ML-12 Clinical impact and management of skin-related disorders during treatment of relapsed PCNSL by tirabrutinib

BACKGROUNDS: Tirabrutinib is a second-generation Bruton’s tyrosine kinase (BTK) inhibitor, approved by the Japanese Pharmaceutical and Medical Devices Agency (PMDA) for relapsed and refractory PCNSL in March 2020. Skin-related disorder (SRD)s are the most prevalent adverse events in tirabrutinib, which accounted for 54.5% in a phase I/II trial. While the use of tirabrutinib is increasingly considered in clinical practice, the prevalence and clinical impact of tirabrutinib-related SRDs in real-world practice remains unclear. METHODS: Relapsed PCNSL patients treated with tirabrutinib at the author’s institution were identified, and divided into those with SRDs (SRD group), and without SRDs (non-SRD group). Response rate and progression-free survival (PFS) were retrospectively analyzed and compared between the two groups. RESULTS: Eleven patients were identified (median age: 73 [range: 50–83], median KPS: 70 [range: 40–90]), which included six (54.5%) from the SRD group and five (45.5%) from the non-SRD group. Response rate was 100% in the SRD group and 60% in the non-SRD group. Median PFS was 2.8 months in the SRD group and 36.3 months in the non-SRD group, which yielded no significant difference (p=0.446). While antihistamine prophylaxis using fexofenadine was performed in seven patients, among them SRDs were observed in three (27.3%). SRDs lead to tirabrutinib interruption (for seven days or more) in two (18.2%), dose reduction in three (27.3%), and discontinuation in two (18.2%) patients. Four patients in whom tirabrutinib was interrupted or discontinued due to SRDs had shorter PFS, compared with the two patients from the SRD group in whom tirabrutinib was continued (median PFS: 2.3 and 29.6 months, respectively) (p=0.049). CONCLUSIONS: SRDs substantially lead to tirabrutinib interruption or discontinuation, which could result in early PD. Since fexofenadine prophylaxis seems ineffective for preventing SRDs, other antihistamines should be considered. Establishment of the optimal management of tirabrutinib-related SRDs is warranted.

Factors associated with surrogate families’ life-sustaining treatment preferences for patients at home or in a geriatric health service facility: A cross-sectional study

Objective Recently, end-of-life preference in palliative care has been gaining attention in Japan. The Ministry of Health, Labor, and Welfare established the Japanese basic policy in November 2018. Patients’ decision-making is recommended; however, patients with dementia or other disorders cannot make such decisions by themselves. Thus, healthcare providers may contact surrogates and consider their backgrounds for better decision-making. Hence, the preferences of home caregivers’ and geriatric health service facility (GHSF) residents’ families on patient life-sustaining treatment (LST) were investigated. Method This cross-sectional study involved home caregivers’ and GHSF residents’ families in Japan. We distributed 925 self-reported questionnaires comprising items, such as the number of people living together, care duration, comprehension of doctor's explanations, the Patient Health Questionnaire (PHQ)-9 and Short Form (SF)-8, and families’ LST preference for patients. Results In all, 619 valid responses were obtained [242 men and 377 women (309 in the HOME Caregivers Group, response rate = 61.1%; 310 in the GHSF Group, response rate = 74.0%)]. LST preference was significantly associated with sex, the number of people living together, care duration, and comprehension of doctors’ explanations in the HOME Caregivers Group but was not significantly associated with the GHSF Group. Furthermore, PHQ-9/SF-8 scores were not significantly associated with LST preference. Significance of results There were many differences in opinions about LST preference between home caregivers’ and GHSF residents’ families. The results suggested that the burden of nursing care was greater and harder in home caregiver families, and these factors may be related to the LST preference for a patient.

Metacognition and Crossmodal Correspondences Between Auditory Attributes and Saltiness in a Large Sample Study

Mounting evidence demonstrates that people make surprisingly consistent associations between auditory attributes and a number of the commonly-agreed basic tastes. However, the sonic representation of (association with) saltiness has remained rather elusive. In the present study, a crowd-sourced online study ( participants) was conducted to determine the acoustical/musical attributes that best match saltiness, as well as participants’ confidence levels in their choices. Based on previous literature on crossmodal correspondences involving saltiness, thirteen attributes were selected to cover a variety of temporal, tactile, and emotional associations. The results revealed that saltiness was associated most strongly with a long decay time, high auditory roughness, and a regular rhythm. In terms of emotional associations, saltiness was matched with negative valence, high arousal, and minor mode. Moreover, significantly higher average confidence ratings were observed for those saltiness-matching choices for which there was majority agreement, suggesting that individuals were more confident about their own judgments when it matched with the group response, therefore providing support for the so-called ‘consensuality principle’. Taken together, these results help to uncover the complex interplay of mechanisms behind seemingly surprising crossmodal correspondences between sound attributes and taste.

Mixed T cell lineage chimerism in acute leukemia/MDS using pre-emptive donor lymphocyte infusion strategy—Is it prognostic?—a single-center retrospective study

Pre-emptive DLI (pDLI) is an effective strategy in lowering the risk of relapse without significantly increasing the risk of graft-versus-host disease (GVHD) in the case of T cell lineage mixed chimerism (MC) post allogeneic transplant in hematological malignancies. Many patients, however, fail to receive timely pDLI and have dismal outcomes, which are not taken into consideration. We compared long-term outcomes of 106 patients having T cell MC after day 60 and undergoing allogeneic stem cell allograft for acute leukemia from an unrelated donor (UD), with 111 patients having complete chimerism (CC). Fifty-three (56%) patients received prophylactic pDLI. Thirty-six patients (67%) had a response (RR), 17 (33%) had no response (NR), and fifty-two (54%) did not receive any pDLI (ND). OS was better in MC group as compared to CC (54% vs 43%, p = 0.04), mainly due to reduction in NRM (14% vs 25%, p = 0.05), and all grade acute and chronic GVHD. Within the MC group, response to pDLI was the only significant factor predicting OS, DFS, and relapses with NR and ND having unfavorable outcomes as compared to RR (p = 0.001). T cell MC in patients undergoing UD allografts with alemtuzumab is no longer an adverse prognostic factor, as compared to patients having CC, after timely implementation of pDLI.

P–468 Fertility-related quality of life in subfertile women undergoing transvaginal hydrolaparoscopy versus hysterosalpingography as a first-line tubal patency test

Study question Is there a difference in fertility-related quality of life (QoL) in subfertile women undergoing transvaginal hydrolaparoscopy (THL) versus hysterosalpingography (HSG) as a first-line tubal-patency test? Summary answer In subfertile women undergoing first-line tubal patency testing, THL and HSG resulted in comparable fertility-related QoL. What is known already Both subfertility itself and subfertility treatment can have a significant impact on QoL. Tubal patency testing as part of fertility work-up is also known as a potential stressor. Pain scores for THL are significantly lower than for HSG (VAS 4.7 vs 5.4 ; SD: 2.5, p 0.038), but acceptability of the procedures was found to be comparable. Fertility-related QoL has not yet been studied in women undergoing tubal patency testing. Study design, size, duration We used data from a randomised clinical trial performed in 4 Dutch teaching hospitals, NTR3462. Between May 2013 and October 2016, we randomly assigned 300 subfertile women to THL or HSG with live birth as primary outcome. We performed a standardized questionnaire study as part of a randomised controlled trial comparing THL and HSG in the work-up for subfertility. Participants/materials, setting, methods Women were eligible if they were undergoing a fertility work-up with an indication for evaluation of tubal patency testing. Fertility-related QoL was measured six weeks after the procedure with the validated FertiQoL questionnaire, which produces a Core (total) score and four subscale domains: Emotional, Relational, Social, and Mind-Body. FertiQoL scores for the Core score and subscales between THL and HSG were compared using Mann-Whitney-U test and multiple linear regression analysis. Main results and the role of chance We allocated 149 women to THL and 151 to HSG. The questionnaire was completed by 84 women in the THL group (response rate 56%) and 96 women in the HSG group (response rate 64%). Core scores were 74.6 ±12.8 for THL and 73.4 ±12.4 for HSG (p = 0.39). Scores for the Emotional domain were 64.5 ±19.0 for THL versus 66.0 ±16.3 (p = 0.67) for HSG. Scores for the ‘Mind-body’ domain for THL were 76.9 ±15.6 versus 74.1 ±18.0 for HSG (p = 0.42), scores for the Relational domain were 79.2 ±12.9 for THL and 76.9 ±15.6 for HSG (p = 0.21). Scores for the Social domain for THL were 77.9 ±15.1 versus 76.7±14.1, (p = 0.42). The optional ‘Treatment FertiQol’ was completed by 156 women. Total scores were 77.5 ±12.1 for THL versus 73.8 ±13.1 (p = 0.08) for HSG. The multiple linear regression analysis showed only a statistical significant positive effect of higher age on the score for the Emotional domain (B:0.90, p = 0.015). Limitations, reasons for caution One of the main limitations of this study was a response rate of 60%. Although this is considered an acceptable rate within questionnaire research, this could lead to selection bias. Wider implications of the findings: In subfertile women, tubal patency testing with THL versus HSG did not result in differences in fertility-related QoL. Trial registration number NTR3462

Measurable residual disease response in acute myeloid leukemia treated with venetoclax and azacitidine.

7018 Background: In the phase 3 VIALE-A trial, rates of composite complete remission (CRc; complete remission [CR] + CR with incomplete hematologic recovery [CRi]) and measurable residual disease response (MRD<10-3) were higher in patients (pts) treated with venetoclax (Ven) + azacitidine (Aza) compared to Aza alone (23.4%/7.6%, p<0.001). There is limited evidence of the clinical significance of MRD monitoring in pts receiving low-intensity chemotherapy. Herein, we explored the outcomes of pts treated with Ven+Aza who achieved both CRc and MRD<10-3 in the VIALE-A trial (NCT02993523). Methods: Enrolled pts were ≥18 years and unfit for intensive chemotherapy. Pts received Ven 400 mg orally; days 1–28 and Aza 75 mg/m2; days 1-7/28-day cycle. Bone marrow aspirate samples for multiparametric flow cytometry assessments by integrated leukemia-associated immunophenotypes and different than normal procedures were collected for central analysis (Covance Central Laboratory Services) at baseline, end of cycle 1, and every 3 cycles thereafter. Assessments were performed independent of disease responses. MRD response was defined as <1 residual blast /1000 leukocytes (<10-3). CRc, DoR, OS, and EFS were assessed. Disease assessments were per modified International Working Group response criteria for AML. Results: 211/286 (74%) pts treated with Ven+Aza with at least one valid post-baseline MRD assessment were considered MRD evaluable; 78/211 (37%) achieved MRD<10-3 and 133/211 (63%) had MRD≥10-3. Median age (MRD<10-3/ MRD≥10-3) was 76 (range: 49-89)/77 (58-91) yrs. Pts (MRD<10-3/ MRD≥10-3) received median of 14.5 (range: 1-28) /7.0 (1-30) cycles of Ven+Aza. At median follow-up of 22.0 (range: 20.1-23.0)/20.8 (19.8-22.3) months (mos), CRc + MRD<10-3/ MRD≥10-3 was achieved by 67 (86%)/ 97 (73%); 20/67 (30%) achieved CRc + MRD<10-3 by end of cycle 1. Median DoR, OS, and EFS were not reached in pts with CRc + MRD<10-3 response (Table). The 12-mo estimates for DoR, OS, and EFS for pts with CRc + MRD<10-3response were 81.2%, 94.0%, and 83.2%, respectively. Adverse events ≥grade 3 (MRD<10-3/ MRD≥10-3) were febrile neutropenia (50%/43%), neutropenia (50%/35%), and thrombocytopenia (44%/44%), similar to the overall population. Conclusions: Pts with best response of CRc who achieved MRD<10-3 response with Ven+Aza treatment had longer DoR, OS, and EFS than pts who were CRc and MRD positive. Clinical trial information: NCT02993523. [Table: see text]

Individual and Group Response of Treatment with Ivacaftor on Airway and Gut Microbiota in People with CF and a S1251N Mutation

Ivacaftor has been shown to restore the functionality of the S1251N (also known as c.3752G>A) mutated CFTR, which may cause alterations in both airway and gut physiology and micro-environment, resulting in a change of microbiota in these organs. The aim of the present study was to analyze the effects of ivacaftor on the microbial community composition of both airway and gut in subjects with CF carrying one S1251N mutation, using a 16S rRNA gene-based sequencing approach. In 16 subjects with CF, repetitive samples from airways and gut were collected just before, and 2 months after, and, for 8 patients, also 9 and 12 months after, start of ivacaftor. 16S rRNA based sequencing identified 344 operational taxonomical units (OTUs) in a total of 139 samples (35 nasopharyngeal, 39 oropharyngeal, 29 sputum, and 36 fecal samples). Ivacaftor significantly enhanced bacterial diversity and overall microbiota composition in the gut (p < 0.01). There were no significant changes in the overall microbial composition and alpha diversity in upper and lower airways of these patients after ivacaftor treatment. Treatment with ivacaftor induces changes in gut microbiota whereas airway microbiota do not change significantly over time.