GMALL-EVOLVE - Optimizing Treatment for Acute Lymphoblastic Leukemia Through a Randomized Trial Comparing Different Treatment Regimens Using Blinatumomab and Ponatinib Versus Imatinib

Acute lymphoblastic leukemia (ALL) is a malignant disease of the blood-forming cells characterized by the uncontrolled production of malignant blasts in the bone marrow and blood. Blasts are an immature form of white blood cells that are part of the body’s immune system. The overproduction of these abnormal blasts disrupts blood formation and the immune response. More than half of patients have swollen lymph nodes and an enlarged spleen. The exact cause of ALL is not fully understood, but genetic mutations and environmental factors play a role. A genetic alteration that occurs in about 30% of adult patients with ALL is the Philadelphia chromosome (Ph+ ALL), in which segments of two chromosomes are exchanged, resulting in the abnormal BCR-ABL1 gene. This gene causes leukemia cells to grow uncontrollably, making the disease more aggressive. However, the altered gene can also be specifically targeted with special medications (tyrosine kinase inhibitors).

Standard treatment begins with what is known as induction therapy, a combination of tyrosine kinase inhibitors (TKIs) and chemotherapy. TKIs include imatinib, the first approved TKI, which remains the drug of choice (first-line therapy), and ponatinib, which is more effective against resistance but is currently used only when other treatments have failed. This is followed by consolidation therapy, which is intended to maintain treatment success and reduce the risk of relapse. During this phase, TKIs continue to be used, and blinatumomab (a so-called bispecific antibody) and chemotherapy are often administered in addition. A bispecific antibody activates the immune system by directing the body’s own immune cells directly to the cancer cells so that they can be attacked. During treatment, minimal residual disease (MRD) is regularly measured to determine whether leukemia cells are still detectable. The effectiveness of the treatment is also measured by the molecular response rate. Following these phases of therapy, a stem cell transplant (SCT) from donors (allogeneic) is performed to permanently replace the diseased blood cells with healthy donor cells. To date, SCT has been recommended in the guidelines for nearly all patients. For older patients, however, SCT may be omitted under certain circumstances even within the framework of guideline-based treatment.

The goal of the GMALL-EVOLVE study is to evaluate first-line treatment for Ph+ ALL during the induction phase and then to compare the efficacy and safety of treatment without a stem cell transplant against standard therapy.

To this end, patients will first be randomly assigned to two groups (Randomization 1). In the experimental study arm, they will receive the tyrosine kinase inhibitor (TKI) ponatinib in combination with chemotherapy. Ponatinib is already approved, though not yet for first-line therapy. In the control arm, patients receive the current standard of care, a combination of imatinib and chemotherapy. The study is open-label, meaning that patients and medical staff know which medications they are receiving. Following this induction treatment, the patients’ response is assessed (MRD, molecular response rate), and patients are treated based on the success of the therapy. In the event of a complete remission (molecular complete response), the patients are once again randomly assigned to 2 groups (Randomization 2). In the experimental arm of the study, patients receive treatment with the TKI they also received in the previous phase (imatinib or ponatinib), combined with chemotherapy and blinatumomab. Blinatumomab is approved for ALL in certain situations; however, in this context, the treatment is experimental. In the control arm, patients receive the standard treatment, namely a stem cell transplant. Assignment is also open-label; patients and medical staff know which study arm they are in. If the disease has not gone into remission after induction therapy (molecular failure), patients continue with their assigned TKI (imatinib/ponatinib) and additionally receive blinatumomab, as in the experimental arm after randomization 2, but without additional chemotherapy. This is followed by standard-of-care treatment with a stem cell transplant, which is no longer part of the study.

Follow-up within the study lasts for up to 4 years; data are collected at specific time points, such as after the end of the treatment phases.

Women and men between the ages of 18 and 65 with untreated ALL are eligible to participate in the study. The ALL must be Philadelphia chromosome-positive or BCR-ABL1-positive. The disease must not have been treated previously. Certain prior pre-phase treatments are theoretically possible.