Hematopoietic stem cell transplantation for purine nucleoside phosphorylase deficiency: an EBMT-IEWP retrospective study

Abstract

Purine nucleoside phosphorylase (PNP) deficiency causes inadequate purine metabolite detoxification, which leads to combined immunodeficiency and variable neurologic symptoms. Hematopoietic stem cell transplantation (HSCT) cures the immunodeficiency, but large studies on the long-term outcomes are lacking. In a retrospective study of the European Society for Blood and Marrow Transplantation, we investigated 46 patients with PNP deficiency from 21 centers. We analyzed the presenting clinical signs and outcomes after HSCT. Cognition (0-3), hearing (0-3), interaction (0-4), movement (0-4), and occupation (0-3) (CHIMO) were scored at the last follow-up (FU) visit (no impairment, 17; mild, 15-16; moderate, 12-14; and severe impairment, <12). The median age at initial presentation was 7.5 (1-48) months. The patients presented with infections (41%), neurological dysfunction (39%), both (15%), or autoimmune disease (5%). At the time of HSCT (median age, 26 [2-192] months), neurological abnormalities were observed in 88% of patients. After a median FU of 7.9 (1.0-22.3) years, 40 patients were alive with a 3-year overall survival (OS)/event-free survival (EFS) probabilities of 86% (confidence interval [CI], 77%-97%)/75% (CI, 64%-89%), respectively. High-level (>50%-100%)/low-level donor chimerism (11%-50%) was observed in 85%/15% of patients, respectively, leading to resolution of T lymphopenia. The median overall CHIMO score was 14 (6-17), while the median scores for each component were 3 (0-3), 3 (1-3), 4 (1-4), 3 (1-4), and 2 (0-3), respectively. Patients who underwent HSCT before 24 months after the initial presentation demonstrated superior OS (P = .049). Neurological symptoms that occurred before 11 months of age were associated with reduced OS (P = .027). While the overall results were satisfactory, earlier diagnosis could further improve outcomes.

Graphical abstract

Figure 1.

Age and clinical manifestations of the cohort. (A) Distribution of the age at first symptom onset (x-axis) across different initial clinical manifestations (y-axis: neurologic, infectious, or autoimmune). (B) Percentage of patients who presented with various clinical features over the whole period of study until HSCT. MAS, macrophage activation syndrome; M.Still-like, Morbus Still-like.

Figure 2.

OS and EFS curves. Kaplan-Meier survival curves illustrating the OS following HSCT. (A) OS and EFS after HSCT. (B) OS based on age at neurologic presentation (NP) (<11 months vs ≥11 months). (C) OS stratified by time from diagnosis to HSCT (<24 months vs ≥24 months). (D) EFS based on donor type, namely matched family donor (MFD), mismatched family donor (MMFD), MUD. (E) OS by age at HSCT (<28 months vs ≥28 months). (F) OS according to conditioning regimen, namely MAC, RIC, or none.

Figure 3.

Distribution of CHIMO scores at last FU visit. Plot illustrating the distribution of CHIMO scores across different domains, namely cognition, hearing, interaction, movement, and occupation, as well as the overall CHIMO score. Scores are displayed for individual patients at their specific age at their respective time of FU for the assessment of the CHIMO score.

Figure 4.

Severity of categorized symptoms before and after HSCT. Heat map depicting the severity scores of clinical symptoms before and after HSCT divided into the categories, namely neurology, infection, and autoimmunity. Scores were based on clinical descriptions and CHIMO scores (refer to the supplemental Material). Asterisk (∗) marks the 6 patients diagnosed perinatally by family history.