Gregory A. Yanik

Anti-CD20 Chimeric Monoclonal Antibody Treatment of Refractory Immune-Mediated Thrombocytopenia in a Patient with Chronic Graft-versus-Host Disease

Chronic graft-versus-host disease occurs in approximately 50% of long-term survivors of transplantation with marrow from HLA-identical donors (1); the risk for this disease increases with use of peripheral blood stem cells (2). Chronic graft-versus-host disease shares many of the clinical manifestations of autoimmune collagen vascular diseases, including oral ulceration, lichen planus, xerostomia, keratoconjunctivitis sicca, polyserositis, esophagitis and esophageal stricture, vaginal ulceration and stricture, intrahepatic obstructive liver disease, obstructive pulmonary disease, scleroderma, morphea, fasciitis, and myositis (3). Cytopenias, particularly thrombocytopenia, are a common feature of both chronic graft-versus-host disease and collagen vascular disease, and thrombocytopenia in chronic graft-versus-host disease is associated with poorer survival (4, 5). Antiplatelet antibodies are frequently detected in patients with thrombocytopenia associated with chronic graft-versus-host disease (6). Most patients with chronic graft-versus-host disease have evidence of B-cell dysregulation, with a high prevalence of autoantibodies to several cell surface and intracellular antigens (7). The role of these autoantibodies in the pathogenesis of chronic graft-versus-host disease is unclear. Autoimmune thrombocytopenia in chronic graft-versus-host disease may represent an instance of B-cell dysregulation leading to clinical disease. Rituximab is a humanized murine monoclonal antibody commonly used to treat B-cell lymphomas (8). This antibody is highly effective for in vivo depletion of B cells. Circulating B cells become undetectable after a single 375-mg/m2 infusion of rituximab; recovery of B cells begins at 6 to 9 months after treatment, and counts normalize by 9 to 12 months (9). Because of these biological properties of rituximab and the association of antiplatelet autoantibody with thrombocytopenia in patients with chronic graft-versus-host disease (6), we hypothesized that rituximab might have clinically significant activity in the treatment of refractory immune-mediated thrombocytopenia. We describe a patient with chronic graft-versus-host disease who developed severe refractory thrombocytopenia that responded to anti-CD20 chimeric antibody therapy. The rationale for this treatment was to eliminate B cells producing autoantibodies and thereby reverse the thrombocytopenia. Case Report A 32-year-old woman, gravida 3 para 1, presented with blurred vision and was found to have retinal hemorrhages. Complete blood count showed a leukocyte count of 451 109 cells/L with 2% basophils. A diagnosis of chronic myelogenous leukemia was confirmed by the presence of the Philadelphia chromosome in the marrow sample. The patient began receiving hydroxyurea to reduce her leukocyte count and was referred for stem-cell transplantation. She received 16 doses of busulphan (1 mg/kg of body weight every 6 hours) followed by cyclophosphamide (60 mg/kg daily for 2 days) in preparation for transplantation. Filgrastim-mobilized peripheral blood stem cells were harvested from an HLA-matched brother and were infused into the patient 3 months after diagnosis. The patients blood group was A+, and she was seropositive for cytomegalovirus; the donors blood group was O+, and he was seronegative for cytomegalovirus. Prophylaxis against graft-versus-host disease consisted of tacrolimus and methotrexate (10). The patient had prompt hematologic reconstitution, with an absolute neutrophil count of 0.5 109 cells/L on day 12 after transplantation and a platelet count greater than 100 109 cells/L on day 16 after transplantation. Therapy with ganciclovir, 5 mg/kg twice weekly, was started on day 16 as prophylaxis against cytomegalovirus infection. On day 28 after transplantation, the patient developed a maculopapular rash of the upper torso and diarrhea. Skin biopsy confirmed acute graft-versus-host disease, and she began receiving methylprednisolone, 1 mg/kg daily. The ganciclovir dose was increased prophylactically to 5 mg/kg 5 times per week. Bone marrow aspirate on day 100 after transplantation showed a normal male karyotype, and full donor chimerism was confirmed by polymerase chain reaction of microsatellite markers. The patient responded well to steroid therapy for the skin and gastrointestinal symptoms of graft-versus-host disease, but symptoms of xerophthalmia and xerostomia developed and steroid therapy was continued through day 127. On day 142, she underwent punctal occlusion of both eyes for severe xerophthalmia. Other manifestations of chronic graft-versus-host disease were progressive xerostomia with lichenoid changes of the oral mucosa. During the patients course of therapy with steroids and the increased dose of ganciclovir, her platelet count remained greater than 100 109 cells/L. On day 211, a complete blood count showed an absolute neutrophil count of 2.7 109 cells/L, hemoglobin value of 131 g/L, and platelet count of 178 109 cells/L. On day 230, the patients platelet count decreased to 88 109/cells/L. On day 238, it decreased further to 28 109 cells/L. No microangiopathic changes were seen on peripheral smear. Bone marrow aspiration and biopsy showed normal trilineage hematopoietic maturation with an adequate number of megakaryocytes. Flow cytometry showed the presence of platelet-associated IgG on washed, formalin-fixed platelets. Intravenous immunoglobulin, 500 mg/kg, was administered daily for 3 days; the platelet count increased to 159 109 cells/L, but for only 2 weeks. The patient then received 5 doses of intravenous immunoglobulins with methylprednisolone, 64 mg/d. On day 278, therapy with mycophenolate was started to provide additional immunosuppression. The combination of intravenous immunoglobulins, steroids, and mycophenolate resulted in an increase in platelet count to 114 109 cells/L by day 299. On day 308, the patients platelet count decreased to 51 109 cells/L. A dose of anti-D antibody (50 g/kg) was given, and the platelet count increased to 127 109 cells/L. However, the patient experienced significant hemolysis; her hemoglobin value decreased from 131 g/L to 78 g/L, an expected side effect related to the destruction of Rho (D)positive red cells. On day 337, she underwent laparoscopic splenectomy; an accessory spleen was also removed. By day 341, the platelet count increased to 139 109 cells/L but decreased to 2 109 cells/L 1 week later. Intravenous vincristine, 2 mg, was administered in four weekly doses starting on day 356, but it did not produce a response. The patient subsequently received intravenous cyclophosphamide, 1.5 g/m2, on day 384, again without response. On day 404, the patient received the first of four weekly doses of anti-CD20 antibody (rituximab [Rituxan, Genentech/IDEC, South San Francisco, California]). Peripheral blood flow cytometry on day 377 showed a CD19+ cell count (B cells) of 0.116 109 cells/L; by day 474, after rituximab therapy, CD19+ cells were absent. A gradual but sustained increase in the platelet count was noted after 2 doses of rituximab. The dose of mycophenolate mofetil was tapered and therapy was discontinued 3 weeks after initiation of rituximab therapy. At the time of this report, the patient has no clinically significant signs or symptoms of chronic graft-versus-host disease despite continued tapering of the tacrolimus dose and discontinuation of this therapy on day 667. The platelet-associated antibody assay remained weakly positive at day 485 and became negative on day 532. The patient has now been followed for 11 months since initiation of rituximab therapy, and the platelet count has not decreased (Table and Figure). Table. Chronological Clinical Course of the Patient Figure. Clinical course of a patient with chronic graft-versus-host disease in whom severe refractory immune-mediated thrombocytopenia responded to treatment with anti-CD20 monoclonal antibody. Discussion The reversal of our patients immune-mediated thrombocytopenia was especially noteworthy because of the lack of a sustained response to intensive immunosuppression, including treatment with steroids, mycophenolate, tacrolimus, vincristine, cyclophosphamide, intravenous immunoglobulins, anti-D antibody, and splenectomy. The improvement of thrombocytopenia was also associated with decreased levels of platelet-associated antibody and lack of progression of chronic graft-versus-host disease despite the discontinuation of immunosuppression. It is possible that cyclophosphamide therapy contributed in part to the platelet response. Reiner and colleagues (11) reported a series of 20 cases of refractory idiopathic thrombocytopenia purpura treated with pulse cyclophosphamide (1 to 1.5 g/m2), with complete remission in 65% of patients and partial remission in 20%. However, most patients required multiple pulses (mean, 2; maximum, 4), and the mean time to response was 7 weeks. Considering the intensity of the immunosuppressive therapy that our patient received and the lack of platelet response at the time of neutrophil recovery, it is unlikely that cyclophosphamide contributed substantially. Studies of B cells in patients with chronic graft-versus-host disease have not convincingly explained the clinical abnormalities, including reduced B-cell count, decreased Ig production, and increased spontaneous Ig production (12), seen in this condition. Clonal dysregulation of B cells in chronic graft-versus-host disease has been suggested by the presence of monoclonal gammopathy (13, 14) and elevated serum IgG and IgM levels (15). Antibody production is a prominent feature of many animal models of chronic graft-versus-host disease (16, 17). Mechanistic studies showed that secretion of Th2 cytokines, such as interleukin-4 and interleukin-5, by donor CD4+ cells are critical to B-cell activation and autoantibody production. Most of the autoantibodies are of the IgG subclass (16), and abnormal cross-linking of IgG receptors on t

Phase II Study on the Effect of Disease Sites, Age, and Prior Therapy on Response to Iodine-131-Metaiodobenzylguanidine Therapy in Refractory Neuroblastoma

PURPOSE To evaluate the effect of disease sites and prior therapy on response and toxicity after iodine-131-metaiodobenzylguanidine (131I-MIBG) treatment of patients with resistant neuroblastoma. PATIENTS AND METHODS One hundred sixty-four patients with progressive, refractory or relapsed high-risk neuroblastoma, age 2 to 30 years, were treated in a limited institution phase II study. Patients with cryopreserved hematopoietic stem cells (n = 148) were treated with 18 mCi/kg of 131I-MIBG. Those without hematopoietic stem cells (n = 16) received 12 mCi/kg. Patients were stratified according to prior myeloablative therapy and whether they had measurable soft tissue involvement or only bone and/or bone marrow disease. RESULTS Hematologic toxicity was common, with 33% of patients receiving autologous hematopoietic stem cell support. Nonhematologic grade 3 or 4 toxicity was rare, with 5% of patients experiencing hepatic, 3.6% pulmonary, 10.9% infectious toxicity, and 9.7% with febrile neutropenia. The overall complete plus partial response rate was 36%. The response rate was significantly higher for patients with disease limited either to bone and bone marrow, or to soft tissue (compared with patients with both) for patients with fewer than three prior treatment regimens and for patients older than 12 years. The event-free survival (EFS) and overall survival (OS) times were significantly longer for patients achieving response, for those older than 12 years and with fewer than three prior treatment regimens. The OS was 49% at 1 year and 29% at 2 years; EFS was 18% at 1 year. CONCLUSION The high response rate and low nonhematologic toxicity with 131I-MIBG suggest incorporation of this agent into initial multimodal therapy of neuroblastoma.

Elafin is a biomarker of graft-versus-host disease of the skin.

Plasma elafin concentrations correlate with graft-versus-host disease of the skin and long-term survival. Progress toward biomarker commercialization requires the discovery, qualification, verification, optimization, and clinical validation of a candidate before it is incorporated into existing therapeutic diagnostic platforms. The tremendous value that could be derived from the advancement of methods to detect disease at earlier and more treatable stages puts this pipeline approach at the forefront of biomarker development. However, to date there are no clear success stories in which discovery proteomics has led to a deployed protein biomarker. There is no polymerase chain reaction equivalent available to detect, quantify, and amplify proteins. Rather, proteomics-based biomarker discovery across a wide assortment of diseases is enabled by technologies such as mass spectrometry to sift through a large span of complex analytes at variable concentrations. Now, Paczesny and colleagues use a mass spectrometry–based technique to unambiguously identify candidate plasma biomarkers of skin acute graft-versus-host disease (GVHD)—the primary cause of nonrelapse mortality after bone marrow transplantation (BMT). Rashes are common after BMT and can be caused by a variety of reasons, but because the consequences of GVHD are serious, physicians initiate treatment of suspected GVHD without a bona fide confirmed diagnosis. In the discovery set of this work, the authors examined plasma samples from patients who had received BMT with and without clinical diagnosis of skin GVHD, and found that in patients with skin GVHD, the concentration of one lead marker, elafin, was three times as high. In a follow-up independent validation of 492 BMT patients, skin biopsies stained with elafin stratified the patients consistently according to GVHD parameters, and elafin plasma concentrations were concordantly higher in patients with GVHD. The specificity and sensitivity of elafin relative to other markers revealed that it was the single best discriminator for the diagnosis of GVHD in BMT patients with a rash, and was correlated with the severity of the disease. Elafin concentrations also correlated with the eventual maximum grade of GVHD and with nonrelapse mortality. These results show that elafin concentrations may serve as a noninvasive diagnostic test as well as a prognostic marker in determining GVHD grading in the clinic. Graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation, affects the skin, liver, and gastrointestinal tract. There are no plasma biomarkers specific for any acute GVHD target organ. We used a large-scale quantitative proteomic discovery procedure to identify biomarker candidates of skin GVHD and validated the lead candidate, elafin, with enzyme-linked immunosorbent assay in samples from 492 patients. Elafin was overexpressed in GVHD skin biopsies. Plasma concentrations of elafin were significantly higher at the onset of skin GVHD, correlated with the eventual maximum grade of GVHD, and were associated with a greater risk of death relative to other known risk factors (hazard ratio, 1.78). We conclude that elafin has significant diagnostic and prognostic value as a biomarker of skin GVHD.

Phase I Dose Escalation of Iodine-131–Metaiodobenzylguanidine With Myeloablative Chemotherapy and Autologous Stem-Cell Transplantation in Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy Consortium Study

PURPOSE To determine the maximum-tolerated dose (MTD) and toxicity of iodine-131-metaiodobenzylguanidine ((131)I-MIBG) with carboplatin, etoposide, melphalan (CEM) and autologous stem-cell transplantation (ASCT) in refractory neuroblastoma. PATIENTS AND METHODS Twenty-four children with primary refractory neuroblastoma and no prior ASCT were entered; 22 were assessable for toxicity and response. (131)I-MIBG was administered on day -21, CEM was administered on days -7 to -4, and ASCT was performed on day 0, followed by 13-cis-retinoic acid. (131)I-MIBG was escalated in groups of three to six patients, stratified by corrected glomerular filtration rate (GFR). RESULTS The MTD for patients with normal GFR (> or = 100 mL/min/1.73 m2) was 131I-MIBG 12 mCi/kg, carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and melphalan 210 mg/m2. In the low-GFR cohort, at the initial dose level using 12 mCi/kg of 131I-MIBG and reduced chemotherapy, one in six patients had dose limiting toxicity (DLT), including veno-occlusive disease (VOD). Three more patients in this group had grade 3 or 4 hepatotoxicity, and two had VOD, without meeting DLT criteria. There was only one death as a result of toxicity among all 24 patients. All assessable patients engrafted, with median time for neutrophils > or = 500/microL of 10 days and median time for platelets > or = 20,000/microL of 26 days. Six of 22 assessable patients had complete or partial response, and 15 patients had mixed response or stable disease. The estimated probability of event-free survival and survival from the day of MIBG infusion for all patients at 3 years was 0.31 +/- 0.10 and 0.58 +/- 0.10, respectively. CONCLUSION 131I-MIBG with myeloablative chemotherapy is feasible and effective for patients with neuroblastoma exhibiting de novo resistance to chemotherapy.

Integrative Clinical Sequencing in the Management of Refractory or Relapsed Cancer in Youth

IMPORTANCE Cancer is caused by a diverse array of somatic and germline genomic aberrations. Advances in genomic sequencing technologies have improved the ability to detect these molecular aberrations with greater sensitivity. However, integrating them into clinical management in an individualized manner has proven challenging. OBJECTIVE To evaluate the use of integrative clinical sequencing and genetic counseling in the assessment and treatment of children and young adults with cancer. DESIGN, SETTING, AND PARTICIPANTS Single-site, observational, consecutive case series (May 2012-October 2014) involving 102 children and young adults (mean age, 10.6 years; median age, 11.5 years, range, 0-22 years) with relapsed, refractory, or rare cancer. EXPOSURES Participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed by a precision medicine tumor board, which made recommendations to families and their physicians. MAIN OUTCOMES AND MEASURES Proportion of patients with potentially actionable findings, results of clinical actions based on integrative clinical sequencing, and estimated proportion of patients or their families at risk of future cancer. RESULTS Of the 104 screened patients, 102 enrolled with 91 (89%) having adequate tumor tissue to complete sequencing. Only the 91 patients were included in all calculations, including 28 (31%) with hematological malignancies and 63 (69%) with solid tumors. Forty-two patients (46%) had actionable findings that changed their cancer management: 15 of 28 (54%) with hematological malignancies and 27 of 63 (43%) with solid tumors. Individualized actions were taken in 23 of the 91 (25%) based on actionable integrative clinical sequencing findings, including change in treatment for 14 patients (15%) and genetic counseling for future risk for 9 patients (10%). Nine of 91 (10%) of the personalized clinical interventions resulted in ongoing partial clinical remission of 8 to 16 months or helped sustain complete clinical remission of 6 to 21 months. All 9 patients and families with actionable incidental genetic findings agreed to genetic counseling and screening. CONCLUSIONS AND RELEVANCE In this single-center case series involving young patients with relapsed or refractory cancer, incorporation of integrative clinical sequencing data into clinical management was feasible, revealed potentially actionable findings in 46% of patients, and was associated with change in treatment and family genetic counseling for a small proportion of patients. The lack of a control group limited assessing whether better clinical outcomes resulted from this approach than outcomes that would have occurred with standard care.

Pilot Study of Iodine-131–Metaiodobenzylguanidine in Combination With Myeloablative Chemotherapy and Autologous Stem-Cell Support for the Treatment of Neuroblastoma

PURPOSE The survival for children with relapsed or metastatic neuroblastoma remains poor. More effective regimens with acceptable toxicity are required to improve prognosis. Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) selectively targets radiation to catecholamine-producing cells, including neuroblastoma cells. A pilot study was performed to examine the feasibility of a novel regimen combining (131)I-MIBG and myeloablative chemotherapy with autologous stem-cell rescue. PATIENTS AND METHODS Twelve patients with neuroblastoma were treated after relapse (five patients) or after induction therapy (seven patients). Eight patients had metastatic and four had localized disease at the time of therapy. All patients received (131)I-MIBG 12 mCi/kg on day -21, followed by carboplatin (1,500 mg/m(2)), etoposide (800 mg/m(2)), and melphalan (210 mg/m(2)) administered from day -7 to day -4. Autologous peripheral-blood stem cells or bone marrow were infused on day 0. Engraftment, toxicity, and response rates were evaluated. RESULTS The (131)I-MIBG infusion and myeloablative chemotherapy were both well tolerated. Grade 2 to 3 oral mucositis was the predominant nonhematopoietic toxicity, occurring in all patients. The median times to neutrophil (> or = 0.5 x 10(3)/microL) and platelet (> or = 20 x 10(3)/microL) engraftment were 10 and 28 days, respectively. For the eight patients treated with metastatic disease, three achieved complete response and two had partial responses by day 100 after transplantation. CONCLUSION Treatment with (131)I-MIBG in combination with myeloablative chemotherapy and hematopoietic stem-cell rescue is feasible with acceptable toxicity. Future study is warranted to examine the efficacy of this novel therapy.

Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

Background In a single‐center phase 1–2a study, the anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B‐cell acute lymphoblastic leukemia (ALL). Methods We conducted a phase 2, single‐cohort, 25‐center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B‐cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. Results For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event‐free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. Conclusions In this global study of CAR T‐cell therapy, a single infusion of tisagenlecleucel provided durable remission with long‐term persistence in pediatric and young adult patients with relapsed or refractory B‐cell ALL, with transient high‐grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849.)

Change in plasma tumor necrosis factor receptor 1 levels in the first week after myeloablative allogeneic transplantation correlates with severity and incidence of GVHD and survival

Acute graft-versus-host disease (GVHD) remains a significant cause of mortality after hematopoietic cell transplantation (HCT). Tumor necrosis factor-alpha (TNF-alpha) mediates GVHD by amplifying donor immune responses to host tissues and by direct toxicity to target organs. We measured TNF receptor 1 (TNFR1) as a surrogate marker for TNF-alpha in 438 recipients of myeloablative HCT before transplantation and at day 7 after transplantation. Increases in TNFR1 levels more than or equal to 2.5 baseline correlated with eventual development of GVHD grade 2 to 4 (58% vs 32%, P < .001) and with treatment-related mortality (39% vs 17%, P < .001). In a multivariate analysis including age, degree of HLA match, donor type, recipient and donor sex, disease, and status at HCT, the increase in TNFR1 level at day 7 remained a significant predictor for outcome. Measurement of TNFR1 levels early after transplantation provides independent information in advance of important clinical outcomes, such as GVHD and death.

The impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation

Idiopathic pneumonia syndrome (IPS) refers to a diffuse, noninfectious, acute lung injury after hematopoietic stem cell transplantation. Historically, IPS is associated with respiratory failure and mortality rates exceeding 50%. Preclinical studies have implicated tumor necrosis factor-alpha as an important effector molecule in the development of disease. We studied the tumor necrosis factor-alpha inhibitor, etanercept, combined with corticosteroids in treating 15 patients (median age, 18 years; range, 1-60 years) with IPS. Eight of 15 patients required mechanical ventilation at therapy onset. Etanercept was administered subcutaneously at a dose of 0.4 mg/kg (maximum 25 mg) twice weekly, for a maximum of 8 doses. Therapy was well tolerated with no infectious pulmonary complications noted. Ten of 15 patients had a complete response, defined as the ability to discontinue supplemental oxygen support during study therapy. The median time to complete response was 7 days (range, 3-18 days), with a day 28 survival of 73%. IPS onset was associated with elevations of several inflammatory proteins in the bronchoalveolar lavage fluid and plasma, and response to therapy correlated with reductions in pulmonary and systemic inflammation. The combination of etanercept and corticosteroids is safe and is associated with high response rates and improved survival in patients with IPS.

Semiquantitative mIBG Scoring as a Prognostic Indicator in Patients with Stage 4 Neuroblastoma: A Report from the Children’s Oncology Group

Radiolabeled metaiodobenzylguanidine (mIBG) is a highly sensitive and specific marker for detecting neuroblastoma. A semiquantitative mIBG score (Curie score [CS]) was assessed for utility as a prognostic indicator for a cohort of patients with high-risk metastatic disease. Methods: mIBG scans from 280 patients with mIBG-avid, stage 4 neuroblastoma enrolled on the Children’s Oncology Group (COG) protocol A3973 were evaluated at diagnosis (n = 280), after induction chemotherapy (n = 237), and after an autologous stem cell transplantation (n = 178). Individual mIBG scans were evaluated at 10 different anatomic regions, with the scoring of each site (0–3) based on the extent of disease at that anatomic region. Results: There was no correlation between CS at diagnosis and subsequent treatment outcome. Patients with a CS > 2 after induction therapy had a significantly worse event-free survival (EFS) than those with scores ≤ 2 (3-y EFS: 15.4% ± 5.3% vs. 44.9% ± 3.9%, respectively; P < 0.001). A postinduction CS > 2 identified a cohort of patients at greater risk for an event, independent of other known neuroblastoma factors, including age, MYCN status, ploidy, mitosis-karyorrhexis index, and histologic grade. For MYCN-amplified tumors, the presence (CS > 0) versus absence (CS = 0) of residual mIBG avidity after induction was associated with a significantly worse outcome (3-y EFS: 11.8% ± 7.8% vs. 49.6% ± 7.7%, respectively; P = 0.003). After transplantation, patients with a CS > 0 had an EFS inferior to that of patients with a CS of 0 (3-y EFS: 28.9% ± 6.8% vs. 49.3% ± 4.9%, respectively [n = 133]; P = 0.009). Conclusion: Curie scoring carries prognostic significance in the management of patients with high-risk neuroblastoma. In particular, patients with CSs > 2 after induction have extremely poor outcomes and should be considered for alternative therapeutic strategies.