Mycophenolate mofetil and Sirolimus as second or further line treatment in children with chronic refractory Primitive or Secondary Autoimmune Cytopenias: a single centre experience

Abstract

SummaryThe management of refractory autoimmune cytopenias in childhood is challenging due to the lack of established evidence on escalating treatments. The long-term efficacy of immunosuppressive drugs was evaluated in children with refractory autoimmune cytopenias referred to the Haematology Unit of the Gaslini Children's Hospital between 2001 and 2014. Patients were grouped into three categories: autoimmune lymphoproliferative syndrome (ALPS), ALPS-related syndrome (at least one absolute/primary additional criterion for ALPS) and primary autoimmune cytopenia (PAC, cytopenia with no other immunological symptoms/signs). Fifty-eight children (aged 1-16 years) entered the study: 12 were categorized with ALPS, 24 were ALPS-related and 22 had PAC. Five didn't receive treatment. Fiftythree were initially treated with steroids/intravenous immunoglobulin. Fourteen responded, whereas 39 did not. Of these 39 patients, 34 (87%) received mycophenolate mofetil (MMF) as second/further-line treatment and 22 (65%) responded. Within these 34 subjects, ALPS patients responded better (11/11, 100%) than the two other groups pooled together (11/23, 48%; P = 0Á002). Sirolimus was given as second/further-line treatment to 16 children, and 12 (75%) responded, including 8 who previously failed MMF therapy. Median follow-up was 3Á46 years. MMF and Sirolimus were well-tolerated and enabled partial/complete and sustained remission in most children. These drugs may be successfully and safely used in children with refractory autoimmune cytopenias with or without ALPS/ALPSrelated disorders and may represent a valid second/further line option.

Clinical features and therapeutic challenges of cytopenias belonging to alps and alps‐related (ARS) phenotype

“…Another difficulty when dealing with ALPS patients is that subjects with autoimmune cytopenias, reported to occur in about 70% of ALPS cases, may fulfil some, but not all, criteria required for the diagnosis of definitive or probable ALPS. These patients were recently categorized as having ALPS‐related syndrome (ARS) (Miano et al , ). The diagnostic characterization of autoimmune cytopenias as idiopathic or within the context of ALPS or ARS, has treatment implications, given that a significant proportion of these subjects are refractory to classical first‐ and second‐line treatments, such as steroids and intravenous immunoglobulin (IVIG), but benefit instead from drugs typically used in ALPS and ARS, like mycophenolate mofetil (MMF) and rapamycin (Rao & Oliveira, ; Bride et al , ; Miano et al , ).…”

“…These patients were recently categorized as having ALPS‐related syndrome (ARS) (Miano et al , ). The diagnostic characterization of autoimmune cytopenias as idiopathic or within the context of ALPS or ARS, has treatment implications, given that a significant proportion of these subjects are refractory to classical first‐ and second‐line treatments, such as steroids and intravenous immunoglobulin (IVIG), but benefit instead from drugs typically used in ALPS and ARS, like mycophenolate mofetil (MMF) and rapamycin (Rao & Oliveira, ; Bride et al , ; Miano et al , ). The present study investigated the biological and clinical phenotype and treatment sensitivity that may differentiate ALPS from ARS patients, by analysing the records of 90 patients who were referred to our centre between January 2001 and March 2017.…”

Mechanism-Based Strategies for the Management of Autoimmunity and Immune Dysregulation in Primary Immunodeficiencies

“…The conventional first-line therapy for ALPS-associated autoimmune cytopenias has been corticosteroids, but second-line therapies including mycophenolate mofetil (MMF, a prodrug of mycophenolic acid that inhibits inosine monophosphate dehydrogenase and suppresses T and B cells) and sirolimus (an mTOR inhibitor) that more effectively target DN T cells are increasingly being used as primary therapy (35, 36). Sirolimus was first trialed in four corticosteroid-refractory ALPS patients in 2009 and resulted in marked improvements in both autoimmune cytopenias and associated systemic inflammatory features (arthritis, colitis, lymphadenopathy, and splenomegaly) (10).…”

Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults

“…Among this second group of patients, fewer patients responded, and of those who did, their response time was generally slower. The success of sirolimus in ALPS has led investigators to use this drug in Evans syndrome, CVID, SLE, and other single lineage cytopenias with varying levels of success …”