Management of Cytopenias in CTLA4 Haploinsufficiency Using Abatacept and Sirolimus

Abstract Background: CTLA4 is a homodimeric cell surface inhibitory receptor that plays a critical role in maintaining immune system homeostasis by suppressing T-lymphocyte activation and proliferation. Heterozygous germline, loss-of-function mutations in CTLA4, present with a diverse clinical phenotype of recurrent infections, lymphoproliferation, autoimmunity, and lymphocytic infiltration of target organs. Cytopenias are common in CTLA4 Haploinsufficiency and can be often multifactorial due to autoimmune destruction, splenic sequestration and bone marrow failure.(Kuehn HS …. Uzel G. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4.Science. 2014 Sep 26;345(6204):1623-1627. doi: 10.1126/science.1255904.) Patients and Methods: We have identified 95 CTLA4 mutation-positive subjects at the NIH CC, and a subset (n=74, 77%) of them exhibit symptomatic disease affecting brain, lungs, gut, spleen and bone marrow. Mean age for the affected cohort is 25 ± 2.0 years, and average age of onset of cytopenia is 16 years (range 6-43years). Of all patients with confirmed mutations, there are roughly equal numbers of females to males (1.15:1 ratio), but males dominate the affected cohort (69% males vs 31% females). Cytopenias due to autoimmune destruction, splenic sequestration and/or bone marrow failure with polyclonal lymphocytic infiltration are the most frequent initial presentation (59%; n=33): Thrombocytopenia (n=13), anemia (n=4), Evans' syndrome (n=7), and multilineage cytopenia (n=9). Splenomegaly is seen in 60% of the affected cohort. Results: We share our experience with short and long term immunomodulatory therapy in treating autoimmune cytopenias in 22 patients with CTLA4 deficiency, including our experience with off-label use of the CTLA4 mimetic, abatacept(n=10), given at a dose of 500-750mg X2 as monthly intravenous infusions and sirolimus (n=19) with a target to maintain 24hr trough levels of 10-15ng/dL. The most frequent other concomitant immunomodulatory medication used was rituximab (n=10), azathioprine (n=5), mycophenolate mofetil (n=4), cyclosporine (n=3), hydroxychloroquine (n=1), ruxolitinib (n=1), mercaptopurine (n=1), and cyclophosphamide (n=1). Three patients received romiplostim and/or eltrombopag. All 22 patients received more than one course of pulse dose steroids. We have cumulative retrospective data of 17 patient-years in 10 CTLA4-deficient patients followed at NIH CC on abatacept. All of them showed either complete or partial response in terms stabilization of their cytopenias and/or improvement of their gastrointestinal symptoms and brain lesions. We did not observe any abatacept related adverse events: including infusion reactions, EBV reactivation, or diagnosis of malignancy. One patient died secondary to Klebsiella pneumoniae sepsis 3 months after stopping abatacept. His disease was complicated by large granular lymphocyte leukemia and treatment with alemtuzumab prior to his diagnosis with CTLA4 deficiency and abatacept treatment. Overall, we used mTOR inhibitors in 19 patients for a total of 37 patient years to treatment. Three most common recorded adverse events were: Clostridium difficile colitis (n=9, in 4 patients), lipid abnormalities (n =7, 3 patients required treatment) and bacterial pneumonia (n=6, in 4 patients). Conclusion: As abatacept replaces the missing CTLA4 protein, it should be part of the treatment regimen in patients with CTLA4 haploinsufficiency presenting with cytopenias. Both long term treatment outcomes and schedule of administration are yet to be determined in a larger cohort in the setting of a clinical trial. Disclosures Uzel: Novartis: Research Funding. Rao: novartis: Research Funding.