RESUMO
Ruxolitinib was well tolerated and superior to best available therapy (including interferon [IFN]) in controlling hematocrit without phlebotomy eligibility, normalizing blood counts, and improving polycythemia vera-related symptoms in the Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care (RESPONSE) studies. This ad hoc analysis focuses on ruxolitinib in relation to IFN in the RESPONSE studies, with attention on the following: (1) safety and efficacy of ruxolitinib and best available therapy in patients who received IFN before study randomization, (2) safety and efficacy of IFN during randomized treatment in best available therapy arm, and (3) use of ruxolitinib after crossover from best available therapy in IFN-treated patients. IFN exposure before randomization had little effect on the efficacy or safety of ruxolitinib. In the randomized treatment arms, ruxolitinib was superior to IFN in efficacy [hematocrit control (RESPONSE = 60% of ruxolitinib vs 23% of IFN patients; RESPONSE-2 = 62% of ruxolitinib vs 15% of IFN patients)] and was tolerated better in hydroxyurea-resistant or hydroxyurea-intolerant patients. After crossing over to receive ruxolitinib, patients who had initially received IFN and did not respond had improved hematologic and spleen responses (62% of patients at any time after crossover) and an overall reduction in phlebotomy procedures. Rates and incidences of the most common adverse events decreased after crossover to ruxolitinib, except for infections (primarily grade 1 or 2). These data suggest that ruxolitinib is efficacious and well tolerated in patients who were previously treated with IFN. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies were registered at clinicaltrials.gov .
Assuntos
Antineoplásicos/uso terapêutico , Interferons/uso terapêutico , Janus Quinases/antagonistas & inibidores , Policitemia Vera/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Sangria/efeitos adversos , Terapia Combinada/efeitos adversos , Estudos Cross-Over , Monitoramento de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Interferons/efeitos adversos , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Nitrilas , Policitemia Vera/metabolismo , Policitemia Vera/fisiopatologia , Policitemia Vera/terapia , Padrões de Prática Médica , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas , Reprodutibilidade dos Testes , Esplenomegalia/etiologia , Esplenomegalia/prevenção & controleRESUMO
In patients with polycythemia vera (PV), an elevated JAK2 p.V617F allele burden is associated with indicators of more severe disease (e.g., leukocytosis, splenomegaly, and increased thrombosis risk); however, correlations between allele burden reductions and clinical benefit in patients with PV have not been extensively evaluated in a randomized trial. This exploratory analysis from the multicenter, open-label, phase 3 Randomized Study of Efficacy and Safety in Polycythemia Vera With JAK Inhibitor INCB018424 Versus Best Supportive Care trial evaluated the long-term effect of ruxolitinib treatment on JAK2 p.V617F allele burden in patients with PV. Evaluable JAK2 p.V617F-positive patients randomized to ruxolitinib (n = 107) or best available therapy (BAT) who crossed over to ruxolitinib at week 32 (n = 97) had consistent JAK2 p.V617F allele burden reductions throughout the study. At all time points measured (up to weeks 208 [ruxolitinib-randomized] and 176 [ruxolitinib crossover]), mean changes from baseline over time in JAK2 p.V617F allele burden ranged from -12.2 to -40.0% (ruxolitinib-randomized) and -6.3 to -17.8% (ruxolitinib crossover). Complete or partial molecular response was observed in 3 patients (ruxolitinib-randomized, n = 2; ruxolitinib crossover, n = 1) and 54 patients (ruxolitinib-randomized, n = 33; ruxolitinib crossover, n = 20; BAT, n = 1), respectively. Among patients treated with interferon as BAT (n = 13), the mean maximal reduction in allele burden from baseline was 25.6% after crossover to ruxolitinib versus 6.6% before crossover. Collectively, the data from this exploratory analysis suggest that ruxolitinib treatment for up to 4 years provides progressive reductions in JAK2 p.V617F allele burden in patients with PV who are resistant to or intolerant of hydroxyurea. The relationship between allele burden changes and clinical outcomes in patients with PV remains unclear.
Assuntos
Janus Quinase 2/genética , Mutação de Sentido Incorreto , Policitemia Vera/tratamento farmacológico , Pirazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos Cross-Over , Feminino , Frequência do Gene , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Nitrilas , Policitemia Vera/enzimologia , Policitemia Vera/genética , Pirimidinas , Fatores de Tempo , Resultado do TratamentoAssuntos
Talassemia , Talassemia beta , Células Eritroides , Eritropoese , Humanos , Nitrilas , Pirazóis , PirimidinasRESUMO
PURPOSE: Panobinostat, a pan-deacetylase inhibitor, is a promising anti-cancer agent that increases acetylation of proteins associated with growth and survival pathways of malignant cells. The primary objective of this phase I dose-escalation study was to determine the maximum tolerated dose (MTD) of intravenous (i.v.) panobinostat administered on different dosing schedules in patients with advanced solid tumors or lymphoma. Secondary objective was to characterize safety and tolerability, pharmacokinetic profiles, and activities of the i.v. formulation. METHODS: i.v. panobinostat was administered at escalating doses on a daily (days 1-3 and 8-10 of a 21-day cycle; days 1-3 and 15-17 of a 28-day cycle) or weekly (days 1, 8, and 15 of a 28-day cycle; days 1 and 8 of a 21-day cycle) schedule, and safety and tolerability were monitored. Serial blood samples were collected following dosing for pharmacokinetic and pharmacodynamic analyses. RESULTS: The MTD for the daily administration schedule was 7.2 g/m(2), whereas the MTD for the weekly schedule was 20.0 mg/m(2). In addition to fatigue and cardiac arrhythmias, including prolonged QTcF, DLTs associated with the study drug were principally due to myelosuppressive effects. Maximum concentrations and bioavailability of i.v. panobinostat increased dose-proportionally across all doses evaluated. CONCLUSIONS: Based on the results of this study and others, the i.v. formulation of panobinostat was well tolerated in many patients, but concerns remain regarding its potential suitability outside the study setting due to potential electrocardiogram abnormalities. Therefore, further development will focus on the panobinostat oral formulation.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/uso terapêutico , Indóis/administração & dosagem , Indóis/uso terapêutico , Linfoma/tratamento farmacológico , Acetilação , Administração Intravenosa , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Demografia , Relação Dose-Resposta a Droga , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Ácidos Hidroxâmicos/farmacocinética , Indóis/efeitos adversos , Indóis/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Panobinostat , Resultado do TratamentoRESUMO
Phase I testing of the hu14.18-IL2 immunocytokine in melanoma patients showed immune activation, reversible toxicities, and a maximal tolerated dose of 7.5 mg/m(2)/day. In this phase II study, 14 patients with measurable metastatic melanoma were scheduled to receive hu14.18-IL2 at 6 mg/m(2)/day as 4-h intravenous infusions on Days 1, 2, and 3 of each 28 day cycle. Patients with stable disease (SD) or regression following cycle 2 could receive two additional treatment cycles. The primary objective was to evaluate antitumor activity and response duration. Secondary objectives evaluated adverse events and immunologic activation. All patients received two cycles of treatment. One patient had a partial response (PR) [1 PR of 14 patients = response rate of 7.1 %; confidence interval, 0.2-33.9 %], and 4 patients had SD and received cycles 3 and 4. The PR and SD responses lasted 3-4 months. All toxicities were reversible and those resulting in dose reduction included grade 3 hypotension (2 patients) and grade 2 renal insufficiency with oliguria (1 patient). Patients had a peripheral blood lymphocytosis on Day 8 and increased C-reactive protein. While one PR in 14 patients met protocol criteria to proceed to stage 2 and enter 16 additional patients, we suspended stage 2 due to limited availability of hu14.18-IL2 at that time and the brief duration of PR and SD. We conclude that subsequent testing of hu14.18-IL2 should involve melanoma patients with minimal residual disease based on compelling preclinical data and the confirmed immune activation with some antitumor activity in this study.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Interleucina-2/administração & dosagem , Melanoma/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Antineoplásicos/imunologia , Antineoplásicos/efeitos adversos , Antineoplásicos/imunologia , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Interleucina-2/efeitos adversos , Interleucina-2/imunologia , Masculino , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
The huKS-IL2 immunocytokine (IC) consists of IL2 fused to a mAb against EpCAM, while the hu14.18-IL2 IC recognizes the GD2 disialoganglioside. They are under evaluation for treatment of EpCAM(+) (ovarian) and GD2(+) (neuroblastoma and melanoma) malignancies because of their proven ability to enhance tumor cell killing by antibody-dependent cell-mediated cytotoxicity (ADCC) and by antitumor cytotoxic T cells. Here, we demonstrate that huKS-IL2 and hu14.18-IL2 bind to tumor cells via their antibody components and increase adhesion and activating immune synapse (AIS) formation with NK cells by engaging the immune cells' IL-2 receptors (IL2R). The NK leukemia cell line, NKL (which expresses high affinity IL2Rs), shows fivefold increase in binding to tumor targets when treated with IC compared to matching controls. This increase in binding is effectively inhibited by blocking antibodies against CD25, the α-chain of the IL2R. NK cells isolated from the peritoneal environment of ovarian cancer patients, known to be impaired in mediating ADCC, bind to huKS-IL2 via CD25. The increased binding between tumor and effector cells via ICs is due to the formation of AIS that are characterized by the simultaneous polarization of LFA-1, CD2 and F-actin at the cellular interface. AIS formation of peritoneal NK and NKL cells is inhibited by anti-CD25 blocking antibody and is 50-200% higher with IC versus the parent antibody. These findings demonstrate that the IL-2 component of the IC allows IL2Rs to function not only as receptors for this cytokine but also as facilitators of peritoneal NK cell binding to IC-coated tumor cells.
Assuntos
Sinapses Imunológicas/imunologia , Imunoterapia/métodos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Interleucina-2/análogos & derivados , Células Matadoras Naturais/imunologia , Anticorpos Monoclonais , Linhagem Celular Tumoral , Separação Celular , Feminino , Citometria de Fluxo , Gangliosídeos/imunologia , Humanos , Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Ativação Linfocitária/imunologia , Microscopia Confocal , Neoplasias Ovarianas/imunologia , Transporte Proteico/imunologia , Proteínas Recombinantes de FusãoRESUMO
The fifth multistakeholder Paediatric Strategy Forum focussed on epigenetic modifier therapies for children and adolescents with cancer. As most mutations in paediatric malignancies influence chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. The Research to Accelerate Cures and Equity (RACE) for Children Act FDARA amendments to section 505B of the FD&C Act was implemented in August 2020, and as there are many epigenetic targets on the FDA Paediatric Molecular Targets List, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development. Companies are also required to submit to the EMA paediatric investigation plans aiming to ensure that the necessary data to support the authorisation of a medicine for children in EU are of high quality and ethically researched. The specific aims of the forum were i) to identify epigenetic targets or mechanisms of action associated with epigenetic modification relevant to paediatric cancers and ii) to define the landscape for paediatric drug development of epigenetic modifier therapies. DNA methyltransferase inhibitors/hypomethylating agents and histone deacetylase inhibitors were largely excluded from discussion as the aim was to discuss those targets for which therapeutic agents are currently in early paediatric and adult development. Epigenetics is an evolving field and could be highly relevant to many paediatric cancers; the biology is multifaceted and new targets are frequently emerging. Targeting epigenetic mechanisms in paediatric malignancy has in most circumstances yet to reach or extend beyond clinical proof of concept, as many targets do not yet have available investigational drugs developed. Eight classes of medicinal products were discussed and prioritised based on the existing level of science to support early evaluation in children: inhibitors of menin, DOT1L, EZH2, EED, BET, PRMT5 and LSD1 and a retinoic acid receptor alpha agonist. Menin inhibitors should be moved rapidly into paediatric development, in view of their biological rationale, strong preclinical activity and ability to fulfil an unmet clinical need. A combination approach is critical for successful utilisation of any epigenetic modifiers (e.g. EZH2 and EED) and exploration of the optimum combination(s) should be supported by preclinical research and, where possible, molecular biomarker validation in advance of clinical translation. A follow-up multistakeholder meeting focussing on BET inhibitors will be held to define how to prioritise the multiple compounds in clinical development that could be evaluated in children with cancer. As epigenetic modifiers are relatively early in development in paediatrics, there is a clear opportunity to shape the landscape of therapies targeting the epigenome in order that efficient and optimum plans for their evaluation in children and adolescents are developed in a timely manner.
Assuntos
Antineoplásicos/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Criança , Desenvolvimento de Medicamentos , Epigenômica/métodos , Europa (Continente) , Humanos , Oncologia/métodos , Estados Unidos , United States Food and Drug AdministrationRESUMO
PURPOSE: Ruxolitinib is metabolized by cytochrome P450 (CYP)3A4 and CYP2C9. Dual inhibitors of these enzymes (like fluconazole) lead to increased ruxolitinib exposure relative to a single pathway inhibition of CYP3A4 or CYP2C9. The magnitude of this interaction, previously assessed via physiologically based pharmacokinetic (PBPK) models, was confirmed in an open-label, phase 1 study in healthy subjects. METHODS: The effect of multiple doses (200 mg) of fluconazole on single-dose (10 mg) PK of ruxolitinib was investigated including evaluation of the safety and tolerability. The PK parameters of ruxolitinib alone (reference) were compared to those of ruxolitinib combined with fluconazole (test). The point estimate and corresponding two-sided 90% confidence interval for the difference between means of test and reference parameters were determined. RESULTS: All enrolled subjects (N = 15) completed the study. When coadministered with fluconazole, geometric means of ruxolitinib PK parameters Cmax, AUClast, and AUCinf increased by 47%, 234%, and 232%, respectively, vs ruxolitinib alone. The median Tmax decreased slightly, apparent clearance decreased approximately threefold, and elimination half-life increased approximately 2.5-fold, upon ruxolitinib administration with fluconazole vs ruxolitinib alone. These results were consistent with the prospective predictions from a SimCYP PBPK model. Adverse events (AEs) were reported in six subjects (none were suspected to be related to ruxolitinib); no death or on-treatment serious AE was reported. CONCLUSIONS: Coadministration of ruxolitinib with fluconazole significantly increased ruxolitinib systemic exposure; however, no AEs were attributed to ruxolitinib. Concomitant use of ruxolitinib with fluconazole (dose ≤ 200 mg) may require dose reduction/modification of ruxolitinib.
Assuntos
Relação Dose-Resposta a Droga , Fluconazol/farmacocinética , Taxa de Depuração Metabólica/efeitos dos fármacos , Pirazóis/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Adulto , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Esquema de Medicação , Interações Medicamentosas , Inibidores Enzimáticos/farmacocinética , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Nitrilas , PirimidinasRESUMO
For patients with hematologic malignancies and disorders, allogeneic hematopoietic stem cell transplantation offers a potentially curative treatment option. Many patients develop graft-versus-host disease (GVHD), a serious complication and leading cause of nonrelapse mortality. Corticosteroids are the standard first-line treatment for GVHD; however, patients often become steroid-refractory or remain corticosteroid-dependent. New second-line treatment options are needed to improve patient outcomes. Here we review the role of JAK1 and JAK2 in acute and chronic GVHD. We also describe the study designs of the Phase II REACH1 (NCT02953678) and the Phase III REACH2 (NCT02913261) and REACH3 (NCT03112603) clinical trials that are currently recruiting patients to evaluate the JAK1/JAK2 inhibitor ruxolitinib in patients with corticosteroid-refractory acute or chronic GVHD.
Assuntos
Corticosteroides , Doença Enxerto-Hospedeiro/tratamento farmacológico , Pirazóis/uso terapêutico , Humanos , Nitrilas , Estudos Prospectivos , Pirimidinas , Resultado do TratamentoRESUMO
Ruxolitinib, a potent JAK1/JAK2 inhibitor, was found to be superior to the best available therapy (BAT) in controlling hematocrit, reducing splenomegaly, and improving symptoms in the phase 3 RESPONSE study of patients with polycythemia vera with splenomegaly who experienced an inadequate response to or adverse effects from hydroxyurea. We report findings from a subgroup analysis of Japanese patients in RESPONSE (n = 18). The composite response rate (hematocrit control and spleen response) was higher in patients receiving ruxolitinib (50.0%) than in those receiving BAT (8.3%). A total of 50.0% of patients randomized to ruxolitinib achieved a spleen response vs 8.3% of those receiving BAT; 100 and 33.3% of patients in the respective groups achieved hematocrit control, with mean hematocrit in ruxolitinib-treated patients remaining stable at < 45% throughout the study. Similarly, a higher proportion of ruxolitinib-treated patients achieved complete hematologic remission (33.3 vs 16.7%). Ruxolitinib also led to rapid improvements in pruritus. All responses with ruxolitinib were durable to week 80, and its safety profile was consistent with that in the overall study. These findings suggest that ruxolitinib is an effective and well-tolerated treatment option for Japanese patients with polycythemia vera with an inadequate response to or adverse effects from hydroxyurea.
Assuntos
Hidroxiureia/efeitos adversos , Inibidores de Janus Quinases/uso terapêutico , Policitemia Vera/tratamento farmacológico , Pirazóis/uso terapêutico , Esplenomegalia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Feminino , Hematócrito , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Policitemia Vera/sangue , Policitemia Vera/complicações , Pirimidinas , Esplenomegalia/etiologia , Resultado do TratamentoRESUMO
In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27-1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89-4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 - not reached) with pasireotide versus 6.8 months (5.6 - not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20-0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR.
Assuntos
Antineoplásicos/uso terapêutico , Tumor Carcinoide/tratamento farmacológico , Neoplasias do Sistema Digestório/tratamento farmacológico , Octreotida/uso terapêutico , Somatostatina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Tumor Carcinoide/mortalidade , Tumor Carcinoide/secundário , Preparações de Ação Retardada , Neoplasias do Sistema Digestório/mortalidade , Neoplasias do Sistema Digestório/patologia , Intervalo Livre de Doença , Método Duplo-Cego , Resistencia a Medicamentos Antineoplásicos , Substituição de Medicamentos , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Octreotida/efeitos adversos , Razão de Chances , Modelos de Riscos Proporcionais , Somatostatina/efeitos adversos , Somatostatina/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Carga TumoralRESUMO
PURPOSE: The hu14.18-IL2 fusion protein consists of interleukin-2 molecularly linked to a humanized monoclonal antibody that recognizes the GD2 disialoganglioside expressed on neuroblastoma cells. This phase II study assessed the antitumor activity of hu14.18-IL2 in two strata of patients with recurrent or refractory neuroblastoma. PATIENTS AND METHODS: Hu14.18-IL2 was given intravenously (12 mg/m(2)/daily) for 3 days every 4 weeks for patients with disease measurable by standard radiographic criteria (stratum 1) and for patients with disease evaluable only by [(123)I]metaiodobenzylguanidine (MIBG) scintigraphy and/or bone marrow (BM) histology (stratum 2). Response was established by independent radiology review as well as BM histology and immunocytology, and durability was assessed by repeat evaluation after more than 3 weeks. RESULTS: Thirty-nine patients were enrolled (36 evaluable). No responses were seen in stratum 1 (n = 13). Of 23 evaluable patients in stratum 2, five patients (21.7%) responded; all had a complete response (CR) of 9, 13, 20, 30, and 35+ months duration. Grade 3 and 4 nonhematologic toxicities included capillary leak, hypoxia, pain, rash, allergic reaction, elevated transaminases, and hyperbilirubinemia. Two patients required dopamine for hypotension, and one patient required ventilatory support for hypoxia. Most toxicities were reversible within a few days of completing a treatment course and were expected based on phase I results. CONCLUSION: Patients with disease evaluable only by MIBG and/or BM histology had a 21.7% CR rate to hu14.8-IL2, whereas patients with bulky disease did not respond. Hu14.18-IL2 warrants further testing in children with nonbulky high-risk neuroblastoma.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Interleucina-2/uso terapêutico , Neuroblastoma/tratamento farmacológico , Adolescente , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Criança , Pré-Escolar , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Humanos , Lactente , Interleucina-2/efeitos adversos , Interleucina-2/sangue , Interleucina-2/imunologia , Contagem de Linfócitos , Neuroblastoma/mortalidade , Receptores de Interleucina-2/sangueRESUMO
Response to immunocytokine (IC) therapy is dependent on natural killer cells in murine neuroblastoma (NBL) models. Furthermore, killer immunoglobulin-like receptor (KIR)/KIR-ligand mismatch is associated with improved outcome to autologous stem cell transplant for NBL. Additionally, clinical antitumor response to monoclonal antibodies has been associated with specific polymorphic-FcγR alleles. Relapsed/refractory NBL patients received the hu14.18-IL2 IC (humanized anti-GD2 monoclonal antibody linked to human IL2) in a Children's Oncology Group phase II trial. In this report, these patients were genotyped for KIR, HLA, and FcR alleles to determine whether KIR receptor-ligand mismatch or specific FcγR alleles were associated with antitumor response. DNA samples were available for 38 of 39 patients enrolled: 24 were found to have autologous KIR/KIR-ligand mismatch; 14 were matched. Of the 24 mismatched patients, 7 experienced either complete response or improvement of their disease after IC therapy. There was no response or comparable improvement of disease in patients who were matched. Thus KIR/KIR-ligand mismatch was associated with response/improvement to IC (P = 0.03). There was a trend toward patients with the FcγR2A 131-H/H genotype showing a higher response rate than other FcγR2A genotypes (P = 0.06). These analyses indicate that response or improvement of relapsed/refractory NBL patients after IC treatment is associated with autologous KIR/KIR-ligand mismatch, consistent with a role for natural killer cells in this clinical response.