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Blood Cancer Journal

Yuan Xiao Zhu, Chang-Xin Shi, Laura A Bruins, Xuewei Wang, Daniel L Riggs, Brooke Porter, Jonathan M Ahmann, Cecilia Bonolo de Campos, Esteban Braggio, P Leif Bergsagel, A Keith Stewart
To understand immunomodulatory drug (IMiD) resistance in multiple myeloma (MM), we created isogenic human multiple myeloma cell lines (HMCLs) sensitive and resistant to lenalidomide, respectively. Four HMCLs were demonstrated to be resistant to all IMiDs including lenalidomide, pomalidomide, and CC-220, but not to Bortezomib. In three HMLCs (MM.1.SLenRes, KMS11LenRes and OPM2LenRes), CRBN abnormalities were found, including chromosomal deletion, point mutation, and low CRBN expression. The remaining HMCL, XG1LenRes, showed no changes in CRBN but exhibited CD147 upregulation and impaired IRF4 downregulation after lenalidomide treatment...
February 11, 2019: Blood Cancer Journal
Francesco Mannelli, Francesca Gesullo, Giada Rotunno, Annalisa Pacilli, Lisa Pieri, Paola Guglielmelli, Alessandro M Vannucchi
No abstract text is available yet for this article.
February 11, 2019: Blood Cancer Journal
A Keith Stewart, Amrita Y Krishnan, Seema Singhal, Ralph V Boccia, Manish R Patel, Ruben Niesvizky, Asher A Chanan-Khan, Sikander Ailawadhi, Jochen Brumm, Kirsten E Mundt, Kyu Hong, Jacqueline McBride, Quyen Shon-Nguyen, Yuanyuan Xiao, Vanitha Ramakrishnan, Andrew G Polson, Divya Samineni, Douglas Leipold, Eric W Humke, James Scott McClellan, Jesus G Berdeja
FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3-2.4 mg/kg every 3 weeks or 0.8-1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients...
February 4, 2019: Blood Cancer Journal
Faye A Sharpley, Richa Manwani, Shameem Mahmood, Sajitha Sachchithanantham, Helen J Lachmann, Julian D Gillmore, Carol J Whelan, Marianna Fontana, Philip N Hawkins, Ashutosh D Wechalekar
No abstract text is available yet for this article.
February 4, 2019: Blood Cancer Journal
Dickran Kazandjian, Elizabeth Hill, Malin Hultcrantz, Evan H Rustad, Venkata Yellapantula, Theresia Akhlaghi, Neha Korde, Sham Mailankody, Alex Dew, Elli Papaemmanuil, Irina Maric, Mary Kwok, Ola Landgren
Caucasian Americans (CA) compared with African Americans (AA) have a twofold increased incidence of multiple myeloma (MM) and have an earlier age of diagnosis. However, there is sparse information regarding underlying biological differences across racial/ethnic groups. We characterized genetic alterations using a targeted next-generation sequencing assay called myTYPE, developed at MSKCC, allowing capture of somatic mutations, IgH translocations, gains/losses, and hyperdiploidy. Samples were obtained from the NIH Plasma Cell Dyscrasia Racial Disparity Cohort...
February 4, 2019: Blood Cancer Journal
Katharina Kriegsmann, Marc-Andrea Baertsch, Mohamed H S Awwad, Maximilian Merz, Dirk Hose, Anja Seckinger, Anna Jauch, Natalia Becker, Axel Benner, Marc S Raab, Jens Hillengass, Uta Bertsch, Jan Dürig, Hans Jürgen Salwender, Mathias Hänel, Roland Fenk, Markus Munder, Katja Weisel, Carsten Müller-Tidow, Hartmut Goldschmidt, Michael Hundemer
Immunomodulatory drugs (IMIDs) are very effective in the treatment of multiple myeloma (MM). The description of their cereblon-mediated mechanism of action was a hallmark in MM research. Although the importance of IMID-induced degradation of cereblon-binding proteins is well described in vitro, the prognostic value of their expression levels in MM cells is less clear. Based on recently published data showing somewhat conflicting RNA levels, we analyzed the association between the levels of the Ikaros family zinc finger protein 1 (IKZF1), IKZF3, and karyopherin subunit alpha 2 (KPNA2) proteins measured by flow cytometry and prognostic parameters in 214 newly diagnosed MM patients who were randomized in the GMMG HD6 trial...
January 29, 2019: Blood Cancer Journal
Sudhakiranmayi Kuravi, Elizabeth Parrott, Giridhar Mudduluru, Janice Cheng, Siddhartha Ganguly, Yogen Saunthararajah, Roy A Jensen, Brian S Blagg, Joseph P McGuirk, Ramesh Balusu
No abstract text is available yet for this article.
January 29, 2019: Blood Cancer Journal
Rangit R Vallapureddy, Mythri Mudireddy, Domenico Penna, Terra L Lasho, Christy M Finke, Curtis A Hanson, Rhett P Ketterling, Kebede H Begna, Naseema Gangat, Animesh Pardanani, Ayalew Tefferi
Among 1306 patients with primary myelofibrosis (PMF), we sought to identify risk factors that predicted leukemic transformation (LT) in the first 5 years of disease and also over the course of the disease. 149 (11%) LT were documented; patients who subsequently developed LT (n = 149), compared to those who remained in chronic phase disease (n = 1,157), were more likely to be males (p = 0.02) and display higher circulating blasts (p = 0.03), ASXL1 (p = 0.01), SRSF2 (p = 0.001) and IDH1 (p = 0...
January 25, 2019: Blood Cancer Journal
Naseema Gangat, Amy Phelps, Terra L Lasho, Christy M Finke, Rangit Vallapureddy, Curtis A Hanson, Rhett P Ketterling, Mrinal M Patnaik, Animesh Pardanani, Ayalew Tefferi
No abstract text is available yet for this article.
January 24, 2019: Blood Cancer Journal
George Hucks, Susan R Rheingold
Outcomes of pediatric and young adult patients diagnosed with acute lymphoblastic leukemia (ALL) have improved significantly in the past few decades. Treatment advances have provided 5-year survival rates ranging from 78 to 91% depending on the age at diagnosis. However, approximately 2-3% of patients will present with refractory disease that is unresponsive to chemotherapy, and 10-15% of patients will relapse. Outcomes post-relapse show significantly reduced 5-year survival rates that continue to decrease with each subsequent relapse...
January 22, 2019: Blood Cancer Journal
Imad Maatouk, Susanne He, Manuela Hummel, Stefan Hemmer, Michaela Hillengass, Hartmut Goldschmidt, Mechthild Hartmann, Wolfgang Herzog, Jens Hillengass
No abstract text is available yet for this article.
January 21, 2019: Blood Cancer Journal
Morten O Holmström, Shamaila M Ahmad, Uffe Klausen, Simone K Bendtsen, Evelina Martinenaite, Caroline H Riley, Inge M Svane, Lasse Kjær, Vibe Skov, Christina Ellervik, Niels Pallisgaard, Hans C Hasselbalch, Mads H Andersen
Mutations in exon 9 of the calreticulin gene (CALR) frequently occur in patients with chronic myeloproliferative neoplasms (MPN). Patients exhibit spontaneous cellular immune responses to epitopes derived from the mutant CALR C-terminus, and CALR-mutant-specific T cells recognize autologous CALR-mutant malignant cells. This study investigated whether CALR-mutant-specific T cells occur naturally in CALRwt MPN-patients and in healthy individuals. Specific immune responses against epitopes in the mutant CALR peptide sequence were detected in both CALRwt MPN-patients and in healthy individuals...
January 17, 2019: Blood Cancer Journal
Musa Yilmaz, Feng Wang, Sanam Loghavi, Carlos Bueso-Ramos, Curtis Gumbs, Latasha Little, Xingzhi Song, Jianhua Zhang, Tapan Kadia, Gautam Borthakur, Elias Jabbour, Naveen Pemmaraju, Nicholas Short, Guillermo Garcia-Manero, Zeev Estrov, Hagop Kantarjian, Andrew Futreal, Koichi Takahashi, Farhad Ravandi
Late relapse, defined as relapse arising after at least 5 years of remission, is rare and occurs in 1-3% of patients with acute myeloid leukemia (AML). The underlying mechanisms of late relapse remain poorly understood. We identified patients with AML who achieved remission with standard induction chemotherapy and relapsed after at least five years of remission (n = 15). Whole exome sequencing was performed in available bone marrow samples obtained at diagnosis (n = 10), remission (n = 6), and first relapse (n = 10)...
January 16, 2019: Blood Cancer Journal
Daniel Ernst, Brent A Williams, Xing-Hua Wang, Nara Yoon, Kyung-Phil Kim, Jodi Chiu, Zhi Juan Luo, Karin G Hermans, Joerg Krueger, Armand Keating
CD123 (IL-3Rα) is frequently expressed by malignant Hodgkin lymphoma (HL) cells. Naked monoclonal antibodies (mAb) against HL lack clinical benefit, partially due to absence of natural killer (NK) cells in the tumor microenvironment. Here we show that the combination of a fully humanized anti-CD123 mAb (CSL362) and high-affinity Fcγ-receptor NK-92 cells (haNK) effectively target and kill HL cells in vitro. First, we confirmed high expression of CD123 in 2 of the 3 HL cell lines (KM-H2 and L-428), and its absence in NK cells...
January 15, 2019: Blood Cancer Journal
Sausan A Moharram, Kinjal Shah, Fatima Khanum, Lars Rönnstrand, Julhash U Kazi
No abstract text is available yet for this article.
January 15, 2019: Blood Cancer Journal
Warren Fiskus, Tianyu Cai, Courtney D DiNardo, Steven M Kornblau, Gautam Borthakur, Tapan M Kadia, Naveen Pemmaraju, Prithviraj Bose, Lucia Masarova, Kimal Rajapakshe, Dimuthu Perera, Cristian Coarfa, Christopher P Mill, Dyana T Saenz, David N Saenz, Baohua Sun, Joseph D Khoury, Yu Shen, Marina Konopleva, Kapil N Bhalla
First-generation bromodomain extra-terminal protein (BETP) inhibitors (BETi) (e.g., OTX015) that disrupt binding of BETP BRD4 to chromatin transcriptionally attenuate AML-relevant progrowth and prosurvival oncoproteins. BETi treatment induces apoptosis of AML BPCs, reduces in vivo AML burden and induces clinical remissions in a minority of AML patients. Clinical efficacy of more potent BETis, e.g., ABBV-075 (AbbVie, Inc.), is being evaluated. Venetoclax and A-1210477 bind and inhibit the antiapoptotic activity of BCL2 and MCL1, respectively, lowering the threshold for apoptosis...
January 15, 2019: Blood Cancer Journal
Jonathan L Kaufman, Roberto Mina, Andrzej J Jakubowiak, Todd L Zimmerman, Jeffrey J Wolf, Colleen Lewis, Charise Gleason, Cathy Sharp, Thomas Martin, Leonard T Heffner, Ajay K Nooka, R Donald Harvey, Sagar Lonial
Proteasome (PIs) and hystone deacetylase inhibitors (HDACis) have previously shown synergistic activity in the treatment of relapesed/refractory multiple myeloma (RRMM) patients. In this phase 1 study, we combined carfilzomib, a second generation PI, with panobinostat, a HDACi, to determine the maximum tolerated dose (MTD) of the combination (CarPan) and assess safety and efficacy among RRMM patients. Thirty-two patients (median of 4 prior lines of therapy) were enrolled. The MTD was carfilzomib 36 mg/m2 (on days 1, 2, 8, 9, 15, and 16) and panobinostat 20 mg (TIW, 3 weeks on/1 week off, every 28 days), administered until progression...
January 4, 2019: Blood Cancer Journal
Jin Sung Jang, Ying Li, Amit Kumar Mitra, Lintao Bi, Alexej Abyzov, Andre J van Wijnen, Linda B Baughn, Brian Van Ness, Vincent Rajkumar, Shaji Kumar, Jin Jen
We used single cell RNA-Seq to examine molecular heterogeneity in multiple myeloma (MM) in 597 CD138 positive cells from bone marrow aspirates of 15 patients at different stages of disease progression. 790 genes were selected by coefficient of variation (CV) method and organized cells into four groups (L1-L4) using unsupervised clustering. Plasma cells from each patient clustered into at least two groups based on gene expression signature. The L1 group contained cells from all MGUS patients having the lowest expression of genes involved in the oxidative phosphorylation, Myc targets, and mTORC1 signaling pathways (p < 1...
January 3, 2019: Blood Cancer Journal
Molly Went, Amit Sud, Helen Speedy, Nicola J Sunter, Asta Försti, Philip J Law, David C Johnson, Fabio Mirabella, Amy Holroyd, Ni Li, Giulia Orlando, Niels Weinhold, Mark van Duin, Bowang Chen, Jonathan S Mitchell, Larry Mansouri, Gunnar Juliusson, Karin E Smedby, Sandrine Jayne, Aneela Majid, Claire Dearden, David J Allsup, James R Bailey, Guy Pratt, Chris Pepper, Chris Fegan, Richard Rosenquist, Rowan Kuiper, Owen W Stephens, Uta Bertsch, Peter Broderick, Hermann Einsele, Walter M Gregory, Jens Hillengass, Per Hoffmann, Graham H Jackson, Karl-Heinz Jöckel, Jolanta Nickel, Markus M Nöthen, Miguel Inacio da Silva Filho, Hauke Thomsen, Brian A Walker, Annemiek Broyl, Faith E Davies, Markus Hansson, Hartmut Goldschmidt, Martin J S Dyer, Martin Kaiser, Pieter Sonneveld, Gareth J Morgan, Kari Hemminki, Björn Nilsson, Daniel Catovsky, James M Allan, Richard S Houlston
The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg  = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk...
December 21, 2018: Blood Cancer Journal
Ashley R Paquin, Shaji K Kumar, Francis K Buadi, Morie A Gertz, Martha Q Lacy, Angela Dispenzieri, David Dingli, Lisa Hwa, Amie Fonder, Miriam Hobbs, Suzanne R Hayman, Steven R Zeldenrust, John A Lust, Stephen J Russell, Nelson Leung, Prashant Kapoor, Ronald S Go, Yi Lin, Wilson I Gonsalves, Taxiarchis Kourelis, Rahma Warsame, Robert A Kyle, S Vincent Rajkumar
Overall survival (OS) of multiple myeloma has improved remarkably over time, with the recent Intergroupe Francophone du Myelome (IFM) 2009 randomized trial reporting a 4-year OS rate of approximately 82% in patients receiving modern therapy. However, survival estimates from clinical trials may overestimate outcomes seen in clinical practice even with the adjustment for age and other key characteristics. The purpose of this study was to determine the OS of myeloma patients seen in routine clinical practice who resembled the cohort studied in the IFM 2009 trial...
December 11, 2018: Blood Cancer Journal
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