HSCT for adults with immunodeficiencies

In this issue of Blood, Albert et al¹ present compelling evidence that allogeneic hematopoietic stem cell transplantation (HSCT) is a highly feasible and potentially curative approach for adults with inborn errors of immunity (IEI).

Inborn errors of immunity (IEI) include a constellation of diseases that cause immune system dysfunction. The classic example of IEI is severe combined immunodeficiency (SCID), which usually presents with life-threatening infections in infants with T-cell (and potentially other lymphoid) defects found on molecular testing to identify the genetic mutation. Allogeneic hematopoietic stem cell transplantation (HSCT) is indicated for SCID and many other IEI that present in early childhood. HSCT in SCID, Wiskott-Aldrich syndrome, and similar diseases has an excellent outcome when performed at an earlier age, partly attributable to children having accumulated fewer infections and IEI-related complications.^2-6 

By contrast, IEI in adolescents and adults represent an entirely different category of disease. Many adults lack a definitive molecular diagnosis, making it a challenge to predict the natural history of their disease. This also makes the risk/benefit ratio for allogeneic HSCT difficult to calculate. Adult patients with IEI may accumulate complications such as lung disease, hepatic dysfunction, or prior splenectomy, which may increase a patient’s risk for HSCT. There are limited data on the outcomes of HSCT in adults with IEI and whether they have higher rates of HSCT-associated complications, including transplant-related mortality, graft failure, or graft-versus-host-disease (GVHD).^7-9 Collectively, this has left hematologists, immunologists, and HSCT physicians with insufficient data to make the crucial decision of when and if an adult with IEI should be referred for transplantation. In addition, it is unclear whether specific comorbidities make HSCT-associated risks unacceptable. To address this issue, Albert et al performed the largest (>300 patients) retrospective, multicenter analysis to date of adult patients with IEI who received allogeneic HSCT. From these data, several critical conclusions can be drawn.

First, survival exceeded 70% at 5 years after HSCT across this highly heterogenous group of IEI patients. Additionally, even with most patients receiving unrelated donors as their graft source, the incidence of GVHD was acceptable (8% with grade III-IV acute GVHD and 19% with chronic GVHD at 5 years) and the incidence of graft failure was <10%. Many researchers had assumed that adult patients with IEI would have high rates of GVHD and graft failure, thus representing a contraindication to HSCT, especially if a nonmyeloablative conditioning regimen was chosen.

Second, patient-specific prognostic indicators were identified. Specifically, IEI-associated complications such as bronchiectasis, prior splenectomy, and hepatic dysfunction were associated with inferior outcomes. While higher Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI)¹⁰ scores portend inferior survival,¹ this risk score often lacks granularity. These additional comorbidities, which are often specific to patients with IEI, can help guide treatment decisions in this specific patient population. This finding suggests that either referral for HSCT should occur prior to the development of these comorbidities or treatments should be given to mediate these comorbidities to decrease transplant-associated risks.

Ultimately, the data from Albert and colleagues with the Inborn Errors Working Group of the EBMT has given compelling evidence to support the finding that adults with IEI have excellent outcomes with allogeneic HSCT, especially if done prior to end-organ damage from the IEI. This conclusion suggests that early referral to transplantation be considered for adults diagnosed with IEI because it represents a curative option. However, IEI are a heterogeneous group of disorders, and each specific subtype has different long-term outcomes and complications that must be considered independently. In addition, given the retrospective nature of the study, the indications for referral for HSCT were not available. Selection bias may skew the findings (patients referred as a “last resort” or referred because they are deemed in favorable health). Therefore, a prospective trial is the only way to definitively address this issue. Additionally, a prospective study would help determine whether HSCT helps improve or reverse complications associated with underlying disease in this age group, as can be seen in younger patients.⁵ It is promising to note that post-HSCT adults have good performance scores and high rates of participation in school or work, but further information on disease status and ongoing medical needs would be helpful to guide decision-making.

This study has the potential to change the paradigm of how adults with IEI are treated with HSCT. Age alone should not be a barrier to transplantation. Adult patients with IEI should be considered for transplantation, especially prior to accumulating complications that raise their HSCT-related risks.

Conflict-of-interest disclosure: The authors declare no competing financial interests.