Rosane Bittencourt

Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL.

Thanks to modern treatment with all-trans retinoic acid and chemotherapy, acute promyelocytic leukemia (APL) is now the most curable type of leukemia. However, this progress has not yielded equivalent benefit in developing countries. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) was established to create a network of institutions in developing countries that would exchange experience and data and receive support from well-established US and European cooperative groups. The IC-APL formulated expeditious diagnostic, treatment, and supportive guidelines that were adapted to local circumstances. APL was chosen as a model disease because of the potential impact on improved diagnosis and treatment. The project included 4 national coordinators and reference laboratories, common clinical record forms, 5 subcommittees, and laboratory and data management training programs. In addition, participating institutions held regular virtual and face-to-face meetings. Complete hematological remission was achieved in 153/180 (85%) patients and 27 (15%) died during induction. After a median follow-up of 28 months, the 2-year cumulative incidence of relapse, overall survival (OS), and disease-free survival (DFS) were 4.5%, 80%, and 91%, respectively. The establishment of the IC-APL network resulted in a decrease of almost 50% in early mortality and an improvement in OS of almost 30% compared with historical controls, resulting in OS and DFS similar to those reported in developed countries.

Confirmation of the utility of the International Staging System and identification of a unique pattern of disease in Brazilian patients with multiple myeloma

Multiple myeloma (MM) is one of the most frequent hematologic malignancies, and its incidence varies worldwide. Except for occasional case series or correlative biological studies, little is known about the incidence and clinical features of MM in Latin America. In Brazil, national estimates for the

Patient socioeconomic status as a prognostic factor for allo-SCT

The aim of the present study was to assess the influence of socioeconomic status (SeS) on the outcome of allo-SCT at a Brazilian SCT center. In total, 201 patients receiving HLA-identical related allo-SCTs were studied. The median age was 30 years. Overall, 163 patients had malignancies (CML 68, ALL/AML 63, myelodysplastic syndrome 12 and others 20). SeS was defined according to the Brazilian Association of Market Research Agencies classification, where people are clustered in groups A–E (richest to poorest). In total, 146 patients (72%) were classified as richest (A+B+C) and 55 (28%) as poorest (D+E). The D+E SeS group was associated with a higher incidence of chronic GVHD and acute GVHD (hazard ratio (HR)=2.61; P=0.001 and HR=2.62; P=0.001, respectively), better platelet and neutrophil engraftment (HR=1.94; P=<0.001 and HR=2.12; P=0.001) and with a higher TRM in multivariate analysis (HR=1.92; P=0.039). Estimated overall survival at 5 years was 55.2%. A D+E SeS (HR=2.13; P=0.001) was associated with a worse survival on multivariate analysis. In conclusion, a lower SeS is a strong prognostic factor in patients undergoing allo-SCT in Brazil, influencing engraftment, TRM and overall survival.

High prevalence of anemia in children and adult women in an urban population in southern Brazil.

This population-based study was designed to detect the prevalence of anemia in a healthy population of children (18 months to 7 years) and women (14 to 30 years) tested in 2006–2007 in the state of Rio Grande do Sul, Brazil as part of an effort to tackle this massive problem that still affects so many people in the XXI century. Anemia was defined according to the WHO. Capillary blood was measured and socioeconomic status was determined according to the Brazilian Association of Market Research Agencies. The median prevalence of anemia in 2198 children was 45.4% and in 1999 women 36.4%. Anemia decreased with age during childhood; although significantly more prevalent in lower classes individuals, it was also high in the upper classes. There are indirect evidences that the lack of iron supplementation and/or iron fortified food may play a role in it. Professionals and society wise measures of education have to be implemented in order to address possible biologic factors involved in childhood psychosocial development in southern Brazil.

Erratum to “DNMT3A Mutations in Patients with Acute Myeloid Leukemia in South Brazil”

The purpose of this note is to correct both the analysis and typographical errors. The typos are as follows.   The abstract, line 6: In “in 6 patients (8%)” should read “in 5 patients (6%)”.   Page 4, line 12: In “8% (6) of the samples, being 5 missens” should read “6% (5) of the samples, being 4 missense”.   Page 4, line 19: In “Of the 6 cases” should read “Of the 5 cases”.   Page 4, line 20: In “(5, or 83.3%)” should read “(4, or 80%)”.   Page 4, second column, line 8: In “OS for patients with wild DNMT3A gene was 41.4% and for patients with mutated DNMT3A was 44.4% (P = 0.59)” should read “OS for patients with wild DNMT3A gene was 45.7% and for patients with mutated DNMT3A was 60.0% (P = 0.47)”.   Page 6, line 4: In “found in 8%” should read “found in 6%”.   Page 6, second column, line 13: In “3 of 6 mutations” should read “3 of 5 mutations”.   Page 6, second column, line 16: In “Five, or 80%,” should read “Four, or 80%,”.   Page 6, second column, line 18: In “(P = 0.28)” should read “(P = 0.34)”.   Page 6, second column, line 20: In “(20.7 × 109/L)” should read “(15.6 × 109/L)”.   Table 4, column 2, line 6: In “H896*” should read “P896*”. Table 4 Description of somatic mutations found in gene DNMT3A.   Table 4: Entire line 7 was excluded.   Table 5, line 2: In “40.2, 44.8 and 0.56” should read “47.4, 40.4 and 0.42”. Table 5 Clinical characteristics of patients with Acute Myeloid Leukemia with or without DNMT3A mutations.   Table 5, line 4: In “50% (3), 59.3% (45) and 0.68” should read “60% (3), 57.9% (44) and 0.92”.   Table 5, line 5: In “50% (3), 40.7% (31)” should read “40% (2), 42.1% (32)”.   Table 5, line 19: In “50% (3), 51.4% (37) and 1.000” should read “40% (2), 52.7% (39) and 0.66”.   Table 5, line 20: In “50% (2), 30.9% (17) and 0.58” should read “40% (2), 29.2% (21) and 0.63”.   We changed Figure 3 as shown above. Figure 3

The expression of CD56 antigen is associated with poor prognosis in patients with acute myeloid leukemia

Background The expression of CD56 is considered a bad prognostic factor for overall survival, lower rates or short complete remission and extramedullary invasion but the results are controversial. The importance of validating new prognostic parameters in acute leukemias was the reason to investigate the CD56 expression in blast cells of patients with acute myeloid leukemia. Methods A cohort of 48 patients treated at Hospital de Clinicas de Porto Alegre and diagnosed with acute myeloid leukemia as classified by the French-American-British group (FAB) criteria using cell morphology, cytochemistry and flow cytometry were evaluated. Results Eight cases (16.7%) were CD56 positive without correlation to age or gender. The highest incidence of CD56 positivity was in FAB subtypes M4 and M5. The death rate during induction was not significantly different between patients with and without CD56 expression (62.5% vs. 27.5%; p-value = 0.097). However, patients that expressed CD56 had significantly lower overall survival than those who did not (mean 4.0 months vs. 14.5 months; p-value = 0.03). Conclusions The data suggest that expression of CD56 in acute myeloid leukemia may be indicative of poor prognosis because it is associated with a shorter overall survival. The death rate during induction was not significantly different despite an apparent difference in proportions between groups.

High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia

The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (ΔNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between ΔNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher ΔNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high ΔNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P = .0035). Our data support the hypothesis that the ΔNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells.

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

Prognostic impact of KMT2E transcript levels on outcome of patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukaemia study

The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid–induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline‐based chemotherapy. Univariate analysis showed that complete remission (P = 0·006), 2‐year overall survival (OS) (P = 0·005) and 2‐year disease‐free survival (DFS) rates (P = 0·037) were significantly lower in patients with low KMT2E expression; additionally, the 2‐year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0·04). Multivariate analysis revealed that low KMT2E expression was independently associated with lower remission rate (odds ratio [OR]: 7·18, 95% confidence interval [CI]: 1·71–30·1; P = 0·007) and shorter OS (hazard ratio [HR]: 0·27, 95% CI: 0·08–0·87; P = 0·029). Evaluated as a continuous variable, KMT2E expression retained association with poor remission rate (OR: 10·3, 95% CI: 2·49–43·2; P = 0·001) and shorter survival (HR: 0·17, 95% IC: 0·05–0·53; P = 0·002), while the association with DFS was of marginal significance (HR: 1·01; 95% CI: 0·99–1·02; P = 0·06). In summary, low KMT2E expression may predict poor outcome in APL patients.

Outcome of Treatment in Adult Acute Lymphoblastic Leukemia in Southern Brazil Using a Modified German Multicenter Acute Lymphoblastic Leukemia Protocol

Reports on treatment outcomes in adults with acute lymphoblastic leukemia (ALL) in Brazil are sparse. To evaluate the outcome of patients with ALL managed by the public healthcare system, we studied 42 adults treated from 1990 to 1997 in the Division of Hematology at Hospital de Clínicas, Porto Alegre, Brazil. Of these patients, 14/42 were females and their median age at diagnosis was 26 (17–64) years. The diagnosis of ALL was based on cytological examination of marrow smears, and immunophenotypic and cytogenetic studies, when available. Fifty percent of the patients expressed CD10, 30% were CD10 negative and CD19 positive and 20% expressed T markers. Philadelphia chromosome was found in 4 (7.14%). The chemotherapy protocol was adapted from the German Multicenter ALL (GMALL) 02-84 protocol. The complete remission rate was 93% and the overall survival at 5 years was 41%. No particular risk factor was identified in our series. These results are comparable to the findings of other international studies.