Abatacept is useful in auto-immune cytopenia with immunopathologic manifestations caused by CTLA-4 defects

Chloé DHUNPUTH (Bordeaux University Hospital, France) Stéphane DUCASSOU (CHU Bordeaux, France) Helder FERNANDES (University Hospital of Bordeaux, France) Capucine PICARD (Université de Paris, France) Frédéric Rieux-Laucat (Institut Imagine-INSERM-UMR-1163, France) Jean-François VIALLARD (Haut-Leveque Hospital, France) Estibaliz LAZARO (CHU Bordeaux, France) Hermine Olivier (NeckerEnfants Malades University Hospital, France) Mathieu JOUVRAY (Hospital of Arras, France) Irène MACHELART (Hospital of Bayonne, France) Anne LAMBILLIOTTE (CHRU de Lille France, France) Marion MALPHETTES (Hôpital Saint Louis, France) Despina MOSHOUS (Hôpital Necker-Enfants Malades, France) Bénédicte Neven (Institut Imagine, (UMR) 1163, INSERM, France) Alexandra GAUTHIER (Hospices Civils de Lyon, France) Nathalie GARNIER (Hospices Civils de Lyon, France) Thierry LEBLANC (Hôpital Robert DEBRE APHP, France) Judith LANDMAN-PARKER (Armand-Trousseau Sorbonne University Hospital, AP-HP, France) Guy LEVERGER (Hôpital Armand Trousseau, France) Nathalie Aladjidi (Bordeaux University Hospital, France)


Keypoints
 Abatacept shows long-term efficacy and safety profile in young patients with CTLA-4 defects and severe refractory immune manifestations.
 Our study provides rational for the early initiation of new off-label treatments for which literature data are still scarce in children. Anchor (LRBA) 5,6 or DEF6 variants 7 . Abatacept, a CTLA-4 fusion protein labeled in rheumatoid arthritis 8 is a logical targeted option for those patients.
In 2019, a preliminary study of the French OBS'CEREVANCE cohort of children with AIC identified CTLA-4 pathway pathogenic variants in 10/80 pediatric-onset Evans syndrome (pES) cases 9 . pES is now recognized as a severe long-lasting disease : numerous IM appearing with increasing age in 78% of cases; high burden of second-line treatments to control severe bleeding or hemolytic flares or organ specific IM; mortality rate reaching 10% 10,11 . Targeted therapies are urgently warranted to improve outcome in those patients.
In May 2020, 19/1613 children from this national cohort were identified with CTLA-4 defects and 9 of them were treated with abatacept. We aimed to describe the impact of this treatment on the course of their disease.
This was a national observational study. Of note, patients under 18 years of age with AIC are routinely included in real time in the OBS'CEREVANCE cohort, prospectively followed and screened for an underlying diagnosis of IM and PID 9,11,12 (Table 1).
Regarding AIC, CR was obtained in patient 2, and sustained PR in patients 3 and 9. Moreover, no relapse was observed despite cessation or decrease in ongoing treatments in all 6 patients already in CR. Regarding active IM, significant improvement was seen in 7/8 patients, particularly in lung disease. The benefit was enhanced when abatacept was infused every two weeks. Abatacept allowed steroid, rapamune or everolimus discontinuation (patients 2, 7, 8,9) and rapamune or romiplostim sparing (patients 3,9). In patient 6 abatacept was replaced by vedolizumab after 3.1 year due to refractory enteropathy.
No severe adverse effects occurred. Three patients suffered from recurrent mouth ulcers, which were attenuated by a reduction in abatacept dose and/or by increased immunoglobulin replacement therapy. AIC in CTLA-4-insufficient patients often have a severe, chronic and relapsing course 13 . We have herein reported a national prospective observational analysis of 9 children and young adults with refractory AIC and IM despite extensive treatments. The response to abatacept was excellent as well as long-term benefit-risk ratio with treatment duration up to 4.9 years.
A significant sparing of associated immunosuppressive therapies was also noted.
Similar results were reported in a first case report in 2016 1 . In 2020, 22 LRBA-deficient Turkish children received abatacept for a shorter median duration of 12.5 months, and regarding the IM, the best response was observed in AIC 14 .
In our study, as previously reported in the context of rheumatoid arthritis, drug efficacy appears to be dose-dependent, with a better response rate with one-week or two-weeks interval in comparison to four-weeks. An initial dosage of 20 mg/kg/15d, until complete response of all target organs, appears to be well tolerated and facilitates progressive spacing of infusions as proposed in juvenile arthritis 15 . The tolerance was excellent for treatment duration up to 5 years, assuming that optimal prevention of recurrent infections and nonmalignant lymphoproliferation is provided by immunoglobulin replacement and antibioprophylaxis. In the field of pediatric rheumatic diseases, with up to 5 years of followup, the long-term safety profile of abatacept is favorable, especially for the risk of malignancies [16][17][18][19] . The risk of relapse upon abatacept discontinuation is not known. So far, HSCT is the only regarded as a long-term cure for CTLA-4 insufficiency and LRBA deficiency 20,21 , and abatacept pre-HSCT may improve the organ function and lead to superior outcomes conditions in which it is conducted.
A multidisciplinary approach is warranted in patients with AIC associated with hypogammaglobulinemia and/or severe multi-organ manifestations. It is essential to perform genetic studies looking for an underlying PID. Our results clearly demonstrate that patients with different CTLA-4 pathway defects, even young children, may benefit from early treatment with off-label new targeted treatment options in order to avoid heavy nonspecific immunosuppression and the development of severe multi-organ manifestations.
National and International collaborative cohorts or registries will allow to validate therapeutic guidelines and standardization of evaluation criteria for the various organ manifestations in those diseases. Two ongoing prospective trials may answer questions raised by our work on the benefit-risk ratio of abatacept, and on its specific impact in AIC (ClinicalTrials.gov : NCT03733067; ABACHAI : EudraCT No.2019-000972-40).