Gilteritinib as Post-Transplant Maintenance for AML With Internal Tandem Duplication Mutation of FLT3.

PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 (FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS: Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS: Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION: Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Health state utility values associated with advanced gastric, oesophageal, or gastro-oesophageal junction adenocarcinoma: a systematic review.

OBJECTIVES: To systematically identify utility values associated with advanced gastric cancer (GC), oesophageal cancer (OC), or gastro-oesophageal junction (GEJ) cancer. Utility values relating to health states are an essential component for cost-utility analysis (CUA). METHODS: MEDLINE, Embase, Cochrane Library, and EconLit databases were reviewed for relevant studies using a pre-defined search strategy. Studies eligible for inclusion reported health state utility values (HSUVs) using direct (standard gamble [SG] and time-trade-off [TTO]) and indirect (such as EuroQol 5D [EQ-5D], short-form 6D [SF-6D], and the 15-dimensional instrument [15D]) methods for patients with advanced GC, OC, or GEJ cancer. RESULTS: A total of 539 unique publications were identified, of which eight met the inclusion criteria (GC, n = 2; mixed population [gastrointestinal cancers], n = 4; OC, n = ). The most commonly used instrument to estimate HSUVs was the EQ-5D (n = 7). Utilities were also estimated using the SF-6D and the 15D in the same study (n = 1). Direct elicitation methods included the TTO (n = 2) and SG (n = 1). Across the eight identified publications, health states and study populations were heterogeneous and sample sizes were limited. LIMITATIONS: This review, as with all summaries of this nature, is only as robust as the data derived from the identified studies. The systematic review process does not resolve any design issues or biases associated with the original studies. CONCLUSIONS: Limited data estimate HSUVs in patients with advanced GC, OC, or GEJ cancer. Utilities for advanced GC alone and advanced OC alone were reported in only two publications for each cancer type. No publications considered advanced GEJ utilities alone, and four publications considered utilities for a mixed population of gastrointestinal cancer types. Comparisons are confounded by heterogeneity across the identified publications. Further research into HSUVs associated with advanced GC and OC is required to improve the evidence available for use in CUAs.

Differential expression of GRK isoforms in nonmalignant and malignant human granulosa cells.

Granulosa cell tumors are serious ovarian neoplasms that can occur in women of all ages. While there have been numerous attempts to understand the cause of these malignancies, the pathogenesis of granulosa cell tumors (GCTs) still remains largely unknown. G-protein coupled receptor kinases (GRKs) are important regulators of signal transduction through the process of receptor desensitization and internalization. Receptors that are regulated by GRKs are members of the large family of seven-transmembrane receptors and include the follicle stimulating hormone receptor (FSHR). In granulosa cells, the FSH signaling system is responsible for cell proliferation, differentiation, and steroidogenesis. In the studies presented, we examined GRK mRNA and protein expression in nonmalignant human granulosa cells, in KGN cells, a human GCT cell line, and in a panel of human GCT samples. The KGN tumor cells express significantly less GRK4 alpha/beta protein and higher levels of GRK2 and GRK4 gamma/delta protein as compared to nonmalignant human granulosa cells. In human GCT samples, GRK4 alpha/beta protein was detected in 3 of the 13 tumor samples, whereas gamma/delta proteins expression was detected in all samples. These findings suggest that GRK protein expression is altered in GCTs and may be involved in the pathogenesis of these tumors.

Premature thelarche and granulosa cell tumors: a search for FSH receptor and G5alpha activating mutations.

Activating mutations of the Gsalpha gene are responsible for McCune-Albright syndrome and have also been identified in sporadic tumors of the pituitary and thyroid. When associated with malignancy, activating Gsalpha mutations are known as gsp-oncogenes. We hypothesized that similar activating mutations might also account for some cases of premature thelarche and/ or granulosa cell tumors. Polymerase chain reaction and DNA sequencing was used to screen for activating mutations of Gsalpha genes in children with premature thelarche and in pathologic specimens from juvenile and adult granulosa cell tumors. Because these disorders involve over-activity of the FSH-signaling pathway, we also screened for activating mutations of the FSH receptor. No mutations were detected in either the Gsalpha or the FSHR fragment studied. Previously reported polymorphisms (Ser680Asn and Ala307Thr) of the FSHR were detected in 25/27 tumor samples and 9/9 premature thelarche samples. We conclude that activating mutations in previously identified mutation 'hot-spots' in the Gsalpha and FSH receptor genes are probably not a major cause of premature thelarche or granulosa cell tumors. In contrast, polymorphisms of the FSH receptor are common.