e14a2 Transcript Favors Treatment-Free Remission in Chronic Myeloid Leukemia When Associated with Longer Treatment with Tyrosine Kinase Inhibitors and Sustained Deep Molecular Response.

e13a2 and e14a2 are the most frequent transcript types of the BCR::ABL1 fusion gene in chronic myeloid leukemia (CML). The current goal with tyrosine kinase inhibitors (TKI) is to achieve sustained deep molecular response (DMR) in order to discontinue TKI treatment and remain in the so-called treatment-free remission (TFR) phase, but biological factors associated with these goals are not well established. This study aimed to determine the effect of transcript type on TFR in patients receiving frontline treatment with imatinib (IM) or second-generation TKI (2G-TKI). Patients treated at least 119 months with IM presented less post-discontinuation relapse than those that discontinued IM before 119 months (p = 0.005). In addition, cases with the e14a2 transcript type treated at least 119 months with IM presented a better TFR (p = 0.024). On the other hand, the type of transcript did not affect the cytogenetic or molecular response in 2G-TKI treated patients; however, the use of 2G-TKI may be associated with higher and earlier DMR in patients with the e14a2 transcript.

Flow cytometry to detect bone marrow involvement by follicular lymphoma.

BACKGROUND: High-quality data on bone marrow involvement (BMI) assessed by flow cytometry (FC) in follicular lymphoma (FL) is lacking. AIMS: We set up a prospective protocol with a 10-color tube and acquisition of 500.000 leukocytes on a Nav flow cytometer for evaluation of BMI in FL by FC. MATERIALS AND METHODS: FC was compared with a combination of histopathology and IGH gene rearrangement, which were considered the gold standard. We also compared BMI by FC with PET. RESULTS: Fifty-two patients were included (median 67 years, 54% female). BMI by FC was seen in 35 (67%), with a median involvement of 1.2% (interquartile range: 0.3%-7%) of leukocytes. Comparison with the gold standard revealed two false negatives and two false positives (potentially true involvement undetected by the gold standard). BMI by PET was seen in 14/46 (30%). Immunophenotype of FL in the bone marrow was highly heterogeneous. The most common phenotypic abnormality was dim expression of CD19 (>0.5 log loss in 30% of patients). CD10 was negative in 13 (37%) and incompletely positive (overlap with the negative population) in a further 8 (28%) while entirely positive only in 14 (48%). Other abnormalities (loss of CD20, gain or loss of CD79b, expression of CD43, and substantial loss of CD45) were rare. Computational analysis by means of FlowSOM confirmed the heterogeneous phenotype, with FL from different patients clustering in unrelated metaclusters. CONCLUSION: BMI by FL was frequent and immunophenotype was heterogeneous. However, this protocol enabled detection of FL in bone marrow in the vast majority of patients with bone marrow involvement by the gold standard.

FMOD expression in whole blood aids in distinguishing between chronic lymphocytic leukemia and other leukemic lymphoproliferative disorders. A pilot study.

BACKGROUND: Within the hematopoietic compartment, fibromodulin (FMOD) is almost exclusively expressed in chronic lymphocytic leukemia (CLL) lymphocytes. We set out to determine whether FMOD could be of help in diagnosing borderline lymphoproliferative disorders (LPD). METHODS: We established 3 flow cytometry-defined groups (CLL [n = 65], borderline LPD [n = 28], broadly defined as those with CLLflow score between 35 and -20 or discordant CD43 and CLLflow, and non-CLL LPD [n = 40]). FMOD expression levels were determined by standard RT-PCR in whole-blood samples. Patients were included regardless of lymphocyte count but with tumor burden ≥40%. RESULTS: FMOD expression levels distinguished between CLL (median 98.5, interquartile range [IQR] 37.8-195.1) and non-CLL LPD (median 0.012, IQR 0.003-0.033) with a sensitivity and specificity of 1. Most borderline LPDs were CD5/CD23/CD200-positive with no loss of B-cell antigens and negative or partial expression of CD43. 16/22 patients with available cytogenetic analysis showed trisomy 12. In 25/28 (89%) of these patients, FMOD expression levels fell between CLL and non-CLL (median 3.58, IQR 1.06-6.21). DISCUSSION: This study could suggest that borderline LPDs may constitute a distinct group laying in the biological spectrum of chronic leukemic LPDs. Future studies will have to confirm these results with other biological data. Quantification of FMOD can potentially be of help in the diagnosis of phenotypically complex LPDs.

Recomendaciones del Grupo Catalán de Trombosis (Tromboc@t Working Group) para el tratamiento de los pacientes que reciben anticoagulantes orales directos / Tromboc@t Working Group recommendations for management in patients receiving direct oral anticoagulants

Antecedentes y objetivos: En los últimos años los anticoagulantes orales directos (ACOD) se han convertido en una alternativa a los antagonistas de la vitamina K (AVK) para la prevención del ictus y embolia sistémica en pacientes con fibrilación auricular no valvular (FANV), así como para la prevención y tratamiento de la trombosis venosa profunda. Los ensayos clínicos han demostrado la no inferioridad y la potencial superioridad en comparación con la warfarina, lo cual permite ampliar las opciones de anticoagulación. En nuestro medio, las Unidades de Tratamiento Anticoagulante (UTA) y los Centros de Atención Primaria (CAP) son los encargados de la educación, seguimiento, control de adherencia y del manejo en situaciones especiales de los pacientes anticoagulados. Estas consideraciones han motivado la preparación del presente documento de consenso, que tiene como objetivo establecer recomendaciones que incorporen los hallazgos de la investigación científica a la práctica clínica para mejorar la calidad asistencial en el ámbito de la anticoagulación. Material y métodos: Un grupo de expertos del Grupo Catalán de Trombosis (TROMBOC@T) ha revisado la bibliografía publicada entre 2007 y 2016 para poder establecer recomendaciones basadas en la evidencia clínica. Resultados: Como resultado del proyecto se han establecido un conjunto de recomendaciones de carácter práctico que facilitarán el tratamiento, educación, seguimiento y manejo en situaciones especiales de los pacientes anticoagulados con ACOD. Conclusiones: El aumento progresivo del uso de los ACOD requiere establecer y homogeneizar las directrices de actuación clínica en el paciente anticoagulado con estos antitrombóticos tanto en las UTA como en los CAP

Background and objectives: In recent years, direct oral anticoagulants (DOACs) have become an alternative to vitamin K antagonists (VKA) for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) as well as for prevention and treatment of deep venous thrombosis. Pivotal trials have demonstrated non-inferiority and potential superiority compared to warfarin, which increases the options of anticoagulant treatment. In our setting, the Anticoagulant Treatment Units (ATUs) and Primary Care Centres (PCCs) play an important role in the education, follow-up, adherence control and management in special situations of anticoagulated patients. These considerations have motivated us to elaborate the present consensus document that aims to establish clear recommendations that incorporate the findings of scientific research into clinical practice to improve the quality of care in the field of anticoagulation. Material and methods: A group of experts from the Catalan Thrombosis Group (TROMBOC@T) reviewed all published literature from 2009 to 2016, in order to provide recommendations based on clinical evidence. Results: As a result of the project, a set of practical recommendations have been established that will facilitate treatment, education, follow-up and management in special situations of anticoagulated patients with ACODs. Conclusions: Progressive increase in the use of DOACs calls for measures to establish and homogenise clinical management guidelines for patients anticoagulated with DOACs in ATUs and PCCs

Tromboc@t Working Group recommendations for management in patients receiving direct oral anticoagulants. / Recomendaciones del Grupo Catalán de Trombosis (Tromboc@t Working Group) para el tratamiento de los pacientes que reciben anticoagulantes orales directos.

BACKGROUND AND OBJECTIVES: In recent years, direct oral anticoagulants (DOACs) have become an alternative to vitamin K antagonists (VKA) for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) as well as for prevention and treatment of deep venous thrombosis. Pivotal trials have demonstrated non-inferiority and potential superiority compared to warfarin, which increases the options of anticoagulant treatment. In our setting, the Anticoagulant Treatment Units (ATUs) and Primary Care Centres (PCCs) play an important role in the education, follow-up, adherence control and management in special situations of anticoagulated patients. These considerations have motivated us to elaborate the present consensus document that aims to establish clear recommendations that incorporate the findings of scientific research into clinical practice to improve the quality of care in the field of anticoagulation. MATERIAL AND METHODS: A group of experts from the Catalan Thrombosis Group (TROMBOC@T) reviewed all published literature from 2009 to 2016, in order to provide recommendations based on clinical evidence. RESULTS: As a result of the project, a set of practical recommendations have been established that will facilitate treatment, education, follow-up and management in special situations of anticoagulated patients with ACODs. CONCLUSIONS: Progressive increase in the use of DOACs calls for measures to establish and homogenise clinical management guidelines for patients anticoagulated with DOACs in ATUs and PCCs.

Highly variable mutational profile of ASXL1 in myelofibrosis.

OBJECTIVE: Somatic mutations in ASXL1 seem to have a negative prognostic impact in patients with several myeloid neoplasms, including myelofibrosis (MF). The aim of this work was to determine the prevalence and profile of ASXL1 mutations in MF. METHODS: We analyzed mutations in ASXL1 in 70 consecutive MF patients from 8 Spanish hospitals by means of Sanger sequencing, as well as JAK2, CALR, and MPL mutations. RESULTS: ASXL1 mutations were found in 16/70 (23%) of cases, most commonly p.Gly646TrpfsX12 (5/16). Most mutations (13/16) were frameshift mutations. Of 54 ASXL1- wild-type patients, 32 (59%) had at least one single nucleotide polymorphism (SNP), 27 of them had g.78128C>T, g.79017A>C, and g.79085T>C [triple SNP (TSNP) patients]. The 5-yr overall survival probability of TSNP patients was 67% (95% CI, 43-91%) vs. 90% (95% CI, 77-100%) in ASXL1-WT patients (P = 0.152). CONCLUSION: ASXL1 mutations were found in 23% of cases, p.Gly646TrpfsX12 being the most frequent. About 85% of mutations were found only in individual cases and 46% had not previously been reported, a pattern also seen in other series. Fifty percent of ASXL1-WT patients had a combination of three specific SNPs that might have a prognostic correlation that needs to be determined in larger series.

Hernioplastia inguinal electiva en pacientes con anticoagulación oral. ¿Son candidatos a cirugía ambulatoria? / Elective inguinal hernioplasty in patients on chronic anticoagulation therapy. Management and outcome

Introducción El tratamiento perioperatorio de los pacientes con anticoagulantes orales (ACO) incrementa la complejidad de la hernioplastia inguinal electiva. Objetivo Analizar la seguridad de nuestro protocolo de tratamiento en pacientes con ACO intervenidos de hernioplastia inguinal electiva y valorar el porcentaje de pacientes tratados mediante cirugía ambulatoria y cirugía de corta estancia. Material y métodos Se revisaron los datos administrativos de 1.184 pacientes intervenidos de hernioplastia inguinal en 2005 2007 y se identificó a 47 pacientes en tratamiento con ACO. Se utilizó, como tratamiento puente perioperatorio, un protocolo estandarizado con heparinas de bajo peso molecular (HBPM). Los resultados se analizaron hasta 30 días después del procedimiento e incluían las siguientes variables: hemorragia, episodios tromboembólicos o muerte y régimen hospitalario (cirugía mayor ambulatoria, corta estancia o ingreso convencional).Resultados La media de edad fue 74±10 años; 12 (25%) pacientes tenían un alto riesgo tromboembólico y 31 (67%) pacientes tenían la categoría ASA III. La técnica quirúrgica de elección fue la hernioplastia sin tensión con mallas de polipropileno. En 6 (13%) pacientes se diagnosticó hematoma de la herida quirúrgica y 1 (2,1%) paciente sufrió una hemorragia mayor que precisó de reintervención. Ningún paciente tuvo episodios tromboembólicos y no hubo fallecimientos. A 11 (23%) pacientes se trató de forma ambulatoria y a 16 (34%), en régimen de cirugía de corta estancia. La media de estancia hospitalaria fue 2,4±5,1 días. Conclusiones La hernioplastia inguinal electiva en pacientes con ACO, mediante una terapia puente con HBPM, es un procedimiento seguro. La anticoagulación oral no es una contraindicación absoluta para la cirugía ambulatoria (AU)

Background Perioperative management of patients on anticoagulant therapy increases the complexity of elective inguinal hernia repair. We assessed the safety of our standardised anticoagulation protocol and investigated the outpatient and one day surgery rates. Material and methods The records of 1184 patients undergoing elective inguinal hernioplasty between 2005 and 2007 were reviewed; 14 patients on chronic anticoagulation therapy were identified. We used a standard bridging therapy protocol with low-molecular-weight heparins. Outcomes were assessed at 30 days post-procedure and included bleeding, thromboembolic events or death and type of hospital admission. Results Mean age was 74±10 years; 12 (25%) patients were high risk for thromboembolism and 31 (67%) patients were ASA III. Almost all inguinal repairs were performed using a polypropylene mesh; 6 (13%) patients had a surgical site haematoma and there was 1 (2.7%) major bleeding, that was re-operated on. No thromboembolic events or deaths occurred; 11 (23%) patients were treated on an outpatient basis and 16 (34%) on a one day surgery regimen. Mean hospital stay was 2.4±5.1 days. Conclusions Elective inguinal hernioplasty in patients on chronic oral anticoagulation therapy using a standard bridging protocol is a safe procedure. Chronic anticoagulation therapy is not a contraindication for ambulatory surgery (AU)

[Elective inguinal hernioplasty in patients on chronic anticoagulation therapy. Management and outcome]. / Hernioplastia inguinal electiva en pacientes con anticoagulación oral. ¿Son candidatos a cirugía ambulatoria?

BACKGROUND: Perioperative management of patients on anticoagulant therapy increases the complexity of elective inguinal hernia repair. We assessed the safety of our standardised anticoagulation protocol and investigated the outpatient and one day surgery rates. MATERIAL AND METHODS: The records of 1184 patients undergoing elective inguinal hernioplasty between 2005 and 2007 were reviewed; 14 patients on chronic anticoagulation therapy were identified. We used a standard bridging therapy protocol with low-molecular-weight heparins. Outcomes were assessed at 30 days post-procedure and included bleeding, thromboembolic events or death and type of hospital admission. RESULTS: Mean age was 74+/-10 years; 12 (25%) patients were high risk for thromboembolism and 31 (67%) patients were ASA III. Almost all inguinal repairs were performed using a polypropylene mesh; 6 (13%) patients had a surgical site haematoma and there was 1 (2.7%) major bleeding, that was re-operated on. No thromboembolic events or deaths occurred; 11 (23%) patients were treated on an outpatient basis and 16 (34%) on a one day surgery regimen. Mean hospital stay was 2.4+/-5.1 days. CONCLUSIONS: Elective inguinal hernioplasty in patients on chronic oral anticoagulation therapy using a standard bridging protocol is a safe procedure. Chronic anticoagulation therapy is not a contraindication for ambulatory surgery.

[Prevalence and prognostic significance of myeloid markers in adults with high-risk acute lymphoblastic leukemia]. / Prevalencia y significado pronóstico de los marcadores mieloides en adultos con leucemia aguda linfoblástica de alto riesgo.

BACKGROUND AND OBJECTIVE: The prognostic value of myeloid antigen expression in adult acute lymphoblastic leukemia (ALL) is controversial. The objective of this study was to evaluate the frequency and prognostic significance of myeloid antigen expression in adults with high risk ALL. PATIENTS AND METHOD: Between June 1993 and July 2002, 222 adults patients with high-risk ALL were treated according to the PETHEMA LAL 93 protocol. The frequency of myeloid antigen expression, its association with other clinical and biologic variables and the prognostic significance in terms of complete remission (CR) rate, event free survival (EFS) and overall survival (OS) were analyzed. RESULTS: Myeloid antigen expression was present in 96 out of 222 patients (43%). No association was observed between myeloid antigen expression and the main clinical and biologic characteristics of ALL. Response to treatment was slower in patients expressing myeloid antigens, but no differences were found in CR achievement, EFS or OS. The probability of EFS at 10 years for ALL patients without and with myeloid antigen expression was 35% and 34%, respectively, while the probability of OS at 10 years was 30% and 33%, respectively. This absence of differences in EFS and OS probabilities was also observed when only slow responding patients were analyzed. CONCLUSIONS: In this study, myeloid antigen expression did not have prognostic influence in adult patients with high risk ALL.

Prevalencia y significado pronóstico de los marcadores mieloides en adultos con leucemia aguda linfoblástica de alto riesgo / Prevalence and prognostic significance of myeloid markers in adults with high-risk acute lymphoblastic leukemia

Fundamento y objetivo: El valor pronóstico de los marcadores mieloides en la leucemia aguda linfoblástica (LAL) del adulto es controvertido. El objetivo de este estudio fue evaluar la frecuencia y el significado pronóstico de los marcadores mieloides en adultos con LAL de alto riesgo. Pacientes y método: Entre junio de 1993 y julio de 2002, 222 pacientes adultos con LAL de alto riesgo se trataron según el protocolo PETHEMA LAL 93. Se analizó la frecuencia de los marcadores mieloides, su asociación con otras variables clínico-biológicas de la LAL y el significado pronóstico expresado como la probabilidad de obtención de la remisión completa (RC), supervivencia libre de evento (SLE) y supervivencia global (SG). Resultados: La presencia de marcadores mieloides se constató en 96 de los 222 pacientes (43%). No se observó ninguna relación entre la presencia de marcadores mieloides y las principales características clínico-biológicas de la LAL. La rapidez de la respuesta al tratamiento fue menor en los pacientes con marcadores mieloides, pero no se hallaron diferencias en la tasa de obtención de la RC, la SLE y la SG. La probabilidad de SLE a los 10 años fue, respectivamente, del 35 y del 34% para las LAL con marcadores mieloides y sin ellos. La probabilidad de SG a los 10 años fue del 33% para las LAL con marcadores mieloides y del 30% para las que no los presentaban. Cuando se estudiaron de manera aislada los pacientes con respuesta lenta al tratamiento, tampoco se hallaron diferencias en términos de SLE y SG entre ambos tipos de LAL. Conclusiones: En este estudio los marcadores mieloides no tuvieron significado pronóstico en los pacientes adultos con LAL de alto riesgo

Background and objective: The prognostic value of myeloid antigen expression in adult acute lymphoblastic leukemia (ALL) is controversial. The objective of this study was to evaluate the frequency and prognostic significance of myeloid antigen expression in adults with high risk ALL. Patients and method: Between June 1993 and July 2002, 222 adults patients with high-risk ALL were treated according to the PETHEMA LAL 93 protocol. The frequency of myeloid antigen expression, its association with other clinical and biologic variables and the prognostic significance in terms of complete remission (CR) rate, event free survival (EFS) and overall survival (OS) were analyzed. Results: Myeloid antigen expression was present in 96 out of 222 patients (43%). No association was observed between myeloid antigen expression and the main clinical and biologic characteristics of ALL. Response to treatment was slower in patients expressing myeloid antigens, but no differences were found in CR achievement, EFS or OS. The probability of EFS at 10 years for ALL patients without and with myeloid antigen expression was 35% and 34%, respectively, while the probability of OS at 10 years was 30% and 33%, respectively. This absence of differences in EFS and OS probabilities was also observed when only slow responding patients were analyzed. Conclusions: In this study, myeloid antigen expression did not have prognostic influence in adult patients with high risk ALL