Patrick Campbell

Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms

UNLABELLED Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAF(V600E) mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAF(V600E)-wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAF(V600E)-wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. SIGNIFICANCE We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders.

Utility of Early Screening Magnetic Resonance Imaging for Extensive Hip Osteonecrosis in Pediatric Patients Treated With Glucocorticoids

PURPOSE Hip osteonecrosis frequently complicates treatment with glucocorticoids. When extensive (affecting ≥ 30% of the epiphyseal surface), 80% of joints collapse within 2 years, so interventions are needed to prevent this outcome. PATIENTS AND METHODS This prospective cohort magnetic resonance imaging (MRI) screening study included all consecutive children treated for acute lymphoblastic leukemia on a single protocol. Hip MRI was performed at 6.5 and 9 months from diagnosis (early screening) and at completion of chemotherapy (final evaluation) to determine whether screening could identify extensive hip osteonecrosis before symptom development. RESULTS Of 498 patients, 462 underwent screening MRI. Extensive asymptomatic osteonecrosis was identified by early screening in 26 patients (41 hips); another four patients (seven hips) were detected after the screening period, such that screening sensitivity was 84.1% and specificity was 99.4%. The number of joints screened to detect one lesion was 20.1 joints for all patients, 4.4 joints for patients older than 10 years, and 198 joints for patients ≤ 10 years old (P < .001). Of the 40 extensive lesions in patients older than 10 years, 19 required total hip arthroplasty and none improved. Of eight extensive lesions in younger patients, none required arthroplasty and four improved. CONCLUSION In patients age 10 years old or younger who require prolonged glucocorticoid therapy, screening for extensive hip osteonecrosis is unnecessary because their risk is low and lesions tend to heal. In children older than 10 years, early screening successfully identifies extensive asymptomatic lesions in patients who would be eligible for studies of interventions to prevent or delay joint collapse.

Clofarabine salvage therapy for refractory high‐risk langerhans cell histiocytosis

Pediatric patients with refractory multisystem Langerhans cell histiocytosis (LCH) have a poor prognosis despite aggressive chemotherapy. Salvage therapy with cytarabine and cladribine has shown promise as an effective treatment but is associated with significant toxicity. A previous report described two patients with refractory LCH who had a rapid response to single‐agent clofarabine with minimal toxicity. In this report, we describe four children with refractory, risk‐organ‐positive LCH who were treated with clofarabine and provide follow‐up for the two previously reported cases. The results support development of a formal trial evaluating clofarabine as front‐line salvage for refractory LCH. Pediatr Blood Cancer 2013; 60: E19–E22.

Prognostic Impact of Absolute Lymphocyte Counts at the End of Remission Induction in Childhood Acute Lymphoblastic Leukemia

Absolute lymphocyte counts (ALC) during treatment have been associated with outcome in children and adults with hematologic malignancies. However, the impact of ALC relative to that of other prognostic factors on the outcome of children with acute lymphoblastic leukemia (ALL) treated in recent trials is unknown.

The Role of Leukapheresis in the Current Management of Hyperleukocytosis in Newly Diagnosed Childhood Acute Lymphoblastic Leukemia.

Hyperleukocytosis in children with acute lymphoblastic leukemia (ALL) has been associated with early morbidity and mortality. The use of leukapheresis in these children treated with contemporary therapy remains controversial.

CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions

Central nervous system Langerhans cell histiocytosis (CNS‐LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH‐ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS‐LCH.