Evandro M. Fagundes

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.

Association of Human Development Index with rates and outcomes of hematopoietic stem cell transplantation for patients with acute leukemia

Human Development Index (HDI) is used by the United Nations Organization to measure socioeconomic achievements of countries. We evaluated the association of HDI with rates and outcomes of hematopoietic stem cell transplantation (HSCT) for patients with acute leukemia. For the analysis of HSCT rates, all adults with acute leukemia (n = 16 403) treated in 30 European countries, between 2001 and 2005, were included. Association of HDI with the outcome was analyzed for 2015 patients with acute myeloid leukemia treated with myeloablative allotransplantation. Countries were classified according to HDI quintiles. Highly significant correlation was found for HDI and the total number of HSCT per population (R = 0.78; P < .001), as well as separately for sibling HSCT (R = 0.84; P < .001), unrelated HSCT (R = 0.66; P < .001), and autologous HSCT (R = 0.43; P = .02). The probabilities of leukemia-free survival for 5 consecutive groups of countries with increasing HDI were: 56%, 59%, 63%, 58%, and 68% (P = .01). In a multivariate analysis, transplantations performed in countries belonging to the upper HDI category were associated with higher leukemia-free survival compared with the remaining ones (HR = 1.36, P = .008), which resulted mainly from reduced risk of relapse (HR = 0.72, P = .04). We conclude that, in Europe, the HDI is associated with both rates and results of HSCT for acute leukemia.

Granulocytic sarcoma of the small intestine with CBFβ/MYH11 fusion gene: report of an aleukaemic case and review of the literature

Granulocytic sarcomas (GS) are rare extramedullary tumours composed of immature myeloid cells. Inversion of chromosome 16 [inv(16)] is a cytogenetic marker for M4Eo subtype of acute myeloid leukaemia (AML). The possibility of an association between the development of granulocytic sarcoma of the small intestine (GSSI) and the M4Eo subtype of AML was suggested in nine previous case reports. Here we report an aleukaemic case of GSSI with inv(16) and its molecular equivalent, the CBFbeta/MYH11 fusion gene, detected by reverse transcriptase-polymerase chain reaction (RT-PCR), that after treatment with conventional AML chemotherapy followed by autologous bone marrow transplantation, achieved complete haematological and molecular remission on bone marrow examination. After chemotherapy, a thickened ileum wall positive for CBFbeta/MYH11 on tumour mass samples was still observed on computed tomography (CT) studies, raising the question of residual GS representing a reservoir of malignant cells. This case demonstrates the critical need of multidisciplinary diagnosis and follow-up of this entity combining immunopathologic, cytogenetic and molecular studies, reinforcing the potentiality of risk-adapted therapy strategies, as it is increasingly claimed for patients with overt AML.

De novo acute myeloid leukemia in adults younger than 60 years of age: socioeconomic aspects and treatment results in a Brazilian university center.

We retrospectively studied the outcomes of adults with de novo acute myeloid leukemia treated in a reference center in Brazil and analyzed the association with the human development index (HDI) of the United Nations used as a socioeconomic factor. Among 123 patients, 46 (37%) died during induction, 65 (53%) reached complete remission and 45 (37%) received high-dose cytarabine (Hidac) consolidation. The 5-year overall survival and leukemia-free survival (LFS) were 17 and 26%, respectively, for all patients and 36 and 30%, respectively, for those receiving Hidac. In multivariate analysis, an HDI <0.660 was associated with a lower probability to receive Hidac (P = 0.001), a trend for higher mortality in remission induction (P = 0.062) and a decreased LFS (P < 0.0001). However, it was not associated with outcomes for patients receiving Hidac. In conclusion, survival for patients who received Hidac consolidation is satisfactory; however, socioeconomic factors may have selected patients to receive intensive Hidac consolidation.

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.

The impact of medical education and networking on the outcome of leukemia treatment in developing countries. The experience of International Consortium on Acute Promyelocytic Leukemia (IC-APL)

Abstract Objectives: Several clinical trials conducted in Europe and US reported favorable outcomes of patients with APL treated with the combination of all trans retinoic acid (ATRA) and anthracyclines. Nevertheless, the results observed in developing countries with the same regimen was poorer, mainly due to high early mortality mainly due bleeding. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) is an initiative of the International Members Committee of the ASH and the project aims to reduce this gap through the establishment of international network, which was launched in Brazil, Mexico and Uruguay. Methods: The IC-APL treatment protocol is similar to the PETHEMA 2005, but changing idarubicin to daunorubicin. All patients with a suspected diagnosis of APL were immediately started on ATRA, while bone marrow samples were shipped to a national central lab where genetic verification of the diagnosis was performed. The immunofluorescence using an anti-PML antibody allowed a rapid confirmation of the diagnosis and, the importance of supportive measures was reinforced. Results: The interim analysis of 97 patients enrolled in the IC-APL protocol showed that complete remission (CR) rate was 83% and the 2-year overall survival and disease-free survival were 80% and 90%, respectively. Of note, the early mortality rate was reduced to 7.5%. Discussion: The results of IC-APL demonstrate the impact of educational programs and networking on the improvement of the leukemia treatment outcome in developing countries.

Acute promyelocytic leukemia presenting as an extradural mass

Acute promyelocytic leukemia is potentially a highly curable type of leukemia that usually presents with pancytopenia, coagulopathies and bleeding. We describe a case of an unusual presentation of acute promyelocytic leukemia. A 53 year-old male was admitted complaining of pain and weakness in his legs. He presented at examination a spastic paraparesis with a sensitive level at the eighth thoracic medullar (T8) segment. Magnetic resonance imaging showed a posterolateral extradural mass from T6 through T8 segments with medullar compression. A complete blood count showed anemia, thrombocytopenia and the presence of promyelocytes and blasts. Marrow examination was compatible with the diagnosis of acute promyelocytic leukemia by cytogenetics and polymerase chain reaction for the PML-RARα gene. He was treated with all-trans-retinoic acid therapy plus daunorubicin and presented an all-trans-retinoic acid syndrome. Despite hematological remission, the patient presented neurologic deterioration and had to be treated with radiotherapy (total dose 3000 cGy) of the extradural lesion. The patient evolved with severe sepsis and died without any recovery from his neurologic deficit. Extramedullary infiltration is a very rare complication in acute promyelocytic leukemia. Most cases are related to relapse after initial treatment with all-trans-retinoic acid. The skin and the central nervous system are the most frequently involved sites. This is possibly the first case reported of this condition in which the patient had a symptomatic extradural mass.

Evaluation of the European LeukemiaNet recommendations for predicting outcomes of patients with acute myeloid leukemia treated in low- and middle-income countries (LMIC): A Brazilian experience

BACKGROUND Current results regarding treatment outcomes in acute myeloid leukemia (AML) point to significant differences between low- and middle-income countries (LMIC) and high-income countries (HIC). Excluding well-known socioeconomic issues, genetic markers important for prognosis have not been properly incorporated into the clinical practice so far and their usefulness outside of well-controlled clinical trials remain unknown. METHODS Here, we assessed the clinical significance of the European LeukemiaNet (ELN) recommendations in 196 consecutive patients with AML in a real-life setting. All patients were younger than 60 years of age (49% male) and treated with conventional chemotherapy for induction and consolidation in three Brazilian Institutions that well represent Brazilian geographic and socioeconomic diversity. FINDINGS Multivariable analysis showed that ELN recommendations had a slight association with complete remission achievement (odds ratio: 0.74, 95% confidence interval, CI: 0.53-1.01; P=0.06), but were independently associated with poor overall survival (OS) (hazard ratio, HR: 1.3, 95% CI: 1.1-1.54; P=0.002), disease-free survival (DFS) (HR: 1.42, 95% CI: 1.03-1.95; P=0.028) and event-free survival (EFS) (HR: 1.24, 95% CI: 1.06-1.47; P=0.007), considering initial leukocyte counts and age as confounders. ELN recommendations had no impact on cumulative incidence of relapse (P=0.09). INTERPRETATION Our results suggest that within the context of LMIC, the prognostic markers recommended by ELN may be useful to predict patients clinical outcomes; however, the OS, DFS and EFS were shorter than the reported in Europe and US for the respective risk groups.

Guidelines on the treatment of acute myeloid leukemia: Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular

Rosane Bittencourt, Teresa Cristina Bortolheiro, Maria de Lourdes Lopes Ferrari Chauffaille, Evandro Maranhao Fagundes, Katia Borgia Barbosa Pagnano, Eduardo Magalhaes Rego, Wanderley Marques Bernardo a Universidade Federal do Rio Grande do Sul (UFGRS), Porto Alegre, RS, Brazil b Irmandade da Santa Casa de Misericordia de Sao Paulo, Sao Paulo, SP, Brazil c Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, SP, Brazil d Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil e Universidade Estadual de Campinas (Unicamp), Campinas, SP, Brazil f Universidade de Sao Paulo (USP), Ribeirao Preto, SP, Brazil g Universidade de Sao Paulo (USP), Sao Paulo, SP, Brazil