Adolescent psychopathic traits and adverse environments: Associations with socially adaptive outcomes.

Researchers have suggested that psychopathic traits among adults may be, at least in part, an adaptive and/or a learned response for securing socially adaptive outcomes in adverse environments, but there is a lack of developmental evidence supporting this hypothesis among adolescents. Therefore, we examined the indirect links from self-perceived adverse environments (parental neglect, socioeconomic status, school competition, neighborhood violence) to evolutionarily relevant social outcomes (social power, dating behavior) through psychopathic traits. A community sample of 396 adolescents completed measures for the study (Mage = 14.64, SD = 1.52). As predicted, there were significant indirect effects from higher levels of parental neglect, school competition, and neighborhood violence to both forms of socially adaptive outcomes through psychopathic traits, but unexpectedly, there were no indirect effects with socioeconomic status. There were also direct effects between environment and socially adaptive outcomes. Results support the hypothesis that psychopathic traits may be, in part, an adaptive and/or learned response to cues from adverse social environments as a means to acquire evolutionarily relevant social outcomes. Interventions could be designed to target the adverse social issues that might be facilitating the development of psychopathy and should be sensitive to the social outcomes adolescents may acquire from these traits.

Epigenetic Silencing of RIPK3 in Hepatocytes Prevents MLKL-mediated Necroptosis From Contributing to Liver Pathologies.

BACKGROUND & AIMS: Necroptosis is a highly inflammatory mode of cell death that has been implicated in causing hepatic injury including steatohepatitis/ nonalcoholic steatohepatitis (NASH); however, the evidence supporting these claims has been controversial. A comprehensive, fundamental understanding of cell death pathways involved in liver disease critically underpins rational strategies for therapeutic intervention. We sought to define the role and relevance of necroptosis in liver pathology. METHODS: Several animal models of human liver pathology, including diet-induced steatohepatitis in male mice and diverse infections in both male and female mice, were used to dissect the relevance of necroptosis in liver pathobiology. We applied necroptotic stimuli to primary mouse and human hepatocytes to measure their susceptibility to necroptosis. Paired liver biospecimens from patients with NASH, before and after intervention, were analyzed. DNA methylation sequencing was also performed to investigate the epigenetic regulation of RIPK3 expression in primary human and mouse hepatocytes. RESULTS: Identical infection kinetics and pathologic outcomes were observed in mice deficient in an essential necroptotic effector protein, MLKL, compared with control animals. Mice lacking MLKL were indistinguishable from wild-type mice when fed a high-fat diet to induce NASH. Under all conditions tested, we were unable to induce necroptosis in hepatocytes. We confirmed that a critical activator of necroptosis, RIPK3, was epigenetically silenced in mouse and human primary hepatocytes and rendered them unable to undergo necroptosis. CONCLUSIONS: We have provided compelling evidence that necroptosis is disabled in hepatocytes during homeostasis and in the pathologic conditions tested in this study.

Indirect aggression, anxiety, and empathy: Disaggregating between and within person longitudinal associations during childhood and adolescence.

Although indirectly aggressive behavior and anxiety symptoms can co-occur, it is unclear whether anxiety is an antecedent or outcome of indirect aggression at the individual level and whether other personality traits can contribute to these longitudinal associations. Therefore, the between- and within-person associations among indirect aggression, anxiety symptoms, and empathic concern were examined across adolescence from ages 11 to 16 in a cohort of individuals followed annually (N = 700; 52.9% girls; 76.0% White) controlling for direct aggression and demographic variables. Results of autoregressive latent trajectory models with structured residuals supported an acting out model at the within-person level. Specifically, anxiety symptoms positively predicted indirect aggression and indirect aggression negatively predicted empathic concern at each adjacent time point. These findings suggest that methods of reducing worries about the self and increasing healthy self-confidence could prevent indirect aggression and help build concern and compassion toward others.

Bullying involvement and the transition to high school: A brief report.

School transitions are common educational experiences for children and adolescents and many of them worry about being bullied during this type of major life-changing point. In a sample of 701 Canadians assessed yearly from grade 5 (age 10) to grade 12 (age 18), we examined heterogeneous patterns of bullying involvement while statistically accounting for the transition into high school. Gender differences were also examined. Results indicated that on average, bullying victimization declined over time with a significant drop noted between grade 8 and grade 9 (the transition into high school), with few differences between girls and boys. Bullying perpetration also declined for most students (no gender differences), with a notable drop found at the transition into high school. However, for a subset of adolescents, the transition into high school was accompanied by an increase in bullying perpetration. These varied experiences highlight the need to model heterogeneity when examining the impact of school transitions on bullying, a neglected focus of inquiry to date. Our results suggest that moving into high school is beneficial for most adolescents involved in bullying, but not for all.

Childhood Predictors of Adolescent Joint Trajectories: A Multi-Informant Study on Bullying Perpetration and Hypercompetitiveness.

OBJECTIVE: Bullying perpetration has been proposed to be a strategic behavior used by adolescents to compete for social resources, yet the co-development of bullying perpetration and trait hypercompetitiveness is understudied. The joint developmental trajectories of self-rated bullying perpetration and parent-rated hypercompetitiveness were investigated in a sample of adolescents and childhood social, emotional, and physical predictors were explored. METHOD: In a sample of 607 adolescents (Mage = 13.02 years in Grade 7 [SD = 0.38]; 54.4% girls; 76.4% White) self-rated bullying perpetration and parent-rated hypercompetitiveness were assessed across six years of development (Grades 7 to 12). Childhood (i.e., Grades 5 and 6) social, emotional, and physical predictors of trajectory group membership were also examined. RESULTS: Using latent class growth analyses, the three expected joint trajectory groups of primary interest were found: (1) a pattern of moderate stable bullying perpetration and high increasing hypercompetitiveness (high-risk group), (2) a pattern of low decreasing bullying and high increasing hypercompetitiveness (hypercompetitive only group), and (3) a pattern of low decreasing bullying and low stable hypercompetitiveness (low-risk group). Adolescents reflecting the high-risk joint trajectory pattern were differentiated from adolescents reflecting the other two trajectory patterns by having more adverse childhood social, emotional, and physical predictors. CONCLUSIONS: Findings indicate that bullying is a developmental and context-dependent behavior that can reflect trait hypercompetitiveness. Bullying prevention efforts should focus on reducing emphasis on outcompeting peers and instead facilitate a sense of self-acceptance, awareness, and accomplishment within prosocial school and family environments.

Systematic Review of PD-1/PD-L1 Inhibitors in Oncology: From Personalized Medicine to Public Health.

BACKGROUND: To review and summarize all U.S. Food and Drug Administration (FDA) approvals of programmed death (PD)-1 and PD-ligand 1 blocking antibodies (collectively referred to as PD-[L]1 inhibitors) over a 6-year period and corresponding companion/complementary diagnostic assays. MATERIALS AND METHODS: To determine the indications and pivotal trials eligible for inclusion, approval letters and package inserts available on Drugs@FDA were evaluated for approved PD-[L]1 inhibitors to identify all new indications granted from the first approval of a PD-[L]1 inhibitor on September 4, 2014, through September 3, 2020. The corresponding FDA drug and device reviews from the marketing applications for the approved indications were identified through FDA internal records. Two reviewers independently extracted information for the endpoints, efficacy data, basis for approval, type of regulatory approval, and corresponding in vitro diagnostic device test. The results were organized by organ system and tumor type. RESULTS: Of 70 Biologic Licensing Application or supplement approvals that resulted in new indications, 32 (46%) were granted based on response rate (ORR) and durability of response, 26 (37%) on overall survival, 9 (13%) on progression-free survival, 2 (3%) on recurrence-free survival, and 1 (1%) on complete response rate. Most ORR-based approvals were granted under the accelerated approval provisions and were supported with prolonged duration of response. Overall, 21% of approvals were granted with a companion diagnostic. Efficacy results according to tumor type are discussed. CONCLUSION: PD-[L]1 inhibitors are an effective anticancer therapy in a subset of patients. This class of drugs has provided new treatment options for patients with unmet need across a wide variety of cancer types. Yet, the modest response rates in several tumor types signal a lack of understanding of the biology of these diseases. Further preclinical and clinical investigation may be required to identify a more appropriate patient population, particularly as drug development continues and additional treatment alternatives become available. IMPLICATIONS FOR PRACTICE: The number of PD-[L]1 inhibitors in drug development and the associated companion and complementary diagnostics have led to regulatory challenges and questions regarding generalizability of trial results. The interchangeability of PD-L1 immunohistochemical assays between PD-1/PD-L1 drugs is unclear. Furthermore, robust responses in some patients with low levels of PD-L1 expression have limited the use of PD-L1 as a predictive biomarker across all cancers, particularly in the setting of diseases with few alternative treatment options. This review summarizes the biomarker thresholds and assays approved as complementary and companion diagnostics and provides regulatory perspective on the role of biomarkers in oncology drug development.

Adolescent empathic concern and perspective taking: Heterogeneous developmental trajectories and childhood social and psychological factors.

OBJECTIVE: The joint developmental trajectories of empathic concern and perspective taking were examined across adolescence, along with childhood social and psychological predictors. METHOD: Adolescents completed self-report measures of empathy annually from Grades 7 to 10 (i.e., ages 13 to 16; N = 609; 53.9% girls; 76.2% White). Childhood social and psychological predictors were assessed in Grades 5 and 6 using self- and parent-reports. RESULTS: As predicted, the majority of individuals reflected a joint trajectory of moderate stable empathic concern and moderate increasing perspective taking (31.9%), followed by joint high increasing (17.2%) and joint low stable (7.4%) empathy. Fewer adolescents reflected joint trajectories of being high on one form of empathy but not the other (e.g., high empathic concern only, 1.6%; high increasing perspective taking only, 2.8%). High increasing perspective taking was a better indicator of high increasing empathic concern than the reverse. Higher childhood hyperactivity, higher bullying perpetration, and lower perceived school climate were prominent predictors of developing low levels of at least one form of empathy, but childhood anxiety was a predictor of developing high empathy. CONCLUSIONS: The skills and abilities associated with perspective taking and empathic concern should be promoted, with special attention paid to early indicators of affective, cognitive, and behavioral self-regulation.

Mean kids become mean adults: Trajectories of indirect aggression from age 10 to 22.

Although much is known about the development of physical aggression across the lifespan, far less is known about the developmental pattern of indirect aggression from childhood to adulthood. Accordingly, we examined the self-reported use of indirect aggression from age 10 to 22 in a randomly drawn sample of 704 Canadians. A person-centered approach was used to capture intraindividual change and heterogeneity in development. Four childhood (age 10-18) indirect aggression trajectories were identified: (1) a very low decreasing group (64.8%), (2) a low decreasing group (26.0%), (3) a low-to-moderate increasing group (5.1%), and (4) a moderate increasing group (4.1%). There were more girls than boys in the moderate increasing group (75.9% vs. 24.1%). Two adulthood (age 19-22) indirect aggression trajectory groups were also identified: (1) a low decreasing group (82.6%), and (2) a moderate stable group (17.4%). No sex differences were found among adults' use across the two trajectories. When we examined the prediction of indirect aggression use in adulthood from indirect aggression use in childhood, we found that children who followed a moderate increasing trajectory from age 10 to 18 were nine times more likely to follow a moderate stable trajectory from age 19 to 22, while children who followed a low-to-moderate increasing trajectory across childhood were 14 times more likely to follow a moderate stable trajectory across adulthood (compared to the very low decreasing group). Given the negative impact indirect aggression has on others, intervening early to derail this pattern of abuse is justified.

School bullying before and during COVID-19: Results from a population-based randomized design.

We examined the impact of COVID-19 on bullying prevalence rates in a sample of 6578 Canadian students in Grades 4 to 12. To account for school changes associated with the pandemic, students were randomized at the school level into two conditions: (1) the pre-COVID-19 condition, assessing bullying prevalence rates retrospectively before the pandemic, and (2) the current condition, assessing rates during the pandemic. Results indicated that students reported far higher rates of bullying involvement before the pandemic than during the pandemic across all forms of bullying (general, physical, verbal, and social), except for cyber bullying, where differences in rates were less pronounced. Despite anti-Asian rhetoric during the pandemic, no difference was found between East Asian Canadian and White students on bullying victimization. Finally, our validity checks largely confirmed previous published patterns in both conditions: (1) girls were more likely to report being bullied than boys, (2) boys were more likely to report bullying others than girls, (3) elementary school students reported higher bullying involvement than secondary school students, and (4) gender diverse and LGTBQ + students reported being bullied at higher rates than students who identified as gender binary or heterosexual. These results highlight that the pandemic may have mitigated bullying rates, prompting the need to consider retaining some of the educational reforms used to reduce the spread of the virus that could foster caring interpersonal relationships at school such as reduced class sizes, increased supervision, and blended learning.

The Impact of Childhood Bullying Trajectories on Young Adulthood Antisocial Trajectories.

Long-term outcomes of childhood bullying perpetration have been explored, but heterogeneity in outcomes reflecting nonclinical antisocial tendencies including indirect aggression, psychopathic personality, and interpersonal relations have not been examined from a person-centered approach. Accordingly, latent class growth analyses were used to examine trajectory groups of childhood bullying perpetration across ages 10 to 18 and multi-trajectory groups of young adulthood outcomes across ages 19 to 23 (indirect aggression, psychopathic personality, interpersonal relations). In a sample of 701 participants (52.9% girls/women) followed annually, the majority of individuals reflected a low stable trajectory of bullying (81.2%) and fewer reflected moderate increasing bullying (18.8%). In young adulthood, the majority of participants reflected a prosocial multi-trajectory profile (61.6%; below average decreasing indirect aggression, below average decreasing psychopathy, above average stable interpersonal relations). Fewer participants reflected a below average antisocial profile (21.6%; below average decreasing indirect aggression, below average stable psychopathy, below average stable interpersonal relations) or an above average antisocial profile (16.8%; above average decreasing indirect aggression, above average decreasing psychopathy, below average stable interpersonal relations). Individuals following the moderate bullying trajectory in childhood had a significantly higher odds of following the above average antisocial profile but not the prosocial profile in young adulthood, when contrasted against the below average antisocial profile. These findings indicate that the prevention of childhood bullying can help prevent the continuity of an antisocial profile in young adulthood that is characterized by continued aggressive behavior, higher psychopathy, and poorer quality relationships.

FDA approval summary: Dalteparin for the treatment of symptomatic venous thromboembolism in pediatric patients.

On May 16, 2019, the U.S. Food and Drug Administration (FDA) approved dalteparin sodium for the treatment of symptomatic venous thromboembolism (VTE) to reduce the risk of recurrence in pediatric patients 1 month of age and older. Approval was primarily based on FDA review of a single-arm trial evaluating dalteparin administered subcutaneous twice daily in 38 pediatric patients with symptomatic VTE. Efficacy was based on the achievement of therapeutic plasma anti-Xa levels. The FDA concluded that dalteparin has efficacy and acceptable safety for pediatric patients.

FDA review summary of patient-reported outcome results for ibrutinib in the treatment of chronic graft versus host disease.

PURPOSE: On August 2, 2017, the Food and Drug Administration approved ibrutinib (IMBRUVICA) for the treatment of patients with chronic graft versus host disease (cGVHD) after the failure of one or more lines of systemic therapy. The approval was based on results from a single-arm, multicenter trial that enrolled patients with refractory cGVHD. This paper describes the FDA review of patient-reported outcomes (PRO) data from Study PCYC-1129-CA and the decision to incorporate descriptive PRO data in the FDA label to support the primary clinician-reported outcome results. METHODS: In this trial, the Lee Chronic GVHD Symptom Scale (LSS) was used to capture patient-reported symptom bother. The 42 patients who received treatment were included in the analysis and completed the PRO tool. Post hoc descriptive analyses were conducted to further understand the measurement properties of the LSS. RESULTS: The analysis submitted to FDA reported that 18 patients had a ≥ 7-point improvement on the LSS overall summary score at any point during the assessment period. For 10 patients, the ≥ 7-point improvement was sustained for ≥ 2 consecutive PRO assessments. An assessment of the responder threshold suggested the threshold submitted to the FDA was reasonable and in line with clinical findings. CONCLUSIONS: Overall, study PCYC-1129-CA demonstrated favorable clinician-reported cGVHD efficacy results that were complemented by results from PRO data, supporting the FDA's positive benefit-risk assessment leading to regular approval. Limitations included the single-arm trial design, responder definition, and instrument shortcomings. These limitations were thoroughly explored through additional FDA post hoc analyses.

U.S. Food and Drug Administration Benefit-Risk Assessment of Nilotinib Treatment Discontinuation in Patients with Chronic Phase Chronic Myeloid Leukemia in a Sustained Molecular Remission.

On December 22, 2017, the U.S. Food and Drug Administration (FDA) updated the product label for nilotinib to include information for providers on how to discontinue this drug in certain patients. With the updated dosing recommendations, select patients with chronic phase myeloid leukemia (CML) taking nilotinib for 3 years or more and whose leukemia has responded with sustained molecular remission (MR4.5, BCR-ABL transcripts of ≤0.0032%) as determined by a FDA-approved test may be eligible to discontinue nilotinib. The updated dosing regimen was based on the efficacy results from two trials that measured how long patients could stop taking nilotinib without the leukemia returning (treatment-free remission). Trial results demonstrated that, among selected patients who received nilotinib as first-line therapy or after transition from imatinib, approximately 50% continued to be in remission at 96 weeks after stopping therapy. Relapses continued to occur throughout the study, indicating that long-term monitoring is needed for safety and disease monitoring. Discontinuation of treatment was associated with an increased risk of low grade musculoskeletal adverse events, some of which were prolonged. Overall, the results support the approval of updates to the dosing recommendations with regard to treatment discontinuation in selected patients who have received nilotinib for at least 3 years, are in a sustained molecular remission, and who can undergo appropriate monitoring. IMPLICATIONS FOR PRACTICE: The updated dosing information provides eligibility criteria for treatment discontinuation, strict monitoring criteria after nilotinib discontinuation, and guidance for treatment reinitiation in eligible patients with chronic phase myeloid leukemia. About half of appropriately selected patients remained in remission 96 weeks after treatment discontinuation. Patients may experience musculoskeletal pain on withdrawal of treatment, incidence of which appears to decrease over time; however, some patients may have long lasting events. The decision to withdraw or continue treatment with nilotinib should be based on clinical condition and patient preferences.

FDA Approval Summary: Brentuximab Vedotin in First-Line Treatment of Peripheral T-Cell Lymphoma.

In November 2018, the U.S. Food and Drug Administration (FDA) approved brentuximab vedotin (BV) for the treatment of adult patients with previously untreated systemic anaplastic large cell lymphoma or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone (CHP). Approval was based on ECHELON-2, a randomized, double-blind, actively controlled trial that compared BV+CHP with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in 452 patients with newly diagnosed, CD30-expressing PTCL. Efficacy was based on independent review facility-assessed progression-free survival (PFS). The median PFS was 48.2 months with BV+CHP versus 20.8 months with CHOP, resulting in a hazard ratio (HR) of 0.71 (95% confidence interval [CI]: 0.54-0.93). The trial also demonstrated improvement in overall survival (HR 0.66; 95% CI: 0.46-0.95), complete response rate (68% vs. 56%), and overall response rate (83% vs. 72%) with BV+CHP. The most common adverse reactions (incidence ≥20%) observed ≥2% more with BV+CHP were nausea, diarrhea, fatigue or asthenia, mucositis, pyrexia, vomiting, and anemia. Peripheral neuropathy rates were similar (52% with BV+CHP, 55% with CHOP). Through the Real-Time Oncology Review pilot program, which allows FDA early access to key data, FDA granted this approval less than 2 weeks after official submission of the application. IMPLICATIONS FOR PRACTICE: This is the first U.S. Food and Drug Administration approval for treatment of patients with newly diagnosed peripheral T-cell lymphomas (PTCL). Improvement in progression-free and overall survival over cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, which has been the standard of care for decades, is unprecedented. The new regimen represents a major advance for the frontline treatment of patients with CD30-expressing PTCL.

FDA Supplemental Approval: Blinatumomab for Treatment of Relapsed and Refractory Precursor B-Cell Acute Lymphoblastic Leukemia.

On July 11, 2017, the Food and Drug Administration granted approval for blinatumomab for the treatment of relapsed or refractory (R/R) precursor B-cell acute lymphoblastic leukemia (ALL). Blinatumomab is a bispecific CD19-directed CD3 T-cell engager. The basis for the approval included results from two clinical trials, TOWER and ALCANTARA. TOWER, a randomized trial comparing overall survival in patients with Philadelphia chromosome (Ph)-negative R/R ALL receiving blinatumomab versus standard-of-care (SOC) chemotherapy, demonstrated a hazard ratio of 0.71 favoring blinatumomab (p = .012; median survival, 7.7 months with blinatumomab and 4.0 months with SOC chemotherapy). Complete remission (CR) rates were 34% for patients receiving blinatumomab and 16% for those receiving SOC. Adverse events were consistent with those observed in prior trials, with cytokine release syndrome and some neurologic events, including tremor, encephalopathy, peripheral neuropathy, and depression, observed more frequently in the blinatumomab arm, whereas neutropenia and infection were less common among patients receiving blinatumomab. Depression emerged as a rare but potentially severe neurologic event associated with blinatumomab. In ALCANTARA, a single-arm trial of blinatumomab in patients with Ph-positive R/R ALL, the CR rate was 31%, and adverse events were similar to those observed previously in Ph-negative R/R ALL. These results support conversion from accelerated to regular approval of blinatumomab for R/R ALL and broadening of the intended population to include both Ph-positive and Ph-negative precursor B-cell R/R ALL. IMPLICATIONS FOR PRACTICE: In TOWER, a randomized trial in patients with relapsed or refractory Philadelphia chromosome (Ph)-negative precursor B-cell acute lymphoblastic leukemia (ALL), treatment with blinatumomab showed superiority over conventional chemotherapy for complete remission (CR) rate (34% vs. 16%) and survival (3.7-month improvement in median; hazard ratio, 0.71). In ALCANTARA, a single-arm trial of blinatumomab for treatment of relapsed or refractory Ph-positive precursor B-cell ALL, the CR rate was 31%. Blinatumomab is now approved for treatment of relapsed or refractory precursor B-cell ALL that is Ph positive or Ph negative.

FDA Approval Summary: Lenalidomide as Maintenance Therapy After Autologous Stem Cell Transplant in Newly Diagnosed Multiple Myeloma.

On February 22, 2017, the U.S. Food and Drug Administration (FDA) granted approval for the use of lenalidomide as maintenance therapy after autologous hematopoietic stem cell transplantation (auto-HSCT) for patients with multiple myeloma. The approval was based on evidence from two randomized, blinded trials of maintenance lenalidomide versus placebo in patients with myeloma who had undergone auto-HSCT along with a third trial of lenalidomide versus no therapy. Each of the trials demonstrated superior progression-free survival for the patients treated with lenalidomide. The effect on overall survival was mixed, with one trial showing longer overall survival and another showing no effect. Subgroup analysis suggested better results for patients with International Staging System stage I or II disease compared with stage III disease. Safety evaluation did not reveal any new safety concerns. More second primary malignancies were observed in the lenalidomide arm compared with the placebo arm. The FDA concluded that lenalidomide maintenance showed a favorable benefit-to-risk ratio when used as maintenance therapy after auto-HSCT. IMPLICATIONS FOR PRACTICE: Prior to this approval, there were no U.S. Food and Drug Administration-approved maintenance therapies for patients with multiple myeloma (MM) who have undergone autologous hematopoietic stem cell transplantation (auto-HSCT). Maintenance therapy with lenalidomide after auto-HSCT in patients with MM demonstrated an approximately 15- to 18-month advantage in progression-free survival compared with placebo at the time of the primary analysis. Patients treated with lenalidomide also appeared to have a survival advantage compared with patients treated with placebo. Because of the high rate of relapse of MM in patients following auto-HSCT and because MM is a serious and often fatal disease, these results appear to be clinically meaningful.

FDA Approval Summary: Midostaurin for the Treatment of Advanced Systemic Mastocytosis.

In April 2017, the U.S. Food and Drug Administration granted regular approval to midostaurin for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL). Approval was based on results from CPKC412D2201, a single-arm trial of midostaurin (100 mg orally twice daily) in previously treated or untreated patients. For the patients with ASM and SM-AHN, efficacy was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by modified Valent criteria with six cycles of midostaurin. There were no CRs reported; ICR was achieved by 6 of 16 patients (38%; 95% confidence interval [CI]: 15%-65%) with ASM and by 9 of 57 patients (16%; 95% CI: 7%-28%) with SM-AHN. Within the follow-up period, the median duration of response was not reached for the patients with ASM (range, 12.1+ to 36.8+ months) or with SM-AHN (range, 6.6+ to 52.1+ months). For the patients with MCL, efficacy was established on the basis of confirmed CR using modified 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis criteria. Of 21 patients with MCL, 1 (5%) achieved a CR. Of 142 patients with SM evaluated for safety, 56% had dose modifications for toxicity, and 21% discontinued treatment due to a toxicity. Over 50% reported nausea, vomiting, or diarrhea, and ≥30% reported edema, musculoskeletal pain, fatigue, abdominal pain, or upper respiratory tract infection. New or worsening grade ≥3 lymphopenia, anemia, thrombocytopenia, or neutropenia developed in ≥20%. Although midostaurin is an active drug for treatment of advanced SM, it is not clear that the optimal dose has been identified. IMPLICATIONS FOR PRACTICE: Midostaurin is the only U.S. Food and Drug Administration-approved therapy for patients with systemic mastocytosis with associated hematological neoplasm and mast cell leukemia and is the only therapy approved for patients with aggressive systemic mastocytosis regardless of KIT D816V mutation status. Based on response rate and duration, midostaurin has meaningful clinical activity in these rare, life-threatening diseases.

FDA Approval Summary: Vemurafenib for the Treatment of Patients with Erdheim-Chester Disease with the BRAFV600 Mutation.

On November 6, 2017, the U.S. Food and Drug Administration (FDA) granted regular approval to vemurafenib for the treatment of adult patients with Erdheim-Chester disease (ECD) with BRAFV600 mutation. ECD is a type of histiocytosis, a rare disorder characterized by an abnormal accumulation and behavior of cells of the mononuclear phagocytic system, which includes antigen-processing cells, dendritic cells, monocytes, or macrophages. Recently published data confirm a frequency of 54% of BRAFV600E mutations in patients with ECD.Approval was based on a cohort of 22 patients who received 960 mg of vemurafenib twice daily within the VE Basket Trial (MO28072), a single-arm, multicenter, multiple cohort study. Patients in the ECD cohort had histologically confirmed ECD with BRAFV600 mutations that were refractory to standard therapy. The ECD cohort achieved an overall response rate of 54.5% (95% confidence interval: 32.2-75.6), with a complete response rate of 4.5%. With a median duration of follow-up of 26.6 months, the median duration of response has not been reached. The most frequently reported adverse reactions (>50%) in the ECD cohort were arthralgia, rash maculo-papular, alopecia, fatigue, electrocardiogram QT interval prolonged, and skin papilloma. The median treatment duration for ECD patients in this study was 14.2 months. This article describes the FDA review of the vemurafenib efficacy supplement for patients with ECD with BRAFV600 mutations. IMPLICATIONS FOR PRACTICE: Vemurafenib, an oral monotherapy targeting a mutation in BRAF, is the first U.S. Food and Drug Administration approval for the treatment of Erdheim-Chester disease (ECD). ECD is an extremely rare hematopoietic neoplasm that represents clonal proliferation of myeloid progenitor cells. ECD may involve bone and one or more organ systems, primarily affecting adults in their 5th and 7th decades of life, with a slight male predominance. This approval provides an effective and reasonably safe therapy for patients with a serious and life-threatening condition for which no approved therapy exists.

FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome.

On August 30, 2017, the U.S. Food and Drug Administration approved Actemra (tocilizumab, Genentech, Inc., South San Francisco, CA) for the treatment of severe or life-threatening chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome (CRS) in adults and in pediatric patients 2 years of age and older. The approval was based on a retrospective analysis of data for patients who developed CRS after treatment with CTL019 and KTE-C19 on prospective clinical trials. Evaluable patients had been treated with intravenous tocilizumab 8 mg/kg (12 mg/kg for patients <30 kg) for severe or life-threatening CRS; only the first episode of CRS was included in the analysis. The efficacy population for the CTL019 cohort included 24 male and 21 female patients (total 45 patients) of median age 12 years. The median time from the start of CRS to the first dose of tocilizumab was 4 days (range, 0-18 days). Patients were considered responders if CRS resolved within 14 days of the first dose of tocilizumab, if no more than 2 doses of tocilizumab were needed, and if no drugs other than tocilizumab and corticosteroids were used for treatment. Thirty-one patients (69%; 95% confidence interval, 53%-82%) achieved a response as defined. In an independent cohort of 15 patients with KTE-C19-induced CRS, 53% responded. Further study is needed to determine the optimal dose of tocilizumab and to confirm the safety of its use for treatment of patients with CAR T cell-induced CRS. IMPLICATIONS FOR PRACTICE: Severe or life-threatening chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome (CRS) requires urgent treatment to prevent fatal outcomes. In two independent cohorts, the majority of patients with severe or life-threatening CAR T cell-induced CRS responded to treatment with one or two doses of tocilizumab in addition to advanced supportive care. More research is needed to determine the optimal dose and schedule of tocilizumab for treatment of CAR T cell-induced CRS.

FDA Approval Summary: Mylotarg for Treatment of Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia.

On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (GO; Mylotarg; Pfizer, New York City, NY) for treatment of relapsed or refractory (R/R) CD33-positive acute myeloid leukemia (AML) in patients 2 years of age and older. GO is a CD33-directed antibody drug conjugate linked to the cytotoxic antibiotic calicheamicin. It originally received accelerated approval for treatment of older patients with relapsed CD33-positive AML in 2000, but it was withdrawn from the market in 2010 when the confirmatory trial failed to demonstrate clinical benefit among safety concerns, such as a higher rate of induction fatalities on the GO combination arm compared with chemotherapy alone. In addition, GO was associated with hepatic veno-occlusive disease (VOD), which has substantial morbidity and mortality. Pharmacokinetic analyses suggested a lower maximum concentration of GO would result in less VOD without affecting target saturation or efficacy. A meta-analysis across dose schedules of GO in patients with R/R AML showed that a lower-dose "fractionated" schedule of 3 mg/m2 days 1, 4, and 7 was associated with less early mortality, hemorrhage, and VOD, without an apparent decrease in complete remission (CR) rate. MyloFrance 1 was a single-arm study evaluating response rates in patients with relapsed CD33-positive AML treated with the lower-dose fractionated GO regimen. The CR rate was 26% (95% confidence interval 16%-40%). Common adverse reactions were fever, infections, nausea, vomiting, constipation, bleeding, increased liver enzymes, and mucositis. There were no cases of VOD. These results supported the approval of GO as monotherapy for R/R CD33-positive AML using the lower-dose fractionated regimen. IMPLICATIONS FOR PRACTICE: Gemtuzumab ozogamicin (GO) 3 mg/m2 days 1, 4, and 7 is an active regimen for induction of remission when used to treat patients with relapsed or refractory CD33-positive acute myeloid leukemia without curative intent. The risks of hepatic veno-occlusive disease and early mortality with this regimen appear to be lower than reported previously for GO 9 mg/m2 days 1 and 15. The data were not sufficient to enable conclusions about the safety of GO in children younger than 2 years of age.