A Multicenter Prospective Clinical Study of Venetoclax Combined with Azactidine in the Treatment of Newly Diagnosed Acute Leukaemias of Ambiguous Lineage: Interim Analysis of a Phase 2 Trial
Authors: Huang Si-Man , Zhang Tong-Tong , Dai Lan , Wan Chao-Ling , Cao Han-Yu , Dai Hai-Ping , Xu Ming-Zhu , Wu Depei , Xue Sheng-Li 
Published: December 2024

Background: Acute Leukaemias of Ambiguous Lineage(ALAL) accounts for less than 4% of AL. It represents a rare type of leukaemia and is reported to have a poor prognosis. Retrospective studies have suggested that acute lymphoblastic leukemia (ALL) regimens are more effective than acute myeloid leukemia (AML) regimens. However, Both treatment showed limited effect for ALAL, so management of ALAL patients is still challenging. The efficacy and safety of venetoclax with azacitidine or chemotherapy has been reported in refractory/relapse ALAL but not in newly diagnosed population. Here, we designed a multicenter, phase 2 study utilizing the venetoclax and azacitidine (VA) regimen for the treatment of ALAL (NCT05901974).
Methods: The VA regimen consisted of azacitidine 75 mg/m2 subcutaneously once daily from day 1 to day 7 and venetoclax 100mg d1, 200 mg d2, 400 mg/day from day 3 to day 28. ALAL patients with Philadelphia chromosome(Ph)-positive received a concomitant BCR::ABL1 tyrosine kinase inhibitor (TKI). Bone aspiration evaluation was performed at 14-28 days after the completion of VA regimen. ALAL was diagnosed according to 2022 WHO classification. Treatment responses were evaluated according to the 2022 NCCN guidelines. Measurable Residual Disease(MRD) was assessed by multicolor flow cytometry (MFC). MRD negative remission in Ph-negative ALAL was defined as &lt;0.01%, and in Ph-positive ALAL was defined as &lt;0.01% by MFC and the absence of quantifiable BCR::ABL1 transcripts by PCR &lt;0.01% on the international scale. Patients were considered non-responders if the criteria for overall response were not achieved after two induction cycles.
Results: Since Janary 2022, a total of 10 patients with ALAL were enrolled in this study. The median age was 45 years (range, 22-61years)，with 4 (60%) female and 6 (60%) male patients. Among them, 3 patients were diagnosed with acute undifferentiated leukaemia (AUL). 3 patients were diagnosed with T/myeloid mixed phenotype acute leukemia (MPAL), 2 were B/myeloid MPAL, 2 were Ph+ B/myeloid MPAL. Among them, seven patients were biphenotypic and one was bilineal with the coexistence of B lineage and myeloid lineage . Eight patients responded to VA regimen after one cycle of regimen, with 7/10 (70%) with complete remission (CR), 1/10 (10%) with complete remissioni with incomplete hematologic recovery(CRi). Two patients with no remission(NR) are currently receiving re-induction therapy, and for the rest having completing two cycles of regimen, 6/8(75%) achieved CR, 2/8(25%) achieved CRi. Among patients who achieved treatment response, 5/8 (62.5%) patients attained MRD negativity. Four patients (40%) received an allogeneic haematopoetic stem cell transplantation (HSCT).
During the treatment with the VA regimen, the most frequent grade 3 or higher adverse events were hematologic toxicity, including neutropenia (100%), thrombocytopenia (50%) and anemia (50%). One patient had temporary discontinuation due to grade 4 infections. Grade 2 infections and Grade 1 to 2 liver dysfunction were observed in 1/10(10%) and 2/10(20%) patients. Disease relapse occurred in 2 (20%) patients. One patient revceived salvage chemotherapy whereas one died of disease progression. With a median follow-up of 8.3 months (range, 1.4-31.2 months), the estimated 1-year overall survival rate was 50% and 1-year event-free survival rate was 68.6% when data were censored for HSCT. The median OS and EFS were not reached. The 2-year cumulative relapse rate was 31.4%.
Conclusion: Our results demonstrated that VA regimen had encouraging efficacy and would possibly be an successful bridge to transplant in ALAL patients.