The Elevated Expression of FBP1, a Key-Enzyme of Gluconeogenesis Gene, Is Associated to High Sokal Risk In Chronic Myeloid Leukemia Patients.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3399-3399
Author(s):  
Carolina Terragna ◽  
Sandra Durante ◽  
Annalisa Astolfi ◽  
Francesca Palandri ◽  
Fausto Castagnetti ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Pentose Phosphate ◽  
Differentially Expressed ◽  
Over Expression ◽  
High Risk Patients ◽  
Key Enzyme ◽  
Risk Patients ◽  
Cell Fractions ◽  
Pentose Phosphate Shunt

Abstract Abstract 3399 The oncogenic transformation of Chronic Myeloid Leukemia (CML) cell of origin has been associated to an increased glucose metabolism, where the glycolytic pyruvate is directed away from the mitocondria, converted into lactate and secreted from the cell. This metabolic conversion is termed aerobic glycolysis, or Warburg effect and very essentially, it serves to support the tumor cell proliferation, by providing nucleotides, aminoacids and lipids enough to replicate all of cellular content. CML patients are historically stratified according to their Sokal risk score, which for more than 30 years has been regarded as the most significant prognostic factor in this hematological malignancies. The putative genetic and/or genomic basis driving this stratification are still not known. Aim of the present study was to explore the molecular mechanisms associated to the CML patients stratification according to the Sokal risk score, by analyzing the transcriptome of the CD34+ cell fractions obtained at diagnosis from a cohort of high and non-high Sokal risk CML patients. Overall, 67 patients with previously untreated CML in chronic phase (CP) entered the study; all of them have been enrolled in GIMEMA CML protocols and provided highly enriched CD34+ cell fractions from peripheral blood. Gene expression profiling (GEP) was performed, in order to identify genes most significantly and most differentially expressed between high and non-high Sokal risk patients. All other cases were used in Real-time experiments, in order to validate the GEP data. By GEP, 82 probe-sets, corresponding to 78 genes resulted significantly differentially expressed between high and non-high Sokal risk patients in a supervised analysis of gene profiles. A gene enrichment analysis of this profile showed that genes involved in the Wnt, in the Notch signaling pathways and in the response to hypoxia and oxidative stress resulted significantly overexpressed in the comparison between high and non-high risk patients. We focused our attention on genes involved in the glycolysis and gluconeogenesis metabolic pathways (FBP1, SEPP1, GSTM3, GSTT1, PRDX2, MPO). We validated by Real-time the de-regulated expression of these genes in a different set of newly diagnosed CP-CML patients, thus confirming that they are differentially expressed between high and non-high risk patients, with trends similar to those observed by GEP. Particularly interesting resulted a significantly higher expression in high Sokal risk patients of FBP1 (fructose 1,6 bisphosphatase), a key-enzyme of gluconeogenesis, together with a significant over-expression of genes coding for enzyme involved in gluthatione biosynthesis (GSTM3, GSTT1, and PRDX2). These data suggest that CD34+ cells obtained from high Sokal risk patients might exhibit an unexpected moderation of the glycolytic flux, mainly due to the over-expression of FBP1, which might cause a re-direction of the pathway into the pentose phosphate shunt. A similar metabolic reprogramming has been already described in imatinib resistant bcr-abl positive cell lines and is supported also by the over-expression in high risk patients of G6PDH (Glucose-6-phosphate 1-dehydrogenase) and TK (Transketolase), which are key enzyme of the pentose phosphate shunt. Overall, our data demonstrate for the first time, that the expression at diagnosis of sugar metabolic enzymes, might drive the evolutive Sokal risk of CML patients. Supported by: European LeukemiaNet, BolognAIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, Ateneo RFO grants, Project of integrate program (PIO), Programma di Ricerca Regione – Università 2007 – 2009. Disclosures: Rosti: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Baccarani:NOVARTIS: Honoraria; BRISTOL MYERS SQUIBB: Honoraria. Martinelli:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy.

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.

Should Hematopoietic Stem Cell Transplantation in First Complete Remission Be Restricted to High-Risk Patients in Childhood Acute Myeloid Leukemia?.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1094-1094
Author(s):  
Hideki Muramatsu ◽  
Nobuhiro Nishio ◽  
Asahito Hama ◽  
Hiroshi Yagasaki ◽  
Yoshiyuki Takahashi ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Low Risk ◽  
Hematopoietic Stem ◽  
High Risk Patients ◽  
Risk Patients ◽  
Group A ◽  
Group B ◽  
First Complete Remission

Abstract Hematopoietic stem cell transplantation (HSCT) has been used as an effective consolidation therapy for children with acute myeloid leukemia (AML) in first complete remission (CR). Although it is effective in relapse prevention, often it causes severe late sequelae, such as short stature and infertility. There is a recent trend to restrict the use of HSCT in first CR for high-risk patients. However, there is no study comparing which strategy is better, risk-adapted or general recommendation for HSCT in AML children in first CR. In our institutes, all such children in first CR were recommended either allogeneic or autologous HSCT until 1997. After 1998, patients were classified into three risk-groups. Low-risk patients (t(8;21) and inv(16)) were not recommended to undergo HSCT. High-risk patients (−7, 5q-, Ph1, t(16;21) and remission failure) were recommended to undergo HSCT. Intermediate-risk (other karyotypes) patients received HSCT in first CR if a suitable donor was available. In this study, we retrospectively compared the prognosis of 66 patients who were diagnosed with de novo AML between 1991 and 1997 (group A; n=37) and between 1998 and 2003 (group B; n=29). AML with Down syndrome and AML-M3 were excluded. The median (range) age was five (0–15) years. FAB classifications were M0 (n = 1), M1 (n = 10), M2 (n = 22), M4 (n = 6), M4E (n = 5), M5 (n = 14), M6 (n = 0), and M7 (n = 8). Chromosome analysis data were t(8;21) (n = 18), inv(16) (n = 4), 11q23 (n = 10), other abnormalities (n = 14), normal karyotype (n = 14), and unknown (n = 6). Induction chemotherapy comprised VP-16, cytarabine, and mitoxantrone. Sixty-three of 66 patients (95.5%) achieved CR. HSCT in first CR was done in 24 patients (64.9%) in group A and seven patients (24.1%) in group B (p = 0.0044). Age, sex, WBC count at diagnosis, FAB classification and chromosomal abnormalities did not differ between the two groups. Fourteen (five in group A and nine in group B) patients relapsed. Six (three in group A and three in group B) of them were salvaged by HSCT. Both 5-year event-free survival (EFS) and overall survival (OS) were statistically higher in group A than in group B (5-year EFS: 83.8 ± 6.1% versus 62.1 ± 9.0%, p = 0.0404; 5-year OS: 91.6 ± 4.7% versus 71.6 ± 8.5%, p = 0.0364). Although intensified chemotherapy without HSCT for low-risk AML patients is desirable to avoid the late complications of HSCT, our analysis showed that the introduction of risk-stratified treatment strategy significantly worsened the chances of EFS and OS. Our risk stratification based on chromosomal abnormalities only may be insufficient to identify low-risk AML children. Development of more sophisticated risk classification, including molecular markers, may be required to identify true low-risk patients who should avoid HSCT in first CR.

scholarly journals Results of the AIEOP AML 2002/01 multicenter prospective trial for the treatment of children with acute myeloid leukemia

Blood ◽  
2013 ◽  
Vol 122 (2) ◽  
pp. 170-178 ◽  
Author(s):  
Andrea Pession ◽  
Riccardo Masetti ◽  
Carmelo Rizzari ◽  
Maria Caterina Putti ◽  
Fiorina Casale ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Prospective Trial ◽  
High Risk Patients ◽  
Key Points ◽  
Risk Patients ◽  
Leukemia Relapse ◽  
Acute Myeloid

Key Points Risk-adapted therapy and broad use of HSCT resulted in a significant improvement in outcome. AUTO- or ALLO-HSCT in high-risk patients resulted in a cumulative incidence of leukemia relapse superimposable to that of SR.

Genetic biomarkers identify a subgroup of high-risk patients within low-risk NPM1-mutated acute myeloid leukemia

2020 ◽  
pp. 1-12
Author(s):  
Diego Carbonell ◽  
Julia Suárez-González ◽  
María Chicano ◽  
Cristina Andrés-Zayas ◽  
Miriam Díez-Díez ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Low Risk ◽  
High Risk Patients ◽  
Genetic Biomarkers ◽  
Risk Patients ◽  
Acute Myeloid

Changes in the dynamics of the excess mortality rate in chronic phase-chronic myeloid leukemia over 1990-2007: a population study

Blood ◽  
2011 ◽  
Vol 118 (16) ◽  
pp. 4331-4337 ◽  
Author(s):  
Selim Corm ◽  
Laurent Roche ◽  
Jean-Baptiste Micol ◽  
Valérie Coiteux ◽  
Nadine Bossard ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Mortality Rate ◽  
Myeloid Leukemia ◽  
Excess Mortality ◽  
Chronic Phase ◽  
Relative Survival ◽  
High Risk Patients ◽  
Risk Patients ◽  
Sokal Score

Abstract Imatinib has transformed the prognosis and the management of chronic myeloid leukemia (CML) and has probably changed the patterns of mortality rates. We explored this change at each disease severity level (Sokal score) through a flexible statistical modeling of the effect of the year of diagnosis on the excess mortality rate. The study included 691 chronic-phase patients from Nord-Pas-de-Calais French CML registry diagnosed from 1990 to 2007. Imatinib was given to 93% of the patients diagnosed after 2000. Comparing the 1990-1994, 1995-1999, and 2000-2007 periods of diagnosis, the 5-year relative survival improved from 64% to 66% and 88%. The year of diagnosis was associated with a significant reduction of the excess mortality, but only in patients with intermediate to high Sokal scores. In high-risk patients diagnosed in the early 1990s, a peak of excess mortality was observed during the second year of follow-up. That peak decreased progressively over the years of diagnosis until disappearing in patients diagnosed after 2000. This study showed different effects according to Sokal scores of the use of imatinib on mortality in patients with chronic-phase CML and showed that since 2000 the pattern of mortality of high-risk patients became similar to that of intermediate-risk ones.

Chronic myeloid leukemia and interferon-α: a study of complete cytogenetic responders

Blood ◽  
2001 ◽  
Vol 98 (10) ◽  
pp. 3074-3081 ◽  
Author(s):  
Francesca Bonifazi ◽  
Antonio de Vivo ◽  
Gianantonio Rosti ◽  
François Guilhot ◽  
Joëlle Guilhot ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Collaborative Study ◽  
Chronic Phase ◽  
Low Risk ◽  
Interferon Α ◽  
Term Survival ◽  
High Risk Patients ◽  
Risk Patients

Abstract Achieving a complete cytogenetic response (CCgR) is a major target in the treatment of chronic myeloid leukemia (CML) with interferon-α (IFN-α), but CCgRs are rare. The mean CCgR rate is 13%, in a range of 5% to 33%. A collaborative study of 9 European Union countries has led to the collection of data on 317 patients who were first seen between 1983 and 1997 and achieved CCgRs with IFN-α alone or in combination with hydroxyurea. The median time to first CCgR was 19 months (95% CI, 17-21; range, 3-84 months). At last contact, 212 patients were still alive and in continuous CCgR; 105 patients had lost CCgR, but 53% of them were still alive and in chronic phase. IFN-α treatment was discontinued permanently in 23 cases for response loss, in 36 cases for chronic toxicity (15 are still in unmaintained continuous CCgR), and in 8 cases because it was believed that treatment was no longer necessary (7 of these 8 patients are still in unmaintained continuous CCgR). The 10-year survival rate from first CCgR is 72% (95% CI, 62%-82%) and is related to the risk profile. High-risk patients lost CCgR more frequently and more rapidly and none survived more than 10 years. Low-risk patients survived much longer (10-year survival probability 89% for Sokal low risk and 81% for Euro low risk). These data point out that a substantial long-term survival in CCgRs is restricted mainly to low-risk and possibly intermediate-risk patients and occurs significantly less often in high-risk patients.

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