Genomic instability in a chronic lymphocytic leukemia patient with mono-allelic deletion of the DLEU and RB1 genes.

BACKGROUND: The most frequent cytogenetic abnormality detected in chronic lymphocytic leukemia (CLL) patients is the presence of a deletion within the chromosome band 13q14. Deletions can be heterogeneous in size, generally encompassing the DLEU1 and DLEU2 genes (minimal deleted region), but at times also including the RB1 gene. The latter, larger type of deletions are associated with worse prognosis.Genomic instability is a characteristic of most cancers and it has been observed in CLL patients mainly associated with telomere shortening. CASE PRESENTATION: Cytogenetic and fluorescence in situ hybridization studies of a CLL patient showed a chromosomal translocation t(12;13)(q15;q14), a mono-allelic 13q14 deletion encompassing both the DLEU and RB1 genes, and genomic instability manifested as chromosomal breaks, telomeric associations, binucleated cells, nucleoplasmic bridges, and micronucleated cells.In conclusion, our CLL patient showed genomic instability in conjunction with a 13q14 deletion of approximately 2.6 megabase pair involving the DLEU and RB1 genes, as well as other genes with potential for producing genomic instability due to haploinsufficiency.

F8 inversions of introns 22 and 1 confer a moderate risk of inhibitors in Mexican patients with severe hemophilia A. Concordance analysis and literature review.

Intron-22 (Inv22) and intron-1 (Inv1) inversions account for approximately one half of all severe cases of hemophilia A (SHA) worldwide. Inhibitor development against exogenous factor VIII (FVIII) represents a major complication in HA. The causative F8 mutation is considered the most decisive factor conditioning inhibitor development. We aimed to investigate prevalence of Inv22 and Inv1 mutations, and its association as risk factors for developing inhibitors to FVIII. We investigated Inv22 and Inv1 in 255 SHA Mexican patients from 193 unrelated families using the inverse shifting-polymerase chain reaction (IS-PCR). We analyzed the association between inversions and inhibitor development via logistic regression introducing as covariates the populations, the inversions, F8-haplotypes and the age of patients at enrollment. Inv22 was found in 91/193 (47.2%: 38.9% exhibited Inv22-1 and 8.3% Inv22-2), and Inv1 in 2/193 (1.0%) independent families. Absolute inhibitor prevalence (IP) for Inv22 in unrelated patients was 15% (10-19). The cohorts and age of patients were independent predictors of inhibitor risk, but not inversions or haplotypes. Inversions presence in our population was associated to a moderate risk of developing inhibitors. Inv1 was found for the first time in two Mexican families. A relevant genetic component was observed by the strong concordance among brother-pairs.

[Response to treatment with tyrosine kinase inhibitors in chronic myeloid leukemia]. / Respuesta a inhibidores de tirosina cinasa en pacientes con leucemia mieloide crónica.

BACKGROUND: Chronic myeloid leukemia represents 15 % of all the leukemias in adults. With the introduction of tyrosine kinase inhibitors, overall survival at 10 years is 80-90 %. The objective was to describe the epidemiology, complete cytogenetic response and major molecular response with tyrosine kinase inhibitors in patients with chronic myeloid leukemia. METHODS: It was performed a descriptive cross-sectional study of patients with chronic myeloid leukemia and Philadelphia chromosome-positive in treatment with tyrosine kinase inhibitors. RESULTS: The sample included 54 patients with a mean age of 41 years; 78 % of patients were in chronic phase, and in 8 % of patients were identified complex karyotype at diagnosis. All patients received imatinib as first-line treatment. We identified mutations in 8 %. The patients with primary or secondary resistance (30%) received second-generation tyrosine kinase inhibitors as a second-line therapy. Of 35 patients treated with imatinib, 23 had complete cytogenetic response, 23 had major molecular response, and 16 had loss of response to treatment. Of nine patients treated with nilotinib, two presented complete cytogenetic response, two major molecular response, and five loss of response to treatment. Of seven patients treated with dasatinib, two had complete cytogenetic response, two major molecular response, and four loss of response to treatment. CONCLUSIONS: Of patients studied, 30 % was resistant to imatinib, 52 % achieved a complete cytogenetic response, and 42 % major molecular response. The use of second generation tyrosine kinase inhibitors led to obtain a complete cytogenetic and major molecular response in fewer time.

INTRODUCCIÓN: la leucemia mieloide crónica representa 15 % de las leucemias en los adultos. Con los inhibidores de la tirosina cinasa, la sobrevida a 10 años es de 80 a 90 %. El objetivo de esta investigación fue describir las características epidemiológicas, respuesta citogenética completa y respuesta molecular mayor con inhibidores de tirosina cinasa en pacientes con leucemia mieloide crónica. MÉTODOS: se realizó un estudio transversal descriptivo de los expedientes clínicos de pacientes con leucemia mieloide crónica positivos a cromosoma Filadelfia que fueron sometidos a tratamiento con inhibidores de tirosina cinasa. RESULTADOS: se incluyeron 54 pacientes; la edad media fue de 41 años, 78 % estaba en fase crónica y en 8 % se detectaron cariotipos complejos al diagnóstico. Todos recibieron imatinib como tratamiento de primera línea. Se identificaron mutaciones en 8 % de los pacientes. Los pacientes con resistencia primaria o secundaria (30 %) recibieron inhibidores de tirosina cinasa de segunda generación como tratamiento de segunda línea. De 35 pacientes tratados con imatinib, 23 presentaron respuesta citogenética completa, 23 respuesta molecular mayor y 16, pérdida de respuesta. De nueve pacientes tratados con nilotinib, dos presentaron respuesta citogenética completa, dos respuesta molecular mayor y cinco, pérdida de respuesta. De siete pacientes tratados con dasatinib, dos presentaron respuesta citogenética completa, dos respuesta molecular mayor y cuatro, pérdida de respuesta. CONCLUSIONES: 30 % de los pacientes presentó resistencia, 52 % alcanzó una respuesta citogenética completa con imatinib y 42 % una respuesta molecular mayor. El uso de inhibidores de tirosina cinasa de segunda generación permite alcanzar respuestas citogenética completa y molecular mayor en menor tiempo.

[A clinical and therapeutic analysis in acute megakaryoblastic leukemia]. / Análisis clínico-terapéutico de leucemia aguda megacarioblástica.

OBJECTIVE: to show clinical and therapeutic findings in patients with diagnosis of acute megakaryoblastic leukemia (AML). METHODS: twenty four patients with diagnosis AML was carried out. Clinical, laboratory survey results and treatment response were studied. Nineteen patients had primary form and five secondary, attended during a period of eight years. The diagnosis was established by a highly clinical suspicious, with immunophenotype cytometry flow or/and bone biopsy with immunohistochemistry study which proves definitely AML. RESULTS: Fourteen were women, the median age was 43 years, 18 were treated with antineoplasic agents, ten obtained response, six complete and four partial. The response may improve with schemes with high dose of cytosine arabinoside. CONCLUSIONS: our results with the treatment showed that 27 % patients are alive under maintenance treatment long 18 months. The allogeneic bone marrow transplant seems to be one more option in long term.