| Relapsed or refractory is the major cause of treatment failure in acute myeloid leukemia(AML)and are associated with a poor prognosis,currently available treatment options for this group of patients are generally ineffective,Therapeutic options for patients with relapsed or refractory AML are preferred to choose clinical trials according to uniform guidelines.Overexpressed of Bcl2 is konwn to be associated with unsatisfied efficacy of chemotherapy and cause of drug resistance in AML.Venetoclax(VEN)is an inhibitor of the anti-apoptotic protein B-cell lymphoma 2(BCL2),which in combination with demethylating agents(HMAs)or low-dose cytarabine have shown promising antileukaemic activity against acute myeloid leukemia thus has been approved by the FDA for the treatment of elderly AML patients(>75 years).Recent studies have shown a promising efficacy for the treatment in R/R-AML with VEN combination strategies,However,the responses were modest and the remission is transient Overexpression of BCL-xL and/or MCL-1 is the main challenging to the YEN treatment HHT may enhance the anti-tumor effect of VEN by further inhibiting the expression of Mcl-1.Till now,the activity of HHT in venetoclax-based regimen in R/R-AML is not fully studied.In this study,we combined HHT with VEN and azacitidine(AZA)(HVA)to treat 43 patients with refractory/relapsed(R/R)-AML.At the same time,another 11 cases with R/R-AML were treated with YEN combined with hypomethylating agents(HMAs).after one course of salvage therapy,totally 29(67.4%)patients in HVA group,achieved treatment response,and 28(65.1%)obtained CR/CRi,of whom 21(75%)presented minimal residual disease(MRD)negative.The efficacy was higher than with the control regimen(ORR 4/11,36.4%,P=0.059;CR/CRi 3/11,27.2%,P=0.024;MRD negative 3/11,27.2%,P=0.199).Subgroup analysis showed treatment response was comparable in the patients with vs.without allo-HSCT in HVA group(ORR10/14,71.4%vs.19/29,65.5%;CR/CRi 9/14,64.2%vs.19/29,65.5%,respectively).The patients with extramedullary leukemia(EML)seem to responded better to VEN combined regimens than those without EML(EML vs.non-EML:ORR,8/10vs.25/44,P=0.175;MMR,7/10vs.19/44,P=125).With a median follow-up of 5(1-14)months,7 patient in the HVA group were bridged to allo-HSCT,and 5/28(17.8%)patients relapsed Totally 4(9.3%)patients in the HVA group vs.4(36.4%)in the HMAs are died of disease progression(P=0.055).There was no significant difference in commonly occurring toxicities such as bone marrow suppression and febrile neutropenia between the two treatment regimens(P>0.05).This study also confirmed that HHT combined with ABT-199 can significantly induce cell apoptosis and inhibit cell proliferation in vitro,the underlying mechanisms regarding its synergistic anti-tumor effect may result from an downregulative effect upon Mcl-1 expression caused by HHT,which ultimately induces cellular apoptosis.thus enhancing the anti-tumor activity of ABT-199.Taking together,HVA regimes showed a meaningful antileukemic activity in vitro against R/R-AML,without an increased risk of treatment-related toxicity.Which may contribute to a synergistic effect among HHT and ABT-199,thus further reducing anti-apoptotic proteins,These results provides theoretical basis for the combination of this drug in future clinical trial studies of R/R-AML. |
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