A Phase 2 Study of Bcl-2 Inhibitor Combined With Azacitidine for Newly Diagnosed Mixed Phenotype Acute Leukemia

• BCL-2 indibitor (Drug), also known as Sonrotoclax: Sonrotoclax:40mg qd (D1), 80mg qd (D2), 160mg qd (D3), 320mg qd (D4-D21), oral; * 2 cycles.
• Azacitidine (AZA) (Drug), also known as Azacitidine: 75mg/m² qd (D1-D7), subcutaneous injection; 28-day cycle, ≥2 cycles
• Blinatumomab (Drug): 9μg/day (D8-D14), 28μg/day (D15-D21), continuous intravenous infusion

Primary outcomes

• Composite Complete Response (CRc) rate after 2 cycles of induction therapy [From randomization to 2 cycles of induction before consolidation therapy（100 days）]: CRc = CR + CRi; CR: bone marrow blasts <5%, no extramedullary disease, no peripheral blasts, ANC ≥1.0×10⁹/L, PLT ≥100×10⁹/L; CRi: bone marrow blasts <5%, no extramedullary disease, no peripheral blasts, incomplete hematologic recovery (ANC <1.0×10⁹/L or PLT <100×10⁹/L)

Secondary outcomes

• MRD negativity rate [From randomization to 2 cycles of induction before consolidation therapy（100 days）]: Bone marrow MRD <0.01% detected by MFC
• NGS-MRD negativity rate [From randomization to 2 cycles of induction before consolidation therapy（100 days）, and test Every 3 months during follow-up]: NGS-MRD can not detected by IgH/TCR NGS (NGS-based MRD will be incorporated as an exploratory complementary assay in patients with trackable clonotypic rearrangements at diagnosis)
• CR1 bridge-to-allo-HSCT rate [Up to 6 months after enrollment]: Proportion of subjects who achieve CR/CRi and successfully receive allo-HSCT within 2-3 cycles
• Overall Survival (OS) [From the time from randomization to time for up to 2 years]: Time from C1D1 to death from any cause; data censored at last follow-up for surviving subjects
• Event-Free Survival (EFS) [From the time from randomization to time for up to 2 years]: Time from C1D1 to first event (no CRc after 2 cycles, morphological/extramedullary relapse, disease progression, off-protocol anti-leukemia therapy, death from any cause); data censored at last follow-up for event-free subjects
• Relapse-Free Survival (RFS) [From the time from randomization to time for up to 2 years]: Time from first CR/CRi to relapse or death from any cause; relapse defined as bone marrow blasts ≥5%, extramedullary disease, peripheral blasts, or molecular MRD ≥10-⁴ in previously MRD-negative patients;data censored at last follow-up for relapse-free subjects
• 100-day Non-Relapse Mortality (100-day NRM) [Up to 100 days after initial MPAL diagnosis]: Proportion of deaths from non-relapse causes within 100 days of diagnosis
• Incidence of grade ≥3 adverse events (AEs) [From treatment initiation to the end of Induction]: Type, frequency and severity of grade ≥3 AEs graded by CTCAE v5.0

Sex: All, ages: 16 Years to 70 Years

Inclusion Criteria:

1. Aged 16 to 70 years old
2. Newly diagnosed MPAL confirmed by the 2022 WHO/ICC classification criteria for hematopoietic and lymphoid neoplasms
3. Previously untreated; use of glucocorticoids or hydroxyurea for ≤7 days to control tumor burden before enrollment is allowed, no other systemic anti-leukemia therapy
4. ECOG performance status score 0-3
5. No severe combined heart, brain, lung, liver or kidney disease, judged by the investigator to tolerate the study regimen
6. Able to understand and voluntarily sign a written informed consent form

Exclusion Criteria:

1. BCR::ABL-positive MPAL patients
2. Presence of active, uncontrolled infection
3. Known uncontrolled active central nervous system leukemia (CNSL)
4. Life-threatening extramedullary disease requiring urgent radiotherapy or surgical debulking
5. Severe cardiac insufficiency with left ventricular ejection fraction (LVEF) <40%
6. Previous receipt of systemic anti-leukemia therapy
7. Pregnant or lactating female subjects
8. Judged by the investigator to be ineligible for the study for other reasons

• Suning Chen, Principal investigator, The First Affiliated Hospital of Soochow University Principal Investigator