sirolimus and Anemia--Hemolytic--Autoimmune

Autoimmune haemolytic anaemia (AIHA) and autoimmune thrombocytopenia are common complications of childhood-onset lupus, which may be life-threatening. A greater understanding of the pathogenesis of these haematologic manifestations will enhance our understanding of the biology of systemic lupus erythematosus (SLE) and inform the identification of novel treatments.. The mechanisms underlying AIHA and autoimmune thrombocytopenia are incompletely understood and likely multifactorial. Although the development of auto-antibodies is central to the disease process, recent studies have demonstrated the importance of cytokines in the underlying pathologic process. In-vitro and in-vivo evidence points to a role for IL17 in the pathogenesis of AIHA, which involves loss of tolerance to red cell auto-antigens and the development of autoantibodies. Sirolimus, an mTor inhibitor, has benefited patients with primary autoimmune cytopenias, possibly by stimulating T regulatory cells, and may also have efficacy for SLE-associated cytopenias. Similarly, low-dose recombinant human IL-2 therapy has shown promising results for improving platelet counts in patients with autoimmune thrombocytopenia, possibly by restoring the balance between T regulatory, T helper and Th17 cells.. The emergence of new agents directed at restoring immune dysregulation hold promise for the treatment of AIHA and autoimmune thrombocytopenia and should provide better tolerated alternatives to high-dose corticosteroids.

Topics: Anemia, Hemolytic, Autoimmune; Autoantibodies; Humans; Immunologic Factors; Lupus Erythematosus, Systemic; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin; Rituximab; Sirolimus

Autoimmune hemolytic anemia (AIHA) may occur after any type of allogeneic hematopoietic stem cell transplantation (HCT), even ABO-matched transplantation. It tends to be refractory to standard corticosteroid treatment and requires multiple transfusions. Though, there is no consensus regarding the optimal treatment for post-transplant severe AIHA. We present a pediatric patient with refractory AIHA after umbilical cord blood transplantation. She developed severe AIHA at 3months after transplantation and was unresponsive to multiple treatment modalities, including corticosteroids, intravenous immunoglobulin, plasma exchange and rituximab, resulting in persistent transfusion dependency. Sirolimus, a mammalian target of rapamycin inhibitor, was started on day 67 after the onset of AIHA, and this patient was successfully rescued without any complications. Sirolimus induces apoptosis in autoreactive lymphocytes, increases regulatory T cells and has been reported to have a positive effect on AIHA following solid organ transplantation (SOT). We reviewed the literature regarding post-transplant AIHA in the PubMed database and evaluated the treatment outcome of sirolimus in AIHA after SOT.

Topics: Anemia, Hemolytic, Autoimmune; Drug Resistance; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Sirolimus; Transplantation, Homologous

The management of Evans Syndrome in children is challenging due to the lack of evidence-based data on treatment. Steroids, the first-choice therapy, are successful in about 80% of cases. For children who are resistant, relapse or become steroid-dependent, rituximab is considered a valid second-line treatment, with the exception of those with an underlying diagnosis of autoimmune lymphoproliferative syndrome who may benefit from other options such as mycophenolate mofetil and sirolimus. Better knowledge of the immunological mechanisms underlying cytopenias and the availability of new immunosuppressive drugs can be helpful in the choice of more targeted therapies that would enable the reduction of the use of long-term steroid administration or other more aggressive options, such as splenectomy or stem cell transplantation. This manuscript provides an overview of the pathogenic background of the disease, and suggests a clinical approach to diagnosis and treatment with a particular focus on the management of relapsing/resistant disease.

Topics: Alemtuzumab; Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal, Humanized; Bortezomib; Child; Cyclophosphamide; Cyclosporine; Drug Resistance; Erythrocyte Transfusion; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Mycophenolic Acid; Recurrence; Rituximab; Sirolimus; Splenectomy; Stem Cell Transplantation; Steroids; Thrombocytopenia

We hypothesized that sirolimus, an mTOR inhibitor, may be effective in patients with autoimmune lymphoproliferative syndrome (ALPS) and treated patients who were intolerant to or failed other therapies. Four patients were treated for autoimmune cytopenias; all had a rapid complete or near complete response. Two patients were treated for autoimmune arthritis and colitis, demonstrating marked improvement. Three patients had complete resolution of lymphadenopathy and splenomegaly and all patients had a reduction in double negative T cells, a population hallmark of the disease. Based on these significant responses, we recommend that sirolimus be considered as second-line therapy for patients with steroid-refractory disease.

Topics: Anemia, Hemolytic, Autoimmune; Child; Child, Preschool; Drug Administration Schedule; Follow-Up Studies; Humans; Immunosuppressive Agents; Infant; Male; Positron-Emission Tomography; Radiography; Sirolimus

Some patients with warm autoimmune haemolytic anaemia (wAIHA) or Evans syndrome (ES) have no response to glucocorticoid or relapse. Recent studies found that sirolimus was effective in autoimmune cytopenia with a low relapse rate.. Data from patients with refractory/relapsed wAIHA and ES in Peking Union Medical College Hospital from July 2016 to May 2022 who had been treated with sirolimus for at least 6 months and followed up for at least 12 months were collected retrospectively. Baseline and follow-up clinical data were recorded and the rate of complete response (CR), partial response (PR) at different time points, adverse events, relapse, outcomes, and factors that may affect the efficacy and relapse were analyzed.. There were 44 patients enrolled, with 9 (20.5%) males and a median age of 44 (range: 18-86) years. 37 (84.1%) patients were diagnosed as wAIHA, and 7 (15.9%) as ES. Patients were treated with sirolimus for a median of 23 (range: 6-80) months and followed up for a median of 25 (range: 12-80) months. 35 (79.5%) patients responded to sirolimus, and 25 (56.8%) patients achieved an optimal response of CR. Mucositis (11.4%), infection (9.1%), and alanine aminotransferase elevation (9.1%) were the most common adverse events. 5/35 patients (14.3%) relapsed at a median of 19 (range: 15-50) months. Patients with a higher sirolimus plasma trough concentration had a higher overall response (OR) and CR rate (. Sirolimus is effective for patients with primary refractory/relapsed wAIHA and ES, with a low relapse rate and mild side effects. Patients with a higher sirolimus plasma trough concentration had a higher OR and CR rate, and patients who relapsed to glucocorticoid treatment had poorer relapse-free survival than those who were refractory.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Hemolytic, Autoimmune; Female; Glucocorticoids; Humans; Male; Middle Aged; Recurrence; Retrospective Studies; Sirolimus; Treatment Outcome; Young Adult

Topics: Anemia, Hemolytic, Autoimmune; Anemia, Refractory; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Male; Sirolimus

Autoimmune cytopenia includes autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and Evans syndrome (ES) caused by abnormal activation of autoimmunity and has a considerable refractory/relapse rate. To evaluate the efficacy and toxicity of sirolimus of primary relapsed/refractory autoimmune cytopenia, records of 45 patients with primary relapsed/refractory AIHA, ES, or ITP from October 2016 to January 2019 in two institutions, were collected; there were 3 pediatric patients and 42 adult patients. The median age at diagnosis was 31 (1-84) years. Patients were treated for a median of 14 (6-39) months and followed-up for a median of 18 (10-40) months. Thirty-eight patients responded to sirolimus, with 28 complete responses (CRs) and a median of 2 (2-5) months to response. Five patients had mucositis; the incidences of other adverse events were all less than 5%. Four patients relapsed, making the CR and overall response rate 46.7% and 75.6% at the end of follow-up. There were no differences in patient age, sex, time from diagnosis to sirolimus, serum sirolimus concentration, and disease distribution between CR and non-CR patients, or between responders and nonresponders, though AIHA patients were likely to relapse less and respond better. In conclusion, sirolimus is effective for patients with primary relapsed/refractory autoimmune cytopenia with a low relapse rate and good tolerance.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Hemolytic, Autoimmune; Autoimmunity; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Male; Middle Aged; Mucositis; Patient Safety; Purpura, Thrombocytopenic, Idiopathic; Recurrence; Retrospective Studies; Sirolimus; T-Lymphocytes, Regulatory; Thrombocytopenia; Treatment Outcome

Autoimmune cytopenias are characterized by immune-mediated destruction of hematopoietic cell lines with immune thrombocytopenia (ITP) affecting platelets and Evans syndrome (ES) affecting platelets and red blood cells. For patients with persistent disease, limited options for effective and well-tolerated therapies exist.. Our aim is to describe our institution's experience with sirolimus as therapy for pediatric patients with persistent ITP and ES.. A retrospective analysis was performed in patients with persistent ITP and ES treated with sirolimus. Responses were categorized as complete response (CR), partial response, modest response, or no response.. Of the 17 patients treated, 12 had ITP and 5 had ES. Seventy-three percent of ITP patients achieved a CR, 78% of them by 3 months. Only 2 patients did not achieve a durable response. Eighty percent of ES patients had a response, with 50% of them achieving CR and the other 50% an asymptomatic partial response. One patient with ES achieved modest response, but discontinued therapy due to an adverse effect. Of the patients that achieved CR, 90% remain off all therapy for a median of 2 years.. Our data suggest that sirolimus is a safe and effective steroid-sparing agent in the treatment of persistent ITP and ES.

Topics: Adolescent; Anemia, Hemolytic, Autoimmune; Child; Female; Humans; Infant; Male; Purpura, Thrombocytopenic, Idiopathic; Remission Induction; Retrospective Studies; Sirolimus; Thrombocytopenia; Treatment Outcome; Young Adult

Topics: Anemia, Hemolytic, Autoimmune; Disease Management; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Middle Aged; Salvage Therapy; Sirolimus; Tacrolimus; Transplantation, Homologous; Waldenstrom Macroglobulinemia

A 9-month-old boy with life-threatening multiresistant pure red cell anemia/autoimmune hemolytic anemia within the frame of a possible, undiagnosed immune-mediated disease was initially treated with prednisone. Further-line therapies of the following 7 relapses included immunoglobulins, rituximab, cyclophosphamide, and alentuzumab followed by other maintenance treatments as cyclosporine, methotrexate, and mycophenolate. After all the administered therapies failed, the patient was successfully treated by splenectomy followed by fludarabine and then sirolimus as maintenance treatment. Relapses might have been caused by the lack of a complete debulking of triggering cells and/or ineffective maintenance therapy. Splenectomy and sirolimus may have played a complementary role in the management of both situations.

Topics: Anemia, Hemolytic, Autoimmune; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drug Resistance; Humans; Infant; Male; Red-Cell Aplasia, Pure; Sirolimus; Splenectomy; Treatment Outcome; Vidarabine

Topics: Anemia, Hemolytic, Autoimmune; Child, Preschool; Drug Resistance; Female; Humans; Immunosuppressive Agents; Infant; Male; Sirolimus

AIHA is a rare and serious complication of solid organ transplantation. Herein, we report four cases of warm or mixed AIHA in pediatric patients following combined liver, small bowel and pancreas transplant. The hemolysis was refractory to multiple treatment modalities including steroids, rituximab, IVIG, plasmapheresis, cytoxan, discontinuation of prophylactic penicillin, and a change in immunosuppression from tacrolimus to cyclosporine. All patients had resolution or marked improvement of hemolysis after discontinuation of maintenance of CNI and initiation of sirolimus immunosuppression. One patient developed nephrotic syndrome but responded to a change in immunosuppression to everolimus. Three of the four patients continue on immunosuppression with sirolimus or everolimus without further hemolysis, evidence of rejection or medication side effects. Based on our experience and review of similar cases in the literature, we have proposed a treatment algorithm for AIHA in the pediatric intestinal transplant patient population that recommends an early change in immunosuppressive regimen from CNIs to sirolimus therapy.

Topics: Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal, Murine-Derived; Calcineurin; Cyclophosphamide; Cyclosporine; Everolimus; Female; Hemolysis; Humans; Immunoglobulins, Intravenous; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Intestines; Liver Transplantation; Male; Medical Records; Nephrotic Syndrome; Pancreas Transplantation; Penicillins; Plasmapheresis; Retrospective Studies; Rituximab; Sirolimus; Steroids; Tacrolimus; TOR Serine-Threonine Kinases; Transplantation; Treatment Outcome

Topics: Adolescent; Adult; Anemia, Hemolytic, Autoimmune; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Sirolimus; Treatment Outcome; Young Adult

Autoimmune cytopaenia is a rare, but severe complication after solid organ transplantation. We retrospectively analysed 57 paediatric intestinal transplants performed in 49 patients between 1999 and 2009. Autoimmune cytopaenia was observed in six patients; it appeared after an average of 10 months post-transplant. Warm autoimmune haemolytic anaemia was developed in three patients, cold autoimmune haemolytic anaemia in one and two presented a mixed type. Incidence and causes for haematological cytopaenia such as the following were investigated: immunosuppression, major blood mismatch, viral infection, malignancy, passenger lymphocyte syndrome and lymphoproliferative disorders. Initial treatment included high-dose steroids, intravenous immunoglobulin, plasmapheresis and maintenance of body temperature above 37°C in those with cold autoantibodies. Inclusion of the spleen in multivisceral transplants seems to be an important risk factor. All patients, except one, relapsed after classic therapy, requiring additional treatments. Sirolimus conversion was performed in four patients. One died after infection. The immunosuppressive therapies associated with other concomitant factors, such as viral infections, lymphoproliferative disorders, graft-versus-host disease, passenger lymphocyte syndrome and the inclusion of the spleen as part of multivisceral graft seem to play an important part in the development of autoimmune processes after intestinal transplantation. Therapy is not well established, especially in those resistant to first-line treatment.

Topics: Alemtuzumab; Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Child; Female; Graft Rejection; Humans; Immunosuppression Therapy; Intestines; Lymphoproliferative Disorders; Male; Retrospective Studies; Sirolimus; Spleen; Transplantation, Homologous; Virus Diseases

Autoimmune hemolytic anemia (AIHA) has been reported to occur after renal transplantation, and typically does so in the first few weeks post-transplant. We report on a 3-yr-old child who developed cold AIHA nearly 1 yr after an ABO identical, living donor renal transplant from his mother. Numerous transfusions, pulse steroids, repeat plasma exchange treatments, and IVIG were unsuccessful. Nearly 3 wk into his illness, tacrolimus was changed to cyclosporine, and then to sirolimus, and resulted in a prompt response. He currently has a normal renal function and a normal hemoglobin level on sirolimus monotherapy.

Topics: Anemia, Hemolytic, Autoimmune; Child, Preschool; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kidney Transplantation; Nephrotic Syndrome; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome