Preface – ASH 2021

Mehta headshot© author’s own

Amitkumar Mehta, MD, Division of Hematology and Oncology, University of Alabama at Birmingham, USA

Dear Colleagues,

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. 

Clinical trials show that chemotherapy-free regimens based on the inhibition of targets such as BTK, BCL2, CD20 and PI3Kδ continue to induce superior outcomes compared to the previous chemo(immuno)therapy-based standards. BTK inhibitors have been a mainstay of treatment from the beginning of the targeted era. While later-generation representatives of this and other drug classes are being investigated as they offer improved efficacy and tolerability profiles over first-generation agents, other compounds such as bispecific antibodies and antibody-drug conjugates are gaining ground in various B-cell malignancies. Newer agents enable us to further increase patient responses even in later lines. 

Potential advantages of modern targeted therapies include their ability to overcome unfavorable cytogenetics and the possibility of limited-duration treatment while providing long-term disease control. Approaches that are driven by the achievement of undetectable minimal residual disease might allow for ­tailored therapy in broad patient populations in the future, thus avoiding overtreatment and unnecessary health expenditures while addressing patient groups with the highest risk. From an economic point of view, adequate and timely treatment is important in these diseases that tend to relapse repeatedly over the course of years, with hospital treatment in particular incurring substantial costs. Local implementation of new insights in the best possible manner will enable us to reduce the significant burden of disease at both the ­patient and the societal level.

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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.

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.

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.

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.

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.

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.