Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1) deficiency

Cytidine triphosphate (CTP) synthase 1 is responsible for the catalytic conversion of uridine triphosphate (UTP) to CTP in lymphocytes. This reaction is important for the biosynthesis of nucleic acids, playing a key role in lymphocyte function and turnover. Lack of this enzyme due to mutation in CTPS gene is associated with impaired capacity of activated T and B-lymphocytes to proliferate in response to antigen-induced activation. Patients with this mutation all have ancestors from the North West of England and present in the first decade of life with severe acute and chronic herpes virus infections and recurrent infections with encapsulated bacteria. There is a high risk of EBV-driven lymphoma. This is a potentially life-threatening primary immune deficiency (PID) and long-term survival has not been reported. We report on 11 patients with CTPS1 mutations who underwent hematopoietic stem cell transplant (HSCT) at three UK centres (London, Manchester and Newcastle). The molecular diagnosis was made pre-HSCT in six patients and retrospectively in five patients who had undergone HSCT for previously undiagnosed life-threatening PID. All patients had the same homozygous NM_001905.3: c.1692-1G>C mutation (rs145092287) mutation and all the parents were heterozygous carriers. This mutation is known to lead to an abnormal transcript lacking exon 18 and complete lack of protein expression. Six patients had an affected 39 sibling. Patient 1 had 2 affected siblings who died of infection and hemophagocytic lymphohistiocytosis (HLH) in early childhood and patient 2 also had a sibling who died of overwhelming VZV and EBV infections before diagnosis. Pre-transplant features are summarized in Table 1. Systemic viral infections were seen in all patients, with acute and chronic EBV infections in nine patients, four suffering from EBV-driven lymphoproliferative disease (LPD) (two CNS and one lung) and one with EBV-driven HLH. Four patients had severe chickenpox. Five patients presented with chronic diarrhea. Four patients with EBV-driven LPD received rituximab and three EBV-specific cytotoxic T-lymphocytes (CTLs) (two pre-transplant and one post-transplant). The age of the patients at transplant ranged from 15 months to 17 years. The source of stem cells was peripheral blood (PB) in seven patients, bone marrow (BM) in three and cord blood (CB) in one. Eight received matched (10/10) donor stem cells, two had 1/10 mismatches and one received a haploidentical 6/10 transplant from his father as there were no suitable matched donor (Table 2). All but one received conditioning with fludarabine in combination with treosulfan (n=3), melphalan (n=4), treosulfan and thiotepa (n=1, the non-reduced intensity conditioning (RIC) protocol) or low dose busulfan (n=2)3 one received treosulfan and cyclophosphamide. All but one patient received serotherapy with alemtuzumab (n=8) or anti T cell globulin (ATG) (n=2). CD34+ cell dose ranged from 0.4 - 16.1 x 106/kg. Neutrophil engraftment (≥0.5 x 109 51 /L) occurred between day 11- 23 post-transplant. Ten had 100% CD3 donor engraftment and one had 76% in last follow up. Eight patients are alive with post-HSCT follow-up of 8 months to 22 years. All surviving patients have discontinued immunosuppression and six are off immunoglobulin replacement therapy. Patient 4 died 76 days post-HSCT following EBV CNS reactivation leading to obstructive hydrocephalus. She was treated with external ventricular drainage and three doses of 2 x 106 55 EBV-CTLs but died of multi-organ failure 4 56 . Patient 7 developed intractable gut inflammation due to a combination of adenovirus and CMV colitis and chronic graft versus host disease (cGvHD) and died at day +290 despite treatment with ganciclovir and cidofovir for the viral infections and corticosteroids, ciclosporin, tacrolimus and infliximab as anti-inflammatory drugs. Patient 8 developed mild acute skin GvHD post-transplant, but later suffered from intractable chronic skin GvHD (but no gut or liver disease) unresponsive to corticosteroids and extracorporeal photophoresis. Twelve months post-transplantation he developed a tremor and altered mental state progressing to coma and died 15 months post-transplant. Brain biopsy and magnetic resonance (MR) scan performed prior to death were indicative of progressive multifocal leukoencephalopathy (PML), although no JC, BK or astrovirus were isolated from cerebrospinal fluid (CSF) or brain tissue. CTPS1 deficiency is a serious life-limiting immunodeficiency with a high risk of death from VZV and EBV in the first decade of life. Seven (41%) of 17 patients worldwide with CTPS1 deficiency have died, three post and four prior to HSCT (one from fulminant VZV and the other three from fulminant EBV LPD). These deaths were prior to clinical availability of rituximab. However, mild clinical phenotype has previously been described. HSCT can be curative but is not without potential risks and complications. Kucuk et al also reported two siblings with this mutation who had successful transplantation. The current report is the largest series of children with CTPS1 deficiency who have undergone HSCT.The overall survival post-HSCT in this series was 72% which is slightly lower than seen after HSCT for other combined PIDs. Pre-transplantation, extra-nodal EBV-driven LPD of the brain and lung as well as fulminant VZV pneumonitis requiring ventilation in intensive care are major risks. The post-transplantation course can be challenging to even the specialist centres because of re-activation of EBV and other herpes viruses, particularly in the brain and gastrointestinal tract, but also because of the risk of unusually severe skin and gut cGvHD, the latter which may be partly fuelled by ongoing underlying low grade chronic viral infection. Both patients that developed fatal GvHD had transplants from 9/10 matched unrelated donors. Viral reactivation can be observed prior to donor T-lymphocyte engraftment post-transplant and perhaps virus-specific CTLs may be helpful in some of these patients. There is no doubt that HSCT can be curative in this condition and we recommend early transplantation before the onset of end-organ damage and for patients without fully matching family or unrelated donors, the consideration of ex-vivo T-cell depletion strategies.