A Multicentre, Double-Blind, Randomized, Phase 2 Trial Comparing Pegfilgrastim with Filgrastim as an Adjunct to Chemotherapy for Acute Myeloid Leukaemia (AML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 866-866 ◽  
Author(s):  
Alberto Bosi ◽  
Jeffrey Szer ◽  
Jeannine Kassis ◽  
Jorge Sierra ◽  
Claire Desborough ◽  
...  
Keyword(s):  
Median Time ◽  
Induction Chemotherapy ◽  
De Novo ◽  
Severe Neutropenia ◽  
Single Administration ◽  
Serious Adverse Events ◽  
Treatment Groups ◽  
Risk Of Death ◽  
Increased Risk ◽  
Significant Difference

Abstract BACKGROUND: Heil et al (Blood ‘97) demonstrated that the duration of neutropenia and its clinical consequences following induction chemotherapy for AML were significantly reduced by the addition of filgrastim, with no increased risk of death, second malignancy or relapse (ASH ‘99). A single injection of pegfilgrastim has been shown to be comparable to daily injections of filgrastim in the management of chemotherapy-induced neutropenia. The primary aim of this trial was to estimate the difference in time to recovery from severe neutropenia (SN, ANC < 0.5 x109/L) in the first induction chemotherapy cycle (Induction 1) in AML subjects treated with pegfilgrastim or filgrastim. METHODS: Subjects with de novo AML received 1 or 2 courses of induction chemotherapy (idarubicin 12mg/m2 IV days 1–3, cytarabine 100mg/m2 IV 12 hourly days 1–7 [IA 3+7]) then, if in remission, consolidation chemotherapy (cytarabine 2 [subjects < 55 years] or 3g/m2 [subjects ≥ 55 years] IV 12 hourly days 1, 3, 5). Subjects received either single administration 6μg pegfilgrastim or daily 5μg/kg filgrastim starting 24 hours after completion of chemotherapy until neutrophil recovery. Time to recovery from SN was defined as the number of days from the first day of chemotherapy until the first of two ANC consecutive values after the nadir that were ≥ 0.5 x 109/L whereas duration of SN was defined as the total number of days during the cycle with an ANC < 0.5 x 109/L. RESULTS: Of 84 subjects randomised into the study, 83 received study drug (42 pegfilgrastim, 41 filgrastim). The treatment groups were generally well balanced for demographics and baseline characteristics. The median time to recovery from SN (ANC < 0.5 x109/L) in Induction 1 was 22 days in both treatment groups (95% CI for treatment difference: −1.9, 1.9). There was also no statistically significant difference in the median duration of SN between the 2 groups (21 days pegfilgrastim, 20 days filgrastim). Subjects in the filgrastim group required a median of 16 daily injections compared to a single administration of pegfilgrastim in the second group. Median serum concentration of pegfilgrastim in Induction 1 remained above clinically relevant concentrations until 21 days after the start of chemotherapy, results that are consistent with the neutrophil-mediated clearance of pegfilgrastim. The incidence of serious adverse events was comparable between the 2 groups except for infectious complications, which were higher in the filgrastim group (5 subjects [12%] pegfilgrastim versus 9 subjects [22%] filgrastim). CONCLUSION: In the setting of the first cycle of IA 3+7 induction chemotherapy in AML patients, once per cycle administration of 6 mg pegfilgrastim or daily administration of 5mg/kg filgrastim result in similar median time to recovery to ANC ≥ 0.5 x109/L. Pegfilgrastim is safe and well tolerated in this subject population.

scholarly journals Enough with the madness: a systematic review and meta-analysis of hydroxychloroquine for COVID-19

2021 ◽  
Vol 13 (2) ◽  
pp. 186-220
Author(s):  
André Santos ◽  
◽  
Érica Gonçalves ◽  
Ananda Oliveira ◽  
Douglas Lima ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adverse Events ◽  
Meta Analysis ◽  
Standard Of Care ◽  
P Value ◽  
Serious Adverse Events ◽  
Risk Of Death ◽  
Increased Risk ◽  
Significant Difference

Objective: Because of preliminary results from in vitro studies, hydroxychloroquine (HCQ) and chloroquine (CQ) have been proposed as possible treatments for COVID-19, but the clinical evidence is discordant. This study aims to evaluate the safety and efficacy of CQ and HCQ for the treatment of COVID-19. Methods: A systematic review with meta-analysis was performed. An electronic search was conducted in four databases for randomized controlled trials that compared HCQ or CQ with standard-of-care. A complementary search was performed. A quantitative synthesis of clinical outcomes was performed using the inverse variance method adjusting for a random-effects model. Results: In total, 16 studies were included. The meta-analysis found no significant difference between intervention and control groups in terms of mortality at the most extended follow-up (RR = 1.09, CI95% = 0.99-1.19, p-value = 0.08), patients with negative PCR results (RR = 0.99, CI95% = 0.89-1.10, p-value = 0.86), or serious adverse events (RR = 2.21, CI95% = 0.89-5.47, p-value = 0.09). HCQ was associated with an increased risk of adverse events (RR = 2.28, CI95% = 1.36-2.83, p-value < 0.01). The quality of evidence varied from very low to high. Conclusion: There is no evidence that HCQ reduces the risk of death or improves cure rates in patients with COVID-19, but it might be associated with an increased risk of adverse events

scholarly journals 416 - Risk of Mortality Associated with Antipsychotics in Alzheimer's Disease

2020 ◽  
Vol 32 (S1) ◽  
pp. 132-132
Author(s):  
Liliana P. Ferreira ◽  
Núria Santos ◽  
Nuno Fernandes ◽  
Carla Ferreira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adverse Events ◽  
Mortality Risk ◽  
Antipsychotic Treatment ◽  
Serious Adverse Events ◽  
Risk Of Death ◽  
Mesh Terms ◽  
Risk Of Mortality ◽  
Increased Risk

Objectives: Alzheimer's disease (AD) is the most common cause of dementia and it is associated with increased mortality. The use of antipsychotics is common among the elderly, especially in those with dementia. Evidence suggests an increased risk of mortality associated with antipsychotic use. Despite the short-term benefit of antipsychotic treatment to reduce the behavioral and psychological symptoms of dementia, it increases the risk of mortality in patients with AD. Our aim is to discuss the findings from the literature about risk of mortality associated with the use of antipsychotics in AD.Methods: We searched Internet databases indexed at MEDLINE using following MeSH terms: "Antipsychotic Agents" AND "Alzheimer Disease" OR "Dementia" AND "Mortality" and selected articles published in the last 5 years.Results: Antipsychotics are widely used in the pharmacological treatment of agitation and aggression in elderly patients with AD, but their benefit is limited. Serious adverse events associated with antipsychotics include increased risk of death. The risk of mortality is associated with both typical and atypical antipsychotics. Antipsychotic polypharmacy is associated with a higher mortality risk than monotherapy and should be avoided. The mortality risk increases after the first few days of treatment, gradually reducing but continues to increase after two years of treatment. Haloperidol is associated with a higher mortality risk and quetiapine with a lower risk than risperidone.Conclusions: If the use of antipsychotics is considered necessary, the lowest effective dose should be chosen and the duration should be limited because the mortality risk remains high with long-term use. The risk / benefit should be considered when choosing the antipsychotic. Further studies on the efficacy and risk of adverse events with antipsychotics are needed for a better choice of treatment and adequate monitoring with risk reduction.

scholarly journals Tiotropium (SPIRIVA®) in mild COPD: Is it worth it?

2019 ◽  
Vol 46 (1) ◽  
Author(s):  
Lina Mahmoud ◽  
Hannah Ng ◽  
Jade Roberts
Keyword(s):  
Quality Of Life ◽  
Exercise Duration ◽  
Cochrane Library ◽  
Chronic Obstructive ◽  
Serious Adverse Events ◽  
Main Trial ◽  
Copd Exacerbations ◽  
Increased Risk ◽  
Significant Difference

Purpose:Tiotropium (SPIRIVA®) is used in the treatment of moderate to severe chronic obstructive pulmonary disease (COPD) in patients with persistent dyspnea despite using a short acting bronchodilator (SABD).This paper explores the role of tiotropium in the treatment of mild COPD. Methods:The Cochrane Library, EMBASE, Pubmed, and Clinicaltrials.gov were searched on February 2018.We included randomized controlled trials (RCTs) that evaluated tiotropium in patients with mild COPD.Three authors assessed studies for eligibility. Outcomes included symptoms, quality of life, exercise duration, lung function, COPD exacerbations and hospitalizations, and serious adverse events. Results: Three RCTs were selected as the best available evidence. Based on the results of the main trial, quality of life and symptoms were improved with tiotropium as compared to placebo with a difference between groups at 24 months to be 1.2 (95% CI: 0.5 to 1.9; p=0.0011) using the COPD Assessment test (CAT) score. Frequency of acute exacerbations of COPD (AECOPD) requiring hospitalization was reduced by 10.3% (28.9% with tiotropium vs 39.2% with placebo) in patients receiving tiotropium. One RCT reported no statistically significant difference in exercise duration (27 ± 27 secs) in the tiotropium group vs 50 ± 21 secs in the placebo group; (p=0.4153). Oropharyngeal discomfort was more common with tiotropium (number needed to harm of 12) compared to placebo. Conclusions: Evidence suggests that tiotropium may reduce COPD exacerbations and hospitalizations and improve quality of life in patients with mild COPD.There is an increased risk of oropharyngeal discomfort with tiotropium.

Survival Varies By Age and Histology in Classical Hodgkin Lymphoma: A Report from the Children's Oncology Group

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-25
Author(s):  
Justine M. Kahn ◽  
Kara M. Kelly ◽  
Qinglin Pei ◽  
Yue Wu ◽  
Debra L. Friedman ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Hodgkin Lymphoma ◽  
Cumulative Incidence ◽  
De Novo ◽  
Oncology Group ◽  
Bulky Disease ◽  
Risk Of Death ◽  
Increased Risk ◽  
Multivariable Models ◽  
Effect Of Age

Introduction While 5-year event-free (EFS) and overall survival (OS) in Hodgkin lymphoma (HL) generally exceed 85% and 95%, respectively, outcomes may not be as favorable in adolescents and young adults (15 - 39 years [y]) compared to children. Small clinical trials have reported better outcomes for pediatric but not adult patients with mixed cellularity (MC) vs. nodular sclerosing (NS) histology, suggesting the possibility of biologic differences across the age-spectrum in HL. We examined survival by age and histology in patients receiving risk-based, response-adapted therapy for de novo HL on contemporary Children's Oncology Group (COG) trials. Methods This was a pooled analysis of individual-level data from 1,907 patients enrolled on three Phase 3 COG clinical trials for treatment of low-risk (AHOD0431), intermediate risk (AHOD0031) and high-risk (AHOD0831) HL between 2002 and 2012. Histologic subgroups included MC, NS and classical HL, not-otherwise-specified (cHL, NOS). Five-year cumulative incidence of relapse, EFS and OS were compared by age group (&lt;15 y vs. ≥15 y) in the pooled cohort, and in histologic subgroups (MC and non-MC) using the Kaplan-Meier method. Effect modification was confirmed between age and histology. Cox proportional hazards regression models were used to examine the influence of age on EFS and OS, adjusted for race/ethnicity, Ann Arbor stage, B symptoms, bulky disease, receipt of radiation therapy (RT), and the interaction between age and histology; COG study was also included in the model, given that the criteria for response adaptation differed across the trials. Results Between 2002 and 2012, N= 2155 patients 1 - 21 y enrolled on three COG trials, 1,907 (88%) of whom were included in this analysis. Mean age of the cohort was 14.6 y (± 3.5) with N= 871 (46%) &lt;15 y and N= 1,036 (54%) ≥15 y. In total, N= 1,547 patients (81%) had NS histology, N= 108 (6%) had cHL, NOS, and N= 196 (10%) had MC histology; by age, MC histology was present in N= 66 patients (7%) ≥15 y and N= 130 patients (15%) &lt;15 y (p&lt; 0.01). A significantly higher proportion of those ≥15 y vs. younger had B-symptoms at diagnosis (29% vs. 21%, p&lt; 0.01), however the presence of bulky disease did not differ by age. Finally, patients ≥15 y (vs. &lt;15 y) were significantly more likely to receive RT as part of their treatment (72% vs. 63%, p&lt;0.01). Survival: Median follow up was 6.9 years. In unadjusted analyses, 5-year EFS and OS were 83% and 97%, respectively. The 5-year EFS was lower for patients ≥15 y vs. &lt;15 y (85% vs 89%, p&lt;0.01), as was the 5-year OS (96% vs. 99%, p&lt; 0.01). In multivariable models, age ≥15 y (vs. younger) was associated with a 1.4-fold increased risk of EFS (HR: 1.4, 95% CI: 1.1, 1.8, p&lt; 0.01), and more than a 3-fold increased risk of death (OS: HR: 3.1, 95% CI: 1.5, 6.4, p&lt; 0.01). The effect of age on EFS varied by histologic subgroup. Among those with non-MC histology, cumulative incidence of relapse did not significantly differ by age in unadjusted models (Figure A), however 5-year EFS was significantly worse in the older group (Figure B). In multivariable analyses, age ≥15 y (vs. younger) was associated with a 1.3-fold increased risk of EFS (HR: 1.3; 1.03 - 1.7, p= 0.03) (Table). Among patients with MC histology, age ≥15 y (vs. younger) was associated with significantly higher relapse rate (22% vs. 5%, p&lt; 0.01) (Figure C) and significantly worse 5-year EFS (75% vs. 94%, p&lt; 0.01) (Figure D). This remained significant in multivariable models: patients with MC histology who were ≥15 y (vs. younger) had a 3.7-fold increased risk of EFS (HR: 3.7, 95% CI: 1.6, 8.9, p&lt; 0.01) (Table). Conclusion In patients receiving response-adapted therapy for de novo HL on contemporary COG trials, adolescents ≥15 y had worse EFS and OS compared to younger groups. The magnitude of the effect of age was higher in patients with MC disease. Although recent pediatric trials in HL have indicated better survival for some children with MC histology, alternative approaches or novel therapies should be considered for older adolescents with MC disease, whose outcomes appear more like adults. Disclosures No relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation (SCT) in Untreated First Relapse or Following Re-Induction Chemotherapy for Patients with Acute Myeloid Leukemia (AML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5143-5143
Author(s):  
Rachanid Pornvipavee ◽  
Walter K. Kremers ◽  
Rachel A. Pedersen ◽  
Michelle Elliott ◽  
William J. Hogan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Induction Chemotherapy ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Multivariate Model ◽  
Lower Percentage ◽  
Risk Of Death ◽  
Increased Risk ◽  
Blast Cells ◽  
First Relapse

Abstract Background The timing of SCT for treatment of AML after first relapse is controversial, i.e.,whether to proceed to SCT at the time of relapse or to proceed to chemotherapy re-induction first in an attempt to reach a second remission. The purpose of this study is to determine the optimal time of allogeneic SCT in AML patients in first relapse by comparing outcomes of allogeneic SCT between patients untreated and patients post re-induction chemotherapy. Method This retrospective study was approved by the Mayo Foundation IRB. Between February 1983 and March 2003, 60 patients with AML in untreated first relapse (REL1) or post re-induction chemotherapy (CT) underwent allogeneic SCT in Mayo Clinic, Rochester. Study outcome included overall survival (OS), disease free survival (DFS), and transplant related mortality (TRM). The outcome was compared between the patients who underwent allogeneic SCT at REL1 and CT. Survival was analyzed using Kaplan-Meier (KM) and groups were compared statistically with the log-rank test. Result Of the 60 patients receiving allogeneic SCT , 25 patients and 35 patients underwent SCT at REL1 and CT, respectively. In the group of CT, 23 patients (66%) achieved CR2 while 12 patients (34%) had refractory disease. Forty-nine of 60 patients received cyclophosphamide and total body irradiation (Cy/TBI) as a conditioning regimen and the remainder received busulfan and cyclophosphamide( Bu/Cy). Patients in REL1 were older at SCT (median age 38 vs 31 years p= 0.024 ) and had lower percentage blast cells in bone marrow at first relapse (median 15% vs 50% p=0.00095) than in CT group. Difference in other baseline characteristics were not significant. KM analysis showed that the two groups did not show statistically differences in OS (p=0.43), DFS (p=0.68), and TRM (p=0.25). However, there were trends toward longer median OS (26.2 vs 5.4 months) and DFS (11.9 vs 3.3 months) with REL1 versus CT. OS at 1 year was 56 % for REL1 and 34.3 % for CT and at 5 year 32.1 % and 28.6 %, respectively. DFS at 1 year was 48 % for REL1 and 31.4 % for CT and at 5 years 22.9 % and 24.5 % respectively. TRM at 1 year was 25% for REL1 and 40 % for CT. A univariate Cox Proportional Hazard analysis for survival showed that unfavorable cytogenetics at diagnosis and relapse, antecedent MDS, and shorter duration of CR1 were significantly associated with a higher risk of death. Higher percentage of blast cells in bone marrow at first relapse was not significantly associated with a higher risk of death. In a multivariate model, unfavorable cytogenetics at first relapse and shorter duration of CR1 were both significantly associated with an increased risk of death. In this study, even after adjusting for other factors in a multivariate model, the difference between REL1 and CT groups was not statistically significant. Conclusion This study suggests that outcome of allogeneic SCT was comparable between REL1 and CT. Patients with AML in first relapse may proceed to allogeneic SCT because there appear to be no statistical differences in REL1 versus re-induction chemotherapy before SCT. REL1 patients tended to have a better outcome than CT patients.

Acute Leukemia in Patients Sixty Years of Age and Older: A Retrospective Review.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4605-4605
Author(s):  
Chantal S. Leger ◽  
Ann Lee ◽  
Heather A. Leitch ◽  
Paul F. Galbraith ◽  
Charles H. Li ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Treatment Outcomes ◽  
Induction Chemotherapy ◽  
De Novo ◽  
Disease Free Survival ◽  
Retrospective Chart Review ◽  
Prolonged Survival ◽  
Entire Group ◽  
Secondary Leukemia ◽  
Significant Difference

Abstract Acute leukemia, especially acute myeloid leukemia (AML), occurs more frequently in the elderly population. Treatment outcomes for this condition have traditionally been poor and very few patients survive for prolonged periods following diagnosis. We performed a retrospective chart review of all patients sixty years of age and older diagnosed with acute leukemia at St. Paul’s hospital, Vancouver, Canada, from June 1984 to July 2004. One hundred and three patients were diagnosed with acute leukemia [AML- 81; ALL- 15; ALN (acute leukemia not otherwise specified)- 7]. The median age was 72 (range 60–88) years. Fifty-seven (55%) and 46 (45%) patients had de novo and secondary leukemia, respectively. Sixteen patients (28%) had an unfavourable karyotype. Fifty-three patients (51%) received induction chemotherapy (treated) and 50 (49%) were provided with supportive care only (untreated). Treated patients were younger [67 years (60–79)] than untreated patients [76 years (61–88)], (p<0.0001), and no patients >/= 80 years were treated (n=17). Of the treated patients, 33 (62%) achieved a complete remission (CR), 10 (19%) had resistant disease and 10 (19%) died from complications related to treatment. The median overall survival for the entire group was 103 (1–1229) days, and for treated versus untreated patients was 216 (1–1213) and 38 (2–1229) days, respectively (p=0.0021). The disease free survival in treated patients achieving a CR (n=33) was 262 days (9–722). Less than 5% of patients were alive at 4 years from diagnosis. Univariate variables predictive of prolonged survival included receiving induction chemotherapy (p=0.0027), de novo as opposed to secondary leukemia (p=0.0420), and younger age, with a relative increase in death in older subgroups (60–69, 70–79, 80+), (p=0.0311). Induction chemotherapy was the only independent predictor of prolonged survival in multivariate analysis (p=0.0027). There was no statistically significant difference in the number of treated patients and treatment outcomes between 1984–1993 and 1994–2004. In conclusion, this single-institution series of 103 patients aged sixty years and older with acute leukemia, shows that the prognosis of this disease in older patients is extremely poor. Even though induction chemotherapy seems to prolong survival in patients who are fit to receive treatment, the prognosis remains grim and most patients ultimately die of leukemia, supporting a role for investigational regimens focusing solely on this age group. It is no longer appropriate to follow regimens that have remained largely unsuccessful and unchanged over 20 years.

The Addition of Gemtuzumab Ozogamicin to Induction Chemotherapy for AML Improves Disease Free Survival without Extra Toxicity: Preliminary Analysis of 1115 Patients in the MRC AML15 Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 13-13 ◽  
Author(s):  
Alan K. Burnett ◽  
William J. Kell ◽  
Anthony H. Goldstone ◽  
Donald Milligan ◽  
Ann Hunter ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Preliminary Analysis ◽  
De Novo ◽  
Remission Rate ◽  
Pilot Trial ◽  
Disease Free Survival ◽  
Gemtuzumab Ozogamicin ◽  
Significant Difference ◽  
The Impact

Abstract The MRC AML15 Trial is primarily for patients with any form of AML who are under 60 years. One of the questions addressed was whether the addition of the immunoconjugate, Gemtuzumab Ozogamicin (GO) to induction (course 1) and/or consolidation (course 3) is beneficial. In induction patients are randomised to receive either DA (Daunorubicin/Ara-C) or ADE (Ara-C/Daunorubicin/Etoposide) or FLAG-Ida (Fludarabine/Ara-C/Idarubicin/G-CSF) and in consolidation either MACE (Amsacrine/Etoposide) or HD Ara-C (3.0g/m2 or 1.5g/m2 per dose). Our prior pilot trial had shown that GO 3mgs/m2 could be safely added to day 1 of each of these treatments (Kell et al Blood102, 4277–4283). Here we report the preliminary results of the effect of combining GO with induction chemotherapy. This randomisation achieved its recruitment target and was closed on 30 June 2006. All other comparisons in the trial, including GO in consolidation, remain open. Patients: A total of 1115 patients were randomised between July 2002 and June 2006. The median age was 49 (range 0–71) years: 53% of patients were male: 92% (n=1027) had de novo disease: 95% had WHO performance score of &lt;2: 43% received DA, 43% FLAG-Ida, and 14% ADE. (Recruitment to ADE+GO opened in June 2005). Patients with WBC &gt; 30 x 109/l and LFT’s &gt; normal were initially excluded but admitted from March 2004. APL patients were not eligible for entry. 15% of patients with data had favourable 71% intermediate, and 14% adverse cytogenetics. Over 83% were CD33 positive. Results: The overall remission rate was 85% with no differences between the arms for GO vs no GO in CR (85% vs 85%) induction death (8% vs 7%) or resistant disease (7% vs 8%). There was a modest increase in mucositis on the GO arm in course 1 only (p=0.04) and increased AST and Alt toxicity in C1 (p=.002; p=.03) but no difference in bilirubin grades. GO patients used more platelets (19 vs 14; p&lt;0.0001), but not red cells, and had more days on IV antibiotics (20.6 vs 18.6 p=0.001). The haemopoietic recovery and days in hospital were similar. With a median follow-up of 15 months (range 0–45), there is no significant difference in deaths in CR (GO vs no GO): 36 vs 45 (HR 0.75; CI.49–1.16 p=0.2), but relapse was reduced: 37% vs 52% at 3 years (HR 0.70 (0.52–0.92) p=0.01) resulting in an improved DFS: 51% vs 40% at 3 years (HR 0.72 (0.56–0.91) p=0.008). There is so far no significant difference in OS (53% vs 46% at 3 years; HR 0.91(0.73–1.14) p=0.4). Conclusion: This preliminary analysis of 1115 randomised patients indicates that the addition of GO to induction chemotherapy can reduce the relapse risk without adding significant extra toxicity and this has significantly improved the DFS in the GO arm. Longer follow up is required to determine the impact on survival.

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 ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Treatment Outcomes ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Remission Induction ◽  
Repair System ◽  
Significant Difference ◽  
Normal Cytogenetics ◽  
Acute Myeloid

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.

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