High cell-free DNA is associated with disease progression, inflammasome activation and elevated levels of inflammasome-related cytokine IL-18 in patients with myelofibrosis.

Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder classified among chronic myeloproliferative neoplasms, characterized by exacerbated myeloid and megakaryocytic proliferation and bone marrow fibrosis. It is induced by driver (JAK2/CALR/MPL) and high molecular risk mutations coupled to a sustained inflammatory state that contributes to disease pathogenesis. Patient outcome is determined by stratification into risk groups and refinement of current prognostic systems may help individualize treatment decisions. Circulating cell-free (cf)DNA comprises short fragments of double-stranded DNA, which promotes inflammation by stimulating several pathways, including inflammasome activation, which is responsible for IL-1ß and IL-18 maturation and release. In this work, we assessed the contribution of cfDNA as a marker of disease progression and mediator of inflammation in MF. cfDNA was increased in MF patients and higher levels were associated with adverse clinical outcome, a high-risk molecular profile, advanced disease stages and inferior overall survival, indicating its potential value as a prognostic marker. Cell-free DNA levels correlated with tumor burden parameters and markers of systemic inflammation. To mimic the effects of cfDNA, monocytes were stimulated with poly(dA:dT), a synthetic double-stranded DNA. Following stimulation, patient monocytes released higher amounts of inflammasome-processed cytokine, IL-18 to the culture supernatant, reflecting enhanced inflammasome function. Despite overexpression of cytosolic DNA inflammasome sensor AIM2, IL-18 release from MF monocytes was shown to rely mainly on the NLRP3 inflammasome, as it was prevented by NLRP3-specific inhibitor MCC950. Circulating IL-18 levels were increased in MF plasma, reflecting in vivo inflammasome activation, and highlighting the previously unrecognized involvement of this cytokine in MF cytokine network. Monocyte counts were higher in patients and showed a trend towards correlation with IL-18 levels, suggesting monocytes represent a source of circulating IL-18. The close correlation shown between IL-18 and cfDNA levels, together with the finding of enhanced DNA-triggered IL-18 release from monocytes, suggest that cfDNA promotes inflammation, at least in part, through inflammasome activation. This work highlights cfDNA, the inflammasome and IL-18 as additional players in the complex inflammatory circuit that fosters MF progression, potentially providing new therapeutic targets.

Clinical Outcomes of Patients With B-Cell Non-Hodgkin Lymphoma in Real-World Settings: Findings From the Hemato-Oncology Latin America Observational Registry Study.

PURPOSE: Real-world evidence on non-Hodgkin lymphoma (NHL) management in Latin America is currently lacking. The objective of this study was to describe treatment characteristics and outcomes of NHL in Latin America. METHODS: A total of 2,967 patients with NHL with aggressive and indolent subtypes, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle-cell lymphoma (MCL), and mucosa-associated lymphoid tissue (MALT) lymphoma, with incident or prevalent diagnosis between 2006 and 2015, were retrospectively identified using clinical charts registered in the Hemato-Oncology Latin America Observational Registry. Associations between treatment regimen and age at diagnosis with clinical outcomes within each subtype were estimated using Cox proportional hazard regression. RESULTS: Most patients with NHL received 1L chemoimmunotherapy, most commonly cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with/without rituximab. Five-year survival rates were higher for MALT lymphoma (90.8%) and FL (87.6%) versus DLBCL (69.0%) and MCL (57.1%), with variations between countries. The median overall survival from first relapse for patients with DLBCL was 6.6 years, with lower risk of death for those diagnosed at age < 65 years (hazard ratio = 0.732; P = .0161). Patients achieved a longer median progression-free survival with 1L rituximab-CHOP (R-CHOP) versus CHOP or rituximab, cyclophosphamide, vincristine, and prednisone (RCVP) (7.7 v 3.0 or 1.8 years, respectively). Use of regimens other than R-CHOP was associated with a higher risk of death/progression for patients with DLBCL (rituximab, ifosfamide, carboplatin, and etoposide/ifosfamide, carboplatin, and etoposide) and FL (CHOP). There was no relationship between treatment prescribed and age at diagnosis with outcomes from first/second relapse in DLBCL and FL. CONCLUSION: Differences in treatment outcomes between NHL subtypes were observed, reflecting variations in NHL management and barriers to treatment access in Latin America. These data provide necessary evidence to understand NHL management in this region and highlight the need to improve treatment outcomes for these patients.

Epidemiology of Hematologic Malignancies in Real-World Settings: Findings From the Hemato-Oncology Latin America Observational Registry Study.

PURPOSE: Limited information is available on multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL) management in Latin America. The primary objective of the Hemato-Oncology Latin America (HOLA) study was to describe patient characteristics and treatment patterns of Latin American patients with MM, CLL, and NHL. METHODS: This study was a multicenter, retrospective, medical chart review of patients with MM, CLL, and NHL in Latin America identified between January 1, 2006, and December 31, 2015. Included were adults with at least 1 year of follow-up (except in cases of death within 1 year of diagnosis) treated at 30 oncology hospitals (Argentina, 5; Brazil, 9; Chile, 1; Colombia, 5; Mexico, 6; Panama/Guatemala, 4). RESULTS: Of 5,140 patients, 2,967 (57.7%) had NHL, 1,518 (29.5%) MM, and 655 (12.7%) CLL. Median follow-up was 2.2 years for MM, 3.0 years for CLL, and 2.2 years for NHL, and approximately 26% died during the study observation period. Most patients had at least one comorbidity at diagnosis. The most frequent induction regimen was thalidomide-based chemotherapy for MM and chlorambucil with or without prednisone for CLL. Most patients with NHL had diffuse large B-cell lymphoma (DLBCL; 49.1%) or follicular lymphoma (FL; 19.5%). The majority of patients with DLBCL or FL received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. CONCLUSION: The HOLA study generated an unprecedented level of high-quality, real-world evidence on characteristics and treatment patterns of patients with hematologic malignancies. Regional disparities in patient characteristics may reflect differences in ethnoracial identity and level of access to care. These data provide needed real-world evidence to understand the disease landscape in Latin America and may be used to inform clinical and health policy decision making.

Flow cytometry "Ogata score" for the diagnosis of myelodysplastic syndromes in a real-life setting. A Latin American experience.

INTRODUCTION: Flow cytometry (FC) is a helpful tool for the diagnosis of myelodysplastic syndrome (MDS). Different FC score systems have been developed. The "Ogata score" is a simple diagnostic score that has been validated having a sensitivity of 69% and a specificity of 92% in low-risk MDS. We aimed to study the feasibility and the utility of the "Ogata score" for the diagnosis of MDS among Latin America (LA) Laboratories. METHODS: This is a case and control study conducted in LA institutions members of Grupo Latinoamericano de Mielodisplasia (GLAM). A total of 146 MDS patients and 57 control patients were included. "Ogata score" was calculated. RESULTS: The sensitivity of "Ogata score" was 75.6% (95% CI, 66.8-81.3), specificity was 91.2% (95% CI, 79.7-96.7), PPV was 95.6% (95% CI, 88.5-98.3), and NPV was 65.4% (95% CI, 49.1-71.9). In low/intermediate-1 IPSS patients group, the sensitivity was 70.1% (95% CI, 60.2-78.2), specificity was 91.2% (CI-95%, 79.7-96.7), PPV was 94.2% (95% CI, 86.4-97.8), and NPV was 62.1% (95% CI, 53.0-78.7). In the group of patients "without MDS specific markers" (patients without ring sideroblasts, blast excess, or chromosomal abnormalities), the sensitivity was 66.7% (CI-95%, 55.8-76.0), specificity was 91.2% (95% CI, 79.7-96.7), PPV was 92.3% (95% CI, 82.2-97.1), and NPV was 63.5% (95% CI, 51.9-73.5). CONCLUSIONS: The diagnostic power found in this study was similar to the reported by Della-Porta et al. Also in LA, the analysis was made in modern equipment with acquisition of at least 100 000 events which permits a good reproducibility of the results.

Influence of Acute Myeloid Leukemia Progression on the Prognosis of 831 Patients With Myelodysplastic Syndromes From the Argentine Database.

BACKGROUND: A large group of patients with myelodysplastic syndromes (MDS) will die of causes intrinsic to bone marrow failure. One third of patients will develop acute myeloid leukemia (AML), which is associated with an extremely poor outcome and a short survival. Our objectives were to analyze the prognostic variables and scoring systems in the attempt to determine the influence of progression on the overall survival of MDS patients. PATIENTS AND METHODS: We performed a retrospective analysis of 831 MDS patients, including those from the Argentine Registry. RESULTS: Of the 831 MDS patients, 158 (19.0%) experienced transformation, with a median overall survival of 17.9 months from diagnosis and 3.5 months after progression. The survival of patients with adverse karyotypes or greater risk, according to the International Prognostic Scoring System-revised (IPSS-R) or World Health Organization-based Prognostic Scoring System (WPSS) was not affected when stratified by patients with and without evolution to AML (P > .05). In contrast, the survival of lower risk patients was significantly reduced for those patients with progression to AML (P < .001) and those younger (P = .024) than those who died of non-AML-related causes. The intermediate-risk patients were heterogeneously distributed; however, an upgrade from a lower IPSS-R to a higher WPSS-hemoglobin risk category was associated with a worse outcome, not affected by progression (P = .420), with a median event-free survival of 16 months. CONCLUSION: The use of the IPSS-R and WPSS systems simultaneously might help in identifying those patients who require more aggressive treatment. Nevertheless, more efforts are needed to improve the identification of those lower risk patients whose survival is significantly reduced by progression to AML.

Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.

The presence of the Philadelphia chromosome is a poor prognosis factor in acute lymphoblastic leukemia (ALL), in both children and adults. Using molecular techniques of the gen bcr/abl, it is possible to detect the abnormality, in up to the 40% of adult patients. The unsatisfactory results with conventional chemotherapy schemes have determined the intensification of the treatments and the consideration of allogenic bone marrow transplants as the best therapeutic instance. The development of tyrosine kinase inhibitors have become a therapeutic improvement in the treatment of Philadelphia chromosome-positive ALL, being combined with chemotherapy schemes, only in a selected group of patients, even in therapeutic programs that include transplant.

Peliosis esplénica: Asociación con leucemia mielomonocítica crónica, presentándose con ruptura espontánea del bazo / Splenic peliosis: Asociation with chronic myelomonocitic leukemia, presenting with spontaneous splenic rupture

La pielosis es una rara entidad, de teología poco clara: tóxica, infecciosa relacionada a inmunodepresión (enfermedades consuntivas) inflamatoria o vascular, caracterizada por la presencia de espacios quísticos múltiples, con secuestro hemático, que hasta puede llegar a producir trastornos de la hemostasia, induciendo una extrema fragilidad y por ende la ruptuta facial o espontánea del órgano, a veces sin aumentar el volúmen del mismo. Mucho más rara es su asociación con la leucemia mioelomonocítica crónica (LMMC) sindrome mieloproliferativo crónico de diagnóstico controvertido. Habiendo estudiado en detalle de médula ósea, el baso y la citogenética, concluimos que se trata de una verdadera mieloproloiferación. Sugerimos además un estricto control clínico-hematológico y por imágenes para evaluar adecuadamente a aquellas patologías que se acompañan de grandes esplenomegalias en algún momento de su evolución (AU)

Peliosis esplénica: Asociación con leucemia mielomonocítica crónica, presentándose con ruptura espontánea del bazo / Splenic peliosis: Asociation with chronic myelomonocitic leukemia, presenting with spontaneous splenic rupture

La pielosis es una rara entidad, de teología poco clara: tóxica, infecciosa relacionada a inmunodepresión (enfermedades consuntivas) inflamatoria o vascular, caracterizada por la presencia de espacios quísticos múltiples, con secuestro hemático, que hasta puede llegar a producir trastornos de la hemostasia, induciendo una extrema fragilidad y por ende la ruptuta facial o espontánea del órgano, a veces sin aumentar el volúmen del mismo. Mucho más rara es su asociación con la leucemia mioelomonocítica crónica (LMMC) sindrome mieloproliferativo crónico de diagnóstico controvertido. Habiendo estudiado en detalle de médula ósea, el baso y la citogenética, concluimos que se trata de una verdadera mieloproloiferación. Sugerimos además un estricto control clínico-hematológico y por imágenes para evaluar adecuadamente a aquellas patologías que se acompañan de grandes esplenomegalias en algún momento de su evolución

Enfermedad de Behcet y trombofilia / Behcet´s disease and thrombophilia

La enfermedadd de Behcet es un desórden inflamatorio crónico, multisisté-rnico, de etiología desconocida, caracterizado por úlceras aftosas orales recu-rrentes, úlceras genitales y uveítis. Se trata de una patología de muy rara frecuencia y su patogenia sería autoinmune, mediada por hiperactividad de poli-morfonucleares (PMNs) y linfocitos T. Una de las causas de muerte más fre-cuentemente asociada a la Enfermedad de Behcet es la afectación oclusiva del sistema circulatorio, arterial y venoso, que está intimamente ligada a un estado de hipercoagulabilidad, ocasionada por activación del endotelio vascular y activación plaquetaria. El tratamiento anticoagulante oral (curnarínicos), aso-ciado al tratamiento específico, puede ayudar a la prevención de fenórnenos tromboembólicos y mejorar el pronóstico de la enfermedad, sobre todo te-niendo en cuenta que en muchos casos la misma tiende a autolímitarse. (AU)

Enfermedad de Behcet y trombofilia / Behcetïs disease and thrombophilia

La enfermedadd de Behcet es un desórden inflamatorio crónico, multisisté-rnico, de etiología desconocida, caracterizado por úlceras aftosas orales recu-rrentes, úlceras genitales y uveítis. Se trata de una patología de muy rara frecuencia y su patogenia sería autoinmune, mediada por hiperactividad de poli-morfonucleares (PMNs) y linfocitos T. Una de las causas de muerte más fre-cuentemente asociada a la Enfermedad de Behcet es la afectación oclusiva del sistema circulatorio, arterial y venoso, que está intimamente ligada a un estado de hipercoagulabilidad, ocasionada por activación del endotelio vascular y activación plaquetaria. El tratamiento anticoagulante oral (curnarínicos), aso-ciado al tratamiento específico, puede ayudar a la prevención de fenórnenos tromboembólicos y mejorar el pronóstico de la enfermedad, sobre todo te-niendo en cuenta que en muchos casos la misma tiende a autolímitarse.