Acute Myeloid Leukemia Induction Research Articles

Influence of Cytarabine Metabolic Pathway Polymorphisms in Acute Myeloid Leukemia Induction Treatment

Background:Cytarabine (Ara C) is considered the most effective chemotherapeutic agent in acute myeloid leukemia (AML) treatment. Several studies suggest that single nucleotide polymorphisms (SNPs) within the genes involving metabolic pathway of Ara C could influence in treatment outcomes, although their clinical relevance remains undetermined.Methods:The SNPs of cytarabine pathway (DCK: rs2306744, rs11544786, rs4694362; CDA: rs2072671, rs3215400, rs532545, rs602950; NT5C2: rs11598702; RRM1: rs9937; NME1: rs2302254) were evaluated in 225 adult patients at initial diagnosis from AML using a mass spectrometry-based multiplex genotyping assay (Sequenom®). All patients received induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA 99, 2007 and 2010 trials).Efficacy of first induction cycle was evaluated comparing complete remission (CR) vs. partial remission (PR) or resistance (patients dying during induction excluded); and overall survival (OS). Induction death was defined as patients dying during induction against CR, excluding these patients with PR or resistance. Based on WHO grading scale, toxicities were grouped as binary variables (grades 0-1 vs. 2-4; or 0 vs. 1-4), assigning the maximum grade of all the specific toxicities within that group (evaluated in all patients). Genotypes were studied with co-dominant model. Association between variables was assessed using linear and logistic regression adjusting for age, gender, cytogenetic risk, ECOG, leukocyte and platelet count, hemoglobin, creatinine, bilirubin, albumin and LDH level at diagnosis (R® version 3.1.2). Kaplan-Meier method and Cox proportional were employed to OS estimates with the same covariates.Results:The median age of patients was 51.1 years (16-78 years). The variant allele of DCK SNP rs2306744, enzyme that catalyzes the limiting first phosphorylation in activation of Ara C, showed higher CR (OR:6.3; 95%CI 1.3-31.1; P=0.024), as well as higher mucositis (OR:3.3; 95%CI 1.1-10.0; P=0.038).CDA is the main inactivating enzyme of Ara C. The variant allele of rs602950 was related to higher CR (OR:3.0; 95%CI 1.02-8.8; P=0.045) and OS at 5 years (HR:0.4; 95%CI 0.2-0.9; P=0.012; Figure 1) and the variant homozygous of rs2072671 to higher OS at 5 years (HR:0.3; 95%CI 0.1-0.96; P=0.018; Figure 2), whereas the wild-type allele of rs532545 was associated to higher OS at 3 years (HR:1.5; 95%CI 1.01-2.4; P=0.039; Figure 3). In addition, variant alleles of rs532545 and rs602950 were related to skin toxicity (OR:2.2; 95%IC 1.1-4.3; P=0.033; OR:2.1; 95%IC 1.01-4.5; P=0.047, respectively).Variant allele of RRM1 (rs9937), enzyme directly associated with Ara C sensitivity, was associated to induction death (OR:0.2; 95%IC 0.03-0.9, P= 0.034). Variant allele of NT5C2 (rs11598702), responsible of nucleotide pools balance, showed higher hepatotoxicity (OR: 4.1; 95%IC 1.1-14.5; P=0.032).Conclusions:This study reveals the influence in Ara C efficacy of DCK and CDA polymorphisms in AML adult patients, previously suggested in other studies. In addition, novel associations between SNPs in metabolic Ara C genes and toxicities were detected. Further studies with larger population are needed to validate these associations. [Display omitted] [Display omitted] [Display omitted] DisclosuresBoluda:Instituto de Investigación Sanitaria La Fe: Employment.

Shorter Remission Telomere Length Predicts Delayed Neutrophil Recovery After Acute Myeloid Leukemia Therapy: A Report From the Children's Oncology Group.

Purpose Suboptimal outcomes for children with acute myeloid leukemia (AML) necessitate maximally intensive therapy. Consequently, serious adverse events, such as prolonged periods of profound myelosuppression, contribute to AML treatment-related mortality. Telomeres, the repetitive DNA-protein structures at chromosome ends, influence cellular replicative capacity in that critically short telomeres can induce cell senescence or apoptosis. Our objective was to evaluate the impact of telomere length on duration of post-therapy neutropenia in a pediatric AML cohort. Patients and Methods Patients were diagnosed with de novo AML, enrolled in Children's Oncology Group study AAML0531, and included those with (n = 53) and without (n = 62) significantly delayed neutrophil recovery after chemotherapy. We used quantitative polymerase chain reaction to measure telomere content (TC), a validated proxy for telomere length, from remission bone marrow samples obtained after the second induction chemotherapy course. Results Less TC was significantly associated with prolonged neutropenia after the fourth ( P < .001) and fifth chemotherapy courses ( P = .002). Cox regression adjusting for age at diagnosis confirmed that TC remained independently predictive of time to recovery of absolute neutrophil count for both the fourth and fifth courses ( P = .002 and .009, respectively). DNA from patients was analyzed for germline mutations in four telomere maintenance genes associated with telomere biology disorders. Sequence analysis revealed no enrichment of rare or novel variants in the delayed recovery group. Conclusion Our results suggest that TC at end of AML induction is associated with hematopoietic reconstitution capacity independently of age and may identify those at highest risk for markedly delayed bone marrow recovery after AML therapy.

Polymorphisms and haplotypes of the CYP2B6 detoxification gene in the predisposition of Acute Myeloid Leukemia (AML) and induction of its cytogenetic abnormalities

CYP2B6 is a polymorphic detoxification gene which plays a vital role in the degradation of genotoxic compounds. In this study we hypothesized that inadequate detoxification due to CYP2B6 polymorphisms may contribute to AML. To evaluate the potential impact of CYP2B6 polymorphisms on AML development and induction of its specific chromosomal abnormalities we studied C777A and A785G polymorphisms for the first time in AML. Furthermore, we investigated the co-existence of the above polymorphisms with G516T polymorphism to determine the CYP2B6 high-risk haplotypes in AML susceptibility. Our study included 619 AML patients and 430 healthy donors. Concerning C777A CYP2B6 polymorphism, no significant difference was found between patients and controls. However, A785G CYP2B6 polymorphism showed a statistically higher frequency of the variant genotypes in patients (48.2%), mainly in secondary AML patients (49.1%) than in controls (26.1%). Moreover, an increased frequency of the variant genotypes was found in those with abnormal karyotypes, especially with -7/del(7q), -5/del(5q), +8, inv(16) and t(8;21). The combination of the three CYP2B6 polymorphisms (G516T, C777A & A785G) revealed seven haplotypes. Four out of six haplotypes with at least one mutant allele were significantly associated with an increased risk for AML. Interestingly, T516A777G785 haplotype, where the three mutant alleles co-existed, had ~3-fold increased risk to be found in patients than controls. The association between haplotypes and cytogenetic aberrations revealed a positive correlation between specific CYP2B6 haplotypes and AML cytogenetic abnormalities. Our data suggest that A785G CYP2B6 gene polymorphism and specific CYP2B6 haplotypes may contribute to AML and its specific chromosomal aberrations.

Peripheral blood blast clearance is an independent prognostic factor for survival and response to acute myeloid leukemia induction chemotherapy.

In patients with acute myeloid leukemia (AML), rapid reduction of circulating blasts with induction chemotherapy may serve as an in vivo marker of chemosensitivity. We performed a retrospective analysis of 363 patients with untreated AML who received induction chemotherapy in order to determine the relationship between day of blast disappearance (DOBD) and complete remission (CR) rates, event-free survival (EFS), and overall survival (OS). DOBD ≤ 5 vs. >5 was identified as the most discriminating cutoff for OS. DOBD > 5 was observed in 35 patients (9.6%). The CR rate for patients with DOBD ≤ 5 vs. >5 was 74.0 and 28.6%, median EFS was 9.4 and 1.8 months, and median OS was 17.1 and 5.8 months, respectively (P < 0.001 for all). DOBD > 5 was independently associated with a lower CR rate and shorter EFS and OS (P < 0.001 for all). DOBD > 5 retained prognostic significance for EFS and OS when patients were stratified by cytogenetic risk group, de novo vs. secondary or therapy-related AML, European LeukemiaNet-based risk groups, and whether CR was achieved. We propose DOBD > 5 as a simple and early marker of disease resistance that identifies patients with poor prognosis who otherwise may not be identified with existing risk stratification systems. Am. J. Hematol. 91:1221-1226, 2016. © 2016 Wiley Periodicals, Inc.

A rare case of blastic plasmacytoid dendritic cell neoplasm with deletion 7q.31, in the setting of heavy pre-treatment with alkylating chemotherapy

Blastic plasmacytoid dendritic cell neoplasm is rare myeloid malignancy clinically characterized by non-pruritic, violaceous and papulo-nodular skin lesions, together with bone marrow and lymph node involvement. Histologically, there is infiltration of dermis by neoplastic mono-nuclear CD4, CD56, CD123 co-expressing cells with epidermal sparing. Most commonly blastic plasmacytoid dendritic cell neoplasm presents as a de-novo condition, and treatment-related blastic plasmacytoid dendritic cell neoplasm is a rare phenomenon. Due to rarity of the disease, there is no established standard of care treatment. Both acute myeloid leukemia and acute lymphoid leukemia type induction regimens have been used for treatment of blastic plasmacytoid dendritic cell neoplasm, with initial response rate of 50%-80%. We present a rare case of therapy-associated blastic plasmacytoid dendritic cell neoplasm in a patient with remote history alkylating agent systemic therapy. A lag period of five to seven years and presence of deletion 7q.31 seen in bone marrow biopsy specimen in our patient are consistent with a likely therapy-associated etiology of his blastic plasmacytoid dendritic cell neoplasm.

Research progress and perspective of acute myeloid leukemia induction therapy

In the last decade, Progress of acute myeloid leukemia (AML) induction therapy included: ① the increased treatment intensity; ② the inclusion of new durg; ③ the decreased early treatment related mortality. The perspective of AML induction therapy in the future included: ①the application of targeted drug; ② individualized stratification; ③ optimization and refinement of support and anti-infection therapy. The article focuses on progress and perspective of acute myeloid leukemia induction therapy. Key words: Leukemia, myeloid, acute; Remission induction; Molecular targeted therapy; Antineoplastic combined chemotherapy protocols; Prognosis; Age factors

The fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) chemotherapy regimen is an alternative to anthracycline-based therapy for the treatment of acute myeloid leukemia for patients with pre-existing cardiac disease.

We conducted a retrospective study assessing FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor) as first-line treatment in 56 newly diagnosed acute myeloid leukemia patients considered ineligible for anthracycline-based treatment due to advanced age, significant comorbidities, or pre-existing cardiac disease. The median age was 69 (21-80); 46% received FLAG for pre-existing cardiac disease and others due to age (32%), non-cardiac comorbidities (20%), or previous anthracycline exposure (2%). The induction mortality was 16% and, among evaluable patients, 48% achieved a complete remission after the first induction course with an additional patient achieving a remission after a second course for a total complete remission rate of 50%. Four patients proceeded to an allogeneic stem cell transplant including two with pre-existing cardiac disease. Among non-transplanted patients, the relapse rate (RR) was 47%. When censored at time of stem cell transplant, the median relapse-free survival was 14.7 months. The median overall survival was 9.3 months with 1- and 2-yr survivals of 44% and 22%, respectively. There was no difference in clinical outcomes between patients treated with FLAG for cardiac reasons vs. other reasons. In conclusion, FLAG is a useful alternative to anthracycline-based induction for Acute myeloid leukemia in those with significant comorbidities including pre-existing cardiac disease.

Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups

AbstractThe initial report of the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group trial E1900 (#NCT00049517) showed that induction therapy with high-dose (HD) daunorubicin (90 mg/m2) improved overall survival in adults <60 years old with acute myeloid leukemia (AML); however, at initial analysis, the benefit was restricted to younger patients (<50 years) and patients without unfavorable cytogenetics or a FLT3-ITD mutation. Here, we update the results of E1900 after longer follow-up (median, 80.1 months among survivors), focusing on the benefit of HD daunorubicin on common genetic subgroups. Compared with standard-dose daunorubicin (45 mg/m2), HD daunorubicin is associated with a hazard ratio (HR) for death of 0.74 (P = .001). Younger patients (<50 years) benefited from HD daunorubicin (HR, 0.66; P = .002), as did patients with favorable and intermediate cytogenetics (HR, 0.51; P = .03 and HR, 0.68; P = .01, respectively). Patients with unfavorable cytogenetics were shown to benefit from HD daunorubicin on multivariable analysis (adjusted HR, 0.66; P = .04). Patients with FLT3-ITD (24%), DNMT3A (24%), and NPM1 (26%) mutant AML all benefited from HD daunorubicin (HR, 0.61, P = .009; HR, 0.62, P = .02; and HR, 0.50, P = .002; respectively). HD benefit was seen in the subgroup of older patients (50-60 years) with the FLT3-ITD or NPM1 mutation. Additionally, the presence of an NPM1 mutation confers a favorable prognosis only for patients receiving anthracycline dose intensification during induction.

Valproic acid may exerts its cytotoxic effect through rassf1a expression induction in acute myeloid leukemia.

In acute myeloid leukemia (AML), despite the acceptance of standard intensive chemotherapy as an optimal induction regimen for all age groups, in the elderly patients, the best treatment should meet the challenge of multiple factors like age, comorbidities, and cytogenetics, making them ineligible for standard induction chemotherapy. Using the current low-intensity therapies like decitabine, azacitidine, and low-dose cytarabine as a single arm, outcomes for these patients remain poor. As a histone deacetylase inhibitor valproic acid (VPA) exhibit anticancer activity by triggering apoptosis, the mechanism of which is not yet completely clarified. To explore the possible connection between VPA treatment and the Hippo pathway as an apoptosis stimulating route, we also explore the expression of major components of this pathway and for the first time we postulate a relationship between VPA treatment and cell death induction through RASSF1A expression induction. Furthermore, we demonstrate that autophagy inhibition by chloroquine (CQ) significantly augmented the cytotoxic effect of VPA on AML cells, especially in those with unfavorable and normal karyotype. Regarding that VPA and CQ are well-tolerated drugs and our presumptive results of usefulness of VPA + CQ in three cytogenetic risk groups of AML, this combinatorial therapy could represent an attractive treatment option for older AML patients unfit for intensive therapy.

Routine interim disease assessment in patients undergoing induction chemotherapy for acute myeloid leukemia: Can we do better?

The presence of >5% blasts at "day 14" (D14), in patients undergoing induction chemotherapy for acute myeloid leukemia (AML) is problematic. It is unclear if a second course of chemotherapy for early persistent disease will alter outcome in these patients. We conducted a retrospective study of AML patients undergoing induction chemotherapy where diagnostic, interim (around day 14), and recovery (days 21-42) bone marrow (BM) evaluations were available for review. Of the 113 patients included in the final analysis, 99 (87.6%) achieved CR at hematologic recovery. At D14, 90 patients (79.6%) had <5% blasts and of these, 87 (96.7%) ultimately achieved CR. At D14, Twenty-three (20.4%) patients had residual leukemia (>5% blasts). Of these, 11 (47.8%) received a second course of chemotherapy (double induction [DI]) and 12 (52.2%) were observed until count recovery (single induction [SI]). No significant difference in CR rates was observed between these two groups (58.3% DI group vs. 45.5% SI group, P value = 0.684). In our analysis, D14 BM evaluation did not uniformly identify patients with primary induction failure. To unequivocally determine the value of a D14 marrow assessment in AML, prospective studies in the context of large cooperative group trials are required. Considering our findings and similar reports from others, we propose that D14 marrow assessment should be individualized, and that other factors, such as cytogenetics and early peripheral blood blast clearance should be considered, to identify patients most likely to benefit from interim disease assessment during AML induction therapy.

Dose-Escalation Study of Azacitidine Followed By High-Dose Cytarabine (HiDAC) and Mitoxantrone (Mito) for Remission Induction in High-Risk Acute Myeloid Leukemia (AML)

Dose-Escalation Study of Azacitidine Followed By High-Dose Cytarabine (HiDAC) and Mitoxantrone (Mito) for Remission Induction in High-Risk Acute Myeloid Leukemia (AML)

The Role of IDH Mutants, Which Are Promising Therapeutic Targets for Acute Myeloid Leukemia

Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are frequently observed in acute myeloid leukemia (AML), glioma, and many other cancers. While wild-type IDHs convert isocitrate to α-ketoglutarate (α-KG), mutant IDHs convert α-KG to oncometabolite 2-hydroxyglutarate (2-HG), which dysregulates a set of α-KG-dependent dioxygenases, such as TETs, histone demethylases, EGLNs, and other enzymes. Because the role of mutant IDH is not necessary for normal cells, inhibitors directed against mutant IDH are not expected to have the side effects as those of anti-cancer agents.To determine whether mutant IDH enzymes are valid targets for cancer therapy, we created a mouse model of mutant IDH-dependent AML. Previously, the IDH mutation alone was shown to be insufficient for the induction of AML, and IDH mutations occur simultaneously with mutations in other genes such as NPM, DNMT3A, and FLT3. In accordance with these observations, we found that NPM+/- hematopoietic progenitor cells transduced with IDH2/R140Q, NPMc, DNMT3A/R882H, and FLT3/ITD cooperatively induced AML in a mouse model. However, when only three of these mutant genes were transduced, myeloproliferative neoplasms (MPNs) rather than AML was more frequently induced and their onset was delayed in any combinations of the mutant genes. These results clearly indicate that all four mutations are necessary for the efficient induction of AML. By using a combination of AML model mice with cre-loxp, we conditionally deleted IDH2/R140Q from AML mice, which blocked 2-HG production and resulted in the loss of leukemia stem cells. Accordingly, the progression of AML was significantly delayed. These results indicate that the function of IDH2 mutation is critical for the development and maintenance of AML stem cells, and that mutant IDHs are promising targets for anticancer therapy. Based on these findings, we developed potent and specific inhibitors of mutant IDH1 and tested their effects in the mutant IDH1-dependent AML mouse model, created by introducing four mutant genes including mutant IDH1. The 2HG level was promptly and dramatically decreased in AML cells soon after treatment with the mutant IDH1 inhibitors, and the number of leukemia cells was reduced after a 4-week treatment. These results indicate that IDH1 mutant inhibitors are effective for the treatment for AML.Because IDH mutations and TET2 mutations are mutually exclusive in AML, the inhibition of TET-mediated conversion of 5mC to 5hmC is considered one of the main roles of mutant IDH. We found that levels of 5hmC on differentiation-inducing genes, such as Ebf1, Spib and Pax5 were decreased in AML cells with IDH2/R140Q and recovered by conditional deletion of IDH2/R140Q. In consistent with levels of 5hmC, expressions of these genes are downregulated in the AML cells and increased by deletion of IDH2/R140Q.Gene expression analysis revealed that IDH2/R140Q up-regulates a set of genes that is activated in response to hypoxia as well as Meis1. As 2HG inhibits EGLN that hydroxylates and marks HIF1α for ubiquitin-proteasomal degradation, it is probable that mutant IDH2-produced 2HG stabilizes HIF1α through inhibition of EGLN. Furthermore, it was reported that Meis1 activates the transcription of HIF1α. In consistent with these information, we showed that IDH2/R140Q increased the protein levels of HIF1α in cultured cells. DisclosuresMatsunaga:Daiichi Sankyo Co., Ltd.: Employment. Seki:Daiichi Sankyo Co., Ltd.: Employment. Araki:Daiichi Sankyo Co., Ltd.: Employment. Kitabayashi:Daiichi Sankyo Co., Ltd.: Research Funding.

Impact of Transporter Genes Polymorphisms in Standard Induction of Acute Myeloid Leukemia

Background:The intake of anthracyclines in blast cells could be affected by several transporters, including influx transporters (SLC22A16 and SLCO1B1) and efflux pumps of ABC family. Previous studies suggested that single nucleotide polymorphisms (SNPs) of genes coding for anthracyclines transporters may influence their effectiveness or toxicity, although their impact in acute myeloid leukemia (AML) induction therapy remains undeterminedMethods:SNPs of anthracycline transporter genes (ABCB1: rs1128503, rs1045642, rs2032582 and haplotype; ABCC1: rs4148350; ABCC2: rs8187710; ABCG2: rs2231142, rs2231137; SLCO1B1: rs4149056; SLC22A16: rs12210538, rs714368) were evaluated in 225 adult patients at initial diagnosis from AML using a Sequenom (iPLEX) mass spectrometry-based multiplex genotyping assay (Sequenom, San Diego, CA). All patients received induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA-LMA 99, 2007 and 2010 trials).Efficacy of first induction cycle was evaluated comparing complete remission (CR) vs. partial remission or resistance. Patients dying during induction were considered as no evaluable for efficacy. Based on WHO grading scale, toxicities were grouped as binary variables (grade 0-1 vs. grade 2-4). The grade of toxicity assigned to an organ group was the maximum grade of all the specific toxicities within that group. Renal and hepatic toxicities were also evaluated with analytic markers (renal function with urea and creatinine; hepatic function with bilirubin, AST, ALT, FA and GGT). Hematologic toxicity was measured with the time to neutropenia and thrombocytopenia recovery since first day of chemotherapy. Genotypes were studied with co-dominant model. Association between variables was assessed using linear and logistic regression adjusting for age, gender, ECOG, leukocyte and platelet count at diagnosis (R® version 3.1.2).Results:The median age of patients was 51.1 years (16-78 years). There were no statistically significant differences in CR or hematologic toxicities. Nevertheless, several associations were obtained between transporter genes polymorphisms and toxicities (significant toxicities were summarized in table 1 and 2). Variant allele of ABCB1 SNPs was previously related with lower activity of ABCB1 pump in kidney cells and lower anthracycline clearance. Accordingly, we obtained nephrotoxicity associated with these SNPs. Association between cardiac toxicity and ABCG2 polymorphisms was found in agreement with previously published works. The ocular toxicity associated with SLCO1B1 was also correlated with low platelet count at diagnosis in multivariable analysis.Table 1Significant association between SNPs in gene transporters and different toxicitiesToxicityGene/SNPGenotypesGrade 0-1 n (%)Grade 2-4 n (%)OR (95%IC)PCardiotoxicityABCG2 rs2231142CC CA171 (83.0) 9 (47.4)35 (17.0) 10 (52.6)5.64 (1.86-17.80)0.002Lung toxicityABCG2 rs2231142CC CA174 (84.5) 12 (63.2)32 (15.5) 7 (36.8)3.37 (1.09-10.40)0.031Skin toxicitySLCO1B1 rs4149056TT TC112 (71.8) 21 (48.8)44 (28.2) 22 (51.2)2.43 (1.17-5.06)0.015NephrotoxicityABCB1 haplotypeOther genotypes TT/TT/TT175 (89.3) 21 (72.4)21 (10.7) 8 (27.6)3.74 (1.24-10.85)0.002Ocular toxicityABCC1 rs4148350GG GT/TT205 (99.0) 16 (88.9)2 (1.0) 2 (11.1)13.7 (2.08-90.47)<0.001Ocular toxicitySLCO1B1 rs4149056TT CC155 (99.4) 23 (92.0)1 (0.6) 2 (8.0)9.97 (1.39-71.39)0.019Table 2Significant association between SNPs in gene transporters and analytic markers of renal and hepatic functionHematologic toxicityGene/SNPGenotypesMean values (mg or U/dL)Logarithm of the difference (95%IC)PUreaABCB1 rs1045642CC TT57.98 70.890.20 (0.01 to 0.40)0.044UreaABCB1 rs2032582GG TT56.34 72.070.23 (0.03 to 0.42)0.021UreaABCB1 haplotypeOther genotypes TT/TT/TT59.29 78.140.24 (0.04 to 0.43)0.019BilirubinABCB1 rs1045642CC CT TT1.77 2.59 2.910.021 (0.01 to 0.40) 0.39 (0.12 to 0.65)0.036 0.004ALTSLCO1B1 rs4149056TT TC90.92 161.020.30 (0.01 to 0.60)0.049Conclusions:This study shows a prognostic impact of transporter genes polymorphisms in adult AML patients regarding induction chemotherapy efficacy and toxicity. Further studies with larger population are needed to validate these associations, which could be useful biomarkers in clinical practice. DisclosuresNo relevant conflicts of interest to declare.

Influence of Single Nucleotide Polymorphisms in Anthracycline Metabolism Pathway in Standard Induction of Acute Myeloid Leukemia

Background:Single nucleotide polymorphisms (SNPs) within the genes involving drug detoxification enzymes of anthracyclines could lead to interindividual differences in treatment outcome. Several studies suggested, in different kinds of cancer, that SNPs of genes coding anthracyclines metabolism may influence their effectiveness or toxicity, being well-known their association with cardiotoxicity. The impact of these polymorphisms in adult acute myeloid leukemia (AML) patients treated with the combination of cytarabine and anthracyclines for induction remains undetermined.Methods:SNPs of anthracycline metabolism genes previously associated with clinical significance in other malignances (CBR3:rs1056892, rs8133052, NQO1 rs1800566, NQO2 rs1143684, NOS3:rs1799983, rs2070744, MnSOD rs4880) were evaluated in 225 adult patients at initial diagnosis from AML using a Sequenom (iPLEX) mass spectrometry-based multiplex genotyping assay (Sequenom, San Diego, CA). All patients received induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA-LMA 99, 2007 and 2010 trials).Efficacy of first induction cycle was evaluated comparing complete remission (CR) vs. partial remission or resistance. Patients dying during induction were considered as no evaluable for efficacy. Based on WHO grading scale, toxicities were grouped as binary variables (grade 0-1 vs. grade 2-4). The grade of toxicity assigned to an organ group was the maximum grade of all the specific toxicities within that group. Hematologic toxicity was measured with the time to neutropenia and thrombocytopenia recovery since first day of chemotherapy. Genotypes were studied with co-dominant model. Association between variables was assessed using linear and logistic regression adjusting for age, gender, ECOG, leukocyte and platelet count at diagnosis (R® version 3.1.2).Results:The median age of patients was 51.1 years (16-78 years). There were no statistically significant differences in CR. Nevertheless, several associations were obtained between NQO1, NQO2, NOS3 and MnSOD polymorphisms and toxicities (significant toxicities were summarized in table 1 and 2).Table 1Significant association between SNPs in gene metabolizers and different toxicitiesToxicityGene/SNPGenotypesGrade 0-1 n (%)Grade 2-4 n (%)OR (95%IC)PCardiotoxicityNQO2 rs1143684TT TC119 (86.2) 74 (94.9)19 (13.8) 4 (5.1)0.26 (0.07-0.77)0.025NeurotoxicityNOS3 rs1799983GG GT71 (84.5) 101 (94.4)13 (15.5) 6 (5.6)0.28 (0.09-0.80)0.022Skin toxicityNOS3 rs1799983GG GT TT45 (53.6) 78 (72.9) 26 (76.5)39 (46.4) 29 (27.1) 8 (23.5)0.44 (0.24-0.82) 0.36 (0.14-0.88)0.010 0.030Skin toxicityNQO1 rs1800566CC CT78 (60.9) 64 (74.4)50 (39.1) 29 (25.6)0.53 (0.28-0.97)0.042Skin toxicityNQO2 rs1143684TT CC5.49 (1.19-38.9)0.044Gastrointestinal toxicityNQO2 rs1143684TT CC91 (65.9) 2 (25.0)47 (34.1) 6 (75.0)5.5 (1.19-38.99)0.043MucositisNQO1 rs1800566CC TT119 (93.0) 8 (72.7)9 (7.0) 3 (27.3)6.1 (1.03-33.1)0.035MucositisNQO2 rs1143684TT CC128 (92.8) 5 (62.5)10 (7.2) 3 (37.5)8.8 (1.53-45.60)0.010NephrotoxicityMnSOD rs4880TT CC47 (81.0) 55 (94.8)11 (19.0) 3 (5.2)0.23 (0.05-0.86)0.042NephrotoxicityNQO1 rs1800566CC TT114 (89.1) 8 (72.7)14 (10.9) 3 (27.3)6.66 (1.07-38.35)0.033Hepatotoxicity grades 3-4NOS3 rs2070744CC CT19 (24.8) 100 (67.1)20 (51.3) 49 (32.9)0.44 (0.20-0.94)0.035Table 2Significant association between SNPs in gene metabolizers and hematologic toxicitiesHematologic toxicityGene/SNPGenotypesMean daysLogarithm of the difference (95%IC)PTime to neutropenia recoveryNOS3 rs2070744CC TT32.7 26.7-0.17 (-0.35 to -0.01)0.048Time to thrombocytopenia recoveryNOS3 rs1799983GG GT TT35.6 28.8 30.3-0.17 (-0.17 to -0.06) -0.15 (-0.28 to -0.01)0.002 0.034Conclusions:This study reveals that, as in other cancers, there is a prognostic impact of anthracycline metabolism gene polymorphisms in adult AML patients. Further studies with larger population are needed to validate these associations, which could be useful biomarkers in clinical practice. DisclosuresNo relevant conflicts of interest to declare.

Symptom Burden, Quality of Life, and Distress in Acute Myeloid Leukemia Patients Receiving Induction Chemotherapy: Results of a Prospective Electronic Patient-Reported Outcomes Study

Background: Induction chemotherapy for acute myeloid leukemia (AML) is more intensive than many other cancer treatments, and may be associated with a different symptom burden. Little is known about the most prevalent symptoms during AML induction, nor how they change over time, and with remission status. Similarly, little is known about the trajectory of quality of life (QoL) and distress scores in this population. We aimed to learn more about the natural history of these issues via a prospective, longitudinal, observational patient-reported outcomes study.Methods: We enrolled 43 inpatients with AML at initiation of induction chemotherapy, and assessed their symptoms, quality of life (QoL), and distress weekly during their month-long hospitalization for induction, and monthly thereafter, using 3 validated instruments: Patient Care Monitor v2.0 (PCM); Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu); and NCCN distress thermometer (DT). We used descriptive statistics and ANOVA to analyze results.Results: Mean age of study participants was 59.4 (SD 13.4); 21 (49%) were female. Patients were mostly high-risk for recurrence, with 25 (58%) being ≥60 years old, 19 (44%) having high-risk cytogenetics, and 10 (23%) having relapsed disease. Among relapsed patients, the mean number of prior treatments was 2.7 (SD 1.3). At the time of this analysis, 5 patients (18%) had gone on to receive a stem cell transplant. As expected, symptoms were most prominent during the second and third weeks of treatment. However, across all 4 weeks of induction patients consistently reported 5 symptoms at a moderate or severe level (scores of 4 to 6, or 7 to 10 out of 10, respectively), including: poor appetite (35%), dry mouth (37%), difficulty sleeping (38%), dysgeusia (44%), and fatigue (56%). Other prominent moderate-to-severe symptoms included diarrhea (35%), daytime sleepiness (30%), and nausea (27.5%), despite standard supportive care. Mean QoL by FACT-Leu worsened substantially from week 1 (121.8, SD 27.6) to week 2 (108.2, SD 26.3), and then slowly recovered thereafter, improving to better than baseline by month 3 and continuing to improve throughout 1-year of follow-up (p<0.01; see Figure 1). The mean distress score across all 4 weeks of induction was 4 (SD 3.2), which is the threshold for recommended referral to additional support services, but was higher in week 1 (4.4; SD 3.5) compared to week 4 (3.0; SD 3.1). Grouping patients by remission status based on bone marrow assessments done between 30 and 45 days post-induction, QoL and DT scores appear markedly different, and diverge at this point (Figures 2 and 3), such that patients with persistent disease after induction have progressively worse QoL and more distress compared to patients in remission.Conclusion: AML patients receiving induction chemotherapy face a significant symptom burden, impaired QoL, and moderate psychological distress. Several of the most prevalent and severe symptoms during induction may be amenable to further targeted intervention. Longitudinal QoL and distress scores diverge markedly on the basis of post-induction remission status, suggesting that further targeted interventions may be needed to address the greater burden of issues among patients with relapsed disease. The overall prevalence and severity of symptom, QoL, and distress issues suggests sizeable unmet palliative care and psychosocial needs among patients with AML. [Display omitted] [Display omitted] [Display omitted] DisclosuresLeBlanc:Flatiron: Consultancy; Epi-Q: Consultancy; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Helsinn Therapeutics: Honoraria, Research Funding. Abernethy:Flatiron: Employment.

Sharing Post-AML Consolidation Supportive Therapy with Local Centers Reduces Patient Travel Burden without Compromising Safety and Efficacy of Care

AML (acute myeloid leukemia) is frequently treated with intensive induction and consolidation chemotherapy that often requires prolonged admissions to hospital. Our group and others demonstrated that consolidation chemotherapy for AML can be safely and effectively administered to selected patients on an ambulatory basis. However, this ambulatory care is centralized in quaternary centers, requiring some patients to travel long distances to these specialized centres. Recently, we developed a shared care model where patients receive their consolidation chemotherapy for AML at the specialized quaternary care center, but receive post-consolidation supportive care including blood checks, transfusions, and treatment for febrile neutropenia at their local hospitals. Here, we reviewed the impact of our new model of care with a focus on savings in travel time and distance.Between 2009-2013, 73 patients with AML (n=61,) or APL (n=12) received post-consolidation care after CR1 at 14 local centers in the province of Ontario. These centers were regional cancer centers staffed by oncologists and/or hematologists experienced in the management of cytopenias and febrile neutropenia. However, these centers did not provide induction or consolidation chemotherapy for AML. Patients were seen at least weekly as out-patients at these hospitals while recovering from their consolidation chemotherapy. These centers were located a median of 70 km (range: 36-190) from the quaternary centre (The Princess Margaret Cancer Centre in Toronto, Canada). The 73 patients received 137 cycles of intensive consolidation where the post-consolidation care was provided by their local centre. The local centers treated a median of 2 patients (range of 1-19 patients) during the time frame evaluated.Patients receiving shared care had a median age of 57 years (range: 21.7-78.6) and 40 (54.8%) were male. 7 (9.6%) had favourable, 42 (57.5%) had intermediate, 6 (8.2%) had poor and 18 (24.7%) had indeterminate cytogenetic profiles.Google Maps (www.google.ca/maps) was used to calculate the distance travelled and estimated travel time between the patient's home and the quaternary centre or their local centre. Use of toll roads was permitted to achieve the fastest and shortest distance. Patients in the shared care model travelled a mean distance of 99.5 km ± 57.8 (median: 87.8 range: 28.4-266 km) each way to the quaternary care centre versus 26.3 km ± 33.6 (median: 14.5 range: 0.55-211 km) each way to their local treatment centre (p <0.001 for difference in means by t-test). The estimated mean time to travel from their home to the quaternary center was 71.6 ± 38 minutes (median: 62 range: 29-170) and the estimated time to travel to their local center was 23.3 ± 21.9 minutes (median: 18 range: 2-137) (p <0.001 for difference in means by t-test). Thus, by receiving post-consolidation care locally, patients saved a mean round trip travel distance of 146.5 km ± 99.6 and 96.7 min ± 63.4 of round trip travel time per visit compared to travelling to the quaternary care centre.To assess the safety and efficacy of the shared care model, we compared the survival of the patients who received shared care to that of the other 344 patients with AML (n=297) or APL (n=47) who received consolidation chemotherapy in CR1 during the same time frame and remained at the quaternary care centre for all of their post-consolidation care. Gender, age and cytogenetic risk did not significantly differ between the shared care group and the group of patients receiving all of their care at the quaternary center (p>0.05). There was no significant difference in overall survival between the 2 groups (p value of log-rank test >0.05). 30, 60, and 90 day survival from start of consolidation chemotherapy was 98.6%, 97.2%, and 95.9% for the patients receiving shared care and 98.8%, 97.1%, and 95.3% for patients receiving all of their care at the quaternary center. Multivariate Cox proportional hazards model revealed no significant increase in hazard of death for the Shared Care patients compared to control when controlling for age, gender, AML vs. APL and cytogenetic prognosis (p value >0.05).Thus, a collaborative care delivery model utilizing partnerships with regional centres for post-consolidation care in AML reduces patient travel burden while maintaining safety and efficacy. DisclosuresNo relevant conflicts of interest to declare.

Astarabine, a Cytarabine Pro-Drug, Is Safe and Efficacious in the Treatment of Leukemia - Results of Animal Studies

The chemotherapy drug cytarabine is a standard of care in the treatment of Acute Myeloid Leukemia (AML) and relapsed Acute Lymphoblastic Leukemia (ALL), and is the backbone of induction and consolidation chemotherapy for AML. However, cytarabine is highly toxic, with severe side effects such as cerebellar toxicity and bone marrow suppression. Moreover, doses are significantly attenuated for older patients and patients with hepatic or renal dysfunction. Hence, the toxicity of cytarabine considerably limits its use.Astarabine is a construct of cytarabine covalently bound to asparagine. Unlike cytarabine, Astarabine's toxicity was shown to be mostly specific to leukemia cells. Leukemia cells lack asparagine synthetase and are dependent on external source for asparagine, hence asparagine was shown to be selectively taken up by leukemia cells by active transport. Astarabine is taken up by leukemia cells, where it is metabolized into the cytotoxic cytarabine molecules, resulting in leukemia cell death.The effect of Astarabine on 14 different cell lines was investigated. The studies demonstrated that most of the hematological cancer cell lines were sensitive to both Astarabine and cytarabine, while solid tumors cell lines were significantly less sensitive. Astarabine metabolite assay in human leukemia cell lines detected both Astarabine and free Cytarabine metabolites, indicating that Astarabine is a pro-drug of cytarabine.Animal pharmacokinetics studies were performed in mice and pigs. Pharmacokinetics analysis in mice was preformed by Astarabine single intraperitoneal (IP) injection. Astarabine half-life t1/2 of distribution and elimination in mice plasma ranged between 0.645-1.105 hours. Pharmacokinetics analysis in pigs preformed by Astarabine single intraveneous (IV) injection indicated that 50% (t1/2) of Astarabine is cleared from the pigs blood within 17.5-22.8 hours, a significantly higher t1/2 compared to the reported Cytarabine half-life.In vivo tolerability/toxicology studies determinedAstarabine IP repeated maximal tolerated dose (MTD) in IRC mice as 781 mg/kg/day, administrated for 7 consecutive days. IP repeated MTD of Astarabine in SCID mice was determined as 1275-1462 mg/kg/day, administrated for 7 consecutive days. IV repeated MTD in SCID mice was determined as 400 mg/kg/day, administrated for 14 days. Astarabine IV repeated MTD in young pigs was determinedto be 28 mg/kg/day, administrated for 6 consecutive days. Hence, it is concluded Astarabine improves drug tolerability and reduce toxicity in animals by 10-20 fold compared to the reported toxicity of cytarabine.In vivo efficacy studies were performed in a leukemia mouse model (L1210). The L1210 mouse leukemia creates a semi-solid tumor in the abdomen of the mice. Leukemia transplanted mice (12 mice per group) received 14 consecutive daily IP doses of 312 mg/kg/day or 1250 mg/kg/day of Astarabine, or saline control. The control mice died or sacrificed on day 17 due to cancer growth. The abdominal diameter of mice in the 312 mg/kg/day dose Astarabine and the control groups increased during the study (by 41% and 57.8%, respectively), while the abdominal diameter of the 1250 mg/kg/day dose Astarabine group decreased by 8.8%. The abdominal diameter results correlated with the rate of tumor growth: tumors were found in necropsies of mice of both control and 312 mg/kg/day dose Astarabine, however, no tumors were found in necropsies of mice treated with the 1250 mg/kg/day dose Astarabine during recovery period and on termination day. The results present a dose response of Astarabine in leukemia models.In conclusion, Astarabine may serve as a safer, non-toxic alternative to cytarabine for treatment of AML and ALL. Furthermore, Astarabine may offer effective treatment to older patients where current available treatment results in poor outcome. Studies in humans are ongoing. DisclosuresGengrinovitch:BioSight Ltd.: Employment, Equity Ownership, Patents & Royalties. Ben Yakar:BioSight Ltd.: Employment, Equity Ownership. Rowe:Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy.

Desuppressed Expressionsof MiR-29 targetsdisturb the Leukemeugenesis of MLL-AF9

The MLL--AF9 fusion oncogene is associated with acute leukemias in adults and children. Retroviral expression of MLL-AF9 in mouse hematopoietic stem/progenitor cells (HSPCs) rapidly induces acute myeloid leukemia (AML) and therefore serves as an excellent model to study MLL-AF9 induced leukemogenesis. We previously showed that miR-29 is highly expressed in human AML and positively regulates hematopoietic stem cell (HSC) self-renewal. Consistent with a role in AML, higher expression of miR-29 predicts poor survival in AML patients using the TCGA dataset. In addition, transduction of MLL-AF9 into microRNA-29 (miR-29a/b1) null Lin-c-Kit+Sca1+ (LSK) cells was sufficient to induce leukemic colony formation in vitro similar to WT LSK cells, but transplantation of MLL-AF9+ miR-29 null cells into lethally irradiated recipients resulted in an increased disease latency (median - 56 vs 151 days, p&lt;0.001). In addition, with a short time transduction (1 weeks) of MLL-AF9, mice of miR-29 null recipients exhibited long-term donor-derived lymphomyeloid engraftment. MiR-29 null and MLL-AF9 positive HSPCs were serially transplantable, and did not generate AML during a 2 year time period during with 5 times transplantation, suggesting no significant alteration in HSPC self-renewal. To understand why miR-29 null cells are relative resistant to MLL-AF9 mediated transformation, we first determined whether miR-29 null cells induce genes properly following MLL-AF9 transduction. RNA-sequencing of miR-29 null spleen B cells revealed that 1147 and 559 genes were significantly up- or down-regulated (adjusted p &lt; 0.001) following MLL-AF9 transduction. The absence of miR-29 resulted in dysregulated expression of class I Hox genes, which were nearly undetectable in miR-29 null mature B cells; however, these genes were significantly up-regulated in MLL-AF9+ cells, including Meis1 (2.68-fold), HoxA5 (4.85-fold), Hoxa7 (3.46-fold), HoxA3 (2.43-fold), and HoxA6 (3.35-fold). One important exception was HoxA9, which was undetectable in both MLL-AF9+ or MLL-AF9- B cells, indicating the inability of MLL-AF9 to induce one of its key leukemogenic mediators, HoxA9, in the absence of miR-29. These data suggest the inability of MLL-AF9 to induce AML in the miR-29 null context might due to its inability to properly induce sufficient MLL-AF9 targets. Analysis of dysregulated genes reveals that the top pathways positively regulated by MLL-AF9 were cytokine receptor interactions, and adhesion molecules. We found Meis1, Ccna2, Hoxa5 and Hoxa9 were significantly down-regulated in miR-29 null versus WT LSK cells, but were similarly induced in MLL-AF9 transformed blasts, suggesting that increased AML latency was not due to lack of ability to induce these known key regulators of leukemogenesis. As miR-29 directly binds to the 3'-UTR of Dnmt3a, we sought to determine whether epigenetic dysregulation underlies the leukemic phenotype in miR-29 null cells. Performing ChIP-Seq for the active epigenetic mark H3K79me2 in c-Kit+Mac-1+ blasts, we identified 4281 and 3649 genes with this mark from WT and miR-29 null blasts, respectively, with an overlap of 3164 genes (66.39%). Next, we compared our data to H3K79me2 positive genes from WT LSK cells, granulocyte-macrophage progenitors (GMP), and MLL-AF9 transformed leukemic-GMP (L-GMP) and found that 45.6%, 48.0%, and 47.1% of these genes were also identified in MLL-AF9+miR-29 null cells, indicating that miR-29 loss reduces the induction ability of MLL-AF9 targets. We also observed that 379 genes associated with the H3K79me2 mark in both normal LSK cells and MLL-AF9+miR-29 null blasts were absent in L-GMP, suggesting that these genes confer self-renewal and proliferation capacity to normal HSCs, that their suppression of these genes are important in MLL-AF9 induction of AML, and that their reactivation in miR-29 null cells compromises MLL-AF9 leukemogenic ability. Interestingly, we were able to identify several potential miR-29 targets including Akt3, Map4k4, and Dnmt3a. Overall, our studies demonstrate that deletion of miR-29 abrogates the leukemogenesis capacity of MLL-AF9, and miR-29 null mice appear to be an important tool for identifying critical mediators of MLL-AF9 induced AML. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Inferior Outcomes with Intensive AML Induction Therapy in Patients Age 70 or Greater Compared to Age 60-69

Background: The median age of diagnosis for acute myeloid leukemia (AML) is between age 65 and 70. While advances in therapy and supportive care in the past several decades has significantly improved outcomes in younger patients, the prognosis in elderly AML patients, defined as age 60 or greater, remains dismal. In addition, many elderly patients are unable to receive such aggressive therapy due to increased treatment-related mortality and poorer clinical response. There remains great interest in identifying factors that are associated with both beneficial and detrimental outcomes in this patient population.Methods: This was a retrospective analysis conducted at Moffitt Cancer Center. The primary study objective was to compare the incidence of 30-day mortality of patients aged 60-69 years vs. patients 70 years or older with newly diagnosed AML who received intensive remission induction chemotherapy. Secondary endpoints included 60-day mortality, overall survival (OS), complete response rate (CR), receipt of allogeneic hematopoietic stem cell transplant, rate of infection, cardiac complications, major organ failure, ICU transfer, and any other treatment-related complications. Baseline patient characteristics at diagnosis were summarized using descriptive statistics including mean, median, standard deviation, and range for continuous measures and proportions and frequencies for categorical measures. The primary outcome was assessed via chi-squared analysis. Assuming treatment-related mortality is 5% in the younger patients and 15% in patients > 70 years old, with a 2-sided p-value of 0.05, a sample size of 300 would provide a power of 0.83 to detect this 10% difference in mortality. Overall survival was estimated using the Kaplan-Meier method, and compared using a log-rank test. Univariate and multivariate analyses using Cox-Regression models were conducted to identify factors affecting OS.Results: A total of 246 patients with newly diagnosed AML between age 60-69 (n=132) and 70 or greater (n=114) who underwent initial remission-induction chemotherapy between July 2009 and July 2014 were identified and included in this analysis. Background characteristics and known factors that affect CR and OS such as overall risk category and performance status were well matched between groups. Sixty-four (56%) patients in the older and 62 (47%) patients in the younger group received 7+3 induction chemotherapy, whereas 41 (36%) in the older and 50 (38%) in the younger group received cladribine-based regimens. The remainder of patients received clinical trial induction chemotherapy. Twenty-three (17.4%) of patients in the younger patient group underwent immediate re-induction chemotherapy, compared to 8 (7%) patients in the older group (p=0.02).Thirty day mortality rate was 6.8% (9) in the younger group and 14% (16) in the older group (p=0.062). By day 60 after initiation of induction chemotherapy, 13.6% (18) and 23.7% (27) of patients in the younger and older cohorts, respectively, were deceased (p=0.031). No difference was noted in infection rate, ICU transfer, major organ failure, percentage of patients intubated, incidence of tumor lysis syndrome, or initiation of parenteral nutrition.Seventy-nine (59.8%) patients in the younger arm achieved CR, compared to 51 (44.7%) patients in the older arm (p=0.003). Median OS was 10.4 months and 8.3 months in the younger and older group respectively (p=0.002). Significantly more patients in the younger group went on to receive stem cell transplant. Multivariate analysis of the composite group revealed age >75, risk category, prior therapy with hypomethylating agents, and number of comorbidities were predictors of poorer survival.Conclusions: The presented study demonstrates that intensively-treated patients age ≥70 have an increased early treatment-related mortality, similar treatment-related morbidity, and a lower incidence of CR and OS compared to patients age 60-69. Additionally, prior hypomethylator use, risk category and comorbidities contribute to poorer survival. These observations give further insight into the role of intensive remission chemotherapy in an elderly AML patient population.Table 1Multivariable Analysis Overall Survival (p = <0.05)Hazard Ratio95% CIAge >751.51.06-2.20Risk Category1.11.01-1.16Prior Hypomethylator1.61.17-2.12No. of Comorbidities1.11.04-1.20 [Display omitted] DisclosuresOff Label Use: Cladribine for use in acute myeloid leukemia.

Comparison of Outcome and Prognosis of 248 Elderly Patients with Acute Myeloid Leukemia Treated with Standard-Dose or Low-Intensity Induction Therapy

Acute myeloid leukemia (AML) is a disease of older adults, with a median onset age at about 65-70 years. The treatment outcome of AML appears to be poorer with the age increasing, in part due to the poor performance status, concomitant end-organ dysfunction, higher incidence of unfavorable cytogenetic findings, frequent involvement of a more immature leukemic precursor clone, multidrug resistance mediated by MDR1/P-glycoprotein, and the presence of antecedent hematopoietic disorders. Treatment of elderly patients with AML remains highly challenging and controversial. The overall survival rates at 5-year of ≥ 60 years old AML patients are still less than 20% by now. At present, standard-dose induction chemotherapy using a cytarabine plus idarubicin(IA regimen) or daunorubicin (DA regimen) was considered by most to be the most effective upfront AML induction therapy. However, there are still quite a number of elderly patients could not tolerate because of poor performance status and complications. Therefore, low-intensity chemotherapy, including CAG regimen, which combine low-dose cytarabine, aclacinomycin and granulocyte colony-stimulating factor(G-CSF), was used for those were not appropriate for receiving standard-dose chemotherapy. Here we retrospectively analyzed the outcome and prognosis of elderly patients with AML treated with standard-dose or low-intensity induction therapy. 248 elderly patients with acute myeloid leukemia(AML) who received standard-dose or low-intensity induction therapy were enrolled in this retrospective clinical study, 186 patients in standard-dose group with 144 in IA and 42 in DA, 62 cases in low-intensityCAG group. The maininclusion criteria included age ≥ 60 years old, ECOG performance status ≤ 2, without severe complication of heart, liver, kidney or other important organ. The patients received standard-dose or low-intensity induction regimen according to their performance status and patient preference. 144 patients received IA regimen(idarubicin 10mg/m2/d ,d1-3; cytarabine 100mg/m2, q12h, d1-5 or 7), 42 patients received DA regimen(daunorubicin 60mg/m2/d, d1-3; cytarabine 100mg/m2 q12h, d1-5 or 7), and 62 patients received CAG regimen (cytarabine 10mg/m2 q12h, d1-14; aclacinomycin 20mg qd, d1-4; G-CSF 200ug/m2 qd, d0-14, or until bone marrow recover). The median survival time was 9.2 months. 1-year , 3-year and 5-year overall survival(OS) were 42.2%, 18.9% and 13.5%, respectively. After first induction cycle, complete remission(CR) rate was 49.3% in IA group, 35.7% in DA group and 32.3% in CAG group (P = 0.046). The median OS for IA, DA and CAG group were 10.0 months, 9.7months and 7.5 months, respectively. The early mortality of induction therapy and recurrence rate of three regimens showed no difference. IA could improve the long term survival compared to CAG and DA, with 3-year OS: 23.5%,15.9% and 8.3%, respectively; 5-year OS: 19.4%, 6.3%, and 0, respectively (P<0.01). The 67.0% patients relapsed within 24 months, with median relapse time of 8.4 months, 14.6 months and 8.3 months for IA, DA and CAG regimen, respectively. Moreover, Kaplan-Meier analysis showed that 7 parameters were adverse prognostic factors for OS, including age ≥ 70 years old, poor ECOG performance status, unfavorable cytogenetics, non-remission after first induction cycle, white blood cell (WBC) counts ≥ 50×10^9/L, percentage of bone marrow (BM) blast ≥ 80% and higher lactic dehydrogenase (LDH) . Multivariable analysis identified non-remission after first induction cycle (HR = 6.141, 95%CI: 3.585-10.52, P = 0.000) and LDH ≥ 490 IU/L(HR = 1.001, 95%CI: 1.000-1.001, P = 0.000) as independent significantly prognostic factors for OS. In conclusion, Our present data showed that standard-dose IA regimen could improve CR rate and prolong the survival time compared to low-intensity CAG regimen, and CAG regimen still has a certain therapeutic effect for those unfit for intensive chemotherapy. Recurrence is still a serious problem for those who do not receive Allo-HSCT for consolidation after CR. All prognostic factors should be considered before induction therapy to make sure the patients receive the best individualized treatment. DisclosuresNo relevant conflicts of interest to declare.