A novel frontline treatment combining dasatinib with sequential CAR T-cell therapy has demonstrated remarkable efficacy in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), achieving an 85% complete molecular remission rate in a phase 2 clinical trial published in JAMA Oncology.
The single-arm study, conducted at the First Affiliated Hospital of Zhejiang University School of Medicine, enrolled 28 patients with newly diagnosed Ph+ ALL between March 2021 and April 2024. All patients completed a 2-week induction treatment with vindesine, dexamethasone, and continuous dasatinib at 100 mg daily, achieving a 100% complete hematological remission (CHR) rate and a 25% complete molecular remission (CMR) rate.
Treatment Protocol and Patient Outcomes
Following induction therapy, 27 patients received CD19-targeted CAR T-cell therapy at a target dose of 2 × 10⁶ cells/kg after lymphodepletion with fludarabine and cyclophosphamide. The CMR rate increased dramatically to 85% (95% CI, 66%-96%) post-CD19 CAR T-cell therapy, significantly exceeding the prespecified critical value of P < .001.
Twenty-five patients subsequently completed sequential CD22-targeted CAR T-cell therapy, achieving a CMR rate of 76% (95% CI, 55%-91%). The sequential approach was designed based on previous evidence showing reduced relapse rates in relapsed/refractory B-cell ALL.
"The results of this trial suggest that the combination of CAR T-cell therapy and dasatinib was associated with encouraging efficacy and acceptable toxic effects as frontline therapy in adults with newly diagnosed Ph-positive ALL," wrote lead author Mingming Zhang, MD, PhD, and colleagues.
Long-term Survival and Safety Profile
At a median follow-up of 23.9 months, the treatment demonstrated impressive durability. The 2-year overall survival and leukemia-free survival rates both reached 92% (95% CI, 82%-100%). At the data cutoff date, 78% of patients remained in complete molecular remission, while 4 patients maintained durable BCR/ABL1-positive complete hematological remission.
The safety profile proved favorable, with hematologic toxicities being the most common grade 3 or higher adverse events, attributed to induction and lymphodepletion. Of the 52 CAR T-cell therapies administered, only 21 cases of grade 1 cytokine release syndrome occurred, with no cases of immune effector cell-associated neurotoxicity syndrome reported.
Patient Characteristics and Risk Factors
The study population had a median age of 48.5 years, with 64% being male. The median white blood cell count at diagnosis was 19,400 μL, and 57% had the p190 fusion protein. Additional genetic abnormalities included IKZF1 alterations (21%), PAX5 rearrangements (7%), and various other mutations.
Notably, patients with baseline IKZF1 alterations showed significantly inferior outcomes, with both overall survival and leukemia-free survival rates of 66.7% compared to 100% in patients without these alterations (P = .01 for both comparisons). Two hematological relapses occurred during follow-up, both in patients with baseline IKZF1 deletions who subsequently died of disease progression.
Clinical Implications and Future Directions
The study represents the first trial evaluating CAR T-cell therapy combined with dasatinib as frontline treatment for newly diagnosed Ph+ ALL. The results compare favorably to recent trials investigating tyrosine kinase inhibitors with blinatumomab, which achieved molecular response rates of 60% to 87% and 3-year leukemia-free survival rates higher than 75%.
An additional potential advantage of CAR T-cell therapy is its ability to cross the blood-brain barrier, which may help prevent central nervous system relapse—a concern with blinatumomab-based regimens. Despite administering only 2 doses of intrathecal chemotherapy compared to 8-12 doses typically used with blinatumomab protocols, no central nervous system relapses were observed in this study.
The researchers acknowledged limitations including the relatively short follow-up period and small sample size, emphasizing that "continued monitoring and larger future studies are warranted." Only one patient required consolidative allogeneic stem cell transplantation, highlighting the potential of this approach to reduce the need for intensive consolidation strategies.
The trial's success in achieving high molecular remission rates with acceptable toxicity profiles suggests that CAR T-cell therapy combined with targeted agents may represent a paradigm shift in treating newly diagnosed Ph+ ALL, potentially offering patients improved outcomes while avoiding the morbidity associated with traditional intensive chemotherapy regimens.
