The earlier, the better: RAG-deficient transplants

In this issue of Blood, Schuetz et al¹ describe the largest international cohort of patients with combined immunodeficiency and autoimmunity caused by hypomorphic RAG variants who received a hematopoietic stem cell transplant (HSCT).^2-4 The only curative option for these patients with hypomorphic mutations in RAG1 and RAG2 genes is HSCT, but the outcome data are sparse, mostly reported for complete loss of function.

The data reported in this comprehensive international multicenter effort examined risk factors for HSCT such as older age of diagnosis, persistent infection prior to and at time of transplant, organ damage at the time of transplant, and presence of autoimmunity at the time of transplant. Residual T-cell function in these patients can lead to a higher risk of graft rejection, increasing the risk of morbidity and mortality after transplant. Donor selection as well as type of conditioning used are extremely important elements to consider at the time of preparing these patients for an HSCT.⁵ HSCT was performed at a median age of 3.5 years. Most patients received a matched unrelated donor transplant (48%), with the remainder receiving matched sibling/family donor (22%), mismatched family donor (18%), or mismatched unrelated donor (12%). T-cell depletion of the graft was performed in 25% of the patients, either by CD34 selection or αβ depletion. Serotherapy was administered in 49 patients. There was an equal distribution of the different intensity conditioning regimens: myeloablative, reduced toxicity, and reduced intensity/nonmyeloablative. Overall survival of the entire cohort was 77.5% at 1 year and 67.5% at 4 years after HSCT, with most patients dying of infections. Pre-HSCT organ damage (univariate and multivariate) and/or active infections (univariate) were associated with decreased overall survival, whereas autoimmunity had no impact. Therefore, prevention of infection and subsequent end organ damage are paramount to improved survival. T-cell depletion of the graft had a significant negative impact on survival, in addition to using a mismatched family donor, whereas intensity of the regimen posed no impact on survival. Interestingly, only 7 patients had graft failure, with most patients with donor chimerism (>90%), further delineating that good donor chimerism is achieved with a variety of conditioning regimens. Severe acute graft-versus-host disease was minimal, whereas chronic graft-versus-host disease (22%) remained problematic. Prompt and more robust CD4 immune recovery was seen in patients without infections, organ damage, or autoimmunity. Although autoimmunity had no impact on survival, it did seem to impact the CD4 recovery, suggesting that tight control of autoimmune manifestations leads to better CD4 recovery. Therefore, lower disease burden, early diagnosis, and HSCT improve thymic recovery and enhance survival.

Given that conditioning regimens did not impact survival but infections did, future studies are needed to evaluate the use of serotherapy and the kinetics of immune recovery in respect to infection-related mortality. In addition, mismatched family donors and T-cell depletion should be avoided because of their negative impact on survival. Alternatively, cord blood products could be an attractive donor option to avoid delayed transplantation with its increased risk of end organ damage and life-threatening infections, as the regimens avoid serotherapy.^6,7 Recently, a single center cohort of 45 patients with immunodeficiency (35 severe combined immunodeficiency [SCID]), including 7 RAG cord blood transplants, showed very robust engraftment and early immune recovery with 91% survival after 2 years.⁸ 

In the era of newborn screening (NBS) for SCID, early detection and diagnosis has led to decreased infection-related mortality after transplant. As reported by Schuetz et al in 2014,⁵ 8 patients were diagnosed by NBS, and survival was improved in patients aged <3.5 months, which is in line with historic data for transplant in SCID.^3,4 Hypomorphic RAG variants may still be missed, making early diagnosis more challenging. In addition, approximately one-third of these patients still present to transplant with active infections, even in the NBS era. For patients with complicated immune deficiency/dysregulation disorders such as hypomorphic RAG deficiency, efforts should be directed towards selecting donors and conditioning regimens associated with a prompt and more robust immune recovery, especially in the setting of pretransplant infections.

Conflict-of-interest disclosure: L.R.F.S. was a consultant for Enzyvant, Takeda, Grifols, ADMA, Incyte, and Horizon. C.M. reports no competing financial interests.