Efficacy and safety of azacitidine in pediatric patients with newly diagnosed advanced myelodysplastic syndromes before hematopoietic stem cell transplantation in the AZA-JMML-001 trial.

Here we report efficacy, pharmacokinetics, and safety data obtained in treatment-naive, pediatric patients with newly diagnosed advanced MDS receiving azacitidine in the AZA-JMML-001 study. The primary endpoint was response rate (proportion of patients with complete response [CR], partial response [PR], or marrow CR, sustained for ≥4 weeks). Of the 10 patients enrolled, one had an unconfirmed marrow CR and none had confirmed responses after three cycles; the study was therefore closed after stage 1. Azacitidine was well tolerated. The lack of efficacy of azacitidine in pediatric patients with newly diagnosed advanced MDS highlights the need for effective new treatments in these patients.

Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma.

BACKGROUND: Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide. METHODS: In this phase 1-2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1. RESULTS: In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class-refractory multiple myeloma, 30 patients (30%) had received previous anti-B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9). CONCLUSIONS: The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).

Longitudinal Relations Between Childhood Maltreatment, Emotion Regulation Difficulties, and Suicidal Ideation and Non-Suicidal Self-Injury: An 18-Month Investigation of Psychiatrically Hospitalized Adolescents.

Within the Dimensional Model of Adversity and Psychopathology, extant research shows that exposure to threat-including emotional, physical, and sexual abuse-is linked to psychopathology among adolescents; problems with emotion regulation may, at least in part, explain this association. Both theoretical and empirical work also suggests that emotion regulation difficulties-particularly access to emotion regulation strategies-may mediate the relation between threat and self-injurious thoughts and behavior, though no studies to date have explicitly tested this model. The current study tested relations between threat, limited access to emotion regulation strategies, and self-injurious thoughts and behaviors among high-risk youth across an 18-month follow-up. The sample consisted of 180 adolescents (Mage = 14.89; SD = 1.35; ages 12-17; 71.7% female; 78.9% White; 55.0% heterosexual) recruited from an inpatient psychiatric unit. Threat was assessed at baseline using the abuse subscales from Childhood Trauma Questionnaire. Access to emotion regulation strategies was assessed using the Difficulties in Emotion Regulation Scale at baseline, 6-, and 12-months. Presence (versus absence) of non-suicidal self-injury and suicidal ideation severity were assessed at baseline, 12-, and 18-months using the Self-Injurious Thoughts and Behaviors Interview and the Suicidal Ideation Questionnaire-JR, respectively. After accounting for baseline levels of the mediator, outcome, and depressive symptoms, structural equation models supported the role of 12-month access to emotion regulation strategies as a mediator between baseline threat and 18-month suicidal ideation and non-suicidal self-injury. Treatment aimed at bolstering access to emotion regulation strategies may help reduce suicide risk among youth who have experienced childhood abuse.

The Affective Consequences of Minority Stress Among Bisexual, Pansexual, and Queer (Bi+) Adults: A Daily Diary Study.

Bisexual, pansexual, and queer (bi+) individuals are at increased risk for depression and anxiety. These disparities are hypothesized to be due to the unique, minority-specific stressors that they experience. Prior research supports that bi+ stressors are associated with depression and anxiety, but nearly all studies have been cross-sectional, limiting our understanding of how experiencing bi+ stress influences individuals' levels of depression and anxiety as they occur in their day-to-day lives. To address this gap, we examined the daily associations between bi+ stressors (discrimination, internalized stigma, rejection sensitivity, and identity concealment) and depressed/anxious mood in a 28-day diary study. Participants were 208 bi+ individuals who completed daily measures of bi+ stressors and depressed/anxious mood. We tested unlagged (same-day) and lagged (next-day) associations, and we also tested whether internalized stigma, rejection sensitivity, and identity concealment functioned as mechanisms underlying the daily associations between discrimination and depressed/anxious mood. Participants reported higher depressed/anxious mood on days when they reported higher discrimination, internalized stigma, rejection sensitivity, and identity concealment. There were significant unlagged indirect effects of discrimination on depressed and anxious mood via internalized stigma and rejection sensitivity, and there was also a significant unlagged indirect effect of discrimination on anxiety via identity concealment. However, none of the lagged associations were significant. Results suggest that bi+ stress is related to same-day, but not next-day, depressed/anxious mood. The nonsignificant lagged associations could reflect that bi+ individuals are using adaptive coping skills in response to bi+ stress, or that other experiences throughout the day have stronger influences on next-day mood.

Dialectical behavior therapy for adolescents (DBT-A): Outcomes among sexual minorities at high risk for suicide.

The alarming rates and pervasiveness of suicidal and self-destructive behaviors (e.g., non-suicidal self-injury) among young sexual minorities represent a major public health concern. We set out to examine whether an empirically driven treatment for suicide and self-harm, dialectical behavior therapy for adolescents (DBT-A), provides benefits for adolescents who identify as gay, lesbian, bisexual, or questioning (LGBQ). LGBQ adolescents (n = 16) were compared with non-LGBQ peers (n = 23). Psychological measures were collected before and after participation in a comprehensive DBT-A program. LGBQ participants demonstrated significant improvements in emotion regulation, depression, borderline symptoms, and coping strategies; changes were comparable to their heterosexual peers.

Task-based functional connectivity patterns: Links to adolescent emotion regulation and psychopathology.

Adolescence is a developmental period characterized by heightened emotional reactivity, neurobiological changes, and increased rates of anxiety and depression. Emotion regulation (ER) difficulties-or the inability to effectively regulate one's emotions-have been theoretically and empirically conceptualized as a transdiagnostic factor implicated in virtually all forms of psychopathology among youth. The current fMRI study investigates how young adolescents' ER abilities longitudinally mediate the relationship between their task-based (n=67) limbic-prefrontal functional connectivity values and subsequent levels of internalizing and externalizing symptoms. Findings revealed that adolescents with stronger limbic-prefrontal connectivity when viewing negative emotional images reported more ER difficulties one year later which, in turn, predicted higher levels of adolescent-reported internalizing and externalizing symptoms (with the exception of ADHD) two years later. This is the only study to date that provides compelling-albeit preliminary-evidence that ER problems longitudinally mediate the association between task-based functional connectivity patterns and future psychological symptoms among adolescents. Of note, participants were only scanned at baseline, limiting our ability to assess change in adolescents' task-based functional connectivity patterns as a function of developing ER abilities or burgeoning psychological symptomology. In sum, rather than conferring risk for any particular disorder, our results suggest that functional connectivity and subsequent ER abilities may serve a transdiagnostic risk factor for psychopathology. These findings may inform future emotion-focused prevention and intervention efforts aimed at youth susceptible to future internalizing and externalizing problems.

Sexual Identity and its Association with Trajectories of Depressive Symptoms and Emotion Regulation Difficulties from Early to Middle Adolescence.

Few studies have examined how changes in sexual identity impact trajectories of depressive symptoms and emotion regulation difficulties. The current study addresses this gap in the literature by examining these associations over a three-year period in a community sample of adolescents (N = 177; Mage = 12.56; SD = 0.60; nmale = 95). Multilevel modeling revealed that youth who consistently held sexual minority identities from early to middle adolescence-but not youth with inconsistent sexual identity-demonstrated increases in depressive symptoms and emotion regulation difficulties relative to their heterosexual peers. Findings suggest that treatments that bolster emotion regulation abilities and address depressive symptoms may be of particular benefit to youth with consistent sexual minority identities from early to middle adolescence.

Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients. Eighteen patients enrolled from September 2015 to November 2017 were treated with azacitidine (75 mg/m2) administered IV once daily on days 1 to 7 of a 28-day cycle. The primary end point was the number of patients with clinical complete remission (cCR) or clinical partial remission (cPR) after 3 cycles of therapy. Pharmacokinetics, genome-wide DNA-methylation levels, and variant allele frequencies of leukemia-specific index mutations were also analyzed. Sixteen patients completed 3 cycles and 5 patients completed 6 cycles. After 3 cycles, 11 patients (61%) were in cPR and 7 (39%) had progressive disease. Six of 16 patients (38%) who needed platelet transfusions were transfusion-free after 3 cycles. All 7 patients with intermediate- or low-methylation signatures in genome-wide DNA-methylation studies achieved cPR. Seventeen patients received HSCT; 14 (82%) were leukemia-free at a median follow-up of 23.8 months (range, 7.0-39.3 months) after HSCT. Azacitidine was well tolerated and plasma concentration--time profiles were similar to observed profiles in adults. In conclusion, azacitidine monotherapy is a suitable option for children with newly diagnosed JMML. Although long-term safety and efficacy remain to be fully elucidated in this population, these data demonstrate that azacitidine provides valuable clinical benefit to JMML patients prior to HSCT. This trial was registered at www.clinicaltrials.gov as #NCT02447666.

Phase 2 Study of Pomalidomide (CC-4047) Monotherapy for Children and Young Adults With Recurrent or Progressive Primary Brain Tumors.

INTRODUCTION: Treatment of recurrent primary pediatric brain tumors remains a major challenge, with most children succumbing to their disease. We conducted a prospective phase 2 study investigating the safety and efficacy of pomalidomide (POM) in children and young adults with recurrent and progressive primary brain tumors. METHODS: Patients with recurrent and progressive high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), ependymoma, or medulloblastoma received POM 2.6 mg/m2/day (the recommended phase 2 dose [RP2D]) on days 1-21 of a 28-day cycle. A Simon's Optimal 2-stage design was used to determine efficacy. Primary endpoints included objective response (OR) and long-term stable disease (LTSD) rates. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: 46 patients were evaluable for response (HGG, n = 19; DIPG, ependymoma, and medulloblastoma, n = 9 each). Two patients with HGG achieved OR or LTSD (10.5% [95% CI, 1.3%-33.1%]; 1 partial response and 1 LTSD) and 1 patient with ependymoma had LTSD (11.1% [95% CI, 0.3%-48.2%]). There were no ORs or LTSD in the DIPG or medulloblastoma cohorts. The median PFS for patients with HGG, DIPG, ependymoma, and medulloblastoma was 7.86, 11.29, 8.43, and 8.43 weeks, respectively. Median OS was 5.06, 3.78, 12.02, and 11.60 months, respectively. Neutropenia was the most common grade 3/4 adverse event. CONCLUSIONS: Treatment with POM monotherapy did not meet the primary measure of success in any cohort. Future studies are needed to evaluate if POM would show efficacy in tumors with specific molecular signatures or in combination with other anticancer agents. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03257631; EudraCT, identifier 2016-002903-25.

Results of a phase 2, multicenter, single-arm, open-label study of lenalidomide in pediatric patients with relapsed or refractory acute myeloid leukemia.

BACKGROUND: Outcomes after relapse remain poor in pediatric patients with acute myeloid leukemia (AML), and new therapeutic approaches are needed. Lenalidomide has demonstrated activity in adults with lower risk myelodysplastic syndromes and older adults with relapsed or refractory (R/R) AML. METHODS: In this phase 2 study (NCT02538965), pediatric patients with R/R AML who received two or more prior therapies were treated with lenalidomide (starting dose 2 mg/kg/day on days 1-21 of each 28-day cycle) for a maximum of 12 cycles. The primary endpoint was rate of complete response (CR) and CR with incomplete blood count recovery (CRi) within the first four cycles. RESULTS: Seventeen patients enrolled and received one or more dose of lenalidomide. Median age was 12 years (range 5-18 years), median white blood cell count was 3.7 × 109 /L, and median peripheral blood blast count was 1.0 × 109 /L. One patient (5.9%) with a complex karyotype including del(5q) achieved CRi after two cycles of lenalidomide. This responder proceeded to a second hematopoietic stem cell transplantation and has remained without evidence of disease for 3 years. All patients experienced one or more of grades 3-4 treatment-emergent adverse event (TEAE). The most common grades 3-4 TEAEs were thrombocytopenia (58.8%), febrile neutropenia (47.1%), anemia (41.2%), and hypokalemia (41.2%). CONCLUSIONS: In this population of pediatric patients with R/R AML, safety data were consistent with the known safety profile of lenalidomide. As only one patient responded, further evaluation of lenalidomide at the dose and schedule studied is not warranted in pediatric AML, with the possible exception of patients with del(5q).

Sex-Differentiated Associations among Negative Parenting, Emotion-Related Brain Function, and Adolescent Substance Use and Psychopathology Symptoms.

Parenting is a critical factor in adolescent social-emotional development, with maladaptive parenting leading to risk for the development of psychopathology. However, the emotion-related brain mechanisms underlying the influence of parenting on psychopathology symptoms are unknown. The present study utilized functional magnetic resonance imaging and laboratory measures to examine sex-differentiated associations among parenting, adolescent emotion-related brain function, and substance use and psychopathology symptoms in 66 12-14 year olds. Maternal parenting behaviors (warmth, negative parenting) were observed in a laboratory task. Adolescent brain responses to negative emotional stimuli were assessed in emotion processing regions of interest (left [L] and right [R] amygdala, anterior insula, anterior cingulate cortex [ACC]). Adolescents reported on substance use and depressive, anxiety, and externalizing symptoms. Maternal negative parenting predicted adolescent brain activation differently by sex. For girls, negative parenting predicted heightened R ACC activation to negative emotional stimuli. For boys, negative parenting predicted blunted L and R anterior insula and L ACC activation. Furthermore, for girls, but not boys, heightened L anterior insula and heightened L and R ACC activation were associated with substance use and depressive symptoms, respectively. Findings suggest neural response to negative emotion as a possible sex-specific pathway from negative parenting to psychopathology.

Attention-Deficit Hyperactivity Disorder, Disruptive Behaviors, and Drug Shortage.

CASE: Kyle is a 10-year-old boy with Down syndrome and intellectual disability who is being followed up by a developmental behavioral pediatrician for attention-deficit hyperactivity disorder (ADHD) and anxiety. Kyle was initially taking a long-acting liquid formulation of methylphenidate for ADHD and fluoxetine for anxiety. Several months ago, the liquid formulation was on back order, and the methylphenidate formulation was changed to an equal dose of a long-acting capsule. Kyle is not able to swallow pills; therefore, the contents of the capsule were sprinkled onto 1 bite of yogurt each morning. Over the course of the next month, Kyle's behaviors became increasingly difficult. He was not able to tolerate loud or crowded places, and despite a visual schedule and warnings, he would become aggressive toward adults when directed to transition away from preferred activities. Fluoxetine was increased from 0.4 to 0.6 mg/kg/day at that time.One month later, his parents reported that although there may have been slight improvement in Kyle's irritability since the increase in fluoxetine, they felt he was nonetheless more aggressive and less cooperative than his previous baseline. Kyle was returned to the long-acting liquid formulation of methylphenidate at that time, and a follow-up was scheduled 2 weeks later.On return to clinic, his parents reported that Kyle's behaviors had continued to become increasingly difficult. He was described as uncooperative and aggressive at home and school. Kyle was easily upset any time he was not given his way, his behavior was corrected, or he felt that he was not the center of attention. When upset, he would yell, bite, kick, spit, or throw his body to the ground and refuse to move. At 110 pounds, Kyle's parents were no longer able to physically move his body when he dropped to the ground. This was a safety concern for his parents because he had displayed this behavior in the parking lot of a busy shopping area. Because of Kyle's aggressive and unpredictable behavior, parents no longer felt comfortable taking him to public places. Family members who had previously been comfortable staying with Kyle while his parents were out for short periods would no longer stay with him. Overall, the behaviors resulted in parents being unable to go to dinner as a couple or provide individual attention to their other children. The parents described the family as "on edge." How would you approach Kyle's management?

Adolescents' Reward-related Neural Activation: Links to Thoughts of Nonsuicidal Self-Injury.

Adolescence is a critical developmental period marked by an increase in risk behaviors, including nonsuicidal self-injury (NSSI). Heightened reward-related brain activation and relatively limited recruitment of prefrontal regions contribute to the initiation of risky behaviors in adolescence. However, neural reward processing has not been examined among adolescents who are at risk for future engagement for NSSI specifically, but who have yet to actually engage in this behavior. In the current fMRI study (N = 71), we hypothesized that altered reward processing would be associated with adolescents' thoughts of NSSI. Results showed that NSSI youth exhibited heightened activation in the bilateral putamen in response to a monetary reward. This pattern of findings suggests that heightened neural sensitivity to reward is associated with thoughts of NSSI in early adolescence. Implications for prevention are discussed.

Associations Between Parent Emotional Arousal and Regulation and Adolescents' Affective Brain Response.

Parents' emotional functioning represents a central mechanism in the caregiving environment's influence on adolescent affective brain function. However, a paucity of research has examined links between parental emotional arousal and regulation and adolescents' affective brain function. Thus, the present study examined associations between parents' self-rated negative emotion, parent emotion regulation difficulties, and adolescent brain responsivity to negative and positive emotional stimuli. Participants included 64 12-14 year-old adolescents (31 females) and their female primary caregivers. Adolescents viewed negative, positive, and neutral emotional stimuli during an fMRI scanning session. Region of interest analyses showed that higher parent negative emotion was related to adolescents' greater ACC and vmPFC response to both negatively- and positively-valenced emotional stimuli; whereas, parent negative emotion was related to adolescents' greater amygdala response to negative emotional stimuli only. Furthermore, parent emotion regulation moderated the association between parent negative emotion and adolescents' brain response to negative emotional stimuli, such that parents with high negative emotion and high emotion regulation difficulties had adolescents with the greatest affective brain response. Findings highlight the importance of considering both parent emotional arousal and regulation in understanding the family affective environment and its relation to adolescent emotion-related brain development.

Phase 1 safety, pharmacokinetic and pharmacodynamic study of the cyclin-dependent kinase inhibitor dinaciclib administered every three weeks in patients with advanced malignancies.

BACKGROUND: Dinaciclib is a potent inhibitor of cell cycle and transcriptional cyclin-dependent kinases. This Phase 1 study evaluated the safety, tolerability and pharmacokinetics of various dosing schedules of dinaciclib in advanced solid tumour patients and assessed pharmacodynamic and preliminary anti-tumour activity. METHODS: In part 1, patients were enrolled in escalating cohorts of 2-h infusions administered once every 3 weeks, utilising an accelerated titration design until a recommended phase 2 dose (RP2D) was defined. In part 2, 8- and 24-h infusions were evaluated. Pharmacokinetic parameters were determined for all schedules. Pharmacodynamic effects were assessed with an ex vivo stimulated lymphocyte proliferation assay performed in whole blood.Effects of dinaciclib on retinoblastoma (Rb) phosphorylation and other CDK targets were evaluated in skin and tumour biopsies. In addition to tumour size, metabolic response was evaluated by 18F-fluorodeoxyglucose-positron emission tomography. RESULTS: Sixty-one patients were enrolled to parts 1 and 2. The RP2Ds were 50, 7.4 and 10.4 mg m-2 as 2- 8- and 24-hour infusions, respectively. Dose-limiting toxicities included pancytopenia, neutropenic fever, elevated transaminases, hyperuricemia and hypotension. Pharmacokinetics demonstrated rapid distribution and a short plasma half-life. Dinaciclib suppressed proliferation of stimulated lymphocytes. In skin and tumour biopsies, dinaciclib reduced Rb phosphorylation at CDK2 phospho-sites and modulated expression of cyclin D1 and p53, suggestive of CDK9 inhibition. Although there were no RECIST responses, eight patients had prolonged stable disease and received between 6 and 30 cycles. Early metabolic responses occurred. CONCLUSIONS: Dinaciclib is tolerable at doses demonstrating target engagement in surrogate and tumour tissue.

Adolescent Substance Use & Psychopathology: Interactive Effects of Cortisol Reactivity and Emotion Regulation.

How are emotional processes associated with the increased rates of substance use and psychological disorders commonly observed during adolescence? An index of emotion-related physiological arousal-cortisol reactivity-and subjective emotion regulation have both been independently linked to substance use and psychological difficulties among youth. The current study (N = 134 adolescents) sought to elucidate the interactive effects of cortisol reactivity following a stressful parent-child interaction task and self-reported emotion regulation ability on adolescents' substance use and externalizing and internalizing behavior problems. Results revealed that adolescents with low levels of cortisol reactivity and high emotion regulation difficulties were more likely to use substances, and also had the highest parent-reported symptoms of oppositional defiant disorder. With respect to internalizing symptoms, high emotion-related physiological reactivity coupled with high emotion regulation difficulties were associated with higher self-reported major depression symptoms among youth. Findings reveal that different profiles of HPA axis arousal and emotion regulation are associated with substance use and symptoms of psychopathology among adolescents.

A longitudinal examination of emotion regulation: pathways to anxiety and depressive symptoms in urban minority youth.

BACKGROUND: Difficulty regulating emotions is a symptom of many psychological disorders yet little research has examined the longitudinal relations of particular facets of emotion regulation (ER) that may differentiate between internalizing symptoms. METHOD: At-risk youth (n = 102; 44.1% boys, 77.5% Black; Mage  = 9.65) and caregivers (n = 74; 87.1% mothers) participated in a 2-year longitudinal study. Children reported on their ER, and children and caregivers on symptomatology. RESULTS: Different patterns, varying by emotion facet (dysregulation, inhibition, coping) and type (anger, sadness, worry), predicted anxiety and depression symptoms. CONCLUSIONS: Anxiety and depression are entities with distinct patterns of emotion-related antecedents.