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ISSN (Print) 0006-4971 - ISSN (Online) 1528-0020
Published by American Society of Hematology Homepage  [2 journals]
  • Quest of biomarkers for venetoclax-treated CLL
    • Authors: Rossi D.
      Pages: 97 - 98
      Keywords: Free Research Articles
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019001189
      Issue No: Vol. 134, No. 2 (2019)
  • Facing lenalidomide-refractory myeloma
    • Authors: Cavo M.
      Pages: 99 - 101
      Keywords: Free Research Articles
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood-2019-04-901157
      Issue No: Vol. 134, No. 2 (2019)
  • Novel pathways of self- and cross-tolerance in monocytes
    • Authors: Farsky; S. H. P.
      Pages: 101 - 103
      Keywords: Free Research Articles
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019001532
      Issue No: Vol. 134, No. 2 (2019)
  • Calming the storm in HLH
    • Authors: Zinter, M. S; Hermiston, M. L.
      Pages: 103 - 104
      Keywords: Free Research Articles
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019001333
      Issue No: Vol. 134, No. 2 (2019)
  • The Pandoras box of thalidomide analogs and their substrates
    • Authors: Neri P.
      Pages: 105 - 106
      Keywords: Free Research Articles
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019001420
      Issue No: Vol. 134, No. 2 (2019)
  • Deconstructing myelodysplastic syndromes
    • Authors: del Rey Gonzalez, M; Park, C. Y.
      Pages: 106 - 107
      Keywords: Free Research Articles
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019001179
      Issue No: Vol. 134, No. 2 (2019)
  • Finding Neo (antigens, that is)
    • Authors: Olweus, J; Lund-Johansen, F.
      Pages: 108 - 109
      Keywords: Free Research Articles
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019001334
      Issue No: Vol. 134, No. 2 (2019)
  • Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is
           influenced by disease and response variables
    • 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.
      Pages: 111 - 122
      Abstract: 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 response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time to progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy (≥5 cm) and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or TP53 mutation and NOTCH1 mutation were consistently associated with shorter DoR, but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit.
      Keywords: Lymphoid Neoplasia, Clinical Trials and Observations
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2018882555
      Issue No: Vol. 134, No. 2 (2019)
  • A phase 1b study of isatuximab plus pomalidomide/dexamethasone in
           relapsed/refractory multiple myeloma
    • 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.
      Pages: 123 - 133
      Abstract: 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 evaluation of pharmacokinetics, immunogenicity, and efficacy. Forty-five patients received isatuximab (5 [n = 8], 10 [n = 31], or 20 [n = 6] mg/kg). Patients received a median of 3 (range, 1-10) prior lines; most were refractory to their last regimen (91%), with 82% lenalidomide-refractory and 84% PI-refractory. Median treatment duration was 9.6 months; 19 patients (42%) remain on treatment. Most common adverse events included fatigue (62%), and upper respiratory tract infection (42%), infusion reactions (42%), and dyspnea (40%). The most common grade ≥3 treatment-emergent adverse event was pneumonia, which occurred in 8 patients (17.8%). Hematologic laboratory abnormalities were common (lymphopenia, leukopenia, anemia, 98% each; neutropenia, 93%; and thrombocytopenia, 84%). Overall response rate was 62%; median duration of response was 18.7 months; median progression-free survival was 17.6 months. These results demonstrate potential meaningful clinical activity and a manageable safety profile of isatuximab plus pomalidomide/dexamethasone in heavily pretreated patients with RRMM. The 10 mg/kg weekly/every 2 weeks isatuximab dose was selected for future studies. This trial was registered at as #NCT02283775.
      Keywords: Multiple Myeloma, Lymphoid Neoplasia, Clinical Trials and Observations
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood-2019-02-895193
      Issue No: Vol. 134, No. 2 (2019)
  • Signaling mechanisms inducing hyporesponsiveness of phagocytes during
           systemic inflammation
    • 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.
      Pages: 134 - 146
      Abstract: 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 can also be triggered by endogenous TLR4 ligands, such as the alarmins myeloid-related protein 8 (MRP8, S100A8) and MRP14 (S100A9), under sterile conditions. However, signaling pathways that trigger hyporesponsiveness of phagocytes in clinically relevant diseases are only barely understood. Through our work, we have now identified 2 main signaling cascades that are activated during MRP-induced tolerance of phagocytes. We demonstrate that the phosphatidylinositol 3-kinase/AKT/GSK-3β pathway interferes with NF-B–driven gene expression and that inhibition of GSK-3β mimics tolerance in vivo. Moreover, we identified interleukin-10–triggered activation of transcription factors STAT3 and BCL-3 as master regulators of MRP-induced tolerance. Accordingly, patients with dominant-negative STAT3 mutations show no tolerance development. In a clinically relevant condition of systemic sterile stress, cardiopulmonary bypass surgery, we confirmed the initial induction of MRP expression and the tolerance induction of monocytes associated with nuclear translocation of STAT3 and BCL-3 as relevant mechanisms. Our data indicate that the use of pharmacological JAK-STAT inhibitors may be promising targets for future therapeutic approaches to prevent complications associated with secondary hyporesponsiveness during SIRS.
      Keywords: Immunobiology and Immunotherapy, Phagocytes, Granulocytes, and Myelopoiesis
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019000320
      Issue No: Vol. 134, No. 2 (2019)
  • Mechanisms of action of ruxolitinib in murine models of hemophagocytic
    • Authors: Albeituni, S; Verbist, K. C, Tedrick, P. E, Tillman, H, Picarsic, J, Bassett, R, Nichols, K. E.
      Pages: 147 - 159
      Abstract: 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 its beneficial effects in HLH by inhibiting IFN- signaling or by targeting signaling initiated by other proinflammatory cytokines. To address this question, we compared the effects of ruxolitinib with those obtained using an IFN-–neutralizing antibody (αIFN-) in 2 murine HLH models. In both models, ruxolitinib and αIFN- reduced inflammation-associated anemia, indicating that ruxolitinib operates in an IFN-–dependent manner to reverse this HLH manifestation. In contrast, the number and activation status of T cells and neutrophils, as well as their infiltration into tissues, were significantly reduced following treatment with ruxolitinib, but they remained unchanged or were increased following treatment with αIFN-. Notably, despite discontinuation of ruxolitinib, LCMV-infected Prf1–/– mice exhibited enhanced survival compared with mice in which αIFN- was discontinued. This protective effect could be mimicked by transient treatment with αIFN- and a neutrophil-depleting antibody. Thus, ruxolitinib operates through IFN-–dependent and -independent mechanisms to dampen HLH by targeting the deleterious effects of T cells and neutrophils, with the latter representing an unappreciated and understudied cell type that contributes to HLH pathogenesis.
      Keywords: Immunobiology and Immunotherapy
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019000761
      Issue No: Vol. 134, No. 2 (2019)
  • Patterns of substrate affinity, competition, and degradation kinetics
           underlie biological activity of thalidomide analogs
    • 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, Kuhn, E, Letai, A, Munshi, N. C, Carr, S. A, Ebert, B. L.
      Pages: 160 - 170
      Abstract: 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 ubiquitin ligase and induce degradation of particular proteins, but each of the molecules studied has distinct patterns of substrate specificity that likely underlie the clinical activity and toxicities of each drug. Our results demonstrate that the activity of molecules that induce protein degradation depends on the strength of ligase-substrate interaction in the presence of drug, the levels of the ubiquitin ligase, and the expression level of competing substrates. These findings highlight a novel mechanism of resistance to this class of drugs mediated by competition between substrates for access to a limiting pool of the ubiquitin ligase. We demonstrate that increased expression of a nonessential substrate can lead to decreased degradation of other substrates that are critical for antineoplastic activity of the drug, resulting in drug resistance. These studies provide general rules that govern drug-dependent substrate degradation and key differences between thalidomide analog activity in vitro and in vivo.
      Keywords: Myeloid Neoplasia, Lymphoid Neoplasia
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019000789
      Issue No: Vol. 134, No. 2 (2019)
  • A novel model of controlling PD-L1 expression in ALK+ anaplastic large
           cell lymphoma revealed by CRISPR screening
    • Authors: Zhang, J.-P; Song, Z, Wang, H.-B, Lang, L, Yang, Y.-Z, Xiao, W, Webster, D. E, Wei, W, Barta, S. K, Kadin, M. E, Staudt, L. M, Nakagawa, M, Yang, Y.
      Pages: 171 - 185
      Abstract: The success of programmed cell death protein 1 (PD-1)/PD-L1-based immunotherapy highlights the critical role played by PD-L1 in cancer progression and reveals an urgent need to develop new approaches to attenuate PD-L1 function by gaining insight into how its expression is controlled. Anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 as a result of the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent on the nucleophosmin-ALK oncoprotein activation of STAT3, as well as a signalosome containing GRB2/SOS1, which activates the MEK-ERK and PI3K-AKT signaling pathways. These signaling networks, through STAT3 and the GRB2/SOS1, ultimately induce PD-L1 expression through the action of transcription factors IRF4 and BATF3 on the enhancer region of the PD-L1 gene. IRF4 and BATF3 are essential for PD-L1 upregulation, and IRF4 expression is correlated with PD-L1 levels in primary ALK+ ALCL tissues. Targeting this oncogenic signaling pathway in ALK+ ALCL largely inhibited the ability of PD-L1-mediated tumor immune escape when cocultured with PD-1-positive T cells and natural killer cells. Thus, our identification of this previously unrecognized regulatory hub not only accelerates our understanding of the molecular circuitry that drives tumor immune escape but also provides novel opportunities to improve immunotherapeutic intervention strategies.
      Keywords: Immunobiology and Immunotherapy, Lymphoid Neoplasia
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019001043
      Issue No: Vol. 134, No. 2 (2019)
  • Reprogramming identifies functionally distinct stages of clonal evolution
           in myelodysplastic syndromes
    • Authors: Hsu, J; Reilly, A, Hayes, B. J, Clough, C. A, Konnick, E. Q, Torok-Storb, B, Gulsuner, S, Wu, D, Becker, P. S, Keel, S. B, Abkowitz, J. L, Doulatov, S.
      Pages: 186 - 198
      Abstract: Myeloid neoplasms, including myelodysplastic syndromes (MDS), are genetically heterogeneous disorders driven by clonal acquisition of somatic mutations in hematopoietic stem and progenitor cells (HPCs). The order of premalignant mutations and their impact on HPC self-renewal and differentiation remain poorly understood. We show that episomal reprogramming of MDS patient samples generates induced pluripotent stem cells from single premalignant cells with a partial complement of mutations, directly informing the temporal order of mutations in the individual patient. Reprogramming preferentially captured early subclones with fewer mutations, which were rare among single patient cells. To evaluate the functional impact of clonal evolution in individual patients, we differentiated isogenic MDS induced pluripotent stem cells harboring up to 4 successive clonal abnormalities recapitulating a progressive decrease in hematopoietic differentiation potential. SF3B1, in concert with epigenetic mutations, perturbed mitochondrial function leading to accumulation of damaged mitochondria during disease progression, resulting in apoptosis and ineffective erythropoiesis. Reprogramming also informed the order of premalignant mutations in patients with complex karyotype and identified 5q deletion as an early cytogenetic anomaly. The loss of chromosome 5q cooperated with TP53 mutations to perturb genome stability, promoting acquisition of structural and karyotypic abnormalities. Reprogramming thus enables molecular and functional interrogation of preleukemic clonal evolution, identifying mitochondrial function and chromosome stability as key pathways affected by acquisition of somatic mutations in MDS.
      Keywords: Hematopoiesis and Stem Cells, Myeloid Neoplasia
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2018884338
      Issue No: Vol. 134, No. 2 (2019)
  • Mutational landscape of the transcriptome offers putative targets for
           immunotherapy of myeloproliferative neoplasms
    • Authors: Schischlik, F; Jäger, R, Rosebrock, F, Hug, E, Schuster, M, Holly, R, Fuchs, E, Milosevic Feenstra, J. D, Bogner, E, Gisslinger, B, Schalling, M, Rumi, E, Pietra, D, Fischer, G, Fae, I, Vulliard, L, Menche, J, Haferlach, T, Meggendorfer, M, Stengel, A, Bock, C, Cazzola, M, Gisslinger, H, Kralovics, R.
      Pages: 199 - 210
      Abstract: Ph-negative myeloproliferative neoplasms (MPNs) are hematological cancers that can be subdivided into entities with distinct clinical features. Somatic mutations in JAK2, CALR, and MPL have been described as drivers of the disease, together with a variable landscape of nondriver mutations. Despite detailed knowledge of disease mechanisms, targeted therapies effective enough to eliminate MPN cells are still missing. In this study of 113 MPN patients, we aimed to comprehensively characterize the mutational landscape of the granulocyte transcriptome using RNA sequencing data and subsequently examine the applicability of immunotherapeutic strategies for MPN patients. Following implementation of customized workflows and data filtering, we identified a total of 13 (12/13 novel) gene fusions, 231 nonsynonymous single nucleotide variants, and 21 insertions and deletions in 106 of 113 patients. We found a high frequency of SF3B1-mutated primary myelofibrosis patients (14%) with distinct 3' splicing patterns, many of these with a protein-altering potential. Finally, from all mutations detected, we generated a virtual peptide library and used NetMHC to predict 149 unique neoantigens in 62% of MPN patients. Peptides from CALR and MPL mutations provide a rich source of neoantigens as a result of their unique ability to bind many common MHC class I molecules. Finally, we propose that mutations derived from splicing defects present in SF3B1-mutated patients may offer an unexplored neoantigen repertoire in MPNs. We validated 35 predicted peptides to be strong MHC class I binders through direct binding of predicted peptides to MHC proteins in vitro. Our results may serve as a resource for personalized vaccine or adoptive cell–based therapy development.
      Keywords: Immunobiology and Immunotherapy, Myeloid Neoplasia
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019000519
      Issue No: Vol. 134, No. 2 (2019)
  • Haploidentical hematopoietic cell and kidney transplantation for
           hematological malignancies and end-stage renal failure
    • Authors: Chen, Y.-B; Elias, N, Heher, E, McCune, J. S, Collier, K, Li, S, Del Rio, C, El-Jawahri, A, Williams, W, Tolkoff-Rubin, N, Fishman, J. A, McAfee, S, Dey, B. R, DeFilipp, Z, ODonnell, P. V, Cosimi, A. B, Sachs, D, Kawai, T, Spitzer, T. R.
      Pages: 211 - 215
      Abstract: At Massachusetts General Hospital, we pioneered simultaneous hematopoietic cell (HCT)/kidney transplantation from HLA-identical related donors for the treatment of hematological malignancies with end-stage renal failure. We have now extended this to HLA-haploidentical donors in a pilot trial. Six recipients, 5 of whom were conditioned with fludarabine, cyclophosphamide, and total-body irradiation, underwent combined HCT/kidney transplantation from haploidentical donors; graft-versus-host disease (GVHD) prophylaxis included post-HCT cyclophosphamide, tacrolimus, and mycophenolate mofetil. One patient died as a result of complications of fludarabine neurological toxicity. No neurological toxicity was observed in subsequent patients who received lower fludarabine doses and more intense postfludarabine dialysis. There were no cases of grade 2 to 4 acute GVHD and 1 case of moderate chronic GVHD by 12 months. One patient experienced relapse of multiple myeloma at 30 months after HCT and died 4 years posttransplantation. Overall, 4 of 6 patients remain alive, without disease relapse and with long-term renal rejection–free survival. This trial was registered at as #NCT01758042.
      Keywords: Transplantation, Brief Reports
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019000775
      Issue No: Vol. 134, No. 2 (2019)
  • Marked lymphocytosis and atypical cells with a cleft nucleus in a
           1-month-old child
    • Authors: Rieu, J.-B; Vergez, F.
      Pages: 216 - 216
      Keywords: Hematopoiesis and Stem Cells, Free Research Articles, BloodWork
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019001433
      Issue No: Vol. 134, No. 2 (2019)
  • Unusual histiocytes in a pleural effusion: signature of a rare disease
    • Authors: El Khoury, C; Farhat, H.
      Pages: 217 - 217
      Keywords: Free Research Articles, Stem Cells in Hematology, Phagocytes, Granulocytes, and Myelopoiesis
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019001131
      Issue No: Vol. 134, No. 2 (2019)
  • Ward-Caviness CK, Huffman JE, Everett K, et al. DNA methylation age is
           associated with an altered hemostatic profile in a multiethnic
           meta-analysis. Blood. 2018;132(17):1842-1850.
    • Pages: 218 - 218
      Keywords: Free Research Articles
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019001686
      Issue No: Vol. 134, No. 2 (2019)
  • Table of contents. Blood. 2019;133(18):iii-iv.
    • Pages: 218 - 218
      Keywords: Free Research Articles
      PubDate: 2019-07-11T09:00:35-07:00
      DOI: 10.1182/blood.2019001895
      Issue No: Vol. 134, No. 2 (2019)
School of Mathematical and Computer Sciences
Heriot-Watt University
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