RESUMEN
While there is clear evidence to suggest poorer outcome associated with multi-hit (MH) TP53 mutation compared to single-hit (SH) in lower-risk myelodysplastic syndrome (MDS), data are conflicting in both higher-risk MDS and acute myeloid leukemia (AML). We conducted an indepth analysis utilizing data from 10 US academic institutions to study differences in molecular characteristics and outcomes of SH (n= 139) versus MH (n= 243) TP53MTAML. Complex cytogenetics (CG) were more common in MH compared to SH TP53MT AML (p <0.001); whereas ASXL1 (p= <0.001), RAS (p<0.001), splicing factor (p= 0.003), IDH1/2 (p= 0.001), FLT3 ITD (p= <0.001) and NPM1 (p= 0.005) mutations significantly clustered with SH TP53MT AML. Survival after excluding patients who received best supportive care alone was dismal but not significantly different between SH and MH (event free survival [EFS]: 3.0 vs 2.20 months, p= 0.22/ overall survival [OS]: 8.50 vs 7.53 months, respectively, p= 0.13). In multivariable analysis, IDH1 mutation and allogeneic hematopoietic stem cell transplantation (allo-HCT) as a time-dependent covariate were associated with superior EFS (HR; 0.44, 95% CI: 0.19-1.01, p= 0.05/ HR; 0.34, 95% CI: 0.18-0.62, p<0.001) and OS (HR; 0.24, 95% CI: 0.08-0.71, p= 0.01/ HR; 0.28, 95% CI: 0.16-0.47, p<0.001). While complex CG (HR; 1.56, 95% CI: 1.01-2.40, p= 0.04) retained unfavorable significance for OS. Our analysis suggests that unlike in MDS, multihit TP53MT is less relevant in independently predicting outcomes in patients with AML.
RESUMEN
Patients with myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) with hypomethylating agent failure have a poor prognosis. Myeloid-derived suppressor cells (MDSCs) can contribute to MDS progression and mediate resistance to anti-PD1 therapy. As histone deacetylase inhibitors (HDACi) decrease MDSCs in preclinical models, we conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program-sponsored, multicenter, dose escalation, and expansion phase Ib trial (NCT02936752) of the HDACi entinostat and the anti-PD1 antibody pembrolizumab. Twenty-eight patients (25 MDS and 3 AML) were enrolled. During dose escalation (n=13 patients), there was one dose-limiting toxicity (DLT) on dose level (DL) 1 (G5 pneumonia/bronchoalveolar hemorrhage) and two DLTs at DL 2 (G3 pharyngeal mucositis and G3 anorexia). Per the 3 + 3 dose escalation design, DL 1 (entinostat 8 mg PO days 1 and 15 + pembrolizumab 200 mg IV day 1 every 21 days) was expanded and another 15 patients were enrolled. Hematologic adverse events (AEs) were common. The most common non-hematologic ≥G3 AEs were infection (32%), hypoxia/respiratory failure (11%), and dyspnea (11%). There were no protocol-defined responses among the 28 patients enrolled. Two patients achieved a marrow complete remission (mCR). Using a systems immunology approach with mass cytometry and machine learning analysis, mCR patients had increased classical monocytes and macrophages but there was no significant change of MDSCs. In conclusion, combining entinostat with pembrolizumab in patients with advanced MDS and AML was associated with limited clinical efficacy and substantial toxicity. Absence of an effect on MDSCs could be a potential explanation for the limited efficacy of this combination. ClinicalTrial.gov Identifier: NCT02936752.
Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Inhibidores de Histona Desacetilasas/efectos adversos , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/etiología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Venetoclax (VEN) combined with hypomethylating agents (HMAs) is the standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, real-world data published on HMAs plus VEN have been either single-center studies or using community-based electronic databases with limited details on mutational landscape, tolerability, and treatment patterns in elderly patients. Therefore, we conducted a multicenter retrospective study to assess the real-world experience of 204 elderly patients (≥75 years) with newly diagnosed AML treated with HMAs plus VEN from eight academic centers in the United States. Overall, 64 patients achieved complete remission (CR; 38%) and 43 CR with incomplete count recovery (CRi; 26%) for a CR/CRi rate of 64%, with a median duration of response of 14.2 months (95% CI: 9.43, 22.1). Among responders, 63 patients relapsed (59%) with median overall survival (OS) after relapse of 3.4 months (95% CI, 2.4, 6.7). Median OS for the entire population was 9.5 months (95% CI, 7.85-13.5), with OS significantly worse among patients with TP53-mutated AML (2.5 months) and improved in patients harboring NPM1, IDH1, and IDH2 mutations (13.5, 18.3, and 21.1 months, respectively). The 30-day and 60-day mortality rates were 9% and 19%, respectively. In conclusion, HMAs plus VEN yielded high response rates in elderly patients with newly diagnosed AML. The median OS was inferior to that reported in the VIALE-A trial. Outcomes are dismal after failure of HMAs plus VEN, representing an area of urgent unmet clinical need.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Anciano , Humanos , Estudios Retrospectivos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Sulfonamidas/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
TP53-altered myelodysplastic syndrome with excess blasts and TP53-altered acute myeloid leukemia should be considered under one unifying classification term for their study in clinical trials. Ultimately, such a unification would simplify the screening processes for clinical trials and allow a focus on treating the patient for a genetically defined disorder rather than one based on an arbitrary blast threshold.
Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Síndromes Mielodisplásicos/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucocitos , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: Although the clinical outcomes of patients with TP53-mutated acute myeloid leukemia (AML) are dismal, subsets of patients eligible for curative-intent therapies may fare better. Because racial disparities are known to affect outcome in hematologic malignancies, the authors sought to explore disparities among patients with TP53-mutated AML. METHODS: A multicenter, retrospective study was conducted in a cohort of 340 patients who had TP53-mutated AML (275 non-Hispanic White [NHW] and 65 non-Hispanic Black [NHB]) to analyze differences in treatment and outcome among NHW and NHB patients. RESULTS: The median patient age was comparable between NHW and NHB patients (p = .76). A higher proportion of NHB patients had therapy-related AML (31% vs. 20%; p = .08) and had co-mutations (74% vs. 61%; p = .06). A higher proportion of NHW patients received intensive chemotherapy compared with NHB patients (47% vs. 31%; p = .02). Conversely, a higher proportion of NHB patients received low-intensity chemotherapy (9% vs. 5.5%; p = .02) or best supportive care (22% vs. 7%; p < .001). The complete response rate (including complete responses with or without complete count recovery) was 31% versus 24.5% (p = .39) in NHW and NHB patients, respectively. Only 5% of NHB patients received allogeneic stem cell transplantation compared with 15.5% of NHW patients (p = .02). The proportion of patients who were event-free (18.5% vs. 8.5%; p = .49) or who remained alive (24.9% vs. 8.3%; p = .13) at 18 months was numerically higher in NHW versus NHB patients, respectively, but was not statistically significant. CONCLUSIONS: The current study highlights disparities between NHW and NHB patients with TP53-mutated AML. Efforts are warranted to eliminate treatment disparities in minority populations.
Asunto(s)
Disparidades en Atención de Salud , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Estudios Retrospectivos , Proteína p53 Supresora de Tumor/genética , Población Blanca/genética , Población Negra/genéticaRESUMEN
Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) often receive antibacterial prophylaxis. Antibacterial agents can cause elevations in the prothrombin time and international normalized ratio (INR). The impact of prophylactic antibacterials on the coagulation profiles and bleeding risk in patients with AML/MDS is unknown. We evaluated patients with AML or MDS who were being admitted to the hospital. The cohort was divided into two groups of patients: (1) those receiving and (2) those not receiving prophylactic antibacterials, at the time of admission. We conducted a retrospective cohort study of adult patients with AML/MDS admitted to Yale-New Haven Hospital between 2015-2019. The study was approved by the Yale Institutional Review Board. Inclusion criteria included patients >18 years old with a diagnosis of AML or MDS admitted to the hospital. We identified 150 individual patient encounters with active AML/MDS admitted to Yale-New Haven of which 32 occurred while on and 118 while off antibacterial prophylaxis. Median duration of pre-admission antibacterial exposure was 2 (range: 0.07-24) months. Patients on antibacterial prophylaxis had higher INR (median 1.14 vs. 1.03, p = 0.0002), and higher partial thromboplastin time prolongation (median 26.5 vs. 24.3, p < 0.0014), than patients without antibacterial prophylaxis. Patients without antibacterial prophylaxis had higher rates of bleeding using the ISTH-defined criteria (24.6% vs. 6.3%, p = 0.043), including higher rates of ISTH major (2 vs. 0) and clinically relevant bleeding (9 vs. 0). Patients with AML/MDS on antibacterial prophylaxis were more likely to have an abnormal coagulation profile when compared with their counterparts not on prophylaxis. Conversely, rates of bleeding were higher in patients not on prophylaxis. These data suggest that prophylactic antibacterials do not increase bleeding risk in patients with AML/MDS.
Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Adulto , Humanos , Adolescente , Estudios Retrospectivos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/diagnósticoRESUMEN
PURPOSE OF REVIEW: Maintenance therapy for acute myeloid leukemia (AML) has been studied for decades with mixed results. However, the application of modern agents has renewed interest and the recent data from randomized trials has provided evidence for the use of maintenance therapy in certain populations of AML patients. RECENT FINDINGS: Unselected patients are unlikely to benefit from maintenance therapy as has been previously and consistently demonstrated. The increasing availability of newer and targeted agents like oral hypomethylating agents, protein modifiers, as well as FLT3, IDH1/2 BCL-2 and immune checkpoint inhibitors have restoked interest in maintenance therapy for which randomized, placebo-controlled trials have recently demonstrated benefits, including in the post-transplant setting. Patients with high-risk disease, suboptimal consolidation or remission associated with measurable residual disease (MRD) appear to be beneficiaries of this strategy. The influence of MRD status and the platform by which it is measured are important factors in the current understanding of when maintenance therapy works and how future studies should be designed. SUMMARY: The recent positive findings in support of maintenance therapy for certain AML patient populations are practice changing and bolster the need for properly designed, randomized studies using unified and standardized MRD techniques.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/terapia , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Toma de Decisiones Clínicas , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiología , Quimioterapia de Mantención , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión , Resultado del TratamientoRESUMEN
BACKGROUND: The availability of novel agents (NAs), including blinatumomab and inotuzumab ozogamicin (InO), has improved the outcomes of patients with relapsed/refractory (RR) B-cell acute lymphoblastic leukemia (ALL). Because of the relative effectiveness, it is often a challenge for clinicians to determine how to best sequence these NAs with respect to efficacy and toxicity. METHODS: In this multicenter, retrospective study of patients with RR ALL treated with blinatumomab, InO, or both, their efficacy as a first or second NA was compared. RESULTS: Among 276 patients, 221 and 55 received blinatumomab and InO, respectively, as a first NA therapy. The complete remission (CR)/complete remission with incomplete count recovery (CRi) rate was 65% and 67% for the blinatumomab and InO groups, respectively (P = .73). The rate of treatment discontinuation due to adverse events was 4% and 7% in the blinatumomab and InO groups, respectively. Ninety-two patients (43%) in the blinatumomab group and 13 patients (29%) in the InO group proceeded with allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) was 15 and 11.6 months in the blinatumomab and InO groups, respectively. A subset analysis was performed for 61 patients who received both NAs (blinatumomab and then InO [n = 40] or InO and then blinatumomab [n = 21]). The CR/CRi rate was 58% for patients who received InO as the second NA and 52% for patients who received blinatumomab as the second NA. The median OS was 10.5 for patients who received InO as the second NA and 5.9 months for patients who received blinatumomab as the second NA (P = .09). CONCLUSIONS: Although the limited power of this study to detect a significant difference between subgroups is acknowledged, the data suggest that blinatumomab and InO may have comparable efficacy as a first or second NA therapy in RR ALL.
Asunto(s)
Anticuerpos Biespecíficos/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Inotuzumab Ozogamicina/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Biespecíficos/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Humanos , Inotuzumab Ozogamicina/efectos adversos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Inducción de Remisión , Estudios Retrospectivos , Resultado del Tratamiento , Privación de Tratamiento/estadística & datos numéricos , Adulto JovenRESUMEN
BACKGROUND: Many patients with myelodysplastic syndromes (MDS) receive red cell transfusions to relieve symptoms associated with anemia, with transfusions triggered by hemoglobin level. It is not known if patients' quality of life (QOL) improves after transfusion, nor if peri-transfusion QOL assessment (PTQA) can guide future transfusion decisions. STUDY DESIGN AND METHODS: We conducted a prospective pilot study of adults with MDS at three centers. Participants, who had to have hemoglobin ≥7.5, completed an MDS-specific measure of QOL (the Quality of Life in Myelodysplasia Scale, [QUALMS]) 1 day before and 7 days after red cell transfusion. A report was sent to each patient and provider before the next transfusion opportunity, indicating whether there were clinically significant changes in QOL. We assessed the proportion of patients experiencing changes in QOL, and with a follow-up questionnaire, whether they perceived their PTQA data were used for future transfusion decisions. RESULTS: From 2018 to 2020, 62 patients enrolled (mean age 73 years) and 37 completed both pre- and post-transfusion QOL assessments. Of these, 35% experienced a clinically significant increase in QUALMS score 7 days after transfusion; 46% no change; and 19% a decrease. Among those completing the follow-up questionnaire, 23% reported that PTQA results were discussed by their provider when considering repeat transfusion. CONCLUSIONS: These data suggest PTQA is feasible for patients with MDS. Moreover, while helpful for some, for many others, red cell transfusion may not achieve its intended goal of improving QOL. PTQA offers a strategy to inform shared decision-making regarding red cell transfusion.
Asunto(s)
Anemia/terapia , Transfusión de Eritrocitos , Síndromes Mielodisplásicos/terapia , Calidad de Vida , Anciano , Anciano de 80 o más Años , Anemia/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/complicaciones , Proyectos Piloto , Estudios ProspectivosRESUMEN
BACKGROUND: The majority of patients with acute myeloid leukemia (AML) are aged >65 years at the time of diagnosis and are not actively treated. The objective of the current study was to determine the prevalence, temporal trends, and factors associated with no active treatment (NAT) among older patients with AML in the United States. METHODS: A retrospective analysis was performed of Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 14,089 patients with AML residing in the United States who were diagnosed with AML at age ≥66 years during 2001 through 2013. NAT was defined as not receiving any chemotherapy, including hypomethylating agents. Multivariable logistic regression models were used to analyze sociodemographic, clinical, and provider characteristics associated with NAT. RESULTS: The percentage of patients with NAT decreased over time from 59.7% among patients diagnosed in 2001 to 42.8% among those diagnosed in 2013. The median overall survival for the entire cohort was 82 days from the time of diagnosis. Patients treated with NAT had worse survival compared with those receiving active treatment. Variables found to be associated with higher odds of NAT included older age, certain sociodemographic characteristics (household income within the lowest quartile, residence outside the Northeast region of the United States, and being unmarried), and clinical factors (≥3 comorbidities, the presence of mental disorders, recent hospitalization, and disability). CONCLUSIONS: Greater than one-half of older patients with AML residing in the United States do not receive any active leukemia-directed therapy despite the availability of lower intensity therapies such as hypomethylating agents. Lack of active therapy receipt is associated with inferior survival. Identifying predictors of NAT might improve the quality of care and survival in this patient population, especially as novel therapeutic options with lower toxicity are becoming available.
Asunto(s)
Leucemia Mieloide Aguda/epidemiología , Programa de VERF/normas , Anciano , Femenino , Humanos , Masculino , Estudios Retrospectivos , Estados UnidosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Quimioterapia de Inducción , Isocitrato Deshidrogenasa , Leucemia Mieloide Aguda , Mutación , Sulfonamidas , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Estudios de CohortesAsunto(s)
Linfoma de Células del Manto , Adulto , Humanos , Anciano , Rituximab/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Recurrencia Local de Neoplasia , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del TratamientoRESUMEN
In patients suspected to have myelodysplastic syndrome (MDS), especially in those patients without cytogenetic abnormalities or blast excess, accurate morphologic review by an expert hematopathologist and meticulous exclusion of other secondary causes of myelodysplasia are vital to establish the diagnosis. Errors in diagnosis can lead to dangerous consequences such as the administration of hypomethylating agents, lenalidomide, or even the use of intensive chemotherapy or allogeneic hematopoietic cell transplantation in patients who do not have an underlying MDS or even a malignant hematopoietic process. Additionally, beyond the possible harm and lack of efficacy of such therapies if the diagnosis of MDS is erroneous, the secondary myelodysplasia and resultant cytopenias are not likely to resolve unless the underlying etiology is identified and addressed. Discriminating a malignant process such as MDS from non-malignant secondary myelodysplasia can be quite challenging, and community hematologists/oncologists should consider referral to specialized physicians (both clinical experts and experienced hematopathologists) if there is any doubt regarding the diagnosis. In this article, we present a representative case series of patients from our own practice who posed diagnostic dilemmas and propose a systematic approach for assessment for secondary causes of myelodysplasia.
Asunto(s)
Neoplasias Hematológicas/diagnóstico , Síndromes Mielodisplásicos/diagnóstico , Adulto , Diagnóstico Diferencial , Femenino , Neoplasias Hematológicas/terapia , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapiaRESUMEN
Aplastic anemia (AA) is rare disorder of bone marrow failure which if severe and not appropriately treated is highly fatal. AA is characterized by morphologic marrow features, namely hypocellularity, and resultant peripheral cytopenias. The molecular pathogenesis of AA is not fully understood, and a uniform process may not be the culprit across all cases. An antigen-driven and likely autoimmune dysregulated T-cell homeostasis is implicated in the hematopoietic stem cell injury which ultimately founds the pathologic features of the disease. Defective telomerase function and repair may also play a role in some cases as evidenced by recurring mutations in related telomerase complex genes such as TERT and TERC. In addition, recurring mutations in BCOR/BCORL, PIGA, DNMT3A, and ASXL1 as well as cytogenetic abnormalities, namely monosomy 7, trisomy 8, and uniparental disomy of the 6p arm seem to be intimately related to AA pathogenesis. The increased incidence of late clonal disease has also provided clues to accurately describe plausible predispositions to the development of AA. The emergence of newer genomic sequencing and other techniques is incrementally improving the understanding of the pathogenic mechanisms of AA, the detection of the disease, and ultimately offers the potential to improve patient outcomes. In this comprehensive review, we discuss the current understanding of the immunobiology, molecular pathogenesis, and future directions of such for AA.
Asunto(s)
Anemia Aplásica/etiología , Anemia Aplásica/metabolismo , Anemia Aplásica/diagnóstico , Animales , Apoptosis , Médula Ósea/metabolismo , Médula Ósea/patología , Aberraciones Cromosómicas , Evolución Clonal/genética , Susceptibilidad a Enfermedades , Hematopoyesis/genética , Hematopoyesis/inmunología , Células Madre Hematopoyéticas/metabolismo , Humanos , Mutación , Telómero/genética , Telómero/metabolismo , Homeostasis del Telómero , Trombopoyetina/metabolismoRESUMEN
Myelodysplastic syndromes (MDS) comprise a diverse group of clonal and malignant myeloid disorders characterized by ineffective hematopoiesis, resultant peripheral cytopenias, and a meaningful increased risk of progression to acute myeloid leukemia. A wide array of recurring genetic mutations involved in RNA splicing, histone manipulation, DNA methylation, transcription factors, kinase signaling, DNA repair, cohesin proteins, and other signal transduction elements has been identified as important substrates for the development of MDS. Cytogenetic abnormalities, namely those characterized by loss of genetic material (including 5q- and 7q-), have also been strongly implicated and may influence the clonal architecture which predicts such mutations and may provoke an inflammatory bone marrow microenvironment as the substrate for clonal expansion. Other aspects of the molecular pathogenesis of MDS continue to be further elucidated, predicated upon advances in gene expression profiling and the development of new, and improved high-throughput techniques. More accurate understanding of the genetic and molecular basis for the development of MDS directly provides additional opportunity for treatment, which to date remains limited. In this comprehensive review, we examine the current understanding of the molecular pathogenesis and pathophysiology of MDS, as well as review future prospects which may enhance this understanding, treatment strategies, and hopefully outcomes.
Asunto(s)
Predisposición Genética a la Enfermedad , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/metabolismo , Biomarcadores , Aberraciones Cromosómicas , Evolución Clonal/genética , Descubrimiento de Drogas , Epigénesis Genética , Regulación de la Expresión Génica/efectos de los fármacos , Estudios de Asociación Genética , Humanos , Terapia Molecular Dirigida , Mutación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapia , Fenotipo , Pronóstico , Transducción de Señal/efectos de los fármacosRESUMEN
The human intestinal microbiota is essential for microbial homeostasis, regulation of metabolism, and intestinal immune tolerance. Rapidly evolving understanding of the importance of the microbiota implicates changes in the composition and function of intestinal microbial communities in an assortment of systemic conditions. Complications following allogeneic stem cell transplant now join the ever-expanding list of pathologic states regulated by intestinal microbiota. Dysbiosis, or disruption of the normal ecology of this microbiome, has been directly implicated in the pathogenesis of entities such as Clostridium difficile infections, graft-versus-host disease (GVHD), and most recently disease relapse, all of which are major causes of morbidity and mortality in patients undergoing allogeneic stem cell transplant. In this review, we elucidate the key origins of microbiotic alterations and discuss how dysbiosis influences complications following allogeneic stem cell transplant. Our emerging understanding of the importance of a balanced and diverse intestinal microbiota is prompting investigation into the appropriate treatment of dysbiosis, reliable and early detection of such, and ultimately its prevention in patients to improve the outcome following allogeneic hematopoietic stem cell transplant.
Asunto(s)
Microbioma Gastrointestinal/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodosRESUMEN
CD38, an adenine dinucleotide phosphate (ADP) ribose cyclase and a cyclic ADP ribose hydrolase, is widely expressed on the surface of multiple myeloma (MM) cells. It is known to play a pivotal role in the downstream pathways that mediate MM cell growth, signal transduction, and adhesion. The clinical use of CD38 monoclonal antibodies (MoAbs), such as daratumumab, either as monotherapy or in combination with other anti-MM agents, has produced impressive results in patients who have failed standard MM therapy. CD38 MoAbs exhibit several cytotoxic mechanisms on MM cells. In addition to the classical effector mechanisms associated with antibody therapy, CD38 MoAbs induce MM apoptosis and clonal T-cell expansion. Here, we summarize the results of some pivotal clinical studies using a human CD38 MoAb, daratumumab, in patients with MM, discuss the anti-MM effector mechanisms induced by CD38 MoAbs, and review the potential tumor antigens that may be suitable targets for immunotherapy of MM. Finally, we present a paradigm of immunotherapy for MM patients using CD38 MoAbs followed by GM-CSF and an immune checkpoint inhibitor in patients who have undergone high dose chemotherapy and autologous stem cell transplant. CD38 MoAbs have emerged as a novel and ultimately very promising immunotherapeutic agent for MM because of its ability to induce MM cytotoxicity through both arms of the adaptive immune responses.