Effect of gilteritinib on survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) AML who have common AML co-mutations or a high FLT3-ITD allelic ratio.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7000-7000 ◽  
Author(s):  
Mark J. Levis ◽  
Alexander E. Perl ◽  
Giovanni Martinelli ◽  
Jorge E. Cortes ◽  
Andreas Neubauer ◽  
...  
Keyword(s):  
Salvage Chemotherapy ◽  
Wild Type ◽  
Phase 3 ◽  
Allelic Ratio ◽  
Flt3 Inhibitor ◽  
The Difference ◽  
Mutation Assay ◽  
The Impact ◽  
Generation Sequencing ◽  
Clinical Trial Information

7000 Background: The FLT3 inhibitor, gilteritinib, showed superior response and overall survival (OS) compared with salvage chemotherapy (SC) in patients (pts) with FLT3mut+ R/R AML in the phase 3 ADMIRAL study. We analyzed the impact of baseline co-mutations and FLT3-ITD allelic ratio (AR) on response and OS. Methods: A total of 37 recurrently mutated genes in AML (Archer Core Myeloid Panel) were analyzed by next-generation sequencing; the cutoff for co-mutation positivity (co-mut+) was ≥0.027. Baseline FLT3-ITD AR ( FLT3-ITD to FLT3 wild-type DNA) was measured by the LeukoStrat CDx FLT3 Mutation Assay. The median FLT3-ITD AR value of 0.77 was used to define high (≥0.77) vs low (<0.77) FLT3-ITD AR. Results: Analysis of 361 FLT3mut+ pts identified four major co-mutation cohorts, each with ≥10% of pts: NPM1 (n=173; 47.9%), DNMT3A (n=115; 31.9%), DNMT3A/NPM1 (n=86; 23.8%) , and WT1 (n=65; 18.0%). In addition, seven pts (1.9%) had all three co-mutations (ie, NPM1, DNMT3A, and WT1). The gilteritinib arm had superior response rates and OS across all four major co-mutation cohorts, with the greatest survival benefit in pts with DNMT3A/NPM1 co-mut+ (Table). In FLT3-ITD AR analyses (n=335), gilteritinib conferred longer OS than SC in pts with a high or low FLT3-ITD AR (gilteritinib: high FLT3-ITD AR, 7.1 mos vs low FLT3-ITD AR, 10.6 mos; SC: high FLT3-ITD AR, 4.3 mos vs low FLT3-ITD AR, 6.9 mos). In both arms, OS was longer in the low FLT3-ITD AR cohort than the high FLT3-ITD AR cohort but the difference in the gilteritinib arm was not statistically significant (gilteritinib: HR=1.341, P=0.0712; SC: HR=2.01, P=0.0021). Conclusions: The ADMIRAL trial shows that the clinical benefit of gilteritinib in FLT3mut+ R/R AML is maintained regardless of NPM1, DNMT3A, DNMT3A/ NPM1, or WT1 co-mut+ or high FLT3-ITD AR. Clinical trial information: NCT02421939. [Table: see text]

128 Differences in PRRSV Resilience for Reproductive Performance Between Landrace and Duroc Sows

2021 ◽  
Vol 99 (Supplement_1) ◽  
pp. 18-19
Author(s):  
Felipe Hickmann ◽  
José Braccini Neto ◽  
Luke M Kramer ◽  
Kent A Gray ◽  
Yijian Huang ◽  
...  
Keyword(s):  
Reproductive Performance ◽  
Mixed Model ◽  
Performance Data ◽  
The Other ◽  
Wild Type ◽  
Prrs Virus ◽  
The Difference ◽  
The Impact

Abstract Studies on differences in resilience to porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV) between breeds are scarce in the literature. Thus, the objective of this work was to assess PRRSV resilience in PRRSV wild-type infected sows from two breeds. Farrowing data included 2546 and 2522 litters from 894 Duroc and 813 Landrace sows, respectively, which were housed together and experienced the same PRRSV outbreak. Traits used for this study were number of piglets born alive (NBA), number born dead (NBD), total number born (TNB), and number weaned (NW). The impact of PRRSV infection was evaluated by comparing the reproductive performance of breeds between PRRS phases (pre-PRRS, PRRS, and post-PRRS). PRRS phases were defined based on the reproductive performance data. NBA, NBD, and NW were analyzed as a proportion of TNB using a Poisson mixed model. Pre-defined contrasts were used to evaluate the effect of breed on PRRSV resilience and on return to PRRSV-free performance, representing the differences between breeds for the difference between pre-PRRS and PRRS phases, and pre-PRRS and post-PRRS phases, respectively. There was a significant (P ≤ 0.003) interaction between PRRS phase and breed for all traits, as shown in Table 1. In general, reproductive performance reduced from pre-PRRS to PRRS, and then increased from PRRS to post-PRRS, as expected. The resilience contrast was significant for all traits (P ≤ 0.003). In all cases, the drop in percent reproductive performance from pre-PRRS to PRRS was lower for Duroc than for Landrace, indicating that Duroc sows have greater PRRSV resilience than Landrace sows. The return to PRRSV-free performance contrast had a trending effect for NBD (P = 0.055), and it was not significant for the other traits (P ≥ 0.515). These results indicate that Duroc sows have overall greater phenotypic PRRSV resilience for reproductive performance than Landrace sows.

Impact of adding plinabulin to pegfilgrastim for the prevention of TAC chemotherapy (Chemo) induced neutropenia (CIN), on patient quality of life (QoL).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e24031-e24031
Author(s):  
Ramon Mohanlal ◽  
Yvette Lelorier ◽  
Dominic Mitchell ◽  
Lan Huang ◽  
Douglas W. Blayney
Keyword(s):  
Clinical Trial ◽  
Energy Levels ◽  
Breast Cancer Patients ◽  
Emotional Wellbeing ◽  
Phase 3 ◽  
Tac Chemotherapy ◽  
Physical Wellbeing ◽  
The Impact ◽  
Clinical Trial Information

e24031 Background: Plinabulin is a novel non-G-CSF small molecule being developed for the prevention of chemotherapy in conjunction with pegfilgrastim and is administered via 30 min IV infusion, 30 min after chemo on Day (D) 1. The QoL was analyzed using the Functional Assessment of Cancer Therapy - General questionnaire (FACT-G) as part of a phase 3 (Ph3) clinical trial comparing pegfilgrastim alone versus pegfilgrastim and plinabulin for the prevention of neutropenia in newly diagnosed breast cancer patients being treated with Docetaxel (75 mg/m2), Doxorubicin (50 mg/m2), and Cyclophosphamide (500 mg/m2) (TAC) on D1 for four 21 D cycles and study treatment. Methods: The FACT-G was administered to patients in China and Ukraine using an ePRO app downloaded onto patients' phones as part of the Phase 3 PROTECTIVE-2 trial (NCT0329457) with TAC. Patients completed the FACT-G during each chemo cycle at D-1, D1, D8 and D15. Patients received reminders 1 hour before the required completion time and all entries were time stamped. The FACT-G measured the impact of cancer on four categories: Physical wellbeing, Social wellbeing, Emotional wellbeing and Functional wellbeing. Results: Compared to pegfilgrastim alone, patients on plinabulin + pegfilgrastim performed significantly better for Physical wellbeing on D8 and D15 of Cycle 2 (p < 0.0589 and p < 0.0039 respectively) and Cycle 3 (p < 0.0360 and p < 0.0343 respectively). Further analysis of the sub questions showed that both energy levels “I have a lack of energy” and pain”(I have pain” were significantly better for the plinabulin + pegfilgrastim combination versus pegfilgrastim alone (p < 0.0377 and p < 0.0420 respectively). Overall FACT-G completion compliance for the trial was 91%. Conclusions: The Physical wellbeing (in particular, pain and for energy levels) of patients receiving plinabulin in combination with pegfilgrastim for the prevention of TAC CIN, was significantly less impacted by chemo dosing compared to the pegfilgrastim alone arm. In addition, the results suggest that patients receiving the combination therapy recovered their pre-chemo Physical wellbeing levels more rapidly. Clinical trial information: NCT03531099.

Impact of age on efficacy and safety of daratumumab in combination with lenalidomide and dexamethasone (D-Rd) in patients (pts) with transplant-ineligible newly diagnosed multiple myeloma (NDMM): MAIA.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8035-8035
Author(s):  
Saad Zafar Usmani ◽  
Thierry Facon ◽  
Shaji Kumar ◽  
Torben Plesner ◽  
Philippe Moreau ◽  
...  
Keyword(s):  
Dose Intensity ◽  
Standard Of Care ◽  
Newly Diagnosed ◽  
Median Dose ◽  
Phase 3 ◽  
Risk Of Progression ◽  
Grade 3 ◽  
The Impact ◽  
Clinical Trial Information

8035 Background: D-Rd significantly reduced the risk of progression/death by 44% in transplant-ineligible NDMM pts vs Rd in the phase 3 MAIA study. To examine the impact of age on efficacy/safety of D-Rd vs Rd in this population, a subgroup analysis was conducted in pts <75 and ≥75 y of age. Methods: Transplant-ineligible NDMM pts were randomized 1:1 to Rd ± DARA; stratification was based on age (<75 vs ≥75 y), ISS (I, II, III), and region (North America vs Other). Pts received 28-day cycles of either R 25 or 10 mg (based on renal function) PO QD on Days 1-21 and either d 40 or 20 mg (based on age or BMI) PO/IV weekly until progression. In the D-Rd arm, pts received daratumumab 16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter until progression. PFS is the primary endpoint. Results: Among 737 randomized pts (D-Rd, n=368; Rd, n=369), 321 (44%) were ≥75 y of age. For D-Rd vs Rd, relative median dose intensity for R was 79% vs 93% for <75 y subgroup and 66% vs 89% for ≥75 y subgroup, respectively. After median follow-up of 28 mo, significant PFS benefit of D-Rd vs Rd was maintained in both <75 and ≥75 y subgroups (Table). Deeper responses and MRD-negative rate (10-5 threshold) remained higher with D-Rd vs Rd in both subgroups (Table). Most common (≥10%; D-Rd/Rd) grade 3/4 TEAEs in ≥75 y pts were neutropenia (60%/41%), lymphopenia (19%/12%), anemia (16%/22%), pneumonia (15%/10%), leukopenia (12%/6%), and thrombocytopenia (8%/11%). Fewer pts receiving D-Rd vs Rd discontinued treatment due to TEAEs (<75 y: 5% vs 12%; ≥75 y: 10% vs 21%). Conclusions: D-Rd pts received less R vs Rd group regardless of age. Efficacy of D-Rd in <75 and ≥75 y pts was consistent with the ITT population, and D-Rd demonstrated acceptable tolerability regardless of age. Together with the phase 3 ALCYONE study, these studies confirm clinical benefit of daratumumab plus standard-of-care in transplant-ineligible NDMM pts ≥75 y of age. Clinical trial information: NCT02252172. [Table: see text]

A phase I study of milademetan in combination with quizartinib in patients (pts) with newly diagnosed (ND) or relapsed/refractory (R/R) FLT3-ITD acute myeloid leukemia (AML).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7067-TPS7067 ◽  
Author(s):  
Naval Guastad Daver ◽  
Weiguo Zhang ◽  
Richard Graydon ◽  
Vikas Dawra ◽  
Jingdong Xie ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Salvage Chemotherapy ◽  
Wild Type ◽  
Open Label ◽  
Flt3 Inhibitor ◽  
Open Label Phase ◽  
Expansion Cohort ◽  
Mdm2 Inhibitor

TPS7067 Background: Fms -like tyrosine kinase 3 internal tandem duplication ( FLT3-ITD) mutations occur in ≈ 25% of pts with AML and are associated with poor prognosis. Quizartinib is a highly potent, selective, next-generation type II FLT3 inhibitor. In the phase 3 QuANTUM-R trial, quizartinib prolonged overall survival vs salvage chemotherapy in pts with R/R FLT3-ITD AML. MDM2 downregulates the p53 tumor suppressor and is upregulated in pts with AML. Targeting MDM2 may restore p53 activity in pts with wild-type p53 AML. Milademetan, a novel and specific MDM2 inhibitor, showed activity in an ongoing phase 1 trial in pts with AML or myelodysplastic syndromes (MDS). Preclinical studies have shown that quizartinib plus milademetan may act synergistically to target FLT3-ITD and restore p53 activity in FLT3-ITD/ TP53 wild-type AML [Andreeff et al. ASH 2018, abstract 2720]. Methods: This open-label phase 1 study (NCT03552029) has 2 parts: dose escalation (part 1) followed by dose expansion (part 2), with 2 planned cohorts. Key inclusion criteria include FLT3-ITD AML (primary or secondary to MDS) and adequate renal, hepatic, and clotting functions. Key exclusion criteria include acute promyelocytic leukemia, prior treatment with a MDM2 inhibitor, QTcF interval > 450 ms, significant cardiovascular disease, and unresolved toxicities from prior therapies. Dose escalation and expansion cohort 1 includes R/R pts. Expansion cohort 2 includes ND pts unfit for intensive chemotherapy. During dose escalation, quizartinib will be administered once daily in 28-day cycles, with 3 proposed levels (30, 40, and 60 mg). Milademetan will be administered on days 1-14 of each 28-day cycle, with 3 proposed levels (90, 120, and 160 mg). The quizartinib dose will be escalated first, followed by the milademetan dose with no simultaneous escalation, guided by modified continual reassessment with overdose control. Primary objectives are safety and tolerability, optimum dosing schedule, maximum tolerated dose, recommended dosing for the expansion cohort, and phase 2 dosing. Secondary objectives are pharmacokinetics and preliminary efficacy. This study is recruiting. Clinical trial information: NCT03552029.

Effect of epigenetic modifier-based combinations on efficacy in patients with peripheral T-cell lymphoma (PTCL): Deciphering impact of mutations in epigenetic operations on response.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7565-7565
Author(s):  
Owen A. O'Connor ◽  
Lubomir Sokol ◽  
Andrei R. Shustov ◽  
Lorenzo Falchi ◽  
Jennifer Kimberly Lue ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Histone Deacetylase Inhibitors ◽  
Phase 1 ◽  
Phase 2 ◽  
Treatment Naïve ◽  
Marked Activity ◽  
Next Generation Sequencing Ngs ◽  
The Impact ◽  
Generation Sequencing ◽  
Clinical Trial Information

7565 Background: Recurring mutations in epigenetic functions in PTCL, coupled with marked activity of epigenetic drugs, raises a question regarding whether these mutations might portend greater vulnerability to one drug over another. For example, do mutations in genes governing DNA methylation suggest these patients might benefit from a hypomethylating (HMA) agent? Preclinical data from our group suggests marked synergism between histone deacetylase inhibitors (HDACi) and HMA, as well as HDACi and pralatrexate (PDX), irrespective of mutations in epigenetic genes. Phase 1 studies (romidepsin [R] plus PDX or R plus 5-azacytidine [Aza]) are completed, and the Phase 2 studies are near completion. This clinical trial scenario affords a unique opportunity to decipher the impact of a HMA on response as a function of TET2, IDH2, DNMT3 and other mutations in PTCL. Methods: Patients with R/R lymphoma were eligible for the phase 1, whereas the phase 2 only enrolled patients with PTCL, either R/R or treatment-naïve individuals. Exploratory endpoints included next generation sequencing (NGS) and methylation arrays. Results: In toto, 89 patients have been enrolled on both trials across all histology’s, 58 have PTCL. NGS and efficacy data is available for the majority of patients, with some from the PDX + R study in process. The ORR among the PTCL patients for PDX+R and Aza+R has been 71% and 73% respectively. Eight of 9 angioimmunoblastic TCL patients responded. Among those with TET2 mutations, 7 of 8 responded to the Aza based treatment, while only 3 of 6 (50%) who were TET2 negative responded. Similarly, of 3 patients with DNMT3 treated with Aza based therapy, all 3 responded. Remarkably one patient with a TET2 mutation experienced progression to PDX+R, and CR to Aza+R. Among the PTCL patients treated with Aza, the global demethylation score (GDMS) demonstrated marked demethylation among all patients, with no correlation between the score and likelihood of response. Conclusions: We will share the completely annotated analysis correlating clinical metrics to the spectrum of epigenetic mutations and GDMS and across all histology’s and treatments. Clinical trial information: NCT01998035; NCT01947140.

scholarly journals EUCAST Reference Testing of Rezafungin Susceptibility and Impact of Choice of Plastic Plates

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Maiken Cavling Arendrup ◽  
Karin Meinike Jørgensen ◽  
Rasmus Krøger Hare ◽  
Manuel Cuenca-Estrella ◽  
Oscar Zaragoza
Keyword(s):  
Antifungal Susceptibility ◽  
Reference Method ◽  
Wild Type ◽  
Phase 3 ◽  
Content Type ◽  
Microtiter Plates ◽  
The Difference ◽  
Long Acting ◽  
Interlaboratory Reproducibility ◽  
Type Strains

ABSTRACT Rezafungin is a new long-acting echinocandin currently in phase 3 development. Epidemiological cutoff values are necessary for breakpoint setting but have not been established due to unexplained interlaboratory MIC variations observed in a prior multicenter study. Here we investigated if the choice of microtiter plates affected the variability when anidulafungin was included as a comparator. Testing by the EUCAST E.Def 7.3.1 reference method using tissue and cell culture-treated polystyrene plates (TC plates) and untreated polystyrene plates (UT plates) from four manufacturers was performed. Six control strains (Candida albicans, n = 3; C. krusei, n = 2; C. parapsilosis, n = 1) were tested (520 MICs). Subsequently, 5 or 6 wild-type isolates and 4 or 5 fks mutants of C. albicans, C. glabrata, C. krusei, C. parapsilosis (wild type only), and C. tropicalis were tested (930 MICs). For each strain-plate combination, ≥98% of the repetitive MICs were within 3 dilutions. The rezafungin modal MICs for the collated C. albicans control strain distributions were 0.016 mg/liter across TC plates but 0.03 mg/liter across UT plates, whereas they were 0.004 mg/liter and 0.016 mg/liter, respectively, for anidulafungin. The difference was most pronounced with Falcon plates and was not observed for C. krusei and C. parapsilosis. Eleven rezafungin MICs for mutants overlapped with the MICs for wild-type isolates (TC plates, n = 4; UT plates, n = 7). For anidulafungin, five overlaps (all UT plates) were observed. Most overlaps (rezafungin, n = 5; anidulafungin, n = 3) were caused by fks mutants of C. tropicalis (Fks1, F650F/L) and C. glabrata (Fks2. D666Y; rezafungin, n = 2; anidulafungin, n = 1). Interlaboratory variation was low. The use of TC plates resulted in lower MICs, particularly for C. albicans and Falcon plates, ad this was more often the case for anidulafungin than for rezafungin. Adoption of TC plates for EUCAST antifungal susceptibility testing would improve interlaboratory reproducibility and the separation of non-wild-type and wild-type strains.

scholarly journals FLT3-ITD allelic ratio and HLF expression predict FLT3 inhibitor efficacy in adult AML

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jarno Kivioja ◽  
Disha Malani ◽  
Ashwini Kumar ◽  
Mika Kontro ◽  
Alun Parsons ◽  
...  
Keyword(s):  
Drug Testing ◽  
Ex Vivo ◽  
Disease Recurrence ◽  
Response To Therapy ◽  
High Rate ◽  
Fragment Analysis ◽  
Internal Tandem Duplication ◽  
Allelic Ratio ◽  
Flt3 Inhibitor ◽  
Generation Sequencing

AbstractFLT3 internal tandem duplication (FLT3-ITD) is a frequent mutation in acute myeloid leukemia (AML) and remains a strong prognostic factor due to high rate of disease recurrence. Several FLT3-targeted agents have been developed, but determinants of variable responses to these agents remain understudied. Here, we investigated the role FLT3-ITD allelic ratio (ITD-AR), ITD length, and associated gene expression signatures on FLT3 inhibitor response in adult AML. We performed fragment analysis, ex vivo drug testing, and next generation sequencing (RNA, exome) to 119 samples from 87 AML patients and 13 healthy bone marrow controls. We found that ex vivo response to FLT3 inhibitors is significantly associated with ITD-AR, but not with ITD length. Interestingly, we found that the HLF gene is overexpressed in FLT3-ITD+ AML and associated with ITD-AR. The retrospective analysis of AML patients treated with FLT3 inhibitor sorafenib showed that patients with high HLF expression and ITD-AR had better clinical response to therapy compared to those with low ITD-AR and HLF expression. Thus, our findings suggest that FLT3 ITD-AR together with increased HLF expression play a role in variable FLT3 inhibitor responses observed in FLT3-ITD+ AML patients.

Follow-up of patients with FLT3-mutated R/R AML in the phase 3 ADMIRAL trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7013-7013
Author(s):  
Alexander E. Perl ◽  
Richard A. Larson ◽  
Nikolai Alexandrovich Podoltsev ◽  
Stephen Strickland ◽  
Eunice S. Wang ◽  
...  
Keyword(s):  
Relapse Rate ◽  
Kinase Inhibitors ◽  
Salvage Chemotherapy ◽  
Primary Analysis ◽  
Phase 3 ◽  
Intention To Treat ◽  
Long Term Survivors ◽  
Clinical Trial Information

7013 Background: The phase 3 ADMIRAL trial demonstrated the superiority of gilteritinib to salvage chemotherapy (SC) in patients (pts) with FLT3-mutated ( FLT3mut+) R/R AML. Aim/Objective: A follow-up of ADMIRAL assessed long-term survivors, transplant (HSCT) outcomes. and gilteritinib safety beyond 1 year. Methods: A data cut was performed on September 20, 2020—2 years after the primary analysis. Patients who were alive without relapse, pts who underwent HSCT, and adverse events of interest (AEIs) in Years 1 (≤12 months) and 2 ( > 12 months) of gilteritinib therapy were evaluated. Results: As of September 20, 2020, 17% (n = 63/371) of pts in the intention-to-treat (ITT) population were alive (gilteritinib, n = 49; SC, n = 14); 16 pts assigned to gilteritinib remained on treatment. After a median follow-up of 37.1 months, 26 of the 49 pts in the gilteritinib arm who were alive were also without relapse; 18 of these 26 pts underwent HSCT, with 16 receiving post-HSCT gilteritinib maintenance therapy. Nineteen of the 26 pts in the gilteritinib arm without relapse continued gilteritinib beyond 1 year and remained in CR. Of the 371 ITT pts, 83 (22%) underwent HSCT during the study (gilteritinib, n = 64; SC, n = 19). Pre-HSCT CRc rates were similar across arms (gilteritinib: n = 40/64; 63%; SC: n = 11/19; 58%); 10 of 11 pts preselected for low-intensity SC achieved pre-HSCT CRc (gilteritinib, n = 9; SC, n = 1). Forty of 64 (63%) transplanted pts in the gilteritinib arm received post-HSCT gilteritinib maintenance after achieving pre-HSCT CRc; the 24-month relapse rate in pts who resumed gilteritinib after pre-HSCT CRc was 19%. Post-HSCT treatment with chemotherapy or other tyrosine kinase inhibitors was administered in 26 pts who received gilteritinib before transplantation. Cumulative 24-month relapse rates in gilteritinib-treated pts who achieved pre-HSCT CR and CRc were 20% and 45%, respectively. Median post-HSCT overall survival (landmarked to HSCT date), was similar across arms (gilteritinib, 16.1 months; SC, 15.3 months; HR = 1.076; 95% CI: 0.536, 2.160). Overall, 10.2% (n = 25/246) had ≥24 months of gilteritinib exposure. Most common AEIs during Years 1 and 2 of gilteritinib therapy were elevated ALT/AST levels. Incidences of all AEIs declined in Year 2. Cardiac AEIs in Year 2 were nonfatal cardiorespiratory arrest (n = 1) and ventricular tachycardia (n = 1). One case of differentiation syndrome and cutaneous squamous cell carcinoma occurred in Years 1 and 2, respectively. Conclusions: A high proportion of gilteritinib-treated R/R FLT3mut+ AML pts who were alive without relapse had received HSCT followed by gilteritinib maintenance. Among all transplanted pts in ADMIRAL, pre-HSCT remission rates and post-HSCT survival were similar across arms. Post-HSCT gilteritinib maintenance may relate to the low post-HSCT relapse rate in the gilteritinib arm. The safety profile of gilteritinib is stable at 2 years with no new or significant safety signals. Clinical trial information: NCT02421939.

Subtle Impact of Akt1 and Akt3 on Exploratory Behavior in Gene Targeted Mice

2015 ◽  
Vol 223 (3) ◽  
pp. 173-180 ◽  
Author(s):  
Christina Leibrock ◽  
Michael Hierlmeier ◽  
Undine E. Lang ◽  
Florian Lang
Keyword(s):  
Forced Swimming Test ◽  
Open Field Test ◽  
Wild Type ◽  
Average Speed ◽  
Closed Area ◽  
Light Area ◽  
Swimming Test ◽  
The Impact ◽  
Center Area ◽  
Dark Transition

Abstract. The present study explored the impact of Akt1 and Akt3 on behavior. Akt1 (akt1-/-) and Akt3 (akt3-/-) knockout mice were compared to wild type (wt) mice. The akt1-/- mice, akt3-/- mice, and wt mice were similar in most parameters of the open-field test. However, the distance traveled in the center area was slightly but significantly less in akt3-/- mice than in wt mice. In the light/dark transition test akt1-/- mice had significantly lower values than wt mice and akt3-/- mice for distance traveled, number of rearings, rearing time in the light area, as well as time spent and distance traveled in the entrance area. They were significantly different from akt3-/- mice in the distance traveled, visits, number of rearings, rearing time in the light area, as well as time spent, distance traveled, number of rearings, and rearing time in the entrance area. In the O-maze the time spent, and the visits to open arms, as well as the number of protected and unprotected headdips were significantly less in akt1-/- mice than in wt mice, whereas the time spent in closed arms was significantly more in akt1-/- mice than in wt mice. Protected and unprotected headdips were significantly less in akt3-/- mice than in wt mice. In closed area, akt3-/- mice traveled a significantly larger distance at larger average speed than akt1-/- mice. No differences were observed between akt1-/- mice, akt3-/- mice and wt-type mice in the time of floating during the forced swimming test. In conclusion, akt1-/- mice and less so akt3-/ mice display subtle changes in behavior.

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