Dasatinib/Startacel plus CAR T-cell therapy: first-line Tx option for Ph+ ALL?

The combination of dasatinib and sequential anti-CD19 and anti-CD22 chimeric antigen receptor (CAR) T-cell therapy proved to be an effective first-line treatment option for patients with Philadelphia chromosome (Ph) acute lymphoblastic leukemia (ALL), according to new research published in the journal Cell. This research offers new hope for treatments in this area, especially in patient populations that face treatment challenges. Below is a detailed interpretation and expansion of this research.

The study is based on a single-arm Phase 2 clinical trial with registration number NCT04788472. The trial enrolled a total of 28 newly diagnosed adults with Ph-positive ALL, with a wide age range. The treatment plan was designed to evaluate the synergy and clinical effect of dasatinib and CAR T cell therapy. Participants were all diagnosed for the first time before the trial and had not received any treatment for their condition, ensuring the authenticity and applicability of the research data.

In the trial, all patients first received two weeks of induction therapy, including vindesine, dexamethasone and dasatinib. This induction regimen was chosen mainly because it has shown good results in previous studies and can significantly improve the patient's hematological remission rate. The results showed that all 28 patients successfully completed induction therapy and achieved complete hematological remission. This result laid a solid foundation for subsequent treatment.

In patients who achieve complete hematological remission, lymphodepletion is next performed to reduce the T cell burden in the body and create a better environment for receiving CAR T cell therapy. After completion of clearance, the patient received CD19-targeted CAR T-cell therapy. At this stage, 27 patients participated in CD19-targeted therapy, and 85% of patients achieved complete molecular response (CMR). This high 85% CMR rate marks a successful treatment and demonstrates the effectiveness of CAR T-cell therapy when used in combination with dasatinib.

It is worth noting that afterCD19 therapy, two patients withdrew from the study due to personal reasons, but continued to maintain good therapeutic response under maintenance therapy with dasatinib. The remaining 25 patients entered CD22-targeted CAR T cell therapy, and data showed that 76% of patients achieved CMR at this stage. Together, these results indicate that the combination of dasatinib and CAR T cell therapy can significantly improve the remission rate of patients with Ph-positive ALL.

PassedAt 23.9 months of follow-up, hematological relapse was observed in 2 patients. Both patients had IKZF1 deletion at baseline and both eventually died due to disease progression. The study showed that 78% of patients remained in CMR at the time of data cutoff, supporting the long-term effectiveness of the treatment regimen.

In addition, the study also focused on the assessment of survival rates. During the 2-year follow-up period, the overall survival rate (OS) and leukemia-free survival rate (LFS) were both 92%. Specifically, the 2-year OS rate of patients without IKZF1 changes at baseline was 100%, while that of patients with IKZF1 changes was 66.7% (P=0.01), demonstrating the importance of genetic changes in prognosis. Similar trends were observed in leukemia-free survival rates, which were 100% and 66.7% respectively (P=0.01).

Regarding safety, the researchers pointed out that the treatment regimen has a good safety profile. Most grade 3 or higher adverse events with induction regimens were related to lymphocyte depletion. Nine cases of grade 1 cytokine release syndrome (CRS) were documented during CD19-targeting CAR T-cell therapy, compared with 12 cases of grade 1 CRS during CD22-targeting CAR T-cell therapy. Notably, no cases of higher-grade CRS and the occurrence of immune effector cell-associated neurotoxic syndrome (ICANS) were observed in the study, further confirming the safety of this combination treatment.

Reference materials:https://www.hematologyadvisor.com/news/dasatinib-car-t-cell-all/