Abstract Topic: 4. Acute myeloid leukemia - Clinical
Background: Treatment of relapsed and refractory acute myeloid leukemia (AML) is still very challenging, with poor response rates and low chance for cure. Patients with relapsed and/or refractory (R/R) AML experience inferior CR rates (20%-60%) with reinduction, and few patients obtain durable remissions with salvage therapy. Although no proven optimal salvage regimen exists, CLAG ± M regimens [cladribine + cytarabine (Ara-C) + granulocyte colony-stimulating factor (G-CSF) ± mitoxantrone (Mito)] is commonly used, resulting in a sobering CR or CR with incomplete hematologic recovery (CRi) rate of 30%-50%. The advantages of liposomal formulation stem from its ability to enhance drug stability, sustain release, and target tumor tissues. Therefore, improved anti-tumor efficacy and reduced toxicity are both expected. The in vivo studies have shown that pegylated liposomal formulation altered the pharmacokinetics and tissue distribution of mitoxantrone, resulting in a more favorable therapeutic response. The previous clinical study demonstrated that much fewer adverse events were observed in the cancer patients in the pegylated mitoxantrone liposome group compared to those using the mitoxantrone at the same dose level, which was a promising improvement in the safety outcomes.
Aims: To explore the dose-limiting toxicity (DLT) of PLM in combination with cladribine and Ara-C and G-CSF in refractory and relapsed AML, to explore the maximum tolerated dose (MTD) of PLM combined administration and to assess its safety and efficacy.
Methods: This is a single-center, phase I dose-escalation study following the 3 + 3 dose escalation and de-escalation algorithm. Patients with refractory and relapsed AML, other than acute promyelocytic leukemia (APL), diagnosed by clinical diagnosis were selected as study subjects, and their age range was 18-60 years. Specific regimen: cladribine 5 mg/m2, iv, 2h, qd, d1-5; cytarabine 1 g/m2, iv, 4h, qd, d1-5, G-CSF 300μg SC, d1-6 (started 24h before chemotherapy); mitoxantrone liposome injection starting at the 0 dose level 18mg/m2 in the first cycle.
Results: Six cases are currently included in the study. Three cases in the first cycle (PLM 18 mg/m2): the first patient was male, age 44 years, who achieved CRi after one cycle of treatment and achieved CR after two circles of treatment without DLT; the second patient was male, age 39 years, who achieved CRi after one cycle of treatment with DLT(grade 4 thrombocytopenia); the third patient was female, age 58 years, who achieved CR after one cycle of treatment with DLT(grade 4 thrombocytopenia and neutropenia).
Because of two DLT(pronounced grade 4 neutropenia and thrombocytopenia) in the original PI dose 0 level, the mitoxantrone liposome was reduced to -1 dose level 12mg/m2.Three cases in -1 dose level: the first patient was male, age 48 years, who achieved CR after one cycle of treatment; the second patient was male, age 48 years, who achieved CR after one cycle of treatment without DLT; the third patient was male, age 53 years, who achieved CR after one cycle of treatment without DLT.
Summary/Conclusion: The clinical trial is still in enrollment. Now, 6 patients were enrolled and effectively evaluated, all of them achieving CR or CRi, the recommended dose of PLM when treated with the combined CLAG regimen is 12mg/m2.
Figure 1 Study design.
Keywords: Chemotherapy, relapsed/refractory, Acute myeloid leukemia