Search

Isolated extramedullary relapse (EMR) without bone marrow relapse (BMR) after allogeneic hematopoietic cell transplantation (allo-HCT) is a rare condition in patients with acute lymphoblastic leukemia (ALL), and the role of immunotherapeutic agents for these patients remains unclear. We analyzed treatment outcomes of blinatumomab or inotuzumab ozogamicin (INO) as first- or second-line salvage therapy in nine patients with Philadelphia chromosome-negative B-cell precursor ALL presenting with isolated EMR after previous allo-HCT. In seven patients receiving blinatumomab as first-line salvage therapy, 4 (57.1%) achieved complete remission (CR). Among the three patients without remission after blinatumomab, two switched to INO and subsequently showed responses {one CR and one partial response [PR]}, and one switched to multiagent chemotherapy that led to CR. In the two patients receiving first-line salvage therapy with INO, one showed PR and the other achieved CR. Overall, 6 (66.7%) of nine patients achieved CR, and five of them proceeded to allo-HCT in CR. The median overall survival after relapse was 27.8 months. In conclusion, both blinatumomab and INO showed good response rates and a safe bridging role to second allo-HCT in patients with isolated EMR. However, clinical differences between isolated EMR and EMR with BMR remain to be elucidated.

Background aims Immunotherapeutic approaches using γδ T cells have emerged as the function of γδ T cells in tumor surveillance and clearance has been discovered. In vitro expansion methods of γ9δ2 T cells have been based on phosphoantigens and cytokines, but expansion methods using feeder cells to generate larger numbers of γδ T cells have also been studied recently. However, there are no studies that directly compare γδ T cells cultured with phosphoantigens with those cultured with feeder cells. Therefore, this study aimed to compare the expansion, characteristics and effector functions of γδ T cells stimulated with K562-based artificial antigen-presenting cells (aAPCs) (aAPC-γδ T cells) and γδ T cells stimulated with only zoledronic acid (ZA) (ZA-γδ T cells). Methods Peripheral blood mononuclear cells were stimulated with ZA for 7 days, and aAPC-γδ T cells were stimulated weekly with K562-based aAPCs expressing CD32, CD80, CD83, 4-1BBL, CD40L and CD70, whereas ZA-γδ T cells were stimulated with only IL-2. Cultured γδ T cells were analyzed by flow cytometry for the expression of co-stimulatory molecules, activating receptors and checkpoint inhibitors. Differentially expressed gene (DEG) analysis was also performed to determine the difference in gene expression between aAPC-γδ T cells and ZA-γδ T cells. In vitro cytotoxicity assay was performed with calcein AM release assay, and in vivo anti-tumor effect was compared using a U937 xenograft model. Results Fold expansion on day 21 was 690.7 ± 413.1 for ZA-γδ T cells and 1415.2 ± 1016.8 for aAPC- γδ T cells. Moreover, aAPC-γδ T cells showed continuous growth, whereas ZA-γδ T cells showed a decline in growth after day 21. The T-cell receptor Vγ9+δ2+ percentages (mean ± standard deviation) on day 21 were 90.0 ± 2.7% and 87.0 ± 4.5% for ZA-γδ T cells and aAPC-γδ T cells, respectively. CD25 and CD86 expression was significantly higher in aAPC-γδ T cells. In DEG analysis, aAPC-γδ T cells and ZA-γδ T cells formed distinct clusters, and aAPC-γδ T cells showed upregulation of genes associated with metabolism and cytokine pathways. In vitro cytotoxicity revealed superior anti-tumor effects of aAPC-γδ T cells compared with ZA-γδ T cells on Daudi, Raji and U937 cell lines. In addition, in the U937 xenograft model, aAPC-γδ T-cell treatment increased survival, and a higher frequency of aAPC-γδ T cells was shown in bone marrow compared with ZA-γδ T cells. Conclusions Overall, this study demonstrates that aAPC-γδ T cells show long-term proliferation, enhanced activation and anti-tumor effects compared with ZA-γδ T cells and provides a basis for using aAPC-γδ T cells in further studies, including clinical applications and genetic engineering of γδ T cells.

Background Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potentially curative treatment option for acute leukemia. We aimed to identify the comorbidity factors affecting survival outcomes after alloSCT and develop a new comorbidity index tool for predicting overall survival (OS). Methods A Korean nationwide cohort of 3,809 adults with acute leukemia treated with alloSCT between January 2002 and December 2018 was analyzed as the development cohort. A retrospective cohort comprising 313 consecutive adults with acute leukemia who underwent alloSCT between January 2019 and April 2020 was analyzed as the validation cohort. Results In the development cohort, advanced age, male sex, and comorbidities such as previous non-hematologic malignancy, hypertension, and coronary or cerebral vascular disease were significantly related to poor OS. Subsequently, a new comorbidity scoring system was developed, and risk groups were created, which included the low-risk (score ≤0.17), intermediate-risk (0.17< score ≤0.4), high-risk (0.4< score ≤0.55), and very high-risk (score ＞0.55) groups. The 1-year OS rates were discriminatively estimated at 73.5%, 66.2%, 61.9%, and 50.9% in the low-risk, intermediate-risk, high-risk, and very high-risk groups in the development cohort, respectively (P

Given the controversies in the prognostic value of KIT mutations and optimal thresholds and time points of MRD monitoring for AML with CBFB-MYH11, we retrospectively evaluated 88 patients who underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT, n = 60) or autologous HSCT (Auto-HSCT, n = 28). The D816V KIT mutation was significantly associated with post-transplant relapse, contrasting with other types of mutations in KIT. Pre- and post-transplant (3 months after transplant) CBFB-MYH11 MRD assessments were useful in predicting post-transplant relapse and poor survival. The optimal threshold was determined as a 2 log reduction at both time points. In multivariate analysis, the D816V KIT mutation and CBFB-MYH11 MRD assessments were independently associated with post-transplant relapse and survival. Stratification by D816V KIT and pre-transplant CBFB-MYH11 MRD status further distinguished the risk of relapse and survival. Auto-HSCT was superior to Allo-HSCT in MRD negative patients without D816V KIT, while Allo-HSCT trended to be superior to Auto-HSCT in patients with MRD positivity or the D816V KIT mutation. In conclusion, this study demonstrated the differentiated prognostic value of the D816V KIT mutation in AML with CBFB-MYH11 and clarified optimal time points and thresholds for CBFB-MYH11 MRD monitoring in the setting of HSCT.

Leukapheresis is used for the mechanical removal of leukaemic cells in hyperleukocytosis. However, the effectiveness of leukapheresis remains unclear due to selection and confounding factors in the cohorts. We compared the effectiveness of leukapheresis among the subgroups according to either the 2016 World Health Organization classification or the number of cytogenetic abnormalities with a retrospective, single-centre study from January 2009 to December 2018. Acute myeloid leukaemia (AML, n = 212) and acute lymphoblastic leukaemia (ALL, n = 97) were included. The 30-day survival rates (95% confidence interval, 95% CI) for AML and ALL were 86.3% (81.6–90.9%) and 94.8% (90.3–99.2%), respectively. For AML, ‘primary AML with myelodysplasia-related changes’ and ‘AML with biallelic mutation of CEBPA’ showed better 30-day survival outcomes (P = 0.026) than the other subgroups. A higher platelet count after leukapheresis was associated with better 30-day survival in AML patients (P = 0.029). A decrease in blast percentage count after leukapheresis was associated with better 30-day survival in ALL patients (P = 0.034). Our study suggested that prophylactic platelet transfusion to raise the platelet count to 50 × 109/L or greater might improve clinical outcome in AML patients undergoing leukapheresis.

Next-generation sequencing (NGS) panels have recently been introduced to efficiently detect genetic variations in hematologic malignancies. Our aim was to evaluate the performance of the commercialized Oncomine™ myeloid research assay (OMA) for myeloid neoplasms. Certified reference materials and clinical research samples were used, including 60 genomic DNA and 56 RNA samples. NGS was performed using OMA, which enables the interrogation of 40 target genes, 29 gene fusions, and five expression target genes with five expression control genes by the Ion S5 XL Sequencer. The analyzed data were compared with clinical data using karyotyping, reverse transcription polymerase chain reaction (PCR), fluorescence in situ hybridization, Sanger sequencing, customized NGS panel, and fragment analysis. All targets of reference materials were detected except three (two ASXL1 and one CEBPA) mutations, which we had not expected OMA to detect. In clinical search samples, OMA satisfactorily identified DNA variants, including 90 single nucleotide variants (SNVs), 48 small insertions and deletions (indels), and eight FLT3 internal tandem duplications (ITDs) (Kappa agreement 0.938). The variant allele frequencies of SNVs and indels measured by OMA correlated well with clinical data, whereas those of FLT3-ITDs were significantly lower than with fragment analysis (P = 0.008). Together, OMA showed strong ability to identify RNA gene fusions (Kappa agreement 0.961), except one RUNX1-MECOM. The MECOM gene was highly expressed in all five samples with MECOM-associated rearrangements, including inv(3), t(3;3), and t(3;21). OMA revealed excellent analytical and potential clinical performance and could be a good replacement for conventional molecular tests.

Background DNMT3A mutations occur in approximately 20% of AML cases and are associated with changes in DNA methylation. CDKN2B plays an important role in the regulation of hematopoietic progenitor cells and DNMT3A mutation is associated with CDKN2B promoter methylation. We analyzed the characteristics of DNMT3A mutations including their clinical significance in AML and their influence on promoter methylation and CDKN2B expression. Methods A total of 142 adults, recently diagnosed with de novo AML, were enrolled in the study. Mutations in DNMT3A, CEBPA, and NPM1 were analyzed by bidirectional Sanger sequencing. We evaluated CDKN2B promoter methylation and expression using pyrosequencing and RT-qPCR. Results We identified DNMT3A mutations in 19.7% (N=28) of enrolled patients with AML, which increased to 29.5% when analysis was restricted to cytogenetically normal-AML. Mutations were located on exons from 8-23, and the majority, including R882, were found to be present on exon 23. We also identified a novel frameshift mutation, c.1590delC, in AML with biallelic mutation of CEBPA. There was no significant difference in CDKN2B promoter methylation according to the presence or type of DNMT3A mutations. CDKN2B expression inversely correlated with CDKN2B promoter methylation and was significantly higher in AML with R882H mutation in DNMT3A. We demonstrated that DNMT3A mutation was associated with poor AML outcomes, especially in cytogenetically normal-AML. The DNMT3A mutation remained as the independent unfavorable prognostic factor after multivariate analysis. Conclusion We characterized DNMT3A mutations in AML and revealed the association between the DNMT3A mutation and CDKN2B expression and clinical outcome.

Introduction: Donor lymphocyte infusion (DLI) is one of the effective options for post-transplant disease control of myelodysplastic syndrome (MDS). Its success or failure depends on the induction of antitumor immune reactions, durability of clinical responses, and severity of unwanted toxicities mainly from graft- versus-host disease (GVHD). Methods: By analyzing 61 patients receiving DLI for post-transplant MDS relapse, we assessed treatment outcomes and affecting factors, especially focusing on the level of relapse (hematological, molecular, and imminent relapse). Results: The response rate (42.1%, 36.4%, 72.7%), and overall survival (OS) at 2 years (27.8%, 45.5%, 70.1%) were different for each relapse level with imminent relapse group showing the most promising results. For OS, response to DLI or pre-DLI chemotherapy, and time to relapse were independent prognostic factors. Meanwhile, post-DLI GVHD and time to relapse were independently predictive for DLI response; post-DLI GVHD was predictive for DLI response, but not for OS, suggesting a potential detrimental impact of GVHD on survival. The incidence of GVHD and GVHD-related deaths were 37.7% and 10.0%, respectively, and CD3+ cell doses triggering GVHD tended to be lower in cases with haploidentical donor or imminent relapse. Conclusion: Despite being limited by small number of cases and its retrospective nature, this study again demonstrated the therapeutic effects of DLI in relapsed MDS, and that earlier detection and intervention at lower level relapse might possibly be associated with better results. Furthermore, we propose that tailored cell dosing schedule based on relapse level and donor source may be helpful in minimizing fatal GVHD.

Background/Aims: Idiopathic multicentric Castleman disease (iMCD) comprises approximately 30% of all cases of Castleman disease. It is characterized by con stitutional symptoms, enlarged lymph nodes at multiple anatomical sites, and laboratory test abnormalities, which are primarily related to the overproduction of interleukin 6 (IL-6). Siltuximab is a human-mouse chimeric immunoglobulin G1κ monoclonal antibody against human IL-6. In view of the limited treatment options for iMCD, this study aimed to evaluate the efficacy and safety of siltux imab in the management of this condition. Methods: In this real-world retrospective study, we administered siltuximab to 15 patients with iMCD who previously received conventional chemotherapy and/or steroid pulse therapy. The median time to a durable symptomatic response was 22 days (range, 17 to 56). The serum hemoglobin and albumin levels and erythrocyte sedimentation rates significantly normalized after the first 3 months of siltux imab treatment. Lymph node involution, assessed using imaging, was relatively gradual, demonstrating a complete or partial response at 6 months. Results: On an average, the improvements in clinical, laboratory, and radiologic parameters of iMCD in responders were observed after one, three, and eight cy cles of siltuximab treatment, respectively. Siltuximab demonstrated a favorable safety profile, and prolonged treatment was well-tolerated. Conclusions: Despite the small sample size of the present study, the results are encouraging and demonstrate the potential of siltuximab as the first-line treat ment of iMCD. Further large multicenter studies are needed to evaluate the clini cal outcomes and adverse events associated with siltuximab.

In 27% of diffuse large B cell lymphoma (DLBCL) cases, bone marrow (BM), assessed by BM biopsy, is involved. BM involvement, an extranodal site involvement, affects the International Prognostic Index (IPI) score adversely. However, chromosomal abnormalities are neither included as a prognostic factor nor are they considered in the IPI risk classification category. We retrospectively analyzed 600 DLBCL patients at diagnosis for BM involvement (by both BM biopsy immunohistochemistry [BMI] with karyotyping and 18-fluorodeoxyglucose-positron emission tomography [FDG-PET] high uptake [BMP]). The BM-involved DLBCL patients identified by both BMI and BMP showed significantly inferior survival outcomes. Chromosomal abnormalities, especially complex karyotype (CK) of the involved BM, are related to much worse survival outcomes due to the inadequate treatment response including frontline auto-hematopoietic stem cell transplantation (HSCT). Therefore, CK population should either be considered for more aggressive treatment modalities, such as frontline allo-HSCT, or those further clinical trials are explored for alternative or novel treatment approaches. Furthermore, if the FDG-PET shows high possibility of marrow involvement, bilateral BM biopsy with cytogenetic evaluation should be incorporated into the routine workup for newly diagnosed DLBCL patients. This is to look for other markers of poor-risk factors, such as CK or further genetic mutations.

Ibrutinib is highly effective in patients with relapsed or refractory mantle cell lymphoma (MCL) in major clinical trials. Although there has been a dramatic improvement in survival outcomes in the salvage setting, nonresponders to ibrutinib have a bleak prognosis. Therefore, this retrospective study was conducted to identify the most appropriate therapeutic strategy and prognosis‐related factors to predict the response of patients with relapsed or refractory MCL to ibrutinib monotherapy. Thirty‐three consecutive refractory or relapsed MCL patients treated with ibrutinib were analyzed in this study. The median overall survival (OS) and progression‐free survival (PFS) after initiation of ibrutinib were 35.1 months and 27.4 months, respectively. Risk factor analysis showed that high risk according to the Mantle Cell Lymphoma International Prognostic Index (MIPI) and nonresponse to ibrutinib at the first three cycles were significantly associated with inferior OS. Poor PFS was associated with high‐risk biologic MIPI, prior bendamustine exposure, and nonresponse to ibrutinib during the first three cycles. After ibrutinib failure, primary nonresponders had poorer OS and PFS than inconsistent responders. The overall response rate for the first salvage therapy was only 33%, with a median TTP of 3.2 months. There was no effective therapeutic strategy except for allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Although ibrutinib responders exhibited favorable survival outcomes, nonresponders had a dismal prognosis. To overcome these limitations, it may be necessary to modify therapeutic strategies, such as selecting inconsistent responders for earlier allo‐HSCT., Although ibrutinib responders exhibited favorable survival outcomes, nonresponders had a dismal prognosis. To overcome these limitations, it may be necessary to modify therapeutic strategies.

In adult patients with relapsed or refractory (R/R) Philadelphia chromosome‐negative (Ph‐negative) B‐cell presursor acute lymphoblastic leukemia (BCP‐ALL), complete remission (CR) and overall survival (OS) rates are poor. We analyzed treatment outcomes and prognostic factors for 32 adult patients with R/R Ph‐negative BCP‐ALL who received blinatumomab at first salvage. Patients who achieved CR proceeded to allogeneic hematopoietic cell transplantation (allo‐HCT). At the time of blinatumomab treatment, 11 patients (34.3%) were primary refractory, 10 (31.4%) had relapsed with first CR duration (CRD1) ≥12 months, and 11 (34.3%) had relapsed with CRD1, Blinatumomab is effective for achieving good quality CR and bridging to allo‐HCT for adult patients with R/R Ph‐negative BCP‐ALL in first salvage. The role of blinatumomab in relapsed patients with short CR duration, extramedullary disease, and high tumor burden should be cautiously considered due to poor response.

Objective This study aimed to assess the anxiety and depression in patients undergoing hematopoietic stem cell transplantation (HSCT). Methods Eighty-seven adult patients with various hematologic diseases, who were scheduled to receive autologous or allogeneic HSCT, were enrolled. The M.D. Anderson Symptom Inventory and the Hospital Anxiety Depression Scale were applied prospectively at hospital admission (D-14), on the day of transplantation (D day), and at 7 (D7) and 14 days (D14) after transplantation. Results The severity of both anxiety and depressive symptoms increased over time, with a peak at D7, and then showed a downturn at D14. Physical distresses also started with mild intensity at base line, which were continuously aggravated until D7, and then a partial recovery afterwards. Approximately, 52% of the participants had significantly high anxiety or depression before the start of HSCT. The occurrence of aggravation of pain, nausea, shortness of breath, and lack of appetite was associated with the development of anxiety during isolation period. The patients with significant baseline anxiety had higher scores on fatigue and shortness of breath items at D7 compared to those without. Conclusion Our finding suggests the importance of psychiatric approaches, including preventive measures, for the patients undergoing HSCT.

Objectives This study aimed to identify the natural course of cytomegalovirus (CMV)/Epstein-Barr virus (EBV) after rabbit antithymocyte globulin and cyclosporine (rATG-CsA) for aplastic anemia (AA). Methods In 113 prospectively observed AA patients treated with rATG-CsA, the CMV/EBV cohort was classified into two groups by baseline viremic status: no viremia (CMV-G1, n = 112; EBV-G1, n = 98) and the presence of viremia (CMV-G2, n = 1; EBV-G2, n = 13). Results In CMV-G1, the mean CMV load increased up to 3 months but was completely resolved from 6 months. The mean EBV load of EBV-G1 showed a peak at 1 month and then gradually decreased over time but remained detectable throughout the observation period. EBV-G2 showed fluctuating EBV dynamics. With reactivation rates of 38.4% in CMV-G1 and 62.2% in EBV-G1, a longer time to rATG-CsA from diagnosis and a lower absolute lymphocyte count at 1 month from rATG-CsA were significantly associated with CMV and EBV reactivation, respectively. The mean peak CMV and EBV loads of patients with CMV-related (3.5%) and EBV-related (0.9%) diseases were evidently higher than those of the remaining patients without CMV and EBV diseases in the respective cohort. Conclusion Considering frequent reactivation and distinct courses of CMV/EBV, virologic surveillance is recommended after rATG-CsA for AA.

Acute promyelocytic leukemia (APL) is generally held to have favorable risk, but we have observed a high incidence of early deaths caused by fatal bleeding and differentiation syndrome (DS). We retrospectively analyzed 259 APL patients from 2002 to 2014 who all received all-trans retinoic acid (ATRA) with the support of sufficient transfusions, followed by 4 days of idarubicin. High-risk status was determined as a diagnostic leukocyte count (WBCdx) >10 × 109/L (Sanz criteria). For patients with hyperleukocytosis, we sometimes conducted leukapheresis and also used hydroxyurea and prophylactic dexamethasone. Because we frequently observed patient fatalities from progressive hyperleukocytosis, we also checked the maximum leukocyte count (WBCmax) and stratified patients by their incremental ratios. The 8-week cumulative incidence of early death and DS was 13.5% and 17.8%, respectively. We found that WBCmax correlated better with early death and DS, even in the low-risk group, than WBCdx. Among the patients with WBCdx 9/L, a WBCmax >43 × 109/L correlated with early death (26.7%) and DS (40.0%). Also, having a WBCdx of 10 to 43 × 109/La that increased to a WBCmax >43 × 109/L correlated with increased early death (33.3%). The multivariate analysis revealed that a WBCmax >43 × 109/L correlated significantly with both early death and DS.

Despite expanding knowledge in the molecular landscape of acute myeloid leukemia (AML) and an increasing understanding of leukemogenic pathways, little has changed in the treatment of AML in the last 40 years. Since introduction in the 1970s, combination chemotherapy consisting of anthracycline and cytarabine has been the mainstay of treatment, with major therapeutic advances based on improving supportive care rather than the introduction of novel therapeutics. Over the last decades, there have been extensive efforts to identify specific target mutations or pathways with the aim of improving clinical outcomes. Finally, after a prolonged wait, we are witnessing the next wave of AML treatment, characterized by a more "precise" and "personalized" understanding of the unique molecular or genetic mapping of individual patients. This new trend has since been further facilitated, with four new FDA approvals granted in 2017 in AML therapeutics. Currently, a total of eight targeted agents have been approved since 2017 (as of Jan. 2020). In this review, we will briefly discuss these newer agents in the context of their indication and the basis of their approval.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still considered a definitive curative modality for refractory or relapsed non-Hodgkin’s lymphoma (NHL). However, transplant-related morbidity and mortality remain a considerable challenge. The graft-versus-host disease (GVHD)–free with relapse-free survival (GRFS) rate and GRFS-related prognostic factors have not been fully examined for NHL alone. We evaluated 104 consecutive patients with refractory or relapsed aggressive NHL receiving allo-HSCT at a single institution. With a median follow-up of 31.5 months, the estimated 3-year overall survival (OS), disease-free survival (DFS), the cumulative incidence rates of relapse, and non-relapse mortality were 45.9%, 45.9%, 36.0%, and 17.0%, respectively. The patients with overall grades III–IV acute GVHD had markedly inferior OS and DFS (p = 0.040 for OS and p = 0.028 for DFS). However, patients with more than mild stage chronic GVHD showed superior OS and DFS (p = 0.004 and p = 0.008, respectively). The 1- and 3-year GRFS rates were 44.5% and 36.9%, respectively. The negative bone marrow involvement at diagnosis, chemosensitive disease status, and fewer exposure lines of chemotherapy before transplantation significantly increased the GRFS incidence. However, no transplant-associated factors were related to GRFS incidence. Furthermore, applying dynamic GRFS method which excepted patients whose chronic GVHD was fully resolved within short-period, survival rate significantly increased over time (36.9% vs. 41.9%, p = 0.045 for conventional GRFS vs. dynamic GRFS at 3 years after transplantation). In conclusion, these results suggest that GRFS is also a useful endpoint to assess transplant outcomes, and the dynamic GRFS calculation, including rapidly manageable chronic GVHD, is a more practical method for patients with refractory or relapsed heterogenous subtypes of NHL. Electronic supplementary material The online version of this article (10.1007/s00277-019-03714-x) contains supplementary material, which is available to authorized users.

BCR-ABL1–positive acute leukemia can be classified into three disease categories: B-lymphoblastic leukemia (B-ALL), acute myeloid leukemia (AML), and mixed-phenotype acute leukemia (MPAL). We conducted an integrative analysis of RNA sequencing (RNA-seq) data obtained from 12 BCR-ABL1–positive B-ALL, AML, and MPAL samples to evaluate its diagnostic utility. RNA-seq facilitated the identification of all p190 BCR-ABL1 with accurate splicing sites and a new gene fusion involving MAP2K2. Most of the clinically significant mutations were also identified including single-nucleotide variations, insertions, and deletions. In addition, RNA-seq yielded differential gene expression profile according to the disease category. Therefore, we selected 368 genes differentially expressed between AML and B-ALL and developed two differential diagnosis models based on the gene expression data using 1) scoring algorithm and 2) machine learning. Both models showed an excellent diagnostic accuracy not only for our 12 BCR-ABL1–positive cases but also for 427 public gene expression datasets from acute leukemias regardless of specific genetic aberration. This is the first trial to develop models of differential diagnosis using RNA-seq, especially to evaluate the potential role of machine learning in identifying the disease category of acute leukemia. The integrative analysis of gene expression data by RNA-seq facilitates the accurate differential diagnosis of acute leukemia with successful detection of significant gene fusion and/or mutations, which warrants further investigation.

Despite the proven efficacy of anti-T-cell or antithymocyte globulin (ATG) for chronic graft-versus-host disease (GVHD) prevention in transplantation from an unrelated donor, dosing protocols and the effects of ATG on relapse and infection remain controversial. In the setting of transplantation from an HLA-matched sibling (MSD-T), few randomized studies have been conducted. We conducted a prospective, single-center, open-label, randomized study of low-dose thymoglobulin (2.5 mg/kg) for chronic GVHD prevention. A total of 120 patients with acute leukemia were randomly assigned in a 1:1 ratio. After a median follow-up of 27 months, the cumulative incidence of chronic GVHD in the ATG and non-ATG groups was 25.0% and 65.4% (p < 0.001), respectively. The ATG group had an increased relapse rate compared with the non-ATG-group (20.0% vs. 9.3%; p = 0.055), with risks that differed according to cytogenetic subgroup (high-risk, 29.6% vs. 9.3%, p = 0.042; non-high-risk, 12.2% vs. 9.2%, p = 0.596). Chronic GVHD-free and relapse-free survival (cGRFS) was higher in the ATG group (46.7% vs. 19.4%; p = 0.070), and the difference was significant in a cytogenetic non-high-risk subgroup (45.5% vs. 0%; p = 0.038). No differences were observed in other survival outcomes. Improved physical components in quality-of-life scores were observed in the ATG group at 12 months after transplantation. A higher rate of Epstein-Barr virus reactivation was observed in the ATG group (21.8% vs. 5.1%; p = 0.013), whereas no between-group differences for other complications. In conclusion, the low-dose thymoglobulin effectively prevented chronic GVHD in MSD-T, resulting in improvement in quality-of-life and cGRFS, whereas the necessity of caution for high-risk acute leukemia.

Given limited studies on next-generation sequencing-based measurable residual disease (NGS-MRD) in acute myeloid leukemia (AML) patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT), we longitudinally collected samples before and after allo-HSCT from two independent prospective cohorts (n = 132) and investigated the prognostic impact of amplicon-based NGS assessment. Persistent mutations were detected pre-HSCT (43%) and 1 month after HSCT (post-HSCT-1m, 20%). All persistent mutations at both pre-HSCT and post-HSCT-1m were significantly associated with post-transplant relapse and worse overall survival. Changes in MRD status from pre-HSCT to post-HSCT-1m indicated a higher risk for relapse and death. Isolated detectable mutations in genes associated with clonal hematopoiesis were also significant predictors of post-transplant relapse. The optimal time point of NGS-MRD assessment depended on the conditioning intensity (pre-HSCT for myeloablative conditioning and post-HSCT-1m for reduced-intensity conditioning). Serial NGS-MRD monitoring revealed that most residual clones at both pre-HSCT and post-HSCT-1m in patients who never relapsed disappeared after allo-HSCT. Reappearance of mutant clones before overt relapse was detected by the NGS-MRD assay. Taken together, NGS-MRD detection has a prognostic value at both pre-HSCT and post-HSCT-1m, regardless of the mutation type, depending on the conditioning intensity. Serial NGS-MRD monitoring was feasible to compensate for the limited performance of the NGS-MRD assay.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the most effective postremission therapy conferring the chance of cure for acute myeloid leukemia (AML), including elderly patients. Although the number of transplantations for elderly patients with AML (eAML) is increasing owing to greater availability of various graft sources together with the adoption of advanced supportive care and reduced-intensity conditioning (RIC) regimen, there are relatively limited data on the impact of donor type in eAML compared to younger patients. In addition, few studies have evaluated the role of pretransplantation measurable residual disease (MRD) in the elderly population. Given the lack of prospective comparative study, we retrospectively compared transplantation outcomes of elderly patient with AML receiving allo-HSCT from matched sibling donor (MSD-HSCT), matched unrelated donor (MUD-HSCT) or haploidentical related donor (Haplo-HSCT), or autologous HSCT (Auto-HSCT). A total of 154 patients with a median age of 63 years (range 60-74) underwent MSD-HSCT (n = 41), MUD-HSCT (n = 36), Haplo-HSCT (n = 55), or Auto-HSCT (n = 22) for AML. RIC regimens were used in the majority of patients. In Haplo-HSCT, T-cell-replete peripheral blood stem cells with unique RIC regimens using anti-thymocyte globulin (ATG)-based GVHD prophylaxis was used. In the analysis, adjustment for MRD status at the time of transplantation was performed. MRD was measured by the quantitative molecular assays of the targets, including RUNX1-RUNX1T1, CBFB-MYH11, and NPM1, or WT1 in the absence of abnormalities in the aforementioned targets. At a median follow-up of 48 months, survival rates were similar between different donor types, whereas nonrelapse mortality (NRM) was lower in MUD-HSCT compared to MSD-HSCT (P = .002). MSD-HSCT, in which the majority of patients received a conditioning regimen not including ATG, showed more frequent severe chronic graft-versus-host disease (cGVHD). The major causes of non-relapse deaths in MSD-HSCT were related to cGVHD (71%), whereas infectious complications were mainly related to NRM in Haplo-HSCT (50%) or Auto-HSCT (100%). In the MUD-HSCT, GVHD (57%) and infection (43%) contributed similarly to non-relapse death. Cytomegalovirus infection was more frequent in Haplo-HSCT. In multivariate models, pre-transplant MRD-positivity was an independent risk factor for relapse (P = .001), whereas older age (P = .002) and the hematopoietic cell transplantation-comorbidity index (P = .009) were useful in predicting NRM. The current study demonstrated comparable outcomes after alternative and matched sibling donor HSCT in eAML aged 60 years or older, and the results also suggest the necessity for more sophisticated strategies to reduce NRM or relapse according to each donor type. The usefulness of molecular MRD assays demonstrated herein will facilitate trials for MRD-driven decision-making or risk-adaptive approaches in eAML.

Context: Controversies exist in the prognostic value of KIT mutations and the optimal thresholds and time points for measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with CBFB-MYH11. Objective: This study aimed to evaluate the prognostic value of different types of KIT mutations and CBFB-MYH11 quantification in AML patients with CBFB-MYH11 who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) or autologous HSCT (auto-HSCT) and the clinical relevance of each transplant strategy in each risk group. Design: We retrospectively evaluated 88 patients who underwent allo-HSCT (n=60) or auto-HSCT (n=28). Setting: A referral center. Patients: Ninety-six consecutive AML patients with CBFB-MYH11 in remission who underwent HSCT at the Catholic Hematology Hospital between 2009 and 2019. After excluding two patients who underwent second HSCT and four patients without data for KIT mutations or pre-transplant CBFB-MYH11 MRD data, 88 patients were finally included in this study. Interventions: Not applicable. Main Outcome Measures: We retrospectively compared survival outcomes according to different types of KIT mutations and CBFB-MYH11 MRD levels. Results: The D816V KIT mutation was significantly associated with post-transplant relapse, contrasting with other types of mutations in KIT. Pre- and post-transplant (3 months after transplant) CBFB-MYH11 MRD assessments were useful for predicting post-transplant relapse and poor survival. The optimal threshold was determined as a 2-log reduction at both time points. In multivariate analysis, the D816V KIT mutation and CBFB-MYH11 MRD assessments were independently associated with post-transplant relapse and survival. Stratification by D816V KIT and pre-transplant CBFB-MYH11 MRD status further distinguished the risk of relapse and survival. Auto-HSCT was superior to allo-HSCT in MRD-negative patients without D816V KIT, while allo-HSCT trended to be superior to auto-HSCT in patients with MRD positivity or the D816V KIT mutation. Conclusions: This study demonstrated the differentiated prognostic value of the D816V KIT mutation in AML with CBFB-MYH11 and clarified the optimal time points and thresholds for CBFB-MYH11 MRD monitoring in the setting of HSCT.

Background: Hemophagocytic lymphohistiocytosis (HLH) can be life-threatening if not detected and treated appropriately. The diagnosis of HLH can be confusing due to other similar febrile diseases that present with cytopenia. Natural-killer cell (NK)-cytotoxicity is an important diagnostic parameter for primary HLH; however, its role in secondary HLH in adults has not been well-elucidated. Methods: We prospectively enrolled 123 adult patients with febrile conditions accompanied by cytopenia or marrow hemophagocytosis. A diagnosis of HLH was based on HLH-2004 criteria and treated based on HLH-94 protocol. NK-cytotoxicity was calculated at the time of diagnosis by K562-cell direct lysis using flow-cytometry. Results: HLH ( n = 60) was determined to be caused by Epstein–Barr virus (EBV) ( n = 11), infection other than EBV ( n = 16), malignancies ( n = 19), and unknown ( n = 14). Febrile diseases other than HLH ( n = 63) were diagnosed as autoimmune disease ( n = 22), malignancies ( n = 21), infection ( n = 12), non-malignant hematological diseases ( n = 6), and unknown ( n = 2). A lower NK-cytotoxicity level was observed at diagnosis in patients with HLH, compared with other causes of febrile disease (12.1% versus 26.2%, p Conclusions: Febrile disease with cytopenia was associated with decreased NK-cytotoxicity, especially in adults with HLH; however, its diagnostic role for adult HLH is still arguable. The diagnostic criteria for adult HLH should be further discussed. Trial registration: Clinical Research Information Service [Internet]; Osong (Chungcheongbuk-do), Korea, Centers for Disease Control and Prevention, Ministry of Health and Welfare (Republic of Korea); https://cris.nih.go.kr/cris/index.jsp ; Feb, 16th 2016; KCT0001886 (KC15TISE0936)

The prognostic significance of KIT mutations and optimal thresholds and time points of measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with RUNX1-RUNX1T1 remain controversial in the setting of hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated 166 high-risk patients who underwent allogeneic (Allo-HSCT, n = 112) or autologous HSCT (Auto-HSCT, n = 54). D816V KIT mutation, a subtype of exon 17 mutations, was significantly associated with post-transplant relapse and poor survival, while other types of mutations in exons 17 and 8 were not associated with post-transplant relapse. Pre- and post-transplant RUNX1&ndash, RUNX1T1 MRD assessments were useful for predicting post-transplant relapse and poor survival with a higher sensitivity at later time points. Survival analysis for each stratified group by D816V KIT mutation and pre-transplant RUNX1&ndash, RUNX1T1 MRD status demonstrated that Auto-HSCT was superior to Allo-HSCT in MRD-negative patients without D816V KIT mutation, while Allo-HSCT was superior to Auto-HSCT in MRD-negative patients with D816V KIT mutation. Very poor outcomes of pre-transplant MRD-positive patients with D816V KIT mutation suggested that this group should be treated in clinical trials. Risk stratification by both D816V KIT mutation and RUNX1&ndash, RUNX1T1 MRD status will provide a platform for decision-making or risk-adapted therapeutic approaches.

We attempted to identify the incidence and survival outcome of hepatic sinusoidal obstruction syndrome/veno-occlusive disease (VOD/SOS) after hematopoietic cell transplantation (HCT) under strategy of prophylactic ursodiol and intravenous heparin or prostaglandin E1 (PGE1). From 2009 to 2018, 2572 consecutive allogeneic-HCT cases were reviewed. We used oral ursodiol for all transplants, and most were administered low-dose heparin, while PGE1 in selected cases with low platelet count at the time of preconditioning. Diagnosis and severity grades were reassessed by revised EBMT criteria. The overall incidence of hepatic VOD/SOS was 3.4% (Mild 0.9%, Moderate 0.6%, Severe 0.7%, Very severe 1.2%) after allogeneic-HCT under strategy of intravenous prophylaxis. The 1-year overall survival of VOD/SOS was 41.4% which was divided into 73.9% for mild, 66.7% for moderate, 38.9% for severe, and 6.5% for very severe grade. Very high disease risk index, male gender, donor other than matched sibling donor, and busulfex > 9 mg/kg were affecting factors for development of VOD/SOS. For severe to very severe VOD/SOS, history of pre-HCT liver dysfunction was an additionally affecting factor. Allogeneic-HCT using ursodiol and intravenous prophylaxis was considered safe without significant bleeding complications and should be evaluated in future clinical trials. For those with high-risk of VOD/SOS, early intervention and management is important.

Despite comparable outcomes of haploidentical transplants (Haplo-HSCT) with HLA-matched unrelated transplants (MUD-HSCT) in retrospective comparisons, few studies have prospectively compared Haplo-HSCT with MUD-HSCT in AML. Here, we prospectively compared the outcomes of Haplo-HSCT with MUD-HSCT for AML in remission (n = 110) to prove non-inferiority of overall survival in Haplo-HSCT. Both groups were well balanced in factors related to biological features of AML and measurable residual disease (MRD) status by Wilms' tumor gene 1 (WT1) assay. A unique, reduced-toxicity preparative regimen was used for Haplo-HSCT, whereas mostly-myeloablative regimen was for MUD-HSCT. Both groups showed similar patterns of neutrophil and platelet recovery, whereas delayed T-cell reconstitution in Haplo-HSCT was found compared with MUD-HSCT. No significant differences were found in acute or chronic graft-vs-host-disease (GVHD) and post-transplant infectious events with an exception of EBV or CMV infection, which occurred more frequently in Haplo-HSCT. After a median follow-up of 47 months, no significant differences in overall survival (65% vs 54%, P = .146), disease-free survival (67% vs 53%, P = .142), relapse (20% vs 21%, P = .858), non-relapse mortality (14% vs 26%, P = .103), or GVHD-free/relapse-free survival (54% vs 41%, P = .138) were observed for Haplo-HSCT vs MUD-HSCT. In multivariate analysis, WT1 expression before transplantation independently predicted relapse, resulting in inferior survival. Separate analysis of unenrolled patients (n = 110) who were excluded or refused to participate in this study showed consistent results with enrolled patients. This prospective study demonstrated the non-inferiority of Haplo-HSCT to MUD-HSCT for AML in remission, and validated the role of WT1 quantification as an MRD marker (ClinicalTrial.gov identifier: NCT01751997).

We assessed the impact of donor type on long-term outcomes of allogeneic hematopoietic cell transplantation (HCT) in 440 consecutive adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1), particularly focusing on the donor type-specific difference in graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS). Donor sources were matched sibling donor (MSD; n = 199), matched unrelated donor (MUD; n = 110), 1-allele-mismatched unrelated donor (1-MMUD; n = 83), and cord blood (CB; n = 48). Cumulative incidence of severe chronic GVHD was 14.8% for MSD-HCT, 30.1% for MUD-HCT, 9.6% for 1-MMUD-HCT, and 4.2% for CBT, respectively (P

Background Regarding patients with severe aplastic anemia (SAA) who fail immunosuppressive therapy and lack an HLA-matched sibling donor (MSD), the best alternative donor including unrelated (URD) and haploidentical (HAPLO) donors for allogeneic stem cell transplantation (SCT) remains to be established. Methods We analyzed the comprehensive outcomes of 153 consecutive adult SAA patients treated with SCT from alternative donors: 73 HLA-well matched (8/8) URDs (WM-URDs), 34 mismatched (6-7/8) URDs (MM-URDs), and 46 HAPLOs. Results Neutrophil/platelet engraftments were achieved at a median of 11/15 days for WM-URDs, 13/16.5 days for MM-URDs, and 12/14 days for HAPLOs, respectively. The 3-year overall survival (OS), failure-free survival, cumulative incidence of graft-failure, and transplant-related mortality were statistically not different among the 3 groups: 90.3%, 87.5%, 2.7%, and 9.8% for WM-URDs; 85.3%, 81.7%, 0%, and 14.7% for MM-URDs, and 84.4%, 82.3%, 6.5%, and 11.2% for HAPLOs, respectively. The rates of other complications, including graft-versus-host disease, cytomegalovirus DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancies, and sinusoidal obstruction syndrome, were also statistically not different. Subgroup analysis of the MM-URD group showed that the 3-year OS of patients receiving SCTs from 6/8-URDs were worse than those receiving SCTs from 7/8-URDs (75.0% versus 94.4%, P = 0.26). Conclusions There was no significant difference in the SCT outcomes with WM-URDs, MM-URDs, or HAPLO donors. The clinician can make the best choice among these alternative donor sources based on the host/donor features and the urgency of the need for SCT. However, the selection of 6/8-URDs should be avoided due to inferior survival outcomes.

Deferasirox is an oral iron‐chelating agent having possible antileukemia and immune modulatory effects. Few reports have evaluated deferasirox in the setting of allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We investigated the impact of deferasirox after allo‐HSCT in acute myeloid leukemia (AML). Of 326 consecutive patients undergoing allo‐HSCT in remission, analysis of 198 patients not receiving deferasirox revealed the negative prognostic effect of hyperferritinemia (≥1000 ng/mL) before and after allo‐HSCT on survival mainly due to increase in relapse. Of 276 patients with hyperferritinemia at 1 month after allo‐HSCT, 128 patients (46%) received deferasirox. Deferasirox induced a faster decline in serum ferritin level with a manageable safety profile, which significantly reduced relapse rather than nonrelapse mortality, resulting in better survival compared to patients not receiving deferasirox. Of note, the deferasirox group had a significantly higher incidence of chronic graft‐vs‐host disease, indicating improved graft‐vs‐leukemia (GVL) effects evidenced by the presence of suppressed regulatory T cells and sustained higher proportion of NK cells in peripheral blood. This study firstly demonstrates the improved survival and restoration of GVL effects of patients with AML by deferasirox, which also clarifies the detrimental effect of hyperferritinemia through after allo‐HSCT.

We reviewed our leukemia database to reclassify 610 patients previously diagnosed as having acute myeloid leukemia (AML) according to the updated 2016 WHO classification. Nine patients were categorized as having myelodysplastic syndrome and myeloid neoplasms with germline predisposition. AML with recurrent genetic abnormalities accounted for 57.4% (345/601) of the patients under the 2016 WHO classification. AML with mutated NPM1 was the most common form (16.5%), with the majority associated with monocytic differentiation (63.6%). AML with double CEBPA mutations accounted for 8.3% of these cases, and the majority were previously diagnosed as AML with/without maturation (78.0%). These newly classified mutations were mutually exclusive without overlapping with other forms of AML with recurrent genetic abnormalities. AML with mutated NPM1 and AML with myelodysplasia-related changes comprised the oldest patients, whereas AML with RUNX1-RUNX1T1 included the youngest patients. The leukocyte count was highest in AML with mutated NPM1, and the percentage of peripheral blood blasts was the highest in AML with double CEBPA mutations. Our results indicate that implementation of the 2016 WHO classification of AML would not pose major difficulties in clinical practice. Hematopathologists should review and prepare genetic tests for the new classification, according to their clinical laboratory conditions.

Relapse is a major concern with reduced-intensity conditioning. We analyzed 257 patients with acute myeloid leukemia (AML) who received allogeneic stem cell transplantation (SCT) and fulfilled the following criteria: intermediate- or poor-risk disease by National Comprehensive Cancer Network guidelines (2017, version 3), in first complete remission (CR1) at SCT, received either myeloablative conditioning (MAC; busulfan plus cyclophosphamide or cyclophosphamide plus total body irradiation) or reduced-intensity conditioning (RIC; FluBu2TBI400) peripheral blood SCT from 8/8 matched sibling or unrelated donor, and having bone marrow Wilms tumor gene 1 (WT1) expression results before transplant. We and other groups serially published a predictive value for pretransplant WT1 expression in patients with AML to identify patients at higher risk of relapse. Among the total 257 patients, 191 (74.3%) and 66 (25.7%) patients received MAC and RIC transplants, respectively. WT1 ≥250 copies/104 ABL was defined as WT1high. WT1high before SCT was found to be an independent prognostic factor for inferior overall survival (OS), disease-free survival (DFS), and higher cumulative incidence of relapse (CIR). There were 201 patients with WT1 low expression based upon pretransplant analysis. There was no significant difference in OS, DFS, CIR, and nonrelapse mortality between MAC and RIC patients. To conclude, post-transplant survival or relapse was not different by conditioning intensity in AML CR1 patients whose WT1 level was below 250 copies per 104 ABL at transplantation.

This prospective study explored an optimal conditioning regimen to ensure engraftment with minimal toxicity in adult patients with severe aplastic anemia (SAA) who received haplo-identical stem cell transplantation from a related mismatched donor (Haplo-SCT). We explored a safe and sufficient dose of rabbit ATG (Thymoglobulin) in combination with 800 cGy total body irradiation (TBI) and fludarabine (Flu, 30 mg/m2 /day) for 5 days using step-by-step dose de-escalation. The dose of ATG was de-escalated from 10 mg/kg (group 1), to 7.5 mg/kg (group 2), to 5 mg/kg (group 3), and the TBI dose was reduced to 600 cGy (group 4) beginning in October 2014. If one patient developed transplant-related mortality (TRM) with engraftment in a group, we moved to the next lower dose group. Thirty-four patients were enrolled in groups 1-3 (n = 10) and 4 (n = 24). All patients achieved primary engraftment. The incidence of acute GVHD (grade ≥ 2) and chronic GVHD (≥ moderate) was 29.4% and 14.7%, respectively. With a median follow-up of 56.6 and 21.8 months in groups 1-3 and group 4, respectively, the 2-year probability of overall survival (91.7% in group 4 vs 70% in groups 1-3, P = 0.155) and GVHD-free survival (78.4% in group 4 vs 50% in groups 1-3, P = 0.115) was shown tended to be better in group 4. This study explored an optimal conditioning with step-by-step de-escalation dosage of ATG and TBI to reduce TRM with sustained graft function. TBI-600 cGy/Flu/intermediate-dose ATG resulted in feasible outcomes of Haplo-SCT for adult patients with SAA.

The incidence of Philadelphia chromosome positivity (Ph+) in adults with acute myeloid leukemia (AML) is very low. Ph+ AML is considered to be high risk for failure to attain remission or for early relapse after standard chemotherapy. Because of the low incidence of the disease, it has been difficult to determine the best treatment, including the effects of tyrosine kinase inhibitors. We retrospectively analyzed 29 patients with Ph+ AML (median age, 45 years; range, 18 to 80) managed at our center between 2002 and 2016. Two patients were not treated at all, 3 received repeated low-dose cytarabine, and 24 were treated with 3 + 7 standard induction chemotherapy. All 27 treated patients also received interim imatinib 400 mg orally until the day of the next chemotherapy cycle began or as conditioning for allogeneic hematopoietic cell transplantation (HCT), which was performed in 17 patients. Of the 29 patients with Ph+ AML, 7 (24.1%) had additional inv(16), 3 of whom had therapy-related AML. In the 7 with inv(16), the median age was younger (31 versus 44 years, P = .083) and the complete remission (CR) rate was relatively higher (85.7% versus 54.5%, P = .214) than in those without inv(16). Among the 27 treated patients, 20 (74.1%) achieved CR after standard chemotherapy with interim imatinib and 2 (7.4%) achieved CR after low-dose cytarabine with interim imatinib. After a median follow-up of 65.5 months (range, 13.4 to 156.6), the 5-year overall survival (OS) among all 27 treated patients was 43.1%. For the 17 patients who underwent HCT the 5-year OS of 17 patients (10 in subgroup without inv(16) and 7 in subgroup with inv(16)) treated with allogeneic HCT was 69.3%. All 7 with inv(16) were still alive at the end of the study. In contrast, all patients not treated with HCT died within a median of 6.25 months (range, .2 to 18.2). Interim imatinib combined with chemotherapy yielded an acceptable remission rate in adult patients with Ph+ AML. Allogeneic HCT as a postremission therapy provided long-term disease control in two-thirds of those who underwent the transplant. We also demonstrated that inv(16) was related to a favorable outcome in Ph+ AML, including therapy-related AML.

OBJECTIVES We intended to identify the predictive abilities of recently published transplant-specific prognostic scoring systems in patients with myelodysplastic syndrome (MDS) receiving haploidentical transplantation. METHODS The outcomes of 73 patients with MDS receiving haploidentical transplantation were analyzed, according to the MTPSS, the TRI, and the CIBMTR scoring systems. RESULTS The median age of patients at transplantation was 50 (range, 19-69) years. The IPSS-R cytogenetic risks of very good/good, intermediate, and poor/very poor were, respectively, observed in 35 (48.0%), 25 (34.2%), and 13 (17.8%) patients, including 4 (5.5%) with a monosomal karyotype. Pretransplant treatment failure and high (≥3) HCT-CI were observed in 30 (41.1%) and 35 (48.0%) patients, respectively. With survivor's median follow-up of 42.3 months, the overall survival rate at 4 years of all patients was 65.5% (95% CI, 52.4-75.9). The MTPSS (100%, 77.3%, 62.5%, and 42.0% at 4 years; P = .02) and the TRI (100%, 79.9%, 76.0%, and 17.1% at 4 years; P

The aim of this study was to explore the predictive implications of the composition of immune cell populations prior to lenalidomide plus high-dose dexamethasone (Len-Dex) initiation for the occurrence of infections. We prospectively examined immune cell populations in peripheral blood taken at baseline of lenalidomide plus low-dose dexamethasone (Len-dex) therapy and reviewed clinical and microbiology records in 90 patients with refractory/relapsed multiple myeloma (RRMM). Risk factors for infection were analyzed using logistic regression. During a median of 11 cycles of Len-dex treatment, 52 (57.8%) patients experienced at least 1 infection episode. Of a total of 92 episodes of infection, 58 (63%) episodes were clinically defined, 29 (31.5%) episodes were microbiologically defined, and 5 (5.4%) episodes were fever of unknown origin. Severe episodes were more frequently observed during the first 3 cycles. After adjusting for risk factors for infection based on univariate analyses, multivariate analyses showed that lower Hb (

The recovery of myeloid-derived suppressor cells (MDSCs) and its relevance in clinical acute graft-versus-host disease (GVHD) and post-hematopoietic stem cell transplantation (HSCT) infections remain to be fully characterized. We examined the expansion of circulating monocytic (M-) MDSCs and granulocytic (G-) MDSCs at the time of engraftment in 130 patients undergoing allogeneic HSCT (allo-HSCT). Compared with the G-MDSC group, the high M-MDSC group had a higher infection rate within 100 days, along with worse 1-year cumulative incidence of treatment-related mortality (TRM) and 2-year probability of event-free survival (EFS). The frequency of M-MDSCs was associated with preceding severe mucositis. Transcriptome profiling analysis of 2 isolated MDSC subtype showed significantly greater matrix metalloproteinase-9 (MMP-9) expression in M-MDSCs than in G-MDSCs. M-MDSCs produced abundantly more MMP-9. Importantly, compared with G-MDSCs, M-MDSCs isolated from patients post-HSCT had a greater capacity to suppress T cell responses, and MMP-9 blockade more forcefully inhibited their immunosuppressive effect. MMP-9 levels also were associated with the occurrence of infections and with transplantation outcomes. Based on these findings, we identify M-MDSCs as a major contributor to infections early after allo-HSCT and worse clinical outcomes via MMP-9.

Despite recent emergence of novel target agents, allogeneic stem cell transplantation is still the favored option for disease control in relapsed patients with acute myeloid leukemia (AML). Allotransplant from alternative donors such as haploidentical donor or cord blood can be done when fully HLA matched donor is not available. As for patients relapsed after the first stem cell transplantation (SCT1), these alternative stem cell sources often become only available options for the second transplantation. However, there has been no report comparing haploidentical stem cell (HIT) and cord blood transplantation (CBT), especially for the second transplantation. We performed a retrospective cohort study on AML patients who relapsed after SCT1 and underwent second allogeneic SCT from either alternative donor at our institution. We identified a total of 50 corresponding patients between January 2008 and February 2021 where 31 HIT and 19 CBT were included, and analyzed SCT outcomes including overall survival (OS), disease free survival (DFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and the incidence of SCT complications with comparing between the 2 groups. Conditioning regimens for HIT and for CBT were as follows: Fludarabine (30mg/m2/day intravenous (IV) for 5 days), busulfan (3.2mg/kg/day IV for 2 days), fractionated total body irradiation (fTBI, 4-8Gy total) and rabbit antithymoglobulin at a dose of 1.25mg/kg/day for four days for in vivo T cell depletion from D-5 to D-2 was given for HIT. G-CSF-mobilized peripheral blood stem cell was used as allograft. Graft-versus-host disease (GVHD) prophylaxis was done with tacrolimus and methotrexate. For CBT, fludarabine (30mg/m2/day IV for 5 days), cytarabine (1.5g/m2 twice daily for 3 days) with fTBI (12Gy). All CBT patients received double cord blood units. GVHD prophylaxis was done with tacrolimus and mycophenolate mofetil. The median follow-up period for survivors was 64.6 months (range 5.3-154.1). The type of SCT1 differed between the two groups; more patients of HIT were the recipient of prior autologous transplantation (41.9%), and 63.2% of CBT had underwent prior HIT (p Overall respective outcomes of HIT and CBT were as follows; 41% and 29% for 2-year OS (p=0.017), 41% and 16% for 2-year DFS (p=0.016), 36% and 36% for 2-year CIR (p=0.91) and 23% and 48% for 2-year NRM (p=0.021). Early NRM within 100 days of SCT2 was more frequent in CBT than HIT although not statistically significant (26.3% vs 9.7%, p=0.23). Median days to neutrophil and platelet engraftment were 12 (range 11-23) and 13 (range 9-38) in HIT, and 29 (range 16-48), 51 (range 27-167) for CBT, respectively (p This is the first report, to the best of our knowledge, to compare outcomes of the second transplantation from alternative donors for relapsed AML patients after SCT1. Our unique T-cell replete HIT using a reduced-toxicity conditioning regimen seems to provide better survival than CBT. Figure 1 Figure 1. Disclosures Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria.

Background Although European Leukemia Net (ELN) risk classification was introduced in 2017 and has been applied as an important prediction tool for prognosis, there has been limited data on its value among the patients with allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the prognostic value of ENL 2017 criteria on post-HSCT outcomes and compared it with pre-HSCT measurable residual disease (MRD) status determined by Wilms tumor gene 1 (WT1) expression level. Methods: Patients who underwent HSCT and fulfilled following criteria were eligible in this current study: first HSCT in complete remission (CR) or CR with incomplete hematologic recovery and having bone marrow WT1 expression results before transplant. We found a total of 275 patients between Nov 2017 and July 2020, and we adopted the WT1 cut-off level of 250 copies per 10 4 ABL for defining MRD negative vs positive (Biol Blood Marrow Transplant. 2019;25:1925) . Results: Among 180 patients, , 110 (61%) and 70 (39%) patients were classified as a , intermediated (INT) and adverse (ADV) risk group by ELN 2017 classification. After a median follow-up of 18.3 months (range, 0.4 to 43.2 months), the Kaplan-Meier survival curve could not discriminate overall survival (OS), relapse free survival (RFS), or cumulative incidence of relapse (CIR) between the INT and ADV risk groups (p=0.2, p=0.68, p=0.061, respectively). On the other hand, we found that OS, RFS and CIR were unfavorable in MRD (+) group compared to either MRD negative INT or ADV risk group (35.8 % vs 59.1 % for OS, p=0.05; 24.7% vs 55.9% for RFS, p=0.002; 60.9% vs 20.4 % for CIR, p C onclusions: The ELN 2017 risk classification was not available to predict post-HSCT outcomes in INT and ADV risk group. We found that pre-HSCT MRD rather than ELN 2017 could more likely to predict post-HSCT relapse. The prognostic value of WT1 MRD was more prominent in ELN INT group compared to ADV group. A subset of INT patients had the worst prognosis if their pre-HSCT WT1 MRD remained positive, who they need additional therapeutic strategies to prevent relapse. Figure 1 Figure 1. Disclosures Kim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria.

Backgound The Philadelphia-negative myeloproliferative neoplasms (MPNs) share similar molecular characteristics, in which the excessive myeloproliferations are driven by mutations in JAK2, CALR, MPL, and uncommon variants. More recently, the biological basis on acquisition of somatic mutations have been accumulated. However, symptoms, histomorphologic characteristics, and natural histories are different between MPN subsets. Although there are increasing evidences that inflammation have a key role in promoting MPN initiation and influencing disease evolution, characteristics of the bone marrow immune microenvironment between MPN subsets remains unclear exactly. Aims To characterize the bone marrow immune microenvironment of Philadelphia-negative MPNs, we carried out immune-related gene expression profiling of bone marrow aspirates (BMAs) from 33 MPN patients (6 PV, 6 ET, 6 early PMF, and 15 overt MF including 10 primary MF, 5 post-PV/ET MF) using nCounter Immunology Panel. Methods BMA samples collected at diagnosis using EDTA-coated tubes. Those samples were processed within 24 hours from collection to obtain mononuclear cells by density centrifugation using Ficoll-Paque. NanoString analysis using a 594-gene nCounter Immunology panel (Human v2 - nanoString) was performed on RNAs extracted from 33 MPN bone marrow aspirates. Results First, to investigate whether there are distinct gene expression signatures of immune cells between three subcategories of MPNs, we compared gene expression profiles (GEPs) between ET, PV, and overt PMF. Using a P-value cutoff of ≤0.05 and fold-change ≥ 2, 10 upregulated and 32 downregulated differentially expressed genes (DEGs) were identified in ET than PMF, and 9 upregulated and 11 downregulated DEGs were identified in PV than PMF, while we found no significant DEGs between ET versus PV, except seven genes. Second, we investigated differences in GEPs between early PMF and overt PMF. Thirty-two downregulated and 4 upregulated DEGs were identified in early PMF than overt PMF. Gene set analysis revealed that the expression of genes related to almost processes decreased in early PMF than overt PMF. Then, we questioned differences between PMF and post-PV/ET MF. Using a P-value cutoff of ≤0.05 and fold-change ≥ 2, 12 upregulated and 12 downregulated DEGs were identified. Next, we computed relative abundances of immune cell subpopulations, estimated based on expression counts from the entire panel of surveyed genes, and compared them between the subcategories of MPNs. The abundance measurement of exhausted CD8 + T cell genes were significantly lower in ET and PV, compared with overt PMF, suggesting T cell exhaustion was distinct in overt PMF, compared to ET and PV. Conclusions The results demonstrated that immune microenvironment signature was distinguishable in the subcategories of MPNs. In addition, inflammatory signature was enriched in the bone marrow of overt PMF and exhausted CD8 + T cell genes were distinct in overt PMT. Further investigation is warranted to determine the immunological factors critical for potential therapeutic targets to alleviate progress to myelofibrosis. Disclosures Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction Although many new therapeutic agents have been introduced in the field of AML, the most important intensive induction regimen of AML patients is still 7+3 chemotherapy based on cytarabine and anthracycline. Currently, major guidelines recommend to exam bone marrow (BM) assessment in 14-21 days after the initiation of induction to determine whether to proceed with intensification chemotherapy. However, there is no solid evidence that these timings are most optimal. If the evaluation at an earlier time point is prognostic for response, earlier intensification could be considered. In this regard, we investigated if the BM blast rate at the 7th day after the start of 7+3 chemotherapy (D7 BM blast) was useful in predicting the treatment response of induction chemotherapy. Methods We retrospectively collected the data of patients who were newly diagnosed with AML from February 2002 to February 2021, received induction chemotherapy by 7+3, had a D7 BM examination without any intensification. A total of 665 patients were enrolled and we analyzed the prognostic significance of the D7 BM blast for the induction treatment response (complete remission or complete remission with incomplete hematologic recovery (CR/CRi)). In addition, we analyzed whether the predictive significance of the D7 BM blast varies by the patient's cytogenetic features by Medical Research Council classification (MRC risk). Then, we evaluated the diagnostic ability of the D7 BM blast by the receiver operating characteristic (ROC) curve for treatment response prediction. To find an optimal D7 BM blast cut-off value, the value that maximizes Youden's index was investigated. Results Among 665 AML patients who underwent 7+3 without intensification, the proportion of patients who acquired CR/CRi after single induction was 68.3%. A significant decrease in the CR/CRi rate was observed in the intermediate/adverse MRC group according to the increase of the D7 BM blast (tests for the trends in the intermediate and adverse group, p Conclusion The BM assessment performed at 7 days after 7+3 chemotherapy was available to predict the treatment response in intermediate and adverse cytogenetic risk patients. In particular, it can be practically used in patients with adverse cytogenetics, and a value of around BM blast 5% can be used as cut-off for response prediction. Early intensification in these patients could be considered, which would be beneficial in various aspects such as shorter nadir period or hospital stay and possibly better treatment response compared with the current strategies of later intensification or second induction. Figure 1 Figure 1. Disclosures Kim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria.

Introduction: Venetoclax (VEN) combined regimen received FDA approval for newly diagnosed elderly or unfit acute myeloid leukemia (AML) patients. Recently, with increasing use as off-label for relapsed or refractory setting in real practice, the evidence that the regimen is potentially effective in R/R AML is emerging. However, there is no answer to the question how VEN combined treatment compares to intensive chemotherapy (IC) in R/R AML when the patients were intended to be cured with bridging to stem cell transplantation (SCT) after either of these treatments. Methods: Adult AML patients (age ≥18 years) who were refractory to or relapsed after anthracycline plus cytarabine induction were subjected to this analysis. As a group of interest, R/R AML patients who received VEN combined regimen were screened first, and we found a total of 54 corresponding patients between Feb 2020 and Jan 2021. As a comparison, we searched historical controls who were treated with salvage IC during the past two years, revealing a total of 89 patients between Jan 2018 and Jan 2020. Patients analyzed here received VEN-combination or IC as their first or second-line salvage therapy. Results: Overall, the median age was 49 years (range, 18 to 72), and the patients of first line salvage (n=125, 87.4%) were more included. When comparing IC and VEN-combination groups, there were no differences in age, sex, ELN risk groups, cytogenetics, disease type or mutation status. However, more patients in VEN-combination group were in their second line salvage setting (IC vs VEN-combination; 5.6% vs 24.1%, p Conclusion: These findings suggest that VEN-combined treatment is a feasible option for R/R AML and could be chosen over salvage IC in R/R AML based on its anti-leukemic response, bridging to SCT with disease control and survival, which were comparable to IC in overall patients and were tended to be superior in patients of first salvage setting only. Disclosures Kim: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AIMS Biosciense: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; BMS & Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boryung Pharm Co.: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Pintherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Speakers Bureau; SL VaxiGen: Consultancy, Honoraria; VigenCell: Consultancy, Honoraria. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: venetoclax use in R/R AML: off label use

Stem cell transplantation (SCT) from an unrelated donor (URD) is often considered in patients with severe aplastic anemia (SAA) whom immunosuppressive therapy failed and matched sibling donor is not available. To reduce the incidence of graft-versus-host disease (GVHD) in URD SCT, introducting antithymocyte globulin (ATG) into the conditioning regimen has been proposed. Although ATG was shown to play a role in reducing GVHD in a cohort with diverse hematologic diseases, its role in SAA remains uncertain. The aim of this study was to determine the efficacy and toxicity of ATG in URD SCT for adult patients with SAA. We investigated 83 adult patients with SAA who underwent URD SCT between 2003 and 2014. The transplantation strategy consisted of total body irradiation (total 800 cGy) and cyclophosphamide (total 100 mg/kg to 120 mg/kg), followed by tacrolimus and a short-term methotrexate. We divided patients into 2 groups: group 1 (n = 25), which received HLA-matched (8/8) bone marrow (BM) without ATG, and group 2 (n = 58), which received SCT from either an HLA-mismatched donor or peripheral blood (PB). Thereafter, group 2 was subdivided according to ATG use into group 2A (without ATG, n = 26), which served as a historical cohort, and group 2B (with ATG, n = 32). Rabbit ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France) was used in group 2B at a dose of 2.5 mg/kg. The median age of all patients was 30 years (range, 17 to 59 years). The incidence of GVHD was significantly lower in group 2B than group 2A, as demonstrated by the rate of grade II to IV acute GVHD at day 100 (31.2% versus 61.5%, P = .003) and the rate of chronic GVHD at 3 years (21.9% versus 65.4%, P = .002). The overall survival rates of the 3 groups were similar. However, GVHD-free, failure-free survival (GFFS) was significantly higher in group 2B than group 2A (P = .034). A multivariable model identified use of ATG as an independent factor affecting grades II to IV acute GVHD (hazard ratio [HR], 2.902; 95% confidence interval [CI], 1.417 to 5.942; P = .004), chronic GVHD (HR , 3.005; 95% CI, 1.279 to 7.059; P = .012), and GFFS (HR, 2.363; 95% CI, 1.162 to 4.805; P = .014). Toxicities, including infectious complications, were not different among the 3 groups. In conclusion, low-dose ATG (2.5 mg/kg) can reduce the incidence of acute and chronic GVHD and improve the quality of life in patients with SAA who receive stem cells from either an HLA-mismatched donor or PB; importantly, these benefits are achieved without increased toxicity. Furthermore, ATG can be considered in URD SCT from HLA-matched BM cells.

This retrospective study aimed to compare the clinical features of paramedullary lesions (PLs) and extramedullary lesions (ELs) of plasmacytomas at diagnosis, using positron emission tomography integrated with computed tomography, using glucose labeled with the positron-emitting radionuclide 18F (18F-FDG-PET/CT) in newly diagnosed multiple myeloma (NDMM), and to address their prognostic impact. Sixty-four patients with NDMM presenting ELs (n=22) and/or PLs (n=42) were included. Patients with ELs at initial presentation had unfavorable laboratory parameters of calcium and lactate dehydrogenase, a higher percentage of bone marrow plasma cells, and showed a trend toward advanced international staging system (ISS), compared to patients with PLs. Using X-ray imaging, high bone disease (HBD) was observed in 50% and 71% of patients with ELs and PLs, respectively. After a median follow-up of 29.2 months (range, 3.4-76.5 months) in survivors, patients with ELs had a significantly lower overall survival (OS) (p=0.033) than patients with PLs did, whereas the progression-free survival (PFS) did not differ significantly (p=0.818). However, the PFS after 1st progression was significantly worse in patients with ELs than in those with PLs (p=0.017). In the multivariate analyses, the negative impact of initial ELs on OS (p=0.033) was sustained. Our results demonstrated the different clinical features and outcomes of ELs and PLs in NDMM. Patients with initial ELs showed a shorter PFS after 1st progression, which translated into poor OS, providing insight into the different biological effect of ELs.