Preface – ASH 2022

©Lebens.Med Zentrum Bad Erlach – Stefan Vogt, MD, Lebens.Med Zentrum Bad Erlach, Department of Oncological Rehabilitation, Austria

Dear Colleagues,

The 64th Annual Meeting of the American Society of Hematology (ASH) took place as a hybrid event that hosted participants both online and on-site in New Orleans, Louisiana, USA. Among the multitude of updates and new insights presented from December 10th to 13th, 2022, attendees had access to thousands of scientific abstracts highlighting cutting-edge research in hematology. Thus, this issue of memo inHaematology summarizes results obtained for targeted ­therapies in B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, Waldenström’s macro­globulinemia, follicular lymphoma, and diffuse large B cell lymphoma (DLBCL), as well as acute myeloid leukemia.

The initial treatment in various types of hematologic malignancies is continuously evolving due to the introduction of new targeted agents, either as monotherapy or in combination with other agents, allowing for response-adapted adjustment of treatment intensity to minimize toxicity. While in the relapsed/refractory setting, the therapeutic options following chemoimmunotherapy and covalent BTK inhibitor therapy are often limited, new potential strategies such as non-covalent BTK inhibitors or checkpoint inhibition are on the horizon.

In CLL patients, the second-generation BTK inhibitor zanubrutinib and the combination of ibrutinib and venetoclax are gaining ground, as well as a triplet consisting of BTK- and Bcl-2-inhibition and CD20-targeted therapy. Another class of drugs showing synergistic effects with venetoclax is PI3K-δ/γ inhibitors which are also highlighted in this report. Potential advances are further described in the setting of DLBCL.

The need for novel, efficacious and well tolerated agents is especially high for advanced-stage follicular lymphoma. This report outlines data from promising bispecific antibody, oral PI3Kδ and BTK inhibitor regimens alone or in combination with other agents. Moreover, results for monotherapies and combinations in patients with mantle cell lymphoma are reported.

Last but not least, this issue looks closely at the efficacy and safety of new agents for the treatment of patients with acute myeloid leukemia whose standard therapy has long consisted of intensive chemotherapy followed by allogeneic hematopoietic stem cell transplant.

Once again, the ASH meeting facilitated the exchange of scientific information and clinical results related to the field of hematology while assisting physicians and scientists in developing and maintaining academic collaborations to generate new knowledge, ultimately benefiting patients.

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Clinical findings with sundry targets in various B-cell malignancies

Recurrent follicular lymphoma (FL) and marginal zone lymphoma (MZL) are treated similarly, mostly with single-agent rituximab. In patients with relapsed/refractory FL, the combination of lenalidomide with rituximab (R2) has previously demonstrated promising efficacy. The multicenter, double-blind, randomized, phase III AUGMENT study was initiated to compare time-limited treatment for approximately one year with R2 vs. rituximab plus placebo in patients with FL grade I-IIIa or MZL who had already received ≥ 1 prior systemic chemotherapy, immunotherapy or chemoimmunotherapy but who were not refractory to rituximab.

Follicular lymphoma: bispecific and PI3Kδ-targeted approaches

Advanced-stage follicular lymphoma (FL) remains incurable, with most patients eventually experiencing disease progression despite therapeutic advances. Relapsed or refractory FL is challenging to treat, particularly in high-risk patients who are refractory to prior treatments and have progressed within 24 months. The combination of rituximab and lenalidomide (R2) is commonly used in this setting, although complete response (CR) rates are suboptimal.

New approaches in relapsed and refractory DLBCL

Approximately one third of patients with diffuse large B-cell lymphoma (DLBCL) develop relapsed or refractory disease, which remains a major cause of mortality. In patients relapsing more than 1 year after first-line treatment, the standard of care is salvage treatment followed by autologous stem cell transplantation (ASCT), although responses to platinum-based salvage therapy are generally suboptimal.

Chronic lymphocytic leukemia: moving towards new horizons

The first-in-class, covalent BTK inhibitor ibrutinib has transformed the treatment of patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). However, toxicities frequently lead to treatment discontinuation. Moreover, exposure coverage between dosing intervals falls below the IC50 threshold, and BTK occupancy at trough levels is variable.

Further steps to improve efficacy and safety in acute myeloid leukemia

Venetoclax 400 mg QD in combination with azacitidine 75 mg/m2 on days 1–7 has been approved for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy based on the phase III VIALE-A trial that met its primary endpoint of overall survival (OS) at the time of the interim analysis conducted in March 2020.

Active monotherapies and combinations in mantle cell lymphoma

The initial treatment of patients with mantle-cell lymphoma (MCL) is continuously evolving due to the introduction of new targeted agents. Ruan et al. conducted a single-arm phase II study based on the hypothesis that the addition of the next-generation BTK inhibitor acalabrutinib to lenalidomide plus rituximab (ALR) would synergize activity and accelerate minimal residual disease (MRD)-negative complete response (CR), thus allowing for response-adapted adjustment of treatment intensity to minimize toxicity.