“…Notably, 51% (54/106) of patients that obtained a cytological CR after induction, reached complete molecular remission, as assessed by WT1 expression. These findings highlight the ability of the FLAI‐GO regimen to induce a good debulking effect and a deep response, supporting the value of WT1 as a marker of MRD, although WT1 is not still worldwide considered a standard tool for MRD assessment . Furthermore, in the present study both univariate and multivariate analysis showed that the achievement of a molecular response after FLAI‐GO (WT1 less than 70 copies) significantly improved OS and DFS (Table ).…”
The aim of this prospective clinical trial was to evaluate the efficacy and safety of a combination of Gemtuzumab-Ozogamicin (GO) and FLAI scheme (fludarabine, cytarabine, idarubicin) as a first-line therapy in CD33 positive AML. We treated 130 patients, aged <65, with a median age of 52 years. FLAI-GO induction regimen included fludarabine (30 mg/sqm) and cytarabine (2 g/sqm) on days 1-5; idarubicin (10 mg/sqm) on days 1, 3, and 5; and GO (3 mg/sqm) on day 6. SCT was planned for all high-risk AML patients, after consolidation with intermediate doses of cytarabine and idarubicin and a high dose of cytarabine. CD33 expression exceeded 20% in all cases. Primary endpoints of the study included feasibility, overall response rate (ORR) and toxicity. Secondary endpoints included the evaluation of MRD by WT1 expression, feasibility and outcome of consolidation with SCT, overall survival (OS) and disease-free survival (DFS). After induction with FLAI-GO, complete remission (CR) rate was 82%. Four patients achieved partial remission (PR) and 12% were resistant (ORR 85%); death during induction (DDI) was 3%. The hematological and extra hematological toxicity of FLAI-GO was manageable; 45% of patients experienced transient and reversible GO infusion related adverse events. In the setting of patients who achieved a cytological CR after FLAI-GO, the mean of WT1 copies dropped from 8337±9936 copies/10 ABL (diagnosis) to 182 ± 436 copies after induction therapy (p = 0.0001) showing a very good disease debulking. After a median follow-up of 54 months, 67/130 (52%) patients were alive. The probability of 1, 2, and 5-year OS was 80%, 63%, and 52%, respectively. The probability of 1, 2, and 5-year DFS was 77%, 58%, and 52%, respectively. Allogeneic and autologous SCT was performed in 60 (46%) and 23 (18%) patients, respectively. In summary, the final results of this trial confirm that FLAI-GO is an active and safe treatment strategy for CD33-positive AML patients aged ≤ 65 years, allowing a high ORR, a good disease debulking, favorable safety profile, low DDI, and subsequent high SCT rate. The encouraging results of this trial, consolidated by a long follow-up, support the reintroduction of GO in clinical practice.
“…Notably, 51% (54/106) of patients that obtained a cytological CR after induction, reached complete molecular remission, as assessed by WT1 expression. These findings highlight the ability of the FLAI‐GO regimen to induce a good debulking effect and a deep response, supporting the value of WT1 as a marker of MRD, although WT1 is not still worldwide considered a standard tool for MRD assessment . Furthermore, in the present study both univariate and multivariate analysis showed that the achievement of a molecular response after FLAI‐GO (WT1 less than 70 copies) significantly improved OS and DFS (Table ).…”
The aim of this prospective clinical trial was to evaluate the efficacy and safety of a combination of Gemtuzumab-Ozogamicin (GO) and FLAI scheme (fludarabine, cytarabine, idarubicin) as a first-line therapy in CD33 positive AML. We treated 130 patients, aged <65, with a median age of 52 years. FLAI-GO induction regimen included fludarabine (30 mg/sqm) and cytarabine (2 g/sqm) on days 1-5; idarubicin (10 mg/sqm) on days 1, 3, and 5; and GO (3 mg/sqm) on day 6. SCT was planned for all high-risk AML patients, after consolidation with intermediate doses of cytarabine and idarubicin and a high dose of cytarabine. CD33 expression exceeded 20% in all cases. Primary endpoints of the study included feasibility, overall response rate (ORR) and toxicity. Secondary endpoints included the evaluation of MRD by WT1 expression, feasibility and outcome of consolidation with SCT, overall survival (OS) and disease-free survival (DFS). After induction with FLAI-GO, complete remission (CR) rate was 82%. Four patients achieved partial remission (PR) and 12% were resistant (ORR 85%); death during induction (DDI) was 3%. The hematological and extra hematological toxicity of FLAI-GO was manageable; 45% of patients experienced transient and reversible GO infusion related adverse events. In the setting of patients who achieved a cytological CR after FLAI-GO, the mean of WT1 copies dropped from 8337±9936 copies/10 ABL (diagnosis) to 182 ± 436 copies after induction therapy (p = 0.0001) showing a very good disease debulking. After a median follow-up of 54 months, 67/130 (52%) patients were alive. The probability of 1, 2, and 5-year OS was 80%, 63%, and 52%, respectively. The probability of 1, 2, and 5-year DFS was 77%, 58%, and 52%, respectively. Allogeneic and autologous SCT was performed in 60 (46%) and 23 (18%) patients, respectively. In summary, the final results of this trial confirm that FLAI-GO is an active and safe treatment strategy for CD33-positive AML patients aged ≤ 65 years, allowing a high ORR, a good disease debulking, favorable safety profile, low DDI, and subsequent high SCT rate. The encouraging results of this trial, consolidated by a long follow-up, support the reintroduction of GO in clinical practice.
“…Although MFC-based AML MRD testing is applicable to most cases with a rapid turnaround, it also has a few limitations, including potential changes in phenotype over time, relatively less sensitivity, heterogeneity of leukemic phenotypes, operator-dependent bias because of the need for considerable expertise and experience, and subjective elements of analysis and data interpretation [2]. To identify another universal marker for MRD assessment, extensive efforts have been made to develop MRD tests targeting transcripts aberrantly expressed in AML [35,36], such as WT1 [17][18][19][20][22][23][24][25][26][27][28][29][30][31]. Overexpression of the WT1 gene in most patients with AML provides a target for novel immunotherapeutic approaches [37][38][39].…”
Section: Discussionmentioning
confidence: 99%
“…In 2009, ELN researchers used an optimized and standardized WT1 assay and established reference ranges for WT1 expression in normal blood and bone marrow (BM), with a large number of control samples, and transcript levels indicative of residual leukemia distinguished from background levels [22]. Despite several reports demonstrating the promising role of WT1 in MRD assessment under chemotherapy [22,23] and allo-HSCT settings [24][25][26][27][28][29][30][31], the WT1 MRD assay is not widely used in AML because of the lack of large-scale, controlled studies, particularly for allo-HSCT. Indeed, recent ELN guidelines for MRD in AML recommend the WT1 MRD assay only if other MRD assays, including flow cytometric ones, are unavailable as the condition to use a validated WT1 MRD assay by ELN researchers [22].…”
The absence of relevant guidelines for Wilms tumor 1 (WT1) gene quantification as a measurable residual disease (MRD) assessment for patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) has limited the widespread use in practice. We investigated optimal time points, thresholds, and candidates for the bone marrow WT1 MRD assay in 425 consecutive patients with AML who underwent allo-HSCT. WT1 expression kinetics before allo-HSCT and at 1 or 3 months after allo-HSCT were determined by real-time PCR using the European LeukemiaNet (ELN) normalized method. Relapsed patients had significantly higher WT1 levels before allo-HSCT and at 3 months after allo-HSCT. The best time point for the WT1 MRD assay was before allo-HSCT by the receiver operating characteristic curve. Among various thresholds, 250 copies recommended from ELN researchers were mostly predictive of post-transplant relapse. In multivariate analysis, WT1 MRD positivity independently predicted relapse, resulting in inferior survival. In subgroup analyses, pretransplant WT1 MRD positivity was predictive of post-transplant relapse in the intermediate group, whereas WT1 MRD positivity occurred at 3 months after allo-HSCT in favorable and adverse risk groups. Among MRD-positive patients before allo-HSCT, all patients who were MRD positive at 3 months relapsed within 6 months. The WT1 MRD assay before allo-HSCT or 3 months after allo-HSCT is useful for predicting post-transplant relapse with a different significance in each risk group by time points, showing the benefit of multiple tests over time. Such monitoring is particularly available in patients with AML without specific molecular targets.
“…Thus, IDH, TET2 and WT1 mutations alter the epigenetic expression of cells in analogous ways; these are shown in Figure 1 28. Mutant WT1, specifically, is very commonly overexpressed in AML; its presence and levels may be useful markers for detection of minimal residual disease as well as prognostication 27,29,30. Given that IDH and WT1 do not frequently co-occur, this may be a less useful strategy in IDH-mutated disease.Figure 1Hypermethylation phenotype in acute myeloid leukemia (AML).…”
Introduction:
Acute myeloid leukemia (AML) remains a disease with high mortality, especially for older patients and those with relapsed/refractory (R/R) disease. With recent advances in molecular testing, targeting particular leukemogenic mutations such as those occurring in isocitrate dehydrogenase (IDH) became possible. Enasidenib is a new small-molecule inhibitor of mutant isocitrate dehydrogenase-2 (IDH2).
Aim:
The objective of this article is to review the evidence for the use of enasidenib in R/R AML, as well as to outline future directions of enasidenib therapy.
Evidence Review:
Enasidenib was approved in August 2017, after a successful Phase I/II trial showing an overall response rate (ORR) of 40.3% in R/R disease, with 19.3% of patients achieving complete remission (CR). Enrollees in the trial were mostly older adults. The most prominent toxicities were hyperbilirubinemia and IDH-differentiation syndrome (IDH-DS), though the drug was generally well tolerated and the maximum tolerated dose was not reached. A Phase III trial is currently ongoing.
Conclusion:
Enasidenib provides a new therapeutic option for patients with R/R AML. Further studies are ongoing to ascertain its role in combination with other agents and newly diagnosed disease.
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