Treatment of adenosine deaminase (ADA) deficient severe combined immune deficiency (SCID) via gene therapy (GT) or allogeneic hematopoietic cell transplant (alloHCT) using a matched sibling or matched family donor both confer a five-year overall survival (OS) rate of 100%, according to a report published in Blood. The report showed no statistically significant difference in survival outcomes between alloHCT and GT in patients treated in the contemporary era (i.e., after the year 2000) with no active infection at the time of transplant.
These results may change clinical practice when it comes to the treatment of ADA-SCID, explained corresponding author Geoffrey Cuvelier, MD, of CancerCare Manitoba in Canada.
SCID newborn screening has been widely available in the U.S. and most of Canada since the year 2000, increasing the likelihood of early diagnosis prior to infection, which can predict successful hematopoietic cell transplant (HCT). Consequently, contemporary era HCT outcomes should be re-examined, the authors noted.
There are three main treatment courses for ADA-SCID including PEGylated ADA enzyme replacement therapy (ERT), alloHCT, and ex vivo autologous GT. However, ERT alone often fails to foster complete immune reconstitution, so many patients are treated with ERT followed by alloHCT (ERT-HCT) or GT (ERT-GT). These treatment regimens still pose challenges, though, as GT remains limited in availability and ERT-HCT has raised concerns about engraftment success.
Dr. Cuvelier and colleagues evaluated 131 patients with ADA-SCID who were enrolled in the Primary Immune Deficiency Treatment Consortium (PIDTC) and diagnosed between 1982-2017, the largest cohort to date, to analyze various treatment outcomes.
Researchers sought to answer the following questions:
- Does ERT-HCT affect survival outcomes?
- What are the differences in immune reconstitution, event-free survival (EFS), and OS between alloHCT and GT?
- How do alloHCT and GT compare as ADA-SCID treatments in the contemporary era when newborn screening increases the chance of diagnosis soon after birth and while free of infection?
Patients were enrolled in one of two PIDTC protocols: 6,901, a prospective natural history study that included patients diagnosed with SCID from 2010 on; or 6,902, a retrospective and cross-sectional study that included patients diagnosed with SCID from 1968-2012.
Patients were grouped based on the type of treatment received: ERT only, HCT only, ERT-HCT, or ERT-GT. Median age at diagnosis was 58 days (range = 0-4,635 days). Most patients were diagnosed in the contemporary era (n=85, 64.8%) and met criteria for typical SCID (85.5%). The remaining 14.5% met criteria for leaky SCID.
To address survival outcomes in patients who receive ERT in addition to cellular therapy, Dr. Cuvelier and colleagues compared the frequency of autoimmunity at the time of first definitive cellular therapy for the HCT only group versus the ERT-HCT and ERT-GT groups. Results showed no statistically significant difference (p=0.45) in the impact on survival outcomes.
No significant difference in immune reconstitution across groups was noted, although data were incomplete. However, results showed a five-year EFS of 49.5% with HCT, 73% with ERT-HCT, and 75.3% with ERT-GT. Results also demonstrated a five-year OS of 72.5% with HCT (100% for HCT from a matched sibling or matched family donor), 79.6% with ERT-HCT, and 100% with ERT-GT.
According to Dr. Cuvelier, medical professionals have previously avoided alternative donor sources for alloHCT like matched unrelated donors based on the results of a 2009 study that showed less successful outcomes with HCT from these sources.
In the current PIDTC study, patients who received HCT from any donor source without active infection and at 3.5 months of age or younger had no significant differences in EFS or OS compared to those who received ERT-GT with the same parameters (five-year EFS and OS were 75.3% and 90.9%, respectively, for HCT and 75.3% and 100%, respectively, for GT.)
“We showed, however, that when any form of transplant was done in a contemporary era, and when the patient was free from infection at the time of transplant, five-year [EFS] and five-year [OS] were not statistically significantly different than gene therapy,” Dr. Cuvelier said.
Moreover, patients who are unable to access GT after completing ERT may be considered for alternative donor HCT so long as they are without active infection. Looking forward, a new PIDTC study, 6,907, will continue to explore the outcomes of cellular therapy across 47 North American centers.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Cuvelier GDE, Logan BR, Prockop SE, et al. Outcomes following treatment for adenosine deaminase deficient severe combined immunodeficiency: a report from the PIDTC [published online ahead of print, 2022 June 7]. Blood. doi:10.1182/blood.2022016196.