Expression of genes potentially involved in loss of response in patients with chronic myeloid leukemia.

Chronic Myeloid Leukemia (CML) is a hematological malignancy characterized by the presence of the BCR::ABL1 fusion gene, which leads to uncontrolled cell growth and survival. Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML, but a significant proportion of patients develop resistance or lose response to these drugs. Understanding the molecular mechanisms underlying treatment response and resistance is crucial for improving patient outcomes. This study aimed to analyze the expression patterns of genes involved in treatment response and resistance in CML patients receiving TKI therapy. The expression levels of MET, FOXO3, p15, p16, HCK, and FYN genes were examined in CML patients and compared to healthy donors. Gene expression levels were compared between optimal responders (OR) and resistant patients (R) vs. healthy donors (HD). The MET and FOXO3 OR group showed significant differences compared with the HD, (p < 0.0001) and (p = 0.0003), respectively. p15 expression showed significant differences between OR and HD groups (p = 0.0078), while no significant differences were found in p16 expression between the HD groups. FYN showed a statistically significant difference between R vs. HD (p = 0.0157). The results of HCK expression analysis revealed significant differences between OR and HD (p = 0.0041) and between R and HD (p = 0.0026). When we analyzed OR patients with undetectable BCR::ABL1 transcripts, a greater expression of HCK was observed in the R group. These findings suggest that monitoring the expression levels of MET and FOXO3 genes could be valuable in predicting treatment response and relapse in CML patients. Our study provides important insights into the potential use of gene expression analysis as a tool for predicting treatment response and guiding treatment decisions in CML patients. This knowledge may ultimately contribute to the development of personalized treatment strategies to improve patient outcomes in CML.

Implicancia pronóstica de características basales en trombocitopenia esencial / Prognostic implication of basal characteristics in essential thrombocythemia

OBJETIVO: evaluar asociación entre características basales de Trombocitemia Esencial (TE) y eventos. Materiales-métodos: estudio observacional retrospectivo, datos capturados prospectivamente. Población: adultos con TE confirmada seguidos en CH del IIHEMA. Resultados: 67 pacientes evaluables. Md 68 años. Femenino 44, Masculino 23. Seguimiento Md 6 años. Score riesgo Alto 40, Intermedio 15, Bajo 12. Hematocrito Md 41%. Hemoglobina Md 13.4 g/dL. Leucocitos Md 9.7x109/L. Plaquetas Md 852x109/L. Esplenomegalia 12. Cariotipo normal 40, alterado 5. JAK2 V617F positivo 29/41. BCR/ABL1 negativo 45/45. FRV 40. Eventos: 67. Sangrado, 21 pacientes, presentó asociación con leucocitosis: Md 12.2x109/L en el grupo con sangrado y 8.8x109/L en el grupo sin evento (p=0.003). El 76% del grupo con sangrado y el 36,96% del grupo sin evento tenían leucocitos >10.0x109/L (p= 0.003). Trombocitosis Md 1.204x109/L en el grupo con sangrados y 814.5x109/L en el grupo sin evento (p=0.0098), no alcanzó significación estadística al comparar proporción de pacientes con recuento normal (p=0.46). Tromboembolia, 16 pacientes, se asoció con leucocitosis (Md 11.9x109/L en el grupo con tromboembolia y 9.2x109/L en el grupo sin evento (p=0.02). 75% del grupo con eventos y 41% del grupo sin eventos tenían leucocitos >10.0x109/L (p=0.018)) y con trombocitosis (Md 1.182x109/L en el grupo con tromboembolia y 809x109/L en el grupo sin evento (p=0.04), pero no alcanzó significación estadística al comparar proporción de pacientes con recuento normal (p=0.5)). CONCLUSIÓN: la asociación entre trombocitosis extrema/leucocitosis y sangrado coincidió con la literatura; leucocitosis se asoció a tromboembolia. El JAK2 V617F no mostró asociación: analizaremos prospectivamente aumentando la población para esclarecer asociación y posible rol de terapias dirigidas en esta entidad. (AU)

OBJETIVE: asses association basal characteristics of Essential Trombocitemia (ET) and events. MATERIALS-METHODS: retrospective observational study, data captured prospectively. Population: adults with confirmed ET treated in CH of IHEMA. RESULTS: 67 evaluable patients. Md 68-years-old. Female 44, Male 23. Follow up Md 6 years. Risk Score High 40, Intermeddle 15, Low 12. Hematocrit Md 41%. Hemoglobin Md 13.4 g/dL. Leukocytes Md 9.7x109/L. Platelets Md 852x109/L. Splenomegaly 12. Normal karyotype 40, abnormal 5. JAK2V617F positive 29/41. BCR-ABL1 negative 45/45. Vascular risk factors 40. EVENTS: 67. Bleeding, 21 patients, showed association with leukocytosis: Md 12.2x109/L in the group with bleeding and 8.8x109/L in the group without event (p=0.003). Leukocytes >10.0x109/L was seen in 76% of the group with bleeding versus 36.96% of the group without event (p= 0.003). Thrombocytosis Md 1.204x109/L in the group with bleeding and 814.5x109/L in the group without event (p=0.0098), but did not reach statistical significance when comparing with the proportion of patients with normal counts (p=0.46). Thromboembolism, 16 patients, showed association with both leukocytosis (Md 11.9x109/L in the group with thromboembolism and 9.2x109/L in the group without event (p=0.02). Leukocytosis >10.0x109/L was seen in 75% of the group with events and 41% of the group without event (p=0.018)) and with thrombocytosis (Md 1.182x109/L in the group with thromboembolism and 809x109/L in the group without event (p=0.04), but did not reach statistical significance when comparing with the proportion of patients with normal counts (p=0.5)). CONCLUSION: the association between extreme thrombocytosis/leukocytosis and bleeding was consistent with literature; leukocytosis was associated also with thromboembolism. JAK2 V617F mutated did not show association, we will prospectively analyze increasing the population to clarify its association and possible role of target therapies in this disease. (AU)

An unusual translocation, t(1;11)(q21;q23), in a case of chronic myeloid leukemia with a cryptic Philadelphia chromosome.

Chronic myeloid leukemia (CML) is characterized by the translocation t(9;22)(q34;q11) [Philadelphia (Ph) chromosome). Although not frequently occurring, additional chromosome abnormalities (ACAs) can be detected at diagnosis and a number have been associated with an adverse cytogenetic and molecular outcome. The present study reports a case of CML presenting with the translocation t(1;11)(q21;q23) and a cryptic Ph chromosome. The presence of ACAs could generate greater genetic instability, promoting the emergence of further alterations. The present findings suggest that t(1;11)(q21;q23) can prevent a good response to tyrosine kinase inhibitor (TKI) therapy developing a primary resistance. In the present patient, at a recent follow-up, the T315I mutation was detected. This mutation confers full resistance to all available TKI, except ponatinib, which was not a therapeutic option due to comorbidities.

GSTM1 and GSTP1, but not GSTT1 genetic polymorphisms are associated with chronic myeloid leukemia risk and treatment response.

BACKGROUND: Chronic myeloid leukemia (CML) is associated to the BCR-ABL1 oncogene and can successfully be treated with tyrosine kinase inhibitors (TKIs). However, it remains still under investigation which molecular factors may influence CML risk or varying responses to TKIs. The aim of this study was to assess the role of Glutathione-S-transferases (GSTs) genetic polymorphisms in CML susceptibility and TKI clinical outcome. MATERIALS: Deletion polymorphisms in GSTM1 and GSTT1 genes and the single nucleotide polymorphism in GSTP1 c.319A>G (rs1695; p.105Ile>Val) were genotyped by PCR methods in 141 CML treated patients and 141 sex- and age-matched healthy individuals. RESULTS: Individual analysis of each GST gene showed no association with CML risk. A trend toward significance (p=0.07) for a recessive model was found for GSTP1 (OR: 2.04; CI: 0.94-4.4). However, the combined analysis showed that GSTM1-null/GSTP1-GG as well as GSTT1-null/GSTP1-GG were associated with CML development (p=0.03; OR: 3.54 CI: 1.2-14.57; p=0.05; OR: 12.65; CI: 1.17-21.5). The relationship with treatment outcome showed that the presence of GSTM1 gene was significantly linked with an inferior rate of major molecular response (p=0.048) and poor event free-survival (EFS) (p=0.02). Furthermore, a group of patients with GSTP1-GG genotype were significantly associated with reduced EFS comparing to those carrying other GSTP1 genotypes (p=0.049). GSTP1-GG genotypes had short time to treatment failure in a group of patients unresponsive to TKIs comparing to other GSTP1 genotypes (p=0.03). CONCLUSIONS: This study highlights the significance of GSTM1 and GSTP1 polymorphisms on CML susceptibility and response to TKIs in the Argentinean population.

TP53 codon 72 polymorphism predicts chronic myeloid leukemia susceptibility and treatment outcome.

BCR-ABL1 gene is a key molecular marker of chronic myeloid leukemia (CML), but it is still unclear which molecular factors may influence CML risk or lead to variable responses to tyrosine kinase inhibitors (TKIs). The aim of this study was to investigate the impact of TP53 c.213 G>C(Arg72Pro; rs1042522) polymorphism on CML risk and its correlation with clinical outcome. Peripheral blood samples from 141 treated CML patients and 141 sex- and age-matched healthy individuals were genotyped by PCR-RFLP. Standard genetic models for disease penetrance were evaluated by logistic regression analysis and Kaplan-Meier method was performed to estimate survival curves. Our study suggests that TP53 c.213 G>C polymorphism may be involved in CML development considering a recessive model (p=0.01; OR: 0.19; CI: 0.06-0.68). In addition, a non-homogenous distribution was found for this polymorphism in males and patients youngers than 50years (p=0.02). According to clinical response, TP53-GG genotype was associated with higher levels of BCR-ABL1 transcripts (p=0.04) and shorter event free survival (p=0.04). Moreover, a trend toward significance was found for failure free survival (p=0.06) and time to imatinib failure (p=0.08). In conclusion, our data suggest that a;TP53 c.213 G>C may be a potential biomarker of CML susceptibility and clinical outcome.

BCR-ABL mutations in chronic myeloid leukemia treated with tyrosine kinase inhibitors and impact on survival.

This is the largest Latin American study of BCR-ABL mutations in chronic myeloid leukemia (CML) patients, resistant to imatinib (IM). In 195/467 (41%) patients, mutations were detected. The most frequent mutation was T315I (n = 31, 16%). Progression-free (PFS) and overall survival (OS) at 5 years were lower in patients with BCR-ABL mutations (43% vs. 65%, p = 0.07 and 47% vs. 72%, p = 0.03, respectively) and in those with the T315I mutation (p = 0.003 and p = 0.03). OS and PFS were superior in subgroup who switched to second generation inhibitors (SGIs) after IM failure (OS: 50% vs. 39% p = 0.01; PFS: 48% vs. 30% p = 0.02). BCR-ABL mutations conferred a significant poor prognosis in CML patients.

Polymorphisms in TNF and IFNG are associated with clinical characteristics of aplastic anemia in Argentinean population.

The impaired hematopoiesis in acquired aplastic anemia (AA) results from immune-mediated mechanisms. We characterized polymorphisms implicated in controlling type-1 cytokine production in 69 patients with AA. Our data suggest that the studied polymorphisms are not associated with susceptibility in the overall AA population. However, the presence of the higher expressing TNF - 308A allele was associated with younger age (p = 0.0297) and more profound neutropenia (p = 0.0312), and over-represented in patients with very severe AA (p = 0.0168). The higher producing IFNG 12 CA-repeat allele showed strong linkage disequilibrium with the + 874T allele, and was associated with a lower hemoglobin level (p = 0.0351). Also, the presence of at least one higher expressing variant was more frequent among patients responding to immunosuppressive treatment (p = 0.0519). Our findings suggest that the presence of higher expressing variants of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in AA patient genotypes could be related to clinical parameters, disease severity and therapy outcomes.

Clinical activity of ponatinib in one patient with chronic myeloid leukemia in chronic phase with e19a2 transcript and T315I mutation.

BACKGROUND: Chronic myeloid leukemia (CML) is a hematological disorder that in rare cases, mainly in CML neutrophilic, presents the e19a2 rearrangement. The encoded product is a 230-KDa protein. Despite the remarkable responses to treatment of most patients, a small but significant fraction of them develop clinical resistance to the tyrosine kinase inhibitors (TKIs). The most common mechanism of resistance is point mutations in the ABL1 kinase domain. The recently approved third-generation TKI ponatinib demonstrated remarkable activity in patients with multi-TKI-resistant disease. Particularly impressive was its efficacy in patients with T315I mutation that is resistant to all other TKIs. METHODS: Qualitative PCR was carried out by multiplex approach. Relative transcripts quantification was performed by one-step real-time PCR, with a specific Taqman probe and primers for the e19a2 rearrangement. We carried out a mutational screening by high-resolution melting, and the mutation was identified by Sanger method. The mutation burden was quantified by quantitative PCR using allele-specific primers. RESULTS: In a patient with CML, we identified a PCR product corresponding to e19a2 rearrangement harboring T315I mutation. At the time of mutational analysis, during dasatinib treatment, the T315I clone was 100% and the quantification of BCR-ABL1 was 18%. After ponatinib therapy, the T315I mutation burden decreased down to undetectable levels and the BCR-ABL1 transcripts showed a very low value (0.011%). CONCLUSIONS: Here, we report the hematological, cytogenetic, and molecular response of a patient with refractory CML in chronic phase with e19a2 transcripts, carrying T315I mutation that was successfully treated with ponatinib.

CAMKIIγ, HSP70 and HSP90 transcripts are differentially expressed in chronic myeloid leukemia cells from patients with resistant mutated disease.

Patients with chronic myeloid leukemia (CML) can develop disease resistance to tyrosine kinase inhibitor (TKI) therapy, which is mainly attributable to the presence of point mutations in the tyrosine kinase domain of BCR-ABL1. In order to examine suitable markers to monitor treatment efficacy, we investigated transcript expression profiles of genes known to be involved in myeloid cell proliferation, such as CAMKIIγ and KI67, and in protein stability and ultimately cell survival under physiological and stress conditions, such as heat shock proteins HSP70 and HSP90. We studied 101 patients with CML in different stages of disease and with different responses to TKI treatment. The results of quantitative real-time polymerase chain reaction (qPCR) analyses showed that the expression levels of CAMKIIγ, KI67, HSP70 and HSP90 genes were up-regulated at diagnosis, and in cases with signs of treatment resistance both in chronic and advanced phases (accelerated and blastic phases) with respect to chronic phase in remission and healthy donors. When only 56 resistant cases, 31 with mutations (MT) and 25 without mutations (WT), in the BCR-ABL1 tyrosine kinase domain were considered, the transcript expression profile showed an unexpected significant increase in CAMKIIγ and HSP70, and a significant decrease in HSP90 in MT versus WT cases. This differential transcript expression prompted us to design an expression score, log(CAMKIIγ × HSP70/HSP90), which can be used to provide rapid screening to discriminate the presence or absence of mutations in resistant cells and to monitor TKI treatment efficacy in patients with CML.

Expression of LYN and PTEN genes in chronic myeloid leukemia and their importance in therapeutic strategy.

Tyrosine kinase inhibitors (TKIs), imatinib, nilotinib and dasatinib, are the current treatment of chronic myeloid leukemia (CML). BCR-ABL1 point mutations are the principal cause of resistance to treatment; however other mechanisms could be involved in failure to TKI therapy. LYN is a src kinase protein that regulates survival and responsiveness of tumor cells by a BCR-ABL1 independent mechanism. PTEN tumor suppressor gene is downregulated by BCR-ABL1 in CML stem cells and its deletion is associated with acceleration of disease. In this study we evaluated the expression of LYN, PTEN and the ratio of both genes in 40 healthy donors (HD) and in 139 CML patients; 88 of them resistant to TKI in different phases of disease and 51 in chronic phase classified as optimal responders (OR) to TKI [40 treated with imatinib or nilotinib (OR-IN) and 11 treated with dasatinib (OR-D) therapy]. When we analyzed the gene expression values of LYN, an increase was observed only in advanced stages of the disease, however, when we analyzed the ratio between LYN and PTEN genes, the group of resistant patients in chronic phase in imatinib or nilotinib treatment (CP-IN) also showed a significant increase. Resistant patients treated with dasatinib, a src kinase inhibitor, presented a similar ratio to the observed in HD. In addition, the LYN/PTEN ratio and the LYN expression showed a direct significant correlation with BCR-ABL1 transcript levels in unmutated resistant patients treated with non-src kinase inhibitors. We were able to identify 8/35 (23%) of cases in CP-IN and 4/12 (33%) in accelerated phase and blast phase (AP/BC-IN), in which resistance could be associated with an increase in the ratio of the LYN/PTEN. Our data suggest that the LYN/PTEN expression ratio may be a sensitive monitor of disease progression in unmutated CML patients under imatinib or nilotinib treatment. This ratio could detect cases when resistance is related to altered LYN expression, suggesting that the treatment change to a src kinase inhibitor would be most suitable to overcome resistance.

Early detection and quantification of mutations in the tyrosine kinase domain of chimerical BCR-ABL1 gene combining high-resolution melting analysis and mutant-allele specific quantitative polymerase chain reaction.

BCR-ABL1 point mutations are the most common cause of resistance in patients with chronic myeloid leukemia (CML) who fail or lose response to tyrosine kinase inhibitors. We have developed a rapid method to screen BCR-ABL1 mutations by high resolution melting (HRM). We designed a strategy based on amplification refractory mutational system-quantitative polymerase chain reaction (ARMS-qPCR) to identify and quantify several clinically relevant mutations. From 856 patients with CML studied during 2 years in our laboratory, we selected 32 who showed persistent levels of BCR-ABL1 transcripts (>0.1%) in at least two consecutive studies. Using our strategy, we identified mutations in 11/32 cases (34.4%), while only two of them (6.2%) were detectable by sequencing. Furthermore, we were able to estimate the timing and dynamics of mutated clones, evaluating retrospective samples from the same patient. In cases with lack or loss of molecular response this analysis might be useful for designing early therapeutic strategies.

The presence of -308A TNFα is associated with anemia and thrombocytopenia in patients with myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematological diseases characterized by refractory cytopenia(s). MDS patients show increased levels of tumor necrosis factor alpha (TNFα) which is a multifunctional proinflammatory cytokine. The aim of this work is to examine the presence of -308A/G TNFα variants and to analyze whether it is associated with clinical parameters in a cohort of 101 Argentinean de novo MDS patients. The A/A+A/G genotype at TNFα -308 was overrepresented 2-fold in our population (p=0.0499, odds ratio-OR: 2.107) and these differences were more evident in RA-FAB subtype (p=0.0424, OR: 2.502). The presence of the high expressing -308A allele was associated with lower hemoglobin level (8.3 vs 9.9g/dL; p=0.0206), reduced platelet counts (89,000 vs 130,000/µL; p=0.0381) and younger age (59 vs 68years; p=0.0122) at diagnosis. Also, these patients showed 3.8-fold higher risk of transfusion requirement (76% vs 46%, p=0.0105) during the follow up. In conclusion, the presence of an inherited -308A TNFα, which increases its transcription level, was associated with the MDS phenotype in our cohort of Argentine MDS patients. Also, an overexpression of TNFα may promote an underlying proinflammatory state that cooperates with intrinsic defects within MDS progenitors to increase the severity of certain phenotypic features of the disease.

Partial and total monosomal karyotypes in myelodysplastic syndromes: comparative prognostic relevance among 421 patients.

Myelodysplastic syndromes (MDS) include a group of heterogeneous hematological disorders with a variable risk of leukemic evolution and short survival. Around 40-50% of patients show abnormal karyotypes that are mostly characterized by monosomies or deletions. Cytogenetic findings are an independent prognostic factor and the International prognostic scoring system (IPSS) differentiates three cytogenetic categories, despite the Intermediate one being heterogeneous. The aim of this study, including 421 Argentinean patients with primary MDS, is to characterize the cytogenetic profile, to test its prognostic value and to compare partial and monosomal karyotypes against other cytogenetic findings. An abnormal karyotype (median survival: 26 months) was observed in 176 patients. The presence of complex karyotypes, number of alterations, and the IPSS cytogenetic groups showed significant differences for predicting outcome. Behavior of patients with isolated deletions (median survival: 49 months) did not differ from those with normal karyotype (56 months, P = 0.654) or Good prognostic findings (43 months, P = 0.371). However, a worse prognosis was observed when another alteration was added (31 months, P = 0.043). Karyotypes with autosomal monosomies (median survival: 16 months) had a prognostic impact similar to other Poor cytogenetic findings (17 months, P = 0.626). In our population classified according to French-American-British (FAB) or World Health Organization (WHO), this new categorization of cytogenetic abnormalities, recognizing three different risk groups, showed an independent prognostic impact and a better discriminating power than the IPSS categories. It can be concluded that all isolate deletions (excluding 7q-) are good prognostic findings and all monosomies (excluding Y chromosome loss) are bad indicators.

Molecular monitoring of imatinib in chronic myeloid leukemia patients in complete cytogenetic remission: does achievement of a stable major molecular response at any time point identify a privileged group of patients? A multicenter experience in Argentina and Uruguay.

BACKGROUND: Monitoring minimal residual disease (MRD) by real-time quantitative polymerase chain reaction (RT-PCR) in chronic myeloid leukemia (CML) patients is mandatory in the era of tyrosine kinase inhibitors. Achieving a major molecular response (MMR) at 12 and 18 months predicts a better progression and event-free survival. PATIENTS AND METHODS: The objective of this prospective, multicentric study was to evaluate MRD by standardized RT-PCR in 178 patients with chronic-phase CML who were treated with imatinib at different institutions in Argentina and Uruguay and to determine if achievement of a stable MMR (BCR-ABL transcript levels < 0.1%) identifies a low-risk cytogenetic relapse group. The median age of the patients was 50 years, and 55% of them had received imatinib as first-line therapy. BCR-ABL transcript levels were measured after achievement of complete cytogenetic remission (CCyR) and at 6-month intervals. RESULTS: MMR was detected in 44% patients at the start of the study. This value increased to 79% at month 36 of evaluation. Complete molecular response (CMR) also increased from 24% to 52% of patients. Not achieving a stable MMR determined a higher risk of cytogenetic relapse (9% of MMR patients not achieving an MMR vs. 1% of patients who achieved MMR). Patients with sustained MMR had a significantly better cytogenetic relapse-free survival at 48 months (97% vs. 87%; P = .008) but showed no differences in overall survival. Patients who did not remain in CCyR changed treatment. CONCLUSIONS: A stable MMR is a strong predictor for a durable CCyR. Standardized molecular monitoring could replace cytogenetic analysis once CCyR is obtained. These results emphasize the validity and feasibility of molecular monitoring in all standardized medical centers of the world.

Clinical outcome of chronic myeloid leukemia imatinib-resistant patients: do BCR-ABL kinase domain mutations affect patient survival? First multicenter Argentinean study.

In imatinib-treated patients with chronic myeloid leukemia (CML), BCR-ABL mutations are the most common mechanism of resistance. Here we report the first multicenter Argentinean study investigating mutations in those patients with CML who fail or lose response to imatinib, with or without previous interferon treatment. Point mutations were detected in 36 of 154 patients by direct sequencing. In our series, the single most common mutations were G250E, E255K/V, and M351T. The presence of mutations correlated significantly with accelerated phase, lack of molecular response, and lower cytogenetic and hematological responses. While overall survival did not differ between patients with or without mutations, the probability of progression was higher in patients with mutations. Cases with non-P-loop mutations showed a significantly better overall survival from diagnosis. Multivariate analysis showed that the most significant variables related to the development of mutations were accelerated phase, duration of imatinib treatment, and time delay to starting imatinib. Our results demonstrated that mutation frequency increased with the progression of disease, and suggest that imatinib treatment should be started early.

BAX/BCL-XL gene expression ratio inversely correlates with disease progression in chronic myeloid leukemia.

BCR-ABL fusion gene is implicated in the pathogenesis of chronic myeloid leukemia (CML), encoding the oncoprotein p210(BCR-ABL) with anti-apoptotic activity. The inability to undergo apoptosis is an important mechanism of drug resistance and neoplastic evolution in CML. The gene transcript expression of mitochondrial apoptotic related genes BAX and BCL-XL was evaluated by quantitative Real Time PCR (qPCR) in vitro in K562 cells and in vivo in peripheral blood of 66 CML patients in different stages of the disease: 13 cases at diagnosis, 34 in chronic phase (CP), 10 in accelerated phase (AP) and 9 in blast crisis (BC). Our results in K562 cells showed that all treatments with different tyrosine kinase inhibitors (TKIs) induced a decreased expression of the antiapoptotic oncogene BCL-XL, whereas the proapoptotic gene BAX remains constant with minor modifications. A significantly lower BAX/BCL-XL expression ratio (mean±SEM) than a group of healthy individuals (4.8±0.59) were observed in CML patients at diagnosis (1.28 ± 0.16), in AP (1.14±0.20), in BC (1.16±0.30) and in 18% of cases of patients in CP (2.71±0.40). Most CP cases (82%) showed a significantly increased ratio (10.03±1.30), indicating that the treatment with TKIs efficiently inhibited the expression of BCL-XL by blocking BCR-ABL oncoprotein. The BAX/BCL-XL ratio showed a significant inverse correlation (Spearman P<0.0001) with BCR-ABL/ABL relative expression indicating that low BAX/BCL-XL was associated with disease progression. Accordingly, the follow up of a cohort of eight cases during 6months from diagnosis showed that while the BAX/BCL-XL ratio rapidly increased after treatment in seven cases with good evolution, it decreased in the single case that showed rapid evolution and short survival. Our data suggest that BAX/BCL-XL expression ratio may be a sensitive monitor of disease progression and an early predictor of TKI therapy responsiveness in CML patients.

Síndromes mieloproliferativos crónicos y embarazo: revisión de casos de pacientes del Departamento de Clínica Hematológica / Chronic myeloproliferative syndromes and pregnancy: a case review of Clinical Hematological Department patients

El manejo convencional de los síndromes mieloproliferativos crónicos (SMP) es un problema cuya frecuencia se ha incrementado. Los datos existentes en la literatura provienen principalmente de series de casos. Esta serie reporta la evolución y el tratamiento de 9 embarazos en 7 pacientes con SMP, 4 con diagnóstico de leucemia mieloide crónica (LMC) y 3 con trombocitemia esencial (TE) asistidos en nuestro Departamento durante los últimos 20 años. La evolución del primer embarazo incluyó: nacido vivo a término 29 por ciento, aborto espontáneo 14 por ciento, nacido vivo pretérmino 29 por ciento y desconocida 14 por ciento. Un embarazo está en curso (14 por ciento). No se registraron muertes fetales. Las complicaciones maternas fueron: sangrado en una paciente con LMC y desprendimiento placentario en otro caso con TE. La segunda gestación resultó en un nacido vivo pretérmino (N=1) y otra está en curso. Todas las pacientes con TE recibieron interferón alta y aspirina durante el embarazo y profilaxis con enoxaparina durante el puerperio. Las pacientes con LMC recibieron: interferón alfa (N=1), hidroxiurea luego del primer trimestre e interferón alfa (N= 1) e imatinib durante el primer trimestre y nilotinib en el tercero la tercer paciente, dando a luz un feto vivo normal. Un mayor número de casos sería necesario para establecer factores pronósticos en este grupo de pacientes.

Chronic myeloproliferative syndromes and pregnancy. A case review of Clinical Hematological Department patients. The management of pregnancy in chronic myeloproliferative disorders (CMPD) is an increasingly frequent problem. Available data in the literature belong to case reports or single centers series. In the current study we report the outcome and treatment of 9 pregnancies among 7 patients with CMPD, 4 with chronic myeloid leukemia (CML) and 3 with essential thrombocythemia (ET) seen in our Department from 1989 to 2009. First pregnancy outcome included full term normal delivery 29 per cent, spontaneous abortion 14 per cent, premature delivery 29 per cent and unknown 14 per cent. No stillbirth was recorded and one pregnancy is currently ongoing. Maternal complications included: bleeding in one CML patient and abruptio placentae in a TE patient. Among second pregnancies, 1 is ongoing and the other resulted in premature delivery. AII TE patients received alpha interferon and aspirin during pregnancy. Prophylaxis with enoxaparin was administered for six weeks postpartum. CML patient were treated as follows: alpha interferon (N=1), hydroxyurea after first trimester plus alpha interferon (N=1). The remaining patient received imatinib and nilotinib giving birth to a normal baby. Further study is necessary to evaluate prognostic factors in these patients.