Prognostic Significance of NQO1 Polymorphism and GST-M1 Deletion in De Novo Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4846-4846
Author(s):  
Yeo-Kyeoung Kim ◽  
Hee-Je Kim ◽  
Woo-Sung Min ◽  
Jong- Ho Won ◽  
Deog-Yeon Jo ◽  
...  

Abstract Background: Although the most powerful prognostic factor of acute myeloid leukemia (AML) patients is the karyotype of the leukemic blast, data have not been obtained almost entirely in patients with heterogeneous cytogenetics. Further, some patients with favorable cytogenetics may show the poor treatment outcomes. Previous reports suggested that the single nucleotide polymorphisms of genes coding drug detoxification enzymes such as cytochrome P450 family or DNA repair system may influence the treatment outcomes in the patients with AML. We evaluated the role of polymorphisms in XRCC1, XRCC4, CYP1A1, GST-T1, GST-M1, NOQ1, and NAT2*6A in predicting therapeutic outcomes of adults with AML. Methods: XRCC1 (rs25487), XRCC4 (rs1056503), NQO1 (rs1800566), CYP-4501A1*2B (rs1048943), NAT2*6A (rs1799930) gene polymorphisms and deletion of GST-M1/GST-T1 were evaluated in 460 bone marrow (BM) samples obtained at initial diagnosis from de novo AML patients. Genotyping method is pyrosequencing using genomic DNA from BM samples. Homozygous deletions of GST-M1 and GST-T1 genes were detected with a multiplex PCR technique. All patients except APL (acute promyelocytic leukemia) received one or two rounds of intensive induction chemotherapy consisting of 3 days of idarubicin and 7 days of cytarabine. APL patients treated with AIDA regimen consisting of 45 days of ATRA (all-trans retinoic acid) and 3 days of idarubicin. Results: Of total 460 patients, ninety-nine patients (21.5%) were APL. Seventy-one (15.4%) were AML with t(8;21), twenty-three (5%) were AML with inv(16), and 179 patients (38.9%) showed normal cytogenetics. The median age of patients was 44 years (range, 14–75 years). In all cytogenetic risk group, the patients carrying homozygous NQO1 gene polymorphism (TT) showed significantly lower rate of complete remission (CR) than in those with negative or heterogyzous polymorphisms (TT: 72.7% vs. CC/CT: 85.9%, p=0.03). There was no significant difference in relapse rate, leukemia-free survival (LFS) and overall survival between homo- and heterozygote groups in these polymorphsims. In subgroup analysis, APL patients carrying TT genotype in NQO1 also showed lower rate of CR (TT: 77.8% vs. CC/CT: 95.4%, p=0.04). In AML patients except APL, NQO1 homozygous polymorphsim (TT) was also associated with lower CR rate (TT: 69.6% vs. CC/CT: 84.2%, p=0.005). In normal cytogenetics, the patients with del GST-M1 showed shorter LFS compared with those carrying GST-M1 (18.0 ± 5.7ms. vs. 34.6 ± NA. p=0.04). Conclusions: This study revealed an association between NQO1 polymorphism and GST-M1 deletion and the treatment outcomes for AML patients. Further study and larger sample size are needed to reach the definite conclusion on these associations. However, a stratified treatment plan in remission induction chemotherapy such as augmentation or addition of other chemotherapeutic agents may be warranted for AML patients harvoring homozygous NQO1 polymorphism (TT) or del GST-M1.

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3402-3402
Author(s):  
Seung-Ah Yahng ◽  
Jae-Ho Yoon ◽  
Sung-Eun Lee ◽  
Seung-Hwan Shin ◽  
Byung-Sik Cho ◽  
...  

Abstract Background The successful induction chemotherapy of acute myeloid leukemia (AML) depends on the ability to achieve complete remission (CR) and to maintain remission status as long as possible. Approach to improve the rate of CR includes the intensification of induction chemotherapy for AML. The primary goal of this study was to evaluate and compare the long-term outcomes between remission induction therapy with and without early intensification added to the standard 3+7 remission induction regimen. Methods A retrospective analysis was performed on de novo AML patients diagnosed and treated at Catholic Blood and Marrow Transplantation Center between January 2001 and December 2010. Six hundred forty-one adults of ages between 16 and 60 were included, all of whom received induction chemotherapy starting with 3 days of idarubicin and 7 days of cytarabine or behenoyl cytarabine (BHAC). Cases with t(9;22) and t(15;17) were excluded. Bone marrow (BM) aspiration study was assessed on day 7 of induction in all patients. Factors which were considered for early intensification of induction were the presence of ≥ 5% BM blasts, patient performance, and other high risk clinical characteristics, such as karyotype. Groups according to early intensification on days 8 to 10 of induction were as followings: no intensification (3+7), n=156; cytarabine or BHAC for 3 days (3+10), n=233; addition of idarubicin for 2 days to 3+10 regimen (5+10), n=252. After a median duration of 5.5 months (3.3-19.0) from diagnosis, 479 patients underwent stem cell transplantation (autologous [auto-SCT], n=144; allogeneic [allo-SCT], n=335). Conditioning regimen for auto-SCT consisted of fractionated total body irradiation (TBI), melphalan, and cytarabine, whereas 83% (n=278) of patients with allo-SCT received myeloablative conditioning, of which was mostly TBI-based regimen (92%). Donors were matched sibling (n=213), matched unrelated (n=63), mismatched unrelated (n=39), and haploidentical related (n=20). Results The median age at diagnosis was 39 years (16-60). Mean values of BM blast % on day 7 of induction was 3.5 in 3+7 group, 7.9 in 3+10, and 33.6 in 5+10 (p=<0.0001), while no significant difference in the proportion of adverse karyotype was shown (11.7% vs. 12.8%, p=0.804). After first induction (3+7, n=165; 3+10/5+10, n=465), the CR/CRi rate was significantly higher in 3+10/5+10 versus 3+7 (78.1% vs. 69.2%, p=0.023), while the rate for death in aplasia was lower (4.3% vs. 9.6%, p=0.013). After re-induction with various regimens, the CR/CRi rate was still significantly higher in intensified group (p=0.012). The relapse rates between the groups in 536 patients achieving CR (83.6%), however, was not significantly different (8.9% vs. 9.9%, p=0.737). SCT was performed at CR1 (n=459), CR2 (n=10), or relapsed/refractory status (n=10). Patients with auto-SCT mostly had better/intermediate cytogenetic risk (96%) at diagnosis, while 12% of allo-SCT had poor karyotype. After the median follow-up duration of 60.2 months (2.2-143.5), the median overall survival (OS) in all patients (n=641) was 65.6 months. The 5-year disease-free survival (DFS) of patients with auto- and allo-SCT was 58.4±4.2 and 64.9±2.7, respectively. Of 334 patients receiving allo-SCT, the 5-year DFS was significantly higher in patients achieving CR1 (n=299) after first induction therapy (p<0.0001), in whom 75% of them had early intensification. Other factors with significant impact on DFS after allo-SCT (n=334) were karyotype at diagnosis (p=0.032) and donor type (HLA-matched vs. HLA-mismatched sibling or unrelated, 58.1%±3.8 vs. 45.1±8.0, p=0.016). The significances were confirmed in multivariate analysis, which demonstrated that achieving CR1 after first induction regimen and its maintenance until SCT was the most powerful predictor for DFS after allo-SCT (67.1±2.9 vs. 34.6±7.8, p=<0.0001). When all patients were analyzed, according to induction intensification, a statistically significant benefit in 10-year OS was observed in 5+10 intensified group (44.8% vs. 52.9%, p=0.032). Conclusion Our results suggest possible benefit of examining day 7 BM aspiration for the strategy of early intensification of induction chemotherapy for adult AML patients and our intensification doses can be safely added with high efficacy in the achievement of CR1 compared to 3+7 standard regimen, and may have affected for better DFS after allo-SCT. Disclosures: Kim: BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.


2021 ◽  
Vol 10 (24) ◽  
pp. 5768
Author(s):  
You-Cheng Li ◽  
Yu-Hsuan Shih ◽  
Tsung-Chih Chen ◽  
Jyh-Pyng Gau ◽  
Yu-Chen Su ◽  
...  

The therapeutic strategies for acute myeloid leukemia (AML) patients ineligible for remission induction chemotherapy have been improving in the past decade. Therefore, it is important to define ineligibility for remission induction chemotherapy. We retrospectively assessed 153 consecutive adult de novo AML patients undergoing remission induction chemotherapy and defined early mortality as death within the first 60 days of treatment. The 153 patients were stratified into the early mortality group (n = 29) and the non-early mortality group (n = 124). We identified potential factors to which early mortality could be attributed, investigated the cumulative incidence of early mortality for each aspect, and quantified the elements. The early mortality rate in our study cohort was 19.0%. Age ≥ 65 years (odds ratio (OR): 3.15; 95% confidence interval (CI): 1.05–9.44; p = 0.041), Eastern Cooperative Oncology Group performance status ≥ 2 (OR: 4.87; 95% CI: 1.77–13.41; p = 0.002), and lactate dehydrogenase ≥ 1000 IU/L (OR: 4.20; 95% CI: 1.57–11.23; p = 0.004) were the risk factors that substantially increased early mortality in AML patients. Patients with two risk factors had a significantly higher early mortality rate than those with one risk factor (68.8% vs. 20.0%; p < 0.001) or no risk factors (68.8% vs. 9.2%; p < 0.001). In conclusion, older age, poor clinical performance, and a high tumor burden were risks for early mortality in AML patients receiving remission induction chemotherapy. Patients harboring at least two of these three factors should be more carefully assessed for remission induction chemotherapy.


2020 ◽  
Vol 11 ◽  
pp. 204062072096584
Author(s):  
Tsung-Chih Chen ◽  
Ren Ching Wang ◽  
Yu-Hui Lin ◽  
Kuang-Hsi Chang ◽  
Li-Ya Hung ◽  
...  

Background: Posaconazole prophylaxis during remission induction chemotherapy not only decreases the incidence of invasive aspergillosis (IA) but also improves the overall survival rate among patients with acute myeloid leukemia (AML). However, it remains debatable whether this result applies to patients in a real-world setting. Methods: We retrospectively assessed 208 adult patients with newly diagnosed AML who underwent remission induction therapy. These 208 patients were stratified into the posaconazole prophylaxis group ( n = 58) and no antifungal prophylaxis group ( n = 150). Results: Multivariate analyses showed that induction failure significantly increased the risk of proven or probable IA during the first induction chemotherapy [hazard ratio (HR), 10.47; 95% confidence interval (CI), 1.73–63.45; p = 0.011] and the entire course of AML treatment (HR, 4.48; 95% CI, 1.71–11.75; p = 0.002). However, posaconazole prophylaxis did not reduce the risk of IA during the first induction chemotherapy (HR, 1.47; 95% CI, 0.14–15.04; p = 0.746) and during the entire course of AML treatment (HR, 1.09; 95% CI, 0.29–4.09; p = 0.896). Furthermore, there was no significant difference in overall survival between these two groups of patients (514 versus 689 days; p = 0.454). Conclusion: Successful induction remains fundamental to reducing the risk of IA among AML patients undergoing remission induction chemotherapy.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3866-3866
Author(s):  
Manu Pandey ◽  
Mahesh Swaminathan ◽  
Elizabeth A. Griffiths ◽  
James E. Thompson ◽  
Amanda Przespolewski ◽  
...  

In the past year, there has been a paradigm shift in the treatment of elderly and/or unfit patients with newly diagnosed acute myeloid leukemia (AML) with the approval of venetoclax (Ven) plus hypomethylating agents (HMA) or low dose Ara-C (LDAC). Ven/ HMA has shown an impressive complete response + complete response with incomplete count recovery (CR+ CRi) rate of 67% and a median overall survival (OS) of 17.5 months in older patients (pts) (median age 74 years) with intermediate and poor risk cytogenetics (Dinardo C et. Blood 2019). Similarly, Ven/LDAC resulted in a CR+ CRi rate of 54% with a median overall survival of 10.1 mos (Wei A et al JClinOnc 2019). However, to date, it is not known how the outcomes of Ven/HMA and Ven/LDAC compare with HMA or intensive chemotherapy in newly diagnosed AML pts. Methods To address this issue, we conducted a retrospective analysis of newly diagnosed AML adult pts treated with Ven-based regimens at our institution. All data was collected under an IRB approved protocol. Demographics, disease characteristics (including cytogenetics and molecular profiles), treatment details (drugs, duration, mortality and causes of death), and clinical outcomes including response and OS were analyzed. Results were compared to a historical cohort of elderly pts treated with HMA alone or intensive (7+3 based) induction chemotherapy as previously reported1. Results 31 newly diagnosed AML patients treated at our single academic institution between 2017-2019 were identified. The median age of the group was 75 years (51-90; 29 patients ≥ 60 years) with 20/31 (64.5%) males and 11/31(35.5%) females. 13/31(41.9%) patients had de-novo AML whereas 18/31 (58.1%) had high risk AML (AML with prior hematological abnormality, t-AML). By ELN 2017 risk stratification 2(6.4%),12(38.7%),17(54.8%) were favorable, intermediate, adverse risk respectively. Molecular profiling results was available for 23/31(74.2%) patients, TET2 and TP53 were the most common mutations present in 9 (29.0%) and 8 (25.8%) patients, respectively. 3/31(9.6%) patients subsequently received an allogeneic-HSCT as of August 1, 2019. The median follow-up was 112 days (9-600 days). Median number of cycles received were 2 (1-21). 15/31 (48%) pts were considered responders (CR, CRi, MLFS), 9 of 31(29%) were non-evaluable (N/E). Of these 7/9 patients died before repeat biopsy, 2/9 patient did not have a repeat biopsy. 2/31(6.4%) experienced partial response, 2/31(6.4%) had stable disease and 3/31(9.6%) had refractory disease. 30-day and 60-day mortality was 2/31(6.4%) and 6/31(19.3%) respectively. Two thirds of treated patients (20/31, 64.5%) are alive. Of the 11 patients who died 5 (45.5%) died due to pneumonia/sepsis, 3 (27.3%) died due to progressive disease, 2 (18.2%) withdrew therapy due to poor performance status and 1(9.1%) CNS bleed. There was no statistical difference in de-novo vs high risk AML, ELN 2017 risk stratification (favorable + intermediate vs adverse) when compared for response (responders vs others) or status (alive vs dead). We then compared our Ven/chemotherapy outcomes with prior data from our institution of newly diagnosed elderly pts treated with HMA or intensive chemotherapy (IC)1. There was a statistically significant difference for response favoring Ven based regimen vs HMA (48.3% vs 25.6% p=0.02); however, no significant difference was seen when comparing Ven/chemo with IC (48.3% vs 50%, p=0.87) (table 1). Similarly, no significant difference was observed in 60-day mortality when IC and HMA based therapy was compared with Ven based regimen (p=0.85 and 0.87 respectively) (table 2). Longer follow up in the Ven/chemotherapy arm is required to make any meaningful conclusion for differences in OS if any (figure A). Conclusion In our single institution retrospective review, we found higher rates of 60-day mortality than reported in a prior phase 1 multi-institute clinical trial (DiNardo et al. Blood 2019). However, response rates with Ven/chemo were significantly better than HMA alone and were equivalent to those of IC in similar elderly AML pts at our institute. We conclude that induction chemotherapy with Ven/based regimens could result in similar responses as IC in older AML pts. References 1-Gupta, Neha, et al. "Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients≥ 60 years old." American journal of hematology90.7 (2015): 639-646. Disclosures Griffiths: Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; New Link Genetics: Consultancy; New Link Genetics: Consultancy; Persimmune: Consultancy; Genentech, Inc.: Research Funding; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Genentech, Inc.: Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Persimmune: Consultancy; Celgene, Inc: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Partner Therapeutics: Consultancy; Celgene, Inc: Consultancy, Research Funding; Novartis Inc.: Consultancy; Abbvie, Inc.: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy, PI on a clinical trial. Thota:Incyte, Inc.: Speakers Bureau. Wang:Jazz: Other: Advisory role; Kite: Other: Advisory role; Abbvie: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role.


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4271-4271
Author(s):  
Yeo-Kyeoung Kim ◽  
Hee-Nam Kim ◽  
Il-Kwon Lee ◽  
Soo-Mee Bang ◽  
Deog-Yeon Jo ◽  
...  

Abstract Background: Reciprocal translocations like t(8;21) or inv(16) in acute myeloid leukemia (AML) usually predicts a good response to chemotherapy with a high remission rate and a relatively long median survival. MDR1/Pgp, the gene product of MDR1, is recognized as an important class of proteins for regulating pharmacokinetics. Several reports showed the effects of ABCB1 (mutidrug resistance 1 gene, MDR1, PgP) genotypes such as single nucleotide polymorphisms (SNPs) on pharmacotherapy in various malignancies including AML. However, it remains to be clarified that these SNPs of ABCB1 gene play an significant role in the treatment outcome of AML patients with favorable cytogenetics especially t(8;21) or inv(16). Aims: To determine the prevalence and the prognostic role of ABCB1 polymorphisms in de novo AML patients with t(8;21) or inv (16). Methods: Twenty ABCB1 gene polymorphisms (SNP numbers: rs1055302, rs1002205, rs4148750, rs7779562, rs6980101, rs1922242, rs2235013, rs4728702, rs1922240, rs1922241, rs4148734, rs6950978, rs10256836, rs1202172, rs17327442, rs7802773, rs13229143, rs4148732, rs1978095, rs10264856) were evaluated by performing DNA polymerase chain reaction assays on 49 bone marrow samples obtained at initial diagnosis from the AML patients with t(8;21) or inv(16). DNA sequencing and GeneScan analysis was performed to confirm the the genotyping results. All patients received one round of intensive induction chemotherapy consisting of 3 days of idarubicin and 7 days of cytarabine. Results: Of total 49 patients, 39 (79.6%) were AML with t(8;21) and 10(20.4%) were AML with inv(16). The median age of patients was 37 years (range, 17–69 years). There were 29 males (59.2%) and 20 females (40.8%). There was no statistically significant difference in age, gender, leukocyte count, and percentage of peripheral or bone marrow blasts in the patients according to the ABCB1 polymophisms or cytogenetic abnormalities. However, there was significant difference in complete response (CR) rate according to the zygocities of SNPs in the intron of ABCB1 gene such as rs6980101 (genotype C/C: 68.4% vs. C/T: 100%, p=0.03), rs10256836 (G/G: 91.3% vs. G/C: 50%, p=0.03), rs17327442 (T/T: 88.9% vs. T/A: :40%, p=0.01), rs4148732 (A/A: 95.8% vs. A/G: 50%, p=0.00). CR rates were not significantly influenced by cytogenetic abnormalities. There was no significant difference in relapse rate, leukemia-free survival and overall survival between homo- and heterozygote groups in these polymorphsims. Conclusions: This study revealed an association between ABCB1 SNPs and the treatement outcomes for AML patients with t(8;21) or inv(16). Further study is needed to reach the definite conclusion on these associations. However, a stratified treatment plan in remission induction chemotherapy such as augmentation or addition of other chemotherapeutic agents may be warranted for the AML with t(8;21) or inv(16) harvoring such ABCB1 polymophrisms.


2021 ◽  
Vol 10 ◽  
pp. e2288
Author(s):  
Mahdiyar Iravani Saadi ◽  
Mani Ramzi ◽  
Aliasghar Karimi ◽  
Maryam Owjfard ◽  
Mahmoud Torkamani ◽  
...  

Background: Acute Myeloid Leukemia syndrome (AML) is a hematologic malignancy which is due to clonal extensive proliferation of leukemic precursor cells and is rapidly fatal unless treated or response to chemotherapy. Cytogenetic findings have important role in prognosis and categorization of AML. The aim of this study was to investigate the expression changes in CX3CL1 and Interlukin-6 (IL-6) genes before and after chemotherapy as remission induction therapy in AML patients. Materials and Methods: In this study 69 patients (36 males, 33 female) with AML was selected from tertiary medical heath center. A quantitative polymerase chain reaction (PCR) was done for mRNA expression of CX3CL1 and IL-6genes before and after induction chemotherapy. To obtain expression changes in CX3CL1 and IL-6genes, we used 2-ΔΔCT method. Results: The expression of CX3CL1 and IL-6 was significantly increased after induction chemotherapy. Also, the ΔCt mean of CX3CL1 and IL-6 mRNA was not significant between AML subtype groups. Conclusion: In conclusion, as we showed that chemotherapy significantly increase the expression of CX3CL1 and IL-6 which can be used as a prognostic factor of AML.


2019 ◽  
Vol 08 (04) ◽  
pp. 193-197
Author(s):  
Anudishi Tyagi ◽  
Raja Pramanik ◽  
Radhika Bakhshi ◽  
Sreenivas Vishnubhatla ◽  
Sameer Bakhshi

AbstractThis prospective study aimed to compare the pattern of mitochondrial deoxyribonucleic acid D-loop (mt-DNA D-loop) variations in 41 paired samples of de novo pediatric acute myeloid leukemia (AML) (baseline vs. relapse) patients by Sanger's sequencing. Mean mt-DNA D-loop variation was 10.1 at baseline as compared with 9.4 per patients at relapse. In our study, 28 (68.3%) patients showed change in number of variations from baseline to relapse, 11 (26.8%) patients showed increase, 17 (41.6%) patients showed decrease, and 7 (17.1%) patients who suffered a relapse had a gain at position T489C. No statistically significant difference was observed in the mutation profile of mt-DNA D-loop region from baseline to relapse in the evaluated population of pediatric AML.


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