Incidence, timing, and management of infections in patients receiving teclistamab for the treatment of relapsed/refractory multiple myeloma in the MajesTEC-1 study.

BACKGROUND: Patients with relapsed/refractory multiple myeloma are at increased risk of infection. Infections during treatment with teclistamab, the first B-cell maturation antigen-directed bispecific antibody approved for triple-class-exposed relapsed/refractory multiple myeloma, was examined in the phase 1/2 MajesTEC-1 study. METHODS: Patients (N = 165) received subcutaneous teclistamab 1.5 mg/kg weekly after a step-up dosing schedule (0.06 mg/kg and 0.3 mg/kg, each separated by 2-4 days). Patients were monitored frequently for infections; prophylaxis and management were per institutional guidelines. RESULTS: At a median follow-up of 22.8 months (range, 0.3-33.6), infections were reported in 132 patients (80.0%). Grade 3/4 infections occurred in 91 patients (55.2%), including COVID-19 (21.2%), respiratory infections (19.4%), Pneumocystis jirovecii pneumonia (4.2%), viral infections (4.2%), and gastrointestinal infections (1.2%). Twenty-one patients died from infections (18 from COVID-19). Median time to first onset of any-grade and grade 3 to 5 infections was 1.7 and 4.2 months, respectively. Overall, 70.9% of patients had ≥1 postbaseline immunoglobulin G (IgG) level <400 mg/dL; median time to IgG <400 mg/dL was 1.2 months (range, 0.2-19.8) and 46.1% received ≥1 dose of IgG replacement. Grade 3/4 neutropenia occurred in 65.5% of patients (median time to grade ≥3 neutropenia/febrile neutropenia was 2.3 months [range, 0-18.1]). CONCLUSION: Based on the infection profile of B-cell maturation antigen-targeted bispecific antibodies such as teclistamab, it is recommended that clinicians and patients remain vigilant for a range of infection types throughout treatment to facilitate prompt intervention. Appropriate screening, prophylaxis, and management of infections, hypogammaglobulinemia, and neutropenia are important. CLINICAL TRIAL REGISTRATION: NCT03145181/NCT04557098 (ClinicalTrials.gov) PLAIN LANGUAGE SUMMARY: Before starting teclistamab, patients should be up to date with vaccinations (including COVID-19) and screened for hepatitis B and C and HIV. Teclistamab should not be given to patients with any active infections. Prophylactic antimicrobials should be administered per institutional guidelines. Prophylaxis for Pneumocystis jirovecii pneumonia and herpes simplex/varicella zoster virus is recommended during teclistamab treatment. Close monitoring of infections and immunoglobulin G (IgG) levels should continue throughout teclistamab treatment. IgG replacement (administered every 3-6 weeks) should be used to maintain IgG ≥400 mg/dL. Growth factors should be considered for grade ≥3 neutropenia with infection/fever and grade 4 neutropenia.

Anaplastic Lymphoma Kinase Inhibitor in Treatment of Inflammatory Myofibroblastic Tumor of the Tongue in Infancy.

Inflammatory myofibroblastic tumors (IMTs) are rare in neonates. IMTs of the tongue are also very rare in infancy, with only 1 case reported in this age group. The mainstay of therapy has traditionally been surgery, which can be devastating to surrounding structures and negatively impact prognosis. Approximately 50% of IMTs harbor a translocation involving the anaplastic lymphoma kinase gene. We describe a case of IMT of the tongue in a neonate treated with debulking and an anaplastic lymphoma kinase inhibitor. The patient achieved complete response and remains disease-free 1.5 year following completion of therapy.

Neuroblastoma in Adolescents and Children Older than 10 Years: Unusual Clinicopathologic and Biologic Features.

Neuroblastoma (NB) in children older than 10 years is rare. We reviewed our archives for patients with NB aged 10 to 18 years and summarized their clinicopathologic/genetic records. Of 96 patients, 4 patients were identified in this age group. Four tumors were abdominal; 1 patient had 2 tumors at diagnosis, one of which was presacral. Tumor sizes ranged from 3 to 20 cm. All tumors were high risk at clinical stages 3 and 4, with metastasis to bone marrow and other areas. Four tumors were poorly differentiated with unfavorable histology and one patient with bilateral adrenal disease had an intermixed ganglioneuroblastoma on one side. Another tumor exhibited pheochromocytoma-like morphology. MYCN amplification was present in bone marrow metastasis in one case. Complex chromosomal gains and 19p deletions were common. Exome sequencing revealed ALK variants in 2 cases and previously unreported MAGI2, RUNX1, and MLL mutations. All patients received standard chemotherapy and 2 patients received ALK-targeted trial therapy. Three patients died of disease, ranging 18 to 23 months after diagnosis. One patient has active disease and is receiving trial therapy. In conclusion, NB in children older than 10 years may exhibit unusual clinicopathologic and genetic features with large tumors, bilateral adrenal disease, rare morphologic features, complex DNA microarray findings and novel mutations. Patients often have grim prognoses despite genomic profiling-guided targeted therapy.

A Case of Adult Intestinal Toxemia Botulism During Prolonged Hospitalization in an Allogeneic Hematopoietic Cell Transplant Recipient.

We report a laboratory-confirmed case of adult intestinal toxemia botulism in an allogeneic hematopoietic stem cell transplantation (allo-HCT) recipient. Onset of symptoms occurred within the hospitalized setting, making this case particularly unique. Botulism may have arisen because of significant intestinal disruption and compromise, and not directly from immune compromise.

Pediatric 8p11 eosinophilic myeloproliferative syndrome (EMS): A case report and review of the literature.

The 8p11 eosinophilic myeloproliferative syndrome (EMS) is an aggressive neoplasm driven by translocation of the fibroblast growth factor receptor 1 and often transforms to leukemias and lymphomas that are refractory to treatment. The first case was identified in 1983, and to date over 70 cases have been reported in the literature. Despite those reports, no consensus exists on management of this condition, and inconsistency in treatment regimens is even more pronounced in the pediatric literature. We report a case of a male infant with the 8p11 EMS, review the published pediatric experience with EMS, and discuss treatment strategies for this enigmatic hematological disorder.

Morbidity and mortality after treatment of Ewing sarcoma: A single-institution experience.

BACKGROUND: Children, adolescents, and young adults treated for Ewing sarcoma (ES) are at risk for disease-related and treatment-related complications. We aimed to describe early and late overall mortality, cause-specific mortality, and key adverse health outcomes in a large, single-institutional cohort of patients with ES. METHODS: Patients with ES diagnosed at age less than 40 years and treated at Memorial Sloan Kettering between 1974 and 2012 were included. Overall survival was estimated using Kaplan-Meier methods. Cox proportional hazards were used to examine the association of clinical and pathologic variables with overall survival. Cause-specific mortality was evaluated with the cumulative incidence function accounting for competing risks. RESULTS: Three hundred patients with ES (60.3% male; median age at diagnosis: 16.8 years [range: 0.3-39]; 30.0% with metastatic disease at diagnosis) were followed for a median of 7.8 years (range: 0.2-37). Five-year overall survival was 65.2% (95% confidence interval [95% CI], 59.8-71.1%) for the entire cohort; 78.6% for those with localized disease; 40.1% for those with isolated pulmonary metastases; and 28.1% for those with extrapulmonary metastases. In multivariable analysis, older age at diagnosis, minority race/ethnicity, and metastatic disease at diagnosis were associated with inferior survival. Ten-year cumulative incidence of relapse/progression was 40.1%, with eight late relapses occurring at a median of 6.3 years after diagnosis (range: 5-14). Seventeen patients developed subsequent neoplasms (treatment-related myelodysplastic syndrome/acute myelogenous leukemia = 9; solid tumors = 6; nonmelanoma skin cancer [NMSC] = 4). Excluding NMSC and melanoma in situ, the cumulative incidence of subsequent malignant neoplasms at 25 years was 15% (95% CI, 4.8-25.1%). CONCLUSION: Patients with ES are at high risk for relapse/progression and second cancers.

Primary thrombocytosis in children.

Myeloproliferative neoplasms are uncommon disorders in children, for which we have limited understanding of the pathogenesis and optimal management. JAK2 and MPL mutations, while common drivers of myeloproliferative neoplasms in adult patients, are not clearly linked to pediatric disease. Management and clinical outcomes in adults have been well delineated with defined recommendations for risk stratification and treatment. This is not the case for pediatric patients, for whom there is neither a standard approach to workup nor any consensus regarding management. This review will discuss thrombocytosis in children, including causes of thrombocytosis in children, the limited knowledge we have regarding pediatric primary thrombocytosis, and our thoughts on potential risk stratification and management, and future questions to be answered by laboratory research and collaborative clinical study.

Teclistamab: Mechanism of action, clinical, and translational science.

Multiple myeloma (MM) remains incurable despite improvements in treatment options. B-cell maturation antigen (BCMA) is predominantly expressed in B-lineage cells and represents a promising new target for MM. Teclistamab (TECVAYLITM ) is the first T-cell redirecting bispecific antibody approved for patients with MM. Targeting both CD3 receptor complex on T cells and BCMA on myeloma cells, teclistamab leads to T-cell activation and subsequent lysis of BCMA+ cells. The recommended dose of teclistamab is 1.5 mg/kg subcutaneous weekly after two step-up doses of 0.06 and 0.3 mg/kg, which was selected after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Exposure-response analyses of efficacy and safety data were also used to confirm the teclistamab dose. Teclistamab resulted in a high rate of deep and durable responses (63% overall response, 45.5% complete response or better, with 22 months median duration of response) in patients with triple-exposed relapsed/refractory MM. Common adverse reactions included cytokine release syndrome, hematologic abnormalities, and infections. Teclistamab is currently being investigated as monotherapy as well as combination therapy across different MM indications.

Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma: importance of immunoglobulin supplementation.

ABSTRACT: Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received once-weekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P < .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.

Perinucleolar Compartment (PNC) Prevalence as an Independent Prognostic Factor in Pediatric Ewing Sarcoma: A Multi-Institutional Study.

The perinucleolar compartment (PNC) is a small nuclear body that plays important role in tumorigenesis. PNC prevalence correlates with poor prognosis and cancer metastasis. Its expression in pediatric Ewing sarcoma (EWS) has not previously been documented. In this study, we analyzed 40 EWS tumor cases from Caucasian and Hispanic patients for PNC prevalence by immunohistochemical detection of polypyrimidine tract binding protein and correlated the prevalence with dysregulated microRNA profiles. EWS cases showed staining ranging from 0 to 100%, which were categorized as diffuse (≥77%, n = 9, high PNC) or not diffuse (<77%, n = 31) for low PNC. High PNC prevalence was significantly higher in Hispanic patients from the US (n = 6, p = 0.017) and in patients who relapsed with metastatic disease (n = 4; p = 0.011). High PNC was associated with significantly shorter disease-free survival and early recurrence compared to those with low PNC. Using NanoString digital profiling, high PNC tumors revealed upregulation of eight and downregulation of 18 microRNAs. Of these, miR-320d and miR-29c-3p had the most significant differential expression in tumors with high PNC. In conclusion, this is the first study that demonstrates the presence of PNC in EWS, reflecting its utility as a predictive biomarker associated with tumor metastasis, specific microRNA profile, Hispanic ethnic origin, and poor prognosis.

Suppressing STAT5 signaling affects osteosarcoma growth and stemness.

Osteosarcoma (OS) is the most common primary bone tumor that primarily affects children and adolescents. Studies suggested that dysregulation JAK/STAT signaling promotes the development of OS. Cells treated with pimozide, a STAT5 inhibitor suppressed proliferation and colony formation and induced sub G0/G1 cell cycle arrest and apoptosis. There was a reduction in cyclin D1 and CDK2 expression and Rb phosphorylation, and activation of Caspase-3 and PARP cleavage. In addition, pimozide suppressed the formation of 3-dimensional osteospheres and growth of the cells in the Tumor in a Dish lung organoid system. Furthermore, there was a reduction in expression of cancer stem cell marker proteins DCLK1, CD44, CD133, Oct-4, and ABCG2. More importantly, it was the short form of DCLK1 that was upregulated in osteospheres, which was suppressed in response to pimozide. We further confirmed by flow cytometry a reduction in DCLK1+ cells. Moreover, pimozide inhibits the phosphorylation of STAT5, STAT3, and ERK in OS cells. Molecular docking studies suggest that pimozide interacts with STAT5A and STAT5B with binding energies of -8.4 and -6.4 Kcal/mol, respectively. Binding was confirmed by cellular thermal shift assay. To further understand the role of STAT5, we knocked down the two isoforms using specific siRNAs. While knockdown of the proteins did not affect the cells, knockdown of STAT5B reduced pimozide-induced necrosis and further enhanced late apoptosis. To determine the effect of pimozide on tumor growth in vivo, we administered pimozide intraperitoneally at a dose of 10 mg/kg BW every day for 21 days in mice carrying KHOS/NP tumor xenografts. Pimozide treatment significantly suppressed xenograft growth. Western blot and immunohistochemistry analyses also demonstrated significant inhibition of stem cell marker proteins. Together, these data suggest that pimozide treatment suppresses OS growth by targeting both proliferating cells and stem cells at least in part by inhibiting the STAT5 signaling pathway.

Targeted inhibition of histone deacetylase leads to suppression of Ewing sarcoma tumor growth through an unappreciated EWS-FLI1/HDAC3/HSP90 signaling axis.

Ewing sarcoma (ES) are aggressive pediatric bone and soft tissue tumors driven by EWS-ETS fusion oncogenes, most commonly EWS-FLI1. Treatment of ES patients consists of up to 9 months of alternating courses of 2 chemotherapeutic regimens. Furthermore, EWS-ETS-targeted therapies have yet to demonstrate clinical benefit, thereby emphasizing a clinical responsibility to search for new therapeutic approaches. Our previous in silico drug screening identified entinostat as a drug hit that was predicted to reverse the ES disease signatures and EWS-FLI1-mediated gene signatures. Here, we establish preclinical proof of principle by investigating the in vitro and in vivo efficacy of entinostat in preclinical ES models, as well as characterizing the mechanisms of action and in vivo pharmacokinetics of entinostat. ES cells are preferentially sensitive to entinostat in an EWS-FLI1 or EWS-ERG-dependent manner. Entinostat induces apoptosis of ES cells through G0/G1 cell cycle arrest, intracellular reactive oxygen species (ROS) elevation, DNA damage, homologous recombination (HR) repair impairment, and caspase activation. Mechanistically, we demonstrate for the first time that HDAC3 is a transcriptional target of EWS-FLI1 and that entinostat inhibits growth of ES cells through suppressing a previously unexplored EWS-FLI1/HDAC3/HSP90 signaling axis. Importantly, entinostat significantly reduces tumor burden by 97.4% (89.5 vs. 3397.3 mm3 of vehicle, p < 0.001) and prolongs the median survival of mice (15.5 vs. 8.5 days of vehicle, p < 0.001), in two independent ES xenograft mouse models, respectively. Overall, our studies demonstrate promising activity of entinostat against ES, and support the clinical development of the entinostat-based therapies for children and young adults with metastatic/relapsed ES. KEY MESSAGES: • Entinostat potently inhibits ES both in vitro and in vivo. • EWS-FLI1 and EWS-ERG confer sensitivity to entinostat treatment. • Entinostat suppresses the EWS-FLI1/HDAC3/HSP90 signaling. • HDAC3 is a transcriptional target of EWS-FLI1. • HDAC3 is essential for ES cell viability and genomic stability maintenance.

Metastatic Tumor-in-a-Dish, a Novel Multicellular Organoid to Study Lung Colonization and Predict Therapeutic Response.

Metastasis is a major cause of cancer-related deaths. A dearth of preclinical models that recapitulate the metastatic microenvironment has impeded the development of therapeutic agents that are effective against metastatic disease. Because the majority of solid tumors metastasize to the lung, we developed a multicellular lung organoid that mimics the lung microenvironment with air sac-like structures and production of lung surfactant protein. We used these cultures, called primitive lung-in-a-dish (PLiD), to recreate metastatic disease using primary and established cancer cells. The metastatic tumor-in-a-dish (mTiD) cultures resemble the architecture of metastatic tumors in the lung, including angiogenesis. Pretreating PLiD with tumor exosomes enhanced cancer cell colonization. We next tested the response of primary and established cancer cells to current chemotherapeutic agents and an anti-VEGF antibody in mTiD against cancer cells in two-dimensional (2D) or 3D cultures. The response of primary patient-derived colon and ovarian tumor cells to therapy in mTiD cultures matched the response of the patient in the clinic, but not in 2D or single-cell-type 3D cultures. The sensitive mTiD cultures also produced significantly lower circulating markers for cancer similar to that seen in patients who responded to therapy. Thus, we have developed a novel method for lung colonization in vitro, a final stage in tumor metastasis. Moreover, the technique has significant utility in precision/personalized medicine, wherein this phenotypic screen can be coupled with current DNA pharmacogenetics to identify the ideal therapeutic agent, thereby increasing the probability of response to treatment while reducing unnecessary side effects. SIGNIFICANCE: A lung organoid that exhibits characteristics of a normal human lung is developed to study the biology of metastatic disease and therapeutic intervention.

Potential Value of YAP Staining in Rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a common malignancy of soft tissue, subclassified as alveolar (ARMS), pleomorphic (PRMS), spindle cell/sclerosing (SRMS), and embryonal (ERMS) types. The Yes-associated protein (YAP) is a member of the Hippo pathway and a transcriptional regulator that controls cell proliferation. We have studied the immunohistochemical expression of YAP in different RMSs, arranged in tissue microarray (TMA) and whole slide formats. Pertinent clinical data including patient age, gender, tumor location, and clinical stage were collected. Out of 96 TMA cases, 30 cases (31%) were pleomorphic, 27 (28%) were embryonal, 24 (25%) alveolar, and 15 (16%) spindle cell. Positive nuclear YAP staining was seen in the PRMS (17/30, 56.7%), SRMS (7/15, 46.7%), ERMS (19/27 or 70%), and less in ARMS (37.5%). YAP nuclear staining was significantly more prevalent in ERMS than ARMS ( p=0.02). Of the 41 whole slide cases, nuclear staining was detected in all ARMS but was restricted in distribution to <30% of the cells, in contrast to ERMS and SRMS, which had diffuse or >30% staining. These results highlight the role of YAP in RMS tumorigenesis, a fact that can be useful in engineering targeted therapy. Restricted nuclear YAP staining (<30% of cells) may be of value in the diagnosis of ARMS.

Natural compounds targeting major cell signaling pathways: a novel paradigm for osteosarcoma therapy.

Osteosarcoma is the most common primary bone cancer affecting children and adolescents worldwide. Despite an incidence of three cases per million annually, it accounts for an inordinate amount of morbidity and mortality. While the use of chemotherapy (cisplatin, doxorubicin, and methotrexate) in the last century initially resulted in marginal improvement in survival over surgery alone, survival has not improved further in the past four decades. Patients with metastatic osteosarcoma have an especially poor prognosis, with only 30% overall survival. Hence, there is a substantial need for new therapies. The inability to control the metastatic progression of this localized cancer stems from a lack of complete knowledge of the biology of osteosarcoma. Consequently, there has been an aggressive undertaking of scientific investigation of various signaling pathways that could be instrumental in understanding the pathogenesis of osteosarcoma. Here, we review these cancer signaling pathways, including Notch, Wnt, Hedgehog, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT, and JAK/STAT, and their specific role in osteosarcoma. In addition, we highlight numerous natural compounds that have been documented to target these pathways effectively, including curcumin, diallyl trisulfide, resveratrol, apigenin, cyclopamine, and sulforaphane. We elucidate through references that these natural compounds can induce cancer signaling pathway manipulation and possibly facilitate new treatment modalities for osteosarcoma.

Clinical variables and Staphylococcus aureus virulence factors associated with venous thromboembolism in children.

OBJECTIVES: Children with Staphylococcus aureus (SA) bacteremia risk developing venous thromboembolism (VTE). We sought to identify clinical variables and bacterial virulence factors associated with VTE in SA bacteremia. STUDY DESIGN: This is a single-institution retrospective study of 229 children with SA bacteremia hospitalized from 2005 to 2008. Clinical data were abstracted from patient charts. Two-hundred three SA isolates were analyzed by polymerase chain reaction. The Pediatric Health Information System (PHIS) database was queried to identify subjects with a central venous line (CVL) or complex chronic conditions (CCC). Logistic regression analysis was employed to determine which factors most greatly influenced VTE. RESULTS: VTE was present in 9.2% (n=21/229). Superficial thrombi were excluded. Mortality was greater in patients with VTE [24% vs. 6% (p=0.016)]. Among SA isolates available for virulence testing, the majority (70%; n=139) were methicillin-sensitive SA (MSSA). Methicillin-resistant SA (MRSA) infection was associated with VTE (p=0.01). The most common sites of thrombosis were extremity deep vein (58%; n=14/24), head/neck (29%; n=7), and visceral (13%; n=3). One subject had a pulmonary embolism. The presence of a CVL or a CCC was not associated with VTE. Independent predictors of VTE were C-reactive protein (CRP)≥20mg/dl [OR 4.2, 95% CI 1.16-15.25] and hemoglobin nadir ≤9g/dl [OR 5.2, 95% CI 1.3-20.64]. CONCLUSIONS: In addition to MRSA infection, CRP≥20mg/dl and hemoglobin nadir ≤9g/dl were associated with VTE in SA bacteremia. These factors may serve as markers for increased risk of VTE with invasive SA disease.