Subsequent malignant neoplasms among children with Hodgkin lymphoma: a report from the Children's Oncology Group.

Survivors of Hodgkin lymphoma (HL) have an increased risk of subsequent malignant neoplasms (SMNs). Response-adapted treatment may decrease this risk by reducing exposure to therapy associated with SMN risk. The Children's Oncology Group study AHOD0031 evaluated response-adapted therapy for children and adolescents with intermediate-risk HL. We report the SMNs among 1711 patients enrolled in AHOD0031. Patients were treated with 4 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide with or without involved-field radiation therapy (RT). Patients with a slow early response to initial chemotherapy were randomized to 2 additional cycles of dexamethasone, etoposide, cisplatin and cytarabine or no additional chemotherapy, and all received RT. At a median follow-up of 7.3 years, an analysis of SMNs was performed. The 10-year cumulative incidence of SMN was 1.3% (95% confidence interval [CI], 0.6-2.0). SMNs included 3 patients with acute myeloid leukemia (AML), 11 with solid tumors, and 3 with non-Hodgkin lymphoma. Sixteen of 17 patients with an SMN had received combined modality therapy. The standardized incidence ratio for SMN was 9.5 (95% CI, 4.5-15.2) with an excess absolute risk of 1.2 per 1000 person-years. The cumulative incidence of SMNs was higher among patients who received RT (P = .037). In multivariate analysis, RT, B symptoms, and race were associated with SMN risk. Given the latency from exposure, we have likely captured all cases of secondary leukemia and myelodysplastic syndrome (MDS). Longer follow-up is needed to determine the risk of solid tumors. Avoidance of RT without sacrificing disease control should remain a goal for future therapeutic approaches. This trial was registered at www.clinicaltrials.gov as #NCT00025259.

Prognostic value of baseline metabolic tumor volume in children and adolescents with intermediate-risk Hodgkin lymphoma treated with chemo-radiation therapy: FDG-PET parameter analysis in a subgroup from COG AHOD0031.

BACKGROUND: Positron emission tomography (PET)-based measures of baseline total-body tumor burden may improve risk stratification in intermediate-risk Hodgkin lymphoma (HL). MATERIALS AND METHODS: Evaluable patients were identified from a cohort treated homogeneously with the same combined modality regimen on the Children's Oncology Group AHOD0031 study. Eligible patients had high-quality baseline PET scans. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were each measured based on 15 thresholds for every patient. Univariate and multivariable Cox regression and Kaplan-Meier survival analyses assessed for an association of MTV and TLG with event-free survival (EFS). RESULTS: From the AHOD0031 cohort (n = 1712), 86 patients were identified who (i) were treated with four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC) chemotherapy followed by involved field radiotherapy, and (ii) had a baseline PET scan that was amenable to quantitative analysis. Based on univariate Cox regression analysis, six PET-derived parameters were significantly associated with EFS. For each of these, Kaplan-Meier analyses and the log-rank test were used to compare patients with highest tumor burden (i.e., highest 15%) to the remainder of the cohort. EFS was significantly associated with all six PET parameters (all p < .029). In a multivariable model controlling for important covariates including disease bulk and response to chemotherapy, MTV2BP was significantly associated with EFS (p = .012). CONCLUSION: Multiple baseline PET-derived volumetric parameters were associated with EFS. MTV2BP was highly associated with EFS when controlling for disease bulk and response to chemotherapy. Incorporation of baseline MTV into risk-based treatment algorithms may improve outcomes in intermediate-risk HL.

Results of the AHOD0431 trial of response adapted therapy and a salvage strategy for limited stage, classical Hodgkin lymphoma: A report from the Children's Oncology Group.

BACKGROUND: The Children's Oncology Group AHOD0431 study evaluated a response-directed treatment paradigm in which minimal initial chemotherapy and low-dose radiation was received only by patients who did not achieve a complete remission, and a chemotherapy/low-dose radiation salvage regimen was received by those who had a protocol-defined, low-risk recurrence. METHODS: Patients younger than 21 years who had stage IA or IIA nonbulky disease were eligible. The treatment strategy was evaluated by determining the proportion that received minimal chemotherapy alone, the proportion that had a first or second remission without the receipt of high-dose chemotherapy/stem cell rescue or higher dose involved-field radiation therapy (>21 grays), and overall survival. RESULTS: In total, 278 patients were eligible. At 4 years, 49.0% had received minimal chemotherapy and no radiation, 88.8% were in remission without receiving high-dose chemotherapy with stem cell rescue or >21 grays of involved-field radiation therapy, and the overall survival rate was 99.6%. Patients who had mixed cellularity histology had a 4-year event-free survival (EFS) rate of 95.2%, which was significantly better than the 75.8% EFS for those who had nodular sclerosis histology (P = .008). A red blood cell sedimentation rate ≤20 mm/hour and a negative fluorodeoxyglucose-positron emission tomography scan after 1 cycle of chemotherapy (PET1) were associated with a favorable EFS outcome. The study was closed early when the receipt of radiation therapy exceeded the predefined monitoring boundary. CONCLUSIONS: This limited chemotherapy response-based approach was successful in patients who had a negative PET1 result, had MC histology, or had a low red blood cell sedimentation rate. In this treatment paradigm, evaluation of increased chemotherapy intensity or the integration of active new agents is indicated for patients who have nodular sclerosis histology with a high ESR or who have a positive PET1 result. Cancer 2018. © 2018 American Cancer Society.

Outcomes in intermediate-risk pediatric lymphocyte-predominant Hodgkin lymphoma: A report from the Children's Oncology Group.

PURPOSE: Optimal management of patients with intermediate-risk lymphocyte-predominant Hodgkin lymphoma (LPHL) is unclear due to their small numbers in most clinical trials. Children's Oncology Group AHOD0031, a randomized phase III trial of pediatric patients with intermediate-risk Hodgkin lymphoma (HL), included patients with LPHL. We report the outcomes of these patients and present directions for future therapeutic strategies. PROCEDURE: Patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) followed by response evaluation. Slow early responders were randomized to two additional ABVE-PC cycles ± two dexamethasone, etoposide, cisplatin, and cytarabine cycles and all received involved field radiotherapy (IFRT). Rapid early responders (RERs) received two additional ABVE-PC cycles. RERs with complete response (CR) were randomized to IFRT or no further therapy. RERs without CR received IFRT. RESULTS: Ninety-six (5.6%) of 1711 patients on AHOD0031 had LPHL. Patients with LPHL were more likely to achieve RER (93.6% vs. 81.0%; P = 0.002) and CR (74.2% vs. 49.3%; P = 0.000005) following chemotherapy compared with patients with classical HL. Five-year event-free survival (EFS) was superior in patients with LPHL (92.2%) versus classical HL (83.5%) (P = 0.04), without difference in overall survival (OS). Among RERs with CR following chemotherapy (n = 33), there was no difference in EFS or OS between those randomized to receive or not receive IFRT. CONCLUSION: Children and adolescents with intermediate-risk LPHL represent ideal candidates for response-adapted therapy based on their favorable outcomes. The majority of patients treated with the ABVE-PC backbone achieve RER with CR status and can be treated successfully without IFRT.

Variant histology, IgD and CD30 expression in low-risk pediatric nodular lymphocyte predominant Hodgkin lymphoma: A report from the Children's Oncology Group.

BACKGROUND: Histologic prognostic factors have been described for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). This study examines histologic and immunophenotypic variants in a clinical trial for pediatric NLPHL. PROCEDURE: One hundred sixty-eight cases of localized NLPHL were examined for histologic variants, CD30 and immunoglobulin D (IgD) expression, and outcome. Histologic types were scored categorically as 0 = 0, 1 ≤ 25%, and 2 > 25% of the sample. RESULTS: Fifty-eight (35.1%) cases showed only typical nodular with or without serpiginous histology (types A and B). The remainder showed mixtures of histologies. The numbers of patients with score 2 are 85 (50.6%) type A, 21 (12.5%) type B, 46 (27.4%) with extranodular large B cells (type C), 3 with T-cell-rich nodular pattern (type D), 55 (32.7%) with diffuse T-cell-rich (type E) pattern, and 2 (1.2%) with diffuse B-cell pattern (type F). Higher level of types C (P = 0.048) and D (P = 0.033) resulted in lower event-free survival (EFS). Cytoplasmic IgD was found in 65 of 130 tested (50%), did not significantly associate with EFS but positively correlated with types C and E histology (P < 0.0001) and negatively correlated with types A (P = 0.0003) and B (P = 0.006). Seventeen (10%) expressed CD30, with no adverse effect. CONCLUSIONS: Variant histology is common in pediatric NLPHL, especially types C and E, which are associated with IgD expression. Type C variant histology and possibly type D are associated with decreased EFS, but neither IgD nor CD30 are adverse features. Variant histology may warrant increased surveillance, but did not affect overall survival.

A phase 2 study of bortezomib in combination with ifosfamide/vinorelbine in paediatric patients and young adults with refractory/recurrent Hodgkin lymphoma: a Children's Oncology Group study.

A Children's Oncology Group clinical trial aimed to determine if bortezomib (B) increased the efficacy of ifosfamide and vinorelbine (IV) in paediatric Hodgkin lymphoma (HL). This study enrolled 26 relapsed HL patients (<30 years) treated with two to four cycles of IVB. The primary endpoint was anatomic complete response (CR) after two cycles. Secondary endpoints included overall response (OR: CR + partial response) at study completion compared to historical controls [72%; 95% confidence interval (CI): 59-83%]. Although few patients achieved the primary objective, OR with IVB improved to 83% (95% CI: 61-95%; p = 0.32). Although not statistically different, results suggest IVB may be a promising combination.

Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial.

BACKGROUND: Myeloablative chemoradiotherapy and immunomagnetically purged autologous bone marrow transplantation has been shown to improve outcome for patients with high-risk neuroblastoma. Currently, peripheral blood stem cells (PBSC) are infused after myeloablative therapy, but the effect of purging is unknown. We did a randomised study of tumour-selective PBSC purging in stem-cell transplantation for patients with high-risk neuroblastoma. METHODS: Between March 16, 2001, and Feb 24, 2006, children and young adults (<30 years) with high-risk neuroblastoma were randomly assigned at diagnosis by a web-based system (in a 1:1 ratio) to receive either non-purged or immunomagnetically purged PBSC. Randomisation was done in blocks stratified by International Neuroblastoma Staging System stage, age, MYCN status, and International Neuroblastoma Pathology classification. Patients and treating physicians were not masked to treatment assignment. All patients were treated with six cycles of induction chemotherapy, myeloablative consolidation, and radiation therapy to the primary tumour site plus meta-iodobenzylguanidine avid metastases present before myeloablative therapy, followed by oral isotretinoin. PBSC collection was done after two induction cycles. For purging, PBSC were mixed with carbonyl iron and phagocytic cells removed with samarium cobalt magnets. Remaining cells were mixed with immunomagnetic beads prepared with five monoclonal antibodies targeting neuroblastoma cell surface antigens and attached cells were removed using samarium cobalt magnets. Patients underwent autologous stem-cell transplantation with PBSC as randomly assigned after six cycles of induction therapy. The primary endpoint was event-free survival and was analysed by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT00004188. FINDINGS: 495 patients were enrolled, of whom 486 were randomly assigned to treatment: 243 patients to receive non-purged PBSC and 243 to received purged PBSC. PBSC were collected from 229 patients from the purged group and 236 patients from the non-purged group, and 180 patients from the purged group and 192 from the non-purged group received transplant. 5-year event-free survival was 40% (95% CI 33-46) in the purged group versus 36% (30-42) in the non-purged group (p=0·77); 5-year overall survival was 50% (95% CI 43-56) in the purged group compared with 51% (44-57) in the non-purged group (p=0·81). Toxic deaths occurred in 15 patients during induction (eight in the purged group and seven in the non-purged group) and 12 during consolidation (eight in the purged group and four in the non-purged group). The most common adverse event reported was grade 3 or worse stomatitis during both induction (87 of 242 patients in the purged group and 93 of 243 patients in the non-purged group) and consolidation (131 of 177 in the purged group vs 145 of 191 in the non-purged group). Serious adverse events during induction were grade 3 or higher decreased cardiac function (four of 242 in the purged group and five of 243 in the non-purged group) and elevated creatinine (five of 242 in the purged group and six of 243 non-purged group) and during consolidation were sinusoidal obstructive syndrome (12 of 177 in the purged group and 17 of 191 in the non-purged group), acute vascular leak (11 of 177 in the purged group and nine of 191 in the non-purged group), and decreased cardiac function (one of 177 in the purged group and four of 191 in the non-purged group). INTERPRETATION: Immunomagnetic purging of PBSC for autologous stem-cell transplantation did not improve outcome, perhaps because of incomplete purging or residual tumour in patients. Non-purged PBSC are acceptable for support of myeloablative therapy of high-risk neuroblastoma.

Vorinostat, temozolomide or bevacizumab with irradiation and maintenance BEV/TMZ in pediatric high-grade glioma: A Children's Oncology Group Study.

Background: Outcomes for children with high-grade gliomas (HGG) remain poor. This multicenter phase II trial evaluated whether concurrent use of vorinostat or bevacizumab with focal radiotherapy (RT) improved 1-year event-free survival (EFS) compared to temozolomide in children with newly diagnosed HGG who received maintenance temozolomide and bevacizumab. Methods: Patients ≥ 3 and < 22 years with localized, non-brainstem HGG were randomized to receive RT (dose 54-59.4Gy) with vorinostat, temozolomide, or bevacizumab followed by 12 cycles of bevacizumab and temozolomide maintenance therapy. Results: Among 90 patients randomized, the 1-year EFS for concurrent bevacizumab, vorinostat, or temozolomide with RT was 43.8% (±8.8%), 41.4% (±9.2%), and 59.3% (±9.5%), respectively, with no significant difference among treatment arms. Three- and five-year EFS for the entire cohort was 14.8% and 13.4%, respectively, with no significant EFS difference among the chemoradiotherapy arms. IDH mutations were associated with more favorable EFS (P = .03), whereas H3.3 K27M mutations (P = .0045) and alterations in PIK3CA or PTEN (P = .025) were associated with worse outcomes. Patients with telomerase- and alternative lengthening of telomeres (ALT)-negative tumors (n = 4) had an EFS of 100%, significantly greater than those with ALT or telomerase, or both (P = .002). While there was no difference in outcomes based on TERT expression, high TERC expression was associated with inferior survival independent of the telomere maintenance mechanism (P = .0012). Conclusions: Chemoradiotherapy with vorinostat or bevacizumab is not superior to temozolomide in children with newly diagnosed HGG. Patients with telomerase- and ALT-negative tumors had higher EFS suggesting that, if reproduced, mechanism of telomere maintenance should be considered in molecular-risk stratification in future studies.

Outcome after reduced chemotherapy for intermediate-risk neuroblastoma.

BACKGROUND: The survival rate among patients with intermediate-risk neuroblastoma who receive dose-intensive chemotherapy is excellent, but the survival rate among patients who receive reduced doses of chemotherapy for shorter periods of time is not known. METHODS: We conducted a prospective, phase 3, nonrandomized trial to determine whether a 3-year estimated overall survival of more than 90% could be maintained with reductions in the duration of therapy and drug doses, using a tumor biology-based therapy assignment. Eligible patients had newly diagnosed, intermediate-risk neuroblastoma without MYCN amplification; these patients included infants (<365 days of age) who had stage 3 or 4 disease, children (≥365 days of age) who had stage 3 tumors with favorable histopathological features, and infants who had stage 4S disease with a diploid DNA index or unfavorable histopathological features. Patients who had disease with favorable histopathological features and hyperdiploidy were assigned to four cycles of chemotherapy, and those with an incomplete response or either unfavorable feature were assigned to eight cycles. RESULTS: Between 1997 and 2005, a total of 479 eligible patients were enrolled in this trial (270 patients with stage 3 disease, 178 with stage 4 disease, and 31 with stage 4S disease). A total of 323 patients had tumors with favorable biologic features, and 141 had tumors with unfavorable biologic features. Ploidy, but not histopathological features, was significantly predictive of the outcome. Severe adverse events without disease progression occurred in 10 patients (2.1%), including secondary leukemia (in 3 patients), death from infection (in 3 patients), and death at surgery (in 4 patients). The 3-year estimate (±SE) of overall survival for the entire group was 96±1%, with an overall survival rate of 98±1% among patients who had tumors with favorable biologic features and 93±2% among patients who had tumors with unfavorable biologic features. CONCLUSIONS: A very high rate of survival among patients with intermediate-risk neuroblastoma was achieved with a biologically based treatment assignment involving a substantially reduced duration of chemotherapy and reduced doses of chemotherapeutic agents as compared with the regimens used in earlier trials. These data provide support for further reduction in chemotherapy with more refined risk stratification. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003093.)

Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma.

BACKGROUND: Preclinical and preliminary clinical data indicate that ch14.18, a monoclonal antibody against the tumor-associated disialoganglioside GD2, has activity against neuroblastoma and that such activity is enhanced when ch14.18 is combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-2. We conducted a study to determine whether adding ch14.18, GM-CSF, and interleukin-2 to standard isotretinoin therapy after intensive multimodal therapy would improve outcomes in high-risk neuroblastoma. METHODS: Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive standard therapy (six cycles of isotretinoin) or immunotherapy (six cycles of isotretinoin and five concomitant cycles of ch14.18 in combination with alternating GM-CSF and interleukin-2). Event-free survival and overall survival were compared between the immunotherapy group and the standard-therapy group, on an intention-to-treat basis. RESULTS: A total of 226 eligible patients were randomly assigned to a treatment group. In the immunotherapy group, a total of 52% of patients had pain of grade 3, 4, or 5, and 23% and 25% of patients had capillary leak syndrome and hypersensitivity reactions, respectively. With 61% of the number of expected events observed, the study met the criteria for early stopping owing to efficacy. The median duration of follow-up was 2.1 years. Immunotherapy was superior to standard therapy with regard to rates of event-free survival (66±5% vs. 46±5% at 2 years, P=0.01) and overall survival (86±4% vs. 75±5% at 2 years, P=0.02 without adjustment for interim analyses). CONCLUSIONS: Immunotherapy with ch14.18, GM-CSF, and interleukin-2 was associated with a significantly improved outcome as compared with standard therapy in patients with high-risk neuroblastoma. (Funded by the National Institutes of Health and the Food and Drug Administration; ClinicalTrials.gov number, NCT00026312.)

Phase II Randomized Trial of Lenalidomide in Children With Pilocytic Astrocytomas and Optic Pathway Gliomas: A Report From the Children's Oncology Group.

PURPOSE: Children with low-grade glioma often require long-term therapy and suffer from treatment morbidity. Although targeted agents are promising, tumor targets often encompass normal developmental pathways and long-term effects of inhibition are unknown. Lenalidomide is an immunomodulatory agent with wide-ranging properties. Phase I studies indicated greater tolerability of lenalidomide in children compared with adults and a potential dose-response effect. PATIENTS AND METHODS: We performed a phase II trial of lenalidomide in children with pilocytic astrocytomas and optic pathway gliomas who failed initial therapy. Primary objectives included determination of objective response rate of children randomly assigned to regimen A, low-dose (20 mg/m2/dose), or regimen B, high-dose (115 mg/m2/dose) lenalidomide, and assessment for early progression. Secondary objectives included estimation of event-free survival, overall survival, incidence of toxic events, and assessment of plasma lenalidomide concentrations. Lenalidomide was administered once daily × 21 days of each 28-day cycle for each regimen. RESULTS: Seventy-four eligible patients were enrolled (n = 37, each arm). The predefined activity level of interest was achieved for both arms. Four objective responses were observed in each arm, and the number of early progressors was low. Eighteen patients completed 26 cycles of therapy (regimen A, n = 12; regimen B, n = 6). The median number of cycles was 14 (range, 2-26) for regimen A and 11 for regimen B (range, 1-26). Of 74 eligible patients who received study drug, 30 required dose reduction for toxicity (regimen A, n = 6; regimen B, n = 24) and 16 discontinued because of toxicity (regimen A, n = 2; regimen B, n = 14). CONCLUSION: Lenalidomide demonstrates a sufficient level of activity in children with low-grade glioma to warrant further exploration. Low-dose (20 mg/m2/dose administered once daily × 21 days of each 28-day cycle) lenalidomide appears to have better tolerability with comparable activity.

Long-Term Outcomes in Patients With Localized Ewing Sarcoma Treated With Interval-Compressed Chemotherapy on Children's Oncology Group Study AEWS0031.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Long-term outcomes from Children's Oncology Group study AEWS0031 were assessed to determine whether the survival advantage of interval-compressed chemotherapy (ICC) was maintained over 10 years in patients with localized Ewing sarcoma (ES). AEWS0031 enrolled 568 eligible patients. Patients were randomly assigned to receive vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide alternating once every 3 weeks (standard timing chemotherapy [STC]) versus once every 2 weeks (ICC). For this updated report, one patient was excluded because of uncertainty of original diagnosis. The 10-year event-free survival (EFS) was 70% with ICC compared with 61% with STC (P = .03), and 10-year overall survival (OS) was 76% with ICC compared with 69% with STC (P = .04). There was no difference in the 10-year cumulative incidence of second malignant neoplasms (SMNs; PC [see Data Supplement, online only] = .5). A test for interaction demonstrated that ICC provided greater risk reduction for patients with tumor volume ≥200 mL than for patients with tumors <200 mL, but no evidence for a significant interaction in other subgroups defined by age, primary site, and histologic response. With longer-term follow-up, ICC for localized ES is associated with superior EFS and OS without an increased risk for SMN compared with STC. ICC is associated with improved outcomes even in adverse-risk patient groups.

Randomized Phase III Trial of Ganitumab With Interval-Compressed Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma: A Report From the Children's Oncology Group.

PURPOSE: Monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) have shown activity in patients with relapsed Ewing sarcoma. The primary objective of Children's Oncology Group trial AEWS1221 was to determine if the addition of the IGF-1R monoclonal antibody ganitumab to interval-compressed chemotherapy improves event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma. METHODS: Patients were randomly assigned 1:1 at enrollment to standard arm (interval-compressed vincristine/doxorubicin/cyclophosphamide alternating once every 2 weeks with ifosfamide/etoposide = VDC/IE) or to experimental arm (VDC/IE with ganitumab at cycle starts and as monotherapy once every 3 weeks for 6 months after conventional therapy). A planned sample size of 300 patients was projected to provide 81% power to detect an EFS hazard ratio of 0.67 or smaller for the experimental arm compared with the standard arm with a one-sided α of .025. RESULTS: Two hundred ninety-eight eligible patients enrolled (148 in standard arm; 150 in experimental arm). The 3-year EFS estimates were 37.4% (95% CI, 29.3 to 45.5) for the standard arm and 39.1% (95% CI, 31.3 to 46.7) for the experimental arm (stratified EFS-event hazard ratio for experimental arm 1.00; 95% CI, 0.76 to 1.33; 1-sided, P = .50). The 3-year overall survival estimates were 59.5% (95% CI, 50.8 to 67.3) for the standard arm and 56.7% (95% CI, 48.3 to 64.2) for the experimental arm. More cases of pneumonitis after radiation involving thoracic fields and nominally higher rates of febrile neutropenia and ALT elevation were reported on the experimental arm. CONCLUSION: Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of EFS event in patients with newly diagnosed metastatic Ewing sarcoma, with outcomes similar to prior trials without IGF-1R inhibition or interval compression. The addition of ganitumab may be associated with increased toxicity.

Impact of low-dose involved-field radiation therapy on pediatric patients with lymphocyte-predominant Hodgkin lymphoma treated with chemotherapy: a report from the Children's Oncology Group.

BACKGROUND: Treatment of pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) is controversial but has typically consisted of both chemotherapy and radiation. Radiation therapy is associated with potential late effects in children and adolescents. We examined the impact of radiation therapy on long-term outcome of patients with LPHL treated on CCG-5942, a large pediatric cooperative group study of Hodgkin lymphoma (HL). PROCEDURE: Eighty-two patients with LPHL were registered on CCG-5942. Fifty-two patients (63%) received chemotherapy alone; 29 patients (35%) received chemotherapy followed by involved-field radiation therapy (IFRT). RESULTS: The median follow-up of the LPHL patients is 7.7 years; 63 patients (77%) have >5 years of follow-up. The 5-year event-free survival (EFS) and overall survival (OS) were 97% and 100%. Two relapses occurred, both in patients who did not receive IFRT. There were no significant differences in EFS or OS between patients who received or did not receive IFRT. CONCLUSIONS: This subset analysis demonstrates the chemosensitivity of pediatric LPHL. Patients who had a complete response to chemotherapy had an excellent EFS and OS without the addition of radiotherapy.

Life-threatening and fatal infections in children with acute myeloid leukemia: a report from the Children's Oncology Group.

To determine among children with acute myeloid leukemia, whether the proportions of life-threatening or fatal infections differed according to the intensity of induction or type of intensification treatment. Participants were children enrolled to the Children's Cancer Group (CCG) 2891 with de novo acute myeloid leukemia. In phase 1 (induction) patients were randomized to 4 cycles of chemotherapy either administered as intensive or standard timing. In phase 2 (intensification), those achieving remission were allocated to allogeneic stem cell transplantation (SCT) if a suitable family donor was available while the remainder were randomized to autologous SCT or chemotherapy. Each infection was classified prospectively as nonlife-threatening, life-threatening, or fatal. The proportion of all infections that were considered life-threatening or fatal was higher with intensive timing compared with standard timing induction (60.3% vs. 37.3%, P<0.0001). Infections caused by Gram-positive and Gram-negative bacteria and fungi were significantly more likely to be severe during intensive compared with standard timing induction. Most molds were life-threatening or fatal. Chemotherapy intensification was not associated with less severe infections compared with SCT. Intensive timing was associated with more severe infections compared with standard timing induction. Prophylactic strategies are likely more important with intensive induction regimens.

Phase I/II trial of vorinostat and radiation and maintenance vorinostat in children with diffuse intrinsic pontine glioma: A Children's Oncology Group report.

BACKGROUND: A phase I/II trial of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor, was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) through the Children's Oncology Group (COG) to: 1) determine the recommended phase II dose (RP2D) of vorinostat given concurrently with radiation therapy; 2) document the toxicities of continuing vorinostat as maintenance therapy after radiation; and 3) to determine the efficacy of this regimen by comparing the risk of progression or death with a historical model from past COG trials. METHODS: Vorinostat was given once daily, Monday through Friday, during radiation therapy (54 Gy in 30 fractions), and then continued at 230 mg/m2 daily for a maximum of twelve 28-day cycles. RESULTS: Twelve patients enrolled in the phase I study; the RP2D of vorinostat given concurrently with radiation was 230 mg/m2/day, Monday through Friday weekly. The six patients enrolled at the RP2D and an additional 64 patients enrolled in the phase II study contributed to the efficacy assessment. Although vorinostat was well-tolerated, did not interrupt radiation therapy, and was permanently discontinued in only 8.6% of patients due to toxicities, risk for EFS-event was not significantly reduced compared with the target risk derived from historical COG data (P = 0.32; 1-sided). The 1-year EFS was 5.85% (95% CI 1.89-13.1%) and 1-year OS was 39.2% (27.8-50.5%). CONCLUSIONS: Vorinostat given concurrently with radiation followed by vorinostat monotherapy was well tolerated in children with newly diagnosed DIPG but failed to improve outcome.

Phase 2 study of anti-disialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma: A report from the Children's Oncology Group.

PURPOSE: Novel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease control rate (DCR) in patients with recurrent osteosarcoma treated with the anti-GD2 antibody dinutuximab plus cytokine therapy as compared to historical outcomes. METHODS: AOST1421 was a single-arm Phase 2 study for patients with recurrent pulmonary osteosarcoma in complete surgical remission. Patients received up to five cycles of dinutuximab (70 mg/m2/cycle) with granulocyte-macrophage colony-stimulating factor (GM-CSF). Two different dinutuximab infusion schedules were studied: 35 mg/m2/day over 20 h (2 days) and 17.5 mg/m2/day over 10 h (4 days). Primary end point was DCR, defined as a proportion of patients event free at 12 months from enrolment. The historical benchmark was 12-month DCR of 20% (95% CI 10-34%). Dinutuximab would be considered effective if ≥ 16/39 patients remained event free. Secondary objectives included toxicity evaluation and pharmacokinetics. RESULTS: Thirty-nine eligible patients were included in the outcome analysis. Dinutuximab did not demonstrate evidence of efficacy as 11/39 patients remained event free for a DCR of 28.2% (95% CI 15-44.9%). One of 136 administered therapy cycles met criteria for unacceptable toxicity when a patient experienced sudden death of unknown cause. Other ≥ Grade 3 toxicities included pain, diarrhoea, hypoxia, and hypotension. Pharmacokinetic parameters were similar in the two schedules. CONCLUSIONS: The combination of dinutuximab with GM-CSF did not significantly improve DCR in recurrent osteosarcoma. Dinutuximab toxicity and pharmacokinetics in adolescent and young adult osteosarcoma patients were similar to younger patients. Other strategies for targeting GD2 in osteosarcoma are being developed.

Patterns of Translocation Testing in Patients Enrolling in a Cooperative Group Trial for Newly Diagnosed Metastatic Ewing Sarcoma.

CONTEXT.­: Molecular diagnostics play an increasing role in the diagnosis of Ewing sarcoma. The type of molecular testing used in clinical practice has been poorly described. OBJECTIVE.­: To describe patterns of translocation testing for newly diagnosed Ewing sarcoma. DESIGN.­: Children's Oncology Group (COG) trial AEWS1221 was a phase III randomized trial enrolling patients with newly diagnosed metastatic Ewing sarcoma from 2014 to 2019. Patients were required to have a histologic diagnosis of Ewing sarcoma, but translocation testing was not required. Sites provided types and results of any molecular diagnostics performed. RESULTS.­: Data from 305 enrolled patients were available. The most common type of molecular testing was fluorescence in situ hybridization (FISH) performed on the primary tumor (236 of 305 patients; 77.4%), with positive testing for an EWSR1 or FUS translocation in 211 (89.4%). Reverse transcription-polymerase chain reaction (RT-PCR) on the primary tumor was performed in 61 of 305 patients (20%), with positive results in 48 of 61 patients (78.7%). Next-generation sequencing was reported in 7 patients for the primary tumor and in 3 patients for metastatic sites. For all types of testing on either primary or metastatic tumor, 16 of 305 patients (5.2%) had no reported translocation testing. When evaluating all results from all testing, 44 of 305 patients (14.4%) lacked documentation of an abnormality consistent with a molecular diagnosis of Ewing sarcoma. CONCLUSIONS.­: COG sites enrolling in a Ewing sarcoma trial have high rates of testing by FISH or PCR. A small proportion of patients have no translocation testing on either primary or metastatic sites. Next-generation sequencing techniques are not yet commonly used in this context.

Phase III Trial Adding Vincristine-Topotecan-Cyclophosphamide to the Initial Treatment of Patients With Nonmetastatic Ewing Sarcoma: A Children's Oncology Group Report.

PURPOSE: The primary aim of this phase III randomized trial was to test whether the addition of vincristine, topotecan, and cyclophosphamide (VTC) to interval compressed chemotherapy improved survival outcomes for patients with previously untreated nonmetastatic Ewing sarcoma. METHODS: Patients were randomly assigned to receive standard five-drug interval compressed chemotherapy (regimen A) for 17 cycles or experimental therapy with five cycles of VTC within the 17 cycles (regimen B). Patients were stratified by age at diagnosis (< 18 years and ≥18 years) and tumor site (pelvic bone, nonpelvic bone, and extraosseous). Tumor volume at diagnosis was categorized as < 200 mL or ≥ 200 mL. Local control occurred following six cycles. Histologic response was categorized as no viable or any viable tumor. Event-free survival (EFS) and overall survival (OS) were compared between randomized groups with stratified log-rank tests. RESULTS: Of 642 enrolled patients, 309 eligible patients received standard and 320 received experimental therapy. The 5-year EFS and OS were 78% and 87%, respectively. There was no difference in survival outcomes between randomized groups (5-year EFS regimen A v regimen B, 78% v 79%; P = .192; 5-year OS 86% v 88%; P = .159). Age and primary site did not affect the risk of an EFS event. However, age ≥ 18 years was associated with an increased risk of death at 5 years (hazard ratio 1.84; 95% CI, 1.15 to 2.96; P = .009). The 5-year EFS rates for patients with pelvic, nonpelvic bone, and extraosseous primary tumors were 75%, 78%, and 85%, respectively. Tumor volume ≥ 200 mL was significantly associated with lower EFS. CONCLUSION: While VTC added to five-drug interval compressed chemotherapy did not improve survival, these outcomes represent the best survival estimates to date for patients with previously untreated nonmetastatic Ewing sarcoma.