Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR). METHODS: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months). RESULTS: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival. CONCLUSION: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.

Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries.

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.

Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial.

The Children's Cancer Group 1952 (CCG-1952) clinical trial studied the substitution of oral 6-thioguanine (TG) for 6-mercaptopurine (MP) and triple intrathecal therapy (ITT) for intrathecal methotrexate (IT-MTX) in the treatment of standard-risk acute lymphoblastic leukemia. After remission induction, 2027 patients were randomized to receive MP (n = 1010) or TG (n = 1017) and IT-MTX (n = 1018) or ITT (n = 1009). The results of the thiopurine comparison are as follows. The estimated 7-year event-free survival (EFS) for subjects randomized to TG was 84.1% (+/- 1.8%) and to MP was 79.0% (+/- 2.1%; P = .004 log rank), although overall survival was 91.9% (+/- 1.4%) and 91.2% (+/- 1.5%), respectively (P = .6 log rank). The TG starting dose was reduced from 60 to 50 mg/m(2) per day after recognition of hepatic veno-occlusive disease (VOD). A total of 257 patients on TG (25%) developed VOD or disproportionate thrombocytopenia and switched to MP. Once portal hypertension occurred, all subjects on TG were changed to MP. The benefit of randomization to TG over MP, as measured by EFS, was evident primarily in boys who began TG at 60 mg/m(2) (relative hazard rate [RHR] 0.65, P = .002). The toxicities of TG preclude its protracted use as given in this study. This study is registered at http://clinicaltrials.gov as NCT00002744.

Unusual manifestations of astroblastoma: a radiologic-pathologic analysis.

Astroblastoma is a very rare primary glial tumor occurring in children and young adults that is almost exclusively supratentorial in location. We report an extremely unusual presentation of a densely calcified posterior fossa astroblastoma with disseminated spinal and supratentorial metastasis. The mass exhibited neoplastic bone formation, which has not been reported, although calcifications are commonly seen in astroblastomas. A companion case of a low-grade astroblastoma that demonstrated classic histologic features but nonspecific and atypical imaging findings is also included. These cases expand the imaging and pathologic spectrum of this controversial tumor that shows highly variable biologic behavior and is difficult to distinguish from ependymoma.

Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: results of the Children's Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children's Oncology Group.

The Children's Cancer Group (CCG) 1952 clinical trial for children with standard-risk acute lymphoblastic leukemia (SR-ALL) compared intrathecal (IT) methotrexate (MTX) with IT triples (ITT) (MTX, cytarabine, and hydrocortisone sodium succinate [HSS]) as presymptomatic central nervous system (CNS) treatment. Following remission induction, 1018 patients were randomized to receive IT MTX and 1009 ITT. Multivariate analysis identified male sex, hepatomegaly, CNS-2 status, and age younger than 2 or older than 6 years as significant predictors of isolated CNS (iCNS) relapse. The 6-year cumulative incidence estimates of iCNS relapse are 3.4% +/- 1.0% for ITT and 5.9% +/- 1.2% for IT MTX; P = .004. Significantly more relapses occurred in bone marrow (BM) and testicles with ITT than IT MTX, particularly among patients with T-cell phenotype or day 14 BM aspirate containing 5% to 25% blasts. Thus, the estimated 6-year event-free survivals (EFS) with ITT or IT MTX are equivalent at 80.7% +/- 1.9% and 82.5% +/- 1.8%, respectively (P = .3). Because the salvage rate after BM relapse is inferior to that after CNS relapse, the 6-year overall survival (OS) for ITT is 90.3% +/- 1.5% versus 94.4% +/- 1.1% for IT MTX (P = .01). It appears that ITT improves presymptomatic CNS treatment but does not improve overall outcome.

Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group.

PURPOSE: To evaluate response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors and to estimate control intervals without irradiation in children with no residual tumor after initial surgery and induction chemotherapy and with delayed irradiation in patients with residual tumor or metastatic disease at diagnosis. PATIENTS AND METHODS: Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide). Maintenance chemotherapy began after induction in children without progressive disease. Children with no residual tumors after induction therapy and no metastatic disease at diagnosis were not to receive radiation therapy unless their tumors progressed. RESULTS: Two hundred ninety-nine infants were enrolled. Forty-two percent of patients responded to induction chemotherapy. At 5 years from study entry, the EFS rate was 27% +/- 3%, and the survival rate was 43% +/- 3%. There was no significant difference between the two arms in terms of response rate or EFS. For medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, and rhabdoid tumors, 5-year EFS rates were 32% +/- 5%, 17% +/- 6%, and 32% +/- 6%, and 14% +/- 7%, respectively. Fifty-eight percent of patients who were alive 5 years after study entry had not received radiation therapy. CONCLUSION: Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.

Portal hypertension develops in a subset of children with standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance therapy.

BACKGROUND: 6-Thioguanine (TG) was recently studied to determine whether TG in maintenance therapy achieves better event free survival than 6-mercaptopurine (MP) for standard risk acute lymphoblastic leukemia (ALL) on the clinical trial, CCG-1952 (5/1996-1/2000). Veno-occlusive disease was previously recognized as a complication of TG on CCG-1952. We report a newly recognized pediatric complication of TG: splenomegaly and portal hypertension (PH) developing during maintenance or after completion of therapy. PROCEDURE: Twelve patients (3-10 years) had been randomized to receive a targeted dose of 50 mg/m(2)/day of TG during maintenance phases. Actual TG dose ranged from 25 to 77 mg/m(2)/day (median 34 mg/m(2)/day). RESULTS: The initial patient, a boy who had marked thrombocytopenia and intermittent splenomegaly during maintenance therapy, was evaluated for persistent pancytopenia and progressive splenomegaly 3 months after completion of therapy. Dilated splenic vein and collaterals consistent with PH were documented by MRI/MRA. Esophagogastroduodenoscopy found esophageal varices. Liver biopsy showed periportal fibrosis and marked dilatation of veins and venules. Of the other 12 patients, 9 patients studied had abnormal MRI/MRAs with evidence of varices in 4. Eight patients had splenomegaly on physical examination. Liver biopsies in a girl after 3.3 courses of TG and a boy after 4.6 courses of TG showed periportal fibrosis and dilatation of venules and sinusoids and minimal focal fatty changes. Subsequent MRI/MRAs have been stable or improved. CONCLUSIONS: The evaluations of these 12 patients suggest that treatment with TG causes injury to the liver leading to PH and that thrombocytopenia and splenomegaly are clinical hallmarks of this toxicity.

Epstein-Barr virus-associated lymphoma in a child undergoing an autologous stem cell rescue.

Epstein-Barr virus-associated lymphoproliferative disease (EBV-LPD) is a serious disorder seen in various states of immunodeficiency, often with a fatal outcome. In this article, a patient with EBV-lymphoma after autologous stem cell rescue for treatment of a nonhematologic solid tumor is described. The child, a 4-year-old boy, had unilateral retinoblastoma with metastatic spread to the central nervous system. He had previously received both local tumor bed and craniospinal radiation therapy together with intensive myeloablative alkylator chemotherapy before autologous stem cell rescue. Histologically confirmed lymphoma with evidence of active EBV proliferation developed within cervical lymph nodes 3 weeks after his first autologous stem cell rescue. A complete clinical remission of the lymphadenopathy was obtained after infusions of rituximab (an anti-CD20 monoclonal antibody), acyclovir, and high-titer anticytomegalovirus immunoglobulin. The patient died approximately 6 months later of persistent and progressive retinoblastoma without any clinical evidence of lymphoma. It is concluded that EBV-LPD should be included in the differential diagnosis in patients in whom lymphadenopathy develops after autologous stem cell rescue.