A chemotherapy-free regimen combining ponatinib (Iclusig) and blinatumomab (Blincyto) has shown promising results in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), achieving high rates of deep minimal residual disease (MRD) negativity and durable remissions. The findings, presented at the American Society of Hematology (ASH) annual meeting, suggest a potential shift away from traditional chemotherapy-based approaches and stem cell transplantation in this patient population.
The phase II study, led by Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center, involved 76 patients with newly diagnosed Ph+ ALL. The treatment protocol consisted of five cycles of blinatumomab in combination with ponatinib, initiated at 30 mg daily and subsequently reduced to 15 mg daily upon achieving MRD negativity. Patients then received at least 5 years of ponatinib maintenance.
High Response Rates and MRD Negativity
The results demonstrated a high overall response rate, with nearly all patients responding to the treatment. Notably, 98% of patients achieved MRD negativity, as determined by next-generation sequencing (NGS) with a sensitivity of 1 × 10-6. This deep level of response is a key indicator of long-term remission and improved survival outcomes.
Survival Benefits and Reduced Transplant Needs
Updated survival data revealed a 3-year overall survival rate of 88% with this regimen. A significant advantage of the chemotherapy-free approach was the reduced need for stem cell transplantation. Only two of the 76 patients underwent transplantation, highlighting the potential of this regimen to spare patients from the toxicities and complications associated with chemotherapy and transplant.
Predictors of Relapse
Despite the promising results, 10 patients (13%) experienced relapse. To identify potential predictors of relapse, the researchers conducted genomic sequencing and analyzed various clinical and genetic factors. Univariate analysis identified elevated white blood cell count (above 70,000 at diagnosis), the presence of a VPREB1 deletion, and central nervous system (CNS) disease at diagnosis as predictive factors for relapse. However, multivariate analysis identified high white blood cell count as the only independent predictor of relapse.
"So these are patients that we now consider as high risk for relapse with this regimen. In fact, these patients had a cumulative incidence of relapse of almost 50%," Dr. Short noted.
Future Directions for High-Risk Patients
The identification of high-risk patients based on white blood cell count has prompted the investigation of novel strategies to further reduce the risk of relapse. CAR T-cell consolidation is being considered as a potential approach to improve outcomes in this subgroup. The researchers aim to continue avoiding transplant for these patients while exploring additional strategies to enhance remission durability.
"We're now investigating other strategies for this high-risk population and considering novel strategies, such as potentially CAR T-cell consolidation. And we're still trying to avoid transplant for these patients, but we do need more strategies to reduce the risk of relapse."
