Rapid health technology assessment of zanubrutinib in the treatment of B cell lymphomas / 中国药房

OBJECTIVE To rapidly assess the efficacy， safety and cost-effectiveness of novel highly selective Bruton’s tyrosine kinase （BTK） inhibitor zanubrutinib in the treatment of chronic lymphocytic leukemia （CLL）， small lymphocytic lymphoma （SLL） and mantle cell lymphoma （MCL）. METHODS Retrieved from PubMed， Cochrane Library， CNKI， Wanfang database， VIP， and health technology assessment （HTA） websites， systematic reviews/meta-analyses， randomized controlled trials （RCTs）， pharmacoeconomic studies and HTA reports related to zanubrutinib were collected from the database/website establishment to July 2023. The literature was screened according to inclusion and exclusion criteria， and its quality was assessed by using relevant evaluation tools. Data extraction was presented by qualitative description. RESULTS A total of 5 literature were included， comprising of 3 RCTs and 2 cost-effectiveness analyses. In terms of efficacy， compared with the control group， zanubrutinib treatment resulted in significantly longer progression-free survival （P＜0.05） and a higher overall response rate （P＜0.05）. However， there was no statistical significance in overall survival between 2 groups （P＞0.05）. In terms of safety， zanubrutinib had lower incidence of cardiac adverse events， incidence of major bleeding events， and drug discontinuation rate due to adverse drug events， compared to first-generation BTK inhibitors ibrutinib； but the risk of bleeding events caused by zanubrutinib was still higher， compared to traditional chemoimmunotherapy （bendamotine+rituximab）. In terms of cost-effectiveness， zanubrutinib was found to be cost-effective in the treatment of recurrent or refractory MCL， compared to ibrutinib. CONCLUSIONS Zanubrutinib demonstrates sound efficacy and safety in patients with CLL/SLL and MCL patients. Furthermore， it exhibits economic advantages for patients with relapsed or refractory MCL.

Infections in patients with chronic lymphocytic leukemia

ABSTRACT Introduction: Infection is a major complication in patients with chronic lymphocytic leukemia (CLL). Newly diagnosed patients are at high risk of developing infection caused by encapsulated bacteria, such as Streptococcus pneumoniae and Haemophylus influenzae. Method and Results: However, once treatment is initiated, the spectrum of pathogens causing infection broadens, depending on the treatment regimens. With disease progression, cumulative immunosuppression occurs as a consequence of multiple treatment lines and the risk of infection further increases. On the other hand, the use of targeted therapies in the treatment of CLL have brought new risks of infection, with an increased incidence of invasive fungal diseases, particularly aspergillosis, in patients receiving Bruton kinase inhibitors. Conclusion: In this article, we review the epidemiology of infection in patients with CLL, taking into account the treatment regimen, and briefly discuss the management of infection.

Zeta-associated protein 70 expression in chronic lymphocytic leukemia: Relevance in Indian context

Background: Chronic lymphocytic leukemia (CLL) is prognosticated using the Rai and the Binet's staging. In the past few years, new parameters have been considered for prognostication. One such marker that has been a subject of speculation and found useful by some western studies is zeta-associated protein 70 (ZAP-70). Aim: To investigate the prevalence of ZAP-70 and find out its association with other prognostic markers like Rai and Binet's stage and CD38 in Indian CLL patients. Materials and Methods: Twenty-nine newly diagnosed cases of CLL were selected over 1 year. Immunophenotyping was done and expression of CD38 and ZAP-70 was evaluated on gated CLL cells. Statistical Analysis: Qualitative data were expressed as frequency and percentage. Differences between groups were evaluated using Student's t-test for quantitative data and Chi-square test/Fisher's exact t-test for qualitative variables. A P value less than 0.05 was considered significant. Results and Conclusion: We found a lower prevalence rate of ZAP-70 (2/29, 6.89%) with no association with any of the conventional poor prognostic factors. A large number of our CLL patients fall into the good prognostic group (22/29, ZAP 70?/CD38?) with a least number in the poor prognostic group (2/29, ZAP-70 + CD38+). Also, no association was found between ZAP-70 and CD38. The findings of the present study suggest that the majority of CLL patients in India have a good prognosis, may not require treatment, and have good overall survival. Geographical variations, genetic makeup, and natural history of the CLL could be the cause of such differences from western literature.

Rare case of multiple primary malignant neoplasms

Multiple Primary Malignant Neoplasms (MPMNs) are rarely reported and are defined as the diagnosis of ?2 independent, primary malignancies of different histologies/ origins in a single individual. In this study, we report a patient with Male Breast Cancer (MBC) and coexisting Small Lymphocytic Lymphoma (SLL) and Chronic Lymphocytic Leukemia (CLL). A 65-year-old male with complaints of a lump in his left breast since 2 years. CT scan findings were a non-homogeneous mass in the left breast along with bilateral axillary lymphadenopathy. Modified radical mastectomy was done. Microscopic examination showed the features of infiltrating duct carcinoma NOS: Modified Nottingham Bloom Richardson抯 Grade II in breast specimen. A peripheral smear of the patient showed features of chronic lymphocytic leukemia (absolute lymphocyte count was 16400 cells/mm3). IHC of breast tumor showed ER/PR positivity with H scores of 350 and 240 respectively and HER- 2/Neu protein expression was negative with a score of (1+). Lymph nodes were immunoreactive for CD 19, CD 23 and CD 5. Cells were non-reactive for Cyclin D1a and CD3. This is probably the first case of MBC with SLL and CLL. The diagnosis is consistent with synchronous MPMNs, which are increasingly reported nowadays.

Expression and Clinical Significance of Helper T Cells 9 and Its Sytokines Interleukin 9 in Chronic Lymphocytic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate the expression and clinical significance of T helper cell 9 (Th9) and its cytokine interleukin 9(IL-9) in peripheral blood of patients with chronic lymphocytic leukemia(CLL).@*METHODS@#A total of 43 newly diagnosed patients with chronic lymphocytic leukemia in the First Affiliated Hospital of Xinjiang Medical University from June 2021 to June 2022 were selected as the case group. The patients were divided into Binet A group (13 cases), Binet B group (20 cases) and Binet C group (10 cases) by Binet staging system, and 20 healthy volunteers who underwent physical examinationin in our hospital in the same period served as control group. The proportion of Th9 cells in peripheral blood was detected by flow cytometry, the expression level of Th9 specific transcription factors PU.1 and IRF4 was detected by Western blot, and the expression level of serum cytokine IL-9 was detected by ELISA. The proportion of Th9, the expression of PU.1, IRF4 and IL-9 in each group were compared, and the correlation between the proportion of Th9, IL-9 and clinicopathological indexes of CLL patients was analyzed.@*RESULTS@#The proportion of Th9, the expression of PU.1, IRF4 and IL-9 in CLL group were significantly higher than those in control group (P<0.05), the proportion of Th9 and the expression of IL-9 in Binet B and C group were higher than those in Binet A group (P<0.05), but there was no significant difference in the proportion of Th9 cells between Binet B group and C group (P>0.05). The expression of IL-9 in Binet C group was significantly higher than that in Binet B group (P<0.05) . The proportion of Th9 cells and IL-9 were highly expression in patients with β2 microglobulin abnormality, IGHV unmutation, P53 abnormality and hepatosplenic lymph node enlargement(P<0.05), but not related to age and sex (P>0.05). The results of Spearman correlation analysis showed that the proportion of Th9 in patients with CLL was negatively correlated with the lymphocytic account and lymphocyte proportion(rs=-0.32，rs=-0.34). The proportion of Th9 and IL-9 were positively correlated with Binet stage, Rai stage and CLL-IPI Scoring (rs=0.79，rs=0.54，rs=0.58； rs=0.72，rs=0.63，rs=0.45), but not with WBC, CD4+ T cells and CD8+T cells (P>0.05). The proportion of Th9 was positively correlated with IL-9 (rs=0.53).@*CONCLUSION@#Th9 cells and IL-9 are abnormally highly expressed in CLL, which is related to the poor prognosis of CLL.

A novel differential diagnosis algorithm for chronic lymphocytic leukemia using immunophenotyping with flow cytometry

Abstract Introduction The availability of a clinical decision algorithm for diagnosis of chronic lymphocytic leukemia (CLL) may greatly contribute to the diagnosis of CLL, particularly in cases with ambiguous immunophenotypes. Herein we propose a novel differential diagnosis algorithm for the CLL diagnosis using immunophenotyping with flow cytometry. Methods The hierarchical logistic regression model (Backward LR) was used to build a predictive algorithm for the diagnosis of CLL, differentiated from other lymphoproliferative disorders (LPDs). Results A total of 302 patients, of whom 220 (72.8%) had CLL and 82 (27.2%), B-cell lymphoproliferative disorders other than CLL, were included in the study. The Backward LR model comprised the variables CD5, CD43, CD81, ROR1, CD23, CD79b, FMC7, sIg and CD200 in the model development process. The weak expression of CD81 and increased intensity of expression in markers CD5, CD23 and CD200 increased the probability of CLL diagnosis, (p < 0.05). The odd ratio for CD5, C23, CD200 and CD81 was 1.088 (1.050 - 1.126), 1.044 (1.012 - 1.077), 1.039 (1.007 - 1.072) and 0.946 (0.921 - 0.970) [95% C.I.], respectively. Our model provided a novel diagnostic algorithm with 95.27% of sensitivity and 91.46% of specificity. The model prediction for 97.3% (214) of 220 patients diagnosed with CLL, was CLL and for 91.5% (75) of 82 patients diagnosed with an LPD other than CLL, was others. The cases were correctly classified as CLL and others with a 95.7% correctness rate. Conclusions Our model highlighting 4 markers (CD81, CD5, CD23 and CD200) provided high sensitivity and specificity in the CLL diagnosis and in distinguishing of CLL among other LPDs.

Clinical outcomes and early immune reconstitution in patients with acute lymphoblastic leukemia underwent allogeneic hematopoietic stem cell transplantation / 中国输血杂志

【Objective】 To investigate the correlation between early immune reconstitution and clinical outcomes in patients with acute lymphoblastic leukemia (ALL) underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). 【Methods】 The basic information and treatment data of 99 patients with ALL undering allo-HSCT from December 2018 to February 2022 were collected. The proportions of CD3+ T, CD3+CD4+ T, CD3+CD8+ T and CD3-CD16+CD56+ NK cells were detected before and 30, 60 and 90 days after transplantation using flow cytometry. The correlation between early cellular immune reconstitution and neutrophil engraftment, platelet engraftment, infection, and acute and chronic graft-versus-host disease (GVHD) was analyzed. 【Results】 Among 99 ALL patients, the median time of neutrophil engraftment was day +11 (range, 8-28), and the median time of platelet engraftment was day +14 (range, 10-120). The cumulative incidence of blood stream infection (BSI) was 11.10% and the cumulative incidence of CMV within 100 days of transplantation was 40.40%. The cumulative incidence of EBV within 100 days was 7.10%. The cumulative incidence of acute graft-versus-host disease (aGVHD) was 22.30%. The cumulative incidence of chronic graft-versus-host disease (cGVHD) within 1 year of transplantation was 16.20%. 1 -year cumulative relapse rate was 13.84%. The 1 -year cumulative disease-free survival (DFS) for all patients was 80.60% and the 1-year overall survival (OS) was 90.30%. The CD4+/CD8+ ratio was positively associated with the development of aGVHD at 30 days post-transplant (OR 1.21, 95CI 1.01-1.45, P<0.05). The proportion of CD16+ CD56+ NK cell were higher in the group without BSI than that in the BSI group before and 30 days after transplantation (P < 0.05). The proportion of CD4+ T-cell were lower in the CMV infection group than that in the group without CMV infection at 60 and 90 days post-transplant(P<0.05). The higher level of CD4+ T-cells at 60 days post-transplant was a protective factor for CMV infection within 100 days (HR 0.91, 95CI 0.84-0.99, P<0.05). 【Conclusion】 Early immune reconstitution after allo-HSCT in patients with ALL is associated with aGVHD, CMV and BSI.

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.

Research Progress in Treatment of Chronic Lymphocytic Leukemia --Review / 中国实验血液学杂志

Chronic lymphocytic leukemia (CLL) is a low-grade lymphoproliferative tumor that occurs frequently in middle-aged and elderly people. Early and precise intervention can effectively improve the clinical prognosis of CLL patients. In the past, chemotherapy was the main treatment plan. With the development of molecular biology and the continuous advent of immune targeting drugs, targeted drugs targeting B cell receptor signaling pathway have shown high clinical application value in the diagnosis and treatment path of CLL. Cellular immunotherapies such as CAR-T also offer hope for patients with relapsed and refractory CLL. Allogeneic hematopoietic stem cell transplantation and multi-drug combination have also shown remarkable results in clinical practice. The purpose of this article is to review the latest research progress in the treatment of CLL.

Radioterapia en pacientes pediátricos con leucemia linfocítica aguda: experiencia de 9 años

Objetivo: Describir las características epidemiológicas y clínicas de los pacientes con leucemia linfocítica aguda atendidos en el Hospital Nacional de Niños "Dr. Carlos Sáenz Herrera", que recibieron radioterapia externa, durante el periodo de enero de 2009 a diciembre de 2017. Métodos: Estudio observacional, descriptivo. Se revisaron retrospectivamente los expedientes clínicos de pacientes pediátricos (0-13 años) con leucemia linfocítica aguda, que recibieron radioterapia externa en el periodo mencionado. Se aplicó un análisis estadístico descriptivo de las variables cualitativas y cuantitativas. Resultados: Se analizó un total de 58 pacientes, de estos el 79,3% fueron hombres. La edad promedio fue de 7,3 años. El 84,2% fueron clasificados como L1, 84,2% con inmunofenotipo B común y el 56,9% eran grupo de alto riesgo al diagnóstico. La principal indicación de radioterapia fue recaída (67,7%). Aproximadamente la mitad se irradió a sistema nervioso central y la otra mitad a testículos. Los principales efectos adversos fueron cutáneos. Conclusiones: Los resultados obtenidos fueron comparables con los reportados en la literatura. La radioterapia es importante en el tratamiento de leucemias, especialmente en pacientes de recaída y de alto riesgo.

Aim: To describe the epidemiological and clinical characteristics of patients with acute lymphocytic leukemia, attended at the National Children´s Hospital "Dr. Carlos Sáenz Herrera" that received external radiation therapy between January 2009 and December 2017. Methods: It is an observational, descriptive study. Clinical records of pediatric patients (0-13 years) with acute lymphoblastic leukemia that received external radiotherapy in the study period were retrospectively reviewed. A descriptive statistical analysis of the qualitative and quantitative variables was applied. Results: 58 patients were studied, 79,3% were males. The mean age was 7,3 years. 84,2% were classified as L1, 84,2% had common B immunophenotype and 56,9% were in the high risk group at diagnosis. The main indication for radiotherapy was relapse (67,7%). About half the patients received radiotherapy to central nervous system and the other half to testicles. The main side effects were cutaneous. Conclusions: The results obtained were comparable to those seen in literature. Radiotherapy is important in leukemia treatment, particularly in relapse and high risk patients.

Inhibidores de bruton tirosina quinasa. ¿Qué necesita saber el oncohematólogo y el cardiólogo? / Bruton tyrosine kinase inhibitors. What does the oncohematologist and the cardiologist need to know?

Resumen Los avances en el conocimiento incorporados en la última década han modificado en gran parte el paradigma del tratamiento de las enfermedades hematológicas malignas. Particularmente la intro ducción de los inhibidores de la Bruton tirosina quinasa (iBTK) y otras drogas blanco junto a nuevos anticuerpos monoclonales se han transformado en los agentes de elección, tanto para la leucemia linfática crónica (LLC) como para otros linfomas "B" periféricos como el linfoma de células del manto (LCM). Los resultados de eficacia frente a la terapia genotóxica son tan exitosos que el fin de la quimio inmunoterapia, sobre todo para la LLC, es ya un postulado reconocido por los principales grupos de investigación. Por otra parte, los nuevos fármacos modificaron el perfil de eventos adversos lo que obligó al desarrollo de nuevas subespecialidades como la cardio-oncología, la cual constituye actualmente un baluarte para el manejo racional de estos pacientes. La presente revisión tiene como objetivo destacar el estado actual del conocimiento sobre estas enfermedades, los principios farmacológicos junto a los nuevos eventos adversos de los iBTK y el invalorable aporte de la cardiología para un correcto tratamiento y control de estos pacientes.

Abstract Advances in knowledge incorporated in the last decade have modified the treatment paradigm in most of the malignant hematological diseases. In particular, the introduction of Bruton tyrosine kinase inhibitors (BTKi) and other target drugs together with new monoclonal antibodies have become agents of choice for both chronic lym phocytic leukemia (CLL) and other peripheral "B" lymphomas such as mantle cell lymphoma (MCL). The results of efficacy against genotoxic therapy are so successful that the end of chemoimmunotherapy, especially for CLL, is already a postulate recognized by the main research groups. On the other hand, the new drugs modified the profile of adverse events, which forced the development of new subspecialties such as cardio-oncology, which currently constitutes a bastion for the rational management of these patients. This review aims to highlight the current state of knowledge on these pathologies, pharmacological principles together with new adverse events of iBTK and the invaluable contribution of cardiology for correct management of these patients.

Leucemia linfocítica aguda con infiltración en la piel. Presentación de un caso y revisión de la literatura

RESUMEN La leucemia cutánea es una patología muy poco frecuente y se puede presentar en diferentes tipos de leucemias asociadas o no a síndromes genéticos. Es una forma muy poco común de presentación inicial de malignidad. Por sus lesiones inespecíficas en la piel y la similitud con diversas patologías cutáneas representa un gran desafío diagnóstico para el dermatólogo pediátrico. Se presenta el caso de un niño de 5 años con antecedentes de leucemia linfocítica aguda con lesiones papulosas descamativas de aspecto liquenoide diseminadas en tegumento cutáneo. Se realizó una biopsia bajo la sospecha de infiltración a piel o leucemia cutis. Se discutió el caso para llegar a la confirmación diagnóstica de leucemia cutánea. Se inició el tratamiento en el Servicio de Hematología. Esta enfermedad hematológica se manifiesta ocasionalmente en la piel y cuando lo hace es necesario reconocerla para completar su diagnóstico y tratamiento y salvar la vida del paciente afectado como en este caso. El interés de esta presentación radica en que la aparición de lesiones cutáneas, aunque sean inespecíficas, en un paciente con leucemia, debe alertar al equipo médico tratante para su rápido estudio y así orientar la conducta terapéutica y por su baja incidencia de presentación.

ABSTRACT Cutaneous leukemia is a very rare pathology and can occur in different types of leukemia associated or not with genetic syndromes. It is a very uncommon form of initial presentation of malignancy. Due to its non-specific skin lesions and the similarity with various skin pathologies, it represents a great diagnostic challenge for the pediatric dermatologist. We present the case of a 5-year-old boy with a history of acute lymphocytic leukemia with scaly papular lesions of a lichenoid appearance disseminated in the cutaneous integument. A skin biopsy was performed on suspicion of skin infiltration or leukemia cutis. The case was discussed to reach diagnostic confirmation of cutaneous leukemia. Treatment was started in the Hematology Service. This hematological disease occasionally manifests itself on the skin and when it does, it is necessary to recognize it to complete its diagnosis and treatment and save the life of the affected patient, as in this case. The interest of this presentation lies in the fact that the appearance of skin lesions, even if they are non-specific, in a patient with leukemia, should alert the treating medical team for their rapid study and thus guide therapeutic behavior and due to their low incidence of presentation.

Impacto orçamentário da incorporação do rituximabe para o tratamento de leucemia linfocítica crônica no SUS / Budget impact of the incorporation of rituximab for the treatment of chronic lymphocytic leukemia in Brazil

Objetivo: O presente estudo objetiva desenvolver um modelo de análise de impacto orçamentário (AIO) relacionada à incorporação do rituximabe no tratamento de primeira linha da leucemia linfocítica crônica (LLC) no Sistema Único de Saúde (SUS). Métodos: A elaboração da AIO foi realizada de acordo com as recomendações metodológicas das diretrizes brasileiras, considerando a perspectiva do SUS, horizonte temporal de cinco anos, população a ser tratada, diferentes cenários de market share do rituximabe e custos diretos envolvidos no tratamento atual e no tratamento proposto, e também foi executada uma análise de sensibilidade para avaliar possíveis incertezas futuras. Resultados: A cada ano e ao final do horizonte temporal de cinco anos, a incorporação do rituximabe promoverá aumento dos custos, quando comparado com o valor de ressarcimento do SUS para o tratamento de primeira linha da LLC. No cenário de maior participação de mercado do rituximabe, os custos totais foram menores em relação ao cenário de menor market share. Dado que a estimativa da AIO é para gastos futuros, incertezas relacionadas como a possível elevação do custo do medicamento foi o fator que promoveu o cenário de maiores gastos. Conclusões: A projeção de custos estimados pela AIO demonstrou menores gastos financeiros no cenário de maior difusão do medicamento, o que pode ter correlação com o atraso da progressão da doença ao utilizar o rituximabe, e consequentemente menos pacientes irão requerer segunda linha de tratamento, que tem custo mais elevado.

Objective: This study aims to develop a budget impact analysis (BIA) model related to the incorporation of rituximab in the first-line treatment of chronic lymphocytic leukemia (CLL) in the Unified Health System (SUS). Methods: The preparation of the BIA was carried out in accordance with the methodological recommendations of the Brazilian guidelines, considering the perspective of the SUS, a time horizon of five years, population to be treated, different market share scenarios for rituximab and direct costs involved in the current treatment and treatment proposed, a sensitivity analysis was also performed to assess possible future uncertainties. Results: Each year and at the end of the five-year time horizon, the incorporation of rituximab will increase costs, when compared to the SUS reimbursement value for the first-line treatment of CLL. In the scenario of higher market share for rituximab, total costs were lower compared to the scenario of lower market share. Given that the BIA estimate is for future expenses, uncertainties related to the possible increase in the cost of the drug were the factor that promoted the scenario of higher expenses. Conclusions: The projection of costs estimated by the BIA showed lower financial expenses in the scenario of greater diffusion of the drug, which may be correlated with the delay in the progression of the disease when using rituximab and, consequently, fewer patients will require second-line treatment, which has a higher cost.

Análise de custo do sequenciamento dos novos agentes para o tratamento de leucemia linfocítica crônica sob a perspectiva do sistema de saúde suplementar brasileiro / Cost analysis of sequencing new agents for the treatment of chronic lymphocytic leukemia from the perspective of the Brazilian supplementary health system

Objetivo: Estimar o custo do sequenciamento de tratamentos e por desfecho dos novos agentes disponíveis para o tratamento de pacientes com leucemia linfocítica crônica (LLC) em primeira linha (1L) e segunda linha (2L) em um horizonte temporal de 15 anos sob a perspectiva do sistema de saúde suplementar brasileiro. Métodos: Foi desenvolvido um modelo de sobrevida particionada com quatro transições de estados de saúde (sem progressão em 1L, sem progressão em 2L, pós-progressão e morte), considerando os seguintes regimes: venetoclax + obinutuzumabe (VenO), venetoclax + rituximabe (VenR), ibrutinibe (Ibru) e acalabrutinibe (Acala). Foram consideradas na análise as posologias em bula e as curvas de sobrevida livre de progressão (SLP) dos respectivos estudos pivotais em cada uma das linhas terapêuticas. O custo total de cada sequência considerou a soma dos custos dos regimes utilizados em 1L e 2L, baseado no preço fábrica de cada medicamento. Resultados: As sequências de tratamento iniciadas com VenO apresentaram menores custos, especialmente o regime VenO>VenR (R$ 982.447), que apontou redução de aproximadamente R$ 3 milhões em 15 anos, quando comparada às sequências de Ibru>VenR ou Acala>VenR. Na análise de custo por desfecho, a sequência VenO>VenR apresentou o menor custo por ano de SLP (R$ 104.437), até 76% inferior em relação ao sequenciamento com maior custo por ano de SLP (Ibru>VenR). Conclusões: Os resultados desta análise demonstram o impacto significativo que a 1L de tratamento possui na jornada do paciente com LLC. Adicionalmente, o presente estudo aponta o menor custo de tratamento acumulado para o sequenciamento dos regimes VenO>VenR, sugerindo que os regimes de tratamento à base de venetoclax podem contribuir de maneira substancial em uma maior eficiência na alocação de recursos pelo gestor do sistema de saúde suplementar brasileiro.

Objective: To estimate the cost of treatment sequencing and per outcome of the new agents available for the treatment of patients with chronic lymphocytic leukemia (CLL) in 1st line (1L) and 2nd line (2L) in a 15-years time horizon from the perspective of the Brazilian supplementary health system. Methods: A partitioned survival model including four health state transitions (no progression in 1L, no progression in 2L, post-progression and death) was developed, considering the following regimens: venetoclax + obinutuzumab (VenO), venetoclax + rituximab (VenR), ibrutinib (Ibru) and acalabrutinib (Acala). The package insert dosages and progression-free survival (PFS) curves of the respective pivotal studies in each of the therapeutic lines were considered in the analysis. The total cost of each sequence considered the sum of the costs of the regimens used in 1L and 2L, based on the factory price of each drug. Results: Lower costs were observed when treatment sequences were initiated with VenO, especially the VenO>VenR regimen (R$ 982,447), which showed a reduction of approximately R$ 3 million in 15 years when compared to the Ibru>VenR or Acala>VenR sequences. In the cost per outcome analysis, the sequence VenO>VenR had the lowest cost per year of PFS (R$ 104,437), up to 76% lower than the sequencing with the highest cost per year of PFS (Ibru>VenR). Conclusions: Results show the significant impact that 1L treatment has on the CLL patient's journey. Additionally, the present study points to the lowest accumulated treatment cost for the sequencing of VenO>VenR regimens, suggesting that venetoclax-based treatment regimens can substantially contribute to greater efficiency in the allocation of resources by the manager of the Brazilian supplementary health system.

Chronic Lymphocytic Leukemia (CLL): evaluation of AKT protein kinase and microRNA gene expression related to disease pathogenesis

Abstract The present study evaluated 56 patients diagnosed with Chronic Lymphocytic Leukemia (CLL) and a control group of 44 clinically healthy subjects with no previous history of leukemia. Genetic expressions of AKT and microRNAs were evaluated by quantitative PCR (qPCR). A significant increase in AKT gene expression in patients when compared to controls was observed (p = 0.017). When the patients were stratified according to Binet subgroups, a significant difference was observed between the subgroups, with this protein kinase appearing more expressed in the B+C subgroup (p = 0.013). Regarding miRNA expression, miR-let-7b and miR-26a were reduced in CLL patients, when compared to controls. However, no significant differences were observed in these microRNA expressions between the Binet subgroups (A versus B+C). By contrast, miR-21 to miR-27a oncogenes showed no expression difference between CLL patients and controls. AKT protein kinase is involved in the signaling cascade that occurs with BCR receptor activation, leading to increased lymphocyte survival and protection against the induction of cell death in CLL. Thus, increased AKT protein kinase expression and the reduction of miR-let-7b and miR-26a, both tumor suppressors, may explain increased lymphocyte survival in CLL patients and may be promising markers for the prognostic evaluation of this disease.

Leucemia linfocítica crônica associada a melanoma metastático em homem de 53 anos / Metastatic melanoma in a 53-year-old male with relapsed chronic lymphocytic leukemia

Introdução: A associação de leucemia linfocítica crônica (LLC) e melanoma tem sido estudada nos últimos anos. Acredita-se que a imunossupressão causada pelo tratamento da doença seja o fator de risco mais importante para o aumento da susceptibilidade ao desenvolvimento e disseminação do câncer de pele. Relato de Caso: Este relato de caso descreve homem de 53 anos, em tratamento de leucemia linfocítica crônica desde 2018, já submetido a diversos ciclos de quimioterapia com fludarabina. Apresentou histórico de exérese de melanoma nodular epitelioide no couro cabeludo em 2019, removido com margens livres. Um ano após a cirurgia, paciente evoluiu com piora do estado geral com necessidade de hospitalização. Investigação adicional revelou focos de metástase em pulmões, fígado, rins, estômago, sistema nervoso central e linfonodos. Análise histopatológica foi positiva para melanoma. A possibilidade de tratamento foi descartada pela equipe de oncologia, que sugeriu cuidados paliativos. Discussão: Um dos mecanismos mais discutidos para explicar esta associação de neoplasias é a imunossupressão resultante do tratamento da LLC, que deixa o paciente suscetível ao desenvolvimento e à disseminação do melanoma. Além disso, a fludarabina, quimioterápico geralmente usado para remissão da LLC, é conhecida por depletar células T-helper e tem sido descrita como cofator deste processo. A associação de leucemia e melanoma cutâneo têm sido descrita nos últimos anos, porém não há nenhum protocolo de tratamento para esta condição.

BACKGROUND: The association of Chronic Lymphocytic Leukemia (CLL) and melanoma have been studied in the last years. The immunosuppression caused by the treatment of CLL seems to be the major factor of increasing patients' susceptibility to the development and spread of skin cancer. CASE REPORT: This case report describes a 53-year-old male patient, in CLL treatment since 2018, already submitted to many cycles of chemotherapy with fludarabine. History of an exeresis of epithelioid nodular melanoma of the scalp in 2019, which was removed with a clear margin. One year later, he presented with a poor general condition with hospitalization indication. Additional investigation revealed metastatic lesions in lungs, liver, kidneys, stomach, central nervous system, and lymph nodes. Histopathologic analysis positive for melanoma. The possibility of treatment was discarded by the Oncology team, which suggested palliative care. DISCUSSION: One of the most discussed mechanisms to explain this cancer association is the immunosuppression developed during the treatment of CLL, increasing patients' susceptibility to the development and spread of melanoma. In addition, the use of fludarabine, a chemotherapy commonly used in relapsed CLL, is known to deplete T-helper cells and has been described as a cofactor of this process. The association of leukemia and cutaneous melanoma has been reported in the last years, yet there is no surveillance protocol.

Application of modified Matutes score containing CD200 in diagnosis of chronic lymphocytic leukemia / 中南大学学报(医学版)

OBJECTIVES@#Immunophenotyping technique is a powerful tool for the diagnosis and differential diagnosis of chronic lymphocytic leukemia (CLL) and other B-cell chronic lymphoproliferative diseases (B-CLPD). CD200 is strongly expressed in CLL. This study aims to analyze the clinical value of modified Matutes score (MMS) containing CD200 in the diagnosis of CLL.@*METHODS@#We retrospectively analyzed 103 B-CLPD patients diagnosed from January 2020 to July 2021, including 64 CLL patients, 11 follicular lymphoma (FL) patients, 14 mantle cell lymphoma (MCL) patients, 6 marginal zone lymphoma (MZL) patients, 1 hairy cell leukemia (HCL) patient, and 7 lymphoplasmic lymphoma/Waldenstrom macroglobulinemia (LPL/WM) patients. The expression of CD markers between the CLL group and the non-CLL group was compared, and the sensitivity, specificity, and clinical consistency of MMS and Royal Marsden Hospital (RMH) immunophenotyping score system were analyzed.@*RESULTS@#There were significant differences in the expressions of CD5, CD23, FMC7, CD22, CD79b, CD200, and sIg between the CLL group and the non-CLL group (χ2 values were 37.42, 54.98, 30.71, 11.67, 55.26, 68.48, and 17.88, respectively, all P<0.01). When the RMH immunophenotyping score≥4, the sensitivity was 79.7%, and the specificity was 100%. When the MMS≥3, the sensitivity was 95.3%, and the specificity was 100%. The Kappa coefficient of RMH immunophenotyping system was 0.677, and the Kappa coefficient of MMS system was 0.860.@*CONCLUSIONS@#The MMS system containing CD200 has better sensitivity and same specificity compared with RMH immunophenotyping system, and MMS system may be more useful in the diagnosis of CLL.

Expression Level and Correlation of miR-211, miR-155, C-myc in Acute T Lymphocytic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate the expression and correlation of miR-211, miR-155, and C-myc in acute T lymphocytic leukemia (T-ALL), aiming to provide evidence for the diagnosis and treatment.@*METHODS@#A total of 96 T-ALL patients who were diagnosed and treated in People's Hospital of Zhengzhou from June 2014 to June 2017 were selected, and 69 healthy volunteers who had a physical examination were selected as control group in the same period. Real-time fluorescent quantitative PCR (RT-PCR) was used to determine the expression levels of miR-211, miR-155, and C-myc in peripheral blood mononuclear cells in each group. Kaplan-Meier was used to analyze the survival of T-ALL patients and correlation of miR-211, miR-155, and C-myc with prognosis. Pearson correlation analysis was used to evaluate the correlation of miR-211, miR-155, and C-myc with disease risk.@*RESULTS@#The expression levels of miR-211 mRNA, miR-155 mRNA, and C-myc mRNA in T-ALL group were higher than those in the control group (P<0.01), those in non-remission group were higher than those in remission group (P<0.01), and those in high-risk group were also higher than those in low-risk group and intermediate-risk group (P<0.01). The survival time of T-ALL patients with low miR-211 expression was longer than that with high miR-211 expression (P<0.01), that with low miR-155 expression was longer than that with high miR-155 expression (P<0.01), and that with low C-myc expression was also longer than that with high C-myc expression (P<0.01). The high expression of miR-211, miR-155, and C-myc was linearly positively correlated with high risk of disease (r=0.749, 0.781, 0.804).@*CONCLUSION@#The expressions of miR-211, miR-155, and C-myc are up-regulated in T-ALL patients, closely related to prognosis, and linearly positively correlated with disease risk.

Cerebrospinal Fluid β2-Microglobulin for Prognostic Evaluation of Patients with Central Nervous System Infiltration in Acute Lymphoblastic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate the prognostic value of serum and cerebrospinal fluid β2-microglobulin (β2-MG) in acute lymphoblastic leukemia (ALL) with central nervous system invasion after chemotherapy.@*METHODS@#40 patients with leukemia who had been confirmed to have central nervous system infiltration were selected for treatment at the Second Affiliated Hospital of Chongqing Medical University from January 2015 to May 2017, and the serum levels of β2-MG and CSF-β2MG were dynamically monitored and performed statistical analysis.@*RESULTS@#After chemotherapy, the changes in serum β2-MG were not statistically significant (P>0.05); the absolute level of CSF-β2MG and the percentage of relative baseline changes were statistically different in different clinical outcome groups(P<0.05), and the decreasing CSF-β2MG levels suggest a better prognosis, with cut-off values of 1.505 and -25%, respectively.@*CONCLUSION@#The best cut-off point may be a predictor of complete remission; the reduction of the absolute and relative levels of CSF-β2MG can suggest a good prognosis for patients.

The Relationship between PPP2R5C and Molt-4 Cell Viability, HSP90-GR Signal in Childhood Acute T Lymphocytic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect of PPP2R5C to the activity of Molt-4 cells in childhood acute T lymphocytic leukemia and its mechanism.@*METHODS@#The small interfering RNA (siRNA) technology targeting PPP2R5C gene was used to down-regulate the expression of PPP2R5C in Molt-4 cells. At the same time, a blank control group, a negative control group and a 17-DMAG group were set up. The cells in the negative control group were transfected with siRNA-NC, the cells in 17-DMAG group were treated with the HSP90 inhibitor 17-DMAG at a final concentration of 6.4 μmol/L for 48 h. Real-time fluorescent quantitative PCR (RT-qPCR) and Western blot were used to detect transfection efficiency; CCK-8 method was used to detect the proliferation activity of the cells in each group, EdU was used to detect the proliferation level of the cells in each group, flow cytometry was used to detect the cell cycle distribution ratio of the cells in each group, Annexin V-FITC/PI staining was used to detect the apoptosis of the cell, RT-qPCR and Western blot were used to detect the expression changes of heat shock protein 90 (HSP90) and glucocorticoid receptor (GR) of the cells in each group.@*RESULTS@#After Molt-4 cells were transfected with siRNA-PPP2R5C, the expression of PPP2R5C mRNA and protein in the cells were down-regulated significantly compared with those in the blank control group and the si-NC group (P<0.05); compared with cells in the blank control group and the si-NC group, the proliferation activity of the cells in the siRNA-PPP2R5C group and the 17-DMAG group significantly decreased (P<0.05), and the rate of EdU positive cells was significantly reduced (P<0.05); the proportion of the cells in G1 phase decreased while the proportion of the cells in G2 phase increased (P<0.05), the apoptosis rate of the cells also increased significantly (P<0.05); in addition, the expression of PPP2R5C mRNA and protein of the cells in siRNA-PPP2R5C group was significantly down-regulated compared with those in the blank control group and si-NC group (P<0.05). The expressions of PPP2R5C mRNA and protein in the 17-DMAG group were also significantly down-regulated compared with those in the blank control group and si-NC group (P<0.05).@*CONCLUSION@#Down-regulation of PPP2R5C gene expression can inhibit Molt-4 cell activity in childhood acute T lymphocytic leukemia, block the cells in G2 phase, and promote cell apoptosis, the mechanism may be related to the inhibition of HSP90-GR signaling pathway.