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Treon, Steven

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Steven

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Treon, Steven
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    Discovery of a Potent, Covalent BTK Inhibitor for B-Cell Lymphoma
    (American Chemical Society, 2014) Wu, Hong; Wang, Wenchao; Liu, Feiyang; Weisberg, Ellen; Tian, Bei; Chen, Yongfei; Li, Binhua; Wang, Aoli; Wang, Beilei; Zhao, Zheng; McMillin, Douglas W.; Hu, Chen; Li, Hong; Wang, Jinhua; Liang, Yanke; Buhrlage, Sara J.; Liang, Junting; Liu, Jing; Yang, Guang; Brown, Jennifer R.; Treon, Steven; Mitsiades, Constantine; Griffin, James; Liu, Qingsong; Gray, Nathanael
    BTK is a member of the TEC family of non-receptor tyrosine kinases whose deregulation has been implicated in a variety of B-cell-related diseases. We have used structure-based drug design in conjunction with kinome profiling and cellular assays to develop a potent, selective, and irreversible BTK kinase inhibitor, QL47, which covalently modifies Cys481. QL47 inhibits BTK kinase activity with an IC50 of 7 nM, inhibits autophosphorylation of BTK on Tyr223 in cells with an EC50 of 475 nM, and inhibits phosphorylation of a downstream effector PLCγ2 (Tyr759) with an EC50 of 318 nM. In Ramos cells QL47 induces a G1 cell cycle arrest that is associated with pronounced degradation of BTK protein. QL47 inhibits the proliferation of B-cell lymphoma cancer cell lines at submicromolar concentrations.
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    The Cyclophilin A-CD147 complex promotes bone marrow colonization of B-cell malignancies: implications for therapy
    (2015) Zhu, Di; Wang, Zhongqiu; Zhao, Jian-Jun; Calimeri, Teresa; Meng, Jiang; Hideshima, Teru; Fulciniti, Mariateresa; Kang, Yue; Ficarro, Scott; Tai, Yu-Tzu; Hunter, Zachary; McMilin, Douglas; Tong, Haoxuan; Mitsiades, Constantine; Wu, Catherine; Treon, Steven; Dorfman, David M.; Pinkus, Geraldine; Munshi, Nikhil; Tassone, Pierfrancesco; Marto, Jarrod; Anderson, Kenneth; Carrasco, Ruben
    B-cell malignancies frequently colonizes the bone marrow (BM). The mechanisms responsible for this preferential homing are not entirely known. Using multiple myeloma (MM) as a model of a terminally differentiated B-cell malignancy that selectively colonizes the BM, we demonstrated that BM endothelial cells (BMECs), secrete cyclophilin A (eCyPA), which promotes migration, proliferation, and BM colonization of MM cells via binding to its receptor, CD147, on MM cells. The clinical and translational implications of this work are highlighted by the observation of significantly higher eCyPA levels in BM serum than in peripheral blood (PB) in MM persons, and that eCyPA-CD147 blockade supresses BM-homing and tumor growth in a mouse xenograft model of MM. eCyPA also promoted migration of CLL and LPL cells, two other B-cell malignancies that colonize the BM and express CD147. These findings offer a compelling rationale for exploring the eCyPA-CD147 axis as therapeutic target for these malignancies.
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    The importance of the genomic landscape in Waldenström's Macroglobulinemia for targeted therapeutical interventions
    (Impact Journals LLC, 2017) Sacco, Antonio; Fenotti, Adriano; Affò, Loredana; Bazzana, Stefano; Russo, Domenico; Presta, Marco; Malagola, Michele; Anastasia, Antonella; Motta, Marina; Patterson, Christopher J.; Rossi, Giuseppe; Imberti, Luisa; Treon, Steven; Ghobrial, Irene; Roccaro, Aldo M.
    The Literature has recently reported on the importance of genomics in the field of hematologic malignancies, including B-cell lymphoproliferative disorders such as Waldenström's Macrolgobulinemia (WM). Particularly, whole exome sequencing has led to the identification of the MYD88L265P and CXCR4C1013G somatic variants in WM, occurring in about 90% and 30% of the patients, respectively. Subsequently, functional studies have demonstrated their functional role in supporting WM pathogenesis and disease progression, both in vitro and in vivo, thus providing the pre-clinical evidences for extremely attractive targets for novel therapeutic interventions in WM. Of note, recent evidences have also approached and defined the transcriptome profiling of WM cells, revealing a signature that mirrors the somatic aberrations demonstrated within the tumor clone. A parallel research field has also reported on microRNAs (miRNAs), highlighting the oncogenic role of miRNA-155 in WM. In the present review, we focus on the latest reports on genomics and miRNAs in WM, providing an overview of the clinical relevance of the latest acquired knowledge about genomics and miRNA aberrations in WM.
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    Advances in the Treatment of Monoclonal Gammopaties: The Emerging Role of Targeted Therapy in Plasma Cell Dyscrasias
    (Dove Medical Press, 2008) Roccaro, Aldo M.; Ghobrial, Irene; Blotta, Simona; Treon, Steven; Malagola, Michele; Anderson, Kenneth; Russo, Domenico
    The paradigm for the treatment of monoclonal gammopaties has dramatically changed: therapeutic options in multiple myeloma (MM) have evolved from the introduction of melphalan and prednisone in the 1960s, high-dose chemotherapy and stem cell transplantation in the late 1980s and 1990s, to the rapid introduction of small novel molecules within the last seven years. Based on the understanding of the complex interaction of the MM cells with the bone marrow microenvironment and the signaling pathways that are dysregulated in this process, a number of novel therapeutic agents are now available. Specifically, three novel agents with a specific-targeted anti-MM activity, have been FDA-approved for the treatment of this disease, namely Bortezomib, thalidomide, and lenalidomide which are now all playing a key role in the treatment of MM. The success of targeted therapy in MM has since led to the development and investigation of more than 30 new compounds in this disease and in other plasma cell dyscrasias such as Waldenström’s macroglobulinemia and primary amyloidosis, both in the preclinical settings and as part of clinical trials.
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    Ibrutinib in Previously Treated Waldenström’s Macroglobulinemia
    (Massachusetts Medical Society, 2015-04-09) Treon, Steven; Tripsas, Christina K.; Meid, Kirsten; Warren, Diane; Varma, Gaurav; Green, Rebecca; Argyropoulos, Kimon V.; Yang, Guang; Cao, Yang; Xu, Lian; Patterson, Christopher J.; Rodig, Scott; Zehnder, James L.; Aster, Jon; Harris, Nancy; Kanan, Sandra; Ghobrial, Irene; Castillo, Jorge; Laubach, Jacob; Hunter, Zachary; Salman, Zeena; Li, Jianling; Cheng, Mei; Clow, Fong; Graef, Thorsten; Palomba, M. Lia; Advani, Ranjana H.
    Background: MYD88(L265P) and CXCR4(WHIM) mutations are highly prevalent in Waldenström's macroglobulinemia. MYD88(L265P) triggers tumor-cell growth through Bruton's tyrosine kinase, a target of ibrutinib. CXCR4(WHIM) mutations confer in vitro resistance to ibrutinib. Methods: We performed a prospective study of ibrutinib in 63 symptomatic patients with Waldenström's macroglobulinemia who had received at least one previous treatment, and we investigated the effect of MYD88 and CXCR4 mutations on outcomes. Ibrutinib at a daily dose of 420 mg was administered orally until disease progression or the development of unacceptable toxic effects. Results: After the patients received ibrutinib, median serum IgM levels decreased from 3520 mg per deciliter to 880 mg per deciliter, median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter, and bone marrow involvement decreased from 60% to 25% (P<0.01 for all comparisons). The median time to at least a minor response was 4 weeks. The overall response rate was 90.5%, and the major response rate was 73.0%; these rates were highest among patients with MYD88(L265P)CXCR4(WT) (with WT indicating wild-type) (100% overall response rate and 91.2% major response rate), followed by patients with MYD88(L265P)CXCR4(WHIM) (85.7% and 61.9%, respectively) and patients with MYD88(WT)CXCR4(WT) (71.4% and 28.6%). The estimated 2-year progression-free and overall survival rates among all patients were 69.1% and 95.2%, respectively. Treatment-related toxic effects of grade 2 or higher included neutropenia (in 22% of the patients) and thrombocytopenia (in 14%), which were more common in heavily pretreated patients; postprocedural bleeding (in 3%); epistaxis associated with the use of fish-oil supplements (in 3%); and atrial fibrillation associated with a history of arrhythmia (5%). Conclusions: Ibrutinib was highly active, associated with durable responses, and safe in pretreated patients with Waldenström's macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug.
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    Guideline for the Diagnosis, Treatment and Response Criteria for Bing-Neel Syndrome
    (Ferrata Storti Foundation (Haematologica), 2017-01) Minnema, Monique C.; Kimby, Eva; D’Sa, Shirley; Fornecker, Luc-Matthieu; Poulain, Stéphanie; Snijders, Tom J.; Kastritis, Efstathios; Kremer, Stéphane; Fitsiori, Aikaterini; Simon, Laurence; Davi, Frédéric; Lunn, Michael; Castillo, Jorge; Patterson, Christopher J.; Le Garff-Tavernier, Magali; Costopoulos, Myrto; Leblond, Véronique; Kersten, Marie-José; Dimopoulos, Meletios A.; Treon, Steven
    Bing Neel syndrome is a rare disease manifestation of Waldenström’s macroglobulinemia that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. In this guideline we describe the clinical symptoms, as well as the appropriate laboratory and radiological studies, that can aid in the diagnosis. The presentation of Bing Neel syndrome may be very diverse, and includes headaches, cognitive deficits, paresis, and psychiatric symptoms. The syndrome can present in patients with known Waldenström’s macroglobulinemia, even in the absence of systemic progression, but also in previously undiagnosed patients. Diagnostic work-up should include cerebral spinal fluid analysis with multiparameter flow cytometry to establish B-cell clonality, protein electrophoresis and immunofixation for the detection and classification of a monoclonal protein as well as molecular diagnostic testing for immunoglobulin gene rearrangement and mutated MYD88. MRI of the brain and spinal cord is also essential. The second challenge is to expand our knowledge of prognosis and treatment outcome. Prospective clinical trials on Bing Neel syndrome patients that employ uniform treatment along with appropriate laboratory cerebral spinal fluid assessments and standardized MRI protocols will be invaluable, constituting a significant step forward in delineating treatment outcome for this intriguing disease manifestation.
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    Clonal Architecture of CXCR4 WHIM-Like Mutations in Waldenström Macroglobulinaemia
    (Wiley, 2016-03) Xu, Lian; Hunter, Zachary; Tsakmaklis, Nicholas; Cao, Yang; Yang, Guang; Chen, Jie; Liu, Xia; Kanan, Sandra; Castillo, Jorge; Tai, Yu-Tzu; Zehnder, James L.; Brown, Jennifer; Carrasco, Ruben; Advani, Ranjana; Sabile, Jean M.; Argyropoulos, Kimon; Lia Palomba, M.; Morra, Enrica; Trojani, Alessandra; Greco, Antonino; Tedeschi, Alessandra; Varettoni, Marzia; Arcaini, Luca; Munshi, Nikhil; Anderson, Kenneth; Treon, Steven
    CXCR4WHIM somatic mutations are distinctive to Waldenstrom Macroglobulinaemia (WM), and impact disease presentation and treatment outcome. The clonal architecture of CXCR4WHIM mutations remains to be delineated. We developed highly sensitive allele-specific polymerase chain reaction(AS-PCR) assays for detecting the most common CXCR4WHIM mutations (CXCR4S338X C>A and C>G) in WM. The AS-PCR assays detected CXCR4S338X mutations in WM and IgM monoclonal gammopathy of unknown significance (MGUS) patients not revealed by Sanger sequencing. By combined AS-PCR and Sanger sequencing, CXCR4WHIM mutations were identified in 44/102 (43%), 21/62 (34%), 2/12 (17%) and 1/20 (5%)untreated WM, previously treated WM, IgM MGUS and marginal zonelymphoma patients, respectively, but no chronic lymphocytic leukaemia, multiple myeloma, non-IgM MGUS patients or healthy donors. Cancer cellfraction analysis in WM and IgM MGUS patients showed CXCR4S338X mutations were primarily subclonal, with highly variable clonal distribution(median 35·1%, range 1·2–97·5%). Combined AS-PCR and Sangersequencing revealed multiple CXCR4WHIM mutations in many individual WM patients, including homozygous and compound heterozygous mutations validated by deep RNA sequencing. The findings show thatCXCR4WHIM mutations are more common in WM than previously revealed, and are primarily subclonal, supporting their acquisition after MYD88L265P in WM oncogenesis. The presence of multiple CXCR4WHIM mutations within individual WM patients may be indicative of targeted CXCR4 genomic instability.
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    Central Nervous System Involvement by Waldenström Macroglobulinaemia (Bing-Neel Syndrome): A Multi-Institutional Retrospective Study
    (Wiley, 2016-03) Castillo, Jorge; D'Sa, Shirley; Lunn, Michael P.; Minnema, Monique C.; Tedeschi, Alessandra; Lansigan, Frederick; Palomba, M. Lia; Varettoni, Marzia; Garcia-Sanz, Ramon; Nayak, Lakshmi; Lee, Eudocia Q.; Rinne, Mikael; Norden, Andrew D.; Ghobrial, Irene; Treon, Steven
    Bing-Neel syndrome (BNS) is a rare complication seen in patients with Waldenström macroglobulinaemia (WM), in which lymphoplasmacytic lymphoma (LPL) cells colonize the central nervous system (CNS). In this retrospective multi-centre study, we present the clinicopathological features, imaging findings, therapy, response and outcomes of 34 patients with BNS. The median time from WM diagnosis to BNS diagnosis was 3 years, 15% of patients were diagnosed with BNS at the time of WM diagnosis, and 22% of patients developed BNS when responding to active treatment for WM. Patients with BNS presented with variable clinical features including limb motor deficits, change in mental status and cranial nerve palsies. The diagnosis was made using a combination of cerebrospinal fluid cytology, flow cytometry and detection of the MYD88 L265 mutation, and magnetic resonance imaging. The estimated 3-year overall survival rate was 59%. Of the survivors, 40% have evidence of pathological or radiological persistence of disease. Age older than 65 years, platelet count lower than 100 x 109/l, and treatment for WM prior to BNS diagnosis were associated with worse outcome. Exposure to rituximab for treatment of BNS was associated with a better outcome. Multi-institutional collaboration is warranted to improve treatment and outcomes in patients with BNS.
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    Recommendations for the Diagnosis and Initial Evaluation of Patients with Waldenström Macroglobulinaemia: A Task Force from the 8th International Workshop on Waldenström Macroglobulinaemia
    (Wiley, 2016-10) Castillo, Jorge; Garcia-Sanz, Ramon; Hatjiharissi, Evdoxia; Kyle, Robert A.; Leleu, Xavier; McMaster, Mary; Merlini, Giampaolo; Minnema, Monique C.; Morra, Enrica; Owen, Roger G.; Poulain, Stephanie; Stone, Marvin J.; Tam, Constantine; Varettoni, Marzia; Dimopoulos, Meletios A.; Treon, Steven; Kastritis, Efstathios
    The diagnosis of Waldenström macroglobulinemia (WM) can be challenging given the variety of signs and symptoms patients can present. Furthermore, once the diagnosis of WM is established, the initial evaluation should be thorough as well as appropriately directed. During the 8th International Workshop for WM in London, United Kingdom, a multi-institutional task force was formed to develop consensus recommendations for the diagnosis and initial evaluation of patients with WM. In this document, we present the results of the deliberations taken place to address these issues. We provide recommendations for history taking and physical examination, laboratory studies, bone marrow aspiration and biopsy analysis and imaging studies. We also provide guidance on the initial evaluation of special situations such as anemia, hyperviscosity, neuropathy, Bing-Neel syndrome and amyloidosis. We hope these recommendations serve as a practical guidance to clinicians taking care of patients with a suspected or an established diagnosis of WM.