Current status of diagnosis and treatment of chronic lymphocytic leukemia in China: A national multicenter survey research / 中华血液学杂志

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.

Clinical Features and Outcomes of the Patients with B-Cell Chronic Lymphoproliferative Disease in the New Drug Era / 中国实验血液学杂志

OBJECTIVE@#To analyze the clinical characteristics of the patients with B-cell chronic lymphoproliferative disease（B-CLPD） in the new drug era and the effect of new drug treatment on efficacy and survival.@*METHODS@#The clinical and laboratory data of 200 cases B-CLPD patients diagnosed between April 2015 and August 2021 were analyzed retrospectively. The clinical efficacy and survival of the patients under different treatments including Bruton tyrosine kinase（BTK） inhibitors， rituximab， and chemotherapy alone were analyzed. The prognostic factors affecting the survival of patients were analyzed by univarite analysis and multivariate analysis.@*RESULTS@#There were 119 male（59.5％） and 81 female（40.5%） in 200 cases B-CLPD patients， the sex ratio(male/female) was 1.5∶1 with median age of 61（30- 91） years old. The distribution of subtypes were as fallows: 51 cases (25.5%) of chronic lymphocytic leukemia/small lymphocytic lymphoma（CLL/SLL）， 64（32.0%） cases of follicular lymphoma（FL）， 40（20.0%） cases mantle cell lymphoma（MCL）， 30（15.0%） cases of marginal zone lymphoma（MZL）， 10（5%） cases of lymphoplasmacytic lymphoma/waldenstrom macroglobulinemia（LPL/WM）， 5（2.5%） cases of B cell chronic lymphoproliferative disorders unclassified（B-CLPD-U） . The main clinical manifestation of 102 patients was lymph node enlargement, 32 cases were complicated with B symptoms. Among CLL/SLL patients， there were 12（23.5%） cases in Binet A and 39（76.5%） cases in Binet B/C. There were 29 patients（20.9%） in Ann Arbor or Lugano stage I-II and 110 cases（79.1%） in stage III-IV of other subtypes. The complete remission（CR） rate was 43.1%（25/58）， 40.2%（39/97）， 7.1%（1/14）， and overaIl response rate（ORR） was 87.9%（51/58）， 62.9%（61/97）， 28.6%（4/14） in the groups of BTK inhibitors， rituximab-based therapy， and chemotherapy alone. The 3-year OS rate and PFS rate in all patients was 79.2% and 72.4% respectively. The 3-year OS rate of patient with MZL, CLL/SLL, FL,WM was 94.7%, 87.7%, 86.8% and 83.3% respectively, while the 3-year OS rate of MCL was only 40.6%, which was significantly lower than other subtypes. The median OS of patients treated with BTK inhibitors and rituximab-based therapy was 20.5 and 18.5 months respectively， and the 3-year OS rate was 97.4% and 90.7%. However， the median PFS of patients receiving chemotherapy alone was 4 months， and the 1-year OS rate was 52.7%， which was statistically significant compared with the other two groups（P<0.05）. Univarite analysis showed that anemia， elevated lactate dehydrogenase， elevated β2-microglobulin， and splenomegaly were the poor prognostic factors for OS（P<0.05）， elevated lactate dehydrogenase was also poor prognostic factors for PFS（P<0.05）. Multifactor analysis showed that anemia and elevated lactate dehydrogenase were the independent poor prognostic factors for survival（P<0.05）.@*CONCLUSION@#The clinical features of B-CLPD was various， anemia and elevated lactate dehydrogenase are the prognostic factors for poor survival. BTK inhibitors and new immunotherapy can improve the survival and prognosis of patients in the new drug era.

Cutaneous leukemic infiltration following varicella - a case of Wolf's isotopic response

Abstract Wolf's isotopic response designates the appearance of two subsequent unrelated dermatoses in the same anatomic location. We report the case of a 51-year-old man with a medical history of chronic lymphocytic leukemia without known extra-hematopoietic involvement. The patient developed a disseminated papulo-vesiculous eruption, diagnosed as varicella. Few days after recovering, an erythematous and violaceous papular dermatosis with histopathological examination compatible with leukemic infiltration appeared on the scars of previous herpetic lesions. Complete remission was obtained under systemic corticotherapy, without cutaneous recurrence or blastic transformation. Wolf's isotopic response is attributed to a localized immunologic imbalance following a certain stimulus. In this patient, herpetic infection acted as a local spur for inaugural cutaneous leukemic infiltration, with no impact on the prognosis for the underlying disease.

Rituximab e hipogammaglobulinemia / Rituximab and hypogammaglobulinemia

El rituximab (RTX), un anticuerpo quimérico anti-CD20 que induce la depleción de linfocitos B, es utilizado para el tratamiento de enfermedades linfoproliferativas y autoinmunes. La inmunodeficiencia humoral relacionada al tratamiento con RTX comenzó a ser un motivo de derivación a nuestro Servicio, por lo que decidimos analizar a los pacientes con el antecedente de haber sido tratados con RTX que consultaron por hipogammaglobulinemia o infecciones recurrentes desde noviembre de 2010 hasta diciembre de 2014. Evaluamos a ocho pacientes, siete mujeres y un varón. El tiempo promedio de seguimiento fue de 19.3 ± 18.8 meses, rango 1 a 54, con una mediana de 13. Tres tenían proteinogramas normales previo a la administración de RTX, tres hipogammaglobulinemia, y de dos no hay datos. A ninguno se le realizó una determinación cuantitativa de inmunoglobulinas previa al tratamiento. Cuatro recibieron RTX por linfoma B no Hodgkin, dos por leucemia linfocítica crónica, uno por púrpura trombocitopénica autoinmune y otro por poliangeítis microscópica. A seis se les diagnosticó hipogammaglobulinemia y a uno deficiencia de IgM, IgA e IgG2. Cinco presentaron infecciones, cuatro con buena respuesta al tratamiento de reemplazo con gammaglobulina. La inmunodeficiencia humoral relacionada a RTX es una causa de consulta cada vez más frecuente. Resulta fundamental disponer de los niveles de inmunoglobulinas previo al inicio de su administración para poder establecer una relación etiológica y durante el seguimiento, para disminuir el retraso diagnóstico. El tratamiento con gammaglobulina en dosis sustitutivas parece ser de utilidad en pacientes con infecciones graves o recurrentes.

Rituximab, a chimeric monoclonal antibody against CD20, induces the depletion of B lymphocytes. It is used for the treatment of lymphoproliferative and autoimmune diseases. Antibody immunodeficiency associated to RTX treatment is a new motif for consultation to our service. We decided to study those patients that having been treated with RTX, consulted for hypogammaglobulinemia or recurrent infections between November 2010 and December 2014. We evaluated eight patients, seven female and one male. The average follow up time was 19.3 ± 18.8 months, range 1 to 54, median 13. Three had a normal electrophoretic proteinogram before receiving RTX, three had hypogammaglobulinemia and in two data was not available. None of them had a quantitative determination of immunoglobulins before receiving RTX. Four received RTX as a treatment of non Hodking lymphoma, two as a treatment of chronic lymphocytic leukemia, one for immune thrombocytopenic purpura and other for microscopic polyangiitis. Six were diagnosed with hypogammaglobulinemia and one with combined IgM, IgA and IgG2 deficiency. Five presented infections, four of them with good response to intravenous immunoglobulin. RTX related antibody deficiency consultations are increasing. It is important to determine the immunoglobulin levels previously to RTX use in order to establish an etiologic relationship with RTX and a quick diagnosis of antibody deficiency. The substitutive treatment with gammaglobulin seems to be useful in patients with severe or recurrent infections.

Anticuerpo monoclonal humanizado itolizumab (anti-cd6) en síndromes linfoproliferativos cd 6+. Experiencia preliminar / Itolizumab humanized monoclonal antibody (anti-cd6) in patients with cd6+ lymphoproliferative disorders. Preliminary experience

Introducción: la molécula CD6 es una glicoproteína de membrana considerada un antígeno de diferenciación leucocitario. El anticuerpo monoclonal humanizado itolizumab (anti-CD6) reconoce la molécula CD6 humana en las células mononucleares periféricas malignas de pacientes con leucemia linfocítica crónica- B y en los linfocitos de lesiones cutáneas de pacientes con linfoma T cutáneo. Objetivo: exponer los resultados preliminares de tres pacientes con leucemia linfocítica crónica-B tratados con el itolizumab, con dosis de 0.8 mg/kg/dosis semanal por 12 semanas. Métodos: la evaluación de la toxicidad asociada a la administración del itolizumab se realizó según Common Terminology Criteria for Adverse Events, versión 3.0, y la evaluación del beneficio clínico se definió según los criterios de respuesta, previamente establecidos por el National Cancer Institute Work Group, en remisión completa, remisión parcial, enfermedad estable, progresión y recaída. La evaluación de la respuesta se realizó después de haber recibido 6 administraciones del itolizumab (semana 7), después de haber recibido las 12 administraciones del itolizumab (semana 13), 6 semanas después de la última dosis (semana 18) y 12 semanas después de la última dosis (semana 24). Los datos de cada paciente se recogieron en las historias clínicas. Resultados: se evaluó la seguridad de la administración del producto en pacientes con síndromes linfoproliferativos CD6+ y se obtuvieron evidencias preliminares del efecto terapéutico de dicho fármaco. Conclusiones: en el 100 por ciento de los pacientes incluidos se reportó la aparición de fiebre y escalofríos relacionados con la primera infusión. No se observaron efectos adversos serios. Todos los pacientes evaluados tuvieron al menos alguna mejoría clínica o hematológica...

CD6 molecule is a membrane glycoprotein considered a leukocyte differentiation antigen. Itolizumab, humanized monoclonal antibody (anti-CD6) recognizes the human CD6 molecule in malignant peripheral mononuclear cells of patients with B-cell chronic lymphocytic leukemia and in lymphocytes of cutaneous lesions in patients with cutaneous T- cell lymphoma. We describe preliminary results of 3 patients with B-cell chronic lymphocytic leukemia treated with itolizumab at a weekly dose of 0.8mg/kg/dose for 12 weeks. Product administration safety was evaluated in patients with CD6+ lymphoproliferative disorders and preliminary evidence of therapeutic effect of the drug was obtained. In 100 percent of the patients the onset of fever and chills associated to the first infusion were reported. No serious adverse effects were observed. All patients evaluated had at least some clinical or hematological improvement...

Rituximab en leucemia linfocítica crónica en recaída y anemia hemolítica autoinmune: presentación de un caso / Use of Rituximab in recurrent chronic lymphocytic leukemia and autoimmune hemolytic anemia: A case presentation

La anemia hemolítica autoinmune es la manifestación inmunológica más frecuente en la leucemia linfocítica crónica (LLC) y se presenta entre el 10-20 por ciento de los casos. Su prevalencia está relacionada con el estadio y progresión de esta hemopatía, así como con el estado mutacional de los genes de la región variable de la cadena pesada de las inmunoglobulinas. Los corticosteroides constituyen la primera línea de tratamiento en esta anemia hemolítica autoinmune, pero solo la tercera parte de los pacientes responden y logran una remisión duradera, mientras que otros requieren tratamientos de mantenimiento o alternativos. Recientemente, se ha demostrado la efectividad del rituximab en el tratamiento de la anemia hemolítica autoinmune refractaria a la terapéutica esteroidea, incluso en los pacientes asociados con LLC. Se expone nuestra experiencia con el esquema R-COP (rituximab, ciclofosfamida, vincristina, prednisona) en el tratamiento de un paciente con LLC en recaída y anemia hemolítica autoinmune, que después de 20 meses de concluido este esquema se mantiene en remisión completa.

The autoimmune hemolytic anemia is the more frequent immunologic manifestation in chronic lymphocytic leukemia (CLL) and it is present between 10-20 percent of cases. Its prevalence is related to stage and progression of this blood disease, as well as to mutation state of genes from the heavy chain variable region of immunoglobulins. The corticosteroids are the first line treatment in this autoimmune hemolytic anemia, but only the third part of patients responds and achieves a lasting remission, whereas others require support treatment or of alternative type. Recently, it has been shown the effectiveness of Rituximab in treatment of refractory autoimmune hemolytic anemia that after 20months of ended this scheme it is maintained in complete remission.

Chronic lymphocytic leukemia in the recent 10 years and treatment effects of Fludarabin.

OBJECTIVE: CLL (Chronic Lymphocytic Leukemia) is the most common form of leukemia in the western world and because of prolonged survival of patients, the prevalence is high. Chemotherapy is usually not indicated in early and stable disease and using Chlorambucil with or without steroids has been the drug of choice in the treatment of CLL for many years .Clinical studies have shown that using Fludarabin can cause a complete response in significant number of untreated and/or previously treated CLL patients. The aim of this study is evaluating of CLL patients and determining the effects of treatment with Fludarabin. METHODS: A retrospective (descriptive/cross sectional) study of CLL patients who admitted to Hematology and Oncology Research Center of Tabriz university of Medical Sciences, between 1995-2005 was made and 126 patients enrolled. Collection of data was carried out according to special questionnaire and response to Fludarabin was analyzed by SPSS 11 software. RESULTS: The patients mean age of diagnosis was 63.7 years (SD=8.9), 69.8% were males. Illness and fatigue were the commonest presenting symptoms in 54% and lymphadenopathy was the most common clinical sign in 88.9%.Most of the patients were in stage C in Binet system (52.4%) and/or stage IV in Rai system (44.4%).Chemotherapy with chlorambucil and Prednisolone was the most common regimen used (60.3%) and 49.2% of patients were in partial remission with this treatment. Forty two patients treated with Fludarabin and 50% were in partial remission, 35% in static disease, 10% in progressive disease and 5% in complete remission (P=0.053). CONCLUSION: The median survival with Fludarabin was 43.9 months (SD=27.2) and in the case of Chlorambucil+Prednisolone and CVP or Chop it was 45 months (SD=26.5) and 50 months (SD=32.2), respectively (P>0.05). P value in the relationship with survival and response to Fludarabin was more than 0.05.Above all, Fludarabin is the choice treatment as first and second line therapy, as well as for patients who have failed therapy with standard regimens.

Estudo prognóstico em pacientes portadores de leucemia linfocítica crônica (LLC) / Prognostic factor in chronic lymphocytic leukemia (CLL)

Introdução e objetivo: a LLC, neoplasia clonal de células B, é a leucemia mais freqüente nos países ocidentais. Este trabalho avalia retrospectivamente as características clínicas dos portadores de LLC no Serviço de Hematologia do Hospital das Clínicas da UFMG. Metodologia: foram analisados os prontuários médicos de 77 pacientes com diagnóstico de LLC de 1992 a 2005. Resultados: dentre dos pacientes estudados 47 eram do sexo masculino (61%) e 30 (39%) do sexo feminino. A sobrevida média foi de 115 meses, a idade mediana de 65 anos, variando de 38 a 91 anos. A anormalidade citogenética mais freqüente foi a trissomia do 12, presente em 16% dos pacientes que apresentaram metáfases para análise. O sistema de estadiamento de Raí modificado foi o que melhor se correlacionou à sobrevida (p=0,001) e mostrou baixo risco – 21 pacientes (27,2%); risco intermediário – 36 pacientes (46,7%) e alto risco – 20 pacientes (25,9%), com sobrevida média de 154 meses, 65 meses e 43 meses, respectivamente. Entre as variáveis, nenhuma se mostrou significante em análise multivariada. Dez pacientes (13%) não haviam recebido quimioterapia até o momento do estudo e 67 (87%) foram tratados com esquemas de mono ou poliquimioterapia. Os pacientes tratados receberam clorambucil, fludarabina, fludarabina associada à ciclofostamida, COP, CHOP e radioterapia. Conclusão: não houve diferença significante na sobrevida entre as diversas formas de tratamento.

Leucemia cutis: expressión clínica de recaída de leucemia linfocítica crônica / Leukaemia cutis: clinical manifestation of chronic lymphocytic leukaemia relapse

Presentamos un paciente varón de 71 años con lesión tumoral en piel y antecedente de LLC. Los estudios histopatológicos y de inmunohistoquímica confirman el diagnóstico de Leucemia Cutis. Se realiza tratamiento con Clorambucilo y corticoides vía oral, remitiendo su enfermedad hematológica y cutánea. Actualmente luego de ocho meses del diagnóstico de LC, el paciente se encuentra libre de enfermedad.

We present a 71 year old male patient with previous records of Chronic Lymphocytic Leukaemia who presented with a tumoral skin lesion. Histological and immunohistochemical studies confirmed the Leukaemia Cutis diagnosis. The patient underwent treatment with clorambucile and systemic steroids with remision of both haemathological and skin manifestation. The patient is still under close clinical follow up and remission continues eight months so far.

Consenso Colombiano sobre el tratamiento de la Leucemia linfocítica crónica / Colombian consensus for the treatment of chronic lymphocytic leukemia

Introducción: El Consenso Colombiano de Hematología Oncológica (CC CCHO) es un proyecto apoyado por el Instituto Nacional de Cancerología, E.S.E y por la Sociedad Colombiana de Hematología y Oncología. Su propósito es mejorar los resultados de las intervenciones realizadas en los pacientes con cáncer, ayudando a los profesionales en salud a suministrar la mejor evidencia disponible; a fin de optimizar las decisiones clínicas y promover el uso racional de los recursos. La actividad del CCHO permite desarrollar pautas para la práctica clínica, siguiendo la metodología del grupo nominal; los informes resultantes representan la síntesis de las recomendaciones extraídas de la información recolectada por medio de búsquedas sistemáticas de la literatura médica. La aprobación de las recomendaciones por parte de los miembros del CCHO no significa necesariamente que deba ser adoptada como política;depende del lector.Métodos: Se revisaron las bases Medline (1966-2005), Cochrane Library (Issue 2, 2005), Embase (1974-2005), Biosis (1992-2005), Lilacs (1989-2005) y otras bases de datos relevantes. Los artículos publicados fueron seleccionados y revisados por el comité central del CCHO. Este documento ha sido revisado y aprobada por todos los miembros del Consenso, que incluyó: hematólogos, oncólogos, epidemiólogos, hematopatólogos, un especialista en políticas de salud y un miembro de la comunidad. Tres hematólogos internacionales, de manera independiente, hicieron la revisión externa del documento de resumen. El documento final del consenso requirió un proceso formal de estandarización. Será obligatoria la revisión periódica y continua de la literatura científica y,cuando se considere apropiado, se integrará la nueva información relevante al consenso original.Población: El ámbito del consenso son los pacientes adultos con diagnóstico de leucemia linfocítica crónica (LLC). Los estudios realizados hasta el momento, o el diseño y desarrollo de nuevos experimentos clínicos fa...

Isolated Richter's syndrome in central nervous system: case report

Linfoma não Hodgkin difuso de grandes células em paciente portador de leucemia linfóide crônica (LLC), ou síndrome de Richter, é complicação rara e grave nesta leucemia. Síndrome de Richter isolada no sistema nervoso central é muito rara, tendo sido encontrados apenas 12 casos descritos. Descrevemos paciente de 74 anos, que apresentou linfoma não Hodgkin difuso de grandes células em região frontal direita, simulando glioblastoma multiforme.

Radiation-induced chondrosarcoma of the maxilla 7-year after combined chemoradiation for tonsillar lymphoma.

Radiation-induced sarcoma is a rare complication of radiation therapy. We report a case of radiation-induced chondrosarcoma of the maxilla. An 80-year-old Persian woman developed radiation-induced chondrosarcoma of the left maxilla 7 years after combined chemotherapy and external beam radiation therapy for the Ann Arbor stage IE malignant lymphoma of the right tonsil. She underwent suboptimal tumour resection and died due to extensive locoregional disease 8 months later. An English language literature search of Medline using the terms chondrosarcoma, radiation-induced sarcoma and maxilla revealed only one earlier reported case. We describe the clinical and pathological features of this case and review the literature on radiation-induced sarcomas.

Leucemia linfoblástica aguda e envolvimento ocular / Leukemia lymphoblastic acute and ocular envolvement

Os autores relatam 3 casos de Leucemia Linfoblástica Aguda com envolvimento ocular, discorrem a respeito dos modos pelos quais o globo ocular e órbita podem ser envolvidos, seja em consequência das alteraçöes hematológicas inerentes às leucemias ou pela infiltraçäo neoplásica. Comentam acerca do globo ocular como santuário das leucemias e relatam complicaçöes terapêuticas que com evoluçäo da oftalmologia podem ser manejadas com o objetivo de melhorar a qualidade de vida destes pacientes