The ASH Annual Meeting took place under a new virtual congress platform from 5–8 December 2020. As the world’s most comprehensive haematology event of the year, the meeting continued its tradition of providing an invaluable educational experience and the opportunity to access updates in the hottest topics in haematology. The mission of ASH is to further the understanding, diagnosis, treatment, and prevention of disorders affecting the blood, bone marrow, and the immunologic, haemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in haematology.

Chemoresistance remains a challenging clinical problem in the treatment of many lymphoma patients, with epigenetic derangements being implicated in both intrinsic and acquired chemoresistance. Jennifer Amengual, New York, explored the use of epigenetics to prime chemoresistant lymphomas. Epigenetic derangements appear to have global effects, simultaneously influencing a greater set of pathways than direct genetic alterations of specific tumour-suppressor genes. The use of epigenetic priming to resensitise chemotherapy causes derangements in multiple epigenetic processes which lead to:

Consequences of epigenetic process derangement

“Recognising patterns of epigenetic derangements in specific disease entities could create an opportunity for precision medicine.”

Jennifer Amengual, New York, USA

Kami Maddocks, Upper Arlington, USA, explored novel approaches in the treatment of aggressive lymphomas, with a focus on non-Hodgkin lymphoma. While targeting CD20 with rituximab has improved survival in patients with aggressive B-cell lymphomas patients progressing through or relapsing after their treatment have a poor prognosis. However, significant progress has been made over the last few years with the emergence of therapies that harness the patient’s immune system to fight disease. The approval of two second-generation chimeric antigen receptor T (CART-T)-cell products – axicabtagene ciloleucel and tisagenlecleucel – offers potential for curative therapy, although challenges remain with toxicities and access. A number of novel therapies are active but have limited single-agent activity, and durable responses will require combination therapy. Novel combinations targeting biologic drivers of disease are of high interest.

Potential therapeutic targets for aggressive lymphomas

“Targeting CD19 with other immunotherapies remains attractive, with additional agents showing promising responses and favourable toxicity profiles.”

Kami Maddocks, Upper Arlington, USA

Significant challenges remain in the delivery of care for patients with aggressive lymphomas. These include the appropriate application of treatment advances to older patients with significant comorbidities, selection of effective treatments for patients with relapsed/refractory T-cell lymphomas, and timely integration of palliative care with disease-directed care. Around 40% of patients with diffuse large B-cell lymphoma (DLBCL) are aged over 70 years, meaning that frailty and comorbidities may limit treatment options. Nancy Bartlett, Saint Louis, USA, explored the challenges of providing intensive treatment for patients with aggressive B-cell lymphomas who are aged >80 years or have significant comorbidities. These factors typically preclude the use of standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), with prednisone, vincristine, and doxorubicin each posing special risks to vulnerable patients. In addition, clinical trials often exclude the oldest and least fit patients, and no prospective randomised studies have yet addressed the appropriate regimen for this population.

The assessment of ‘fitness’ in this population also remains subjective, with no consensus on best practice or how to integrate suitable tools into medical decision making. Dr Bartlett suggested that the incorporation of prephase steroids for all unfit patients may markedly improve performance status (PS) with consideration of standard dose therapy, especially in patients aged <80 years, with decisions regarding treatment reassessed based on PS after prephase. Available data suggest that patients aged ≥80 years and those with significant limitations of activities of daily living do not benefit from full-dose chemotherapy and should be treated with R-miniCHOP or an anthracycline-free regimen. If an anthracycline-based regimen is selected, a multidisciplinary approach including a cardiologist should be considered for all unfit and older patients, with cardiovascular profiling and risk stratification before treatment if feasible. When anthracyclines are contraindicated, one approach could be to simply omit the doxorubicin and administer R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone). Replacing doxorubicin with an alternative active, but less toxic agent, such as etoposide or gemcitabine, is also an option.

“Unfit patients with aggressive lymphomas often benefit from co-management with gerontologists, cardio-oncologists, and endocrinologists depending on age and the nature of comorbidities.”

Nancy Bartlett, Saint Louis, USA

Gilles Salles, Lyon, France, explored the different therapeutic options currently available for the first-line treatment of follicular lymphoma, along with sequencing of therapy following subsequent progression. Despite numerous studies, there remains no single standard of care for patients undergoing second-line treatment or beyond, with patients recruited into these studies typically having characteristics that rarely represent the full spectrum of possible clinical presentations. Thus, the optimal individualisation of treatment requires the physician to weigh the benefits and risks of each available option and define the goals of therapy. Several parameters should be evaluated:

Parameters to consider for individualisation of treatment

For patients with no formal indication for treatment (low tumour burden, asymptomatic, and no rapid clinical progression), watchful waiting remains the standard course. However, rituximab single-agent therapy has become a popular option for these patients. Combinations of either bendamustine, CHOP, or CVP with rituximab (R-benda, R-CHOP, and R-CVP, respectively) or obinutuzumab (O-benda, O-CHOP, and O-CVP) make up the current standard treatment options for patients with a high tumour burden. First-line treatment choice can have significant consequences for potential next sequences. For chemotherapy-naive patients (treated with radiation therapy or rituximab single-agent therapy who need a new line of treatment), the next sequence typically consists of an immunochemotherapy regimen in most cases. For those patients who initially receive immunochemotherapy, an alternative cytotoxic regimen such as one combined with an anti-CD20 antibody may be proposed. In cases where CHOP or CVP was used as the chemotherapy backbone in the first-line setting, bendamustine is a popular choice. O-benda followed by obinutuzumab maintenance has become an established therapeutic option for patients with rituximab-refractory disease who have previously received R-CVP or R-CHOP. For patients receiving a third line of therapy or beyond, several new options are available, such as the PI3K inhibitors.

“Not all patients with progressive disease need a therapeutic intervention.”

Gilles Salles, Lyon, France

ASH 2020 was a successful meeting with attendees able to remotely access new data and insights, which will hopefully stimulate new ways of thinking and ultimately translate into optimal patient care within the haematology field. In addition, the virtual format provided the opportunity for participants, particularly those outside the US, to attend ASH perhaps for the first time. This revised format for 2020 will have also enabled more institutions around the world to gain access to the meeting content.