scholarly journals Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia

Blood ◽  
1994 ◽  
Vol 83 (6) ◽  
pp. 1603-1611 ◽  
Author(s):  
A Neubauer ◽  
RK Dodge ◽  
SL George ◽  
FR Davey ◽  
RT Silver ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Univariate Analysis ◽  
Bone Marrow Blast ◽  
Ras Mutations ◽  
Ras Genes ◽  
Oligonucleotide Hybridization ◽  
Acute Myeloid

Abstract Mutations of the N- and K-ras genes are the most frequent genetic aberrations in acute myeloid leukemia (AML) and their detection in preleukemic conditions such as the myelodysplastic syndrome (MDS) suggests a role in the earliest phases of leukemogenesis. Despite these observations, little is known about the clinical importance of ras mutations in AML. We studied the clinical impact of ras mutations in 99 patients with de novo AML. All patients were treated in two prospective multicenter trials. The polymerase chain reaction was used to amplify areas surrounding the codons 12, 13, and 61 of the three ras genes N-, K-, and H-ras from DNA from bone marrow cells, ras mutations were detected by an algorithm based on allele-specific oligonucleotide hybridization. Eighteen of 99 (18%) patients harbored mutations in either N- or K-ras. All of the observed mutations occurred in N-ras (N = 10) and K-ras (N = 5) or concurrently in both N- and K-ras (N = 3). There were no significant differences between ras-negative and ras- positive patients according to age, sex, blood counts, cytogenetic abnormalities, or French-American-British classification. However, univariate analysis suggested a longer survival in ras-positive patients (P = .11). When adjusted for age, which was the most important factor affecting outcome, the presence of a ras mutation emerged as a significant predictor for improved survival (P = .03) and along with lower bone marrow blast counts (P = .02) and better cytogenetic category (P = .01). However, the presence of an aberrant ras allele was strongly correlated with lower bone marrow blast counts (P = .007). Thus, whether a mutation in the N-ras or K-ras proto-oncogenes directly affects treatment outcome or indirectly through an association with lower leukemic burden remains to be determined. Nevertheless, these findings counter the prevailing bias that oncogene mutations lead to more aggressive behavior in human malignancies.

scholarly journals Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia

Blood ◽  
1994 ◽  
Vol 83 (6) ◽  
pp. 1603-1611 ◽  
Author(s):  
A Neubauer ◽  
RK Dodge ◽  
SL George ◽  
FR Davey ◽  
RT Silver ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Univariate Analysis ◽  
Bone Marrow Blast ◽  
Ras Mutations ◽  
Ras Genes ◽  
Oligonucleotide Hybridization ◽  
Acute Myeloid

Mutations of the N- and K-ras genes are the most frequent genetic aberrations in acute myeloid leukemia (AML) and their detection in preleukemic conditions such as the myelodysplastic syndrome (MDS) suggests a role in the earliest phases of leukemogenesis. Despite these observations, little is known about the clinical importance of ras mutations in AML. We studied the clinical impact of ras mutations in 99 patients with de novo AML. All patients were treated in two prospective multicenter trials. The polymerase chain reaction was used to amplify areas surrounding the codons 12, 13, and 61 of the three ras genes N-, K-, and H-ras from DNA from bone marrow cells, ras mutations were detected by an algorithm based on allele-specific oligonucleotide hybridization. Eighteen of 99 (18%) patients harbored mutations in either N- or K-ras. All of the observed mutations occurred in N-ras (N = 10) and K-ras (N = 5) or concurrently in both N- and K-ras (N = 3). There were no significant differences between ras-negative and ras- positive patients according to age, sex, blood counts, cytogenetic abnormalities, or French-American-British classification. However, univariate analysis suggested a longer survival in ras-positive patients (P = .11). When adjusted for age, which was the most important factor affecting outcome, the presence of a ras mutation emerged as a significant predictor for improved survival (P = .03) and along with lower bone marrow blast counts (P = .02) and better cytogenetic category (P = .01). However, the presence of an aberrant ras allele was strongly correlated with lower bone marrow blast counts (P = .007). Thus, whether a mutation in the N-ras or K-ras proto-oncogenes directly affects treatment outcome or indirectly through an association with lower leukemic burden remains to be determined. Nevertheless, these findings counter the prevailing bias that oncogene mutations lead to more aggressive behavior in human malignancies.

EZH2 Mutations Are Associated with Low Blast Percentage in Bone Marrow and −7/Del(7q) Karyotype in De Novo Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2544-2544
Author(s):  
Xiuli Wang ◽  
Haiping Dai ◽  
Qian WANG ◽  
Qinrong Wang ◽  
Yang Xu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Myelogenous Leukemia ◽  
Prognostic Impact ◽  
Coding Region ◽  
Acute Myeloid

Abstract Abstract 2544 Somatic mutation of the EZH2 gene is seen in myelodisplastic syndrome, myelofibrosis, and chronic myelomonocytic leukemia patients. The prevalence and prognostic impact of somatic mutations of EZH2 in patients with acute myelogenous leukemia (AML) remains unknown. In this study, we sought to determine the incidence and clinical implications of somatic EZH2 mutations in 714 patients with de novo AML by PCR amplification of the entire coding region followed by direct bidirectional DNA sequencing. EZH2 mutations were identified in 13/714 (1.8%) of AML patients and occurred almost exclusively in males (11/13, P=0.033). In univariate analysis, the presence of EZH2 mutations was significantly associated with lower blast percentage (21–30%) in bone marrow (P=0.0001) and −7/del(7q) (P=0.025). There was no difference in the incidence of mutations in 13 genes, including ASXL1, CBL, c-KIT, DNMT3A, FLT3, IDH1, IDH2, MLL, NPM1, NRAS, RUNX1, TET2, and WT1, between patients with and without EZH2 mutations. Complete remission, event-free survival or overall survival was similar between AML patients with and without EZH2 mutation (p>0.05). These results demonstrated EZH2 mutation as a recurrent genetic abnormality associated with lower blast percentage in BM and −7/del(7q) in de novo acute myeloid leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Pretreatment platelet count predicts survival outcome of patients with de novo non-M3 acute myeloid leukemia

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e4139 ◽  
Author(s):  
Qianying Zhang ◽  
Kanchun Dai ◽  
Laixi Bi ◽  
Songfu Jiang ◽  
Yixiang Han ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Platelet Count ◽  
Predictive Value ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Univariate Analysis ◽  
Survival Outcome ◽  
Cox Regression Analysis ◽  
High Platelet Count ◽  
Acute Myeloid

Background Pretreatment platelet count has been reported as a potential tool to predict survival outcome in several solid tumors. However, the predictive value of pretreatment platelet count remains obscure in de novo acute myeloid leukemia (AML) excluding acute promyelocytic leukemia (M3). Methods We conducted a retrospective review of 209 patients with de novo non-M3 AML in our institute over a period of 8 years (2007–2015). Receiver operating characteristic (ROC) curve analysis was used to determine the optimal platelet (PLT) cutoff in patients. We analyzed the overall survival (OS) and disease free survival (DFS) using the log-rank test and Cox regression analysis. Results By defining the platelet count 50 × 109/L and 120 × 109/L as two cut-off points, we categorized the patients into three groups: low (<50 × 109/L), medium (50–120 × 109/L) and high (>120 × 109/L). On univariate analysis, patients with medium platelet count had longer OS and DFS than those with low or high platelet count. However, the multivariate analysis showed that only longer DFS was observed in patients with medium platelet count than those with low or high platelet count. Conclusion Our findings indicate that pretreatment platelet count has a predictive value for the prognosis of patients with non-M3 AML.

Clinical Activity, Pharmacokinetics, and Pharmacodynamics of Sorafenib In Pediatric Acute Myeloid Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1073-1073
Author(s):  
Hiroto Inaba ◽  
Jeffrey E Rubnitz ◽  
Elaine Coustan-Smith ◽  
Lie Li ◽  
Brian D Furmanski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Leukemic Cells ◽  
Clinical Activity ◽  
Newly Diagnosed ◽  
Pediatric Acute Myeloid Leukemia ◽  
Rtk Signaling ◽  
Acute Myeloid

Abstract Abstract 1073 Background: Aberrant receptor tyrosine kinase (RTK) signaling arising from genetic abnormalities, such as FLT3-internal tandem duplications (FLT3-ITD), is an important mechanism in the development and growth of acute myeloid leukemia (AML) and is often associated with a poor outcome. Hence, inhibition of RTK signaling is an attractive novel treatment option, particularly for disease that is resistant to conventional chemotherapy. We evaluated the clinical activity of the multikinase inhibitor sorafenib in children with de novo FLT3-ITD–positive AML or relapsed/refractory AML. Methods: Fourteen patients were treated. Six patients with newly diagnosed FLT3- ITD–positive AML (aged 9–16 years; median, 12 years) received 2 cycles of remission induction therapy and then started sorafenib (200 mg/m2 twice daily for 20 days) the day after completing induction II (low-dose cytarabine, daunorubicin, and etoposide). Nine patients (aged 6–17 years; median, 9 years) with relapsed AML (including one treated on the above regimen) received sorafenib alone (2 dose levels; 200 and 150 mg/m2) twice daily for the first week of therapy, concurrently with clofarabine and cytarabine on days 8–12, and then alone from days 13 to 28. Sorafenib pharmacokinetics were analyzed at steady-state on day 8 of sorafenib in patients with newly diagnosed AML and on day 7 in patients with relapsed AML. In patients with relapsed AML, the effect of sorafenib on signaling pathways in AML cells was assessed by flow cytometry. Results: All 6 newly diagnosed patients, including 2 whose AML was refractory to induction I, achieved a complete remission (CR) after induction II; 5 had negative minimal residual disease (MRD; <0.1% AML cells in bone marrow) after induction II. Both patients in this group who relapsed achieved second remissions, one with sorafenib alone and one on the relapse regimen described above. Of the 9 patients with relapsed AML, 6 (4 with FLT3-ITD) were treated with sorafenib 200 mg/m2. All 6 had a >50% decrease in blast percentage and/or bone marrow cellularity after 1 week of sorafenib. After concurrent sorafenib and chemotherapy, 5 of the 9 patients with relapsed AML achieved CR (2 had negative MRD) and 2 achieved a partial remission (PR; 5%-25% AML cells in bone marrow); all 4 patients with FLT3-ITD had a CR or PR. After sorafenib treatment, 6 patients underwent HSCT while 2 with FLT3-ITD who could not receive HSCT were treated with single-agent sorafenib and have maintained CR for up to 8 months. Hand-foot skin reaction (HFSR) or rash occurred in all patients and improved with cessation of sorafenib. Dose-limiting toxicity (DLT, grade 3 HFSR and/or rash) was observed in 3 of the 6 patients with relapsed AML treated with 200 mg/m2 of sorafenib; no DLT was observed at 150 mg/m2. The effect of sorafenib on downstream RTK signaling was tested in the leukemic cells of 4 patients: in most samples, phosphorylation of S6 ribosomal protein and 4E-BP1 was inhibited. The mean (± SD) steady-state concentration (Css) of sorafenib was 3.3 ± 1.2 mg/L in the newly diagnosed group and 6.5 ± 3.6 mg/L (200 mg/m2) and 7.3 ± 3.6 mg/L (150 mg/m2) in those with relapsed AML. In both groups, the mean conversion of sorafenib to sorafenib N-oxide was 27%-35% (approximately 3 times greater than previously reported), and mean sorafenib N-oxide Css was 1.0–3.2 mg/L (2.1-6.7 μM). In a 442-kinase screen, the inhibitory profiles of sorafenib N-oxide and sorafenib were similar, and FLT3-ITD phosphorylation was potently inhibited by both forms (sorafenib N-oxide Kd = 0.070 μM; sorafenib Kd = 0.094 μM). Sorafenib N-oxide inhibited the growth of an AML cell line with FLT3-ITD (IC50 = 0.026 μM) and 4 AML cell lines with wild-type FLT3 (IC50 = 3.9–13.3 μM) at approximately half the potency of sorafenib. Conclusion: In children with de novo FLT3-ITD and relapsed/refractory AML, sorafenib given alone or with chemotherapy induced dramatic responses and inhibited aberrant RTK signaling in leukemic cells. Sorafenib and its active metabolite (sorafenib N-oxide) likely contribute to both efficacy and toxicity. These results warrant the incorporation of sorafenib into future pediatric AML trials. Disclosures: Inaba: Bayer/Onyx: Research Funding. Off Label Use: Sorafenib and clofarabine: both used for treatment of pediatric acute myeloid leukemia.

The Prognostic Impact and Stability of IDH2 Mutation and the Insufficiency of the Mutation Alone for Leukemogenesis In Adult Patients with Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2697-2697
Author(s):  
Weng-Chi Lei ◽  
Wen-Chien Chou ◽  
Bor-Shen Ko ◽  
Hsin-An Hou ◽  
Hwei-Fang Tien
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Normal Karyotype ◽  
Idh1 Mutation ◽  
Group 12 ◽  
Worse Prognosis ◽  
Idh2 Mutation ◽  
Acute Myeloid

Abstract Abstract 2697 Purpose: Although the clinical and biological features of Isocitrate dehydrogenase (IDH) mutations in acute myeloid leukemia (AML) have been characterized, its stability and in vivo sufficiency of the mutation alone for leukemogenesis remain uninvestigated. Patients and Methods: Mutations of IDH and other clinically relevant genes were analyzed in the bone marrow from 446 adult patients with de novo non-M3 AML. IDH2 mutations were examined serially in 140 patients at diagnosis and after chemotherapy. Results: Among the 446 adults with de novo non-M3 AML, IDH2 R172, R140, and IDH1 R132 mutations occurred at a frequency of 2.9%, 9.2%, and 6.1%, respectively. IDH2 mutation was associated with higher platelet counts (p=0.046), intermediate-risk (p=0.002) or normal karyotype (p=0.023), and isolated +8 (p=0.014), but was inversely correlated with expression of HLA-DR (p=0.002), CD34 (p=0.039), CD15 (p=0.003), CD7 (p=0.010), and CD56 (p=0.048), and was mutually exclusive with WT1 mutation (p=0.037) and core-binding factor translocations (p=0.001). All these correlations became stronger when IDH1 and IDH2 mutations were considered together, suggesting similarity of biological roles between these 2 mutations. However, IDH2 but not IDH1 mutation conferred a better prognosis (Fig 1), especially in those with normal karyotype or intermediate cytogenetics (median overall survival: not reached vs. 58 months, p=0.044 and not reached vs. 19 months, p=0.027 for normal and intermediate karyotype group, respectively). Importantly, IDH2 but not IDH1 mutation was an independent favorable prognostic factor (HR: 0.332, 95% CI: 0.159–0.694; p=0.003). Patients with IDH2−/FLT3-ITD+ genotype had especially worse prognosis (median OS of IDH2−/FLT3-ITD+ vs. IDH2+/FLT3-ITD− group: 12 months vs. not reached; p=0.003; median OS of IDH2−/FLT3-ITD+ vs. IDH2+/FLT3-ITD+ or IDH2−/FLT3-ITD− group : 12 months vs. 35 months; p<.0001) (Fig 2A). The worse prognosis was also seen in patients with IDH−/FLT3-ITD+ genotype (Fig 2B). Serial analyses of IDH2 mutations during the clinical course of 140 patients confirmed the stability of this mutation; all the patients with IDH2 mutations at diagnosis harbored the same mutation at relapse with the exception of one patient who had extramedullary but not bone marrow relapse, while none of the IDH2-wild patients acquired this mutation at relapse. Importantly, sequential samples from two patients in long-term remission retained the original R140Q mutation while other accompanied mutations, FLT3-ITD in the first patient and NPM1 in the second, respectively, disappeared. In the first patient, the skin tissue was absent of the mutation and in the second, the mutation was restricted in myeloid cells but spared in lymphocytes indicating the mutation was acquired in these two patients. Conclusion: IDH2 mutation is a stable marker during disease evolution and confers favorable prognosis. FLT3-ITD combined with wild type IDH2 exerted synergistic negative impact on survival. IDH2 mutation alone is insufficient for leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

Achieving Hematologic Remission with Combination Chemotherapy and Donor Leukocyte Infusions for Relapse of Acute Myeloid Leukemia Six Years After Human Leukocyte Antigen-Mismatched Transplantation: A Case Report

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4476-4476
Author(s):  
Jingyan Xu ◽  
Jian Ouyang ◽  
Rong-Fu Zhou
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Combination Chemotherapy ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Mononuclear Cells ◽  
Bone Marrow Examination ◽  
Intensive Chemotherapy ◽  
Bone Marrow Blast ◽  
Acute Myeloid

Abstract Abstract 4476 Hematopoietic Stem Cell Transplantation (HSCT) from partially HLA-matched (haploidentical) family donors represents a promising therapy for high-risk acute myeloid leukemia (AML). However, for patients with AML relapsed after HSCT from an HLA-mismatched familial donor, there is no standard therapy. They may receive conventional chemotherapy, cyclosporine withdrawal, second HSCT, and donor leukocyte infusion (DLI) with or without prior mobilization. Recently, combination chemotherapy and DLI showed achieving hematologic remission. We report a case of successful combination chemotherapy and donor leukocyte infusions from original donor in a patient with AML relapsing 6 years after HSCT from an HLA-Mismatched Familial Donor. A 37-year-old male presented with fever in June 2003.Bone marrow aspirate confirmed the diagnosis of AML(M5 subtype according to FAB classification). The patient initially received intensive chemotherapy. However, the patient with AML that was refractory to conventional therapy. He received HSCT in first CR from his mother 1-loci HLA-mismatched (HLA-A) using BuCY- Conditioning regimen on June 11, 2004. He showed a medullary relapse 6 years after HSCT. His bone marrow blast counts exceeded 80% with 8.25% of donor karyotypes (46 XX FISH). We decided to try to use his mother as the donor for DLI. Cytoreductive chemotherapy was commenced prior to DLI. He was treated twice with DLI on August 02, 2010 and September 23, 2011. He was treated chemotherapy before in first DLI, chemotherapy regimens; FLAG-ida [fludarabine 30 mg/m2/d from day-6 to-2 of cell infusion, cytosine arabinoside 2 g/m2/d from day-6 to-2 of cell infusion, idarubicine 20 mg/d day-1 and G-CSF 300μ g/day from day-7 to +30]. The donors received G-CSF 10μ g/kg subcutaneously daily starting day-3 of cell infusion for 5 days. Donor peripheral blood mononuclear cells were collected by CS-3000 Plus cell separator (Baxter Corp.) on the fifth days of G-CSF administration and infused through a central venous catheter into the patients on the same day. 8.33×107/kg mononuclear cells, 6×107/kg CD3+ cells were reinfused without manipulation. Cyclosporine at the dose of 3 mg/kg were administered for the prevention of GVHD. On days 36 Bone marrow blast counts exceeded 45% with 44% of donor karyotypes (46 XX FISH) after first Chemo-DLI. He received cyclosporine withdrawal. He was treated chemotherapy by low-dose Ara-C and aclarubicin with concomitant use of G-CSF before in second DLI.,chemotherapy regimens;CAG[ Low-dose Ara-C was given subcutaneously at a dosage of 10 mg/m2 every 12 hours on days-14 to-1. Aclarubicin was administered intravenously at a dosage of 7 mg/m2 on days-14 to-7. Recombinant G-CSF was given subcutaneously at a dosage of 200μ g/m2 per day on days-14 to-1]. On day 0,1.4×108/kg mononuclear cells,1×108/kg CD3+ cells were reinfused. On days 25 bone marrow examination showed CR with 89% of donor karyotypes (46 XX FISH). He was treated consolidation chemotherapy by regimens; CAG.On days 62 bone marrow examination showed CR with 100% of donor karyotypes (46 XX FISH). He developed chronic GVHD with limited disease at day 123 of DLI. In the patient whose cGVHD resolved with the use of steroid, cyclosporine plus methotrexate. The patient died from pneumonia without evidence of recurrent leukemia on day +230. From the cases reported, combination chemotherapy and subsequent mobilized DLI produced a CR with AML in relapse six years after HLA-Mismatched transplantation. We demonstrate that of the patient who relapsed after 6 years, treatment with chemotherapy followed by intensive chemotherapy followed by DLI, can effectively salvage a patient with attainment of durable remissions. Although limited by the small number of one patient, AML in relapse six years after HLA-Mismatched transplantation requires particular attention in future studies, as well as in designing future treatment programs. Clearly a large number of patients is required to confirm the real efficacy of this treatment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Analysis of the Proteomes of Primary, De Novo Acute Myeloid Leukemia Cells from Adults

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3427-3427
Author(s):  
Michael H Kramer ◽  
Qiang Zhang ◽  
Robert W. Sprung ◽  
Petra Erdmann-Gilmore ◽  
Daniel R George ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Protein Expression ◽  
Mrna Expression ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Rna Seq ◽  
Proteomic Data ◽  
Complex Figure ◽  
Acute Myeloid

Abstract Introduction: Proteins, despite being the primary effectors of cellular processes, are often studied only indirectly through analysis of the transcriptome. However, it is clear that the relationship between mRNA expression and protein expression is approximate at best. In Acute Myeloid Leukemia (AML), the genome and transcriptome have been thoroughly characterized, but the proteome has been less well studied. Here, we present a deep-scale study of the proteomes of 44 primary AML bone marrow samples representing a wide range of AML across the spectrum of cytogenetic risk, common mutations, and driver fusions. Methods: Bone marrow samples were collected at presentation from 44 adult patients with de novo AML as part of an institutional banking protocol, and buffy coat cells were immediately cryopreserved without further manipulation. Cryovials were thawed in the presence of the cell permeable serine protease inhibitor diisopropyl fluorophosphate (DFP) to inactivate the abundant neutrophil serine proteases (ELANE, CTSG, PRTN3, and PRSS57), and further processed for nano-liquid chromatography mass spectrometry in the presence of an extensive cocktail of protease inhibitors. Both label-free quantification (LFQ) and tandem-mass-tag (TMT) deep-scale proteomics were performed on these 44 patient samples, as well as 3 lineage-depleted bone marrow samples from healthy adult donors. Matching RNA-seq and exome sequencing data were available for the same samples as part of The Cancer Genome Atlas (TCGA) AML project. Results: 10,651 and 6,679 unique proteins were detected in the TMT and LFQ experiments, respectively. Correlations between measurements derived from the independent proteomic platforms (i.e. TMT and LFQ) is higher (mean Spearman correlation, 0.60, Figure 1A) than correlation between proteomic (TMT) and transcriptomic measurements from bulk RNA-seq data (Spearman 0.43, Figure 1B). Quality checks of the proteomic data strongly supported the reliability of quantification of protein measurements; for example, the mean ratio of beta globin protein (HBB) to alpha globin (HBA1) was 1.2 +/- 0.25 (Figure 1C), and several proteins known to be dysregulated by specific AML-initiating fusion proteins (for PML-RARA, HGF and RARA; for RUNX1-RUNX1T1, RUNX1T1; and for CBFB-MYH11, MYH11) were detected in the expected samples (Figure 1D). Globally, 1,364 proteins were differentially expressed in the AML samples (corrected p-value &lt;0.05, fold change ≥ 1.5) compared to the lineage-depleted, healthy bone marrow samples. Globally overexpressed proteins were enriched for ribosomal RNA modification, mitochondrial protein import, nuclear export, and the mitochondrial electron transport chain, among others. These overexpressed proteins include 61 cell surface proteins that could potentially represent therapeutic targets (overexpressed on average in 82% of AML samples, range 25-97%). Globally downregulated proteins in AML samples were enriched for glycogen metabolism and protein groups associated with mature neutrophils (reflecting the expected maturation block in AML), among others. 771 of the 1364 differentially expressed proteins (56.5%) showed only minimal variability in mRNA expression levels (fold change of &lt;1.1 between AML and normal marrow CD34 cell mRNA) that could not explain dysregulated protein expression. Several protein complexes likewise showed coordinated differential expression in the proteomic data, but no change in the transcriptome, including the THO complex (Figure 1E) and the phosphorylase kinase complex (Figure 1F), among others, indicating the presence of posttranscriptional regulation of the levels of many proteins in AML samples. Conclusion: We have created a deep-scale proteomic database from a set of well-characterized AML samples, allowing for a proteogenomic study of AML. We have identified many examples of post-transcriptional regulation of key metabolic pathways that may be relevant for better understanding AML cell metabolism and therapeutic vulnerabilities. Additional studies linking patterns of protein dysregulation with a variety of AML covariates are underway. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Pegylated Arginine Deiminase (ADI-PEG20) in Relapsed/Refractory and/or Elder Acute Myeloid Leukemia: The Preliminary Result of Phase II Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 984-984
Author(s):  
Hui-Jen Tsai ◽  
Ming-Chung Wang ◽  
Sheng-Fung Lin ◽  
Ya-Ping Chen ◽  
Hui-Hwa Hsiao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Phase Ii Trial ◽  
Arginine Deiminase ◽  
Arginine Deprivation ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background: Deprivation of circulating L-asparagine by L-asparaginase, which can lead to the inhibition of RNA and DNA synthesis and subsequent apoptosis of blastic cell, has been implemented as part of multidrug chemotherapy for acute lymphoblastic leukemia since decades ago. Arginine, a semi-essential amino acid in human, is involved in diverse aspects of tumor metabolism and plays critical role for the growth of human cancers. Deficiency of argininosuccinate synthase (ASS), the rate-limiting enzyme for endogenous arginine production in urea cycle, has been found in various cancer tissues. In preclinical studies, pegylated arginine deiminase (ADI-PEG20), which can rapidly convert arginine into citrulline and serve as an arginine depriving agent, was shown to exert in vitro and in vivo anti-proliferative effect on ASS-deficient cancers, such as hepatocellular carcinoma, melanoma, small cell lung cancer, lymphoma and acute myeloid leukemia (AML). The efficacy of ADI-PEG20 is currently under evaluation for various solid tumors in clinical trial setting, including a global phase III trial for hepatocellular carcinoma. Absence of ASS expression has been noted in 87% (46/53) of bone marrow biopsy samples of patients with AML.1 In xenograft model, ADI-PEG20 could reduce the leukemic burden in mice transplanted with primary AML cells.2Herein, we reported the preliminary result of a phase II trial evaluating the therapeutic efficacy of ADI-PEG20 in relapsed/refractory and/or elderly AML patients. Patients and Methods: Patients ≥ 18 years with ASS deficient (by western blotting of bone marrow leukemia cells and/or immunohistochemical staining of bone marrow biopsy), relapsed/refractory or poor-risk AML were eligible. The poor-risk AML includes treatment-related AML, antecedent hematologic disease, unfavorable cytogenetics and de novo AML ≥ 70 years of age. Patients received ADI-PEG20 at 320IU/m2IM weekly (4 weeks as one cycle). Bone marrow aspiration was performed at the time of enrollment, and after the first and second cycle of treatment to evaluate the response. Treatment was continued for each patient until the occurrence of disease progression, development of unacceptable toxicity, death, or withdrawal of consent for any reason. If patients achieved complete remission (CR) or CR with incomplete blood count recovery, the treatment was finished after another 4 cycles of ADI-PEG20. Results: Between October 2013 and May 2014, 9 patients were enrolled, with a male/female ratio of 5/4 and a median age of 62 years (ranged 27 to 79 years old). They were all de novo AML except for 1 with blast-transformed chronic myelomonocytic leukemia. All patients received at least one prior treatment regimen, except for two treatment-naïve elderly patients. After a mean 1.5 cycles of ADI-PEG20 treatment, 2 of 8 evaluable patients achieved CR after 3 and 1 cycles of ADI-PEG20, respectively, while 6 patients had disease progression after an average of 1 cycle of treatment. One patient was not evaluable for response due to withdrawal of consent after the first 2 doses of treatment. Two patients, who died within 2 weeks after the first dose of ADI-PEG20, were considered to have progressive disease. Of the 2 CR patients, 1 was 79 years old with chemo-naïve acute megakaryocytic leukemia (M7) and the other was 69 years old with low-dose Ara-C refractory M2. The most common treatment-related severe adverse events (AE) included grade 4 tumor lysis syndrome, grade 4 infection and treatment-related grade 4 neutropenia occurring in one patient each. The episode of grade 4 neutropenia occurred in the ADI-PEG20 responsive M7 patient. Minor AE included grade 1 hyperuricemia and skin rash in 2 and 1 patients, respectively. Conclusions: ADI-PEG20 is an effective treatment for some patients with ASS-deficient AML with minimal toxicities. Further investigation with genetic and epigenetic profiling to identify patients who will benefit from arginine deprivation therapy is warranted. References. Szlosarek P, et al. Pegylated arginine deiminase (ADI-PEG 20) as a potential novel therapy for argininosuccinate synthetase-deficient acute myeloid leukemia. (AACR Abstract # 467, 2012). 2. Miraki-Moud F, et al. Arginine deprivation with pegylated arginine deiminase induces death of acute myeloid leukaemia cells in vivo. Blood 2012 122:1458. Disclosures Tsai: TWD Pharmaceuticals, Inc: Honoraria.

Feasibility and results of bone marrow transplantation after remission induction and intensification chemotherapy in de novo acute myeloid leukemia. Catalan Group for Bone Marrow Transplantation.

1996 ◽  
Vol 14 (4) ◽  
pp. 1353-1363 ◽  
Author(s):  
J Sierra ◽  
S Brunet ◽  
A Grañena ◽  
T Olivé ◽  
J Bueno ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Statistical Significance ◽  
Human Leukocyte ◽  
Remission Induction ◽  
Acute Myeloid

PURPOSE To evaluate prospectively the feasibility and results of bone marrow transplantation (BMT) after induction and intensification chemotherapy (CT) in patients with de novo acute myeloid leukemia (AML). PATIENTS AND METHODS A total of 159 patients less than 51 years of age were treated. Induction CT consisted of daunorubicin 60 mg/m2 for 3 days, cytarabine (ARA-C) 100mg/m2 for 7 days, and etoposide 100 mg/m2 for 3 days. The first intensification therapy included mitoxantrone 10 mg/m2 for 3 days and ARA-C 1.2 g/m2 every 12 hours for 4 days. Amsacrine (100 or 150 mg/m2 for 3 days) and ARA-C (1.2 g/m2 every 12 hours for 2 or 4 days) were given as the second intensification therapy. Depending on the availability of a human leukocyte antigen (HLA)-identical sibling, the intention of treatment after CT was allogeneic BMT (allo-BMT) or autologous BMT (ABMT). RESULTS Complete remission (CR) was obtained in 120 patients (75%) and partial remission (PR) in 11 (7%), while 15 patients (10%) were refractory and 13 (8%) died during induction. There was a trend for better leukemia-free survival (LFS) at 4 years for patients assigned to the ABMT group (50% +/- 6%) compared with the allo-BMT group (31% +/- 7%) (P = .08). This difference in LFS reached statistical significance when considering only transplanted patients (63% +/- 3% at 4 years after ABMT and 38% +/- 11% after allo-BMT, P = .02). The favorable results in patients who received ABMT (no toxic deaths and 37% +/- 7% probability of relapse at 4 years) contrast with the poor outcome of allografted patients (11 patients with transplant-related mortality). CONCLUSION Our study reflects the difficulties in the completion of a therapeutic strategy that include BMT and suggests that intensification before BMT may be useful in the setting of ABMT, but this approach was associated with a high mortality rate in allo-BMT patients.

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