Currently approved and standard of care therapies for ADA-SCID
Table 1 shows the three management options to treat ADA deficiency.
Table 1. Summary of historic outcomes from treatments for ADA SCID using different therapeutic modalities. IgRT, immunoglobulin replacement therapy; MUD inc UCB, matched unrelated donor including umbilical cord blood; mMUD, mismatched unrelated donor. Adapted from: Kohn, D.B. & Gaspar, H.B. J Clin Immunol (2017).
Haematopoietic stem cell transplantation (HSCT)
To date, there has been broad consensus among transplant physicians that donation from HLA-matched sibling (MSD) or family (MFD) donors without conditioning have been the standard of care when treating ADA-SCID. The current evidence base supports transplantation as early as possible, thus preventing infection and reducing the toxic impact of the high levels of systemic adenine metabolites that occur. In patients who already have an infection, it is recommended that transplantation, if done without conditioning, should occur as early as possible, the aim being to restore immune function. In specific incidences, transplantation may be used alongside enzyme-replacement therapy (ERT) to provide some endogenous immunity.
Both MSD and MFD are associated with good survival outcomes and good immune recovery has been observed with patients displaying effective T- and B-cell reconstitution. The role of cytoreductive conditioning in MSD/MFD transplantation has been raised, with some proponents suggesting that higher engraftment rates would be possible if it were used. However, the good outcomes observed over several decades of implementing unconditioned MSD/MFD transplants may make clinicians reluctant to alter a therapy they know is working well.
Historically, allogeneic HSCT from unrelated or haplo-identical donors produce less successful patient outcomes than those from MSD/MFD donors. However, despite their limitations, they have provided a vital, life-saving option for SCID disorders. To improve outcomes with allogeneic HSCT, new approaches, such as improved methods for graft manipulation (eg selective T-cell subset depletion) and improved supportive measures, have been developed. Improved survival and immune recovery outcomes have been shown when using haplo-identical transplants with α/β T-cell depletion for both SCID patients and those with other primary immune deficiencies, but no data currently exist for outcomes employing this depletion technique in ADA-SCID patients.
The choice between unrelated and haplo-identical donors is often based on the expertise and preference of the treating centre, and is complicated by the development of new methods to facilitate engraftment and minimising the risk of graft versus host disease. As such, many leading experts recommend that patients be referred to specialist SCID centres that have greater experience of managing these conditions and state-of-the-art approaches to treatment.
Enzyme replacement therapy (ERT)
ERT provides another option for the management of ADA SCID patients. Since approval by the FDA in 1990, purified bovine ADA conjugated to polyethylene glycol (PEG-ADA) has proven to be both life saving and sustaining in more than 100 patients. However, existing data point to long-term immune reconstitution being suboptimal and, compared with other methods which aim to provide immune restoration, PEG-ADA ERT is considered as supportive or a holding therapy until definitive curative treatment can be administered. Treatment is required throughout life and has a high cost ($200,000–$500,000 per year), meaning that the availability of PEG-ADA ERT is variable. Additional complicating factors are the maintenance of compliance in adolescent patients and the need for a successful transition to adult care centres.
An important clinical consideration for patients undergoing ERT is how it may impact on subsequent HSCT and gene therapy (GT) transplantation. ERT has been suggested to increase the risk of graft rejection in allogeneic HSCT via maintenance of the host immune system. Although some centres have not observed outcome differences in patients who did or did not receive PEG-ADA prior to transplant. For autologous GT transplants, withdrawal of ERT prior to marrow harvest has been used to produce a lymphopenic environment to drive de novo lymphocyte production from the gene-corrected graft. The optimal timeframes for stopping ERT prior to HSCT and GT transplant are still debateable, but currently these are thought to be 1–3 months and 1–2 weeks, respectively. These timeframes must be balanced, however, against the increased risk for infection once ERT is withdrawn.
PEG-ADA is also used as a bridging therapy to promote immune restoration and recovery from infection before allogeneic HSCT or autologous GT.
One of these subsequent trials investigated the use of an autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector encoding for the human ADA cDNA sequence. Starting in 2000, the trial used reduced-intensity, cytoreductive conditioning with low-dose busulfan – targeted to a specific low exposure – as a single agent in children with ADA-SCID who lacked an HLA-identical sibling donor. Compared with the combination of cytoreduction or myeloablative chemotherapy and pre- and post-transplant immune suppressive agents, this regimen showed low toxicity in the post-transplant clinical course. Additionally, the use of autologous cells eliminated the risk of graft-versus-host disease. In concordance with other ADA-SCID GT trials no cases of leukemic proliferation were observed. This is in sharp contrast with trials for other primary immune deficiencies such as X-linked SCID, Wiskott–Aldrich syndrome and chronic granulomatous disease. As reported in July 2016, for a median follow-up period, which included additional patients, of 6.9 years, the treatment was not associated with adverse events attributable to the ADA-transduced cells and 15/18 of the patients had restored immune function and protection against severe infection.3
On the basis of these trial results, the use of an autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence was approved for licensure by the European Medicines Agency.
- Hassan A, Booth C, Brightwell A, Allwood Z, Veys P, Rao K, et al. Inborn Errors Working Party of the European Group for Blood and Marrow Transplantation and European Society for Immunodeficiency. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency. Blood. 2012;120:3615–24.
- Gaspar HB, Aiuti A, Porta F, Candotti F, Hershfield MS, Notarangelo LD. How I treat ADA deficiency. Blood. 2009;114:3524–32.
- Cicalese MP, Ferrua F, Castagnaro L, Pajno R, Barzaghi F, Giannelli S, et al. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood. 2016;128:45–54.