Julie R. Park

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.

A phase I study of zoledronic acid and low‐dose cyclophosphamide in recurrent/refractory neuroblastoma: A new approaches to neuroblastoma therapy (NANT) study

Zoledronic acid, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone is a common metastatic site of advanced neuroblastoma. We previously reported efficacy of zoledronic acid in a murine model of neuroblastoma bone invasion prompting this Phase I trial of zoledronic acid with cyclophosphamide in children with neuroblastoma and bone metastases. The primary objective was to determine recommended dosing of zoledronic acid for future trials.

Toxicity and efficacy of intensive chemotherapy for children with acute lymphoblastic leukemia (ALL) after first bone marrow or extramedullary relapse

Approximately 25% of children newly diagnosed with acute lymphoblastic leukemia (ALL) will eventually experience leukemic relapse, with bone marrow being the most common site of recurrence. The ability to achieve a durable second remission is complicated by toxicity and resistant disease. We report a novel combination of chemotherapy for relapsed pediatric ALL.

Growth plate abnormalities in pediatric cancer patients undergoing phase 1 anti‐angiogenic therapy: A report from the children's oncology group phase I consortium

Pre‐clinical studies suggest that anti‐angiogenic agents may be toxic to the developing growth plate. The purpose of this study was to evaluate the incidence of growth plate abnormalities in children with refractory cancer undergoing anti‐angiogenic therapy.

Significance of clinical and biologic features in Stage 3 neuroblastoma: A report from the International Neuroblastoma Risk Group project

International Neuroblastoma Staging System (INSS) Stage 3 neuroblastoma is a heterogeneous disease. Data from the International Neuroblastoma Risk Group (INRG) database were analyzed to define patient and tumor characteristics predictive of outcome.

Time to disease progression in children with relapsed or refractory neuroblastoma treated with ABT‐751: A report from the Children's Oncology Group (ANBL0621)

ABT‐751, an orally bioavailable sulfonamide binds the colchicine site of beta‐tubulin and inhibits microtubule polymerizaton. Prior phase I studies established the recommended dose in children with solid tumors as 200 mg/m2 PO daily × 7 days every 21 days and subjects with neuroblastoma experienced prolonged stable disease. We conducted a phase 2 study (NCT00436852) in children and adolescents with progressive neuroblastoma to determine if ABT‐751 prolonged the time to progression (TTP) compared to a hypothesized standard based on a historical control population.

When Life Expectancy is Not Short Enough: A Perspective on the National Institute for Health and Care Excellence (NICE) Preliminary Guidance for Dinutuximab

OnNovember 5, 2015, the United Kingdom’s National Institute for Health and Care Excellence (NICE) issued its preliminary guidance to not recommend dinutuximab (Unituxin, ch. 14.18) for the treatment of children with high-risk neuroblastoma.[1] As a final decision to be rendered in 2016 could have a significant impact for children with high-risk neuroblastoma in the United Kingdom, along with a potential impact on the development of cancer drugs for children with cancer in general, we believe it is important to offer a perspective onNICE’s preliminary findings. The treatment for children with high-risk neuroblastoma is among the most intensive regimens administered to children with cancer and involves multiagent chemotherapy, surgery, external beam radiotherapy, myeloablative consolidation with autologous hematopoietic stem cell recue, and administration of biologic agents. Despite the progressive increase in treatment intensity over the past two decades, only approximately 50%of patients with newly diagnosed high-risk neuroblastoma, and well less than 10% of patients whose disease recurs, will survive.[2–4] Dinutuximab, a chimeric human–murine anti-GD2monoclonal antibody, was initially developed and studied by the Children’s Oncology Group (COG) through collaboration and with support from the United State’s National Cancer Institute (NCI). The original findings of a randomized clinical trial in children with high-risk neuroblastoma found that 2-year eventfree survival in children treated with dinutuximab combined with interleukin-2 (IL-2) and granulocyte-macrophage colonystimulating factor (GM-CSF) with standard maintenance therapy (isotretinoin) was superior to standard therapy (2-year EFS 66 ± 5% vs. 46 ± 5%).[5] The NCI and COG then partnered withUnited Therapeutics Corporation to conduct additional research that allowed the drug to ultimately be approved by the Food and Drug Administration and the European Medicines Agency (EMA). In the COG, dinutuximab is now considered as a part of standard therapy for most children with high-risk neuroblastoma. Appraisal Committees and Evidence Review Groups (ERG) of NICE are charged with the difficult task of advising on the clinical and cost effectiveness of new drugs. The consultation document for dinutuximab details the Appraisal Committee’s initial assessment that concluded that the drug is “not recommended within its marketing authorization, for treating high-risk neuroblastoma in children and young people... .”[1] While we disagree with certain components of the Committee’s analysis, our focus here is on whether the approach and standards utilized by the Committee are, in fact, appropriate for children with cancer or other life-threatening illnesses. In 2014, as a part of the drug approval process in Europe, the EMA asked United Therapeutics and COG for an updated survival analysis 4 years after randomization had ended and publication of the primary results had occurred. The fact that such data were readily available reflects the commitment of the academic pediatric cancer community to continue to follow patients for many years following original diagnosis. The 2014 results, which were not part of the original statistical design and thus not necessarily powered to answer the question posed, found a smaller event-free survival advantage (59.3% vs. 48.3%, P = 0.15) and overall survival advantage (75.1% vs. 61.0%, P = 0.03) for children who had received dinutuximab, IL-2, and GM-CSF. After undertaking a number of sophisticated modeling approaches, the ERG found that “for overall survival, the proportion of patients cured was 66% in the dinutuximab arm and 48.8% in the isotretinoin arm, suggesting that the dinutuximab regimen delays and possibly prevents mortality.”[1] Moreover, using its preferred assumptions, the ERG concluded, “1.97 incremental life years ... were gained for the dinutuximab regimen compared with isotretinoin alone.” However, when taking many factors into account, the Committee found that the cost of quality adjusted life years associated with dinutuximab did not meet the cost-effective standards for use of National Health Services (NHS) resources. NICE does offer flexibility to Appraisal Committees when considering treatments that may extend the life of patients with a short life expectancy. For such advice to be applied, however, the following three criteria must be met[6]: “(i) The treatment is indicated for patients with a short life expectancy, normally less than 24 months. (ii) There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment. (iii) The treatment is licensed or otherwise indicated for small patient populations.” Dinutuximab readily met the second and third criteria. Quite remarkably, it failed on the criterion for shortened life expectancy. Children with high-risk neuroblastoma treated on the control arm of the study have a median life expectancy of

Validation of Postinduction Curie Scores in High-Risk Neuroblastoma: A Children’s Oncology Group and SIOPEN Group Report on SIOPEN/HR-NBL1

A semiquantitative 123I-metaiodobenzylguanidine (123I-MIBG) scoring method (the Curie score, or CS) was previously examined in the Children’s Oncology Group (COG) high-risk neuroblastoma trial, COG A3973, with a postinduction CS of more than 2 being associated with poor event-free survival (EFS). The validation of the CS in an independent dataset, International Society of Paediatric Oncology European Neuroblastoma/High-Risk Neuroblastoma 1 (SIOPEN/HR-NBL1), is now reported. Methods: A retrospective analysis of 123I-MIBG scans obtained from patients who had been prospectively enrolled in SIOPEN/HR-NBL1 was performed. All patients exhibited 123I-MIBG–avid, International Neuroblastoma Staging System stage 4 neuroblastoma. 123I-MIBG scans were evaluated at 2 time points, diagnosis (n = 345) and postinduction (n = 330), before consolidation myeloablative therapy. Scans of 10 anatomic regions were evaluated, with each region being scored 0–3 on the basis of disease extent and a cumulative CS generated. Cut points for outcome analysis were identified by Youden methodology. CSs from patients enrolled in COG A3973 were used for comparison. Results: The optimal cut point for CS at diagnosis was 12 in SIOPEN/HR-NBL1, with a significant outcome difference by CS noted (5-y EFS, 43.0% ± 5.7% [CS ≤ 12] vs. 21.4% ± 3.6% [CS > 12], P < 0.0001). The optimal CS cut point after induction was 2 in SIOPEN/HR-NBL1, with a postinduction CS of more than 2 being associated with an inferior outcome (5-y EFS, 39.2% ± 4.7% [CS ≤ 2] vs. 16.4% ± 4.2% [CS > 2], P < 0.0001). The postinduction CS maintained independent statistical significance in Cox models when adjusted for the covariates of age and MYCN gene copy number. Conclusion: The prognostic significance of postinduction CSs has now been validated in an independent cohort of patients (SIOPEN/HR-NBL1), with a postinduction CS of more than 2 being associated with an inferior outcome in 2 independent large, cooperative group trials.

Intravenous immunoglobulin with prednisone and risk-adapted chemotherapy for children with opsoclonus myoclonus ataxia syndrome associated with neuroblastoma (ANBL00P3): a randomised, open-label, phase 3 trial

Purpose No previous clinical trial has been conducted for patients with neuroblastoma associated opsoclonus myoclonus ataxia syndrome (OMA), and current treatment is based on case reports. To evaluate the OMA response to prednisone and risk-adapted chemotherapy and determine if the addition of intravenous gammaglobulin (IVIG) further improves response, the Children’s Oncology Group designed a randomized therapeutic trial. Patient and Methods Eligible subjects were randomized to receive twelve cycles of IVIG (IVIG+) or no IVIG (NO-IVIG) in addition to prednisone and neuroblastoma risk-adapted chemotherapy. All low-risk patients were treated with cyclophosphamide. The severity of OMA symptoms was evaluated at 2, 6, and 12 months using a scale developed by Mitchell and Pike and baseline versus best response scores were compared. A single patient who did not undergo neurologic assessment was excluded from OMA response analysis. This study is registered with Clinical Trials.gov (identifier NCT00033293). Results Of the 53 patients enrolled in the study, 62% (33/53) were female. There were 44 low-risk, 7 intermediate-risk, and 2 high-risk neuroblastoma patients. Twenty-six subjects were randomized to receive IVIG+ and 27 were randomized to NO-IVIG. The neuroblastoma 3-year event-free survival (95% confidence interval (CI)) was 94.1% (87.3%, 100%) and overall survival was 98.0% (94.1%, 100%). Significantly higher rates of OMA response were observed in patients randomized to IVIG+ compared to NO-IVIG [21/26=80.8% for IVIG+; 11/27=40.7% for NO-IVIG (odds ratio=6.1; 95% CI: (1.5, 25.9), p=0.0029)]. For the majority of patients, the IVIG+ OMA regimen combined with cytoxan or other risk-based chemotherapy was well tolerated, although there was one toxic death in a high-risk subject. Conclusion This is the only randomized prospective therapeutic clinical trial in children with neuroblastoma-associated OMA. The addition of IVIG to prednisone and risk-adapted chemotherapy significantly improves OMA response rate. IVIG+ constitutes a back-bone upon which to build additional therapy.

About the Benefits of Immunotherapy for High-Risk Neuroblastoma

porting the Memorial Sloan-Kettering Cancer Centers institutional experience using immunotherapy for the treatment of high-risk neuroblastoma. There is an unmet need to develop novel ther- apies for children with neuroblastoma, and the longstanding efforts of the Memorial Sloan-Kettering Cancer Center team in developing immunotherapy approaches over the last three de- cades should be commended. The article 1 presents interesting data about the changing pattern of relapse after immunotherapy as well as about novel biomarkers, such as the clearance of minimal residual disease before and after immunotherapy using an mRNA marker panel andtheuseof FCGR2Apolymorphisms,humanleukocyteantigen, and killer immunoglobulin-like receptor genotyping. FivelevelsofevidencehavebeendescribedbytheOxfordCentre