sirolimus and Anemia--Aplastic

Immune-mediated hemocytopenia is a common cytopenic diseases without bone marrow hematopoietic abnormalities, the patient's quality of life is significantly reduced when first-line treatments are ineffective. Rapamycin, possesses a clear mechanism of targeting mTOR protein, can upregulate regulatory T cells and induces apoptosis of specific cells, by regulating the lymphocyte subsets, so as to treat various types of immune-mediated hemocytopenia with a certain therapeutic effect. In this reviews, the action mechanism and clinical application of rapamycin in immune thrombocytopenia（ITP）, autoimmune hemolytic anemia（AIHA）, acquired aplastic anemia and autoimmune lymphoproliferative syndrome（ALPS） etc. are summarized.

Topics: Anemia, Aplastic; Humans; Quality of Life; Sirolimus; T-Lymphocytes, Regulatory; TOR Serine-Threonine Kinases

Topics: Anemia, Aplastic; Animals; Antilymphocyte Serum; Bone Marrow Transplantation; Child; Combined Modality Therapy; Cyclosporine; Diagnosis, Differential; Drug Therapy, Combination; Granulocyte Colony-Stimulating Factor; Histocompatibility; HLA Antigens; Humans; Immunosuppression Therapy; Myelodysplastic Syndromes; Rabbits; Sirolimus

Severe aplastic anemia (SAA) has a poor prognosis in the absence of treatment. Current accepted therapeutic strategies include allogeneic stem-cell transplantation and immunosuppression, both resulting in long-term survival in the majority of patients. Although human leukocyte antigen (HLA)-matched sibling stem-cell transplantation is highly effective, the 25% probability of finding a suitable sibling donor within a family renders this approach available to only a minority of patients. Transplantation using HLA-matched, unrelated donors carries a high risk of treatment failure along with considerable toxicity. While combined immunosuppression with both antithymocyte globulin (ATG) and cyclosporine A (CSA) produces hematologic improvement in most patients, relapse is common. Late evolution of aplastic anemia to other serious hematologic disorders, including paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia, and acute leukemia, is also a significant problem following treatment with ATG/CSA. Recently, results of immunosuppression in SAA with another potent immunosuppressive agent, cyclophosphamide, were reported in a small number of patients. The overall response rate was similar to that seen with ATG/CSA, but relapse and late clonal disease were not observed during a long period of follow-up. A larger randomized trial comparing sustained hematologic response rates to either conventional immunosuppression with ATG/CSA or high-dose cyclophosphamide and CSA is now underway; secondary end points include response duration, event-free survival, and overall survival. Additionally, a number of protocols designed to test the efficacy of alternative immunosuppressive or immunomodulatory agents are being developed.

Topics: Anemia, Aplastic; Antibodies, Monoclonal; Cyclophosphamide; Humans; Immunosuppressive Agents; Mycophenolic Acid; Receptors, Interleukin-2; Sirolimus; Tacrolimus

We conducted a pilot study employing extended T cell costimulation blockade (COSBL) with Abatacept along with sirolimus and post-transplantation cyclophosphamide (PTCy) in 10 patients (median age 12) with severe aplastic anemia (SAA). Nine patients engrafted in the COSBL group, compared to all 10 patients (median 14 vs 13days) treated on PTCy protocols without abatacept (CONTROL group). The incidence of acute graft-versus-host disease (GVHD) was 10.5% in the COSBL group compared to 50% in the CONTROL group (p=0.04). Chronic GVHD (12.5% vs 56%, p=0.02) and CMV reactivation (30% vs 80%, p=0.03) were also reduced in the COSBL group. T and NK cell subset analysis revealed higher CD56

Topics: Adolescent; Adult; Allografts; Anemia, Aplastic; Child; Child, Preschool; Chronic Disease; Cyclophosphamide; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Sirolimus; T-Lymphocytes, Regulatory; Transplantation Tolerance

Topics: Adolescent; Adult; Allografts; Anemia, Aplastic; Child; Child, Preschool; Cyclophosphamide; Disease-Free Survival; Female; Humans; Male; Middle Aged; Peripheral Blood Stem Cell Transplantation; Sirolimus; Survival Rate

We hypothesized that the addition of sirolimus to standard horse antithymocyte globulin (h-ATG) and cyclosporine (CsA) would improve response rates in severe aplastic anemia, due to its complementary and synergistic properties to cyclosporine A.. To test this hypothesis, we conducted a prospective randomized study comparing hATG/CsA/sirolimus to standard h-ATG/CsA. A total of 77 patients were treated from June 2003 to November 2005; 35 received h-ATG/CsA/sirolimus and 42 h-ATG/CsA. The two groups were well matched demographically and in blood counts prior to therapy. The primary end-point was hematologic response rate at 3 months, defined as no longer meeting the criteria for severe aplastic anemia. The study was powered to show a superior hematologic response rate of h-ATG/CsA/sirolimus compared to standard h-ATG/CsA.. The overall response rate at 3 months was 37% for h-ATG/CsA/sirolimus and 50% for h-ATG/CsA and at 6 months 51% for h-ATG/CsA/sirolimus and 62% for h-ATG/CsA. After a planned interim analysis of 30 evaluable patients in each arm, accrual to the h-ATG/CsA/sirolimus arm was closed, as the conditional power for rejecting the null hypothesis was less than 1%. The rate of relapse, clonal evolution, and survival (secondary outcomes) did not differ significantly between patients treated with the two different regimens.. Despite a theoretical rationale for its use, sirolimus did not improve the response rate in patients with severe aplastic anemia when compared to standard h-ATG/CsA.

Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Animals; Antilymphocyte Serum; Child; Child, Preschool; Cyclosporine; Drug Therapy, Combination; Female; Horses; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Recurrence; Sirolimus; Treatment Outcome; Young Adult

The natural history of EBV and CMV reactivation and the potential for serious complications following antibody-based immunosuppressive treatment for bone marrow failure syndromes in the absence of transplantation is not known. We monitored blood for EBV and CMV reactivation by polymerase chain reaction (PCR) weekly in 78 consecutive patients (total of 99 immunosuppressive courses) with aplastic anemia. Four regimens were studied: (1) HC, horse ATG/cyclosporine; (2) HCS, horse ATG/CsA/sirolimus; (3) RC, rabbit ATG/CsA; and (4) CP, alemtuzumab. There were no cases of EBV or CMV disease, but EBV reactivation occurred in 82 (87%) of 94 and CMV reactivation in 19 (33%) of 57 seropositive patients after starting immunosuppression. The median peak EBV copies were higher in the RC group when compared with HC, HCS, and alemtuzumab (P < .001). The median duration of PCR positivity for EBV was higher in the RC group compared with HC, HCS, and alemtuzumab (P = .001). Subclinical reactivation of both EBV and CMV is common and nearly always self-limited in patients with bone marrow failure receiving immunosuppression; different regimens are associated with different intensity of immunosuppression as measured by viral load and lymphocyte count; and viral reactivation patterns differ according to immunosuppressive regimens.

Topics: Adolescent; Adult; Aged; Alemtuzumab; Anemia, Aplastic; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antilymphocyte Serum; Antineoplastic Agents; Child; Child, Preschool; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Horses; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Male; Middle Aged; Monitoring, Physiologic; Polymerase Chain Reaction; Rabbits; Sirolimus; Time Factors; Virus Activation

Myeloid-derived suppressor cells (MDSC) are a group of heterogeneous immature myeloid cells and display immunosuppressive function. In this study, MDSC populations were evaluated in acquired aplastic anemia (AA) (n=65) in which aberrant immune mechanisms contributed to bone marrow destruction. Our data demonstrate that both the proportion and immunosuppressive function of MDSC are impaired in AA patients. Decreased percentage of MDSC, especially monocytic MDSC, in the blood of AA patients (n=15) is positively correlated with the frequency of T-regulatory cells, bone marrow level of WT1 and decreased plasma level of arginase-1. RNA sequencing analyses reveal that multiple pathways including DNA damage, interleukin 4, apoptosis, and Jak kinase singnal transducer and activator of transcription are upregulated, whereas transcription, IL-6, IL-18, glycolysis, transforming growth factor and reactive oxygen species are downregulated in MDSC of AA (n=4), compared with that of healthy donors (n=3). These data suggest that AA MDSC are defective. Administration of rapamycin significantly increases the absolute number of MDSC and levels of intracellular enzymes, including arginase-1 and inducible nitric-oxide synthase. Moreover, rapamycin inhibits MDSC from differentiating into mature myeloid cells. These findings reveal that impaired MDSC are involved in the immunopathogenesis of AA. Pharmacologically targeting of MDSC by rapamycin might provide a promising therapeutic strategy for AA.

Topics: Anemia, Aplastic; Arginase; Cell Differentiation; Humans; Immunosuppressive Agents; Myeloid-Derived Suppressor Cells; Sirolimus

It is very difficult to treat patients with aplastic anemia accompanied by chronic kidney disease. The nephrotoxicity of cyclosporine limits its use in these patients. Most of these patients also lack suitable sibling donors. Sirolimus, as a new type of immunosuppressive agent, has good therapeutic effect, lower toxicity, especially lower nephrotoxicity, thus attracting the attention of hematologists.. This 55-year-old Chinese male patient suffered from pancytopenia and renal insufficiency and has a poor quality of life.. The patient was diagnosed as severe aplastic anemia with chronic kidney disease-G3a.. We started the sirolimus therapy with the initial dose of 1 mg per day. Based on the good tolerability and clinical effect, we increased the dose of sirolimus to 2 mg per day after 2 weeks.. By taking sirolimus, the patient's peripheral blood cell count gradually increased, and he achieved blood transfusion independent, and eventually the blood cell count was completely normal.. We consider that sirolimus is a safe, effective, and well-tolerated oral drug that can be used as a treatment for aplastic anemia patients with chronic kidney disease.

Topics: Administration, Oral; Anemia, Aplastic; Humans; Immunosuppressive Agents; Male; Middle Aged; Renal Insufficiency, Chronic; Sirolimus

Aplastic anemia (AA) is a serious blood system disease that threatens human health. At present, the main cause of this disease is believed to be immune hyperfunction. However, the specific metabolic mode involved in the occurrence of lymphocytes in AA is still unknown. In addition, whether rapamycin, a specific blocker of the mTOR signaling pathway, plays a therapeutic role by inhibiting lymphocyte metabolism remains unclear. We induced an AA mouse model through the classical immune-mediated pathway and simultaneously administered rapamycin intervention therapy. First, the AA-associated phenotypic changes and the efficacy of rapamycin in the treatment of AA were discussed. Second, the proliferation and metabolic pathway of bone marrow (BM) lymphocytes in AA and the effect of rapamycin on this process were determined. Finally, the expression levels of mTOR pathway-related proteins were analyzed. By inhibiting the mTOR signaling pathway, rapamycin could ameliorate the phenotype of the immune-mediated AA model and inhibit the proliferation of T cells by preventing cell cycle transition from G0 to G1 phase. Moreover, we found that mitochondrial oxidative phosphorylation is involved in the metabolic reprogramming of T cells in AA and that rapamycin can inhibit this process. We confirmed that mitochondrial oxidative phosphorylation is involved in the metabolic reprogramming of T cells in AA and further extended the mechanism of rapamycin in treating AA by inhibiting the mTOR signaling pathway. This viewpoint may provide a new therapeutic idea for clinical applications.

Topics: Anemia, Aplastic; Animals; Cell Proliferation; Cells, Cultured; Immunosuppressive Agents; Male; Mice; Mice, Congenic; Mice, Inbred BALB C; Mice, Inbred C57BL; Mitochondria; Sirolimus; T-Lymphocytes

Acquired aplastic anemia, the prototypical bone marrow failure disease, is characterized by pancytopenia and marrow hypoplasia. Most aplastic anemia patients respond to immunosuppressive therapy, usually with anti-thymocyte globulin and cyclosporine, but some relapse on cyclosporine withdrawal or require long-term administration of cyclosporine to maintain blood counts. In this study, we tested efficacy of rapamycin as a new or alternative treatment in mouse models of immune-mediated bone marrow failure. Rapamycin ameliorated pancytopenia, improved bone marrow cellularity, and extended animal survival in a manner comparable to the standard dose of cyclosporine. Rapamycin effectively reduced Th1 inflammatory cytokines interferon-γ and tumor necrosis factor-α, increased the Th2 cytokine interleukin-10, stimulated expansion of functional regulatory T cells, eliminated effector CD8

Topics: Anemia, Aplastic; Animals; Bone Marrow; Bone Marrow Diseases; Bone Marrow Failure Disorders; Disease Models, Animal; Epitopes, T-Lymphocyte; Hemoglobinuria, Paroxysmal; Immunologic Memory; Immunosuppressive Agents; Mice; Pancytopenia; Signal Transduction; Sirolimus; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Treatment Outcome

Topics: Anemia, Aplastic; Animals; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Disease Models, Animal; Mice; Mice, Inbred C57BL; Pancytopenia; Sirolimus

This study was aimed to investigate the effects of rapamycin on biological function and autophagy of bone marrow mesenchymal stem cells (BM-MSC) from patients with aplastic anemia so as to provide experimental basis for the clinical treatment of aplastic anemia (AA) with rapamycin. BM-MSC were treated with different concentrations of rapamycin (0, 10, 50, 100 nmol/L) for 48 h, the expression of LC3B protein was detected by Western blot to observe the effect of rapamycin on cell autophagy; cell apoptosis and cell cycles were detected by flow cytometry; the proliferation of BM-MSC of AA patients was measured by cell counting kit-8; the adipogenic differentiation of BM-MSC were tested by oil red O staining after adipogenic induction for 2 weeks; the adipogenic related genes (LPL, CFD, PPARγ) were detected by real-time PCR. The results showed that the proliferation and adipogenesis of BM-MSC of AA patients were inhibited by rapamycin. Moreover, the autophagy and apoptosis of BM-MSC were increased by rapamycin in a dose-dependent way.Rapamycin arrested the BM-MSC in G0/G1 phase and prevented them into S phase (P < 0.05). It is concluded that rapamycin plays an critical role in inhibiting cell proliferation, cell cycles, and adipogenesis, these effects may be related with the autophagy activation and mTOR inhibition resulting from rapamycin.

Topics: Anemia, Aplastic; Apoptosis; Autophagy; Bone Marrow Cells; Cell Cycle; Cell Proliferation; Cells, Cultured; Humans; Mesenchymal Stem Cells; Signal Transduction; Sirolimus

Aplastic anemia (AA) is an immune-mediated disease. Although most patients are responsive to immunosuppressive therapy (IST) with a combination of anti-thymocyte globulin (ATG) and cyclosporine (CsA), some patients relapse or are refractory to IST. Sirolimus (rapamysin) inhibits the serine-threonine kinase mammalian target of rapamysin (mTOR), and blocks CsA-resistant and calcium-independent pathways late in the progression of the T-cell cycle. We report two cases of AA which relapsed after CsA and ATG plus CsA, respectively. They achieved transfusion independence after retreatment with sirolimus in combination with a CsA.

Topics: Anemia, Aplastic; Antilymphocyte Serum; Child; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Recurrence; Sirolimus; Treatment Outcome

A 24-year-old man from Ecuador presents to your clinic with dyspnea on exertion, bruising, and petechiae. He is noted to be pancytopenic with ANC 430, hemoglobin 7.4 g/dL (reticulocyte count 0.9%), and platelets 18 000. His BM biopsy is hypocellular for age. Ultimately, he is diagnosed with severe aplastic anemia. He is the only child of 2 South American parents without any matches in the unrelated donor registry, including cord blood. He is red cell- and platelet transfusion-dependent. He has been recommended therapy with antithymocyte globulin and cyclosporine but declined it. He seeks recommendations about new alternatives to this regimen to improve his chance of response.

Topics: Anemia, Aplastic; Antilymphocyte Serum; Cyclosporine; Drug Therapy, Combination; Humans; Male; Randomized Controlled Trials as Topic; Sirolimus; Tacrolimus; Young Adult

Topics: Anemia, Aplastic; Antilymphocyte Serum; Cyclosporine; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Recurrence; Sirolimus; Treatment Outcome

To explore the activation status of signal pathway of mTOR/S6 in bone marrow (BM) T lymphocytes of refractory/relapsed aplastic anemia patients (AA), and the effects of rapamycin (RAPA) and CTLA-4 immunoglobulin (CTLA-4Ig) on this pathway.. BM was collected from 13 refractory/relapsed AA patients, 8 newly diagnosed severe AA (SAA) patients and 10 iron deficiency anemia (IDA) (as controls) patients, and cocultured with RAPA and CTLA-4 Ig. The expression of p-mTOR, p-S6 and Interferon gamma (IFN-gamma) in CD3(+)T cells was measured by flow cytometry (FCM).. (1) The expression of p-mTOR, p-S6 and IFN-gamma in CD3(+)T cells in refractory/relapsed AA group were significantly higher than those in controls (P < 0.01). (2) The expression of p-mTOR and p-S6 in T cells in newly diagnosed SAA group, was similar to those in controls (P > 0.05), but significantly lower than those in refractory/relapsed AA group (P < 0.01). The expression level of IFN-gamma in T cells were significantly higher than that in controls (P < 0.01). (3) On exposure to RAPA, the levels of p-mTOR, p-S6 and IFN-gamma in T cells in refractory/relapsed AA patients were significantly lower than those before the exposure (all P < 0.05). And so were when exposed to CTLA-4 Ig (all P < 0.01).. (1) The mTOR/S6 signal pathway is activated in refractory/relapsed AA. (2) The expression of p-mTOR, p-S6 and IFN-gamma in refractory/relapsed AA can be suppressed by RAPA or CTLA-4Ig. (3) The signal pathway of CD28/mTOR/S6/IFN-gamma might take part in immune pathogenesis of refractory/relapsed AA.

Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Antigens, CD; Child; CTLA-4 Antigen; Female; Humans; Interferon-gamma; Male; Middle Aged; Ribosomal Protein S6; Signal Transduction; Sirolimus; T-Lymphocytes; TOR Serine-Threonine Kinases; Young Adult

Interactions between azole antifungal agents and immunosuppressants that are metabolized by cytochrome P450 3A4 (chiefly calcineurin inhibitors) are well documented. Interactions between itraconazole and sirolimus are known to occur in patients after solid organ transplantation, but interactions in hematopoietic stem cell transplant (HSCT) recipients have yet to be reported in the literature. We describe an allogeneic HSCT recipient who experienced supratherapeutic trough levels of sirolimus as a result of its coadministration with itraconazole. This patient was a 20-year-old African-American man who underwent HSCT for treatment of myelodysplastic syndrome with severe aplastic anemia. After several regimen changes, the patient received oral itraconazole 200 mg every 12 hours and sirolimus at a dosage of 7 mg/day on days 76-80 and 5 mg/day on days 81 and 82. His sirolimus whole blood trough levels were 17.5 and 35.6 ng/ml on days 80 and 82, respectively (therapeutic range 5-15 ng/ml). An interaction between itraconazole and sirolimus was suspected, and sirolimus was withheld on days 83-90. On day 90, the patient's sirolimus trough level had normalized to 4.4 ng/ml. Sirolimus was resumed at 1-2 mg/day, with adjustments as needed to maintain trough levels of 10-15 ng/ml. Both the itraconazole and sirolimus were eventually were discontinued. The patient died, however, from a disseminated adenovirus infection leading to end-organ failure. Sirolimus is extremely sensitive to the inhibitory potential of azole antifungals. We propose that itraconazole also has a potent effect on sirolimus metabolism. Preemptive sirolimus dosage reduction and close monitoring of its whole blood trough levels are required whenever this combination is considered to avoid immunosuppressant toxicity in already critically ill patients.

Topics: Adenoviridae Infections; Adult; Anemia, Aplastic; Antifungal Agents; Bone Marrow Transplantation; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Fatal Outcome; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Itraconazole; Male; Myelodysplastic Syndromes; Sirolimus

Topics: Anemia, Aplastic; Cyclosporine; Female; Humans; Immunosuppressive Agents; Male; Melanoma; Remission Induction; Sirolimus; Tacrolimus