Prognostic Value of FLT3-Internal Tandem Duplication Residual Disease in Acute Myeloid Leukemia.

PURPOSE: The applicability of FLT3-internal tandem duplications (FLT3-ITD) for assessing measurable residual disease (MRD) in acute myeloid leukemia (AML) in complete remission (CR) has been hampered by patient-specific duplications and potential instability of FLT3-ITD during relapse. Here, we comprehensively investigated the impact of next-generation sequencing (NGS)-based FLT3-ITD MRD detection on treatment outcome in a cohort of patients with newly diagnosed AML in relation to established prognostic factors at diagnosis and other MRD measurements, ie, mutant NPM1 and multiparameter flow cytometry. METHODS: In 161 patients with de novo FLT3-ITD AML, NGS was performed at diagnosis and in CR after intensive remission induction treatment. FLT3-ITD MRD status was correlated with the cumulative incidence of relapse and overall survival (OS). RESULTS: NGS-based FLT3-ITD MRD was present in 47 of 161 (29%) patients with AML. Presence of FLT3-ITD MRD was associated with increased risk of relapse (4-year cumulative incidence of relapse, 75% FLT3-ITD MRD v 33% no FLT3-ITD MRD; P < .001) and inferior OS (4-year OS, 31% FLT3-ITD MRD v 57% no FLT3-ITD MRD; P < .001). In multivariate analysis, detection of FLT3-ITD MRD in CR confers independent prognostic significance for relapse (hazard ratio, 3.55; P < .001) and OS (hazard ratio 2.51; P = .002). Strikingly, FLT3-ITD MRD exceeds the prognostic value of most generally accepted clinical and molecular prognostic factors, including the FLT3-ITD allelic ratio at diagnosis and MRD assessment by NGS-based mutant NPM1 detection or multiparameter flow cytometry. CONCLUSION: NGS-based detection of FLT3-ITD MRD in CR identifies patients with AML with profound risk of relapse and death that outcompetes the significance of most established prognostic factors at diagnosis and during therapy, and furnishes support for FLT3-ITD as a clinically relevant biomarker for dynamic disease risk assessment in AML.

A systematic review and meta-analysis of adjuvant chemotherapy after chemoradiation for locally advanced cervical cancer.

We investigated whether the addition of adjuvant chemotherapy to chemoradiation improves overall survival (OS) and progression-free survival (PFS) by conducting a systematic review and meta-analysis. Systematic searches in the databases of PubMed, Embase and Web of Science yielded 881 articles. Two reviewer authors independently selected 31 articles for full text review and deemed eight studies eligible for inclusion. Two were randomised controlled trials (RCT), one was a large (n = 609) matched-case study and the remaining were small retrospective cohort studies; in total 2150 patients. Risk of bias assessment showed that the RCTs were at low risk and all other studies were at high risk of bias. Pooled hazard ratios for OS and PFS were 0.78 (95%CI 0.45-1.33, p = 0.36) and 0.85 (95%CI 0.65-1.10, p = 0.22), respectively. Analysis stratified by study design and sensitivity analysis showed similar results. Funnel plots showed significant publication bias due to a lack of small studies with negative outcomes.

Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome.

Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity.

Adjuvant Systemic Therapy after Chemoradiation and Brachytherapy for Locally Advanced Cervical Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Standard of care for locally advanced cervical cancer is chemoradiation and brachytherapy. The addition of adjuvant systemic treatment may improve overall survival. A systematic review and meta-analysis was conducted to summarize evidence on survival outcomes, treatment completion and toxicity. METHODS: PubMed, EMBASE and Web of Science were systematically searched for relevant prospective and retrospective studies. Two authors independently selected studies, extracted data and assessed study quality. Pooled hazard ratios for survival endpoints were estimated using random effect models. Weighted averages of treatment completion and toxicity rates were calculated and compared by the Fisher exact test. RESULTS: The search returned 612 articles; 35 articles reporting on 29 different studies on adjuvant chemotherapy or immunotherapy were selected for systematic review. Twelve studies on an adjuvant platinum-pyrimidine antagonist or platinum-taxane were included for meta-analysis. The pooled hazard ratios for overall survival were 0.76 (99%CI: 0.43-1.34, p = 0.22) and 0.47 (99%CI: 0.12-1.86, p = 0.16) for the addition of, respectively, a platinum-pyrimidine antagonist or platinum-taxane to chemoradiation and brachytherapy. Completion rates were 82% (95%CI: 76-87%) for platinum-pyrimidine antagonist and 74% (95%CI: 63-85%) for platinum-taxane. Severe acute hematological and gastro-intestinal toxicities were significantly increased by adding adjuvant chemotherapy to chemoradiation and brachytherapy. CONCLUSIONS: The addition of adjuvant platinum-pyrimidine antagonist or platinum-taxane after chemoradiation and brachytherapy does not significantly improve overall survival, while acute toxicity is significantly increased. These adjuvant treatment strategies can therefore not be recommended for unselected patients with locally advanced cervical cancer.

Molecular Minimal Residual Disease in Acute Myeloid Leukemia.

BACKGROUND: Patients with acute myeloid leukemia (AML) often reach complete remission, but relapse rates remain high. Next-generation sequencing enables the detection of molecular minimal residual disease in virtually every patient, but its clinical value for the prediction of relapse has yet to be established. METHODS: We conducted a study involving patients 18 to 65 years of age who had newly diagnosed AML. Targeted next-generation sequencing was carried out at diagnosis and after induction therapy (during complete remission). End points were 4-year rates of relapse, relapse-free survival, and overall survival. RESULTS: At least one mutation was detected in 430 out of 482 patients (89.2%). Mutations persisted in 51.4% of those patients during complete remission and were present at various allele frequencies (range, 0.02 to 47%). The detection of persistent DTA mutations (i.e., mutations in DNMT3A, TET2, and ASXL1), which are often present in persons with age-related clonal hematopoiesis, was not correlated with an increased relapse rate. After the exclusion of persistent DTA mutations, the detection of molecular minimal residual disease was associated with a significantly higher relapse rate than no detection (55.4% vs. 31.9%; hazard ratio, 2.14; P<0.001), as well as with lower rates of relapse-free survival (36.6% vs. 58.1%; hazard ratio for relapse or death, 1.92; P<0.001) and overall survival (41.9% vs. 66.1%; hazard ratio for death, 2.06; P<0.001). Multivariate analysis confirmed that the persistence of non-DTA mutations during complete remission conferred significant independent prognostic value with respect to the rates of relapse (hazard ratio, 1.89; P<0.001), relapse-free survival (hazard ratio for relapse or death, 1.64; P=0.001), and overall survival (hazard ratio for death, 1.64; P=0.003). A comparison of sequencing with flow cytometry for the detection of residual disease showed that sequencing had significant additive prognostic value. CONCLUSIONS: Among patients with AML, the detection of molecular minimal residual disease during complete remission had significant independent prognostic value with respect to relapse and survival rates, but the detection of persistent mutations that are associated with clonal hematopoiesis did not have such prognostic value within a 4-year time frame. (Funded by the Queen Wilhelmina Fund Foundation of the Dutch Cancer Society and others.).

Does adjuvant chemoradiotherapy improve the prognosis of gastric cancer after an r1 resection? Results from a dutch cohort study.

OBJECTIVE: The aim of this study was to investigate the impact of adjuvant chemoradiotherapy (CRT) on survival of non-metastatic gastric cancer patients who had undergone an R1 resection. METHODS: We compared the survival of patients after an R1 gastric cancer resection from the population-based Netherlands Cancer Registry who did not receive adjuvant CRT (no-CRT group) with the survival of resected patients who had been treated with adjuvant CRT (CRT group) at our institute. Patients who had a resection between 2002 and 2011 were included. CRT consisted of radiotherapy (45 Gy) combined with concurrent cisplatin- or 5-fluorouracil-based chemotherapy. The impact of CRT treatment on overall survival was assessed using multivariable Cox regression and stratified propensity score analysis. RESULTS: A series of 409 gastric cancer patients who had undergone an R1 resection were studied (no-CRT, N = 369; CRT, N = 40). In the no-CRT group, median age was higher (70 vs. 57 years; p < 0.001) and the percentage of patients with diffuse-type tumors was lower (43 vs. 80 %; p < 0.001). There were no significant differences in pathological T- and N-classification. There was a significant difference in median overall survival between the no-CRT and CRT group (13 vs. 24 months; p = 0.003). In a multivariable analysis, adjuvant CRT was an independent prognostic factor for improved overall survival (hazard ratio 0.54; 95 % confidence interval 0.35-0.84). This effect of CRT was further supported by propensity score analysis. CONCLUSIONS: Adjuvant CRT was associated with an improved survival in patients who had undergone an R1 resection for gastric cancer.