ASH 2021 – virtual
Shirley D’Sa discusses the results of the first clinical trial investigating checkpoint inhibition in relapsed/refractory Waldenström’s macroglobulinemia as well as other immunotherapeutic agents or combinations that might be worth investigating in this setting and explains the association of type I cryoglobulinemia with WM, IgM monoclonal gammopathy of undetermined significance or non-Hodgkin Lymphoma.
Preface
The 63rd Annual Meeting of the American Society of Hematology (ASH) took place as a hybrid event that hosted participants both online and on-site in Atlanta, Georgia, USA. Among the multitude of updates and new insights presented from December 11 to 14, 2021, results obtained for targeted therapies in B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, Waldenström’s macroglobulinemia, and marginal zone lymphoma are summarized in this issue of memo inHaematology.
Determining first-line CLL/SLL treatment strategies with optimized efficacy and safety
The international, randomized, phase III GAIA/CLL13 study was conducted to identify the optimal time-limited first-line treatment regimen for fit patients with chronic lymphocytic leukemia (CLL). Standard chemoimmunotherapy (CIT) consisting of fludarabine, cyclophosphamide and rituximab (FCR; patients ≤ 65 years) or bendamustin plus rituximab (BR; patients > 65 years) was compared to venetoclax-based, limited-duration strategies.
Management of patients with relapsed/refractory CLL: what is new?
The optimal novel-agent approach for patients with chronic lymphocytic leukemia (CLL) is subject to research. Targeted therapies have become the undisputed standard of care in both relapsing/refractory and treatment-naïve settings. The choice of regimen remains, however, disputable. Continuous BTK inhibition confers the risk of cumulative toxicity and acquired resistance, while time-limited combination therapies may result in relatively high adverse event (AE) rates and lead to overtreatment of patients with favorable risk.
Mantle cell lymphoma: refining clinical outcomes beyond the current boundaries
Targeted therapies including BTK inhibitors are used in the second- and later-line treatment of patients with mantle cell lymphoma (MCL), although intolerance and treatment failure are common, with poor survival outcomes in the relapsed and refractory setting. This highlights the need for novel agents such as the potent and highly selective next-generation PI3Kδ inhibitor parsaclisib.
Marginal zone lymphoma: PI3Kδ inhibition and beyond
First-line treatment for patients with marginal zone lymphoma (MZL) typically includes anti-CD20-based regimens that generally evoke high response rates. However, in most cases, serial relapses eventually require several lines of therapy. The phase II CITADEL-204 trial evaluated the highly selective, next-generation PI3Kδ inhibitor parsaclisib in patients with relapsed/refractory MZL with or without prior exposure to ibrutinib.
Phase II data on novel BTK inhibitors for patients with Waldenström’s macroglobulinemia
Second-generation BTK inhibitors such as orelabrutinib and tirabrutinib are currently being evaluated in the treatment of Waldenström’s macroglobulinemia (WM). Orelabrutinib is a BTK inhibitor with excellent target selectivity and almost 100 % BTK occupancy. At ASH 2021, Zhou et al. reported the results for 47 patients with relapsed/refractory WM who received orelabrutinib 150 mg/d in the single-arm, multicenter, open-label, phase II ICP-CL-00105 study.
Promising novel approaches in various B-cell malignancies
For more than 20 years, the R-CHOP regimen consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone has been the standard of care in the first-line treatment of diffuse large B-cell lymphoma (DLBCL). However, as only 60-70 % of patients achieve cure, there is a need to improve on these results. The antibody-drug conjugate polatuzumab vedotin that targets CD79b has already shown activity in combination with rituximab or obinutuzumab plus cyclophosphamide, doxorubicin, and prednisone (CHP) in a phase II study conducted in the first-line setting of DLBCL.
Real-world risk assessment, outcomes and adoption of novel drugs in CLL patients: insights from US databases
Prognostic testing including IGHV mutation status, cytogenetic abnormalities by FISH, and immunophenotyping has been recommended after diagnosis of CLL/SLL prior to treatment initiation. This also applies to previously treated patients in some settings. As disease with high-risk genetic features is better managed with novel agents than with chemoimmunotherapy, the need for testing has recently become more relevant as all patients are advised to complete risk-factor testing for both prognostication and selection of optimal, evidence-based therapy.
EXPERT VIDEOS
All video interviews from ASH 2021
Constantine Tam gives an overview of the results obtained by the SEQUOIA trial, the advantages and disadvantages of BTKi and BCL2i 1L therapy versus their drawbacks and explains which CLL-patients might benefit from BTK inhibitor monotherapy and who might be better off receiving combination treatment including a BTK inhibitor and how novel BCL2 inhibitors improve CLL treatment compared to the standard agent venetoclax.
Jennifer A. Woyach explains which factors need to be considered when choosing the frontline regimen for patients with early-stage CLL, how resistance to BTK inhibition can be tackled in later lines, if chemoimmunotherapy still has a role in the treatment of CLL and highlights the most interesting findings on the management of treatment-naïve CLL patients.
Paolo Ghia highlights what modern targeted agents can achieve in terms of undetectable minimal residual disease in the management of patients with CLL and important methodological recommendations to ensure correct assessment of TP53 and IGHV mutational status. He explains how the three epigenetic subgroups (m-CLL, n-CLL, i-CLL) are related, what effect a thorough immunogenetic analysis has on the risk stratification of patients with CLL and gives an overview about the most interesting findings on the management of pretreated CLL patients.
Alessandra Tedeschi depicts her personal highlights reported at ASH 2021 and explains the results obtained in treatment-naïve CLL patients with a deletion of 17p in the SEQUOIA study. The influence of age, fitness, and concomitant medications on the management and outcomes of patients with CLL treated with targeted agents, the most notable progress in B-cell malignancies over the last years and the role of BTK inhibitors in the treatment of patients with Waldenström’s macroglobulinemia are summarized, too.