Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency

Abstract

Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunodeficiency (SCID) known as severe combined immune deficiency caused by adenosine deaminase defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. We review the evidence currently available and propose a consensus management strategy. In addition to treatment of the immune deficiency seen in patients with ADA-SCID, patients should be followed for specific noninfectious respiratory, neurological, and biochemical complications associated with ADA deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal first-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in more than 100 patients with ADA-SCID who received gammaretrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT can be continued or reinstituted, and HSCT with alternative donors should be considered. The outcomes of novel HSCT, ERT, and HSC-GT strategies should be evaluated prospectively in "real-life" conditions to further inform these management guidelines.

Keywords: Adenosine deaminase deficiency; enzyme replacement therapy; gene therapy; hematopoietic stem cell transplantation; lentivirus; severe combined immune deficiency.

Conflict of interest statement

Conflict-of-interest disclosure:

A.A.: Principal Investigator of long-term follow up clinical trial of HSC-GT, sponsored by Orchard Therapeutics, who is the marketing authorization holder of Strimvelis in the European Union.

A.B.: No conflicts to declare.

E.G.: No conflicts to declare.

H.B.G.: Chief Scientific Officer at Orchard Therapeutics, who are the owners of Strimvelis in the European Union and who are the license holder for the lentiviral vector gene therapy studies. HBG is co-founder, employee and equity holder in the company.

D.B.K.: Consultant to Orchard Therapeutics as a member of their Scientific Advisory Board. Inventor on intellectual property licensed by UCLA and the UC Regents to Orchard Therapeutics.

J.M.P.: Spousal employment at Invitae, a clinical DNA sequencing company.

L.D.N.: No conflicts to declare.

M.S.H.: Has grants support from, and is a consultant to, Leadiant Biosciences.

Copyright © 2018 American Academy of Allergy, Asthma & Immunology. All rights reserved.

Figures

Figure 1:. Timeline for the institution of treatments for adenosine deaminase deficiency

Since the identification of adenosine deaminase defects as a cause for severe combined immune deficiency in 1972, there have been 3 main treatment approaches. Allogeneic hematopoietic stem cells with HLA matched sibling donors (MSD) or matched family donors (MFD) are most commonly used followed by HLA haploidentical and HLA matched unrelated donors (MUD). The stem cells have been obtained from bone marrow, peripheral blood mononuclear cells or umbilical cord blood. Enzyme replacement therapy relied initially on transfusions of red blood cells from healthy donors and subsequently on frequent injections of polyethylene glycol coupled to bovine ADA (PEG-ADA). Autologous ex-vivo corrected hematopoietic stem cell gene therapy used initially gamma-retroviruses to transduce the gene of interest into stem cells, while in recent years the ability of lentivirus is being studied. The addition of reduced intensity conditioning prior to gene therapy is now recognized as critical for the success of the procedure. In the last year, benefits from cryopreservation of the lentiviral vector transduced hematopoietic stem cells are being explored.

Figure 2:. Scheme of gamma-retrovirus and lentivirus based gene therapy with busulfan and discontinuation of enzyme replacement therapy.

After obtaining consent of patients/guardians for autologous hematopoietic stem cell (HSC) gene therapy, patients are screened and admitted for bone marrow (BM) harvest and conditioning with low dose busulfan, with adjustment in accordance to pharmacokinetics (pK) predetermined targets. CD34+ HSC are isolated, transduced with gamma retroviral vector (A) or lentiviral vector (B) containing the ADA gene, and reinfused through a central venous catheter (CVC). (A) For gamma-retrovirus, enzyme replacement therapy (ERT) is usually discontinued 14–21 days before gene therapy and patients are treated for 2 days with busulfan. (B) For Lentivirus based HSC-GT, patients are treated for 1 day with busulfan, and ERT is continued during gene therapy until 30 days after infusion.

Figure 3:. Effects of busulfan and continued enzyme replacement therapy for 30 days following lentiviral vector gene therapy for ADA deficiency on ADA and dAXP in patients’ red blood cells and Immune reconstitution.

Adenosine deaminase (ADA) activity (A), expressed as units of activity and deoxyadenosine phosphates (dAXP) percentage in red blood cells (B), as well as the number of CD3+ T cells (C) and CD19+ B cells (D) in the peripheral blood of patients with ADA deficiency 0–24 months after hematopoietic stem cell gene therapy. Results are the mean and standard deviation from interim analysis of 20 patients treated at the UCLA Mattel Children’s Hospital, Los Angeles, Cal, through their most recent study time-point. Normal ranges are ADA activity (A) are 63 ±41 nmol/h/mg, %dAXP (B) th-90th%ile) at 1–2 years of age for CD3+ and CD19+ cells are 2.10–6.20 cells/μl × 10–3 and 0.72–2.60 cells/μl × 10–3; respectively.

Figure 4:. Timeline for the development of adenosine deaminase deficiency hematopoietic stem cell gene therapy

After the identification and cloning of the cDNA for ADA, retrovirus vectors were developed to efficiently deliver ADA. In 1990 the first gene therapy trial was initiated at the National Institute of Health (NIH), using patient’s peripheral blood lymphocytes (PBL) followed by the use of CD34+ hematopoietic stem cells. Since 2000, the use of busulfan has been gradually incorporated into HSCT-GT, including lentivirus based trials. In 2016, Strimvelis was approved for clinical use in the EU. Currently the effect of cryopreservation of transduced cells is being explored.

Figure 5:. Scheme of cryopreserved lentivirus based gene therapy with pK-adjusted busulfan and continued enzyme replacement therapy.

After obtaining consent of patients/guardians for autologous hematopoietic stem cell gene therapy patients are screened and admitted for bone marrow (BM) harvest. CD34+ cells are isolated from the bone marrow, transduced by lentivirus containing the ADA gene, and cryopreserved. Approximately 30 days later, the patient is admitted again, central venous catheter (CVC) is inserted and the patient is treated with busulfan at dosages that are adjusted in accordance to predetermined pharmacokinetics (pK) targets. Enzyme replacement therapy is discontinued 30 days after the hematopoietic stem cell-gene therapy (HSC-GT).

Figure 6:. Consensus algorithm for the management of infants diagnosed with ADA-SCID

Following the diagnosis of severe combined immune deficiency (SCID) caused by inherited defects in adenosine deaminase (ADA) deficiency is established, all patients should receive enzyme replacement therapy, while monitoring for efficacy. Human Leukocyte Antigens (HLA) typing of the patient and close family members should be completed. Infections prophylaxis should be provided in accordance to the guidelines for SCID. Two equal first line treatment options should then be considered. Patients should proceed to receive allogeneic hematopoietic stem cell transplantation (HSCT) from HLA matched sibling donor (MSD) or HLA matched family donor (MFD) donor, if available. Alternatively, eligible patients should proceed to receive autologous hematopoietic stem cell gene therapy (HSC-GT), if available. If HSC-GT or HSCT are not available or are unsuccessful, patients should continue ERT while considering HSCT using alternative sources such as HLA matched unrelated donor (MUD) or HLA haploidentical family members. Following treatment, patients should be monitored for abnormalities associated with ADA deficiency and for maintained immune reconstitution. Should treatment fail, patients should be re-considered for the different management options.