Ukwuru Therapeutics is an Ukwuru science research journal. It spans all therapeutics research conducted by Ukwuru Science Study Group (USSG), Independent Researchers (IR), and Companies.
Ukw Thera. 2024; 24(10): 1-20. Published Online 2024 October 16
UkwSciID: USThera1
FLT3 DUAL THERAPY IS MORE EFFECTIVE AND SAFER THAN FLT3 MONO THERAPY FOR TREATMENT OF AML: A SYSTEMATIC REVIEW AND META-ANALYSIS
Edmund Ikpechi Ukwuru, and Onyinye Lydia Okeke
1
1, 2
Ukwuru, E.I. and . (2024). FLT3 Dual Therapy is more Effective and safer than FLT3 Mono Therapy For Treatment of AML: A Systematic Review And Meta-Analysis. Ukwuru Therapeutics, 24(10): 1-20.
Abstract
Background
Acute myeloid leukaemia is a debilitating health condition that has evolved to pose serious threat and resistance to treatment. This has led to the development of FLT3 dual therapies that can resolve the problem of resistance faced by FLT3 monotherapy.
Method
We identified 258 studies from EMBASE and PubMed. We screened them in line with PRISMA flowchart and included 14 randomised controlled trial studies. Review Manager version 5.4.1 was used to carry out dichotomous analysis on the two types of therapies. We applied Mantel-Haezel, odds ratio, risk ratio, and Fixed Effects meta-analysis, and set confidence interval at 95%. Significance was tested at 0.00001.
Findings
FLT3 dual therapy is significantly more effective than the monotherapy (p<.00001). Both FLT3 dual therapy and FLT3 monotherapy are equally safe (p<.00001).
Conclusion
FLT3 dual therapy is more effective and safe for treating AML. They surmount the effect of resistance that is faced by FLT3 monotherapy.
Recommendations
FLT3 dual therapy should be used for the management of AML.
Keywords: FLT3, dual therapy, monotherapy, inhibitors, resistance
Introduction
There are various molecular conformations of Acute myeloid leukemia (AML) that have been documented (Ravandi et al., 2013). According to Serve et al. (2013) these different molecular conformations are linked to different expressions of the disease. Serve et al. (2013) also asserts that severe clinical outcomes can be anticipated if patients present with tyrosine kinase (TK) mutations as well as mutations to FMS-like tyrosine kinase 3 (FLT3) receptor-internal tandem duplications (ITD). FLT3 is a known type III receptor; other types of type III receptors include PDGFR, KIT, and FMS. There are five (5) immunoglobulin-like domains within the extracellular region; these Ig-like domains include, the jusxtamembrane (JM) domain, the TK domain which is separated by a Kinase insert (KI) domain, and a C-terminal domain that is identified in the intracellular region (Röllig et al., 2015).
FLT3 is commonly expressed on lineage-limited progenitor cells as well as FLT3 ligand (FL) that can activate FLT3 (Stone et al., 2017). This causes a chain-like reaction that involves the activation of FLT3 and the several signal pathways for the upregulation of FLT3 on leukemic blasts. Also, the activation of FL signalling regulates the expression of leukemic blast apoptosis (serve et al., 2013). Ravandi et al. (2013) noted that the coding sequence domain of the justamembrane is characterized by an internal tandem duplication (ITD), a missense point mutation located on residue of deletions to D855, as well as insertions in D835 within the mutations to FLT3-TKD. These type of mutations involving FLT3-ITD and FLT-TKD can be identified in 25%-50% of patients diagnosed with acute myeloid leukaemia (Lange et al., 2018). Röllig et al. (2015) noted that these frequently identified mutations of FLT3 contribute to severe clinical presentation.
Figure 1
There are five domains of FLT3 tyrosine kinase; these are, the tyrosine kinase domain (TKD), the extracellular receptor tyrosine kinase (RTK), the justamembrane domain, the kinase insertion domain, and the C-terminus intracellular domain. It is the justamembrane domain that binds the internal tandem duplication (ITD) mutation and is implicated in the RTK function gain. In the event that there is a loss of auto-inhibition, it results from deletions or mutations in the TKD. A highly prevalent TKD mutation involves residue D835 that is identified in the activation loop of TKD and is capable of lowering the binding affinity of type II inhibitors. Mutations involving the gate keeper residue F691 can be identified in the TKD and can bring about resistance to type I and II inhibitors. When ITD and TKD are mutated, it causes constitutive activation of the downstream proliferative signalling cascades. Types I inhibitors are capable of binding to both the active and inactive structural forms of FLT3 at the ATP binding site while type II inhibitors are capable of binding to a site that is positioned adjacent to the ATP binding site only in the active conformation.
In the management of acute myeloid leukaemia (AML), there are several important molecular markers; however, mutation to FLT3 presents as the most remarkable for managing acute myeloid leukaemia. Until recently, the 7+3 induction therapy has served as the front-line standard chemotherapy that is used in the management of acute myeloid leukaemia. The advent of FLT3 inhibitors became a highly effective alternative for managing AML in people who are carriers of mutations to FLT3 (Feldman et al., 2017). The most prominent therapies include midostaurin which was approved by the FDA in 2017 (Loschi et al., 2021). Gilteritinib – a FLT3 inhibitor with a small molecular size, and is suitable for managing patients with relapsed or refractory (R/R) AML and patients who present with mutations to FLT3. Despite the efficacy of FLT3 inhibitors in people who present with high risk of FLT3 mutation, the major challenge is in the possibility of administering them to patients who present with complicated conditions (Wang et al., 2021).
Some of the first-line therapy for FLT3-ITD-mutated AML include; Midostaurin, Sorafenib, and Lestauritinib. Sorafenib is a first generation FLT3 inhibitor that is capable of acting within the kinase inhibition domain; examples include, PDGFR, RAF-1, VEGFR, ERK, FLT3, and c-KIT. Sorafenib is important as an anti-cancer agent for cells of AML that are FLT3 mutated. Liu et al. (2018) pointed out that the activity of FLT3-ITD inhibition results in an IC50 of 68.3 ng/mL. There are various mechanisms that can be used to explain the clinical implications of sorafenib in managing AML. Sorafenib can facilitate secretion of interleukin-15 through the cells of AML that are FLT-ITD mutated; this results in increased survival rate among AML patients who present with FLT-ITD mutation (Serve et al., 2013; Ravandi et al., 2013; Röllig et al., 2015; Lange et al., 2018; Feldman et al., 2017; Ohanian et al., 2018; Röllig et al. 2021).
The effectiveness of Midostaurin has also been demonstrated (Fiedler et al., 2015). Midostaurin is also a first-generation FLT3-inhibitor like sorafenib; however, it is a dual inhibitor that targets ITD and TKD, and a major activity against c-KIT, PDGFR- β, protein kinase C, and VEGFR. Midostaurin is capable of inhibiting the signalling pathways that are regulated by kinases, this leads to cellular growth inhibition. The activation of midostaurin occurs on FLT3-ITD, as well as the kinases that are derived from TKD. The metabolism of Midostaurin by CYP3A4 causes drug-drug interaction, a major disadvantage (Fiedler et al., 2015). Midostaurin is intended mainy for people who are experiencing relapse from AML and patients diagnosed with FLT3-WT and FLT3-mutation. These groups of patients are commonly identified with cytoreduced or terminated PB leukemic blasts. Patients who have recently been diagnosed with FLT3 mutation or systemic mastocytosis, midostaurin presents as an effective option for treatment.
Another known agent is Lestauritinib. Lestauritinib is a polyarinatic infolocarbazole that is very effective in the inhibition of receptor kinase of tropomyosin. It can target Trk A, Trk B, and FLT3, as well as inihibits JAK2 and JAK3 (Stone et al., 2017; Loschi et al., 2021). Crenolanib is another agent whose activity is somewhat like that of Lestauritinib, and it can inhibit FLT3 against the mutations of ITD and TKD. It is also a known inhibitor of PDGFR, but has no activity against c-KIT. Crenolanib is a dual inhibitor of FLT3; this makes it very important for preventing relapse in patients who have received FLT3 specific inhibitors. Mutations involving the gate keeper residue F691 can be identified in the TKD and is likely to lead to resistance in both inhibitors of type I and II. When a mutation to ITD and TKD occurs, a constitutive activation of the downstream proliferative signalling cascade is recorded. It is possible for type I inhibitors to bind to both the active and inactive structural forms of FLT3 as well as the ATP binding site. On the other hand, type II inhibitors are capable of binding to sites that are located adjacent to ATP binding sites in the inactive conformation only.
Wu et al. (2018) noted that FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) was the first gene identified in 1996 as a frequently mutated gene in AML. It is this mutation that causes resistance to conventional therapy, causing the need to use an alternative therapy such as hematopoietic stem cell transplantation (HSCT). Despite the use of HSCT, 60% of patients are still likely to relapse, causing a 30%-40% cure rate in AML. About 30% of AML patients possess the FLT3/ITD gene; for this reason, drugs like sorafenib were developed to inhibit the gene. Findings from Yuan et al. (2019) have noted that the specific targeted inhibition of FLT3 receptor tyrosine kinase has been remarkable in treating FLT3 mutation AML. Nonetheless, there is a potential challenge of presenting with resistance to treatment due to the use of a specific or mono inhibitor such as sorafenib. This problem led to the development of dual inhibitors such as Crenolanib, Gilteritinib, Lestauritinib, and Midostaurin. These dual inhibitors are capable of inhibiting FLT3 and another target; example, FLT3 and CDK4, or Mer, JAK2, MEK, and Pim. This prevents the expression of any resistance. There are other inhibitors such as KX2-391 Wang et al. (2021), HSD1169 Dayal et al. (2018). This study sought to confirm whether dual inhibitors were more effective than specific inhibitors.
Method
Search Strategy
The study search lasted a total of 65 days. PubMed, SCOPUS, Web of Science, and Clinicaltriasl.gov were searched during that time. The Population, Intervention, Comparator, and Outcome (PICO) research framework was used to frame the search string.
The population was individuals in a randomized controlled studies who were above the age of 18 years and had received either monotherapy or dual-therapy of FLT3 inhibitors for treatment of AML.
The intervention was FLT3 dual inhibitors of any kind, while the comparator was FLT3 monotherapy.
The primary outcome was the efficacy of FLT3 dual inhibitors, viewed as preventing of resistance within the first four-months of treatment.
The Preferred reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist (figure II) was used for the screening of studies to be included in the meta-analysis.
Figure II: PRISMA Flowchart
Figure II: The initial study search on EMBASE and PubMed resulted in 258 studies among which fourteen (14) studies met the inclusion criteria for the final quantitative analysis. After excluding the duplicate studies, there were 240 studies left for screening based on abstracts, which yielded 38 studies. All 38 studies underwent full text screening based on the inclusion and exclusion criteria, leaving a total 14 randomised controlled trial studies that featured several specific and dual FLT3 inhibitors
Critical Appraisal
Cochrane Critical Appraisal Skills Programme (CASP) tool was used for the appraisal of studies. Afterwards, data was extracted from the studies in line with the PICO framework.
Data Extraction and Data Analysis
Data was extracted in line with the PICO framework. Review Manager version 5.4.1 was used for the analysis. A fixed effects meta-analysis was carried out using odds ratio analysis because an I2 value >50% (98%) as obtained. Mantel-Hazel test, and 95% confidence interval were also used. Chi square analysis was used to determine the level of heterogeneity and it was significant at p<.00001. Z score test was also used to determine the level of significance at p<.00001.
Results
Characteristics of Included Studies
Drug
Only one study was carried out on Sorafenib Borthakur et al. (2020), There were also single studies identified on four other drugs; Pacritinib Jeon et al. (2020); Ponatinib Shah et al. (2013), Pexidartinib Smith et al. (2020), and EMND-2076 Yee et al. (2016). Three studies were conducted on Gilteritinib Perl et al. (2017); Perl et al. (2019); and Usuki et al. (2018). There were six studies conducted on quizartinib Cortes et al. (2013); Cortes et al. (2018a); Cortes et al. (2018b); Cortes et al. (2019); Takahash et al. (2019); and Usuki et al. (2019) (Table I).
Phase
Nine of the studies were in their first phase Cortes et al. (2013); Shah et al. (2013); Yee et al. (2016); Perl et al. (2017); Usuki et al. (2018); Usuki et al. (2019); Jeon et al. (2020); Borthakur et al. (2020); Smith et al. (2020). Three of the studies were in their second phase included; Cortes et al. (2018a); Cortes et al. (2018b); and Takahash et al. (2019). Only two studies were in their third phase; Cortes et al. (2019) and Perl et al. (2019) (Table I).
Table I: The Baseline features of the included studies
Table I: The summary of all the studies included in the Meta-Analysis; their respective clinical trial registration number are also indicated. Other information in the table include, the median age range, the population of participants, and the population of male participants. (a) refers to FLT3 dual inhibitors while (b) refers to specific FLT3 inhibitors.
Based on table II; Usuki et al. (2018); Cortes et al. (2019); Takahashi et al. (2019) revealed that majority of the participants went into remission after receiving the medicines.
There were no adverse events recorded among majority of the participants in the trials by Perl et al. (2019); Smith et al. (2020); Cortes et al. (2018a); Cortes et al. (2013); Cortes et al. (2018b); Takahashi et al. (2019); Borthakur et al. (2020).
Table II: Summary of outcomes of the included studies
Table II: The efficacy or remission data as well as the results for adverse events are recorded. Most of the participants presented with no incidence of remission. There were also few presentations of adverse events.
The Efficacy of Specific and Dual FLT3 inhibitors
The efficacy of the included studies was carried out (figure IIIA), and studies were organised based on the type of inhibitors that had been trialed. Also, the drugs that had been trialled were indicated alongside the study reference.
The specific inhibitors included [Quizartinib Cortes et al. (2013); Cortes et al. (2018a); Cortes et al. (2018b); Cortes et al. (2019); Takahashi et al. (2019); Usuki et al. (2019); and Sorafenib Borthakur et al. (2020)].
The dual inhibitors included ENMD-2076 Yee et al. (2016); Gilteritinib Perl et al. (2017); Perl et al. (2019); Usuki et al., 2018; Pacritinib Jeon et al. (2019); Pexidartinib Smith et al. (2020); Ponatinib Shah et al. (2013).
Comparison carried out for remission or no remission as seen in figure 3A shows that the largest study weight (20.4%) was recorded for Cortes et al. (2018b); apparently, it had the highest number of study participants. The implication of having such a large sample size or study weight is that it contributes to the reliability of the findings. Also, the larger the study weight, the shorter the arms of the confidence interval. In contrast, the longer the arms of the confidence interval, the smaller the study weight and the less reliable the study is.
Among the dual inhibitors, Perl et al. (2017) presented with the largest study weight of (25.2%), this was seconded by Perl et al. (2019) with a study weight of 22.8%. this large study weights explains the short arms of their confidence intervals, an indication of high level of reliability.
The alignment of the confidence intervals is heterogeneous; this is indicated by the disordered or non-uniform sequential arrangement. Also, the confidence interval plots for all the studies are not on the same size of the forest plot; Cortes te al. (2018a) and Cortes et al. (2019) are on the side of no remission. Some of the studies Takahashi et al. (2019); Usuki et al. (2019) have made contact with the line of no significant difference. The black diamond at the base is on the side that favours no remission, indicating that specific inhibitors are more likely to result in no remission. The difference is statistically significant (p<.00001) for the level of heterogeneity of the studies, and the Z score is also statistically significant (p<.00001) – an indication that the meta-analysis is conclusive.
For the analysis of dual inhibitors, majority of studies were on the side that favoured remission; only the study by Usuki et al. (2018) was on the side that favours no remission, yet it crossed the line of no significance. The heterogeneity of the studies was low, and the difference was no statistically significant (p=.00005). The Z score was statistically significant (p<.00001). The black diamond was on the side of remission, an indication that the dual inhibitors were more likely to result in remission.
The combined outcomes of the meta-analysis of both specific and dual inhibitors shows that the meta-analysis favoured no-remission; meaning that dual inhibitors were more likely to achieve remission than the specific inhibitors. The meta-analysis was significant (p<.00001).
Figure IIIA: FLT3 Dual Inhibitors are more likely to result in remission of Acute myeloid leukaemia.
A. The forest plots show that the likelihood of remission due to treatment is higher compared to no remission, this is evidenced by the forest plot favoring remission over non-remission, and Dual inhibitors are the better alternative for achieving remission, when compared to specific inhibitors.
The heterogeneity of the studies is also indicated by figure IIIB which shows that the studies are disorderly arranged around the line of average rather than forming a funnel shape within the lines of no effect.
Figure IIB: The funnel plot analysis shows that there is a large heterogeneity between the study sub-groups. The black circles are the Specific inhibitors, the red boxes are the dual inhibitors. Majority of the circles and boxes do not align within the confidence intervals, instead they are randomly distributed around the sides of the funnel. Larger studies ought to align at the top of the funnel, near the center line of average, while smaller studies are to be distributed at the base.
The Safety and Tolerability of Specific and Dual FLT3 inhibitors
For the specific inhibitors (figure IVA); Cortes et al. (2018b) had the largest study weight (28.7%) while Cortes et al. (2019) had the second largest study weight (21.1%). Cortes et al. (2013); (2018b), Takahashi et al. (2019) and Borthakur et al. (2020) were all on the side that favours incidence of adverse events. The rest of the studies on specific inhibitors were on the side that favours no adverse events. The black diamond at the base is also on the side that favours adverse events; an indication that specific inhibitors were likely to result in adverse events. The Z score resulted in a statistically significant difference (p<.00001).
For the dual inhibitors, Jeon et al. (2019) had its centre on the line of no effect; Perl et a. (2019) and Shah et al. (2013) are both on the side that favors adverse events, while Yee et al. (2016) and Usuki et al. (2018) are on the side that favours no adverse events. The black diamond is on the side that favours adverse events. The implication is that dual inhibitors are more likely to result in adverse events. The p value for the Z score was statistically significant (p<.00001).
The overall meta-analysis shows that both specific and dual inhibitors are likely to result in adverse events (black diamond is on the side that favours adverse events). The Z score was statistically significant (p<.00001).
Figure IVA: Administering either specific or dual FLT3 inhibitors can result in adverse events.
Figure IVA: The majority of the forest plots are on the side that favours adverse events in both the specific inhibitor subgroup, and the dual inhibitor subgroup. The black diamonds for the subgroups and the overall effect are on the side that favors adverse events which supports the claim that either drug could result in adverse events.
High level of heterogeneity was also recorded. This is evident in the distribution of studies in a non-funnel pattern in figure IVB.
Figure IVB: The heterogeneity between the studies is demonstrated by the funnel plots, the circles represent the specific inhibitors, while the boxes represent the dual inhibitors. The larger studies did not align near the top of the line of average, neither are the smaller studies randomly distributed at the base, in stead they can be found at other parts of the plot and outside the funnel.
Discussion
The findings here an indication that FLT3 dual inhibitors are better for achieving remission than FLT3 specific inhibitors. This is in line with the findings of Swaminathan et al. (2022) in which, the effectiveness of FLT3 dual inhibitors over FLT3 specific inhibitors was much higher. In another study, Yang et al. (2018) and Xu et al. (2021) also revealed that FLT3 dual inhibitors were more effective for achieving remission that the FLT3 specific inhibitors. The effectiveness of FLT3 dual inhibitors over FLT3 specific inhibitors can be explained by looking at the effectiveness of combination therapies compared to single therapies. Combination therapies utilise two or more active ingredients that target either one or more etiologic sites. FLT3 dual inhibitors were designed to combat two crucial sites and prevent the development of resistance that is observed with FLT3 specific inhibitors. Our findings are also like that of Ghobain et al. (2022) on the basis that a dual combination drug can achieve more positive outcomes than a single target drug.
Adverse events commonly present when providing treatment for some illnesses. Our study revealed that both specific and dual inhibitors were likely to result in adverse events. The meta-analysis showed that more studies carried out on specific inhibitors leaned towards adverse events than the parity observed for dual therapy studies. This implies that there is a possibility that dual inhibitors may be less likely to result in an adverse events. Adverse events commonly recorded include; anaemia, diarrhoea, hypoxia, hypokalemia, and elevated levels of aspartate aminotransferase. Studies conducted by Majothi et al. (2020); Xu et al. (2021); and Swaminathan et al. (2022) revealed that FLT3 inhibitors are safe. Especially because they do not result in severe or fatal damages, they can be administered with caution.
In general, our findings imply is that FLT3 dual inhibitors can be used for achieving effective outcomes in treatment of AML. Further efforts can focus on monitoring manifestations of adverse events that may be dose-related, or influenced by other physiological factors. Studies such as Wang et al. (2021) and Alotaibi et al. (2021) have conformed that dual therapies are very suitable for achieving the best care outcomes. Apparently future studies can take this into consideration in attempting to minimize the effect of sample size.
Conclusion
Due to increased resistance to specific inhibitors, dual inhibitors were developed to combat any form of resistance, and they have proven to be effective in the treatment of acute myeloid leukaemia in randomised controlled trial studies. Thus, this study was conducted to determine the efficacy and safety of FLT3 specific inhibitors compared to dual inhibitors in a systematic review and meta-analysis. Studies retrieved from databases, screened, and included in the final quantitative synthesis were grouped into two subgroups; specific inhibitors and dual inhibitors. The analysis was carried out on review manager, and findings showed that specific inhibitors were less effective in achieving complete remission when compared to dual inhibitors. Both specific inhibitors, and dual inhibitors are likely to result in adverse events, and dual inhibitors are more likely to result in adverse events compared to specific inhibitors based on the distribution of studies in the forest plot. The findings in this study; on the basis of efficacy, confirm the evidence in randomised controlled trials that assert the efficacy of dual inhibitors, and when compared to other meta-analysis, the findings are similar. In the case of adverse events, there is difference between this study and other studies. Overall, this study demonstrates that FLT3 dual inhibitors are highly effective for achieving composite complete remission with non-lethal adverse events in the treatment of acute myeloid leukaemia.
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Acknowledgements
We acknowledge the efforts of Ukwuru Science Management team and Ukwuru Science Study Group in bringing this study to reality.
Funding
Funding was provided by Ukwuru Science.
Author Information
Edmund Ikpechi, Ukwuru is the research director at Ukwuru Science Lagos. He works with a number of private organisations and individuals, consulting on public health and biomedical science research. He is also a Management Consultant and holds a Honorary Doctor of Business Administration (DBA) for his expertise in business practices.
Corresponding Author
Edmund Ikpechi, Ukwuru
Competing Interests
There are no competing interests for this study.
Rights
The publication is open for public use; credits must be provided by acknowledging the authors of the study.
Cite as
Ukwuru, E.I. and . (2024). FLT3 Dual Therapy is more Effective and safer than FLT3 Mono Therapy For Treatment of AML: A Systematic Review And Meta-Analysis. Ukwuru Therapeutics, 24(10): 1-20.
Received: 1 August 2024
Accepted: 1 October 2024
Published: 10 October, 2024
Keywords: FLT3, dual therapy, monotherapy, inhibitors, resistance.