New Triple-Drug Combination Therapy with Acalabrutinib, Obinutuzumab, and Venetoclax for Untreated High-Risk Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a type of blood cancer characterized by the uncontrolled proliferation of B lymphocytes in the bone marrow. Lymphocytes are a type of white blood cell that is part of the immune system. In CLL, the lymphocytes are released into the bloodstream. If, instead, the lymphocytes are found primarily in the lymph nodes and the spleen, the condition is referred to as small-cell lymphocytic lymphoma (SLL), which is grouped together with CLL under a single clinical classification. CLL is a type of non-Hodgkin lymphoma; it typically grows slowly and occurs primarily in older adults. The causes of CLL are not yet fully understood, but genetic factors play a role (this refers to acquired genetic changes in the cancer cells, not inheritance from parents to a child). Treatment depends on the severity of the symptoms and the patient’s overall physical condition. If patients show no symptoms, treatment is generally not initiated; instead, regular monitoring (“watch and wait”) is performed. In cases of symptomatic disease, standard therapy depends on the presence of certain risk factors, which are determined by genetic testing of the affected cells. Typically, a combination of immunotherapy and chemotherapy is used as first-line therapy.

If specific genetic alterations are detected (17p deletion, TP53 mutation, or complex karyotype), the disease is classified as high-risk CLL. This requires a tailored approach to treatment selection. The standard treatment in these cases is immunotherapy, for example with the new drug acalabrutinib or obinutuzumab plus venetoclax. There are various treatment regimens and combination options for these drugs. The combination of acalabrutinib, venetoclax, and obinutuzumab has not yet been established, although all three drugs are approved for the treatment of CLL/SLL.  Acalabrutinib is a so-called Bruton’s tyrosine kinase inhibitor (BTK inhibitor), which inhibits the proliferation of cancer cells. Venetoclax is a so-called Bcl-2 inhibitor, and obinutuzumab is an antibody that targets the CD20 surface receptor on B lymphocytes. All of these drugs directly or indirectly induce the death of cancer cells.

The goal of this Phase 3 study is to investigate the efficacy and safety of the combination immunotherapy of acalabrutinib, venetoclax, and obinutuzumab in a larger number of patients. The treatment is administered as first-line therapy; therefore, the patients have not yet received any prior treatment. As part of the study, patients are randomly assigned to two groups. Group 1 receives the combination immunotherapy consisting of acalabrutinib, venetoclax, and obinutuzumab for up to 24 cycles of 28 days each, although not all medications are administered in every cycle. Group 2 receives a combination therapy consisting of venetoclax and obinutuzumab over 12 cycles. The study is open-label, meaning that both the medical staff and the patient know which medications are being administered. Treatments and follow-up visits as part of the study will continue for up to 50 months, during which the effectiveness of the therapy and the occurrence of side effects from the various medications will be evaluated. The key factor is whether or when the disease progresses again during therapy (progression-free survival). The primary endpoint of the study is the survival rate without disease progression for up to 50 months after treatment of the first participant.

Patients aged 18 and older with CLL or SLL are eligible to participate in this study. The disease must not have been previously treated and must have at least one high-risk genetic factor (17p deletion, TP53 mutation, complex karyotype).