Liposomal Annamycin (l-ann) In Combination With Cytarabine For Treatment Of Patients
Background:Anthracyclines remain the backbone for the treatment of patients with AML (e.g., “7 + 3”), however, increasedcumulative doses are associated with significant cardiotoxicity with these compounds. L-ANN, a noveldoxorubicin (DOX) congener formulated in multilamellar liposomes, was found to be active against multidrugresistant (mdr-1) cancers and a strong topoisomerase IIα/β(TOPO II) poison. Importantly, in contrast to theparental compound DOX, L-ANN appeared to be non-cardiotoxic in preclinical studies. L-ANN as monotherapyin r/r AML patients demonstrated an overall response rate (ORR) of 80% (240 mg/m², administered on threeconsecutive days (MB-105 study, NCT03388749, Gil et al. 2023) with no cardiotoxicity noted in any patient.Since preclinical animal data have shown that L-ANN in combination with cytarabine demonstrated a significantimprovement in median overall survival (mOS) when compared to both, L-ANN as a single agent (68%improvement) and to cytarabine alone (241% increase), the MB-106 trial (NCT05319587) has been initiated.
Aims:To evaluate L-ANN and cytarabine in r/r AML patients
Methods:MB-106 is a phase I/II, multicentre, open-label dose-escalation study to evaluate the safety and efficacy of L-ANN in combination with cytarabine in adult r/r AML patients after induction therapy. The dose escalation partof the study explored two levels of L-ANN (190 mg/m² and 230 mg/m² for three consecutive days,respectively). All patients received cytarabine (2.0 g/m²/day for five consecutive days). Monitoring includedECHO, ECG, and GLS measurements, cardiac biomarkers, and bone marrow assessments. Almost all cardiacsafety data were sent for an independent review (Cleveland Clinic, Ohio, USA). Dose escalation was concludedafter the 230 mg/m²/day cohort due to safety and efficacy with data identifying this as the recommendedphase II dose.
Results:As of February 2024, a total of 19 patients were enrolled (ITT), 17 of whom completed treatment with L-ANNand cytarabine as first-line (N = 2), second-line therapy (N = 9) and beyond (N = 6). A total of 13 patients hadrelapsed AML and 4 patients were refractory to prior treatment. The median age was 69 years. Two patientsdiscontinued early due to allergic reactions. All patients who completed treatment had undergone post-therapy bone marrow assessment (day 15 or later). No clinically significant signs of cardiotoxicity were notedduring or after treatment in any of the patients enrolled. The combination was well tolerated withmyelosuppression and infections being the main adverse events (AEs). The CR/CRi rates for the ITT populationwere as follows: first-line 50% (1/2), second-line 60% (6/10), third-line and greater 0% (0/7). After a follow-upperiod of 12 months mOS was not reached in the second-line cohort.
Conclusion:The combination of L-ANN and cytarabine is safe and active in r/r AML patients without any signs ofcardiotoxicity. Since there continues to be a significant unmet medical need for second-line treatment for r/rAML patients who lack the gene mutations required for existing targeted therapies (e.g., FLT3, IDH1,2 etc.), theobserved CR/CRi rate of 60% (67% in the per protocol population) is remarkable and clearly warrants furtherclinical evaluation in confirmatory trials.
Keywords: Acute myeloid leukemia, Salvage therapy, Resistance, Refractory
https://clin.larvol.com/abstract-detail/EHA 2024/70978369