Patterns of substrate affinity, competition, and degradation kinetics underlie biological activity of thalidomide analogs
Pharmacologic agents that modulate ubiquitin ligase activity to induce protein degradation are a major new class of therapeutic agents, active in a number of hematologic malignancies. However, we currently have a limited understanding of the determinants of activity of these agents and how resistance develops. We developed and used a novel quantitative, targeted mass spectrometry (MS) assay to determine the relative activities, kinetics, and cell-type specificity of thalidomide and 4 analogs, all but 1 of which are in clinical use or clinical trials for hematologic malignancies. Thalidomide analogs bind the CRL4CRBN ubiqui...
Source: Blood - July 10, 2019 Category: Hematology Authors: Sperling, A. S., Burgess, M., Keshishian, H., Gasser, J. A., Bhatt, S., Jan, M., Słabicki, M., Sellar, R. S., Fink, E. C., Miller, P. G., Liddicoat, B. J., Sievers, Q. L., Sharma, R., Adams, D. N., Olesinski, E. A., Fulciniti, M., Udeshi, N. D., Ku Tags: Myeloid Neoplasia, Lymphoid Neoplasia Source Type: research
Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal disorder characterized by the overactivation of T cells and macrophages that excessively produce proinflammatory cytokines, including interferon- (IFN-). Previously, we reported that the JAK inhibitor ruxolitinib dampens T-cell activation and lessens inflammation in a model of HLH in which perforin-deficient (Prf1–/–) mice are infected with lymphocytic choriomeningitis virus (LCMV). Ruxolitinib inhibits signaling downstream of IFN-, as well as several other JAK-dependent cytokines. As a consequence, it remained unclear whether ruxolitinib was exerting i...
Source: Blood - July 10, 2019 Category: Hematology Authors: Albeituni, S., Verbist, K. C., Tedrick, P. E., Tillman, H., Picarsic, J., Bassett, R., Nichols, K. E. Tags: Immunobiology and Immunotherapy Source Type: research
Signaling mechanisms inducing hyporesponsiveness of phagocytes during systemic inflammation
The inflammatory responsiveness of phagocytes to exogenous and endogenous stimuli is tightly regulated. This regulation plays an important role in systemic inflammatory response syndromes (SIRSs). In SIRSs, phagocytes initially develop a hyperinflammatory response, followed by a secondary state of hyporesponsiveness, a so-called "tolerance." This hyporesponsiveness can be induced by endotoxin stimulation of Toll-like receptor 4 (TLR4), resulting in an ameliorated response after subsequent restimulation. This modification of inflammatory response patterns has been described as innate immune memory. Interestingly, tolerance ...
Source: Blood - July 10, 2019 Category: Hematology Authors: Freise, N., Burghard, A., Ortkras, T., Daber, N., Imam Chasan, A., Jauch, S.-L., Fehler, O., Hillebrand, J., Schakaki, M., Rojas, J., Grimbacher, B., Vogl, T., Hoffmeier, A., Martens, S., Roth, J., Austermann, J. Tags: Immunobiology and Immunotherapy, Phagocytes, Granulocytes, and Myelopoiesis Source Type: research
A phase 1b study of isatuximab plus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma
This phase 1b dose-escalation study evaluated isatuximab plus pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior MM therapies, including lenalidomide and a proteasome inhibitor (PI), were enrolled and received isatuximab at 5, 10, or 20 mg/kg (weekly for 4 weeks, followed by every 2 weeks), pomalidomide 4 mg (days 1-21), and dexamethasone 40 mg (weekly) in 28-day cycles until progression/intolerable toxicity. The primary objective was to determine the safety and recommended dose of isatuximab with this combination. Secondary objectives included eva...
Source: Blood - July 10, 2019 Category: Hematology Authors: Mikhael, J., Richardson, P., Usmani, S. Z., Raje, N., Bensinger, W., Karanes, C., Campana, F., Kanagavel, D., Dubin, F., Liu, Q., Semiond, D., Anderson, K. Tags: Multiple Myeloma, Lymphoid Neoplasia, Clinical Trials and Observations Source Type: research
Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables
To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 early-phase trials were pooled. Rates of response, complete remission (CR/CRi), and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n = 436) and for those patients who were planned to receive 400 mg/day monotherapy (n = 347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with re...
Source: Blood - July 10, 2019 Category: Hematology Authors: Roberts, A. W., Ma, S., Kipps, T. J., Coutre, S. E., Davids, M. S., Eichhorst, B., Hallek, M., Byrd, J. C., Humphrey, K., Zhou, L., Chyla, B., Nielsen, J., Potluri, J., Kim, S. Y., Verdugo, M., Stilgenbauer, S., Wierda, W. G., Seymour, J. F. Tags: Lymphoid Neoplasia, Clinical Trials and Observations Source Type: research
Finding Neo (antigens, that is)
(Source: Blood)
Source: Blood - July 10, 2019 Category: Hematology Authors: Olweus, J., Lund-Johansen, F. Tags: Free Research Articles COMMENTS Source Type: research
Deconstructing myelodysplastic syndromes
(Source: Blood)
Source: Blood - July 10, 2019 Category: Hematology Authors: del Rey Gonzalez, M., Park, C. Y. Tags: Free Research Articles COMMENTS Source Type: research
The Pandoras box of thalidomide analogs and their substrates
(Source: Blood)
Source: Blood - July 10, 2019 Category: Hematology Authors: Neri, P. Tags: Free Research Articles COMMENTS Source Type: research
Calming the storm in HLH
(Source: Blood)
Source: Blood - July 10, 2019 Category: Hematology Authors: Zinter, M. S., Hermiston, M. L. Tags: Free Research Articles COMMENTS Source Type: research
Novel pathways of self- and cross-tolerance in monocytes
(Source: Blood)
Source: Blood - July 10, 2019 Category: Hematology Authors: Farsky, S. H. P. Tags: Free Research Articles COMMENTS Source Type: research
Facing lenalidomide-refractory myeloma
(Source: Blood)
Source: Blood - July 10, 2019 Category: Hematology Authors: Cavo, M. Tags: Free Research Articles COMMENTS Source Type: research
Quest of biomarkers for venetoclax-treated CLL
(Source: Blood)
Source: Blood - July 10, 2019 Category: Hematology Authors: Rossi, D. Tags: Free Research Articles COMMENTS Source Type: research
Dasmahapatra G, Lembersky D, Kramer L, Fisher RI, Friedberg J, Dent P, Grant S. The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo. Blood. 2010;115(22):4478-4487.
(Source: Blood)
Source: Blood - July 3, 2019 Category: Hematology Tags: Free Research Articles RETRACTIONS Source Type: research
Dasmahapatra G, Rahmani M, Dent P, Grant S. The tyrphostin adaphostin interacts synergistically with proteasome inhibitors to induce apoptosis in human leukemia cells through a reactive oxygen species (ROS)-dependent mechanism. Blood. 2006;107(1):232-240.
(Source: Blood)
Source: Blood - July 3, 2019 Category: Hematology Tags: Free Research Articles RETRACTIONS Source Type: research
Artuso I, Lidonnici MR, Altamura S, et al. Transferrin receptor 2 is a potential novel therapeutic target for {beta}-thalassemia: evidence from a murine model. Blood. 2018;132(21):2286-2297.
(Source: Blood)
Source: Blood - July 3, 2019 Category: Hematology Tags: Free Research Articles ERRATUM Source Type: research
