Background The standard treatment for patients with diffuse large-B-cell lymphoma is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Rituximab, a chimeric monoclonal antibody against the CD20 B-cell antigen, has therapeutic activity in diffuse large-B-cell lymphoma. We conducted a randomized trial to compare CHOP chemotherapy plus rituximab with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. Methods Previously untreated patients with diffuse large-B-cell lymphoma, 60 to 80 years old, were randomly assigned to receive either eight cycles of CHOP every three weeks (197 patients) or eight cycles of CHOP plus rituximab given on day 1 of each cycle (202 patients). Results The rate of complete response was significantly higher in the group that received CHOP plus rituximab than in the group that received CHOP alone (76 percent vs. 63 percent, P=0.005). With a median follow-up of two years, event-free and overall survival times were significantly higher in the CHOP-plus-rit...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa011795

CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma

Purpose Standardized response criteria are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies. Methods The International Working Group response criteria (Cheson et al, J Clin Oncol 17:1244, 1999) were widely adopted, but required reassessment because of identified limitations and the increased use of [ 18 F]fluorodeoxyglucose-positron emission tomography (PET), immunohistochemistry (IHC), and flow cytometry. The International Harmonization Project was convened to provide updated recommendations. Results New guidelines are presented incorporating PET, IHC, and flow cytometry for definitions of response in non-Hodgkin’s and Hodgkin’s lymphoma. Standardized definitions of end points are provided. Conclusion We hope that these guidelines will be adopted widely by study groups, pharmaceutical and biotechnology companies, and regulatory agencies to facilitate the development of new and more effective therapies to improve the outcome of patients with lymphoma. J Clin Oncol 25:579-586. © 2007 by American Society of Clinical Oncology

/pdf/revised-response-criteria-for-malignant-lymphoma-41zde6csg7.pdf

Revised response criteria for malignant lymphoma

PURPOSE: The European Association of Hematopathologists and the Society for Hematopathology have developed a new World Health Organization (WHO) classification of hematologic malignancies, including lymphoid, myeloid, histiocytic, and mast cell neoplasms. DESIGN: Ten committees of pathologists developed lists and definitions of disease entities. A clinical advisory committee (CAC) of international hematologists and oncologists was formed to ensure that the classification would be useful to clinicians. The CAC met in November 1997 to discuss clinical issues related to the classification. RESULTS: The WHO uses the Revised European-American Lymphoma (REAL) classification, published in 1994 by the International Lymphoma Study Group, to categorize lymphoid neoplasms. The REAL classification is based on the principle that a classification is a list of “real” disease entities, which are defined by a combination of morphology, immunophenotype, genetic features, and clinical features. The relative importance of ea...

World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997.

The purpose of this work was to modernize recommendations for evaluation, staging, and response assessment of patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). A workshop was held at the 11th International Conference on Malignant Lymphoma in Lugano, Switzerland, in June 2011, that included leading hematologists, oncologists, radiation oncologists, pathologists, radiologists, and nuclear medicine physicians, representing major international lymphoma clinical trials groups and cancer centers. Clinical and imaging subcommittees presented their conclusions at a subsequent workshop at the 12th International Conference on Malignant Lymphoma, leading to revised criteria for staging and of the International Working Group Guidelines of 2007 for response. As a result, fluorodeoxyglucose (FDG) positron emission tomography (PET)–computed tomography (CT) was formally incorporated into standard staging for FDG-avid lymphomas. A modification of the Ann Arbor descriptive terminology will be used for ana...

/pdf/recommendations-for-initial-evaluation-staging-and-response-5zfzjttmb3.pdf

Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification

Macrophages are crucial drivers of tumour-promoting inflammation. Tumour-associated macrophages (TAMs) contribute to tumour progression at different levels: by promoting genetic instability, nurturing cancer stem cells, supporting metastasis, and taming protective adaptive immunity. TAMs can exert a dual, yin-yang influence on the effectiveness of cytoreductive therapies (chemotherapy and radiotherapy), either antagonizing the antitumour activity of these treatments by orchestrating a tumour-promoting, tissue-repair response or, instead, enhancing the overall antineoplastic effect. TAMs express molecular triggers of checkpoint proteins that regulate T-cell activation, and are targets of certain checkpoint-blockade immunotherapies. Other macrophage-centred approaches to anticancer therapy are under investigation, and include: inhibition of macrophage recruitment to, and/or survival in, tumours; functional re-education of TAMs to an antitumour, 'M1-like' mode; and tumour-targeting monoclonal antibodies that elicit macrophage-mediated extracellular killing, or phagocytosis and intracellular destruction of cancer cells. The evidence supporting these strategies is reviewed herein. We surmise that TAMs can provide tools to tailor the use of cytoreductive therapies and immunotherapy in a personalized medicine approach, and that TAM-focused therapeutic strategies have the potential to complement and synergize with both chemotherapy and immunotherapy.

/pdf/tumour-associated-macrophages-as-treatment-targets-in-3gdbul5s9u.pdf

Tumour-associated macrophages as treatment targets in oncology

Refractory Hodgkin Lymphoma: Time for Targeted Therapies?

ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) patients (pts) who have failed brentuximab vedotin (BV) have a poor prognosis with a median OS after BV failure of 2.9 months and 2-year OS of 27.1% (Chihara D, 2019). ALK-inhibitors have shown interesting results in relapsed ALK+ ALCL, but in these studies, most pts had not received prior BV, which does not correspond to current standards of treatment in adults. Furthermore, there are currently several ALK-inhibitors, but too few pts available to test them in this rare and difficult-to-treat population. It is therefore important to evaluate these ALK-inhibitors in preclinical studies, before selecting one for a clinical study. We carried out a preclinical study and then a real-life clinical study. We generated a patient-derived xenograft (PDX) model from a fresh lymph node biopsy of a 41-year-old man newly diagnosed with ALK+ ALCL. Our PDX closely mimicked the patient’s primary tumor, as assessed by pathology, FISH, TCR gene rearrangement, WES and RNA-seq. We used this model to assess 8 ALK-inhibitors (alectinib, brigatinib, ceritinib, crizotinib, ensartinib, entrectinib, lorlatinib, gilteritinib). We selected and recommended brigatinib for clinical off-label use based on our preclinical results and the safety profile in pts with ALK-positive non-small cell lung cancer (NSCLC). Between Jan 2020 and Oct 2022, 15 French adults who have failed BV started brigatinib. At brigatinib initiation, the median age was 35 y (19–73; 2 pts > 60 y), 8/15 were male, the median number of prior treatment lines was 2 (1–8), 4/15 (27%) had received prior crizotinib, including 3 crizotinib-resistant (crizo-R) and 1 crizotinib-sensitive (crizo-S) who relapsed after discontinuation of the drug. 4 pts had previously undergone stem cell transplantation (3 autoSCT, 1 alloSCT). ALCL was refractory to the last treatment in 10/15 pts. 10/11 pts had detectable ALK transcript in blood by RT-PCR. Pts received brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg), as recommended in ALK-positive NSCLC. The best ORR was 93% (14/15) with 73% (11/15) CR according to Lugano response criteria. 2 crizo-R and the crizo-S pts achieved CR, and 1 crizo-R pt reached PR. Time to achieve CR ranged from 8 to 325 days. 9 pts were monitored for ALK transcript in blood over time and kinetics correlated with response. 5 CR pts were bridged to alloSCT. There were 4 progressions/relapses after brigatinib initiation, all occurring within the first 6 months. After a median follow-up of 1.3 years, 1-year PFS and OS were 72% and 85%, respectively. There was no permanent discontinuation of brigatinib related to adverse event (AE), and 3 pts had dose reduction for moderate AE (1 dyspnea and 2 cramps), with complete resolution. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. D. Sibon Consultant or advisory role: Takeda, AbbVie, Janssen, Roche 

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/hon.3164_373

Brigatinib in patients with ALK‐positive anaplastic large cell lymphoma who have failed brentuximab vedotin

Should Adolescents and Young Adults with Hodgkin Lymphoma be Treated As Children or Adults?

Resume Touchant preferentiellement les jeunes adultes, le lymphome de Hodgkin (LH) classique est une hemopathie maligne dont le traitement par chimiotherapie plus ou moins radiotherapie engendre de bons taux de guerison (> 80 %) avec cependant une toxicite a long terme significative. Certains cas sont refractaires a la chimiotherapie ou rechutent precocement et necessitent des chimiotherapies intensives aux lourds effets secondaires. L’etude de la physiopathologie des LH revele que d’importantes alterations des interactions entre les cellules de Reed-Sternberg et leur micro-environnement impliquent la voie de signalisation Programmed Cell Death 1 (PD-1)/PD-Ligand-1. Recemment, les anticorps anti-PD-1 ont montre des resultats spectaculaires dans les LH refractaires ou en rechute avec une toxicite moderee, mais leur efficacite a long terme n’est pas encore etablie. La place de ces traitements dans la strategie globale de prise en charge des LH reste a determiner.

L’arrivée de l’immunothérapie dans le lymphome de Hodgkin.

Hodgkin lymphoma is a well-known clinico-pathological entity with a stable incidence among time accounting for 1200 new cases each year in France. The disease is one of the most curable cancer and occurs often in young patients with a median age at 33 years, the major clinical symptoms are lymph nodes mostly above the diaphragm (mediastinal and supra-clavicular). The diagnosis should be suggested with non-specific symptoms such as fever, night sweats, pruritus, weight-loss, lymph node, cough.. leading to prescribe routine exams like blood test with leucocyte count, erythrocyte sedimentation rate and chest Xray. Treatments always include chemotherapy and radiotherapy in localized disease and at a low dose only in involved fields. The usually good prognostic of Hodgkin lymphoma may not let us forget that there are still deaths in patients with refractory or early relapse of the disease. There is still an unmet need is these patients and the search for new drugs is essential.

Pauline Brice

Papers

Refractory Hodgkin Lymphoma: Time for Targeted Therapies?

Brigatinib in patients with ALK‐positive anaplastic large cell lymphoma who have failed brentuximab vedotin

Should Adolescents and Young Adults with Hodgkin Lymphoma be Treated As Children or Adults?

L’arrivée de l’immunothérapie dans le lymphome de Hodgkin.

Actualités thérapeutiques dans le lymphome hodgkinien classique