scholarly journals Safety and Efficacy of Tyrosine Kinase Inhibitors in Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-18
Author(s):  
Farwah N. Fatima ◽  
Faiz Anwer ◽  
Muhammad Ashar Ali ◽  
Muhammad Yasir Anwar ◽  
Sana Khan ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Placebo Group ◽  
Myeloid Leukemia ◽  
Randomized Clinical Trials ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Salvage Chemotherapy ◽  
Grade 3 ◽  
Acute Myeloid

Introduction: Five year overall survival for acute myeloid leukemia (AML) is estimated to be less than 30%. Encouraging results seen with the tyrosine kinase inhibitors (TKIs), midostaurin and gilteritinib resulted in the approval of these molecular targeted therapies for patients with FLT3 Mutated AML. Other TKIs like sorafenib and quizartinib, have ongoing clinical trials. In this systematic review and meta-analysis, we assessed the efficacy and safety of TKIs for the treatment of newly diagnosed (ND) and relapsed refractory (R/R) AML. Methods: A search was performed on PubMed, Cochrane, Embase, and clinicaltrials.gov. We used the keywords "tyrosine kinase inhibitors" AND "acute myeloid leukemia" from the inception of literature till 07/10/2020. We screened 3245 articles and included 5 randomized clinical trials (RCTs) (N=1919) in this meta-analysis. We extracted data for efficacy (i-e, OS, CR, ORR, EFS) and safety (≥grade 3 treatment related adverse events (TRAE). We excluded case reports, case series, preclinical studies, review articles, meta-analysis, observational studies, and controlled clinical studies not providing any information about the efficacy or safety of TKI. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: In the 5 RCTs (n=1919), the age range was 18-85 years. 1675 participants had FLT-3 mutation (Table 1). In 2 RCTs (N=738), two TKIs (gilteritinib and quizartinib) (N=492) were compared with salvage chemotherapy (N=246). Risk ratio (RR) of overall response rate (ORR) and complete remission (CR) was 2.43 (95% CI=1.97-3.00, I2=0) and 2.09 (95% CI=1.5-2.90, I2=48%), respectively in favor of TKIs. The hazard ratio (HR) for overall survival (OS) was 0.70 (95% CI=0.58-0.84, I2=0) in favor of TKIs. (Fig 1-3). The median OS was 6.2 months in the quizartinib group vs. 4.7 months in the chemotherapy group. Similarly, median OS was 9.3 months in the gilteritinib group vs. 5.6 months in the chemotherapy group. Grade 3 or higher TRAEs (anemia, infections, sepsis, febrile neutropenia, and liver toxicity) were reported more often in the TKI group vs. salvage chemotherapy group. (Fig 4-6). In 3 RCTs (N=1181), two TKIs (midostaurin and sorafenib) (N=597) were compared with placebo (N=582). In the RCT evaluating role of sorafenib in older patients (>60 years) (N=197), RR of CR was 0.75 (95% CI=0.58-0.96) in favor of placebo. Although more patients died in the sorafenib group than the placebo group (23 vs 10 within 60-day period), TRAEs were similar in the two groups. In the remaining 2 RCTs, sorafenib and midostaurin were compared with placebo in younger patients (<60 years old) (N=982). RR of CR was 1.07 (95% CI=0.96-1.19, I2=0) in favor of TKIs and the hazard ratio for OS was 0.80 (95% CI=0.66-0.96, I2=0) in favor of TKIs (Fig 7,8). Median event-free survival (EFS) was 21 months in the sorafenib group vs. 9 months in the placebo group. Similarly, median EFS was 8.2 months in the midostaurin group vs. 3 months in the placebo group. Grade 3 or higher TRAEs (anemia, liver toxicity, infections, and diarrhea) were more common in the TKI group as compared to the placebo group. (Fig 9,10) Conclusion: Gilteritinib and quizartinib were not only better tolerated but also more effective than salvage chemotherapy in patients with FLT-3 mutated AML. In older patients, sorafenib appeared to have lower efficacy and higher toxicity when compared with placebo. In contrast, for younger patients, sorafenib and midostaurin had better efficacy and lower toxicity than placebo. Additional multicenter double-blind randomized clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

Thirty-year analysis of randomized clinical trials in patients with acute myeloid leukemia.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 7032-7032
Author(s):  
Sagar Suresh Patel ◽  
Tomas Radivoyevitch ◽  
Aaron Thomas Gerds ◽  
Navneet S. Majhail ◽  
Hetty Carraway ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Randomized Clinical Trials ◽  
Acute Myeloid

A Phase I Study Of Azacitidine After Donor Lymphocyte Infusion For Relapsed Acute Myeloid Leukemia Post Allogeneic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3320-3320 ◽  
Author(s):  
Armin Ghobadi ◽  
Mark A. Fiala ◽  
Camille N. Abboud ◽  
Amanda F Cashen ◽  
Linda Eissenberg ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Salvage Chemotherapy ◽  
Neutrophil Recovery ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Background Disease relapse remains a significant cause of morbidity and mortality for patients with acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT). In the event of relapse, remissions may be re-established with salvage chemotherapy, but are rarely durable. Reinfusion of additional donor lymphocytes (DLI) from the same donor without prophylactic immunosuppression has been used to potentially augment the graft vs leukemia (GVL) effect, and shown to prolong survival in the post alloSCT relapse setting (Schmid et al, JCO 2007). However, DLI is also associated with an increased incidence of acute graft versus host disease (aGVHD). Regulatory T cells (Tregs) are characterized by increased FoxP3 gene expression and have been correlated with a reduced incidence and severity of GVHD. Using a mouse model, Choi et al (Blood, 2010) observed that administration of azacitidine post stem cell infusion resulted in increases in both FoxP3 expression and Treg numbers, and reduced the incidence and severity of GVHD without hindering neutrophil engraftment. Based on these findings, we conducted a study of azacitidine following salvage chemotherapy and subsequent DLI for AML patients with post alloSCT relapse, with the goal of reducing the incidence and severity of aGVHD. Objectives (i) To establish the MTD of azacitidine administered after salvage chemotherapy and DLI in patients with relapsed AML after alloSCT and (ii) to determine the response rate, the rate of aGVHD, and overall survival of this regimen. Patient/Methods Patients with relapsed AML after allogeneic stem cell transplant undergoing salvage chemotherapy followed by DLI were eligible for enrollment. Patients with prior exposure to azacitidine were not excluded. Salvage chemotherapy was determined by the treating physician. Six to twenty-one days following the completion of chemotherapy, a DLI was administered consisting of > 1x106 CD3+ cells/kg. Azacitidine was administered on Days 4, 6, 8 and 10 post-DLI. G-CSF was administered daily beginning Day +11 post-DLI until neutrophil recovery. Dose escalation was done using a 3+3 design with two azacitidine dose levels, 45mg/m2 and 75mg/m2. Dose-limiting toxicity (DLT) was defined as treatment-related grade 3-5 non-hematologic toxicities or bone marrow suppression lasting past Day +32 in the absence of persistent AML. Results Eight patients were enrolled from June 2012-July 2013. The median age was 54.5 years (range 31-68) and five were female. Four of eight patients received stem cells from sibling donors. The median time post alloSCT until salvage chemotherapy was 109 days (range 56-1102). Pre-DLI chemotherapy consisted of: FLAG-Ida (3), FLAG (1), MEC (1), 7+3 (1), CLAM (1), or Azacitidine (1). Three patients were treated in the 45mg/m2 dose level and 5 patients were treated in the 75mg/m2dose level; no DLTs or grade 3-5 treatment related toxicities were observed. Five patients experienced aGVHD, all of which was grade I or II and easily controlled. The median duration of time to neutrophil recovery was 17 days post DLI (range 6-34) and 24 days from last day of salvage chemotherapy (range 16-41), similar to historical controls. Six patients achieved responses, including two cytogenetic complete remissions, one hematologic complete remission, and three complete remissions with incomplete blood count recovery; two patients failed to achieve remission. At the time of abstract submission, the median follow-up for all patients was 102 days (range 31-308). Four responders have subsequently relapsed and three patients have expired from refractory disease. Conclusion Administration of azacitidine post salvage chemotherapy and DLI is well tolerated and does not hinder neutrophil recovery. The recommended dose for further studies is 75mg/m2. Disclosures: Off Label Use: vidaza for GVHD prophylaxis. Abboud:Novartis: Honoraria; Ariad: Honoraria; Alexion: Honoraria; Teva: Speakers Bureau. Schroeder:sanofi-aventis: Research Funding; celgene: Research Funding. Stockerl-Goldstein:Celgene : Speakers Bureau; Millennium: Speakers Bureau. Vij:celgene: Honoraria, Research Funding. Westervelt:celgene: Honoraria, Research Funding.

scholarly journals Gilteritinib: a novel FLT3 inhibitor for acute myeloid leukemia

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Juanjuan Zhao ◽  
Yongping Song ◽  
Delong Liu
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Domain ◽  
Salvage Chemotherapy ◽  
Tyrosine Kinase Domain ◽  
Dual Inhibitor ◽  
Acute Myeloid

Abstract FMS-like tyrosine kinase 3- internal tandem duplication (FLT3-ITD) remains as one of the most frequently mutated genes in acute myeloid leukemia (AML), especially in those with normal cytogenetics. The FLT3-ITD and FLT3-TKD (tyrosine kinase domain) mutations are biomarkers for high risk AML and are associated with drug resistance and high risk of relapse. Multiple FLT3 inhibitors are in clinical development, including lestaurtinib, tandutinib, quizartinib, midostaurin, gilteritinib, and crenolanib. Midostaurin and gilteritinib have been approved by FDA for Flt3 mutated AML. Gilteritinib (ASP2215, Xospata) is a small molecule dual inhibitor of FLT3/AXL. The ADMIRAL study showed that longer overall survival and higher response rate are associated with gilteritinib in comparison with salvage chemotherapy for relapse /refractory (R/R) AML. These data from the ADMIRAL study may lead to the therapy paradigm shift and establish gilteritinib as the new standard therapy for R/R FLT3-mutated AML. Currently, multiple clinical trials are ongoing to evaluate the combination of gilteritinib with other agents and regimens. This study summarized clinical trials of gilteritinib for AML.

Gilteritinib use in the treatment of relapsed or refractory acute myeloid leukemia with a FLT3 mutation

2020 ◽  
Author(s):  
Octavio Ballesta-López ◽  
Antonio Solana-Altabella ◽  
Juan Eduardo Megías-Vericat ◽  
David Martínez-Cuadrón ◽  
Pau Montesinos
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Salvage Chemotherapy ◽  
Mechanisms Of Resistance ◽  
Flt3 Inhibitor ◽  
Refractory Acute Myeloid Leukemia ◽  
Dose Reductions ◽  
Acute Myeloid

The prognosis of patients with relapsed or refractory acute myeloid leukemia (R/R AML) is dismal with salvage standard approaches, and mutations of FMS-like tyrosine kinase 3 ( FLT3) gene, occurring in around 30% of AML patients may confer even poorer outcomes. Several targeted tyrosine kinase inhibitors have been developed to improve FLT3-mutated AML patient´s survival. Gilteritinib, a highly specific second-generation class I oral FLT3 inhibitor, has demonstrated superiority to salvage chemotherapy (SC) in R/R FLT3 mutated AML based on significantly longer OS in the gilteritinib arm than in the SC arm. Gilteritinib is generally well tolerated, but some clinically relevant adverse events should be monitored, especially myelosuppression, QTc prolongation and differentiation syndrome, usually manageable (dose reductions, interruption or discontinuation) and reversible. We discuss clinical development, efficacy, safety and mechanisms of resistance of gilteritinib in the treatment of R/R patients with FLT3 mutated AML.

scholarly journals How I treat refractory and early relapsed acute myeloid leukemia

Blood ◽  
2015 ◽  
Vol 126 (3) ◽  
pp. 319-327 ◽  
Author(s):  
Felicitas Thol ◽  
Richard F. Schlenk ◽  
Michael Heuser ◽  
Arnold Ganser
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Treatment Options ◽  
Salvage Chemotherapy ◽  
Hematopoietic Stem ◽  
Bridge To Transplant ◽  
Unfit Patients ◽  
Clinical Conditions ◽  
Acute Myeloid

AbstractBetween 10% and 40% of newly diagnosed patients with acute myeloid leukemia (AML) do not achieve complete remission with intensive induction therapy and are therefore categorized as primary refractory or resistant. Few of these patients can be cured with conventional salvage therapy. They need to be evaluated regarding eligibility for allogeneic hematopoietic stem cell transplantation (HSCT) as this is currently the treatment with the highest probability of cure. To reduce the leukemia burden prior to transplantation, salvage chemotherapy regimens need to be employed. Whenever possible, refractory/relapsed patients should be enrolled in clinical trials as we do not have highly effective and standardized treatments for this situation. Novel therapies include tyrosine kinase inhibitors, small-molecule inhibitors (eg, for Polo-like kinase 1 and aminopeptidase), inhibitors of mutated isocitrate dehydrogenase (IDH) 1 and IDH2, antibody-based therapies, and cell-based therapies. Although the majority of these therapies are still under evaluation, they are likely to enter clinical practice rapidly as a bridge to transplant and/or in older, unfit patients who are not candidates for allogeneic HSCT. In this review, we describe our approach to refractory/early relapsed AML, and we discuss treatment options for patients with regard to different clinical conditions and molecular profiles.

scholarly journals Gilteritinib versus chemotherapy in Japanese patients with FLT3-mutated relapsed/refractory acute myeloid leukemia

2021 ◽  
Author(s):  
Naoko Hosono ◽  
Hisayuki Yokoyama ◽  
Nobuyuki Aotsuka ◽  
Kiyoshi Ando ◽  
Hiroatsu Iida ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Drug Exposure ◽  
Japanese Patients ◽  
Salvage Chemotherapy ◽  
Flt3 Inhibitor ◽  
Common Grade ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Background Until recently, no effective targeted therapies for FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P < 0.001). Methods We evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC. Results Median OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%). Conclusion Findings in Japanese patients are consistent with those of the overall ADMIRAL study population.

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&lt;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.

scholarly journals Comparison Between Decitabine and Azacitidine for Patients With Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndrome: A Systematic Review and Network Meta-Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiale Ma ◽  
Zheng Ge
Keyword(s):  
Systematic Review ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Cochrane Library ◽  
Grade 3 ◽  
Acute Myeloid

Background: The hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DAC) have been widely used in patients with acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (HR-MDS). However, few direct clinical trials have been carried out to compare the efficacy and adverse events (AEs) between these two agents. The clinical choice between them is controversial. A systematic review and network meta-analysis (NMA) was performed to compare the efficacy, safety, and survival of DAC and AZA in AML and HR-MDS patients.Methods: We systematically searched MEDLINE, Embase, Web of Science, and Cochrane Library through March 15, 2021. Randomized controlled trials (RCTs) on AML or HR-MDS patients comparing the efficacy and safety between DAC and AZA or comparing one of HMAs to conventional care regimens (CCR) were selected.Results: Eight RCTs (n = 2,184) were identified in the NMA. Four trials compared AZA to CCR, and four compared DAC to CCR. Direct comparisons indicated that, compared to CCR, both AZA and DAC were associated with higher overall response (OR) rate (AZA vs. CCR: relative risk (RR) = 1.48, 95% CI 1.05–2.1; DAC vs. CCR: RR = 2.14, 95% CI 1.21–3.79) and longer overall survival (OS) (AZA vs. CCR: HR = 0.64, 95% CI 0.50–0.82; DAC vs. CCR: HR = 0.84, 95% CI 0.72–0.98), and AZA showed higher rate of complete remission with incomplete blood count recovery (CRi) (HR = 2.52, 95% CI 1.27–5). For the indirect method, DAC showed a higher complete remission (CR) rate than AZA in patients with both AML (RR = 2.28, 95% CI 1.12–4.65) and MDS (RR = 7.57, 95% CI 1.26–45.54). Additionally, DAC significantly increased the risk of 3/4 grade anemia (RR = 1.61, 95% CI: 1.03–2.51), febrile neutropenia (RR = 4.03, 95% CI: 1.41–11.52), and leukopenia (RR = 3.43, 95% CI 1.64–7.16) compared with AZA. No statistical significance was found for the other studied outcomes.Conclusion: Compared to CCR, both AZA and DAC can promote outcomes in patients with AML and HR-MDS. DAC showed higher efficacy especially CR rate than AZA (low-certainty evidence), while AZA experienced lower frequent grade 3/4 cytopenia than patients receiving DAC treatment.

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