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Haematologica Jan 2020Immunosuppressive therapy (IST) is one therapy option for treatment of patients with lower-risk myelodysplastic syndromes (MDS). However, the use of several different... (Meta-Analysis)
Meta-Analysis
Immunosuppressive therapy (IST) is one therapy option for treatment of patients with lower-risk myelodysplastic syndromes (MDS). However, the use of several different immunosuppressive regimens, the lack of high-quality studies, and the absence of validated predictive biomarkers pose important challenges. We conducted a systematic review and meta-analysis according to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines and searched MEDLINE PubMed, Ovid EMBASE, COCHRANE registry of clinical trials (CENTRAL), and the Web of Science without language restriction from inception through September 2018, as well as relevant conference proceedings and abstracts, for prospective cohort studies or clinical trials investigating IST in MDS. Fixed and Random-effects models were used to pool response rates. We identified nine prospective cohort studies and 13 clinical trials with a total of 570 patients. Overall response rate was 42.5% [95% confidence interval (CI): 36.1-49.2%] including a complete remission rate of 12.5% (95%CI: 9.3-16.6%) and red blood cell transfusion independence rate of 33.4% (95% CI: 25.1-42.9%). The most commonly used forms of IST were anti-thymocyte globulin alone or in combination with cyclosporin A with a trend towards higher response rates with combination therapy. Progression rate to acute myeloid leukemia was 8.6% per patient year (95%CI: 3.3-13.9%). Overall survival and adverse events were only inconsistently reported. We were unable to validate any biomarkers predictive of a therapeutic response to IST. IST for treatment of lower-risk MDS patients can be successful to alleviate transfusion burden and associated sequelae.
Topics: Antilymphocyte Serum; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Myelodysplastic Syndromes; Prospective Studies
PubMed: 31004015
DOI: 10.3324/haematol.2019.219345 -
ClinicoEconomics and Outcomes Research... 2019AML is a rapidly progressing bone marrow cancer, with poor survival rates compared to other types of leukemia. IC and NIC as well as BSC treatment options are available;...
BACKGROUND
AML is a rapidly progressing bone marrow cancer, with poor survival rates compared to other types of leukemia. IC and NIC as well as BSC treatment options are available; however, there is scant published literature on the impact of disease and treatment on the HRQoL in patients receiving NIC.
AIM
This study determined the HRQoL among NIC AML patients.
MATERIALS AND METHODS
Embase, Medline, Cochrane database, and conference abstracts were searched using the prespecified PICOS criteria from January 2000 to November 2017 for studies reporting HRQoL and patient preference utilities in NIC AML. Studies on patients with RAEB-t MDS, randomized clinical trials (RCTs), prospective observational studies, and patient surveys were included, while systematic reviews and meta-analyses were used for bibliographic searching.
RESULTS
Thirteen records from 12 original studies were identified. These included five records from four RCTs, three prospective studies, four patient survey studies, and one cost-effectiveness analysis. At baseline, NIC AML patients had poor HRQoL scores especially in fatigue (33) and GHS (50) on a 0-100 scale, with higher scores indicating better health. Low baseline HRQoL scores, especially PF and fatigue (<50) were shown to be significant independent predictors of poor survival. Clinical responders demonstrated meaningful improvements, especially in PF and fatigue, along with other health domains after being treated with NIC agents across several studies.
CONCLUSION
HRQoL is poor for patients with NIC AML; measures such as fatigue and PF at baseline have been identified as independent prognostic factors for overall survival with several studies showing improvement in both domains with treatment. RCTs should incorporate evaluation of treatment impact on patients' PF and fatigue as important measures of effectiveness.
PubMed: 30679915
DOI: 10.2147/CEOR.S187409 -
British Journal of Haematology Jan 2019Many patients with lower-risk myelodysplastic syndrome (MDS) experience anaemia, which has negative consequences. Erythropoiesis-stimulating agents (ESAs) and their... (Review)
Review
Clinical effectiveness and safety of erythropoietin-stimulating agents for the treatment of low- and intermediate-1-risk myelodysplastic syndrome: a systematic literature review.
Many patients with lower-risk myelodysplastic syndrome (MDS) experience anaemia, which has negative consequences. Erythropoiesis-stimulating agents (ESAs) and their biosimilars are used to treat anaemia in MDS and, currently, epoetin alfa and darbepoetin alfa are commonly used and recommended by clinical guidelines. To better understand the evidence available on the use of ESAs for anaemia in lower-risk MDS, we conducted a systematic literature review to identify randomized and nonrandomized prospective studies reporting on clinical efficacy/effectiveness, patient-reported quality of life (QoL), and safety. We extended our review to include retrospective studies for darbepoetin alfa specifically and to ascertain the feasibility of completing an indirect network meta-analysis comparing epoetin and darbepoetin alfa. Overall, 53 articles reporting on 35 studies were included. The studies indicated a clinical benefit of ESAs, with benefits observed across key clinical outcomes. ESAs showed consistent improvement in erythroid response rates (ESA-naïve, 45-73%; previous ESA exposure, 25-75%) and duration of response. Comparative studies demonstrated similar progression to acute myeloid leukaemia and several showed improved overall survival and QoL. Limited safety concerns were identified. This analysis confirmed ESA therapy should be the foremost first-line treatment of anaemia in most patients with lower-risk MDS who lack the 5q deletion.
Topics: Biosimilar Pharmaceuticals; Darbepoetin alfa; Epoetin Alfa; Hematinics; Humans; Myelodysplastic Syndromes; Prospective Studies; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 30549002
DOI: 10.1111/bjh.15707 -
Biology of Blood and Marrow... Apr 2019Fludarabine with busulfan (FB) or melphalan (FM) are 2 more commonly used reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (HCT).We... (Meta-Analysis)
Meta-Analysis
Choosing a Reduced-Intensity Conditioning Regimen for Allogeneic Stem Cell Transplantation, Fludarabine/Busulfan versus Fludarabine Melphalan: A Systematic Review and Meta-Analysis.
Fludarabine with busulfan (FB) or melphalan (FM) are 2 more commonly used reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (HCT).We present a systematic review and meta-analysis of studies comparing these 2 RIC regimens. We searched electronic databases from inception through November 1, 2017 for literature searches to identify relevant studies. A DerSimonian random effects model was used to measure efficacy outcomes; hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) are reported. Seven studies, including a total of 1955 patients, met criteria for inclusion, of which 6 were included in the overall pooled analysis because of repetition of some patients in 2 studies. Three studies were included in the subgroup analysis of acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) and 2 in the subgroup analysis of lymphoid malignancies. Overall survival (OS) and progression-free survival were not statistically significantly different between the 2 RIC regimens in analysis of all studies. However, OS was better with FM in subgroup analysis of AML/MDS studies (HR, .83; 95% CI, .73 to .95). Nonrelapse mortality was lower with FB (HR, .64; 95% CI, .46 to .89), whereas relapse was lower with FM (HR, 1.52; 95% CI, 1.13 to 2.06) in the analysis of all studies. This meta-analysis shows that FB and FM are associated with a similar OS in patients undergoing HCT. Relapse rates are lower with FM but at the cost of higher nonrelapse mortality.
Topics: Busulfan; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Melphalan; Transplantation Conditioning; Transplantation, Homologous; Vidarabine
PubMed: 30471339
DOI: 10.1016/j.bbmt.2018.11.016 -
Cancer Management and Research 2018Lenalidomide is effective for the treatment of low-risk myelodysplastic syndromes with deletion 5q abnormalities. However, whether lenalidomide leads to a significant...
BACKGROUND
Lenalidomide is effective for the treatment of low-risk myelodysplastic syndromes with deletion 5q abnormalities. However, whether lenalidomide leads to a significant improvement in treatment response and overall survival (OS) in cases of acute myeloid leukemia (AML) remains controversial. A systematic review and a meta-analysis were performed to evaluate the efficacy and safety of lenalidomide in the treatment of AML.
METHODS
Clinical studies were identified from the Cochrane Central Register of Controlled Trials, PubMed, Embase, and ClinicalTrials.gov. Efficacy outcomes included overall response rate (ORR), complete remission (CR), and OS. Safety was evaluated based on the incidence of grade 3 and 4 treatment-related adverse events (AEs).
RESULTS
Eleven studies were included in our meta-analysis; collectively these studies featured 407 AML patients. Pooled estimates for overall ORR and CR were 31% (95% CI: 26%-36%) and 21% (95% CI: 16%-27%), respectively. Thrombocytopenia, anemia, neutropenia, and infection were the most common grade 3 and 4 AEs.
CONCLUSION
Lenalidomide may have some clinical activity in AML, but the population that would benefit from lenalidomide and incorporating lenalidomide into combination drug strategies need to be better defined.
PubMed: 30271212
DOI: 10.2147/CMAR.S168610 -
Systematic Reviews Sep 2018Hypomethylating agents (HMA), azacitidine, and decitabine are frequently used in the management of myelodysplastic syndromes (MDS). However, there are no clinical trials... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Hypomethylating agents (HMA), azacitidine, and decitabine are frequently used in the management of myelodysplastic syndromes (MDS). However, there are no clinical trials that have directly compared these agents. We conducted a systematic review and indirectly compared the efficacy of azacitidine to decitabine in MDS.
METHODS
We conducted a comprehensive search of several databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus) through June 28, 2018, without language or time restrictions. Studies were screened by two independent reviewers, and differences were resolved by consensus. The fixed effect model and adjusted indirect comparison methods were used to pool relative risks (RR) of major outcomes of interest (mortality, response rate, quality of life, hematologic improvement, hospitalization, leukemia transformation, transfusion independence).
RESULTS
Only four trials met the eligibility criteria. Two trials compared azacitidine to the best supportive care (BSC) and included 549 patients, and the other two compared decitabine to BSC and included 403 patients. The risk of bias was unclear overall. Compared to BSC, azacitidine was significantly associated with lower mortality (RR = 0.83, 95% CI 0.74-0.94, I = 89%) whereas decitabine did not significantly reduce mortality (RR = 0.88, 95% CI 0.77-1.00, I = 53%). Both drugs were associated with higher partial and complete response compared to BSC. Indirect comparisons were not statistically significant for all the studied outcomes, except for complete response where azacitidine was less likely to induce complete response compared to decitabine (RR = 0.11, 95% CI = 0.01-0.86, very low-certainty evidence).
CONCLUSIONS
Azacitidine and decitabine are both associated with improved outcomes compared to BSC. The available indirect evidence comparing the two agents warrants very low certainty and cannot reliably confirm the superiority of either agent. Head-to-head trials are needed. In the meantime, the choice of agent should be driven by patient preferences, adverse effects, drug availability, and cost.
Topics: Humans; Azacitidine; Blood Transfusion; Decitabine; Mortality; Myelodysplastic Syndromes; Network Meta-Analysis; Quality of Life
PubMed: 30227896
DOI: 10.1186/s13643-018-0805-7 -
Medicine Aug 2018Hypomethylating agents (HMAs) are believed to have reliable efficacy in treating myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Meanwhile, the adverse... (Meta-Analysis)
Meta-Analysis Review
Incidence and risk of hematologic toxicities with hypomethylating agents in the treatment of myelodysplastic syndromes and acute myeloid leukopenia: A systematic review and meta-analysis.
BACKGROUND
Hypomethylating agents (HMAs) are believed to have reliable efficacy in treating myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Meanwhile, the adverse events of HMAs have become an increasing concern. There is, however, no systematic meta-analysis available to evaluate overall hematologic toxicities for HMAs. In this meta-analysis, we aim to determine the risk of hematologic toxicities in patients treated with HMAs.
METHODS
Relevant studies were identified from PubMed, Embase, Cochrane Library, and the Clinical Trials. gov databases incepted to February 2018. All phase II and III trials meeting the inclusion criteria included adequate safety data. We calculated the relative risk (RR) of high-grade hematologic toxicities (HTEs) with corresponding 95% CI using Review Manager. The incidences of HTEs were also evaluated by R. Heterogeneity was calculated and reported mainly via I analyses.
RESULTS
A total of 2337 MDS or AML patients from 14 studies were identified in this meta-analysis. The overall incidences of high-grade hematologic toxicities in patients who received HMAs were: 27% of the patients with anemia, 45% with neutropenia, 38% with thrombocytopenia, and 25% with febrile neutropenia, respectively. There was a significantly increased RR of neutropenia and thrombocytopenia using HMAs, in comparison with conventional care regimens (CCR) based on the drug type (decitabine vs azacitidine).
CONCLUSIONS
We conclude that the use of HMAs are associated with an increased risk of neutropenia and thrombocytopenia in MDS or AML patients, and our results also demonstrate that HMAs exposure does not significantly increase the risk of high-grade anemia, leukopenia, or febrile neutropenia compared with CCR.
Topics: Antimetabolites, Antineoplastic; Hematologic Diseases; Humans; Incidence; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Risk
PubMed: 30142779
DOI: 10.1097/MD.0000000000011860 -
Annals of Oncology : Official Journal... Sep 2018The use of supportive granulocyte colony-stimulating factor (G-CSF) to reduce the risk of neutropenic complications in high-risk cancer patients is consistently... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
The use of supportive granulocyte colony-stimulating factor (G-CSF) to reduce the risk of neutropenic complications in high-risk cancer patients is consistently recommended by several clinical practice guidelines. However, in a previous meta-analysis, G-CSF prophylaxis was associated with an increased risk of secondary malignancies while reducing long-term mortality. We present here an updated systematic review and meta-analysis.
MATERIALS AND METHODS
A systematic literature search was carried out to identify randomized controlled trials of cancer patients receiving conventional-dose chemotherapy, assigned to primary G-CSF support or a control group without initial G-CSF, with at least 2 years of follow-up. Studies were categorized into one of the four groups, based on the chemotherapy regimen and study design. An updated meta-analysis was carried out; relative risk (RR) and 95% confidence intervals (CIs) for all-cause mortality and secondary malignancies were calculated.
RESULTS
Of 2604 articles screened, 14 eligible studies were identified and combined with studies identified in the previous systematic literature searches. The updated meta-analysis included a total of 68 studies presenting 71 separate comparisons. Survival was significantly improved in patients receiving primary G-CSF support, compared with patients without primary G-CSF support (mortality RR=0.92; 95% CI 0.90-0.95; ARD=-3.3%; 95% CI -4.2--2.4; P < 0.0001). The largest improvement in survival was observed with dose-dense chemotherapy regimens with G-CSF support, compared with controls receiving no G-CSF support (mortality RR=0.86; 95% CI 0.80-0.92; P < 0.0001). Patients who received primary G-CSF support experienced a significantly higher risk of secondary malignancies, compared with controls (RR=1.85; 95% CI 1.19-2.88; ARD=0.47; 95% CI 0.21-0.73; P < 0.01).
CONCLUSIONS
Our findings demonstrate that overall survival is improved in patients receiving intensified chemotherapy with primary G-CSF support, compared with those receiving standard chemotherapy. Primary G-CSF support was also associated with a higher risk of developing secondary malignancies, including secondary acute myeloid leukemia and myelodysplastic syndrome.
Topics: Antineoplastic Agents; Chemotherapy-Induced Febrile Neutropenia; Granulocyte Colony-Stimulating Factor; Humans; Neoplasms; Neoplasms, Second Primary; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Risk Assessment
PubMed: 30099478
DOI: 10.1093/annonc/mdy311 -
The Cochrane Database of Systematic... Aug 2018Acute myeloid leukaemia (AML) is the most common acute leukaemia affecting adults. Most patients diagnosed with AML are at advanced age and present with co-morbidities,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Acute myeloid leukaemia (AML) is the most common acute leukaemia affecting adults. Most patients diagnosed with AML are at advanced age and present with co-morbidities, so that intensive therapy such as stem cell transplantation (SCT) is impossible to provide or is accompanied by high risks for serious adverse events and treatment-related mortality. Especially for these patients, it is necessary to find out whether all-trans retinoic acid (ATRA), an intermediate of vitamin A inducing terminal differentiation of leukaemic cell lines, added to chemotherapy confers increased benefit or harm when compared with the same chemotherapy alone.
OBJECTIVES
This review aims to determine benefits and harms of ATRA in addition to chemotherapy compared to chemotherapy alone for adults with AML (not those with acute promyelocytic leukaemia (non-APL)).
SEARCH METHODS
We searched the Central Register of Controlled Trials (CENTRAL), MEDLINE, study registries and relevant conference proceedings up to July 2018 for randomised controlled trials (RCTs). We also contacted experts for unpublished data.
SELECTION CRITERIA
We included RCTs comparing chemotherapy alone with chemotherapy plus ATRA in patients with all stages of AML. We excluded trials if less than 80% of participants were adults or participants with AML, and if no subgroup data were available. Patients with myelodysplastic syndrome (MDS) were included, if they had a refractory anaemia and more than 20% of blasts.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed the quality of trials. We contacted study authors to obtain missing information. We used hazard ratios (HR) for overall survival (OS) and disease-free survival (DFS; instead of the pre-planned event-free survival, as this outcome was not reported), and we calculated risk ratios (RR) for the other outcomes quality of life, on-study mortality and adverse events. We presented all measures with 95% confidence intervals (CIs). We assessed the certainty of evidence using GRADE methods.
MAIN RESULTS
Our search resulted in 2192 potentially relevant references, of which we included eight trials with 28 publications assessing 3998 patients. Overall, we judged the potential risk of bias of the eight included trials as moderate. Two of eight trials were published as abstracts only. All the included trials used different chemotherapy schedules and one trial only evaluated the effect of the hypomethylating agent decitabine, a drug know to affect epigenetics, in combination with ATRA.The addition of ATRA to chemotherapy resulted in probably little or no difference in OS compared to chemotherapy only (2985 participants; HR 0.94 (95% confidence interval (CI) 0.87 to 1.02); moderate-certainty evidence). Based on a mortality rate at 24 months of 70% with chemotherapy alone, the mortality rate with chemotherapy plus ATRA was 68% (95% CI 65% to 71%).For DFS, complete response rate (CRR) and on-study mortality there was probably little or no difference between treatment groups (DFS: 1258 participants, HR 0.99, 95% CI 0.87 to 1.12; CRR: 3081 participants, RR 1.02, 95% CI 0.96 to 1.09; on-study mortality: 2839 participants, RR 1.02, 95% CI 0.81 to 1.30, all moderate-certainty evidence).Three trials with 1428 participants reported the adverse events 'infection' and 'cardiac toxicity': There was probably no, or little difference in terms of infection rate between participants receiving ATRA or not (RR 1.05, 95% CI 0.96 to 1.15; moderate-certainty evidence). We are uncertain whether ATRA decreases cardiac toxicity (RR 0.46, 95% CI 0.24 to 0.90; P = 0.02, very low certainty-evidence, however, cardiac toxicity was low).Rates and severity of diarrhoea and nausea/vomiting were assessed in two trials with 337 patients and we are uncertain whether there is a difference between treatment arms (diarrhoea: RR 2.19, 95% CI 1.07 to 4.47; nausea/vomiting: RR 1.46, 95% CI 0.75 to 2.85; both very low-certainty evidence).Quality of life was not reported by any of the included trials.
AUTHORS' CONCLUSIONS
We found no evidence for a difference between participants receiving ATRA in addition to chemotherapy or chemotherapy only for the outcome OS. Regarding DFS, CRR and on-study mortality, there is probably no evidence for a difference between treatment groups. Currently, it seems the risk of adverse events are comparable to chemotherapy only.As quality of life has not been evaluated in any of the included trials, further research is needed to clarify the effect of ATRA on quality of life.
Topics: Adult; Antineoplastic Agents; Decitabine; Diarrhea; Disease Progression; Heart; Humans; Infections; Leukemia, Myeloid, Acute; Nausea; Recurrence; Tretinoin; Vomiting
PubMed: 30080246
DOI: 10.1002/14651858.CD011960.pub2 -
The Cochrane Database of Systematic... May 2018Bone marrow disorders encompass a group of diseases characterised by reduced production of red cells, white cells, and platelets, or defects in their function, or both.... (Comparative Study)
Comparative Study Review
BACKGROUND
Bone marrow disorders encompass a group of diseases characterised by reduced production of red cells, white cells, and platelets, or defects in their function, or both. The most common bone marrow disorder is myelodysplastic syndrome. Thrombocytopenia, a low platelet count, commonly occurs in people with bone marrow failure. Platetet transfusions are routinely used in people with thrombocytopenia secondary to bone marrow failure disorders to treat or prevent bleeding. Myelodysplastic syndrome is currently the most common reason for receiving a platelet transfusion in some Western countries.
OBJECTIVES
To determine whether a therapeutic-only platelet transfusion policy (transfusion given when patient is bleeding) is as effective and safe as a prophylactic platelet transfusion policy (transfusion given to prevent bleeding according to a prespecified platelet threshold) in people with congenital or acquired bone marrow failure disorders.
SEARCH METHODS
We searched for randomised controlled trials (RCTs), non-RCTs, and controlled before-after studies (CBAs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2017, Issue 9), Ovid MEDLINE (from 1946), Ovid Embase (from 1974), PubMed (e-publications only), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 12 October 2017.
SELECTION CRITERIA
We included RCTs, non-RCTs, and CBAs that involved the transfusion of platelet concentrates (prepared either from individual units of whole blood or by apheresis any dose, frequency, or transfusion trigger) and given to treat or prevent bleeding among people with congenital or acquired bone marrow failure disorders.We excluded uncontrolled studies, cross-sectional studies, and case-control studies. We excluded cluster-RCTs, non-randomised cluster trials, and CBAs with fewer than two intervention sites and two control sites due to the risk of confounding. We included all people with long-term bone marrow failure disorders that require platelet transfusions, including neonates. We excluded studies of alternatives to platelet transfusion, or studies of people receiving intensive chemotherapy or a stem cell transplant.
DATA COLLECTION AND ANALYSIS
We used the standard methodological procedures outlined by Cochrane. Due to the absence of evidence we were unable to report on any of the review outcomes.
MAIN RESULTS
We identified one RCT that met the inclusion criteria for this review. The study enrolled only nine adults with MDS over a three-year study duration period. The trial was terminated due to poor recruitment rate (planned recruitment 60 participants over two years). Assessment of the risk of bias was not possible for all domains. The trial was a single-centre, single-blind trial. The clinical and demographic characteristics of the participants were never disclosed. The trial outcomes relevant to this review were bleeding assessments, mortality, quality of life, and length of hospital stay, but no data were available to report on any of these outcomes.We identified no completed non-RCTs or CBAs.We identified no ongoing RCTs, non-RCTs, or CBAs.
AUTHORS' CONCLUSIONS
We found no evidence to determine the safety and efficacy of therapeutic platelet transfusion compared with prophylactic platelet transfusion for people with long-term bone marrow failure disorders. This review underscores the urgency of prioritising research in this area. People with bone marrow failure depend on long-term platelet transfusion support, but the only trial that assessed a therapeutic strategy was halted. There is a need for good-quality studies comparing a therapeutic platelet transfusion strategy with a prophylactic platelet transfusion strategy; such trials should include outcomes that are important to patients, such as quality of life, length of hospital admission, and risk of bleeding.
Topics: Adult; Humans; Myelodysplastic Syndromes; Platelet Transfusion
PubMed: 29758592
DOI: 10.1002/14651858.CD012342.pub2