Clinical, Immunological and Genetic Analyses of ALPS and Related Immunedysregulatory Disorders

National Institute Of Allergy And Infectious Diseases

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Abstract

Research accomplishments of this project include: 1) This project allows us to study the largest cohort of patients with ALPS, one of the first genetic disorders of immunedysregulation. ALPS natural history study based on follow up of these patients over 20 yeas has been completed and a manuscript summarizing the critical features of the clinical and molecular pathogenesis in 150 patients with ALPS-FAS with a median followup of 13 years has been published as a plenary paper in an eminent hematological journal (Blood. 2014 Mar 27;123(13):1989-99). This included the validation of novel biomarkers of disease activity such as increased serum Vitamin B12 levels as well as establishing new modes of treatment for the disorder. Study of ALPS has elucidated the role of fas mediated apoptosis in lymphocyte homeostasis and lymphoma genesis. 2)This project has also led to identifying new genetic causes of ALPS like disorders by identification of mutations affecting RAS pathway in 14 patients, otherwise known as Ras Associated Leukoproliferative Disorder (RALD) : RALD: Patients with this ALPS like syndrome caused by somatic mutations in NRAS and KRAS are currently classified separately as ALPS related apoptosis disorders. These patients with somatic NRAS and KRAS mutations present with autoimmune phenomena, massive splenomegaly, modest lymphadenopathy and normal or only marginally elevated TCR alpha/beta+ DNT cells. Their lymph node histopathology is also not typical of ALPS-FAS. Additionally, these patients show abnormalities of the myeloid compartment, with chronic persistent monocytosis, mimicking juvenile myelomonocytic leukemia (JMML) in otherwise asymptomatic young patients. (Blood 2015 Apr 30;125(18):2753-8). 3) Continued search for novel pathogenic genetic variants in the subgroup of patients with ALPS and ALPS like disorders with undetermined genetic defects using emerging genomic and cell biology tools. Currently a large group of patients with unknown molecular etiologies are being subjected to whole exome DNA sequencing and analysis. Some novel immunedysregulatory syndromes are identified leading to validation of novel candidate genes and therapeutic targets such as pathogenic variants in the CTLA4, LRBA, STAT3 gain of function, MagT1 and PI3Kinase gene family and most recently TLR8 genetic disorder. 5) We completed enrolling patients for a randomized placebo controlled trial to assess the safety and efficacy of a targeted small molecule, Leniolisib (CDZ173) in patients with APDS/PASLI (Activated phosphoinositide 3-kinase delta syndrome/ p110-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency). We have recruited 19 patients in our clinic at NIHCC into this 2:1 placebo controlled international multicenter clinical trial, so that this investigational agent can be licensed for this rare genetic disease. Data analysis is in progress for this study and we hope to publish our results in 2022. Part of the long term data follow up related to published work was presented in ASH meeting in December 2018: Abstract: Gain-of-function mutations in PIK3CD encoding PI3K defat (phosphoinositide 3-kinase delta) lead to accumulation of senescent T cells, lymphadenopathy, splenomegaly and immune-deficiency (Activated PI3Kd Syndrome, APDS). Clinical manifestations include multilineage cytopenias and susceptibility to B cell Non-Hodgkins lymphoma. We recently reported use of leniolisib (CDZ173), a novel, potent and selective oral PI3Kd inhibitor in six APDS patients in a 12-week, open-label, multi-center, within-subject dose-escalation study (Rao et al, Blood 23 November 2017). Leniolisib was safe and well tolerated and led to a dose-dependent reduction in PI3K/AKT pathway activity and improved the immune dysregulation with normalization of circulating transitional and nave B cells and reduction in PD-1+CD4+ and senescent CD57+CD8+ T cells. Elevated serum IgM and other biomarkers including IFNalpha, TNF, CXCL13 and CXCL10 normalized or decreased with leniolisib. Cytopenias and lymphoprolferation improved in all patients with index lymph node sizes and spleen volumes reduced by 39% and 40%, respectively. Here we report the long term follow up safety and efficacy data in all six patients (Table 1) who have continued treatment with leniolisib in an extension study at 70 mg b.i.d (ClinicalTrials.gov number NCT02859727). These patients have been treated for up to 868 days. Three of them were lymphoma survivors. Three patients were treated with rapamycin prior to starting leniolisib. No patient in the 12-week clinical trial or in the extension study has experienced any significant adverse events. Notably, side effects prevalent with mTOR or other PI3K inhibitors such as diarrhea/colitis, skin rashes, susceptibility to infections or liver enzyme elevation were absent. Three patients have stopped immunoglobulin supplementation as a reflection of the normalization of their B cell function. Cytopenias, including anemia, thrombocyopenia, neutropenia and lymphopenia have continued to improve. (Figure 1: Shows representative laboratory data for patient 002, on 18 months of treatment with leniolisib). Available data on longterm safety, effects on lymphoproliferation and immune dysregulation in the ongoing leniolisib extension study will be shared during the meeting. The results support long term inhibition of PI3Kinase as a new targeted therapeutic approach in APDS and other disorders of nonmalignant lymphopoliferation associated with hyperactive PI3Kinase pathway. Reference: Rao VK, Webster S, Dalm VASH, ediv A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M, Joshi AD, de Buck S, Doucet J, Guerini D, Kalis C, Pylvaenaeinen I, Soldermann N, Kashyap A, Uzel G, Lenardo MJ, Patel DD, Lucas CL, Burkhart C. Effective 'Activated PI3K Syndrome'-targeted therapy with the PI3K inhibitor leniolisib. Blood. 2017 Sep 29. pii: blood-2017-08-801191. doi: 10.1182/blood-2017-08-801191. PubMed PMID: 28972011; PubMed Central PMCID: PMC5701526.