Does adjunctive therapy with the BTK inhibitor acalabrutinib, in addition to standard immunochemotherapy with R-miniCHOP, improve survival in older patients with diffuse large B-cell lymphoma (DLBCL)?

Diffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma, a specific group of malignant blood disorders. The disease results from the uncontrolled growth of B cells, a subtype of white blood cells that are part of the immune system. It usually manifests as swollen lymph nodes and general symptoms such as fatigue and weakness. A standard treatment frequently used is immunochemotherapy following the R-CHOP regimen, which includes the antibody rituximab and a combination of several chemotherapy drugs (cyclophosphamide, doxorubicin, vincristine, prednisone). This treatment is usually highly effective, but it is often too intensive for older patients or those with underlying health conditions. Therefore, a milder version with a lower dose—known as R-miniCHOP—is frequently used for these patients.  The drug acalabrutinib is a so-called Bruton’s tyrosine kinase inhibitor (BTK inhibitor) that specifically blocks signaling pathways necessary for the growth of lymphoma cells. This ultimately destroys the cells. It belongs to the “second generation,” meaning it has been further developed from comparable drugs to make it even more effective than other BTK inhibitors. Acalabrutinib is already approved for other forms of lymphoma, but not for DLBCL.

The goal of the ARCHED study is to investigate whether the combination of acalabrutinib with a reduced dose of the standard therapy (R-miniCHOP) is more effective and well-tolerated in older adults with DLBCL. The study is a randomized, open-label Phase 3 trial with two treatment groups: One group receives the standard treatment consisting of 6 cycles of R-miniCHOP and 2 cycles of rituximab. The second group also receives 6 cycles of R-miniCHOP and 2 cycles of rituximab, plus acalabrutinib over a period of 8 cycles. Patients are randomly assigned to one of the groups and are aware of which group they are in (open-label). The treatment lasts approximately 24 weeks (8 cycles of 21 days each). The study will then monitor patients for up to 5 years to assess how effective the treatment with acalabrutinib was compared to R-miniCHOP alone.

Patients aged 61 and older who have been newly diagnosed with DLBCL and who, due to age or health status, are not eligible for a full dose of R-CHOP may participate in the study. Patients must not have previously received therapy with another BTK inhibitor. The study is primarily aimed at patients with DLBCL; however, patients with any of the following conditions may also participate: primary cutaneous DLBCL, intravascular large B-cell lymphoma, EBV-positive DLBCL, unspecified, HHV-8-positive DLBCL, unspecified, primary mediastinal (thymic) large B-cell lymphoma, B-cell lymphoma with intermediate features between DLBCL and classical Hodgkin lymphoma, grade 3B follicular lymphoma, high-grade B-cell lymphoma, unspecified, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, T-cell/histiocyte-rich large B-cell lymphoma, DLBCL associated with chronic inflammation, ALK-positive large B-cell lymphoma, and large B-cell lymphoma with IRF4 rearrangement.