scholarly journals Assessing the Impact of Prophylactic Anidulafungin during Remission Induction of Acute Myeloid Leukemia - a Propensity-Score Matching Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1988-1988
Author(s):  
Wellington F Silva ◽  
Fernanda Rodrigues Mendes ◽  
Raphael Bandeira Melo ◽  
Elvira Velloso ◽  
Vanderson Rocha ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Propensity Score ◽  
Genetic Risk ◽  
Myeloid Leukemia ◽  
Complete Response ◽  
Remission Induction ◽  
Fusarium Sp ◽  
The Impact ◽  
Acute Myeloid

Abstract Introduction: Invasive fungal disease (IFD) accounts for substantial morbidity during the treatment of acute myeloid leukemia (AML) in adults. Antifungal prophylaxis (AP) is needed during intensive chemotherapy, and posaconazole has recently emerged as a drug of choice for this purpose. In our setting, alternative strategies such as no upfront prophylaxis, fluconazole, or echinocandins have been used during the remission induction, as posaconazole is not available. While few reports have pointed to micafungin as an option for this aim, studies addressing the use of anidulafungin in AML are lacking. In this study, we aimed to examine the impact of prophylactic anidulafungin during intensive AML remission induction. Methods: This retrospective cohort encompassing newly diagnosed AML adult patients (pts) treated at Instituto do Cancer do Estado de Sao Paulo, Brazil, between June 2011 and June 2020. We used a slight modification of European LeukemiaNet 2010 classification previously published by our group - Adapted Genetic Risk (AGR) (Silveira et al., 2020). Over these years, local policies regarding AP changed. All patients received the "7+3" regimen and were divided into three groups: pts who did not receive any AP and pts who received fluconazole (15-400 mg/day) or anidulafungin (100 mg/day) as AP. Local recommendations for IFD treatment were followed, and they also changed over time. The primary endpoint was IFD rate during the first 60 days from the beginning of chemotherapy, following the recommendation of EORTC/MSG. Multivariable analysis (MVA) was performed by logistic regression. Aiming to equalize subgroups for IFD risk factors, a propensity-score matching was performed using the nearest neighbor method. Results: Overall, 204 pts were included, with a median age of 54 years (range,17-74). The main baseline features of this cohort are summarized in Table 1. Regarding AP, 108 pts received anidulafungin, 82 pts did not receive AP, and 14 pts received fluconazole. The incidence of IFI was 26.6% (95% CI 20.8-33.3), classified as possible, probable, and proven in 65.5%, 1.8%, and 32.7%, respectively. Regarding the fungus specimen, Aspergillus sp. responded for most cases (60%), followed by Fusarium sp. (23%), Candida sp. (11%), and Zygomycetes (4%). Complete response was documented at the end of induction in 49%, with the remaining patients being either refractory (27%) or not available (24%). The 60-day mortality was 25.8%. MVA showed that lower neutrophil counts at the AML diagnosis are associated with IFD during induction (OR=2.8, 95% CI 1.3-6.2), whereas age, genetic classification, and lymphocyte counts were not. Comparing the three abovementioned groups (AP: none, anidulafungin, or fluconazole), significant differences could be seen in AGR and anthracycline doses (Table 2). To analyze the impact of anidulafungin in comparison with 'no AP', a post-matched cohort with 164 subjects was created, matching for neutrophil and lymphocyte counts and AGR. The use of anidulafungin was not significantly related to less IFD during induction (OR=0.7, 95% CI 0.3-1.6), while neutrophil counts remained significant. Few subjects received fluconazole as AP, and it also was not related to less IFD (p=0.35). At the end of induction, complete response status did not relate to IFD during this period (p=1). Treatment for IFD with amphotericin B and voriconazole was given for 60.2% and 13.1% during induction, respectively. Patients under prophylactic anidulafungin received less amphotericin B (p<0.001) but not voriconazole (p=0.49). Fusarium sp. cases that occurred during induction (n=12) received mostly prophylactic fluconazole (42%), which was statistically relevant in comparison to other AP (p<0.001). Among these 12 cases, no favorable genetic risk was found. The occurrence of IFD during induction did not correlate with early mortality (HR=0.97, 95% CI 0.5-1.8) in our cohort. Conclusion: To our knowledge, this is the first study addressing the role of anidulafungin during AML induction. Here, the use of AP did not decrease IFD incidence within this phase. Our results point to the fact that the fungistatic activity of echinocandins in molds might be suboptimal for immunocompromised pts. Furthermore, these results strengthen the role of posaconazole in this setting, especially for baseline neutropenic patients or higher risk subsets, such as primary refractory cases. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Age and remission induction therapy for acute myeloid leukemia: An analysis of data from the Korean acute myeloid leukemia registry

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251011
Author(s):  
Kwai Han Yoo ◽  
Hyeoung-Joon Kim ◽  
Yoo Hong Min ◽  
Dae-Sik Hong ◽  
Won Sik Lee ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Therapeutic Strategy ◽  
Median Overall Survival ◽  
Complete Response ◽  
Remission Induction ◽  
The Impact ◽  
Acute Myeloid

Objective The clinical characteristics and therapeutic strategy in acute myeloid leukemia (AML) are influenced by patients’ age. We evaluated the impact of age on remission induction therapy for AML. Methods We retrospectively analyzed 3,011 adult AML patients identified from a nationwide database between January 2007 and December 2011. Results Three hundred twenty-nine (10.9%) acute promyelocytic leukemia (APL) and 2,682 (89.1%) non-APL patients were analyzed. The median age was 51 years and 55% of patients were male. Six hundred twenty-three patients (21%) were at favorable risk, 1522 (51%) were at intermediate risk, and 743 (25%) were at poor risk. As the age increased, the proportion of those at favorable risk and who received induction chemotherapy decreased. After induction therapy, complete response (CR) was achieved in 81.5% (243/298) of APL and 62.4% (1,409/2,258) of non-APL patients; these rates decreased as the age increased, with an obvious decrement in those older than 60 years. The median overall survival of non-APL patients was 18.7 months, while that of APL patients was not reached, with a 75% five-year survival rate. Conclusions Age impacts both the biology and clinical outcomes of AML patients. Further studies should confirm the role of induction remission chemotherapy by age group.

Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2637-2644 ◽  
Author(s):  
Teresa Padró ◽  
Sandra Ruiz ◽  
Ralf Bieker ◽  
Horst Bürger ◽  
Martin Steins ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Chemotherapy ◽  
Microvessel Density ◽  
Myeloid Leukemia ◽  
Remission Induction ◽  
Bone Marrow Biopsies ◽  
Acute Myeloid

The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. In contrast, only few data are available for hematologic neoplasms. To investigate the role of angiogenesis in acute myeloid leukemia (AML), bone marrow biopsies from 62 adults with newly diagnosed, untreated AML (day 0) were evaluated. Further studies were done after the completion of remission induction chemotherapy (day 16 of induction chemotherapy, n = 21; complete remission, n = 20). Microvessels were scored in at least 3 areas (×500 field, 0.126 mm2) of the highest microvessel density in representative sections of each bone marrow specimen using immunohistochemistry for von Willebrand factor and thrombomodulin. Microvessel counts were significantly higher in patients with AML (n = 62) compared with control patients (n = 22): median (interquartile range) 24.0 (21.0-27.8)/×500 field vs 11.2 (10.0-12.0)/×500 field, respectively (P < .001). On day 16 of induction chemotherapy, microvessel density was reduced by 60% (44-66) (P < .001) in hypoplastic marrows without residual blasts, in contrast to only 17% (0-37) reduction in hypoplastic marrows with ≥ 5% residual blasts (P < .001 for the difference between both groups). Bone marrow biopsies taken at the time of complete remission displayed a microvessel density in the same range as the controls. In conclusion, there is evidence of increased microvessel density in the bone marrow of patients with AML, which supports the hypothesis of an important role of angiogenesis in AML. Furthermore, these findings suggest that antiangiogenic therapy might constitute a novel strategy for the treatment of AML.

scholarly journals Ecological principle meets cancer treatment: treating children with acute myeloid leukemia with low-dose chemotherapy

2019 ◽  
Vol 6 (3) ◽  
pp. 469-479 ◽  
Author(s):  
Yixin Hu ◽  
Aili Chen ◽  
Xinchang Zheng ◽  
Jun Lu ◽  
Hailong He ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Randomized Study ◽  
Remission Induction ◽  
Molecular Response ◽  
Standard Chemotherapy ◽  
Low Dose Chemotherapy ◽  
The Impact ◽  
Acute Myeloid

Abstract Standard chemotherapy regimens for remission induction of pediatric acute myeloid leukemia (AML) are associated with significant morbidity and mortality. We performed a cohort study to determine the impact of reducing the intensity of remission induction chemotherapy on the outcomes of selected children with AML treated with a low-dose induction regimen plus granulocyte colony stimulating factor (G-CSF) (low-dose chemotherapy (LDC)/G-CSF). Complete response (CR) after two induction courses was attained in 87.0% (40/46) of patients receiving LDC/G-CSF. Post-remission therapy was offered to all patients, and included standard consolidation and/or stem cell transplantation. During the study period, an additional 94 consecutive children with AML treated with standard chemotherapy (SDC) for induction (80/94 (85.1%) of the patients attained CR after induction II, P = 0.953) and post-remission. In this non-randomized study, there were no significant differences in 4-year event-free (67.4 vs. 70.7%; P = 0.99) and overall (70.3 vs. 74.6%, P = 0.69) survival in the LDC/G-CSF and SDC cohorts, respectively. After the first course of induction, recovery of white blood cell (WBC) and platelet counts were significantly faster in patients receiving LDC/G-CSF than in those receiving SDC (11.5 vs. 18.5 d for WBCs (P < 0.001); 15.5 vs. 22.0 d for platelets (P < 0.001)). To examine the quality of molecular response, targeted deep sequencing was performed. Of 137 mutations detected at diagnosis in 20 children who attained hematological CR after two courses of LDC/G-CSF (n = 9) or SDC (n = 11), all of the mutations were below the reference value (variant allelic frequency <2.5%) after two courses, irrespective of the treatment group. In conclusion, children with AML receiving LDC/G-CSF appear to have similar outcomes and mutation clearance levels, but significantly lower toxicity than those receiving SDC. Thus, LDC/G-CSF should be further evaluated as an effective alternative to remission induction in pediatric AML.

Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2637-2644 ◽  
Author(s):  
Teresa Padró ◽  
Sandra Ruiz ◽  
Ralf Bieker ◽  
Horst Bürger ◽  
Martin Steins ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Chemotherapy ◽  
Microvessel Density ◽  
Myeloid Leukemia ◽  
Remission Induction ◽  
Bone Marrow Biopsies ◽  
Acute Myeloid

Abstract The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. In contrast, only few data are available for hematologic neoplasms. To investigate the role of angiogenesis in acute myeloid leukemia (AML), bone marrow biopsies from 62 adults with newly diagnosed, untreated AML (day 0) were evaluated. Further studies were done after the completion of remission induction chemotherapy (day 16 of induction chemotherapy, n = 21; complete remission, n = 20). Microvessels were scored in at least 3 areas (×500 field, 0.126 mm2) of the highest microvessel density in representative sections of each bone marrow specimen using immunohistochemistry for von Willebrand factor and thrombomodulin. Microvessel counts were significantly higher in patients with AML (n = 62) compared with control patients (n = 22): median (interquartile range) 24.0 (21.0-27.8)/×500 field vs 11.2 (10.0-12.0)/×500 field, respectively (P &lt; .001). On day 16 of induction chemotherapy, microvessel density was reduced by 60% (44-66) (P &lt; .001) in hypoplastic marrows without residual blasts, in contrast to only 17% (0-37) reduction in hypoplastic marrows with ≥ 5% residual blasts (P &lt; .001 for the difference between both groups). Bone marrow biopsies taken at the time of complete remission displayed a microvessel density in the same range as the controls. In conclusion, there is evidence of increased microvessel density in the bone marrow of patients with AML, which supports the hypothesis of an important role of angiogenesis in AML. Furthermore, these findings suggest that antiangiogenic therapy might constitute a novel strategy for the treatment of AML.

The Role of Decitabine for the Treatment of Acute Myeloid Leukemia

2012 ◽  
Vol 46 (11) ◽  
pp. 1511-1517 ◽  
Author(s):  
Alex Ganetsky
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Remission Induction ◽  
Phase 2 ◽  
Phase 3 ◽  
Hematopoietic Stem ◽  
Phase 2 Trial ◽  
Acute Myeloid

OBJECTIVE: To review the available literature addressing the role of decitabine for the treatment of acute myeloid leukemia (AML). DATA SOURCES: Relevant literature was identified by a PubMed search (January 1970-March 2012) of English-language literature using the terms decitabine, acute myeloid leukemia, and DNA methyltransferase inhibitors. STUDY SELECTION AND DATA EXTRACTION: All published studies and abstracts, as well as relevant consensus guidelines, evaluating the current literature about the role of decitabine for the treatment of AML were included. DATA SYNTHESIS: Decitabine has been evaluated for the treatment of AML in several different settings. In patients with newly diagnosed AML who are not candidates for standard remission induction chemotherapy, a Phase 2 trial of decitabine administered for 5 days per cycle demonstrated a 24% complete remission rate (CR). A subsequent Phase 3 trial comparing decitabine and low-dose cytarabine or best supportive care in a similar patient population showed a greater CR rate (18% vs 8%; p = 0.001) but no overall survival benefit. A Phase 2 trial demonstrated a 47% CR rate with decitabine initially administered for 10 days per cycle, with subsequent doses customized to individual response and toxicity. This novel dosing schedule has yet to be evaluated in a Phase 3 trial. Decitabine is also being investigated for the treatment of relapsed/refractory AML and as bridge therapy to allogeneic hematopoietic stem cell transplantation. CONCLUSIONS: Decitabine offers a promising alternative therapeutic option for patients with AML who are not candidates for standard remission induction chemotherapy. Because of its acceptable safety profile, research is investigating the clinical benefit of decitabine in combination with other antileukemic therapies. The potential roles of decitabine in the treatment of AML continue to be explored in numerous clinical trials.

scholarly journals Assessing Early Mortality in Intensively-Treated Acute Myeloid Leukemia in a Developing Country: Genetic, Laboratory Findings, and Comorbidities Add Prognostic Information

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Fernanda Rodrigues Mendes ◽  
Wellington F Silva ◽  
Raphael Bandeira Melo ◽  
Douglas R. A. Silveira ◽  
Elvira Velloso ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Genetic Risk ◽  
Myeloid Leukemia ◽  
Cox Regression ◽  
Newly Diagnosed ◽  
Laboratory Findings ◽  
Tumor Lysis ◽  
Acute Myeloid

Background: Early death (ED) during first-line therapy for acute myeloid leukemia (AML) is acknowledged as a pending issue worldwide. Few pivotal studies from developed countries have identified baseline characteristics related to poor outcome. Retrospective reports from Brazil and Mexico indicate alarming ED rates from real-world data, raising the question of which factors contribute towards this finding in low-income centers. In this study, we aimed to identify risk factors for ED in AML to increase the prediction power of previously known tools such as Charlson's Comorbidity Index (CCI) as well as to examine the role of anti-infective prophylaxis in our cohort. Methods: This is a retrospective cohort study involving adult patients (pts) newly diagnosed with AML treated at Instituto do Cancer do Estado de Sao Paulo, Brazil between June 2011 and June 2020. Only pts receiving the classic "7+3" regimen were included. We used a slight modification of European LeukemiaNet 2010 classification previously published by our group - Adapted Genetic Risk (AGR) (Silveira et al., 2020). The primary endpoint was ED rate, calculated by the Kaplan-Meier method. A Cox regression model selected by a stepwise method was used to find risk factors. Post-chemotherapy events (secondary endpoints) constituted any documented infection, bleeding, thrombosis, and acute kidney injury (AKI) during the first 30 days. Results: Overall, 206 out of 337 pts (61%) entered in the analysis. The median age was 54 years (range,17-74) and 50.5% were male. The median time between symptoms' onset and hospital admission was 7 weeks (0-48). Thirteen pts (6.3%) presented with leukostasis, of which 9 proceeded leukapheresis. At the presentation, clinical tumor lysis syndrome was seen in 12% of patients (associated with extramedullary disease [p&lt;0.001], among other factors). Other baselines clinical and laboratory findings are summarized in table 1. Pre-chemotherapy infection was found in 67% of patients (positive blood culture: 26.3%). 45-day mortality was 23.8% (95% CI 17.8-29.4) (Figure 1), being 39.8% in pts above 60y. Dose reductions for liver or kidney dysfunction were not, per si, associated with higher ED. Multivariable Cox regression models examined the utility of baseline markers in predicting ED in our cohort and the best-fitted model by Akaike information criteria (AIC) is outlined in a forestplot (Figure 2). Briefly, in a model controlled for age, adding phenotype, genetic risk, platelets and C-reactive protein (CRP) to CCI resulted in improved prediction in our cohort (AIC 479 vs 542). CRP, AGR, and CCI were independently associated with short-term survival in AML (figure 3, 4, and 5). Noticeably, 13/20 diabetic patients died during the first 45 days (unadjusted HR 4.29 [95% CI 2.33-7.92]). Only antibacterial prophylaxis with quinolone was associated with decreased ED (unadjusted HR 0.38 [95% CI 0.15-0.95]), while the use of fluconazole or anidulafungin did not affect survival. Colonization during hospitalization occurred in 71% (mainly vancomycin-resistant Enterococcus [77%] and carbapenemase-producing Enterobacteriaceae [44%]). Any sort of colonization was associated with ED (OR 4.41 [95% CI 1.89-12.08]). Thromboembolic events were registered in 11.9% (95% CI 7.9-17.4, mostly catheter-related) and were marginally associated with central nervous system disease (OR 4.31 [95% CI 0.84-18.25) and diabetes mellitus (DM) (OR 3.24 [95% CI 0.94-9.82) 20.8 vs 7.9%, p=0.097). Bleeding was observed in 17.6% and was associated with monocytic AML subtypes, tumor lysis, and DM. Complete response was attained in 50.5% (95% CI 43.4- 57.5). Presumed or confirmed invasive fungal infection was diagnosed during induction in 26.6%, but empirical amphotericin was prescribed in 60.2%. 66.5% of subjects developed any grade of AKI, with the need for hemodialysis in 10.3%. Conclusion: This is the first Brazilian study to evaluate risk factors for ED in newly diagnosed AML in the public setting, as well as to address which events explain such higher mortality in comparison to American and European reports. In line with the literature, age itself was not associated with mortality when adjusted for other variables such as CCI and genetic stratification. Interestingly, we found that the baseline CRP levels are significantly correlated with ED, highlighting the role of infection and inflammation at the AML diagnosis. Disclosures No relevant conflicts of interest to declare.

A Phase II Study of Elacytarabine/Idarubicin As Second Course Remission-Induction in Patients with Acute Myeloid Leukemia Who Failed Cytarabine/Anthracycline, and Evaluation of the Impact of the Nucleoside Transporter hENT1 on Response

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1533-1533
Author(s):  
David A. Rizzieri ◽  
Norbert Vey ◽  
Richard F. Schlenk ◽  
Xavier Thomas ◽  
Françoise Huguet ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Confidence Interval ◽  
Myeloid Leukemia ◽  
Fatty Acid Derivative ◽  
Expression Level ◽  
Remission Induction ◽  
Clinical Activity ◽  
Nucleoside Transporter ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract 1533 Background: Elacytarabine is a fatty acid derivative (elaidic acid ester) of cytarabine. The mechanism of action is similar to cytarabine, but unlike cytarabine, cellular uptake and activity of elacytarabine are independent of nucleoside transporters. Resistance to cytarabine has been associated with decreased expression of the human equilibrative nucleoside transporter 1 (hENT1) (Hubeek et al., 2005). An agent such as elacytarabine, active in low hENT1 expressing, cytarabine resistant acute myeloid leukemia (AML), could therefore improve clinical outcome in patients. Aims: To determine the efficacy and safety of elacytarabine given in combination with idarubicin to patients who have failed the first ”standard” induction course with a cytarabine based regimen, as well as to explore the relationship between the hENT1 status in AML cells and response. Methods: Study therapy consisted of one course elacytarabine 1000 mg/m2/d CIV on d1-5 administered in combination with idarubicin 12 mg/m2/d IV d1-3 in adult patients with AML who after a first cytarabine based induction course have not attained blast clearance (bone marrow (BM) >5 % blasts, circulating blasts, or chloroma etc). Assessment of response was at least 12d after induction start. Responding patients could receive the same course or elacytarabine 2000 mg/m2/d CIV on d1-5 d and then consolidation therapy with two courses of either elacytarabine monotherapy or combination with idarubicin as described above or could proceed to allogeneic SCT at any time point. The hENT1 expression level of BM blasts was analyzed by immunocytochemistry at time of initial AML diagnosis (pre-cytarabine course) and/or before elacytarabine treatment. The planned sample size is 50 evaluable patients, and with a target of 40% CR/CRi rate, the lower limit of the 90% confidence interval for the CR/CRi rate will be greater than 22% with at least 80% probability. The CR/CRi rate will be estimated and its corresponding two-sided 90% confidence interval will be provided. The significance of the association between the hENT1 expression level and response status will be assessed through a Chi-square test of hENT1 expression level (high, low) versus CR/CRi (yes, no). Results: In the ongoing study, 26 patients [16 male, 10 female, median age 61 years (range 18–71), ECOG PS 0–2] have been treated with elacytarabine and idarubicin. 23 patients have currently been response evaluated, and 11 attained a CR/CRi and 3 a PR (post one elacytarabine course). The most frequently reported related non-hematologic adverse events (AEs) CTCAE grade ≥ 3 were febrile neutropenia, infections/sepsis and increased liver function tests. 30 patients have been scored for hENT1 expression level at time of diagnosis. Preliminary results indicate that approximately 50 % of the patients hENT1 expression is low (defined as less than 10% of blasts stained). As to response, only approximately 1/3 of patients with low hENT1 blasts respond to cytarabine while for the high hENT1 2/3 respond. Three deaths occurred within 30 days after start of treatment and were all due to sepsis. All 3 patients had secondary leukemia. Summary/Conclusion: Elacytarabine administered at 1000 mg/m2/d CIV d1-5 in combination with idarubicin 12mg/m2/d IV d1-3 showed promising clinical activity with a CR/CRi rate of approximately 45 %. The adverse event profile, is as expected for cytarabine combination therapy. Preliminary data indicate that the assessment of hENT1 transporter expression in blasts could be used to select patients less likely to benefit from cytarabine and for whom elacytarabine could be an effective therapy. Disclosures: Gianelli-Borradori: Clavis Pharma: Employment. Flem Jacobsen:Clavis Pharma: Employment. Krug:MedA Pharma: Honoraria; Novartis: Honoraria; Alexion: Honoraria; Boehringer Ingelheim: Research Funding; Sunesis: Honoraria.

scholarly journals Clinical Role of microRNAs in Cytogenetically Normal Acute Myeloid Leukemia: miR-155 Upregulation Independently Identifies High-Risk Patients

2013 ◽  
Vol 31 (17) ◽  
pp. 2086-2093 ◽  
Author(s):  
Guido Marcucci ◽  
Kati S. Maharry ◽  
Klaus H. Metzeler ◽  
Stefano Volinia ◽  
Yue-Zhong Wu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Expression Profile ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Disease Free Survival ◽  
Microrna Expression ◽  
Risk Of Death ◽  
The Impact ◽  
Acute Myeloid

Purpose To evaluate the impact of miR-155 on the outcome of adults with cytogenetically normal (CN) acute myeloid leukemia (AML) in the context of other clinical and molecular prognosticators and to gain insight into the leukemogenic role of this microRNA. Patients and Methods We evaluated 363 patients with primary CN-AML. miR-155 levels were measured in pretreatment marrow and blood by NanoString nCounter assays that quantified the expression of the encoding gene MIR155HG. All molecular prognosticators were assessed centrally. miR-155–associated gene and microRNA expression profiles were derived using microarrays. Results Considering all patients, high miR-155 expression was associated with a lower complete remission (CR) rate (P < .001) and shorter disease-free survival (P = .001) and overall survival (OS; P < .001) after adjusting for age. In multivariable analyses, high miR-155 expression remained an independent predictor for a lower CR rate (P = .007) and shorter OS (P < .001). High miR-155 expressers had approximately 50% reduction in the odds of achieving CR and 60% increase in the risk of death compared with low miR-155 expressers. Although high miR-155 expression was not associated with a distinct microRNA expression profile, it was associated with a gene expression profile enriched for genes involved in cellular mechanisms deregulated in AML (eg, apoptosis, nuclear factor-κB activation, and inflammation), thereby supporting a pivotal and unique role of this microRNA in myeloid leukemogenesis. Conclusion miR-155 expression levels are associated with clinical outcome independently of other strong clinical and molecular predictors. The availability of emerging compounds with antagonistic activity to microRNAs in the clinic provides the opportunity for future therapeutic targeting of miR-155 in AML.

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