Ibrutinib and venetoclax as primary therapy in symptomatic, treatment-naïve Waldenström macroglobulinemia.

ABSTRACT: Concurrent Bruton tyrosine kinase and BCL2 inhibition has not yet been investigated in Waldenström macroglobulinemia (WM). We performed an investigator-initiated trial of ibrutinib and venetoclax in symptomatic treatment-naïve patients with MYD88-mutated WM. Patients received ibrutinib 420 mg once daily (cycle 1), followed by a ramp-up of venetoclax to 400 mg daily (cycle 2). The combination was then administered for 22 additional 4-week cycles. The attainment of very good partial response (VGPR) was the primary end point. Forty-five patients were enrolled in this study. The median baseline characteristics were as follows: age 67 years, serum IgM 43 g/L, and hemoglobin 102 g/L. Seventeen patients (38%) carried CXCR4 mutations. Nineteen patients (42%) achieved VGPR. Grade 3 or higher adverse events included neutropenia (38%), mucositis (9%), and tumor lysis syndrome (7%). Atrial fibrillation occurred in 3 (9%), and ventricular arrhythmia in 4 (9%) patients that included 2 grade 5 events. With a median follow-up of 24.4 months, the 24-month progression-free survival (PFS) and overall survival (OS) rates were 76% and 96%, respectively, and were not impacted by CXCR4 mutations. The median time on therapy was 10.2 months, and the median time after the end of therapy (EOT) was 13.3 months. Eleven of the 12 progression events occurred after EOT, and the 12-month PFS rates after EOT were 79%; 93% if VGPR was attained, and 69% for other patients (P = .12). Ibrutinib and venetoclax induced high VGPR rates and durable responses after EOT, although they were associated with a higher-than-expected rate of ventricular arrhythmia in patients with WM, leading to early study treatment termination. This trial was registered at www.clinicaltrials.gov as #NCT04273139.

Dose reductions in patients with Waldenström macroglobulinaemia treated with ibrutinib.

Waldenström macroglobulinaemia (WM) is characterized by the presence of a MYD88L265P mutation. This mutation promotes growth and survival of malignant cells through Bruton tyrosine kinase (BTK) activation. Ibrutinib was the first BTK inhibitor approved for WM. Intolerance to ibrutinib frequently leads to dose reductions, though the impact of reducing ibrutinib dosing has not been systematically studied. We performed a retrospective study to determine the frequency and impact of reducing ibrutinib dosing in WM patients. With a median treatment time of 64 months, 96 (27%) of 353 WM patients required a dose reduction due to adverse events such as musculoskeletal symptoms, cardiac events, dermatologic symptoms, cytopenias, and gastrointestinal symptoms. The median time to initial dose reduction was 9.3 months (range, 0.5-74). Dose reductions were more common in those 65 years of age or older versus under 65 [hazard ratio (HR) 2.46, 95% confidence interval (CI) 1.55-3.90; p < 0.001], and in females versus males (HR 2.20, 95% CI 1.41-3.28, p < 0.001). Most patients (65%) had improvement or resolution of adverse effects after initial dose reduction. With a median follow-up of three years from dose reduction, hematologic response sustained or deepened in 79% of patients. These data suggest that dose reduction of ibrutinib is a reasonable treatment approach for patients with intolerable side effects.

Phase 1 study of ibrutinib and the CXCR4 antagonist ulocuplumab in CXCR4-mutated Waldenström macroglobulinemia.

MYD88 and CXCR4 mutations are common in Waldenström macroglobulinemia (WM). Mutated CXCR4 (CXCR4Mut) impacts BTK-inhibitor response. We conducted a phase 1 trial of the CXCR4-antagonist ulocuplumab with ibrutinib in this first-ever study to target CXCR4Mut in WM. Ibrutinib was initiated at 420 mg/d with cycle 1 and continued until intolerance or progression; ulocuplumab was given cycles 1 to 6, with a 3 + 3 dose-escalation design. Each cycle was 4 weeks. Thirteen symptomatic patients, of whom 9 were treatment-naive patients were enrolled. Twelve were evaluable for response. At best response, their median serum immunoglobulin M declined from 5574 to 1114 mg/dL; bone marrow disease decreased from 65% to 10%, and hemoglobin increased from 10.1 to 14.2 g/dL (P < .001). The major and VGPR response rates were 100% and 33%, respectively, with VGPRs observed at lower ulocuplumab dose cohorts. Median times to minor and major responses were 0.9 and 1.2 months, respectively. With a median follow-up of 22.4 months, the estimated 2-year progression-free survival was 90%. The most frequent recurring grade ≥2 adverse events included reversible thrombocytopenia, rash, and skin infections. Ulocuplumab dose-escalation did not impact adverse events. The study demonstrates the feasibility of combining a CXCR4-antagonist with ibrutinib and provides support for the development of CXCR4-antagonists for CXCR4Mut WM. This trial was registered at www.clinicaltrials.gov as #NCT03225716.

Natural history of Waldenström macroglobulinemia following acquired resistance to ibrutinib monotherapy.

Ibrutinib is highly active and produces long-term responses in patients with Waldenström macroglobulinemia (WM), but acquired resistance can occur with prolonged treatment. We therefore evaluated the natural history and treatment outcomes in 51 WM patients with acquired resistance to ibrutinib monotherapy. The median time between ibrutinib initiation and discontinuation was 2 years (range, 0.4-6.5 years). Following discontinuation of ibrutinib, a rapid increase in serum immunoglobulin M level was observed in 60% (29/48) of evaluable patients, of whom ten acutely developed symptomatic hyperviscosity. Forty-eight patients (94%) received salvage therapy after ibrutinib. The median time to salvage therapy after ibrutinib cessation was 18 days (95% confidence interval [CI]: 13-27). The overall and major response rates to salvage therapy were 56% and 44%, respectively, and the median duration of response was 48 months (95% CI: 34-not reached). Quadruple-class (rituximab, alkylator, proteasome inhibitor, ibrutinib) exposed disease (odds ratio [OR] 0.20, 95% CI: 0.05-0.73) and salvage therapy ≤7 days after discontinuing ibrutinib (OR 4.12, 95% CI: 1.07- 18.9) were identified as independent predictors of a response to salvage therapy. The 5-year overall survival (OS) following discontinuation of ibrutinib was 44% (95% CI: 26-75). Response to salvage therapy was associated with better OS after ibrutinib (hazard ratio 0.08, 95% CI: 0.02-0.38). TP53 mutations were associated with shorter OS, while acquired BTK C481S mutations had no impact. Our findings reveal that continuation of ibrutinib until subsequent treatment is associated with improved disease control and clinical outcomes.

"It Made Me so Vulnerable": Victim-blaming and Disbelief of Child Sexual Abuse as Triggers of Social Exclusion Leading Women to Homelessness.

Although the association between child sexual abuse (CSA) and homelessness among women is well documented, few studies have investigated this topic from a feminist standpoint, examining the impact of sociocultural factors such as rape culture. Based on a qualitative life course approach, individual interviews were conducted with 21 women who experienced both CSA and homelessness. Participants were between 29 to 60 years old (M = 45 years of age). Analyses revealed that CSA disclosure experiences were characterized by victim-blaming and disbelief. Women's traumatic experiences were further aggravated by these types of reactions. Finally, CSA and negative social reactions to women's disclosures of CSA were perceived as the onset of social exclusion, which lead to their homelessness. This study shows how traumatic CSA experiences and negative social reactions to their disclosure can both contribute to social exclusion and isolation, and to homelessness through the internalization of rape myths. These findings support the importance of focusing on CSA prevention to reduce social exclusion and homelessness.

Contact experiences and needs of children of prisoners before and during COVID-19: Findings from an Australian survey.

Most of the research examining children visiting a parent in prison indicates that visits have a positive impact on children's well-being, their connection to the imprisoned parent and the parent themselves. However, the COVID-19 pandemic brought about a significant change to prison visits worldwide, with limits or bans on face-to-face contact. Understanding the experiences and needs of children during this period remains limited. This paper presents the findings of a survey of 84 carers of 184 children across Australia, investigating children's experiences of contact with their imprisoned parent both before and during COVID-19 restrictions. Although most carers reported maintaining contact during restrictions, a range of difficulties were noted: reduced availability; the effect of prison-based issues, including lockdowns; and the suitability of video/telephone visits for young children. Some described the benefits of videoconferencing, including reduced travel time and cost, and not needing to take children into a prison environment. Despite this, respondents typically described the negative impact of restrictions, and lack of physical contact, on children's emotional well-being. Our findings suggest that, for video visiting to be successful, it should be complementary to in-person visits, tailored to the needs of children, with support offered to families.

Partial response or better at six months is prognostic of superior progression-free survival in Waldenström macroglobulinaemia patients treated with ibrutinib.

Ibrutinib is associated with durable responses in patients with Waldenström macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression-free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P = 0·29). In the learning cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 81% and 57% respectively (P = 0·009). In the validation cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 83% and 54% respectively (P = 0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38; P = 0·01] and validation cohorts (HR 0·18; P = 0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM.

Deepening of response after completing rituximab-containing therapy in patients with Waldenstrom macroglobulinemia.

Rituximab-containing regimens are commonly used for frontline therapy in patients with symptomatic Waldenström macroglobulinemia (WM). We had observed that a portion of WM patients experienced deepening of response months to years after therapy completion. We carried a retrospective study aimed at describing this phenomenon. We gathered baseline data, and responses at end of induction, end of maintenance and best response. Deepening of response was defined as ≥25% decrease in serum IgM achieved at a later time from therapy completion. Of 178 patients included, 116 (65%) received maintenance therapy and 62 (35%) were observed. In patients who received maintenance, 44 (38%) had ≥25% decrease in serum IgM level after the end of maintenance with a median time from end of maintenance to lowest IgM level of 1.6 years (range 0.1-7.9 years). In patients who were observed, 19 (31%) had ≥25% decrease in serum IgM level after the end of induction with a median time from end of induction to lowest IgM level of 1.6 years (range 0.2-5.1 years). Baseline hemoglobin <11.5 g/dL, bone marrow involvement ≥50%, CXCR4 mutations and serum IgM ≥4000 mg/dL were associated with lower odds of deepening of response after therapy completion. Deepening of response was associated with better progression-free survival (PFS; HR 0.46, 95% CI 0.26-0.80; P = .006) and better survival after frontline treatment initiation (SAFTI; HR 0.21, 95% CI 0.06-0.73; P = .01). In conclusion, deepening of response occurs in one third of WM patients after completing rituximab-containing regimens and was associated with better PFS and SAFTI.

Antecedents of red cell transfusion in a large contemporary obstetric cohort.

Background Hemorrhage is a critical contributor to maternal morbidity but estimation of blood loss at delivery is frequently inaccurate. Due to this inaccuracy we sought to examine blood transfusion as a surrogate marker for morbidity in a large non-population based consecutive cohort. Methods A retrospective analysis of prospectively gathered data was carried out at two university institutions serving a heterogeneous urban obstetric population from January to December 2016. Data were analyzed to determine whether individual characteristics were associated with perinatal transfusion. Hematological indices and requirement for other blood products were also characterized. Results A total of 16,581 deliveries were recorded during the study and 1.7% (289/16,581) of the cohort required red cell transfusion. Those who received transfusion were more likely to be nulliparous, and to deliver <37 weeks' or >42 weeks' gestation. They were also more likely to have a macrosomic infant (birthweight >4 kg) and to have had a multiple pregnancy. Characteristics not associated with risk of transfusion included obesity [18% (52/289) vs. 15% (2445/16,292); P=0.18], and maternal age ≥35 years [28% (82/289) vs. 33% (5537/16,292); P=0.05]. Additional blood products were necessary in a small number of patients who received red cells. Conclusion The rate of transfusion in a contemporary Irish cohort has risen compared with previous data. Several variables associated with transfusion are consistent with older studies but importantly; maternal obesity and advanced maternal age are not associated with transfusion. These data may encourage the investment of resources in a population previously considered low-risk and, following future studies, to improve strategies aimed at limiting blood transfusion.

Prison Experiences and Psychological Distress among Older Inmates.

This study investigates relationships between older prisoners' social experiences and their levels of distress. One hundred and seventy-three older prisoners (aged ≥ 50 years) from 8 Australian prisons were administered the Kessler Psychological Distress (K10) Scale, with additional information collected via individual interviews. Psychological distress scores were significantly associated with measures of self-reported safety (p < .001), prison victimization (p < .05), perceived social support from staff (p < .01) and inmates (p < .001), current employment (p < .05), and level of exercise (p < .001) among older inmates. Findings suggest that strategies for improving sense of safety, social support and level of exercise may ameliorate distress among older prisoners.

Non-attendance and utilization of a speech and language therapy service: a retrospective pilot study of school-aged referrals.

BACKGROUND: Non-attendance and inappropriate referrals affect the effective and efficient running of healthcare services. Non-engagement with speech and language therapy (SLT) services may lead to negative long-term consequences for children in need of SLT intervention. Currently there is a dearth of research on non-attendance and non-engagement with SLT services. AIMS: To identify factors associated with (1) non-attendance and (2) parents' non-engagement with SLT services. METHODS & PROCEDURES: Demographic data were collected from 140 case files of children (aged 5;0-17;11 years) discharged from a public community SLT service (November 2011-October 2013) with no intervention provided. Logistic regression analyses explored relationships between demographic data and (1) non-attendance and (2) non-engagement with the SLT service. OUTCOMES & RESULTS: There was an increased probability of non-attendance during winter (i.e. September-February inclusive; OR = 3.14; p = 0.028) relative to summer, and with each month a child waited for SLT assessment (OR = 1.19; p = 0.066). There was decreased probability of non-attendance with children referred for speech (OR = 0.08; p = 0.011) or language difficulties (OR = 0.15; p = 0.050) relative to dysfluency. The probability of non-engagement with the SLT service increased in each of the following conditions: with each month a child waited for assessment (OR = 1.27; p = 0.004); in urban (OR = 2.40; p = 0.066) relative to rural locations; during winter (OR = 2.65; p = 0.021) relative to summer; and with referrals made by occupational therapists, physiotherapists, psychologists and social workers (OR = 18.65; p = 0.016) relative to doctor referrals. CONCLUSIONS & IMPLICATIONS: Non-attendance is influenced by wait times, season and the reason for referral. Location (urban versus rural), referral source, wait times and season are factors related to non-engagement with SLT services. Targeted policies to improve efficiency and effectiveness of SLT services could be designed around these study findings.

How Social Responses to Child Sexual Abuse and Intimate Partner Violence Affect Homelessness Among Women in Two Rural Regions With Resource-Based Economies in Eastern Quebec.

This study presents findings from a qualitative study conducted in two relatively remote, primarily rural regions of the Canadian province of Quebec whose resource-based economic structures exacerbate inequalities between men and women. The purpose of this study was to understand how violence and homelessness intertwine in women's life courses in such regions. On the basis of past research showing that gender socialization around traditional roles and conservative values is particularly tenacious in non-urban areas, we conducted life-course interviews with 22 women in 13 different towns and villages of these two regions. Our content analysis of these interviews showed that specific social responses have forced women to maintain relationships with their aggressors or with people who have protected them, thus relegating these women's lives to the private sphere while reducing their opportunities for social participation in the public sphere. These social responses, together with women's economic and social disadvantages in these regions, were also the main factors that explain homelessness experienced by the participants in this study. Our analysis of these responses illustrates the patriarchal social structure of power in these regions, which is perpetuated in the interpersonal, institutional, and representational dimensions and keeps women in precarious, subordinate social positions, while ostracizing or punishing women who try to resist.

Infant food allergy phenotypes and association with lung function deficits and asthma at age 6 years: a population-based, prospective cohort study in Australia.

BACKGROUND: Food allergy is considered a precursor to asthma in the context of the atopic march, but the relationship between infant food allergy phenotypes and lung function and asthma in childhood is unclear. We aimed to examine the association between food sensitisation and challenge-confirmed food allergy in infancy, as well as persistent and resolved food allergy up to age 6 years, and the risk of lung function deficits and asthma at age 6 years. METHODS: The longitudinal, population-based HealthNuts cohort study in Melbourne, VIC, Australia, recruited 5276 infants children aged 1 year who attended council-run immunisation sessions between Sept 28, 2007, and Aug 5, 2011. At age 1 year, all children completed skin prick testing to four food allergens (egg, peanut, sesame, and either shrimp or cow's milk) and an oral food challenge (egg, peanut, and sesame) at the Royal Children's Hospital in Melbourne. Parents completed questionnaires about their infant's allergy history, demographic characteristics, and environmental exposures. At age 6 years, children were invited for a health assessment that included skin prick testing for ten foods (milk, egg, peanut, wheat, sesame, soy, shrimp, cashew, almond, and hazelnut) and eight aeroallergens (alternaria, cladasporum, house dust mite, cat hair, dog hair, bermuda grass, rye grass, and birch mix), oral food challenges, and lung function testing by spirometry. Questionnaires completed by parents (different to those completed at age 1 year) captured the child's allergy and respiratory history and demographics. We investigated associations between food allergy phenotypes (food-sensitised tolerance or food allergy; and ever, transient, persistent, or late-onset food allergy), lung function spirometry measures (forced expiratory volume in 1 sec [FEV1] and forced vital capacity [FVC] z-scores, FEV1/FVC ratio, forced expiratory flow at 25% and 75% of the pulmonary volume [FEF25-75%], and bronchodilator responsiveness), and asthma using regression methods. Only children with complete data on the exposure, outcome, and confounders were included in models. Infants without food sensitisation or food allergy at age 1 year and 6 years served as the reference group. FINDINGS: Of 5276 participants, 3233 completed the health assessment at age 6 years and were included in this analysis. Food allergy, but not food-sensitised tolerance, at age 1 year was associated with reduced FEV1 and FVC (aß -0·19 [95% CI -0·32 to -0·06] and -0·17 [-0·31 to -0·04], respectively) at age 6 years. Transient egg allergy was associated with reduced FEV1 and FVC compared with never having egg allergy (-0·18 [95% CI -0·33 to -0·03] and -0·15 [-0·31 to 0·00], respectively), whereas persistent egg allergy was not (FEV1 -0·09 [-0·48 to 0·31]; FVC -0·20 [-0·62 to 0·21]). Transient peanut allergy was associated with reduced FEV1 and FVC (FEV1 aß -0·37 [-0·79 to 0·04] and FVC aß -0·55 [-0·98 to -0·12]), in addition to persistent peanut allergy (FEV1 aß -0·30 [-0·54 to -0·06] and FVC aß-0·30 [-0·55 to -0·05]), and late-onset peanut allergy (FEV1 aß -0·62 [-1·06 to -0·18] and FVC aß-0·49 [-0·96 to -0·03]). Estimates suggested that food-sensitised tolerance and food allergy were associated with reduced FEF25-75%, although some estimates were imprecise. Food allergy phenotypes were not associated with an FEV1/FVC ratio. Late-onset peanut allergy was the only allergy phenotype that was possibly associated with increased risk of bronchodilator responsiveness (2·95 [95% CI 0·77 to 11·38]). 430 (13·7%) of 3135 children were diagnosed with asthma before age 6 years (95% CI 12·5-15·0). Both food-sensitised tolerance and food allergy at age 1 year were associated with increased asthma risk at age 6 years (adjusted odds ratio 1·97 [95% CI 1·23 to 3·15] and 3·69 [2·81 to 4·85], respectively). Persistent and late-onset peanut allergy were associated with higher asthma risk (3·87 [2·39 to 6·26] and 5·06 [2·15 to 11·90], respectively). INTERPRETATION: Food allergy in infancy, whether it resolves or not, is associated with lung function deficits and asthma at age 6 years. Follow-up studies of interventions to prevent food allergy present an opportunity to examine whether preventing these food allergies improves respiratory health. FUNDING: National Health & Medical Research Council of Australia, Ilhan Food Allergy Foundation, AnaphylaxiStop, the Charles and Sylvia Viertel Medical Research Foundation, the Victorian Government's Operational Infrastructure Support Program.

Bone marrow versus peripheral blood as the stem cell source for sibling transplants in acquired aplastic anemia: survival advantage for bone marrow in all age groups.

BACKGROUND: Bone marrow has been shown to be superior to peripheral blood, as a stem cell source, in young patients (<20 years of age) with acquired aplastic anemia undergoing a matched sibling transplant. The aim of this study was to test whether this currently also holds true for older patients with acquired aplastic anemia. DESIGN AND METHODS: We analyzed 1886 patients with acquired aplastic anemia who received a first transplant from a human leukocyte antigen identical sibling between 1999 and 2009, with either bone marrow (n=1163) or peripheral blood (n=723) as the source of stem cells. RESULTS: In multivariate Cox analysis negative predictors for survival were: patient's age over 20 years (RR 2.0, P<0.0001), an interval between diagnosis and transplantation of more than 114 days (RR 1.3, P=0.006), no anti-thymocyte globulin in the conditioning (RR 1.6, P=0.0001), a conditioning regimen other than cyclophosphamide (RR=1.3, P=0.008) and the use of peripheral blood as the source of stem cells (RR 1.6, P<0.00001). The survival advantage for recipients of bone marrow rather than peripheral blood was statistically significant in patients aged 1-19 years (90% versus 76% P<0.00001) as well as in patients aged over 20 years (74% versus 64%, P=0.001). The advantage for recipients of bone marrow over peripheral blood was maintained above the age of 50 years (69% versus 39%, P=0.01). Acute and chronic graft-versus-host disease were more frequent in peripheral blood transplants. Major causes of death were graft-versus-host disease (2% versus 6% in bone marrow and peripheral blood recipients, respectively), infections (6% versus 13%), and graft rejection (1.5% versus 2.5%). CONCLUSIONS: This study shows that bone marrow should be the preferred stem cell source for matched sibling transplants in acquired aplastic anemia, in patients of all age groups.

A pilot study on dasatinib in patients with Waldenström macroglobulinemia progressing on ibrutinib.

The hematopoietic cell kinase (HCK) regulates BTK activation and represents a potential therapeutic target in Waldenstrom macroglobulinemia (WM). We investigated dasatinib, a potent HCK inhibitor, in patients with WM progressing on ibrutinib. Study treatment consisted of dasatinib administered at 100 mg by mouth once daily in four-week cycles for up to 24 cycles. This study was registered under ClinicalTrials.Gov ID NCT04115059. Three participants were enrolled and received at least one cycle of dasatinib. The best response was stable disease. Two patients received 5 months and one patient received 1 month of therapy. The dose of dasatinib was decreased in one participant due to volume overload. Based on the lack of responses observed, the study was terminated. Dasatinib might not be effective in patients with WM progressing on ibrutinib.