Abstract

ALPS is an inherited disorder of lymphocyte apoptosis leading to childhood onset of chronic lymphadenopathy, hepatosplenomegaly, autoimmunity, and an increased risk of lymphoma in a subset of patients with mutations in the intracellular domain of Fas (ALPS Type Ia). Similarly, MRL/lpr −/− mice are homozygous for Fas mutations and develop massive lymphadenopathy and splenomegaly associated with hypergammaglobulinemia, glomerulonephritis, and expansion of TCR αβ+, CD4−/CD8−double-negative (DN) T cells that are pathognomonic of ALPS. There remain no proven therapies for the lymphoproliferation underlying ALPS itself, although investigators in Europe reported that some children with ALPS showed reductions in spleen and lymph node sizes while on a weekly regimen of pyrimethamine/sulfadoxine (Fansidar@) (

Br J Haematol.
2002
;
117
:
176
). However, in vitro studies using stimulated human PBMCs, revealed that lymphocyte apoptosis is induced by the antifolate agent, pyrimethamine (Pyr) at an EC50 of 2.5ug/mL, and not sulfadoxine. This suggested that Pyr alone might prove clinically beneficial, thus avoiding risks of allergy and hypersensitivity associated with sulfa drugs. Hence, studies were conducted in the MRL/lpr−/− murine model of ALPS with Pyr alone given 2mg/kg twice weekly by gavage for 8 weeks, and in combination with sulfadoxine. Neither Pyr nor Fansidar yielded significant shrinkage of lymphoid mass in mice. A pilot study of the safety and efficacy of Pyr was conducted under an FDA IND in 6 children with ALPS Type 1a and one with ALPS Type III (with no identifiable mutation). Aged 6 to 17 yrs (median; 13 y), these 6 males and 1 female patient were enrolled following informed consent to be treated with oral Pyr at escalating doses (25–50mg) given twice weekly for 12 weeks. Computerized tomography was done before and after treatment to determine whether these patients would show 40 and 50% reductions in the sizes of their lymphadenopathy and/or splenomegaly, respectively. Lymph node sizes were assessed as sums of the bi-dimensional products of 3 to 5 nodes. Spleen sizes were measured as products of their craniocaudal and anterioposterior dimensions at the superior mesenteric artery level, as well as spleen volumes computed by digital image processing. The effects of treatment on other well-defined laboratory features of ALPS were also assessed. Pyr was discontinued after 11 days in one patient due to skin rash. Dose escalation was interrupted transiently in 3 others because of neutropenia, aphthous ulcer, or leucopenia. There were no significant changes in study outcome measures. The aggregate experience with Pyr and Fansidar in mice, as well as with Pyr alone in ALPS patients (Table) lead us to conclude that these agents do not manifest sufficient effectiveness to warrant larger trials.

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