scholarly journals A Clinically Applicable Gene Expression based Score predicts Resistance to Induction Treatment in Acute Myeloid Leukemia

2021 ◽  
Author(s):  
Christian Moser ◽  
Vindi Jurinovic ◽  
Sabine Sagebiel-Kohler ◽  
Bianka Ksienzyk ◽  
Aarif M.N. Batcha ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Risk Classification ◽  
Significant Variable ◽  
Risk Patients ◽  
Induction Failure ◽  
Acute Myeloid

Prediction of resistant disease at initial diagnosis of acute myeloid leukemia (AML) can be achieved with high accuracy by using cytogenetic data and 29 gene expression markers (PS29MRC). Our aim was to establish PS29MRC as a clinically usable assay by using the widely implemented NanoString platform and further validate the classifier in a more recently treated patient cohort. 351 patients with newly diagnosed AML intensively treated within the AMLCG registry were analyzed. As a continuous variable, PS29MRC performed best in predicting induction failure in comparison to previously published risk models (OR=2.37; p=1.20·10-9). The classifier was strongly associated with overall survival (HR=1.38; p=2.62·10-6). We were able to establish a previously defined cut-off that allows a classifier dichotomization (PS29MRCdic). PS29MRCdic significantly identified induction failure with 59% sensitivity, 77% specificity and 72% overall accuracy (OR=4.81; p=4.15·10-10). PS29MRCdic was able to improve the ELN-2017 risk classification within every category (favorable: OR=5.44; p=0.017; intermediate: OR=4.43; p=0.011; adverse: OR=2.52; p=0.034). Median patients' overall survival with high PS29MRCdic was 1.8 years compared to 4.3 years of low-risk patients. In multivariate analysis including ELN-2017, clinical and genetic markers, only age and PS29MRCdic were independent predictors of refractory disease. In patients aged 60 or older, only PS29MRCdic was left as significant variable. In summary, we confirmed PS29MRC as a valuable classifier that can be calculated and reproduced on a widely available platform to identify high-risk patients in AML. Risk classification can still be refined beyond ELN-2017 and predictive classifiers might facilitate clinical trials focusing on these high-risk AML patients.

Prospective Evaluation of Allogeneic Hematopoietic Stem-Cell Transplantation From Matched Related and Matched Unrelated Donors in Younger Adults With High-Risk Acute Myeloid Leukemia: German-Austrian Trial AMLHD98A

2010 ◽  
Vol 28 (30) ◽  
pp. 4642-4648 ◽  
Author(s):  
Richard F. Schlenk ◽  
Konstanze Döhner ◽  
Silja Mack ◽  
Michael Stoppel ◽  
Franz Király ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Younger Adults ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Risk Patients ◽  
Unrelated Donors ◽  
Acute Myeloid

Purpose To assess the impact of allogeneic hematopoietic stem-cell transplantation (HSCT) from matched related donors (MRDs) and matched unrelated donors (MUDs) on outcome in high-risk patients with acute myeloid leukemia (AML) within a prospective multicenter treatment trial. Patients and Methods Between 1998 and 2004, 844 patients (median age, 48 years; range, 16 to 62 years) with AML were enrolled onto protocol AMLHD98A that included a risk-adapted treatment strategy. High risk was defined by the presence of unfavorable cytogenetics and/or by no response to induction therapy. Results Two hundred sixty-seven (32%) of 844 patients were assigned to the high-risk group. Of these 267 patients, 51 patients (19%) achieved complete remission but had adverse cytogenetics, and 216 patients (81%) had no response to induction therapy. Allogeneic HSCT was actually performed in 162 (61%) of 267 high-risk patients, after a median time of 147 days after diagnosis. Graft sources were as follows: MRD (n = 62), MUD (n = 89), haploidentical donor (n = 10), and cord blood (n = 1). The 5-year overall survival rates were 6.5% (95% CI, 3.1% to 13.6%) for patients (n = 105) not proceeding to HSCT and 25.1% (95% CI, 19.1% to 33.0%; from date of transplantation) for patients (n = 162) receiving HSCT. Multivariable analysis including allogeneic HSCT as a time-dependent covariable revealed that allogeneic HSCT significantly improved outcome; there was no difference in outcome between allogeneic HSCT from MRD and MUD. Conclusion Allogeneic HSCT in younger adults with high-risk AML has a significant beneficial impact on outcome, and allogeneic HSCT from MRD and MUD yields similar results.

scholarly journals Measurable Residual Disease at Induction Redefines Partial Response in Acute Myeloid Leukemia and Stratifies Outcomes in Patients at Standard Risk Without NPM1 Mutations

2018 ◽  
Vol 36 (15) ◽  
pp. 1486-1497 ◽  
Author(s):  
Sylvie D. Freeman ◽  
Robert K. Hills ◽  
Paul Virgo ◽  
Naeem Khan ◽  
Steve Couzens ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
High Risk Factors ◽  
Risk Patients ◽  
Standard Risk ◽  
Acute Myeloid

Purpose We investigated the effect on outcome of measurable or minimal residual disease (MRD) status after each induction course to evaluate the extent of its predictive value for acute myeloid leukemia (AML) risk groups, including NPM1 wild-type (wt) standard risk, when incorporated with other induction response criteria. Methods As part of the NCRI AML17 trial, 2,450 younger adult patients with AML or high-risk myelodysplastic syndrome had prospective multiparameter flow cytometric MRD (MFC-MRD) assessment. After course 1 (C1), responses were categorized as resistant disease (RD), partial remission (PR), and complete remission (CR) or complete remission with absolute neutrophil count < 1,000/µL or thrombocytopenia < 100,000/μL (CRi) by clinicians, with CR/CRi subdivided by MFC-MRD assay into MRD+ and MRD−. Patients without high-risk factors, including Flt3 internal tandem duplication wt/− NPM1-wt subgroup, received a second daunorubicin/cytosine arabinoside induction; course 2 (C2) was intensified for patients with high-risk factors. Results Survival outcomes from PR and MRD+ responses after C1 were similar, particularly for good- to standard-risk subgroups (5-year overall survival [OS], 27% RD v 46% PR v 51% MRD+ v 70% MRD−; P < .001). Adjusted analyses confirmed significant OS differences between C1 RD versus PR/MRD+ but not PR versus MRD+. CRi after C1 reduced OS in MRD+ (19% CRi v 45% CR; P = .001) patients, with a smaller effect after C2. The prognostic effect of C2 MFC-MRD status (relapse: hazard ratio [HR], 1.88 [95% CI, 1.50 to 2.36], P < .001; survival: HR, 1.77 [95% CI, 1.41 to 2.22], P < .001) remained significant when adjusting for C1 response. MRD positivity appeared less discriminatory in poor-risk patients by stratified analyses. For the NPM1-wt standard-risk subgroup, C2 MRD+ was significantly associated with poorer outcomes (OS, 33% v 63% MRD−, P = .003; relapse incidence, 89% when MRD+ ≥ 0.1%); transplant benefit was more apparent in patients with MRD+ (HR, 0.72; 95% CI, 0.31 to 1.69) than those with MRD− (HR, 1.68 [95% CI, 0.75 to 3.85]; P = .16 for interaction). Conclusion MFC-MRD can improve outcome stratification by extending the definition of partial response after first induction and may help predict NPM1-wt standard-risk patients with poor outcome who benefit from transplant in the first CR.

A Risk Score Combined Clinical and Molecular Profiles Identifies a High-Risk Subgroup within AML1-ETO-Positive Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-19
Author(s):  
Min Yang ◽  
Yi Zhang ◽  
Jinghan Wang ◽  
Lixia Liu ◽  
Chengcheng Wang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Risk Score ◽  
Myeloid Leukemia ◽  
Validation Cohort ◽  
Concordance Index ◽  
Scoring Model ◽  
Mutation Burden ◽  
Acute Myeloid

Background: AML1-ETO-positive acute myeloid leukemia, is classified as a favorable leukemia subtype according to the European Leukemia Net (ELN) risk stratification. Nevertheless, studies show the biology and prognosis within the AML1-ETO-positive AML are highly different, which suggests that more prognostic factors are needed to be identified. Aims: This study mainly revealed the genomic mutation characteristics and explored more factors which affect the prognosis of Chinese AML1-ETO-positive AML patients. Methods: A total of 167 AML1-ETO-positive patients who diagnosed and treated in Zhejiang Institute of Hematology had cryopreserved DNA for deep target 185-gene regional sequencing. Variants were detected with a variant allele frequency (VAF) cutoff of 0.5%. We used a LASSO Cox regression model to build risk score for predicting overall survival. A nomogram was constructed to display the risk of death in individuals. The discrimination of the risk score was measured by the concordance index (C-index) and areas under time-dependent receiver-operating characteristics (ROC) curves (AUCs), and the calibration of the risk score was explored graphically by calibration plots. Patients (n=75) from other hospital were used as a validation cohort. Results: The median age in analyzed patients was 42(6-78) years. The most common recurrent mutations occurred in KIT(n=84,50%), ASXL2(n=46,28%), NRAS(n=37,22%), FLT3-ITD(n=35,21%) and TET2(n=30,18%). We observed that high KIT mutant allele burden predicts for poor outcome in t(8:21) AML. High KIT VAF(≥15%) correlated with shortened overall survival compared to the other KIT mutated cases including low VAF and wild-type KIT (3-year OS 26.6% vs 59.0% vs 69.6%, HR 1.50, 95%CI 0.78-2.89, P=0.0005). In addition, we also identified some other mutated genes influence the prognosis of patients with t (8;21), such as FLT3-ITD high mutation burden(VAF≥44% vs other cases, 3-year OS 30.0% vs 56.2%, HR 2.94, 95%CI 0.43-20.18, P=0.056), TET2 high mutation burden (VAF≥43% vs other cases, 3-year OS 33.3% vs 56.5%, HR 2.87, 95%CI 0.66-12.46, P=0.018) and DHX15 high mutation burden (VAF≥22% vs other cases, 3-year OS 15.0% vs 58.3%, HR 2.65, 95%CI 0.81-8.73, P=0.011). In univariate analyses for OS, age&gt;42 (3-year OS 46.3% vs 64.4%, HR 1.91, 95%CI 1.14-3.14, P=0.012), WBC&gt;27.1×109/L(3-year OS 34.3% vs 60.0%, HR 2.59, 95%CI 1.13-5.9, P=0.001), BM blast&gt;20% (3-year OS 52.2% vs 92.8%, HR 6.36, 95%CI 2.7-14.97, P =0.035), LDH &gt; 504U/L (3-year OS 44.1% vs 67.1%, HR 2.62, 95%CI 1.50-4.59, P=0.0007), PLT≤28×109/L (3-year OS 47.1% vs 66.9%, HR 1.89, 95%CI 1.13-3.17, P=0.019), HB≤87g/L (3-year OS 49.4% vs 73.8%, HR 2.20, 95%CI 1.27-3.84, P=0.019) were significantly associated with poor OS. Six variables were incorporated in our scoring model by LASSO, including age, WBC, PLT, KIT mutation, FLT3-ITD mutation and TET2 mutation. A risk scoring model was developed incorporating the weighted coefficients of these variables. The risk score grouped AML1-ETO AML patients into two subgroup: low risk (LR, n=68) and high risk (HR, n=86) groups. The 3-year OS for LR and HR groups were 72.7% and 43.0% (P&lt;0.0001, Figure A). The similar results were also observed in validation cohort (3-year OS 79.1% vs 49.5%, P= 0.01; Figure B). Concordance index [train: 0.708, 95% CI (0.680, 0.736), validation: 0.722, 95% CI (0.666, 0.778)] demonstrated well discrimination power and calibration plots showed that the nomograms did well compared with an ideal model. Conclusion: In this study, our findings indicate that the prognostic effect of gene mutation in de novo t(8:21) AML may be influenced by the relative abundance of the mutated allele. A novel scoring model was developed and validated that incorporated molecular and clinical profiles. According to our score model, AML1-ETO AML patients could be further stratified into two subgroups with distinct clinical outcomes. Our data can serve as a basis for guided and risk-adapted treatment strategies for CBF-AML patients. The results are needed to be validated in other independent cohorts and prospective studies before implementation into clinics. Disclosures No relevant conflicts of interest to declare.

Autologous Bone Marrow Transplantation as an Intensive Consolidation Therapy for Adult Patients in Remission from Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5121-5121
Author(s):  
Andre S. Jung ◽  
Asad Bashey ◽  
Peter R. Holman ◽  
Eva Carrier ◽  
Januario Castro ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Consolidation Therapy ◽  
Free Survival ◽  
Risk Patients ◽  
Disease Free ◽  
Acute Myeloid

Abstract Introduction: Autologous peripheral blood stem/progenitor cell transplantation (APBSCT) has been investigated as a potential therapeutic option to improve outcome in patients with acute myeloid leukemia. The optimal consolidation therapy for adults in remission without a histo-compatible donor has yet to be clearly established. Patients and Methods: This was a retrospective analysis of forty patients (23 females and 17 males) diagnosed with de novo acute myeloid leukemia, who were without a histo-compatible donor, that underwent APBSCT between the year 2000 and 2006 at a single institution. The patients’ age ranged from 18 to 73 with a median age of 50. Cytogenetic analysis was available on 37 of the patients. Complete remission (CR) was confirmed by bone marrow morphology and immunophenotype analysis by flow cytometry. Patients in remission were further consolidated with variable cycles of chemotherapy prior to stem cell transplantation. For stem cell mobilization, patients received high-dose cytarabine (2000mg/m2) and etoposide (5mg/kg) for three days followed by G-CSF at 10μg/kg, starting 10 days after the chemotherapy, before the peripheral stem cell collection. The preparative regimen prior to transplantation with unpurged stem/progenitor cells consisted of a combination of intravenous busulfan (0.8 mg/kg for 16 doses) and cyclophosphamide (60 mg/kg for two doses) (37 patients) or busulfan and melphalan (3 patients). Patients were then followed for treatment-related mortality, disease free survival, and overall survival. The analysis was stratified according to age, cytogenetic risk, and remission state. Results: There was no treatment-related mortality. Nineteen out of forty patients had relapse of their disease. The relapse rate was lowest in the low risk cytogenetic group who were under the age of 60 and highest in the high risk cytogenetic group who were over the age of 60. The overall 5 year survival for all patients was 47%. When stratified for cytogenetic risk and age, the overall survival for low, intermediate, and high cytogenetic risk patients under the age of 60 were 67%, 59%, and 75% respectively. The overall survival for intermediate and high cytogenetic risk patients over the age of 60 were 33% and 0% respectively. The projected rate of disease free survival at 5 years was 40%. When stratified for cytogenetic risk and age, the disease free survival for low, intermediate, and high cytogenetic risk patients under the age of 60 were 33%, 52%, and 50% respectively. Disease free survival for intermediate and high cytogenetic risk patients over the age of 60 were 33% and 0%. Comparing patients in CR1 versus patients in CR2, the overall survival was 47% in CR1 and 50% in CR2. The disease free survival, when grouped as above, were 41% for those in CR1 and 33% for those in CR2. Conclusion: APBSCT is a reasonable and safe intensive consolidation therapy for those patients without a compatible HLA matched donor in first or second complete remissions, notably for those under the age of 60 regardless of their cytogenetic risk. The number of standard consolidations prior to APBSCT may be an important variable predicting outcome.

scholarly journals Augmented Reduced-Intensity Regimen Does Not Improve Postallogeneic Transplant Outcomes in Acute Myeloid Leukemia

2020 ◽  
pp. JCO.20.02308
Author(s):  
Charles Craddock ◽  
Aimee Jackson ◽  
Justin Loke ◽  
Shamyla Siddique ◽  
Andrea Hodgkinson ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Conditioning Regimen ◽  
Hazard Ratio ◽  
Prognostic Impact ◽  
Reduced Intensity ◽  
Acute Myeloid

PURPOSE Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.

Twice Daily Fludarabine and Cytarabine Combination Is Effective in Patients with Relapsed/Refractory Acute Myeloid Leukemia, High-Risk Myelodysplastic Syndromes, and Blast Phase Chronic Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3629-3629
Author(s):  
Naval Daver ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Jorge E. Cortes ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Complete Remission ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Abnormal Karyotype ◽  
Blast Phase ◽  
Acute Myeloid

Abstract Abstract 3629 Background: High dose cytarabine containing regimens are still considered standard options for patients (pts) with AML relapsing after a first CR lasting more than 12 months. In a phase I study, 65 patients received fludarabine 15 mg/m2 every 12 hours and cytarabine 0.5 g/m2. Five days of administration were found to be safe and effective with a CR rate of 28%. Aim: This phase II study was conducted to evaluate the efficacy and safety of the combination of twice daily fludarabine and cytarabine (BIDFA) in patients with refractory/relapsed (R/R) acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), and chronic myeloid leukemia in myeloid blast phase (CML-BP). Methods: Pts with R/R AML, intermediate-2 and high-risk MDS, and CML-BP, whose disease relapsed or was refractory to frontline and/or salvage therapy were eligible. Pts with performance status 0–3 and adequate organ function, received fludarabine 15 mg/m2 intravenously (IV) q12 hours on Days 1 to 5 and cytarabine 0.5 g/m2 IV over 2 hours q12 hours on Days 1 to 5. Gentuzumab ozogamycin (GO) was administered at 3 mg/m2 IV on day 1 in the first 59 pts. Pts with CML-BP were allowed to receive concomitant tyrosine kinase inhibitors. Results: 107 pts were enrolled. The median age was 62 years (range, 19 to 85). 93 pts had AML, 5 had high-risk MDS, and 9 had CML-BP. All pts had received prior therapy. 65 (61%) pts had failed previous intensive chemotherapy, while 42 (39%) had failed targeted and hypomethylating agents. Cytogenetics analysis showed diploid karyotype in 36 (33%) and unfavorable chromosomal abnormalities involving chromosome 5 and 7 in 22 (21%). Of the 107 pts, 52 were in first salvage: first CR duration of less than 12 months in 43 (40%) pts, and more than 12 months in 9 (9%). Overall, 22 pts (21%) achieved complete remission (CR) and 5 (5%) achieved a complete remission without platelet recovery (CRp), for an overall response rate (ORR) of 26% (Table 1). The CR rates for patients with relapsed AML with first CR duration (CRD1) ≥12 months, relapsed AML with CRD1< 12 months, and R/R AML beyond first salvage were 56%, 26%, and 11%, respectively. These compare favorably with the expected response rates in matched cohorts treated at our institution where the ORR were 50%, 11%, and 7%, respectively. A multivariate analysis identified the following 3 factors to be independent adverse prognostic factors for response: abnormal karyotype (versus diploid), second salvage (versus first salvage regardless of the duration of the first CR), and older age (Table 2). With a median follow-up of 7 months, the 6-month event-free survival, overall survival, and complete remission duration (CRD) rates were 18%, 35%, and 70%, respectively. Abnormal karyotype, older age, an increasing in the peripheral blood blasts percentage, and low platelets count (<30 × 109/L) were independently associated with a significant worse overall survival. The most common side effects observed were gastro-intestinal toxicities, including nausea, vomiting, diarrhea, and mucositis. The overall 4-week mortality rate was 9%. Conclusion: BIDFA is active with an ORR of 26% in a heavily pre- treated population. This combination is safe with a low rate of 4-week-mortality of 9%. Disclosures: No relevant conflicts of interest to declare.

Risk-Adapted, MRD-Refined Therapeutic Approach for the Treatment of Acute Myeloid Leukemia: From a Single Center Experience to the Cooperative Gimema Protocol AML1310

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1422-1422
Author(s):  
Adriano Venditti ◽  
Francesco Buccisano ◽  
Luca Maurillo ◽  
Maria Ilaria Del Principe ◽  
Paola Fazi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Young Patients ◽  
High Risk Patients ◽  
Risk Patients ◽  
Related Donor ◽  
Family Donor ◽  
Acute Myeloid

Abstract Abstract 1422 The outcome of young adult (< 60 years) with acute myeloid leukemia (AML) still remains unsatisfactory. In fact, in spite of complete remission (CR) rates ranging from 60 to 80%, only 30–40% of young patients will be long-term survivors. Advances in biologic characterization of AMLs are expected to enhance a more realistic assessment of disease aggressiveness so that therapies will be delivered in the context of a stratified approach. Cytogenetic/genetic profile is the most relevant prognostic factor established at diagnosis. Nevertheless, it is well recognized that it cannot always reliably predict outcome in individual patients. Minimal residual disease (MRD) detection promises to be an efficient tool to establish on an individual basis the leukemia's susceptibility to treatment and guide delivery of risk-tailored therapies. A further element underlying the dismal long-term outcome of young patients with AML pertains the chance to get access to allogeneic stem cell transplantation (ASCT) when carrying high-risk features. The extensive use of ASCT option is precluded by the paucity of full matched family donor (25–30%). These premises are the background to the risk-adapted approach, developed at the Institute of Hematology, University Tor Vergata, based on the following strategies: 1) combination of upfront cytogenetics/genetics and MRD status (< or ≥3.5×10−4 residual leukemic cells as counted by flow cytometry) at the end of consolidation to determine risk assignment; 2) once a given patients was categorized as high-risk (due to the expression of an unfavorable karyotype, FLT3-ITD positivity or post-consolidation positive MRD status) and therefore selected as candidate for ASCT, the transplant procedure was given whatever the source of stem cells. The present analysis includes 30 high-risk patients treated according to this design (prospective cohort = PC) and, for comparative purposes, 55 consecutive high-risk patients treated in an “old fashion” design based on donor availability (retrospective cohort = RC). The PC included 4 patients with favorable-karyotype (FK) and a MRD+ status, 12 with intermediate kayotype (IK) and a MRD+ status, 5 with unfavorable karyotype (UK) and 9 with FLT3-ITD mutation. The RC included 8 FK/MRD+, 34 IK/MRD+, 1 UK and 12 with FLT3-ITD mutation. In the PC, 22 (73%) of 30 patients received ASCT (8 matched family donor, 7 matched unrelated donor, 7 haploidentical related donor), 8 did not due to relapse (6) or because too early (2). In the RC, 12 (22%) received ASCT (11 matched family donor, 1 haploidentical related donor) whereas 24 (44%) autologous SCT (AuSCT); 19 were not transplanted at all due to relapse (13) or mobilization failure (6). Therefore, using the risk-adapted approach, 73% of high-risk patients in the PC received ASCT versus 22% of those in the RC (p <0.001). With a median follow-up of 30 and 50 months for the PC and RC, respectively, DFS is 73% vs 15% (p=0.011), OS 69% vs 20% (p=0.020), CIR 21% vs 76% (p<0.001). Based on these results, the GIMEMA Group has activated a clinical trial (AML1310, ClinicalTrials.gov.Identifier NCT01452646) of “risk-adapted, MRD directed therapy for young adult with AML”. The trial relies on a stringent disease characterization at diagnosis in terms of cytogenetic/genetic definition and identification of “leukemia associated immunophenotype” for MRD assessment at the post-consolidation time-point. The 2 parameters are exploited to qualify the category of risk which the patients belong to: low vs intermediate vs high. All patients will receive induction and consolidation according to the previous GIMEMA LAM99P protocol. After the first consolidation, patients belonging to the low-risk category (CBF+ AML without c-Kit mutations, NPM1+FLT3-ITD- AML) will receive AuSCT and those with high-risk features (UK, FLT3-ITD mutations) ASCT. Patients with FLT3-TKD mutations or c-Kit mutated CBF+ AML and those belonging to the IK category will be stratified according to the post-consolidation MRD status and will receive AuSCT or ASCT. All patients who meet the criteria for high-risk definition will be offered ASCT regardless of the availability of a HLA identical sibling, therefore all the other sources of hematopoietic stem cells will be considered. Applying this strategy, we expect a 10% survival advantage at 24 months as compared to the historical control (LAM99P protocol) where OS at 2 years was 50%. Disclosures: No relevant conflicts of interest to declare.

Reduced TET2 expression in Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2822-2822
Author(s):  
Renata Scopim-Ribeiro ◽  
Joao Machado-Neto ◽  
Paula de Melo Campos ◽  
Patricia Favaro ◽  
Adriana S. S. Duarte ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Erythroid Differentiation ◽  
Low Risk ◽  
High Risk Disease ◽  
Cd34 Cells ◽  
Acute Myeloid

Abstract Abstract 2822 Introduction: Acquired mutations in TET2 and DNMT3A have been found in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and may predict a worse survival in these diseases. TET2 mutations are considered to be a loss-of-function mutation and results in decreased 5-hydroxymethylcitosine (5-hmc) levels. In normal CD34+ cells, TET2 silencing skews progenitor differentiation towards the granulomonocytic lineage at the expense of lymphoid and erythroid lineages. Dnmt3a participates in the epigenetic silencing of hematopoietic stem cell regulatory genes, enabling efficient differentiation. Here, we attempted to evaluate the expression of TET2 and DNMT3A in total bone marrow cells from normal donors, patients with MDS and AML, and in CD34+ cells from MDS and normal controls during erythroid differentiation. Materials and Methods: The study included normal donors (n = 21), patients with MDS (n = 43) and AML (n = 42) at diagnosis. All normal donors and patients provided informed written consent and the study was approved by the ethics committee of the Institution. MDS patients were stratified into low and high-risk according to WHO classification (RCUD/RCMD/RARS=31 and RAEB1/RAEB2=12). TET2 and DNMT3A mRNA expression was assessed by quantitative PCR. CD34+ cells from normal donors (n = 9) and low-risk MDS patients (n = 7) were submitted to erythroid differentiation. Cells were collected and submitted to immunophenotyping for GPA and CD71 (days 6 and 12) and q-PCR for TET2 and DNMT3A expression (days 6, 8 and 12). Results of gene expression in normal donors and patients are presented as median, minimum-maximum, and were compared using Mann-Whitney test. Student t test was used for comparison of gene expression during CD34+ erythroid diferentiation. Overall survival was defined from the time of sampling to the date of death or last seen. Univariate analysis for overall survival was conducted with the Cox proportional hazards model. Results: TET2 expression was significantly reduced in both AML (0.62; 0.01–32.69) and MDS (1.46; 0.17–21.30) compared to normal donors (2.72; 0.43–31.49); P<0.0001 and P=0.01, respectively. TET2 expression was also significantly reduced in AML compared to MDS (P=0.0007). MDS patients were stratified into low and high-risk disease, and we still observed a significant reduction in TET2 expression in high-risk (0.73, 0.17–7.25) when compared to low-risk (1.58; 0.48–21.30; P=0.02) patients, but no difference was noted between normal donors vs. low-risk MDS, and high-risk MDS vs. AML. In MDS cohort, the median overall survival was 14 months (range 1–83), increased TET2 expression was associated with a longer survival (HR, 0.44; 95% CI, 0.21–0.91, P=0.03), and, as expected, WHO high-risk disease was associated with a shorter survival (HR, 10.16; 95% CI, 3.06–33.72, P<0.001), even though the confidence interval (CI) was large. TET2 expression did not impact survival in our cohort of AML patients. The erythroid differentiation was effective in cells from normal donors and MDS patients, as demonstrated by the flow cytometry analyses of GPA and CD71. TET2 expression was significantly increased on day 12 of erythroid differentiation, P<0.05. On the other hand, DNMT3A expression was similar between normal donors (0.74; 0.22–1.53), MDS (0.78; 0.26–3.46) and AML (0.95, 0.15–6.46), and during erythroid differentiation, with no impact on survival. Conclusion: These data suggest that decreased TET2 expression may participate in leukemogenesis, and supports the participation of TET2 in the erythroid differentiation of MDS. DNMT3A was not differentially expressed in AML and MDS, indicating that the presence of mutations in this gene may be the predominant mechanism of changes in protein function. We thus suggest that decreased TET2 expression may explain the reduced levels of 5-hmc found in TET2 wild type patients, and may become a predictive marker for outcomes in MDS and other myeloid diseases. Further studies would be necessary to better elucidate the clinical relevance and biologic significance of our findings, and whether the decreased TET2 expression results in hypermethylation in these diseases. Disclosures: Maciejewski: NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding.

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