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Resistance to chemotherapy remains a formidable obstacle in acute myeloid leukemia (AML) therapeutic management, necessitating the exploration of optimal strategies to maximize therapeutic benefits. Venetoclax with 3+7 daunorubicin and cytarabine (DAV regimen) in young adult de novo AML patients is evaluated. 90% of treated patients achieved complete remission, underscoring the potential of this regimen as a compelling therapeutic intervention. To elucidate underlying mechanisms governing response to DAV in AML, quantitative phosphoproteomics to discern distinct molecular signatures characterizing a subset of DAV‐sensitive patients is used. Cluster analysis reveals an enrichment of phosphoproteins implicated in chromatin organization and RNA processing within DAV‐susceptible and DA‐resistant AML patients. Furthermore, kinase activity profiling identifies AURKB as a candidate indicator of DAV regimen efficacy in DA‐resistant AML due to AURKB activation. Intriguingly, AML cells overexpressing AURKB exhibit attenuated MCL‐1 expression, rendering them receptive to DAV treatment and maintaining them resistant to DA treatment. Moreover, the dataset delineates a shared kinase, AKT1, associated with DAV response. Notably, AKT1 inhibition augments the antileukemic efficacy of DAV treatment in AML. Overall, this phosphoproteomic study identifies the role of AURKB as a predictive biomarker for DA, but not DAV, resistance and proposes a promising strategy to counteract therapy resistance in AML. [ABSTRACT FROM AUTHOR]

Summary: Gilteritinib, a potent FMS‐like tyrosine kinase 3 (FLT3) inhibitor, was approved for relapsed/refractory (R/R) FLT3‐mutated acute myeloid leukaemia (AML) patients but still showed limited efficacy. Here, we retrospectively analysed the efficacy and safety of different gilteritinib‐based combination therapies (gilteritinib plus hypomethylating agent and venetoclax, G + HMA + VEN; gilteritinib plus HMA, G + HMA; gilteritinib plus venetoclax, G + VEN) in 33 R/R FLT3‐mutated AML patients. The composite complete response (CRc) and modified CRc (mCRc) rates were 66.7% (12/18) and 88.9% (16/18) in patients received G + HMA + VEN, which was higher compared with that in G + HMA (CRc: 18.2%, 2/11; mCRc: 45.5%, 5/11) or G + VEN (CRc: 50.0%, 2/4; mCRc: 50.0%, 2/4). The median overall survival (OS) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 160.0 days and 231.0 days. The median duration of remission (DOR) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 82.0 days and 77.0 days. Four patients in the G + HMA + VEN group received alloHSCT after remission exhibited prolonged median DOR. The most common grade 3/4 adverse events were cytopenia, febrile neutropenia and pulmonary infection; there were no differences among the three groups. In conclusion, our data demonstrated promising response of G + HMA + VEN combination therapy in R/R FLT3‐mutated AML, and it may be considered an effective therapy bridge to transplantation. [ABSTRACT FROM AUTHOR]

Summary: There have been reports of haematological cancer patients achieving spontaneous remission after being infected with the influenza A or SARS‐COV‐2 virus. Here, we present the first case of long‐term complete remission (CR) induced by influenza A (IAV, H1N1 subtype) in a refractory AML patient and have functionally validated this finding in two different animal disease models. We observed a significant increase in the proportion of helper T cells in the patient after IAV infection. The levels of cytokines, including IL‐2, IL‐4, IL‐6, IL‐10, IL‐17A, IFN‐γ and TNF‐α, were higher in IAV‐infected patients compared with control groups. These findings indicate that the anti‐tumour effects induced by IAV are closely related to the modification of the immune response. Our study provides new evidence of the anti‐tumour effects of IAV from a clinical practice perspective. [ABSTRACT FROM AUTHOR]

(C and D) PFS and OS of patients with increased mean ctDNA VAF versus patients with no increased mean ctDNA VAF based on pre- and post-treatment ctDNA change, respectively. Twenty-seven patients had pre- and post-treatment plasma-derived ctDNA, and paired baseline BM DNA NGS assessments were included for both concordance analysis and dynamic ctDNA analysis. Three patients with only pre- and post-treatment ctDNA assessments and one patient with only post-treatment ctDNA assessments were used for dynamic ctDNA analysis (Figure 1). [Extracted from the article]

Summary: As reported, SETD2 is recurrently mutated in acute myeloid leukaemia (AML), but knowledge about the specifics is limited. We enrolled 530 consecutive newly diagnosed AML patients in our study, and we analysed the distribution pattern and prognostic role of SETD2 mutation in AML. SETD2 mutation was found to affect 6.3% of AML patients, and it frequently co‐occurred with IDH2, NRAS and CEBPA mutations. SETD2‐mutated patients saw excellent therapeutic responses but failed to gain better survival time than other patients. This could be because of the high recurrence and mortality in SETD2‐mutated patients who have additional mutations, such as NRAS mutation. [ABSTRACT FROM AUTHOR]

Patients with adverse risk according to ELN received allo-HSCT if a suitable donor was available, regardless of MRD status; otherwise, they received venetoclax plus modified intermediate-dose cytarabine-based chemotherapy consolidation unless they developed progressive disease or unacceptable toxicity or stopped due to physician or patient decisions. Keywords: acute myeloid leukaemia; DAV; efficacy; safety; venetoclax EN acute myeloid leukaemia DAV efficacy safety venetoclax 568 572 5 04/20/23 20230501 NES 230501 AUTHOR CONTRIBUTIONS Huafeng Wang and Yiyi Yao designed the study, collected and analysed the data, and wrote the first draft of the manuscript. 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). [Extracted from the article]

Abstract: Currently, there are few studies that address the prognostic significance of baseline additional chromosomal abnormalities (ACAs) in newly diagnosed acute promyelocytic leukemia (APL) patients treated with arsenic trioxide (ATO) as the front-line therapy. A series of 271 consecutive APL patients has been cytogenetically investigated between 2004 and 2011 in our institution. The incidence of ACAs was 27% (46/172) in APL cases with t(15;17). Trisomy 8 was the most recurrent abnormality, accounting for 30% (14/46) of patients with ACAs, followed by +21 (7%, 3/46) and −7/7q (7%, 3/46). Nine cases (14.1%) were found to have additional balanced translocation aberrations, most of them are new and non-recurrent. Treatment protocols consisted of all-trans retinoic acid (ATRA) and chemotherapy with or without the ATO therapy. Overall, patients with and without ACAs had similar complete remission (CR) rates (94% and 98%, respectively, P =0.344). With a median follow-up of 41 months, univariate analysis showed that ACAs did not show any prognostic significance in relapse-free survival (RFS) and overall survival (OS). In addition, ATO treatment was an independent favorable predictor for RFS. Thus, this data provides insights into cytogenetic features of APL, and suggests that ATO-based combination therapy improved RFS in de novo APL patients, while ACAs had no impact on prognosis. [Copyright &y& Elsevier]

It is controversial whether acute myeloid leukemia (AML) patients with 20–29% bone marrow (BM) blasts should be considered AML or myelodysplastic syndromes (MDS). We retrospectively studied 382 patients, including 108 AML with 20–29% BM blasts (AML20–29), 210 AML with ≥30% BM blasts (AML ≥ 30), and 64 MDS with 10–19% BM blasts (MDS-EB2). We found that AML20–29 were more similar to MDS-EB2 in terms of advanced age, less blood count, the increased presence of poor-risk cytogenetics. The frequency of mutated genes in AML20–29 had both the characters of AML and MDS. Median overall survival of AML20–29 and MDS-EB2 were similar and shorter than those of AML ≥ 30 (p =.045). Multivariate analysis showed inferior survival with increased age, low platelet count and FLT3 mutations. Our findings suggest that AML20–29 have clinical features more similar to MDS than AML. [ABSTRACT FROM AUTHOR]

With limited data available on the low-dose cytarabine, aclarubicin and granulocyte colony-stimulating factor (CAG) regimen in newly diagnosed older patients with acute myeloid leukemia (AML), this study aimed at comparing the efficacy and toxicity of CAG with idarubicin plus cytarabine (IA) remission induction therapy in these patients. A total of 154 consecutive patients (52 with CAG and 102 with IA) were retrospectively analyzed. The patients in the CAG group had a higher median age (68 vs. 65 years, p = 0.002) and a higher proportion of previous myelodysplastic syndrome (25.0% vs. 2.9%, p < 0.0001) compared to those in the IA group. The complete remission rates with the CAG and IA regimens were 55.8% and 52.9% ( p = 0.864). The median overall survival (12.1 vs. 11.7 months, p = 0.650) and 3-year disease-free survival rates (29.6% vs. 48.6%, p = 0.657) were not statistically different in the two groups. The CAG regimen might be an alternative to conventional chemotherapy in older patients with AML. [ABSTRACT FROM AUTHOR]

Venetoclax has emerged as a breakthrough for treatment of leukemia with a wide interindividual variability in pharmacokinetics. Herein, a rapid, sensitive, and reliable UPLC-MS/MS method for quantification of venetoclax in plasma was developed and validated. The method was operated in the multiple-reaction monitoring (MRM) mode to detect venetoclax at m/z transition 868.5 > 321.0 and IS at 875.5 > 321.0, respectively. Protein precipitation prior to injection into the LC-MS/MS and the analyte was separated on an ACQUITY UPLC BEH C18 column by gradient elution with acetonitrile and 0.1% formic acid in water. Linear calibration curves were obtained in the range of 25–8000 ng/mL. The specificity, recovery, matrix effect, and stability also met the acceptance criteria of FDA guidance. The method was successfully applied to analyze plasma in acute myeloid leukemia (AML) patients. The peak plasma concentration (Cmax) of venetoclax in Chinese AML patient was 2966.0 ± 1595.0 ng/mL while the trough concentration (Cmin) was 1018.0 ± 729.4 ng/mL. Additionally, Cmax and Cmin showed a positive correlation with AST levels. Furthermore, Cmax was significantly higher in the older patients. The present method can be applied for TDM of venetoclax in treatment of hematological cancers. [ABSTRACT FROM AUTHOR]

To assess the efficacy and toxicity of HAA regimen (Homoharringtonine 4 mg/m/day, days 1-3; cytarabine 150 mg/m/day, days 1-7; aclarubicin 12 mg/m/day, days 1-7) as a salvage therapy in the treatment of refractory and/or relapsed acute myeloid leukemia (AML), 46 patients with refractory and/or relapsed AML, median age 37 (16-65) years, participated in this clinical study. The median follow-up was 41 (10-86) months. Eighty percent of patients achieved complete remission (CR), and the first single course of re-induction HAA regimen resulted in CR rate of 76.1 %. The study protocol allowed two courses of induction. The CR rates of patients with favorable, intermediate and unfavorable cytogenetics were 90 %, 88.9 %, and 37.5 %, respectively. For all patients, the estimated 3-year overall survival (OS) rate was 42 %, and the estimated relapse free survival (RFS) at 3 years for the 36 CR cases was 49 %. The toxicities associated with HAA regimen were acceptable. HAA is a good choice in cases with refractory/relapsing AML for salvage chemotherapy, preferably with a high-efficacy and low-toxicity profile. [ABSTRACT FROM AUTHOR]