Immunomodulatory drugs (IMiDs) are thalidomide analogues, which possess pleiotropic anti-myeloma properties including immune-modulation, anti-angiogenic, anti-inflammatory and anti-proliferative effects. Their development was facilitated by an improved understanding in myeloma (MM) biology and initiated a profound shift in the therapeutic approach towards MM. Despite the diverse effects of IMiDs in vitro, the relative contribution of each effect towards their ultimate anti-MM activity is still unclear. Based on in vitro data, it appears that anti-proliferative effects and downregulation of crucial cytokines are their most important anti-MM attributes. Although the co-stimulatory effects on T and NK cells have been heralded as a unique and important property of IMiDs towards enhancing anti-MM immune activity, these in vitro effects have yet to be firmly corroborated in vivo. Much is yet to be elucidated regarding the complex interplay of immunomodulatory cytokines that occurs in vivo, which ultimately dictates the net effects of IMiDs in MM—the understanding of which is necessary to facilitate optimal manipulation of these drugs in future MM management.

Over the last 5 years, a plethora of histone deacetylase inhibitors (HDACi) have been evaluated in clinical trials. These drugs have in common the ability to hyperacetylate both histone and nonhistone targets, resulting in a variety of effects on cancer cells, their microenvironment, and immune responses. To date, responses with single agent HDACi have been predominantly observed in advanced hematologic malignancies including T-cell lymphoma, Hodgkin lymphoma, and myeloid malignancies. Therefore, in this review we focus upon hematologic malignancies. Generally HDACi are well tolerated with the most common acute toxicities being fatigue, gastrointestinal, and transient cytopenias. Of note, few patients have been treated for prolonged periods of time and little is known about long-term toxicities. The use of the biomarker of histone hyperacetylation has been useful as a guide to target specificity, but generally does not predict for response and the search for more clinically relevant biomarkers must continue.

PurposeHodgkin's lymphoma (HL) has no standard of care for patients who are relapsed or refractory to autologous stem-cell transplantation (ASCT). This phase II study examined safety and activity of panobinostat in this population.Patients and MethodsPanobinostat 40 mg was administered orally three times per week. The primary end point was objective response rate (ORR) based on investigator assessment of radiologic imaging. Secondary end points included ORR by independent central review, time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival, and safety. Exploratory biomarker analyses were performed.ResultsThe 129 treated patients (median age, 32 years; range, 18 to 75 years) were heavily pretreated with a median of four (range, two to seven) prior systemic regimens, and 41% did not respond to the regimen immediately preceding panobinostat. Tumor reductions occurred in 96 patients (74%). Objective response was achieved by 35 patients (27%), including 30 (23%) partial responses and five (4%) complete responses. The median TTR was 2.3 months, median DOR was 6.9 months, and median PFS was 6.1 months. The estimated 1-year overall survival rate was 78%. Common nonhematologic adverse events (AEs)—diarrhea, nausea, vomiting, and fatigue—were generally grade 1 and 2. Most common grade 3 and 4 hematologic AEs—thrombocytopenia, anemia, and neutropenia—were manageable. Early reductions in thymus and activation-regulated chemokine were observed in patients achieving complete or partial response.ConclusionIn the largest, prospective, multicenter, international trial conducted in heavily pretreated patients with HL who relapsed or were refractory to ASCT, panobinostat monotherapy demonstrated antitumor activity, resulting in durable responses.

It is widely accepted that complex interactions between cancer cells and their surrounding microenvironment contribute to disease development, chemo-resistance and disease relapse. In light of this observed interdependency, novel therapeutic interventions that target specific cancer stroma cell lineages and their interactions are being sought. To this end, we studied a mouse model of human T cell acute lymphoblastic leukaemia (T-ALL) and used intravital microscopy to monitor the progression of disease within the bone marrow at both the tissue-wide and single cell level over time, from bone marrow seeding to development/selection of chemo-resistance. We observed highly dynamic cellular interactions and promiscuous distribution of leukaemia cells that migrated across the bone marrow, without showing any preferential association with bone marrow sub-compartments. Unexpectedly, this behaviour was maintained throughout disease development, from the earliest bone marrow seeding to response and resistance to chemotherapy. Our results reveal that T-ALL cells do not depend on specific bone marrow microenvironments for propagation of disease, nor for the selection of chemo-resistant clones, suggesting a stochastic mechanism underlies these processes. Yet, while T-ALL infiltration and progression are independent of the stroma, accumulated disease burden leads to rapid, selective remodelling of the endosteal space, resulting in a complete loss of mature osteoblastic cells whilst perivascular cells are maintained. This outcome leads to a shift in the balance of endogenous bone marrow stroma, towards a composition associated with less efficient haematopoietic stem cell function1. This novel, dynamic analysis of T-ALL interactions with the bone marrow microenvironment in vivo, supported by evidence from human T-ALL samples, highlights that future therapeutic interventions should target the migration and promiscuous interactions of cancer cells with the surrounding microenvironment, rather than specific bone marrow stroma, in order to combat the invasion by and survival of chemo-resistant T-ALL cells.

We defined the epidemiology and clinical predictors of infection in patients with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs), proteasome inhibitors (PI) and autologous haematopoietic stem cell transplant (ASCT) in a large longitudinal cohort study. Clinical and microbiology records of patients with MM diagnosed between January 2008 and December 2012 were reviewed to capture patient demographics, characteristics of myeloma and infections (type, severity, outcomes). Conditional risk set modelling was used to determine clinical predictors of infection. One hundred and ninety-nine patients with MM with 771 episodes of infection were identified. 44·6% of infections were clinically defined, 35·5% were microbiologically defined and 19·9% were fever of unknown focus. There was a bimodal peak in incidence of bacterial (4-6 and 70-72 months) and viral infections (7-9 and 52-54 months) following disease diagnosis. Chemotherapy regimens high-dose melphalan [hazard ratio (HR) = 2·07], intravenous cyclophosphamide (HR = 1·96) and intensive combination systemic chemotherapy (HR = 1·86) and cumulative doses of corticosteroid (HR = 3·06 at highest dose) were independently associated with increased risk of infection overall (P < 0·05). IMiDs and PI and other clinical factors were not independently associated with increased risk of infection. New approaches to prevention and treatment of infection should focus upon identified periods of risk and treatment-related risk factors.

Lenalidomide combined with dexamethasone is an effective treatment for refractory/ relapsed multiple myeloma (MM). Lenalidomide stimulates natural killer (NK) cells and enhances antitumor responses.We assessed NK cell number and function in 25 patients with MM participating in a clinical trial of lenalidomide and dexamethasone. NK cell numbers increased from a mean of 2.20 ؎ 0.05 ؋ 10 5 /mL (baseline) to a mean of 3.90 ؎ 0.03 ؋ 10 5 /mL (cycle 6; P ‫؍‬ .05); however, in vitro NKcell-mediated cytotoxicity decreased from 48.9% ؎ 6.8% to 27.6% ؎ 5.1% (P ‫؍‬ .0028) and could not be rescued by lenalidomide retreatment. Lenalidomide increased normal donor NK-cell cytotoxicity in vitro from 38.5% to 53.3%, but this was completely abrogated by dexamethasone. Dexamethasone suppression of NK cellmediated cytotoxicity was partially reversed by a 3-day washout, but these cells remained refractory to lenalidomideinduced enhanced function. Lymphocyte subset depletion experiments revealed that lenalidomide's enhancement of NK cell-mediated cytotoxicity was mediated by CD4 ؉ T-cell production of interleukin 2 and that dexamethasone acted by suppressing interleukin-2 production. Similarly, the reduced ability of NK cells from patients with MM to respond to lenalidomide was also due to impaired CD4 T-cell function. IntroductionMultiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells in the bone marrow (BM) and accumulation of monoclonal paraprotein in the serum of the majority of affected patients. 1 There is evidence that MM, at least in its early stages, is under the control of innate and adaptive immune responses, 2-9 which are ultimately subverted by the production of plasma cell and BMderived immunosuppressive cytokines including interleukin 6 (IL-6), transforming growth factor ␤ (TGF-␤), insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), and tumor necrosis factor ␣ (TNF-␣). 10 The disease-associated immunoparesis of MM is further compounded by the immunosuppressive effects of anti-MM therapy. 10 Conventional MM therapy has used alkylator or anthracyclinebased chemotherapy in combination with the corticosteroids dexamethasone or prednisolone. Increasingly, nonchemotherapy agents such as the immunomodulatory (IMiD) drugs thalidomide and lenalidomide or the proteasome inhibitor Bortezomib have been incorporated into induction regimens commonly to replace chemotherapy agents, but are still used in combination with high-dose corticosteroids such as dexamethasone. 11,12 The anti-MM effect of immunomodulatory drugs is thought to be mediated by the combined effects of tumor necrosis factor ␣ inhibition, direct inhibition of plasma cell proliferation, suppression of angiogenesis, and promotion of T-cell costimulation, [13][14][15][16] and disruption of adhesion between malignant plasma cells and BM stroma. [17][18][19] Lenalidomide also shows substantial capacity to activate natural killer (NK) cell cytotoxicity and NK cell-driven antibodydependent cell-mediat...

Background:Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is a devastating complication; the optimal prophylactic strategy remains unclear.Methods:We performed a multicentre, retrospective analysis of patients with DLBCL with high risk for CNS relapse as defined by two or more of: multiple extranodal sites, elevated serum LDH and B symptoms or involvement of specific high-risk anatomical sites. We compared three different strategies of CNS-directed therapy: intrathecal (IT) methotrexate (MTX) with (R)-CHOP ‘group 1' R-CHOP with IT MTX and two cycles of high-dose intravenous (IV) MTX ‘group 2' dose-intensive systemic antimetabolite-containing chemotherapy (Hyper-CVAD or CODOXM/IVAC) with IT/IV MTX ‘group 3'.Results:Overall, 217 patients were identified (49, 125 and 43 in groups 1–3, respectively). With median follow-up of 3.4 (range 0.2–18.6) years, 23 CNS relapses occurred (12, 10 and 1 in groups 1–3 respectively). The 3-year actuarial rates (95% CI) of CNS relapse were 18.4% (9.5–33.1%), 6.9% (3.5–13.4%) and 2.3% (0.4–15.4%) in groups 1–3, respectively (P=0.009).Conclusions:The addition of high-dose IV MTX and/or cytarabine was associated with lower incidence of CNS relapse compared with IT chemotherapy alone. However, these data are limited by their retrospective nature and warrant confirmation in prospective randomised studies.

Resistance in virus-infected stem cell transplant recipients illustrates the need for surveillance.