A first-in-class Wiskott-Aldrich syndrome protein activator with anti-tumor activity in hematologic cancers.

Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization.

IELSG38: phase II trial of front-line chlorambucil plus subcutaneous rituximab induction and maintenance in mucosa-associated lymphoid tissue lymphoma.

The IELSG38 trial was conducted to investigate the effects of subcutaneous (SC) rituximab on the complete remission (CR) rate and the benefits of SC rituximab maintenance in patients with extranodal marginal zone lymphoma (MZL) who received front-line treatment with chlorambucil plus rituximab. Study treatment was an induction phase with oral chlorambucil 6 mg/m2/day on weeks 1-6, 9-10, 13-14, 17-18, and 21-22, and intravenous rituximab 375 mg/m2 on day 1 of weeks 1-4, and 1,400 mg SC on weeks 9, 13, 17, and 21. Then, a maintenance phase followed with rituximab administered at 1,400 mg SC every two months for two years. Of the 112 patients enrolled, 109 were evaluated for efficacy. The CR rates increased from 52% at the end of the induction phase to 70% upon completion of the maintenance phase. With a median follow-up of 5.8 years, the 5-year event-free, progression-free, and overall survival rates were 87% (95% CI: 78-92), 84% (95% CI: 75-89), and 93% (95% CI: 86-96), respectively. The most common grade ≥3 toxicities were neutropenia (33%) and lymphocytopenia (16%). Six patients experienced treatment-related serious adverse events, including fever of unknown origin, sepsis, pneumonia, respiratory failure, severe cerebellar ataxia, and fatal acute myeloid leukemia. The trial showed that SC rituximab did not improve the CR rate at the conclusion of the induction phase, which was the main endpoint. Nevertheless, SC rituximab maintenance might have facilitated long-term disease control, potentially contributing to enhanced event-free and progression-free survival.

International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia.

Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.

Changing the landscape of European School of Oncology-European Society for Medical Oncology masterclasses in clinical oncology during the COVID-19 pandemic.

Aims: This study aimed to assess the participants' evaluation of the European School of Oncology-European Society for Medical Oncology virtual masterclasses in clinical oncology (MCOs) organized during the pandemic in 2021. Materials & methods: The participants answered an online evaluation questionnaire at the end of each MCO to evaluate the content and organization of the MCO. Results: The clinical session and case presentation scores ranged between 4.6 and 4.8 over 5. The participants strongly agreed that the MCOs offered updates to improve their knowledge and practice in 68-83% and 52-76%, respectively; 74-90% of the participants considered the quality of the meetings to be excellent. Conclusion: The participants were satisfied with the virtual MCOs during the COVID-19 pandemic. Virtual MCO may be an acceptable alternative educational modality in specific circumstances.

In 2002, the European School of Oncology (ESO) established masterclasses in clinical oncology (MCOs) and provided 41 in-person courses over the past two decades. As the COVID-19 pandemic forced travel restrictions and social distancing, the ESO and the European Society for Medical Oncology (ESMO) adapted the traditional MCOs to create virtual MCOs presented on e-ESO, an ESO e-learning platform. To date, five virtual MCOs have been organized for oncologists from western Europe, Latin America, Arab countries and southern Europe, the Baltic and Eurasia, eastern Europe and the Balkans. This study aimed to assess the participants' evaluation of the ESO-ESMO virtual MCOs organized during the pandemic in 2021 and to compare the participants' evaluation with that of previous in-person MCOs conducted between 2002 and 2019.

Eight-Year Experience of the Certificate of Competence and Advanced Studies Program Organized by the European School of Oncology.

The Certificate of Competence and Advanced Studies Program is an academically recognized postgraduate program that is organized by the European School of Oncology in collaboration with the University of Ulm and the University of Zurich. It is a part-time educational activity that aims to provide physicians and scientists with advanced knowledge in the management of patients with breast cancer, lymphoma, and lung cancer. The program encloses three attendance seminars and four to five e-learning modules that extend over 12 to 14 months. To be certified, participants have to pass an online test after each module followed by a final certification exam at the end of the program. This article reports on the 8-year experience of the 166 graduated fellows who have attended the program.

The Contribution of the European School Of Oncology Education to the Central Asian and Caucasian Regions.

The European School of Oncology (ESO) organizes educational activities within Europe, the Mediterranean region, Central Asia, and the Caucasus. In this paper, we report on the participation of oncologists from Uzbekistan, Kazakhstan, Kirgizstan, Tajikistan, Azerbaijan, Georgia, and Armenia in various ESO activities including the masterclass, courses, refresher courses, conventions, conferences, consensus conferences, clinical training centers fellowship program, and the medical students' courses in oncology. Over the last 15 years, 428 oncologists and medical students have successfully attended one or more of the above activities organized in various European countries. This article details the implementation and coordination of the ESO educational events in the Central Asian and the Caucasian regions.

A phase II trial of bendamustine in combination with ofatumumab in patients with relapsed or refractory marginal zone B-cell lymphomas.

Marginal zone lymphomas (MZLs) are indolent yet incurable lymphomas with frequent relapses following therapy. For patients with relapsed/refractory disease, no standard therapies exist. Here we report results of an exploratory phase II study aimed at assessing the efficacy and safety of the alkylator agent bendamustine in combination with the second-generation anti-CD20 monoclonal antibody, ofatumumab, in patients with relapsed or refractory MZL. Patients with MZL and previously treated with at least one line of systemic therapy were eligible. Treatment consisted in bendamustine (90 mg/m2 on days 1 and 2) and ofatumumab (1000 mg on day 1) in 28-day cycles for up to six cycles. Sixteen patients were included in the trial. In one patient, the diagnosis was revised after two cycles of treatment and was excluded from the efficacy analysis. Among 15 patients with MZL, 14 were evaluable for response: the overall and complete response rates were 92.9% and 57.1%, respectively. The median duration of response was 30.4 months (95% confidence interval [CI], 15.5 -not estimable) and 2-years progression-free survival 77% (95% CI, 43%-92%). Fifteen patients (94%) experienced grade 3-4 adverse events. Toxicity was mostly hematological. Neutropenia grade ≥3 was recorded in 27% of patients, lymphocytopenia in 93%, and infections and febrile neutropenia each in 13%. One patient discontinued treatment due to myocardial infarction; no treatment-related deaths occurred. The combination of bendamustine with ofatumumab was active with an acceptable toxicity profile in this small phase II trial and can be considered for further investigation in relapsed/refractory MZL patients.

Educational contribution of the College of the European School of Oncology to the Latin American Oncologists.

The European School of Oncology (ESO) offers a wide range of educational activities in Europe, the Middle East and Latin America. International experts are invited to provide proper education in the diagnosis and treatment of patients with cancer according to a holistic model of care. This activity is currently structured in the ESO College (ESCO) through masterclasses in clinical oncology, international conferences, clinical training centers fellowship programs, certificate of competence and advanced studies, patients' advocacy events, e-learning sessions and medical students' courses in oncology. This institutional profile highlights the ESO-ESCO educational activities dedicated to Latin American oncologists and reports on the experience of the 869 participants that have attended these programs.

ESO-ESMO Masterclass in Clinical Oncology: Analysis and Evaluation of the Learning Self-Assessment Test.

Masterclass in Clinical Oncology (MCO) represents the "key educational event" of European School of Oncology's (ESO) teaching program. MCO in collaboration with European Society for Medical Oncology (ESMO) is a multidisciplinary and clinical oriented educational event offered mainly to young oncologists worldwide. It provides full immersion in oncology with clinical case presentations and a Learning Self-Assessment Test (LSAT).LSAT is consisting of 45 multiple choice questions on an electronic platform referring to the material taught during the MCO. Three questions related to their topics are requested in advance from each faculty member. The major intentions of LSAT are the following: (a) the learning reflection of the massive information given during 4-5 days of intensive teaching and (b) to offer the opportunity to the participants to prepare themselves for their National Boards or for ESMO examination.In this article, we are analyzing and evaluating the results of LSAT from the ESO-ESMO Central European MCOs. We used the information of Central European MCOs for analysis due to the homogeneity of the available data. We assessed the level of participants' knowledge in relation to their oncology specialty or to their country of origin and the level of the quality of faculty teaching.

Clinical Case Presentation and Discussion During ESO-ESMO Masterclass: a 10-Year Interactive Educational Experience.

In this article, we report on the clinical case presentations that have been delivered during the ESO or ESO-ESMO Masterclasses in Clinical Oncology in the last 10 years. Masterclasses have been held in three different geographical continents including Europe, Middle East, and Latin America, in which participants had to submit a clinical case and present it either in front of a tumor board (multidisciplinary-like sessions) or in small groups. Clinical case presentation is a unique part of the educational program preparing young oncologists to present and discuss their own patients with distinguished experts. In each Masterclass, between 40 and 55 clinical cases-depending on the number of participants-are presented. All presentations are assessed and evaluated by faculty members as well as by the rest of the participants.

Metabolic heterogeneity on baseline 18FDG-PET/CT scan is a predictor of outcome in primary mediastinal B-cell lymphoma.

An important unmet need in the management of primary mediastinal B-cell lymphoma (PMBCL) is to identify the patients for whom first-line therapy will fail to intervene before the lymphoma becomes refractory. High heterogeneity of intratumoral 18F-fluorodeoxyglucose (18FDG) uptake distribution on positron emission tomography/computed tomography (PET/CT) scans has been suggested as a possible marker of chemoresistance in solid tumors. In the present study, we investigated the prognostic value of metabolic heterogeneity (MH) in 103 patients with PMBCL prospectively enrolled in the International Extranodal Lymphoma Study Group (IELSG) 26 study, aimed at clarifying the role of PET in this lymphoma subtype. MH was estimated using the area under curve of cumulative standardized uptake value-volume histogram (AUC-CSH) method. Progression-free survival at 5 years was 94% vs 73% in low- and high-MH groups, respectively (P = .0001). In a Cox model of progression-free survival including dichotomized MH, metabolic tumor volume, total lesion glycolysis (TLG), international prognostic index, and tumor bulk (mediastinal mass > 10 cm), as well as age as a continuous variable, only TLG (P < .001) and MH (P < .001) retained statistical significance. Using these 2 features to construct a simple prognostic model resulted in early and accurate (positive predictive value, 89%; negative predictive value, ≥90%) identification of patients at high risk for progression at a point that would allow the use of risk-adapted treatments. This may provide an important opportunity for the design of future trials aimed at helping the minority of patients who harbor chemorefractory PMBCL. The study is registered at ClinicalTrials.gov as NCT00944567.

Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma.

The rarity of neoplastic cells in the biopsy imposes major technical hurdles that have so far limited genomic studies in classical Hodgkin lymphoma (cHL). By using a highly sensitive and robust deep next-generation sequencing approach for circulating tumor DNA (ctDNA), we aimed to identify the genetics of cHL in different clinical phases, as well as its modifications on treatment. The analysis was based on specimens collected from 80 newly diagnosed and 32 refractory patients with cHL, including longitudinal samples collected under ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) chemotherapy and longitudinal samples from relapsing patients treated with chemotherapy and immunotherapy. ctDNA mirrored Hodgkin and Reed-Sternberg cell genetics, thus establishing ctDNA as an easily accessible source of tumor DNA for cHL genotyping. By identifying STAT6 as the most frequently mutated gene in ∼40% of cases, we refined the current knowledge of cHL genetics. Longitudinal ctDNA profiling identified treatment-dependent patterns of clonal evolution in patients relapsing after chemotherapy and patients maintained in partial remission under immunotherapy. By measuring ctDNA changes during therapy, we propose ctDNA as a radiation-free tool to track residual disease that may integrate positron emission tomography imaging for the early identification of chemorefractory patients with cHL. Collectively, our results provide the proof of concept that ctDNA may serve as a novel precision medicine biomarker in cHL.

Early progression of disease predicts shorter survival in MALT lymphoma patients receiving systemic treatment.

Early progression of disease (POD) within two years from diagnosis is linked with poor overall survival (OS) in follicular lymphoma but its prognostic role is less clear in extranodal marginal zone B-cell lymphoma (EMZL). We sought to identify prognostic factors associated with early POD and to determine whether is associated with inferior OS. We analyzed the impact of early POD in the IELSG19 clinical trial dataset (training set of 401 patients randomly assigned to chlorambucil or rituximab or chlorambucil plus rituximab). Reproducibility was examined in a validation set of 287 patients who received systemic treatment. In both sets, we excluded from the analysis the patients who, within 24 months from treatment start, died without progression or were lost to follow-up without prior progression. OS was calculated from progression in patients with early POD and from 24 months after start of treatment in those without (reference group). Early POD was observed in 69 of the 384 (18%) evaluable patients of the IELSG19 study. Patients with high-risk MALT-IPI were more likely to have early POD (p=0.006). The 10-year OS rate was 64% in the early POD group and 85% in the reference group (HR= 2.42, 95%CI, 1.35-4.34; log-rank P=0.002). This prognostic impact was confirmed in the validation set, in which early POD was observed in 64 out of 224 (29%) evaluable patients with 10-year OS rate of 48% in the early POD group and 71% in the reference group (HR= 2.15, 95%CI, 1.19-3.90; log-rank P=0.009). In patients with EMZL who received front-line systemic treatment, early POD is associated with poorer survival and may represent a useful endpoint in future prospective clinical trials.

The development of liquid biopsy for research and clinical practice in lymphomas: Report of the 15-ICML workshop on ctDNA.

This report summarizes a closed workshop cosponsored by the American Association for Cancer Research, the European School of Oncology, and the 15th-International Conference on Malignant Lymphoma to discuss critical open questions on liquid biopsy in lymphoid malignancies, develops a roadmap for their analytical and clinical validation, and prioritizes research areas.

The clinical training centers fellowships: a European School of Oncology career development program (2013-2019).

Aim: This article refers to the European School of Oncology Clinical Training Centers (CTCs) program, which is a granted Fellowships program dedicated to young oncologists in training. Materials & methods: A total of 74 fellowships were offered by several CTCs during the last 7 years. Candidates were enrolled for 3-6 months of training rotations as fellows or observers in more than 30 training programs in well known Cancer Centers around Europe. Fellowships were covering medical, surgical, radiation and pediatric oncology specialties, laboratory diagnostic training and experimental, translational and clinical research. Fellows originated from Europe, Latin America and Mediterranean Africa. Results: Analysis of the questionnaire assessment showed that 95.5% of the fellows evaluated CTC programs with an 'excellent' or 'very good' score, while 100% declare that they had reached their objectives. Conclusion: The European School of Oncology CTC program designed for an additional practical education abroad meets the needs of young oncologists.

A MALT lymphoma prognostic index.

There are no widely accepted prognostic indices for extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). This study aimed to develop and validate a specific prognostic tool to personalize and optimize treatment of patients with MALT lymphoma. A prognostic index was built by Cox regression (stepwise selection) using data from 401 patients enrolled in the international randomized International Extranodal Lymphoma Study Group 19 (IELSG-19) trial (NCT 00210353). A validation set, including 633 patients, was obtained by merging 3 independent cohorts of MALT lymphoma patients. The 3 individual features maintaining the greatest prognostic significance for event-free survival (EFS, the main endpoint of the IELSG-19 trial) were age ≥70 years (hazard ratio [HR], 1.72; 95% confidence interval [CI], 1.26-2.33), Ann Arbor stage III or IV (HR, 1.79; 95% CI ,1.35-2.38), and an elevated lactate dehydrogenase level (HR, 1.87; 95% CI, 1.27-2.77). The prognostic index (MALT-IPI) constructed using these 3 parameters identified 3 groups: low, intermediate, and high risk (corresponding to the presence of 0, 1, or ≥2 of these factors, respectively). The 5-year EFS rates in the low-, intermediate-, and high-risk groups were 70%, 56%, and 29%, respectively. The MALT-lymphoma International Prognostic Index (MALT-IPI) also significantly discriminated between patients with different progression-free, overall, and cause-specific survival. The prognostic utility was retained in gastric and nongastric lymphomas, in each treatment arm (chlorambucil, rituximab, and rituximab plus chlorambucil), and was confirmed in the validation set. The new index, MALT-IPI, is a simple, accessible, and effective tool to identify MALT lymphoma patients at risk of poor outcomes. It may help define appropriate treatment approaches for individual patients.

Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study.

BACKGROUND: In the LYM-3002 study, the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were compared in transplant-ineligible patients with untreated, newly diagnosed, mantle cell lymphoma. We report the final overall survival and safety outcomes for patients in the long-term follow-up phase after the primary progression-free-survival endpoint was met. METHODS: LYM-3002 was a randomised, open-label, phase 3 study done at 128 clinical centres in 28 countries in Asia, Europe, North America, and South America. Adult patients with confirmed stage II-IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomisation was done according to a computer-generated randomisation schedule prepared by the sponsor; permuted blocks central randomisation was used (block size of 4), and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00722137, and is closed to new participants with follow-up completed. FINDINGS: Between May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1-94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51-0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease. INTERPRETATIONS: Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma. FUNDING: Janssen Research & Development.

Non-Hodgkin lymphoma.

Lymphomas can affect any organ in the body, present with a wide range of symptoms, and be seen by primary care physicians and physicians from most specialties. They are traditionally divided into Hodgkin's lymphoma (which accounts for about 10% of all lymphomas) and non-Hodgkin lymphoma, which is the topic of this Seminar. Non-Hodgkin lymphoma represents a wide spectrum of illnesses that vary from the most indolent to the most aggressive malignancies. They arise from lymphocytes that are at various stages of development, and the characteristics of the specific lymphoma subtype reflect those of the cell from which they originated. Since this topic was last reviewed in The Lancet in 2012, advances in understanding the biology and genetics of non-Hodgkin lymphoma and the availability of new diagnostic methods and therapies have improved our ability to manage patients with this disorder.

Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma.

BACKGROUND: The proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma. We investigated whether substituting bortezomib for vincristine in frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could improve outcomes in patients with newly diagnosed mantle-cell lymphoma. METHODS: In this phase 3 trial, we randomly assigned 487 adults with newly diagnosed mantle-cell lymphoma who were ineligible or not considered for stem-cell transplantation to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11). The primary end point was progression-free survival. RESULTS: After a median follow-up of 40 months, median progression-free survival (according to independent radiologic review) was 14.4 months in the R-CHOP group versus 24.7 months in the VR-CAP group (hazard ratio favoring the VR-CAP group, 0.63; P<0.001), a relative improvement of 59%. On the basis of investigator assessment, the median durations of progression-free survival were 16.1 months and 30.7 months, respectively (hazard ratio, 0.51; P<0.001), a relative improvement of 96%. Secondary end points were consistently improved in the VR-CAP group, including the complete response rate (42% vs. 53%), the median duration of complete response (18.0 months vs. 42.1 months), the median treatment-free interval (20.5 months vs. 40.6 months), and the 4-year overall survival rate (54% vs. 64%). Rates of neutropenia and thrombocytopenia were higher in the VR-CAP group. CONCLUSIONS: VR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity. (Funded by Janssen Research and Development and Millennium Pharmaceuticals; LYM-3002 ClinicalTrials.gov number, NCT00722137.).