Chemotherapy For Acute Myeloid Leukemia Research Articles

5-Demethylnobiletin Inhibits Cell Proliferation, Downregulates ID1 Expression, Modulates the NF-κB/TNF-α Pathway and Exerts Antileukemic Effects in AML Cells.

Acute myeloid leukemia (AML) is characterized by the dysregulation of hematopoietic cell proliferation, resulting in the accumulation of immature myeloid cells in bone marrow. 5-Demethylnobiletin (5-demethyl NOB), a citrus 5-hydroxylated polymethoxyflavone, has been reported to exhibit various bioactivities, such as antioxidant, anti-inflammatory and anticancer properties. In this study, we investigated the antileukemic effects of 5-demethyl NOB and its underlying molecular mechanisms in human AML cells. We found that 5-demethyl NOB (20–80 μM) significantly reduced human leukemia cell viability, and the following trend of effectiveness was observed: THP-1 ≈ U-937 > HEL > HL-60 > K562 cells. 5-Demethyl NOB (20 and 40 μM) modulated the cell cycle through the regulation of p21, cyclin E1 and cyclin A1 expression and induced S phase arrest. 5-Demethyl NOB also promoted leukemia cell apoptosis and differentiation. Microarray-based transcriptome, Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) of differentially expressed genes (DEGs) analysis showed that the expression of inhibitor of differentiation/DNA binding 1 (ID1), a gene associated with the GO biological process (BP) cell population proliferation (GO: 0008283), was most strongly suppressed by 5-demethyl NOB (40 μM) in THP-1 cells. We further demonstrated that 5-demethyl NOB-induced ID1 reduction was associated with the inhibition of leukemia cell growth. Moreover, DEGs involved in the hallmark gene set NF-κB/TNF-α signaling pathway were markedly enriched and downregulated by 5-demethyl NOB. Finally, we demonstrated that 5-demethyl NOB (20 and 40 μM), combined with cytarabine, synergistically reduced THP-1 and U-937 cell viability. Our current findings support that 5-demethyl NOB dramatically suppresses leukemia cell proliferation and may serve as a potential phytochemical for human AML chemotherapy.

Alternative chemotherapy for acute myeloid leukemia with Down syndrome

Abstract Myeloid leukemia with Down syndrome (ML-DS) is a unique entity of acute myeloid leukemia (AML) with superior treatment response and overall survival compared with children with AML. However, despite the advances in treatment approaches, ML-DS survival rates for children in low- and middle-income countries remain poor. In this article, we describe 3 cases of ML-DS, which were treated with a novel protocol using vincristine, cytarabine, and daunorubicin plus triple intrathecal drugs. All the 3 patients successfully finished the treatment, with 2 patients in complete remission until now. One patient died because of uncontrolled bleeding for 2 days after finishing the chemotherapy regimen. Our findings indicate that using our treatment protocol, ML-DS is treatable in limited-resource settings such as that in Manado, Indonesia.

Association of leukocyte nadir with complete remission in Indonesian acute myeloid leukemia patients undergoing 7+3 remission induction chemotherapy.

Background: The 7+3 regimen is still the main choice of remission induction chemotherapy in acute myeloid leukemia (AML). Successfully achieving complete remission (CR) and the time required to achieve it determine patient's survival. Hence, bone marrow examination on 14 th day of chemotherapy is recommended to predict CR. However, the examination is invasive and still inaccurate. Methods: A prognostic study with retrospective cohort design was conducted at two central hospitals in Indonesia based on medical record data of AML patients who underwent 7+3 induction chemotherapy from January 1st, 2015, to December 31st, 2019. The association of nadir leukocyte level and the time required to achieve it with CR occurrence was assessed. Results: One hundred and one subjects were recruited with median age 39 years and 55% men. A total of 55.4% subjects achieved CR. Nadir leukocyte level below 200/mcl was the most optimal cut-off point and independently associated with CR (OR 2.48; 95% CI 1.03-5.97) while time required to achieve it was not. Conclusions: The nadir leukocyte level is associated with an increase probability of CR but not for the time required to achieve it in AML patients undergoing 7+3 induction chemotherapy.

Hemostatic and thrombotic parameters in acure leukemia- A comparison of pre and post remission induction phase

This study was aimed to compare hemostatic, fibrinolytic and thrombotic parameters in pre and post induction chemotherapy in acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). A total of 110 diagnosed acute leukemia patients and 40 normal individuals were enrolled in the study. Questionnaire were filled and patients’ blood specimens were collected before the commencement and post induction chemotherapy. Prothrombin time (PT), activated partial thromboplastin time (aPTT), von Willebrand factor antigen (vWF Ag), fibrinogen level, factor VIIIc (FVIIIc), D-Dimers, fibrinogen degradation products (FDPs), anti-thrombin III (AT), lupus anticoagulant (LA), protein C (PC), protein S and diluted russel viper venom test (DRVVT) were conducted in all the participants. A significant rise was identified in post-induction levels of PT, aPTT, vWF Ag, fibrinogen and factor VIII in acute leukemia patients. Analysis of fibrinolytic markers indicated increased D-Dimers and plasminogen levels while the levels of alpha 2 anti-plasmin were reduced in pretreated patients. Thrombotic markers’ assessment showed increased levels of AT and LA while decreased level of PC in pretreated acute leukemia patients. It was concluded that remission induction chemotherapy, in acute leukemia patients, significantly affects the coagulation, fibrinolytic and thrombotic parameters.

PB1776: ABC TRANSPORTERS AFFECT THE SENSITIVITY OF ACUTE MYELOID LEUKEMIA BLASTS TO CHEMOTHERAPY

Background: Approximately 40 % of acute myeloid leukemia (AML) patients does not achieve a complete hematologic remission (CR) after the first cycle of 3 + 7 induction therapy and thus face an adverse prognosis. Mechanisms of chemoresistance are still poorly understood, but drug export from cytosol plays a crucial role. 7 ABC transporters (ABCA2, ABCA5, ABCB1, ABCB6, ABCC1, ABCC3, ABCG2) were selected from literature for expression, methylation, genotype and efflux activity analysis. Aims: The aim of this study is to clarify the role of selected ABC transporters in reduced sensitivity to chemotherapy in AML. Methods: Peripheral blood was collected at diagnosis (day 0) and at the third day of 3 + 7 therapy (day 3). Leukemic blasts were separated on MACS (CD34+ or CD117+, Miltenyi Biotec). Gene expression was measured on StepOne Plus (Applied Biosystems) using TaqMan assays, B2M and YWHAZ were used as reference genes (n=85). Promotor, exons and splicing regions were sequenced on MiSeq (V2, Illumina) using Roche reagents (n=109). Methylation analysis was performed on Pyromark Q24 (Qiagen) for 85 CpGs in promoters of ABCA2, ABCC1 and ABCG2 (n=51). Efflux activity was assessed with Efflux-ID kit (Enzo) (n=12). For data analysis, we divided patients by primary response status into responding and refractory group based on a CR achievement after the first cycle of 3 + 7 therapy. Data analysis was performed in GraphPad Prism 9.1.2 and R software 4.0.0. Results: Higher expression of ABCA2 (p=0.005), ABCA5 (p=0.016), ABCC1 (p<0.0001) and ABCG2 (p=0.001) at day 0 was associated with primary treatment failure. ABCA2 (p=0.018) and ABCC1 (p=0.008) remained significant in the Cox regression analysis adjusted to age, leukocyte count at diagnosis and ELN risk stratification. Moreover, higher number of concurrently overexpressed ABC transporters (threshold defined by Cutoffinder) was predictive of failure in CR achievement (p=0.006) by Cox regression. We detected a significant rise of expression at day 3 in ABCA5 (p=0.003), ABCB6 (p=0.001) and ABCC3 (p<0.0001). Significantly higher rise of ABCC3 (p=0.029) expression was detected in responders compared to refractory patients. In terms of a CR achievement, we identified 6 unfavorable DNA variants (rs2301837, rs8077268, rs17563146, rs1373970189, rs113369901, 9:137022522-137022522), and 3 favorable DNA variants (rs556735807, rs2235048, rs1407267536). The risk variant rs113369901 correlated with higher expression of ABCC1 (p=0.039), which was also associated with chemoresistance. Cox regression analysis confirmed prognostic relevance for four variants: rs2301837 (p=0.032), rs8077268 (p=0.033), 9:137022522-137022522 (p=0.003) and rs1373970189 (p=0.039). Higher methylation of ABCG2 promoter correlated with its lower expression (p=0.0001). Promoters of ABCA2 and ABCC1 were basically unmethylated, especially ABCC1, which had the highest expression among the studied genes. The greatest contribution to cell efflux had transporters inhibited by MK-571 inhibitor, following by Verapamil. These influence activity of ABCC1 and ABCB1. Summary/Conclusion: We described differences in expression levels and genetic variants of selected ABC transporters in association with treatment response in AML. ABCC1 seems to contribute substantially as illustrated by expression, genotyping, DNA methylation as well as activity data. With such detailed knowledge of chemoresistance mechanisms in leukemic cells and an emergence of new drugs, a different therapeutic strategy for chemoresistant patients may be considered in the future. Supported by MHCR (00023736, IHBT).

PB1748: DIFFERENTIAL IRON HOMEOSTASIS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA IN VITRO MODELS

Background: Iron is an essential element which plays several physiological activities in different human organs. Current studies suggest that dysregulation of iron proteins and subsequent accumulation of iron are associated with the response of leukemia to treatments. In particular, it has been reported that low levels of ferroportin-1 (FPN1), lead to an increased sensitivity to chemotherapy in acute myeloid leukemia. Aims: We aimed at analyzing the gene expression profile of iron-related genes in childhood B acute lymphoblastic leukemia (ALL) and characterize the iron metabolism in vitro models. Methods: Iron related genes (Ceruloplasmin (CP), Ferroportin-1 (SLC40A1), Transferrin Receptor 1 (TFR1) and Ferritin Light Chain (FTL)) were analyzed by qRT-PCR in BM samples of 87 childhood ALL and 8 healthy donors. Cases were selected to be representative of t(12;21), t(4;11), t(9;22) or t(1;19) subgroups, as well as MRD-based standard-risk (SR), medium-risk (MR) and high-risk (HR) response. Furthermore, we evaluated the cellular viability in REH, RS4;11, 697 and TOM-1 cell lines after exposure to iron as ferric ammonium citrate (FAC 100 to 400 µM), deferoxamine (DFO 25 µM) and FAC+DFO (100 µM + 25 µM), using MTT assay at 24-48 and 72h. TFR1 and FTL mRNA levels were assessed at 8h, 16h, 24h, 48h. Labile Iron Pool (LIP) was measured by flow-cytometry using Calcein-AM technique after the exposure to FAC (100-200-400 µM) at 48h. Results:TFR1, SLC40A1 and CP were up-regulated in HR group vs. controls. SLC40A1 and CP were down-regulated in all genetic subgroups, except for CP in t(9;22). TFR1 was slightly expressed in all subgroups. In the t(1;19) subgroup all the iron genes were downregulated, suggesting that this subgroup may not be responsive to iron, as also confirmed by our in vitro data. Iron supplementation by FAC [100 µM] resulted in a boost of viability for TOM-1, REH and RS4;11. TOM-1 and REH viability decreased with FAC 200-400 µM, while RS4;11 proliferation was stimulated by all concentrations. Together with low transcriptional levels of iron genes, 697 viability did not change with different FAC treatments. DFO reduced cell viability in a time-dependent manner. At 48h the viability started to drop for all cell lines (TOM-1 80% - RS4;11 66% - REH 71% - 697 51%) and the co-administration of iron restored the viability to levels similar or even higher than the untreated (TOM-1 100%-RS4;11 80% -REH 92% - 697 81%). FTL expression was significantly up-regulated in all cell lines, while the TFR1 was down-regulated at 8, 16 and 24h vs. untreated. Still, some differences were detected within the cellular models: RS4;11 showed highest level of FTL expression, while in 697 the transcript was slightly upregulated. In 697 cell line, the LIP increased with higher dosages of FAC, suggesting that this cell line was not able to handle high amount of free iron. TOM-1, RS4;11 and REH presented LIP levels higher than the untreated condition, still no significant differences were noticed between the concentrations. Summary/Conclusion:SLC40A1 and CP high levels of HR group potentially suggest that their refractory behavior may be correlated with ability to keep regulate iron intracellular concentration. TOM-1, REH and RS4;11 behave as resistant cell lines, whilst the 697 appear as not sensitive to iron metabolism. In conclusion, leukemia cell lines can be considered as trustable in vitro models for further studies in ALL to investigate whether iron metabolism can be determinant for survival and resistance, and consequently a target for treatment.

Daunorubicin-60 versus daunorubicin-90 versus idarubicin-12 for induction chemotherapy in acute myeloid leukemia: a retrospective analysis of the Mayo Clinic experience.

Not available.

P387: UNRAVELING LEUKEMIC STEM CELLS MITOCHONDRIAL DEPENDENCY IN PEDIATRIC ACUTE MYELOID LEUKEMIA

Background: Relapse still represents an unsolved problem for children with acute myeloid leukemia (AML), therefore more effective therapeutic strategies are needed for a complete blasts eradication. Leukemic stem cells (LSCs) have been proposed as the therapy-resistant reservoir of cells responsible for failure of antiproliferative chemotherapy and disease recurrence in AML due to their self-renewal capacity and quiescence allowing evasion from chemotherapy. Thus, the identification of LSCs-specific vulnerabilities is needed for more efficacious treatments. Aims: We aim to dissect novel LSCs characteristics to unravel mechanisms of chemoresistance and disease recurrence, and characterize biological properties of LSCs that can be targeted to completely eradicate AML. Methods: To study LSCs derived from primary pediatric AML samples, we based on reactive oxygen species (ROS) content since it was shown that functionally defined LSCs have relatively low levels of ROS. We isolated the lowest 20% of cells fluorescing with CellROX probe (ROS low) and the highest 20% (ROS high) by cell sorting, and analyzed cell cycle, engraftment in mice and RNA sequencing to identify deregulated pathways. Results: After isolating ROS low and ROS high cells, we first assessed classical stemness features. By colony-forming assay, we observed that ROS low and ROS high cells have similar colony-forming capacity, but only ROS low cells preserve this capacity after a second replating whereas the ROS high population does not (p=0.002). By BrdU assay, we found that ROS low cells are relatively dormant, being more in G0/G1 cell cycle phase (41.9%) than the ROS high counterpart (7.9%, p=0.001), also confirmed by CFSE staining, revealing that ROS low cells proliferate more slowly (at day 4, 31% undivided cells in ROS low vs 8% in ROS high). According to our previously published data, we confirmed that ROS low cells express higher levels of CDK6-AS1 (RQ=1.38) and CDK6 genes (RQ=2.69; RQ=1 for ROS high) and that, being more quiescent, are characterized by lower levels of mitochondrial membrane potential by TMRE and lower content of mitochondrial ROS, byproducts of mitochondrial activity, by MitoSOX staining. We also verified that ROS low cells have a lower mitochondrial mass by MitoTracker and TOMM20 staining (mitochondria to nucleus ratio 1.18 vs 1.35 for ROS high, p=0.0005), suggesting that mitochondrial mass and functions might be involved in quiescent cells properties. However, engraftment experiments did not reveal different capacity of ROS low or ROS high cells in recreating leukemia in NSG mice, neither in terms of human CD45+ cells in mice peripheral blood (23.3% vs 41.9% respectively, p=0.12) nor bone marrow infiltration (73% vs 84.8%, p=0.44) at 8 weeks post-engraftment, opening for further dissection of the presence of LSCs within ROS high cells. By RNA sequencing, we found that the top 150 differentially expressed genes between ROS low and ROS high cells are involved in focal adhesion (logP=-13.51), regulation of hemopoiesis (logP=-12.31), cell response to stress (logP=-8.73) and cytokine production (logP=-8.67). Further analyses will confirm the role of these pathways in maintaining ROS low LSCs. Moreover, we identified 5 differentially expressed surface antigens that are under investigation as putative ROS low LSCs markers. Summary/Conclusion: In conclusion, the ROS low strategy permits to identify a quiescent AML subpopulation with peculiar mitochondrial features and transcriptome allowing to pinpoint novel molecular pathways that might be targeted to enhance LSCs clearance.

Efficacy of conventional-dose cytarabine, idarubicin and thioguanine versus intermediate-dose cytarabine and idarubicin in the induction treatment of acute myeloid leukemia: Long-term results of the prospective randomized nationwide AML-2003 study by the Finnish Leukemia Group.

AML-2003 study sought to compare the long-term efficacy and safety of IAT and IdAraC-Ida in induction chemotherapy of acute myeloid leukemia (AML) and introduce the results of an integrated genetic and clinical risk classification guided treatment strategy. Patients were randomized to receive either IAT or IdAraC-Ida as the first induction treatment. Intensified postremission strategies were employed based on measurable residual disease (MRD) and risk classification. Structured questionnaire forms were used to gather data prospectively. A total of 356 AML patients with a median age of 53 years participated in the study. Long-term overall survival (OS) and relapse-free survival (RFS) were both 49% at 10 years. The median follow-up was 114 months. No significant difference in remission rate, OS or RFS was observed between the two induction treatments. Risk classification according to the protocol, MRD after the first and the last consolidation treatment affected the OS and RFS significantly (p < .001). Intensified cytarabine dose in the first induction treatment was not better than IAT in patients with AML. Intensification of postremission treatment in patients with clinical risk factors or MRD seems reasonable, but randomized controlled studies are warranted in the future.

#41 Manual Validation of an Automated Tool to Extract Blood Culture and Susceptibility Data from the Electronic Health Record for Children with Acute Myeloid Leukemia

Abstract Background Children with acute myeloid leukemia (AML) receive high-intensity chemotherapy to achieve durable remission. AML chemotherapy causes bone marrow suppression resulting in vulnerability to infection, most frequently bloodstream infections (BSI). While the most commonly described organisms include Gram-negative pathogens and streptococci, the epidemiology and resistant profile of these pathogens can change. It is important to monitor the epidemiology of these infections over time to inform clinical care. Previously capture of these microbiology data required laborious manual chart reviews that are often done intermittently and with variable accuracy, limiting the impact of the results. We sought to develop and validate an automated process for extracting blood culture results, including antimicrobial susceptibility profiles for positive results from the electronic health record (EHR). Method An automated tool to extract blood culture results from the EHR (Epic Systems, Verona WI) was developed using SQL (Structured Query Language). The tool was applied to the EHR of all children with newly diagnosed AML treated at the Children’s Hospital of Philadelphia from January 1, 2011 to December 31, 2020, regardless of subsequent relapse and treatment. Data from all blood cultures (including standard, fungal, mycobacterial, and subacute bacterial endocarditis blood cultures) were captured. Manual chart review was performed by an Infectious Diseases physician to abstract the same blood culture results to determine accuracy of the automated extraction tool. The manual abstraction was considered the gold standard. The BSI epidemiology of AML patients during this time period were described to illustrate the utility of this tool. Results There were 91 children with newly diagnosed AML who received chemotherapy during the study period. Of the collected 3,150 cultures obtained and resulted, 206 (6.5%) were positive. There were 37 distinct pathogens identified (Table 1). Of positive cultures, 114 (55.3%) were reflexed to antimicrobial susceptibility testing (AST) per institutional standards. In total, 1,427 AST results were captured in the automated tool. Manual validation confirmed that concordance between the automated abstraction and chart review was 100% for the organisms grown on culture and accurately identified all AST results. The majority of organisms were Gram-positive. The most frequently identified species was Streptococcus mitis/oralis, found in 40/206 (19.4%) of positive cultures (Table 1). Of S. mitis/oralis that underwent AST, only 8/21 (38.1%) were susceptible to penicillin. Escherichia coli was the most common Gram-negative pathogen. Candida spp. accounted for 9.3% of detected pathogens, with C. krusei identified most commonly. Conclusion We developed and automated tool to extract blood culture results from the EHR of children and adolescents with AML at a single center. This tool was manually validated and found to be 100% accurate. This tool has the ability to efficiently capture the BSI epidemiology of a specific patient population at high risk for BSI. Further work is needed to confirm the accuracy of this tool at more centers. Implementation at other sites will allow this tool to be employed for various purposes including large, multicenter epidemiology research studies or quality improvement projects.

Phase 1/2 Trial of CLAG-M with Dose-Escalated Mitoxantrone in Combination with Fractionated-Dose Gemtuzumab Ozogamicin for Newly Diagnosed Acute Myeloid Leukemia and Other High-Grade Myeloid Neoplasms.

Simple SummarySeveral studies have demonstrated that gemtuzumab ozogamicin (GO) improves outcomes with intensive chemotherapy in some adults with acute myeloid leukemia (AML), but it has remained unclear which dosing schedule of GO is best. Here, we conducted a phase 1/2 study in 66 adults with newly diagnosed AML or other high-grade myeloid neoplasm, and found that a fractionated dosing schedule of GO (GO3) can be safely combined with cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone (CLAG-M). Fifty-two out of sixty (87%) patients treated with CLAG-M/GO3 achieved a complete remission (CR)/CR with incomplete hematologic recovery (CRi), 45/52 (87%) without flow cytometric measurable residual disease. Six- and twelve-month event-free survival were 73% and 58%; among favorable-risk patients, these estimates were 100% and 95%. Compared to 186 medically matched adults treated with CLAG-M alone, CLAG-M/GO3 was associated with better survival in patients with favorable-risk disease. These data indicate that CLAG-M/GO3 is safe and more efficacious than CLAG-M alone in favorable-risk AML/high-grade myeloid neoplasm.Gemtuzumab ozogamicin (GO) improves outcomes when added to intensive AML chemotherapy. A meta-analysis suggested the greatest benefit when combining fractionated doses of GO (GO3) with 7 + 3. To test whether GO3 can be safely used with high intensity chemotherapy, we conducted a phase 1/2 study of cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone (CLAG-M) in adults with newly diagnosed AML or other high-grade myeloid neoplasm (NCT03531918). Sixty-six patients with a median age of 65 (range: 19–80) years were enrolled. Cohorts of six and twelve patients were treated in phase 1 with one dose of GO or three doses of GO (GO3) at 3 mg/m2 per dose. Since a maximum-tolerated dose was not reached, the recommended phase 2 dose (RP2D) was declared to be GO3. At RP2D, 52/60 (87%) patients achieved a complete remission (CR)/CR with incomplete hematologic recovery (CRi), 45/52 (87%) without flow cytometric measurable residual disease (MRD). Eight-week mortality was 0%. Six- and twelve-month event-free survival (EFS) were 73% and 58%; among favorable-risk patients, these estimates were 100% and 95%. Compared to 186 medically matched adults treated with CLAG-M alone, CLAG-M/GO3 was associated with better survival in patients with favorable-risk disease (EFS: p = 0.007; OS: p = 0.030). These data indicate that CLAG-M/GO3 is safe and leads to superior outcomes than CLAG-M alone in favorable-risk AML/high-grade myeloid neoplasm.

Adjunction of a fish oil emulsion to cytarabine and daunorubicin induction chemotherapy in high-risk AML

The treatment of acute myeloid leukemia (AML) with unfavorable cytogenetics treatment remains a challenge. We previously established that ex vivo exposure of AML blasts to eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or fish oil emulsion (FO) induces Nrf2 pathway activation, metabolic switch, and cell death. The FILO group launched a pilot clinical study to evaluate the feasibility, safety, and efficacy of the adjunction of a commercial FO emulsion to 3 + 7 in untreated AML with unfavorable cytogenetics. The primary objective was complete response (CR). Thirty patients were included. FO administration raised the plasma levels of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids (p < 0.001). The pharmacokinetics of cytarabine and daunorubicin were unaffected. A historical comparison to the LAM2001 trial (Lioure et al. Blood 2012) found a higher frequency of grade 3 serious adverse events, with no drug-related unexpected toxicity. The CR rate was 77%, and the partial response (PR) 10%, not significantly superior to that of the previous study (CR 72%, PR 1%). RT-qPCR analysis of Nrf2 target genes and antioxidant enzymes did not show a significant in vivo response. Overall, FO emulsion adjunction to 3 + 7 is feasible. An improvement in CR was not shown in this cohort of high-risk patients. The present data does not support the use of FO in adjunction with 3 + 7 in high-risk AML patients.ClinicalTrials.gov identifier: NCT01999413.

Association of leukocyte nadir with complete remission in Indonesian acute myeloid leukemia patients undergoing 7+3 remission induction chemotherapy

Background: The 7+3 regimen is still the main choice of remission induction chemotherapy in acute myeloid leukemia (AML). Successfully achieving complete remission (CR) and the time required to achieve it determine patient’s survival. Hence, bone marrow examination on 14 th day of chemotherapy is recommended to predict CR. However, the examination is invasive and still inaccurate. Methods: A prognostic study with retrospective cohort design was conducted at two central hospitals in Indonesia based on medical record data of AML patients who underwent 7+3 induction chemotherapy from January 1st, 2015, to December 31st, 2019. The association of nadir leukocyte level and the time required to achieve it with CR occurrence was assessed. Results: One hundred and one subjects were recruited with median age 39 years and 55% men. A total of 55.4% subjects achieved CR. Nadir leukocyte level below 200/mcl was the most optimal cut-off point and independently associated with CR (OR 2.48; 95% CI 1.03–5.97) while time required to achieve it was not. Conclusions: The nadir leukocyte level is associated with an increase probability of CR but not for the time required to achieve it in AML patients undergoing 7+3 induction chemotherapy.

Expression and Clinical Significance of CAS in Acute Myeloid Leukemia Patients

To explore the expression of cellular apoptosis susceptibility protein （CAS） in acute myeloid leukemia （AML） and its correlation with clinical characteristics. The expression of CAS in bone marrow tissue of 54 patients with AML and 24 patients with non-hematological malignant diseases was detected by Western blot and immune-histochemical method, and compared between AML group and control group. Also the relationship of CAS expression in AML and sex, age, WBC count, Hb, platelet count, bone marrow blast cell ratio, ki-67 index, cytogenetic and molecular biological prognostic risk stratification, extramedullary infiltration and other clinical characteristics was analyzed. Western blot showed that the expression of CAS protein in bone marrow biopsies of AML patients was significantly higher than that in control group (P<0.05). Immune-histochemical method revealed that CAS was mainly located in the cytoplasm in both AML group and control group. Among 54 AML patients, 14 patients (25.9%) showed high expression of CAS, while all the 24 patients in the control group showed low expression of CAS. The high expression rate of CAS in AML patients was significantly higher than that in the control group (P<0.05). There were statistically significant differences in prognostic risk stratification and the remission rate of the first chemotherapy between CAS high expression group and CAS low expression group in AML (P<0.05). The proportion of high risk patients and unremission patients after the first chemotherapy in CAS high expression group were significantly higher than those in CAS low expression group (57.1% vs 27.5%, 30.8% vs 7.9%), while the proportion of low risk patients and complete remission patients after the first chemotherapy were significantly lower than those in CAS low expression group (14.3% vs 37.5%, 53.8% vs 84.2%). In AML patients, the ki-67 index of bone marrow tissue in CAS high expression group was higher than that in CAS low expression group (60% vs 50%) (P<0.05). CAS is localized in cytoplasm in both AML and non-hematological malignant diseases, and its expression increases in AML. CAS is related to the risk stratification of cytogenetics and molecular biology, the remission rate after the first chemotherapy and ki-67 index in AML, which suggests that CAS may be involved in the occurrence and development of AML.

Association of leukocyte nadir with complete remission in Indonesian acute myeloid leukemia patients undergoing 7+3 remission induction chemotherapy

Background: The 7+3 regimen is still the main choice of remission induction chemotherapy in acute myeloid leukemia (AML). Successfully achieving complete remission (CR) and the time required to achieve it determine patient's survival. Hence, bone marrow examination on 14 th day of chemotherapy is recommended to predict CR. However, the examination is invasive and still inaccurate. Methods: A prognostic study with retrospective cohort design was conducted at two central hospitals in Indonesia based on medical record data of AML patients who underwent 7+3 induction chemotherapy from January 1st, 2015, to December 31st, 2019. The association of nadir leukocyte level and the time required to achieve it with CR occurrence was assessed. Results: One hundred and one subjects were recruited with median age 39 years and 55% men. A total of 55.4% subjects achieved CR. Nadir leukocyte level below 200/mcl was the most optimal cut-off point and independently associated with CR (OR 2.45; 95% CI 1.01-5.94) while time required to achieve it was not. Conclusions: The nadir leukocyte level is associated with an increase probability of CR but not for the time required to achieve it in AML patients undergoing 7+3 induction chemotherapy.

Efficacy and safety of voriconazole as invasive fungal infection prophylaxis in patients with acute myeloid leukemia

Invasive fungal infections (IFIs) are commonly observed in patients, who are at high risk of severe infections during the neutropenic phase. The aim of this retrospective single-center study was to evaluate the efficacy and safety of voriconazole as a fungal prophylaxis after induction chemotherapy for acute myeloid leukemia (AML) in adult patients. Six proven/probable IFIs were diagnosed in 213 patients with AML (median age 61 years, range 18–85), who received a total of 377 induction chemotherapies. This yielded an incidence rate of 1.6% based on all induction cycles administered. Voriconazole prophylaxis was administered as intended in 317 out of 377 (84%) induction cycles until the end of neutropenia with a median duration of 20 days (range: 2–101 days). In conclusion, voriconazole demonstrates efficacy and safety as a first-line IFI prophylaxis comparable to published data on posaconazole, which is the standard fungal prophylaxis recommendation for AML patients in international guidelines today.

Tailoring a physical activity intervention to older adults receiving intensive chemotherapy for acute myeloid leukemia (AML): One size does not fit all

Older adults are at risk for functional decline during acute myeloid leukemia (AML) therapy [ [1] Klepin H.D. Tooze J.A. Pardee T.S. et al. Effect of intensive chemotherapy on physical, cognitive, and emotional health of older adults with acute myeloid leukemia. J Am Geriatr Soc. 2016; 64: 1988-1995 Crossref PubMed Scopus (55) Google Scholar ]. While some survivors demonstrate resilience [ [2] Mohamedali H. Breunis H. Timilshina N. et al. Older age is associated with similar quality of life and physical function compared to younger age during intensive chemotherapy for acute myeloid leukemia. Leuk Res. 2012; 36: 1241-1248 Crossref PubMed Scopus (38) Google Scholar , [3] Timilshina N. Breunis H. Tomlinson G.A. et al. Long-term recovery of quality of life and physical function over three years in adult survivors of acute myeloid leukemia after intensive chemotherapy. Leukemia. 2019; 33: 15-25 Crossref Scopus (13) Google Scholar ], short-term declines in physical function can be dramatic during an induction hospitalization [ [1] Klepin H.D. Tooze J.A. Pardee T.S. et al. Effect of intensive chemotherapy on physical, cognitive, and emotional health of older adults with acute myeloid leukemia. J Am Geriatr Soc. 2016; 64: 1988-1995 Crossref PubMed Scopus (55) Google Scholar ]. Physical performance (measured by the Short Physical Performance Battery [SPPB]) is predictive of survival at the time of diagnosis [ [4] Klepin H.D. Geiger A.M. Tooze J.A. et al. Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia. Blood. 2013; 121: 4287-4294 Crossref PubMed Scopus (254) Google Scholar ], declines during induction therapy [ [1] Klepin H.D. Tooze J.A. Pardee T.S. et al. Effect of intensive chemotherapy on physical, cognitive, and emotional health of older adults with acute myeloid leukemia. J Am Geriatr Soc. 2016; 64: 1988-1995 Crossref PubMed Scopus (55) Google Scholar ], and is associated with shorter survival when measured at the time of remission [ [5] Saad M. Loh K.P. Tooze J.A. et al. Geriatric assessment and survival among older adults receiving post-remission therapy for acute myeloid leukemia. Blood. 2020; 136: 2715-2719 Crossref PubMed Google Scholar ]. Interventions designed to maintain physical performance may enhance the quality of survivorship, eligibility for subsequent therapies, and could potentially improve survival [ 6 Alibhai S.M. Durbano S. Breunis H. et al. A phase II exercise randomized controlled trial for patients with acute myeloid leukemia undergoing induction chemotherapy. Leuk Res. 2015; (S0145-2126(15)30365-9) Crossref Scopus (39) Google Scholar , 7 Alibhai S.M. O’Neill S. Fisher-Schlombs K. et al. A pilot phase II RCT of a home-based exercise intervention for survivors of AML. Support Care Cancer. 2014; 22: 881-889 Crossref PubMed Scopus (33) Google Scholar , 8 Klepin H.D. Danhauer S.C. Tooze J.A. et al. Exercise for older adult inpatients with acute myelogenous leukemia: a pilot study. J Geriatr Oncol. 2011; 2: 11-17 Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar , 9 Thomas R. Kenfield S.A. Yanagisawa Y. et al. Why exercise has a crucial role in cancer prevention, risk reduction and improved outcomes. Br Med Bull. 2021; 139: 100-119 Crossref Scopus (3) Google Scholar , 10 Ezzatvar Y. Ramírez-Vélez R. Sáez de Asteasu M.L. et al. Physical function and all-cause mortality in older adults diagnosed with cancer: a systematic review and meta-analysis. J Gerontol A Biol Sci Med Sci. 2021; 76: 1447-1453 Crossref Scopus (13) Google Scholar ].

Health Supervision for Children and Adolescents With Down Syndrome.

Health Supervision for Children and Adolescents With Down Syndrome.

Prediction of survival with intensive chemotherapy in acute myeloid leukemia.

Progress with intensive chemotherapy and supportive care measures has improved survival in newly diagnosed acute myeloid leukemia (AML). Predicting outcome helps in treatment decision making. We analyzed survival as the treatment endpoint in 3728 patients with newly diagnosed AML treated with intensive chemotherapy from 1980 to 2021. We divided the total study group (3:1 basis) into a training (n=2790) and a validation group (n=938). The associations between survival and 27 characteristics were investigated. In the training cohort, the multivariate analysis identified 12 consistent adverse prognostic variables independently associated with worse survival: older age, therapy-related myeloid neoplasm, worse performance status, cardiac comorbidity, leukocytosis, anemia, thrombocytopenia, elevated creatinine and lactate dehydrogenase, cytogenetic abnormalities, and the presence of infection at diagnosis except fever of unknown origin. We categorized patients into four prognostic groups, favorable (7%), intermediate (43%), poor (39%), and very poor (11%) with estimated 5-year survival rates of 69%, 36%, 13%, and 3% respectively (p < .001). The predictive model was validated in an independent cohort. In a subset of patients with molecular mutation profiles, adding the mutation profiles after accounting for the effects of previous factors identified NPM1 (favorable), PTPN11, and TP53 (both unfavorable) mutations as molecular prognostic factors. The new proposed predictive model for survival with intensive chemotherapy in patients with AML is robust and can be used to advise patients regarding their prognosis, to modify therapy in remission (e.g., proposing allogeneic stem cell transplantation in first remission), and to compare outcome and benefits on future investigational therapies.

Sorafenib in Combination With Standard Chemotherapy for Children With High Allelic Ratio FLT3/ITD+ Acute Myeloid Leukemia: A Report From the Children's Oncology Group Protocol AAML1031.

High allelic ratio (HAR) FLT3/ITD (AR > 0.4) mutations confer poor prognosis in pediatric acute myeloid leukemia (AML). COG AAML1031 studied the feasibility and efficacy of adding sorafenib, a multikinase tyrosine kinase inhibitor to standard chemotherapy and as single-agent maintenance therapy in this population. Patients were treated in three cohorts. The initial safety phase defined the maximum tolerated dose of sorafenib starting in induction 2. Cohorts 2 and 3 added sorafenib in induction and as single-agent maintenance. Clinical outcome analysis was limited to n = 72 patients in cohorts 2/3 and compared with n = 76 HAR FLT3/ITD+ AML patients who received identical chemotherapy without sorafenib. Sorafenib pharmacokinetics and plasma inhibitory activity were measured in a subset of patients. The maximum tolerated dose of sorafenib was 200 mg/m2 once daily; dose-limiting toxicities included rash (n = 2; 1 grade 3 and 1 grade 2), grade 2 hand-foot syndrome, and grade 3 fever. Pharmacokinetics/plasma inhibitory activity data demonstrated that measured plasma concentrations were sufficient to inhibit phosphorylated FLT3. Although outcomes were superior with sorafenib in cohorts 2 and 3, patients treated with sorafenib also underwent hematopoietic stem-cell transplant more frequently than the comparator population. Multivariable analysis that accounted for both hematopoietic stem-cell transplant and favorable co-occurring mutations confirmed sorafenib's benefit. Specifically, risk of an event was approximately two-fold higher in HAR FLT3/ITD+ patients who did not receive sorafenib (event-free survival from study entry: hazard ratio [HR] 2.37, 95% CI, 1.45 to 3.88, P < .001, disease-free survival from complete remission: HR 2.28, 95% CI, 1.08 to 4.82, P = .032, relapse risk from complete remission: HR 3.03, 95% CI 1.31 to 7.04, P = .010). Sorafenib can be safely added to conventional AML chemotherapy and may improve outcomes in pediatric HAR FLT3/ITD+ AML.