Hematopoietic Stem Cell Transplantation for C1q Deficiency: A Study on Behalf of the EBMT Inborn Errors Working Party

Abstract

C1q deficiency is a rare inborn error of immunity characterized by increased susceptibility to infections and autoimmune manifestations mimicking SLE, with an associated morbidity and mortality. Because C1q is synthesized by monocytes, to date, four patients treated with allogeneic HSCT have been reported, with a positive outcome in three. We conducted an international retrospective study to assess the outcome of HSCT in C1q deficiency. Eighteen patients, fourteen previously unreported, from eleven referral centres, were included. Two patients had two HSCTs, thus 20 HSCTs were performed in total, at a median age of 10 years (range 0.9-19). Indications for HSCT were autoimmune manifestations not controlled by ongoing treatment in seventeen, and early development of MALT lymphoma in one patient. Overall survival (OS) was 71% and event-free survival was 59% at two years (considering an event as acute GvHD ≥ grade III, disease recurrence and death). In eleven patients HSCT led to resolution of autoimmune features and discontinuation of immunosuppressive treatments (follow-up time range 3-84 months). Five patients died due to transplant-related complications. Patients with a severe autoimmune phenotype, defined as neurological and/or renal involvement, had the worst OS (40% vs 84%; p = 0.034). Reviewing data of 69 genetically confirmed C1q deficient patients, we found that anti-Ro antibodies are associated with neurologic involvement, and anti-RNP and anti-DNA antibodies with renal involvement. In conclusion, HSCT may be a valid curative option for C1q deficiency, but careful selection of patients, with an accurate assessment of risk and benefit, is mandatory.

Keywords: Allogeneic HSCT; C1q deficiency; SLE.

Fig. 1

Possible markers of disease severity. Data are summarised as the percentage of specific mutations and autoantibodies within four different clinical groups defined according to the presence or absence of CNS and renal involvement: No-CNS, CNS, No-Renal and Renal

Fig. 2

Clinical features and HSCT outcome. Gray squares represent the presence of a clinical feature/phenotype. Green squares indicate that patients survive after HSCT. Yellow squares indicate that patients had a graft failure. Red squares indicate that patients died after HSCT. For patients P3 and P13 that had two HSCT the outcome of both transplants is indicated. * Recurrent fever, arthralgia and weight loss

Fig. 3

Overall survival (OS) and Event Free Survival (EFS) of the whole cohort. The overall survival at two years was 71% (95%CI 44–87%). For patients who had two HSCT, 2nd HSCT was considered as baseline. The event free survival at two years was 59% (95%CI 32–78%). Event: aGvHD ≥ grade III; disease recurrence due to loss of chimerism; death

Fig. 4

Comparison of overall survival and of event free survival between patients with severe and no-severe baseline disease. The presence of neurological and/or renal involvement were considered as markers of severe disease. Patients in severe group had worst OS (40% vs 84%; p = 0.034), while there was no difference in EFS at two years (60% vs 59%; p = 0.596) between the two groups. In the overall survival analys for the patients who had two HSCT, 2nd HSCT was considered as baseline