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BACKGROUND: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors. METHODS: We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed. RESULTS: Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time. CONCLUSIONS: Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.).
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Anticuerpos Monoclonales Humanizados , Hemofilia A , Tromboembolia , Humanos , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Peso Corporal , Hemofilia A/complicaciones , Hemofilia A/tratamiento farmacológico , Tromboembolia/prevención & control , Inyecciones SubcutáneasRESUMEN
BACKGROUND: Improvement in medical management has enabled transfusion dependent thalassaemia (TDT) patients to survive beyond childhood, building families, and contributing to the labour force and society. Knowledge about their adult life would provide guidance on how to support their needs. This study aims to explore the general well-being of adults with TDT, their employment status and challenges. METHODS: This study recruited 450 people with TDT, aged 18 and above, of both genders through all regional Thalassaemia societies in Malaysia and from the two participating hospitals, over five months in year 2016. A self-administered questionnaire including 'Healthy Days Core Module', WHOQOL-BREF and employment measurements was used. Multiple linear regression models were fitted with associations adjusted for several potential confounders. RESULTS: A total of 196 adults with TDT responded to the survey (43.6% response rate). Almost half (45%) had comorbidities and 9% suffered multiple complications: bone-related (13%), hormonal (12%), cardiac (3%) and infections (2%), resulting in 23% seeking treatment more than twice monthly. Within a month, they suffered from at least three days with poor physical and or mental health and their normal daily activities were disrupted up to three days. 36% were jobless and 38% of those with a job were receiving salaries below RM1000. The mean WHOQOL-BREF score (mean (SD)) was: physical health 62.6 (15.5), psychological health 64.7 (15.7), social relationship 64 (15.9), environmental health 60.8 (16.7). Having days with mental issues, financial status, education level, ethnic and marital status were main factors affecting QOL scores. Open questions showed dissatisfaction with health service provision, conflicting judgement in prioritising between health and job, and poor public empathy. CONCLUSION: The adults with TDT perceived their health as good and had less unhealthy days when compared with people with other chronic diseases. However, some perceived themselves to be facing more life disruption in a rather non-supportive community and that health services do not meet their needs. Future qualitative studies are needed to focus on their perceived needs and to look for more tailored supportive approaches.
WHAT IS THE PROBLEM?: With advancements in medical care, more people with transfusion dependent thalassaemia (TDT) reached adulthood, something which was uncommon decades ago. They should have similar physical-mental capabilities as people without TDT. However, the stigma of their condition has remained and their potential capabilities have often been underestimated by the public. We need to understand their adult life in order to assist them further. WHAT DID WE DO?: We surveyed 196 TDT patients, using a set of questionnaires. We enquired of their perceptions about their health status and quality of life (QOL: physical, mental, social relationship, environment). We asked them open questions on challenges they were facing during adulthood and employment. WHAT DID WE FIND?: Some participants (45%) were found to have other medical problems and that they could be feeling unwell at least three days in a month. Participants scored above 60 out of 100 for all of the QOL aspects (a higher score denotes a better QOL). We noted some continued to lose career advancement opportunities, face discrimination and had difficulties managing their health, in a rather non-supportive community. WHAT IS OUR CONCLUSION?: People with TDTs were doing relatively well as young adults. Life challenges persist. More qualitative studies are needed to understand their challenges better and to look for more tailored supportive approaches.
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Calidad de Vida , Talasemia , Adulto , Estudios Transversales , Femenino , Humanos , Malasia/epidemiología , Masculino , Salud Mental , Encuestas y Cuestionarios , Talasemia/epidemiología , Talasemia/terapiaRESUMEN
Background: Clinical significance of germinal center B-cell (GCB) and non-GCB sub-categorization, expression of MYC, BCL2, BCL6, CD5 proteins and Epstein Barr virus encoded RNA (EBER) positivity in diffuse large B-cell lymphoma (DLBCL) remain controversial. Could these biomarkers accurately identify high risk DLBCL patients? Are MYC, BCL2 and BCL6 proteins expression feasible as baseline testing to predict c-Myc, BCL2 or BCL6 gene rearrangements? Aims: To investigate prognostic values of GCB/non-GCB sub-categorization, Double Protein Expression Lymphoma (DPL), Triple Protein Expression Lymphoma (TPL), positivity of CD5 protein and EBER in patients with DLBCL disease. To evaluate correlation between BCL2 , c-Myc and BCL6 gene rearrangements with BCL2, MYC and BCL6 proteins expression. Methods: Diagnostic tissue samples of 120 DLBCL patients between January 2012 to December 2013 from four major hospitals in Malaysia were selected. Samples were subjected to immunohistochemical staining, fluorescent in-situ hybridization (FISH) testing, and central pathological review. Pathological data were correlated with clinical characteristics and treatment outcome. Results: A total of 120 cases were analysed. Mean age of diagnosis was 54.1 years ± 14.6, 64 were males, 56 were females, mean follow up period was 25 months (ranged from 1 to 36 months). Of the 120 cases, 74.2% were non-GCB whereas 25.8% were GCB, 6.7% were EBER positive, 6.7% expressed CD5 protein, 13.3% were DPL and 40% were TPL. The prevalence of c-Myc, BCL2, BCL6 gene rearrangements were 5.8%, 5.8%, and 14.2%, respectively; and 1.6% were Double Hit Lymphoma (DHL). EBER positivity, DPL, TPL, c-Myc gene rearrangement, BCL2 gene rearrangement, extra copies of BCL2 gene and BCL6 gene rearrangement were associated with shorter median overall survival (P<0.05). IPI score was the significant determinants of median overall survival in DPL and TPL (P<0.05). CD5 protein expression and GCB/non-GCB sub-categorization did not affect treatment outcome (P>0.05). Overall, c-Myc, BCL2 and BCL6 gene rearrangements showed weak correlation with expression of MYC, BCL2 and BCL6 proteins (P>0.05). Fluorescent in situ hybridization is the preferred technique for prediction of treatment outcome in DLBCL patients. Conclusion: c-Myc, BCL2, and BCL6 gene rearrangements, EBER expression, DHL, TPL and IPI score are reliable risk stratification tools. MYC, BCL2 and BCL6 proteins expression are not applicable as baseline biomarkers to predict c-Myc, BCL2, and BCL6 gene rearrangements.
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Infecciones por Virus de Epstein-Barr/genética , Regulación Neoplásica de la Expresión Génica/genética , Linfoma de Células B Grandes Difuso/genética , Pronóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígenos CD5/genética , Supervivencia sin Enfermedad , Infecciones por Virus de Epstein-Barr/patología , Infecciones por Virus de Epstein-Barr/virología , Femenino , Reordenamiento Génico/genética , Humanos , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/virología , Malasia , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-myc/genética , Serpinas/genética , Resultado del Tratamiento , Adulto JovenRESUMEN
Some patients with relapsed/refractory Hodgkin lymphoma (HL) are not considered suitable for stem cell transplant (SCT) and have a poor prognosis. This phase IV study (NCT01990534) evaluated brentuximab vedotin (1·8 mg/kg intravenously once every 3 weeks) in 60 patients (aged ≥18 years) with CD30-positive relapsed/refractory HL, a history of ≥1 prior systemic chemotherapy regimen, who were considered unsuitable for SCT/multi-agent chemotherapy. Primary endpoint was overall response rate (ORR) per independent review facility (IRF). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) per IRF, overall survival (OS), proportion proceeding to SCT and safety. The ORR was 50%, with 12% CR; 47% proceeded to SCT. Median DOR was 4·6 months and median duration of CR was 6·1 months. After a median follow-up of 6·9 and 16·6 months, median PFS and OS were 4·8 months (95% confidence interval, 3·0-5·3) and not reached, respectively; estimated OS rate was 86% at 12 months. Most common adverse events (≥10%) were peripheral neuropathy (35%), pyrexia (18%), diarrhoea and neutropenia (each 10%). Brentuximab vedotin showed notable activity with a safety profile consistent with known toxicities, and may act as a bridge to SCT, enabling high-risk patients who achieve suboptimal response to frontline/salvage chemotherapy/radiotherapy to receive potentially curative SCT.
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Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/mortalidad , Inmunoconjugados/administración & dosificación , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica , Brentuximab Vedotina , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Inmunoconjugados/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Trasplante de Células Madre , Tasa de SupervivenciaRESUMEN
BACKGROUND: Adherence to long-term chelation therapy in transfusion-dependent patients is critical to prevent iron overload-related complications. Once-daily deferasirox dispersible tablets (DT) have proven long-term efficacy and safety in patients ≥2 years old with chronic transfusional iron overload. However, barriers to optimal adherence remain, including palatability, preparation time, and requirements for fasting state. A new film-coated tablet (FCT) formulation was developed, swallowed once daily (whole/crushed) with/without a light meal. METHODS: The open-label, Phase II ECLIPSE study evaluated patient-reported outcomes (PROs) in transfusion-dependent thalassemia or lower-risk myelodysplastic syndromes patients randomized 1:1 to receive deferasirox DT or FCT over 24 weeks as a secondary outcome of the study. Three PRO questionnaires were developed to evaluate both deferasirox formulations: 1) Modified Satisfaction with Iron Chelation Therapy Questionnaire; 2) Palatability Questionnaire; 3) Gastrointestinal (GI) Symptom Diary. RESULTS: One hundred seventy three patients were enrolled; 87 received the FCT and 86 the DT formulation. FCT recipients consistently reported better adherence (easier to take medication, less bothered by time to prepare medication and waiting time before eating), greater satisfaction/preference (general satisfaction and with administration of medicine), and fewer concerns (less worry about not swallowing enough medication, fewer limitations in daily activities, less concern about side effects). FCT recipients reported no taste or aftertaste and could swallow all their medicine with an acceptable amount of liquid. GI summary scores were low for both formulations. CONCLUSIONS: These findings suggest a preference in favor of the deferasirox FCT formulation regardless of underlying disease or age group. Better patient satisfaction and adherence to chelation therapy may reduce iron overload-related complications. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02125877; registered April 26, 2014.
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Deferoxamina/uso terapéutico , Quelantes del Hierro/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Satisfacción del Paciente , Talasemia/tratamiento farmacológico , Adulto , Transfusión Sanguínea , Terapia por Quelación/métodos , Femenino , Humanos , Sobrecarga de Hierro/prevención & control , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/psicología , Calidad de Vida , Talasemia/psicologíaRESUMEN
Once-daily deferasirox dispersible tablets (DT) have a well-defined safety and efficacy profile and, compared with parenteral deferoxamine, provide greater patient adherence, satisfaction, and quality of life. However, barriers still exist to optimal adherence, including gastrointestinal tolerability and palatability, leading to development of a new film-coated tablet (FCT) formulation that can be swallowed with a light meal, without the need to disperse into a suspension prior to consumption. The randomized, open-label, phase II ECLIPSE study evaluated the safety of deferasirox DT and FCT formulations over 24 weeks in chelation-naïve or pre-treated patients aged ≥10 years, with transfusion-dependent thalassemia or IPSS-R very-low-, low-, or intermediate-risk myelodysplastic syndromes. One hundred seventy-three patients were randomized 1:1 to DT (n = 86) or FCT (n = 87). Adverse events (overall), consistent with the known deferasirox safety profile, were reported in similar proportions of patients for each formulation (DT 89.5%; FCT 89.7%), with a lower frequency of severe events observed in patients receiving FCT (19.5% vs. 25.6% DT). Laboratory parameters (serum creatinine, creatinine clearance, alanine aminotransferase, aspartate aminotransferase and urine protein/creatinine ratio) generally remained stable throughout the study. Patient-reported outcomes showed greater adherence and satisfaction, better palatability and fewer concerns with FCT than DT. Treatment compliance by pill count was higher with FCT (92.9%) than with DT (85.3%). This analysis suggests deferasirox FCT offers an improved formulation with enhanced patient satisfaction, which may improve adherence, thereby reducing frequency and severity of iron overload-related complications.
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Benzoatos/administración & dosificación , Síndromes Mielodisplásicos/tratamiento farmacológico , Talasemia/tratamiento farmacológico , Triazoles/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Química Farmacéutica/métodos , Niño , Deferasirox , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Calidad de Vida , Comprimidos Recubiertos/administración & dosificación , Comprimidos Recubiertos/efectos adversos , Comprimidos Recubiertos/química , Adulto JovenRESUMEN
A middle-aged gentleman who was diagnosed with high-risk chronic lymphocytic leukaemia (CLL), Rai stage IV, Binet C with del(17p) and del(13q) underwent allogeneic haematopoeitic stem cell transplantation (allo-HSCT) from a human leukocyte antigen (HLA) identical sister. The patient developed extensive skin, oral, and liver chronic graft versus host disease (GVHD) required tacrolimus, mycophenolate mofetil (MMF), and prednisolone. At seventh month after allo-HSCT, the patient presented with systemic symptoms, right cervical lymphadenopathy, splenomegaly, marked pancytopaenia, and elevated lactate dehydrogenase (LDH). Bone marrow study, immunophenotyping (IP), chromosome analysis, and PET-CT scan confirmed relapsed CLL with no evidence of Richter's transformation or posttransplant lymphoproliferative disease (PTLD). Withdrawal of immunosuppressant (IS) worsened cutaneous and liver GVHD. Chemotherapy was not a suitable treatment option in view of immunodeficiency. The patient underwent extracorporeal photopheresis (ECP) therapy eventually for extensive chronic GVHD, and the IS were gradually tapered to the minimal effective dose. The relapsed CLL was treated successfully with oral venetoclax accessible via a compassionate drug program. This case highlights challenges in managing relapsed CLL and loss of graft-versus-leukaemia (GVL) effect despite extensive chronic GVHD. Venetoclax is an effective and well-tolerated oral novel agent for relapsed CLL after allo-HSCT.
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Vitamin B12 deficiency and folate deficiency are common causes of macrocytic anaemia and both are important for many cellular processes. These deficiencies could be due to inadequate dietary intake, impaired absorption or drug ingestion. We present a case of a 47-year-old male with a history of diffuse large B-cell lymphoma (DLBCL) who was admitted for fatigue, persistent frontal headache and left upper-quadrant abdominal pain. Further investigation showed that he had pancytopenia with microangiopathic haemolytic anaemia (MAHA) and intracranial bleeding (ICB). Serum vitamin B12 and folate were later found to be low and a diagnosis of combined vitamin B12 and folate deficiency mimicking thrombotic thrombocytopenic purpura (TTP) was made. The patient responded well to vitamin B12 and folate replacement.
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Anemia Hemolítica , Púrpura Trombocitopénica Trombótica , Deficiencia de Vitamina B 12 , Anemia Hemolítica/diagnóstico , Anemia Hemolítica/etiología , Ácido Fólico , Humanos , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Trombótica/complicaciones , Púrpura Trombocitopénica Trombótica/diagnóstico , Vitamina B 12 , Deficiencia de Vitamina B 12/complicaciones , Deficiencia de Vitamina B 12/diagnósticoRESUMEN
Background: Diffuse large B-cell lymphoma (DLBCL) with double expression of c-MYC and BCL2 protein is associated with dismal outcome after treatment with R-CHOP. Local data on disease burden and survival outcome in DLBCL is limited. We investigated the prognostic values of c-MYC/BCL2 protein co-expression and cell of origin subtypes using immunohistochemistry (IHC) and to determine their associations with multiethnic groups under resource limited setting. Methods: This was a retrospective study which recruited 104 patients in between June 2012 and December 2015 for IHC review and analysis. Result: We demonstrated that patients with high International Prognostic Index (IPI) (score 3-5) and co-expression of c-MYC/BCL2 protein had significant inferior overall survival (OS) and event free survival (EFS) respectively (P<0.05). c-MYC/BCL2 protein co-expression was more common in non-germinal center B-cell (non-GCB) (P=0.048) and contributed to adverse prognosis in this group of patients (OS, P=0.004; EFS, P=0.005). In multivariate analysis, double-protein co-expression was a significant independent predictor of inferior outcome after adjusted for IPI and cell of origin subtypes (OS hazard ratio [HR], 2.11; 95% CI, 1.01 to 4.04; P=0.048; EFS HR, 2.31; 95% CI, 1.05 to 5.04; P=0.036). In addition, non-GCB subtype was more common than GCB in Malays (60% vs 40%, P=0.106) and Chinese (81.2% vs 18.8%, P=0.042). Indians had more DLBCL without c-MYC/ BCL2 protein co-expression compared to double-protein positive cases (66.7% vs 33.3%, P=0.414). Otherwise, the prognostic impact of ethnicity on survival outcome was insignificant (P=0.961). Conclusion: c-MYC/BCL2 protein co-expression in non-GCB subtype constituted a unique group with extremely inferior outcome regardless of ethnicity. Gene expression profile (GEP) may possibly provide insights into the cause of discrepancies in DLBCL subtypes and protein expression among the multiethnic groups.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Centro Germinal/metabolismo , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Centro Germinal/patología , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: The evolution of molecular studies in myeloproliferative neoplasms (MPN) has enlightened us the understanding of this complex disease consisting of polycythaemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The epidemiology is well described in the western world but not in Asian countries like Malaysia. MATERIALS AND METHODS: This retrospective national registry of MPN was conducted from year 2009 to 2015 in Malaysia. RESULTS: A total of 1010 patients were registered over a period of 5 years. The mean age was 54 years with male predominance. The ethnic distribution revealed that Chinese had a relatively high weighted incidence proportion (43.2%), followed by Indian (23.8%), Malay (15.8%) and other ethnic groups (17.2%). The types of MPN reported were 40.4% of ET (n = 408), 38.1% of PV (n = 385), 9.2% of PMF (n = 93), 3.1% of hypereosinophilic syndrome (HES) (n = 31) and 7.9% of unclassifiable MPN (MPN-U) (n = 80). Splenomegaly was only palpable clinically in 32.2% of patients. The positive JAK2 V617F mutation was present in 644 patients with 46.6% in PV, 36.0% in ET, 9.0% in PMF, and 7.4% in MPN-U, and had significantly lower haemoglobin (p < 0.001), haematocrit (p < 0.001) and white blood cells (WBC) (p < 0.001) than those with negative mutation. Significant differences in platelet and WBC count were detected in ethnic groups and MPN sub-types. There were more arterial thrombosis events seen in those with JAK2 V617F mutation as compared to venous thrombosis events (23.1% vs 4.4%). The bleeding rate was only 6.6%. Among the risk factors, previous thrombosis, old age (≥ 60 years) and hypertension were significantly correlated to positive JAK2 V617F mutation. The arterial thrombosis event is associated with higher presenting HB, HCT and PLT while the bleeding event is associated with lower presenting HB, HCT but higher PLT. The presence of JAK2 V617F mutation is associated with higher risk of arterial thrombosis. CONCLUSION: Chinese ethnicity is associated with higher rates of MPN. The history of thrombosis, age ≥ 60 years and hypertension are risk factors that can be correlated to JAK2 V617F mutation. This study is instrumental for policy makers to ensure preventive strategies can be implemented in future.
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Haemoglobin (Hb) Adana (HBA2:c.179>A) interacts with deletional and nondeletional α-thalassaemia mutations to produce HbH disorders with varying clinical manifestations from asymptomatic to severe anaemia with significant hepatosplenomegaly. Hb Adana carriers are generally asymptomatic and haemoglobin subtyping is unable to detect this highly unstable α-haemoglobin variant. This study identified 13 patients with compound heterozygosity for Hb Adana with either the 3.7 kb gene deletion (-α(3.7)), Hb Constant Spring (HbCS) (HBA2:c.427T>C) or Hb Paksé (HBA2:429A>T). Multiplex Amplification Refractory Mutation System was used for the detection of five deletional and six nondeletional α-thalassaemia mutations. Duplex-PCR was used to confirm Hb Paksé and HbCS. Results showed 84.6% of the Hb Adana patients were Malays. Using DNA studies, compound heterozygosity for Hb Adana and HbCS (α(codon 59)α/α(CS)α) was confirmed in 11 patients. A novel point in this investigation was that DNA studies confirmed Hb Paksé for the first time in a Malaysian patient (α(codon 59)α/α(Paksé)α) after nine years of being misdiagnosis with Hb Adana and HbCS (α(codon 59)α/α(CS)α). Thus, the reliance on haematology studies and Hb subtyping to detect Hb variants is inadequate in countries where thalassaemia is prevalent and caused by a wide spectrum of mutations.
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Hemoglobinas Anormales/genética , Talasemia alfa/diagnóstico , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Heterocigoto , Humanos , Lactante , Masculino , Técnicas de Diagnóstico Molecular , Eliminación de Secuencia , Talasemia alfa/genéticaRESUMEN
The introduction and success of imatinib mesylate (IM) has become a paradigm shift in chronic myeloid leukemia (CML) treatment. However, the high efficacy of IM has been hampered by the issue of clinical resistance that might due to pharmacogenetic variability. In the current study, the contribution of three common single nucleotide polymorphisms (SNPs) of ABCB1 (T1236C, G2677T/A and C3435T) and two SNPs of ABCG2 (G34A and C421A) genes in mediating resistance and/or good response among 215 CML patients on IM therapy were investigated. Among these patients, the frequency distribution of ABCG2 421 CC, CA and AA genotypes were significantly different between IM good response and resistant groups (P=0.01). Resistance was significantly associated with patients who had homozygous ABCB1 1236 CC genotype with OR 2.79 (95%CI: 1.217-6.374, P=0.01). For ABCB1 G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with variant TT/AT/AA genotype, compared to other genotype groups (OR=0.48, 95%CI: 0.239-0.957, P=0.03). Haplotype analysis revealed that ABCB1 haplotypes (C1236G2677C3435) was statistically linked to higher risk to IM resistance (25.8% vs. 17.4%, P=0.04), while ABCG2 diplotype A34A421 was significantly correlated with IM good response (9.1% vs. 3.9%, P=0.03). In addition, genotypic variant in ABCG2 421C>A was associated with a major molecular response (MMR) (OR=2.20, 95%CI: 1.273-3.811, P=0.004), whereas ABCB1 2677G>T/A variant was associated with a significantly lower molecular response (OR=0.49, 95%CI: 0.248-0.974, P=0.04). However, there was no significant correlation of these SNPs with IM intolerance and IM induced hepatotoxicity. Our results suggest the usefulness of genotyping of these single nucleotide polymorphisms in predicting IM response among CML patients.