Mitoxantrone Hydrochloride Liposome in Combination with Cytarabine and Venetoclax (MAV) Regimen in Relapsed or Refractory Acute Myeloid Leukemia

Background:

Acute myeloid leukemia (AML), a heterogeneous hematologic malignancy, is the most common type in adult acute leukemia. Currently, the primary drug resistance and recurrence rate of AML are still high, while the remission rate of those relapsed or refractory AML is limited and the survival rate is extremely poor. Previous research has shown that mitochondrial calcium is a key mediator of resistance or sensitivity of leukemia stem cells (LSCs) to venetoclax, mitochondrial calcium uniporter (MCU) inhibitor mitoxantrone may be an effective drug for the treatment of venetoclax-resistant AML. Mitoxantrone hydrochloride liposome (Lipo-MIT) is an innovative anthracycline nano-drug, which has been demonstrated favorable pharmacokinetic characteristics and shown preliminary efficacy in adult AML. Here, we reported efficacy and safety of combination treatment of Lipo-MIT, cytarabine and venetoclax (MAV) regimen in relapsed or refractory AML.

Methods:

Clinical studies are currently underway to explore efficacy and safety of the MAV regimen in patients (pts) with adult relapsed or refractory AML (ChiCTR2400080273 and ChiCTR2400086528). Lipo-MIT was administered on day 1 at 24 or 30 mg/m². Cytarabine was given at 1g/m² every 12 hours on days 1, 3, 5 or 100mg/m² on days 1-7 (dosage options were based on the age and physical condition of the patient). Venetoclax was given at 100mg d2, 200mg d3, and 400mg d4-10. The primary endpoint was composite complete remission (CRc) rate. Secondary endpoints were measurable residual disease (MRD) negative rate by flow cytometry, overall response rate (ORR), relapse-free survival (RFS), event-free survival (EFS), overall survival (OS) and safety.

Results:

Since now, six eligible pts were enrolled. The median age was 64 (range 48-71) years, with 83.3% were male. Risk stratification (ELN,2022) based on cytogenetic and molecular abnormalities was available for 6 pts: 2 intermediate risk and 4 adverse risk. Adverse prognostic factors included 1 pt with complex karyotype, 3 pts with ASXL1 mutations, 2 pts with RUNX1 mutations, and 1 pt with TP53 mutation. All pts were venetoclax resistance. Three pts relapsed within the first 6 months after CR/CRi and 3 pts relapsed after 12 months.

Four pts were evaluable for efficacy and safety, and two another pts were still under the first cycle of re-induction treatment. The CRc rate was 75% (3/4), of which 2 out of 3 pts achieved CRc in the intermediate-dose cytarabine group, and 1 pt achieved CRi in the standard-dose cytarabine group. all CRc pts achieved MRD-negative. The AEs were mainly hematological toxicity, with all pts experiencing grade 4 thrombocytopenia, neutropenia, and leukopenia. Three pts developed grade 3 anemia. Grade 3 or higher non-hematological toxicities were not observed.

In addition, we explored the efficacy of 2 newly diagnosed elderly AML pts treated with MAV regimen. one patient achieved CR and MRD-negative, and one patient had a >50% decrease in bone marrow blasts after cycle 1. A prospective study on the efficacy and safety of MAV regimen in newly diagnosed elderly AML pts is ongoing (ChiCTR2400086614).

Conclusions:

Our results showed that the MAV regimen exhibited preliminary efficacy and safety in pts with relapsed or refractory AML, who were resistant to venetoclax combined with other drugs. The clinical trials are still ongoing.

No relevant conflicts of interest to declare.

Mitoxantrone hydrochloride liposome is an anthracycline anti-tumor drug approved by the National Medical Products Administration (NMPA) for the treatment of relapsed or refractory Peripheral T-cell Lymphoma patients who have previously undergone at least one line of therapy.