RESUMEN
Ruxolitinib is a potent Janus kinase (JAK)1/JAK2 inhibitor that has demonstrated rapid reductions in splenomegaly and marked improvement in disease-related symptoms and quality of life in patients with myelofibrosis (MF). The present analysis reports the 3-year follow-up (median, 151 weeks) of the efficacy and safety of Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II (the COMFORT-II Trial), comparing ruxolitinib with the best available therapy (BAT) in 219 patients with intermediate-2 and high-risk MF. In the ruxolitinib arm, with continued therapy, spleen volume reductions of ≥35% by magnetic resonance imaging (equivalent to approximately 50% reduction by palpation) were sustained for at least 144 weeks, with the probability of 50% (95% confidence interval [CI], 36-63) among patients achieving such degree of response. At the time of this analysis, 45% of the patients randomized to ruxolitinib remained on treatment. Ruxolitinib continues to be well tolerated. Anemia and thrombocytopenia were the main toxicities, but they were generally manageable, improved over time, and rarely led to treatment discontinuation (1% and 3.6% of patients, respectively). No single nonhematologic adverse event led to definitive ruxolitinib discontinuation in more than 1 patient. Additionally, patients randomized to ruxolitinib showed longer overall survival than those randomized to BAT (hazard ratio, 0.48; 95% CI, 0.28-0.85; log-rank test, P = .009).
Asunto(s)
Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/mortalidad , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirazoles/administración & dosificación , Anemia/inducido químicamente , Anemia/tratamiento farmacológico , Anemia/enzimología , Anemia/mortalidad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Masculino , Nitrilos , Mielofibrosis Primaria/enzimología , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/efectos adversos , Pirimidinas , Tasa de Supervivencia , Trombocitopenia/inducido químicamente , Trombocitopenia/tratamiento farmacológico , Trombocitopenia/enzimología , Trombocitopenia/mortalidad , Factores de TiempoRESUMEN
Patients with myelofibrosis (MF) have significant debilitating symptoms, physical disabilities, and poor health-related quality of life (HRQoL). Here, we report post-hoc analyses of the impact of ruxolitinib, a potent and selective JAK1 and JAK2 inhibitor, on disease-related symptoms and HRQoL in MF patients from the large phase 3 COMFORT-II study (N = 219). During the follow-up period of 48 weeks, HRQoL and MF-associated symptoms improved from baseline for ruxolitinib-treated patients but remained the same or worsened for best available therapy (BAT)-treated patients. Based on the European Organization for Research and Treatment of Cancer QoL Questionnaire core 30 items (EORTC QLQ-C30), treatment-induced differences in physical and role functioning, fatigue, and appetite loss significantly favoured ruxolitinib versus BAT from week 8 (P < 0·05) up to week 48 (P < 0·05). Ruxolitinib resulted in significantly higher response rates in global health status/QoL and Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) summary scores versus BAT at most time points (P < 0·05). Significant improvements in the Lymphoma subscale (including symptoms of pain, fever, itching, fatigue, weight loss, loss of appetite, and other patient concerns), FACT-General, FACT-Lym trial outcome index, and FACT-Lym total were also observed with ruxolitinib versus BAT starting at week 8 and continuing thereafter. Overall, these data demonstrated that ruxolitinib improved HRQoL in MF patients and further support the use of ruxolitinib for the treatment of symptomatic MF.
Asunto(s)
Mielofibrosis Primaria/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Anciano , Femenino , Humanos , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Masculino , Nitrilos , Mielofibrosis Primaria/enzimología , Mielofibrosis Primaria/patología , Pirimidinas , Calidad de Vida , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
Immunoglobulin E (IgE) is a key driver of type 1 hypersensitivity reactions and allergic disorders, which are globally increasing in number and severity. Although eliminating pathogenic IgE may be a powerful way to treat allergy, no therapeutic strategy reported to date can fully ablate IgE production. Interleukin-4 receptor α (IL-4Rα) signaling is required for IgE class switching, and IL-4Rα blockade gradually reduces, but does not eliminate, IgE. The persistence of IgE after IL-4Rα blockade may be due to long-lived IgE+ plasma cells that maintain serological memory to allergens and thus may be susceptible to plasma cell-targeted therapeutics. We demonstrate that transient administration of a B cell maturation antigen x CD3 (BCMAxCD3) bispecific antibody markedly depletes IgE, as well as other immunoglobulins, by ablating long-lived plasma cells, although IgE and other immunoglobulins rapidly rebound after treatment. Concomitant IL-4Rα blockade specifically and durably prevents the reemergence of IgE by blocking IgE class switching while allowing the restoration of other immunoglobulins. Moreover, this combination treatment prevented anaphylaxis in mice. Together with additional cynomolgus monkey and human data, our studies demonstrate that allergic memory is primarily maintained by both non-IgE+ memory B cells that require class switching and long-lived IgE+ plasma cells. Our combination approach to durably eliminate pathogenic IgE has potential to benefit allergy in humans while preserving antibody-mediated immunity.
Asunto(s)
Anafilaxia , Inmunoglobulina E , Ratones , Humanos , Animales , Macaca fascicularis , Células Plasmáticas , AlérgenosRESUMEN
Although many patients with diffuse large B cell lymphoma (DLBCL) may achieve a complete response to frontline chemoimmunotherapy, patients with relapsed/refractory disease typically have poor outcomes. Odronextamab, a CD20xCD3 bispecific antibody that provides "signal 1" through the activation of the T cell receptor/CD3 complex, has exhibited early, promising activity for patients with highly refractory DLBCL in phase 1 trials. However, not all patients achieve complete responses, and many relapse, thus representing a high unmet medical need. Here, we investigated whether adding a costimulatory "signal 2" by engaging CD28 receptors on T cells could augment odronextamab activity. We demonstrate that REGN5837, a bispecific antibody that cross-links CD22-expressing tumor cells with CD28-expressing T cells, enhances odronextamab by potentiating T cell activation and cytolytic function. In preclinical DLBCL studies using human immune system-reconstituted animals, REGN5837 promotes the antitumor activity of odronextamab and induces intratumoral expansion of reprogrammable T cells while skewing away from a dysfunctional state. Although REGN5837 monotherapy shows limited activity and no toxicity in primate studies, it augments T cell activation when dosed in combination with odronextamab. In addition, analysis of non-Hodgkin lymphoma clinical samples reveals an increase in CD28+CD8+ T cells after odronextamab treatment, demonstrating the presence of a population that could potentially be targeted by REGN5837. Collectively, our data demonstrate that REGN5837 can markedly enhance the antitumor activity of odronextamab in preclinical NHL models, and the combination of these two bispecific antibodies may provide a chemotherapy-free approach for the treatment of DLBCL.
Asunto(s)
Anticuerpos Biespecíficos , Antineoplásicos , Linfoma de Células B Grandes Difuso , Linfoma no Hodgkin , Animales , Humanos , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Antígenos CD28 , Linfocitos T CD8-positivos , Antígenos CD19 , Recurrencia Local de Neoplasia/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Antineoplásicos/farmacología , Lectina 2 Similar a Ig de Unión al Ácido Siálico/uso terapéuticoRESUMEN
PURPOSE: Proteasome inhibition results in cytotoxicity to the leukemia stem cell in vitro. We conducted this phase I study to determine if the proteasome inhibitor bortezomib could be safely added to induction chemotherapy in patients with acute myelogenous leukemia (AML). EXPERIMENTAL DESIGN: Bortezomib was given on days 1, 4, 8, and 11 at doses of 0.7, 1.0, 1.3, or 1.5 mg/m(2) with idarubicin 12 mg/m(2) on days 1 to 3 and cytarabine 100 mg/m(2)/day on days 1 to 7. RESULTS: A total of 31 patients were enrolled. The median age was 62 years, and 16 patients were male. Nine patients had relapsed AML (ages, 18-59 years, n = 4 and > or = 60 years, n = 5). There were 22 patients of > or = 60 years with previously untreated AML (eight with prior myelodysplasia/myeloproliferative disorder or cytotoxic therapy). All doses of bortezomib, up to and including 1.5 mg/m(2), were tolerable. Nonhematologic grade 3 or greater toxicities included 12 hypoxia (38%; 11 were grade 3), 4 hyperbilirubinemia (13%), and 6 elevated aspartate aminotransferase (19%). Overall, 19 patients (61%) achieved complete remission (CR) and three had CR with incomplete platelet recovery. Pharmacokinetic studies revealed that the total body clearance of bortezomib decreased significantly (P < 0.01, N = 26) between the first (mean +/- SD, 41.9 +/- 17.1 L/h/m(2)) and third (18.4 +/- 7.0 L/h/m(2)) doses. Increased bone marrow expression of CD74 was associated with CR. CONCLUSIONS: The combination of bortezomib, idarubicin, and cytarabine showed a good safety profile. The recommended dose of bortezomib for phase II studies with idarubicin and cytarabine is 1.5 mg/m(2).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Leucemia Mieloide Aguda/metabolismo , Adolescente , Adulto , Anciano , Biomarcadores de Tumor , Ácidos Borónicos/administración & dosificación , Bortezomib , Estudios de Cohortes , Citarabina/administración & dosificación , Femenino , Perfilación de la Expresión Génica , Humanos , Idarrubicina/administración & dosificación , Leucemia Mieloide Aguda/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Análisis de Secuencia por Matrices de Oligonucleótidos , Pirazinas/administración & dosificación , Distribución Tisular , Resultado del TratamientoRESUMEN
Objective: We report the characterization of MCLA-117, a novel T cell-redirecting antibody for acute myeloid leukaemia (AML) treatment targeting CD3 on T cells and CLEC12A on leukaemic cells. In AML, CLEC12A is expressed on blasts and leukaemic stem cells. Methods: The functional capacity of MCLA-117 to redirect resting T cells to eradicate CLEC12APOS tumor cells was studied using human samples, including primary AML samples. Results: Within the normal hematopoietic compartment, MCLA-117 binds to cells expressing CD3 and CLEC12A but not to early myeloid progenitors or hematopoietic stem cells. MCLA-117 induces T cell activation (EC50 = 44 ng/mL), T cell proliferation, mild pro-inflammatory cytokine release, and redirects T cells to lyse CLEC12APOS target cells (EC50 = 68 ng/mL). MCLA-117-induced targeting of normal CD34POS cells co-cultured with T cells spares erythrocyte and megakaryocyte differentiation as well as preserves mono-myelocytic lineage development. In primary AML patient samples with autologous T cells, MCLA-117 robustly induced AML blast killing (23-98%) at low effector-to-target ratios (1:3-1:97). Conclusion: These findings demonstrate that MCLA-117 efficiently redirects T cells to kill tumour cells while sparing the potential of the bone marrow to develop the full hematological compartment and support further clinical evaluation as a potentially potent treatment option for AML.
Asunto(s)
Anticuerpos Biespecíficos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Linfocitos T/inmunología , Animales , Anticuerpos Biespecíficos/metabolismo , Anticuerpos Biespecíficos/farmacocinética , Complejo CD3/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular , Citocinas/análisis , Citocinas/metabolismo , Células HL-60 , Semivida , Humanos , Lectinas Tipo C/inmunología , Leucemia Mieloide Aguda/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Receptores Mitogénicos/inmunología , Linfocitos T/metabolismoRESUMEN
BACKGROUND: The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. Dysregulated JAK-STAT signaling has been implicated in the pathogenesis of multiple human malignancies. OBJECTIVE: Given this pivotal role of JAK-STAT dysregulation, it is important to identify patients with an overactive JAK-STAT pathway for possible treatment with JAK inhibitors. METHODS: We developed a gene signature assay to detect overactive JAK-STAT signaling. The cancer cell line encyclopedia and associated gene-expression data were used to correlate the activation status of STAT5 with the induction of a set of STAT5 target genes. RESULTS: Four target genes were identified (PIM1, CISH, SOCS2, and ID1), the expression of which correlated significantly with pSTAT5 status in 40 hematologic tumor cell lines. In pSTAT5-positive models, the expression of the gene signature genes decreased following ruxolitinib treatment, which corresponded to pSTAT5 downmodulation. In pSTAT5-negative cell lines, neither pSTAT5 modulation nor a change in signature gene expression was observed following ruxolitinib treatment. CONCLUSIONS: The gene signature can potentially be used to stratify or enrich for patient populations with activated JAK-STAT5 signaling that might benefit from treatments targeting JAK-STAT signaling. Furthermore, the 4-gene signature is a predictor of the pharmacodynamic effects of ruxolitinib.
Asunto(s)
Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Animales , Línea Celular Tumoral , Femenino , Neoplasias Hematológicas/tratamiento farmacológico , Xenoinjertos , Humanos , Quinasas Janus/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Nitrilos , Pirazoles/farmacología , Pirimidinas , Transducción de Señal/efectos de los fármacosRESUMEN
It has been 12 years since the simultaneous discovery of the unique sensitivity of acute promyelocytic leukaemia (APL) to differentiation therapy with all-trans retinoic acid (ATRA) and the discovery that the retinoic acid receptor alpha (RARalpha) gene was rearranged in APL. Nearly 98% of cases of APL are associated with t(15;17) chromosomal translocation and fusion of the PML gene to that encoding RARalpha to yield an abnormal receptor with the capability of de-regulating gene expression in the haematopoietic cell, causing differentiation block and eventually the development of leukaemia. Since this original discovery, four other translocations were described in APL. In each of these the RARalpha gene is fused to different partner genes, all yielding aberrant nuclear receptors. These fusion proteins share in common the ability to repress rather than activate retinoic acid targets, one so strongly that the result is an ATRA-resistant form of the disease. In addition each of the partner proteins is important for normal cell growth and development. In this chapter we explore the biology of the RARalpha, the fusion proteins created in APL and the normal forms of the partner proteins. Through continued study of this disease it is hoped that novel treatments, potentially more applicable to other forms of leukaemia, may arise.
Asunto(s)
Leucemia Promielocítica Aguda/genética , Receptores de Ácido Retinoico/genética , Reordenamiento Génico , Heterogeneidad Genética , Humanos , Leucemia Promielocítica Aguda/clasificación , Leucemia Promielocítica Aguda/etiología , Proteínas de Fusión Oncogénica , Receptor alfa de Ácido Retinoico , Translocación GenéticaRESUMEN
PURPOSE: To quantify gastrointestinal stromal tumor (GIST) patients' preferences for reducing treatment toxicities and the likely effect of toxicities on patients' stated adherence. METHODS: English-speaking members of the Life Raft Group, a GIST patient advocacy and research organization, aged 18 years and older, completed a web-enabled survey including a series of treatment-choice questions, each presenting a pair of hypothetical GIST medication toxicity profiles. Each profile was defined by common or concerning toxicities verified via pretest interviews including: severity of edema, diarrhea, nausea, fatigue, rash, hand-foot syndrome, and heart failure; and risk of serious infection. Each subject answered 13 choice-format questions based on a predetermined experimental design with known statistical properties. Subjects were asked to rate the likelihood that they would miss or skip doses of medications with different toxicity profiles. Random-parameters logit was used to estimate a relative preference weight for each level of toxicity. RESULTS: 173 subjects completed the survey. Over the ranges of toxicity levels included in the study, heart failure was the most important toxicity. Edema was the least important. For all toxicities, reducing severity from severe to moderate was more important to subjects than reducing severity from moderate to mild. Reducing heart failure from moderate to mild and diarrhea from severe to moderate had the largest effects on subjects' evaluation of adherence. CONCLUSIONS: All toxicities included in the study are important to patients. Treating or reducing severe toxicities is much more important to patients than treating or reducing moderate toxicities. Focused reductions of certain toxicities may improve treatment adherence.
RESUMEN
MMSET, identified by its fusion to the IgH locus in t(4;14)-associated multiple myeloma, possesses domains found within chromatin regulators, including the SET domain. MMSET protein is overexpressed and highly associated with chromatin in myeloma cell lines carrying t(4;14). MMSET possesses methyltransferase activity for core histone H3 lysine 4 and histone 4 lysine 20, whereas MMSET made in cells only modified H4. Segments of MMSET fused to the Gal4 DNA binding domain repressed transcription of a chromatin-embedded Gal4 reporter gene. MMSET-mediated repression was associated with increased H4K20 methylation gene and loss of histone acetylation. Consistent with this repressive activity, MMSET could form a complex with HDAC1 and HDAC2, mSin3a, and the histone demethylase LSD1, suggesting that it is a component of corepressor complexes. Furthermore, MMSET coexpression enhances HDAC1- and HDAC2-mediated repression in transcriptional reporter assays. Finally, shRNA-mediated knockdown of MMSET compromised viability of a myeloma cell line, suggesting a biologic role for the protein in malignant cell growth. Collectively, these data suggest that, by acting directly as a modifier of chromatin as well as through binding of other chromatin-modifying enzymes, MMSET influences gene expression and potentially acts as a pathogenic agent in multiple myeloma.