Abstract

ALPS is a heritable disorder of apoptosis resulting in accumulation of autoreactive lymphocytes, leading to childhood onset of marked lymphadenopathy, hepatosplenomegaly with multilineage cytopenias due to splenic sequestration and/or autoimmunity. Affected individuals have characteristic increases (≥1%) in circulating (TCRαβ+ CD4-CD8-) double negative T lymphocytes. ALPS Type Ia, Ib, II and IV are associated with genetic mutations in Fas, FasL, Caspases and NRAS respectively, while patients without identified mutations are classified as Type III or ALPS phenotype. Of the estimated 350 ALPS patients reported worldwide, 241 individuals with ALPS, belonging to 166 families are enrolled in studies at the NIH Clinical Center. Nearly 50% of them with refractory cytopenias associated with hypersplenism have undergone splenectomy leading to associated long term risk of pneumococcal sepsis. Currently published reports include occasional cases of rituximab used for refractory ITP and AIHA with variable response in patients classified as ALPS. We summarize experience of rituximab use during the last 7yrs in 11 ALPS patients (8 males and 3 females), including 2 adults aged 45, 46yrs and 9 children with a median age of 11yrs (range 1–14yrs) at commencement of this therapy for refractory grade 4 immune thrombocytopenia (platelet count <20,000) in 8 and AIHA in 3 patients. Eight of them are ALPS Type Ia and 3 are ALPS phenotype. The 46yr old adult male patient had hepatitis C and ALPS Type Ia comorbidity. Among them, 7 patients were asplenic (prior surgical splenectomy); 3 had significant splenomegaly; and 1 had no palpable spleen. Interventions prior to rituximab therapy included: red cell transfusions, IVIG, WinRho, corticosteroids and mycophenolate mofetil (MMF). Seven patients (including 2 adults) with thrombocytopenia responded with durable normalization of platelet counts over a > 12 months follow up; 2 of them (aged 14 and 15yrs) relapsed at +18 and +22 months after completion of therapy: only one of them responded to a second course of rituximab. Thrombocytopenia in the second patient is currently under control with MMF. One out of the 4 non-responders underwent splenectomy, while the other 3 patients, including the 2 asplenics, required prednisone pulses (5–30 mg/kg) followed by MMF and weekly vincristine for 6 wks (in 1 patient) as a steroid sparing measure. Noted toxicities include prolonged neutropenia in 1 patient, profound and prolonged hypogammaglobulinemia in 4 patients requiring replacement IVIG, and total absence of antibody response to polysaccharide vaccines lasting up to 4years after rituximab infusions in 1 patient. Rituximab therapy relieved thrombocytopenia for 12–18 months in 7 out of 11 ALPS patients. However associated toxicities, including quantitative and qualitative IgG deficiencies that are additional infection risk burden, especially in asplenic individuals, warrant further investigation and long term follow up of ALPS patients with cytopenias.

Author notes

Disclosure: No relevant conflicts of interest to declare.