Treatment Of Acute Myelogenous Leukemia Research Articles

New Approaches for the Treatment of AML beyond the 7+3 Regimen: Current Concepts and New Approaches

Fifty years have passed since the development of the first chemotherapy regimen for treating acute myelogenous leukemia (AML), with the approval in 1973 of the cytarabine daunorubicin (7+3) regimen. Until recently, patients diagnosed with AML had very limited treatment options and depended primarily on chemotherapy in combinations, doses, or schedules of the same drugs. Patients with advanced age, comorbidities, or relapsed or refractory disease were left with no effective options for treatment. New advances in the understanding of the biology and the molecular and genetic changes associated with leukemogenesis, as well as recent advances in drug development, have resulted in the introduction over the last few years of novel therapeutic agents and approaches to the treatment of AML as well as a new classification of the disease. In this article, we will discuss the new classification of AML; the mechanisms, actions, and indications of the new targeted therapies; the chemotherapy combinations; and the potential role of cellular therapies as new treatment options for this terrible disease.

Discovery of novel selective phosphodiesterase‑1 inhibitors for the treatment of acute myelogenous leukemia

Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. PDE1 (Phosphodiesterase 1) is a subfamily of the PDE super-enzyme families that can hydrolyze the second messengers cAMP and cGMP simultaneously. Previous research has shown that suppressing the gene expression of PDE1 can trigger apoptosis of human leukemia cells. However, no selective PDE1 inhibitors have been used to explore whether PDE1 is a potential target for treating AML. Based on our previously reported PDE9/PDE1 dual inhibitor 11a, a series of novel pyrazolopyrimidinone derivatives were designed in this study. The lead compound 6c showed an IC50 of 7.5 nM against PDE1, excellent selectivity over other PDEs and good metabolic stability. In AML cells, compound 6c significantly inhibited the proliferation and induced apoptosis. Further experiments indicated that the apoptosis induced by 6c was through a mitochondria-dependent pathway by decreasing the ratio of Bcl-2/Bax and increasing the cleavage of caspase-3, 7, 9, and PARP. All these results suggested that PDE1 might be a novel target for AML.

Real-World Validation of the European Leukemia Network 2022 Risk Stratification in Acute Myelogenous Leukemia

Background: The 2017 European LeukemiaNet (ELN 2017) guidelines have become foundational for the risk stratification, prognostication, and treatment of acute myelogenous leukemia (AML). The updated 2022 European LeukemiaNet (ELN 2022) guidelines include additional cytogenetic abnormalities and genetic mutations for risk group assignment. It remains unknown how these updated guidelines compare for risk stratification and prognosis. Methods: We studied (N=287) adults with newly diagnosed AML from MedStar Georgetown University, MedStar Washington Hospital Center, and Baylor University Medical Center from 2012 to June 2023. Patients were stratified as favorable (fav), intermediate (int), or adverse (adv) risk according to ELN 2017 and ELN 2022 criteria. Overall survival (OS) was compared by age, race, and sex. Statistical analysis performed with SAS. Results: Median age was 65+16 years with a predominance of males (N=168, 59%). African-Americans (AA) composed 15% (N=44) of the cohort. Myelodysplastic-related mutations were present in 33 patients (15%), whereas the prevalence of epigenetic mutations was 25% (N=55). By ELN 2017 criteria, 19 (7%) patients were characterized as fav, 64 (23%) as int, and 198 (70%) as adv risk. Using ELN 2022 criteria, 18 (6%) patients were categorized as fav, 52 (19%) as int, and 211 (75%) as adv risk. Kaplan-Meier (KM) curves revealed a median overall survival of 200 days (d), 400 d, and 1532 d in the adv, int, and fav risk groups, respectively (log-rank p<0.001) by ELN 2017 criteria. Median OS was 379 d, 527 d, and 1552 d for the adv, int, and fav groups, respectively (log-rank p<0.001) in the ELN 2022 cohort. Stratifying by age <60 years, median OS was 390 d in the adv group and 832 d in the int group (log-rank p=.021)by ELN 2017 criteria,as compared to 350 d in the adv group and 757 d in the int group (log-rank p=.0012) by ELN 2022 criteria.Among those >60 years of age, median OS was 244 d and 349 d in the adv and int groups, respectively by ELN 2017 criteria (Anova p<0.25). In the ELN 2022 cohort, median OS among those >60 years of age was 284 d for the adv group and 209 days in the int group (Anova p<0.62). Among females, median OS in the adv group was 224 d and 342 d in the int group by ELN 2017 criteria (Anova p=0.4). In the ELN 2022 cohort, median OS among females was 214 d in the adv group and 421 d in the int group (Anova p=.13). Median OS among male patients in the ELN 2017 cohort was 324 d for those of adv risk and 623 d for those of int risk (Anova p<0.004). In the ELN 2022 cohort, median OS in males was 352 d and 563 d in the adv and int groups, respectively (Anova p<0.07) . In the ELN 2017 cohort, median OS was 259 d in AA patients as compared to 719 d in non-AA patients; this was not statistically significant (Anova p=0.16). Comparatively, in the ELN 2022 cohort, median OS for the AA patients was 153 d as compared to 212 d for the non-AA patient population (Anova p=0.86) .Conclusions: In this real-world dataset, the updated ELN 2022 guidelines reproduce differential survival for proposed favorable, intermediate, and adverse risk categories. When considering time to endpoint survival [Kaplan Meier curves] in our study, ELN 2022 seems to lack the ability to clearly discriminate among the adverse and intermediate risk subgroups. It is possible that patients seen in academic institutions not participating in FLT3 directed therapy trials retained inferior survival whereas similar patients fared better through early enrollment in trials using molecular targeted therapy. Finally, neither ELN 2017 nor ELN 2022 discriminate survival in AA populations for either adverse or intermediate subgroups. Efforts should be directed to develop novel risk stratification schemas to better encapsulate this vulnerable population.

Fludarabine, Cytarabine (ARA-C) and Pegylated Erwinase (PEGCRISANTASPASE) in Patients with Relapsed or Refractory Leukemia

Background: Asparaginase, which depletes serum asparagine by breaking it down into asparagine, is part of the standard of care along with chemotherapy, in adolescent and young adult patients with acute lymphoblastic leukemia (ALL). Leukemic blasts require asparagine for survival, therefore serving as an important therapeutic target; among the mechanisms of resistance includes the upregulation of expression of asparagine synthetase (AS) (gene located in chromosome 7). Depletion of asparagine and more recently glutamine may also have an important role in the treatment of acute myelogenous leukemia, either alone or in combination with chemotherapy. Pegcristaspase (PegC) is a long-acting pegylated asparaginase derived from Erwinia that also has a glutaminase activity. We hypothesize that the combination of chemotherapy and PegC might overcome resistance and provide therapeutic benefit pts with relapsed and/or refractory leukemias. Methods: This is a phase Ib study of fludarabine, cytarabine (ara-c), and PegC in patients with relapsed or refractory leukemia (NCT 04526795). Pts received induction cycle (C) (defined as 5 weeks) with PegC on day (D) 1 and 15 as single agent. Fludarabine (30mg/m 2/D) and 4 hours later Cytarabine (1.5g/m 2/D) are given D 8 to D 11. A 3+3 dose-escalation approach was implemented to evaluate 3 different dose levels for pegcrisantaspase (level -2: 350 IU/m 2; level -1: 500 IU/m 2; and level 1: 750UI/m 2). Once the MTD is established, an expansion cohort to further evaluate safety and efficacy was opened. Endpoints included safety, overall response rate (complete remission [CR], CR with incomplete count recovery [CRi], partial remission [PR], or morphologic leukemia free state [MLFS] ) of fludarabine, araC, and pegcrisantaspase in patients with relapsed and refractory leukemias. Response was denoted as per the ELN 2017 criteria. Results: From April 2021, 15 pts have been treated on the trial, 12 (80%) pts with AML, 2 pts (13%) with ALL (one patient was Ph+ ALL), and 1 patient with isolated myeloid sarcoma. The median age was 46 years (range, 22-61), median bone marrow blasts were 37% (1-90) . 9/15 (60%) patients had complex karyotype. Patient characteristics are summarized in Table 1. The median lines of prior therapy was 4 (range, 1-9). Six pts were treated at dose level -1 and then at dose level 1. There were no dose limiting toxicities to proceed to the expansion cohort. From the 15 treated pts, 2 patients from the dose level -1 died from sepsis related to disease progression within the first 4 weeks. Overall, 3 pts (20%) responded to treatment (2CRp and 1 CRi). The patient with Ph+ B-ALL achieved CRp, proceeded to SCT, and remains alive in remission. The 2 other patients (both with AML) relapsed after 6 weeks and 4 months, respectively. The median overall survival was 2.6 months. (Figure 1) A total of 29 adverse events (AE) were noted in 13/15 patients. The most common AEs was grade ≥ grade 3 neutropenic fever (10 pts, 67%; including 2 grade 5 events). The only possibly related AE was tumor lysis syndrome in one patient, grade 3, and was successfully managed per institutional guidelines. Conclusion: In this high-risk, heavily treated population, the combination of fludarabine, cytarabine, and PegC is feasible. Responding patients included 2 AML and 1 ALL. Further exploratory analysis about the relation between response and asparagine depletion as well as specific sensitive subsets could clarify which patients might benefit the most from this combination.

Establishing an AML Ex Vivo Platform to Generate Physiologically Relevant Models

Acute myelogenous leukemia (AML) comprises a highly polyclonal and heterogeneous disease containing leukemic stem cells, progenitors, and differentiated blasts. Despite advances in treatment, the long-term relapse-free survival for AML remains poor. Due to complex mutational profiles and highly divergent subtypes in AML, the use of physiologically relevant, patient-derived models is needed. Traditional cell line models of AML almost exclusively represent differentiated blasts, are homogenous in clonality, and often do not encompass major genetic subtypes. To address these gaps, we have established a culture system that supports the growth of higher-order AML samples ex vivo. By optimizing culture conditions, we successfully cultivated 70% (10/14) of AML disseminated PDX models ex vivo and demonstrated they continue to proliferate after long term cultures. We established a 16-color flow panel to characterize their cell maturity state and show they maintain cell surface heterogeneity. Importantly, these models have not ‘drifted’ transcriptomically after multiple passages. Our platform includes 2 NPM1c mutant and 3 IDH1/2 mutant ex vivo lines, in addition to other subtypes underrepresented in traditional culture methods. Furthermore, we treated AML PDXs in vivo with a clinically-relevant dose of venetoclax + azacytidine (Ven/AZA) for 2 cycles (14 days) and then evaluated post-VEN/AZA cells in our ex vivo assay. Growing these models ex vivo, we show using our flow panel that Ven/AZA treatment shifts the differentiation status from a stem-like state to a more mature-like cell state which is consistent with literature evidence of treatment resistance. Additionally, a second PDX model treated with three cycles of Ven/AZA in vivo and harvested in ex vivo culture conditions maintained both Ven and AZA resistance. Interestingly, compared with the vehicle treatment, Ven/AZA treatment caused resistance to other cell death agents including selective MCL1 and dual Bcl2/xL inhibitors. Lastly, we performed a 7-day cell compound panel screen using common standard of care agents for the treatment of AML. Many of the targeted agent activity correlated with expected genetic subtypes, such as FLT3 inhibitors in FLT3-ITD mutants and venetoclax in WT TP53 models. This established ex vivo platform provides physiologically relevant models to explore novel target biology, better understand compound mechanism of action (MoA), and generate drug resistant models through in vivo driven clinically relevant dose scheduling using standard of care agents.

2722. Risk of Infectious Adverse Events of Venetoclax Therapy in the Treatment of Hematologic Malignancies: A Systematic Review and Bayesian Meta-Analysis of Randomized Controlled Trials

Abstract Background Venetoclax is a small molecule inhibitor of BCL-2 used in the treatment of acute myelogenous leukemia and chronic lymphocytic leukemia. Recent post-marketing studies on venetoclax suggested that it may predispose to opportunistic infections (OIs). We sought to systematically review the randomized controlled trial (RCT) evidence on venetoclax to assess whether it predisposes patients to infectious adverse events (IAEs) and neutropenia. Methods We systematically reviewed the RCTs comparing venetoclax therapy to active (i.e., a regimen with additional anti-cancer agents) or placebo controls in patients with hematologic malignancies, irrespective of treatment line. Data on IAEs and neutropenia were pooled by Bayesian meta-analysis and we computed the probability of any increased risk in infectious or neutropenic complications (Risk Ratio [RR] >1). Subgroup analyses were conducted based on treatment line, use of an inactive comparator, malignancy type, and prophylaxis strategy. Additionally, we pooled the incidence rates of fatal OIs between venetoclax and comparator arms and compared them by univariate meta-regression. Results Seven RCTs were included comprising 2067 patients. In venetoclax versus comparator regimens there was a 81.1% probability of any increase in IAEs (RR=1.14, 95% Confidence Interval [95%CI]=0.76-1.66). The probabilities of venetoclax increasing the risk of grade 3-5 and fatal IAEs were 86.6% (RR=1.16, 95%CI=0.86-1.55) and 81.1% (RR=1.40, 95%CI=0.66-2.94), respectively. There was a 97.2% likelihood that venetoclax increased the risk of grade 3-5 neutropenia (RR=1.44, 95%CI=1.01-2.10). Venetoclax treatment did not increase the incidence of fatal OIs (P=0.55). Conclusion Our results suggest that venetoclax likely increases the risk of high-grade neutropenia and IAEs overall, but not fatal OIs. However, our analyses did not identify any specific IAEs that would benefit from routine anti-infective prophylaxis or pre-emptive testing. Disclosures Michael Sebag, MD, PhD, Amgen: Advisor/Consultant|BMS: Advisor/Consultant|Focus Therapeutics: Advisor/Consultant|Gilead: Advisor/Consultant|Janssen: Advisor/Consultant|Novartis: Advisor/Consultant|Pfizer: Advisor/Consultant|Sanofi: Advisor/Consultant Matthew Cheng, MD, Amplyx Pharmaceuticals: Grant/Research Support|AstraZeneca: Advisor/Consultant|AstraZeneca: Honoraria|Cidara Therapeutics: Grant/Research Support|GEn1E lifesciences: Advisor/Consultant|GEn1E lifesciences: Stocks/Bonds|Kanvas Biosciences, Inc.: Board Member|Kanvas Biosciences, Inc.: Pending patents|Kanvas Biosciences, Inc.: Ownership Interest|Merck: Honoraria|nomic bio: Advisor/Consultant|nomic bio: Stocks/Bonds|Pfizer: Honoraria|Scynexis Inc.: Grant/Research Support|Takeda: Advisor/Consultant|Takeda: Honoraria

Financial Trends of AML Patients over the Past Decade

Background: Over the past 30 years, the incidence of acute myelogenous leukemia (AML) has progressively increased across the globe, and until recently, therapeutic options were primarily limited to the standard “7 + 3” cytotoxic chemotherapy. The economic burden associated with the management of AML has steadily increased and significantly escalated with the introduction of new targeted therapies. To our knowledge, there are very few studies that have looked at the major drivers of cost in AML treatment over the past decade and how they have evolved. Methods: We conducted a retrospective review with IRB approval of all the medical costs associated with the initial course of chemotherapy, administered in the hospital setting, in newly diagnosed AML patients at the Georgia Cancer Center (GCC) from 2011 to 2022. All medical costs were obtained through the accounting system at Augusta University Medical Center (AUMC) using the Patient Billing Department. Every direct cost from the patient's first to last day of hospitalization during which they received induction was included. Results: A total of 183 patients were identified. Patients were excluded for the following reasons: 3 patients left to receive induction elsewhere, and 2 patients left against medical advice for unclear reasons. A total of 178 newly diagnosed AML patients fit the above criteria during this period with a median age of 61 years. The median length of stay (LOS) of these 178 patients was 30 days. Between 2011 to 2016, 71 patients were treated and had a median age of 65 years, while 107 patients were treated between 2017 to 2022 with a median age of 57 years. Major drivers of total direct cost were identified which included inpatient bed (~40%), medications (~20%), blood bank products (~15%), and lab tests (~14%). Medication costs were further reviewed with breakdown as follows: chemotherapy (~3%), antibiotics (~10%), and all other medications (~7%). These medication costs were based on 340B pricing. The average and median direct costs from the above categories were compared from 2011-2016 to 2017-2022 (Table 1). The 2017-2022 group had significantly lower median and average bed cost, blood bank product cost, and overall total cost. The LOS was also noted to be shorter in the 2017-2022 group. We then analyzed the subset of patients (n=64) who received standard induction chemotherapy and excluded patients who required reinduction (n=8) or who died during induction (n=13). The same trends were identified in this subset analysis. AML patients with FLT3 mutations, which consisted of 41 of the total 178 patients, were of particular interest given the increased number of targeted therapies that have been approved since 2017. This was investigated further by comparing the direct average and median costs of the categories noted above between the 2011-2016 group with 11 FLT3+ AML patients to the 2017-2022 group with 30 FLT3+ AML patients (Table 2). The average and median medication costs, including chemotherapy, antibiotics, and all other medications, were higher in the 2017-2022 group. This resulted in the total direct cost being higher in the 2017-2022 group despite having lower blood bank and inpatient bed costs. Conclusion: Over the past decade, many significant changes have occurred in several of the driving factors associated with the cost of AML therapy. Still, there has been a decrease in length of stay, inpatient bed costs, blood bank costs, and overall total costs from 2017-2022 compared to 2011-2016. In the subset of FLT3+ AML patients, there was a shift in the financial landscape with an increase in medication costs that influenced the overall cost. It is likely that the economic impact from this will continue to grow as novel therapies become more available and the number of patients being treated continues to increase.

Hematopoietic stem cells suppress proliferation and enhance differentiation of leukemia cells through regulating apoptotic and inflammatory genes.

Stem cells are known to play an important role in tumor treatment and many of them have shown tumor-suppressing ability in different cancers; however, whether hematopoietic stem cells (HSCs) have growth-inhibiting effects on leukemia cells has not been fully evaluated. Herein, we aimed to demonstrate the growth-restraining function of HSCs in acute leukemia treatment. Cell fusion experiment was conducted by PEG-1500. The viability, proliferation, apoptosis and differentiation of leukemia cells were evaluated by cell counting, CCK-8 and flow cytometry analysis. The morphological changes were imaged using a fluorescence microscope. The expression of genes was detected by quantitative reverse transcription PCR (qRT-PCR). We observed that HSCs and their lytic extracts had the capability to suppress leukemia cells proliferation, promote apoptosis and especially induce acute myelogenous leukemia (AML) cells differentiation, which might have an effect on differentiation therapy to leukemia especially AML treatment. The expression levels of Bcl-2, Survivin decreased and Bax increased following HSCs extracts treatment. Furthermore, the expression of inflammatory cytokines also changed in AML cells which might have to do with the mechanism of HSCs/extracts suppressing effect. HSCs and their extracts can suppress the proliferation of leukemia cells and enhance the differentiation of AML cells and using the extracts of HSCs might be a probable therapeutic option for acute leukemia.

Shorter duration of venetoclax administration to 14 days has same efficacy and better safety profile in treatment of acute myeloid leukemia

Venetoclax (VEN) is now widely used in the treatment of acute myelogenous leukemia (AML) in elderly patients who are not eligible for intensive remission induction therapy. Prolonged myelosuppression, increased incidence of infection, and long duration of hospital stay were major concerns for VEN treatment cases, and we thought that shortening the duration of VEN administration during induction therapy might solve these problems. Thirteen newly diagnosed AML patients who underwent VEN+azacitidine (AZA) induction therapy from March 2021 to June 2022 at Kushiro Rosai Hospital were analyzed retrospectively. The median age was 79 (range, 68–86) years, and 8 of the patients (61.5%) were classified as high risk according to the ELN 2017 risk stratification. Eight patients received VEN for 14 days (VEN14 group), and 5 patients received VEN for 28 days (VEN28 group). The composite complete remission (CRc) rate was 76.9% in total, and the CRc rates in the VEN14 and VEN28 groups were almost the same (75.0% and 80.0%, respectively). The median overall survival (OS) was not reached in the VEN14 group and was 254 days in the VEN28 group. The median event-free survival (EFS) was not reached in the VEN14 group and was 178 days in the VEN28 group. The VEN14 group might have a possibility to reduce febrile neutropenia (37.5% vs. 80%) and reduce the duration of hospital stay (median, 21.5 vs. 31 days) compared with the VEN28 group. VEN14 produced the same CRc rate and survival rate, safer profile, and shorter duration of hospital stay than VEN28.

Defining Primary Vs Secondary AML: Correlation between Pathology and NGS/FISH

Introduction: The treatment of acute myelogenous leukemia (AML) is often determined by factors that include an antecedent dysplasia. At presentation it is often unknown whether a patient has had dysplastic bone marrow features or not. We opted to look back at our leukemia patients to determine the frequency of antecedent dysplasia and to determine if next generation sequencing (NGS) or Florescent in situ hybridization (FISH) findings correlate with the pathologic review. Methods: We chart reviewed 43 charts from a period of 9/21/2021 to current from Orlando Health records. We focused on 29 charts that we could gather complete information from. We reviewed initial bone marrow biopsies and NGS/ FISH findings. We determined if a patient had a known history of myelodysplasia from previous records. If there was no known history of myelodysplastic syndrome (MDS) but dysplasia was seen on the bone marrow biopsy, we looked at NGS/FISH. While there can be overlap with AML, findings that suggest MDS are as follows: NGS: TET2, NRAS, U2AF1, RUNX1, TP53, SF3B1 FISH: 5q-, -5 (5p15, 5q31, 5q33), 7q-, -7 (Cen 7, 7q22, 7q31), Trisomy 8 (Cen 8), MLL (11q23), 20q- (20q12, 20qter) We then examined what treatments were used based on these findings. Results: Overall: 11/29 patients had dysplasia mentioned in their initial pathology report. 4/11 had a known preexistent dysplasia. Of the 7 who didn't have known dysplasia, 6/7 had an NGS or FISH suggesting MDS. Age: Of the patient who had dysplastic findings as well as NGS/FISH to support those findings, the patients had an average age of 57. The one patient without MDS/FISH findings has an age of 69. The average age of all patients with dysplastic findings on their bone marrow was 60. Of the patients who did not have any dysplastic findings on the bone marrow, the average age was 58. Treatment: Vyexos (liposomal daunorubicin and cytarabine), a therapy generally used for secondary leukemias was only used in two patients. Age and performance status was cited as a reason to use alternative therapy. Although one patient did receive 7+3 (idarubicin and cytarabine) instead of Vyxeos. One patient also had severe COVID pneumonia at diagnosis as the reason for not getting induction with Vyexos and instead getting venetoclax/azacitidine. Four patients were either treated with hypomethylating agent of either azacitidine or decitabine, again this was normally chosen due to performance status, age, or active COVID pneumonia as above. Conclusion: These results show that pathology findings of underlying dysplastic changes seem to correlate with NGS or FISH findings. Of the 7 patients with these bone marrow changes but no known MDS, 6 of them had NGS or FISH to support an underlying disease. Factors such as age did not help to predict antecedent MDS. Based on this information it may be appropriate to start with induction therapies such as Vyxeos when dysplastic changes are seen on the bone marrow while FISH and NGS are still pending, if their performance status and age allow to do so. Further larger retrospective studies to compare underlying dysplastic findings versus FISH/NGS findings should be done to further support this concept.

Efficient delivery of the Bcl-2 antisense oligonucleotide G3139 via nucleus-targeted aCD33-NKSN nanoparticles

G3139 is an antisense oligodeoxyribonucleotide (ODN) developed as a Bcl-2 down-regulating agent for the treatment of acute myelogenous leukemia (AML). However, the clinical efficacy of G3139 has been shown to be limited due to its rapid plasma clearance and low permeability. To enhance the effective delivery of G3139, this work prepared a novel nano gene delivery vector (aCD33-NKSN) consisting of a CD33 antigbody (aCD33), a nuclear localization signal (NLS), gene fusion peptides (KALA), and stearic acid (SA) for CD33 antigen targeting and nuclear localization. The aCD33-NKSN/G3139 nanoparticles were spherical and uniformly sized with a positive charge and sustained release. They had an excellent G3139 loading capacity and colloidal stability. The aCD33-NKSN/G3139 delivered G3139 into the nucleus of Kasumi-1 cells and aCD33-NKSN/G3139 could more effectively inhibited Bcl-2 expression and induced apoptosis in Kasumi-1 cells versus free G3139. The aCD33-NKSN/G3139 administration was more effective at inhibiting tumor growth, and significantly prolonged the survival time of mice in contrast to free G3139. The results illustrate that aCD33-NKSN/G3139 nanoparticles could improve the antitumor activity of encapsulated G3139 due to aCD33 targeting and the ability to perform nuclear localization, The results offer a promising clinical application potential for the treatment of acute myeloid leukemia.

Stabilization of SAMHD1 by NONO is crucial for Ara-C resistance in AML

Cytarabine (Ara-C) is the first-line drug for the treatment of acute myelogenous leukemia (AML). However, resistance eventually develops, decreasing the efficacy of Ara-C in AML patients. The expression of SAMHD1, a deoxynucleoside triphosphate (dNTP) triphosphohydrolase, has been reported to be elevated in Ara-C-resistant AML patients and to play a crucial role in mediating Ara-C resistance in AML. However, the mechanism by which SAMHD1 is upregulated in resistant AML remains unknown. In this study, NONO interacted with and stabilized SAMHD1 by inhibiting DCAF1-mediated ubiquitination/degradation of SAMHD1. Overexpression of NONO increased SAMHD1 expression and reduced the sensitivity of AML cells to Ara-C, and downregulation of NONO had the opposite effects. In addition, the DNA-damaging agents DDP and adriamycin (ADM) reduced NONO/SAMHD1 expression and sensitized AML cells to Ara-C. More importantly, NONO was upregulated in Ara-C-resistant AML cells, resulting in increased SAMHD1 expression in resistant AML cells, and DDP and ADM treatment resensitized resistant AML cells to Ara-C. This study revealed the mechanism by which SAMHD1 is upregulated in Ara-C-resistant AML cells and provided novel therapeutic strategies for Ara-C-resistant AML.

Identification of Human Dihydroorotate Dehydrogenase Inhibitor by a Pharmacophore-Based Virtual Screening Study.

Human dihydroorotate dehydrogenase (hDHODH) is an enzyme belonging to a flavin mononucleotide (FMN)-dependent family involved in de novo pyrimidine biosynthesis, a key biological pathway for highly proliferating cancer cells and pathogens. In fact, hDHODH proved to be a promising therapeutic target for the treatment of acute myelogenous leukemia, multiple myeloma, and viral and bacterial infections; therefore, the identification of novel hDHODH ligands represents a hot topic in medicinal chemistry. In this work, we reported a virtual screening study for the identification of new promising hDHODH inhibitors. A pharmacophore-based approach combined with a consensus docking analysis and molecular dynamics simulations was applied to screen a large database of commercial compounds. The whole virtual screening protocol allowed for the identification of a novel compound that is endowed with promising inhibitory activity against hDHODH and is structurally different from known ligands. These results validated the reliability of the in silico workflow and provided a valuable starting point for hit-to-lead and future lead optimization studies aimed at the development of new potent hDHODH inhibitors.

Cytarabine delivered by CD44 and bone targeting redox-sensitive liposomes for treatment of acute myelogenous leukemia.

Acute myelogenous leukemia (AML) remains a serious fatal disease for the patients and effective treatment strategies are urgently needed. Based on the characteristics of the AML, we developed the CD44 and bone targeting liposomes delivery system decorated with the redox-cleavable polymer. First, ALN-HA was obtained by amination between alendronate (ALN) and hyaluronic acid (HA), and cholesterol (Chol) was coupled by a disulfide linker (-SS-) with biological reducibility to obtain the goal polymer, ALN-HA-SS-Chol, decorated the liposomes loaded with the Cytarabine (AraC). ALN-HA-SS-AraC-Lip exhibited a spherical morphology with the diameter of 117.5 nm and expanded at the environment of 10 mM dithiothreitol. Besides, compared with other groups, ALN-HA-SS-AraC-Lip showed benign hydroxyapatite affinity in vitro and bone targeting in C57/BL6 mice, also, ALN-HA-SS-AraC-Lip exhibited encouraging antitumor which significantly reduced the white blood cell amount in bone marrow and blood smear caused by AML model, besides, the dual targeting liposomes also prolong the survival time of mice. In conclusion, the bone and CD44 dual targeting liposomes with redox sensitivity could target to the leukemia stem cells regions and then uptake by the tumor cells, which would be a valuable target for the treatment of the AML.

Nano-drug delivery system for the treatment of acute myelogenous leukemia.

Administration of therapeutic drugs has been the core strategy for acute myelogenous leukemia (AML), but it is generally limited by its low bioavailability, toxic side effects and intravenous administration. The nano-drug delivery system significantly improves the anti-AML activity through targeted optimization of the drug delivery system. Organic nanocarriers include polymers, liposomes, nanoemulsion, nanomicelle and proteins, which have the advantages of high loading capacity, biocompatibility and functionalization. Inorganic nanocarriers include gold nanoparticles, silicon nanoparticles, iron nanoparticles and other inorganic nanoparticles, which exhibit diverse physical and chemical properties, and have a wide range of biomedical applications including drug carriers. Both organic and inorganic nanocarriers exhibit the potential to alter the pharmacokinetics and pharmacodynamics of drugs. This article reviews the recent progress of nanocarriers as drug delivery system in clinical applications of AML treatment.

Treatment stratification by fitness for chemotherapy in acute myeloid leukemia

Acute myelogenous leukemia (AML) is a hematopoietic malignancy that is characterized by clonal autonomous proliferation of myeloid cells with impaired differentiation and maturation. Recent advances in next-generation sequencing technology have elucidated the pathogenesis of AML at the genetic level. Furthermore, the molecular targeted therapy to efficiently eradicate leukemic cells has been rapidly expanding since 2017. In Japan, gilteritinib and quizartinib, which target FMS-like tyrosine kinase 3, and venetoclax, which targets B-cell lymphoma 2, have finally become available after resolving the drug launch lag between Japan and the United States. The combination of venetoclax and azacitidine, which was simultaneously approved with venetoclax for AML, is expected to be more effective than conventional therapy in patients who are ineligible for transplantation. Herein, we review the National Comprehensive Cancer Network guidelines for intensive chemotherapy in Japan and the United States and discuss the future of AML treatment, including the development of novel agents.

Dr. Elihu H. Estey (1946–2021)

Dr. Elihu H. Estey (1946–2021)

FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells

FMS-like tyrosine kinase 3 (FLT3) in hematopoietic cells binds to its ligand at the plasma membrane (PM), then transduces growth signals. FLT3 gene alterations that lead the kinase to assume its permanently active form, such as internal tandem duplication (ITD) and D835Y substitution, are found in 30–40% of acute myelogenous leukemia (AML) patients. Thus, drugs for molecular targeting of FLT3 mutants have been developed for the treatment of AML. Several groups have reported that compared with wild-type FLT3 (FLT3-wt), FLT3 mutants are retained in organelles, resulting in low levels of PM localization of the receptor. However, the precise subcellular localization of mutant FLT3 remains unclear, and the relationship between oncogenic signaling and the mislocalization is not completely understood. In this study, we show that in cell lines established from leukemia patients, endogenous FLT3-ITD but not FLT3-wt clearly accumulates in the perinuclear region. Our co-immunofluorescence assays demonstrate that Golgi markers are co-localized with the perinuclear region, indicating that FLT3-ITD mainly localizes to the Golgi region in AML cells. FLT3-ITD biosynthetically traffics to the Golgi apparatus and remains there in a manner dependent on its tyrosine kinase activity. Tyrosine kinase inhibitors, such as quizartinib (AC220) and midostaurin (PKC412), markedly decrease FLT3-ITD retention and increase PM levels of the mutant. FLT3-ITD activates downstream in the endoplasmic reticulum (ER) and the Golgi apparatus during its biosynthetic trafficking. Results of our trafficking inhibitor treatment assays show that FLT3-ITD in the ER activates STAT5, whereas that in the Golgi can cause the activation of AKT and ERK. We provide evidence that FLT3-ITD signals from the early secretory compartments before reaching the PM in AML cells.

S3650 Isolated Direct Hyperbilirubinemia After Cytarabine for the Treatment of Acute Myelogenous Leukemia

S3650 Isolated Direct Hyperbilirubinemia After Cytarabine for the Treatment of Acute Myelogenous Leukemia

Safety and Efficacy of Pembrolizumab Prior to Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia

Programmed death 1 (PD-1) is an integral component of acute myelogenous leukemia (AML) immune evasion, chemotherapy resistance, and disease progression. PD-1 inhibitors are being investigated as treatment for AML in combination with hypomethylating agents and cytotoxic chemotherapy with encouraging findings. Although allogeneic stem cell transplantation (alloSCT) remains the most established curative treatment for patients with relapsed and refractory AML in complete remission, there are limited data on the clinical outcomes and safety of immune checkpoint inhibitors (ICIs) prior to alloSCT in AML. In the present study, we compared clinical outcomes of 9 patients with AML receiving high-dose cytarabine followed by pembrolizumab in a phase II clinical trial (NCT02768792) prior to alloSCT versus a historical control group of 18 AML patients who underwent alloSCT without prior ICI exposure. The nonparametric Jonckheere-Terpstra test was used to test for a difference in the ordered severity categories of acute graft-versus-host disease (GVHD) within 100 days of transplantation. Time-to-event estimates for overall survival and relapse-free survival were calculated using the Kaplan-Meier method and compared using a log-rank test. One-year survival was not significantly different between the treatment groups (67% versus 78%; P=.34). 100-day mortality was 0% in the ICI group versus 17% in the control group, and there was no increase in grade III-IV acute GVHD in patients treated with pembrolizumab prior to alloSCT. No chronic GVHD was seen in patients treated with pembrolizumab prior to alloSCT and who received post-transplantation cyclophosphamide (PTCy) as part of their conditioning regimen. These findings reinforce the safety and feasibility of ICI therapy prior to alloSCT in patients with AML, and suggest that PTCy may abrogate GVHD risk and severity in patients who receive ICI prior to undergoing alloSCT for AML.