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JAMA Jun 2009The optimal treatment of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. Current consensus, based on cytogenetic risk, recommends... (Meta-Analysis)
Meta-Analysis Review
CONTEXT
The optimal treatment of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. Current consensus, based on cytogenetic risk, recommends myeloablative allogeneic stem cell transplantation (SCT) for poor-risk but not for good-risk AML. Allogeneic SCT, autologous transplantation, and consolidation chemotherapy are considered of equivalent benefit for intermediate-risk AML.
OBJECTIVE
To quantify relapse-free survival (RFS) and overall survival benefit of allogeneic SCT for AML in CR1 overall and also for good-, intermediate-, and poor-risk AML.
METHODS
Systematic review and meta-analysis of prospective trials evaluating allogeneic SCT vs nonallogeneic SCT therapies for AML in CR1. The search used the combined search terms allogeneic; acut* and leukem*/leukaem*/leucem*/leucaem*/aml; myelo* or nonlympho* in the PubMed, Embase, and Cochrane Registry of Controlled Trials databases in March 2009. The search identified 1712 articles.
STUDY SELECTION
Prospective trials assigning adult patients with AML in CR1 to undergo allogeneic SCT vs nonallogeneic SCT treatment(s) based on donor availability and trials reporting RFS and/or overall survival outcomes on an intention-to-treat, donor vs no-donor basis were identified.
DATA EXTRACTION
Two reviewers independently extracted study characteristics, interventions, and outcomes. Hazard ratios (HRs) with 95% confidence intervals (CIs) were determined.
DATA SYNTHESIS
Overall, 24 trials and 6007 patients were analyzed (5951 patients in RFS analyses and 5606 patients in overall survival analyses); 3638 patients were analyzed by cytogenetic risk (547, 2499, and 592 with good-, intermediate-, and poor-risk AML, respectively). Interstudy heterogeneity was not significant. Fixed-effects meta-analysis was performed. Compared with nonallogeneic SCT, the HR of relapse or death with allogeneic SCT for AML in CR1 was 0.80 (95% CI, 0.74-0.86). Significant RFS benefit of allogeneic SCT was documented for poor-risk (HR, 0.69; 95% CI, 0.57-0.84) and intermediate-risk AML (HR, 0.76; 95% CI, 0.68-0.85) but not for good-risk AML (HR, 1.06; 95% CI, 0.80-1.42). The HR of death with allogeneic SCT for AML in CR1 was 0.90 (95% CI, 0.82-0.97). Significant overall survival benefit with allogeneic SCT was documented for poor-risk (HR, 0.73; 95% CI, 0.59-0.90) and intermediate-risk AML (HR, 0.83; 95% CI, 0.74-0.93) but not for good-risk AML (HR, 1.07; 95% CI, 0.83-1.38).
CONCLUSION
Compared with nonallogeneic SCT therapies, allogeneic SCT has significant RFS and overall survival benefit for intermediate- and poor-risk AML but not for good-risk AML in first complete remission.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Leukemia, Myeloid, Acute; Remission Induction; Risk Assessment; Stem Cell Transplantation; Survival Analysis; Transplantation, Homologous
PubMed: 19509382
DOI: 10.1001/jama.2009.813 -
PloS One 2014DNA methyltransferase 3A (DNMT3A) mutations were considered to be independently associated with unfavorable prognosis in adults with de novo acute myeloid leukemia... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
DNA methyltransferase 3A (DNMT3A) mutations were considered to be independently associated with unfavorable prognosis in adults with de novo acute myeloid leukemia (AML), however, there are still debates on this topic. Here, we aim to further investigate the association between DNMT3A mutations and prognosis of patients with AML.
METHODS
Eligible studies were identified from several data bases including PubMed, Embase, Web of Science, ClinicalTrials and the Cochrane Library (up to June 2013). The primary endpoint was overall survival (OS), while relapse-free survival (RFS) and event-free survival (EFS) were chosen as secondary endpoints. If possible, we would pool estimate effects (hazard ratio [HR] with 95% confidence interval[CI]) of outcomes in random and fixed effects models respectively.
RESULTS
That twelve cohort studies with 6377 patients exploring the potential significance of DNMT3A mutations on prognosis were included. Patients with DNMT3A mutations had slightly shorter OS (HR = 1.60; 95% CI, 1.31-1.95; P<0.001), as compared to wild-type carriers. Among the patients younger than 60 years of age, DNMT3A mutations predicted a worse OS (HR = 1.84; 95% CI, 1.36-2.50; P<0.001). In addition, mutant DNMT3A predicted inferior OS (HR = 2.30; 95% CI, 1.78-2.97; P = 0.862) in patients with unfavorable genotype abnormalities. Similar results were also found in some other subgroups. However, no significant prognostic value was found on OS (HR = 1.40; 95% CI, 0.98-1.99; P = 0.798) in the favorable genotype subgroup. Similar results were found on RFS and EFS under different conditions.
CONCLUSIONS
DNMT3A mutations have slightly but significantly poor prognostic impact on OS, RFS and EFS of adults with de novo AML in total population and some specific subgroups.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; Disease-Free Survival; Humans; Leukemia, Myeloid, Acute; Middle Aged; Mutation; Prognosis; Recurrence; Young Adult
PubMed: 24936645
DOI: 10.1371/journal.pone.0093353 -
American Journal of Hematology Aug 2011Imatinib at a dose of 400 mg daily is considered frontline treatment in chronic phase chronic myeloid leukemia (CP-CML). We conducted a systematic review and... (Meta-Analysis)
Meta-Analysis Review
Imatinib at a dose of 400 mg daily is considered frontline treatment in chronic phase chronic myeloid leukemia (CP-CML). We conducted a systematic review and meta-analysis of randomized controlled trials comparing frontline treatment with imatinib 400 mg daily versus higher doses (≥600 mg daily) in patients with CP-CML. The search yielded four trials, randomizing 1,673 patients. At 12 months, high dose compared with standard dose imatinib improved complete cytogenetic response (CCyR) (RR 1.17, 95% CI 1.08-1.26, four trials, I(2) = 33%) as well as major molecular response (MMolR) (RR 1.26, 95% CI 1.12-1.42, four trials, I(2) = 0%). There was no difference in all-cause mortality or disease progression at the end of follow up. Adverse events requiring discontinuation were more common in the high-dose arm (RR 1.98, 95% CI 1.20-3.26, three trials, I(2) = 0%), as were Grade III/IV neutropenia and thrombocytopenia: RR 1.56, 95% CI 1.15-2.12 and RR 1.86, 95% CI 1.28-2.70, respectively. There is currently insufficient evidence to support the routine use of higher doses of imatinib as frontline treatment for CP-CML. Extended follow up is needed to evaluate if the superior CCyR and MMolR with higher doses of imatinib will translate to long-term clinical benefit.
Topics: Antineoplastic Agents; Benzamides; Disease Progression; Dose-Response Relationship, Drug; Humans; Imatinib Mesylate; Leukemia, Myeloid, Chronic-Phase; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Randomized Controlled Trials as Topic
PubMed: 21761431
DOI: 10.1002/ajh.22076 -
Frontiers in Oncology 2021Given the controversial roles of FMS-like tyrosine kinase 3 inhibitors (FLT3i) in various treatment stages of acute myeloid leukemia (AML), this study was designed to...
Clinical Benefits and Safety of FMS-Like Tyrosine Kinase 3 Inhibitors in Various Treatment Stages of Acute Myeloid Leukemia: A Systematic Review, Meta-Analysis, and Network Meta-Analysis.
BACKGROUND
Given the controversial roles of FMS-like tyrosine kinase 3 inhibitors (FLT3i) in various treatment stages of acute myeloid leukemia (AML), this study was designed to assess this problem and further explored which FLT3i worked more effectively.
METHODS
A systematic review, meta-analysis and network meta-analysis (NMA) were conducted by filtering PubMed, Embase, Cochrane library, and Chinese databases. We included studies comparing therapeutic effects between FLT3i and non-FLT3i group in AML, particularly (+) patients, or demonstrating the efficiency of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in (+) AML. Relative risk (RR) with 95% confidence intervals (CI) was used for estimating complete remission (CR), early death and toxicity. Hazard ratio (HR) was used to assess overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) and cumulative incidence of relapse (CIR).
RESULTS
After addressing all criteria, 39 studies were eventually analyzed. Better CR was accomplished by FLT3i in untreated AML (RR 0.88, = 0.04) and refractory and relapsed (+) AML (rrAML) (RR 0.61, < 0.01) compared to non-FLT3i arm, followed by improved survival (untreated AML: OS, HR 0.76; EFS, HR 0.67; RFS, HR 0.72; all < 0.01; (+) rrAML: OS, HR 0.60, < 0.01; RFS, HR 0.40, = 0.01). In addition, allo-HSCT improved survival in (+) AML (OS, HR 0.53; EFS, HR 0.50; RFS, HR 0.57; CIR, HR 0.26; all < 0.01), which was further prolonged by FLT3i administrated after allo-HSCT (OS, HR 0.45; RFS, HR 0.34; CIR, HR 0.32; all < 0.01). Additionally, FLT3i consistently improved OS (p < 0.05) regardless of ratio, when compared to non-FLT3i group. Besides, FLT3i showed significantly increased risk of thrombocytopenia, neutropenia, anemia, skin- and cardiac-related adverse effects, increased alanine aminotransferase, and increased risk of cough and dyspnea ( < 0.05). In NMA, gilteritinib showed the highest probability for improved prognosis.
CONCLUSIONS
FLT3i safely improved prognosis in induction/reinduction stage of (+) AML and further boosted survival benefits from allo-HSCT as maintenance therapy, suggesting better prognosis if FLT3i is combined before and after allo-HSCT. In NMA, gilteritinib potentially achieved the best prognosis, which should be identified in direct trials.
PubMed: 34150652
DOI: 10.3389/fonc.2021.686013 -
International Journal of Clinical... May 2024Although granulocyte colony-stimulating factor (G-CSF) reduces the incidence, duration, and severity of neutropenia, its prophylactic use for acute myeloid leukemia... (Meta-Analysis)
Meta-Analysis
Effectiveness and safety of primary prophylaxis with G-CSF after induction therapy for acute myeloid leukemia: a systematic review and meta-analysis of the clinical practice guidelines for the use of G-CSF 2022 from the Japan society of clinical oncology.
Although granulocyte colony-stimulating factor (G-CSF) reduces the incidence, duration, and severity of neutropenia, its prophylactic use for acute myeloid leukemia (AML) remains controversial due to a theoretically increased risk of relapse. The present study investigated the effects of G-CSF as primary prophylaxis for AML with remission induction therapy. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis of pooled data was conducted, and the risk ratio with corresponding confidence intervals was calculated in the meta-analysis and summarized. Sixteen studies were included in the qualitative analysis, nine of which were examined in the meta-analysis. Although G-CSF significantly shortened the duration of neutropenia, primary prophylaxis with G-CSF did not correlate with infection-related mortality. Moreover, primary prophylaxis with G-CSF did not affect disease progression/recurrence, overall survival, or adverse events, such as musculoskeletal pain. However, evidence to support or discourage the use of G-CSF as primary prophylaxis for adult AML patients with induction therapy remains limited. Therefore, the use of G-CSF as primary prophylaxis can be considered for adult AML patients with remission induction therapy who are at a high risk of infectious complications.
Topics: Humans; Leukemia, Myeloid, Acute; Granulocyte Colony-Stimulating Factor; Remission Induction; Practice Guidelines as Topic; Induction Chemotherapy; Japan; Neutropenia
PubMed: 38494578
DOI: 10.1007/s10147-023-02465-0 -
Scientific Reports Jun 2017Despite technological advances, the prognosis and survival of acute myeloid leukemia (AML) adult patients remain low, compared with other hematologic malignancies. Some... (Meta-Analysis)
Meta-Analysis Review
Despite technological advances, the prognosis and survival of acute myeloid leukemia (AML) adult patients remain low, compared with other hematologic malignancies. Some antigens detected by immunophenotyping may soon play a significant role in the pathophysiologic, prognostic, and overall survival (OS) rate of AML patients. Therefore, we conducted a systematic review and meta-analysis of PubMed, Scopus, Science Direct, Web of Science, and the Cochrane Library (using PRISMA guidelines). We analyzed 11 studies and 13 antigens, detected through the immunophenotyping of 639 patients. From them, twelve exhibited a negative impact with AML prognosis. The meta-analysis demonstrated a high expression of AML markers, which have been associated with a decrease in survival over 10 months (RR 2.55; IC 95%; 1.49-4.37) and over 20 months (RR 2.46; IC 95%; 1.75-3.45). Knowing that the expression of immunophenotypic markers, which are not used on a routine basis, might be able to influence disease behavior, looks promising. However, they have been associated with a poor prognosis as well as a decrease in survival. This may allow for different chemotherapeutical protocols, including future studies for new therapeutic targets.
Topics: Biomarkers; Female; Humans; Immunophenotyping; Leukemia, Myeloid, Acute; Male; Prognosis; Publication Bias
PubMed: 28646224
DOI: 10.1038/s41598-017-00816-2 -
Frontiers in Pharmacology 2021The hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DAC) have been widely used in patients with acute myeloid leukemia (AML) and higher-risk...
Comparison Between Decitabine and Azacitidine for Patients With Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndrome: A Systematic Review and Network Meta-Analysis.
The hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DAC) have been widely used in patients with acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (HR-MDS). However, few direct clinical trials have been carried out to compare the efficacy and adverse events (AEs) between these two agents. The clinical choice between them is controversial. A systematic review and network meta-analysis (NMA) was performed to compare the efficacy, safety, and survival of DAC and AZA in AML and HR-MDS patients. We systematically searched MEDLINE, Embase, Web of Science, and Cochrane Library through March 15, 2021. Randomized controlled trials (RCTs) on AML or HR-MDS patients comparing the efficacy and safety between DAC and AZA or comparing one of HMAs to conventional care regimens (CCR) were selected. Eight RCTs ( = 2,184) were identified in the NMA. Four trials compared AZA to CCR, and four compared DAC to CCR. Direct comparisons indicated that, compared to CCR, both AZA and DAC were associated with higher overall response (OR) rate (AZA vs. CCR: relative risk (RR) = 1.48, 95% CI 1.05-2.1; DAC vs. CCR: RR = 2.14, 95% CI 1.21-3.79) and longer overall survival (OS) (AZA vs. CCR: HR = 0.64, 95% CI 0.50-0.82; DAC vs. CCR: HR = 0.84, 95% CI 0.72-0.98), and AZA showed higher rate of complete remission with incomplete blood count recovery (CRi) (HR = 2.52, 95% CI 1.27-5). For the indirect method, DAC showed a higher complete remission (CR) rate than AZA in patients with both AML (RR = 2.28, 95% CI 1.12-4.65) and MDS (RR = 7.57, 95% CI 1.26-45.54). Additionally, DAC significantly increased the risk of 3/4 grade anemia (RR = 1.61, 95% CI: 1.03-2.51), febrile neutropenia (RR = 4.03, 95% CI: 1.41-11.52), and leukopenia (RR = 3.43, 95% CI 1.64-7.16) compared with AZA. No statistical significance was found for the other studied outcomes. Compared to CCR, both AZA and DAC can promote outcomes in patients with AML and HR-MDS. DAC showed higher efficacy especially CR rate than AZA (low-certainty evidence), while AZA experienced lower frequent grade 3/4 cytopenia than patients receiving DAC treatment.
PubMed: 34483903
DOI: 10.3389/fphar.2021.701690 -
Frontiers in Pharmacology 2023Autophagy is a cellular process where damaged organelles or unwanted proteins are packaged into a double-membrane structure and transported to lysosomes for...
Autophagy is a cellular process where damaged organelles or unwanted proteins are packaged into a double-membrane structure and transported to lysosomes for degradation. Autophagy plays a regulatory role in various hematologic malignancies, including acute myeloid leukemia (AML). However, there are few bibliometric studies on the role of autophagy in AML. The purpose of this study is to clarify the role of autophagy in acute myeloid leukemia through bibliometric analysis. The literature on autophagy and AML research from 2003 to 2023 was searched in Web of Science Core Collection, and bibliometric tools such as VOSviewer 1.6.18, Cite Space (6.1.R3), RStudio (R package bibliometrix), and Scimago Graphica were used to understand the current status and hotspots of autophagy and AML research. The study conducted an analysis of various dimensions including the quantity of publications, countries, institutions, journals, authors, co-references, keywords, and to predict future development trends in this field by drawing relevant visualization maps. A total of 343 articles were obtained, published in 169 journals, written by 2,323 authors from 295 institutions in 43 countries. The journals with the most publications were Blood and Oncotarget. China had the most publications, and Chongqing Medical University and Sun Yat-sen University had the most publications. The author with the highest number of publications was Tschan, Mario P. The main types of research included clinical research, experiments, experiments, public database information, and reviews, and the forms of therapeutic effects mainly focused on genetic regulation, traditional Chinese medicine combination, autophagy inhibitors, and drug targets. The research hotspots of autophagy and AML in the past 17 years have focused on genetic regulation, autophagy inhibition, and targeted drugs. Chemotherapy resistance and mitochondrial autophagy will be the forefront of research. The gradual increase in the literature on autophagy and AML research and the decline after 2022 could be a result of authors focusing more on the type of research and the quality of the literature. The current research hotspots are mainly genetic regulation, autophagy inhibition, and autophagy-related targeted drugs. In future, autophagy will remain the focus of the AML field, with research trends likely to focus more on AML chemotherapy resistance and mitochondrial autophagy.
PubMed: 38322702
DOI: 10.3389/fphar.2023.1291195 -
American Journal of Blood Research Dec 2013Granulocytic sarcoma also called myeloid sarcoma is an extramedullary tumor of immature granulocytic cells. It is a rare entity, and mostly accompanied by acute myeloid... (Review)
Review
Granulocytic sarcoma also called myeloid sarcoma is an extramedullary tumor of immature granulocytic cells. It is a rare entity, and mostly accompanied by acute myeloid leukemia. It is observed during the course of myeloproliferative disorders especially in chronic myeloid leukemia and myelodysplastic syndromes. In some rare circumstances, it is detected before clinical signs of leukemia or other diseases. When the bone marrow biopsy reveals no other hematologic malignancies, the granulocytic sarcoma is described as nonleukemic, primary or isolated. It is observed at any part of the body but the most common locations are soft tissues, bone, peritoneum and lymph nodes. Presenting signs or symptoms are mainly due to mass effect of the tumor and dysfunction of the organ, or the tissue that is affected. The diagnosis is performed by biopsy of the tumor. The tumor consists of immature granulocytic cells, which could be documented by H&E, immunohistochemistry, and flow cytometric methods. Fluorescence in-situ hybridization and molecular analysis are also performed. The optimal time and type of treatment is not clear. Surgery could be an option especially for tumors, which cause organ dysfunction and/or obstruction. Systemic treatment should be considered in all patients because without systemic treatment, relapses and progression to acute myeloid leukemia is the ultimate fate of the disease in many cases. Cytarabine-containing remission-induction chemotherapies have been the most applied therapeutic strategies, but it is not clear whether the consolidation therapies are required or not, and what kind of regimens are appropriate. The role of hematopoietic stem cell transplantation (HSC) as a consolidation regimen is not clear, but, after the relapse of the disease with or without bone marrow involvement, HSC transplantation should be considered in suitable patients after the reinduction performed by AML chemotherapies. There is only limited data about the role of radiotherapy in these patients. It could be used in patients with relapsed disease, organ dysfunction which should be quickly relieved and inadequate response to chemotherapy. The effect of radiotherapy on overall survival is not known. New prospective studies and clinical trials are needed to generate guidelines for the treatment of primary granulocytic sarcomas.
PubMed: 24396704
DOI: No ID Found -
Transplantation and Cellular Therapy Dec 2021Disease relapse remains the major cause of death among patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who receive an allogeneic... (Meta-Analysis)
Meta-Analysis
Hypomethylating Agents and FLT3 Inhibitors As Maintenance Treatment for Acute Myeloid Leukemia and Myelodysplastic Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation-A Systematic Review and Meta-Analysis.
BACKGROUND
Disease relapse remains the major cause of death among patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who receive an allogeneic hematopoietic cell transplant (allo-HCT). Maintenance treatment with FLT3 inhibitors and hypomethylating agents (HMA) has been studied in various clinical trials with mixed results.
OBJECTIVE
To synthesize the current evidence on the efficacy and safety of FLT3 inhibitors and HMA for maintenance therapy after allo-HCT in AML and MDS.
METHODS
For this systematic review and meta-analysis Cochrane Library, Google Scholar, Ovid Medline, Ovid Embase, PubMed, Scopus, and Web of Science Core Collection were searched from inception to March 2021 for studies on maintenance therapies after allo-HCT in AML and MDS. Studies were excluded if they were reviews, commentaries, case series with <5 patients, or basic research articles, not published in English, not on post-allo-HCT maintenance with FLT3 inhibitors or HMA in AML or MDS, or if they were clinical trials without published results or duplicate publications from the same patient cohort. Studies with insufficient reporting of the primary endpoint (2-year overall survival [OS]) and studies using FLT3 inhibitors or HMA for pre-emptive treatment of imminent relapse based on positive measurable residual disease testing were excluded. Random-effects models were used to pool response rates for the primary outcome of 2-year OS. Hazard ratios (HR) for death and relapse were calculated for studies that included a control group. Rates of relapse-free survival (RFS), non-relapse mortality, and acute and chronic graft-versus-host-disease (GVHD) were studied as secondary endpoints. Downs and Black checklist and risk of bias assessments were used to gauge the quality of individual studies. The study protocol has been registered on PROSPERO (CRD42020187298).
RESULTS
Our search strategy identified 5559 studies. Twenty-one studies with a total of 809 patients were included in the meta-analysis. The 2-year OS rates were 81.7% (95% confidence interval [CI], 73.8%-87.7%) and 65.7% (95% CI, 55.1%-74.9%) among patients treated with FLT3 inhibitors and HMA, respectively. In sensitivity analyses restricted to studies that included a control group, maintenance therapy with FLT3 inhibitors (HR for death = 0.41; 95% CI, 0.26-0.62) or HMA (HR = 0.45; 95% CI, 0.31-0.66) appeared superior to no maintenance therapy. The 2-year RFS rates were 79.8% (95% CI, 75.0%-83.9%) and 62.4% (95% CI, 50.6%-72.9%) among patients treated with FLT3 inhibitors and HMA, respectively. Rates of any grade acute and chronic GVHD were 33.1% (95% CI, 25.4%-41.8%; grade 3/4: 16.5%) and 42.5% (95% CI, 26.3%-60.4%) among FLT3 inhibitor and 42.7% (95% CI, 33.5%-52.4%; grade 3/4: 8.1%) and 41.5% (95% CI, 32.0%-51.6%) among HMA-treated patients, respectively.
CONCLUSION
Maintenance therapy with either FLT3 inhibitors or HMA after allo-HCT can lead to prolonged and improved OS and RFS with a favorable safety profile. Additional studies are needed to define the optimal duration of treatment, the role of measurable residual disease status, and transplant characteristics in patient selection.
Topics: Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Protein Kinase Inhibitors; fms-Like Tyrosine Kinase 3
PubMed: 34551341
DOI: 10.1016/j.jtct.2021.09.005