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The Cochrane Database of Systematic... Jun 2015Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by systemic intravascular activation of coagulation, leading to deposition of fibrin... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by systemic intravascular activation of coagulation, leading to deposition of fibrin in the bloodstream. It may occur in patients with acute and chronic leukemia and is particularly associated with acute promyelocytic leukemia (a subtype of acute myeloid leukemia).
OBJECTIVES
To assess the clinical benefits and harms of any pharmacological intervention for treating DIC in patients with acute or chronic leukemia.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2015, Issue 05), MEDLINE (1946 to 7 May 2015), LILACS (1982 to 7 May 2015) and African Index Medicus (7 May 2015). There was no language restrictions. We sought additional randomized controlled trials (RCTs) from the World Health Organization International Clinical Trials Registry Platform and the reference lists of primary studies identified.
SELECTION CRITERIA
RCTs assessing the clinical benefits and harms of interventions for treating DIC in patients with acute and chronic leukemia.
DATA COLLECTION AND ANALYSIS
Two review authors independently performed trial selection, 'Risk of bias' assessment and data extraction. Primary outcomes were overall mortality, in-hospital mortality from any cause (15-day and 30-day) and adverse events.
MAIN RESULTS
In this Cochrane Review update we did not include any new RCT compared with the first review version. Accordingly, four RCTs (388 participants) met the inclusion criteria. These trials evaluated the human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate. Included trials reported data on mortality and bleeding. The studies were conducted in Japan, Italy and the Netherlands. We classified the included trials as: 1) including patients with or without leukemia which did not report data for the leukemia subgroup (366 participants); and 2) only including patients with leukemia (22 participants). Overall, the risk of bias of the included trials was high, since the trial authors did not provide a detailed description about trial design and execution.According to the GRADE recommendations, we judged the overall quality of the body of evidence for all prefixed outcomes as 'very low', due to methodological limitations and very small sample size.One trial, including 10 participants with leukemia and comparing dermatan sulphate with heparin, reported no deaths during trial treatment.In terms of bleeding data, we were unable to pool results from two studies that were only conducted with leukemia patients due to the inconsistency in the measurement and reporting of this outcome. One trial, including 12 participants with leukemia, found very low quality evidence that tranexamic acid can reduce the cumulative hemorrhagic score in participants compared with those assigned to placebo (P = 0.0015, very low quality evidence). On the contrary, there is no evidence that dermatan sulphate compared with placebo reduces new events of hemorrhagic diathesis (1/5 (20%) versus 2/5 (40%); RR 0.50; 95% CI 0.06 to 3.91; P = 0.51, very low quality evidence).No thromboembolic complications were reported in either trial that included patients with leukemia only (very low quality evidence). The safety profile was inconclusive.The included trials did not assess overall mortality, resolution of respiratory failure, renal failure or shock.
AUTHORS' CONCLUSIONS
Due to a lack of new RCTs, our conclusions in this Cochrane Review update are the same as the previous review version. We included four RCTs which reported mortality and bleeding data. It is not possible to determine whether human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate are effective or harmful for patients presenting with DIC related to acute or chronic leukemia. The quality of the evidence was low to very low. Therefore, prescription of these interventions for treating DIC in patients with acute and chronic leukemia can neither be supported nor rejected, unless new evidence from a large high-quality trial alters this conclusion.
Topics: Acute Disease; Anticoagulants; Chronic Disease; Dermatan Sulfate; Disseminated Intravascular Coagulation; Humans; Leukemia; Protein C; Randomized Controlled Trials as Topic; Thrombomodulin; Tranexamic Acid
PubMed: 26107113
DOI: 10.1002/14651858.CD008562.pub3 -
Leukemia & Lymphoma 2016The outcomes of acute promyelocytic leukemia (APL) in pregnancy are largely unknown. The MEDLINE database was systematically searched to obtain 43 articles with 71... (Meta-Analysis)
Meta-Analysis
The outcomes of acute promyelocytic leukemia (APL) in pregnancy are largely unknown. The MEDLINE database was systematically searched to obtain 43 articles with 71 patients with new-onset APL during pregnancy. Induction therapy included various regimens of all-trans retinoic acid (ATRA), cytarabine, and anthracycline and resulted in a complete remission rate of 93%. Obstetric and fetal complications included pre-term deliveries (46%), spontaneous/therapeutic abortion/intrauterine death (33.3%) and other neonatal complications (25.9%). Mothers diagnosed in the first trimester were more likely to experience obstetric (p < 0.01) and fetal (p < 0.01) complications. To our knowledge, this is the largest systematic review of APL in pregnancy. The vast majority of APL patients in pregnancy may achieve remission with initial induction therapy. APL or its therapy in pregnancy, however, is associated with a high risk of fetal and obstetrical complications. The results of our study may help in patient counseling and informed decision-making.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Consolidation Chemotherapy; Female; Humans; Leukemia, Promyelocytic, Acute; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Remission Induction; Treatment Outcome; Tretinoin; Young Adult
PubMed: 26110880
DOI: 10.3109/10428194.2015.1065977 -
Journal of Clinical Medicine Oct 2020Differentiation syndrome (DS) is a potentially fatal adverse drug reaction caused by the so-called differentiating agents such as all-trans retinoic acid (ATRA) and... (Review)
Review
Differentiation syndrome (DS) is a potentially fatal adverse drug reaction caused by the so-called differentiating agents such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), used for remission induction in the treatment of the M3 subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL). However, recent DS reports in trials of isocitrate dehydrogenase (IDH)-inhibitor drugs in patients with IDH-mutated AML have raised concerns. Given the limited knowledge of the incidence of DS with differentiating agents, we conducted a systematic literature review of clinical trials with reports of DS to provide a comprehensive overview of the medications associated with DS. In particular, we focused on the incidence of DS reported among the IDH-inhibitors, compared to existing ATRA and ATO therapies. We identified 44 published articles, encompassing 39 clinical trials, including 6949 patients. Overall, the cumulative incidence of DS across all treatment regimens was 17.7%. Incidence of DS was notably lower in trials with IDH-inhibitors (10.4%) compared to other regimens, including ATRA and/or ATO (15.4-20.6%). Compared to other therapies, the median time to onset was four times longer with IDH-inhibitors (48 vs. 11 days). Treating oncologists should be mindful of this potentially fatal adverse drug reaction, as we expect the current trials represent an underestimation of the actual incidence.
PubMed: 33081000
DOI: 10.3390/jcm9103342 -
Thrombosis Research Jun 2019The safety and efficacy of venous thromboembolism (VTE) treatment in patients with acute leukemia (AL) are not well understood and the optimal treatment strategy is...
BACKGROUND
The safety and efficacy of venous thromboembolism (VTE) treatment in patients with acute leukemia (AL) are not well understood and the optimal treatment strategy is unclear.
METHODS
We conducted a systematic review of the literature aiming to identify observational studies and randomized trials describing treatment of VTE in the setting of AL including, acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), and acute lymphoblastic leukemia (ALL). Due to the heterogeneity of findings, no meta-analysis was attempted.
RESULTS
A total of 13 observational studies (11 cohorts and 2 case-control) totaling 5359 participants were included. The number of patients with VTE among the total population was 304 (5.7%; 95% CI 5.1-6.3). In patients with VTE, 221 patients received treatment with anticoagulation using either of low-molecular-weight heparin, unfractionated heparin, and/or vitamin K antagonists. Most studies adjusted the anticoagulant dose based on platelet count. The reported recurrence rate ranged from 0 to 29% among different studies and varied according to the duration of anticoagulant treatment and follow up. Bleeding events were not uniformly reported but the total number was low among anti-coagulated patients.
CONCLUSION
There is a significant lack of data in this area with a high degree of heterogeneity in the choice of anticoagulant, dose adjustments for thrombocytopenia, and duration of anticoagulation. Further studies are required to develop guidelines and suggestions for treatment of VTE in AL.
Topics: Humans; Leukemia, Myeloid, Acute; Venous Thromboembolism
PubMed: 30921533
DOI: 10.1016/j.thromres.2019.03.014 -
PharmacoEconomics Jul 2019The National Institute for Health and Care Excellence (NICE) invited Teva, the company manufacturing arsenic trioxide (ATO; tradename Trisenox), to submit evidence for...
The National Institute for Health and Care Excellence (NICE) invited Teva, the company manufacturing arsenic trioxide (ATO; tradename Trisenox), to submit evidence for the clinical and cost effectiveness of ATO for untreated and relapsed or refractory acute promyelocytic leukaemia (APL). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the independent Evidence Review Group (ERG). This paper presents a summary of the company submission (CS), the ERG's critical review of the clinical and cost effectiveness evidence in the CS, key methodological considerations and the development of the NICE guidance by the Appraisal Committee (AC). The CS presented three randomized controlled trials (RCTs). Two of these were trials in newly diagnosed APL (APL0406 and AML17) and the third trial was in patients with relapsed APL. Results from APL0406 showed that more people having AATO [ATO plus all-trans retinoic acid (ATRA)] were alive at 50 months compared with people having AIDA (ATRA in combination with idarubicin) (99% vs. 93%; p = 0.007). There was also a statistically significant lower cumulative incidence of relapse with AATO compared with AIDA at 50 months (2% vs. 14%; p = 0.001). At 4 years, results from AML17 showed a significant difference in event-free survival (91% vs. 70%; p = 0.002) favouring AATO but not in overall survival (93% vs. 89%; p = 0.250). The only trial presented for relapsed/refractory patients compared AATO with ATO, which was not a relevant comparison according to the NICE scope. The AC concluded that AATO was effective for untreated APL while for relapsed or refractory APL the effectiveness of ATO was considered uncertain and the long-term safety remains unexplored. In the CS base-case, AATO was less expensive (£31,088 saved) and more effective (2.546 quality-adjusted life-years (QALYs) gained) than AIDA and thus the dominating strategy for newly diagnosed low- to intermediate-risk APL. However, the ERG's critical assessment highlighted a number of concerns, including deviations from the NICE reference case and a lack of detailed description and justification of parameters and assumptions related to (the extrapolation of) treatment effectiveness. However, it was reassuring that AATO for untreated APL remained dominant in the ERG base-case, and that the worst-case scenario produced by the ERG resulted in an incremental cost-effectiveness ratio (ICER) of £21,622. The AC concluded that although there was uncertainty in the model, it could recommend ATO for both untreated and relapsed or refractory APL.
Topics: Antineoplastic Agents; Arsenic Trioxide; Cost-Benefit Analysis; Disease-Free Survival; Humans; Leukemia, Promyelocytic, Acute; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Survival Rate; Technology Assessment, Biomedical
PubMed: 30426463
DOI: 10.1007/s40273-018-0738-y -
Pediatric Hematology and Oncology Aug 2020Disseminated intravascular coagulation (DIC) may complicate malignant disease. Numerous studies have investigated this association in adults, however only sparse...
Disseminated intravascular coagulation (DIC) may complicate malignant disease. Numerous studies have investigated this association in adults, however only sparse knowledge exists on DIC in pediatric cancer patients. The objective of this article was to systematically review the literature regarding DIC in pediatric malignancies. PubMed and Embase were searched for relevant articles on January 31, 2020. In total, 6,070 articles were identified out of which 24 articles met inclusion and exclusion criteria. These were included in the qualitative synthesis. The National Institutes of Health's Quality Assessment Tools was used to assess bias in the included articles. The studies were of only moderate quality mainly based on medical charts and demonstrated high heterogeneity, especially as regards to diagnostic criteria. DIC was reported most frequently in patients with acute leukemia, particularly the subtype acute promyelocytic leukemia (APL). Standard coagulation parameters were used as diagnostic laboratory tests supporting the diagnosis of DIC. Hemorrhage was the predominant clinical manifestation, whereas thromboembolic events and organ failure were reported less frequently. Unfractionated heparin, platelet concentrate and fresh frozen plasma were the most frequently used supportive treatment agents. Hemorrhage accounted for the majority of deaths in children with acute leukemia and solid tumors. In conclusion, only a limited number of studies, being heterogenous and of moderate quality, have investigated DIC in pediatric malignancy. Notably, this entity seems to be complicated mainly by hemorrhage. High quality studies are needed to evaluate diagnosis, clinical manifestations and optimal treatment of DIC in childhood cancers.
Topics: Adolescent; Anticoagulants; Blood Coagulation; Child; Child, Preschool; Disseminated Intravascular Coagulation; Hemorrhage; Heparin; Humans; Infant; Leukemia; Leukemia, Promyelocytic, Acute; Neoplasms; Plasma; Thrombosis
PubMed: 32202958
DOI: 10.1080/08880018.2020.1733717 -
Cancers Apr 2020The management of pregnant women with acute promyelocytic leukemia (APL) is a challenging situation where limited evidence-based information is available. We performed a...
The management of pregnant women with acute promyelocytic leukemia (APL) is a challenging situation where limited evidence-based information is available. We performed a systematic literature review to analyze the outcomes reported for both mother and fetus when APL is diagnosed during pregnancy. PubMed, Scopus and Web of Science databases were systematically searched to identify studies reporting cases of APL during pregnancy. Sixty-six articles met the eligibility criteria (53 single case reports). Ninety-two patients were eligible for induction therapy, with most them being treated with all-trans retinoic acid alone (32%) or combined with chemotherapy (43%), while the remaining patients received chemotherapy alone. Three patients were treated with arsenic-based regimens after delivery. Overall complete remission rate was 89%, with no statistically significant differences according to the type of induction and gestational age. During the first trimester, women were more likely to experience spontaneous and induced abortion compared to those during the second trimester (88% vs. 30%) ( < 0.0001), while only one patient diagnosed during the third trimester terminated in stillbirth. Twelve of 16 infants with neonatal complications had respiratory distress syndrome. Except two early deaths (Potter's syndrome and pulmonary hemorrhage), all neonates evolved favorably. This study confirms that gestational age does not affect the results in the mother, but is closely related to fetal viability. Our results may be useful for the process of decision making that requires the involvement of the patient, hematologist, obstetrician and neonatologist.
PubMed: 32295152
DOI: 10.3390/cancers12040968 -
Expert Review of Hematology Jul 2021: Remarkable advances have been made in acute promyelocytic leukemia (APL) research over the past decades and many patients can now also be cured without traditional...
: Remarkable advances have been made in acute promyelocytic leukemia (APL) research over the past decades and many patients can now also be cured without traditional chemotherapy. Therefore, the assessment of health-related quality of life (HRQoL) and other types of patient-reported outcomes (PROs) is highly relevant in the current APL treatment landscape.: A systematic literature review was performed to identify APL studies assessing HRQoL that were published over the last 15 years. Eligible studies were evaluated on a predetermined data extraction form including information on the study design, PRO measure used, as well patient characteristics and summary of HRQoL findings. For descriptive purposes, selected studies were grouped and discussed based on the type of treatment: standard chemotherapy only versus those also including more recent targeted arsenic trioxide (ATO)-based strategies.: Inclusion of HRQoL in APL research was important to better understand the benefit-risk profile of intravenous ATO compared to traditional chemotherapy. While some information on HRQoL and symptoms in APL survivors treated with standard chemotherapy is available, the long-term effects of ATO therapy on patients' HRQoL are largely unknown. Additionally, future studies are needed to evaluate the potential advantages of oral ATO over intravenous administration.
Topics: Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Humans; Leukemia, Promyelocytic, Acute; Quality of Life; Treatment Outcome; Tretinoin
PubMed: 34125642
DOI: 10.1080/17474086.2021.1943352 -
Annals of Hematology Apr 2023Severe bleeding is the leading cause of early death in patients with newly diagnosed acute promyelocytic leukemia (APL). However, there are no means for hemorrhagic risk...
Severe bleeding is the leading cause of early death in patients with newly diagnosed acute promyelocytic leukemia (APL). However, there are no means for hemorrhagic risk stratification in APL. This study aimed to identify optimized predictors of severe bleeding events related to APL. A total of 109 consecutive patients with newly diagnosed APL from January 2015 to April 2022 were retrospectively investigated. A systematic review of computer-based patient medical records was conducted to obtain clinical date, including baseline characteristics, routine blood examination findings, coagulation and fibrinolysis indexes, and bleeding events. Among the 109 patients, 89 were classified into the no-severe bleeding group, while 20 had severe bleeding. Compared with the patients with no severe bleeding, the patients with severe bleeding had significantly higher circulating leukemic cell percentages, disseminated intravascular coagulation (DIC) scores, D-dimer (D-D) levels, and fibrin degradation product (FDP) levels. They also had lower fibrinogen (FIB) levels and a longer prothrombin time. Multivariate analysis revealed that the circulating leukemic cell percentage (OR = 1.040, CI = 1.008-1.072, P = 0.012), FIB level (OR = 0.101, CI = 0.011-0.896, P = 0.040), and FDP level (OR = 1.012, CI = 1.000-1.024, P = 0.047) were independent risk factors for severe bleeding. FDP/FIB, D-D/FIB, and seven meaningful indicators in the single-factor analysis were included in the receiver operating characteristic (ROC) curve analysis. The results showed that FDP/FIB was the best indicator for predicting severe bleeding related to newly diagnosed APL. The area under the ROC curve of FDP/FIB was 0.915, and the best cutoff value was 61.77, with 100% sensitivity and 74.2% specificity. Statistical analysis showed a higher incidence of severe bleeding and higher DIC scores when FDP/FIB was >61.77 in APL patients. FDP/FIB has obvious advantages in predicting the degree of bleeding associated with primary promyelocytic leukemia; the greater the FDP/FIB value, the more severe the bleeding. The risk of severe bleeding was the highest when FDP/FIB > 61.77.
Topics: Humans; Blood Coagulation; Disseminated Intravascular Coagulation; Hemorrhage; Leukemia, Promyelocytic, Acute; Retrospective Studies
PubMed: 36750485
DOI: 10.1007/s00277-023-05122-8 -
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