Chronic Myeloid Leukemia: causes of treatment failure with imatinib

Imatinib is currently the treatment of choice of CML, but despite of the excellent results, it is not able to completely eradicate the disease and resistance may occur. The most studied mechanism is the presence of ABL kinase mutations that interfere with imatinib binding and action, gene amplification and clonal evolution. However, there are other mechanisms involved and less studied such as drug absorption and influx and efflux of imatinib. Besides the true causes of resistance, compliance is always a concern and also drug interaction should be checked. An understanding of these mechanisms will certainly contribute to develop new strategies for the treatment of resistant cases.O mesilato de imatinibe (MI) é atualmente o tratamento de escolha da Leucemoa Mielóide Crônica (LMC), mas, apesar dos excelentes resultados, não é capaz de erradicar completamente a doença, podendo ocorrer resistência ao tratamento. O mecanismo mais conhecido de resistência é o desenvolvimento de mutações do BCR-ABL, que impedem a ação ligação adequada do imatinibe à quinase, além de amplificação gênica e evolução clonal. No entanto, há uma série de outros mecanismos envolvidos e ainda pouco estudados, como alterações na absorção, efluxo e influxo de droga para o interior das células. Devem-se também considerar outros fatores, como aderência ao tratamento e uso de medicamentos concomitantes que podem interferir com imatinibe, diminuindo sua ação. O entendimento desses mecanismos poderá contribuir no desenvolvimento de novas estratégias para o tratamento dos casos resistentes.222

JUNB methylation and expression in chronic myeloid leukemia

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Development and mechanical testing of a short intramedullary nail for fixation of femoral rotational osteotomy in cerebral palsy patients

<p>Abstract</p> <p>Background</p> <p>Rotational osteotomy is frequently indicated to correct excessive femoral anteversion in cerebral palsy patients. Angled blade plate is the standard fixation device used when performed in the proximal femur, but extensile exposure is required for plate accommodation. The authors developed a short locked intramedullary nail to be applied percutaneously in the fixation of femoral rotational osteotomies in children with cerebral palsy and evaluated its mechanical properties.</p> <p>Methods</p> <p>The study was divided into three stages. In the first part, a prototype was designed and made based on radiographic measurements of the femoral medullary canal of ten-year-old patients. In the second, synthetic femoral models based on rapid-prototyping of 3D reconstructed images of patients with cerebral palsy were obtained and were employed to adjust the nail prototype to the morphological changes observed in this disease. In the third, rotational osteotomies were simulated using synthetic femoral models stabilized by the nail and by the AO-ASIF fixed-angle blade plate. Mechanical testing was done comparing both devices in bending-compression and torsion.</p> <p>Results</p> <p>The authors observed proper adaptation of the nail to normal and morphologically altered femoral models, and during the simulated osteotomies. Stiffness in bending-compression was significantly higher in the group fixed by the plate (388.97 ± 57.25 N/mm) than in that fixed by the nail (268.26 ± 38.51 N/mm) as torsional relative stiffness was significantly higher in the group fixed by the plate (1.07 ± 0.36 Nm/°) than by the nail (0.35 ± 0.13 Nm/°).</p> <p>Conclusions</p> <p>Although the device presented adequate design and dimension to fit into the pediatric femur, mechanical tests indicated that the nail was less stable than the blade plate in bending-compression and torsion. This may be a beneficial property, and it can be attributed to the more flexible fixation found in intramedullary devices.</p

Differential expression of ABCF2 in newly diagnosed and dasatinib-treated chronic myeloid leukemia patients

sem informação1001PB173168568520th Congress of European-Hematology-Associatio

Screening for hotspot mutations in PI3K, JAK2, FLT3 and NPM1 in patients with myelodysplastic syndromes

INTRODUCTION: Myelodysplastic syndromes encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, refractory cytopenia and a tendency to progress toward acute myeloid leukemia. The accumulation of genetic alterations is closely associated with the progression of myelodysplastic syndromes toward acute myeloid leukemia. OBJECTIVE: To investigate the presence of mutations in the points most frequent for mutations (hotspot mutations) in phosphatidylinositol-3-kinase (PI3K), Janus kinase 2 (JAK2), FMS-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1), which are involved in leukemia and other cancers, in a population of Brazilian MDS patients. METHODS: Fifty-one myelodysplastic syndromes patients were included in the study. According to French-American-British classification, the patients were distributed as follows: 31 with refractory anemia, 8 with refractory anemia with ringed sideroblasts, 7 with refractory anemia with excess blasts, 3 with refractory anemia with excess blasts in transformation and 2 with chronic myelomonocytic leukemia. Bone marrow samples were obtained and screened for the presence of hotspot mutations using analysis based on amplification with the polymerase chain reaction, sequencing, fragment size polymorphisms or restriction enzyme digestion. All patients were screened for mutations at the time of diagnosis, and 5 patients were also screened at the time of disease progression. RESULTS: In the genes studied, no mutations were detected in the patients at the time of diagnosis. One patient with chronic myelomonocytic leukemia was heterozygous for a Janus kinase 2 mutation after disease progression. CONCLUSIONS: These results show that hotspot mutations in the PI3K, JAK2, FLT3 and NPM1 genes are not common in MDS patients; nevertheless, JAK2 mutations may be present in myelodysplasia during disease progression

Treatment Outcome of Acute Promyelocytic Leukemia with Modified Aida Protocol

We analyzed the outcome of a series of 19 newly diagnosed patients with acute promyelocytic leukemia treated with AIDA modified protocol, using mitoxantrone in place of idarubicin. Eleven patients achieved morphologic CR (58%). The remaining 8 patients had induction failure due to death during induction. Ten of eleven patients in CR achieved molecular remission after induction therapy and all the 8 patients had molecular remission after consolidation. Eight patients completed the three consolidation courses as scheduled and then proceeded to maintenance therapy. After a median follow up of 52 months, no molecular or hematological relapse has occurred. The 4-year disease-free survival is 82%. The study showed the antileukemic efficacy of mitoxantrone and that it could be used as a reasonable option in anthracycline-based strategies in APL

Efficacy and safety of dasatinib vs. Imatinib in Latin american subpopulation from the dasision trial in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP)

sem informação100120th Congress of European-Hematology-Associationsem informaçã

Experiência brasileira utilizando terapia sequencial de alta dose seguido de transplante autólogo de célula-tronco hematopoética para linfomas malignos

Using the overall survival (OS), disease free survival (DFS) and progression free survival (PFS), as well as associated toxicity, the purpose of this work was to evaluate the effectiveness of HDS followed by ASCT as salvage therapy. A retrospective analysis was performed of 106 patients with high grade non-Hodgkin lymphoma receiving HDS followed by ASCT, between 1998 and 2006. Median age was 45 years (Range: 8-65), with 66 (62%) men. Histopathological classification was: 78% DLBCL patients, 12% T and anaplastic and 9% Mantle cell lymphomas; 87% had B cell and 12% T cell lymphomas; 83% were stage III-IV (Ann Arbor Staging), 63% had B symptoms, 32% had bone marrow involvement, 62% bulky disease and 42% high-intermediate or high risk IPI. After HDCY, 9 patients died, 7 from toxicity and 2 from sepsis. Eighty patients underwent ASCT, 47% were in complete remission (CR) and 15% died, all from toxicity. Their OS was 45% over 8 years. During the follow-up, another 35 patients died [4 CR, 1 partial response (PR), 2 relapsed disease (RD) and 28 disease progression (DP)], 11 (31%) had not performed ASCT. OS was 37%; DFS was 49% and PFS 28%. OS by diagnosis was 42% for DLBCL, 40% for T-cell (8 y) and 20% for Mantle Cell (6 y) (P=NS). OS by B symptom patients was 22% vs. 58% (P=0.002) and PFS was 23% vs. 37% (P=0.03). Patients who achieved CR after HDCY (38) had significantly better OS and PFS (38% and 17%) than patients who remained in DP (P<0.0001). Cox Regression demonstrated therapeutic lines before HDCY (Relative risk - RR = 1.41; CI 95%: 1.04-1.90; P= 0.02) and PD both before (RR = 2.70; CI 95%: 1.49-4.91, P<0.001) and after HDCY (RR = 5.38; 95% CI: 2.93-9.87; P<0.0001). Conclusions: Our study suggests HDS is an efficient treatment to improve status and to reduce tumoral burden. Regardless of toxicity-related mortality it is feasible, especially considering the poor prognosis of patients.A proposta deste trabalho foi avaliar a eficácia da HDS seguida do transplante autólogo como terapia de salvamento através da sobrevida global, livre de doença e livre de progressão bem como sua toxicidade. Realizou-se estudo retrospectivo com 106 pacientes com LNH de alto grau de malignidade entre 1998 e 2006. A mediana de idade foi 45 anos (8-65); 62% homens; DLBCL, 78%; 12%, T e anaplásico e 9%, linfoma da zona do manto; 87%, células B; 83% estádios III-IV; 63% com sintomas B; 32% com infiltração da medula óssea ao diagnóstico; 62% com grande massa e 42% com IPI de alto risco ou intermediário. Após alta dose de ciclofosfamida (HDCY), nove pacientes faleceram. Oitenta pacientes realizaram o transplante, sendo que 47% estavam em RC e 15% faleceram devido à toxicidade. A sobrevida global foi de 45% em oito anos para estes pacientes. Trinta e cinco pacientes não realizaram o transplante por causas diversas. Sobrevida global para todos os pacientes foi de 42%, DLBCL, 40%; T-cell, 40% e zona do manto, 20% (P=NS). Pacientes que obtiveram RC após HDCY tiveram melhor sobrevida global e livre de progressão (38% e 17%, respectivamente) do que os que permaneceram em PD (P<0.0001). O modelo de Cox resultou que o número de linhas terapêuticas antes da HDCY (RR 1.41 IC 95%: 1.04-1.90, P=0.02) e PD antes da HDCY (RR 2.70, IC 95%: 1.49-4.91, P<0.001) e após HDCY (RR 5.38, IC 95%: 2.93-9.87, P<0.0001). Nosso estudo sugere que HDS é um método eficiente de tratamento para melhorar o status e reduzir a massa tumoral. Em relação à toxicidade, é factível, especialmente em pacientes de prognóstico ruim91