The New Approaches to Neuroblastoma Therapy Response Criteria (NANTRC) were developed to optimize response assessment in patients with recurrent/refractory neuroblastoma. Response predictors and associations of the NANTRC version 1.0 (NANTRCv1.0) and prognostic factors with outcome were analyzed.A retrospective analysis was performed of patients with recurrent/refractory neuroblastoma enrolled from 2000 to 2009 on 13 NANT Phase 1/2 trials. NANTRC overall response integrated CT/MRI (Response Evaluation Criteria in Solid Tumors [RECIST]), metaiodobenzylguanidine (MIBG; Curie scoring), and percent bone marrow (BM) tumor (morphology).Fourteen (6.9%) complete response (CR) and 14 (6.9%) partial response (PR) occurred among 203 patients evaluable for response. Five-year progression-free survival (PFS) was 16 ± 3%; overall survival (OS) was 27 ± 3%. Disease sites at enrollment included MIBG-avid lesions (100% MIBG trials; 84% non-MIBG trials), measurable CT/MRI lesions (48%), and BM (49%). By multivariable analysis, Curie score of 0 (P < 0.001), lower Curie score (P = 0.003), no measurable CT/MRI lesions (P = 0.044), and treatment on peripheral blood stem cell (PBSC) supported trials (P = 0.005) were associated with achieving CR/PR. Overall response of stable disease (SD) or better was associated with better OS (P < 0.001). In multivariable analysis, MYCN amplification (P = 0.037) was associated with worse PFS; measurable CT/MRI lesions (P = 0.041) were associated with worse OS; prior progressive disease (PD; P < 0.001/P < 0.001), Curie score ≥ 1 (P < 0.001; P = 0.001), higher Curie score (P = 0.048/0.037), and treatment on non-PBSC trials (P = < 0.001/0.003) were associated with worse PFS and OS.NANTRCv1.0 response of at least SD is associated with better OS in patients with recurrent/refractory neuroblastoma. Patient and tumor characteristics may predict response and outcome. Identifying these variables can optimize Phase 1/2 trial design to select novel agents for further testing.
To create the first structured surgical report form for NBL with international consensus, to permit standardized documentation of all NBL-related surgical procedures and their outcomes.NBL, the most common extracranial solid malignant tumor in children, covers a wide spectrum of tumors with significant differences in anatomical localization, organ or vessel involvement, and tumor biology. Complete surgical resection of the primary tumor is an important part of NBL treatment, but maybe hazardous, prone to complications and its role in high-risk disease remains debated. Various surgical guidelines exist within the protocols of the different cooperative groups, although there is no standardized operative report form to document the surgical treatment of NBL.After analyzing the treatment protocols of the SIOP Europe International Neuroblastoma Study Group, Children's Oncology Group, and Gesellschaft fuer Paediatrische Onkologie und Haematologie - German Association of Pediatric Oncology and Haematology pediatric cooperative groups, important variables were defined to completely describe surgical biopsy and resection of NBL and their outcomes. All variables were discussed within the Surgical Committees of SIOP Europe International Neuroblastoma Study Group, Children's Oncology Group, and Gesellschaft fuer Paediatrische Onkologie und Haematologie - German Association of Pediatric Oncology and Haematology. Thereafter, joint meetings were organized to obtain intercontinental consensus.The "International Neuroblastoma Surgical Report Form" provides a structured reporting tool for all NBL surgery, in every anatomical region, documenting all Image Defined Risk Factors and structures involved, with obligatory reporting of intraoperative and 30 day-postoperative complications.The International Neuroblastoma Surgical Report Form is the first universal form for the structured and uniform reporting of NBL-related surgical procedures and their outcomes, aiming to facilitate the postoperative communication, treatment planning and analysis of surgical treatment of NBL.
131 I-meta-iodobenzylguanidine (131 I-MIBG) is effective in relapsed neuroblastoma. The Children's Oncology Group (COG) conducted a pilot study (NCT01175356) to assess tolerability and feasibility of induction chemotherapy followed by 131 I- MIBG therapy and myeloablative busulfan/melphalan (Bu/Mel) in patients with newly diagnosed high-risk neuroblastoma.Patients with MIBG-avid high-risk neuroblastoma were eligible. After the first two patients to receive protocol therapy developed severe sinusoidal obstruction syndrome (SOS), the trial was re-designed to include an 131 I-MIBG dose escalation (12, 15, and 18 mCi/kg), with a required 10-week gap before Bu/Mel administration. Patients who completed induction chemotherapy were evaluable for assessment of 131 I-MIBG feasibility; those who completed 131 I-MIBG therapy were evaluable for assessment of 131 I-MIBG + Bu/Mel feasibility.Fifty-nine of 68 patients (86.8%) who completed induction chemotherapy received 131 I-MIBG. Thirty-seven of 45 patients (82.2%) evaluable for 131 I-MIBG + Bu/Mel received this combination. Among those who received 131 I-MIBG after revision of the study design, one patient per dose level developed severe SOS. Rates of moderate to severe SOS at 12, 15, and 18 mCi/kg were 33.3%, 23.5%, and 25.0%, respectively. There was one toxic death. The 131 I-MIBG and 131 I-MIBG+Bu/Mel feasibility rates at the 15 mCi/kg dose level designated for further study were 96.7% (95% CI: 83.3%-99.4%) and 81.0% (95% CI: 60.0%-92.3%).This pilot trial demonstrated feasibility and tolerability of administering 131 I-MIBG followed by myeloablative therapy with Bu/Mel to newly diagnosed children with high-risk neuroblastoma in a cooperative group setting, laying the groundwork for a cooperative randomized trial (NCT03126916) testing the addition of 131 I-MIBG during induction therapy.
Abstract Background: In neuroblastoma (NB), Mitosis-Karyorrhexis Index (MKI; low-L, <100/5,000 cells; intermediate-I, 100-200/5,000 cells; high-H, >200/5,000 cells) is one of the histologic indicators for predicting a patient's clinical outcome. Event-Free Survival (EFS) and Overall Survival (OS) are significantly worse as MKI increases (p<0.0001): 3-year EFS for L-MKI (81.2+1.0%), I-MKI (68.6+1.8%), H-MKI (51.0+2.2%); and 3-year OS for L-MKI (92.0+0.7%), I-MKI (81.0+1.6%), H-MKI (64.4+2.1%). MYCN amplification (MYCN-A) is significantly associated with H-MKI, which indicates markedly increased mitotic (cellular proliferation) and karyorrhectic (cellular death) cells. However, about one-third of H-MKI tumors do not have MYCN-A. Study design: A total of 4,712 NB cases reviewed by the Children's Oncology Group (COG) Neuroblastoma Pathology Reference Laboratory (Children's Hospital Los Angeles) between 06/18/2001 and 06/06/2013 included 2,595 L-MKI (3% with MYCN-A), 1,197 I-MKI (16% with MYCN-A), and 920 H-MKI (70% with MYCN-A) tumors. In this study, immunohistochemical detection of MYCN and MYC (C-myc) protein was performed on 82 H-MKI tumors (53 with MYCN-A and 29 without MYCN-A). Results: 50/53 (94%) of H-MKI tumors having MYCN-A were positive for MYCN protein (including one case positive for both MYCN and MYC proteins), and only 3 cases were negative for both proteins immunohistochemically. Among the H-MKI tumors without MYCN-A, 16 cases (55%) showed positive staining for MYC protein, 6 cases (21%) were positive for MYCN protein, 2 cases (7%) were positive for both proteins, and 5 cases (17%) were negative for both proteins. Conclusions: MYCN-A and subsequent MYCN protein expression are considered as the starting point for leading NB tumors to H-MKI status. However, when MYCN is not amplified, high mitotic/karyorrhectic (M/K) activities in NB tumors are often associated with MYC protein expression. Even some MYCN non-amplified tumors can express MYCN protein, which is associated with H-MKI. There is still a small group of H-MKI tumors whose increased M/K activities are not related to MYCN/MYC protein expression. Citation Format: Larry L. Wang, Risa Teshiba, Lejian He, Arlene Naranjo, Wendy B. London, Julie M. Gastier-Foster, Robert C. Seeger, Susan L. Cohn, John M. Maris, Julie R. Park, Michael D. Hogarty, Hiroyuki Shimada. MYCN/MYC protein expression in high-MKI (Mitosis-Karyorrhexis Index) neuroblastomas: A report from the Children's Oncology Group. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B40.
Abstract Purpose: Asparaginase therapy is an important component in the treatment of children with acute lymphoblastic leukemia. Polyethylene glycol-conjugated asparaginase (PEG-ASNase) has significant pharmacological advantages over native Escherichia coli asparaginase. We investigated the pharmacokinetics of PEG-ASNase, presence of antibodies to PEG-ASNase, and concentrations of asparagine in serum and cerebrospinal fluid (CSF) in combination chemotherapy for relapsed pediatric acute lymphoblastic leukemia. Experimental Design: Twenty-eight pediatric patients with relapsed medullary (n = 16) and extramedullary (n = 11) acute lymphoblastic leukemia were enrolled at three pediatric institutions and had at least two serum and CSF samples obtained for analysis. Patients received induction therapy (including PEG-ASNase 2500 IU/m2 intramuscularly weekly on days 2, 9, 16, and 23) and intensification therapy (including PEG-ASNase 2500 IU/m2 intramuscularly once on day 7). Serum samples were obtained weekly during induction and intensification. CSF samples were obtained during therapeutic lumbar punctures during induction and intensification. Results: Weekly PEG-ASNase therapy resulted in PEG-ASNase activity of >0.1 IU/ml in 91–100% of patients throughout induction. During intensification, PEG-ASNase on day 7 resulted in PEG-ASNase activity >0.1 IU/ml in 94% and 80% of patients on days 14 and 21, respectively. Serum and CSF asparagine depletion was observed and maintained during induction and intensification in the majority of samples. PEG-ASNase antibody was observed in only 3 patients. Conclusions: Intensive PEG-ASNase therapy in the treatment of relapsed acute lymphoblastic leukemia reliably results in high-level serum PEG-ASNase activity, and asparagine depletion in serum and CSF is usually achieved. Incorporation of intensive PEG-ASNase in future trials for recurrent acute lymphoblastic leukemia is warranted.
e14014 Background: High-risk neuroblastoma (NBL) patients (pts) enrolled in a COG phase III clinical trial (ANBL0032) were randomized to isotretinoin (RA) alone or RA + immunotherapy (IM): dinutuximab (anti-GD2 mAb) + IL2 + GMCSF (Yu et al., NEJM363:1324, 2010). Dinutuximab acts via antibody-dependent cell-mediated cytotoxicity by innate immune cells, including NK cells. NK cells express Killer Immunoglobulin-like Receptors (KIRs) that bind KIR-Ligands (KIR-Ls), MHC Class I molecules. Prior studies suggest that KIR/KIR-L status impacts outcome for pts with NBL. We investigated whether KIR/KIR-L genotype was associated with event-free survival (EFS) and overall survival (OS) in this trial. Methods: Of the 226 pts randomized, 174 pts had DNA allowing evaluation of genotype correlations with outcome (IM: n=88; RA: n=86; >5yr follow-up if no event). For the inhibitory KIRs, we assessed the impact of all KIR-Ls present vs. missing at least one KIR-L (KIR-L missing) on outcome. Cox regression models and log-rank tests were used to evaluate EFS/OS with genotypes. Results: In contrast to prior reports, outcome for IM pts was not associated with KIR-L present vs. KIR-L missing genotypes (EFS p=0.35; OS p=0.33; Table). Interestingly, we found that IM therapy benefited those pts with KIR-L present as opposed to those with KIR-L missing (OS: p=0.01 vs. p=0.77; Table). Conclusions: IM (vs. RA) treatment resulted in improved outcome (Yu et al., 2010), but IM can have toxic side effects. Our data suggest that KIR/KIR-L genotype could be used prospectively to identify pts most likely to benefit from this therapy. We are continuing to evaluate KIR/KIR-L genotypes in this study to determine if there are certain genotypes that are likely to respond to IM (eg. KIR-L present, Table), and identify KIR/KIR-L genotypes that might benefit from alternate treatment regimens (eg. KIR-L Missing, Table). Clinical trial information: NCT00026312.Treatment EFS OS KIR-L present KIR-L missing Genotype p-value KIR-L present KIR-L missing Genotype p-value RA 5 yr % 39 48 0.24 42 66 0.06 [95% CI] [22-55] [34-61] [24-58] [52-78] Events/n 19/31 27/55 18/31 21/55 RA + IM 5 yr % 72 52 0.35 80 71 0.33 [95% CI] [50-86] [39-64] [58-91] [59-81] Events/n 9/25 30/63 7/25 25/63 Treatment p-value 0.03 0.54 0.01 0.77
