Potency and efficacy of pharmacological PIP4K2 inhibitors in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL), a complex malignancy, displays varying expression profiles of PIP4K2-related genes in adult patients. While PIP4K2A expression is elevated in ALL bone marrow cells compared to healthy bone marrow cells, PIP4K2B is downregulated, and PIP4K2C remains relatively unchanged. Despite the correlation between increased PIP4K2A expression and increased percentage of peripheral blood blasts, clinical outcomes do not strongly correlate with the expression of these genes. Here we investigated the therapeutic potential of three PIP4K2 inhibitors (THZ-P1-2, a131, and CC260) in ALL cell models. THZ-P1-2 emerges as the most effective inhibitor, inducing cell death and mitochondrial damage while reducing cell viability and metabolism significantly. Comparative analyses highlight the superior efficacy of THZ-P1-2 over a131 and CC260. Notably, THZ-P1-2 uniquely disrupts autophagic flux and inhibits the PI3K/AKT/mTOR pathway, indicating a distinct molecular mechanism. In summary, our findings elucidate the differential expression of PIP4K2-related genes in ALL and underscore the potential role of PIP4K2A in disease pathogenesis. The therapeutic promise of THZ-P1-2 in ALL treatment, along with its distinct effects on cell death mechanisms and signaling pathways, enriches our understanding of PIP4K2's involvement in ALL development and offers targeted therapy prospects.

Assessing the impact of prophylactic anidulafungin during remission induction of acute myeloid leukemia - A propensity-score matching analysis.

INTRODUCTION: Invasive fungal infection (IFI) accounts for substantial morbidity during the treatment of acute myeloid leukemia (AML) in adults. Antifungal prophylaxis (AP) is needed during intensive chemotherapy, and posaconazole is not widely available. In this study, we aimed to examine the impact of prophylactic anidulafungin during intensive AML remission induction. METHODS: This is a retrospective cohort encompassing newly diagnosed AML adult patients. All subjects received intensive chemotherapy and were divided into three groups: patients who did not receive any AP and patients who received fluconazole (150-400 mg/day) or anidulafungin (100 mg/day). RESULTS: During AML induction, 82 patients did not receive AP, 108 and 14 patients received anidulafungin and fluconazole, respectively. IFI incidence was 27%, classified as possible, probable, and proven in 65, 2 and 33%, respectively. Multivariable analysis showed that lower neutrophil counts are associated with IFI (OR = 2.8), whereas age, genetic classification, and lymphocyte counts were not. To examine the impact of anidulafungin in comparison with 'no AP', a propensity score matching analysis was performed. Use of anidulafungin was not related to less IFI during induction, while neutrophil counts remained significant. Patients under prophylactic anidulafungin received less amphotericin B (p < 0.001) but not voriconazole (p = 0.49). DISCUSSION: To our knowledge, this is the first study addressing the role of anidulafungin during AML induction. Here, the incidence of mold infections did not decrease with AP, suggesting that in a setting with a high incidence of IFI, broad spectrum AP might be more suitable.

The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy.

The treatment of acute leukemia is challenging because of the genetic heterogeneity between and within patients. Leukemic stem cells (LSCs) are relatively drug-resistant and frequently relapse. Their plasticity and capacity to adapt to extracellular stress, in which mitochondrial metabolism and autophagy play important roles, further complicates treatment. Genetic models of phosphatidylinositol-5-phosphate 4-kinase type 2 protein (PIP4K2s) inhibition have demonstrated the relevance of these enzymes in mitochondrial homeostasis and autophagic flux. Here, we uncovered the cellular and molecular effects of THZ-P1-2, a pan-inhibitor of PIP4K2s, in acute leukemia cells. THZ-P1-2 reduced cell viability and induced DNA damage, apoptosis, loss of mitochondrial membrane potential, and the accumulation of acidic vesicular organelles. Protein expression analysis revealed that THZ-P1-2 impaired autophagic flux. In addition, THZ-P1-2 induced cell differentiation and showed synergistic effects with venetoclax. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed that sensitivity to THZ-P1-2 is associated with mitochondrial metabolism, cell cycle, cell-of-origin (hematopoietic stem cell and myeloid progenitor), and the TP53 pathway. The minimal effects of THZ-P1-2 observed in healthy CD34+ cells suggest a favorable therapeutic window. Our study provides insights into the pharmacological inhibition of PIP4K2s targeting mitochondrial homeostasis and autophagy, shedding light on a new class of drugs for acute leukemia.

Predictive factors associated with induction-related death in acute myeloid leukemia in a resource-constrained setting.

Despite advances in supportive measures, acute myeloid leukemia (AML) remission induction still has a high mortality rate in real-world studies as compared to prospective reports. We analyzed data from 206 AML adult patients treated with conventional chemotherapy. The primary endpoint was the 60-day mortality rate, aiming to find risk factors and to examine the role of anti-infection prophylaxis. The 60-day mortality rate was 26%, raising to 41% among those older than 60 years. Complete response was documented at the end of induction in 49%. The final survival model showed that age > 60 years (HR 3.2), Gram-negative colonization (HR 3), monocytic AML (HR 1.8), C-reactive protein (CRP) > 15 mg/dL (HR 10), and an adverse risk in the genetic stratification (HR 3) were associated with induction death. Multidrug-resistant bacteria colonization, thrombosis, and AKI were documented in 71%, 12%, and 66% of the cohort, respectively. Antibacterial and antifungal prophylaxis did not improve outcomes in this study. Our report corroborated the higher mortality during AML induction compared to real-world data from the USA and Europe. In line with other publications, age and cytogenetic stratification influenced early death in this cohort. Noticeably, Gram-negative colonization, monocytic AML, and CRP were also significant to early mortality.

Salvage treatment for refractory or relapsed acute myeloid leukemia: a 10-year single-center experience.

OBJECTIVES: The outcomes of refractory and relapsed acute myeloid leukemia (AML) patients in developing countries are underreported, even though the similar classic regimens are widely used. METHODS: We conducted a retrospective comparison of "MEC" (mitoxantrone, etoposide, and cytarabine) and "FLAG-IDA" (fludarabine, cytarabine, idarubicin, and filgrastim) in adults with first relapse or refractory AML. RESULTS: In total, 60 patients were included, of which 28 patients received MEC and 32 received FLAG-IDA. A complete response (CR) rate of 48.3% was observed. Of the included patients, 16 (27%) died before undergoing bone marrow assessment. No statiscally significant difference in CR rate was found between the two protocols (p=0.447). The median survival in the total cohort was 4 months, with a 3-year overall survival (OS) rate of 9.7%. In a multivariable model including age, fms-like tyrosine kinase 3 (FLT3) status, and stem-cell transplantation (SCT), only the last two indicators remained significant: FLT3-ITD mutation (hazard ratio [HR]=4.6, p<0.001) and SCT (HR=0.43, p=0.01). CONCLUSION: In our analysis, there were no significant differences between the chosen regimens. High rates of early toxicity were found, emphasizing the role of supportive care and judicious selection of patients who are eligible for intensive salvage therapy in this setting. The FLT3-ITD mutation and SCT remained significant factors for survival in our study, in line with the results of previous studies.

Salvage treatment for refractory or relapsed acute myeloid leukemia: a 10-year single-center experience

OBJECTIVES: The outcomes of refractory and relapsed acute myeloid leukemia (AML) patients in developing countries are underreported, even though the similar classic regimens are widely used. METHODS: We conducted a retrospective comparison of "MEC" (mitoxantrone, etoposide, and cytarabine) and "FLAG-IDA" (fludarabine, cytarabine, idarubicin, and filgrastim) in adults with first relapse or refractory AML. RESULTS: In total, 60 patients were included, of which 28 patients received MEC and 32 received FLAG-IDA. A complete response (CR) rate of 48.3% was observed. Of the included patients, 16 (27%) died before undergoing bone marrow assessment. No statiscally significant difference in CR rate was found between the two protocols (p=0.447). The median survival in the total cohort was 4 months, with a 3-year overall survival (OS) rate of 9.7%. In a multivariable model including age, fms-like tyrosine kinase 3 (FLT3) status, and stem-cell transplantation (SCT), only the last two indicators remained significant: FLT3-ITD mutation (hazard ratio [HR]=4.6, p<0.001) and SCT (HR=0.43, p=0.01). CONCLUSION: In our analysis, there were no significant differences between the chosen regimens. High rates of early toxicity were found, emphasizing the role of supportive care and judicious selection of patients who are eligible for intensive salvage therapy in this setting. The FLT3-ITD mutation and SCT remained significant factors for survival in our study, in line with the results of previous studies.

Overall survival of Brazilian acute myeloid leukemia patients according to the European LeukemiaNet prognostic scoring system: a cross-sectional study.

Prognostic stratification in acute myeloid leukemia (AML) relies, mostly, on cytogenetics and molecular features of leukemic blasts. The LeukemiaNet prognostic scoring system has been proposed as a standardized way of evaluating prognosis in AML. We have analysed outcomes in 65 AML cases (median age of 54 years, range 18-82) treated at five hematology centers in Brazil stritified according to the European Leukemia Net (ELN) recommendations for cytogenetic and molecular analysis. We classified patients as favorable (N = 13), intermediate-1 (N = 25), intermediate-2 (N = 15), or adverse risk (N = 9). Bone marrow transplantation (BMT) was performed in 13 patients (21%). Median follow-up was 12 months. The median overall survival (OS) for all patients was 12.4 months. Median OS was 19.8, 12.4, 10.1, and 10.4 months (p = 0.24) for patients in the favorable, intermediate-1, intermediate-2, and adverse groups, respectively. Among patients receiving BMT, median OS was 26.8 months. The ELN is a valuable tool for prognostic stratification of AML patients treated in Brazil. Nevertheless, its usefulness is limited when compared to data from developed countries.