The Intergroupe Francophone du Myélome conducted a randomized trial to compare bortezomib-thalidomide-dexamethasone (VTD) with bortezomib-cyclophosphamide-dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma. Overall, a total of 340 patients were centrally randomly assigned to receive VTD or VCD. After 4 cycles, on an intent-to-treat basis, 66.3% of the patients in the VTD arm achieved at least a very good partial response (primary end point) vs 56.2% in the VCD arm (P = .05). In addition, the overall response rate was significantly higher in the VTD arm (92.3% vs 83.4% in the VCD arm; P = .01). Hematologic toxicity was higher in the VCD arm, with significantly increased rates of grade 3 and 4 anemia, thrombocytopenia, and neutropenia. On the other hand, the rate of peripheral neuropathy (PN) was significantly higher in the VTD arm. With the exception of hematologic adverse events and PN, other grade 3 or 4 toxicities were rare, with no significant differences between the VTD and VCD arms. Our data support the preferential use of VTD rather than VCD in preparation for ASCT. This trial was registered at www.clinicaltrials.gov as #NCT01564537 and at EudraCT as #2013-003174-27.

Neutrophils are polymorphonuclear leukocytes of the phagocytic system that act as first line of host defense against invading pathogens but are also important mediators of inflammation-induced injury. In contrast to other members of the innate immune system, neutrophils are classically considered a homogenous population of terminally differentiated cells with a well-defined and highly conserved function. Indeed, their short lifespan, the absent proliferative capacity, their limited ability to produce large amounts of cytokines, and the failure to recirculate from the tissue to the bloodstream have sustained this idea. However, increasing evidence over the last decade has demonstrated an unexpected phenotypic heterogeneity and functional versatility of the neutrophil population. Far beyond their antimicrobial functions, neutrophils are emerging as decision-shapers during innate and adaptive immune responses. These emerging discoveries open a new door to understand the role of neutrophils during homeostatic but also pathogenic immune processes. Thus, this review details novel insights of neutrophil phenotypic and functional heterogeneity during homeostasis and disease.

The International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification.

Despite major advances in recent years, graft-versus-host disease (GVHD) remains a major life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). To improve our therapeutic armory against GVHD, preclinical evidence is most frequently generated in mouse and large animal models of GVHD. However, because every model has shortcomings, it is important to understand how predictive the different models are and why certain findings in these models could not be translated into the clinic. Weaknesses of the animal GVHD models include the irradiation only-based conditioning regimen, the homogenous donor/recipient genetics in mice, canine or non-human primates (NHP), anatomic site of T cells used for transfer in mice, the homogenous microbial environment in mice housed under specific pathogen-free conditions, and the lack of pharmacologic GVHD prevention in control groups. Despite these major differences toward clinical allo-HCT, findings generated in animal models of GVHD have led to the current gold standards for GVHD prophylaxis and therapy. The homogenous nature of the preclinical models allows for reproducibility, which is key for the characterization of the role of a new cytokine, chemokine, transcription factor, microRNA, kinase, or immune cell population in the context of GVHD. Therefore, when carefully balancing reasons to apply small and large animal models, it becomes evident that they are valuable tools to generate preclinical hypotheses, which then have to be rigorously evaluated in the clinical setting. In this study, we discuss several clinical approaches that were motivated by preclinical evidence, novel NHP models and their advantages, and highlight the recent advances in understanding the pathophysiology of GVHD.

Follicular lymphoma (FL) represents more than 20% of all non-Hodgkin lymphomas worldwide and approximately 30% of the non-Hodgkin lymphomas diagnosed in the United States. Although occasionally localized at the time of diagnosis, most patients have disseminated disease. However, patients are frequently asymptomatic, and this, in combination with a long median survival, led to the initial studies of observing asymptomatic patients without initial therapy, ie, "watch and wait." Since the initial report of watch and wait as a treatment strategy for patients with low-grade FL, our understanding of the biology of the disease has advanced; multiple active new agents have been introduced into practice, and the survival of patients with low-grade FL has improved. Given these changes, is watch and wait still an acceptable treatment recommendation for a newly diagnosed patient with low-grade FL?

Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy involving the spleen, bone marrow, and frequently the blood. SMZL lymphomagenesis involves antigen and/or superantigen stimulation and molecular deregulation of genes (NOTCH2 and KLF2) involved in the physiological differentiation of spleen marginal zone B cells. Diagnosis requires either spleen histology or, alternatively, the documentation of a typical cell morphology and immunophenotype on blood cells coupled with the detection of intrasinusoidal infiltration by CD20(+) cells in the bone marrow. Among B-cell tumors, deletion of 7q and NOTCH2 mutations are almost specific lesions of SMZL, thus representing promising diagnostic biomarkers of this lymphoma. Although the majority of SMZLs show an indolent course with a median survival of approximately 10 years, nearly 30% of patients experience a poor outcome. No randomized trials are reported for SMZL, and few prospective trials are available. A watch-and-wait approach is advisable for asymptomatic patients. Treatment options for symptomatic patients ranges from splenectomy to rituximab alone or combined with chemotherapy. In some geographic areas, a subset of patients with SMZL associates with hepatitis C virus infection, prompting virus eradication as an effective lymphoma treatment. It would be worthwhile to explore deregulated cellular programs of SMZL as therapeutic targets in the future; improved clinical and biological prognostication will be essential for identifying patients who may benefit from novel approaches.

Despite improvements over the past decade in the overall survival of patients with indolent non-Hodgkin lymphomas, these lymphomas remain largely incurable with standard therapies. Immunochemotherapy with rituximab-based regimens has become a well-established standard of care in the primary and relapsed disease settings. The role of hematopoietic stem cell transplantation in indolent lymphoma has been defined by the adoption of this therapy largely in the relapse setting because randomized trials in the first-line setting have not shown survival advantages. Allogeneic stem cell transplantation has the possibility for cure because of the potential for immunologic graft-versus-lymphoma effect, but there are significant concerns regarding nonrelapse mortality. Autologous stem cell transplantation offers a safe treatment platform, but relapse remains a significant issue. The role of transplantation in the current treatment landscape of immunochemotherapy has not been conclusively proven, and randomized trials are lacking. This review summarizes the current relevant data regarding transplantation in indolent non-Hodgkin lymphoma and highlights the issues relevant to clinicians in the field.

Extranodal marginal zone (MZ) B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) arise from lymphoid populations that are induced by chronic inflammation in extranodal sites. The best evidence of an etiopathogenetic link is provided by the association between Helicobacter pylori-positive gastritis and gastric MALT lymphoma. Indeed, successful eradication of this microorganism with antibiotics can be followed by gastric MALT lymphoma regression in most cases. Other microbial agents have been implicated in the pathogenesis of MZ lymphoma arising at different sites. Apart from gastric MALT lymphoma, antibiotic therapies have been adequately tested only in ocular adnexal MALT lymphomas where upfront doxycycline may be a reasonable and effective initial treatment of patients with Chlamydophila psittaci-positive lymphoma before considering more aggressive strategies. In all other instances, antibiotic treatment of nongastric lymphomas remains investigational. Indeed, there is no clear consensus for the treatment of patients with gastric MALT lymphoma requiring further treatment beyond H pylori eradication or with extensive disease. Both radiotherapy and systemic treatments with chemotherapy and anti-CD20 antibodies are efficacious and thus the experience of individual centers and each patient's preferences in terms of adverse effects are important parameters in the decision process.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. After decades of stagnation, the natural history of FL appears to have been favorably impacted by the introduction of rituximab. Randomized clinical trials have demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Maintenance rituximab strategies can improve progression-free survival. Even chemotherapy platforms have changed in the past 5 years, as bendamustine combined with rituximab has rapidly become a standard frontline strategy in North America and parts of Europe. Recent discoveries have identified patients at high risk for poor outcomes to first-line therapy (m7-Follicular Lymphoma International Prognostic Index [m7-FLIPI]) and for poor outcomes after frontline therapy (National LymphoCare Study). However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, and strategies to reduce the risk of transformation. The development of targeted agents, exploiting our current understanding of FL biology, is a high research priority. A multitude of novel therapies are under investigation in both the frontline and relapsed/refractory settings. It will be critical to identify the most appropriate populations for new agents and to develop validated surrogate end points, so that novel agents can be tested (and adopted, if appropriate) efficiently.

Nodal marginal zone lymphoma (NMZL) is a rare form of indolent small B-cell lymphoma which has only been clearly identified in the last 2 decades and which to date remains incurable. Progress in therapeutic management has been slow, largely due to the very small number of patients treated and the heterogeneity of treatments administered; thus, standard-of-care treatment is currently nonspecific for this lymphoma entity. In this review, treatments routinely used to manage adult NMZL patients are presented, principally based on immunochemotherapy (when treatment is needed). Biological research behind the key axes of agents currently under development is described; development of novel agents is heavily based on data from gene profiling and genome-wide sequencing research, uncovering a number of critical deregulated pathways specific to NMZL tumors. These include B-cell receptor, JAK/STAT, NF-κB, NOTCH, and Toll-like receptor signaling pathways, as well as intracellular processes such as the cell cycle, chromatin remodeling, and transcriptional regulation in terms of epigenetic modifiers, histones, or transcriptional co-repressors, along with immune escape via T-cell-mediated tumor surveillance. These pathways are examined in detail and a projection of how the field may evolve in the near future for an efficient personalized treatment approach for NMZL patients is presented.

GNA13 is the most frequently mutated gene in germinal center (GC)-derived B-cell lymphomas, including nearly a quarter of Burkitt lymphoma and GC-derived diffuse large B-cell lymphoma. These mutations occur in a pattern consistent with loss of function. We have modeled the GNA13-deficient state exclusively in GC B cells by crossing the Gna13 conditional knockout mouse strain with the GC-specific AID-Cre transgenic strain. AID-Cre(+) GNA13-deficient mice demonstrate disordered GC architecture and dark zone/light zone distribution in vivo, and demonstrate altered migration behavior, decreased levels of filamentous actin, and attenuated RhoA activity in vitro. We also found that GNA13-deficient mice have increased numbers of GC B cells that display impaired caspase-mediated cell death and increased frequency of somatic hypermutation in the immunoglobulin VH locus. Lastly, GNA13 deficiency, combined with conditional MYC transgene expression in mouse GC B cells, promotes lymphomagenesis. Thus, GNA13 loss is associated with GC B-cell persistence, in which impaired apoptosis and ongoing somatic hypermutation may lead to an increased risk of lymphoma development.

Maintenance of myeloid cell homeostasis requires continuous turnover of phagocytes from the bloodstream, yet whether environmental signals influence phagocyte longevity in the absence of inflammation remains unknown. Here, we show that the gut microbiota regulates the steady-state cellular lifespan of neutrophils and inflammatory monocytes, the 2 most abundant circulating myeloid cells and key contributors to inflammatory responses. Treatment of mice with broad-spectrum antibiotics, or with the gut-restricted aminoglycoside neomycin alone, accelerated phagocyte turnover and increased the rates of their spontaneous apoptosis. Metagenomic analyses revealed that neomycin altered the abundance of intestinal bacteria bearing γ-d-glutamyl-meso-diaminopimelic acid, a ligand for the intracellular peptidoglycan sensor Nod1. Accordingly, signaling through Nod1 was both necessary and sufficient to mediate the stimulatory influence of the flora on myeloid cell longevity. Stimulation of Nod1 signaling increased the frequency of lymphocytes in the murine intestine producing the proinflammatory cytokine interleukin 17A (IL-17A), and liberation of IL-17A was required for transmission of Nod1-dependent signals to circulating phagocytes. Together, these results define a mechanism through which intestinal microbes govern a central component of myeloid homeostasis and suggest perturbations of commensal communities can influence steady-state regulation of cell fate.

Platelet adhesion to collagen via collagen receptors is an important part of thrombosis. In this issue of Blood, Matsuura et al identify collagen receptors as previously unrecognized targets of the extracellular enzyme lysyl oxidase (LOX), the level of which is increased in myeloproliferative neoplasms (MPNs) and other conditions associated with pathological thromboses.

One of the major goals of hemoglobinopathy research has been to devise improved pharmacologic strategies for the induction of fetal hemoglobin (HbF) in people with sickle cell disease and β-thalassemia. In this issue of Blood, Dulmovits and colleagues report that pomalidomide, a drug approved by the US Food and Drug Administration (FDA) for treatment of multiple myeloma, induces HbF production by decreasing levels of several key transcriptional repressors of fetal globin gene expression. In addition, they show that pomalidomide induces HbF in differentiating erythroid cells from people with sickle cell disease and in myeloma patients.

In this issue of Blood, in a departure from studies of classic platelet function, Huang et al turn their attention to endocytosis and show that adenosine 5′-diphosphate-ribosylation factor 6 (Arf6) plays a key role in fibrinogen engulfment. Although platelets are known to bind, absorb, and load their granules with plasma proteins, this report is one of the first to explore mechanisms that control endocytosis in this anucleate cell. Huang et al demonstrate that Arf6-dependent endocytosis is restricted to fibrinogen, implying that Arf6 also modulates trafficking of αIIbβ3 integrins in platelets. Consistent with this notion, deletion of Arf6 in platelets enhances spreading on fibrinogen and accelerates clot retraction (see figure). However, activation of surface αIIbβ3 is unaffected, and Arf6 deficiency does not alter thrombosis in vivo. These incongruous results point toward the complexity of anucleate platelets and the need for more detailed studies to understand intracellular trafficking, recycling, and endocytosis in platelets and their precurs

In this issue of Blood, Shen et al demonstrate that the vesicular stomatitis virus (VSV)-murine interferon β (IFNβ)-sodium iodide symporter (NIS) (VSV-mIFNβ-NIS) oncolytic virus has significant antileukemia activity, which is enhanced when combined with an anti-programmed death-ligand 1 (PD-L1) antibody.

Inactivating mutations in the sphingosine-1-phosphate (S1P) receptor 2 (S1PR2) promoter have been associated with the germinal center (GC) B-cell diffuse large B-cell lymphoma (GCB-DLBCL) subtype. In this issue of Blood, Flori et al have now identified S1PR2 as a tumor suppressor that is transcriptionally silenced by forkhead box protein 1 (FOXP1) in the aggressive, activated B-cell (ABC-DLBCL) subtype.

In this issue of Blood, Martinelli et al provide reassuring data that women taking oral anticoagulant therapy for venous thromboembolism (VTE) may use estrogen or progestin hormonal therapy to control the menstrual bleeding without increased risk for recurrent thromboembolism.