Rapid full engraftment and successful immune reconstitution after allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in Omenn syndrome

Abstract

OS is a variant of SCID characterized by generalized erythroderma, alopecia, eosinophilia, and elevated IgE levels. It is fatal unless treated with allogeneic HSCT, which is the only curative approach. However, treatment related complications and graft rejection are major obstacles to the success of treatment. In this report, we describe a patient with OS, complicated by prolonged cytomegalovirus infection, successfully treated by reduced intensity conditioning allogeneic HSCT from sibling donor.

Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications

“…[4][5][6][7] To date, allogeneic hematopoietic stem cell transplantation (HSCT) is the only beneficial therapeutic approach, although at high risk because of the myeloablative conditioning regimens necessary to eliminate autoreactive T lymphocytes and achieve successful engraftment. [8][9][10] We have recently generated and characterized a knock-in Rag2 R229Q mouse model, carrying a hypomorphic mutation in the Rag2 gene (R229Q), initially identified in patients with OS or with leaky SCID. [10][11][12] The RAG2 R229Q mouse model closely recapitulates the human disease as mice display an expansion of oligoclonal and activated T cells which infiltrate target organs including skin, gut, liver, and lung, 13 and high levels of serum IgE, despite a severe arrest of B-cell development in the bone marrow.…”

Successful second bone marrow transplantation in Omenn’s syndrome after bone marrow aplasia: A case report

“…Myeloid engraftment was established 11 days post‐second BMT with stable hematological parameters. Conditioning chemotherapy and specific anti‐T‐cell agents are considered necessary before and after hematopoietic stem cell transplantation (11), and because of a high failure rate in case of T‐, B‐SCID (16); our patient underwent BMT with reduced intensity conditioning (based on fludarabine and ATG), which is increasingly used as an alternative to conventional myeloablative conditioning regimens (4, 17), and it is well tolerated even in high‐risk patients with pre‐existing organ dysfunction (18).…”

“…High serum IgE levels, absent or markedly decreased B cells and hypogammaglobulinemia (1–3) are other features of this disease. NK cell function and absolute numbers are unaffected (4). Omenn’s syndrome is inevitably fatal if untreated owing to increased susceptibility to infections with a high mortality rate early in life.…”

“…To date, allogenic hematopoietic stem cell transplantation is the only treatment shown to be potentially curative (5). Transplantation using marrow from a genotypically identical sibling donor remains the treatment of choice in patients with Omenn’s syndrome (4, 6, 7). Standard myeloablative conditioning regimens are used for marrow transplantation in patients with Omenn’s syndrome (7), but non‐myeloablative (5) and non‐preparative regimens have also been attempted (1).…”

Omenn syndrome does not live by V(D)J recombination alone

“…Complete ablation is required to eliminate autoreactive T cells in Omenn syndrome; however, the use of an intense conditioning regimen is one of the main causes of transplant-related mortality, particularly in patients suffering from organ damage [52]. For this reason, reduced intensity conditioning may be an alternative for patients with active infections at the time of transplantation [53], although it has been associated with less engraftment, rejection and graft versus host disease (GVDH) [54,55]. With the aim of avoiding adverse events due to the conditioning regimen and HSCT complications, innovative therapeutic approaches have been explored.…”