ABSTRACT
Atypical acute promyelocytic leukemia (aAPL) presents a complex landscape of retinoic acid receptor (RAR) fusion genes beyond the well-known PML::RARA fusion. Among these, 31 individually rare RARA and RARG fusion genes have been documented, often reported in the canonical X::RAR bipartite fusion form. Intriguingly, some artificially mimicked bipartite X::RAR fusions respond well to all-trans retinoic acid (ATRA) in vitro, contrasting with the ATRA resistance observed in patients. To unravel the underlying mechanisms, we conducted a comprehensive molecular investigation into the fusion transcripts in 27 RARA fusion gene-positive aAPL (RARA-aAPL) and 21 RARG-aAPL cases. Our analysis revealed an unexpected novel form of X::RAR::X or X::RAR::Y-type tripartite fusions in certain RARA- and all RARG-aAPL cases, with shared features and notable differences between these two disease subgroups. In RARA-aAPL cases, the occurrence of RARA 3' splices was associated with their 5' fusion partner genes, mapping across the coding region of helix 11_12 (H11_12) within the ligand-binding domain (LBD), resulting in LBD-H12 or H11_12 truncation. In RARG-aAPL cases, RARG 3' splices were consistently localized to the terminus of exon 9, leading to LBD-H11_12 truncation. Significant differences were also observed between RARA and RARG 5' splice patterns. Our analysis also revealed extensive involvement of transposable elements in constructing RARA and RARG 3' fusions, suggesting transposition mechanisms for fusion gene ontogeny. Both protein structural analysis and experimental results highlighted the pivotal role of LBD-H11_12/H12 truncation in driving ATRA unresponsiveness and leukemogenesis in tripartite fusion-positive aAPL, through a protein allosteric dysfunction mechanism.
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BACKGROUND: Several studies have suggested that short-course antibiotic therapy was effective in Pseudomonas aeruginosa (PA) bloodstream infections (BSI) in immunocompetent patients. But similar studies in patients with hematological malignancies were rare. METHODS: This cohort study included onco-hematology patients at 2 hematology centers in China. Inverse probability of treatment weighting was used to balance the confounding factors. Multivariate regression model was used to evaluate the effect of short-course antibiotic therapy on clinical outcomes. RESULTS: In total, 434 patients met eligibility criteria (short-course, 7-11 days, n = 229; prolonged, 12-21 days, n = 205). In the weighted cohort, the univariate and multivariate analysis indicated that short course antibiotic therapy had similar outcomes to the prolonged course. The recurrent PA infection at any site or mortality within 30 days of completing therapy occurred in 8 (3.9%) patients in the short-course group and in 10 (4.9%) in the prolonged-course group (P = .979). The recurrent infection within 90 days occurred in 20 (9.8%) patients in the short-course group and in 13 (6.3%) patients in the prolonged-course group (P = .139), and the recurrent fever within 7 days occurred in 17 (8.3%) patients in the short-course group and in 15 (7.4%) in the prolonged-course group (P = .957). On average, patients who received short-course antibiotic therapy spent 3.3 fewer days in the hospital (P < .001). CONCLUSIONS: In the study, short-course therapy was non-inferior to prolonged-course therapy in terms of clinical outcomes. However, due to its biases and limitations, further prospective randomized controlled trials are needed to generalize our findings.
Subject(s)
Bacteremia , Febrile Neutropenia , Hematology , Pseudomonas Infections , Sepsis , Humans , Pseudomonas aeruginosa , Cohort Studies , Anti-Bacterial Agents/pharmacology , Pseudomonas Infections/drug therapy , Febrile Neutropenia/complications , Febrile Neutropenia/drug therapy , Sepsis/drug therapy , Bacteremia/drug therapyABSTRACT
Several international centers have used and reported pediatric-inspired regimens for adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL). However, there is a lack of prospective data on the Chinese population. Herein, we performed a prospective study with a pediatric-inspired regimen (IH-2014 regimen) in treating adolescent and adult Ph- ALL patients in our center. From 2014 to 2021, a total of 415 patients aged between 14 and 65 years (median age, 27) were included in this study. After a median follow-up of 40.8 months, the 5-year overall survival, disease-free survival, and event-free survival rates were 53.8%, 51.1% and 45.0%, respectively. The regimen was generally well tolerated and safe, and the overall chemotherapy-related mortality was 3.6%. Age ≥ 40 years and persistent detectable minimal residual disease (MRD) post-induction were independent prognostic factors. Traditional risk factors for adult patients combined with MRD post-induction exhibit predictive significance for survival and relapse, which is helpful in the selection of subsequent treatment. Patients with high risk factors who can achieve deep MRD response after induction do not derive benefit from allogeneic hematopoietic stem cell transplantation.
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INTRODUCTION: New diagnostic methods and antifungal strategies may improve prognosis of mucormycosis. We describe the diagnostic value of metagenomic nextâgeneration sequencing (mNGS) and identify the prognostic factors of mucormycosis. METHODS: We conducted a retrospective study of hematologic patients suffered from mucormycosis and treated with monotherapy [amphotericin B (AmB) or posaconazole] or combination therapy (AmB and posaconazole). The primary outcome was 84-day all-cause mortality after diagnosis. RESULTS: Ninety-five patients were included, with "proven" (n = 27), "probable" (n = 16) mucormycosis confirmed by traditional diagnostic methods, and "possible" (n = 52) mucormycosis with positive mNGS results. The mortality rate at 84 days was 44.2%. Possible + mNGS patients and probable patients had similar diagnosis processes, overall survival rates (44.2% vs 50.0%, p = 0.685) and overall response rates to effective drugs (44.0% vs 37.5%, p = 0.647). Furthermore, the median diagnostic time was shorter in possible + mNGS patients than proven and probable patients (14 vs 26 days, p < 0.001). Combination therapy was associated with better survival compared to monotherapy at six weeks after treatment (78.8% vs 53.1%, p = 0.0075). Multivariate analysis showed that combination therapy was the protective factor (HR = 0.338, 95% CI: 0.162-0.703, p = 0.004), though diabetes (HR = 3.864, 95% CI: 1.897-7.874, p < 0.001) and hypoxemia (HR = 3.536, 95% CI: 1.874-6.673, p < 0.001) were risk factors for mortality. CONCLUSIONS: Mucormycosis is a life-threatening infection. Early management of diabetes and hypoxemia may improve the prognosis. Exploring effective diagnostic and treatment methods is important, and combination antifungal therapy seems to hold potential benefits.
Subject(s)
Amphotericin B , Antifungal Agents , Hematologic Diseases , High-Throughput Nucleotide Sequencing , Mucormycosis , Humans , Mucormycosis/diagnosis , Mucormycosis/drug therapy , Mucormycosis/mortality , Mucormycosis/microbiology , Male , Female , Retrospective Studies , Middle Aged , Prognosis , Antifungal Agents/therapeutic use , Adult , Aged , Hematologic Diseases/complications , Amphotericin B/therapeutic use , Metagenomics/methods , Triazoles/therapeutic use , Young Adult , Drug Therapy, Combination , Survival Analysis , Treatment OutcomeABSTRACT
Chronic myeloid leukemia (CML) is a clonal proliferative disorder of granulocytic lineage, with morphologic evaluation as the first step for a definite diagnosis. This study developed a conditional generative adversarial network (cGAN)-based model, CMLcGAN, to segment megakaryocytes from myeloid cells in bone marrow biopsies. After segmentation, the statistical characteristics of two types of cells were extracted and compared between patients and controls. At the segmentation phase, the CMLcGAN was evaluated on 517 images (512 × 512) which achieved a mean pixel accuracy of 95.1%, a mean intersection over union of 71.2%, and a mean Dice coefficient of 81.8%. In addition, the CMLcGAN was compared with seven other available deep learning-based segmentation models and achieved a better segmentation performance. At the clinical validation phase, a series of seven-dimensional statistical features from various cells were extracted. Using the t-test, five-dimensional features were selected as the clinical prediction feature set. Finally, the model iterated 100 times using threefold cross-validation on whole slide images (58 CML cases and 31 healthy cases), and the final best AUC was 84.93%. In conclusion, a CMLcGAN model was established for multiclass segmentation of bone marrow cells that performed better than other deep learning-based segmentation models.
Subject(s)
Image Processing, Computer-Assisted , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Biopsy , Bone Marrow , Humans , Image Processing, Computer-Assisted/methods , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosisABSTRACT
PURPOSE: This study investigated the clinical and antimicrobial characteristics of Acinetobacter spp. bloodstream infection (BSI) in hematological patients. Risk factors for 30-day mortality and carbapenem-resistant Acinetobacter spp. (CRA) BSI acquisition were also identified. METHODS: We reviewed forty hematological patients with Acinetobacter spp. BSI in a large Chinese blood disease hospital between 2013 and 2022. The remaining CRA isolates were subjected to whole-genome sequencing. RESULTS: The 30-day mortality rate was high at 35%. Hematological patients with Acinetobacter spp. BSI often presented with severe conditions and co-infections at multiple sites. All strains were colistin-susceptible and 40.0% were CR. Multivariate analysis identified several risk factors associated with CRA BSI acquisition, including previous exposure to carbapenems within 30 days and CRA colonization. Very severe aplastic anaemia, tetracycline-resistant Acinetobacter spp. BSI, and unresolved neutropenia after infection were closely associated with 30-day mortality. Non-survivors often presented with higher median PCT and CRP levels and severe complications, such as intracranial infection, cardiac dysfunction, respiratory failure, and severe sepsis or septic shock. Our study also identified inappropriate empirical antibiotic therapy as an independent predictor of 30-day mortality (OR: 11.234, 95% CI: 1.261-20.086, P = 0.030). This study was the first to report A. oleivorans as a human pathogen, and to identify its unique oxacillinase, OXA-325. CONCLUSION: An environment-originated non-pathogenic species can become pathogenic when the body's immunity is compromised. Our results also highlighted the importance of improving neutropenia after infection, treating severe organ dysfunction, and administering appropriate empirical antibiotic therapy to reduce mortality in this patient population.
Subject(s)
Acinetobacter Infections , Acinetobacter , Bacteremia , Cross Infection , Neutropenia , Sepsis , Humans , Acinetobacter Infections/epidemiology , Bacteremia/epidemiology , Cross Infection/epidemiology , Sepsis/drug therapy , Anti-Bacterial Agents/therapeutic use , Retrospective StudiesABSTRACT
The prognostic factors to stratify acute myeloid leukaemia (AML) with double-mutated CCAAT/enhancer-binding protein alpha (CEBPAdm) into different risk groups remains to be determined. In this retrospective study, we evaluated 171 consecutive patients with newly diagnosed AML with CEBPAdm by a Cox proportional hazards regression model. In univariate analyses, colony stimulating factor 3 receptor (CSF3R) and Wilms tumour 1 (WT1) mutations were associated with poor relapse-free survival (RFS). The induction regimens including homoharringtonine (omacetaxine mepesuccinate) or intermediate-dose cytarabine was associated with favourable RFS and overall survival (OS). The induction regimen including both homoharringtonine and intermediate-dose cytarabine was associated with the most favourable RFS (3-year RFS 84.7%) and OS (3-year OS 92.8%) compared to the conventional cytarabine and daunorubicin regimen (3-year RFS 27.7%, hazard ratio [HR] 0.126, 95% confidence interval [CI] 0.051-0.313, Wald p < 0.001; and 3-year OS 56.4%, HR 0.179, 95% CI 0.055-0.586, Wald p = 0.005). In multivariate analyses, the induction regimen including intermediate-dose cytarabine (HR 0.364, 95% CI 0.205-0.646, Wald p < 0.001) and CSF3R mutations (HR 2.667, 95% CI 1.276-5.572, Wald p = 0.009) were independently associated with RFS. Taken together, we found that induction regimen and CSF3R mutations were independent prognostic factors for AML with CEBPAdm.
Subject(s)
CCAAT-Enhancer-Binding Protein-alpha , Leukemia, Myeloid, Acute , CCAAT-Enhancer-Binding Protein-alpha/genetics , CCAAT-Enhancer-Binding Proteins/genetics , Cytarabine/therapeutic use , Homoharringtonine , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mutation , Neoplasm Recurrence, Local , Prognosis , Receptors, Colony-Stimulating Factor , Retrospective StudiesABSTRACT
The clinical characteristics and prognosis of intracranial hemorrhage (ICH) in patients with hematological diseases remain controversial. This study aimed to describe the clinical characteristics and explore the prognostic factors in such patients. A total of 238 ICH patients with a hematological disease were recruited from the Institute of Hematology and Blood Diseases Hospital, China, from January 2015 to April 2020. The Cox proportional hazards model was used to identify the prognostic factors for 30-day mortality in ICH patients with a hematological disease. There were 123 cases of acute leukemia (AL), 20 of myelodysplasia/myeloproliferative neoplasm, 35 of aplastic anemia (AA), 29 of immune thrombocytopenia (ITP), 19 of congenital/acquired coagulation factor deficiency, and 12 of other hematological diseases. Furthermore, 121 patients presented with a multi-site hemorrhage (MSH), 58 with a single-site hemorrhage in the brain parenchyma (PCH), 23 with a subarachnoid hemorrhage, 33 with a subdural hemorrhage (SH), and three with an epidural hemorrhage. The Cox proportional hazards model indicated association of SH (vs PCH, hazard ratio [HR]: 0.230; 95% confidence interval [CI]: 0.053-0.996; P = 0.049), low white blood cells (≤ 100 × 109/L vs > 100 × 109/L, HR: 0.56; 95% CI: 0.348-0.910; P = 0.019), AA (vs AL, HR: 0.408; 95% CI: 0.203-0.821; P = 0.012), and ITP (vs AL, HR: 0.197; 95% CI: 0.061-0.640; P = 0.007) with improved 30-day mortality. However, increased age (HR: 1.012; 95% CI: 1.001-1.022; P = 0.034), MSH (vs PCH, HR: 1.891; 95% CI: 1.147-3.117; P = 0.012), and a disturbance of consciousness (HR: 1.989; 95% CI: 1.269-3.117; P = 0.003) were associated with increased risk of 30-day mortality. In conclusion, in this study, we revealed the clinical characteristics of Chinese ICH patients with a hematological disease. Moreover, we identified risk factors (age, white blood cells, AA, ITP, SH, MSH, and a disturbance of consciousness) that may influence 30-day mortality.
Subject(s)
Anemia, Aplastic , Hematologic Diseases , Leukemia, Myeloid, Acute , Thrombocytopenia , Humans , Anemia, Aplastic/complications , Cerebral Hemorrhage/complications , Hematologic Diseases/complications , Hematoma, Subdural , Intracranial Hemorrhages/etiology , Leukemia, Myeloid, Acute/complications , Prognosis , Risk Factors , Thrombocytopenia/complicationsABSTRACT
BACKGROUND: To analyze the clinical features, risk factors and outcomes of Aeromonas bloodstream infections (BSIs) in patients with hematological diseases to establish an effective optimal therapy against it. METHODS: A retrospective study was performed by reviewing medical records of patients admitted to a tertiary blood disease hospital in China. Patients with hematological diseases who suffered from Aeromonas bacteremia during January 2002 to December 2020 were enrolled in this study. RESULTS: A total of 63 patients who developed Aeromonas bacteremia were enrolled in the study, and 91.9% of patients were neutropenic at the onset of BSIs. The major complications were skin and soft tissue infection (SSTI) (22.2%), followed by gastroenteritis (19.0%) and pneumonia (14.3%). High carbapenem resistance rates (70.8% for imipenem, 71.4% for meropenem) were note among the cases. Furthermore, Aeromonas strains isolated from five individuals developed resistance to quinolone, ß-lactams and tigecycline during the therapy. The 30-day mortality rate was 15.9%, while bacteremia with SSTI showed a much worse prognosis, with 50.0% (7/14) of the patients dying within 30 days of initiating the therapy. In the multivariate analysis, SSTI (OR = 28.72; 95% CI, 1.50-551.30; P = 0.026) and shock (OR = 47.58; 95% CI,1.06-2126.80; P = 0.046) were independent risk factors for mortality. CONCLUSIONS: Aeromonas bacteremia usually occurred in patients with neutropenic status, and patients with SSTIs were more likely to show a worse prognosis. Carbapenems should be avoided in patients with Aeromonas BSIs and SSTIs given high resistance rate.
Subject(s)
Aeromonas , Bacteremia , Hematologic Diseases , Bacteremia/drug therapy , Bacteremia/epidemiology , Hematologic Diseases/complications , Humans , Retrospective Studies , Risk FactorsABSTRACT
Through an RNA-seq analysis of an adult patient with unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U), we identified a rare PDGFRB fusion partner gene, PCM1. Conventional chromosome karyotype analysis showed abnormal clones of t(5;8)(q32;p22), and fluorescence in situ hybridization (FISH) confirmed rearrangement of the PDGFRB gene. Reverse transcription PCR (RT-PCR) and Sanger sequencing further confirmed that exon 30 of the PCM1 gene was fused with exon 11 of PDGFRB in frame, and the fusion event was accompanied by a 14 bp deletion of exon 11 of PDGFRB. After low-dose imatinib treatment, the patient achieved complete molecular remission. This study not only broadens the understanding of myeloid/lymphoid neoplasms with PDGFRB rearrangement but also reflects the vital role of RNA-seq in identifying PDGFRB rearrangements.
Subject(s)
Myeloproliferative Disorders , Neoplasms , Humans , Imatinib Mesylate/therapeutic use , In Situ Hybridization, Fluorescence , Myeloproliferative Disorders/drug therapy , Neoplasms/drug therapy , Oncogene Proteins, Fusion/genetics , Receptor, Platelet-Derived Growth Factor beta/genetics , Translocation, GeneticABSTRACT
BACKGROUND: Pseudomonas aeruginosa (PA) bloodstream infection (BSI) is a common complication in patients with acute leukemia (AL), and the prevalence of antibiotic-resistant strains poses a serious problem. However, there is limited information regarding antibiotic resistance, clinical characteristics, and outcomes of PA BSI in AL patients. This study explored characteristics associated with the clinical outcomes of AL patients with PA BSI and analyzed factors associated with BSI caused by multidrug-resistant (MDR) or carbapenem-resistant strains. METHODS: This single-center retrospective study enrolled hospitalized AL patients who developed PA BSI during January 2014-December 2019. The Kaplan-Meier method was used to plot survival curves. Multivariate logistic regression analyses were also performed. RESULTS: Of 293 eligible patients with PA BSI, 55 (18.8%) received inappropriate empirical antibiotic therapy within 48 hours of BSI onset, whereas up to 65.8% MDR-PA BSI patients received inappropriate empirical treatment. The 30-day mortality rate was 8.5% for all patients. However, the 30-day mortality rates were 28.9% and 5.5% in MDR-PA BSI and non-MDR-PA BSI patients, respectively (Pâ <â .001). On multivariate analysis, previous use of quinolones (odds ratio [OR], 5.851 [95% confidence interval {CI}, 2.638-12.975]) and piperacillin/tazobactam (OR, 2.837 [95% CI, 1.151-6.994]) were independently associated with MDR-PA BSI; and MDR-PA BSI (OR, 7.196 [95% CI, 2.773-18.668]), perianal infection (OR, 4.079 [95% CI, 1.401-11.879]), pulmonary infection (OR, 3.028 [95% CI, 1.231-7.446]), and age ≥55 years (OR, 2.871 [95% CI, 1.057-7.799]) were independent risk factors for 30-day mortality. CONCLUSIONS: MDR increases mortality risk in PA BSI patients, and previous antibiotic exposure is important in MDR-PA BSI development. Rational antibiotic use based on local antimicrobial susceptibility and clinical characteristics can help reduce antibiotic resistance and mortality.
Subject(s)
Bacteremia , Leukemia , Pseudomonas Infections , Adult , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Bacteremia/drug therapy , Bacteremia/epidemiology , Drug Resistance, Multiple, Bacterial , Humans , Middle Aged , Pseudomonas Infections/drug therapy , Pseudomonas Infections/epidemiology , Pseudomonas aeruginosa , Retrospective Studies , Risk FactorsABSTRACT
BACKGROUND: Acute myeloid leukemia (AML) is a common hematopoietic malignancy that has a high relapse rate, and the number of regulatory T cells (Tregs) in AML patients is significantly increased. The aim of this study was to clarify the role of Tregs in the immune escape of acute myeloid leukemia. METHODS: The frequencies of Tregs and the expression of PD-1, CXCR4 and CXCR7 were examined by flow cytometry. The expression of CTLA-4 and GITR was tested by MFI. Chemotaxis assays were performed to evaluate Treg migration. The concentrations of SDF-1α, IFN-γ and TNF-α were examined by ELISA. Coculture and crisscross coculture experiments were performed to examine Treg proliferation and apoptosis and the effect of regulatory B cells (Breg) conversion. RESULTS: The frequencies of Tregs in peripheral blood and bone marrow in AML patients were increased compared with those in healthy participants. AML Tregs had robust migration towards bone marrow due to increased expression of CXCR4. AML Treg-mediated immunosuppression of T cells was achieved through proliferation inhibition, apoptosis promotion and suppression of IFN-γ production in CD4+CD25- T cells. AML Bregs induced the conversion of CD4+CD25-T cells to Tregs. CONCLUSION: In AML patients, the Breg conversion effect and robust CXCR4-induced migration led to Treg enrichment in bone marrow. AML Tregs downregulated the function of CD4+CD25- T cells, contributing to immune escape.
Subject(s)
Immunity, Cellular , Leukemia, Myeloid, Acute/immunology , T-Lymphocytes, Regulatory/immunology , Tumor Escape/immunology , Adolescent , Adult , Aged , Bone Marrow , Cell Differentiation , Cell Movement , Cell Proliferation , Chemotaxis, Leukocyte , Female , Glucocorticoid-Induced TNFR-Related Protein/metabolism , Humans , Immunosuppression Therapy , Interferon-gamma/biosynthesis , Leukemia, Myeloid, Acute/metabolism , Male , Middle Aged , Programmed Cell Death 1 Receptor/metabolism , Receptors, CXCR/metabolism , Receptors, CXCR4/metabolism , T-Lymphocytes, Regulatory/metabolism , Young AdultSubject(s)
Antineoplastic Combined Chemotherapy Protocols , Bridged Bicyclo Compounds, Heterocyclic , Cytarabine , Daunorubicin , Leukemia, Myeloid, Acute , Sulfonamides , Humans , Daunorubicin/administration & dosage , Cytarabine/administration & dosage , Cytarabine/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Sulfonamides/administration & dosage , Sulfonamides/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Male , Female , Middle Aged , Aged , AdultABSTRACT
The aim of this study is to investigate the efficacy and safety of nilotinib combined with multi-agent chemotherapy in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Thirty patients with Ph+ ALL were recruited. Standard induction chemotherapy was given for 4 weeks. Nilotinib was administered beginning on day 15 of induction. After achieving hematologic complete remission (HCR), patients received either seven courses of consolidation or hematopoietic cell transplantation (HCT). Nilotinib was continued 2 years after achieving HCR or before stem cell transplantation conditioning. HCR and molecular complete response (MCR), overall survival (OS), hematologic relapse-free survival (HRFS), molecular relapse-free survival (MRFS), toxicity, and nilotinib levels in the serum and cerebrospinal fluid were evaluated. All patients achieved HCR, and cumulative MCR rate was 83.3%. The median HRFS and OS were 18 and 47.5 months, respectively. Four-year HRFS and OS rates were 54% and 45%, respectively. The median MRFS and 4-year MRFS for the patients with MCR were 19 months and 45%, respectively. The molecular response of patients after induction cycle had no impact on HRFS, MRFS, or OS. The patients who achieved MCR after 3 and 6 months had superior HRFS. The HCT cohort in the first HCR had significantly lower rates of relapse and longer MRFS, HRFS, and OS. Most adverse events were reversible with dose reduction or transient interruption of nilotinib therapy. Only traces of nilotinib were detected in cerebrospinal fluid. Nilotinib combined with cytotoxic chemotherapy was effective and translated to a high HCR and MCR for patients with Ph+ ALL. It should be noted that nilotinib cannot cross the blood-brain barrier.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adult , Combined Modality Therapy , Consolidation Chemotherapy , Disease-Free Survival , Female , Follow-Up Studies , Fusion Proteins, bcr-abl/antagonists & inhibitors , Fusion Proteins, bcr-abl/genetics , Hematopoietic Stem Cell Transplantation , Humans , Induction Chemotherapy , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Prospective Studies , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Pyrimidines/analysis , Remission Induction , Salvage Therapy , Young AdultABSTRACT
OBJECTIVE: To explore the value of flow cytometric (FCM) analysis of cerebrospinal fluid (CSF) in the diagnosis of central nervous system involvement in adult patients with acute lymphoblastic leukemia (ALL) during follow-up. METHODS: A total of 2871 CSF samples from 357 adult patients with newly diagnosed ALL between the year of 2009 and 2015 were analyzed retrospectively. These patients were divided into 3 groups according to CSF results, FCM+/conventional cytology (CC)+ group, FCM+/CC- group, and FCM-/CC- group, respectively. The overall survival (OS) of the three groups was analyzed. RESULTS: Fifteen (4.2%) and 26 (7.3%) patients' CSF samples were FCM+/CC+ and FCM+/CC-, respectively. The remaining 316 (88.5%) patients' samples were FCM-/CC-. The 2-year OS for the FCM+/CC+, FCM+/CC-, and FCM-/CC- groups was 40.0%, 20.6%, and 64.2%, respectively (P < .001). There was no statistically significant difference in OS between FCM+/CC+ and FCM+/CC- patients (P = .195). In multivariate analysis, a high WBC count and LDH level were independent risk factors for central nervous system involvement in adult patients with ALL. CONCLUSIONS: FCM demonstrated a superior sensitivity over conventional cytology in the diagnosis of central nervous system involvement in adult patients with ALL. FCM+/CC- patients showed a similar survival with FCM+/CC+ patients, suggesting that an isolated FCM-positive status holds clinical significance.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/cerebrospinal fluid , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Adolescent , Adult , Aged , Central Nervous System/drug effects , Central Nervous System/metabolism , Central Nervous System/pathology , Central Nervous System/radiation effects , Cytarabine/therapeutic use , Dexamethasone/therapeutic use , Female , Flow Cytometry , Humans , Male , Methotrexate/therapeutic use , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Retrospective Studies , Survival Analysis , Transplantation, Homologous , Whole-Body IrradiationSubject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma , Salvage Therapy , Humans , Retrospective Studies , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Remission InductionABSTRACT
BACKGROUND: The incidence of acute erythroid leukemia subtype (AEL) is rare, accounting for 5% of cases of acute myeloid leukemia (AML), and the outcome is dismal. However, in 2016 revision to the WHO classification, the subcategory of AEL has been removed. Myeloblasts are redefined as the percentage of total marrow cells, not non-erythroid cells. Therefore, the previously diagnosed AEL cases are currently diagnosed as AML or myelodyspalstic syndrome (MDS) according to new criteria. METHODS: We respectively reviewed cases of 97 de novo previously diagnosed AEL and all the patients were diagnosed as AML or MDS according to the new classification scheme, and then the clinical characteristics of these two subtypes were compared. Statistical analyses were performed by SPSS software version 18.0. RESULTS: The median age was 37 years-old, the two-thirds of previous AEL cases were diagnosed as MDS, and there was no obvious difference between two subtypes except for male/female ratio and age. Cytogenetic, rather than MDS/AML subtypes, can better represent the prognostic factor of previously diagnosed AEL patients. When the cytogenetic risk of patients belonged to MRC intermediate category and age were below 40 years-old in previous AEL cases, the patients who received induction chemotherapy without transplantation had a similar survival compared with the patients who underwent transplantation (3-year OS: 67.2% vs 68.5%). CONCLUSIONS: Cytogenetic, rather than MDS/AML subtypes, can better represent the prognostic factor of previously diagnosed AEL patients. Transplantation was a better choice for those whose cytogenetic category was unfavorable.
Subject(s)
Leukemia, Erythroblastic, Acute/diagnosis , Adolescent , Adult , Aged , Biomarkers , Bone Marrow/pathology , Child , Combined Modality Therapy , Cytogenetic Analysis , DNA Mutational Analysis , Diagnosis, Differential , Female , Humans , Leukemia, Erythroblastic, Acute/mortality , Leukemia, Erythroblastic, Acute/therapy , Leukemia, Myeloid, Acute/diagnosis , Male , Middle Aged , Myelodysplastic Syndromes/diagnosis , Practice Guidelines as Topic , Prognosis , Retrospective Studies , Survival Analysis , World Health Organization , Young AdultABSTRACT
The majority of acute promyelocytic leukemia (APL) cases are characterized by the PML-RARα fusion gene. Although the PML-RARα fusion gene can be detected in >98% of APL cases, RARα is also found to be fused with other partner genes, which are also related to all-trans retinoic acid (ATRA)-dependent transcriptional activity and cell differentiation. In this study, we identified a novel RARα fusion gene, TBLR1-RARα (GenBank KF589333), in a rare case of APL with a t(3;17)(q26;q21),t(7;17)(q11.2;q21) complex chromosomal rearrangement. To our knowledge, TBLR1-RARα is the 10th RARα chimeric gene that has been reported up to now. TBLR1-RARα contained the B-F domains of RARα and exhibited a distinct subcellular localization. It could form homodimers and also heterodimers with retinoid X receptor α. As a result, TBLR1-RARα exhibited diminished transcriptional activity by recruitment of more transcriptional corepressors compared with RARα. In the presence of pharmacologic doses of ATRA, TBLR1-RARα could be degraded, and its homodimerization was abrogated. Moreover, when treated with ATRA, TBLR1-RARα could mediate the dissociation and degradation of transcriptional corepressors, consequent transactivation of RARα target genes, and cell differentiation induction in a dose- and time-dependent manner.