Combo Therapy for Philadelphia Chromosome-Positive ALL Shows Positive Results

Combo Therapy for Philadelphia Chromosome-Positive ALL Shows Positive Results
Acute lymphoblastic leukaemia. Computer illustration showing abundant lymphoblast cells in human blood.

An ongoing study shows that combining ponatinib and blinatumomab provides remarkable complete responses in patients with newly diagnosed or relapsed/refractory Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). Both are usually treated with tyrosine kinase inhibitors (TKI) and systemic chemotherapy, often with the addition of an allogeneic stem cell transplant to reduce the chance of disease recurrence. The findings suggest that this approach may induce complete remission with front-line therapy.

Researchers from the University of Texas MD Anderson Cancer Center found that overall, 95% of patients responded to treatment. The combination produced a response in 100% of newly diagnosed patients; a complete molecular remission rate of 85%. For patients in the relapsed/refractory group, the complete response rate was 89%, while the complete molecular remission rate was 88%. These interim results will be presented at the ASCO meeting in June.

After a median follow-up of 12 months, the estimated two-year event-free and overall survival rate was 93% for the newly diagnosed patients. In the front-line group, no patients received a stem cell transplant and none have relapsed. For relapsed/refractory patients, the two-year event-free survival rate was 41% and the two-year overall survival rate was 53%. Four patients with relapsed/refractory disease underwent an allogeneic hematopoietic stem cell transplant.

“A complete molecular remission is associated with superior outcomes in patients with Philadelphia chromosome-positive ALL,” said study co-author Nicholas Short, M.D. “This trial shows that the combination of ponatinib and blinatumomab produces high rates of complete molecular response, which reduces the chances that patients will relapse and increases the likelihood that they will be disease-free.”

CML and 30% of adult ALL cancers are characterized by the presence of the Philadelphia chromosome. The results include data from 35 patients with Ph-positive ALL or chronic myeloid leukemia in lymphoid blast crisis (CML-LBC). The study evaluated 20 newly diagnosed patients, 10 relapsed/refractory patients and five CML-LBC patients.

Ponatinib is a targeted TKI inhibitor that blocks the abnormal BCR-ABL protein that causes the disease in Philadelphia chromosome-positive ALL. Ponatinib has an advantage over previous generations of TKIs because it is designed to overcome the T3151 gatekeeper mutation which confers resistance against all other approved TKIs over time.

Blinatumomab is a bispecific T-cell targeted antibody. It works by directing cyotoxic T cells to the CD19 protein on ALL.

Both systemic chemotherapy and stem cell transplant can cause significant side effects. This combination may be an option for older or medically frail patients or for those who are not eligible for allogeneic stem cell transplant or those with a TKI-resistant mutation within the BCR-ABL kinase domain.

“It is encouraging that the majority of patients responded to treatment and none of the newly diagnosed patients relapsed or have required a stem cell transplant,” said Short. “These data suggest that we must reevaluate the need for a stem cell transplant in first remission for Philadelphia chromosome-positive ALL, particularly for those patients who achieve a deep molecular response.”