Combination therapy with venetoclax and blinatumomab for relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL)

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a malignant disease of the hematopoietic system characterized by the uncontrolled production of white blood cell precursors (blasts) in the bone marrow. Depending on the type of blood cells affected or the stage of their development, different types of ALL are distinguished. A common form is B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The overproduction of blasts disrupts normal blood formation and the immune system. In BCP-ALL, other organs or the central nervous system may also be affected. Consequently, fatigue, anemia, blood clotting disorders, fever, and an increased susceptibility to infections may occur. The exact cause of BCP-ALL is not fully understood; genetic mutations and environmental factors play a role. As part of the diagnostic process, tests are conducted to determine which surface receptors are expressed on the cancer cells (e.g., the CD19 protein). The standard treatment for BCP-ALL is divided into several phases: pre-induction, induction, consolidation, and maintenance therapy. The goal of induction therapy is to achieve complete remission. Consolidation and maintenance therapy serve to sustain remission with the goal of complete recovery. In certain situations, a stem cell transplant may also be required as part of the treatment. Ideally, the treatment is so successful that no diseased cells can be detected, even using molecular genetic testing methods. Over time, the disease may recur (relapse) or may no longer respond to treatment (refractory). If the relapse is detectable only through molecular genetic testing, it is referred to as “MRD-positive,” as opposed to a situation where blasts are already detectable again through a standard blood test. One drug that has proven effective in this situation is blinatumomab. Blinatumomab is a so-called bispecific antibody that binds simultaneously to immune cells and to the CD19 protein on the tumor cells. The drug is already approved for the treatment of ALL. Another drug is venetoclax. Venetoclax blocks the Bcl-2 protein on tumor cells, thereby inhibiting their growth and inducing cell death. The active ingredient is not yet approved for the treatment of ALL, but is already being used successfully for other forms of leukemia.

The goal of the GMALL-BLIVEN study is to investigate the efficacy and safety of the combination therapy of venetoclax and blinatumomab. The question addressed by this Phase 1/2 study is therefore whether the combination of both drugs provides additional benefit for patients. In Phase 1 of the study, the maximum tolerated dose (MTD) of the combination therapy will be determined. To this end, defined groups of patients will be formed and treated with specific dosages. Depending on tolerability, this phase may last up to 1 year. In Phase 2, up to two treatment cycles will be administered to a larger group of patients, and the response rate will be assessed 43 days after the first cycle. The study is open-label, meaning that both the medical staff and the patients know which medications are being administered. The treatments and follow-up visits as part of the study continue for up to approximately 3 years, during which the efficacy of the therapy and the occurrence of side effects from the various medications are evaluated. The primary endpoint of the Phase 2 study is complete molecular remission. There are two groups within Phase 2, although the treatment is the same for both groups. The focus here is on determining to what extent the disease can be or was suppressed (distinguishing between clinical and molecular relapse/refractoriness).

Patients aged 18 and older with BCP-ALL are eligible to participate in this study. The disease must have been previously treated and must show signs of relapse or be refractory. For treatment purposes, a distinction is made based on whether disease progression was detected through molecular genetic testing or blood tests. Furthermore, the disease must be CD19-positive and Philadelphia chromosome-negative. There must be no involvement of the central nervous system.