The Prognostic Role of Smac/DIABLO Protein Expression in Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2626-2626
Author(s):  
Agnieszka Pluta ◽  
Agata Wrzesien-Kus ◽  
Barbara Cebula ◽  
Anna Wolska ◽  
Anna Szmigielska-Kaplon ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Protein Expression ◽  
Myeloid Leukemia ◽  
Caspase 3 ◽  
De Novo ◽  
Intracellular Expression ◽  
De Novo Aml ◽  
Acute Myeloid ◽  
Active Caspase

Abstract Abstract 2626 Poster Board II-602 Background: Smac/DIABLO (second mitochondrial derived activator of caspase/direct IAP binding protein with low pI), an antagonist of inhibitor of apoptosis proteins (IAP) family, was shown to trigger both external and internal apoptosis pathways in acute leukemia cell lines. The role, pathway of action and prognostic significance of Smac/DIABLO protein is not clearly determined in acute myeloid leukemia (AML) patients. Aims: The main objective of this study was to verify whether expression of Smac/DIABLO protein has a prognostic impact on response to induction chemotherapy and overall survival (OS) of adult AML patients. Additionally, we aimed to analyse the apoptotic pathway potentially activated by Smac/DIABLO in AML patients. Material and Methods: Intracellular expression of Smac/DIABLO protein was examined in leukemic blasts isolated from bone marrow or peripheral blood of 89 de novo AML patients with median age 54 (range 23-82). Simultaneously, intracellular expression of active caspase-3 was investigated in 30 de novo AML patients with median age 57 (range 23–79). All measurements were done using multi-colour flow cytometry. In parallel, isotype controls were performed for all measurements. The percentage of Smac/DIABLO- and caspase-3-positive cells was assessed. According to median protein expression the patients were divided into “low-expressers” and “high”-expressers groups. Results: The median of intracellular expression of Smac/DIABLO protein was 65,8% (ranged 0–99,8%) and the median of cleaved caspase-3 was 4,95% (ranged 0,5–40,8) of leukemic blasts. Sixty four out of 89 AML patients received standard induction chemotherapy with daunorubicine and cytarabine (Ara-C) (“3+7”), 24/89 were treated with low dose Ara-C and 2/89 received best supportive care. Forty two (47%) of all patients achieved complete remission (CR). It was found that lower CR rate was associated with poor karyotype and low expression of Smac/DIABLO protein (p<0.01, p<0.01, respectively). The median time of the follow up reached 6 months (range 0.1–68.9). It has been shown that the high expression of Smac/DIABLO (above the median value) and percent of leukemic blast in bone marrow less than 50% were associated with significantly better OS in both univariate (p<0.001, p<0.001, respectively; Figure1) and multivariate (p=0.03, p=0.01, respectively) analyses. However, disease free survival was not influenced by baseline expression of Smac/DIABLO protein in AML cells. Additionally, it has been observed that patients with good and intermediate karyotype according to SWOG classification showed significantly higher expression of Smac/DIABLO protein, compare to poor risk group (median 74,7% vs 37,7% respectively; p< 0.01). Expression of Smac/DIABLO as well as caspase-3 did not correlate with tumour burden-associated risk factors as: number of white blood cells (WBC), percentage of leukemic blasts in bone marrow and serum LDH levels. Furthermore, analyses did not show any correlation between expression of Smac/DIABLO protein and cleaved caspase-3. Conclusions: These data demonstrate that high Smac/DIABLO protein expression is associated with higher sensitivity to standard chemotherapy, favorable karyotype and longer OS in AML patients. The lack of the correlation between expression of Smac/DIABLO and active caspase-3 may be due to low number of patients with examined expression of caspase-3 or activation different way of cell death by Smac/DIABLO. Further investigations evaluating the relationship between Smac/DIABLO as well as the other pro- and anti-apoptotic proteins should be undertaken to better demonstrate its pathways of action as well as prognostic and potentially therapeutic value in AML. 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.

Clinical Implications of Reticulin Fibrosis of Bone Marrow in De Novo Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2585-2585
Author(s):  
Tzung-Chih Tang ◽  
Hung Chang ◽  
Chien-Feng Sun ◽  
Lee-Yung Shih ◽  
Po Dunn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Groups ◽  
Prognostic Impact ◽  
Recovery Duration ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 2585 Background: Microenvironment of bone marrow (BM) plays an important role to support proliferation, renewal and differentiation of hematopoietic stem cells. Whether the stroma of BM affects leukemic cells with the same manner, or impacts on the prognosis in leukemia patients, has not been fully investigated. Previous studies have described that increased reticulin content in the BM is associated with poor outcome in patients with acute lymphoblastic leukemia, chronic myeloid leukemia and primary myelofibrosis, but there is no cohort study to determine the clinical correlation between degree of reticulin fibrosis of BM and acute myeloid leukemia (AML). To investigate prognostic impact of reticulin fibrosis on de novo AML, 881 patients diagnosed between Jun 1999 to Dec 2011 in Chang Gung Memorial Hospital and treated with anthracycline-containing induction chemotherapy were retrospectively reviewed. Patients and methods: According to the grading of reticulin content in the bone marrow, we categorized the 881 patients into four groups: A. BM easily aspirated without biopsy, n = 698; B. Reticulin grade 0, n = 99; C. Reticulin grade 1–2, n = 51; D. Reticulin grade 3–4, n = 33. The induction failure (IF) rate after treatment with induction chemotherapy, the recovery duration of absolute neutrophil count (ANC) greater than 0.5 × 109/L in patients who achieved the first complete remission, the overall survival (OS) and relapse-free survival (RFS) in four groups were analyzed. Based on the cytogenetic or molecular features, 648 of the patients were stratified into unfavorable, intermediate and favorable risk groups, and the clinical significance of reticulin fibrosis of BM were also examined for various risk groups. Results: Of the 881 patients, the patients in group D had a statistically higher IF rate (P = 0.0108) and longer ANC recovery duration (P = 0.0008). But the OS and RFS between four groups were not significantly different (P = 0.5146 and 0.3853, respectively). After risk stratified by cytogenetic and molecular analysis, increased reticulin content of BM (group C or D) had an adverse impact on OS in the intermediate and favorable risk groups (P = 0.006 and 0.0215, respectively). Conclusion: Reticulin content of BM influences the IF rate and myeloid recovery for the patients of de novo AML, and affects OS in patients with intermediate or favorable risk factors. Disclosures: No relevant conflicts of interest to declare.

IDH Mutations and Trisomy 8 In Myelodysplastic Syndromes and Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4009-4009
Author(s):  
Domenica Caramazza ◽  
Terra Lasho ◽  
Christy Finke ◽  
Naseema Gangat ◽  
David Dingli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Trisomy 8 ◽  
Idh Mutations ◽  
De Novo Aml ◽  
Idh2 Mutation ◽  
Acute Myeloid

Abstract Abstract 4009 Trisomy 8 is the most common among sole cytogenetic abnormalities in both acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In the very first paper published on isocitrate dehydrogenase (IDH) mutations in AML, 13 of the 16 IDH1 mutations detected were associated with normal karyotype, 2 with trisomy 8 and one with trisomy 13. Trisomy 8 was also recurrent in patients with IDH1/IDH2-mutated post-MDS AML. In the current study we examined the prevalence and disease distribution of IDH1 and IDH2 mutations in a large (n=157) group of patients with hematologic malignancies and isolated trisomy 8. The Mayo Clinic cytogenetic database allowed identification of 157 patients with isolated trisomy 8. Archived bone marrow cell pellets were used to extract DNA for IDH1 and IDH2 mutation analysis. Eighteen IDH mutations were identified: 15 IDH2 (14 R140Q and one R140W) and 3 IDH1 (2 R132C and one R132G). Seventeen of the 18 IDH mutations occurred in myeloid malignancies whereas one (IDH2R140W) occurred in a patient with angioimmunoblastic lymphoma who was not previously exposed to chemotherapy or radiotherapy, and in whom the IDH2 mutation disappeared after effective lymphoma chemotherapy. Among the 17 IDH-mutated myeloid malignancies, disease-specific IDH1/IDH2 mutational frequencies were as follows: 27% (3/11) for post-MDS AML, 25% (3/12) for therapy-related MDS/AML, 15% (8/54) for de novo MDS, 13% (2/15) for de novo AML and 3% (1/32) for myeloproliferative neoplasm (MPN). In contrast, IDH mutational frequencies were significantly lower among 64 additional patients with AML or MDS without isolated trisomy 8: 7% in de novo AML (n=28), 0% in de novo MDS (n=21), 0% in post-MDS AML (n=11) and 0% in therapy-related MDS/AML (n=4). In the 54 patients with trisomy 8-associated de novo MDS, prognosis was similar between IDH mutated (n=8; median survival 14 months) and unmutated (n=46; median survival 16 months) cases (p=0.7). The majority of IDH-mutated cases with de novo MDS belonged to high risk MDS disease category. However, 3 of the 8 IDH-mutated patients with de novo MDS and 2 of the 3 with therapy-related MDS did not display excess bone marrow blasts. The current study suggests a possible association between IDH mutations and trisomy 8 in AML and MDS but not in MPN or MDS/MPN. The fact that the mere presence of trisomy 8 did not result in a more than expected incidence of IDH mutations in MPN or MDS/MPN makes it unlikely that such an association would be secondary to trisomy 8-associated genetic or biologic changes. Instead, it is possible that IDH mutations, which have been shown to cluster with high-risk disease in both MPN and MDS associated with 5q-, promote a selective advantage for the survival of the clone that harbors trisomy 8. Consistent with this contention, we were able to demonstrate in one of our patients with relapsed AML, the presence of IDHR132C both at initial AML diagnosis and time of relapse, whereas the trisomy 8 abnormality was seen only at the time of relapse. Regardless, the presence of molecular heterogeneity among patients with trisomy 8-associated AML or MDS might explain the controversial prognostic influence of the specific cytogenetic abnormality. Disclosures: No relevant conflicts of interest to declare.

Antileukemic activity of rapamycin in acute myeloid leukemia

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2527-2534 ◽  
Author(s):  
Christian Récher ◽  
Odile Beyne-Rauzy ◽  
Cécile Demur ◽  
Gaëtan Chicanne ◽  
Cédric Dos Santos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Mammalian Target Of Rapamycin ◽  
Cell Types ◽  
Mtor Inhibition ◽  
Growth And Survival ◽  
Clinical Responses ◽  
De Novo Aml ◽  
Acute Myeloid

AbstractThe mammalian target of rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers. In this study, we show that mTOR inhibition by rapamycin strongly inhibits the growth of the most immature acute myeloid leukemia (AML) cell lines through blockade in G0/G1 phase of the cell cycle. Accordingly, 2 downstream effectors of mTOR, 4E-BP1 and p70S6K, are phosphorylated in a rapamycin-sensitive manner in a series of 23 AML cases. Interestingly, the mTOR inhibitor markedly impairs the clonogenic properties of fresh AML cells while sparing normal hematopoietic progenitors. Moreover, rapamycin induces significant clinical responses in 4 of 9 patients with either refractory/relapsed de novo AML or secondary AML. Overall, our data strongly suggest that mTOR is aberrantly regulated in most AML cells and that rapamycin and analogs, by targeting the clonogenic compartment of the leukemic clone, may be used as new compounds in AML therapy.

Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): A Phase Ib Dose-Escalation Study of Venetoclax Combined With Modified Intensive Chemotherapy

2020 ◽  
Vol 38 (30) ◽  
pp. 3506-3517 ◽  
Author(s):  
Chong Chyn Chua ◽  
Andrew W. Roberts ◽  
John Reynolds ◽  
Chun Yew Fong ◽  
Stephen B. Ting ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Escalation ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
B Cell Lymphoma ◽  
Intensive Chemotherapy ◽  
Platelet Recovery ◽  
De Novo Aml ◽  
Acute Myeloid

PURPOSE The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax has an emerging role in acute myeloid leukemia (AML), with promising response rates in combination with hypomethylating agents or low-dose cytarabine in older patients. The tolerability and efficacy of venetoclax in combination with intensive chemotherapy in AML is unknown. PATIENTS AND METHODS Patients with AML who were ≥ 65 years (≥ 60 years if monosomal karyotype) and fit for intensive chemotherapy were allocated to venetoclax dose-escalation cohorts (range, 50-600 mg). Venetoclax was administered orally for 14 days each cycle. During induction, a 7-day prephase/dose ramp-up (days −6 to 0) was followed by an additional 7 days of venetoclax combined with infusional cytarabine 100 mg/m2 on days 1-5 and idarubicin 12 mg/m2 intravenously on days 2-3 (ie, 5 + 2). Consolidation (4 cycles) included 14 days of venetoclax (days −6 to 7) combined with cytarabine (days 1-2) and idarubicin (day 1). Maintenance venetoclax was permitted (7 cycles). The primary objective was to assess the optimal dose schedule of venetoclax with 5 + 2. RESULTS Fifty-one patients with a median age of 72 years (range, 63-80 years) were included. The maximum tolerated dose was not reached with venetoclax 600 mg/day. The main grade ≥ 3 nonhematologic toxicities during induction were febrile neutropenia (55%) and sepsis (35%). In contrast to induction, platelet recovery was notably delayed during consolidation cycles. The overall response rate (complete remission [CR]/CR with incomplete count recovery) was 72%; it was 97% in de novo AML and was 43% in secondary AML. During the venetoclax prephase, marrow blast reductions (≥ 50%) were noted in NPM1-, IDH2-, and SRSF2-mutant AML. CONCLUSION Venetoclax combined with 5 + 2 induction chemotherapy was safe and tolerable in fit older patients with AML. Although the optimal postremission therapy remains to be determined, the high remission rate in de novo AML warrants additional investigation (ANZ Clinical Trial Registry No. ACTRN12616000445471).

Expression of c-mpl mRNA, the receptor for thrombopoietin, in acute myeloid leukemia blasts identifies a group of patients with poor response to intensive chemotherapy.

1997 ◽  
Vol 15 (6) ◽  
pp. 2262-2268 ◽  
Author(s):  
M Wetzler ◽  
M R Baer ◽  
S H Bernstein ◽  
L Blumenson ◽  
C Stewart ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Poor Response ◽  
Significant Difference ◽  
De Novo Aml ◽  
Cd34 Expression ◽  
Acute Myeloid

PURPOSE c-mpl, the human homolog of v-mpl, is the receptor for thrombopoietin. Given that c-mpl expression carries an adverse prognosis in myelodysplastic syndrome and given the prognostic significance of expression of other growth factor receptors in other diseases, we attempted to determine whether c-mp/mRNA expression is a prognostic factor in acute myeloid leukemia (AML). PATIENTS AND METHODS We analyzed bone marrow samples from 45 newly diagnosed AML patients by reverse-transcription polymerase chain reaction. RESULTS Samples from 27 patients (60%) expressed c-mpl mRNA (c-mpl+); their clinical and laboratory features were compared with those of the 18 patients without detectable levels of c-mpl(c-mpl-). No significant differences in age, sex, leukocyte count, French-American-British subtype, or karyotype group were found. c-mpl+ patients more commonly had secondary AML (41% v 11%; P = .046) and more commonly expressed CD34 (67% v 12%; P = .0004). There was no significant difference in complete remission (CR) rate. However, c-mpl+ patients had shorter CR durations (P = .008; median, 6.0 v > 17.0 months). This was true when only de novo AML patients were considered and when controlling for age, cytogenetics, or CD34 expression. There was a trend toward shorter survival in c-mpl+ patients (P = .058; median, 7.8 v 9.0 months). CONCLUSION These data suggest that c-mpl expression is an adverse prognostic factor for treatment outcome in adult AML that must be considered in the analysis of clinical studies using thrombopoietin in AML.

scholarly journals Adult Patients With De Novo Acute Myeloid Leukemia and t(9; 11)(p22; q23) Have a Superior Outcome to Patients With Other Translocations Involving Band 11q23: A Cancer and Leukemia Group B Study

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4532-4538 ◽  
Author(s):  
Krzysztof Mrózek ◽  
Kristiina Heinonen ◽  
David Lawrence ◽  
Andrew J. Carroll ◽  
Prasad R.K. Koduru ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Extra Chromosome ◽  
Response To Therapy ◽  
High Dose ◽  
Postremission Therapy ◽  
De Novo Aml ◽  
Group B ◽  
Acute Myeloid

Abstract Following reports of childhood acute myeloid leukemia (AML) showing that patients with t(9; 11)(p22; q23) have a better prognosis than those with translocations between 11q23 and other chromosomes, we compared response to therapy and survival of 24 adult de novo AML patients with t(9; 11) with those of 23 patients with other 11q23 translocations [t(11q23)]. Apart from a higher proportion of French-American-British (FAB) M5 subtype in the t(9; 11) group (83% v 43%, P = .006), the patients with t(9; 11) did not differ significantly from patients with t(11q23) in terms of their presenting clinical or hematologic features. Patients with t(9; 11) more frequently had an extra chromosome(s) 8 or 8q as secondary abnormalities (46% v 9%, P = .008). All patients received standard cytarabine and daunorubicin induction therapy, and most of them also received cytarabine-based intensification treatment. Two patients, both with t(9; 11), underwent bone marrow transplantation (BMT) in first complete remission (CR). Nineteen patients (79%) with t(9; 11) and 13 (57%) with t(11q23) achieved a CR (P = .13). The clinical outcome of patients with t(9; 11) was significantly better: the median CR duration was 10.7 versus 8.9 months (P = .02), median event-free survival was 6.2 versus 2.2 months (P = .009), and median survival was 13.2 versus 7.7 months (P = .009). All patients with t(11q23) have died, whereas seven (29%) patients with t(9; 11) remain alive in first CR. Seven of eight patients with t(9; 11) who received postremission regimens with cytarabine at a dose of 100 (four patients) or 400 mg/m2 (2 patients) or who did not receive postremission therapy (2 patients) have relapsed. In contrast, 7 (64%) of 11 patients who received intensive postremission chemotherapy with high-dose cytarabine (at a dose 3 g/m2) (5 patients), or underwent BMT (2 patients) remain in continuous CR. We conclude that the outcome of adults with de novo AML and t(9; 11) is more favorable than that of adults with other 11q23 translocations; this is especially true for t(9; 11) patients who receive intensive postremission therapy.

An anti-apoptotic pattern correlates with multidrug resistance in acute myeloid leukemia patients: a comparative study of active caspase-3, cleaved PARPs, Bcl-2, Survivin and MDR1 gene

Hematology ◽  
2010 ◽  
Vol 15 (3) ◽  
pp. 135-143 ◽  
Author(s):  
Margarita L. Guenova ◽  
Gueorgui N. Balatzenko ◽  
Vessela R. Nikolova ◽  
Branimir V. Spassov ◽  
Spiro M. Konstantinov
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Comparative Study ◽  
Myeloid Leukemia ◽  
Caspase 3 ◽  
Mdr1 Gene ◽  
Acute Myeloid ◽  
Active Caspase

The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML

Blood ◽  
2011 ◽  
Vol 117 (7) ◽  
pp. 2137-2145 ◽  
Author(s):  
Sabine Kayser ◽  
Konstanze Döhner ◽  
Jürgen Krauter ◽  
Claus-Henning Köhne ◽  
Heinz A. Horst ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
De Novo ◽  
Negative Impact ◽  
Primary Malignancy ◽  
De Novo Aml ◽  
The Impact ◽  
Acute Myeloid

Abstract To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P < .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P < .0001); t-AML patients had NPM1 mutations (P < .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P < .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.

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