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.

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.

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. 

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