scholarly journals FLT3 inhibitors in acute myeloid leukaemia: assessment of clinical effectiveness, adverse events and future research—a systematic review and meta-analysis

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
S. Majothi ◽  
D. Adams ◽  
J. Loke ◽  
S. P. Stevens ◽  
K. Wheatley ◽  
...  
Keyword(s):  
Systematic Review ◽  
Relative Risk ◽  
Adverse Events ◽  
Disease Control ◽  
Meta Analysis ◽  
Clinical Effectiveness ◽  
Disease Stage ◽  
Free Survival ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors

Abstract Background FMS-like tyrosine kinase 3 (FLT3) is the most frequent mutation in AML. With two FLT3 inhibitors recently approved by the FDA (midostaurin and gilteritinib), there is a need to evaluate these targeted agents. Purpose To assess the clinical effectiveness of FLT3 inhibitors in AML patients. Methods Standard systematic review methods were utilised. Searches were conducted to July 2020 for completed and in-progress randomised controlled trials of FLT3 inhibitors in AML. A fixed-effect meta-analysis was undertaken. Results Eight completed trials involving 2656 patients and assessing five different FLT3 inhibitors (sorafenib, lestaurtinib, midostaurin, gilteritinib and quizartinib) were included. The pooled results were as follows (FLT3 inhibitor/control): overall survival hazard ratio (HR) = 0.83 (95% confidence interval [CI] 0.75 to 0.92, p = 0.0005), event-free survival HR = 0.85 (95% CI 0.77 to 0.94, p = 0.002), relapse-free survival HR = 0.76 (95% CI 0.64 to 0.90, p = 0.001), complete remission relative risk (RR) = 1.11 (95% CI 1.00 to 1.22. p = 0.05) and 60-day mortality RR = 1.04 (95% CI 0.77 to 1.40, p = 0.79). Relative risk of grade 3 and above vascular, dermatological, respiratory and hepatobiliary adverse events were found to be statistically significantly higher in the FLT3 inhibitor group compared to control, but the actual numbers of events were relatively small. Nineteen ongoing trials are still in progress, only one of which specifically targets older patients with AML. Conclusions There is evidence to support the use of FLT3 inhibitors in patients with AML, but more data is needed to verify the optimum use of the drugs regarding type of inhibitor, disease stage and patient characteristics, not only in relation to disease control, but adverse events and quality of life. There are a large number of ongoing trials; therefore, the results of this review are not a fait accompli; thus, is it recommended that the review be updated in a couple of years’ time. Given the challenges in extracting the complete data set required to assess clinical effectiveness, it is highly recommended that ongoing and future trials improve transparency and consistency of reporting of all trial outcomes, particularly disease control and adverse events, to enable a global clinical effectiveness assessment. Systematic review registration PROSPERO CRD42017055581

scholarly journals Handwash versus hand-rub practices for preventing nosocomial infection in hospital intensive care units: A systematic review and meta-analysis

2020 ◽  
pp. 82-90
Author(s):  
S Bello ◽  
EA Bamgboye ◽  
DT Ajayi ◽  
EN Ossai ◽  
EC Aniwada ◽  
...  
Keyword(s):  
Systematic Review ◽  
Intensive Care ◽  
Adverse Events ◽  
Nosocomial Infection ◽  
Intensive Care Units ◽  
Meta Analysis ◽  
Healthcare Providers ◽  
Length Of Hospital Stay ◽  
Clinical Effectiveness ◽  
Infection Rates

Background: Compliance with handwashing in busy healthcare facilities, such as intensive care units (ICUs), is suboptimal and alcohol hand-rub preparations have been suggested to improve compliance. There is no evidence on the comparative effectiveness between handwash and hand-rub strategies. This systematic review was to assess the effectiveness of handwash versus hand-rub strategies for preventing nosocomial infection in ICUs. Methods Studies conducted in ICUs and indexed in PubMed comparing the clinical effectiveness and adverse events between handwash and hand-rub groups were included in a systematic review. The primary outcome was nosocomial infection rates. Secondary outcomes included microbial counts on healthcare providers’ hands, mortality rates, patient/hospital cost of treatment of healthcare-associated infections (HCAIs), length of ICU/hospital stays, and adverse events. Studies were independently screened and data extracted by at least two authors. Meta-analyses of risk ratios (RR), incidence rate ratios (IRR), odds ratios (OR) and mean differences (MD), were conducted using the RevMan 5.3 software. Results: Seven studies published between 1992-2009 and involving a total of 11,663 patients were included. Five studies (10,981 patients) contributed data to the ICU acquired nosocomial infection rates. The pooled IRR was 0.71 (95% CI 0.61, 0.82; I2 = 94%). On sensitivity analysis, pooled IRR was 0.39 (95% CI 0.32, 0.48; 4 studies; 8,247 patients; I2 = 0%) in favour of hand rub. The pooled OR for mortality was 0.95 (95% CI 0.78, 1.61; 4 studies; 3,475 patients; I2 = 39%). The pooled MD for length of hospital stay was -0.74 (95% CI -2.83, 1.34; 3 studies; 741 patients; I2 = 0%). The pooled OR for an undesirable skin effect was 0.37 (95% CI 0.23, 0.60; 3 studies;1504 patients; I2 = 0%) in favour of hand rub. Overall quality of evidence was low. Conclusion: Hand rub appeared more effective when compared to handwash in ICUs.

scholarly journals Adverse events of exercise therapy in randomised controlled trials: a systematic review and meta-analysis

2019 ◽  
Vol 54 (18) ◽  
pp. 1073-1080 ◽  
Author(s):  
Andre Niemeijer ◽  
Hans Lund ◽  
Signe Nilssen Stafne ◽  
Thomas Ipsen ◽  
Cathrine Luhaäär Goldschmidt ◽  
...  
Keyword(s):  
Systematic Review ◽  
Relative Risk ◽  
Adverse Events ◽  
Exercise Therapy ◽  
Randomised Controlled Trials ◽  
Meta Analysis ◽  
Control Group ◽  
Controlled Trials ◽  
Serious Adverse Events ◽  
Randomised Controlled

ObjectiveTo evaluate the relative risk (RR) of serious and non-serious adverse events in patients treated with exercise therapy compared with those in a non-exercising control group.DesignSystematic review and meta-analysis.Data sourcesPrimary studies were identified based on The Cochrane Database of Systematic Reviews investigating the effect of exercise therapy.Eligibility criteriaAt least two of the authors independently evaluated all identified reviews and primary studies. Randomised controlled trials were included if they compared any exercise therapy intervention with a non-exercising control. Two authors independently extracted data. The RR of serious and non-serious adverse events was estimated separately.Results180 Cochrane reviews were included and from these, 773 primary studies were identified. Of these, 378 studies (n=38 368 participants) reported serious adverse events and 375 studies (n=38 517 participants) reported non-serious adverse events. We found no increase in risk of serious adverse events (RR=0.96 (95%CI 0.90 to 1.02, I2: 0.0%) due to exercise therapy. There was, however, an increase in non-serious adverse events (RR=1.19 (95%CI 1.09 to 1.30, I2: 0.0%). The number needed to treat for an additional harmful outcome for non-serious adverse events was 6 [95%CI 4 to 11).ConclusionParticipating in an exercise intervention increased the relative risk of non-serious adverse events, but not of serious adverse events. Exercise therapy may therefore be recommended as a relatively safe intervention.PROSPERO registration numberCRD42014014819.

Anthracycline-Containing Regimens for Treatment of Follicular Lymphoma In Adults: Systematic Review and Meta-Analysis.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2820-2820 ◽  
Author(s):  
Gilad Itchaki ◽  
Anat Gafter-Gvili ◽  
Meir Lahav ◽  
Pia Raanani ◽  
Liat Vidal ◽  
...  
Keyword(s):  
Systematic Review ◽  
Overall Survival ◽  
Disease Control ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Response Duration ◽  
Aggressive Lymphoma ◽  
Transformation Rate ◽  
Free Survival ◽  
Significant Difference

Abstract Abstract 2820 Introduction: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma (NHL), yet there are no standard guidelines regarding the best chemotherapeutic regimens for its management. The most prevalent regimens, especially in advanced disease, incorporate anthracyclines. There is no proof, however, that they are superior to non-anthracycline containing regimens, or even to single agent therapy. Methods: Systematic review and meta-analysis of randomized controlled trials comparing anthracycline-containing regimens (ACR) to non-anthracycline containing chemotherapy (non-ACR) for adult patients with FL. Trials assessing rituximab or other immunotherapy were included only if the anthracycline was the only difference between study arms. A comprehensive search was conducted with no restrictions, until July 2010. Two reviewers appraised the quality of trials and extracted data. The primary outcome was overall survival. Time to event data was extracted and pooled hazard ratios (HR) with 95% confidence intervals (CI) were calculated. Secondary outcomes included survival at 5 years, disease control defined as progression free survival (PFS) or response duration (RD), transformation rate to aggressive lymphoma, complete remission (CR), overall response (OR), and adverse events. Risk ratios (RR) for dichotomous outcomes were pooled using random effects model. Heterogeneity was assessed using the I2 measure of inconsistency. Results: We identified ten trials, conducted between the years 1974–2006 and randomizing 2422 adult patients. Nine trials included naïve patients; one included relapsed and refractory FL patients. Six trials compared between the same chemotherapeutic regimens, with the addition of anthracyclines in the intervention arm as the only difference. There was no statistically significant difference between ACR and non-ACR arms, regarding overall survival at the end of follow up or all cause mortality at five years (HR 0.97; 95% CI 0.76 – 1.23 and RR 0.94; 95% CI 0.76 – 1.17, respectively, I2=0% for both analyses). PFS and RD favored the ACR arm, with a HR of 0.69, 95% CI 0.51–0.91 for disease control, 3 studies, I2=11%. There was no significant difference with regard to CR and OR, but analyses were heterogeneous. In four out of the ten trials, different chemotherapeutic regimens were compared, and only one study-arm contained anthracyclines. Similar to the results obtained with the same regimens comparison, there was no benefit for ACR with regard to OS (HR 0.94; 95% CI 0.77 – 1.15) and mortality at five years (RR 0.98; 95% CI 0.84 – 1.16). Disease control was improved with ACR (HR 0.74; 95% CI 0.60–0.93). In all studies, there were no data regarding transformation rate to aggressive lymphoma. Toxicity data reported was insufficient for appropriate meta-analysis. Overall, ACR were more often associated with cytopenias, especially neutropenia, although the frequency of serious infections or death related to chemotherapy was similar to non-ACR. Also, alopecia and gastrointestinal side-effects, including nausea and vomiting, were more common with ACR. Cardiotoxicity was reported in five trials, and albeit rare, was associated with anthracycline use (RR 8.62; 95% CI 1.58 to 47.05). Conclusion: The use of anthracyclines in patients with FL has no demonstrable benefit on overall survival. However, ACR improve disease control, as measured by progression free survival and response duration with an increased risk for side effects, notably cardiotoxicity. Disclosures: Shpilberg: Roche: Consultancy, Honoraria.

scholarly journals Systematic review and meta-analysis of trials evaluating the role of adjuvant radiation after radical prostatectomy for prostate cancer: Implications for early salvage

2020 ◽  
Vol 14 (10) ◽  
Author(s):  
Bimal Bhindi ◽  
Soum D. Lokeshwar ◽  
Zachary Klaassen ◽  
Laurence Klotz ◽  
Christopher J.D. Wallis
Keyword(s):  
Systematic Review ◽  
Radical Prostatectomy ◽  
Adverse Events ◽  
Randomized Trials ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Adjuvant Radiation ◽  
Free Survival ◽  
Biochemical Progression

Introduction: Recent reports suggest that early salvage radiation (esRT) is non-inferior to adjuvant radiation (aRT) for adverse pathological features at radical prostatectomy. However, aRT was accepted as a standard treatment primarily based on effects on biochemical progression-free survival (bPFS). In order to understand the merits of esRT, the objective was to reassess if aRT vs. observation is associated with improved overall survival (OS). Methods: A systematic review and meta-analysis of published randomized trials evaluating aRT was performed. The primary outcome was OS. Secondary outcomes were metastasis-free survival (MFS), loco-regional recurrence-free survival (RFS), bPFS, and adverse events. We performed a random-effects meta-analysis. Results: Four randomized trials including 2068 patients with a median followup of 8.7–12.6 years were identified. While all trials reported a bPFS benefit, only one reported an OS benefit. Upon meta-analysis, no significant OS benefit was detected with aRT vs. observation (hazard ratio [HR] 0.90; 95% confidence interval [CI] 0.61–1.33), although consistent bPFS (HR 0.47; 95% CI 0.41–0.54) and local-RFS (HR 0.54; 95% CI 0.39–0.73) benefits were noted. There is an uncertain MFS benefit with aRT (HR 0.79; 95% CI 0.62–1.01), and the effect is largely driven by one trial with a notable risk of bias. There was also a risk of overtreatment, with 35–60% of patients being biochemical recurrence-free with observation alone. Adverse events risk was greater with aRT vs. observation. Conclusions: Although aRT vs. observation provides a bPFS benefit related to local control, there is no clear OS or MFS benefit, a greater risk of adverse events, and a risk of overtreatment. By extension, these data have implications for patient selection and counselling for esRT.

scholarly journals A Systematic Review and Meta-Analysis: Efficacy and Toxicity Profile of Ixazomib for Treatment of Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5639-5639
Author(s):  
Madeeha Shafqat ◽  
Faiza Jamil ◽  
Zunairah Shah ◽  
Ali Younas Khan ◽  
Seren Durer ◽  
...  
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Meta Analysis ◽  
Drug Regimen ◽  
Pooled Analysis ◽  
Efficacy And Safety ◽  
Free Survival

Abstract Background: Ixazomib (Ixa) is the first FDA approved oral proteasome inhibitor to be used for relapsed and refractory multiple myeloma (MM). We conducted a comprehensive systematic review and meta-analysis of all published prospective clinical trials to analyze the efficacy and safety of ixazomib in newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma (RRMM). Method: After review of literature (last updated June 30, 2018) using database searches (Pubmed, Embase, Cochrane Library, Web of Science and Clinical Trials.gov), from a total of 1290 studies, only fifteen clinical trials (n=1387) met the inclusion criteria for RRMM and eight clinical trials (n=537) met criteria for NDMM. CMA software v.3 was used for meta-analysis. Heterogeneity among studies was assessed using the I2 test. A random-effect model was applied. Result: Based on pooled analysis, an overall response rate (ORR) of 40.6% (95% CI:19.4-66.0) with a very good partial response or better (≥VGPR) of 15.7% (95% CI: 6.8-32.1) in RRMM and ORR (CR+VGPR+PR) of 77.5% (95% CI: 73.1-81.4, I2=48.05) in NDMM was observed. Most common grade (G) ≥ 3 adverse events (AE) based on regimen were calculated using pooled analysis in MM patients. Ixazomib Based Regimen in RRMM: Ixazomib as monotherapy: Four studies (n=192) evaluated the efficacy of ixazomib as a single agent. On subgroup pooled analysis on Ixa as monotherapy, an ORR of 22.7% (95% CI: 13.3-35.9, I2=45%) was observed with ≥VGPR of 7.8% (95% CI: 2.7-20.3). Pooled analysis for safety profile on most common G ≥ 3 adverse events (AEs) were thrombocytopenia 32.3% (95% CI: 22.4-44.2), neutropenia 21.5% (95% CI: 12.6-34.1), diarrhea 13.1% (95% CI: 6.8-23.9), fatigue 11.6% (95% CI: 7.4-17.7) and peripheral neuropathy 2.2% (95% CI: 0.7-6.6). Ixazomib in two drug regimen: In RRMM, two clinical trials (n=92) evaluated the efficacy of Ixa weekly with dexamethasone (D). In this subgroup pooled analysis, ORR of 40.7% (95% CI: 22.8-61.5, I2=41.76%) with ≥VGPR of 19.5% (95% CI: 4.6-52) was calculated. One study reported event-free survival (EFS) of 8.4 months(4.5-12.8) with a 1-year overall survival rate of 96% (95% CI: 91-100). In our analysis for safety (n=102), common G≥ 3 AEs calculated was thrombocytopenia in 20% (95% CI: 7.5-43.7), neutropenia in 14.3% (95% CI: 3.7-41.6), fatigue in 9.1% (95% CI: 5.0-16.2), diarrhea in 5.7% (1.1-25.5), nausea in 5.7% (95% CI: 1.4-20.2) and peripheral neuropathy in 5.7% (95% CI: 1.4-20.2). Ixazomib in three drug regimen: In RRMM, the efficacy of Ixa was evaluated inten clinical trials (n=646), an ORR of 56.3% (95% CI: 41.8-65.5, I2=82%) with ≥VGPR of 22.8% (95% CI: 13.2-36.4) was noted. Best response was seen when Ixa was used in combination with lenalidomide (R) and dexamethasone, with reported ORR of 78.3%. Common AEs were neutropenia 23.5% (95% CI: 16-33.1), thrombocytopenia 18.8% (95% CI: 13.4-25.6) anemia 10.5% (95% CI: 8.2-13.2), diarrhea 6.3% (95% CI: 3.4 -11.3), fatigue 4.2% (95% CI:2.7-6.4), nausea 1.8% (95% CI: 0.9-3.5) and peripheral neuropathy 2.3% (95% CI: 1.3-3.9). Ixazomib Based Regimen In NDMM: Pooled analysis of subgroup study for combination regimen of Ixa as IRD, Ixa-Thalidomide (T)-D, Ixa-Cyclophosphamide (C)-D, and with Ixa -melphalan-prednisone (IMP), their estimated ORR was 83.7% (95% CI: 75.6-89.5), 80.8% (95% CI: 72.8-86.9), 75% (95% CI: 66.6-82) and 66% (95% CI: 52.4-77.4) respectively. We also measured the efficacy of Ixa as a maintenance therapy, estimated ORR was 81.5% (95% CI: 36.6-97.1, I2=90.5%). In one phase II maintenance study (n=64), a combination of IR receiving patients (n=34), an ORR of 90.4% with VGPR of 53% was reported. Median progression-free survival (PFS) was not reached after a median follow up of 37.8 months and estimated 2-year PFS was 81%. Common G≥3 AEs in NDMM patients were neutropenia 21.6% (95% CI: 11.2-37.6), thrombocytopenia 15.9% (95% CI: 4.7- 42), infections 15.2% (95% CI: 10.3-21.9) and peripheral neuropathy 7.9% (95% CI: 4.7-13). Conclusion: In our pooled analysis (95%CI), Ixazomib has shown promising efficacy both in NDMM as well as RRMM. Especially in three drug regimen it showed an estimated ORR of 84.8% in NDMM and 56.3% RRMM.Cytopenia was a common side effect.Peripheral neuropathy was noted to be a rare side-effect (2.6%) in RRMM. Further studies are required to evaluate efficacy and safety of ixazomib in combination therapies in NDMM. Disclosures No relevant conflicts of interest to declare.

Relative Risk of Adverse Events and Treatment Discontinuations Between Older and Non-Older Adults Treated with Antimuscarinics for Overactive Bladder: A Systematic Review and Meta-Analysis

Drugs & Aging ◽  
2019 ◽  
Vol 36 (7) ◽  
pp. 639-645 ◽  
Author(s):  
Silken A. Usmani ◽  
Kristine Reckenberg ◽  
Olivia Johnson ◽  
Paul M. Stranges ◽  
Besu F. Teshome ◽  
...  
Keyword(s):  
Systematic Review ◽  
Older Adults ◽  
Relative Risk ◽  
Overactive Bladder ◽  
Adverse Events ◽  
Meta Analysis

scholarly journals A systematic review and meta-analysis of sarcopenia as a prognostic factor in gynecological malignancy

2020 ◽  
Vol 30 (11) ◽  
pp. 1791-1797
Author(s):  
Emma R Allanson ◽  
Yang Peng ◽  
Angela Choi ◽  
Sandra Hayes ◽  
Monika Janda ◽  
...  
Keyword(s):  
Systematic Review ◽  
Overall Survival ◽  
Adverse Events ◽  
Meta Analysis ◽  
Gynecological Cancer ◽  
Progression Free Survival ◽  
Free Survival ◽  
Gynecological Oncology ◽  
Gynecological Malignancy ◽  
Gynecological Malignancies

IntroductionSarcopenia is a condition described as the progressive generalized loss of muscle mass and strength. While sarcopenia has been linked with poorer outcomes following a variety of malignancies, its relationship with all gynecological cancer clinical outcomes has, to date, not been evaluated. This review interrogates the concept of sarcopenia as a prognostic tool for oncological outcomes and adverse effects of treatments in all primary gynecological malignancies.MethodsThis systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines, searching PubMed, Embase, and CINAHL without date or language restriction for studies reporting on sarcopenia and gynecological malignancies. Random effects meta-analysis models were used to determine the effects of sarcopenia on progression-free survival, overall survival, and treatment-related adverse events.ResultsData were analyzed from 13 studies, including 2446 patients (range 60–323) with ovarian cancer (n=1381), endometrial cancer (n=354), or cervical cancer (n=481). Sarcopenia was associated with lower progression-free survival (HR 1.69, 95% CI 1.03 to 2.76), overall survival (HR 1.33, 95% CI 1.08 to 1.64), and no increase in adverse events (HR 1.28, 95% CI 0.69 to 2.40). The risk of bias of the studies was mostly rated unclear, and Begg’s and Egger’s test revealed a potential publication bias for progression-free survival and overall survval, although the HRs remained significant when adjusting for it.ConclusionSarcopenia is associated with worse progression-free survival and overall survival in gynecological oncology malignancies. Further research is warranted to validate these findings in larger and prospective samples using standardized methodology and to examine if an intervention could reverse its effect in gynecological oncology trials.

Cutaneous Adverse Events in Chronic Hepatitis C Patients Treated With New Direct-Acting Antivirals

2015 ◽  
Vol 20 (1) ◽  
pp. 58-66 ◽  
Author(s):  
Parth Patel ◽  
Kunal Malik ◽  
Karthik Krishnamurthy
Keyword(s):  
Systematic Review ◽  
Chronic Hepatitis ◽  
Relative Risk ◽  
Adverse Events ◽  
Meta Analysis ◽  
Pegylated Interferon ◽  
Direct Acting Antivirals ◽  
Incidence Risk ◽  
Direct Acting ◽  
Chronic Hepatitis C Patients

Background: Direct-acting antivirals (DAAs) are known to present with additional dermatological events over pegylated-interferon/ribavirin (Peg-IFN/RBV). Objective: A systematic review and meta-analysis was conducted to assess the incidence/risk of cutaneous adverse events (AEs) for simeprevir, sofosbuvir, ABT450/r-ombitasvir, dasabuvir, ledipasvir, daclatasvir, and asunaprevir. Methods: The databases searched included PubMed, Clinicaltrials.gov, and Clinicaloptions.com. Data on telaprevir and boceprevir were obtained from a previous study. Results: The incidences of cutaneous AEs were 34.3% (95% CI 18.4%-54.8%) for the old DAAs + Peg-IFN/RBV, 22.0% (95% CI 17.9%-26.8%) for the new DAAs + Peg-IFN/RBV, 9.8% (95% CI 8.6%-11.2%) for the DAAs + RBV, and 3.8% (95% CI 2.4%-6.1%) for DAAs only. Simeprevir + Peg-IFN/RBV was associated with an increased relative risk over Peg-IFN/RBV; RR = 1.319 (95% CI 1.026-1.697). Conclusion: Dermatological events are still an important issue for many of the new DAAs. Appropriate monitoring, management, and patient education are needed to minimize AEs and achieve HCV cure.

scholarly journals Efficacy Analysis of Different FLT3 Inhibitors in Relapsed/Refractory Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome Patients - a Systematic Review and Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1225-1225
Author(s):  
Mahesh Swaminathan ◽  
Mai M M Aly ◽  
Katherine G. Akers ◽  
Seongho Kim ◽  
Harry Ramos ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Meta Analysis ◽  
Complete Response ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Abstract Background: Mutations in FMS like tyrosine kinase gene 3 (FLT3) are the most common genetic aberrations in acute myeloid leukemia (AML). Internal tandem duplications (ITD) are the most frequent FLT3 mutations, occurring in 20-30% of patients (pts) with newly diagnosed AML, and a minority are tyrosine kinase domain mutations. FLT3 mutation confers adverse prognosis in pts treated with standard chemotherapy (chemo) alone, and relapse risk is also higher compared to FLT3-wild type AML (HR-1.75). Studies of FLT3 inhibitors as monotherapy or in combination with chemo in the treatment of pts with FLT3-ITD relapsed/refractory (R/R) AML are associated with mixed results. No evidence synthesis has yet focused on the effect of FLT3 inhibitor alone in the treatment of R/R AML and high-risk myelodysplastic syndrome (HR-MDS). Hence, we analyzed the efficacy of various FLT3 inhibitors from different clinical trials used as monotherapy to treat pts with R/R AML and HR-MDS. Methods: We conducted a systematic review and meta-analysis of clinical trials of FLT3 inhibitors for pts with R/R AML and HR-MDS. We searched EMBASE and PubMed for clinical trials published between 1/1/2000 and 5/26/2021 using a combination of keywords and subject headings related to FLT3 inhibitors and AML. Titles/abstracts and full texts were screened by two independent reviewers, with conflicts arbitrated by a third reviewer. Studies were included if they were (1) full-length published journal articles that (2) reported the results of single-arm or double-arm phase I/II/III clinical R/R AML or HR-MDS. Outcomes of interest were composite response rate (CRc=complete response + complete response with incomplete count recovery) and overall response rate (ORR). Results: Thirty studies were included after the application of inclusion criteria (Figure 1). Two were excluded due to inadequate representation of pts with R/R AML and outcomes reported for stem cell transplant following FLT3 inhibitor use, respectively. Hence, 28 studies were included in the meta-analysis, with a total of 1927 pts. Quizartinib and sorafenib were the most frequently studied inhibitors (6 and 5 studies, respectively, Table 1). Heterogeneity testing was performed using Cochran's Q test and I 2 values. The Cochran's Q test p-value was less than 0.10 (p<0.01), and the I 2 value was more than 50% (I 2=87%), indicating the presence of heterogeneity. Thus, random-effects models were used. Asymmetry test was performed using Egger's linear regression test, which suggested the presence of publication bias (p=0.001; Figure 2). Thus, the trim-and-fill method was used to adjust for publication bias. Pooled ORR was 53% (95% CI, 43-63%) (Figure 2). Similarly, pooled CRc was 34% (95% CI, 26-44%, Figure 3). Pooled CRc and ORR were higher in studies involving quizartinib (40% and 61%, respectively) and gilteritinib (40% and 52%, respectively, Table 1). The CRc rates seen with FLT3 inhibitors are higher than the historical comparison of pts with FLT3-mutated-R/R AML treated with chemo only (CRc ~15%). This meta-analysis shows that FLT3 inhibitors as monotherapy leads to meaningful clinical responses in pts with FLT3-mutated-R/R AML. Conclusion: Most FLT3 inhibitors are effective as monotherapy for the treatment of pts with FLT3-mutated-R/R AML. Pooled response rates are notably higher in studies involving second-generation FLT3 inhibitors, particularly quizartinib and gilteritinib. Though not conclusive, the efficacy spectrum of various FLT3 inhibitors in the R/R setting could help design future studies and guide appropriate treatment selection; however, further validation is needed. Prospective clinical trials are required to compare the effectiveness of newer generation FLT3 inhibitors in pts with FLT3-mutated-R/R AML. Figure 1 Figure 1. Disclosures Maciejewski: Bristol Myers Squibb/Celgene: Consultancy; Novartis: Consultancy; Regeneron: Consultancy; Alexion: Consultancy. Balasubramanian: Servier Pharmaceuticals: Research Funding.

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