Unrelated donor HCT without chemotherapy for SCID: promise and problems

Published Online: August 7, 2014

The recent expansion of newborn screening for early detection of patients with severe combined immunodeficiency (SCID) has highlighted the clinical quandary of how best to perform a hematopoietic cell transplant (HCT) in a very young infant who is lacking an HLA-matched sibling donor (MSD). Patients with SCID are mostly incapable of rejecting cells from well-matched donors, therefore classically MSD HCTs have been performed without any prior conditioning. However, the majority of recipients of cells from an unrelated donor (URD) have been given conditioning chemotherapy.

Now, in a study recently published in The Journal of Allergy and Clinical Immunology, C. Dvorak and colleagues present the multi-center experience of performing unrelated donor HCT without chemotherapy from the North American Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party of the European Blood and Marrow Transplant Society (IEWP-EBMT).

The authors of this study hypothesized that well-matched URDs, including both adults and umbilical cord blood, could approximate the experience of a MSD and be infused without conditioning. They collected data on 37 such cases performed over the last 19 years and compared their outcomes to 66 MSD HCTs performed at the same centers and timeframe.
While most patients were able to achieve donor T-cell engraftment, 5-year survival rates were inferior in the URD compared to the MSD recipients (71% vs. 92%), partly explicable by an approximately one-month additional delay from diagnosis to HCT while locating a URD, and also by significantly higher rates of acute and chronic graft-versus-host disease (GVHD) in the URD recipients. In the surviving patients, there was no significant difference in the degree of T-cell reconstitution, however, far more MSD recipients went on to develop freedom from gammaglobulin replacement. The use of serotherapy before HCT was associated with significantly improved outcomes in the URD patients, possibly via a reduction in GVHD and possibly due to a selective administration only to those patients who were healthier at the time of HCT.

This study provides proof of concept that URD HCT can be performed in patients with SCID without the use of chemotherapy. However, very careful attention must be paid to GVHD prophylaxis and clinicians must recognize that B cell function is unlikely to be restored. Many SCID patients are now being discovered at less than a month of age while still clinically well, and there is a controversy about how and when to proceed with an HCT from a non-MSD if chemotherapy conditioning is planned. These data significantly add to the ensuing discussion about the relative need for chemotherapy-based conditioning, and the highlight the possibility of a two-phase approach, i.e., an initial HCT without conditioning to achieve T cell reconstitution, followed 2-3 years later in those patients who do not reconstitute B cell immunity by a second HCT from the same donor with limited cytoreducing chemotherapy. They also provide a baseline for future prospective trials of low-dose chemotherapy or novel conditioning agents.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

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