20-30% of newly diagnosed Acute myeloid leukemia(AML) patients fail to achieve complete response (CR) following intensive induction chemotherapy. This retrospective study aimed to evaluate the efficacy of reinduction regimens in improving CR rates among newly diagnosed AML patients who did not achieve partial response(PR) after initial intensive induction therapy. We conducted a retrospective analysis of 175 newly diagnosed AML patients aged 18-60 years, treated at the First Affiliated Hospital of China Medical University between January 2020 and March 2024. Patients who did not achieve PR after first line inductive therapy were switched to alternative intensive chemotherapy regimens or regimens including venetoclax and azacitidine. After the first induction cycle, the overall response rate(ORR) was 82.8%. For patients with no response, early replacement of reinduction regimens, especially those containing venetoclax, led to an ORR of 90.2% after two cycles of induction therapy. We recommend that young patients with newly diagnosed AML be primarily treated with DA/IA induction therapy. For those who fail to achieve remission, early replacement of re-induction therapy enhances the therapeutic efficacy of newly diagnosed young adult AML.

Anti-cancer drug's cytotoxicity is determined by their ability to induce predetermined cell demise, commonly called apoptosis. The cancer-causing cells are able to evade cell death, which has been affiliated with both malignancy as well as resistance to cancer treatments. In order to avoid cell death, cancerous tumour cells often produce an abundance of anti-apoptotic proteins, becoming "dependent" on them. Consequently, protein inhibitors of cell death may prove to be beneficial as pharmacological targets for the future creation of cancer therapies. This article examines the molecular routes of apoptosis, its clinical manifestations, anti-cancer therapy options that target the intrinsic mechanism of apoptosis, proteins that prevent cell death, and members of the B-lymphoma-2 subset. In addition, novel approaches to cell death are highlighted, including how curcumin mitigates chemotherapy-induced apoptosis in healthy tissues and the various ways melatonin modifies apoptosis to improve cancer treatment efficacy, particularly through the TNF superfamily. Cancer treatment-induced increases in anti-apoptotic proteins lead to drug resistance; yet, ligands that trigger cell death by inhibiting these proteins are expected to improve chemotherapy's efficacy. The potential of frequency-modulated dietary phytochemicals as a cancer therapeutic pathway, including autophagy and apoptosis, is also explored. This approach may be more efficient than inhibition alone in overcoming drug resistance. Consequently, this method has the potential to allow for lower medication concentrations, reducing cytotoxicity and unwanted side effects.

Alterations in the tumor suppressor gene TP53 are common in human cancers and are associated with an aggressive nature. Approximately 8%-12% of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) harbor TP53 mutations (TP53 mut) and present immense challenges due to inherent chemoresistance and poor outcomes. As TP53 mut are more common in older individuals and those with secondary/therapy-related myeloid neoplasms (MN), their incidence is expected to increase with an aging population and rising proportion of cancer survivors. Treatments used for other MN-intensive chemotherapy, hypomethylating agents, and the BCL-2 inhibitor venetoclax-do not improve the survival of TP53 mut MN patients meaningfully. Additionally, further development of many promising agents has been discontinued, highlighting the challenges. Widespread acknowledgment of these problems led to the recognition of TP53 mut MN as a distinct entity in the 5th edition of the World Health Organization and International Consensus Classifications. However, critical discrepancies between the two classifications may lead to under- or overestimation of the prognostic risk. Here, we review recent advances in the biology, diagnosis, and treatment of TP53 mut MN. The development of TP53 mut MN is positioned at the intersection of age, hereditary predisposition, and anti-cancer therapies. Precursor TP53 mut clones can be detected years prior to the eventual leukemic transformation-raising the possibility of early intervention. We discuss the two classification systems and the bearing of the discrepancies between the two on timely and effective management. We provide novel evidence in the areas of discrepancies. Finally, we review the current therapeutic landscape and the obvious limitations of the currently used therapies.

The standard induction treatment for acute myeloid leukemia (AML) has limited efficacy for patients with non-low-risk AML. We conducted a multicenter study phase 1b/2, Gruppo Italiano Malattie EMatologiche dell'Adulto AML1718, to investigate the safety and efficacy of venetoclax (VEN) combined with fludarabine, cytarabine, and idarubicin (V-FLAI) as an induction therapy for patients with non-low-risk AML aged <65 years and at intermediate or high European LeukemiaNet risk. After a safety run-in, patients were randomly allocated to VEN 400 mg or VEN 600 mg cohorts. The primary objectives were safety and composite complete remission (bone marrow blasts of <5% with any recovery). We report a predefined interim analysis after 57 patients. Median exposure to VEN during induction was 22 days. Effectiveness and safety were similar between VEN 400 mg and VEN 600 mg cohorts. The 60-day mortality rate was 5.8%. Prolonged aplasia was observed in patients receiving high doses of cytarabine during consolidation. Composite CR was achieved in 84% of patients. With a median follow-up of 20.6 months, 1-year overall survival was 71%, 1-year disease-free survival was 66.2%, and 1-year cumulative incidence of relapse was 24%. V-FLAI is an effective induction therapy for young and fit patients. Fifty-five more patients will be enrolled in part 2; they will receive VEN 400 mg + FLAI as predefined and will be evaluated centrally for measurable residual disease. This trial was registered at www.clinicaltrials.gov as #NCT03455504.

Fitness assessment in patients with acute myeloid leukemia (AML) is critical to deliver the right therapy to the right patient. Although several scoring systems are available to aid in determining fitness, the absence of validation studies has resulted in the lack of universally accepted assessment procedures. This limitation, combined with the increasing availability of novel agents expanding the spectrum of less-intensive options, has introduced additional complexity to the fitness assessment process. In this evolving context, fitness should reflect eligibility for a specific treatment among the several available, rather than a generic binary classification of eligibility for intensive chemotherapy. Moreover, the growing emphasis on patient-centered care, further highlights the importance of integrating quality of life, patient preferences, patient self-reported physical and social functioning status, social support, and early integration of palliative care into the assessment framework. A modern interpretation of fitness assessment should incorporate a comprehensive evaluation that extends beyond traditional clinical and biological disease characteristics. Thus, fitness assessment in patients with AML represents only 1 piece of a larger puzzle, encompassing the patient's overall capacity to sustain and benefit from a specific therapeutic program.

Acute myeloid leukemia (AML) is a bone marrow stem cell cancer that is often fatal despite available treatments. Diagnosis, risk assessment, monitoring, and therapeutic management of AML have changed dramatically in the last decade due to increased pathophysiologic understanding, improved assessment technology, and the addition of at least 12 approved therapies.

The diagnosis is based on the presence of immature leukemia cells in the blood, and/or bone marrow or less often in extra-medullary tissues. New biological insights have been integrated into recent classification systems.

The European Leukemia Network has published risk classification algorithms for both intensively and non-intensively treated patients based on cytogenetic and on molecular findings. Prognostic factors may differ based on the therapeutic approach.

Our increasing ability to quantify lower levels of measurable residual disease (MRD) potentially allows better response assessment, as well as dynamic monitoring of disease status. The incorporation of MRD findings into therapeutic decision-making is rapidly evolving.

The availability of 12 newly approved agents has been welcomed; however, optimal strategies incorporating newer agents into therapeutic algorithms are debated. The overarching approach integrates patient and caregiver goals of care, comorbidities, and disease characteristics.

Acute Myeloid Leukemia (AML) remains a formidable clinical challenge, predominantly due to the emergence of resistance to existing therapeutic regimens, including BCL-2 inhibitors like Venetoclax. Here, a novel approach is introduced by engineering BH3 mimetics utilizing non-canonical amino acids (ncAAs) to achieve dual inhibition of MCL-1 and BCL-xL. Through site saturation mutagenesis scanning, the I58(Chg) mutation is identified, significantly enhancing binding affinity with IC50 values of 2.77 nm for MCL-1 and 10.69 nm for BCL-xL, reflecting an increase of fourfold or more. The developed vMIP-II-TAT-I peptide, incorporating a CXCR4-targeted penetrating motif, demonstrated superior cellular uptake, with mean fluorescence intensity (MFI) 7.2-fold higher in CXCR4-positive AML cells and exhibited a high selectivity index (SI) for AML cells, with minimal impact on normal human hematopoietic stem cells (HSCs). When combined with Venetoclax, this peptide induced synergistic apoptosis, reducing tumor burden and prolonging survival in an AML mouse model, with median survival extended to 53 days from 37 days with Venetoclax alone. These findings reveal the therapeutic potential of dual inhibition in overcoming Venetoclax resistance and selectively targeting leukemic cells with reduced off-target effects, while laying the foundation for developing advanced BH3 mimetics with enhanced targeting, binding affinity, and efficacy for AML treatment.

Venetoclax (Ven), when combined with intensive chemotherapy, shows promise for untreated acute myeloid leukemia (AML), but its integration with the 7+3 regimen remains underexplored. In a phase 1b study, we assessed the safety and efficacy of Ven with daunorubicin and cytarabine in patients with newly diagnosed AML. A total of 34 patients (median age, 59 years; 62% non-White) received Ven at escalating durations (8, 11, or 14 days). Adverse events included febrile neutropenia (100%), sepsis (29%), and enterocolitis (23.5%), but there were no induction deaths. The median recovery times for neutrophils (>1.0 × 103/μL) and platelets (>100 × 103/μL) were less than 30 days. Composite complete remission was achieved in 85.3% of patients, and 86.2% were negative for measurable residual disease (MRD). Responses spanned all European Leukemia Net 2022 risk categories. With a median follow-up of 9.6 (2-20) months, the median duration of response, event-free survival, and overall survival were not reached. Ven (400 mg), when combined with 7+3 chemotherapy, was safe and effective in achieving MRD-negative remissions across all durations. Ven dose optimization is being explored in the expansion phase of this trial. Future multicenter studies should confirm our findings. This trial was registered at clinicaltrials.gov as #NCT05342584.

Acute Myeloid Leukemia (AML) is characterized by aggressive proliferation and metabolic reprogramming that support its survival and resistance to therapy. This review explores the metabolic distinctions between AML cells and normal hematopoietic stem cells (HSCs), emphasizing the role of altered mitochondrial function, oxidative phosphorylation (OXPHOS), and biosynthetic pathways in leukemic progression. AML cells exhibit distinct metabolic vulnerabilities, including increased mitochondrial biogenesis, reliance on glycolysis and amino acid metabolism, and unique signaling interactions that sustain leukemic stem cells (LSCs). These dependencies provide potential therapeutic targets, as metabolic inhibitors have demonstrated efficacy in disrupting AML cell survival while sparing normal hematopoietic cells. We examine current and emerging metabolic therapies, such as inhibitors targeting glycolysis, amino acid metabolism, and lipid biosynthesis, highlighting their potential in overcoming drug resistance. However, challenges remain in translating these strategies into clinical practice due to AML's heterogeneity and adaptability. Further research into AML's metabolic plasticity and precision medicine approaches is crucial for improving treatment outcomes. Understanding and exploiting AML's metabolic vulnerabilities could pave the way for novel, more effective therapeutic strategies.

To assess the efficacy and safety of an induction regimen composed of idarubicin, cytarabine, and cladribine (IAC) in patients with de novo acute myeloid leukemia (AML).

Adult patients with newly diagnosed AML were randomized to the IAC group (cladribine 5 mg/m2/day for 5 days, idarubicin 8 mg/m2/day for 3 days, and cytarabine 100 mg/m2/day for 7 days) and the IA group (idarubicin 12 mg/m2/day for 3 days and cytarabine 100 mg/m2/day for 7 days) at a 1:2 ratio. The primary endpoint was complete remission (CR) after induction. Secondary endpoints included 2-year overall survival (OS), disease-free survival, and cumulative incidence of relapse.

A total of 618 adult patients with newly diagnosed AML were enrolled. The overall CR rate was 80.5% in the IAC group compared with 72.4% in the IA group (P = 0.029). The 2-year OS was 81.3% in the IAC group compared with 70.0% in the IA group (P = 0.011). Patients on the IAC regimen achieved a higher CR rate compared to those on the IA regimen, particularly in those with adverse risk (69.8% vs. 49.1%, P = 0.008), 2-year OS (80.1% vs. IA 58.1%, P = 0.014), and disease-free survival (78.8% vs. 51.3%, P = 0.009). In the subgroup of patients older than 45 years of age, the IAC regimen exerted better CR (77.1% vs. 62.6%, P = 0.033) and 2-year OS (74.7% vs. IA 55.0%, P = 0.019). There were no differences in chemotherapy-related toxicities between the groups.

Cladribine added to the IA regimen was safe and effective in de novo AML. Patients with adverse risk or those between 45 and 60 years of age might benefit significantly on both response and survival with the IAC regimen.

Acute myeloid leukemia (AML) is a highly heterogeneous hematopoietic malignancy characterized by elevated mortality. Epigenetic therapy plays an essential role in the treatment of AML. However, the clinical outcomes of the combination of multiple epigenetic agents and conventional chemotherapy remain unclear. We conducted a phase 2 study to evaluate the clinical safety and efficacy of chidamide combined with CAG and venetoclax-azacitidine (referred to as CACAG-VEN) in AML patients (NCT05659992). Patients received induction treatment with aclarubicin (10 mg/m2/d on days 1, 3, and 5), azacitidine (75 mg/m2 on days 1-7), cytarabine (75 mg/m2 bid on days 1-5), chidamide (30 mg, twice/week for 2 weeks), and venetoclax (100 mg on day 1, 200 mg on day 2, 400 mg on days 3-14). Granulocyte colony-stimulating factor 5 μg/kg/day was administered. After one cycle of CACAG-VEN, the overall response rate was 96.7 %, with a composite complete response (CRc) rate of 93.3 %. The CRc rates (86.7 %) were remarkable among patients with adverse NCCN risk. Patients receiving two cycles of CACAG-VEN achieved a CRc rate of 100 %. The 12-month overall survival rate was 69.7 %. The median time to recovery was 19 days for platelets ≥50,000/μL and 17 days for an absolute neutrophil count ≥500 cells/μL after induction therapy. The single-cell RNA sequence showed most immune cells exhibited no significant change in proportion after removing tumor cells. In conclusion, this regimen resulted in a high CRc rate in newly diagnosed AML patients, particularly in adverse-risk patients. And this regimen had minimal impact on immune cells.

Venetoclax with hypomethylating agents (HMA) is the standard of care for acute myeloid leukemia (AML) in patients ineligible for intensive chemotherapy and is associated with tumor lysis syndrome (TLS). TLS prophylaxis and the use of Cairo Bishop versus Howard diagnostic criteria are not standardized. Here we report TLS prophylaxis and incidence in a retrospective cohort of 100 consecutive AML patients treated with venetoclax and HMA. Thirty four patients developed laboratory Cairo Bishop TLS; 8 of these met criteria for clinical Cairo Bishop TLS. Only 6 of patients met Howard TLS criteria. Fourteen patients had spontaneous TLS. Ninety two out of 100 patients had a white blood cell count (WBC) < 25 000 cells/μL at treatment start. Prophylaxis like the original venetoclax trial with allopurinol (56%), intravenous fluids (21%), and frequent lab monitoring (56%) was less common. There was a trend toward increased Cairo Bishop TLS in patients with WBC ≥ 15 000 cells/μL. In our study Howard TLS criteria better identified patients with significant TLS. Aggressive TLS prophylaxis was uncommon in our cohort and is likely unnecessary for most patients at low risk of TLS.

(1) Background: The combination of venetoclax and hypomethylating agents (HMAs) is a standard first-line regimen for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. Since venetoclax-HMAs are usually administered until progression and delayed hematologic recovery is one of the limiting toxicities, cyclic administration including 7-14-day breaks is recommended. However, whether longer venetoclax schedules lead to higher response rates and how venetoclax pharmacokinetics correlate with toxicity and efficacy remains unclarified. In this single-center retrospective study, we analyzed how venetoclax plasma levels and treatment duration impact hematologic toxicity and treatment responses. (2) Methods: We analyzed the safety and efficacy of venetoclax-HMA combination regimens in a cohort of AML patients unfit for intensive chemotherapy treated at our institution between June 2020 and September 2023. The primary endpoint was the correlation between venetoclax plasma levels or administration schedule with hematologic recovery after the first cycle. Secondary endpoints included the following clinical outcomes: correlation with complete response (CR) status, progression-free survival, and overall survival. (3) Results: Within our cohort of 75 AML patients, we found no correlation between venetoclax plasma peak and trough levels, or venetoclax treatment duration (≤ or >14 days), and hematologic toxicity. Patients receiving shorter venetoclax schedules (≤14 days) had similar CR rates compared to patients treated with longer schedules. (4) Conclusions: Our results suggest that shorter (≤14 days) venetoclax schedules may have no negative impact on tumor responses in AML patients receiving venetoclax and HMA combinations. However, prospective validation studies would be required to confirm these findings.

Venetoclax (VEN) received full approval in October 2020 for use in older patients who are unfit with acute myeloid leukemia (AML) combined with either hypomethylating agents or low-dose cytarabine. This ended a semicentennial of stalled clinical progress and initiated a new treatment option with proven capacity to enhance response and prolong survival in older patients with AML. Despite widespread use of azacitidine-VEN (AZA-VEN), there is increasing appreciation that this regimen is myelosuppressive and associated with a higher risk of infectious complications than AZA alone. Key principles of initial management include prevention of tumor lysis syndrome in patients at high risk and minimizing infectious complications during induction. In the postremission phase, limiting cumulative marrow suppression by allowing sufficient time between cycles for optimal marrow recovery and truncating the duration of VEN exposure for those with delayed blood count recovery have emerged as important axioms of effective care. This article casts a clinical spotlight on important challenges and dilemmas encountered in practice. We also outline a structured framework to assist in the safe management of AZA-VEN in the clinic.

The deregulated activation of the phosphoinositide 3-kinase (PI3K) pathway is a hallmark of aggressive tumors with metabolic plasticity, eliciting their adaptation to the microenvironment and resistance to chemotherapy. A significant gap lies between the biological features of PI3K-driven tumors and the specific targeting of their vulnerabilities. Here, we explore the metabolic liabilities of PI3K-altered T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological cancer with dismal outcomes. We report a metabolic crosstalk linking glutaminolysis and glycolysis driven by PI3K signaling alterations. Pharmaceutical inhibition of mTOR reveals the singular plasticity of PI3K-altered cells toward the mobilization of glutamine as a salvage pathway to ensure their survival. Subsequently, the combination of glutamine degradation and mTOR inhibition demonstrates robust cytotoxicity in PI3K-driven solid and hematological tumors in pre-clinical and clinical settings. We propose a novel therapeutic strategy to circumvent metabolic adaptation and efficiently target PI3K-driven cancer.

Currently, there are only a few avaailable treatment options for patients with relapsed and refractory acute myeloid leukemia (R/R AML).

We conducted a single-center, phase 1 prospective study (ChiCTR2200065634) to evaluate the efficacy and safety of chidamide, demethylating drugs (azacitidine), cytarabine, aclacinomycin, and G-CSF plus venetoclax (CDCAG-VEN) in patients with R/R AML. The previous CDCAG regimen was used as a historical control to compare its efficacy and safety. Thirty and 22 patients received one course of CDCAG with or without a 14-day course of venetoclax, respectively.

The overall response rate (ORR) was significantly higher in the CDCAG-VEN group than in the CDCAG-treated group (78.6% vs. 45.5%; p = 0.015), and the CDCAG-VEN group achieved a better trend of measurable residual disease-negative response (61.1% vs. 22.2%, p = 0.134). Compared with the CDCAG group, the CDCAG-VEN group exhibited significantly better 1-year overall survival (63.3% vs. 35.1%, p = 0.005) and progression-free survival (76.7% vs. 36.0%, p = 0.022). The duration of response was notably better in the CDCAG-VEN group than in the CDCAG group (71.2% vs. 34.3%, p = 0.021) and had a lower cumulative incidence of relapse (22.2% vs. 48.9%, p = 0.095). The neutrophil and platelet recovery times were similar between the CDCAG-VEN and CDCAG groups (neutrophil: 18 days vs. 19 days, p = 0.293; platelet: 18 days vs. 19 days, p = 0.311). The frequencies of adverse events were comparable between both groups, except for a lower incidence of thrombosis in the CDCAG-VEN group (0% vs. 22.7%, p = 0.006).

In conclusion, venetoclax in combination with CDCAG is an effective and safe treatment regimen for R/R AML, thereby rapidly identifying chemosensitive patients and inducing measurable residual disease-negative remission in a high proportion of patients with R/R AML.

Backbone therapy for acute myeloid leukemia for younger adults has for 50 years been based on a combination of cytarabine and anthracycline. Over the past 10 years the addition of several targeted agents has been found to improve the outcomes of subsets of AML with particular molecular changes. In this review we will examine the data generated to date on the addition of agents targeting CD33, FLT3, IDH, and BCL2 to standard high intensity therapies. We will also review the potential for future studies evaluating the application of highly active lower intensity therapies developed in older adults to patients considered "fit for high intensity induction." Lastly, we review the data around the role of stem cell transplant in the modern targeted era.

The B-cell lymphoma 2 inhibitor venetoclax (VEN) in combination with hypomethylating agents has been approved for first-line treatment of patients with acute myeloid leukemia (AML) ineligible for intensive treatment. VEN-containing treatment strategies may also be effective in relapsed/refractory (R/R) AML; however, comparative studies with conventional therapies for fit patients as a bridge-to-transplant strategy are limited. Using propensity score matching (PSM), we compared 37 patients with R/R AML, who received VEN-based salvage therapy as bridge to allogeneic hematopoietic stem cell transplantation (allo-HCT), with 90 patients from the German Study Alliance Leukemia AML registry, who were treated with non-VEN-containing salvage therapy according to their treating physician's choice (TPC). The overall response rate among VEN patients was higher than the TPC control cohort (62% vs 42%; P = .049). Overall, 73% of VEN-treated patients vs 63% of TPC patients were bridged to allo-HCT (P = .41). After a median follow-up of 34.3 months for the VEN and 21.0 months for the TPC cohort, the median overall survival (OS) were 15.8 months (95% confidence interval [CI], 10.6 to not evaluable) and 10.5 months (95% CI, 6.8-19.6; P = .15), respectively. PSM revealed a trend toward improved OS for VEN patients (hazard ratio, 0.70; 95% CI, 0.41-1.22; P = .20). Median event-free survival was significantly longer in the VEN cohort (8.0 months) than the TPC cohort (3.7 months; P = .006). Our data suggest that VEN-based salvage therapy is a safe and effective bridge to allo-HCT for this difficult-to-treat AML patient population.

The aim of this study was to investigate the clinical features and outcomes of elderly patients with acute myeloid leukemia (AML) from a real word research. The clinical data of 223 consecutive elderly patients (aged ≥ 60 years) who were newly diagnosed with AML at our medical center between July 2017 and June 2022, including their clinical characteristics, genetic mutations, and survival outcomes, were retrospectively analyzed. Among the 223 patients (median age 67 years), 180 (80.7%) were diagnosed with de novo AML. Genetic mutations were identified in 138 of 149 patients tested (92.6%). The most commonly mutated genes included TET2, DNMT3A, NPM1, FLT3-ITD, ASXL1, IDH2, RUNX1, TP53, and CEBPA. Among these genes, TET2, DNMT3A, FLT3-ITD, and TP53 were associated with a poor outcome. Multivariate Cox's regression analysis revealed that age over 70 years, platelet count less than 100 × 109/L, albumin level less than 35 g/L, presence of infection or bleeding at diagnosis, untreated or best supportive care (BSC) treatment status, and adverse or intermediate ELN 2022 risk classification were independent prognostic factors for overall survival in elderly AML patients. Patients who received at least one induction cycle had longer overall survival times (20 months vs. 6.6 months, P < 0.001) than those who received best supportive care. Patients with ≥ 6 cycles of chemotherapy had longer overall survival times (89.2% vs. 78.5%, P = 0.007) than those with ≤ 5 cycles of therapy. The results of this study indicated that elderly AML patients had multiple genetic abnormalities and poor outcomes. Regular effective treatment can improve patient outcomes and survival. In addition to genetic abnormalities, several other clinical features can influence survival in elderly AML patients.

The aim of this study was to investigate the effects of renal function and CYP3A5 polymorphism on the drug interaction between venetoclax and fluconazole in thirty acute myeloid leukaemia patients.The area under the plasma concentration-time curve (AUC) and trough concentration (C0) of venetoclax and the fluconazole C0 were obtained from plasma samples on day 7 after initiation of venetoclax 200 mg/day combined with fluconazole.The fluconazole C0 values in patients with moderate and severe renal impairment were significantly higher than those in patients with normal or mild impairment (median values 7037, 6234, and 4813 ng/mL, respectively, P = 0.026).In patients with CYP3A5*3/*3 genotype, the AUC0-24 and C0 of venetoclax were not associated with fluconazole C0; however, in patients with a CYP3A5*1 allele, a significant positive correlation was observed between venetoclax C0 and fluconazole C0 (r = 0.782, P = 0.004).The metabolism of venetoclax by CYP3A4 is inhibited even at low fluconazole C0. In patients with a CYP3A5*1 allele, CYP3A5 is inhibited when high fluconazole C0 is induced by renal impairment.The dose of fluconazole for prophylaxis may be 100 mg in patients with severe renal impairment receiving venetoclax therapy.

BackgroundEffective treatment options are limited for elderly patients with acute myeloid leukemia (AML). A prospective phase II study was conducted to investigate the safety and efficacy of pegylated liposomal doxorubicin (PLD) combined with low-dose cytarabine (LDAC) and granulocyte colony-stimulating factor (G-CSF) in newly diagnosed older and unfit AML patients.MethodsTwenty-two patients were enrolled and deemed evaluable. The study included one cycle of induction and four cycles of consolidation, followed by maintenance therapy.ResultsThe median age of enrolled patients was 71.5 years (range, 63 to 82 years), and 16 patients (72.7%) were over 70 years of age. The overall response rate (ORR) was 77.3% (n = 17) and the complete remission (CR)/complete remission with incomplete recovery (CRi) rate was 63.6% (n = 14) after the first induction cycle. With a median follow-up of 12.4 months, eight patients (57.1%) relapsed, with a median time to relapse of 12.3 months. The median duration of response (DOR) was 11.9 months (95% CI, 6.4 to NA months), the median overall survival (OS) was 15 months (95% CI, 8.4 to 21.6 months), and the median progression-free survival (PFS) was 7.5 months (95% CI, 4.6 to 15.1 months). Common grade 3 or greater adverse events included febrile neutropenia (77.8%) and infection (63.6%), with pneumonia being the most common (10, 45.5%). There was one death (4.5%) within 30 days.ConclusionThe combination of PLD, LDAC, and G-CSF is well-tolerated and exhibits high rates of CR/CRi and low early mortality, providing an attractive treatment option for newly diagnosed elderly and unfit AML patients.

The first 5 decades of research in acute myeloid leukemia (AML) were dominated by the cytarabine plus anthracyclines backbone, with advances in strategies including allogeneic hematopoietic stem cell transplantation, high-dose cytarabine, supportive care measures, and targeted therapies for the subset of patients with acute promyelocytic leukemia. Since 2017, a turning point in AML research, 12 agents have received regulatory approval for AML in the United States: venetoclax (BCL2 inhibitor); gemtuzumab ozogamicin (CD33 antibody-drug conjugate); midostaurin, gilteritinib, and quizartinib (fms-like tyrosine kinase 3 inhibitors); ivosidenib, olutasidenib, and enasidenib (isocitrate dehydrogenase 1 and 2 inhibitors); oral azacitidine (a partially absorbable formulation); CPX351 (liposomal encapsulation of cytarabine:daunorubicin at a molar ratio of 5:1); glasdegib (hedgehog inhibitor); and recently revumenib (menin inhibitor; approved November 2024). Oral decitabine-cedazuridine, which is approved as a bioequivalent alternative to parenteral hypomethylating agents in myelodysplastic syndrome, can be used for the same purpose in AML. Menin inhibitors, CD123 antibody-drug conjugates, and other antibodies targeting CD123, CD33, and other surface markers are showing promising results. Herein, the authors review the frontline and later line therapies in AML and discuss important research directions.

Hypomethylating agents (HMAs) such as azacytidine and decitabine are FDA-approved chemotherapy drugs for hematologic malignancy. By inhibiting DNA methyltransferases, HMAs reactivate tumor suppressor genes (TSGs) and endogenous double-stranded RNAs (dsRNAs) that limit tumor growth and trigger apoptosis via viral mimicry. Yet, HMAs show limited effects in many solid tumors despite the strong induction of TSGs and dsRNAs. Here we show that targeting mitochondrial RNAs (mtRNAs) can enhance the HMA-mediated cell death in lung adenocarcinoma cells. We find that HMA treatment accompanies increased mtRNA levels and subsequent enhancement of metabolic activity, resulting in higher ATP production. Compromising the mitochondrial function by downregulating mature mtRNA expression increased cell death by HMAs. We further perform a CRISPR screening on mtRNA processing factors and find that mtRNA polymerase (POLRMT) and ElaC Ribonuclease Z 2 (ELAC2) depleted cells show increased sensitivity to HMAs by suppressing decitabine-triggered enhancement of ATP production. Moreover, we show that a small molecular inhibitor of POLRMT compromises the metabolic activity and synergistically enhances the cytotoxicity of HMAs. Our study unveils the insensitivity to HMAs through the elevation of mtRNAs and suggests mtRNA regulatory factors as potential synergistic targets to improve the therapeutic benefit of HMAs.

The study of circulating peptides in the blood offers significant opportunities for diagnosing, stratifying, and managing various diseases. With recent technological advances and the ongoing need to understand complex diseases such as acute leukemias (AL), peptidomic analysis of peripheral blood, especially serum and plasma, has become increasingly important for studying human biology and pathophysiology. Here, we provide insights and perspectives on technological developments and potential clinical applications using widely used peptidomic analysis methods. We discuss examples where peptidomics using serum or plasma has contributed to the understanding of AL. Specifically, we highlight the scarcity of peptidomic studies applied to AL and emphasize the importance of exploring this area, as the few published studies present promising results that can significantly contribute to precision medicine.

Acute undifferentiated leukemia (AUL) is a clinical rare leukemia with an overall poor prognosis. Currently, there are no well-established treatment guidelines for AUL, further exploration of optimal treatment options is now required.

We report an AUL patient who was complicated by a NRAS mutation and del5q was admitted to our hospital and we present the clinical features. In addition, we conducted a literature review.

The "VA" scheme combines agents Venetoclax and Azacitidine that have synergistic therapeutic effect with a tolerable safety profile. There is no previous report of the "VA" scheme employed in AUL treatment. An AUL patient who was complicated by a NRAS mutation and del5q was admitted to our hospital. The "VA" scheme was administrated, and complete remission (CR) was achieved at the end of the first cycle. The patient then underwent HLA-identical sibling allogeneic hematopoietic stem cell transplantation.

The "VA" scheme has been extensively used in AML treatment, but its application in AUL treatment has not yet been reported. This study is the first to report an AUL patient treated with the "VA" scheme and achieved CR. Our result preliminarily suggested the effectiveness and safety of the "VA" scheme in AUL treatment, but validation is required in more clinical samples. The "VA" scheme provides a new treatment option for AUL patients and deserves further clinical promotion.

To explore the efficacy and safety of venetoclax-based combination therapy for older patients with newly diagnosed acute myeloid leukemia (AML).

We performed a systematic review and meta-analysis of clinical trials comparing venetoclax plus hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) with mono-HMAs or LDAC. The random or fixed effects model was applied to the studies based on heterogeneity. Dichotomous data were summarized using the risk ratio (RR) and 95% confidence interval (CI). Continuous variable data were reported as weighted mean differences (WMDs).

Nine studies, including a total of 1232 patients, were included in this meta-analysis. Thec complete remission (CR)/complete remission with incomplete hematological recovery (CRi) rate of the venetoclax (Ven) + azacytidine (Aza) group was significantly greater than that of the Aza monotherapy group (RR: 2.42; 95% CI: 1.85-3.15; P < 0.001). Similarly, the CR/CRi rate of the Ven + LDAC group was also significantly greater than that of the LDAC monotherapy group (RR: 2.57; 95% CI: 1.58-4.17; P = 0.00). The same results were observed for OS among these groups. However, the incidence of febrile neutropenia was greater in the Ven + Aza group than in the Ven + Decitabine (Dec) or monotherapy Aza group (RR: 0.69; 95% CI: 0.53-0.90; P = 0.006 and RR: 2.19; 95% CI: 1.58-3.03; P < 0.001, respectively). In addition, the Ven + LDAC group had significantly greater rates of constipation, diarrhea, nausea, and vomiting than the LDAC monotherapy group, with RRs and CIs of 0.61 (95% CI 0.44-0.83, P = 0.002), 1.81 (95% CI 1.22-2.67, P = 0.003), 1.39 (95% CI 1.06-1.82, P = 0.016), and 1.80 (95% CI 1.19-2.72, P = 0.005), respectively.

Venetoclax combined with azacitidine, decitabine, or LDAC significantly improved the CR/CRi and OS of patients with previously untreated AML. However, venetoclax plus azacitidine or LDAC was more likely to lead to increased febrile neutropenia and gastrointestinal toxicity.

Despite the approval of new drugs, the inclusion of -omics-derived data and the integration of machine learning in both the diagnostic and therapeutic process, the prognosis of acute myeloid leukemia (AML) remains dismal. The curative path is still aimed at achieving a successful allogeneic hematopoietic stem cell transplant (HSCT) in most patients. Nevertheless, access to this procedure is limited to eligible patients. Moreover, post-HSCT outcomes are influenced by AML heterogeneity and patient-related factors. The rise of venetoclax (VEN)-based combinations as standard of care in the treatment of older or unfit AML patients, together with their peculiar management profile, has led researchers to evaluate the feasibility of this approach in patients proceeding toward HSCT. We reviewed the available evidence to weigh up the advantages and pitfalls of this new therapeutic strategy.

Induction regimens with satisfactory remission rates are limited for patients with acute myeloid leukemia (AML) who are elderly or ineligible for intensive chemotherapy. This study is a single-arm, multicenter, prospective phase I/II study (registered with the Chinese Clinical Trial Registry as ChiCTR 2200059694 on May 8, 2022), aiming to evaluate the efficacy and safety of venetoclax plus decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (VD-CAG) for newly diagnosed AML patients who are elderly or ineligible for intensive chemotherapy. The primary endpoint was composite complete remission (CRc) after 1 cycle of induction chemotherapy. The secondary endpoints were measurable residual disease (MRD) by flow cytometry and adverse events. Forty patients(n = 40) received 1 cycle of the VD-CAG regimen for induction chemotherapy. The median age of the patients was 64 (55-81) years, and 10 patients (25%) had secondary AML. Our results showed that 1 cycle of VD-CAG had a high overall response rate of 97.5% and CRc of 95%, and all 10 patients with secondary AML achieved CRc. Moreover, the patients who achieved CRc had deep remission, with MRD-negativity of 71.1% and 54.2% by flow cytometry and molecular assessment, respectively. In addition, blood cell recovery was quick, with a median time to absolute neutrophil count ≥ 1.0 × 109/L and platelet count ≥ 100 × 109/L at 19 days and 15.5 days, respectively. In conclusion, VD-CAG demonstrates high efficacy as an induction treatment for elderly or unfit patients with newly diagnosed AML, and it could be an alternative upfront therapy for this subpopulation, Trials with large-scale subjects are needed for further validation, especially for secondary AML.

The efficacy and safety of venetoclax in newly diagnosed pediatric acute myeloid leukemia (AML) are not well-established as they are in adults. Children newly diagnosed with AML were recommended for induction therapy with venetoclax and chemotherapy or hypomethylating agents (HMAs) as per for the ChiCTR1900027146 trial. Venetoclax was administered at a consistent dose of 200 mg/m2/day for 28 days, with adjustments when used concurrently with azoles. The study measured both the remission rates and the safety assessments of venetoclax. We enrolled 45 newly diagnosed pediatric patients with AML. The complete remission rates were 94.7% in the low/middle-risk group and 80.8% in the high-risk group; MRD-negative rates were 52.6% and 38.5% in the low/middle-risk group and high-risk group, respectively. Venetoclax based combination therapy was well tolerated by the majority of patients. The median duration of venetoclax dosing was 18 days (range 9-28), with hematological toxicity and infection being the most common adverse events. Venetoclax-based induction regimens demonstrated a high response rate and safety profile in newly diagnosed pediatric AML cases. This underscores the significance of venetoclax as a viable treatment option for untreated AML, extending beyond its role as salvage therapy for refractory/relapsed AML.