Mantle Cell Lymphoma Under the Scope of Personalized Medicine: Perspective and Directions.

Mantle cell lymphoma (MCL) is a rare, incurable non-Hodgkin's lymphoma characterized by naive B cells infiltrating the lymphoid follicle's mantle zone. A key feature of MCL is the cytogenetic abnormality t(11;14) (q13:q14), found in 95% of cases, leading to Cyclin D1 overexpression resulting in uncontrolled cell cycle progression and genetic instability. Occasionally, Cyclin D2 or D3 overexpression can substitute for Cyclin D1, causing similar effects. The transcription factor SOX11 is a hallmark of classical Cyclin D1-positive MCL and also in cases without the typical t(11;14) abnormality, making it an important diagnostic marker. MCL's development necessitates secondary genetic changes, including mutations in the ATM, TP53, and NOTCH1 genes, with the TP53 mutation being the only genetic biomarker with established clinical prognostic value. The Mantle Cell Lymphoma International Prognostic Index (MIPI) score, which considers age, performance status, serum LDH levels, and leukocyte count, stratifies patients into risk groups. Histologic variants of MCL, such as classic, blastoid, and pleomorphic, offer additional prognostic information. Recent research highlights new mutations potentially tied to specific populations among MCL patients, suggesting the benefit of personalized management for better predicting outcomes like progression-free survival. This approach could lead to more effective, risk-adapted treatment strategies. However, challenges remain in patient stratification and in developing new therapeutic targets for MCL. This review synthesizes current knowledge on genetic mutations in MCL and their impact on prognosis. It aims to explore the prognostic value of genetic markers related to population traits, emphasizing the importance of tailored molecular medicine in MCL.

Application of EBMT, MASCC, and qSOFA Scores to Predict Complicated Febrile Neutropenia and Mortality in Autologous Stem Cell Transplant Recipients.

BACKGROUND AND OBJECTIVES: Three different scores were addressed as predictors of outcomes in autologous stem cell transplant (Auto SCT): one was calculated by pretransplant characteristics (European Society for Blood and Marrow Transplantation [EBMT] risk score), and two were calculated at the onset of febrile neutropenia (Multinational Association for Supportive Care in Cancer [MASCC] and Quick Sequential Organ Failure Assessment [qSOFA]). We considered bloodstream infection (BSI), carbapenem prescription, admission to the intensive care unit (ICU), and mortality as outcomes. PATIENTS: A total of 309 patients with a median age of 54 years were enrolled. RESULTS: Patients with EBMT score ≥4 (EBMT 4+) had higher ICU rates (14% vs. 4%; p < 0.01) and more carbapenem prescriptions (61% vs. 38%; p < 0.001) than those with EBMT score <4. MASCC <21 points (MASCC HR) was associated with carbapenem prescription (59% vs. 44%; p = 0.013), ICU (19% vs. 3%; p < 0.01), and death (4% vs. 0; p = 0.014). Patients with at least two points by qSOFA (qSOFA 2+) had more frequent BSI (55% vs. 22%; p = 0.03), ICU admissions (73% vs. 7; p < 0.01), and death (18% vs. 0.7, p = 0.02). EBMT 4+ and MASCC HR achieved the best sensitivities for ICU. For death, the best sensitivity was obtained with MASCC. CONCLUSION: In conclusion, risk scores for Auto SCT showed an association with outcomes and had different performances when combined or used alone. Therefore, risk scores for Auto SCT are useful in supportive care and clinical surveillance in stem cell transplant recipients.

How to manage lymphoid malignancies during novel 2019 coronavirus (CoVid-19) outbreak: a Brazilian task force recommendation

ABSTRACT: The novel Coronavirus (CoVid-19) outbreak is now consider a world pandemic, affecting more than 1,300,000 people worldwide. Cancer patients are in risk for severe disease, including a higher risk of intensive care unit (ICU) admission, need for invasive ventilation or death. Management of patients with lymphoid malignancies can be challenging during the outbreak, due to need of multiple hospital visits and admissions, immunosuppression and need for chemotherapy, radiotherapy and stem cell transplantation. In this article, we will focus on the practical management of patients with lymphoid malignancies during the COVID-19 pandemic, focusing on minimizing the risk for patients.

How to manage lymphoid malignancies during novel 2019 coronavirus (CoVid-19) outbreak: a Brazilian task force recommendation.

The novel Coronavirus (CoVid-19) outbreak is now consider a world pandemic, affecting more than 1,300,000 people worldwide. Cancer patients are in risk for severe disease, including a higher risk of intensive care unit (ICU) admission, need for invasive ventilation or death. Management of patients with lymphoid malignancies can be challenging during the outbreak, due to need of multiple hospital visits and admissions, immunosuppression and need for chemotherapy, radiotherapy and stem cell transplantation. In this article, we will focus on the practical management of patients with lymphoid malignancies during the COVID-19 pandemic, focusing on minimizing the risk for patients.

Diagnosis and treatment of chronic lymphocytic leukemia: recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia

ABSTRACT Chronic lymphocytic leukemia is characterized by clonal proliferation and progressive accumulation of B-cell lymphocytes that typically express CD19+, CD5+ and CD23+. The lymphocytes usually infiltrate the bone marrow, peripheral blood, lymph nodes, and spleen. The diagnosis is established by immunophenotyping circulating B-lymphocytes, and prognosis is defined by two staging systems (Rai and Binet) established by physical examination and blood counts, as well as by several biological and genetic markers. In this update, we present the recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia for the diagnosis and treatment of chronic lymphocytic leukemia. The following recommendations are based on an extensive literature review with the aim of contributing to more uniform patient care in Brazil and possibly in other countries with a similar social-economic profile.

Diagnosis and treatment of chronic lymphocytic leukemia: recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia is characterized by clonal proliferation and progressive accumulation of B-cell lymphocytes that typically express CD19+, CD5+ and CD23+. The lymphocytes usually infiltrate the bone marrow, peripheral blood, lymph nodes, and spleen. The diagnosis is established by immunophenotyping circulating B-lymphocytes, and prognosis is defined by two staging systems (Rai and Binet) established by physical examination and blood counts, as well as by several biological and genetic markers. In this update, we present the recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia for the diagnosis and treatment of chronic lymphocytic leukemia. The following recommendations are based on an extensive literature review with the aim of contributing to more uniform patient care in Brazil and possibly in other countries with a similar social-economic profile.

Molecular responses at 3 and 6 months after switching to a second-generation tyrosine kinase inhibitor are complementary and predictive of long-term outcomes in patients with chronic myeloid leukemia who fail imatinib.

Early molecular response (MR) defined by BCR-ABL(IS) levels has prognostic impact in chronic myeloid leukemia (CML). MR was evaluated at 3 and 6 months after switching to nilotinib or dasatinib in 115 patients with resistance to imatinib. Three groups were delineated at 3 months (< 1%, 1-10% or > 10% BCR-ABL(IS) levels) with different outcomes at 3 years regarding major molecular response (MMR, 91%, 47%, 22%, p < 0.001), failure-free survival (FFS), progression-free survival (PFS, 96%, 89% and 78%, p = 0.05) and overall survival (OS). After 6 months, patients with MR < 1% had higher 3-year MMR (83% vs. 16%, p < 0.001), FFS, PFS (94% vs. 84%, p = 0.05) and OS. Four patients had 3-month and 6-month MR > 10% and < 1%, respectively (3-year FFS 50%). Thirteen had 3-month and 6-month MR < 10% and ≥ 1%, respectively (3-year FFS 38%). These findings confirm the strong predictive value of 3-month and 6-month BCR-ABL(IS) levels in imatinib-resistant patients.

Risk factors for unsuccessful peripheral blood stem cell harvesting using granulocyte-colony stimulating factor mobilization in patients with multiple myeloma.

The aim of this study was to determine factors that influence unsuccessful peripheral blood stem cell (PBSC) harvesting in patients with multiple myeloma (MM). Retrospective data of 186 MM patients who received G-CSF as mobilization were analyzed. Patients with successful harvest were compared with those who failed (using 2 definitions of failure <2 and <4 CD34 cells×10(6)/mm(3)). The groups were compared regarding age, gender, body weight, baseline platelet count, receipt of radiotherapy, number of prior chemotherapy regimens, PBSC count before collection, processed and collected volume, collect replace, number of sessions and final number of PBSC collected. By multivariate analysis, a baseline platelet count <161,000 cells/mm(3) was associated with PBSC harvest lower than 2×10(6)/kg, and age >58 years was related to PBSC harvest lower than 4×10(6)/kg CD34 cells/kg. Patients with these parameters should not receive mobilization protocols with G-CSF alone. Alternative protocols should be tested in this high risk harvest failure population.

Evaluation of intra- and interobserver agreement and its clinical significance for scoring bcl-2 immunohistochemical expression in diffuse large B-cell lymphoma.

Immunohistochemistry (IHC) has become an essential part of diagnosis and clinical research in lymphomas. There is considerable heterogeneity, however, in IHC findings regarding expression rate and positivity cut-offs, which creates a degree of uncertainty that has prevented its incorporation for prognostic purposes. The purpose of the present study was to assess intra- and interobserver agreement in scoring bcl-2 expression on IHC. The study materials were 81 diffuse large B-cell lymphomas. Slides were processed in the same laboratory, and were analyzed independently and in a blinded manner by four pathologists twice, at least 1 month apart. The positivity rates ranged from 31% to 41% in the first evaluation, and from 30% to 43% in the second evaluation. The two analyses by the same pathologist gave concordant results in 88-93% of cases (kappa = 0.71-0.83). Complete agreement among all observers varied from 72% to 79%. The experience of the observer did not influence intra-observer concordance. Cooperative analysis of discordant slides led to consensus in all cases. The variation observed in scoring bcl-2 expression is acceptable for use in lymphoma diagnosis and classification. The use of IHC stratification, however, for clinical decisions regarding treatment will require standardization and centralized consensus review, and must await the results of ongoing prospective trials.

Leucemia Linfoblástica Aguda Filadélfia positiva / Phyladelphia positive Acute Lymphoblastic Leukemia

O cromossomo Filadélfia (Ph1) é a alteração citogenética mais comum da Leucemia Linfoblástica Aguda do adulto (LLA). Esta alteração citogenética predomina nos adultos com mais de 50 anos e na LLA de origem na célula B, principalmente CD10 positiva. O diagnóstico requer a análise citogenética e a pesquisa do mRNA do gene BCR-ABL no sangue periférico ou na medula óssea. A LLA Ph1 apresenta uma sobrevida global em cinco anos inferior a 20 por cento quando tratada com protocolos para LLA. Os poucos casos de cura ocorrem nos pacientes submetidos ao transplante alogênico de medula óssea (TMO). A adição do imatinibe à quimioterapia resultou em melhora na taxa de remissão completa, maior taxa de remissão molecular completa, maior número de pacientes aptos para realizar o TMO, uma maior sobrevida livre de eventos e maior sobrevida global, embora o tempo de seguimento seja ainda muito curto. Entretanto, a taxa de recaídas e o aparecimento de mutações do BCR-ABL resistentes ao imatinibe ainda são preocupantes. No futuro, novos inibidores de tirosina quinase poderão ser incorporados ao tratamento da LLA Ph1.

The Philadelphia chromosome (Ph1) is the most frequent abnormality in acute adult lymphoblastic leukemia (ALL). Ph1 positive ALL is more frequent in over 50-year-old adults, in B-cell ALL and CD10-positive ALL. Diagnosis is based on the identification of the BCR-ABL gene mRNA in peripheral blood or bone marrow. The 5-year overall survival of patients with Ph1 positive ALL treated with chemotherapy alone is less than 20 percent. A few cases may be cured by allogeneic stem cell transplantation. The addition of imatinib to the chemotherapeutic treatment has resulted in more complete remissions, more complete molecular responses, more patients able to perform stem cell transplantation, better event-free survival and better overall survival, although the study follow-up period is very short so far. High relapse rates and the emergence of BCR-ABL mutants resistant to imatinib are still significant. In the future, newer tyrosine-kinase inhibitors may be added to the chemotherapy.

PKC-beta II expression has prognostic impact in nodal diffuse large B-cell lymphoma.

Recent studies of gene expression and immunohistochemistry have shown that protein kinase C-beta II (PKC-beta II) might have prognostic significance in patients with diffuse large B-cell lymphoma (DLBCL). We sought to determine the prognostic significance of the expression of PKC-beta II in patients with nodal DLBCL. Formalin-fixed, paraffin-embedded tissues were stained with a monoclonal antibody to PKC-beta II protein. A total of 125 patients were studied; 83 patients (66%) were in the low-risk International Prognostic Index (IPI) group. Forty-eight patients (38%) were positive for PKC-beta II. Complete remission was obtained in 70%, and was not influenced by the PKC-beta II status (67 vs 71%). The 5-year event-free survival (EFS) was worse in high-risk patients (14 vs 58%, P<0.001) and in those with PKC-beta II positivity (36 vs 49%, P=0.054). In low-risk IPI patients, PKC-beta II expression was related to a worse 5-year overall survival (OS) (60 vs 76%, P=0.033) and a worse 5-year EFS (48 vs 66%, P=0.014). In a Cox regression analysis for EFS, both PKC-beta II expression (hazard ratio=1.68, P=0.037) and the IPI (HR=3.07, P<0.001) were independent poor prognostic factors. PKC-beta II (HR=1.72, P=0.046) and the IPI (HR=5.16, P<0.001) were also independent poor prognostic factors for the OS. PKC-beta II expression, along with the IPI, were associated with a worse EFS and OS in patients with nodal DLBCL specially in low-risk IPI patients.

Leucemia mielóide aguda: experiência do Hospital Universitário, UFRJ, Rio de Janeiro / Acute myeloid leukemia: experience of University Hospital, UFRJ, Rio de Janeiro

Neste relato apresento os resultados de 51 pacientes portadores de leucemia mielóide aguda (39 leucemias primárias, 9 secundárias a síndrome mielodisplásica e 3 de origem indeteminada). Comparamos os resultados desta casuística com resultados anteriores do Serviço de Hematologia do HUCFF e observamos que a percentagem de casos de leucemia subtipo M3 elevou-se de 24 para 38 por cento dos casos e o número de pacientes que não receberam tratamento foi reduzido de 37 para 18 por cento. A taxa de remissão completa em ambas as casuísticas foi idêntica, 59 por cento e a sobrevida global não pode ser terminada devido à diferença do período de observação de 13 anos no primeiro trabalho, contra 5 anos no atual.