Browsing by Author "Suvannasankha, Attaya"

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    Acquired Factor X Deficiency in Patients With Primary Light Chain Amyloidosis
    (Sage, 2019) Dejhansathit, Siroj; Suvannasankha, Attaya; Medicine, School of Medicine
    Acquired factor X (FX) deficiency is a rare but serious complication of primary amyloidosis, presumably caused by the binding of amyloid proteins to the clotting factors. The prolonged prothrombin time, partial thromboplastin time, and low FX level, which are correctable by mixing study, are the disease hallmarks. An immediate goal of care is to stop bleeding. Clotting factor replacement requires close monitoring of coagulogram and FX levels due to varying FX clearance among patients. High-purity FX is currently approved for hereditary FX deficiency and has been successfully used in some acquired FX deficiency cases. Ongoing bleeding risk complicates the treatment decision. Novel therapies yielding rapid and deep response reduce amyloid protein production and improve long-term outcome.
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    Acute lymphoblastic leukaemia with osteolytic bone lesions: diagnostic dilemma
    (BMJ, 2018-08-11) Angsubhakorn, Natthapon; Suvannasankha, Attaya; Medicine, School of Medicine
    A previously healthy 37-year-old man presented with a 10-month history of intractable back pain. On examination, there was tenderness to palpation along lower thoracic and lumbar spine. Complete blood count showed mild anaemia but was otherwise unremarkable. Imaging studies revealed compression deformities with multiple osteolytic lesions involving multiple levels of the thoracic and lumbar spine. Bone marrow aspiration and biopsy were performed and demonstrated blast cells involving 80% of the bone marrow cellularity. Findings on flow cytometry were consistent with B-lymphoblastic leukaemia. He was subsequently started on hyper-CVAD (fractionated cyclophosphamide, vincristine, Adriamycin and dexamethasone) induction chemotherapy.
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    Belantamab mafodotin for the treatment of relapsed/refractory multiple myeloma in heavily pretreated patients: a US cost-effectiveness analysis
    (Taylor & Francis, 2021) Nikolaou, Andreas; Ambavane, Apoorva; Shah, Anshul; Ma, Wenkang; Tosh, Jon; Kapetanakis, Venediktos; Willson, Jenny; Wang, Feng; Hogea, Cosmina; Gorsh, Boris; Gutierrez, Ben; Sapra, Sandhya; Suvannasankha, Attaya; Samyshkin, Yevgeniy; Medicine, School of Medicine
    Background: Patients with relapsed/refractory multiple myeloma (RRMM) require several lines of therapy, with typically shorter remission duration with each additional line. Research design and methods: The cost-effectiveness of belantamab mafodotin (belamaf; DREAMM-2; NCT03525678) was compared with selinexor plus dexamethasone (SEL+DEX; STORM Part 2; NCT02336815) among patients with RRMM who have received at least four prior therapies. The base case used a US commercial payer's perspective over a 10-year time horizon. Efficacy data were based on parametric survival analysis of DREAMM-2 and matching-adjusted indirect treatment comparison between DREAMM-2 and STORM Part 2, which assessed relative treatment effects between belamaf and SEL+DEX. Cost inputs included drug treatment, concomitant medications, adverse event management, subsequent treatments, and disease management. Results: Belamaf decreased total treatment costs per patient by $14,267 and increased patient life years by 0.74 and quality-adjusted life years (QALYs) by 0.49 versus SEL+DEX. Patients receiving belamaf accrued 0.12 fewer progression-free life years versus patients on SEL+DEX. Conclusions: From a US commercial payer's perspective, belamaf had lower costs, and increased QALYs and life-year gain, compared with SEL+DEX. Belamaf is therefore likely to be a cost-effective treatment option for patients with RRMM who have received four or more prior lines of therapy.
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    Cell adhesion molecule CD166 drives malignant progression and osteolytic disease in multiple myeloma
    (American Association for Cancer Research, 2016-12-01) Xu, Linlin; Mohammad, Khalid S.; Wu, Hao; Crean, Colin; Poteat, Bradley; Cheng, Yinghua; Cardoso, Angelo A.; Machal, Christophe; Hanenberg, Helmut; Abonour, Rafat; Kacena, Melissa A.; Chirgwin, John; Suvannasankha, Attaya; Srour, Edward F.; Microbiology and Immunology, School of Medicine
    Multiple myeloma (MM) is incurable once osteolytic lesions have seeded at skeletal sites, but factors mediating this deadly pathogenic advance remain poorly understood. Here we report evidence of a major role for the cell adhesion molecule CD166, which we discovered to be highly expressed in MM cell lines and primary bone marrow (BM) cells from patients. CD166+ MM cells homed more efficiently than CD166− cells to the BM of engrafted immunodeficient NSG mice. CD166 silencing in MM cells enabled longer survival, a smaller tumor burden and less osteolytic lesions, as compared to mice bearing control cells. CD166 deficiency in MM cell lines or CD138+ BM cells from MM patients compromised their ability to induce bone resorption in an ex vivo organ culture system. Further, CD166 deficiency in MM cells also reduced formation of osteolytic disease in vivo after intra-tibial engraftment. Mechanistic investigation revealed that CD166 expression in MM cells inhibited osteoblastogenesis of BM-derived osteoblast progenitors by suppressing RUNX2 gene expression. Conversely, CD166 expression in MM cells promoted osteoclastogenesis by activating TRAF6-dependent signaling pathways in osteoclast progenitors. Overall, our results define CD166 as a pivotal director in MM cell homing to the BM and MM progression, rationalizing its further study as a candidate therapeutic target for MM treatment.
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    Cold agglutinin-mediated autoimmune haemolytic anaemia associated with diffuse large B cell lymphoma
    (BMJ, 2018-07-10) Wongsaengsak, Sariya; Czader, Magdalena; Suvannasankha, Attaya; Medicine, School of Medicine
    Cold agglutinin-mediated autoimmune haemolytic anaemia is associated with the development of autoantibodies that can agglutinate red blood cells at cold temperatures. While primary cold agglutinin disease is an idiopathic lymphoproliferative disorder, secondary cold agglutinin syndrome (CAS) complicates other diseases such as infections, autoimmune diseases and cancers, mostly low-grade lymphomas. Early recognition, treatment of CAS and treatment of its associated underlying diseases are crucial to a successful outcome. We report a case of CAS in a setting of diffuse large B cell lymphoma, in which the treatment course was complicated by worsened anaemia due to chemotherapy-induced myelosuppression. We reviewed previously reported cases and discussed diagnosis and treatment strategies, including novel complement inhibitors, as potential future therapy.
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    Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML
    (Impact Journals, 2017-12-25) Sayar, Hamid; Liu, Yan; Gao, Rui; Zaid, Mohammad Abu; Cripe, Larry D.; Weisenbach, Jill; Sargent, Katie J.; Nassiri, Mehdi; Li, Lang; Konig, Heiko; Suvannasankha, Attaya; Pan, Feng; Shanmugam, Rajasubramaniam; Goswami, Chirayu; Kapur, Reuben; Xu, Mingjiang; Boswell, H. Scott; Medicine, School of Medicine
    Co-occurrence of Flt3ITD and TET2 mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including RUNX3, and by hyperexpression of ID1, encoding Wnt agonist. These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML's, including Flt3ITD+ve, described with a signature of repressed tumor suppressor genes, involving Wnt antagonist RUNX3, occurring along with ID1 and HOXA over-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linking RUNX3/Wnt antagonist de-repression (80%) and ID1 downregulation (85%), to a response, also preceded by profound HOXA9 repression. Response occurred in context of concurrent TET2 mutation/hypomorphy and Flt3ITD+ve mutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in Flt3ITD+ve cases exhibiting such Wnt pathway dysregulation.
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    DREAMM-2: Indirect Comparisons of Belantamab Mafodotin vs. Selinexor + Dexamethasone and Standard of Care Treatments in Relapsed/Refractory Multiple Myeloma
    (Springer, 2021) Prawitz, Thibaud; Popat, Rakesh; Suvannasankha, Attaya; Sarri, Grammati; Hughes, Rachel; Wang, Feng; Hogea, Cosmina; Ferrante, Shannon Allen; Gorsh, Boris; Willson, Jenny; Kapetanakis, Venediktos; Medicine, School of Medicine
    Introduction: Single-agent belantamab mafodotin (belamaf; BLENREP) demonstrated deep and durable responses in patients with relapsed/refractory multiple myeloma and ≥ 3 prior lines of therapy, including an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody (DREAMM-2; NCT03525678). Methods: At the time of this study, STORM Part 2, NCT02336815 (selinexor plus low-dose dexamethasone; sel + dex) was systematically identified as the only feasible comparator to the DREAMM-2 cohort. Matching-adjusted indirect comparisons (MAIC) evaluated efficacy and safety of belamaf (2.5 mg/kg; n = 97) versus sel + dex (80 mg + 20 mg, respectively; n = 123). Populations were weighted for clinically validated effect modifiers and prognostic factors. Outcomes included overall survival (OS), progression-free survival (PFS), duration of response (DoR), overall response rate (ORR), time to response (TTR), and safety. The relative efficacy of belamaf versus standard of care (SoC) on OS was estimated by a Bucher indirect treatment comparison using the MAIC-adjusted hazard ratios (HR) for OS of belamaf (DREAMM-2) versus sel + dex (STORM Part 2) and a HR adjusted for refractoriness to carfilzomib and high-risk cytogenetics of sel + dex (STORM) versus SoC (MAMMOTH). Results: Belamaf demonstrated improved OS (HR 0.53; 95% confidence interval 0.34, 0.83; p = 0.005) and DoR (0.41; 0.21, 0.83; p = 0.013) versus sel + dex. There were no statistically significant differences in ORR, TTR, and PFS. Belamaf had a favorable safety profile for most evaluable hematologic (any-grade, Grade 3-4) and non-hematologic (any-grade) adverse events versus sel + dex. Significantly improved OS was observed with belamaf versus SoC (0.29; 0.16, 0.54; p < 0.001). Conclusion: Single-agent belamaf represents a new treatment option for triple-class refractory patients with RRMM.
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    FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells
    (Oncotarget, 2015-08-14) Suvannasankha, Attaya; Tompkins, Douglas R.; Edwards, Daniel F.; Petyaykina, Katarina V.; Crean, Colin D.; Fournier, Pierrick G.; Parker, Jamie M.; Sandusky, George E.; Ichikawa, Shoji; Imel, Erik A.; Chirgwin, John M.; Department of Medicine, IU School of Medicine
    Multiply myeloma (MM) grows in and destroys bone, where osteocytes secrete FGF23, a hormone which affects phosphate homeostasis and aging. We report that multiple myeloma (MM) cells express receptors for and respond to FGF23. FGF23 increased mRNA for EGR1 and its target heparanase, a pro-osteolytic factor in MM. FGF23 signals through a complex of klotho and a classical FGF receptor (FGFR); both were expressed by MM cell lines and patient samples. Bone marrow plasma cells from 42 MM patients stained positively for klotho, while plasma cells from 8 patients with monoclonal gammopathy of undetermined significance (MGUS) and 6 controls were negative. Intact, active FGF23 was increased 2.9X in sera of MM patients compared to controls. FGF23 was not expressed by human MM cells, but co-culture with mouse bone increased its mRNA. The FGFR inhibitor NVP-BGJ398 blocked the heparanase response to FGF23. NVP-BGJ398 did not inhibit 8226 growth in vitro but significantly suppressed growth in bone and induction of the osteoclast regulator RANK ligand, while decreasing heparanase mRNA. The bone microenvironment provides resistance to some anti-tumor drugs but increased the activity of NVP-BGJ398 against 8226 cells. The FGF23/klotho/heparanase signaling axis may offer targets for treatment of MM in bone.
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    GFI1-Dependent Repression of SGPP1 Increases Multiple Myeloma Cell Survival
    (MDPI, 2022-02-02) Petrusca, Daniela N.; Mulcrone, Patrick L.; Macar, David A.; Bishop, Ryan T.; Berdyshev, Evgeny; Suvannasankha, Attaya; Anderson, Judith L.; Sun, Quanhong; Auron, Philip E.; Galson, Deborah L.; Roodman, G. David; Medicine, School of Medicine
    Multiple myeloma (MM) remains incurable for most patients due to the emergence of drug resistant clones. Here we report a p53-independent mechanism responsible for Growth Factor Independence-1 (GFI1) support of MM cell survival by its modulation of sphingolipid metabolism to increase the sphingosine-1-phosphate (S1P) level regardless of the p53 status. We found that expression of enzymes that control S1P biosynthesis, SphK1, dephosphorylation, and SGPP1 were differentially correlated with GFI1 levels in MM cells. We detected GFI1 occupancy on the SGGP1 gene in MM cells in a predicted enhancer region at the 5' end of intron 1, which correlated with decreased SGGP1 expression and increased S1P levels in GFI1 overexpressing cells, regardless of their p53 status. The high S1P:Ceramide intracellular ratio in MM cells protected c-Myc protein stability in a PP2A-dependent manner. The decreased MM viability by SphK1 inhibition was dependent on the induction of autophagy in both p53WT and p53mut MM. An autophagic blockade prevented GFI1 support for viability only in p53mut MM, demonstrating that GFI1 increases MM cell survival via both p53WT inhibition and upregulation of S1P independently. Therefore, GFI1 may be a key therapeutic target for all types of MM that may significantly benefit patients that are highly resistant to current therapies.
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    Identifying 1q amplification and PHF19 expressing high-risk cells associated with relapsed/refractory multiple myeloma
    (Research Square, 2023-08-16) Johnson, Travis S.; Sudha, Parvathi; Liu, Enze; Blaney, Patrick; Morgan, Gareth; Chopra, Vivek S.; Dos Santos, Cedric; Nixon, Michael; Huang, Kun; Suvannasankha, Attaya; Abu Zaid, Mohammad; Abonour, Rafat; Walker, Brian A.; Biostatistics and Health Data Science, School of Medicine
    Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers have been identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and has already been studied using RNA-seq. In this study a massive (325,025 cells and 49 patients) single cell multiomic dataset was generated with jointly quantified ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identified an association between one plasma cell subtype with myeloma progression that we have called relapsed/refractory plasma cells (RRPCs). These cells are associated with 1q alterations, TP53 mutations, and higher expression of PHF19. We also identified downstream regulation of cell cycle inhibitors in these cells, possible regulation of the transcription factor (TF) PBX1 on 1q, and determined that PHF19 may be acting primarily through this subset of cells.