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Acute Myeloid Leukemia (AML)

Acute myeloid leukemia (AML) is a disease in which too many immature granulocytes (a type of white blood cell) are found in the blood and bone marrow. There are a number of subtypes of AML including acute myeloblastic leukemia, acute promyelocytic leukemia, acute monocytic leukemia, acute myelomonocytic leukemia, erythroleukemia, and acute megakaryoblastic leukemia.

(UK spelling: Leukaemia)

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Childhood AML
Molecular Genetics of AML

Information Patients and the Public (10 links)


Information for Health Professionals / Researchers (8 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Razmkhah F, Soleimani M, Mehrabani D, et al.
Leukemia microvesicles affect healthy hematopoietic stem cells.
Tumour Biol. 2017; 39(2):1010428317692234 [PubMed] Related Publications
Microvesicles are released by different cell types and shuttle mRNAs and microRNAs which have the possibility to transfer genetic information to a target cell and alter its function. Acute myeloid leukemia is a malignant disorder, and leukemic cells occupy all the bone marrow microenvironment. In this study, we investigate the effect of leukemia microvesicles on healthy umbilical cord blood hematopoietic stem cells to find evidence of cell information transferring. Leukemia microvesicles were isolated from acute myeloid leukemia patients and were co-incubated with healthy hematopoietic stem cells. After 7 days, cell count, hematopoietic stem cell-specific cluster of differentiation (CD) markers, colony-forming unit assay, and some microRNA gene expressions were assessed. Data showed a higher number of hematopoietic stem cells after being treated with leukemia microvesicles compared with control (treated with no microvesicles) and normal (treated with normal microvesicles) groups. Also, increased levels of microRNA-21 and microRNA-29a genes were observed in this group, while colony-forming ability was still maintained and high ranges of CD34(+), CD34(+)CD38(-), CD90(+), and CD117(+) phenotypes were observed as stemness signs. Our results suggest that leukemia microvesicles are able to induce some effects on healthy hematopoietic stem cells such as promoting cell survival and some microRNAs deregulation, while stemness is maintained.

Flower A, Cairo MS
The evolution of allogeneic stem cell transplant for children and adolescents with acute myeloid leukemia.
Clin Adv Hematol Oncol. 2017; 15(1):52-62 [PubMed] Related Publications
Survival rates in subsets of pediatric patients who have acute myeloid leukemia (AML) with favorable risk features are now greater than 90%. However, outcomes for patients with high-risk (HR) features remain unacceptably poor. As novel technologies for the identification of HR biomarkers and the detection of residual disease are developed, risk stratification and the application of allogeneic hematopoietic stem cell transplant (HSCT) are evolving. HSCT has been shown to benefit subpopulations of pediatric patients with AML, including those with HR cytogenetic translocations, genetic mutations, and/or residual disease after induction. Targeted therapies have shown promise for improving outcomes, and their integration into standard therapy and HSCT regimens is a critical area of interest. Also, expansion of the donor pool has led to the successful use of alternative donor sources for those patients without a matched sibling. However, transplant-related morbidity and mortality and late effects are major limiting factors. Reduced-intensity conditioning regimens have resulted in outcomes equivalent to those achieved with myeloablative regimens among patients in complete remission. The limitation of transplant-related morbidity and mortality through reduced-intensity conditioning and supportive care, and improved survival through optimal alloreactivity in combination with targeted therapy, are steps toward advancing outcomes for pediatric patients who have AML with HR features.

Lim JW, Yeap FS, Chan YH, et al.
Second Malignant Neoplasms in Childhood Cancer Survivors Treated in a Tertiary Paediatric Oncology Centre.
Ann Acad Med Singapore. 2017; 46(1):11-19 [PubMed] Related Publications
Introduction: One of the most feared complications of childhood cancer treatment is second malignant neoplasms (SMNs). This study evaluates the incidence, risk factors and outcomes of SMNs in a tertiary paediatric oncology centre in Singapore. Materials and Methods: A retrospective review was conducted on patients diagnosed with childhood cancer under age 21 and treated at the National University Hospital, Singapore, from January 1990 to 15 April 2012. Case records of patients with SMNs were reviewed. Results: We identified 1124 cases of childhood cancers with a median follow-up of 3.49 (0 to 24.06) years. The most common primary malignancies were leukaemia (47.1%), central nervous system tumours (11.7%) and lymphoma (9.8%). Fifteen cases developed SMNs, most commonly acute myeloid leukaemia/myelodysplastic syndrome (n = 7). Median interval between the first and second malignancy was 3.41 (0.24 to 18.30) years. Overall 20-year cumulative incidence of SMNs was 5.3% (95% CI, 0.2% to 10.4%). The 15-year cumulative incidence of SMNs following acute lymphoblastic leukaemia was 4.4% (95% CI, 0% to 8.9%), significantly lower than the risk after osteosarcoma of 14.2% (95% CI, 0.7% to 27.7%) within 5 years (P <0.0005). Overall 5-year survival for SMNs was lower than that of primary malignancies. Conclusion: This study identified factors explaining the epidemiology of SMNs described, and found topoisomerase II inhibitor use to be a likely risk factor in our cohort. Modifications have already been made to our existing therapeutic protocols in osteosarcoma treatment. We also recognised the importance of other risk management strategies, including regular long-term surveillance and early intervention for detected SMNs, to improve outcomes of high risk patients.

Tamamyan G, Kadia T, Ravandi F, et al.
Frontline treatment of acute myeloid leukemia in adults.
Crit Rev Oncol Hematol. 2017; 110:20-34 [PubMed] Related Publications
Recent years have highlighted significant progress in understanding the underlying genetic and epigenetic signatures of acute myeloid leukemia(AML). Most importantly, novel chemotherapy and targeted strategies have led to improved outcomes in selected genetic subsets. AML is a remarkably heterogeneous disease, and individualized therapies for disease-specific characteristics (considering patients' age, cytogenetics, and mutations) could yield better outcomes. Compared with the historical 5-to 10-year survival rate of 10%, the survival of patients who undergo modern treatment approaches reaches up to 40-50%, and for specific subsets, the improvements are even more dramatic; for example, in acute promyelocytic leukemia, the use of all-trans retinoic acid and arsenic trioxide improved survival from 30 to 40% up to 80 to 90%. Similar progress has been documented in core-binding-factor-AML, with an increase in survival from 30% to 80% upon the use of high-dose cytarabine/fludarabine/granulocyte colony-stimulating factor combination regimens. AML treatment was also recently influenced by the discovery of the superiority of regimens with higher dose Ara-C and nucleoside analogues compared with the "7+3"regimen, with about a 20% improvement in overall survival. Despite these significant differences, most centers continue to use the "7+3" regimen, and greater awareness will improve the outcome. The discovery of targetable molecular abnormalities and recent studies of targeted therapies (gemtuzumab ozagomycin, FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and epigenetic therapies), future use of checkpoint inhibitors and other immune therapies such as chimeric antigen receptor T-cells, and maintenance strategies based on the minimal residual disease evaluation represent novel, exciting clinical leads aimed to improve AML outcomes in the near future.

Yang Z, Kuang B, Kang N, et al.
Synthesis and anti-acute myeloid leukemia activity of C-14 modified parthenolide derivatives.
Eur J Med Chem. 2017; 127:296-304 [PubMed] Related Publications
Parthenolide (PTL) selectively ablates leukemia stem cells (LSCs). A series of PTL derivatives with modifications on C-14 of PTL was synthesized, and most of the derivatives showed high activities against HL-60 and KG1a. The most potent compound 6j exhibited IC50 values of 0.4 μM and 1.1 μM against KG1a and HL-60, respectively, which were 8.7 and 3.8 folds more potent than those of PTL, respectively. Moreover, compound 6j showed relatively low toxicity to normal cells (IC50 = 12.3 μM) comparing with its high anti-AML activity. The selectivity indexes for AML cells KG1a and HL-60 were 30.8 and 11.2, respectively. Preliminary study revealed that compound 6j could induce apoptosis of KG1a cells.

Konuma T, Kondo T, Yamashita T, et al.
Outcome of allogeneic hematopoietic stem cell transplantation in adult patients with acute myeloid leukemia harboring trisomy 8.
Ann Hematol. 2017; 96(3):469-478 [PubMed] Related Publications
Trisomy 8 (+8) is one of the most common cytogenetic abnormalities in adult patients with acute myeloid leukemia (AML). However, the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in adult patients with AML harboring +8 remains unclear. To evaluate, the outcome and prognostic factors in patients with AML harboring +8 as the only chromosomal abnormality or in association with other abnormalities, we retrospectively analyzed the Japanese registration data of 631 adult patients with AML harboring +8 treated with allogeneic HSCT between 1990 and 2013. In total, 388 (61%) patients were not in remission at the time of HSCT. With a median follow-up of 38.5 months, the probability of overall survival and the cumulative incidence of relapse at 3 years were 40 and 34%, respectively. In the multivariate analysis, two or more additional cytogenetic abnormalities and not being in remission at the time of HSCT were significantly associated with a higher overall mortality and relapse. Nevertheless, no significant impact on the outcome was observed in cases with one cytogenetic abnormality in addition to +8. Although more than 60% of the patients received HSCT when not in remission, allogeneic HSCT offered a curative option for adult patients with AML harboring +8.

Paubelle E, Ducastelle-Leprêtre S, Labussière-Wallet H, et al.
Fractionated gemtuzumab ozogamicin combined with intermediate-dose cytarabine and daunorubicin as salvage therapy in very high-risk AML patients: a bridge to reduced intensity conditioning transplant?
Ann Hematol. 2017; 96(3):363-371 [PubMed] Related Publications
Outcome of patients with primary refractory/relapsed (R/R) acute myeloid leukemia (AML) remains dismal. Herein, we present a retrospective monocentric study of 24 very high-risk AML patients who received a combination of fractionated gemtuzumab ozogamicin (GO) with intermediate-dose cytarabine and daunorubicin as salvage therapy. Median age was 55.3 years. Diagnostic was secondary AML for 33% of them. Seven patients had favorable risk, 8 had intermediate-1 or intermediate-2, and 6 had unfavorable risk of AML according to the European LeukemiaNet prognostic index. Complete remission was achieved in 50% of cases (46% in refractory and 55% in relapsed AML) without excessive toxicity. Thirteen patients could be referred for transplant. Only allogeneic hematopoietic stem cell transplantation provided a benefit in this patient cohort with a 1-year overall survival of 50.7 versus 18.1% in the absence of transplantation. Patients treated with reduced intensity conditioning (RIC) showed a longer survival as compared to those undergoing myeloablative conditioning regimen mainly because of decreased toxicity.Our data suggest that salvage therapy with fractionated GO combined with intermediate-dose cytarabine and daunorubicin in very high-risk patients may serve as a potential bridge therapy to RIC transplant.

Ebrahim EK, Assem MM, Amin AI, et al.
FLT3 Internal Tandem Duplication Mutation, cMPL and CD34 Expressions Predict Low Survival in Acute Myeloid Leukemia Patients.
Ann Clin Lab Sci. 2016; 46(6):592-600 [PubMed] Related Publications
OBJECTIVES: To detect FMS-like tyrosine kinase-3 internal tandem duplicate (FLT3 ITD) mutation, Myeloproliferative leukemia virus oncogene (cMPL) and Ephrin A 4 receptor (EphA4) expressions in Acute myeloid leukemia (AML) and their correlation to patient's clinicopathological characteristics and survival.
METHODS: RNA was extracted from blood samples of 58 AML patients (39 adults and 19 children) and 20 age and sex matched controls. FLT3 ITD mutation, cMPL and EphA4 expression was studied using RT-PCR and correlated to the clinical and survival data of the patients.
RESULTS: FLT3 ITD mutation, cMPL and EphA4 expression was positive in 35.9%, 76.9% and 56.4% of adult AML patients respectively and in 15.8%, 47.4% and 36.8% of pediatric AML patients respectively. 76.9% of adult and 89.5% of pediatric patients expressed CD33. 64.1 % of adults and 42.1% of children expressed CD34. CD34 expression was significantly associated with both FLT3 ITD mutation and cMPL expression. CD34, FLT3 and cMPL negative cases have significantly higher overall survival than positive cases.
CONCLUSION: CD34 expression is significantly associated with both FLT3 ITD mutation and cMPL expression which could be used as a marker for low survival. Normal FLT3 and negative expression of CD34 and cMPL may predict a longer overall survival. Further studies are needed to investigate the mechanism that may correlate CD34 to both markers.

Welch JS, Petti AA, Miller CA, et al.
TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.
N Engl J Med. 2016; 375(21):2023-2036 [PubMed] Article available free on PMC after 24/05/2017 Related Publications
Background The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. Methods We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. Results Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. Conclusions Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).

Sousa DC, Rodrigues FB, Duarte G, et al.
Anterior ischemic optic neuropathy and hematologic malignancy: a systematic review of case reports and case series.
Can J Ophthalmol. 2016; 51(6):459-466 [PubMed] Related Publications
OBJECTIVE: Demographic and clinical characteristics associated with nonarteritic anterior ischemic optic neuropathy (NAION) are well described. Patients with hematologic neoplasms may share some of these characteristics, and it may be useful clinically to better understand this set of patients. Our objective is to review systematically the characteristics of patients with both hematologic malignancies and NAION.
DESIGN: Systematic review.
PARTICIPANTS: Patients with NAION diagnosis related in time to a hematologic neoplasm.
METHODS: Data sources for the study included MEDLINE, Web of Science, LILACS, SciELO, and OpenGrey. The study eligibility criteria included case reports and case series.
RESULTS: We found 261 records, with 15 studies included plus our case report. A total of 19 patients (8 female) with mean age of 54.6 years (range, 12-87) were analyzed: 37% (7) non-Hodgkin lymphoma; 26% (5) myeloproliferative neoplasms; 21% (4) myelodysplasia; 16% (3) leukemias. The limitations included verification bias, inability to test statistical association between NAION and hematologic neoplasms, the small number of cases, and confounding factors related to medical history and specific interventions in each case limited the robustness of our conclusions.
CONCLUSIONS: Our results identified the characteristics of patients with NAION and hematologic neoplasms related in time. Additional observational studies may enlighten the importance of looking for evidence of an occult neoplastic disorder in patients presenting with NAION. A prompt diagnosis would be of invaluable significance for the best management, in terms of follow-up and therapeutics.

Perner F, Schnöder TM, Fischer T, Heidel FH
Kinomics Screening Identifies Aberrant Phosphorylation of CDC25C in FLT3-ITD-positive AML.
Anticancer Res. 2016; 36(12):6249-6258 [PubMed] Related Publications
BACKGROUND/AIM: The presence of FLT3-Internal tandem duplications (ITDs) in human acute myeloid leukemia (AML) is associated with a dismal prognosis. Altered cell-cycle activity has been reported in FLT3-ITD-positive AML; however, the mechanisms by which this oncogene influences cell-cycle activity remained so far elusive.
MATERIALS AND METHODS: A phospho-kinomic screen was used to identify downstream effectors of FLT3-ITD. Validation and functional characterization was performed by western blotting, cell-cycle analysis and apoptosis assays.
RESULTS: We identified aberrant phosphorylation of CDC25C-T48 in FLT3-ITD mutated cells. Forced expression of CDC25C affected cell-cycle progression but did not affect sensitivity to cellular stress.
CONCLUSION: Depending on the oncogenic background, CDC25C may reveal protective or oncogenic functions. Our results identify CDC25C as a downstream target of the mutated tyrosine kinase FLT3-ITD affecting cell-cycle regulation in a model of AML.

Shi J, Fu H, Jia Z, et al.
High Expression of CPT1A Predicts Adverse Outcomes: A Potential Therapeutic Target for Acute Myeloid Leukemia.
EBioMedicine. 2016; 14:55-64 [PubMed] Article available free on PMC after 24/05/2017 Related Publications
Carnitine palmitoyl transferase 1A (CPT1A) protein catalyzes the rate-limiting step of Fatty-acid oxidation (FAO) pathway, which can promote cell proliferation and suppress apoptosis. Targeting CPT1A has shown remarkable anti-leukemia activity. But, its prognostic value remains unclear in Acute Myeloid Leukemia (AML). In two independent cohorts of cytogenetically normal AML (CN-AML) patients, compared to low expression of CPT1A (CPT1A(low)), high expression of CPT1A (CPT1A(high)) was significantly associated with adverse outcomes, which was also shown in European Leukemia Network (ELN) Intermediate-I category. Multivariable analyses adjusting for known factors confirmed CPT1A(high) as a high risk factor. Significant associations between CPT1A(high) and adverse outcomes were further validated whether for all AML patients (OS: P=0.008; EFS: P=0.002, n=334, no M3) or for National Comprehensive Cancer Network (NCCN) Intermediate-Risk subgroup (OS: P=0.021, EFS: P=0.024, n=173). Multiple omics analysis revealed aberrant alterations of genomics and epigenetics were significantly associated with CPT1A expression, including up- and down-regulation of oncogenes and tumor suppressor, activation and inhibition of leukemic (AML, CML) and immune activation pathways, hypermethylation enrichments on CpG island and gene promoter regions. Combined with the previously reported anti-leukemia activity of CPT1A's inhibitor, our results proved CPT1A as a potential prognosticator and therapeutic target for AML.

Holtick U, Herling M, Pflug N, et al.
Similar outcome after allogeneic stem cell transplantation with a modified FLAMSA conditioning protocol substituting 4 Gy TBI with treosulfan in an elderly population with high-risk AML.
Ann Hematol. 2017; 96(3):479-487 [PubMed] Related Publications
The fludarabine, amsacrine, and cytarabine (FLAMSA)-reduced-intensity conditioning (RIC) protocol has been described to be effective in patients with high-risk and refractory acute myeloic leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (aSCT). To increase safety and tolerability of the conditioning, we previously reported the feasibility to substitute the TBI component by treosulfan in elderly AML patients. We now present long-term follow-up data on patients treated with FLAMSA/treosulfan compared to the original FLAMSA/4Gy TBI protocol. We retrospectively analyzed 130 consecutive patients with high-risk or relapsed AML after aSCT following FLAMSA conditioning at our center. Fifty-eight patients were treated with FLAMSA/treosulfan due to age and/or comorbidities. Seventy-two patients were treated with FLAMSA/TBI. Median age of patients treated with FLAMSA/treosulfan was 60 years compared to 46 years in those treated with FLAMSA/TBI. The cumulative incidence of a non-relapse mortality at 4 years was 28% in FLAMSA/treosulfan patients as compared to 13% in FLAMSA/TBI. Cumulative incidence of relapse was higher in patients treated with FLAMSA/TBI (46 vs. 32%). This difference was even more prominent for patients treated in blast persistence prior to transplant (relapse incidence 70% for TBI vs. 35% for treosulfan). The overall and relapse-free survival rates at 4 years were 47 and 41%, respectively, for patients treated with FLAMSA/TBI as compared to 43 and 40% in patients treated with FLAMSA/treosulfan. These data indicate an anti-leukemic activity by FLAMSA/treosulfan especially in patients with a blast persistence prior to transplant. Older age was an independent factor for a higher non-relapse mortality. Translating FLAMSA/treosulfan to younger patients, a lower non-relapse mortality, and an improved anti-leukemic activity might add up to improved overall survival. Randomized studies are required to demonstrate an improved efficacy of treosulfan- versus TBI-based FLAMSA conditioning.

Guenounou S, Borel C, Bérard E, et al.
Prognostic impact of viral reactivations in acute myeloid leukemia patients undergoing allogeneic stem cell transplantation in first complete response.
Medicine (Baltimore). 2016; 95(48):e5356 [PubMed] Article available free on PMC after 24/05/2017 Related Publications
Cytomegalovirus (CMV) serological status of donor and recipient as well as CMV reactivation have been associated with a lower risk of relapse in acute myeloid leukemia (AML) patients after allogeneic stem cell transplantation (alloSCT). Since immunosuppression following transplant allows resurgence of many other viruses, we retrospectively evaluated the impact of viral reactivations on relapse and survival in a cohort of 136 AML patients undergoing alloSCT in first remission from sibling (68%) or unrelated (32%) donors. Myeloablative and reduced-intensity conditioning regimen were given to 71 and 65 patients, respectively. Including CMV reactivations, at least 1 viral reactivation was recorded in 76 patients. Viral reactivations were associated with a lower risk of relapse (adjusted HR 0.14; 95% CI 0.07-0.30; P < 0.01), better disease-free survival (aHR 0.29; 95% CI 0.16-0.54; P < 0.01) but higher non relapse mortality. This translated into a better overall survival (aHR 0.44; 95%CI 0.25-0.77; P < 0.01) in patients who experienced viral reactivation. Thus, viral reactivations, including but not limited to CMV reactivation, are associated with a better outcome particularly with regard to the risk of relapse in AML patients undergoing alloSCT. New guidelines regarding the choice of donor according to the CMV serostatus are needed.

Park H, Chung H, Lee J, et al.
Decitabine as a First-Line Treatment for Older Adults Newly Diagnosed with Acute Myeloid Leukemia.
Yonsei Med J. 2017; 58(1):35-42 [PubMed] Article available free on PMC after 24/05/2017 Related Publications
PURPOSE: Decitabine, a DNA hypomethylating agent, was recently approved for use in Korea for older adults with acute myeloid leukemia (AML) who are not candidates for standard chemotherapy. This study aimed to evaluate the role of decitabine as a first-line treatment for older adults with AML.
MATERIALS AND METHODS: Twenty-four patients with AML who received at least one course of decitabine (20 mg/m²/d intravenously for 5 days every 4 weeks) as a first-line therapy at Severance Hospital were evaluated retrospectively.
RESULTS: The median age of the patients was 73.5 years. The longest follow-up duration was 502 days. A total of 113 cycles of treatment were given to 24 patients, and the median number of cycles was four (range, 1-14). Thirteen patients dropped out because of death, no or loss of response, patient refusal, or transfer to another hospital. Twenty-one (87.5%) and 12 (50%) patients completed the second and fourth cycles, respectively, and responses to treatment were evaluated in 17. A complete response (CR) or CR with incomplete blood-count recovery was achieved in six (35.3%) patients, and the estimated median overall survival was 502 days. Ten patients developed grade >2 hematologic or non-hematologic toxicities. In univariate analysis, bone marrow blasts, lactate dehydrogenase, serum ferritin level, and bone marrow iron were significantly associated with response to decitabine.
CONCLUSION: Five-day decitabine treatment showed acceptable efficacy in older patients with AML who are unfit for conventional chemotherapy, with a CR rate 35.3% and about a median overall survival of 18 months.

Stefanski M, Jamis-Dow C, Bayerl M, et al.
Chest radiographic and CT findings in hyperleukocytic acute myeloid leukemia: A retrospective cohort study of 73 patients.
Medicine (Baltimore). 2016; 95(44):e5285 [PubMed] Related Publications
Hyperleukocytic acute myeloid leukemia (AML) is associated with pulmonary complications and high early mortality rate, but given its rarity, data on chest radiographic presentation are scarce.We retrospectively reviewed the charts of 73 AML patients admitted with white blood cell count >100 × 10/L between 2003 and 2014 in order to describe the chest radiographic and computed tomography (CT) findings and to correlate them with AML subtype and respiratory symptoms.Forty-two of the 73 patients (58%) overall and 36 of the 54 patients (67%) with clinical signs of pulmonary leukostasis had abnormal radiographs on admission. The presence of radiographic abnormalities was significantly associated with dyspnea and oxygen/ventilatory support requirements (P < 0.01) and with day 28 mortality (45% vs 13%, P = 0.005) but not with monocytic subtype of AML. Sixteen patients had isolated focal basilar airspace opacities, unilateral (n = 13) or bilateral (n = 3), while 16 patients had bilateral diffuse opacities, interstitial (n = 12) or airspace and interstitial (n = 4). Two patients had isolated pleural effusion, 2 patients had unilateral midlung airspace opacities, and 6 patients had a combination of focal airspace and diffuse interstitial opacities. Overall, 2 patterns accounted for 75% of abnormal findings: bilateral diffuse opacities tended to be associated with monocytic AML, whereas basilar focal airspace opacities were more frequent in nonmonocytic AML (P < 0.05). Eighteen patients had CT scans, revealing interlobular septal thickening (n = 12), airspace (n = 11) and ground-glass (n = 9) opacities, pleural effusions (n = 12), and acute pulmonary embolism (n = 2).Hyperleukocytic AML is frequently associated with abnormal chest radiographs, involving mostly focal basilar airspace opacities (more frequent in nonmonocytic AML) or diffuse bilateral opacities. CT scan should be considered broadly due to the suboptimal resolution of radiographs for detecting signs of leukostasis.

Inamura J, Ikuta K, Tsukada N, et al.
Acute Promyelocytic Leukemia with i(17)(q10).
Intern Med. 2016; 55(22):3341-3345 [PubMed] Article available free on PMC after 24/05/2017 Related Publications
We herein report a rare chromosomal abnormality observed in an acute promyelocytic leukemia (APL) patient. She had several APL derivative clones including a clone with i(17)(q10) abnormality, which consists of two kinds of structural abnormalities, a cryptic translocation of t(15;17) and an isochromosome of 17q. Although an obvious microscopic t(15;17) change was not observed on either arms of the isochromosome, PML/RARα fusion signals were detected on an interphase fluorescence in situ hybridization analysis. By several cytogenetic analyses of her bone marrow cells, it was confirmed that the i(17)(q10) clone was derived from the classic t(15;17) clone via another intervening clone, cryptic t(15;17).

Yamasaki S, Hirakawa A, Aoki J, et al.
Role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation in older patients with de novo acute myeloid leukemia.
Ann Hematol. 2017; 96(2):289-297 [PubMed] Related Publications
Reduced-intensity conditioning (RIC) regimens extend the therapeutic use of allogeneic hematopoietic cell transplantation (HCT) to older patients. The survival trend in 2325 patients aged >50 years presenting with de novo acute myeloid leukemia (AML) who underwent first reduced-intensity HCT (RIC-HCT) was assessed by retrospectively analyzing outcomes between 2000 and 2013. The annual number of RIC-HCTs in Japan was higher in the 2008-2013 period (n = 205/year [1229/6 years]) than in the 2000-2007 period (n = 137/year [1096/8 years]). Overall and disease-free survival were higher in the 2008-2013 period (P < 0.001) because of the improvement in transplant-related mortality (TRM). Survival regarding RIC-HCT for AML has improved over time, with an increased number of RIC-HCTs in patients with a Karnofsky performance status (KPS) ≥80. However, TRM remains high and the relapse rate has not improved over time. Multivariate analyses showed that a KPS ≥80 and complete remission at HCT were associated with less TRM and relapse, and better survival regardless of age ≥65 years. Accurate timing and prospective identification of patients at risk of TRM may aid the development of risk-adapted strategies for RIC-HCT in AML patients regardless of age.

Lee JS, Cheong HS, Koh Y, et al.
MCM7 polymorphisms associated with the AML relapse and overall survival.
Ann Hematol. 2017; 96(1):93-98 [PubMed] Related Publications
The minichromosome maintenance complex component 7 (MCM7) encodes a member of MCM complex, which plays a critical role in the initiation of gene replication. Due to the importance of MCM complex, MCM7 gene has been regarded as a candidate gene for cancer development. In the present study, seven MCM7 polymorphisms were genotyped in 344 subjects composed of 103 acute myeloid leukemia (AML) patients and 241 normal controls to examine the possible associations between MCM7 polymorphisms and the risk of AML. MCM7 polymorphisms were not associated with the risk of AML (P > 0.05). However, MCM7 polymorphisms were significantly related to the relapse of AML and overall survival. The rs2070215 (N144S) showed a protective effect to the risk of AML relapse (OR = 0.37; P (corr) = 0.02). In haplotype analyses, the ht1 and ht2 showed significant associations with the risk of AML relapse (P (corr) = 0.02-0.03). In addition, rs1534309 showed an association with the overall survival of AML patients. Patients with major homozygote genotype (CC) of rs1534309 showed a higher survival rate than the patients with other genotypes (CG and GG). The results of the present study indicate that MCM7 polymorphisms may be able to predict the prognosis of AML patients.

Keighley CL, Manii P, Larsen SR, van Hal S
Clinical effectiveness of itraconazole as antifungal prophylaxis in AML patients undergoing intensive chemotherapy in the modern era.
Eur J Clin Microbiol Infect Dis. 2017; 36(2):213-217 [PubMed] Related Publications
Antifungal prophylaxis regimens vary between centres, informed by local epidemiology and antifungal stewardship practices. The advantages of itraconazole over posaconazole prophylaxis include maintaining the utility of azole therapy for suspected breakthrough invasive fungal infection (bIFI). We examined the effectiveness and tolerability of itraconazole as prophylaxis in acute myeloid leukaemia (AML) patients. We sought to determine the rate of probable and proven bIFI in the context of itraconazole prophylaxis in a real-life setting. Eighty-four patients corresponded to 175 episodes of primary antifungal prophylaxis with itraconazole solution (200 mg twice daily) as prophylaxis supported by a dedicated clinical pharmacist during induction, re-induction and consolidation chemotherapy for AML between January 2010 and January 2014. Assessment of clinical course included blinded review of all radiology scans. Episodes of bIFI were categorised according to consensus criteria. A low rate of bIFI (6/175, 3.4 %) occurred with the use of itraconazole. Tolerance was excellent with adverse events consisting predominantly of deranged liver function tests reported in 7/175 (4 %). Therapeutic drug monitoring performed at clinicians' discretion demonstrated appropriate levels in 12/14 (86 %). Persisting fever and suspicion of invasive fungal infection (IFI) led to empiric antifungal therapy with voriconazole or caspofungin in 33/175 episodes (19 %), ceased after a median of 5 days following investigation in 16/175 (9 %). In this setting, itraconazole is effective and well-tolerated as prophylaxis. An additional benefit was seen in empiric therapy of suspected bIFI with amphotericin formulations kept in reserve. Local epidemiology is vital in guiding prophylaxis strategy.

Tenti E, Papayannidis C, Marconi G, et al.
Efficacy of Azacitidine in the treatment of adult patients aged 65 years or older with AML.
Expert Opin Pharmacother. 2016; 17(18):2479-2486 [PubMed] Related Publications
INTRODUCTION: Therapy for acute myeloid leukemia (AML) in elderly populations (>65 years) is still a challenge for scientists and hematologists worldwide, and represents an urgent medical need. Notably, the identification and the recognition of molecular and epigenetic mechanisms involved in the pathogenesis of such a heterogeneous disease, are providing new tools for a more successful and 'targeted' approach. Azacitidine is a hypomethylating agent (HMA) with relevant activity in patients affected by myelodysplastic syndrome (MDS) and AML with low blast cells percentage (>30%), in terms of reduction of transfusion dependence, and improvement of quality of life. Areas covered: This review summarizes the mechanism of action, safety profile and efficacy of azacitidine in the field of elderly AML populations, providing up-to-date references on this subset of high-risk patients. Expert opinion: HMAs are the first successful treatment for elderly patients with high-risk MDS and are effective for some AML subtypes. Translational studies based on gene expression profiling and molecular sequencing, would be able to identify, in the near future, patients with a favorable profile of response to these compounds suggesting new potential treatment combinations also.

Schlenk RF, Lübbert M, Benner A, et al.
All-trans retinoic acid as adjunct to intensive treatment in younger adult patients with acute myeloid leukemia: results of the randomized AMLSG 07-04 study.
Ann Hematol. 2016; 95(12):1931-1942 [PubMed] Article available free on PMC after 24/05/2017 Related Publications
The aim of this clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with chemotherapy and to assess the NPM1 status as biomarker for ATRA therapy in younger adult patients (18-60 years) with acute myeloid leukemia (AML). Patients were randomized for intensive chemotherapy with or without open-label ATRA (45 mg/m(2), days 6-8; 15 mg/m(2), days 9-21). Two cycles of induction therapy were followed by risk-adapted consolidation with high-dose cytarabine or allogeneic hematopoietic cell transplantation. Due to the open label character of the study, analysis was performed on an intention-to-treat (ITT) and a per-protocol (PP) basis. One thousand one hundred patients were randomized (556, STANDARD; 544, ATRA) with 38 patients treated vice versa. Median follow-up for survival was 5.2 years. ITT analyses revealed no difference between ATRA and STANDARD for the total cohort and for the subset of NPM1-mutated AML with respect to event-free (EFS; p = 0.93, p = 0.17) and overall survival (OS; p = 0.24 and p = 0.32, respectively). Pre-specified PP analyses revealed better EFS in NPM1-mutated AML (p = 0.05) and better OS in the total cohort (p = 0.03). Explorative subgroup analyses on an ITT basis revealed better OS (p = 0.05) in ATRA for genetic low-risk patients according to ELN recommendations. The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2004-004321-95).

Cattaneo C, Zappasodi P, Mancini V, et al.
Emerging resistant bacteria strains in bloodstream infections of acute leukaemia patients: results of a prospective study by the Rete Ematologica Lombarda (Rel).
Ann Hematol. 2016; 95(12):1955-1963 [PubMed] Related Publications
Multiresistant bacterial infections are a potentially life-threatening condition in acute leukaemia (AL) patients. We aimed to better define the very recent epidemiology and outcome of bloodstream infections (BSIs) in a real-life setting. We prospectively collected all consecutive febrile/infectious episodes occurring in AL patients admitted to 9 haematology units. In 293 AL patients, 433 BSIs were diagnosed. Gram-positive (GP) bacteria were isolated in 44.8 % BSI and Gram-negative (GN) in 38.3 %, while polymicrobial aetiology- or fungi-related events were identified in 15.7 and 1.1 % of the cases, respectively. GP was observed more frequently in patients not in complete remission (p = 0.04), while GN during consolidation cycles (p = 0.003). Extended spectrum β-lactamase-producing strains accounted for 23.2 % of enterobacteria. They were associated with previous antibiotic exposure, including fluoroquinolones prophylaxis (p = 0.01). Carbapenem-resistant (CR) strains occurred in 9 % of enterobacteria. Among Pseudomonas aeruginosa strains, 21.6 % were multiresistant. Overall 30-day mortality was 8.5 %. CR GN and multiresistant P. aeruginosa BSIs were independent predictors of death (p = 0.002), as well as relapsed/resistant AL (18.3 %; p = 0.0002) and the presence of pulmonary infiltrates (26.6 %; p < 0.001). Although GP still predominate over GN BSI, the percentage of antibiotic resistant GN strains is considerable in AL patients and it is associated with poor prognosis.

Juncà J, Garcia O, Garcia-Caro M, et al.
CD34 expression and the outcome of nucleophosmin 1-mutated acute myeloid leukemia.
Ann Hematol. 2016; 95(12):1949-1954 [PubMed] Related Publications
CD34 positivity has been considered as an adverse prognostic factor in acute myeloid leukemia (AML). Although nucleophosmin 1-mutated (NPM1m) AML is usually CD34 negative, this marker may be expressed at diagnosis or acquired at relapse in a variable number of cases. Our objective was to ascertain if CD34 expression has any influence on the general outcome of this form of acute leukemia. Analysis of clinical outcome (complete remissions, relapses, disease-free survival, and overall survival) was performed depending on the degree of expression of CD34 determined by flow cytometry, in 67 adult patients with NPM1m AML. CD34 expression did not have any influence on the variables analyzed whatever the percentage of blasts expressing this marker. In contrast to other forms of AML, CD34 expression is not an unfavorable prognostic factor in NPM1m AML, neither at diagnosis nor at relapse.

Refaei M, Fernandes B, Brandwein J, et al.
Incidence of catheter-related thrombosis in acute leukemia patients: a comparative, retrospective study of the safety of peripherally inserted vs. centrally inserted central venous catheters.
Ann Hematol. 2016; 95(12):2057-2064 [PubMed] Related Publications
Central venous catheters are a leading cause of upper-extremity deep vein thrombosis. Concomitant severe thrombocytopenia makes anticoagulation for catheter-related thrombosis (CRT) in patients with acute leukemia (AL) a challenge. Incidence of CRT has been reported to be increased in those with peripherally inserted central catheters (PICC) vs. those with centrally inserted ones (CICC). Our objective is to compare the incidence rate of CRT in leukemia inpatients who received either a PICC vs. CICC. We retrospectively reviewed adult inpatients admitted to hematology wards with a new diagnosis of AL and who received either a PICC or a CICC. Baseline patient and catheter characteristics were recorded. Our primary outcome was the incidence rate of CRT in each group. The secondary outcomes included rates of infectious and mechanical complications. Six hundred sixty-three patients received at least one PICC (338) or CICC (325) insertion. A total of 1331 insertions were recorded, with 82 (11.7 %) and 41 (6.5 %) CRT in the PICC and CICC groups, respectively. The incidence rates were 1.89 and 0.52 per 1000 catheter day in the PICC and CICC groups, respectively. A PICC, when compared to CICC, was a significant risk factor for CRT (sHR 2.5, p < 0.0001). The prevalence and incidence rates of CRT in our AL patients were higher than predicted for a general cancer patient population. These rates were higher in the PICC group compared to the CICC group. We recommend careful consideration of thrombotic and bleeding risks of AL inpatients when choosing a central venous catheter.

Portich JP, Gil MS, Dos Santos RP, et al.
Low brain-derived neurotrophic factor levels are associated with active disease and poor prognosis in childhood acute leukemia.
Cancer Biomark. 2016; 17(3):347-352 [PubMed] Related Publications
BACKGROUND: Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related receptor kinase B (TrkB) are involved in the maturation of B lymphocytes in the bone marrow (BM), promote cell differentiation in B-cell malignancies, and are associated with poor prognosis in adults with acute leukemia (AL). However, the role of BDNF in pediatric AL remains poorly understood.
OBJECTIVE: We carried out a cohort observational study to evaluate BDNF levels in BM or peripheral blood (PB) samples from children with AL.
METHODS: BM or PB samples were collected from 57 children and adolescents with acute lymphoid leukemia (ALL), 14 children and adolescents with acute myeloid leukemia (AML), and 44 healthy individuals (HI) of the same age range.
RESULTS: BDNF levels at diagnosis in AL patients were significantly lower when compared to HI. Samples from patients in complete remission from disease had higher levels of BDNF compared to those obtained from patients with malignant cells. Moreover, BDNF levels at diagnosis in patients who died were significantly lower compared to those found in survivors.
CONCLUSIONS: These findings provide the first evidence for a possible role of BDNF as a marker of active disease and poor prognosis in pediatric AL.

Karas M, Steinerova K, Lysak D, et al.
Pre-transplant Quantitative Determination of NPM1 Mutation Significantly Predicts Outcome of AIlogeneic Hematopoietic Stem Cell Transplantation in Patients with Normal Karyotype AML in Complete Remission.
Anticancer Res. 2016; 36(10):5487-5498 [PubMed] Related Publications
BACKGROUND/AIM: Minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) before allogeneic hematopoietic stem cell transplantation (alloHSCT) can influence the results of therapy. With the aim of evaluating the potential role of pre-transplant MRD, we studied the impact of pre-transplant MRD level on the outcome of alloHSCT in patients with AML in complete remission (CR).
PATIENTS AND METHODS: From 2/2005 to 9/2014, 60 patients with a median age of 54 years (range=30-66 years) with normal karyotype-AML harboring nucleophosmin 1 (NPM1) mutation [53% Fms-related tyrosine kinase receptor 3 internal tandem duplication (FLT3/ITD)-positive] in first (n=45) or second (n=15) CR underwent myeloablative (n=16) or reduced-intensity (n=44) alloHSCT (27% related, 73% unrelated). The MRD level was determined from bone marrow samples using real-time polymerase chain reaction for detection of NPM1 mutations before starting the conditioning regimen.
RESULTS: The estimated probabilities of 3-year relapse, event-free survival (EFS) and overall survival (OS) for the whole cohort were 28%, 54%, and 59%, respectively. Statistical analysis showed that only age over 63 years and high MRD level affected alloHSCT outcome. Pre-transplant MRD level of 10 mutant copies of NPM1 per 10,000 Abelson murine leukemia viral oncogene homolog 1 (ABL) copies had the strongest statistical significance, and detection of higher MRD level (>10 NPM1-mutant copies) before alloHSCT was associated with increased overall mortality (hazard ratio=3.71; 95% confidence interval=1.55-9.06; p=0.004). The estimated probabilities of 3-year relapse, EFS, and OS were 6%, 72%, and 75% for patients with a low level of MRD and 48%, 35%, and 40% for patients with a higher level.
CONCLUSION: Our data showed that the pre-transplant level of MRD in patients with normal karyotype AML harboring NPM1 mutation in CR provides important prognostic information, which as an independent prognostic factor predicts transplant results.

Kumsaen P, Fucharoen G, Sirijerachai C, et al.
FLT3-ITD Mutations in Acute Myeloid Leukemia Patients in Northeast Thailand.
Asian Pac J Cancer Prev. 2016; 17(9):4395-4399 [PubMed] Related Publications
The FLT3-ITD mutation is one of the most frequent genetic abnormalities in acute myeloid leukemia (AML) where it is associated with a poor prognosis. The FLT3-ITD mutation could, therefore, be a potential molecular prognostic marker important for risk-stratified treatment options. We amplified the FLT3 gene at exon 14 and 15 in 52 AML patients (aged between 2 months and 74 years) from 4 referral centers (a university hospital and 3 regional hospitals in Northeast Thailand), using a simple PCR method. FLT3-ITD mutations were found in 10 patients (19.2%), being more common in adults than in children (21.1% vs. 14.3%) and more prevalent in patients with acute promyelocytic leukemia (AML-M3) than AML-non M3 (4 of 10 AML-M3 vs. 6 of 42 AML- non M3 patients). Duplication sequences varied in size-between 27 and 171 nucleotides (median=63.5) and in their location. FLT3-ITD mutations with common duplication sequences accounted for a significant percentage in AML patients in northeastern Thailand. This simple PCR method is feasible for routine laboratory practice and these data could help tailor use of the national protocol for AML.

Allahyari A, Sadeghi M, Ayatollahi H, et al.
Frequency of FLT3 (ITD, D835) Gene Mutations in Acute Myelogenous Leukemia: a Report from Northeastern Iran.
Asian Pac J Cancer Prev. 2016; 17(9):4319-4322 [PubMed] Related Publications
BACKGROUND: FLT3 is mutated in about 1/3 of acute myelogenous leukemia (AML) patients. The aim of the present study was to report the prevalence of FLT3 mutations and comparison with prognostic factors in AML patients in the Northeastern of Iran.
MATERIALS AND METHODS: This cross-sectional study concerned 100 AML cases diagnosed based on bone marrow aspiration and peripheral blood. DNA for every AML patient was extracted and underwent PCR with FLT3-ITD primers.
RESULTS: The mean age at diagnosis was 28.5 years (range, 1-66 years), 52 patients (52%) being male. Out of 100 AML patients, 21 (21%) had FLT3 mutation, (17 with FLT3- ITD, 81%, and 4 with FLT3-D825, 19%). Of the 21, 14 (66.7%) had heterozygous mutation. There was no significant difference between age, sex and organomegaly between patients with FLT3 mutation versus FLT3 wild-type.
CONCLUSIONS: Our frequency of FLT3 is in line with earlier fidnings of approximately 20 to 30% and also the prevalence of FLT3-ITD is more than FLT3-D35 mutation. There was no significant difference between prognostic factors (age and sex) in the patients with FLT3 mutation versus FLT3 wild-type. The prevalence of FLT3 heterozygous mutations is more that homozygous mutations in AML patients.

Fukushima N, Minami Y, Kakiuchi S, et al.
Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells.
Cancer Sci. 2016; 107(10):1422-1429 [PubMed] Article available free on PMC after 24/05/2017 Related Publications
Aberrant activation of the Hedgehog signaling pathway has been implicated in the maintenance of leukemia stem cell populations in several model systems. PF-04449913 (PF-913) is a selective, small-molecule inhibitor of Smoothened, a membrane protein that regulates the Hedgehog pathway. However, details of the proof-of-concept and mechanism of action of PF-913 following administration to patients with acute myeloid leukemia (AML) are unclear. This study examined the role of the Hedgehog signaling pathway in AML cells, and evaluated the in vitro and in vivo effects of the Smoothened inhibitor PF-913. In primary AML cells, activation of the Hedgehog signaling pathway was more pronounced in CD34(+) cells than CD34(-) cells. In vitro treatment with PF-913 induced a decrease in the quiescent cell population accompanied by minimal cell death. In vivo treatment with PF-913 attenuated the leukemia-initiation potential of AML cells in a serial transplantation mouse model, while limiting reduction of tumor burden in a primary xenotransplant system. Comprehensive gene set enrichment analysis revealed that PF-913 modulated self-renewal signatures and cell cycle progression. Furthermore, PF-913 sensitized AML cells to cytosine arabinoside, and abrogated resistance to cytosine arabinoside in AML cells cocultured with HS-5 stromal cells. These findings imply that pharmacologic inhibition of Hedgehog signaling attenuates the leukemia-initiation potential, and also enhanced AML therapy by sensitizing dormant leukemia stem cells to chemotherapy and overcoming resistance in the bone marrow microenvironment.

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