Efficacy of sirolimus for treatment of autoimmune lymphoproliferative syndrome: a systematic review of open label clinical studies

ABSTRACT

Background

Although autoimmune lymphoproliferative syndrome (ALPS) is an unusual and fatal disorder to which no absolute cure stands, there also remains substantial diversity with majority of subjects exhibiting only slight associated morbidities. Several pre-clinical and clinical evidence in the past have reported sirolimus to be an effective therapeutic option for patients with autoimmune cytopenias who are often resistant and intolerant to standard treatment. Thus, this systematic review aimed to assess the efficacy of sirolimus for treatment of autoimmune cytopenias, particularly ALPS.

Methods

This systematic review was performed in adherence to the PRISMA 2009 checklist for preferred reporting items for systematic reviews and meta-analyses. Data search was carried out in PubMed and clinicaltrials.gov from inception to 10 June 2020. Newcastle-Ottawa Scale (NOS) was used for assessing study quality.

Results

A total of three open label clinical studies comprising 94 patients with ALPS (53.20% males and 46.80% females) were included. The majority of patients with ALPS demonstrated rapid, complete, and durable responses with recovery of their primary disease manifestations. Stabilization of lymphoproliferation and a decrease in abnormal DNT cells was also noted. Moreover, sirolimus was found to be safe with few side effects that could be tolerated well.

Conclusion

This systematic review corroborated on available evidence which jointly emphasizes that complete responses could be seen in estimates of 50% or more patients with ALPS and although, there is a need of larger trials, the findings do support the chronic use of sirolimus for treatment of ALPS.

KEYWORDS:

• Autoimmune cytopenia
• autoimmune lymphoproliferative syndrome
• sirolimus
• systematic review

6. Expert Opinion

As per clinicians, the lymphoproliferation can become severe and then mild randomly, is likely to ameliorate with age but generally becomes worse in adolescence preceding recovery in majority of patients in their initial 20s [6]. However, presently, a remedy for the complete recovery of the genetic defect in autoimmune lymphoproliferative syndrome has not been determined and the management of the disorder targets therapy of the primary disorder characteristics and complexities. Remediation of lymphoproliferation and autoimmune cytopenias with immunosuppression constitute the complicated disease specific targets requiring management.

In patients with autoimmune lymphoproliferative syndrome, sirolimus had shown fruitful results when used as a therapy targeting lymphoproliferation as well as autoimmune cytopenias [5,13,14]. Greater apoptosis and decreased proliferation has been shown in patients by double negative T-cells after Sirolimus therapy in vivo. This blockade of multiplication and selective induction of apoptosis in abnormally differentiated double negative T-cells occurs due to terminated expression of Interleukin-10 in the abnormal T-cells by mTOR inhibition [4].Further, an in-depth investigation revealed that the abnormal differentiation phenotype depicted by double negative T-cells in autoimmune lymphoproliferative syndrome is particularly influenced by sirolimus [4].

Providing assistance to the safety, efficacy and tolerance shown towards sirolimus, additional data have come to light. This doesn’t extend to every patient and is regarded as a fact only for patients with ALPS-FAS mutation. Henceforth, there is a requirement of acquiring deeper knowledge of the dysfunctionality of the immune system underpinning autoimmune lymphoproliferative syndrome as well as similar disorders along with drawing attention to the progressive convolution of these disorders brought about by novel cognizance and their heightened contemplation. Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article Highlights

• Autoimmune lymphoproliferative syndrome is a rare and fatal autoimmune cytopenia to which no absolute cure exists

• Sirolimus is an immunosuppressant shown to be effective in autoimmune lymphoproliferative syndrome resistant or intolerant patients to standard therapy.

• The majority of patients demonstrated rapid, complete and durable responses with stabilization of lymphoproliferation.

• A decrease in abnormal double negative T cells is required for durable action in Autoimmune lymphoproliferative syndrome.

• Sirolimus was found to be safe with few side effects that could be tolerated well thus, supporting it’s chronic use.

Declaration of interest

The authors have no relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownerships or options, expert testimony, grants or patents received or pending, or royalties.

Author contributions

SS and MAK designed the study. SS, MSH and MAK searched databases and performed study selection; SS, MSH and MAK conducted quality assessment of the included studies; SS, NBA and MAK wrote the manuscript; SS, MSH and MAK analyzed and performed data interpretation. All authors have reviewed and revised the draft critically for intellectual content. All authors give final approval of the version to be submitted in journal.

Additional information

Funding

This paper was not funded.