Frontline Combination of 3 rd Generation TKI Olverembatinib and Blinatumomab for Ph+/Ph-like ALL Patients

Background The combination of dasatinib and blinatumomab represented a chemotherapy-free treatment approach, which had been employed in the management of newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). A recent study demonstrated that combination therapy of ponatinib with blinatumomab may achieve better efficacy, with a complete molecular response (CMR) rate of 87%. However, some patients required dose reduction or even discontinuation of ponatinib for the occurrence of cardiovascular adverse events. Olverembatinib, a potent third-generation tyrosine kinase inhibitor (TKI), showed both favorable tolerability and significant efficacy in patients with TKI-resistant chronic myeloid leukemia. But its effectiveness in ALL remained unaddressed. Our recent study, a frontline combination of Olverembatinib and PDT-ALL-2016 regime in Ph+ALL, had shown a promising outcome, achieving a complete molecular response (CMR) rate of 84.6% at day 90. Herein, we explored the clinical efficacy of the frontline combination of Olverembatinib and blinatumomab for the treatment of Ph+ and ABL-class Ph-like ALL. Methods From April 2022 to May 2023, 13 patients with Ph+/Ph-like ALL treated with olverembatinib (40mg once every other day) and blinatumomab (administered for a total of 2 weeks followed by 2 weeks of break) were enrolled (Figure 1a). Two patients (15.4%, 2/13) were in Ph-like ALL group with TEL-ABL and EBF1-PDGFRB fusion gene. Five patients (38.5%, 5/13), with a median age of 58 years old, were received ≥2 cycles and eight patients (61.5%, 8/13), with a median age of 34.5 years old, were treated with 1 cycle before HSCT. Result With a median follow-up of 7 months, all patients (100%, 13/13) achieved complete remission (CR) after one cycle of treatment. Among them, nine patients (72.7%, 9/13) achieved complete molecular remission (CMR) after one cycle, and ten patients (90.1%, 10/13) after two cycles. Notably, all patients (100%, 13/13) achieved CMR within three months of olverembatinib and blinatumomab treatment (Figure 1b). The 6-month overall survival (OS) rate was 100% and the 6-month event-free survival (EFS) rate was 87.5% (Figure 1 c and d). One patient with ABL mutation EE255V died due to relapse after HSCT. The regimen was overall well tolerated. For hematologic toxicity, one patient (7.7%, 1/13) experienced grade 1 neutrophil decrease. Regarding non-hematologic toxicity, five patients (38.4%, 5/13) developed infections during treatment, including COVID-19 and herpes zoster. Five patients (38.4%, 5/13) experienced decreased levels of immunoglobulins. Ten patients (76.9%, 10/13) experienced grade 1 cytokine release syndrome (CRS). Importantly, there were no interruptions in dosing of olverembatinib during treatment while no cardiovascular adverse events were observed. Conclusion This is the first report on the combination of olverembatinib with blinatumomab for the treatment of Ph+/Ph-like ALL. Among the 13 patients enrolled, a notable rate of CR and CMR was observed, which holds promise for improved long-term survival. Additionally, the combination of olverembatinib and blinatumomab exhibited minimal adverse events, both in terms of hematologic and non-hematologic toxicities. Notably, fewer cardiovascular adverse events that required discontinuation of treatment compared to ponatinib were observed. Altogether, these findings strongly indicated that combination therapy of olverembatinib with blinatumomab has the potential to become a new standard of care in the frontline treatment of Ph+/Ph-like ALL. However, further clinical trials are needed to definitively establish the efficacy of this treatment approach and validate the potential benefits. This research was supported by the National Natural Science Foundation of China(NFSC82170163, 81970147), Clinical Study of Nanfang Hospital(LC2016ZD009/2019CR012).