Haematology (Scholarly Publications)
http://hdl.handle.net/2262/130
Haematology (Scholarly Publications)2024-03-28T09:48:31ZA novel aryl-guanidinium derivative, VP79s, targets the signal transducer and activator of transcription 3 signaling pathway, downregulates myeloid cell leukaemia-1 and exhibits preclinical activity against multiple myeloma
http://hdl.handle.net/2262/97864
A novel aryl-guanidinium derivative, VP79s, targets the signal transducer and activator of transcription 3 signaling pathway, downregulates myeloid cell leukaemia-1 and exhibits preclinical activity against multiple myeloma
Mc Elligott, Tony; Rozas, Isabel; Zisterer, Daniela; Hayden, Patrick; Lynam-Lennon, Niamh; Browne, Paul
Aims: We have recently described a novel guanidinium-based compound, VP79s, which induces cytotoxicity in various cancer cell lines. Here, we aim to investigate the activity of VP79s and associated mechanisms of action in multiple myeloma (MM) cells in vitro and ex vivo.
Main methods: The effects of VP79s on cell viability and induction of apoptosis was examined in a panel of drug-sensitive and drug-resistant MM cell lines, as well as ex vivo patient samples and normal donor lymphocytes and platelets. Cell signaling pathways associated with the biological effects of VP79s were analysed by immunoblotting and flow cytometry. Gene expression changes were assessed by quantitative real-time PCR analysis.
Key findings: VP79s was found to rapidly inhibit both constitutively active and IL-6-induced STAT3 signaling with concurrent downregulation of the IL-6 receptors, CD130 and CD126. VP79s induced a rapid and dose-dependent downregulation of anti-apoptotic Bcl-2 family member, myeloid cell leukaemia-1 (MCL-1). VP79s enhanced bortezomib induced cell death and was also found to overcome bone marrow stromal cell induced drug resistance. VP79s exhibited activity in ex vivo patient samples at concentrations which had no effect on peripheral blood mononuclear cells, lymphocytes and platelets isolated from healthy donors.
Significance: As VP79s resulted in rapid inhibition of the key IL-6/STAT3 signaling pathway and downregulation of MCL-1 expression with subsequent selective anti-myeloma activity, VP79s may be a potential therapeutic agent with a novel mechanism of action in MM cells.
PUBLISHED
2022-01-01T00:00:00ZEpidemiology of chronic lymphocytic leukaemia in an Irish subpopulation with total case ascertainment: an additional tool for health economic planning
http://hdl.handle.net/2262/97684
Epidemiology of chronic lymphocytic leukaemia in an Irish subpopulation with total case ascertainment: an additional tool for health economic planning
Vandenberghe, Elisabeth; Mc Elligott, Tony
Chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) is the commonest B-cell malignancy affecting Caucasians, with a variable national incidence depending on the ethnic composition and age profile of the population.1 The National Cancer Registry of Ireland (NCRI) quotes a Republic of Ireland (ROI) CLL incidence of 6·1/100 000, which appeared lower than our clinical experience indicated.2 Establishing accurate CLL incidence figures and numbers of patients requiring therapy would improve health service provision planning.
Chronic lymphocytic leukaemia is a clinically variable disease; up to one-third of patients are never treated, while ‘high-risk’ patients require costly, prolonged targeted therapy to circumvent chemoresistance.3-5 Although unmutated immunoglobulin variable heavy chain (IgVH), tumour protein p53 (TP53), splicing factor 3B subunit 1 (SF3B1), baculoviral IAP repeat-containing 3 (BIRC3) and Notch receptor 1 (NOTCH1) gene mutations confer inferior outcomes, the commonly used targeted therapies that include Bruton tyrosine kinase inhibitors such as ibrutinib and the B-cell lymphoma 2 (BCL2) inhibitor, venetoclax are only available for TP53-disrupted (mutation or deletion) and relapsed CLL.6, 7 The high cost of these drugs is challenging for healthcare budgeting because of the requirement for long-term treatment until toxicity/resistance and the potential for multiple targeted drug combinations.
The present study uses a subpopulation ‘complete ascertainment’ approach to define the incidence of CLL and the numbers of patients requiring treatment annually in the ROI, many of whom may benefit from targeted-therapy treatment in first and second line as being defined by recently completed or ongoing studies.
PUBLISHED
2021-01-01T00:00:00ZThe Impact of Advanced Patient Age on Mortality after Allogeneic Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma: A Retrospective Study by the European Society for Blood and Marrow Transplantation Lymphoma Working Party
http://hdl.handle.net/2262/91335
The Impact of Advanced Patient Age on Mortality after Allogeneic Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma: A Retrospective Study by the European Society for Blood and Marrow Transplantation Lymphoma Working Party
Browne, Paul; Kyriakou, Charalampia; Boumendil, Ariane; Finel, Herve; Schmitz, NN Norbert; Smedegaard Andersen, Niels; Blaise, Didier; Chevallier, Patrice; Browne, Paul; Malladi, Ram; Niederwieser, Dietger; Pagliuca, Antonio; Kroschinsky, Frank; Montoto, Silvia; Dreger, Peter; EBMT Lymphoma Working Party
More than 60% of patients with non-Hodgkin lymphoma (NHL) are age>60 years at presentation. The purpose of thisstudy was to compare the potential risks and benefits of allogeneic hematopoietic cell transplantation (alloHCT) inelderly patients with NHL with younger patients in a large sample, also taking into account comorbidity information. Allpatients age 18 years who had undergone alloHCT from a matched sibling or unrelated donor for NHL between 2003and 2013 and were registered with the European Society forBlood and Marrow Transplantation were eligible for thestudy. The primary study endpoint was 1-year nonrelapse mortality (NRM). A total of 3919 patients were eligible andwere categorized by age: young (Y), 18 to 50 y (n = 1772); middle age (MA), 51 to 65 y (n = 1967); or old (O), 66 to 77 y(n = 180). Follicular lymphoma was present in 37% of the patients; diffuse large B cell lymphoma, in 30%; mantle cell lym-phoma, in 21%, and peripheral T cell lymphoma, in 11%. At thetime of alloHCT, 85% of the patients were chemosensitiveand 15% were chemorefractory. With a median follow-upof 4.5 years in survivors, NRM at 1 year was 13% for theY group. 20% for the MA group, and 33% for the O group (P<.001), whereas relapse incidence and overall survival (OS)at 3 years in the 3 groups were 30%, 31%, and 28% (P= .355) and 60%, 54%, and 38% (P<.001), respectively. Multivariableadjustment for confounders, including sex, NHL subset, time from diagnosis, chemosensitivity, donor, and conditioning,confirmed older age as a significant predictor for NRM and OS, but not for relapse risk. Although comorbidity was a sig-nificant predictor of NRM in a subset analysis restricted to the979 patients with comorbidity information available, ageretained its significant impact on NRM. In conclusion, our data show that alloHCT in patients age>65 y provides similarNHL control as seen in younger patients but is associated with a higher NRM that is not fully explained by comorbidity.Thus, although alloHCT is feasible and effective in very oldpatients, the increased NRM risk must be taken into accountwhen assessing the indication for alloHCT for NHL in this age group.
PUBLISHED
2019-01-01T00:00:00ZIncidence of Second Primary Malignancies after Autologous Transplantation for Multiple Myeloma in the Era of Novel Agents
http://hdl.handle.net/2262/89935
Incidence of Second Primary Malignancies after Autologous Transplantation for Multiple Myeloma in the Era of Novel Agents
Browne, Paul; Sahebi, Firoozeh; Iacobelli, Simona; Sbianchi, Giulia; Koster, Linda; Blaise, Didier; Reményi, Péter; Russell, Nigel H.; Ljungman, Per; Kobbe, Guido; Apperley, Jane; Trneny, Marek; Krejci, Marta; Wiktor-Jedrzejczak, Wieslaw; Sanchez, James F.; Schaap, Nicolaas; Isaakson, Cecilia; Lenhoff, Stig; Scheid, Christof; Wilson, Keith M.O.; Yakoub-Agha, Ibrahim; González Muñiz, Soledad; Schönland, Stefan; Morris, Curly; Garderet, Laurent; Kröger, Nicolaus
The advent of novel agents for multiple myeloma (MM) is cause for a re-examination of the incidence of second primary malignancies (SPMs). We examined the SPM rate in MM patients who were enrolled in the prospective observational CALM (Collaboration to Collect Autologous Transplant outcome in Lymphoma and Myeloma) study. Between 2008 and 2012, 3204 patients with MM underwent a first autologous hematopoietic stem cell transplantation. Plerixafor was used as a mobilizing agent for patients with poor (or potentially poor) stem cell mobilization as defined by the respective centers. A total of 135 patients developed SPMs, with a cumulative incidence of 5.3% (95% confidence interval, 4.4 to 6.3) at 72 months. Ninety-four patients developed solid tumors, 30 developed hematologic malignancies, and 11 developed an SPM of an unknown type. The cumulative incidence of known hematologic and solid malignancies were 1.4% and 3.6%, respectively, at 72 months. In a univariate analysis, use of radiotherapy, type of induction regimen, hematopoietic stem cell dose, poor mobilizer status, plerixafor use, and sex did not influence the cumulative incidence of SPMs. Only age over 65 years was statistically associated with an increased incidence. Overall, the incidence of SPMs was comparable to earlier estimations of SPMs in MM.
2018-01-01T00:00:00Z