Brentuximab Vedotin and Pembrolizumab Combination in Patients with Relapsed/Refractory Hodgkin Lymphoma: A Single-Centre Retrospective Analysis.

Classical Hodgkin lymphoma (HL) patients presenting a relapsed/refractory (R/R) disease are currently managed with salvage chemotherapy followed by autologous stem cell transplantation (ASCT). However, almost 25-30% of these patients fail to achieve a complete response (CR) with standard salvage regimens. In this retrospective study, we evaluated the efficacy of a combination of brentuximab vedotin (BV) and pembrolizumab in a series of HL patients presenting with a high-risk, multi-refractory disease. Patients achieving a Deauville score ≤4 proceeded to ASCT consolidation. After ASCT, patients received BV as maintenance for a total of 16 administrations. We collected data from 10 patients with a median age of 30.7 years. At a median follow-up of 16.5 months, we reported a complete metabolic remission (CMR) in eight patients (80%), with seven patients (70%) directly proceeding to ASCT (the other two patients in CMR are still undergoing treatment). BV consolidation was started in six patients and completed by three patients (one ongoing, two interruption). Two patients (20%) presented a progressive disease (PD) and subsequently died, while the others are still in CMR. The BV and pembrolizumab combination is a very effective bridge treatment to ASCT for high-risk R/R HL patients.

The Association between Patient Characteristics and the Efficacy and Safety of Selinexor in Diffuse Large B-Cell Lymphoma in the SADAL Study.

Selinexor, an oral selective inhibitor of nuclear export, was evaluated in the Phase 2b SADAL study in patients with diffuse large B-cell lymphoma (DLBCL) who previously received two to five prior systemic regimens. In post hoc analyses, we analyzed several categories of patient characteristics (age, renal function, DLBCL subtype, absolute lymphocyte count, transplant status, number of prior lines of therapy, refractory status, Ann Arbor disease stage, and lactate dehydrogenase) at baseline, i.e., during screening procedures, to determine their potential contributions to the efficacy (overall response rate [ORR], duration of response [DOR], overall survival [OS]) and tolerability of selinexor. Across most categories of characteristics, no significant difference was observed in ORR or DOR. OS was significantly longer for patients < 65 vs. ≥ 65 years, and for those with lymphocyte counts ≥ 1000/µL vs. < 1000/µL or lactate dehydrogenase ≤ ULN vs. > ULN. The most common adverse events (AEs) across the characteristics were thrombocytopenia and nausea, and similar rates of grade 3 AEs and serious AEs were observed. With its oral administration, novel mechanism of action, and consistency in responses in heavily pretreated patients, selinexor may help to address an important unmet clinical need in the treatment of DLBCL.

Effect of Prior Therapy and Disease Refractoriness on the Efficacy and Safety of Oral Selinexor in Patients with Diffuse Large B-cell Lymphoma (DLBCL): A Post-hoc Analysis of the SADAL Study.

BACKGROUND: Despite a number of treatment options, patients with diffuse large B-cell lymphoma (DLBCL) whose disease has become refractory to treatment have a poor prognosis. Selinexor is a novel, oral drug that is approved to treat patients with relapsed/refractory DLBCL. In this post hoc analysis of the SADAL study, a multinational, open-label study, we evaluated subpopulations to determine if response to single agent selinexor is impacted by number of lines of prior treatment, autologous stem cell transplant (ASCT), response to first and most recent therapies, and time to progressive disease. PATIENTS: Patients (n = 134) with DLBCL after 2-5 prior therapies were enrolled in SADAL and received 60mg selinexor twice weekly. RESULTS: The median overall survival was 9.0 months and median progression free survival was 2.6 months. Patients who had the best overall response rate (ORR) and disease control rate were those who had prior ASCT (42.5% and 50.0%) or responded to last line of therapy (35.9% and 43.5%). Patients with primary refractory DLBCL also showed responses (ORR 21.8%). Adverse events between subgroups were similar to the overall study population, the most common being thrombocytopenia (29.1%), fatigue (7.5%), and nausea (6.0%). CONCLUSION: Regardless of prior therapy and disease refractory status, selinexor treatment demonstrated results consistent with its novel mechanism of action and lack of cross-resistance. Thus, single agent oral selinexor can induce deep, durable, and tolerable responses in patients with DLBCL who have recurrent disease after several chemoimmunotherapy combination regimens.

Comparison of the Effectiveness and Safety of the Oral Selective Inhibitor of Nuclear Export, Selinexor, in Diffuse Large B Cell Lymphoma Subtypes.

BACKGROUND: The SADAL study evaluated oral selinexor in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior lines of systemic therapy. In this post-hoc analysis, we analyzed the outcomes of the SADAL study by DLBCL subtype to determine the effects of DLBCL subtypes on efficacy and tolerability of selinexor. PATIENTS AND METHODS: Data from 134 patients in SADAL were analyzed by DLBCL subtypes for overall response rate (ORR), overall survival (OS), duration of treatment response, progression-free survival, and adverse events rate. RESULTS: ORR in the entire cohort was 29.1%, and similar in patients with germinal center (GCB) versus non-GCB DLBCL (31.7% vs. 24.2%, P = 0.45); transformed DLBCL showed a trend towards higher ORR than de novo DLBCL: 38.7% vs. 26.2% (P = 0.23). Despite similar prior treatment regimens and baseline characteristics, patients with DLBCL and normal C-MYC/BCL-2 protein expression levels had a significantly higher ORR (46.2% vs.14.8%, P = 0.012) and significantly longer OS (medians 13.7 vs. 5.1 months, hazard ratio 0.43 [95% CI, 0.23-0.77], P = 0.004) as compared with those whose DLBCL had C-MYC and BCL-2 overexpression. Among patients who had normal expression levels of either C-MYC or BCL-2 and baseline hemoglobin levels ≥ 10g/dL, ORR was 51.5% (n = 47), with median OS of 15.5 months and median PFS of 4.6 months. Similar rates of adverse events were noted in all subgroups. CONCLUSIONS: Overall, single agent oral selinexor showed strong responses in patients with limited treatment alternatives regardless of germinal center B-cell type or disease origin.

Cusatuzumab for treatment of CD70-positive relapsed or refractory cutaneous T-cell lymphoma.

BACKGROUND: The clinical benefit of cusatuzumab, a CD70-directed monoclonal antibody with enhanced effector functions, was investigated in patients with relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL). METHODS: In this cohort expansion of the ARGX-110-1201 study, 27 patients with R/R CTCL received cusatuzumab at 1 (n = 11) or 5 mg/kg (n = 16) once every 3 weeks to investigate its safety, dose, and exploratory efficacy. The pharmacokinetics, immunogenicity, CD70 expression, and CD70/CD27 biology were also assessed. RESULTS: The most common adverse events included infusion-related reactions, pyrexia, and asthenia. Eighteen serious adverse events (grade 1-3) were reported in 11 patients; 1 of these (vasculitis) was considered drug-related. For 8 of the 11 patients receiving 1 mg/kg, anti-drug antibodies (ADAs) affected the minimal concentration, and this resulted in undetectable cusatuzumab concentrations at the end of treatment and, in some cases, a loss of response. This effect was greatly reduced in the patients receiving 5 mg/kg. The overall response rate was 23%; this included 1 complete response and 5 partial responses (PRs) in 26 of the 27 evaluable patients. In addition, 9 patients achieved stable disease. The mean duration on cusatuzumab was 5.2 months, and the median duration was 2.5 months. Patients with Sézary syndrome (SS) achieved a 60% PR rate with a dosage of 5 mg/kg and a 33% PR rate with a dosage of 1 mg/kg; this resulted in an overall response rate of 50% for patients with SS at both doses. CONCLUSIONS: Cusatuzumab was well tolerated, and antitumor activity was observed at both 1 and 5 mg/kg in highly pretreated patients with R/R CTCL. The observed dose-dependent effect on exposure supports the use of 5 mg/kg for future development.

Obinutuzumab plus lenalidomide in advanced, previously untreated follicular lymphoma in need of systemic therapy: a LYSA study.

Obinutuzumab and lenalidomide (referred to as the GALEN combination) is an active immunomodulatory combination with a manageable safety profile in multiple types of lymphoma. We report efficacy and safety results for the phase 2 GALEN study in previously untreated patients with advanced follicular lymphoma (FL). Eligible patients aged ≥18 years had an Eastern Cooperative Oncology Group performance status ≤2 and high-tumor burden, grade 1 to 3a FL. Induction treatment was obinutuzumab (1000 mg IV, days 8, 15, and 22, cycle 1; day 1, cycles 2-6) plus lenalidomide (20 mg/d, days 1-21, cycle 1; days 2-22, cycles 2-6) for six 28-day cycles. Maintenance included obinutuzumab (1000 mg every 2 cycles) plus lenalidomide (10 mg, days 2-22) for ≤12 cycles (year 1) followed by obinutuzumab (1000 mg every 56 days) for 6 cycles (year 2). The primary end point was complete response rate (CRR) after induction per the 1999 International Working Group criteria. From October 2015 to February 2017, a total of 100 patients were enrolled. CRR after induction was 47%, and the overall response rate (ORR) was 92%. Post hoc analyses per the 2014 Lugano classification, including patients with missing bone marrow assessments, identified an additional 13 patients fulfilling CRR criteria, resulting in a complete metabolic response of 80% and an ORR of 94%. At a median follow-up of 3.7 years, 3-year progression-free survival and overall survival were 82% and 94%, respectively. The most common adverse event was neutropenia (48% any grade; 47% grade ≥3). Only 2% of patients presented with febrile neutropenia; others were mainly grade ≤2. No other specific grade ≥3 toxicity occurred at a frequency >3%. Overall, these results showed promising clinical efficacy for the chemotherapy-free GALEN backbone in previously untreated patients with high tumor burden FL. Except for neutropenia, the safety profile of the combination is remarkable. The study was registered at clinicaltrials.gov as #NCT01582776.

Intestinal presentation of non-Hodgkin lymphoma: Case report.

BACKGROUND: MEITL (monomorphic epitheliotropic intestinal T-cell lymphoma) is a rare primary intestinal T-cell lymphoma associated with high mortality rate. Being intestinal this implies difficult diagnostic workup and management. CASE: We present a case of 59-year-old male presented with abdominal pain and found to have 15 × 11 cm mass in the right iliac fossa. Decision for surgical excision was retained and the Pathological examination determined monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) with CD30 positive immune-histochemical profile. CONCLUSION: MEITL is a rare entity which retains challenging diagnosis and management as well as variable immune-histochemical profile. In the absence of clear guidelines for the management of intestinal manifestation of lymphoma, surgical approach may have its indications.

Survival among patients with relapsed/refractory diffuse large B cell lymphoma treated with single-agent selinexor in the SADAL study.

Patients with RR DLBCL who have received ≥ 2 lines of therapy have limited treatment options and an expected overall survival (OS) of < 6 months. The SADAL study evaluated single-agent oral selinexor in patients with RR DLBCL and demonstrated an overall response rate (ORR) of 29.1% with median duration of response (DOR) of 9.3 months. The analyses described here evaluated a number of subpopulations in order to understand how response correlates with survival outcomes in order to identify patients who could most optimally benefit from selinexor treatment. Median age was 67 years; 44.8% of patients were ≥ 70 years of age. The median OS was 9.0 months (95% CI 6.2, 13.7) at a median follow-up of 14.8 months. The median OS was not reached in patients with a CR or PR, while patients who did not respond have a median OS of 4.9 months (p < 0.0001). Patients < 70 years had an OS of 11.1 months compared with 7.8 months in patients ≥ 70 years. Among patients with or without prior ASCT, the median OS was 10.9 and 7.8 months, respectively. Among patients with disease refractory to the most recent DLBCL treatment regimen, the median OS was 7.0 months compared with 11.1 months for disease not refractory to the most recent treatment. In a patient population in which survival is expected to be < 6 months, treatment with single-agent oral selinexor was associated with a median survival of 9 months. Increased median OS observed in patients responding to selinexor was consistent across subgroups regardless of age, prior ASCT therapy, or refractory status. Randomized studies of selinexor in combination with a variety of other anti-DLBCL agents are planned. This trial was registered at ClinicalTrials.gov (NCT02227251) on August 28, 2014. https://clinicaltrials.gov/ct2/show/NCT02227251 .

Health-related quality of life and utility outcomes with selinexor in relapsed/refractory diffuse large B-cell lymphoma.

Aim: Evaluate health-related quality of life (HRQoL) and health utility impact of single-agent selinexor in heavily pretreated patients with relapsed/refractory diffuse large B-cell lymphoma. Patients & methods: Functional Assessment of Cancer Therapy (FACT) - Lymphoma and EuroQoL five-dimensions five-levels data collected in the single-arm Phase IIb trial SADAL (NCT02227251) were analyzed with mixed-effects models. Results: Treatment responders maintained higher FACT - Lymphoma (p ≤ 0.05), FACT - General (p < 0.05) and EuroQoL five-dimensions five-levels index scores (p < 0.001) beginning in cycle 3. The estimated difference in health state utilities for treatment response and progressive disease was both statistically significant and clinically meaningful (mean difference: 0.07; p = 0.001). Conclusion: In patients with relapsed/refractory diffuse large B-cell lymphoma, objective response to selinexor was associated with HRQoL maintenance, reduction in disease-related HRQoL decrements and higher health utilities.

Lay abstract This work examined quality of life (QoL) among patients with relapsed/refractory diffuse large B-cell lymphoma with two to five prior therapies who received single-agent selinexor in the SADAL clinical trial. Analysis of patient-reported Functional Assessment of Cancer Therapy ­ Lymphoma and EuroQoL five-dimensions five-levels data showed that patients who had objective clinical response to selinexor maintained their QoL over the course of treatment. Grade ≥3 adverse events and serious adverse events were not associated with clinically meaningful negative QoL impacts. Clinical trial registration: NCT02227251 (ClinicalTrials.gov).

Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial.

BACKGROUND: Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. METHODS: SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling). FINDINGS: Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor. INTERPRETATION: Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting. FUNDING: Karyopharm Therapeutics Inc.

Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study.

BACKGROUND: Anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies are novel immunotherapies for cancer that can induce immune-related adverse events (irAEs). These adverse events can involve all organs, including the haemopoietic system. Thus far, haematological irAEs (haem-irAEs) have not been extensively characterised. This study aims to provide a comprehensive report of the haem-irAEs induced by anti-PD-1 or anti-PD-L1. METHODS: In this descriptive observational study, we included consecutive patients aged at least 18 years with grade 2 or worse haem-irAEs induced by anti-PD-1 or anti-PD-L1 immunotherapy registered in three French pharmacovigilance databases: the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC; a prospective registry of patients treated with anti-PD-1 or anti-PD-L1 at a single centre), the ImmunoTOX committee of Gustave Roussy (a national referral database of suspected irAEs in patients treated with immunotherapy), and the registry of the Centre de Référence des Cytopénies Auto-Immunes de l'Adulte (CeReCAI; a national database of autoimmune cytopenias). Cases were reviewed by a central committee; adverse events had to be classed as certainly or probably related to anti-PD-1 or anti-PD-L1 therapy, and their severity was assessed according to the Common Terminology Criteria for Adverse Events (version 4.03). The primary endpoint was clinical description of haem-irAEs, as reported in all databases, and their frequency, as reported in the prospective REISAMIC registry. FINDINGS: We screened 948 patients registered in the three databases from June 27, 2014, to June 29, 2018 (745 from REISAMIC, 190 from the ImmunoTOX committee, and 13 from CeReCAI). 35 patients (21 men and 14 women) with haem-irAEs related to anti-PD-1 or anti-PD-L1 were included in the study. Of 745 patients in the REISAMIC registry treated with anti-PD-1 or anti-PD-L1, four had haem-irAEs, giving a frequency of 0·5%. Median age in the 35 patients was 65 years (IQR 51-75), and the most common tumour types were melanoma (15 [43%] patients), non-small-cell lung cancer (12 [34%] patients), and lymphoma (four [11%] patients). 20 (57%) patients received nivolumab, 14 (40%) received pembrolizumab, and one (3%) received atezolizumab. Among the 35 patients, neutropenia, autoimmune haemolytic anaemia, and immune thrombocytopenia were the most common types of haem-irAE (each in nine patients [26%]), followed by pancytopenia or aplastic anaemia (five patients [14%]), bicytopenia (one patients with thrombocytopenia plus anaemia and one patient with neutropenia plus anaemia [6%]), and pure red cell aplasia (one patient [3%]). The maximum grade of severity was grade 2 in three (9%) patients, grade 3 in five (14%) patients, and grade 4 in 25 (71%) patients; two (6%) patients died from febrile neutropenia during haem-irAE related to anti-PD-1. Haem-irAEs resolved in 21 (60%) of the 35 patients. INTERPRETATION: Haem-irAEs induced by PD-1 or PD-L1 inhibitors are rare but potentially life-threatening events. The most common clinical presentations are neutropenia, autoimmune haemolytic anaemia, immune thrombocytopenia, and aplastic anaemia. Investigations into earlier detection and better management are warranted. FUNDING: Gustave Roussy and Gustave Roussy Immunotherapy Program.

The Light Chain IgLV3-21 Defines a New Poor Prognostic Subgroup in Chronic Lymphocytic Leukemia: Results of a Multicenter Study.

Purpose: Unmutated (UM) immunoglobulin heavy chain variable region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL) patients. Interestingly, IgHV3-21 is often co-expressed with light chain IgLV3-21, which is potentially able to trigger cell-autonomous BCR-mediated signaling. However, this light chain has never been characterized independently of the heavy chain IgHV3-21.Experimental Design: We performed total RNA sequencing in 32 patients and investigated IgLV3-21 prognostic impact in terms of treatment-free survival (TFS) and overall survival (OS) in 3 other independent cohorts for a total of 813 patients. IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing.Results: Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients express higher levels of genes responsible for ribosome biogenesis and translation initiation (P < 0.0001) as well as MYC target genes (P = 0.0003). Patients with IgLV3-21 rearrangements displayed a significantly shorter TFS and OS (P < 0.05), particularly those with IgHV mutation. In each of the three independent validation cohorts, we showed that IgLV3-21 rearrangements-similar to UM IgHV status-conferred poor prognosis compared with mutated IgHV (P < 0.0001). Importantly, we confirmed by multivariate analysis that this was independent of IgHV mutational status or subset #2 stereotyped receptor (P < 0.0001).Conclusions: We have demonstrated for the first time that a light chain can affect CLL prognosis and that IgLV3-21 light chain usage defines a new subgroup of CLL patients with poor prognosis. Clin Cancer Res; 24(20); 5048-57. ©2018 AACR.

Efficacy of chemotherapy or chemo-anti-PD-1 combination after failed anti-PD-1 therapy for relapsed and refractory Hodgkin lymphoma: A series from Lysa centers.

Anti-PD-1 therapy provides high response rates in Hodgkin lymphoma (HL) patients who have relapsed or are refractory (R/R) to autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV), but median progression free survival (PFS) is only one year. The efficacy of treatment following anti-PD-1 is not well known. We retrospectively investigated the efficacy of salvage therapies for unsatisfactory response to anti-PD-1 therapy, assessed by PET-CT according to the Lugano criteria, in 30 R/R HL patients. Patients were highly pre-treated before anti-PD-1 (70% received ASCT and 93% BV). Unsatisfactory responses to anti-PD1 therapy were progressive disease (PD) (n=24) and partial response (PR) (n=6). For the 24 PD patients, median anti-PD-1 related PFS was 7.5 months (95%CI, 5.7-11.6); 17 received subsequent CT alone (Group 1) and 7 received CT in addition to anti-PD-1 (Group 2). 16/24 patients (67%) obtained an objective response. In the 15 patients treated with the same CT, twelve obtained PR or complete response (CR). In Group 1, there were 7 CR (41%), 3 PR (18%), and 7 PD (41%). In Group 2, there were 4 CR (57%), 2 PR (29%), and 1 SD (14%). No unexpected toxicity was observed. Six patients who achieved response proceeded to allogeneic SCT. With a median follow-up of 12.1 months (7-14.7), the median PFS following the initiation of CT was 11 months (95%CI, 6.3; not reached) and the median of overall survival was not reached. These observations in highly pre-treated HL patients suggest that anti-PD-1 therapy might re-sensitize tumor cells to CT. This article is protected by copyright. All rights reserved.

Phase I Dose-Escalation Study of the Anti-CD70 Antibody ARGX-110 in Advanced Malignancies.

Purpose: The purpose of this study was to evaluate safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of ARGX-110, a glyco-engineered monoclonal antibody, targeting CD70, in patients with CD70 expressing advanced malignancies.Experimental Design: Dose escalation with a sequential 3+3 design was performed in five steps at the 0.1, 1, 2, 5, and 10 mg/kg dose levels (N = 26). ARGX-110 was administered intravenously every 3 weeks until progression or intolerable toxicity. Dose-limiting toxicity was evaluated in the 21 days following the first ARGX-110 administration (Cycle 1). Samples for pharmacokinetics and pharmacodynamics were collected.Results: Dose-limiting toxicity was not observed and the maximum tolerated dose was not reached. ARGX-110 was generally well tolerated, with no dose-related increase in treatment-emergent adverse events (TEAE). The most common TEAE were fatigue and drug related infusion-related reactions (IRR). Of the 20 SAEs reported, five events, all IRRs, were considered related to ARGX-110. ARGX-110 demonstrates dose proportionality over the dose range 1 to 10 mg/kg, but not at 0.1 mg/kg and a terminal half-life of 10 to 13 days. The best overall response was stable disease (14/26) in all 26 evaluable patients with various malignancies and the mean duration of treatment was 15 weeks. No dose-response related antitumor activity was observed, but biomarker readouts provided signs of biological activity, particularly in patients with hematologic malignancies.Conclusions: This dose-escalation phase I trial provides evidence of good tolerability of ARGX-110, pharmacokinetics, and preliminary antitumor activity at all dose levels in generally heavily pretreated patients with advanced CD70-positive malignancies. Clin Cancer Res; 23(21); 6411-20. ©2017 AACR.

Extracellular vesicles of bone marrow stromal cells rescue chronic lymphocytic leukemia B cells from apoptosis, enhance their migration and induce gene expression modifications.

Interactions between chronic lymphocytic leukemia (CLL) B cells and the bone marrow (BM) microenvironment play a major function in the physiopathology of CLL. Extracellular vesicles (EVs), which are composed of exosomes and microparticles, play an important role in cell communication. However, little is known about their role in CLL / microenvironment interactions. In the present study, EVs purified by ultracentrifugation from BM mesenchymal stromal cell (BM-MSC) cultures were added to CLL B cells. After their integration into CLL B cells, we observed a decrease of leukemic cell spontaneous apoptosis and an increase in their chemoresistance to several drugs, including fludarabine, ibrutinib, idelalisib and venetoclax after 24 hours. Spontaneous (P=0.0078) and stromal cell-derived factor 1α -induced migration capacities of CLL B cells were also enhanced (P=0.0020). A microarray study highlighted 805 differentially expressed genes between leukemic cells cultured with or without EVs. Of these, genes involved in the B-cell receptor pathway such as CCL3/4, EGR1/2/3, and MYC were increased. Interestingly, this signature presents important overlaps with other microenvironment stimuli such as B-cell receptor stimulation, CLL/nurse-like cells co-culture or those provided by a lymph node microenvironment. Finally, we showed that EVs from MSCs of leukemic patients also rescue leukemic cells from spontaneous or drug-induced apoptosis. However, they induce a higher migration and also a stronger gene modification compared to EVs of healthy MSCs. In conclusion, we show that EVs play a crucial role in CLL B cells/BM microenvironment communication.

Results from the Belgian mantle cell lymphoma registry.

INTRODUCTION: Mantle cell lymphoma is a B-cell non-Hodgkin's lymphoma characterized by a t(11;14), resulting in overexpression of cyclin D1. Conventional chemotherapy obtains frequent (but short) remissions, leading to a poor median overall survival (OS) of 3-5 years. To obtain more information about the prevalence and current treatment of Mantle cell lymphoma (MCL) in Belgium, we collected data in a Belgian registry of MCL. MATERIALS AND METHODS: All Belgian MCL patients, t(11;14) and/or cyclin D1 positive, seen in hematology departments over a one-year period (April 2013-March 2014) were included. Data about patient characteristics, histology, treatment lines, and response were compiled and retrospectively analyzed. RESULTS: Four hundred and four patients were included with a median age at diagnosis of 64 years (range 23-96 years) and a male predominance (72%). For 2013, we calculated a prevalence of at least 36.2 per million and an incidence of at least 7.0 per million in the Belgian population. Characteristics at diagnosis involved lymphadenopathy (82%), splenomegaly (44%), B-symptoms (39%), and hepatomegaly (10%). Bone marrow invasion was present at diagnosis in 77%. Stage at diagnosis was advanced in the majority of cases. The median number of treatment lines was 1. Type of first line treatment included a combination of anthracyclin and cytarabine-based regimen (34%), anthracyclin (39%), and other. Rituximab was used in 88% of first line treatments. In 44% first line treatment was followed by autologous stem cell transplantation. CONCLUSION: The analysis of this Belgian MCL registry provides insight in the epidemiology, demographics, and current treatment of our Belgian MCL population.

Mediastinal gray zone lymphoma: clinico-pathological characteristics and outcomes of 99 patients from the Lymphoma Study Association.

Mediastinal gray zone lymphoma, B-cell lymphomas with intermediate features between classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma, have not been well described in the literature. We report the clinical characteristics and outcomes of a large retrospective series of 99 cases centrally reviewed by a panel of hematopathologists, with a consensus established for the diagnosis. Cases were defined as classical Hodgkin lymphoma-like morphology (64.6%) with primary mediastinal B-cell lymphoma immunophenotype, primary mediastinal B-cell lymphoma-like morphology (30.3%) with classical Hodgkin lymphoma or composite (5.1%) (synchronous occurrence of classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma). The median age was 32 years (13-83 years); 55% were women. Thirteen of 81 evaluable cases (16%) were Epstein-Barr virus-positive. Twenty-eight percent of patients presented primary refractory disease (progression under first-line treatment or relapse within one year). The 3-year event-free and overall survival rates were 63% and 80%, respectively. Patients treated with a standard regimen (RCHOP/ABVD) had worse event-free survival (P=0.003) and overall survival (P=0.02) than those treated with a dose-intensive chemotherapy (high-dose RCHOP/escalated BEACOPP). Rituximab added to chemotherapy was not associated with better event-free survival (P=0.55) or overall survival (P=0.88). Radiotherapy for patients in complete remission had no impact on event-free survival. In multivariate prognostic analysis, ECOG-PS and anemia were the strongest factors associated with a shorter event-free survival and overall survival, respectively. In conclusion, this report describes the largest series of mediastinal gray zone lymphoma. Our data suggest that a dose-intensive treatment might improve the outcome of this rare and aggressive disease.

Characterization of TET and IDH gene expression in chronic lymphocytic leukemia: comparison with normal B cells and prognostic significance.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common hematological malignancy in western countries, characterized by a heterogeneous clinical course. Although genetic studies have identified chromosomal aberrations or specific mutations, epigenetic changes have been poorly characterized in CLL. METHODS: We assessed ten-eleven translocations (TET) 1, 2, and 3, isocitrate dehydrogenase (IDH) 1, and 2 messenger RNA (mRNA) expression using real-time PCR on purified leukemic B cells from 214 CLL patients (median follow-up = 75 months, range 1-380), normal peripheral blood B cells (n = 20), and umbilical cord blood B cells (n = 21). The microenvironment influence was assessed after 24 h co-culture of CLL cells with bone marrow mesenchymal stromal cells (BMSC). Finally, 5-hydroxymethylcytosine level (%5-hmC) was assessed by ELISA in CLL cells alone or with microenvironment stimuli. RESULTS: TET 1 and 3 and IDH2 were decreased in CLL cells compared with healthy B cells (P = 0.0221, 0.0013, <0.0001, respectively), while IDH1 was overexpressed (P = 0.0037). TET2 and IDH1 were significantly correlated with treatment-free survival (TFS); patients with high TET2/IDH1 expression had a higher median TFS (111 months) than patients with low expression (78 months, P = 0.0071/0.0123). Moreover, TET1 expression decreased (P = 0.0371), while TET3 and IDH2 expression increased (P = 0.0273/0.0039) in co-cultures. However, %5-hmC was not correlated with clinical data and was unchanged following microenvironment stimuli. CONCLUSIONS: Despite a slight deregulation in CLL cells compared with normal B cells, we identified a significant association between TET/IDH gene expression and prognosis, suggesting that epigenetic changes could potentially be associated with disease progression. Moreover, despite an identical %5-hmC, TET gene expression was influenced by contact with BMSC confirming the crucial role of the microenvironment in CLL pathogenesis.