Opportunistic Infections, Mortality Risk, and Prevention Strategies in Patients With Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic (VEXAS) Syndrome.

Background: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a genetic disorder characterized by bone marrow failure and systemic inflammation, putting patients at risk for infections. This study comprehensively examines the prevalence of opportunistic infections in patients with VEXAS, evaluating their impact on clinical outcomes and potential preventive measures. Methods: Patients with confirmed VEXAS were included. Survival analysis and logistic regression were used to identify associations between opportunistic infections and mortality. Infection rates (IRs) for Pneumocystis jirovecii pneumonia (PJP) and alphaherpesviruses were calculated over a prospective 8-month observation period in relationship to prophylaxis. Results: Of 94 patients with VEXAS, 6% developed PJP; 15% had alphaherpesvirus reactivation, with varicella zoster virus (VZV) being the most common herpesvirus; and 10% contracted a nontuberculous mycobacterial (NTM) infection. Risk of death was significantly increased per month following a diagnosis of PJP (hazard ratio [HR], 72.41 [95% confidence interval {CI}, 13.67-533.70]) or NTM (HR, 29.09 [95% CI, 9.51-88.79]). Increased odds for death were also observed in patients with a history of herpes simplex virus (HSV) reactivation (odds ratio [OR], 12.10 [95% CI, 1.29-114.80]) but not in patients with VZV (OR, 0.89 [95% CI, .30-2.59]). Prophylaxis for PJP (IR, 0.001 vs 0 per person-day, P < .01) and VZV (IR, 0.006 vs 0 per person-day, P = .04) markedly decreased infection rates with a number needed to treat of 4 and 7, respectively. Conclusions: Opportunistic infections are common in patients with VEXAS. Patients who develop PJP, HSV, or NTM are at increased risk for death. Prophylaxis against PJP and VZV is highly effective.

Venous and arterial thrombosis in patients with VEXAS syndrome.

ABSTRACT: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, caused by somatic mutations in UBA1, is an autoinflammatory disorder with diverse systemic manifestations. Thrombosis is a prominent clinical feature of VEXAS syndrome. The risk factors and frequency of thrombosis in VEXAS syndrome are not well described, due to the disease's recent discovery and the paucity of large databases. We evaluated 119 patients with VEXAS syndrome for venous and arterial thrombosis and correlated their presence with clinical outcomes and survival. Thrombosis occurred in 49% of patients, mostly venous thromboembolism (VTE; 41%). Almost two-thirds of VTEs were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence of VTE was 17% at 1 year from symptom onset and 40% by 5 years. Cardiac and pulmonary inflammatory manifestations were associated with time to VTE. M41L was positively associated specifically with pulmonary embolism by univariate (odds ratio [OR]: 4.58, confidence interval [CI] 1.28-16.21, P = .02) and multivariate (OR: 16.94, CI 1.99-144.3, P = .01) logistic regression. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival of the entire patient cohort at median follow-up time of 4.8 years was 88%, and there was no difference in survival between patients with or without thrombosis (P = .8). Patients with VEXAS syndrome are at high risk of VTE; thromboprophylaxis should administered be in high-risk settings unless strongly contraindicated.

Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis.

Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, whereas transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these 3 canonical VEXAS variants produce more UBA1b than any of the 6 other possible single-nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with 2 novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but coexpression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis.

A prospective observational cohort study and systematic review of 40 patients with mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome.

OBJECTIVE: Mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome is characterized by overlapping features of relapsing polychondritis (RP) and Behcet's disease (BD). To date, no studies have defined the clinical spectrum of disease in a cohort of patients with MAGIC syndrome. METHODS: Adult patients within an ongoing prospective, observational cohort study in RP were clinically assessed for MAGIC syndrome. A systematic review was conducted to identify additional cases of MAGIC syndrome by searching four databases: PubMed (US National Library of Medicine), Embase (Elsevier), Scopus (Elsevier) and Web of Science: Core Collection (Clarivate Analytics). The inclusion criteria used were: [1] patients of any age or gender who were diagnosed with MAGIC syndrome, or both RP and BD; [2] case report or case series study; [3] published from 1985 - July 2020; and [4] in English language. Risk of bias was assessed using a checklist developed by the authors and based on the Consensus-based Clinical Case Reporting (CARE) Guidelines. Search results screening, article inclusion, data extraction and risk of bais assessment was performed independently by two investigators. Clinical characteristics, particularly BD-related features, were compared between patients with MAGIC syndrome and cases of non-MAGIC RP. The performance characteristics of different criteria to classify MAGIC syndrome were also evaluated. RESULTS: Out of 96 patients with RP, 13 (14%) patients were diagnosed with MAGIC syndrome. For the systematic review, 380 articles were retrieved of which 90 were screened at title and abstract levels. Of these screened, 60 were excluded and 30 proceeded to full text review where an additional 8 were excluded. Twenty-two articles were included in our review and from which 27 additional cases of MAGIC syndrome were identified. Pooling all 40 cases together and comparing them with non-MAGIC RP, there was a significantly higher prevalence of ocular involvement (28% vs 4%, p<0.01), cutaneous involvement (35% vs 1%, p<0.01), GI involvement (23% vs 4%, p<0.01), and CNS involvement (8% vs 0, p = 0.04) in MAGIC syndrome. A higher prevalence of aortitis (23% vs 1%, p<0.01), Raynaud's phenomenon (54% vs 11%, p<0.01), and elevated anti-collagen II antibodies (50% vs 9%, p = 0.04) were observed in MAGIC syndrome. Fulfillment of either McAdam's or Damiani's Criteria for RP plus the International Criteria for Behçet's Disease had excellent sensitivity (98%) to classify cases of MAGIC syndrome. CONCLUSION: A substantial proportion of patients with RP can be clinically diagnosed with MAGIC syndrome. These patients have features of RP, BD, and other unique features including aortitis, Raynaud's phenomenon and elevated anti-collagen II antibodies.

Discordance in patient and physician global assessment in relapsing polychondritis.

OBJECTIVES: Relapsing polychondritis (RP) is a rare, heterogeneous, systemic inflammatory disease that targets cartilage. Patient-reported outcome measures may differ from physician assessment. This study compared patient global assessment (PtGA) and physician global assessment (PhGA) scores in a prospective cohort of patients with RP. METHODS: Adult patients with RP underwent a standardized comprehensive evaluation at ∼6 month intervals. At each visit, three physicians scored PhGA by consensus. The patient independently completed four patient-reported outcomes: PtGA, 36-item Short Form Health Survey (SF-36), Brief Illness Perception Questionnaire (BIPQ) and Multidimensional Fatigue Inventory (MFI). Patient-physician discordance was defined as a difference between PtGA and PhGA of ≥3 on a 0-10 scale. RESULTS: A total of 76 patients were evaluated over 154 visits. The median PhGA was 3 [interquartile range (IQR) 2-3] and the median PtGA was 5 (IQR 4-7). PtGA and PhGA were concordant in 66 visits (42.9%) and patients scored disease severity ≥3 points higher than physicians scored disease activity (positive discordance) in 84 visits (54.5%). Compared with visits with concordance, visits with positive discordance were associated with significantly worse scores on the MFI, BIPQ, SF-36 physical component score and SF-36 mental component score. CONCLUSION: Patients with RP typically self-report high PtGA that does not align with PhGA. Discordance is likely driven by the high physical and psychological burden of illness experienced by patients. Multifaceted treatment approaches that address the burden of disease in RP from the patient perspective are needed.

Physician Global Assessment as a Disease Activity Measure for Relapsing Polychondritis.

OBJECTIVE: Relapsing polychondritis (RP) is a systemic inflammatory disorder of cartilage that lacks validated disease activity measures. Our objective was to test physician global assessment (PhGA), a measure of disease activity commonly used in rheumatic diseases, in a cohort of patients with RP, which has not been done before. METHODS: Adult patients in an observational cohort of RP underwent standardized, comprehensive evaluation at approximately 6-month intervals. PhGA was scored by 3 physicians from the evaluating institution on a scale of 0-10 for each visit. A random subset of 20 visits was scored by 3 independent physicians not affiliated with the evaluating institution. Treatment change between consecutive visits was categorized as increased, decreased, or unchanged. RESULTS: In total, 78 patients were evaluated over 164 visits. The intraclass correlation coefficient (ICC2,1 ) for the 3 raters from the evaluating institution was excellent (0.79 [95% confidence interval (95% CI) 0.73, 0.84]) but was poor in the subset of cases scored by the additional raters (ICC2,1 0.27 [95% CI -0.01, 0.53]). Median PhGA was 3 (range 0-7). PhGA weakly correlated with C-reactive protein level (rs = 0.30, P < 0.01). In response to increased treatment, median PhGA decreased from 3 (interquartile range [IQR] 2, 4) to 2 (IQR 2, 3) (P < 0.01) but rarely went to 0. CONCLUSION: Within a single center, PhGA can be used to quantify disease activity and monitor disease response in RP. Persistent disease activity despite treatment, rather than a relapsing-remitting pattern, is observed for most patients with RP. Reliability of PhGA may not generalize across different institutions. A validated disease-specific activity index is needed in RP.

Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS.

OBJECTIVE: Somatic mutations in UBA1 cause a newly defined syndrome known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome). More than 50% of patients currently identified as having VEXAS met diagnostic criteria for relapsing polychondritis (RP), but clinical features that characterize VEXAS within a cohort of patients with RP have not been defined. We undertook this study to define the prevalence of somatic mutations in UBA1 in patients with RP and to create an algorithm to identify patients with genetically confirmed VEXAS among those with RP. METHODS: Exome and targeted sequencing of UBA1 was performed in a prospective observational cohort of patients with RP. Clinical and immunologic characteristics of patients with RP were compared based on the presence or absence of UBA1 mutations. The random forest method was used to derive a clinical algorithm to identify patients with UBA1 mutations. RESULTS: Seven of 92 patients with RP (7.6%) had UBA1 mutations (referred to here as VEXAS-RP). Patients with VEXAS-RP were all male, were on average ≥45 years of age at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. No patient with VEXAS-RP had chondritis of the airways or costochondritis. Mortality was greater in VEXAS-RP than in RP (23% versus 4%; P = 0.029). Elevated acute-phase reactants and hematologic abnormalities (e.g., macrocytic anemia, thrombocytopenia, lymphopenia, multiple myeloma, myelodysplastic syndrome) were prevalent in VEXAS-RP. A decision tree algorithm based on male sex, a mean corpuscular volume >100 fl, and a platelet count <200 ×103 /µl differentiated VEXAS-RP from RP with 100% sensitivity and 96% specificity. CONCLUSION: Mutations in UBA1 were causal for disease in a subset of patients with RP. This subset of patients was defined by disease onset in the fifth decade of life or later, male sex, ear/nose chondritis, and hematologic abnormalities. Early identification is important in VEXAS given the associated high mortality rate.

Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease.

BACKGROUND: Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders. METHODS: We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function. RESULTS: We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The gene UBA1 lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation. CONCLUSIONS: Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).

Defining Clinical Subgroups in Relapsing Polychondritis: A Prospective Observational Cohort Study.

OBJECTIVE: Relapsing polychondritis (RP) is a systemic disease. Failure to recognize RP can lead to diagnostic delay and further complications, including death. This study was undertaken to identify clinical patterns in a prospective cohort of patients with RP. METHODS: Patient subgroups were identified using latent class analysis based on 8 clinical variables: saddle-nose deformity, subglottic stenosis, tracheomalacia, bronchomalacia, ear chondritis, tenosynovitis/synovitis, inflammatory eye disease, and audiovestibular disease. Model selection was based on Akaike's information criterion. RESULTS: Seventy-three patients were included in this study. Patients were classified into 1 of 3 subgroups: type 1 RP (14%), type 2 RP (29%), and type 3 RP (58%). Type 1 RP was characterized by ear chondritis (100%), tracheomalacia (100%), saddle-nose deformity (90%), and subglottic stenosis (80%). These patients had the shortest median time to diagnosis (1 year), highest disease activity, and greatest frequency of admission to the intensive care unit and tracheostomy. Type 2 RP was characterized by tracheomalacia (100%) and bronchomalacia (52%), but no saddle-nose deformity or subglottic stenosis. These patients had the longest median time to diagnosis (10 years) and highest percentage of work disability. Type 3 RP was characterized by tenosynovitis/synovitis (60%) and ear chondritis (55%). There were no significant differences in sex, race, or treatment strategies between the 3 subgroups. CONCLUSION: Our findings indicate that there are 3 subgroups of patients with RP, with differences in time to diagnosis, clinical and radiologic characteristics, and disease-related complications. Recognizing a broader spectrum of clinical patterns in RP, beyond cartilaginous involvement of the ear and upper airway, may facilitate more timely diagnosis.

Utility of the Brief Illness Perception Questionnaire to Monitor Patient Beliefs in Systemic Vasculitis.

OBJECTIVE: To assess the validity and clinical utility of the Brief Illness Perception Questionnaire (BIPQ) to measure illness perceptions in multiple forms of vasculitis. METHODS: Patients with giant cell arteritis (GCA), Takayasu arteritis (TA), antineutrophil cytoplasmic antibody-associated vasculitis (AAV), and relapsing polychondritis (RP) were recruited into a prospective, observational cohort. Patients independently completed the BIPQ, Multidimensional Fatigue Inventory (MFI), Medical Outcomes Study 36-item Short Form survey (SF-36), and a patient global assessment (PtGA) at successive study visits. Physicians concurrently completed a physician global assessment (PGA) form. Illness perceptions, as assessed by the BIPQ, were compared to responses from the full-length Revised Illness Perception Questionnaire (IPQ-R) and to other clinical outcome measures. RESULTS: There were 196 patients (GCA = 47, TA = 47, RP = 56, AAV = 46) evaluated over 454 visits. Illness perception scores in each domain were comparable between the BIPQ and IPQ-R (3.28 vs 3.47, P = 0.22). Illness perceptions differed by type of vasculitis, with the highest perceived psychological burden of disease in RP. The BIPQ was significantly associated with all other patient-reported outcome measures (rho = |0.50-0.70|, P < 0.0001), but did not correlate with PGA (rho = 0.13, P = 0.13). A change in the BIPQ composite score of ≥ 7 over successive visits was associated with concomitant change in the PtGA. Change in the MFI and BIPQ scores significantly correlated over time (rho = 0.38, P = 0.0008). CONCLUSION: The BIPQ is an accurate and valid assessment tool to measure and monitor illness perceptions in patients with vasculitis. Use of the BIPQ as an outcome measure in clinical trials may provide complementary information to physician-based assessments.

Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors.

BACKGROUND: Based on pre-clinical and clinical activity in adult refractory tumors, and absence of significant neuro-, nephro-, or oto-toxicity, we conducted a pediatric phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and pharmacokinetics of satraplatin, an oral platinum analogue, in children and young adults with refractory solid tumors. PROCEDURE: Satraplatin was administered orally once daily on days 1-5 of a 28-day cycle at dose level (DL) 1 (60 mg/m(2) /dose), and DL2 (80 mg/m(2) /dose). Toxicities, responses, satraplatin pharmacokinetics, and pharmacogenomic expression of specific DNA repair genes were evaluated. RESULTS: Nine patients received 1-15 cycles (median = 2). The MTD was exceeded at DL2 with delayed prolonged myelosuppression as dose-limiting toxicity (DLT) in 2/4 patients. At DL1, 0/5 patients had DLTs. Common non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No significant neuro-, nephro-, or oto-toxicity was observed. No objective responses were observed but 2 patients experienced prolonged disease stabilization (---6-15 cycles). Satraplatin exposure (day 1 plasma ultrafiltrate area under the curve) was similar at DL1 and DL2. A strong correlation between estimated creatinine clearance and satraplatin pharmacokinetic parameters (clearance, area under the curve, and peak concentration) was observed. CONCLUSIONS: The MTD of oral satraplatin in children with solid tumors was 60 mg/m(2) /dose daily ×5 days every 28 days, which is lower than the adult recommended dose of 80-120 mg/m(2) /dose. The toxicity profile was similar to adults and delayed myelosuppression was the DLT. No significant neuro-, nephro- or oto-toxicities were observed.

Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas.

BACKGROUND: Pirfenidone, an oral anti-inflammatory, antifibrotic agent with activity in idiopathic pulmonary fibrosis, may mediate anti-tumor activity in neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN) by inhibition of fibroblast proliferation and collagen synthesis. The primary objective of this open label, single arm phase II trial was to evaluate the activity of pirfenidone in children and young adults with inoperable PN. PROCEDURE: Patients (3-21 years) with NF1-related progressive PN received pirfenidone at the previously determined optimal dose (500 mg/m(2) orally, q8h) on a continuous dosing schedule (one cycle = 28 days). Volumetric MRI analysis was used to assess response. Progression was defined as ≥ 20% PN volume increase compared to baseline. Pirfenidone would be considered active if it doubled the median time to progression (TTP) compared to the TTP on the placebo arm of a phase II trial with the farnesyltransferase inhibitor tipifarnib, which used near identical eligibility criteria. Toxicities, objective response rate, and quality of life (QOL) also were evaluated. RESULTS: Thirty-six patients were enrolled and tolerated pirfenidone well with intermittent nausea and vomiting as the most frequent toxicities. A dose reduction was required in only three patients. The median TTP for pirfenidone was 13.2 months compared to 10.6 months for the placebo control group from the tipifarnib trial (two-tailed P = 0.92; one-tailed P = 0.46). No objective responses were observed. CONCLUSIONS: Pirfenidone was well tolerated, but did not demonstrate activity as defined in this trial and does not warrant further evaluation in children with NF1 and progressive PN.

Phase 1 trial and pharmacokinetic study of the farnesyl transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: a report from the Children's Oncology Group.

BACKGROUND: The objectives of this trial were to define the toxicity profile, dose, pharmacokinetics, and pharmacodynamics of the farnesyl transferase (FTase) inhibitor, tipifarnib, in children and adolescents with hematological malignancies. PROCEDURE: Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at a dose of 300 mg/m(2) /dose. Pharmacokinetic sampling was performed for 36 hr after the first dose and leukemic blasts were collected pre-treatment and at steady state for determination of FTase activity. RESULTS: Of 29 patients enrolled, 18 were fully evaluable for toxicity, and 23 for response; 26 had pharmacokinetic and pharmacodynamic sampling. The recommended dose is 300 mg/m(2) /dose and toxicities included skin rash, mucositis, nausea, vomiting, and diarrhea. Neurotoxicity, which was dose-limiting in adults at doses exceeding 600 mg/dose, was infrequent and mild. The plasma pharmacokinetics of tipifarnib were highly variable but comparable to adults with acute leukemia and children with solid tumors. The median apparent clearance of tipifarnib was 630 ml/min/m(2) and the median half-life was 4.7 hr. At steady state on 300 mg/m(2) /dose, FTase activity was inhibited by 82% in leukemic blasts. No objective responses were observed. CONCLUSIONS: Oral tipifarnib is well tolerated in children with leukemia on a twice daily for 2 days schedule at 300 mg/m(2) /dose.

A phase 1 trial and pharmacokinetic study of cediranib, an orally bioavailable pan-vascular endothelial growth factor receptor inhibitor, in children and adolescents with refractory solid tumors.

PURPOSE: To determine the toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of cediranib administered orally, once daily, continuously in children and adolescents with solid tumors. PATIENTS AND METHODS: Children and adolescents with refractory solid tumors, excluding primary brain tumors, were eligible. DLT at the starting dose of 12 mg/m(2)/d resulted in de-escalation to 8 mg/m(2)/d and subsequent re-escalation to 12 and 17 mg/m(2)/d. Pharmacokinetic and pharmacodynamic studies were performed during cycle 1. Response was evaluated using WHO criteria. RESULTS: Sixteen patients (median age, 15 years; range, 8 to 18 years) were evaluable for toxicity. DLTs (grade 3 nausea, vomiting, fatigue in one; hypertension and prolonged corrected QT interval in another) occurred in patients initially enrolled at 12 mg/m(2)/d. Subsequently, 8 mg/m(2)/d was well tolerated in three patients. An additional seven patients were enrolled at 12 mg/m(2)/d; one had DLT (grade 3 diarrhea). At 17 mg/m(2)/d, two of four patients had DLTs (grade 3 nausea; intolerable grade 2 fatigue). Non-dose-limiting toxicities included left ventricular dysfunction, elevated thyroid stimulating hormone, palmar-plantar erythrodysesthesia, weight loss, and headache. The MTD of cediranib was 12 mg/m(2)/d (adult fixed dose equivalent, 20 mg). At 12 mg/m(2)/d, the median area under the plasma concentration-time curve extrapolated to infinity (AUC(0-∞)) was 900 ng·h/mL, which is similar to adults receiving 20 mg. Objective responses were observed in patients with Ewing sarcoma, synovial sarcoma, and osteosarcoma. CONCLUSION: The recommended monotherapy dose of cediranib for children with extracranial solid tumors is 12 mg/m(2)/d administered orally, once daily, continuously. A phase II study is in development.

Phase II trial of ixabepilone administered daily for five days in children and young adults with refractory solid tumors: a report from the children's oncology group.

PURPOSE: Ixabepilone is a microtubule-stabilizing agent with activity in adult solid tumors and in pediatric tumor xenograft models that are resistant to paclitaxel. The maximum tolerated dose on the daily-for-5-days i.v. schedule was 6 mg/m(2)/dose in adults and 8 mg/m(2)/dose in children, and the primary dose-limiting toxicity (DLT) was neutropenia. This study aimed to determine the response rate to ixabepilone in six solid tumor strata in children and young adults. EXPERIMENTAL DESIGN: We conducted a phase II trial of ixabepilone (8 mg/m(2)/dose for 5 days every 21 days) using a two-stage design in taxane-naïve children and young adults with treatment-refractory, measurable rhabdomyosarcoma, Ewing sarcoma family tumors, osteosarcoma, synovial sarcoma, or malignant peripheral nerve sheath tumor, neuroblastoma, and Wilms tumor. RESULTS: Sixty-one eligible patients (36 male) were enrolled. Median (range) age was 13 years (range, 3-36). Fifty-nine patients were fully evaluable for toxicity and response. DLTs, most commonly myelosuppression, occurred in 11 patients (15% incidence in 3-18 years old and 33% in 19-36 years old; P = 0.2) during cycle 1. The median (range) number of cycles was 2 (range, 1-38). No partial or complete responses (response evaluation criteria in solid tumors) were observed. Seven patients received >or=3 cycles, and two had prolonged stable disease (Wilms' tumor, 38 cycles; synovial sarcoma, 8 cycles). CONCLUSIONS: Ixabepilone at 8 mg/m(2)/dose daily for 5 days was tolerable in children and adolescents, but did not show evidence of clinical activity in the childhood solid tumors studied.

Pharmacokinetics of orally administered ABT-751 in children with neuroblastoma and other solid tumors.

PURPOSE: To describe the pharmacokinetics of orally administered ABT-751 and its conjugated metabolites in children with neuroblastoma and other solid tumors and to relate pharmacokinetic parameters to toxicity and therapeutic outcomes. METHODS: Patients (median age, 11 years) with neuroblastoma (n = 37) or other solid tumors (n = 25) had pharmacokinetic sampling after the first dose of ABT-751 (75-250 mg/m(2)/day) on a 7-day or 21-day schedule. ABT-751 and its glucuronide and sulfate metabolites were quantified with an HPLC/MS/MS assay. Pharmacokinetic parameters were derived with non-compartmental methods. The relative bioavailability of more water soluble capsule and suspension formulations was assessed. RESULTS: ABT-751 peaked in plasma at 2 h and declined monoexponentially with a t (1/2) of 5.1 h. The apparent clearance was 33 ml/min/m(2) and was age-independent. The AUC(0-infinity) increased in proportion to the dose, and at 200 mg/m(2) the median AUC(0-infinity) was 91 mcg h/ml and the C (ave) was 3.9 mcg/ml. Inter-and intra-patient variability was low. The metabolites were detected in plasma 30 min post-dose and peaked 3-5 h after the dose. The glucuronide:sulfate molar AUC(0-infinity) ratio was 0.57. Less than 1% of the dose was excreted in urine as parent drug; 13% of the dose was excreted as sulfate metabolite and 10% as glucuronide metabolite. The relative bioavailability of the water soluble capsule and suspension formulations was 105 and 93%, respectively. AUC(0-infinity) was higher in patients experiencing dose-limiting toxicity. CONCLUSIONS: Oral ABT-751 pharmacokinetics was dose-proportional and age-independent with minimal intra- and inter-patient variability in children.

Phase I trial and pharmacokinetic study of ixabepilone administered daily for 5 days in children and adolescents with refractory solid tumors.

PURPOSE: The objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary response rate for ixabepilone, a microtubule-stabilizing agent, administered intravenously daily for 5 days in children and adolescents. PATIENTS AND METHODS: Patients >or= 2 and 5 days and grade 3 fatigue) were observed in two of three patients receiving 10 mg/m(2)/d. The MTD of ixabepilone administered daily for 5 days every 21 days was 8 mg/m(2)/d. Myelosuppression, GI, and hepatic toxicities were common non-DLTs. Peripheral neuropathy was uncommon. Ixabepilone clearance was 475 +/- 247 mL/min/m(2), volume of distribution at steady-state was 12.2 +/- 5.4 L/kg, and half-life was 14 hours. CONCLUSION: The recommended dose of ixabepilone for phase II trials in solid tumors is 8 mg/m(2)/d daily for 5 days every 21 days. This dose is 33% higher than the MTD in adults receiving the same dosing schedule. Pharmacokinetic parameters in children and adolescents were highly variable but similar to adults.

A phase I study of ABT-751, an orally bioavailable tubulin inhibitor, administered daily for 21 days every 28 days in pediatric patients with solid tumors.

PURPOSE: To determine the toxicity profile, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) of ABT-751 administered orally once daily for 21 days, repeated every 28 days in a pediatric population. EXPERIMENTAL DESIGN: Patients who were < or = 18 years with relapsed or refractory solid tumors and who were able to swallow capsules were eligible. The starting dose was 75 mg/m(2)/d (n = 3) and was escalated to 100 (n = 6), 130 (n = 5), and 165 (n = 3) mg/m(2)/d in cohorts of three to six patients. The MTD was determined from DLTs occurring during the first treatment cycle. RESULTS: Nineteen children (median age, 13 years; range, 5-18 years) were enrolled, and 17 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 9), sarcomas (n = 9), and other solid tumors (n = 1). DLTs included fatigue, sensory neuropathy, transient hypertension, neutropenia, thrombocytopenia, nausea, vomiting, dehydration, abdominal pain, and constipation. The MTD of ABT-751 administered daily for 21 days every 28 days was 100 mg/m(2)/d. Non-DLT at the MTD included bone marrow suppression, gastrointestinal toxicities (anorexia, abdominal pain, nausea, vomiting, and constipation), and sensory and motor neuropathies. The median number of cycles administered was one (range, one to five). Tolerance of repeated treatment cycles was poor. CONCLUSION: Fatigue, hematologic, and gastrointestinal toxicities limited the tolerability of ABT-751 administered to children on the once daily for 21 days every 28 days schedule. The MTD in children with solid tumors (100 mg/m(2)/d daily for 21 days) was similar to the recommended dose in adults with solid tumors (200 mg fixed dose) receiving the same dosing schedule.

Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma.

Arsenic trioxide (ATO) induces remission in 85% of adults with refractory acute promyelocytic leukemia (APL). We conducted a phase 1 trial of ATO in children (median age 13 y, range, 2-19) with refractory leukemia. ATO was administered intravenously over 2 hours, 5 d/wk for 20 doses/cycle. Patients with APL (n=13) received 0.15 mg/kg per day, and patients with other types of leukemia received 0.15 mg/kg per day (n=2) or 0.2 mg/kg per day (n=4). Nineteen of the 24 enrolled patients were fully evaluable for toxicity. At 0.15 mg/kg per day, 2 of 15 patients experienced dose-limiting corrected QT interval (QTc) prolongation, pneumonitis, or neuropathic pain. At 0.2 mg/kg per day, 2 of 4 patients had dose-limiting QTc prolongation or pancreatitis. Non-dose-limiting toxicities included elevated serum transaminases, nausea, vomiting, abdominal pain, constipation, electrolyte imbalance, hyperglycemia, dermatitis, and headache. At 0.15 mg/kg per day, the median (range) plasma arsenic maximum concentration (Cmax) was 0.28 microM (0.11-0.37 microM) and at 0.2 mg/kg per day, Cmax was 0.40 and 0.46 microM; area under the concentration times time curve (AUC0-24) was 2.50 microM-hr (1.28-3.85 microM-hr) and 4.37 microM-hr and 4.69 microM-hr, respectively. Morphologic complete response (CR) was achieved in 85% of patients with APL; no responses were observed in non-APL patients. ATO is well-tolerated in children at the recommended dose of 0.15 mg/kg per day. The response rate in children with relapsed APL is similar to the response rate in adults. This trial was registered as #NCT00020111 at www.ClinicalTrials.gov.

A phase 1 study of ABT-751, an orally bioavailable tubulin inhibitor, administered daily for 7 days every 21 days in pediatric patients with solid tumors.

PURPOSE: To determine the toxicity profile, dose-limiting toxicities, and maximum tolerated dose of ABT-751 administered orally once daily for 7 days, repeated every 21 days. EXPERIMENTAL DESIGN: Patients who were 40% higher than the maximum tolerated dose in adults receiving the same dosing schedule.