Lymphoproliferative Disease in Wiskott-Aldrich Syndrome: Analysis of the French National Registry of Primary Immunodeficiencies

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency (PID) characterized by persistent thrombocytopenia, eczema and immunodeficiency. It has been suggested that these patients had an increased risk of lymphoproliferative diseases (LPD).

We conducted a retrospective study in order to describe LPD occurring in patients with WAS/XLT (X Linked Thrombocytopenia with WAS gene mutation) enrolled in the French national registry for PIDs. Post- hematopoietic stem cell transplantation (HSCT) LPD were excluded. Methodology of the French National Registry for PIDs has been previously described (Clin. Immunol, 2010, ASH 2009 abstract#23950).

Eight patients (4%) with LPD were identified among the 197 patients of our cohort. All patients had a WAS and presented first symptoms of WAS before the age of one year. One patient developed a LPD before the clinical diagnosis of WAS.

All patients for whom histological charts were available (6/8) developed a B-cell LPD. Three of them had diffuse large B-cell lymphomas and three patients had polymorphic B-cell LPD associated with EBV and without detection of clonal IGHV rearrangement. The median age of cancer diagnosis was 18.3 years (range: 2.0-50.7). All LPD were disseminated diseases, mostly with a central nervous system involvement (4/6 patients). All patients received intensive chemotherapy, except one patient with an EBV-associated LPD who only received rituximab. Three patients obtained a complete remission (CR), two patients had a stable disease (SD) and the last one progressed on therapy. Four patients, of whom two were in CR and one in SD, received an allogeneic HSCT during the year following the diagnosis of LPD. Two patients received peripheral blood-derived stem cells and the two other patients received bone marrow-derived stem cells. There were three matched unrelated donor (MUD) and one haplotype-mismatched family donor, with no ex vivo graft manipulation. Three of these four patients were long-term survivors after LPD (2.7, 7.7 and 9.8 years).

The median life expectancy for the entire cohort is 19.1 years (range: 7.8-52.0). Three patients, two of which have received an HSCT, are still alive 2.4, 2.7 and 9.8 years after the cancer onset. The median overall survival among the five remaining patients after diagnosis of LPD was 0.5 years (from 0.3 to 7.7 years).

Additional details on genetic, clinical characteristics and a centralized histopathology review are currently being studied and will be presented.

In conclusion, the occurrence of LPD is less frequent than expected, may occur only in patients with WAS phenotype rather than XLT. As it impairs the prognosis of patients, HSCT could be a therapeutic option for these patients, even in partial remission of LPD.