ABSTRACT
BACKGROUND: Ponatinib is a third-generation tyrosine-kinase inhibitor (TKI), indicated in patients with chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML), who are resistant or intolerant to ≥2 prior TKIs, patients for whom subsequent treatment with imatinib is not appropriate, and patients who have a T315I mutation. PATIENTS AND METHODS: We aimed to evaluate outcomes of ponatinib treatment, including safety, with focus on cardiovascular toxicity, in real-world patients from Argentina. Data from patients with CP CML treated with ponatinib was retrospectively retrieved from 2013 to 2023 in 7 centers. RESULTS: Seventy-two patients were included (median age: 44 years; male: 55.5%; T315I mutation: 32%: median treatment duration: 36 months. At baseline, 57 patients (79%) had a breakpoint cluster region-Abelson (BCR::ABL1) transcript level >10% on the international reporting scale (BCR::ABL1 IS). A molecular response (MR, BCR::ABL1 (IS) <1%) was achieved at 12 months in 51.6% of evaluable patients; 57% maintained MR at last follow-up. Overall, 43% and 25% maintained major MR (MMR) or deep MR (DMR) (MR4.0-MR5.0), respectively at last follow-up. Twelve (16.6%) ponatinib-resistant patients were rescued with allogeneic hematopoietic stem cell transplantation. The estimated 2-year progression-free survival (PFS) was 84%. Ponatinib dose was reduced during treatment in 22 patients; nevertheless, MMR was maintained in 50% of these patients. Severe arterial occlusive events (AOE) were reported in 10.9% of patients after a median treatment of 5 months. CONCLUSION: CV toxicity was consistent with clinical trials and other real-world registries. Older age, hypercholesterolemia and a SCORE risk >2% were significantly associated with higher risk of AOEs. Controlling CV risk factors and reducing doses at optimal time points may help to optimize ponatinib use in daily practice.
Subject(s)
Antineoplastic Agents , Imidazoles , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Pyridazines , Humans , Male , Adult , Follow-Up Studies , Antineoplastic Agents/therapeutic use , Retrospective Studies , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Pyridazines/adverse effects , Blast Crisis/drug therapy , Fusion Proteins, bcr-abl/genetics , Protein Kinase Inhibitors/adverse effectsABSTRACT
Introduction: Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase is considered a safe option if suitable molecular monitoring is available. However, the question arises as to which factors can contribute to the maintenance of TFR, and immunologic surveillance of the remaining leukemic cells is believed to be one of them. Argentina Stop Trial is an open-label, single-arm, multicenter trial assessing TFR after tyrosine kinase inhibitors interruption, that after more than 4 years showed a successful TFR rate of 63%. Methods: In this context, we set up an immunological study by flow cytometry in order to analyze specific NK cell subsets from peripheral blood patient samples both at the time of discontinuation as well as during the subsequent months. Results: At the time of discontinuation, patients show a mature NK cell phenotype, probably associated to TKI treatment. However, 3 months after discontinuation, significant changes in several NK cell receptors occurred. Patients with a higher proportion of CD56dim NK and PD-1+ NK cells showed better chances of survival. More interestingly, non-relapsing patients also presented a subpopulation of NK cells with features associated with the expansion after cytomegalovirus infection (expression of CD57+NKG2C+), and higher proportion of NKp30 and NKp46 natural cytotoxicity receptors, which resulted in greater degranulation and associated with better survival (p<0.0001). Discussion: This NK cell subset could have a protective role in patients who do not relapse, thus further characterization could be useful for patients in sustained deep molecular response.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors , Humans , Killer Cells, Natural , Protein Kinase Inhibitors/therapeutic use , Remission InductionABSTRACT
Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is safe under adequate molecular monitoring, but questions remain regarding which factors may be considered predictive for TFR. Argentina Stop Trial (AST) is a multicenter TFR trial showing that 65% of patients sustain molecular remission, and the prior time in deep molecular response (DMR) was associated with successful TFR. Luminex technology was used to characterize cytokines in plasma samples. Using machine learning algorithms, MCP-1 and IL-6 were identified as novel biomarkers and MCP-1low/IL-6low patients showed eightfold higher risk of relapse. These findings support the feasibility of TFR for patients in DMR and MCP-1/IL-6 plasma levels are strong predictive biomarkers.
Subject(s)
Interleukin-6 , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Humans , Protein Kinase Inhibitors , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Biomarkers , Remission Induction , Treatment OutcomeABSTRACT
Tyrosine kinase inhibitors (TKIs) have dramatically changed the survival of chronic myeloid leukemia (CML) patients, and treatment-free remission (TFR) has recently emerged as a new goal of CML treatment. The aim of this work was to develop recommendations for TKI discontinuation in Latin America (LA), outside of clinical trials. A working group of CML experts from LA discussed 22 questions regarding TFR and reached a consensus for TFR recommendations in the region. TFR is indicated in patients in first chronic phase, with typical BCR-ABL transcripts, under TKI treatment of a minimum of 5 years, in sustained deep molecular response (DMR; molecular response 4.5 [MR4.5]) for 2 years. Sustained DMR must be demonstrated on at least 4 international reporting scale quantitative polymerase chain reaction (PCR) tests, separated by at least 3 months, in the immediate prior 2 years. After second-line therapy, TFR is indicated in previously intolerant, not resistant, patients. Molecular monitoring is recommended monthly for the first 6 months, every 2 to 3 months from months 7 to 12, and every 3 months during the second year, indefinitely. Treatment should be reintroduced if major molecular response is lost. Monitoring of withdrawal syndrome, glucose levels, and lipid profile is recommended after discontinuation. After TKI reintroduction, molecular monitoring is indicated every 2 to 3 months until MR4.0 achievement; later, every 3 to 6 months. For the TFR attempt, having standardized and reliable BCR-ABL PCR tests is mandatory. These recommendations will be useful for safe discontinuation in daily practice and will benefit patients who wish to stop treatment in emergent regions, in particular, with TKI-related chronic adverse events.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Protein Kinase Inhibitors , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Polymerase Chain Reaction , Protein Kinase Inhibitors/therapeutic use , Recurrence , Remission InductionABSTRACT
Objectives The quantitation of BCR-ABL1 mRNA is mandatory for chronic myeloid leukemia (CML) patients, and RT-qPCR is the most extensively used method in testing laboratories worldwide. Nevertheless, substantial variation in RT-qPCR results makes inter-laboratory comparability hard. To facilitate inter-laboratory comparative assessment, an international scale (IS) for BCR-ABL1 was proposed. Methods The laboratory-specific conversion factor (CF) to the IS can be derived from the World Health Organization (WHO) genetic reference panel; however, this material is limited to the manufacturers to produce and calibrate secondary reference reagents. Therefore, we developed secondary reference calibrators, as lyophilized cellular material, aligned to the IS. Our purpose was both to re-evaluate the CF in 18 previously harmonized laboratories and to propagate the IS to new laboratories. Results Our field trial including 30 laboratories across Latin America showed that, after correction of raw BCR-ABL1/ABL1 ratios using CF, the relative mean bias was significantly reduced. We also performed a follow-up of participating laboratories by annually revalidating the process; our results support the need for continuous revalidation of CFs. All participating laboratories also received a calibrator to determine the limit of quantification (LOQ); 90% of them could reproducibly detect BCR-ABL1, indicating that these laboratories can report a consistent deep molecular response. In addition, aiming to investigate the variability of BCR-ABL1 measurements across different RNA inputs, we calculated PCR efficiency for each individual assay by using different amounts of RNA. Conclusions In conclusion, for the first time in Latin America, we have successfully organized a harmonization platform for BCR-ABL1 measurement that could be of immediate clinical benefit for monitoring the molecular response of patients in low-resource regions.
Subject(s)
Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Calibration , Humans , Latin America , Quality Control , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction/methods , Reference Standards , Reproducibility of ResultsABSTRACT
The expected five-year survival of chronic-phase chronic myeloid leukemia patients treated with tyrosine kinase inhibitors is over 90%. Little data is available regarding the results in the Argentinian population. This information might be of interest as generic imatinib is now available in the region. The aim of this study is to provide information on monitoring and the long-term treatment with imatinib outside of a controlled clinical trial, as well as to analyze the predictive effect of early responses to achieve molecular remission 4.0 (RM 4.0) and the detection of variables that may condition treatment failure. We included 106 patients, who received imatinib 400 mg daily as first-line inhibitor for a median of 8.9 years (IQR 5.8-11.7) between June 2000 and December, 2015. Overall survival was 93%. At latest follow-up 74% of patients continues on initial imatinib. The achievement of response at targeted milestones (6, 12 months) was associated with increased failure-free survival: 87% vs. 56%, p = 0.007; 90% vs. 69% p = 0.01 and was independently associated to RM 4.0: OR 5.6 (95% CI: 1.6-19.0); OR 5.3 (95% CI: 1.4-21.0) p = 0.006. After long-term follow-up, imatinib provided high-rates of response and survival. The prognostic value of response at targeted milestones was confirmed. This study reinforces the importance of molecular monitoring under IS standardization at known timepoints and this must continue to be a target in Argentina.
Subject(s)
Antineoplastic Agents/therapeutic use , Imatinib Mesylate/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Male , Middle Aged , Predictive Value of Tests , Survival Analysis , Young AdultABSTRACT
La supervivencia a cinco años de los pacientes con leucemia mieloide crónica en fase crónica tratados con inhibidores de tirosina quinasa es superior al 90%. Existen escasos datos a nivel local. Esta información puede ser de interés, ya que el imatinib genérico se encuentra disponible en la región. El objetivo del presente estudio es proporcionar información del monitoreo y los resultados a largo plazo del tratamiento con imatinib fuera de un ensayo clínico controlado, así como analizar el valor predictivo de respuestas tempranas para el logro de respuesta molecular 4.0 y la detección de variables que puedan condicionar falla al tratamiento. Se incluyeron 106 pacientes tratados con imatinib 400 mg diarios como inhibidor de primera línea durante una mediana de 8.9 años IQR (5.8-11.7) entre junio del 2000 y diciembre del 2015. La supervivencia global fue de 93%. En la última evaluación, 74% de los pacientes continuaba recibiendo el imatinib inicial. La obtención de respuesta en los objetivos temporales específicos (6, 12 meses) se asoció con mayor supervivencia libre de falla: 87% vs. 56%, p = 0.007; 90% vs. 69% p = 0.01 y mayor adquisición de respuesta molecular 4.0: OR 5.6 (IC 95% 1.6-19.0) p = 0.003; OR 5.3 (IC 95% 1.4-21.0) p = 0.006. Luego del prolongado seguimiento, el imatinib proporcionó altas tasas de respuesta y supervivencia. Se confirmó el valor pronóstico de la respuesta en momentos temporales específicos. Este estudio refuerza la importancia del monitoreo estandarizado en los puntos temporales conocidos, que debe continuar siendo un objetivo en Argentina.
The expected five-year survival of chronic-phase chronic myeloid leukemia patients treated with tyrosine kinase inhibitors is over 90%. Little data is available regarding the results in the Argentinian population. This information might be of interest as generic imatinib is now available in the region. The aim of this study is to provide information on monitoring and the long-term treatment with imatinib outside of a controlled clinical trial, as well as to analyze the predictive effect of early responses to achieve molecular remission 4.0 (RM 4.0) and the detection of variables that may condition treatment failure. We included 106 patients, who received imatinib 400 mg daily as first-line inhibitor for a median of 8.9 years (IQR 5.8-11.7) between June 2000 and December, 2015. Overall survival was 93%. At latest follow-up 74% of patients continues on initial imatinib. The achievement of response at targeted milestones (6, 12 months) was associated with increased failure-free survival: 87% vs. 56%, p = 0.007; 90% vs. 69% p = 0.01 and was independently associated to RM 4.0: OR 5.6 (95% CI: 1.6-19.0); OR 5.3 (95% CI: 1.4-21.0) p = 0.006. After long-term follow-up, imatinib provided high-rates of response and survival. The prognostic value of response at targeted milestones was confirmed. This study reinforces the importance of molecular monitoring under IS standardization at known timepoints and this must continue to be a target in Argentina.
Subject(s)
Humans , Male , Female , Adolescent , Adult , Middle Aged , Aged , Aged, 80 and over , Young Adult , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Imatinib Mesylate/therapeutic use , Antineoplastic Agents/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Survival Analysis , Predictive Value of Tests , Follow-Up StudiesABSTRACT
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.
Subject(s)
Glutathione S-Transferase pi/genetics , Glutathione Transferase/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Polymerase Chain Reaction , Polymorphism, Genetic , Risk Factors , Treatment Outcome , Young AdultABSTRACT
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.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Polymorphism, Single Nucleotide , Tumor Suppressor Protein p53/genetics , Biomarkers, Tumor/analysis , Case-Control Studies , Codon/genetics , Disease-Free Survival , Female , Genetic Predisposition to Disease , Humans , Imatinib Mesylate/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Male , Middle Aged , Prognosis , Treatment Failure , Treatment OutcomeABSTRACT
Excellent response rates and a good quality of life have been observed since the introduction of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) treatment. Consequently, some challenges began to appear in CML women in child-bearing age wishing to become pregnant. Currently, many women around the world are in stable major/complete molecular response MMR/CMR (MMR: <0.1% BCR-ABL/ABL and CMR: undetectable BCR-ABL mRNA by RQ-PCR transcript levels on the international scale). The condition of stable MMR/CMR is linked to a long-term virtual absence of progression to the accelerated and blastic phase and to the possibility of stopping the TKI treatment with the maintenance of a condition of CMR in a proportion of cases. Imatinib teratogenic and prescribing information prohibits the use of it during pregnancy. We describe the case of a 36-year-old female patient with CML in chronic phase who stopped imatinib after 2 years in major molecular response (MMR) to plan a pregnancy. Molecular monitoring by RQ-PCR was performed quarterly. She achieved a safe pregnancy and delivery maintaining an optimal molecular response throughout the pregnancy. Isolated literature reports have been described, but no formal advice has been described at present time.
ABSTRACT
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.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Argentina , Benzamides , Female , Fusion Proteins, bcr-abl/genetics , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Male , Middle Aged , Neoplasm, Residual/diagnosis , Neoplasm, Residual/genetics , Prognosis , Remission Induction , Survival Analysis , Treatment Outcome , Uruguay , Young AdultABSTRACT
BACKGROUND: Myelodysplastic syndromes (MDS) are clonal disorders affecting hematopoietic progenitor cells (HPC). Despite the relevance of clonal CD34+ cells in developing MDS, only few studies analyze the phenotype of this cell population. The aim of this study was to evaluate phenotypic changes on HPC in MDS that could reflect abnormalities in the differentiation process of stem cells. METHODS: We analyzed the expression of CD38 and HLA-DR on CD34+ cells by flow cytometry in 36 patients with MDS, as well as in healthy donors (n = 12) and patients with other hematological disorders: non-Hodgkin lymphomas and multiple myeloma, both in complete remission (CR) (n = 32); acute lymphoblastic leukemia in CR (n = 17); de novo acute myeloblastic leukemia (AML) at diagnosis (n = 22) and in CR (n = 37); and AML secondary to MDS at diagnosis (n = 19). Cases with available karyotype were grouped according to the International Prognostic Scoring System (IPSS). RESULTS: Compared to normal BM, the fraction of immature HPC, characterized as CD34+bright, intermediate FSC/SSC, and CD38dim, was significantly increased in high risk MDS and secondary AML, but not in low risk MDS, (P < or = 0.001, P = 0.03, and P = 0.7). De novo AML showed decreased immature HPC. High numbers of immature HPC correlated with higher IPSS risk groups (P = 0.05) and showed significant impact on disease progression (P = 0.03). CONCLUSION: Our study confirms that evaluation of CD38 expression pattern on HPC is an easy and reproducible test that allows evaluating the immature subset of progenitor cells. Increased immature HPC in high risk MDS and secondary AML may reflect blocked differentiation of CD34+ cells in these diseases.
Subject(s)
ADP-ribosyl Cyclase 1/immunology , Antigens, CD34/immunology , Bone Marrow Cells/immunology , Hematopoietic Stem Cells/immunology , Myelodysplastic Syndromes/immunology , Adult , Aged , Aged, 80 and over , Cell Differentiation , Disease Progression , Female , Flow Cytometry , HLA-DR Antigens/immunology , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/immunology , Lymphoma, Non-Hodgkin/diagnosis , Lymphoma, Non-Hodgkin/immunology , Male , Middle Aged , Multiple Myeloma/diagnosis , Multiple Myeloma/immunology , Myelodysplastic Syndromes/diagnosis , Observer Variation , Phenotype , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Prognosis , Reproducibility of Results , Risk FactorsABSTRACT
OBJECTIVES: Genomic aberrations can now be identified in approximately 80% of chronic lymphocytic leukemia, small lymphocytic lymphoma (CLL/SLL) patients. In the present study, four new structural changes involving chromosomes 17 and 12 in CLL/SLL patients are described. METHODS: Five patients were selected for inclusion in the present report among a total of 92 cases with diagnosis of CLL/SLL. Cytogenetic studies and fluorescence in situ hybridization (FISH) analysis to detect some of the most frequent cryptic aberrations occurring in CLL/SLL patients were performed. Clinical studies are also described. RESULTS: Four cases showed structural rearrangements of chromosome 17. A psu dic(17;2)(p11.2;p21), leading to p53 deletion, was observed in a patient who developed a mixed cellularity Hodgkin's disease coexisting with the CLL/SLL in the same lymph node. Epstein Barr virus was detected in the Reed-Sternberg cells. Two cases had a balanced translocation t(2;17)(p21;q23). Both patients showed trisomy 12 and clonal evolution and one of them also had 11q deletion. In addition, a der(17)t(12;17)(q13;q25) as a part of a complex karyotype, and a complex translocation t(5;12;19) (q15;p11;q13) were also found. Four patients had an adverse clinical outcome and died because of disease progression. CONCLUSIONS: Four unreported nonrandom chromosome aberrations in CLL/SLL patients, one of them who might represent a new recurrent abnormality, are described. These uncommon abnormalities, mostly associated with evolving disease, may have implications for the understanding of genetic events associated with disease progression in this pathology.
Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 12/genetics , Chromosomes, Human, Pair 17/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Aged , Biopsy , Bone Marrow/ultrastructure , Female , Gene Deletion , Humans , In Situ Hybridization , In Situ Hybridization, Fluorescence , Karyotyping , Lymph Nodes/ultrastructure , Male , Middle Aged , Translocation, Genetic , TrisomyABSTRACT
La leucemia mieloide aguda, t(15;17)+ y compromiso de los genes PML/RARA, representa una entidad definida con respuesta a una terapia específica que combina el ácido all-trans retinoico (ATRA) con quimioterapia. En función de sus características clínicas y de la urgencia en iniciar el tratamiento, resulta de suma importancia la disponibilidad de metodologías diagnósticas rápidas que permitan objetivar el actual "screening" morfológico, para luego efectuar las evaluaciones moleculares correspondientes. Con este objetivo, en el presente trabajo, se estudio el inmunofenotipo por citometría de flujo (CMF) multiparamétrica de un total de 62 pacientes con leucemia mieloblástica aguda; 14 de ellos clasificados como FAB M3/M3v (9 M3 hipergranular; 5 M3v hipogranular), 12 con confirmación molecular de t(15;17)+ y 2 con t(15;17)- y 48 pacientes con FAB no M3. El perfil inmunofenotípico definido por la presencia simultánea de 6 características: autofluorescencia; patrón CD15/CD34 definido: CD15-/+ débil, nunca positivo intenso y CD34-/+ débil; CD33+ homogéneo; CD13+ heterogéneo; HLA DR- y población única de blastos, fue consistente en la totalidad de los 12 casos de LMA FAB M3 t(15;17)+. Los 2 casos LMA M3 t(15;17)-, presentaron un perfil inmunofenotípico que difiere en sólo una de las características. De los 47 casos LMA no M3, sólo 2 mostraron 5 características de este patrón, mientras que 41 (87 por ciento) presentaron no más de 3. Por análisis de univarianza, cada una de las 6 características resultó discriminatoria entre el grupo LMA M3 t(15;17)+ y los demás pacientes con diagnóstico de LMA: HLA-DR(-), autofluorescencia y patrón CD15/CD34 definido (p=0.000); población única de blastos (p=0.009); CD33+ homogéneo (p=0.034) y CD13+ heterogéneo (p=0.059). El análisis de multivarianza, demostró que la mejor combinación de variables para discriminar entre ambos grupos fue la de autofluorescencia (p=0.000) con el patrón CD15/CD34 (p=0.003). En función del hallazgo de un inmunofenotipo específico para LPA t(15;17)+, se investigó enfermedad mínima residual (EMR) en 19 médulas óseas (MO) de 5 pacientes con LMA M3/M3v t(15;17)+ en remisión completa (RC), por citometría de flujo multiparamétrica (CMF), citogenética, estudios citomoleculares (FISH) y determinación del reordenamiento PML/RARA por biología molecular (RT-PCR), en al menos 4 momentos del tratamiento: fin de inducción, primera y segunda consolidación y mantenimiento...(TRUNCADO)
Subject(s)
Male , Female , Humans , Adult , Flow Cytometry , In Situ Hybridization, Fluorescence , Remission Induction , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/therapy , Leukemia, Promyelocytic, Acute/drug therapy , Neoplasm, Residual , Polymerase Chain Reaction , Follow-Up Studies , Tretinoin/therapeutic useABSTRACT
La leucemia mieloide aguda, t(15;17)+ y compromiso de los genes PML/RARA, representa una entidad definida con respuesta a una terapia específica que combina el ácido all-trans retinoico (ATRA) con quimioterapia. En función de sus características clínicas y de la urgencia en iniciar el tratamiento, resulta de suma importancia la disponibilidad de metodologías diagnósticas rápidas que permitan objetivar el actual "screening" morfológico, para luego efectuar las evaluaciones moleculares correspondientes. Con este objetivo, en el presente trabajo, se estudio el inmunofenotipo por citometría de flujo (CMF) multiparamétrica de un total de 62 pacientes con leucemia mieloblástica aguda; 14 de ellos clasificados como FAB M3/M3v (9 M3 hipergranular; 5 M3v hipogranular), 12 con confirmación molecular de t(15;17)+ y 2 con t(15;17)- y 48 pacientes con FAB no M3. El perfil inmunofenotípico definido por la presencia simultánea de 6 características: autofluorescencia; patrón CD15/CD34 definido: CD15-/+ débil, nunca positivo intenso y CD34-/+ débil; CD33+ homogéneo; CD13+ heterogéneo; HLA DR- y población única de blastos, fue consistente en la totalidad de los 12 casos de LMA FAB M3 t(15;17)+. Los 2 casos LMA M3 t(15;17)-, presentaron un perfil inmunofenotípico que difiere en sólo una de las características. De los 47 casos LMA no M3, sólo 2 mostraron 5 características de este patrón, mientras que 41 (87 por ciento) presentaron no más de 3. Por análisis de univarianza, cada una de las 6 características resultó discriminatoria entre el grupo LMA M3 t(15;17)+ y los demás pacientes con diagnóstico de LMA: HLA-DR(-), autofluorescencia y patrón CD15/CD34 definido (p=0.000); población única de blastos (p=0.009); CD33+ homogéneo (p=0.034) y CD13+ heterogéneo (p=0.059). El análisis de multivarianza, demostró que la mejor combinación de variables para discriminar entre ambos grupos fue la de autofluorescencia (p=0.000) con el patrón CD15/CD34 (p=0.003). En función del hallazgo de un inmunofenotipo específico para LPA t(15;17)+, se investigó enfermedad mínima residual (EMR) en 19 médulas óseas (MO) de 5 pacientes con LMA M3/M3v t(15;17)+ en remisión completa (RC), por citometría de flujo multiparamétrica (CMF), citogenética, estudios citomoleculares (FISH) y determinación del reordenamiento PML/RARA por biología molecular (RT-PCR), en al menos 4 momentos del tratamiento: fin de inducción, primera y segunda consolidación y mantenimiento...(TRUNCADO)(AU)
Subject(s)
Humans , Male , Female , Adolescent , Adult , Middle Aged , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/therapy , Leukemia, Promyelocytic, Acute/drug therapy , Flow Cytometry , Polymerase Chain Reaction , In Situ Hybridization, Fluorescence , Tretinoin/therapeutic use , Remission Induction , Neoplasm, Residual , Follow-Up StudiesABSTRACT
La leucemia mieloide crónica (LMC) es un desorden mieloproliferativo clonal de la stem cell pluripotente, que origina elementos mieloides, eritroides, megacariocíticos y linfoides (B). La enfermedad se caracteriza por la presencia de una translocación recíproca entre los cromosomas 9 y 22, t(9;22) (q34;q11) la cual determina la formación de dos cromosomas marcadores el 22q ó cromosoma Philadelphia (Ph) y el 9q+. En las LMC Ph positiva el punto de ruptura dentro del BCR en el cromosoma 22 puede ocurrir en la región 3 ó 5 dependiendo si la unión se produce entre el exon 3 ó 2 del gen BCR con el exon 2 del gen ABL. Se originan de este modo dos diferentes configuraciones exónicas b3a2 y b2a2 que dan origen a dos RNA mensajeros que difieren en 75 pares de bases. Los tratamientos con O-interferon recombinante (OIFN) sólo o en combinación con quimioterapia intensiva han demostrado respuesta hematológica en un rango de 70 - 80 por ciento de los casos y respuesta citogenética en un rango 40 - 60 por ciento. En nuestra experiencia en el tratamiento con O-IFN, 6-mercatopurina y Ara-C en un grupo de 40 pacientes con LMC en fase crónica, mostró que el 80 por ciento presentaba respuesta hematológica mientras que sólo un 20 por ciento presentaba respuesta citogenética parcial o completa después de tres años de seguimiento. El 15 por ciento de los casos mostró una respuesta cariotipica (RC) menor, el 2,5 por ciento una RC mayor y 2,5 por ciento restante una RC completa. Cuando se correlacionó RC con el punto de ruptura del BCR se observó que el 75 por ciento de los casos que habían tenido algún tipo de RC presentaban el punto de ruptura en la región 5BCR, lo cual haría suponer que las rupturas en 5 serían de mejor pronóstico.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Cytogenetics , Philadelphia Chromosome , Interferon Type IABSTRACT
La leucemia mieloide crónica (LMC) es un desorden mieloproliferativo clonal de la stem cell pluripotente, que origina elementos mieloides, eritroides, megacariocíticos y linfoides (B). La enfermedad se caracteriza por la presencia de una translocación recíproca entre los cromosomas 9 y 22, t(9;22) (q34;q11) la cual determina la formación de dos cromosomas marcadores el 22q ó cromosoma Philadelphia (Ph) y el 9q+. En las LMC Ph positiva el punto de ruptura dentro del BCR en el cromosoma 22 puede ocurrir en la región 3' ó 5' dependiendo si la unión se produce entre el exon 3 ó 2 del gen BCR con el exon 2 del gen ABL. Se originan de este modo dos diferentes configuraciones exónicas b3a2 y b2a2 que dan origen a dos RNA mensajeros que difieren en 75 pares de bases. Los tratamientos con Ó-interferon recombinante (ÓIFN) sólo o en combinación con quimioterapia intensiva han demostrado respuesta hematológica en un rango de 70 - 80 por ciento de los casos y respuesta citogenética en un rango 40 - 60 por ciento. En nuestra experiencia en el tratamiento con Ó-IFN, 6-mercatopurina y Ara-C en un grupo de 40 pacientes con LMC en fase crónica, mostró que el 80 por ciento presentaba respuesta hematológica mientras que sólo un 20 por ciento presentaba respuesta citogenética parcial o completa después de tres años de seguimiento. El 15 por ciento de los casos mostró una respuesta cariotipica (RC) menor, el 2,5 por ciento una RC mayor y 2,5 por ciento restante una RC completa. Cuando se correlacionó RC con el punto de ruptura del BCR se observó que el 75 por ciento de los casos que habían tenido algún tipo de RC presentaban el punto de ruptura en la región 5'BCR, lo cual haría suponer que las rupturas en 5' serían de mejor pronóstico.
Subject(s)
Cytogenetics , Interferon Type I , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Philadelphia ChromosomeABSTRACT
El cromosoma Philadelphia (Ph1), característico de la leucemia mieloide crónica (LMC), deriva de la traslocación recíproca entre los cromosomas 9 y 22. En consecuencia el oncogen c-abl, que mapea en 9q34, se yuxtapone a la zona bcr/abl codifica para una proteína anómala p210, importante en el proceso tumorigénico. El punto de ruptura en el cromosoma 22 es invariable y se restringe a una zona de 5,8 Kb. El intento de demostrar si la evolución clínica de la LMC está condicionada por el sitio de ruptura en el bcr, condujo a resultados contradictorios. Los estudios realizados hasta la fecha en nuestro laboratorio no muestran correlación entre ambos
Subject(s)
Humans , Cytogenetics , Molecular Structure , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Leukemia, Myelogenous, Chronic, BCR-ABL PositiveABSTRACT
El cromosoma Philadelphia (Ph1), característico de la leucemia mieloide crónica (LMC), deriva de la traslocación recíproca entre los cromosomas 9 y 22. En consecuencia el oncogen c-abl, que mapea en 9q34, se yuxtapone a la zona bcr/abl codifica para una proteína anómala p210, importante en el proceso tumorigénico. El punto de ruptura en el cromosoma 22 es invariable y se restringe a una zona de 5,8 Kb. El intento de demostrar si la evolución clínica de la LMC está condicionada por el sitio de ruptura en el bcr, condujo a resultados contradictorios. Los estudios realizados hasta la fecha en nuestro laboratorio no muestran correlación entre ambos