Venetoclax plus '2 + 5' modified intensive chemotherapy with daunorubicin and cytarabine in fit elderly patients with untreated de novo acute myeloid leukaemia: a single-centre retrospective analysis.

Abstract

Treatment options for elderly patients with acute myeloid leukaemia (AML) have been limited considering the poor tolerability of intensive standard chemotherapy. Venetoclax, a highly selective B-cell lymphoma-2 (BCL-2) inhibitor, has been reported to show significant improvement in complete remission (CR) and overall survival (OS) in unfit elderly patients with AML in combination with hypomethylation agents (HMAs) or low-dose cytarabine (LDAC) compared with HMA or LDAC alone.1-3 Recently, we reported that an intensive chemotherapy regimen of venetoclax plus daunorubicin and cytarabine (DAV regimen) showed high CR rates of 91% after one cycle of induction therapy in newly diagnosed young adult patients with AML,4 indicating the strong potential of the venetoclax-based intensive therapy to induce rapid remission. A prospective, phase Ib study demonstrated that venetoclax plus idarubicin and cytarabine regimen achieved high CR rates of 68% with tolerable adverse events in fit elderly patients with AML.5 Unfortunately, delayed haematological recovery was observed during consolidation therapy. Thus, an optimised intensive therapy with the hope of achieving high CR rates and that is well tolerated is urgently needed. Here, we report promising clinical outcomes in our untreated fit elderly patients with AML, receiving modified intensive induction of venetoclax in combination with ‘2 + 5’ (daunorubicin and cytarabine) chemotherapy, followed by venetoclax plus modified intermediate-dose cytarabine consolidation. We retrospectively analysed elderly patients with AML (aged ≥60 years) who were treated with induction chemotherapy that included daunorubicin (60 mg/m2 days 1–2, intravenously), cytarabine (100 mg/m2 days 1–5, intravenously), and venetoclax (100 mg day 3, 200 mg day 4, 400 mg days 5–10, orally) from March 2021 to August 2022 (Figure 1A, Figure S1). Actually, all the elderly patients with AML who were fit for intensive chemotherapy according to the Ferrara criteria received such treatment during that period.6 After induction, patients received three cycles of venetoclax (400 mg days 1–14, orally) in combination with intermediate-dose cytarabine (1 g/m2 days 1–3, intravenously) as consolidation treatment. Informed consent was obtained from all the patients. The study was approved by the Institutional Review Board of the First Affiliated Hospital of Zhejiang University College of Medicine (Hangzhou, China) and was conducted in accordance with the principles of the Declaration of Helsinki. Response assessments were performed according to the National Comprehensive Cancer Network (NCCN) guidelines for AML (version 2. 2022).7 Event-free survival (EFS) was defined as the time interval from treatment initiation to the first observation of induction failure, relapse, or death. OS was defined as the time interval from treatment initiation to death from any cause. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0).8 All statistical analyses were performed using GraphPad Prism 7.0 software (GraphPad Software Inc.) and the Statistical Package for the Social Sciences (SPSS version 23.0, IBM Corp.). A total of 13 untreated elderly patients with AML were analysed and comprised five males and eight females. The median (range) age of the patients was 64 (61–71) years. Next-generation sequencing data were examed (Table S1). The baseline characteristics of patients are summarised in Tables S2 and S3, with patients divided into favourable- (two of 13), intermediate- (six of 13), and adverse-risk groups (five of 13) according to European LeukemiaNet (ELN) risk stratification.9 The most commonly detected genetic mutations were FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD; five of 13), isocitrate dehydrogenase (NADP(+)) 2 (IDH2; five of 13), DNA methyltransferase 3 alpha (DNMT3A; four of 13), and nucleophosmin 1 (NPM1; four of 13). lysine acetyltransferase 6A::nuclear receptor co-activator 2 (KAT6A::NCOA2), nucleoporin 98 and 96 precursor::nuclear receptor binding SET domain protein 1 (NUP98::NSD1) and lysine methyltransferase 2A::elongation factor for RNA polymerase II (KMT2A::ELL) fusion genes were detected in three patients. No patient received moderate or strong cytochrome P450 family 3 subfamily A member 4 (CYP3A4) inhibitors while taking venetoclax. The patients who had a FLT3 mutation did not receive any tyrosine kinase inhibitor as part of the induction. The last follow-up date was 30 January 2023, with 279 days of median follow-up. After one cycle of induction, 10 of 13 patients (76.9%, 95% confidence interval [CI] 46.2%–95.0%) achieved CR, two patients (patients [P]4 and 13) who achieved PR after one cycle of induction attained CR after receiving a second modified DAV induction. Thus, 12 of the 13 patients (92.3%, 95% CI 64.0%–99.8%) achieved CR after the completion of all cycles of induction, one patient (P7) failed to achieve remission after induction therapy (Figure 1B,C, Table 1). In CR responders, all of the patients were measurable residual disease (MRD) negative, detected by multi-parameter flow cytometry (MFC). For patients with favourable or intermediate risk according to the ELN risk stratification, all of them received consolidation chemotherapy, and all of the patients with adverse risks according to the ELN risk stratification chose the consolidation chemotherapy instead of transplantation due to unavailable donors or economic pressure.9 Among 12 CR patients, 11 have completed the first consolidation cycle except one patient (P11) who had received consolidation regimen without venetoclax due to economic pressures, 10 patients have completed the second consolidation cycle (P6 chose to withdraw), and eight patients have completed all cycles of consolidation chemotherapy (P5 relapsed and P4 chose to withdraw; Figure 1C, Table S3). Relapse during consolidation therapy occurred only in one patient (P5), who died 4 months after relapse and one patient (P1) relapsed after 10 months of completion of consolidation chemotherapy, who was resistant to azacytidine plus venetoclax re-induction therapy, while receiving CRi after one cycle of ivosidenib plus decitabine, and then received allo-haematopoietic stem cell transplantation (Figure 1C). The median follow-up was 279 days. The median EFS was not achieved, with an estimated 1-year EFS rate of 83.1%. The median OS was not achieved, with an estimated 1-year OS rate of 87.5%. The adverse events observed during the induction and the consolidation are listed in Table S4. Grade 3–4 neutropenia, anaemia, and thrombocytopenia occurred in most patients during the induction and consolidation cycles. For responders in the first induction cycle, the median (interquartile range [IQR]) time to blood cell count recovery (absolute neutrophil count ≥1 × 109/L and platelet count ≥50 × 109/L) in patients who had a response following induction therapy was 19.0 (18.5–22.0) days (Table 1). The most common Grade 3–4 non-haematological adverse events observed during induction included febrile neutropenia (46.2%), pneumonia (30.8%), and sepsis (15.4%). The most common Grade 3–4 non-haematological adverse events observed during the first consolidation cycle were febrile neutropenia (36.4%) and pneumonia (18.2%). The most common Grade 3–4 non-haematological adverse events observed during the second consolidation cycle were febrile neutropenia (50.0%). The most common Grade 3–4 non-haematological adverse events observed during the third consolidation cycle were febrile neutropenia (37.5%) (Table S4). There were no events of tumour lysis syndrome. Our study focused on evaluating the clinical benefit of the modified DAV regimen in elderly patients with AML. Previous studies based on venetoclax in combination with HMAs or LDAC in elderly patients with de novo AML have reported approximate CR rates of 30%–40% and MFC-MRD rates of 60%–70% in patients with response.2, 10, 11 Our modified DAV regimen demonstrated significantly improved CR rates (92.3%) and MFC-MRD rates in responders (100%), higher than the CR rate previously reported with venetoclax plus idarubicin and cytarabine (2 + 5) regimen (CR rate of 68%).5 In addition, although the follow-up was short, it seemed that patients treated with our modified DAV regimen may have a better survival benefit than patients treated with venetoclax-based low-intensity chemotherapy. The VIALE-A study (ClinicalTrials.gov Identifier: NCT02993523) showed that azacitidine plus venetoclax in untreated elderly patients with AML had an EFS of 9.8 months and an OS of 14.7 months.2 Another study showed that newly diagnosed elderly patients with AML receiving LDAC plus venetoclax had an EFS of 4.7 months and an OS of 8.4 months.3 The estimated median EFS and OS was not reached in our study, with estimated 1-year EFS and OS rates of 83.1% and 87.5%, respectively, suggesting the modified DAV regimen may improve survival benefits. Nonetheless, long-term survival data of the modified DAV regimen in elderly patients needs to be focused upon in the future. The limitations of our study include the retrospective design, small sample size, and lack of long-term follow-up data. Prospective randomised clinical trials are needed to further assess for efficacy and durability of responses. Huafeng Wang and Yiyi Yao designed the study, collected and analysed the data, and wrote the first draft of the manuscript. Liping Mao, Yinjun Lou, Yanling Ren, Xingnong Ye, Min Yang, Liya Ma, Yi Zhang, Yile Zhou, and Jiaying Wu collected and analysed the data, and reviewed the manuscript. Xin Huang, Yungui Wang and Huan Xu performed MRD detection, karyotype analysis and next-generation sequencing. Hongyan Tong read and reviewed the manuscript. Hong-Hu Zhu and Jie Jin designed the study, analysed the data, wrote the first draft of the manuscript, and provided administrative support. Huafeng Wang and Jie Jin accessed and verified the data. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. This work was supported in part by Natural Science Foundation of Zhejiang Province, China (Y23H080018); the Fundamental Research Funds for the Central Universities (226-2022-00003); the Key Research and Development Programme of Zhejiang Province, China (no. 2021C03123); Key Research and Development Programme of Zhejiang Province, China (no. 2022C03005); the Leading Innovative and Entrepreneur Team Introduction Programme of Zhejiang (2020R01006); and Research Project of Jinan Microecological Biomedicine Shandong Laboratory (JNL-2022034C). We declare that we have no competing interests.We also state in the manuscript that ‘the study was approved by the Institutional Review Board of the First Affiliated Hospital of Zhejiang University College of Medicine (Hangzhou, China) and was conducted in accordance with the principles of the Declaration of Helsinki’. All the patients providied signed written informed consent. We also stated in the manuscript that ‘all patients signed written informed consent’. We completely agree with Wiley's Data Sharing policy, all data associated with this study are present in the paper or the supplementary materials. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.