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T-cell prolymphocytic leukemia (T-PLL) is a rare, mature T-cell leukemia which usually presents with aggressive behavior. We report an asymptomatic T-PLL patient diagnosed by clinical features, lymphocyte morphology, and flow cytometry. Incidentally, she was found to have lymphocytosis and lymphadenopathy. Flow cytometry from blood revealed an abnormally increased CD4+ T-cell population. T-cell receptor clonality assessment by next-generation sequencing revealed a dominant clone in the ß-chain constant region. No pathogenic mutations in 25 lymphoma-related genes were found. Due to her asymptomatic T-PLL disease, we observed her clinical situation and blood count every three months for at least one year.
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AIMS: Myeloid neoplasms (MNs) with germline predisposition have been recognised as a distinct entity. Emerging evidence suggests that sporadic myelodysplastic syndromes may also harbour undetected germline predispositions. We investigated germline alterations in a cohort of 122 adult Thai MNs. METHODS: MN patients were recruited and tested for germline variants using deep targeted next-generation sequencing. The germline variant was filtered using American College of Medical Genetics classifications and then evaluated for the association with clinical characteristics and outcomes. RESULTS: Our findings revealed pathogenic/likely pathogenic germline alterations in 12 (10%) of the patients. These germline lesions were commonly found in the DNA damage response pathway (n=6, 50%). We also identified novel deleterious FANCA A1219GfsTer59 variants in two patients diagnosed with secondary acute myeloid leukaemia (sAML) from aplastic anaemia and AML with myelodysplasia related. Among sAML, individuals with germline mutations had inferior overall survival compared with those with wild-type alleles (2 months vs 12 months) with HR 4.7 (95% CI 1.0 to 20), p=0.037. Therefore, the presence of pathogenic or likely pathogenic mutations may be linked to inferior survival outcomes. CONCLUSIONS: Our study highlighted that the prevalence of germline predisposition in Southeast Asian populations is comparable to that in Caucasians. This underscores the importance of germline genetic testing within the Asian population.
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High-dose methotrexate (HD-MTX) is a widely used chemotherapy regimen for hematologic malignancies such as lymphomas and acute lymphoblastic leukemia, but its use can lead to adverse effects, including acute kidney injury (AKI), impaired liver function, and mucositis, causing extended hospital stays and delayed subsequent chemotherapy. Our study aimed to investigate the predictive factors for renal toxicities associated with HD-MTX in Thai patients undergoing treatment for hematologic malignancies. We enrolled 80 patients who underwent MTX-containing regimens, analyzing 132 chemotherapy cycles. The most common disease was primary central nervous system lymphoma (33%). Genetic polymorphisms were examined using the MassARRAY® system, identifying 42 polymorphisms in 25 genes. Serum creatinine and MTX levels were measured 24 and 48 h after MTX administration. For the primary outcome, we found that the allele A of MTRR rs1801394 was significantly related to renal toxicity (odds ratio 2.084 (1.001-4.301), p-value 0.047). Patients who exceeded the MTX threshold levels at 24 h after the dose had a significantly higher risk of renal toxicity (OR (95%CI) = 6.818 (2.350-19.782), p < 0.001). Multivariate logistic regression analysis with a generalized estimated equation revealed hypertension and age as independent predictors of increased MTX levels at 24 h after the given dose.
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Neoplasias Hematológicas , Metotrexato , Humanos , Masculino , Metotrexato/efeitos adversos , Metotrexato/administração & dosagem , Feminino , Pessoa de Meia-Idade , Tailândia/epidemiologia , Idoso , Adulto , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/genética , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/administração & dosagem , Polimorfismo de Nucleotídeo Único , Adulto Jovem , População do Sudeste AsiáticoRESUMO
ABSTRACTObjective Patients living with myeloproliferative neoplasms (MPNs) suffer from symptom burden that affect quality of life. Due to the differences in cultures, climates, and genetic background, we aimed to investigate the symptom burden of Thai MPN patients Methods A comprehensive survey using the MPN-10 questionnaire was carried out between September 1, 2014, and September 30, 2017. The scores obtained were then correlated with clinical outcomes.. Results A total of 145 patients were enrolled. Nearly 90% of patients reported being symptomatic. The mean MPN-10 score was 13.6 (SD = 11). The mean MPN-10 score was highest in PMF, whereas the mean score and intensity of individual items were surprisingly low in ET and PV. Notably, the mean MPN-10 score was significantly higher in patients with documented splenomegaly compared to those with a normal-sized spleen. However, there were no correlations between MPN-10 scores and the mutation status, disease complications such as thrombosis and hemorrhage, progression to myelofibrosis or leukemia, and mortality. Patients who needed regular transfusions reported a higher MPN-10 score compared to those who did not. Conclusion The MPN-10 score did not predict survival outcomes among Thai MPN patients. Higher MPN-10 was associated with more transfusion. Thai MPN patients reported lower MPN-10 compared to western population especially PV and ET.
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Leucemia , Transtornos Mieloproliferativos , Mielofibrose Primária , Humanos , Qualidade de Vida , População do Sudeste Asiático , Transtornos Mieloproliferativos/complicações , Mielofibrose Primária/complicaçõesRESUMO
Hemophagocytic lymphohistiocytosis (HLH) in adults may be idiopathic or secondary to various conditions. Recent studies identified germline hepatitis A virus-cellular receptor 2 (HAVCR2) mutations in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) with HLH. The roles of this mutation in HLH, especially in idiopathic group, have never been explored. Of the 65 HLH cases, we detected germline HAVCR2Y82C mutations in nine (13.8%) cases (five SPTCL and four idiopathic HLH). Other causes of HLH were hematologic malignancies excluding SPTCL (32.3%), idiopathic HLH without HAVCR2 mutation (29.2%), infections (15.3%), and autoimmune diseases (9.2%). Germline HAVCR2 mutation was significantly associated with less anemia and better survival. This defines a distinct subgroup of HLH.
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Linfo-Histiocitose Hemofagocítica , Adulto , Humanos , Linfo-Histiocitose Hemofagocítica/genética , Mutação , Células Germinativas , Prognóstico , Receptor Celular 2 do Vírus da Hepatite A/genéticaRESUMO
Germline HAVCR2 mutations are frequently detected in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients with/without hemophagocytic lymphohistiocytosis (HLH) but factors associated with variable manifestations remain undetermined. To evaluate clinical variations and associated factors in SPTCL and/or HLH with/without HAVCR2 mutations, we performed direct sequencing of HAVCR2 exon 2 using DNA from patients with SPTCL or idiopathic HLH/HLH-like systemic illnesses, defined by HLH alone without secondary causes. The systematic review and individual patient data (IPD) level meta-analysis which included the present and previously published studies reporting HAVCR2 mutations in SPTCL with/without HLH populations was subsequently conducted using random-effects meta-analysis and multivariate logistic regression. Among 34 patients enrolled, ten of 28 SPTCL patients developed HLH/HLH-like systemic illnesses. Six cases with HAVCR2Y82C mutation manifested with HLH without panniculitis. Male sex (P=0.03) and age <18 years (P=0.04) were associated with HLH, corresponding to the inverse correlation between age and HLH-2004 score (r=-0.40; P=0.02). Homozygous HAVCR2Y82C mutation was more common in the presence of HLH compared with the absence (75.0% vs. 44.4%; P=0.02). Using IPD from the present and the other three eligible cohorts (N=127), male sex, heterozygous and homozygous/compound heterozygous HAVCR2 mutations were associated with HLH by the adjusted odds ratio of 2.93 (95% confidence interval [CI]: 1.22-7.06), 4.77 (95% CI: 1.05-21.63) and 8.48 (95% CI: 2.98-24.10), respectively. Patients with male sex and/or germline HAVCR2 mutations showed an increased risk of developing HLH. Younger patients tended to manifest with HLH, while older patients typically presented with SPTCL with less frequent HLH/HLH-like systemic illnesses.
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Linfo-Histiocitose Hemofagocítica , Paniculite , Humanos , Masculino , Adolescente , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/genética , Paniculite/genética , Paniculite/complicações , Paniculite/patologia , Mutação em Linhagem Germinativa , Células Germinativas/patologia , Receptor Celular 2 do Vírus da Hepatite A/genética , Estudos Multicêntricos como AssuntoRESUMO
INTRODUCTION: Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) with a unique clinical presentation and prognosis. This study aimed to investigate the epidemiology, clinical characteristics, treatments, and clinical outcomes of Thai APL patients dominantly treated with all-trans-retinoic acid (ATRA) combined with a chemotherapy-based therapy. METHODS: This was an eight-year prospective, observational study from nine academic hospitals in the Thai Acute Leukemia Working Group (TALWG) of the Thai Society of Hematology, which included newly diagnosed Thai APL patients, aged 18 years or older. The web-based registration collected baseline charateristic, and clinical outcomes. RESULTS: From 992 newly diagnosed AML patients, 79 APL patients were enrolled in this study. Almost all subjects were de novo APL (94.9%), while the others were therapy-related APL. The commonest clinical presentation was disseminated intravascular coagulation (38%). One-third of the patients were categorized as high risk according to the initial WBC. Almost all patients received ATRA combined with idarubicin regimen. The complete response rate was as high as 95.7%, which translated into excellent four-year overall survival (OS) (75.6%) and four-year leukemia-free survival (LFS) (75.4%). The multivariate analysis demonstrated that the older age and WBC count >20 × 109/L conferred a significantly unfavorable OS with the hazard ratios of 3.03 (95% confidence interval [CI]: 1.14-8.05) and 4.18 (95%CI: 1.69-10.35), respectively. Similarly, these two parameters remained independent of the poor prognosis factors for LFS. CONCLUSION: This report confirmed that APL had a favorable prognosis. However, advanced age and high WBC count >20 × 109/L contributed to a worse outcome. ABBREVIATIONS: APL; acute promyelocytic leukemia; ATRA; all-transretinoic acid; CR; complete remission; DS; differentiation syndrome; ECOG; Eastern Cooperative Oncology Group; ED; early death; HR; hazard ratio; IQR; interquartile range; LFS; leukemia-free survival; OS; overall survival; WBC; white blood cell.
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Leucemia Promielocítica Aguda , Humanos , Leucocitose , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Tretinoína/uso terapêutico , Resultado do TratamentoRESUMO
Germ line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained â¼80% of known germ line predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n = 4461) compared with the general population of Japan (n = 20 238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years of age but rapidly increased to 49% by 90 years of age. Patients with myelodysplastic syndromes (MDS) along with a DDX41-mutation rapidly progressed to acute myeloid leukemia (AML), which was however, confined to those having truncating variants. Comutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and WT cases, in which none of the comutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multihit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System. Our findings establish that MDS with DDX41-mutation defines a unique subtype of MNs that is distinct from other MNs.
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RNA Helicases DEAD-box , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Adulto , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , RNA Helicases DEAD-box/genética , Células Germinativas , Leucemia Mieloide Aguda/genética , Mutação , Síndromes Mielodisplásicas/genética , Transtornos Mieloproliferativos/genéticaRESUMO
INTRODUCTION: Risk stratification is essential for treatment decision in myelodysplastic neoplasms (MDS). Molecular international prognostic scoring system (M-IPSS) has been recently developed combining somatic mutations and clinical information being used in the revised international prognostic scoring system (R-IPSS). OBJECTIVE: We aimed to explore the performances of M-IPSS and R-IPSS in Thai patients with MDS. METHOD: MDS patients were stratified into risk categories using R-IPSS and M-IPSS scores. The performance of both models were evaluated for prognostic prediction. RESULTS: One hundred and sixty-two MDS patients were recruited from the multicenter study. Survival analysis revealed that both R-IPSS and M-IPSS were good prediction models with the Concordance Index (C-index) of 0.71 (95% Confidence interval [CI] 0.64-0.78) and 0.75 (95% CI 0.69-0.80), respectively (p = 0.22). Comparing the two, 13 of 162 (8%) cases were re-staged between lower and higher risks which would have affected treatment decisions. CONCLUSION: Our study showed that R-IPSS score can be used for risk stratification in most Thai patients. A prediction model using somatic mutations specifically in Asian patients should be formulated in the future.
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Síndromes Mielodisplásicas , Neoplasias , Humanos , Prognóstico , Estudos Retrospectivos , População do Sudeste Asiático , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genéticaRESUMO
BACKGROUND: Secondary acute myeloid leukemia (sAML) and AML with myelodysplasia-related changes (AML-MRC) both result in dismal outcomes. This retrospective study aimed to determine whether these features are poor prognostic factors independent of older age and adverse cytogenetics, which are commonly associated with a poor prognosis. METHODS: The characteristics and real-world outcomes of sAML and AML-MRC from the Thai AML registry database were investigated. RESULTS: From a total of 992 newly diagnosed AML patients, 315 (31.8%) patients were classified into sAML or AML-MRC subtypes. Older age, low white blood cell (WBC) count, low bone marrow blast, and adverse cytogenetic risk were commonly present in sAML and AML-MRC compared to de novo AML. Complete remission after 7 + 3 induction therapy occurred in 42.3% of patients with sAML or AML-MRC and 62.4% of de novo AML (P < .001). The median overall survival (OS) of sAML, AML-MRC, and de novo AML were 6.9, 7.0, and 12.2 months, respectively (P < .001). The independent prognostic factors for inferior OS were older age, intermediate-risk or adverse-risk cytogenetics, WBC count > 100 × 109/L, poor performance status, and a subgroup of AML-MRC with the morphologic criteria of multilineage dysplasia (AML-MRC-M). In addition, sAML, AML-MRC, and a WBC count > 100 × 109/L were pre-treatment prognostic factors associated with poor relapse-free survival (P = .006, P = .017, and P < .001, respectively). CONCLUSION: Both sAML and AML-MRC are independently associated with poor outcomes in Thai patients. Our study supports AML-MRC-M as an adverse prognostic factor for OS.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Segunda Neoplasia Primária , Humanos , Estudos Retrospectivos , Tailândia/epidemiologia , Síndromes Mielodisplásicas/terapia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Segunda Neoplasia Primária/complicações , PrognósticoRESUMO
BACKGROUND: Intermediate or high doses of cytarabine (IDAC or HiDAC) were recommended as postremission chemotherapy for acute myeloid leukemia (AML). This retrospective study investigated the real-world outcomes of 3-different cytarabine doses from the multicenter Thai AML registry database. PATIENTS AND METHODS: The intermediate- and adverse-risk AML patients (N = 258) who achieved complete remission and proceeded to single-agent cytarabine consolidation were enrolled. RESULTS: The median relapse-free survival (RFS) using IDAC 1.5 g/m2, high-dose cytarabine (HiDAC) 2 g/m2, and HiDAC 3 g/m2 were 12.6, 11.7, and 13 months, respectively. The median overall survival (OS) using IDAC 1.5 g/m2, HiDAC 2 g/m2, and HiDAC 3 g/m2 were 34.9, 22.7, and 23.7 months, respectively. No significant difference in RFS and OS was detected between the 3 doses. Secondary AML, white blood cell > 100×109/L and the adverse-risk AML were independent prognostic factors for inferior survival (P= .008, P < .001, P= .014). Patients who completed 3 to 4 cycles of consolidation had significantly superior RFS and OS (P< .001, P< .001). Febrile neutropenia occurred in 72.9% of IDAC, 73.8% of HiDAC 2 g/m2, and 78.1% of HiDAC 3 g/m2 without statistical significance. However, the incidence of septic shock was significantly higher after HiDAC 3 g/m2 compared to IDAC regimen (8% vs. 3%, P= .037). CONCLUSION: IDAC is an appropriate regimen for postremission chemotherapy for intermediate- and adverse-risk AML. The higher dosing levels may not produce any benefits to patients and may increase incidence of septic shock. The number of consolidation cycles may impact on survivals rather than the intensity of cytarabine.
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Leucemia Mieloide Aguda , Choque Séptico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Citarabina/efeitos adversos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Sistema de Registros , Indução de Remissão , Estudos Retrospectivos , Choque Séptico/tratamento farmacológico , Tailândia/epidemiologiaRESUMO
INTRODUCTION: Myelodysplastic syndromes (MDS) predominantly present with varying degrees of cytopenia, while myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) exhibit proliferative features. Genetic defects underlying different complete blood count (CBC) alterations remain to be defined. OBJECTIVE: We aimed to evaluate mutations and impacts on abnormal blood counts in MDS and MDS/MPN. METHOD: MDS and MDS/MPN patients were recruited and sequenced by targeted next-generation sequencing. Clinical parameters, especially CBC, were evaluated for the association with genetic abnormalities and clinical outcomes. RESULTS: A total of 168 patients with myeloid neoplasms were recruited (92 cases of low-risk MDS, 57 cases of high-risk MDS and 19 cases of MDS/MPN). Compared to low-risk MDS and MDS/MPN, patients with high-risk MDS were presented with more severe neutropenia with 17.5% showing absolute neutrophil counts (ANC) lower than 0.5 × 109/L. Patients with MDS/MPN more commonly harboured mutations and had a higher number of mutations per case than low-risk MDS (94.7% vs. 56.5%; p < 0.001 and 3 vs. 1; p < 0.001, respectively). Patients with SF3B1 mutations showed lower haemoglobin levels than wild-type (7.9 vs. 8.4â g/dL, p = 0.02), but were associated with normal platelet counts (286 vs. 93 × 109/L; p < 0.001). Patients with U2AF1 mutations were associated with more severe leukopenia than wild-type (3 vs. 4.18 × 109/L; p = 0.02). KRAS mutations were associated with monocytosis (p < 0.001). Multivariate analysis revealed high-risk MDS, MDS/MPN, severe neutropenia (ANC < 0.5 × 109/L), and mutations in ASXL1 and SETBP1 were associated with inferior survival outcomes. CONCLUSION: Certain mutations were related to more severe anaemia, lower white blood cell count or monocytosis in Asian MDS and MDS/MPN patients.
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Síndromes Mielodisplásicas , Doenças Mieloproliferativas-Mielodisplásicas , Transtornos Mieloproliferativos , Neoplasias , Neutropenia , Humanos , Mutação , Síndromes Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/genética , Transtornos Mieloproliferativos/genéticaRESUMO
Background: Eosin-5-Maleimide (EMA)-based flow cytometry binds to red blood cell (RBC) membrane-associated proteins which can be used to detect red blood cell (RBC) membrane disorders. Myelodysplastic syndromes (MDS) are stem cell disorders resulting in ineffective hematopoiesis which is commonly present with anemia and erythroid dysplasia. Objectives: We aimed to study RBC membrane defects in MDS using flow cytometry for EMA staining. Methods: We enrolled anemic patients who were diagnosed with low-risk MDS (R-IPSS score ≤ 3.5), RBC membrane disorders [hereditary spherocytosis (HS) and Southeast Asian ovalocytosis (SAO)], and normal controls. Complete blood count (CBC) and flow cytometry for EMA staining were performed. Results: There were 16 cases of low-risk MDS, 6 cases of RBC membrane disorders, and 15 control cases. Mean fluorescence intensity (MFI) of EMA binding test in the RBC membrane disorders was significantly lower than controls (17.6 vs. 24.3, p < 0.001), but the EMA binding test in the low-risk MDS was not significantly different than the controls (26.5 vs. 24.3, p = 0.08). Conclusion: the RBC membrane defect in low-risk MDS was not demonstrated as having detection ability using EMA binding test with flow cytometry.
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Programmed cell death (PD)/PD-ligands (PD-Ls) pathway plays an important role in the regulation of physiologic immune response. Several cancers, including lymphoma exhibit abnormal PD-1/PD-Ls expression, which may contribute to treatment failure, progression, and inferior outcomes. PD-1/PD-Ls expression has predominantly been described in B-cell lymphoma; such data in peripheral T-cell lymphoma (PTCL) is limited. We described PD-1/PD-Ls expression patterns and associations with clinical characteristics and outcomes, in patients with systemic PTCLs. Correlation between PD-1/PD-Ls expression and outcomes was analyzed in patients who received lymphoma-specific therapy. PD-1/PD-Ls expression was observed across all common PTCL histologies at different proportions (PD-1 0%-76.9%, PD-L1 38.5%-62.5%, and PD-L2 62.5%-100%) with PD-1 being highly expressed in angioimmunoblastic T-cell lymphoma. Baseline characteristics were comparable between PD-1/PD-Ls expression status. Of 47 patients who received lymphoma-specific therapy, outcomes were similar across all PD-L1/PD-L2 subgroups. In the Cox proportional hazard analysis, treatment response was the only factor associated with survival outcomes. However, PD-1/PD-Ls expression, either in lymphoma or stroma, was not a predictor for survival outcomes. In conclusion, differential PD-1/PD-Ls expressions were observed among various histological PTCL subtypes. In this study, we were unable to demonstrate an association between PD-1/PD-Ls expression, clinical characteristics, treatment response, and outcomes of PTCL patients.
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Antígeno B7-H1 , Linfoma de Células T Periférico , Apoptose , Antígeno B7-H1/metabolismo , Humanos , Linfoma de Células T Periférico/tratamento farmacológico , Prognóstico , Receptor de Morte Celular Programada 1/metabolismoRESUMO
Fertility is a concern in young female survivors of hematological malignancies. We evaluated post-treatment ovarian function in patients by measuring anti-Müllerian hormone (AMH) and conventional hormone levels to correlate with menstruation and fertility.The prospective cohort study included 29 reproductive-aged women diagnosed with Hodgkin lymphoma (n = 11), non-Hodgkin lymphoma (n = 9) or acute myeloid leukemia (n = 9). Hormone assays were measured after treatment was completed and compared to age-matched healthy controls. Menstrual changes and postmenopausal symptoms were assessed annually.Serum AMH levels were significantly lower compared to controls at 12 months after treatment [1.0 (0.18-1.8) vs. 2.2 (1.8-4.8) ng/mL; P < .001). At 12 months, FSH and LH levels were significantly higher compared to controls. The interruption of menstrual cycles was observed in 80% (22/27) of patients. Normal menstruation returned at a median of 1.5 months after cessation of treatment in 71% of patients, while 29% of patients had persistent amenorrhea. Low AMH levels at 12 months after therapy (<1â ng/mL) correlated more strongly with abnormal menstrual cycles than normal AMH levels (46% vs. 0%, P = .04). Four patients with low AMH consulted an infertility clinic.In summary, low serum AMH at 12 months after chemotherapy was associated with persistent menstrual abnormalities.
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Hormônio Antimülleriano/sangue , Antineoplásicos/efeitos adversos , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/tratamento farmacológico , Adolescente , Adulto , Antineoplásicos/uso terapêutico , Feminino , Doença de Hodgkin/sangue , Doença de Hodgkin/tratamento farmacológico , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/tratamento farmacológico , Menstruação/efeitos dos fármacos , Ovário/efeitos dos fármacos , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Unexplained cytopenia (UC) and low-risk myelodysplastic syndrome (MDS) are distinguished mainly by morphologic dysplasia, which sometimes shows inter-observer discrepancy. We hypothesized that gene mutations are strong prognostic factors for these low-risk patients. MATERIALS AND METHODS: We enrolled patients from 4 medical centers with unexplained cytopenia of at least 1 lineage. Diagnosis of low-risk MDS was made according to WHO 2016 classification and a revised international prognostic scoring system (R-IPSS) score of ≤ 3.5. DNA was extracted from bone marrow or blood and sequenced by targeted next generation sequencing (NGS). RESULTS: One hundred twenty-one patients were recruited: 25% with UC and 75% with low-risk MDS. Complete blood counts were similar, but low-risk MDS patients carried higher numbers of mutations (1 vs. 0; P = .04) than UC patients. Overall, the most frequent mutated genes were TET2 (14.6%), SF3B1 (12.2%), and ASXL1 (9.7%). Survival rates of low-risk MDS patients versus UC patients were not significantly different. UC patients and low-risk MDS patients without genetic abnormalities showed superior 5-year progression free survival compared to MDS patients with mutations (100% vs. 76.0%; P = .005). Overall, ASXL1 mutations were associated with decreased 4-year overall survival compared to wild-type (59% vs. 31%; P = .01). In a multivariate analysis, ASXL1 and DNMT3A mutations in low-risk MDS patients were associated with a higher risk of disease progression with hazard ratios of 7.88 (95% CI 1.76-35.32, P = .01) and 7.45 (95% CI 1.61-34.46, P = .01), respectively. CONCLUSION: Mutation detection is important for proper risk stratification of patients presenting with idiopathic cytopenia.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/complicações , Mutação , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , PrognósticoRESUMO
INTRODUCTION: Erythropoiesis stimulating agents (ESAs) represents the principal treatments for anemia in patients with lower-risk myelodysplastic syndromes (MDS). Pre-treatment erythropoietin (EPO) level and previous blood transfusion requirement are the two major predictors for response to ESAs. However, most evidence was derived from Western countries whereas there have been limited data in patients with Asian background. METHODS: We retrospectively collected data on patients with low-risk MDS who received ESAs. Erythroid response was evaluated according to IWG 2006 criteria. MDS subtypes, r-IPSS, baseline hemoglobin (Hb), ESAs dosage and erythropoietin level were reviewed from medical records. Gene mutations were analyzed in patients' blood or bone marrow at diagnosis by 40-gene myeloid panel targeted sequencing. Clinical and laboratory parameters were compared between erythroid responder and non-responder groups. RESULTS: A total of 47 patients were recruited in the study. The median age at diagnosis of the patients in this cohort was 77 years (IQR, 70-83) and 44.7% were male. The median revised international prognostic scoring system (R-IPSS) score of patients was 2.5. Response rate to ESAs was 46.8% (22/47). Median EPO level in responders was significantly lower than non-responders (27.7 vs. 59.1 U/L, p=0.02). Median ESAs dosage in responder group was 30,000 units per week. Cytogenetic abnormalities were detected in 27.3% and 24% of the responder and non-responder groups, respectively. Of 22 patients with available 40 gene mutation targeted sequencing, ASXL1, IDH2 and TET2 represented the 3 most common mutations and were found in 22%, 22% and 17%, respectively. There were no differences in cytogenetic abnormalities and gene mutations between groups. Patients who responded to ESAs showed a higher 5-year overall survival (OS) compared to non-responders (5-year OS 75% vs. 60.9%; p=0.008). CONCLUSION: We conclude that a low serum EPO level is a predictive factor for responsiveness to ESAs in Asian patients with low-risk MDS.