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Currently, the role of DNA methylation in the IgM-monoclonal gammopathy disease spectrum remains poorly understood. In the present study, a multi-omics prospective analysis was conducted integrating DNA methylation, RNA-seq and WES data in 34 subjects [23 WM, 6 IgM-MGUS, 5 normal controls]. Analysis was focused on defining differences between IgM-gammopathies (WM/IgM-MGUS) compared to controls, and specifically between WM and IgM-MGUS. Between groups, genome-wide DNA methylation analysis demonstrated a significant number of differentially methylated regions which were annotated according to genomic region. Next, integration of RNA-seq data was performed to identify potentially epigenetically deregulated pathways. We found that pathways involved in cell cycle, metabolism, cytokine/immune signaling, cytoskeleton, tumor microenvironment, and intracellular signaling were differentially activated and potentially epigenetically regulated. Importantly, there was a positive enrichment of CXCR4 signaling pathway along with several interleukin (IL-6, IL-8, IL15) signaling pathways in WM compared to IgM-MGUS. Further assessment of known tumor suppressor genes and oncogenes uncovered differential promoter methylation of several targets with concordant change in gene expression, including CCND1 and CD79B. Overall, this report defines how aberrant DNA methylation in IgM-gammopathies may play a critical role in the epigenetic control of oncogenesis and key cellular functions.
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In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.
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Histiocitosis de Células de Langerhans , Neoplasias Primarias Secundarias , Humanos , Adulto , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/genética , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Retrospectivos , Incidencia , Histiocitosis de Células de Langerhans/epidemiología , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/patología , MutaciónRESUMEN
Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai-Dorfman-Destombes disease (RDD) and Erdheim-Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy-proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty-seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non-V600-BRAF, RAF1 and a BICD2-BRAF fusion. A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.
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Enfermedad de Erdheim-Chester , Mutación , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/tratamiento farmacológico , Anciano , Adolescente , Terapia Molecular Dirigida , Adulto Joven , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Niño , Histiocitosis Sinusal/genética , Histiocitosis Sinusal/tratamiento farmacológico , Histiocitosis Sinusal/patología , Proteínas Proto-Oncogénicas B-raf/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , PreescolarRESUMEN
The open reading frame 8 (ORF8) protein, encoded by the SARS-CoV-2 virus after infection, stimulates monocytes/macrophages to produce pro-inflammatory cytokines. We hypothesized that a positive ex vivo monocyte response to ORF8 protein pre-COVID-19 would be associated with subsequent severe COVID-19. We tested ORF8 ex vivo on peripheral blood mononuclear cells (PBMCs) from 26 anonymous healthy blood donors and measured intracellular cytokine/chemokine levels in monocytes by flow cytometry. The % monocytes staining positive in the sample and change in mean fluorescence intensity (ΔMFI) after ORF8 were used to calculate the adjusted MFI for each cytokine. We then tested pre-COVID-19 PBMC samples from 60 CLL patients who subsequently developed COVID-19 infection. Severe COVID-19 was defined as hospitalization due to COVID-19. In the 26 normal donor samples, the adjusted MFI for interleukin (IL)-1ß, IL-6, IL-8, and CCL-2 were significantly different with ORF8 stimulation vs controls. We next analyzed monocytes from pre-COVID-19 PBMC samples from 60 CLL patients. The adjusted MFI to ORF8 stimulation of monocyte intracellular IL-1ß was associated with severe COVID-19 and a reactive ORF8 monocyte response was defined as an IL- 1ß adjusted MFI ≥ 0.18 (sensitivity 67%, specificity 75%). The median time to hospitalization after infection in CLL patients with a reactive ORF8 response was 12 days versus not reached for patients with a non-reactive ORF8 response with a hazard ratio of 7.7 (95% CI: 2.4-132, p=0.005). These results provide new insight on the monocyte inflammatory response to virus with implications in a broad range of disorders involving monocytes.
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Malignant histiocytosis (MH) is an extremely rare neoplasm of the macrophage-dendritic cell lineage. We report the clinical characteristics, molecular aberrations, treatments, and outcomes of patients with MH seen at two referral centers from January 2000 to May 2023. We identified 43 patients with MH, of which 26 had histiocytic sarcoma (MH-H), 9 interdigitating dendritic cell sarcoma (MH-IDC), and 8 Langerhans cell sarcoma (MH-LC). The median age at diagnosis was 61 years (range, 3-83). Thirty-three patients (77%) had multifocal disease, while 10 had unifocal involvement. Tumor specimens from 22 patients (51%) underwent targeted next generation sequencing, and 19 of 22 (86%) had at least one pathogenic mutation, including mutations in MAPK pathway genes (73%). The median overall survival (OS) among the entire cohort was 16 months (95% CI: 8-50). The outcomes of those with multifocal disease were significantly shorter than their unifocal counterpart: median OS of 10 months versus 50 months (p = .07). Patients with risk organ involvement (bone marrow, spleen, or liver) had significantly inferior outcomes. Chemotherapy and surgery were the most common first-line treatments for multifocal and unifocal disease, respectively. While the outcome for patients with multifocal disease was poor, there was a subset of patients who had durable responses to treatment. Our study highlights that MH has heterogeneous clinical presentation, frequent oncogenic mutations, and prognosis, which is strongly tied to disease extent and type of organ involvement.
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Sarcoma Histiocítico , Humanos , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Sarcoma Histiocítico/genética , Sarcoma Histiocítico/terapia , Sarcoma Histiocítico/patología , Macrófagos/patología , Médula Ósea/patología , Pronóstico , Hígado/patologíaRESUMEN
Malignant histiocytoses (MHs), or the 'M group' of the Histiocyte Society classification, are characterized by neoplastic histiocytes with large pleomorphic nuclei. MH encompasses the diagnoses of histiocytic sarcoma, interdigitating dendritic cell sarcoma, and Langerhans cell sarcoma. We aimed to define the phenotypic spectrum of MH and examine the genotypic features across this spectrum. Using immunohistochemistry, we arranged the 22 cases into 4 subtypes that correspond to the lines of differentiation from monocytic and dendritic cell precursors as follows: (1) macrophage (n = 5): CD68+, CD163+, CD14+, and Factor 13a+; (2) monocyte-macrophage (n = 5): CD68+, CD163+, CD14+, S100+, and OCT2+; (3) dendritic cell (n = 6): CD68+, CD11c+, S100+, lysozyme+, ZBTB46+, and CD1a/langerin < 5%; and (4) Langerhans cell (n = 6): CD68+, CD11c+, S100+, ZBTB46+, CD1a+, and langerin+. The phenotypic subtypes align with those seen in low-grade histiocytic neoplasms as follows: MH-macrophage type correlates with Erdheim-Chester disease phenotype; MH-monocyte-macrophage type with Rosai-Dorfman disease phenotype, and MH-Langerhans cell type with Langerhans cell histiocytosis. Activating mutations in MAPK-pathway genes were identified in 80% of MH cases; 29% had mutations in the PI3k-AKT-mTOR pathway and 59% had mutations in epigenetic modulating genes. Strong expression of cyclin D1 was present in all cases, whereas p-ERK and p-AKT were not uniformly expressed. Eight of 22 (36%) MH cases were proven to be clonally related to a prior B-cell lymphoma. Defining the phenotypic spectrum of MH provides a guide to diagnosis and allows further exploration into the potential biological and clinical significance.
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PURPOSE: To evaluate the clinical presentation, treatment, and outcomes in adult patients with histiocytic disorders with ocular, orbital, optic nerve, or cavernous sinus involvement. DESIGN: Observational, retrospective chart review. PARTICIPANTS: Adult patients (age ≥ 18 years) at Mayo Clinic from January 1, 1996, to July 1, 2021, with histiocytic disorders. Inclusion criteria were (1) histiocytic disorder by biopsy and appropriate clinical phenotype; (2) available medical records; and (3) ocular, orbital, optic nerve, or cavernous sinus involvement. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Response to therapy, measured in clinical and radiographic impact. RESULTS: Thirty-two patients were identified: 7 with Langerhans cell histiocytosis (LCH); 15 with Erdheim-Chester disease (ECD); 1 with mixed LCH/ECD phenotype; 8 with Rosai-Dorfman disease (RDD); and 1 with mixed RDD/ECD phenotype. Ophthalmologic involvement was part of the initial presentation in 69% of patients (22/32). Eyelid edema (13/32, 41%) and proptosis (12/32, 38%) were the most frequent presentations. Isolated orbital or cavernous sinus involvement was present in 3 of 7 patients with LCH and 1 of 8 patients with RDD. Optic nerve sheath involvement was present in 2 of 7 LCH patients, 14 of 15 ECD patients, and 1 RDD/ECD patient. Diffuse (> 75%) orbital involvement was seen in 12 of 15 ECD patients and 1 of 7 LCH patients. Ocular involvement was seen in 1 of 15 ECD patients, 6 of 8 RDD patients, and 1 of 1 mixed RDD/ECD patient. The cavernous sinuses were involved in 1 of 7 LCH patients, 5 of 15 ECD patients, and both mixed phenotype patients. Visual acuity was affected in 14 patients (14/24, 58%) with a median logarithm of the minimum angle of resolution visual acuity of 0.1 (range, -0.12 to 3). BRAF V600E mutations were found in 75% (3/4) of LCH patients and 91% (10/11) of ECD patients. Patients received a variety of treatment, and response was variable across disease types. CONCLUSIONS: Orbital involvement was more commonly seen in LCH and ECD, whereas ocular involvement was more common in RDD. Visual acuity may be impacted from ocular involvement or compression of the optic nerve with diffuse orbital involvement.
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Enfermedad de Erdheim-Chester , Exoftalmia , Histiocitosis de Células de Langerhans , Humanos , Estudios Retrospectivos , Enfermedad de Erdheim-Chester/complicaciones , Enfermedad de Erdheim-Chester/diagnóstico , Enfermedad de Erdheim-Chester/tratamiento farmacológico , Histiocitosis de Células de Langerhans/complicaciones , Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Resultado del Tratamiento , Exoftalmia/diagnósticoRESUMEN
Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer therapeutics. Broader application of KPT-330 (selinexor), a first-in-class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the antitumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid-organ cancers ex vivo and in vivo. The K+CS combination was not toxic to nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51, and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell-cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Colina/análogos & derivados , Reparación del ADN/efectos de los fármacos , Hidrazinas/farmacología , Carioferinas/antagonistas & inhibidores , Linfoma no Hodgkin/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Puntos de Control de la Fase S del Ciclo Celular/efectos de los fármacos , Salicilatos/farmacología , Triazoles/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Colina/administración & dosificación , Colina/efectos adversos , Colina/farmacología , Replicación del ADN/efectos de los fármacos , ADN de Neoplasias/efectos de los fármacos , Combinación de Medicamentos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Hidrazinas/administración & dosificación , Hidrazinas/efectos adversos , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/patología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Ftalazinas/administración & dosificación , Ftalazinas/farmacología , Piperazinas/administración & dosificación , Piperazinas/farmacología , Distribución Aleatoria , Salicilatos/administración & dosificación , Salicilatos/efectos adversos , Triazoles/administración & dosificación , Triazoles/efectos adversos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína Exportina 1RESUMEN
PURPOSE OF REVIEW: Histiocytic disorders, including Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD), are rare neoplasms that may present with a spectrum of neurologic involvement. Diagnostic delay is common due to heterogeneity in presentation and challenging pathology. RECENT FINDINGS: Recent advances in the treatment of these diseases targeted towards mutations in the MAP kinase pathway have led to an improved prognosis in these patients with neurologic involvement. It is critical for clinicians to have a high index of suspicion to allow for early targeted treatment and optimize neurologic outcomes. A systematic approach to diagnosis is presented in this article to allow for accurate diagnosis of these rare diseases.
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Enfermedad de Erdheim-Chester , Histiocitosis de Células de Langerhans , Histiocitosis Sinusal , Humanos , Diagnóstico Tardío , Histiocitosis de Células de Langerhans/complicaciones , Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis de Células de Langerhans/genética , Enfermedad de Erdheim-Chester/complicaciones , Enfermedad de Erdheim-Chester/diagnóstico , Enfermedad de Erdheim-Chester/genética , Histiocitosis Sinusal/diagnóstico , Histiocitosis Sinusal/patología , Histiocitosis Sinusal/terapia , PronósticoRESUMEN
Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm with frequent multiorgan involvement. An accurate diagnosis of ECD requires the correlation of clinical features, histopathologic and radiologic findings. We describe a case series of patients with a referral diagnosis of ECD, whereby the diagnosis was changed to non-histiocytic diseases after comprehensive review at a tertiary care center. This accurate revision of the referral diagnosis of ECD enabled initiation of proper disease-directed therapy in a timely manner for these patients and avoided unnecessary exposure to systemic cytotoxic chemotherapy or targeted agents. Our study highlights the value of a multidisciplinary team of histiocytosis experts in confirming the diagnosis of ECD and also brings attention to other conditions to consider that can mimic ECD, including osteopoikilosis, tenosynovial giant cell tumour, IgG4-related disease, fibrous dysplasia and chronic recurrent multifocal osteomyelitis.
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Enfermedad de Erdheim-Chester/diagnóstico , Adulto , Anciano , Enfermedad de Erdheim-Chester/patología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Belantamab mafodotin (BLMF) is a B-cell maturation antigen-directed antibody-drug conjugate, recently approved for advanced multiple myeloma (MM). The impact of BLMF-induced ocular toxicity on patient outcomes is unknown. We studied a cohort of 38 consecutively seen patients treated with BLMF outside of trials. Of those, 75% experienced ocular toxicity, with 69% developing keratopathy. Among patients requiring ocular toxicity-related permanent BLMF discontinuation (14%) or dose reduction (11%), 70% had progression of MM within a median of 3 months (95% confidence interval: 0.2-not reached) following BLMF interruption or dose reduction. Ocular toxicity is a major deterrent to the continuous use of BLMF in routine clinical practice. Measures to successfully prevent and mitigate ocular toxicity should be developed to achieve the full potential of this agent.
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Inmunoconjugados , Mieloma Múltiple , Anticuerpos Monoclonales Humanizados , Antígeno de Maduración de Linfocitos B , Humanos , Inmunoconjugados/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Neuropatía Óptica TóxicaRESUMEN
INTRODUCTION: Histiocytic disorders pose significant diagnostic and management challenges for the clinicians due to diverse clinical manifestations and often non-specific histopathologic findings. Herein, we report the tumor board experience from the first-of-its-kind Histiocytosis Working Group (HWG). MATERIALS AND METHODS: The HWG was established in June 2017 and consists of experts from 10 subspecialties that discuss cases in a multidisciplinary format. We present the outcome of tumor board case discussions during the first 2 years since its inception (June 2017-June 2019). RESULTS: Forty cases with a suspected histiocytic disorder were reviewed at HWG during this time period. Average number of subspecialties involved in HWG case discussion was 5 (range, 2-9). Histiocytosis Working Group tumor board recommendations led to significant changes in the care of 24 (60%) patients. These included change in diagnosis (n = 11, 27%) and change in treatment (n = 13, 33%). CONCLUSION: Our report highlights the feasibility of a multidisciplinary tumor board and its impact on outcomes of patients with histiocytic disorders.
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Histiocitosis , Neoplasias , Histiocitosis/diagnóstico , Histiocitosis/patología , Histiocitosis/terapia , HumanosRESUMEN
Erdheim-Chester disease (ECD) is a histiocytic neoplasm that predominantly harbors mitogen-activated protein kinase (MAPK) pathway variants. MAPK inhibitors typically are effective treatments, but mutations outside the MAPK pathway, such as CSF1R variants, may cause refractory ECD. We describe a patient with a novel somatic mutation in CSF1R (CSF1RR549_E554delinsQ ) that resulted in refractory ECD affecting the central nervous system. Cell model studies, RNA sequencing analysis, and in silico protein modeling suggested that she had a gain-of-function mutation occurring in a region critical for autoinhibition. The patient was treated with pexidartinib, a CSF1R inhibitor, and has had a complete clinical and metabolic response lasting more than 1.5 years to date. To our knowledge, this is the first report to describe successful treatment of a patient with ECD by using an agent that specifically targets CSF1R. This case also highlights the critical role of individualized molecular profiling to identify novel therapeutic targets in ECD.
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Aminopiridinas/administración & dosificación , Enfermedad de Erdheim-Chester , Mutación , Pirroles/administración & dosificación , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Línea Celular , Enfermedad de Erdheim-Chester/tratamiento farmacológico , Enfermedad de Erdheim-Chester/genética , Femenino , HumanosRESUMEN
Patients with asymptomatic/smouldering Waldenström macroglobulinaemia (SWM) have a variable risk of progression to active WM. Our study evaluated 143 patients with SWM consecutively seen between January 1996 and December 2013. With a median [95% confidence interval (CI)] follow-up of 9·5 [8·1-11·5] years, the cumulative rate of progression was 11% at 1 year, 38% at 3 years and 55% at 5 years. On multivariate analysis, haemoglobin (Hb) ≤123 g/l [risk ratio (RR) 2·08; P = 0·009] and ß2 -microglobulin (ß2 M) ≥2·7 µg/ml (RR 2·0; P = 0·01) were independent predictors of a shorter time-to-progression (TTP) to active WM. Patients with myeloid differentiation factor 88 wild type (MYD88WT ) genotype (n = 11) demonstrated a trend toward shorter TTP [median (95% CI) 1·7 (0·7-8·7) vs. 4·7 (2·4-7·7) years for the MYD88L265P cohort, n = 42; P = 0·11]. The presence of C-X-C chemokine receptor type 4 (CXCR4) mutation (n = 29) did not impact the TTP (median: 3 years for CXCR4WT vs. 5·6 years for CXCR4MUT , P = 0·34). The overall survival (OS) for patients with SWM (median: 18·1 years) was comparable to an age-, sex- and calendar year-matched USA population (median: 20·3 years, P = 0·502). In conclusion, Hb and ß2 M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre-emptive intervention in this patient population.
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Hemoglobinas/análisis , Factor 88 de Diferenciación Mieloide/genética , Macroglobulinemia de Waldenström/genética , Microglobulina beta-2/sangre , Anciano , Biomarcadores/análisis , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mutación , Valor Predictivo de las Pruebas , Receptores CXCR4/genética , Estudios Retrospectivos , Factores de Riesgo , Sobrevida , Macroglobulinemia de Waldenström/sangre , Macroglobulinemia de Waldenström/diagnóstico , Macroglobulinemia de Waldenström/patologíaRESUMEN
Ibrutinib is associated with durable responses in patients with Waldenström macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression-free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P = 0·29). In the learning cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 81% and 57% respectively (P = 0·009). In the validation cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 83% and 54% respectively (P = 0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38; P = 0·01] and validation cohorts (HR 0·18; P = 0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM.
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Adenina/análogos & derivados , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Macroglobulinemia de Waldenström/tratamiento farmacológico , Adenina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Estudios Prospectivos , Resultado del Tratamiento , Macroglobulinemia de Waldenström/diagnósticoRESUMEN
Measurable residual disease (MRD) assessment by marrow-based next-generation flow cytometry (NGF) following autologous stem cell transplantation (ASCT) may lead to false-negative results due to patchy marrow involvement and extramedullary disease in patients with multiple myeloma. We assessed the value of simultaneous MRD evaluation with NGF and serum matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MASS-FIX). Of all 61 complete responders who were NGF-negative for MRD, around day-100 post ASCT, 59% were MASS-FIX-positive. At median follow-up of 26 months, 69% of MASS-FIX(+)/NGF(-) patients were alive and progression-free versus 96% of MASS-FIX(-)/NGF(-) patients, P = 0·02. MASS-FIX, a simple peripheral blood-based assay complements marrow-based NGF to accurately prognosticate patients with myeloma.
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Trasplante de Células Madre Hematopoyéticas/efectos adversos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Neoplasia Residual/sangre , Paraproteinemias/sangre , Adulto , Anciano , Médula Ósea/metabolismo , Reacciones Falso Negativas , Femenino , Citometría de Flujo/métodos , Estudios de Seguimiento , Humanos , Subunidades de Inmunoglobulinas/sangre , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Neoplasia Residual/diagnóstico , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodosRESUMEN
Histological transformation into diffuse large B-cell lymphoma is a rare complication in patients with Waldenström macroglobulinemia (WM) usually associated with a poor prognosis. The objective of this study was to develop and validate a prognostic index for survival in transformed WM patients. Through this multicenter, international collaborative effort, we developed a scoring system based on data from 133 patients with transformed WM who were evaluated between 1995 and 2016 (training cohort). Univariate and multivariate analyses were used to propose a prognostic index with 2-year survival after transformation as an end-point. For external validation, a data set of 67 patients was used to evaluate the performance of the model (validation cohort). By multivariate analysis, three adverse covariates were identified as independent predictors of 2-year survival after transformation: elevated serum LDH (2 points), platelet count < 100 x 109/L (1 point) and any previous treatment for WM (1 point). Three risk groups were defined: low-risk (0-1 point, 24% of patients), intermediate-risk (2-3 points, 59%, hazard ratio (HR) = 3.4) and high-risk (4 points, 17%, HR = 7.5). Two-year survival rates were 81%, 47%, and 21%, respectively (P < 0.0001). This model appeared to be a better discriminant than the International Prognostic Index (IPI) and the revised IPI (R-IPI). We validated this model in an independent cohort. This easy-to-compute scoring index is a robust tool that may allow identification of groups of transformed WM patients with different outcomes and could be used for improving the development of risk-adapted treatment strategies.
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Linfoma de Células B Grandes Difuso , Macroglobulinemia de Waldenström , Humanos , Pronóstico , Modelos de Riesgos Proporcionales , Tasa de Supervivencia , Macroglobulinemia de Waldenström/diagnósticoRESUMEN
BACKGROUND: Despite the unprecedented success of ibrutinib in lymphoma therapy, the development of ibrutinib resistance due to acquired BTK or PLCγ2 mutations has become a new clinical problem. However, not all resistance is mediated by these mutations and these mechanisms are poorly understood due to a lack of study tools that truly recapitulate this clinical scenario. METHODS: We established a novel patient-derived ibrutinib-resistant mantle cell lymphoma (MCL) line named MCIR1. Using immunological, molecular, and cytogenetic approaches, we comprehensively characterized MCIR1 and further demonstrated its utility in the study of resistance mechanisms and treatments to overcome this resistance. RESULTS: We show that MCIR1 is a bona fide ibrutinib-resistant MCL cell line with normal BTK-/PLCγ2 but ibrutinib-resistant ERK1/2 and AKT1 signaling. RNA-Seq analysis revealed a robust non-canonical NF-kB signaling that drives the ibrutinib resistance. We also demonstrate the potential utility of a MCIR1-based cell and mouse model for the discovery of new treatments to overcome BTK inhibitor resistance. CONCLUSIONS: We have established the first patient-derived ibrutinib-resistant MCL cell line MCIR1 that lacks BTK or PLCγ2 mutations but exhibits a hyperactive non-canonical NF-kB pathway. We further demonstrate its utility in the discovery and validation of new drugs to overcome this resistance.
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Adenina/análogos & derivados , Antineoplásicos/farmacología , Linfocitos B/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Efecto Fundador , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Adenina/farmacología , Agammaglobulinemia Tirosina Quinasa/genética , Agammaglobulinemia Tirosina Quinasa/metabolismo , Linfocitos B/metabolismo , Linfocitos B/patología , Línea Celular Tumoral , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/metabolismo , Linfoma de Células del Manto/patología , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Modelos Biológicos , FN-kappa B/genética , FN-kappa B/metabolismo , Fosfolipasa C gamma/genética , Fosfolipasa C gamma/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de SeñalRESUMEN
Langerhans cell histiocytosis (LCH) is a histiocytic neoplasm that can involve the lungs as single system (LCH-SSL) or multisystem disease (LCH-MSL). The role of full-body radiographic staging to determine whether patients have LCH-SSL or LCH-MSL is unclear. Long-term outcomes of LCH-SSL versus LCH-MSL and multisystem without lung involvement (LCH-MSNL) are unknown. A retrospective study of adult LCH patients seen at our center from January 2000 to 2020 was performed. In Part 1, we addressed utility of whole-body staging imaging among those presenting with isolated pulmonary signs or symptoms. Staging was defined as fluorodeoxyglucose positron emission tomography-computed tomography (CT) or whole-body CT obtained within 3 months of diagnosis. In Part 2, we examined the frequency of developing extra-pulmonary disease over time and mortality in patients with LCH-SSL. In Part 3, we compared the overall survival of LCH-SSL, LCH-MSL, and LCH-MSNL. Part 1: 240 patients with LCH were identified. A total of 112 (47%) had pulmonary signs or symptoms at presentation. Thirty-four (30%) underwent radiographic staging and only one showed evidence of extra-pulmonary disease. Part 2: 108 (45%) were LCH-SSL. Median follow-up duration of 4.5 years (95% confidence interval [CI]: 2.9-6.0). None developed extra-pulmonary disease. Part 3: 5-year survival: 94% (95% CI: 84%-98%) for LCH-SSL, 78% (95% CI: 59%-90%) for LCH-MSL, and 75% (95% CI: 53%-89%) for LCH-MSNL. LCH patients presenting with isolated pulmonary signs or symptoms rarely have extra-pulmonary involvement at the time of diagnosis and generally do not develop extra-pulmonary progression. LCH-SSL has the best overall survival, while LCH-MSL and LCH-MSNL have similar clinical outcomes.