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•The combination of ibrutinib and venetoclax induced deep and durable responses in treatment-naïve patients with Waldenström macroglobulinemia.•Planned study therapy was stopped early due to a higher-than-expected occurrence of ventricular arrhythmia in 4 of the 45 participants.

Abstract This article focuses on the personal identities of a group of 'Palestinian refugee' women. Here the quotation marks are very important since this article, based on an intersectional analysis, [...]

ABSTRACTIn Argentina, the primary modes of contact between parents in prison and their children are contact visits and telephone calls. Prior to the pandemic, access to mobile telephones was limited and there were established barriers to contact visits, including distance and cost. Maintaining contact during the pandemic via either of these modes was made even more difficult. However, advocacy and multi-agency collaboration facilitated greater access to telephones and the development of support resources for parents in prison and their families in the community. This contemporary comment first provides context about imprisonment in Argentina, then highlights what is known about parents in prison in Argentina, subsequently focusing in on how family contact was negatively impacted by COVID-19. Next, the strategies deployed to reconnect families separated by imprisonment via regular contact are described. The remaining knowledge and evidence gaps, role of multi-agency collaborations and community advocacy are highlighted throughout the commentary.

ABSTRACTIt is generally understood that visits to see incarcerated family members are good for children, families and those in prison. Much research has focused on the impact of prison visits on children and incarcerated mothers, ‘parents’ as a generic group or barriers to contact, while less attention has been paid to the effect of prison visits on incarcerated fathers. When COVID-19 spread across the globe in early 2020, prisons restricted in-person visits. In Australia, alternative forms of communication between prisoners and their families were utilised, including phone calls and video visits. Drawing on data from an online survey of caregivers of children with a family member in prison (n = 84), this paper specifically focuses on a sub-sample, reporting on imprisoned fathers (n = 70), describing and evaluating experiences with video visits. Most respondents reported that the father was not coping well with the lack of face-to-face contact, and almost two-thirds of respondents reported problems with keeping in contact after in-person visits were suspended. However, a small cohort of fathers were found to be coping well. These findings are explored, highlighting barriers to technology-facilitated visits, and point to a range of issues that need to be addressed for such visits to be beneficial.

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.

Speaking by phone to a critic several weeks before the premiere of …(Iphigenia), director Lileana Blain-Cruz announced: ‘esperanza challenges the absurdity of this myth… Men must kill a young woman so they can go to war. Why repeat what does not work? What does it feel like to be a young woman thrust into this absurd story?’ In fact, the Wayne Shorter-esperanza spalding production exaggerates the myth's absurdity, minimizing the pain of Agamemnon and flattening the familial calamity at the heart of Euripides’ play until it becomes a conflict between aggressive men and suffering women. It is easy to judge these toxic male warriors with their Wagnerian helmets and hints of white nationalism. It is also easy for the female members of the audience to identify with Iphigenia, and with the series of Iphigenias whom the warriors put to death. Yet, at our moment, Shorter and spalding's reimagining of a myth about the sacrifice of a virgin to power a fleet invites us to consider our own implication in an urgent calamity, one in which we are both warrior and virgin.

‘Music is mass and it builds things’, esperanza spalding said she dreamt one night as she struggled with the libretto for …(Iphigenia),the phrase forming the turning point for the work. The oneiric formulation extends the material nature of music, granting sonic vibrations architectural abilities. This paradox approaches a paradoxical aim at the heart of Frank Gehry's building practice: to imbue solid matter with motion. His free-form sculptural designs, instanced most famously in the spectacular designs for the Guggenheim Museum at Bilbao and the Walt Disney Concert Hall in Los Angeles, have granted him global auteur status. However, the set design for …(Iphigenia)offered and continues to offer him an attractive state of unknowing, one in which emerges the possibility of non-directed constructive form.

The SRC family kinase (SFK) HCK is transcriptionally upregulated and activated by mutated MYD88 (MYD88Mut), a key adaptor for Toll-receptor signaling. HCK activates BTK, AKT, and ERK in MYD88Mut lymphomas. SYK, a B-cell receptor (BCR) component, is activated in MYD88Mut lymphoma cells. Although the SFK LYN serves as a trigger for SYK activation in MYD88Mut ABC DLBCL cells, LYN activity is muted in MYD88Mut Waldenstrom macroglobulinemia (WM) cells. We therefore investigated a role for HCK in mediating SYK activation. Overexpression of wild-type (WT) (HCKWT) or gatekeeper mutated (HCKThr333Met) HCK in MYD88Mut lymphoma cells triggered SYK activation. Conversely, HCK knockdown reduced p-SYK in MYD88Mut lymphoma cells. Coimmunoprecipitation experiments showed that HCK was complexed with p-SYK in MYD88Mut BCWM.1 and TMD8 cells, but not in MYD88 WT Ramos cells. Rescue experiments in MYD88Mut lymphoma cells expressing HCKThr333Met led to persistent HCK and SYK activation and resistance to the HCK inhibitor A419259. Treatment of primary MYD88Mut WM cells with A419259 reduced p-HCK and p-SYK expression. Taken together, our findings show that SYK is activated by HCK in MYD88Mut B-cell lymphomas cells, broaden the prosurvival signaling generated by aberrant HCK expression in response to MYD88Mut, and help define HCK as an important therapeutic target in MYD88Mut B-cell lymphomas.

Herein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without CXCR4mutations (14% vs. 44%; p= 0.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated CXCR4at 1.7 months (p= 0.07) and 7.3 months (p= 0.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without CXCR4mutations (59% vs. 92%; p= 0.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4mutations impacted VGPR attainment, time to major response, and 4-year PFS rate.

Bruton tyrosine kinase (BTK) inhibitors are the only FDA-approved treatments for Waldenström macroglobulinemia (WM). Factors prognostic of survival and predictive of response to BTK inhibitors remained to be clarified. We evaluated 319 patients with WM to identify predictive and prognostic factors on ibrutinib monotherapy. Logistic and Cox proportional-hazard regression models were fitted for response and survival. Multiple imputation analyses were used to address bias associated with missing data. Major (partial response or better) and deep responses (very good partial response or better) were attained in 78% and 28% of patients. CXCR4 mutations were associated with lower odds of major (odds ratio [OR], 0.2; 95% confidence interval [CI], 0.1-0.5; P < .001) and deep response (OR, 0.3; 95% CI, 0.2-0.6; P = .001). CXCR4 mutations (hazard ratio [HR], 2.0; 95% CI, 1.2-3.4; P = .01) and platelet count 100 K/uL or less (HR, 2.5; 95% CI, 1.3-4.9; P = .007) were associated with worse progression-free survival (PFS). We proposed a scoring system using these 2 factors. The median PFS for patients with 0, 1, and 2 risk factors were not reached, 5 years and 3 years (P < .001). Patients with 2 risk factors had HR 2.2 (95% CI, 1.3-3.8; P = .004) compared with 1 factor, and patients with 1 factor had HR 2.3 (95% CI, 1.1-5.1; P = .03) compared with 0 factors. Age ≥65 years was the only factor associated with overall survival (HR, 3.2; 95% CI, 1.4-7.0; P = .005). Multiple imputation analyses did not alter our results. Our study confirms the predictive and prognostic value of CXCR4 mutations in patients with WM treated with ibrutinib monotherapy.

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.

Feminist research and participatory action research (PAR) share the belief that research should directly serve social justice aims and work to alleviate suffering of marginalized and oppressed people. This article presents the results of a unique feminist PAR (FPAR) approach to designing and implementing an evaluation of an intervention with women who have used violence. The site of our analysis is the steering committee that oversaw this work and the extent to which members adhered to FPAR principles. Over the two decades since feminist critiques of PAR began to emerge, new discourses of collaboration have appeared. As researchers, we must be alert to FPAR discourses that mask ongoing hierarchies. Our findings suggest that, while reflexivity and genuine commitment to collaboration are fundamental to enacting FPAR principles, social workers nevertheless face real challenges confronting structural barriers that impede anti-oppression goals. This study highlights the challenges of adhering faithfully to feminist participatory principles in real-life settings and the need for future research to examine the effectiveness of FPAR processes in achieving authentic collaboration among committee members who are chosen to represent disparate perspectives and are backed by vastly different levels of social and institutional power.

Proteasome inhibition is a standard of care for the primary treatment of patients with Waldenström macroglobulinemia (WM). We present the long-term follow-up of a prospective, phase II clinical trial that evaluated the combination of ixazomib, dexamethasone, and rituximab (IDR) in 26 treatment-naive patients with WM. IDR was administered as 6 monthly induction cycles followed by 6 every-2-month maintenance cycles. The MYD88 L265P mutation was detected in all patients, and CXCR4 mutations were detected in 15 patients (58%). The median time to response (TTR) and time to major response (TTMR) were 2 and 6 months, respectively. Patients with and without CXCR4 mutations had median TTR of 3 months and 1 month, respectively (P = .003), and median TTMR of 10 months and 3 months, respectively (P = .31). The overall, major, and very good partial response (VGPR) rates were 96%, 77%, and 19%, respectively. The rate of VGPR in patients with and without CXCR4 mutations were 7% and 36%, respectively (P = .06). The median progression-free survival (PFS) was 40 months, the median duration of response (DOR) was 38 months, and the median time to next treatment (TTNT) was 40 months. PFS, DOR, and TTNT were not affected by CXCR4 mutational status. The safety profile was excellent with no grade 4 adverse events or deaths to date. IDR provides a safe and effective frontline treatment option for symptomatic patients with WM. This study was registered at www.clinicaltrials.gov as #NCT02400437.

AbstractVarious forms of violence against youth are documented in sport. To date, young athletes’ perceptions of violence in sport remain relatively unstudied. The objective of this study was to examine how violence and its various manifestations in sport have been understood by young athletes. In total, 60 athletes from a variety of sports and ages (12–17 years old) participated in nine semi-structured focus groups. The interview data were submitted to a thematic analysis using NVivo. Results obtained showed that various motivations for participating in sport influenced the ways in which young athletes addressed violence in this context. Additionally, the findings showed that violence in sport is a concept that young athletes partially understand. Even if most of them described various forms of violence in sport, some forms were misunderstood or have not been addressed at all. Finally, young athletes provided their own explanations of this issue in sport. From their perspective, violence in sport can be seen as part of the sport, a strategy to achieve competitive success on the field, a protective mechanism or a result of the valorisation of violence in sport by peers, parents, coaches and sport organisations. Considering that some young athletes normalised violence in sport, it seems crucial to make prevention efforts targeting social norms in sport.

Background:Peripheral neuropathy (PN) occurs in 20-25% of patients with an IgM paraprotein and up to 50% of these patients have an anti-myelin associated glycoprotein (MAG) antibody which is frequently associated with sensory ataxia and distal limb weakness negatively affecting function and quality of life. While rituximab is active, its activity is limited as a monotherapy and often associated with an IgM flare that can potentiate PN. BTK-inhibitors can block rituximab-associated IgM flare and are proven to markedly reduce serum IgM in Waldenström's Macroglobulinemia (WM). We therefore initiated this trial to evaluate a novel treatment for anti-MAG PN.

Background:In previous studies using multi-omic data for 253 treatment-naive patients with Waldenstrom's Macroglobulinemia (WM), we identified three subtypes of WM: B-cell like (BCL), Plasma cell like (PCL), and an intermediate clone enriched for early/smoldering WM from which the other two evolved (Hunter et al, ASH 2022). The BCL and PCL subtypes show distinct mutation and transcriptional signatures, as well as clinical characteristics. Diffusion pseudo-time (DPT) analysis suggests all patient tumors, regardless of subtype have a shared evolutionary path and can be divided into Early and Late DPT determined stages that mirror disease progression. Additional analysis of DPT suggests it represents a continuous process akin to clonal evolution. We therefore sought to further characterize the DPT signal in MYD88 mutated WM.

Background:We previously identified three subtypes of Waldenstrom's Macroglobulinemia (WM): B-cell like (BCL), Plasma cell like (PCL), and an intermediate group enriched for early/smoldering WM from which the other two subtypes evolved (Hunter et al, ASH 2022). Diffusion pseudo-time (DPT) analysis suggested all WM samples could be placed on a shared evolutionary path independent of subtype, and when samples were separated into Early and Late DPT values, it mirrored disease progression. The role of epigenetic dysregulation that underlies subtype classification and disease evolution remains poorly understood in WM.

Background:BTK inhibitors and BCL2 antagonists as monotherapy are highly active and well tolerated in Waldenström macroglobulinemia (WM). We initiated a prospective study evaluating ibrutinib and venetoclax in treatment-naive WM. Study therapy was stopped on March 31, 2022, after four ventricular arrhythmia events, including two grade 5 events. Herein, we present follow-up data after stopping therapy to assess ongoing safety and response durability of this combination in WM.

Background: Our RNA-Seq analysis of 249 untreated MYD88 mutated WM patients showed aberrant expression of stem cell, pre-B-cell, T-cell and myeloid genes in early WM B clones. This expression pattern was associated with inferior progression free survival with BTK inhibitor therapy and diminished with advancing disease. We therefore sought to validate this early signature at the protein level using flow cytometry and evaluate its potential as a clinical assay to monitor WM disease evolution.

Serum IgM measurements represent the current standard for assessing changes in disease burden in Waldenström's Macroglobulinemia (WM). Many agents used to treat WM can significantly affect serum IgM levels without impacting the underlying burden of clonal lymphoplasmacytic cells thereby producing discordant findings. Such agents can raise (CD20-directed monoclonal antibodies, IMiDs), or lower (BTK-, proteasome-, MTOR- inhibitors) serum IgM levels, and impact categorical response assessment. Somatic mutations in MYD88 are found in 95-97% of WM patients, and support tumor growth through activation of multiple pro-survival pathways that include HCK/BTK, SYK and ERK. Nearly all MYD88 mutations in WM are of the L265P variant. Previous studies by us and others have shown that serial quantitative measurements of both bone marrow (BM) and peripheral blood (PB) MYD88 L265P (c.978 T>C) by allele-specific PCR can be used to assess changes in underlying BM disease burden (Blood 121:2051-2058; Leukemia 28:1698-1704). However, the utility of using quantitative allele-specific MYD88 L265P (qMYD88 L265P) analysis has not been studied in prospective clinical trials. As such, we performed a comprehensive study of qMYD88 L265P response assessment utilizing BM and PB CD19-selected tissue across 5 prospective clinical studies in WM: Ixazomib, Dexamethasone and Rituximab (IDR; NCT02400437)Ibrutinib monotherapy (IBR; NCT02604511); Venetoclax monotherapy (VEN; NCT02677324); Ibrutinib plus Ulocuplomab (IBR/ULO; NCT03225716); and Ibrutinib plus Venetoclax (IBR/VEN; NCT04273139). Changes in MYD88 L265P ΔCt were assessed as reported above with ΔCt = Mutant Ct - Wild-type Ct, and higher ΔCt values indicating a lower mutant allele burden, with each ΔCt unit reduction representing a 50% decrease in mutant MYD88 L265P burden. Changes in MYD88 L265P ΔCt were compared to changes in underlying BM disease burden and categorical response assessment using the current (IWWM-11) response criteria (Semin Hematol. 60:97-106). Across all five trials, BM (r=0.52; p<0.001) and PB (r=0.43; p<0.001) MYD88 L265P ΔCt changes from baseline were highly correlated at best response with corresponding changes in underlying BM disease burden determined by repeat BM biopsies. As shown in Fig. 1, comparing changes from baseline in BM MYD88 L265P ΔCt assessments across studies showed marked differences, with greatest reductions observed in patients treated with IBR/VEN, IDR, and VEN alone, than for those treated with IBR alone or IBR/ULO. Similar findings were also observed for corresponding PB MYD88 L265P ΔCt assessments from baseline, with changes in PB MYD88 L265P ΔCt strongly correlating with those of BM MYD88 L265P ΔCt findings across all 5 clinical trials (r=0.67; p<0.001), thereby signifying the ability to use PB MYD88 L265P ΔCt assessments to evaluate treatment responses. We next compared findings from BM and PB MYD88 L265P ΔCt to changes from baseline in serum IgM levels across all 5 trials. At best response, major categorical responses denoted by >50% reduction in serum IgM using IWWM-11 criteria showed commensurate decreases in BM and PB MYD88 L265P ΔCt from baseline in patients receiving IBR/VEN, IDR and VEN alone ( Fig. 2). In contrast, minimal changes in BM and PB MYD88 L265P ΔCt from baseline were observed at best response for most major responders on IBR or IBR/ULO, including individuals who achieved very good partial responses denoted by >90% decrease in IgM by IWWM-11 criteria. In this first prospective evaluation of BM and PB qMYD88 L265P response assessment, we show that both BM and PB L265P qMYD88 analysis can provide more accurate assessment of treatment related changes in disease burden over the current standard of IgM response assessment alone, and can be used to more robustly evaluate clinical trial performance byidentifying treatments or regimens that produce more meaningful tumor reductions in WM patients.

Background:Alternative isoforms can alter regulatory motifs, binding partners, localization, and function of gene or even inhibit its function. While isoform regulation in humans is generally well described, there are still many tissue specific isoforms that remain to be fully documented. Moreover, mutations and broad dysregulation of transcriptional and RNA processing machinery is common in cancer resulting in additional novel isoforms. Analysis of 249 MYD88 mutated patients from our multi-omic data set of 253 treatment-naive patients with Waldenstrom's Macroglobulinemia (WM) identified three subtypes of WM: B-cell like (BCL), Plasma cell like (PCL), and an intermediate clone enriched for early/smoldering WM from which the other two evolved. (Hunter et al, ASH 2022) The BCL and PCL subtypes have distinct clinical as well as mutational and transcriptional characteristics. To investigate isoform usage, including novel disease related isoforms, we utilized PacBio single molecule real-time (SMRT) sequencing which can produce reads up to 10Kb allowing for end-to-end single transcript sequences for most genes.

Background:Waldenström's Macroglobulinemia (WM) patients carry MYD88 (MYD88 MUT) and CXCR4 (CXCR4 MUT) mutations in 95-97% and 30-40% of cases, respectively. The mechanisms of MYD88-driven lymphomagenesis remain to be clarified. Our previous transcriptome analysis highlighted WNK2 as a highly dysregulated gene in MYD88 MUTWM (Guerrera ML et al, Haematologica 2018). WNK2 is a serine/threonine protein kinase that negatively regulates ERK1/2 activation in a kinase-dependent manner; is a known tumor suppressor in certain solid cancers, where it is primarily silenced by promoter methylation. ERK1/2 is a pro-survival signal in WM; its activation is accompanied by the release of inflammatory cytokines and can mediate ibrutinib resistance. We previously demonstrated WNK2 transcriptional and protein upregulation in CXCR4 WTand silencing in CXCR4 MUTWM and identified several mechanisms of WNK2 transcriptional dysregulation including i) the preferential expression of short isoforms lacking the kinase domain; ii) the recurrence of an identical, aberrant, exon skipping event in all gene isoforms; and iii) aberrant methylation and chromatin accessibility in CXCR4 WTvs CXCR4 MUTWM. We therefore hypothesized that spliced WNK2 may contribute to MYD88 MUTWM oncogenesis.

Insertion and/or deletion mutations of the CALRgene have recently been demonstrated to be the second most common driver mutations in the myeloproliferative neoplasms (MPNs) of essential thrombocythemia (ET) and primary myelofibrosis (PMF). Given the diagnostic and emerging prognostic significance of these mutations, in addition to the geographical heterogeneity reported, the incidence of CALRmutations was determined in an Irish cohort of patients with MPNs with a view to incorporate this analysis into a prospective screening program. A series of 202 patients with known or suspected ET and PMF were screened for the presence of CALRmutations. CALRmutations were detected in 58 patients. Type 1 and Type 1-like deletion mutations were the most common (n=40) followed by Type 2 and Type 2-like insertion mutations (n=17). The CALRmutation profile in Irish ET and PMF patients appears similar to that in other European populations. Establishment of this mutational profile allows the introduction of a rational, molecular diagnostic algorithm in cases of suspected ET and PMF that will improve clinical management.

This paper reports on one aspect of data gathered in an Australian Research Council (ARC) funded project which sought to uncover how children are responded to when their parents are arrested and imprisoned. This paper presents initial specific insights into how Victorian schools understand and respond to these children. Due to the limited research previously conducted in this area of study, a flexible and exploratory approach was implemented. Data were obtained from eight Victorian education staff members, from a variety of professional domains, and were analysed using thematic analysis. Results indicate that a school's ability to respond appropriately to this group of students is shaped by the general and specific knowledge of parental imprisonment held by schools. Access to such knowledge is limited, however, by both the stigmatised nature of the problem and the current, fragmented, service system. More optimistically, it seems that when schools have greater awareness, positive responses can be implemented. Implications for this are discussed, with a particular focus on the need for clear channels of communication and collaborative work.

Although there are no national data specifically focused onrecording the intimate partner violence experiences ofyoung women, national secondary school health surveys show61% of young women aged between 14 and 18 report unwantedsex due to partner pressure. Partners Monash University Australian National University Monash University provides funding as a founding partner ofThe Conversation AU. Recent evidence shows the scale of sexual violence againstwomen and children in Australia has been severelyunderestimated. [Extracted from the article]

This article describes the experiences of four young people aged 18 to 25 years whose fathers were absent during their adolescent years. The study, located in regional Western Australia, sought to investigate how young people experience father absence, their needs and preferences in regard to any help seeking, and their evaluation of the effectiveness of supports used. Participants were found to share a combination of risk factors which were linked to negative psychosocial outcomes. Problems identified by young people included no one to talk to about problems and a lack of available services. Participants disclosed involvement in substance use, school misconduct and anti-social behaviour, and all reported early home leaving. Male and female participants reported using similar coping styles and a hierarchy of preference in help-seeking was found with friends and family preferred over counselling. Counselling was considered helpful when offered online or via drop-in services not requiring an appointment. Ethical constraints, however, were found to limit young people's participation in research.

This paper presents the case study of a family which was supported by a Victorian foster care agency over a two-year period whilst both parents were imprisoned. The article aims to raise awareness amongst practitioners across a range of fields of practice about the issues faced by the children of prisoners, and to document effective and collaborative practices which enable the impact of parental incarceration to be managed and minimised for the children involved. The paper is based on data gathered for a study examining the impact of maternal incarceration on young people conducted by one of the authors. Through focusing on one family, the paper discusses the increasing phenomenon of mothers in prison and the challenges this presents both to their families and to practitioners. The paper concludes by reflecting on the process and suggests that collaborative work with the families of prisoners requires not just good intentions but resources, commitment from all parties, and mutually respectful relationships. [ABSTRACT FROM AUTHOR]

Donor cell leukemia (DCL) is a rare complication of hematopoietic cell transplantation (HCT). Its incidence has been reported between 0.12% and 5%, although the majority of cases are anecdotal. The mechanisms of leukemogenesis in DCL may be distinct from other types of leukemia. Possible causes of DCL include oncogenic alteration or premature aging of transplanted donor cells in an immunosuppressed person. Although many studies have recently better characterized leukemic stem cells, it is important to also consider that both intrinsic cell factors and external signals from the hematopoietic microenvironment govern the developmental fate of hematopoietic stem cells (HSCs). Therefore, in cases of DCL, alteration of the microenvironment after HCT may increase the likelihood that some progeny of normal HSCs become leukemic. This complex intercommunication between cells, growth factors, and cytokines in the hematopoietic microenvironment are critical to balance HSC self-renewal, proliferation, and differentiation. However, this homeostasis is likely perturbed in the development of DCL, allowing unique insight into the stimuli that regulate normal and potentially abnormal hematopoietic development. In this article, we discuss the possible pathogenesis of DCL, its association with stem cells, and its likely dependence on a less-supportive stem cell niche.

MYD88mutations (MYD88 MUT) are present in 95-97% of patients with Waldenström's Macroglobulinemia (WM). Transgenic mouse studies show that MYD88 MUTalone is insufficient to drive oncogenesis. We previously reported the occurrence of non-overlapping somatic mutations in either CXCR4(CXCR4 MUT) or deletions in 6q (del6q) in MYD88mutated (MYD88 MUT) WM patients, suggesting either event may serve as a secondary driver of WM oncogenesis. Intersecting the lists of genes differentially modulated by either CXCR4 MUTor del6q revealed WNK2as a top hit (Guerrera ML et al, Haematologica 2018). WNK2 is a serine/threonine protein kinase that negatively regulates ERK1/2 activation and has known tumor suppressor function in several solid tumors, wherein its expression is primarily silenced by aberrant promoter methylation. ERK1/2 pathway plays an important pro-survival role, its activation is accompanied by the release of inflammatory cytokines and can mediate ibrutinib resistance in WM (Chen et al, Blood 2018). We therefore sought to investigate the expression of WNK2, and clarify the mechanisms underlying its aberrant expression by genomic subtypes in WM.

MYD88 mutations are common in B-cell malignancies including Waldenstrom Macroglobulinemia (WM) and ABC subtype of Diffuse Large B-cell Lymphoma (ABC DLBCL). Mutated MYD88 activates BTK, and triggers downstream pro-survival signaling that includes NF-kB and ERK (Yang et al, Blood 2013; Blood 2016). ERK related signaling triggers inflammatory cytokine production including IL-6 and IL-10 (Chen et al, Blood 2016). Ibrutinib covalently binds to BTK Cys481and inactivates BTK and downstream NF-kB and ERK signaling. Ibrutinib is approved for the treatment of WM and is associated with high overall response rates (>90%) and long term progression free survival in WM though intolerance to therapy, as well as resistance related to acquired BTK Cys481mutations frequently leads to treatment discontinuation. We therefore investigated a novel, non-covalent BTK-inhibitor, pirtobrutinib that binds to BTK at non-Cys481 amino acids (G473-K483). Pirtobrutinib showed highly selective anti-proliferative activity against MYD88 mutated WM (BCWM.1, MWCL-1) and ABC DLBCL (TMD-8 and HBL-1) versus MYD88 wild-type (OCI-Ly7, OCI-Ly19, Ramos, and RPMI-8226) cells, with marked apoptotic effect exhibited against primary MYD88 mutated WM cells at pharmacologically achievable levels (100-500 nM). Importantly, pirtobrutinib blocked BTK activity and overcame ibrutinib resistance in BCWM.1 WM and TMD-8 ABC DLBCL cells transduced to express both wild-type and mutated BTK (BTK Cys481Ser) with similar efficacy. The downstream signaling consequences of pirtobrutinib in vector only, wild-type and mutant BTK Cys481expressing BCWM.1, MWCL-1, TMD-8 and HBL-1 cells was also examined. Treatment of vector only and wild-type BTK Cys481expressing WM and ABC DLBCL cells with ibrutinib or pirtobrutinib abrogated both p-BTK and p-ERK signaling. In contrast, only pirtobrutinib blocked p-BTK and p-ERK signaling in mutant BTK Cys481expressing WM and ABC DLBCL cells. In previous studies, we showed that inflammatory cytokine production that included IL-6 and IL-10 driven by ERK triggered ibrutinib resistance in wild-type BTK Cys481MYD88 mutated lymphoma cells co-cultured with their mutated BTK expressing counterparts (Chen et al, BLOOD 2018). ERK-driven cytokine resistance to ibrutinib was postulated to explain how disease progression occurs in patients with modest variant expression of mutated BTK Cys481(Woyach et al, JCO 2017; Xu et al, Blood 2017). Co-culture of BTK Cys481mutated expressing TMD-8 cells with wild-type BTK expressing TMD-8 cells triggered resistance of the latter to ibrutinib. Treatment with pirtobrutinib blocked IL-6 and IL-10 production and overcame the protective effects conferred by BTK Cys481mutated TMD-8 cells in these experiments. Lastly, oral administration of pirtobrutinib blocked p-BTK and p-ERK in BTK Cys481mutated TMD-8 tumors xenografted in mice. Our findings therefore show that pirtobrutinib inhibits growth of MYD88 mutated lymphoma cells in a highly selective manner and can trigger apoptosis of primary WM patient BM lymphoplasmacytic cells at levels comparable to ibrutinib. Moreover, pirtobrutinib effectively blocked mutated BTK Cys481driven BTK and ERK1/2 activation and produced similar cellular efficacy in both BTK wild-type and BTK Cys481mutated cells. Pirtobrutinib also blocked the protective effect conferred to BTK wild-type cells through paracrine cytokines released by BTK Cys481Serexpressing cells. Lastly, pirtobrutinib blocked BTK and ERK1/2 activation in TMD8-BTK Cys481Serxenografted mice. The findings support the development of pirtobrutinib in MYD88 driven lymphomas, including those resistant to ibrutinib on the bases of BTK Cys481mutations.

Multiple myeloma (MM) and Waldenström macroglobulinemia (WM) are associated with significant immunoparesis. Based on the ongoing COVID-19 pandemic, there is an urgent need to understand whether patients are able to mount a sufficient response to COVID-19 vaccines.

The BTK-inhibitor ibrutinib is the first FDA approved therapy for Waldenström macroglobulinemia (WM) and produces overall response rates >90% and long-term disease control in both treatment naïve and previously treated patients. Despite the remarkable efficacy of ibrutinib, dose reduction is often required for intolerance. In this study, we analyzed those patients requiring a dose reduction and evaluated the time to dose reduction, the symptoms leading to dose reduction, the rate of improvement in symptoms after dose reduction, and the hematologic response at 12 months after dose reduction.

Activating mutations in MYD88 (MYD88 Mut) are common in B-cell malignancies including Waldenstrom Macroglobulinemia (WM) and ABC subtype of diffuse B-cell lymphoma (ABC DLBCL). MYD88 is a component of the Toll-like receptor (TLR) pathway. We and others previously showed that MYD88 Muttriggers assembly of a “Myddosome” complex that leads to downstream pro-survival signaling that includes IRAK4/IRAK1 and BTK triggered NF-κB (Ngo et al, Nature 2011; Treon et al, NEJM 2012; Yang et al, Blood 2013) and HCK mediated BTK/NF-κB, PI3K/AKT, and MAPK/ERK signaling (Yang et al, Blood 2016; Liu et al Blood Adv. 2020). The activation of the B-cell receptor (BCR) signaling component SYK has also been observed in MYD88 MutWM (Argyropoulos et al, Leukemia 2016). In ABC DLBCL, chronic active BCR signaling underlies SYK activation that is triggered by the SRC family member LYN (Davis et al, Nature 2010). These observations led us to explore potential drivers of BCR/SYK activation in WM. We previously reported that MYD88 Muttriggered activation of SYK in WM and ABC DLBCL cells (Munshi et al, BCJ 2020). Herein, we investigated if HCK, a SRC family member that is transcriptionally upregulated and activated by MYD88 Mutcould trigger the BCR pathway through SYK activation. Since LYN is an integral part of BCR signaling, we first examined its expression and activation state in MYD88 MutWM and ABC DLBCL cells. While MYD88 MutTMD8, HBL-1 and OCI-Ly3 ABC DLBCL cells showed strong expression of p-LYN, such expression was absent or low in MYD88 MutBCWM.1 and MWCL-1 cells, as well as CD19-selected bone marrow derived primary lymphoplasmacytic cells (LPCs) from WM patients. In view of the above findings, we next interrogated a direct role for HCK in mediating SYK activation. We over-expressed wild-type HCK (HCK WT) or gatekeeper mutated HCK (HCK T333M) in MYD88 MutBCWM.1 and MWCL-1 WM cell lines, and TMD8 ABC DLBCL cells. In all these cell lines, over-expression of HCK WTor HCK T333Mtriggered a robust increase in phosphorylation of SYK Y525/Y526in comparison to vector only transduced cells. Moreover, using an inducible vector system, knockdown of HCK showed a marked reduction in phosphorylation of SYK Y525/Y526in MYD88 MutBCWM.1 WM and TMD8 ABC DLBCL cells. We next sought to clarify if HCK and activated SYK were present in the same signaling complex. We performed co-immunoprecipitation experiments using an HCK antibody in MYD88 MutBCWM.1, TMD8 and wild-type MYD88 (MYD88 WT) Ramos cells. The HCK antibody effectively pulled down p-SYK in MYD88 MutBCWM.1 and TMD8 cells, but not in MYD88 WTRamos cells. To confirm whether SYK activation was a result of HCK kinase activity, we next performed rescue experiments with the HCK inhibitors A419259 and KIN-8194 in MYD88 MutBCWM.1 and MWCL-1 WM and TMD8 ABC DLBCL cells expressing either HCK WTor the HCK T333Mprotein that abrogated the activity of these inhibitors against HCK. Expression of the HCK T333Mprotein produced marked resistance to A419259 as well as KIN-8194 versus vector or HCK WTtransduced BCWM.1 and MWCL-1 cells. By PhosFlow analysis, we observed that expression of HCK T333Mbut not HCK WTled to persistent activation of HCK and SYK in the presence of A419259 or KIN-8194 in BCWM.1 and MWCL-1 WM cells, and TMD8 ABC DLBCL cells. Consistent with these observations, treatment of primary MYD88 mutated WM LPCs cells with either A419259 or KIN-8194 also showed marked reduction in both p-HCK and p-SYK expression by PhosFlow analysis. Taken together, our findings show that SYK is activated by HCK in MYD88 MutB-cell lymphomas cells; broaden the pro-survival signaling generated by aberrant HCK expression in response to MYD88 Mut; and help further establish HCK as an important therapeutic target in MYD88 MutB-cell lymphomas.

Branagan: Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; CSL Behring: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Consultancy; Sanofi Genzyme: Consultancy. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding. Yang: Blueprint Medicines Corporations: Current Employment, Current holder of individual stocks in a privately-held company. Treon: BeiGene: Consultancy, Research Funding; Eli Lily: Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding.

Splenectomy is a surgical intervention for a variety of indications; benign and malignant. Complications of this procedure include Venous thromboembolism (VTE) and infection. The incidence of VTE post-surgery has been reported between 0.8%–3% depending on the type of surgery. A higher incidence of abdominal VTE was reported post splenectomy (6–11%). However, there is limited literature regarding the risk factors for post splenectomy VTE and the optimal strategy for thromboprophylaxis.

Bruton tyrosine kinase (BTK) inhibitors are the only FDA-approved treatments for Waldenström macroglobulinemia (WM). Factors prognostic of survival and predictive of response to BTK inhibitors remained to be clarified. We evaluated 319 patients with WM to identify predictive and prognostic factors on ibrutinib monotherapy. Logistic and Cox proportional-hazard regression models were fitted for response and survival. Multiple imputation analyses were used to address bias associated with missing data. Major (partial response or better) and deep responses (very good partial response or better) were attained in 78% and 28% of patients. CXCR4mutations were associated with lower odds of major (OR 0.2, 95% CI 0.1-0.5; p<0.001) and deep response (OR 0.3, 95% CI 0.2-0.6; p=0.001). CXCR4mutations (HR 2.0, 95% CI 1.2-3.4; p=0.01) and platelet count 100 K/uL or less (HR 2.5, 95% CI 1.3-4.9; p=0.007) were associated with worse progression-free survival (PFS). We proposed a scoring system using these two factors. The median PFS for patients with zero, one and two risk factors were not reached, 5 years and 3 years (p<0.001). Patients with two risk factors had HR 2.2 (95% CI 1.3-3.8; p=0.004) compared with one factor, and patients with one factor had HR 2.3 (95% CI 1.1-5.1; p=0.03) compared with zero factors. Age 65 years or older was the only factor associated with overall survival (HR 3.2, 95% CI 1.4-7.0; p=0.005). Multiple imputation analyses did not alter our results. Our study confirms the predictive and prognostic value of CXCR4mutations in patients with WM treated with ibrutinib monotherapy.