Non-complete Remission Research Articles

Molecular characteristics of NPM1 mutations in AML patients using targeted NGS

ABSTRACT Background Acute myeloid leukemia (AML) is a clonal hematopoietic stem cell malignancy characterized by the accumulation of myeloid progenitor cells with arrested differentiation, leading to the suppression of normal hematopoiesis. The disease exhibits significant heterogeneity, with less than 30% five-year overall survival. Nucleophosmin 1 (NPM1) is the most commonly mutated gene in adult AML, found in approximately 25–35% of patients, and is recognized as a distinct subtype by the WHO. Methods The mutational status of NPM1 was assessed using the Oncomine Myeloid research panel on the Ion5S NGS platform (Thermo Fisher Scientific, USA). Results In our AML cohort, NPM1 was the most frequently mutated gene (75%). Indel mutations in the NPM1 gene, frequently resulting in frameshift consequences, show a statistically significant difference in variant allele frequency (VAF) compared to other mutation types. Specifically, NPM1-mutated cases exhibit a VAF that is positively correlated with initial bone marrow (BM) blast counts. Univariate logistic regression analysis reveals that a high VAF is significantly associated with non-complete remission (Non-CR), while a low VAF is significantly associated with complete remission (CR), indicating a statistically significant difference in outcomes (p = 0.012). Conclusion Targeted NGS technology enables the simultaneous analysis of multiple AML-relevant genes, offering a comprehensive mutational profile that supports risk stratification, diagnosis, and personalized treatment. Our findings highlight the significant impact of NPM1 mutations on patient outcomes, revealing their molecular characteristics and their correlation with different clinical parameters.

Immunological profiling for short-term predictive analysis in PD-1/PD-L1 therapy for lung cancer

BackgroundImmune checkpoint inhibitors, such as anti-programmed cell death-1 (PD-1) and PD-1 ligand-1 (PD-L1) antibodies, have achieved breakthrough results in improving long-term survival rates in lung cancer. Although high levels of PD-L1 expression and tumor mutational burden have emerged as pivotal biomarkers, not all patients derive lasting benefits, and resistance to immune checkpoint blockade remains a prevalent issue. Comprehending the immunological intricacies of lung cancer is crucial for uncovering the mechanisms that govern responses and resistance to immunomodulatory treatments. This study aimed to explore the potential of peripheral immune markers in predicting treatment efficiency among lung cancer patients undergoing PD-1/PD-L1 checkpoint inhibitors.MethodsThis study enrolled 71 lung cancer patients undergoing PD-1/PD-L1 inhibitor therapy and 20 healthy controls. Immune cell subsets (CD4 + T cells, CD8 + T cells, B cells, NK cells, and NKT cells), phenotypic analysis of T cells and B cells, and PMA/Ionomycin-stimulated lymphocyte function assay were conducted.ResultsLung cancer patients exhibited significant alterations in immune cell subsets, notably an increased percentage of Treg cells. Post-treatment, there were substantial increases in absolute numbers of CD3 + T cells, CD8 + T cells, and NKT cells, along with heightened HLA-DR expression on CD3 + T and CD8 + T cells. Comparison between complete remission and non-complete remission (NCR) groups showed higher Treg cell percentages and HLA-DR + CD4 + T cells in the NCR group.ConclusionThe study findings suggest potential predictive roles for immune cell subsets and phenotypes, particularly Treg cells, HLA-DR + CD4 + T cells, and naïve CD4 + T cells, in evaluating short-term PD-1/PD-L1 therapy efficacy for lung cancer patients. These insights offer valuable prospects for personalized treatment strategies and underscore the importance of immune profiling in lung cancer immunotherapy.

Biological relapse in multiple myeloma: Outcome and treatment strategies in a Spanish real-world setting.

Recommendations regarding the best time to start treatment in patients with relapsed/refractory multiple myeloma (RRMM) after biological relapse/progression (BR) are unclear. This observational, prospective, multicenter registry aimed to evaluate the impact on time to progression (TTP) of treatment initiation at BR versus at symptomatic clinical relapse (ClinR) based on the Spanish routine practice in adult patients with RRMM. Patients had two or less previous treatment lines and at least one previous partial response. Baseline characteristics and treatment outcomes were recorded, and survival was analyzed. Of 225 patients, 110 were treated at BR (TxBR group) and 115 at ClinR (TxClinR group) according to the investigators'criteria. The proportion of patients with higher ECOG, previous noncomplete remission (CR), and second relapse were significantly higher in the TxBR group compared to the TxClinR group. TheTxClinR group showed improved outcomes, including TTP, compared to the TxBR group. Progression-free survival increased in the TxClinR group (56.2 months) compared to the TxBR group (32.5 months) (p = 0.0137), and median overall survival also increased (p = 0.0897). Median TTP was significantly longer in patients relapsing from a CR (50.4 months) and in their first relapse (38.7 months) compared to those relapsing from a non-CR response (32.9 months) and in their second relapse (25.2 months). Physicians seemed to start treatment earlier in RRMM patients with poor prognosis features. Previous responses to anti-MM treatment and the number of prior treatment lines were identified as prognosis factors, whereby relapse from CR and first relapse were associated with a longer time to progression.

Impact of cladribine, cytarabine, and G-CSF (CLAG) as a bridging therapy prior to allogeneic hematopoietic stem cell transplantation in relapsed or refractory acute myeloid leukemia.

The combination of cladribine, cytarabine, and G-CSF (CLAG) has exhibited robust synergistic anti-leukemia activity as an induction therapy (IT) in acute myeloid leukemia (AML). However, the impact of CLAG as a bridging therapy (BT) administered between IT and allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with relapsed or refractory (R/R) AML remains uncertain. In this retrospective study, we examined the efficacy of CLAG as a transitional strategy prior to allo-HSCT in R/R AML. We included 234 patients with R/R AML who received the modified busulfan plus cyclophosphamide conditioning regimen for allo-HSCT in our center during the past 6years, performed a propensity-score matching analysis, partitioned them into four distinct cohorts, and further integrated them into the CLAG group and non-CLAG group based on response to IT and utilization of CLAG. Our cohorts encompassed 12 patients in Cohort A (modified composite complete remission (mCRc) after IT, CLAG), 31 in Cohort B (mCRc after IT, non-CLAG), 35 in Cohort C (non-complete remission (non-CR) after IT, CLAG), and 80 in Cohort D (non-CR after IT, non-CLAG). Intriguingly, among patients with non-CR status, the administration of CLAG correlated with a notably statistically diminished risk of relapse and improved survival at 2-year follow-up (Cohort C vs. Cohort D). Employing CLAG as a BT prior to allo-HSCT demonstrates substantial effectiveness, a relative degree of safety, and manageable toxicity in selected R/R AML cases.

Haploidentical and matched unrelated donor allogeneic hematopoietic stem cell transplantation offer similar survival outcomes for acute leukemia.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has emerged as an effective approach for acute leukemia, primarily due to the inherent difficulty in finding human leukocyte antigen-matched unrelated donors (MUD). Nevertheless, it remains uncertain whether haplo-HSCT and MUD-HSCT can provide comparable outcomes in patients with acute leukemia. This study aimed to assess the overall survival (OS) and leukemia-free survival (LFS) outcomes between the MUD-HSCT and haplo-HSCT groups. This retrospective analysis encompassed adult patients with acute leukemia undergoing the initial allo-HSCT. Among these 85 patients, we stratified 33 patients into the MUD-HSCT group and 52 to the haplo-HSCT group. The primary outcomes were OS and LFS. The median OS was not reached in the haplo-HSCT group, while it reached 29.8 months in patients undergoing MUD-HSCT (p = .211). Likewise, the median LFS periods were 52.6 months in the haplo-HSCT group and 12.7 months in the MUD-HSCT group (p = .212). Importantly, neither the OS nor LFS showed substantial differences between the MUD-HSCT and haplo-HSCT groups. Furthermore, univariate analyses revealed that haplo-HSCT did not demonstrate a significantly higher risk of worse LFS (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.25; p = .216) or OS (HR, 0.67; 95% CI, 0.36-1.26; p = .214) than MUD-HSCT. Notably, a high European Group for Blood and Marrow Transplantation risk score (HR, 1.44; 95% CI, 1.10-1.87; p = .007) and non-complete remission (HR, 2.48; 95% CI, 1.17-5.23; p = .017) were significantly correlated with worse OS. Haplo-HSCT may serve as an alternative to MUD-HSCT for the treatment of acute leukemia, offering similar survival outcomes.

Impact of myelofibrosis on patients with myelodysplastic syndromes following allogeneic hematopoietic stem cell transplantation

BackgroundThe prognostic significance of myelofibrosis (MF) grade in patients with myelodysplastic syndrome (MDS) following an allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains elusive.MethodsWe retrospectively analyzed data from 153 patients with MDS who underwent allo-HSCT and divided the patients into the MF-0/1 (N = 119) and MF-2/3 (N = 34) cohorts to explore the impact of MF on outcomes of allo-HSCT.ResultsThe 2-year rates of relapse, non-relapse mortality (NRM), overall survival (OS), and progression-free survival (PFS) were 10.9% (95% confidence interval [CI] 5.9%–17.7%), 16.3% (95% CI 10.2%–23.6%), 76.6% (95% CI 69.0%–85.1%), and 72.8% (95% CI 65.0%–81.5%) in the MF-0/1 cohort, and 16.9% (95% CI 5.8%–32.9%), 14.7% (95% CI 5.3%–28.7%), 71.8% (95% CI 57.6%–89.6%), and 68.4% (95% CI 53.6%–87.2%) in the MF-2/3 cohort, respectively. No significant difference in the outcomes of allo-HSCT was observed between the two cohorts. Both univariate and multivariate analyses confirmed that MF-2/3 in patients with MDS had no effect on the prognosis of transplantation. In addition, major/bidirectional ABO blood type between donors and recipients was an independent risk factor for OS (hazard ratio [HR], 2.55; 95% CI 1.25–5.21; P = 0.010) and PFS (HR, 2.21; 95% CI 1.10–4.42; P = 0.025) in the multivariate analysis. In the subgroup of patients diagnosed with MDS with increased blasts (MDS-IB), it was consistently demonstrated that the clinical outcomes of the MF-2/3 cohort were comparable with those of the MF-0/1 cohort. The risk factors for OS and PFS in patients with MDS-IB were non-complete remission at transplantation and major/bidirectional ABO blood type.ConclusionsIn conclusion, MF grade had no significant effect on prognosis of allo-HSCT in patients diagnosed with MDS. Major/bidirectional ABO blood type should be carefully considered in the context of more than one available donor.

Prognostic factors in haploidentical transplantation with post-transplant cyclophosphamide for acute myeloid leukemia

Background aimsHaploidentical hematopoietic stem cell transplantation (haplo‐HCT) is an appropriate option when an HLA-matched related or unrelated donor is not available. Haplo-HCT using post-transplant cyclophosphamide (PTCy) is being increasingly performed worldwide due to its effective suppression of GVHD and its safety. MethodsWe conducted a large nationwide cohort study to retrospectively analyze 366 patients with acute myeloid leukemia undergoing haplo‐HCT with PTCy between 2010 and 2019 and to identify prognostic factors. ResultsA multivariate Cox analysis revealed that an older recipient age (≥60 years), a male donor to a male recipient, a cytomegalovirus IgG-negative donor to a cytomegalovirus IgG-positive recipient, a poor cytogenetic risk, a noncomplete remission status at the time of transplantation, and a history of HCT were independently associated with worse overall survival (OS). Based on each hazard ratio, these factors were scored (1–2 points) and stratified by their total score into three groups: favorable (0–1 points), intermediate (2–3 points), and poor (4 points or more) groups, and 2-year OS rates were 79.9%, 49.2%, and 25.1%, respectively (P < 0.001). ConclusionsThe present study revealed significant prognostic factors in haplo‐HCT with PTCy, and a scoring system based on these factors may be used to predict outcomes.

Urinary exosomal miRNA-451a can be used as a potential noninvasive biomarker for diagnosis, reflecting tubulointerstitial damage and therapeutic response in IgA nephropathy

To investigate the potential clinical value of urinary exosomal (uE) miR-451a as a biomarker for IgAN, urinary exosomes were isolated from 40 patients with IgAN, 30 patients with primary renal diseases without IgA as disease controls (non-IgAN group) and 21 healthy controls (HCs). The expression of miR-451a within exosomes was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). uE miR-451a was significantly upregulated in patients with IgAN compared to non-IgAN and HCs. The uE miR-451a level was positively correlated with the change in eGFR and negatively correlated with serum creatinine, urinary macrophage migration inhibitory factor (MIF), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α). A dual-luciferase reporter assay confirmed that MIF was a direct target of miR-451a. Receiver operating characteristic (ROC) curve analysis revealed that the expression of uE miR-451a showed potential diagnostic value for IgAN. Additionally, the uE miR-451a level could distinguish patients with IgAN with mild tubular atrophy/interstitial fibrosis from those with severe tubular atrophy/interstitial fibrosis. After a mean follow-up of 14.2 months, the levels of eGFR loss (ml/min/1.73 m2/year) were negatively correlated with baseline miR-451a. The levels of baseline miR-451a in the complete remission group were significantly higher than those in the non-complete remission group. uE miR-451a expression was significantly elevated in patients with IgA nephropathy and may serve as a potential biomarker for the diagnosis of IgAN and evaluation of tubulointerstitial damage, while the baseline levels of uE miR-451a may be predictors of therapeutic efficacy and disease progression.

Prognostic significance of multiparametric flow cytometry minimal residual disease at two time points after induction in pediatric acute myeloid leukemia

BackgroundPrompt response to induction chemotherapy is a prognostic factor in pediatric acute myeloid leukemia. In this study, we aimed to evaluate the prognostic significance of multiparametric flow cytometry-minimal residual disease (MFC-MRD), assessed at the end of the first and second induction courses.MethodsMFC-MRD was performed at the end of the first induction (TP1) in 524 patients and second induction (TP2) in 467 patients who were treated according to the modified Medical Research Council (UK) acute myeloid leukemia 15 protocol.ResultsUsing a 0.1% cutoff level, patients with MFC-MRD at the two time points had lower event-free survival and overall survival. Only the TP2 MFC-MRD level could predict the outcome in a separate analysis of high and intermediate risks based on European LeukemiaNet risk stratification and KMT2A rearrangement. The TP2 MFC-MRD level could further differentiate the prognosis of patients into complete remission or non-complete remission based on morphological evaluation. Multivariate analysis indicated the TP2 MFC-MRD level as an independent adverse prognostic factor for event-free survival and overall survival. When comparing patients with MFC-MRD ≥ 0.1%, those who underwent hematopoietic stem cell transplant during the first complete remission had significantly higher 5-year event-free survival and overall survival and lower cumulative incidence of relapse than those who only received consolidation chemotherapy.ConclusionsThe TP2 MFC-MRD level can predict the outcomes in pediatric patients with acute myeloid leukemia and help stratify post-remission treatment.

Efficacy of Adding Locoregional Therapy in Non-Complete Remission Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab: A Preliminary Study.

Atezolizumab plus bevacizumab (Atez/Bev) therapy is extremely effective and has a high response rate in hepatocellular carcinoma (HCC) treatment. This study investigated the efficacy of adding locoregional therapy with Atez/Bev for non-complete response (CR) HCC cases. Twenty-eight HCC patients without CR during Atez/Bev therapy received locoregional therapy, and treatment efficacy was evaluated based on the modified RECIST criteria. The study included 23 male and five female participants with a mean age of 73.5 years. In the Atez/Bev and locoregional combination therapy effective group, both transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) were combined in all patients. A significant reduction in neutrophil-to-lymphocyte ratio (NLR) was observed after adding locoregional therapy (p=0.039). Moreover, a combination of TACE and RFA was performed in all patients of the CR group. When assessing the add-on effect of the combination of TACE and RFA in the progressive disease (PD) group, seven patients were found to achieve non-PD. For patients who did not achieve PD, a significant NLR reduction was noted after the addition of locoregional therapy. Adding locoregional therapy such as TACE/RFA was found to exert an effect even in non-CR patients who had received Atez/Bev therapy. A reduction in NLR after locoregional therapy was noted. Even when a response is not obtained during Atez/Bev therapy, it is important to avail the option to add locoregional therapy, as it may contribute to improved prognosis via immune modulation with tolerable adverse reactions.

Analysis of risk factors for fatal renal complications after allogeneic hematopoietic cell transplantation.

Various complications can influence hematopoietic cell transplantation (HCT) outcomes. Renal complications can occur during the early to late phases of HCT along with various factors. However, studies focusing on fatal renal complications (FRCs) are scarce. Herein, we analyzed 36,596 first allogeneic HCT recipients retrospectively. Overall, 782 patients died of FRCs at a median of 108 (range, 0-3,440) days after HCT. The cumulative incidence of FRCs was 1.7% and 2.2% at one and five years, respectively. FRCs were associated with older age, male sex, non-complete remission (non-CR), lower performance status (PS), and HCT comorbidity index (HCT-CI) associated with renal comorbidity in multivariate analysis. The risk factors within 100 days included older age, multiple myeloma, PS, and HCT-CI comorbidities (psychiatric disturbance, hepatic disease, obesity, and renal disease). Older age and male sex were risk factors between 100 days and one year. After one year, HCT-CI was associated with the presence of diabetes and prior solid tumor; total body irradiation was identified as a risk factor. Non-CR was a common risk factor in all three phases. Furthermore, acute and chronic graft-versus-host disease, reactivation of cytomegalovirus, and relapse of underlying disease also affected FRCs. Systematic follow-up may be necessary based on the patients' risk factors and post-HCT events.

Analysis of the feasibility and prognostic value of circulating tumor DNA monitoring in detecting gene mutations in patients with diffuse large B-cell lymphoma receiving chimeric antigen receptor T-cell therapy

Objective: To explore the prognostic value of circulating tumor DNA (ctDNA) testing in patients with refractory/relapsed diffuse large B-cell lymphoma (R/R DLBCL) undergoing chimeric antigen receptor T-cell (CAR-T) therapy, and to guide the prevention and subsequent treatment of CAR-T-cell therapy failure. Methods: In this study, 48 patients with R/R DLBCL who received CAR-T-cell therapy at the First Affiliated Hospital of Zhejiang University School of Medicine between December 2017 and March 2022 were included. Furthermore, ctDNA testing of 187 lymphoma-related gene sets was performed on peripheral blood samples obtained before treatment. The patients were divided into complete remission and noncomplete remission groups. The chi-square test and t-test were used to compare group differences, and the Log-rank test was used to compare the differences in survival. Results: Among the patients who did not achieve complete remission after CAR-T-cell therapy for R/R DLBCL, the top ten genes with the highest mutation frequencies were TP53 (41%), TTN (36%), BCR (27%), KMT2D (27%), IGLL5 (23%), KMT2C (23%), MYD88 (23%), BTG2 (18%), MUC16 (18%), and SGK1 (18%). Kaplan-Meier survival analysis revealed that patients with ctDNA mutation genes >10 had poorer overall survival (OS) rate (1-year OS rate: 0 vs 73.8%, P<0.001) and progression-free survival (PFS) rate (1-year PFS rate: 0 vs 51.8%, P=0.011) compared with patients with ctDNA mutation genes ≤10. Moreover, patients with MUC16 mutation positivity before treatment had better OS (2-year OS rate: 56.8% vs 26.7%, P=0.046), whereas patients with BTG2 mutation positivity had poorer OS (1-year OS rate: 0 vs 72.5%, P=0.005) . Conclusion: ctDNA detection can serve as a tool for evaluating the efficacy of CAR-T-cell therapy in patients with R/R DLBCL. The pretreatment gene mutation burden, mutations in MUC16 and BTG2 have potential prognostic value.

UBTF-internal tandem duplication as a novel poor prognostic factor in pediatric acute myeloid leukemia.

The prognosis of pediatric acute myeloid leukemia (AML) has improved via stratification therapy. However, relapse or death occurs in 30%-40% of cases. Novel genetic factors for pediatric AML need to be elucidated to improve prognosis. We detected recurrent internal tandem duplication in upstream binding transcription factor (UBTF-ITD) in 1.2% (6/503) of Japanese pediatric patients with de novo AML. No UBTF-ITD was detected in 175 adult patients with AML or in 65 cell lines that included 15 AML, 39 acute lymphoblastic leukemia, five chronic myeloid leukemia, and six neuroblastoma cell lines. All UBTF-ITDs were found in exon 13 and shared a duplicated region. UBTF-ITD was more frequently detected in patients with trisomy 8, FLT3-ITD, WT1 mutation, and/or high PRDM16 expression (trisomy 8, 3/6; FLT3-ITD, 5/6; WT1 mutation, 2/6; and high PRDM16 expression, 6/6). Gene expression patterns of patients with UBTF-ITD were similar to those of patients with NUP98::NSD1 or FUS::ERG. Survival analysis of the AML-05 cohort revealed that patients with UBTF-ITD had worse outcomes than those without UBTF-ITD (3-year event-free survival, 20% vs. 55%; 3-year overall survival, 40% vs. 74%). Moreover, among the 27 patients with trisomy 8, all three patients with UBTF -ITD had a poor prognosis resulting in early events (relapse or non-complete remission) within 1 year. Our findings suggest that UBTF-ITD may be a novel and significant prognostic factor for pediatric patients with AML.

RISK FACTORS FOR DEVELOPING PNEUMONIA IN PATIENTS WITH ACUTE LEUKEMIA RECEIVING CHEMOTHERAPY

Background: Pneumonia is one of the serious complications during chemotherapy for acute leukemia. The purpose of this study was to determine the incidence rate, clinical characteristics, and risk factors for pneumonia in patients with acute leukemia after chemotherapy. Methods: Two hundred and nine patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) were enrolled in the cohort study, in which 138 patients received chemotherapy, 71 patients had previous pneumonia, so chemotherapy should be delayed. Results: Of the 138 patients who received chemotherapy, 40 patients (29%) developed pneumonia after chemotherapy. Post-chemotherapy pneumonia patients were less likely to have dypsnea, respiratory failure, and severity than those of previous pneumonia patients with P= 0.002, 0.004, and 0.012; respectively. Female patient, non-complete remission (CR) status (include: state of not reaching CR before or previous not received chemotherapy), neutrophil count delay below 0.5 G /L for 7 days, were risk factors for developing pneumonia after chemotherapy with P= 0.036, 0.002 and 0.005; respectively. Conclusions: Pneumonia after chemotherapy for acute leukemia was common. Female patients, non-CR status (include: state of not reaching CR before or previous not received chemotherapy), a delay in neutrophil count below 0.5G /L for 7 days, were high- risk factors of developing pneumonia after chemotherapy.

Early changes in gene expression profiles in AML patients during induction chemotherapy

BackgroundElucidation of the genetic mechanisms underlying treatment response to standard induction chemotherapy in AML patients is warranted, in order to aid in risk-adapted treatment decisions as novel treatments are emerging. In this pilot study, we explored the treatment-induced expression patterns in a small cohort of AML patients by analyzing differential gene expression (DGE) over the first 2 days of induction chemotherapy.MethodsBlood samples were collected from ten AML patients at baseline (before treatment initiation) and during the first 2 days of treatment (Day 1; approximately 24 h, and Day 2; approximately 48 h after treatment initiation, respectively) and RNA was extracted for subsequent RNA sequencing. DGE between time points were assessed by pairwise analysis using the R package edgeR version 3.18.1 in all patients as well as in relation to treatment response (complete remission, CR, vs non-complete remission, nCR). Ingenuity Pathway Analysis (Qiagen) software was used for pathway analysis and visualization.ResultsAfter initial data quality control, two patients were excluded from further analysis, resulting in a final cohort of eight patients with data from all three timepoints. DGE analysis demonstrated activation of pathways with genes directly or indirectly associated with NF-κB signaling. Significant activation of the NF-κB pathway was seen in 50% of the patients 2 days after treatment start, while iNOS pathway effects could be identified already after 1 day. nCR patients displayed activation of pathways associated with cell cycle progression, oncogenesis and anti-apoptotic behavior, including the STAT3 pathway and Salvage pathways of pyrimidine ribonucleotides. Notably, a significant induction of cytidine deaminase, an enzyme responsible for the deamination of Ara-C, could be observed between baseline and Day 2 in the nCR patients but not in patients achieving CR.ConclusionsIn conclusion, we show that time-course analysis of gene expression represents a feasible approach to identify relevant pathways affected by standard induction chemotherapy in AML patients. This poses as a potential method for elucidating new drug targets and biomarkers for categorizing disease aggressiveness and evaluating treatment response. However, more studies on larger cohorts are warranted to elucidate the transcriptional basis for drug response.

Nomograms to predict progression of disease within 24 months in patients with localized natural killer/T-cell lymphoma

Aims: Progression of disease within24 months (POD24) is associated with poor survival in some subtypes of lymphoma.The aim is to identify high-risk patients with localized extranodal natural killer/T-cell lymphoma (ENKTL) and to define clinical factors associated with the risk of early recurrence after antitumor treatment. Methods: The authors retrospectively analyzed 330 cases with localized ENKTL, of which 89 experienced POD24. Results: The 5-year overall survival of the POD24 group was extremely inferior to that of the non-POD24 group. Risk factors for POD24 were Eastern Cooperative Oncology Group performance status ≥2, response evaluation (non-complete remission) after first-line treatment and elevated lactate dehydrogenase concentrations. Also, higher Epstein-Barr virus DNA titer was related to POD24. Based on these data with or without the availability of Epstein-Barr virus DNA, the authors conducted two nomograms to predict POD24, which showed good accuracy with high C statistics. Conclusion: The results showed that POD24 could serve as a marker to identify patients whose medical needs were unmet in ENKTL.

Cytomegalovirus infection in patients with malignant lymphomas who have not received hematopoietic stem cell transplantation

BackgroundLife-threatening cytomegalovirus infection (CMVI) has been reported even in patients with malignant lymphoma (ML) who have not received hematopoietic stem cell transplantation (w/o HSCT) but had been treated with chemotherapy or radiotherapy. However, the CMVI incidence and risk factors (RFs) in patients with ML w/o HSCT have not been fully elucidated. This study aimed to evaluate the clinical aspects, including incidence and RFs, of CMVI in patients with ML w/o HSCT.MethodsWe retrospectively reviewed all patients with ML who received chemotherapy or radiotherapy in our department from 2005 to 2013. The overall survival (OS), incidence and RFs of CMVI, and other characteristics of patients with CMVI were analyzed.ResultsOverall, 236 patients with ML w/o HSCT were evaluated. Of these, 5.5% (13/236) developed CMVI; 54% (7/13) received steroid pretreatment before primary therapy (PT) for ML; and 62% (8/13) received > 2 therapeutic regimens for ML. The OS curve of patients with CMVI was significantly worse than that of patients without CMVI (p < 0.0001, log-rank test). A univariate analysis identified B symptoms (p = 0.00321), serum albumin < 3.5 g/dL (p = 0.0007837), C-reactive protein level > the upper limit of normal (p = 0.0006962), steroid pretreatment before PT for ML (p = 0.0004262), > 2 therapeutic regimens for ML (p = 0.0000818), T cell lymphoma (p = 0.006406), and non-complete remission (p = 0.02311) as RFs for CMVI. A multivariate analysis identified steroid pretreatment before PT for ML [odds ratio (OR): 4.71 (95% confidence interval [CI]: 1.06–21.0); p = 0.0419] and > 2 therapeutic regimens for ML [OR: 9.25 (95% CI: 2.33–36.8); p = 0.00159] as independent RFs for CMVI in patients with ML w/o HSCT.ConclusionsAttention should be paid to CMVI development in patients with ML w/o HSCT pretreated with steroids or who had multiple therapeutic regimens.

Clinical significance of circulating neutrophils and lymphocyte subsets in newly diagnosed patients with diffuse large B-cell lymphoma.

Lymphocytes play crucial roles in tumor surveillance in diffuse large B-cell lymphoma (DLBCL). Neutrophil-to-lymphocyte ratio (NLR), a biomarker for systematic inflammation, has been confirmed to be a prognostic factor for many malignant diseases. Herein, we conducted a systemic in-depth study of circulating neutrophils and lymphocyte subsets in DLBCL patients and their dynamics along with chemoimmunotherapy. A total of 61 patients with DLBCL were enrolled. Detection of lymphocyte subsets by flow cytometry was conducted at diagnosis and after 2/4/6/8 cycles' treatment of R-CHOP. Clinical significance, including incidence of infection, curative effect and disease-free survival (DFS), was analyzed based on the patients' clinical data and the quantity of lymphocyte subsets. The absolute numbers of neutrophils in stage III-IV DLBCL patients were obviously increased (p = 0.012), while the absolute numbers of lymphocytes were decreased (p = 0.025). Consequently, DLBCL patients had significantly higher NLR than healthy controls (p < 0.001). Further analysis of lymphocyte subsets showed a significantly reduced CD4 + T cells in DLBCL patients (p = 0.001). Patients with a lower lymphocyte counts (< 1.26*10E9/L) were more susceptible to infection (p < 0.001). NK cells were much higher in patients achieving complete remission than those of non-complete remission (p = 0.032). Higher neutrophils and NLR were closely associated with poorer DFS (p = 0.001 and p = 0.045, respectively). Circulating cells in DLBCL patients were dysregulated, featured with increased neutrophils and reduced lymphocytes. Higher NK cells before treatment predicted better therapeutic outcome. Higher neutrophils and NLR can be regarded as inferior prognostic predictors for DLBCL patients at diagnosis.

Favorable Outcome with Conditioning Regimen of Flu/Bu4/Mel in Acute Myeloid Leukemia Patients in Remission Undergoing Cord Blood Transplantation

Cord blood transplantation (CBT) is a curative therapeutic option for patients with acute myeloid leukemia (AML) who do not have an HLA-matched donor. The decline in early nonrelapse mortality (NRM) after CBT has significantly improved overall survival (OS) during the past 20 years because of advances in CBT practices, including more careful patient selection, use of safer conditioning regimens, better cord blood unit selection, and improved supportive care. A previous study reported a conditioning regimen comprising fludarabine, busulfan, and melphalan (Flu/Bu4/Mel) developed for patients undergoing CBT in non-complete remission (CR) myeloid malignancies that showed durable engraftment and remission with acceptable nonrelapse mortality (NRM), leading to excellent survival outcomes. However, no prior study has focused on the role of Flu/Bu4/Mel in CBT conditioning and compared it with conventional myeloablative conditioning (MAC) for AML patients in CR. We aimed to investigate the efficacy and safety of Flu/Bu4/Mel compared with cyclophosphamide and total body irradiation (CY/TBI)-based MAC for AML patients in CR who underwent CBT. Patients were selected from the Japanese nationwide transplantation registry according to the following inclusion criteria: (1) patients with AML aged ≥16 years, (2) first single-unit CBT, and (3) CR at the time of transplantation. Of 477 eligible patients, 148 (31.0%) received CY/TBI, 223 (46.8%) received high-dose cytarabine (HDCA)/CY/TBI, and 106 (22.2%) received Flu/Bu4/Mel. The probability of OS at 3 years was 64.8% (95% confidence interval [CI], 56.0% to 72.3%) in the CY/TBI group, 65.1% (95% CI, 57.8% to 71.4%) in the HDCA/CY/TBI group, and 65.5% (95% CI, 53.7% to 74.9%) in the Flu/Bu4/Mel group (P=.71); the cumulative incidence of relapse at 3 years was 22.0% (95% CI, 15.2% to 29.5%), 17.2% (95% CI, 12.2% to 22.9%), and 18.0% (95% CI, 11.2% to 26.2%), respectively (P=.40); and the cumulative incidence of NRM at 3 years was 17.2% (95% CI, 11.5% to 24.0%), 20.7% (95% CI, 15.4% to 26.7%), and 18.6% (95% CI, 11.4% to 27.2%), respectively (P=.95). Multivariate analysis identified Flu/Bu4/Mel as a favorable factor for OS; however, it was not significantly favorable for relapse and NRM in the CY/TBI, HDCA/CY/TBI, and Flu/Bu4/Mel groups (hazard ratio [HR], .50 [95% CI, .29-.88], P=.015; .67 [95% CI, .31-1.46], P=.31; and .55 [95% CI, .26-1.18], respectively; P=.12). Flu/Bu4/Mel was a favorable factor for neutrophil engraftment (HR, 1.51; 95% CI, 1.08 to 2.12; P=.016). Multivariate analysis showed that Flu/Bu4/Mel had a favorable prognostic impact on OS and neutrophil engraftment despite the non-TBI regimen. Our findings suggest that Flu/Bu4/Mel may sustain the antileukemia effect with decreasing NRM and could be a favorable CBT conditioning regimen for patients with AML in CR.

Clinicopathologic Characteristics Associated with Prognosis in Ocular Extranodal Marginal Zone B Cell Lymphoma.

Background and Objectives: Extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT) type is the most common subtype of the ocular adnexal lymphoma. Despite its excellent prognosis, some patients experience partial remission or progressive disease. We aimed to evaluate clinicopathologic differences in the treatment responder group by comparing complete remission (CR) and non-complete remission (non-CR). Materials and Methods: This study retrospectively reviewed 48 patients who were diagnosed with ocular adnexal MALT lymphoma at Ulsan University Hospital between March 2002 and August 2018. Patients who were followed up for less than 6 months were excluded. Histologic and clinical features were analyzed. The patients were divided into two groups: CR and non-CR. Results: Among the 48 patients, 33 achieved CR and 15 achieved non-CR during the median follow-up period of 40.00 months (range, 7–109 months). In univariable analysis, more patients tend to undergo treatment in the CR group, and post-radiotherapy (post-RT) SUVmax, PET and serum lactate dehydrogenase (LDH) levels were higher in the non-CR group (p = 0.043, p = 0.016, and p = 0.042, respectively). In a multivariable analysis, only application of treatment, including radiotherapy or chemotherapy with immunotherapy, was related to CR (odd ratio 7.301, 95% confidence interval 1.273–41.862, p = 0.026). In subgroup analysis according to the site of involvement, none of the variables were significant except for the post-RT SUVmax of PET and level of serum LDH in the non-conjunctiva group (p = 0.026, and p = 0.037, respectively). Seven (14.6%) patients had a recurrence, and those with a recurring site other than the primary site had a higher Ki-67 labeling index, although it was not statistically significant (9.56% vs. 18.00%, p = 0.095). Conclusions: Although belonging to the early stages, the non-CR rate was high in patients with high serum LDH levels, and recurred patients had higher Ki-67. Thus, considering active treatment is recommended in this group of patients.