Successful treatment of mixed‐type autoimmune hemolytic anemia with rituximab in a child following liver transplantation

Haller W, Hind J, Height S, Mitry R, Dhawan A. Successful treatment of mixed‐type autoimmune hemolytic anemia with rituximab in a child following liver transplantation.
Pediatr Transplantation 2010: 14: E20–E25. © 2009 John Wiley & Sons A/S. Abstract: Development of a severe form of mixed‐type AIHA after orthotopic liver transplantation is a rare, but a life‐threatening event. We report a case of mixed‐type AIHA that developed in a child after hepatocyte and living‐related orthotopic liver transplantation for factor VII deficiency.     

Successful treatment with rituximab and mycophenolate mofetil of refractory autoimmune hemolytic anemia post‐hematopoietic stem cell transplant for dyskeratosis congenita due to TINF2 mutation

AIHA following allogeneic HSCT is appearing more frequently in the literature. It occurs as a result of donor cell‐derived antibodies targeting donor red cell antigens. Little guidance exists on the management of such patients, particularly in the pediatric setting. First‐line conventional treatment is corticosteroids and/or immunoglobulin therapy with monoclonal antibody therapy reserved for treatment failure. We report our experience of a child refractory to immunoglobulin and steroid therapy who required several infusions of rituximab and immunomodulatory therapy to obtain a clinically significant response.     

Successful treatment with daratumumab for post‐HSCT refractory hemolytic anemia

Autoimmune cytopenias (AIC) following allogeneic hematopoietic stem cell transplantation (HSCT) may cause significant morbidity and mortality and are often challenging to treat. We present a case of a pediatric patient with primary myelofibrosis of infancy caused by VPS45 protein deficiency, who developed severe refractory hemolytic anemia and immune‐mediated thrombocytopenia 3.5 months following HSCT. After the failure of several treatments, he received daratumumab, an anti‐CD38 specific antibody, and demonstrated fast and sustained response. The only side effect was delayed recovery of humoral immunity. Daratumumab, by targeting antibody‐producing plasma cells, may be a valid treatment option for refractory post‐HSCT AIC.     

Successful treatment of tacrolimus‐related pure red cell aplasia and autoimmune hemolytic anemia with rituximab in a pediatric cardiac transplant patient

Acquired pure red cell aplasia (PRCA) and autoimmune hemolytic anemia (AIHA) are rare complications of immunosuppression in pediatric solid organ transplant patients. We report a 14‐month‐old female child who developed Coombs positive hemolytic anemia and reticulocytopenia while on tacrolimus after cardiac transplantation. She was successfully treated with rituximab after failing treatment with corticosteroids and intravenous immunoglobulins. Clinicians should consider PRCA differential diagnosis in a patient presenting with reticulocytopenia and hemolysis. In addition, the coexistence of PRCA with AIHA, and the response to therapy with rituximab, supports a common immune‐mediated pathogenesis for both disorders.     

Successful treatment with the monoclonal antibody rituximab in two children with refractory autoimmune thrombocytopenia

Rituximab is a chimeric monoclonal antibody directed against normal and malignant mature B-lymphocytes and results in prolonged and severe B-cell depletion. Recently, rituximab has been successfully used in adult and paediatric disorders of B-lymphocytes such as autoimmune haemolytic anaemia and Werlhof disease. We report on two children with chronic immune thrombocytopenic purpura (ITP) refractory to steroids and immunoglobulins who achieved complete normalisation of their platelet counts after treatment with rituximab, 375 mg/m² given weekly in four doses. In both cases the B-lymphocyte count dropped to zero after the second dose of rituximab and an unsupported platelet count >100×10⁹/l was achieved during treatment. Six and 12 months after treatment, both patients remain well with normal platelet counts. Conclusion: this report supports the concept that rituximab may also be a valuable therapeutic option in children with chronic immune thrombocytopenic purpura refractory to standard treatment. Controlled clinical trials are needed to evaluate the efficacy and long-term side-effects of rituximab in this group of patients.Abbreviations ITP immune thrombocytopenic purpura - IVIG intravenous immunoglobulinsSupported in part by the Regione del Veneto Ricerca Sanitaria Finalizzata n 107/02.     

Bortezomib for autoimmune hemolytic anemia after intestinal transplantation

AIHA is rare in the general population and associated with a mortality of 8%. In contrast, AIHA occurs in up to 12.2% of cases after intestinal transplantation and is associated with mortality up to 50%. Treatment entails a “step‐up” approach including corticosteroids, IvIg, plasmapheresis, and rituximab. However, AIHA after transplantation often is refractory to this strategy, contributing to a poor outcome. We describe a child with microvillous inclusion disease who developed AIHA 1 year after multivisceral transplantation that was refractory to standard therapy and was subsequently treated with bortezomib.We observed remission of AIHA within 1 week after the start of bortezomib. Bortezomib was associated with transient diarrhea, leucopenia, and elevated liver enzymes. Three years later, he remains in remission without important complications. Published data on bortezomib for autoimmune cytopenias outside SOT are discussed. This is the first report to support bortezomib as an important therapeutic alternative for AIHA after SOT. The occurrence and treatment of AIHA after SOT, and specifically intestinal transplantation, should be the subject of future registry studies to collect additional experience and explore the optimal therapeutic approach.     

Rituximab for treatment of autoimmune hemolytic anemia

We report the successful use of rituximab as single treatment modality in a five-month-old boy with fulminant warm autoantibody autoimmune hemolytic anemia, resistant to standard treatment. On admission, laboratory tests showed a profound anemia with a hemoglobin of 2.6 g/dL. Indirect and direct antiglobulin tests were strongly positive, and nonspecific IgG autoantibodies were detected. Two days of intravenous corticosteroids (methylprednisolone 4mg/kg) and immunoglobulins (1g/kg) did not halt the hemolysis and the infant was severely transfusion-dependent. Rituximab 375mg/sq m weekly was given for 4 weeks, the hepatosplenomegaly gradually regressed, the lymphocytes normalized and he is free from hemolysis two years after treatment.     

Successful induction and maintenance of long-term remission in a child with chronic relapsing autoimmune hemolytic anemia using rituximab

Childhood autoimmune hemolytic anemia (AIHA) of the warm type is usually successfully managed with corticosteroids and/or immunoglobulin infusions. In a small proportion of patients AIHA follows a more severe and protracted pathway resulting in the use of immunosuppressive therapy and frequently culminating with the need for splenectomy. Rituximab is an anti-CD20 (B-cell) monoclonal antibody used for the treatment of patients with relapsed or refractory low-grade or follicular, CD20 positive, B-cell non-Hodgkin's lymphoma. Case reports on the use of rituximab for childhood AIHA are scant. The authors describe the first report in which rituximab was effectively employed to induce a long-term remission in a young child with the longest history of chronic relapsing AIHA prior to receiving rituximab. All immunosuppressive therapy was successfully discontinued and splenectomy was avoided.     

Successful treatment of refractory Langerhans cell histiocytosis by allogeneic peripheral blood stem cell transplantation

We describe a six-yr-old boy who exhibited typical signs and symptoms of LCH with EBV-associated hemophagocytic syndrome from the age of 15 months. Multiple courses of conventional chemotherapy achieved only marginal improvement over the ensuring five yr. During this period, this boy experienced recurrent episodes of hemophagocytic syndrome associated with CMV infection. Five yr after the first diagnosis of LCH, the patient was treated with allogeneic PBSCT from his HLA-identical eight-yr-old brother. PBSCT was performed using a TBI-incorporating conditioning regimen comprising TBI, busulfan, and cyclophosphamide. Diabetes insipidus, typically a permanent consequence of LCH, was well controlled by DDAVP therapy. At the time of writing, this boy is alive and well, and had been disease-free for more than two yr after the PBSCT.     

Successful treatment of Bacillus cereus meningitis following allogenic stem cell transplantation

We report the case of a 19-yr-old boy, who received an allogeneic stem cell transplantation for the second relapse of Hodgkin's disease. The patient developed seizures and flaccid hemiparesis on day +10. Meningoencephalitis induced by Bacillus cereus was diagnosed. The treatment consisted of appropriate antibiotics, G-CSF and removal of the central venous line. Infection control and nearly full neurological recovery was achieved. Immunocompromised patients susceptible to B. cereus infection, indicated by the isolation of B. cereus in prior cultures, should receive antibiotic treatment covering B. cereus.     

Allogeneic hematopoietic stem cell transplantation in children with sickle cell disease

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment for sickle cell disease (SCD), being successful in around 85-90% of patients. Mortality and long-term morbidity (including infertility, gonadal failure, and chronic graft-vs.-host disease) associated with conventional approaches curtail the number of patients who undergo allo-HSCT. Recently, it has been demonstrated that cord blood is as effective as and possibly safer than bone marrow in pediatric patients with SCD. Likewise, transplant strategies based on the use of reduced-intensity regimens and the induction of mixed chimerism have been explored to decrease allo-HSCT short- and long-term complications.     

Development of hemolytic paroxysmal nocturnal hemoglobinuria without graft loss following hematopoietic stem cell transplantation for acquired aplastic anemia

PNH is the most common clonal hematopoietic disorder arising in patients with aAA. PNH is caused by mutations in PIGA, a gene that encodes the catalytic subunit of an enzyme involved in the biosynthesis of GPI anchors, transmembrane glycolipids required for cell surface expression of many proteins. PNH clones likely arise as immune escape mechanisms in aAA by preventing CD1D‐restricted T‐cell recognition of GPI anchors and GPI‐linked autoantigens. Though many patients with aAA treated with IST will develop subclinical PNH clones, only a subset will develop PNH disease, characterized by increased thrombosis, intravascular hemolysis, and potential for severe organ dysfunction. In contrast to IST, allogeneic HSCT for patients with aAA is thought to cure bone marrow aplasia and prevent hematopoietic clonal evolution to PNH. Herein, we present a phenomenon of host‐derived PNH disease arising in a patient with aAA many years following MSD‐BMT, highlighting the importance of monitoring for this clonal disease in aAA patients with stable mixed donor/recipient chimerism after HSCT. We also provide a literature review for similar occurrences of PNH arising after HSCT.