Study in Adult Ph-positive ALL

Acute lymphoblastic leukemia (ALL) develops when a certain type of immature bone marrow cell called a lymphoblast becomes malignant, resulting in uncontrolled growth and suppression of normal blood cell development. Leukemic blast cells accumulate in the bone marrow and blood and may involve other organs such as the central nervous system (CNS). The most frequent subtype of ALL observed in adults is caused by a genetic aberration called a Philadelphia (Ph) chromosome and is thus referred to as Ph+ ALL. In this type of ALL, a gene called BCR and a gene called ABL are fused by a process known as translocation. This leads to formation of an atypical gene called BCR-ABL and formation of a protein known as the BCR-ABL oncoprotein. This protein, a so-called tyrosine kinase, activates and disrupts many signaling pathways in the cell and is directly responsible for the development of Ph+ ALL, which is one of the most aggressive types of leukaemia.

Treatment options for Ph+ ALL were much improved by a family of drugs called tyrosine kinase inhibitors (TKI), which bind to - and block the activity of - the BCR-ABL kinase. The first of these drugs to be developed is called imatinib (brand name glivec), which has become a standard component of therapy for Ph+ ALL worldwide, usually combined with steroids and/or cytotoxic chemotherapy typically used for ALL. In the vast majority of patients, this treatment is initially able to reduce the burden of the disease to a very low level (complete remission). Unfortunately, the leukemic cells eventually become resistant to imatinib, causing the disease to reappear (relapse). A commonly observed mechanism of resistance to TKI is the development of mutations in the BCR-ABL gene, as a result of which the drug can no longer bind to the kinase, leading to its reactivation. For this reason, stem cell transplantation from a sibling or unrelated donor is considered the most effective treatment to achieve cure.

In the last couple of years, 2nd generation TKI (Dasatinib and Nilotinib) which are more active than imatinib have been tested in clinical trials in patients with Ph+ ALL. Although these newer TKI show activity towards mutated BCR-ABL not inhibited by imatinib, the same basic mechanisms of resistance apply to these drugs, and they have not been shown to result in substantially longer survival than imatinib. In particular, a BCR-ABL mutation known as T315I has been recognized to cause resistance to all approved 1st and 2nd generation TKI.

More recently, a highly potent 3rd generation TKI called ponatinib has been developed and is the only approved TKI shown to be active against the T315I and all other resistance mutations. Initial studies combining ponatinib with chemotherapy have shown excellent response rates and promising survival in adult patients with newly diagnosed Ph+ ALL. However, in this group of patients ponatinib has not yet been directly compared with any of the other drugs, and there may be a moderately increased risk of vascular and cardiac adverse events, such as heart attacks, strokes or thrombosis.

Based on existing data, ponatinib shows great promise for treatment of Ph+ ALL, but its superiority over standard imatinib-based therapy in terms of long-term efficacy and safety need to be proven.

It is the main purpose of this trial to determine whether ponatinib is superior to imatinib when combined with the same chemotherapy that is considered a standard for elderly patients with Ph+ ALL. The study hypothesis is that a greater proportion of patients in the ponatinib arm will achieve a deep (molecular) response, and that survival without leukemia relapse will be superior. The side effects, safety and tolerability of the two treatment regimens will also be compared.

A second trial question will explore whether chemotherapy can be omitted from the treatment regimen by replacing it with an immunotherapy drug called blinatumomab. This is a type of antibody that activated the patient´s own immune cells (T-cells) and directs them to the leukaemia cells, which are then destroyed. This type of treatment has been very effective in patients with ALL that did not respond or returned after other types of therapy, and has been approved in the EU and USA as salvage therapy for ALL. By combining two very different types of targeted therapy, the TKI ponatinib and the antibody blinatumomab, we hope to deliver highly effective therapy for Ph+ ALL while eliminating the toxicity of chemotherapy.

To be able to compare these treatments, patients will be randomly assigned to the three treatment arms in a 1:1:1 ratio, i.e. the likelihood to be assigned to each of the treatment groups is the same. Overall duration of study treatment will be 2 years, followed by treatment with the TKI alone.