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) With support from NCBI we have implemented a web based publication of the existing databases of pathogenic FAS mutations, by far the commonest cause of ALPS, which is publicly available and can be used for diagnostic help by referring to NCBI NIH ALPS website <www.ncbi.nlm.nih.gov/lovd/home.php?select_db=FAS>. We are also continuing our efforts to streamline the techniques of apoptosis assay by evaluating Fas mediated cell death and cell survival with serum starvation in lymphocyte and monocyte subsets so that these test procedures can be readily adapted in more clinical laboratories for patient evaluation in ALPS and RALD respectively. 4) Continued search for new genetic mutations 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. 5) We are actively recruiting 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). Preliminary results are promising in six patients treated with this investigational agent and currently we plan to recruit up to 30 patients with PI3Kinase pathway genetic defects into this 2:1 placebo controlled international multicenter clinical trial. 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.
| Comrie, William A; Faruqi, Aiman J; Price, Susan et al. (2018) RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias. J Allergy Clin Immunol 141:1507-1510.e8 |
| Buchbinder, David; Seppanen, Mikko; Rao, V Koneti et al. (2018) Clinical Challenges: Identification of Patients With Novel Primary Immunodeficiency Syndromes. J Pediatr Hematol Oncol 40:e319-e322 |
| Ucar, Didar; Kim, Jane S; Bishop, Rachel J et al. (2017) Ocular Inflammatory Disorders in Autoimmune Lymphoproliferative Syndrome (ALPS). Ocul Immunol Inflamm 25:703-709 |
| Ozen, Ahmet; Comrie, William A; Ardy, Rico C et al. (2017) CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med 377:52-61 |
| Rao, V Koneti; Webster, Sharon; Dalm, Virgil A S H et al. (2017) Effective ""activated PI3K? syndrome""-targeted therapy with the PI3K? inhibitor leniolisib. Blood 130:2307-2316 |
| Dulau Florea, Alina E; Braylan, Raul C; Schafernak, Kristian T et al. (2017) Abnormal B-cell maturation in the bone marrow of patients with germline mutations in PIK3CD. J Allergy Clin Immunol 139:1032-1035.e6 |
| Xie, Yi; Pittaluga, Stefania; Price, Susan et al. (2017) Bone marrow findings in autoimmune lymphoproliferative syndrome with germline FAS mutation. Haematologica 102:364-372 |
| Weinreich, Michael Alexander; Vogel, Tiphanie P; Rao, V Koneti et al. (2017) Up, Down, and All Around: Diagnosis and Treatment of Novel STAT3 Variant. Front Pediatr 5:49 |
| Rao, V Koneti (2016) Serendipity in splendid isolation: rapamycin. Blood 127:5-6 |
| Cruz, Anthony C; Ramaswamy, Madhu; Ouyang, Claudia et al. (2016) Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction. Nat Commun 7:13895 |
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