Angiogenesis Inhibitors; Antibodies, Monoclonal, Murine-Derived; Antimetabolites; Bone Marrow; Diarrhea; Disease-Free Survival; Drug Resistance; Everolimus; Fatigue; Female; Hematologic Diseases; Humans; Immunoglobulin M; Kaplan-Meier Estimate; Male; Middle Aged; Pain; Paraproteins; Recurrence; Rituximab; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases; Treatment Outcome; Waldenstrom Macroglobulinemia

A pediatric study has established a maximum tolerated dose (MTD) for temsirolimus (Tem) of more than 150 mg/m intravenously/week. A phase I trial was conducted to establish the MTD for Tem in combination with valproic acid (VPA) in children and adolescents with refractory solid tumors. The secondary aims included expression of mammalian target of rapamycin (mTOR) markers on archival tumor tissue; Tem pharmacokinetics; assessment of histone acetylation (HA); and tumor response. Patients were treated with VPA (5 mg/kg orally three times daily) with a target serum level of 75-100 mcg/ml. Tem was started at an initial dose of 60 mg/m/week. Pharmacokinetics and HA measurements were performed during weeks 1 and 5. Two of the first three patients experienced dose-limiting toxicity (grade 3 mucositis). Tem at 35 mg/m/week was found to be tolerable. Peak Tem concentrations were higher in all patients compared with those in previously published reports of single agent Tem. Increases in HA are correlated with VPA levels. All tumor samples expressed mTORC1 and mTORC2. An objective response was observed in one patient (melanoma), whereas transient stable disease was observed in four other patients (spinal cord ependymoma, alveolar soft part sarcoma, medullary thyroid carcinoma, and hepatocellular carcinoma). The MTD of Tem when administered with VPA is considerably lower than when used as a single agent, with mucositis the major dose-limiting toxicity. The combination merits further study and may have activity in melanoma. Attention to drug-drug interactions will be important in future multiagent trials including Tem.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Diphenhydramine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Eruptions; Early Termination of Clinical Trials; Fatigue; Female; Hematologic Diseases; Histone Deacetylase Inhibitors; Humans; Infusions, Intravenous; Male; Mucositis; Neoplasms; Pain; Sirolimus; Valproic Acid

Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease.. In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group.. Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02).. As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468 [ClinicalTrials.gov].).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Female; Hematologic Diseases; Humans; Interferon-alpha; Kidney Neoplasms; Male; Middle Aged; Prognosis; Proportional Hazards Models; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases

Topics: Child; Hematologic Diseases; Humans; Republic of Korea; Sirolimus; Thrombocytopenia; Vestibular Diseases

One of the most frequent non-infectious complications of humoral immunodeficiencies with a CVID-like pattern is a particular form of inflammatory lung disease which is called granulomatous-lymphocytic interstitial lung disease (GLILD). Its development worsens patient prognosis, with a significant decrease in survival. Currently, there are no unified guidelines regarding its management, and different combinations of immunosuppressants have been used with variable success.. Clinical and radiological data were collected from patient's medical charts. Flow cytometry was performed to characterize the immunological features with special focus in regulatory T cells (Tregs).. A 16-year-old girl with Kabuki syndrome and a 12-year-old boy, both with a CVID-like humoral immunodeficiency on immunoglobulin replacement treatment, developed during follow-up an inflammatory complication radiologically, clinically, and histologically compatible with GLILD. They required treatment, and sirolimus was started, with very good response and no serious side effects.. These 2 cases provide insight into the underlying local and systemic immune anomalies involved in the development of GLILD, including the possible role of Tregs. Combined chemotherapy is commonly used as treatment for GLILD when steroids fail, but there have been some reports of successful monotherapy. As far as we know, these are the first 2 GLILD patients treated successfully with sirolimus, suggesting the advisability of further study of mTOR inhibitors as a more targeted treatment for GLILD, if impairment in Tregs is demonstrated.

Topics: Abnormalities, Multiple; Adolescent; Biomarkers; Child; Face; Female; Hematologic Diseases; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Sirolimus; T-Lymphocytes, Regulatory; Vestibular Diseases

Patients with autoimmune multilineage cytopenias are often refractory to standard therapies requiring chronic immunosuppression with medications with limited efficacy and high toxicity. We present data on 30 patients treated on a multicenter prospective clinical trial using sirolimus as monotherapy. All children (N = 12) with autoimmune lymphoproliferative syndrome (ALPS) achieved a durable complete response (CR), including rapid improvement in autoimmune disease, lymphadenopathy, and splenomegaly within 1 to 3 months of starting sirolimus. Double-negative T cells were no longer detectable in most, yet other lymphocyte populations were spared, suggesting a targeted effect of sirolimus. We also treated 12 patients with multilineage cytopenias secondary to common variable immunodeficiency (CVID), Evans syndrome (ES), or systemic lupus erythematosus (SLE), and most achieved a CR (N = 8), although the time to CR was often slower than was seen in ALPS. Six children with single-lineage autoimmune cytopenias were treated and only 2 responded. Sirolimus was well tolerated with very few side effects. All of the responding patients have remained on therapy for over 1 year (median, 2 years; range, 1 to 4.5 years). In summary, sirolimus led to CR and durable responses in a majority of children with refractory multilineage autoimmune cytopenias. The responses seen in ALPS patients were profound, suggesting that sirolimus should be considered as a first-line, steroid-sparing treatment of patients needing chronic therapy. The results in other multilineage autoimmune cytopenia cohorts were encouraging, and sirolimus should be considered in children with SLE, ES, and CVID. This trial was registered at www.clinicaltrials.gov as #NCT00392951.

Topics: Adolescent; Adult; Autoimmune Diseases; Child; Child, Preschool; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Hematologic Diseases; Humans; Immunosuppressive Agents; Infant; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Prospective Studies; Salvage Therapy; Sirolimus; Survival Rate; Tissue Distribution; Young Adult

In this issue of Blood, Bride et al report results of the first prospective multi-institutional trial of a long-term single-agent therapy for refractory cytopenias using rapamycin in 30 patients and show remarkable efficacy in children with autoimmune lymphoproliferative syndrome (ALPS).

Topics: Autoimmune Diseases; Drug Resistance, Neoplasm; Female; Hematologic Diseases; Humans; Immunosuppressive Agents; Male; Neoplasm Recurrence, Local; Salvage Therapy; Sirolimus

Transplantation of T cell-depleted BM (TDBM) under mild conditioning, associated with minimal toxicity and reduced risk of GVHD, offers an attractive therapeutic option for patients with nonmalignant hematologic disorders and can mediate immune tolerance to subsequent organ transplantation. However, overcoming TDBM rejection after reduced conditioning remains a challenge. Here, we address this barrier using donorderived central memory CD8(+) T cells (Tcms), directed against third-party antigens. Our results show that fully allogeneic or (hostXdonor)F1-Tcm, support donor chimerism (> 6 months) in sublethally irradiated (5.5Gy) mice, without GVHD symptoms. Chimerism under yet lower irradiation (4.5Gy) was achieved by combining Tcm with short-term administration of low-dose Rapamycin. Importantly, this chimerism resulted in successful donor skin acceptance, whereas third-party skin was rejected. Tracking of host anti-donor T cells (HADTCs), that mediate TDBMT rejection, in a novel bioluminescence-imaging model revealed that Tcms both induce accumulation and eradicate HADTCs in the LNs,concomitant with their elimination from other organs, including the BM. Further analysis with 2-photon microcopy revealed that Tcms form conjugates with HADTCs, resulting in decelerated and confined movement of HADTCs within the LNs in an antigen-specific manner. Thus, anti-third-party Tcms support TDBMT engraftment under reduced-conditioning through lymph-node sequestration and deletion of HADTCs, offering a novel and potentially safe approach for attaining stable hematopoietic chimerism.

Topics: Animals; Bone Marrow Transplantation; CD8-Positive T-Lymphocytes; Female; Graft vs Host Disease; Hematologic Diseases; Humans; Immunologic Memory; Immunosuppressive Agents; Isoantigens; Lymph Nodes; Lymphocyte Depletion; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Sirolimus; Skin Transplantation; T-Lymphocytes; Tissue Donors; Transplantation Chimera; Transplantation Conditioning

Anaemia and microcytosis are common post kidney transplantation. The aim of this study was to evaluate the potential role of mammalian target of rapamycin (mTOR) inhibition in the development of anaemia and microcytosis in healthy animals and in human erythroid cultures in vitro.. Rats with normal kidney function were treated with sirolimus (n = 7) or vehicle (n = 8) for 15 weeks. Hemograms were determined thereafter. In the sirolimus withdrawal part of the study, rats received sirolimus (SRL) for 67 days (n = 4) 1 mg/kg three times per week or for 30 days (n = 4) and were observed until Day 120. Hemograms were performed regularly. Peripheral blood mononuclear cells from healthy controls (HC; n = 8), kidney transplant patients with sirolimus treatment with (SRL + MC; n = 8) or without microcytosis (SRL - MC; n = 8) were isolated and cultured in the absence or presence of SRL (5 ng/mL).. SRL-treated animals had a reduced mean corpuscular volume (MCV) and elevated erythrocyte count compared with control animals after 15 weeks of treatment. This effect was evident as early as 4 weeks (MCV: 61.5 ± 1.8 versus 57 ± 1.7 fL; P = 0.0156; Red blood count 7.4 ± 0.3 × 10(9)/L versus 8.6 ± 0.5 × 10(9)/L; P = 0.0156) and was reversible 90 days after SRL withdrawal. SRL in the culture medium of erythroid cultures led to fewer colonies in cultures from HC as well as from kidney transplant patients (without SRL: 34.2 ± 11.4 versus with SRL: 27.5 ± 9.9 BFU-E-derived colonies P = 0.03), regardless if the cultures were derived from recipients with normocytic or with microcytic erythrocytes. The presence of tacrolimus in the culture medium had no influence on the number and size of colonies.. mTOR inhibition induces microcytosis and polyglobulia, but not anaemia in healthy rats. This might be caused by growth inhibition of erythroid precursor cells.

Topics: Anemia; Animals; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Erythrocyte Count; Erythrocyte Indices; Erythroid Precursor Cells; Erythropoiesis; Hematologic Diseases; Humans; Immunosuppressive Agents; Infusions, Parenteral; Kidney Transplantation; Leukocytes, Mononuclear; Male; Random Allocation; Rats; Rats, Wistar; Reference Values; Sirolimus; Statistics, Nonparametric; TOR Serine-Threonine Kinases

Proliferation signal inhibitors (PSI) could help to lower the calcineurine inhibitors level to minimize their toxicity and improve long-term graft survival. Side effects of this drugs are specific and must been known. Hyperlipidemia and cutaneous side-effects are the most frequent, angioedema and interstital pneumonitis the most serious. In majority of cases, early and adapted management could limit the impact of these side effects.

Topics: Angioedema; Calcineurin Inhibitors; Cicatrix; Cyclosporine; Graft Rejection; Graft Survival; Hematologic Diseases; Humans; Hyperlipidemias; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Kidney Diseases; Lymphocele; Pneumonia; Protein Serine-Threonine Kinases; Sirolimus; Skin Diseases; TOR Serine-Threonine Kinases

To explore relationships between sirolimus dosing, concentration and clinical outcomes.. Data were collected from 25 kidney transplant recipients (14 M/11 F), median 278 days after transplantation. Outcomes of interest were white blood cell (WBC) count, platelet (PLT) count, and haematocrit (HCT). A naive pooled data analysis was performed with outcomes dichotomized (Mann-Whitney U-tests).. Several patients experienced at least one episode when WBC (n = 9), PLT (n = 12), or HCT (n = 21) fell below the lower limits of the normal range. WBC and HCT were significantly lower (P < 0.05) when sirolimus dose was greater than 10 mg day(-1), and sirolimus concentration greater than 12 microg l(-1). No relationship was shown for PLT and dichotomized sirolimus dose or concentration.. Given this relationship between sirolimus concentration and effect, linked population pharmacokinetic-pharmacodynamic modelling using data from more renal transplant recipients should now be used to quantify the time course of these relationships to optimize dosing and minimize risk of these adverse outcomes.

Topics: Adult; Dose-Response Relationship, Drug; Hematocrit; Hematologic Diseases; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukocyte Count; Platelet Count; Postoperative Complications; Prognosis; Retrospective Studies; Sirolimus