Katia Borgia Barbosa Pagnano

Apoptosis-regulating proteins and prognosis in diffuse large B cell non-Hodgkin's lymphomas.

We evaluated the expression of apoptosis-regulating proteins (p53, Bcl-2, Bax, Bak and Mcl-1) in paraffin-embedded tissues of 33 patients with diffuse large B cell non-Hodgkin’s lymphoma , and assessed the relationship of these proteins to clinical outcome and response to chemotherapy. Our results showed that p53 expression was an independent immunohistochemical parameter related to a poor prognosis in these lymphomas. Bcl-2, Bax, Bak and Mcl-1 proteins, though highly expressed in almost all cases were not associated with prognosis or response to treatment.

Conventional chemotherapy for acute myeloid leukemia: a Brazilian experience

CONTEXTnYoung patients affected by acute myeloid leukemia (AML) achieve complete remission (CR) using conventional chemotherapy in about 55-85%. However, 30% of patients fail to achieve CR and the remission duration is often only about 12 months. More intensive treatment after CR seems to be necessary in order to maintain CR and obtain a definitive cure. In Brazil, few reports have been published on this important subject.nnnOBJECTIVEnThe aim of this study was to describe a Brazilian experience in the treatment of de novo acute myeloid leukemia (AML) in younger adult patients (age < 60 years).nnnDESIGNnRetrospective analysis.nnnSETTINGnUniversity Hospital, Hematology and Hemotherapy Center, State University of Campinas, Brazil.nnnPARTICIPANTSnNewly diagnosed cases of de novo AML in the period from January 1994 to December 1998 were evaluated retrospectively, in relation to response to treatment, overall survival (OS) and disease free survival (DFS). Cases with acute promyelocytic leukemia (APL) were also included in this analysis.nnnRESULTSnOn the basis of an intention to treat, 78 cases of AML, including 17 cases of APL, were evaluated. The overall median follow-up was 272 days. The complete remission (CR) rate was 63.6% in the AML group (excluding APL) and 78% in the APL group. The 5-year estimated disease-free survival (DFS) was 80% for the APL group and 34% for the AML group (P = 0.02). The 5-year estimated overall survival (OS) was 52% for the APL group and 20.5% for the AML group, respectively (P = NS). Relapse was observed in 12/39 (30.7%) patients with AML and 1/11 (9%) with APL.nnnCONCLUSIONSnThese results are similar to those reported in the literature. However, relapse and mortality rates remain high, and a search for more aggressive strategies in order to prevent relapse is recommended.

Frontline Therapy with Early Intensification and Autologous Stem Cell Transplantation versus Conventional Chemotherapy in Unselected High-Risk, Aggressive Non-Hodgkin’s Lymphoma Patients: A Prospective Randomized GEMOH Report

This prospective multicenter randomized trial compares conventional with early intensification with high-dose sequential chemotherapy (HDS) and autologous stem cell transplantation (ASCT) as frontline therapy in high-risk non-Hodgkin lymphomas (NHL). Newly diagnosed patients with aggressive high-risk [intermediate-high (HI) and high-risk (HR)] NHL according to the international prognosis index (IPI) were randomized to receive 12-week VACOP-B (arm A, 27 patients) or 6-week VACOP-B followed by HDS and ASCT (arm B, 29 patients). Complete remission rate was52% in arm A and 55% in B. Nine patients (16%) died early due to progression. According to intention-to-treat, with a median follow-up of 23 months, the 5-year actuarial overall survival, progression-free survival and disease-free survival in arms A and B were 47 and 40% (p = nonsignificant), 47 and 30% (p = nonsignificant), and 97 and 47% (p = 0.02), respectively. Abbreviated chemotherapy followed by intensification with HDS-ASCT does not seem to be superior to conventional chemotherapy in HI/HR aggressive NHL.

BCR-ABL Mutations in Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors and Impact on Survival

This is the largest Latin American study of BCR-ABL mutations in chronic myeloid leukemia (CML) patients, resistant to imatinib (IM). In 195/467 (41%) patients, mutations were detected. The most frequent mutation was T315I (n = 31, 16%). Progression-free (PFS) and overall survival (OS) at 5 years were lower in patients with BCR-ABL mutations (43% vs. 65%, p = 0.07 and 47% vs. 72%, p = 0.03, respectively) and in those with the T315I mutation (p = 0.003 and p = 0.03). OS and PFS were superior in subgroup who switched to second generation inhibitors (SGIs) after IM failure (OS: 50% vs. 39% p = 0.01; PFS: 48% vs. 30% p = 0.02). BCR-ABL mutations conferred a significant poor prognosis in CML patients.

Guidelines on the diagnosis and treatment for acute promyelocytic leukemia: Associacao Brasileira de Hematologia, Hemoterapia e Terapia Celular Guidelines Project: Associacao Medica Brasileira - 2013

Katia Borgia Barbosa Pagnanoa,*, Eduardo Magalhães Regob, Sandra Rohrc, Maria de Lourdes Chauffaillec, Rafael Henriques Jacomod, Rosane Bittencourte, Ana Beatriz Firmatof, Evandro Maranhão Fagundesf, Raul Antonio Moraes Melog, Wanderley Bernardoh a Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil b Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil c Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil d Universidade de Brasília (UnB), Brasília, DF, Brazil e Universidade Federal do Rio Grande do Sul (UFGRS), Porto Alegre, RS, Brazil f Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil g Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil h Universidade de São Paulo (USP), São Paulo, SP, Brazil

Constitutive JunB expression, associated with the JAK2 V617F mutation, stimulates proliferation of the erythroid lineage

The JAK2 V617F mutation, present in the majority of polycythemia vera (PV) patients, causes constitutive activation of JAK2 and seems to be responsible for the PV phenotype. However, the transcriptional changes triggered by the mutation have not yet been totally characterized. In this study, we performed a large-scale gene expression study using serial analysis of gene expression in bone marrow cells of a newly diagnosed PV patient harboring the JAK2 V617F mutation and in normal bone marrow cells of healthy donors. JUNB was one of the genes upregulated in PV, and we confirmed, by quantitative real-time PCR, an overexpression of JUNB in hematopoietic cells of other JAK2 V617F PV patients. Using Ba/F3-EPOR cell lines and primary human erythroblast cultures, we found that JUNB was transcriptionally induced after erythropoietin addition and that JAK2 V617F constitutively induced JunB protein expression. Furthermore, JUNB knockdown reduced not only the growth of Ba/F3 cells by inducing apoptosis, but also the clonogenic and proliferative potential of human erythroid progenitors. These results establish a role for JunB in normal erythropoiesis and indicate that JunB may play a major role in the development of JAK2 V617F myeloproliferative disorders.

JAK2 V617F prevalence in Brazilian patients with polycythemia vera, idiopathic myelofibrosis and essential thrombocythemia

Polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF) are myeloproliferative disorders (MPD) that arise from the clonal proliferation of a pluripotent hematopoietic progenitor, leading to the overproduction of one or more myeloid lineages. Recently, a specific mutation in the JAK2 gene, which encodes a tyrosine kinase, has been shown to be associated with the myeloproliferative phenotype observed in PV, ET and IMF. In this study of Brazilian patients, the JAK2 V617F mutation [c.1887G > T) was detected in four out of 49 patients with PV (96%), 14 out of 25 patients with IMF (56%), and in eight out of 29 patients with ET, which is in accordance with previous screenings of this mutation in other populations.

Monitoring of BCR-ABL levels in chronic myeloid leukemia patients treated with imatinib in the chronic phase: the importance of a major molecular response

Background Real time PCR has become the most common technique to monitor BCR-ABL transcript levels of patients treated with kinase inhibitors. The aim of this study was to evaluate BCR-ABL levels of chronic myeloid leukemia patients treated with imatinib in the chronic phase and correlate the response to therapy and event-free survival. Methods BCR-ABL levels were measured in peripheral blood cell samples using Real time PCR at diagnosis and then every 3 months after starting therapy with imatinib. Major molecular response was defined as a three-log reduction from the standardized baseline value. Major molecular response values were adjusted to international scale using a conversion factor of 1.19. The results are reported as a BCR-ABL/ABL ratio (%). Results Hematological, major cytogenetic and complete cytogenetic responses were achieved by 57 (95%), 45 (75%) and 38 (63%) patients, respectively. Twenty-four out of sixty patients achieved a major molecular response (40%) in a median time of 8.5 months. Overall survival and event free survival were higher for patients with (100%) versus patients without (77%) a complete cytogenetic response (p-value = 0.01) at 48 months. Patients with complete cytogenetic response and major molecular response had a higher event free survival compared to patients with complete cytogenetic response but without major molecular response (p-value = 0.007). Conclusion In conclusion, the prognostic impact of achieving complete cytogenetic response and a major molecular response and also the importance of molecular monitoring in the follow-up of chronic myeloid leukemia patients were demonstrated.s

Primary myelofibrosis: risk stratification by IPSS identifies patients with poor clinical outcome

OBJECTIVES: To evaluate whether risk scores used to classify patients with primary myelofibrosis and JAK-2 V617F mutation status can predict clinical outcome. METHODS: A review of clinical and laboratory data from 74 patients with primary myelofibrosis diagnosed between 1992 and 2011. The IPSS and Lille scores were calculated for risk stratification and correlated with overall survival. RESULTS: A V617F JAK2 mutation was detected in 32 cases (47%), with no significant correlation with overall survival. The patients were classified according to the scores: Lille - low, 53 (73.%); intermediate, 13 (18%); and high, 5 (7%); and IPSS – low, 15 (26%); intermediate-1, 23 (32%); intermediate-2, 19 (26%); and high, 15 (31%). Those patients presenting a higher risk according to the IPSS (high and intermediate-2) had a significantly shorter overall survival relative to the low risk groups (intermediate-1 and low) (pu200a=u200a0.02). CONCLUSIONS: These results emphasize the importance of the IPSS prognostic score for risk assessment in predicting the clinical outcome of primary myelofibrosis patients.

Clinical outcomes of patients with acute myeloid leukemia: evaluation of genetic and molecular findings in a real-life setting

To the editor:nnDespite its undeniable importance, standard cytogenetic analysis is still not a routine practice for most reference centers in developing countries, and its accomplishment is practically limited to university research centers. Particularly in Brazil, little is known about the