Breakthrough invasive fungal infection in patients with myeloid malignancy receiving posaconazole tablet prophylaxis: Clinical features, risk factors, and posaconazole profiles.

Posaconazole (PSC) delayed-release tablet prophylaxis is the standard of care for preventing invasive fungal infection (IFI) in patients with acute myeloid leukemia undergoing myelosuppressive chemotherapy. The clinical features, risk factors, and PSC profiles of breakthrough IFI (bIFI) in patients receiving PSC tablet prophylaxis were investigated. A single-center retrospective cohort study was conducted, including adult patients with myeloid malignancy who received prophylactic PSC tablets while undergoing chemotherapy from June 2016 to June 2021. Logistic regression analysis was used to identify risk factors for bIFI. A receiver operating characteristic curve was used to predict the relationship between PSC trough level at steady state and bIFI. A total of 434 patients with myeloid malignancy who received PSC tablets were screened. A total of 10 patients with bIFI were compared with 208 non-IFI patients. There were four proven and six probable IFI cases, nine due to Aspergillus, and one due to Fusarium species. The bIFI patients had higher in-hospital mortality (30.0%) than the non-IFI patients (1.9%; P < 0.001). History of allogeneic hematopoietic stem cell transplantation (odds ratio [OR] 6.27; 95% confidence interval [CI] 1.63-24.09), prolonged neutropenia ≥28 days (OR 4.33; 95% CI 1.20-15.70), and low plasma PSC concentration <0.7 µg/ml (OR 16.33; 95% CI 4.15-64.26) were risk factors for bIFI. The optimal cutoff value of plasma PSC concentration predicting bIFI was 0.765 µg/ml (sensitivity, 60.0%; specificity, 91.3%; area under the curve, 0.746). bIFI was not uncommon in patients with myeloid malignancy receiving PSC tablet prophylaxis and associated with poor outcomes. Therapeutic drug monitoring may still be necessary, even in patients receiving PSC tablets.

Invasive fungal infections increase mortality in acute myeloid leukemia patients. This study investigated breakthrough invasive fungal infection cases in patients receiving posaconazole tablet prophylaxis. Our results will contribute to improving the outcome of patients with myeloid malignancy.

Risk factors and clinical outcomes of cytomegalovirus diseases in hematologic malignancy patients without hematopoietic stem-cell transplantation.

PURPOSE: This study aims to evaluate the risk factors and prognosis for CMV diseases in hematologic malignancy patients without hematopoietic stem-cell transplantation (HSCT). METHODS: We performed a case-control study (1:2) between 2012 and 2022. Adults with pathologic-confirmed CMV diseases (n=60) among hematologic malignancy patients were matched and compared to whom without CMV disease. RESULTS: Lymphoma was the most common underlying malignancy, and gastrointestinal tract involvement was the most common CMV disease. In the case group, high-dose steroid administration and transfusion within one month before diagnosis were higher (p<0.001). Steroid administration (aOR=5.78; 95% confidence interval: 1.25-26.68, p=0.024), red blood cell transfusion within one month (aOR=14.63; 2.75-77.76, p=0.002), low BMI (aOR=13.46, 2.07-87.45, p=0.006), and hypoalbuminemia (aOR=26.48, 5.93-118.17, p<0.001) were independent risk factors associated with CMV disease. The 30-day mortality was higher in the case group and CMV disease was significantly associated with all-cause mortality (aOR=14.41, 3.23-64.31, p<0.001). CONCLUSION: In hematologic malignancy patients without HSCT, risk factors for CMV organ disease included high-dose steroid administration and RBC transfusion within one month, low BMI, and hypoalbuminemia. Overall mortality was significantly higher with CMV disease, and CMV disease occurrence was a significant risk factor for mortality.

Fatal Prototheca zopfii Algaemia in a Patient with Acute Lymphoblastic Leukemia: a Case Report.

BACKGROUND: Prototheca algaemia is a rare but life-threatening disease that occurs primarily in immunocompromised patients. We report a fatal case of Prototheca zopfii bloodstream infection in a 54-year-old woman receiving chemotherapy for relapsed acute lymphoblastic leukemia. METHODS: The isolate was identified using an automated biochemical identification system (VITEK 2; bioMerieux) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (VITEK MS; bioMerieux). Partial 18S and 28S rDNA sequencing was performed for definitive identification and genotyping. RESULTS: The patient had persistent neutropenic fever, and isolates from blood culture were identified as P. zopfii. Sequencing was performed and the isolate was confirmed to be P. zopfii genotype 2, which was newly named as P. bovis. The patient was treated with liposomal amphotericin B but died of septic shock. CONCLUSIONS: Prototheca spp. should be considered an emerging pathogen, especially in immunocompromised patients, due to its ubiquitous nature.

A case of tuberculosis meningitis after allogeneic hematopoietic stem cell transplantation for relapsed Acute Myeloid Leukemia.

We report a case of tuberculosis (TB) meningitis after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed acute myeloid leukemia. The patient was 52-year-old woman who had relapsed leukemia with a remission duration of 7 months, and she received re-induction with consolidation, allogeneic HSCT. After 4 days of engraftment, she had headache with fever and cerebrospinal fluid (CSF) analysis presented increased intracerebral pressure, white blood cell counts with dominant neutrophils, elevated glucose and protein level. Brain imaging showed diffuse leptomeningeal enhancement with scattered miliary TB lesions suggesting disseminated TB disease. Mycobacterium tuberculosis was detected in CSF and sputum anti-TB medication was started. She was IGRA positive before transplantation but did not receive treatment for LTBI prior or during the transplant. Unfortunately, she expired because of intracerebral hemorrhage. TB meningitis is a rare but important complication of HSCT as it can cause serious neurologic sequelae, even death. So in transplant recipients having high risk of TB reactivation, LTBI treatment is recommended before or along with transplantation. If latent TB is not treated, vigilant suspicion and early diagnosis of TB meningitis could improve the transplant outcome.

Association between body image dissatisfaction and poor quality of life and depression among patients with hematopoietic stem cell transplantation.

PURPOSE: This study aims to evaluate the association between body image dissatisfaction and quality of life and depression among patients after hematopoietic stem cell transplantation (HSCT). METHODS: We conducted a cross-sectional survey at three university-based HSCT outpatient clinics and the Korea Blood Cancer Association. We assessed the body image using the body image scale; quality of life and depression were measured using the World Health Organization Quality of Life-BREF and the Patient Health Questionnaire 9, respectively. Univariate and multivariate linear regression models were used to find an association between body image, quality of life, and depression. RESULTS: Among 163 study participants, 71.8% were male, and the mean age of the participants was 48.3 (SD = 11.2). Over 70% of the participants reported that they felt less physically and sexually attractive due to HSCT, and 39.3% of the patients were dissatisfied with their body image. In fully adjusted models, patients with dissatisfied body image had significantly poorer quality of life (- 13.68, 95% confidence interval [CI] = - 18.16, - 9.21). Moreover, patients with body image dissatisfaction were 8.59 times (95% CI = 3.79, 19.48) more likely to have depressive symptoms than patients without it. CONCLUSION: The majority of HSCT patients experienced body image dissatisfaction, which was significantly associated with poor quality of life and depression. It would be essential to evaluate body image after HSCT and provide appropriate interventions for preventing further psychological consequences.

Correlation between peripheral blood automated hematopoietic progenitor cell counts and flow cytometric CD34+ cell counts differs according to diagnosis in patients undergoing autologous peripheral blood stem cell transplantation.

BACKGROUND: An automated hematopoietic progenitor cell count measurement in Sysmex XN analyzer (XN-HPC) has been developed to assist flow cytometry CD34+ cell count measurement, which requires technical expertise and a long turnaround time. Here, we evaluated the correlation between XN-HPC count and flow cytometric CD34+ cell count in pre-harvest peripheral blood (PB) samples from patients undergoing autologous peripheral blood stem cell (PBSC) transplantation according to diagnosis and investigated the possible cause of the decreased correlation in plasma cell neoplasm patients. MATERIALS AND METHODS: We retrospectively included 399 patient data that had matched PB XN-HPC count and CD34+ cell count of PB and apheresis product from Samsung Medical Center (SMC) and the Hematopoietic Stem Cell (HSC) registry. We assessed the diagnostic accuracy and the potential cutoff values of XN-HPC count for predicting adequate PBSC collection. RESULTS: The PB XN-HPC count was 1.6 and 1.3-fold higher than the CD34+ cell count in SMC (25.0 vs 15.9/µl) and the HSC registry (20.0 vs 15.2/µl), respectively. Overall the correlation between the PB XN-HPC and CD34+ cell count was moderate (SMC, r = 0.71; HSC registry, r = 0.66). A significant proportional and systemic bias with overestimation of XN-HPC count were noted in the plasma cell neoplasm patients in both SMC and the HSC registry. However, no significant difference in correlation was observed according to myeloma-related laboratory parameters in plasma cell neoplasm patients. CONCLUSION: Our results suggest that XN-HPC count should be interpreted cautiously in cancer patients undergoing autologous PBSC transplantation, especially in those with plasma cell neoplasm.

Molecular characteristics of terminal deoxynucleotidyl transferase negative precursor B-cell phenotype Burkitt leukemia with IGH-MYC rearrangement.

Precursor B cell phenotype Burkitt lymphoma/leukemia with IGH-MYC is a rare subtype of Burkitt lymphoma (BL). BL and B lymphoblastic leukemia/lymphoma (B-ALL/LBL) differ as regards treatment and the distinction between these two entities is crucial. Patients demonstrating a terminal deoxynucleotidyl transferase (TdT)-positive precursor B cell phenotype with IGH-MYC rearrangement have been reported to be molecularly distinct from BL and closer to B-ALL/LBL. We investigated the molecular characteristics of two cases of a rare but distinct TdT-negative precursor B cell phenotype BL. Both patients showed FAB L3 morphology with IGH-MYC translocation, but had precursor B cell immunophenotypes including dim to moderate expression of CD45 and absence of BCL6, CD20, monoclonal kappa, and lambda light chain expression. To characterize the molecular features, we performed exome sequencing and analyzed the breakpoint junction of the IGH-MYC rearrangement. We detected KMT2D mutations in both cases, a rarely acquired chromatin modifying gene mutation in BL. The breakpoint analysis revealed that the IGH-MYC rearrangement occurred due to an aberrant VDJ recombination in one case. The treatment protocols differed, including high-grade lymphoma treatment and standard B-ALL treatment. Complete remission was achieved in the patient who received B-ALL treatment. The degree of resemblance of BL and B-ALL differed between two cases, but the molecular pathogenesis and manifesting features of both TdT-negative precursor B cell phenotype BL case were distinct from classic BL, which indicates the need for a better understanding of this uncommon entity that does not fit in current diagnostic and classification categories.

Efficacy of intravenous iron treatment for chemotherapy-induced anemia: A prospective Phase II pilot clinical trial in South Korea.

BACKGROUND: Anemia is the most common and serious cancer-related complication. This study aimed to evaluate the efficacy of administration of ferric carboxymaltose without erythropoiesis-stimulating agents for treating anemia in cancer patients. Moreover, we identified the biomarkers of hemoglobin response to predict the need for iron therapy. METHODS AND FINDINGS: We enrolled patients with solid cancers who were treated at a single institute (Samsung Medical Center, South Korea), from April 2015 to July 2017, in this prospective single-arm Phase II clinical trial. Patients received intravenous ferric carboxymaltose (1,000 mg) infusion on the first day (visit 1) of treatment. The primary end point was the number of hemoglobin responders, defined as patients with an increase in hemoglobin level ≥ 1.0 g/dL from the baseline, a hemoglobin level ≥ 11.0 g/dL, or both, within an 8-week observation period (week 3, 6, or 8). Secondary end points included changes in transferrin saturation and levels of soluble transferrin receptors, hepcidin, erythropoietin, interleukin-6, and C-reactive protein (CRP) at each visit. Of the 103 recruited patients, 92 were eligible for analysis. The mean patient age was 57.3 ± 12.5 years, and 54.3% of the patients were women. The most common diagnoses were breast cancer (n = 23, 25.1%), lung cancer (n = 21, 22.9%), gastrointestinal cancer (n = 20, 20.9%), and lymphoma (n = 16, 17.7%). A hemoglobin response was observed in 36 (39.1%), 53 (57.6%), and 61 (66.3%) patients in the third, fifth, and eighth weeks, respectively. The mean increase in hemoglobin levels from the baseline to the end of treatment was 1.77 ± 1.30 g/dL. Baseline values of hepcidin (p = 0.008), total iron binding capacity (p = 0.014), ferritin (p = 0.048), and CRP (p = 0.044) were significantly different between the responder and nonresponder groups. Multiple logistic regression analysis for baseline anemia-related biochemical variable significantly associated with the hemoglobin response showed that only baseline hepcidin level was a significant factor for hemoglobin response (odds ratio = 0.95, 95% confidence interval 0.90-1.0, p = 0.045). Hemoglobin responders had significantly lower hepcidin levels than nonresponders (mean [±standard deviation], 13.45 [±14.71] versus 35.22 [±40.470 ng/ml]; p = 0.007). However, our analysis had some limitations such as the different patient characteristics in the studies that were included, institutional differences in the measurement of hepcidin level, and missing data on long-term safety. Therefore, our findings need further validation. CONCLUSIONS: Intravenous ferric carboxymaltose (1,000 mg) monotherapy increases hemoglobin levels without serious adverse events in patients with cancer. Hepcidin is a useful biomarker for predicting iron requirement in cancer patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT02599012.

TARGET: a survey of real-world management of chronic myeloid leukaemia across 33 countries.

Despite the availability of guidelines for the management of chronic myeloid leukaemia (CML), various issues may prevent their successful implementation. The TARGET survey examined real-world management of CML patients compared with international recommendations. This online survey was completed in 2017. Results were discussed by a Steering Committee (SC) of eight international haematologists, challenges were identified and practical solutions developed. Of the 1008 haematologists invited (33 countries), 614 completed the survey. Gaps regarding treatment efficacy and molecular monitoring were identified. Half of the physicians did not perform three-monthly testing of during the initial 12 months of treatment, citing cost as the major barrier, although they know it should be done. Treatment-free remission was not considered a primary treatment goal or as a priority factor influencing treatment decisions. European Leukemia Net guidelines interpretation was generally acceptable, but awareness regarding management of persistent adverse events was poor. Practical solutions proposed by the SC were mostly focused on enhancing physician education and awareness, or encouraging hospitals to work with the government, in order to improve the quality of BCR-ABL testing. Gaps in current CML management were identified compared with international recommendations, which the proposed practical solutions would help to address.

Antifungal prophylaxis with posaconazole tablet and oral suspension in patients with haematologic malignancy: Therapeutic drug monitoring, efficacy and risk factors for the suboptimal level.

BACKGROUND: Posaconazole is used to prevent invasive fungal infections (IFIs) in patients with haematologic malignancy. In this study, we compared plasma posaconazole concentrations (PPCs) and the incidence of breakthrough IFIs between patients with haematologic malignancy receiving posaconazole oral suspension vs tablet. METHODS: We retrospectively collected data on adult patients with haematologic malignancies who received posaconazole prophylaxis during chemotherapy from April 2014 through May 2018. A total of 242 cases with PPCs, 88 in the oral suspension group and 154 in the tablet group, were included in this study. RESULTS: Patients receiving tablets achieved a significantly higher mean PPC than did those on oral suspension (1.631 ± 0.878 µg/mL in the tablet group vs. 0.879 ± 0.585 µg/mL in the oral suspension group). One hundred and thirty-seven of 154 patients (89.0%) receiving tablets had PPCs of 0.7 µg/mL or more, while only 41 of 88 patients (46.6%) receiving oral suspension attained an optimal level (P < .001). The incidence of breakthrough IFIs was significantly higher in the oral suspension group compared with in the tablet group (14.8% of oral suspension vs. 4.5% of tablet; P = .005). In the analysis including patients receiving posaconazole tablets, hypoalbuminemia (< 3.5 g/dL) was found to be a risk factor associated with suboptimal levels (odds ratio: 8.872; 95% confidence interval: 3.011 - 26.141; P < .001). CONCLUSIONS: Suboptimal PPCs in the tablet group were less common than those in the oral suspension group. Therapeutic drug monitoring may be still necessary even in patients receiving posaconazole tablets, especially in those with hypoalbuminemia.

Next-generation sequencing reveals unique combination of mutations in cis of CSF3R in atypical chronic myeloid leukemia.

BACKGROUND: Atypical chronic myeloid leukemia (aCML) is a hematologic disorder characterized by leukocytosis with increased dysplastic neutrophils and their precursors. In CSF3R gene, the activation mutation including T618I is frequently reported in aCML but is rarely accompanied by truncation mutations. Herein, we report a unique aCML patient with two CSF3R mutations (T618I and Y779*) in the same DNA strand. METHODS: High-coverage next-generation sequencing for 40 genes related with myeloid leukemia was performed. Sanger sequencing was performed to confirm CSF3R mutations. To confirm whether two CSF3R mutations are in cis or not, TA cloning was used. Clinical information and bone marrow pathology were reviewed by two hematopathologists. RESULTS: In the patient diagnosed with aCML in bone marrow study, two CSF3R mutations, (T618I and Y779*) a SETBP1 mutation (G870S) and an U2AF1 mutation (Q157P), were identified by high-coverage next-generation sequencing. The two CSF3R mutations were confirmed to be located in the same DNA strand by TA cloning, indicating that the two mutations are harbored in one malignant clone. The SETBP1 mutation is known to be related with poor prognosis in aCML. Likewise, the patient was refractory to hydroxyurea and showed disease progression. Additionally, we discussed the potential therapeutic targets by reviewing the molecular profile of the patient. CONCLUSION: We believe that the accurate diagnosis and maximum therapeutic chance could be achieved by profiling the mutations and their characteristics.

Chemical screening identifies ATM as a target for alleviating senescence.

Senescence, defined as irreversible cell-cycle arrest, is the main driving force of aging and age-related diseases. Here, we performed high-throughput screening to identify compounds that alleviate senescence and identified the ataxia telangiectasia mutated (ATM) inhibitor KU-60019 as an effective agent. To elucidate the mechanism underlying ATM's role in senescence, we performed a yeast two-hybrid screen and found that ATM interacted with the vacuolar ATPase V1 subunits ATP6V1E1 and ATP6V1G1. Specifically, ATM decreased E-G dimerization through direct phosphorylation of ATP6V1G1. Attenuation of ATM activity restored the dimerization, thus consequently facilitating assembly of the V1 and V0 domains with concomitant reacidification of the lysosome. In turn, this reacidification induced the functional recovery of the lysosome/autophagy system and was coupled with mitochondrial functional recovery and metabolic reprogramming. Together, our data reveal a new mechanism through which senescence is controlled by the lysosomal-mitochondrial axis, whose function is modulated by the fine-tuning of ATM activity.

Different prognostic effects of core-binding factor positive AML with Korean AML registry data.

Core-binding factor acute myeloid leukemia (CBF-AML) data in Asian countries has been rarely reported. We analyzed 392 patients with CBF-AML [281 with t(8;21), 111 with inv.(16)/t(16;16)] among data from 3041 patients with AML from the Korean AML Registry. Interestingly, del(9q) was less frequently detected in Korean than in German patients with t(8;21) (7.5% vs. 17%), and del(7q) was more frequently detected in Korean patients with inv(16). Overall survival (OS) was similar between patients in the first complete remission (CR) who received allogeneic (alloSCT) and autologous stem cell transplantation (ASCT) for CBF-AML. OS of t(8;21) patients was poor when undergoing alloSCT in second/third CR, while OS of inv(16) patients in second/third CR was similar to that in first CR. Patients with > 3-log reduction of RUNX1/RUNX1T1 qPCR had improved 3-year event-free survival (EFS) than those without (73.2% vs. 50.3%). Patients with t(8;21) AML with D816 mutation of the c-Kit gene showed inferior EFS and OS. These poor outcomes might be overcome by alloSCT. Multivariate analysis for OS in patients with t(8;21) revealed older age, > 1 course of induction chemotherapy to achieve CR, loss of sex chromosome, del(7q), and second/third CR or not in CR before SCT as independent prognostic variables. Especially, del(7q) is the most powerful prediction factor of poor outcomes, especially in patients with t(8;21) (hazard ratio, 27.23; P < 0.001). Further study is needed to clarify the clinical effect of cytogenetics and gene mutation in patients with CBF-AML, between Asian and Western countries.

Anti-leukemic effects of simvastatin on NRASG12D mutant acute myeloid leukemia cells.

The statins are a group of therapeutic drugs widely used for lowering plasma cholesterol level, while it has also been reported to induce cell death in human acute myeloid leukemia (AML) cells. To determine antitumor activity triggered by simvastatin, four AML cell lines-U937, KG1, THP1 (NRASG12D mutant) and HL60 (NRASQ61L mutant)-were cultured with simvastatin and cell viability was assessed using the CellTiter-Glo reagent. For understanding mechanism of antitumor activity, immunoblot analysis for pAkt (Ser473), Akt, pMEK, MEK, pERK (Thr202/Tyr204) and ERK (Thr202/Tyr204) was performed. Apoptotic cell population was calculated using the Annexin V-FITC assay, and cell cycle state was assessed by flow cytometry. Simvastatin showed different cytotoxic effect among AML cells, of which NRASG12D mutant THP1 was the most statin sensitive cell line (IC50 values: 1.96 uM in HL60, 7.87 uM in KG1, 0.83 uM in THP1 and 1.37 uM in U937). Western blot analysis revealed that Ras downstream signaling molecules including Akt, MEK, and ERK1/2 were markedly inhibited in THP1 cells compared to other AML cells when exposed to simvastatin. In addition, only in THP1 cells, increased apoptosis and cell cycle arrest by simvastatin was observed. The combination of simvastatin and MEK inhibitor AZD6244 synergistically reduced THP1 cell proliferation compared to simvastatin alone and AZD6244 alone (IC50 values: 0.88 uM in simvastatin, 0.32 uM in AZD6244, and 0.23 uM in combination of simvastatin and AZD6244). Simvastatin exhibited anti-leukemic effect in human AML cells in vitro, especially at NRASG12D mutant AML cell line.

Clonal dominance of a donor-derived del(20q) clone after allogeneic hematopoietic stem cell transplantation in an acute myeloid leukemia patient with del(20q).

Del(20q) is the most frequently detected large structural genetic mosaicism alteration in the healthy aging population, occurring in approximately 0.1% of older persons. Age-related clonal hematopoiesis of copy number variations (CNVs) is linked to an increased risk of hematologic malignancies, but the clinical impact of hematopoietic stem cells (HSCs) harboring such CNVs, such as del(20q), is not clearly understood. Here, we report an acute myeloid leukemia (AML) patient with known del(20q) who acquired donor-derived del(20q) after allogeneic hematopoietic stem cell transplantation (HSCT). The HSCs with del(20q) engrafted and expanded over time, but the patient did not clinically progress to myeloid neoplasm. Although donor-derived del(20q) from a healthy donor has been reported previously, our case is the first to review the clonal dynamics of a del(20q) clone and its post-transplantation impact. Since recurrent hematology neoplasm-associated CNVs, including del(20q), may not be rare among aged HSCT donors, identifying the origin of such a CNV is necessary for clinical decisions when clonal abnormality appears after HSCT, even in recipients who previously had the same abnormality.

Comparative Evaluation of QuantiFERON-TB Gold In-Tube and QuantiFERON-TB Gold Plus in Diagnosis of Latent Tuberculosis Infection in Immunocompromised Patients.

QuantiFERON-TB Gold Plus (QFT-Plus) is a new-generation QuantiFERON-TB Gold In-Tube (QFT-GIT) assay which has two antigen-coated tubes called TB1, which contains long peptides derived from ESAT-6 and CFP-10, and TB2, which contains the same components as TB1 and additional short peptides which potentially stimulate CD8+ T cells through the presentation of major histocompatibility complex class I. This is the first study to compare QFT-Plus and QFT-GIT for use in the diagnosis of latent tuberculosis infection (LTBI) among immunocompromised patients in the Republic of Korea. Among 317 consecutive patients who underwent screening for LTBI before solid organ or hematopoietic stem cell transplantation and tumor necrosis factor alpha inhibitor treatment, LTBI was identified in 92 (29.0%) and 88 (27.8%) patients by QFT-GIT and QFT-Plus, respectively. The rate of concordance between QFT-GIT and QFT-Plus was 93.7% (κ value, 0.860), and the indeterminate rate (3.2%) was similar between QFT-GIT and QFT-Plus. Of 20 (6.3%) samples with discordant results, 11 (55.0%) and 7 (35.0%) were positive by QFT-GIT alone and QFT-Plus alone, respectively, and 2 (15.0%) were indeterminate by each assay. The interferon gamma level in samples with discordant results ranged from 0.39 to 1.10 IU/ml, except for one sample, in which the gamma interferon level was 2.97 IU/ml only in TB2. Conclusively, there was a high degree of agreement between the results of QFT-GIT and QFT-Plus for the screening of immunocompromised patients for LTBI. The reactivity in TB2 contributed substantially to the difference between QFT-GIT and QFT-Plus, particularly in solid organ transplant candidates. The significance of the discrete responses in TB1 and TB2 of QFT-Plus needs to be explored further by means of an immunological and clinical approach in different patient groups and clinical settings.

Genome-wide genotype-based risk model for survival in core binding factor acute myeloid leukemia patients.

The present study attempted to build a single nucleotide polymorphism (SNP)-based risk model for predicting overall survival (OS) and event-free survival (EFS) in patients with core binding factor acute myeloid leukemia (CBF-AML). Adopting genome-wide SNP array using Affymetrix SNP array 6.0, we analyzed 868,157 SNPs with respect to OS and EFS in 104 patients with CBF-AML. Significant SNPs were identified from single SNP analysis. The risk model was constructed with incorporation of six SNPs and three clinical factors (age, c-kit exon 17 mutation, and LDH) for OS and six SNPs and three clinical factors (age, WBC, and LDH) for EFS. The model was further defined into low- and high-risk groups based on risk scores. The median age was 39 years, and the subgroup of t(8;21) and inv(16) or t(16;16) was assessed in 68 (65.4%) and 36 patients (34.6%). Finally, six SNPs per each OS (rs4353685, rs4908185, rs7709207, rs12034, rs1554844, and rs17241868) and EFS (rs13385610, rs11210617, rs11169282, rs7709207, rs4438401, and rs16894846) were incorporated into the risk model. OS was significantly different in favor of the low risk group (80.4 ± 8.4%) compared to the high-risk group (22.0 ± 7.3% at 3 years; p = 8.75 × 10- 13; HR 8.67). For EFS, there was also a significant difference between the low- (75.0 ± 5.8%) versus high-risk group (17.1 ± 6.3% at 3 years; p = 5.95 × 10- 13; HR 7.67). A genome-wide SNP-based risk model can stratify CBF-AML patients according to their OS and EFS in 104 patients.

Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia.

We investigated the effects of nilotinib plus multiagent chemotherapy, followed by consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with newly diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic leukemia (ALL). Study subjects received induction treatment that comprised concurrent vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for BCR-ABL1/G6PDH ratios ≤10(-3) and MR5 for ratios <10(-5). Ninety evaluable subjects, ages 17 to 71 years, were enrolled in 17 centers. The HCR rate was 91%; 57 subjects received allo-HCT. The cumulative MR5 rate was 94%; the 2-year hematologic relapse-free survival (HRFS) rate was 72% for 82 subjects that achieved HCR, and the 2-year overall survival rate was 72%. Subjects that failed to achieve MR3 or MR5 were 9.1 times (P = .004) or 6.3 times (P = .001) more prone to hematologic relapse, respectively, than those that achieved MR3 or MR5. MRD statuses just before allo-HCT and at 3 months after allo-HCT were predictive of 2-year HRFS. Adverse events occurred mainly during induction, and most were reversible with dose reduction or transient interruption of nilotinib. The combination of nilotinib with high-dose cytotoxic drugs was feasible, and it effectively achieved high cumulative complete molecular remission and HRFS rates. The MRD status at early postremission time was predictive of the HRFS. This trial was registered at www.clinicaltrials.gov as #NCT00844298.

DNMT3A R882 Mutation with FLT3-ITD Positivity Is an Extremely Poor Prognostic Factor in Patients with Normal-Karyotype Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation.

The prognostic relevance of epigenetic modifying genes (DNMT3A, TET2, and IDH1/2) in patients with acute myeloid leukemia (AML) has been investigated extensively. However, the prognostic implications of these mutations after allogeneic hematopoietic cell transplantation (HCT) have not been evaluated comprehensively in patients with normal-karyotype (NK)-AML. A total of 115 patients who received allogeneic HCT for NK-AML were retrospectively evaluated for the FLT3-ITD, NPM1, CEBPA, DNMT3A, TET2, IDH1/2, WT1, NRAS, ASXL2, FAT1, DNAH11, and GATA2 mutations in diagnostic samples and analyzed for long-term outcomes after allogeneic HCT. The prevalence rates for the mutations were as follows: FLT3-ITD positivity (FLT3-ITD(pos)) (32.2%), NPM1 mutation (43.5%), CEBPA mutation (double) (24.6%), DNMT3A mutation (DNMT3A(mut)) (31.3%), DNMT3A R882(mut) (18.3%), TET2 mutation (8.7%), and IDH1/2 mutation (16.5%). The 5-year overall survival (OS) and event-free survival (EFS) rates were 57.3% and 58.1%, respectively. A multivariate analysis revealed that FLT3-ITD(pos) (hazard ratio, [HR], 2.23; P = .006) and DNMT3A R882(mut) (HR, 2.74; P = .002) were unfavorable prognostic factors for OS. In addition, both mutations were significant risk factors for EFS and relapse. People with DNMT3A R882(mut) accompanied by FLT3-ITD(pos) had worse OS and EFS, and higher relapse rates than those with the other mutations, which were confirmed in a propensity score 1:2 matching analysis. These results suggest that DNMT3A R882(mut), particularly when accompanied by FLT3-ITD(pos), is a significant prognostic factor for inferior transplantation survival outcome by increasing relapse risk, even after allogeneic HCT.

Single nucleotide polymorphisms in apoptosis pathway are associated with response to imatinib therapy in chronic myeloid leukemia.

BACKGROUND: The mechanism of action of imatinib is known to involve the Fas-mediated apoptosis pathway. Consequently inter-individual variations in this apoptosis pathway might be associated with imatinib response or resistance. METHODS: This study attempted to focus on eight genotypes in the apoptosis pathway including FAS (rs1800682, rs2229521, rs2234767 and rs2234978), FASLG (rs763110), CASP10 (rs13006529), and APAF1 (rs1439123, rs2288713) and analyzed their association with treatment outcomes including molecular response with 4.5 log reduction (MR4.5), following imatinib therapy in 187 Korean CML patients. RESULTS: The GG/GA genotype in FAS (rs2234767) showed a higher rate of MR4.5 than the AA genotype (at 5 years 59.7 vs 37.4 %, p = 0.013). Using a bootstrap procedure for internal validation we confirmed that FAS (rs2234767) correlates with MR4.5 (p = 0.050). Multivariate analysis confirmed that the FAS genotype (rs2234767) is an independent surrogate for MR4.5 (p = 0.019, HR 0.43, 95 % CI [0.22-0.87]). CONCLUSIONS: The Fas/FasL signaling pathway may represent the major pathway that mediates apoptosis in CML treated with imatinib. SNP markers in the apoptosis pathway including FAS genotype (rs2234767) can be potential surrogates for predicting deeper molecular response after imatinib therapy.