Assessment of Bone Microarchitecture in Patients with Systemic Mastocytosis and its Association with Clinical and Biochemical Parameters of the Disease.

Patients with systemic mastocytosis (SM) are at high risk of bone deterioration. However, the evaluation of bone microarchitecture in this disease remains unclear. We aimed to assess bone microarchitecture in patients with SM. This was a cross-sectional study of 21 adult patients with SM conducted in a quaternary referral hospital in Sao Paulo, Brazil. A healthy, age-, weight-, and sex-matched cohort of 63 participants was used to provide reference values for bone microarchitecture, assessed by high resolution peripheral quantitative computed tomography (HR-pQCT). Total volumetric bone mineral density (vBMD), cortical vBMD, and cortical thickness at the radius were significantly lower in the control group compared with the SM group (all P < 0.001). Patients with aggressive SM had significantly lower trabecular number (Tb.N) (P = 0.035) and estimated failure load (F.load) (P = 0.032) at the tibia compared with those with indolent SM. Handgrip strength was significantly higher in patients who had more Tb.N at the radius (ρ, 0.46; P = 0.036) and tibia (ρ, 0.49; P = 0.002), and lower who had more trabecular separation at the radius (ρ, -0.46; P = 0.035) and tibia (ρ, -0.52; P = 0.016). Strong and positive associations between F.load (ρ, 0.75; P < 0.001) and stiffness (ρ, 0.70; P < 0.001) at the radius, and between F.load at the tibia (ρ, 0.45; P = 0.038) were observed with handgrip strength. In this cross-sectional study, aggressive SM was more susceptible to bone deterioration compared with indolent SM. In addition, the findings demonstrated that handgrip strength was associated with bone microarchitecture and bone strength.

Philadelphia-positive B-lymphoblastic leukemia in a middle-income country - A real-world multicenter cohort.

Outside of clinical trials, few studies have addressed the outcomes of Ph+ acute lymphoblastic leukemia (ALL) in adults, especially from developing world. In this study, we conducted a multicenter analysis on the outcomes of patients aged > 15 years with Ph+ ALL, aiming to get to know an overview of the Brazilian experience as well as to explore baseline factors associated with relapse and mortality in our setting. Over these 10 years, patients were treated with diverse protocols, all of them always combined with a frontline tyrosine-kinase inhibitor. A total of 123 Ph+ ALL patients was included. Imatinib was the first line TKI in 97 %. The complete response rate was 79 %. The early death rate was 15 %, being associated with increasing age at diagnosis (p = 0.06). The use of intensive versus attenuated induction regimen was not associated with higher induction mortality (p = 0.99). Overall, 29 % of patients aged ≤ 60 years underwent allogeneic transplantation, 87 % in first CR. 4-year overall survival (OS) and relapse-free survival were 25 % and 24 %, respectively. The incidence of relapse (death as a competitor) was 29 %, while the non-relapse mortality was 42 %. Only age was independently associated with OS, and lactate dehydrogenase level and central nervous disease at diagnosis were related to relapse in our cohort. This is the first historical cohort multicenter study on Ph+ ALL from Brazil. Reporting these outcomes is essential to encourage public policies to expand access to new drugs and transplantation in middle-income countries.

Prognostic assessment for chronic myelomonocytic leukemia in the context of the World Health Organization 2016 proposal: a multicenter study of 280 patients.

Knowledge on chronic myelomonocytic leukemia (CMML) patients from Argentina and Brazil is limited. Our series of 280 patients depicted an older age at diagnosis (median 72 years old), 26% of aberrant karyotypes, and a prevalence of myelodysplastic (60%) and CMML-0 subtypes (56%). The median overall survival (OS) was 48.2 months for patients in CMML-0 (Ref.), 24.7 months for those in CMML-1 (HR = 2.0, p = 0.001), and 8.8 months for patients in CMML-2 (HR = 4.6, p < 0.001). In the CMML-0 category, median OS were different between myelodysplastic and myeloproliferative subtypes (63.7 vs 21.2 months, p < 0.001); however, no differences were observed within CMML-1 and CMML-2 subtypes (24.7 vs 23.7 months, p = 0.540, and 9.1 vs 8.2 months, p = 0.160). The prognostic impact of 24 variables and 7 prognostic systems was adjusted to the WHO 2016 after validating their usefulness. Multivariate analysis were performed, and the final model revealed Hb ≥ 8 -< 10g/dL (HR 1.7), Hb < 8g/dL (HR 2.8), poor karyotypes (HR 2.1), WHO 2016-CMML-1 (HR 2.1), and CMML-2 (HR 3.5) as independent adverse clinical parameters in our cohort with a borderline influence of platelets count < 50 × 109/L (HR 1.4). We could validate several scoring systems, the WHO 2016 proposal and its prognostic capability, along with accessible covariates, on predicting the outcome in our series of CMML patients from Latin America.

A multicenter comparative acute myeloid leukemia study: can we explain the differences in the outcomes in resource-constrained settings?

Outcomes in acute myeloid leukemia (AML) are dependent on patient- and disease-characteristics, treatment, and socioeconomic factors. AML outcomes between resource-constrained and developed countries have not been compared directly. We analyzed two cohorts: from São Paulo state, Brazil (USP, n = 312) and Oxford, United Kingdom (OUH, n = 158). USP cohort had inferior 5-year overall survival compared with OUH (29% vs. 49%, adjusted-p=.027). USP patients have higher early-mortality (23% vs. 6% p<.001) primarily due to multi-resistant Gram-negative bacterial and fungal infections. USP had higher 5-year cumulative incidence of relapse (60% vs. 50%, p=.0022), were less likely to undergo hematopoietic stem cell transplant (HSCT) (28% vs. 75%, p<.001) and waited longer for HSCT (median, 23.8 vs. 7.2 months, p<.001). Three-year survival in relapsed patients was worse in USP than OUH (10% vs. 39%, p<.001). Our study indicates that efforts to improve AML outcomes in Brazil should focus on infection prevention and control, and access to HSCT.

Toxicity Profile of PEG-Asparaginase in Adult Patients With Acute Lymphoblastic Leukemia in Brazil: A Multicenter Cross-Sectional Study.

BACKGROUND: Currently, pediatric-inspired regimens are commonly applied to adults with acute lymphoblastic leukemia (ALL) after the recent recognition that these protocols improve survival. While asparaginase in whatever available formulation is a key component of modern treatment of ALL, many adult oncologists and hematologists struggle to deal with its particular toxicities in clinical practice. We reviewed toxicity outcomes of pegylated asparaginase (PEG-ASP) in adults with ALL treated in 3 reference centers in Brazil. PATIENTS AND METHODS: This was a cross-sectional retrospective chart-review study encompassing patients aged 15 years and older diagnosed with ALL or ambiguous-lineage leukemia who received at least one dose of PEG-ASP, regardless of the adopted regimen. RESULTS: A total of 57 patients were included (age range, 15-57 years). Most patients (70%) received 2000 IU/m2 as the initial dose, by intravenous route (72%). The incidence of thromboembolic events was 17.5%, and the main site was cerebral venous sinus (4/10). Thrombosis was more frequent in patients receiving second-line treatment. In obese patients, grade 3 hepatotoxicity and hyperbilirubinemia were more common. Clinical pancreatitis (grade 3 or higher) was found in 2 of 57 cases. PEG-ASP had to be discontinued in 19.3% of exposed patients (11/57). CONCLUSION: By reviewing the medical charts of adult patients with ALL from 3 reference centers, we found that our incidence of thrombotic and hepatic adverse events is similar to those reported in other trials involving PEG-ASP. Usually these effects should not preclude further use of the drug because most events are manageable in routine clinical practice.

Integrating clinical features with genetic factors enhances survival prediction for adults with acute myeloid leukemia.

The 2017 European LeukemiaNet 2017 acute myeloid leukemia (AML) risk stratification (ELN2017) is widely used for risk-stratifying patients with AML. However, its applicability in low- and middle-income countries is limited because of a lack of full cytogenetic and molecular information at diagnosis. Here, we propose an alternative for risk stratification (the Adapted Genetic Risk [AGR]), which permits cytogenetic or molecular missing data while retaining prognostic power. We first analyzed 167 intensively treated patients with nonacute promyelocytic leukemia AML enrolled in São Paulo, Brazil (Faculdade de Medicina da Universidade de São Paulo), as our training data set, using ELN2017 as the standard for comparison with our AGR. Next, we combined our AGR with clinical prognostic parameters found in a Cox proportional hazards model to create a novel scoring system (survival AML score, SAMLS) that stratifies patients with newly diagnosed AML. Finally, we have used 2 independent test cohorts, Faculdade de Medicina de Ribeirão Preto (FMRP; Brazil, n = 145) and Oxford University Hospitals (OUH; United Kingdom, n = 157) for validating our findings. AGR was statistically significant for overall survival (OS) in both test cohorts (FMRP, P = .037; OUH, P = .012) and disease-free survival in FMRP (P = .04). The clinical prognostic features in SAMLS were age (>45 years), white blood cell count (<1.5 or >30.0 × 103/µL), and low albumin levels (<3.8 g/dL), which were associated with worse OS in all 3 cohorts. SAMLS showed a significant difference in OS in the training cohort (P < .001) and test cohorts (FMRP, P = .0018; OUH, P < .001). Therefore, SAMLS, which incorporates the novel AGR evaluation with clinical parameters, is an accurate tool for AML risk assessment.

Flow cytometry "Ogata score" for the diagnosis of myelodysplastic syndromes in a real-life setting. A Latin American experience.

INTRODUCTION: Flow cytometry (FC) is a helpful tool for the diagnosis of myelodysplastic syndrome (MDS). Different FC score systems have been developed. The "Ogata score" is a simple diagnostic score that has been validated having a sensitivity of 69% and a specificity of 92% in low-risk MDS. We aimed to study the feasibility and the utility of the "Ogata score" for the diagnosis of MDS among Latin America (LA) Laboratories. METHODS: This is a case and control study conducted in LA institutions members of Grupo Latinoamericano de Mielodisplasia (GLAM). A total of 146 MDS patients and 57 control patients were included. "Ogata score" was calculated. RESULTS: The sensitivity of "Ogata score" was 75.6% (95% CI, 66.8-81.3), specificity was 91.2% (95% CI, 79.7-96.7), PPV was 95.6% (95% CI, 88.5-98.3), and NPV was 65.4% (95% CI, 49.1-71.9). In low/intermediate-1 IPSS patients group, the sensitivity was 70.1% (95% CI, 60.2-78.2), specificity was 91.2% (CI-95%, 79.7-96.7), PPV was 94.2% (95% CI, 86.4-97.8), and NPV was 62.1% (95% CI, 53.0-78.7). In the group of patients "without MDS specific markers" (patients without ring sideroblasts, blast excess, or chromosomal abnormalities), the sensitivity was 66.7% (CI-95%, 55.8-76.0), specificity was 91.2% (95% CI, 79.7-96.7), PPV was 92.3% (95% CI, 82.2-97.1), and NPV was 63.5% (95% CI, 51.9-73.5). CONCLUSIONS: The diagnostic power found in this study was similar to the reported by Della-Porta et al. Also in LA, the analysis was made in modern equipment with acquisition of at least 100 000 events which permits a good reproducibility of the results.

Real-life Outcomes on Acute Promyelocytic Leukemia in Brazil - Early Deaths Are Still a Problem.

INTRODUCTION: Although a considerable improvement in survival of patients with acute promyelocytic leukemia (APL) has been seen over the past decades, real-life outcomes seem to be worse than those reported by prospective studies. We aim to describe clinical characteristics and outcomes of adult patients diagnosed with APL in an academic hospital from the University of Sao Paulo. PATIENTS AND METHODS: We retrospectively reviewed the medical charts of 61 patients with APL diagnosed between January 2007 and May 2017. Baseline clinical features and follow-up data were collected, focusing on early toxicity variables such as infection, bleeding, and thrombosis in the first 30 days from diagnosis. RESULTS: Among the 61 patients with APL, 54 received any chemotherapy. All patients also received all-trans retinoic acid (ATRA). Bleeding events were the main cause of death before receiving chemotherapy. Most patients belonged to the intermediate (43%) and high-risk (41%) groups, according to Sanz score. The '7 + 3 + ATRA' regimen was the most used regimen (n = 38). An early death rate of 20% was found, predominantly owing to sepsis. After a median follow-up of 5 years, only 1 relapse was diagnosed. The overall survival at 5 years was 59%. DISCUSSION: In comparison with prospective trials with ATRA-based regimens, we found an inferior overall survival, mostly on account of a high early-death rate. Our results are in line with other real-life retrospective reports published in the past decades. CONCLUSION: Results of real-life studies differ from those found by prospective trials. Accordingly, early actions and supportive care are still needed, aiming to decrease toxicity, especially in developing countries.

Treating Adult Acute Lymphoblastic Leukemia in Brazil-Increased Early Mortality Using a German Multicenter Acute Lymphoblastic Leukemia-based regimen.

BACKGROUND: Acute lymphoblastic leukemia (ALL) in adults is an invariably aggressive and rare disease. Its treatment is based on the use of multidrug regimens, which have been improved since the 1970s. Few published data are available on the results of adult ALL treatment in Latin America. MATERIALS AND METHODS: We retrospectively analyzed the data from 59 patients with ALL treated from 2009 to 2015 at Hospital of Clinics of University of São Paulo, using an adapted German Multicenter ALL (GMALL) protocol (07/2003). RESULTS: The median patient age was 35 years (range, 16-71 years), with 76% of new cases of B-cell lineage. Central nervous system involvement was present in 29%. Most patients were in the high-risk group, using the original GMALL criteria (68%). The early death rate was 17%, preventing early evaluation of the response in these patients. Despite a reasonable complete remission rate (76%), most patients eventually died of sepsis, especially during the induction phase and salvage regimens. The median overall survival was 17 months. CONCLUSION: Intensified chemotherapy protocols for adult ALL have succeeded in achieving better survival rates in adults, especially younger adults. The low overall survival found with GMALL in Brazil's public hospital denotes the importance of optimizing the adaptations of international protocols for treatment of ALL in nondeveloped countries and, in parallel, improving supportive care in public services.

Características genéticas da leucemia promielocítica aguda de novo / Genetics characteristics of de novo acute promyelocytic leukemia

Geneticamente, a leucemia promielocítica aguda (LPA) caracteriza-se por alterações cromossômicas estruturais recorrentes, na grande maioria das vezes translocações, envolvendo sempre o lócus gênico para o receptor alfa do ácido retinoico (RARα) localizado no braço longo do cromossomo 17 (17q21), levando à formação de genes quiméricos e oncoproteínas de fusão. Em aproximadamente 98 por cento dos casos, o gene RARα se encontra fusionado com o gene PML resultante da translocação cromossômica recíproca t(15;17)(q22;q21) e, em cerca de 2 por cento dos casos, o gene RARα pode estar fusionado com outros genes que não o PML, levando à formação de proteínas de fusão conhecidas genericamente como X-RARα. A leucemia promielocítica aguda é um exemplo de malignidade hematológica onde se tem a combinação de alterações genéticas e epigenéticas (acetilação, desacetilação e metilação) no processo de leucemogênese, alterações cromossômicas estruturais influenciando no equilíbrio dinâmico da cromatina na região promotora de alguns genes. A utilização de técnicas moleculares que auxiliam no diagnóstico genético mais preciso e o desenvolvimento de uma terapia alvo molecular permitiram alcançar alta taxa de cura desta doença.

Acute promyelocytic leukemia (APL) is characterized by structural chromosomal abnormalities involving the RARα (retinoic acid receptor a) gene located on the long arm of chromosome 17 (17q21) that lead to the formation of chimeric genes and fusion oncoproteins. In about 98 percent of cases, the RARα gene is fused to the PML gene, the result of a reciprocal chromosomal translocation t(15;17)(q22;q21) and in the other 2 percent of cases the RARα gene may be fused to other genes, leading to the formation of fusion proteins known generically as X-RARα. Acute promyelocytic leukemia is an example of a hematologic malignancy where there is a combination of genetic and epigenetic (acetylation, deacetylation and methylation) changes in the leukemogenesis process, chromosome structural changes that affect the dynamic equilibrium of chromatin in the promoter region of some genes. The use of molecular techniques that improve genetic diagnosis and the development of targeted molecular therapy have provided a high cure rate of this disorder.