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Resistance to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is a concerning problem. Polo-like kinase 1 (PLK1) is a key cell cycle modulator and is known to be associated with an activation of the PI3K pathway, which is related to the stabilization of DNA methyltransferase 1 (DNMT1), a target of HMAs. We investigated the effects of volasertib on HMA-resistant cell lines (MOLM/AZA-1 and MOLM/DEC-5) derived from MOLM-13, and bone marrow (BM) samples obtained from patients with MDS (BM blasts5%) or AML evolved from MDS (MDS/AML). Volasertib effectively inhibited the proliferation of HMA-resistant cells with suppression of DNMTs and PI3K/AKT/mTOR and ERK pathways. Volasertib also showed significant inhibitory effects against primary BM cells from patients with MDS or MDS/AML, and the effects of volasertib inversely correlated with

Low-dose azacitidine (AZA) regimens, primarily 5-day AZA, have been used in lower risk myelodysplastic syndrome (LrMDS) but they have yet to be directly compared to the standard 7-day, uninterrupted dosing schedule.In this phase 2, multicenter, randomized trial, 55 patients with adult LrMDS (low and intermediate-1 risk by international prognostic scoring system [IPSS]) were randomly assigned and received either 5-day (n = 26) or 7-day (n = 29) AZA between March 2012 and August 2020. The trial was stopped prematurely because of the slow accrual of patients. The primary end point was the overall response rate (ORR) of the 5-day AZA as compared to that of the 7-day regimen.Median patient age was 59 years, and IPSS intermediate-1 risk comprised the majority (81.8%). The median number of cycles in both arms was six. In the ITT subset (n = 53), in each of the 5-day and 7-day arms, the ORR of 48.0% and 39.3%, hematologic improvement of 44.0% and 39.3%, and RBC transfusion independence of 35.3% and 40.0% were observed respectively, and none of these findings were significantly different between the two arms. A cytogenetic response rate was significantly higher in the 7-day arm (8.3% and 53.8%, p = .027). Survival and adverse events were similar between the groups, although gastrointestinal toxicities, grade ≥3 thrombocytopenia, and febrile neutropenia were less frequent in the 5-day arm.The 5-day AZA in LrMDS showed comparable efficacy to a 7-day regimen in terms of similar overall response and other outcomes, despite significantly higher rates of cytogenetic responses in the 7-day regimen.Azacitidine (75 mg/m

In a prospective, explorative study, the donor-source difference of haploidentical family (HF), matched sibling (MS), and unrelated donors (UD) was evaluated for the outcome of haematopoietic cell transplantations (HCT) in 101 patients with acute myeloid leukaemia (AML) in complete remission (CR). To eliminate compounding effects, a uniform conditioning regimen containing antithymocyte globulin (ATG) was used. After transplantation, there was a significantly higher cumulative incidence of acute graft-versus-host disease (GVHD) in HF-HCT patients (49%, 7%, and 16% for HF-, MS- and UD-HCT respectively; p 0.001). A quarter of acute GVHD cases observed in HF-HCT patients occurred within three days of engraftment and were characterized by diffuse skin rash, fever, weight gain, and hypoalbuminaemia. This peri-engraftment acute GVHD was not observed in MS-HCT or UD-HCT patients. Additionally, a significantly higher proportion of HF-HCT patients achieved complete donor chimaerism in the peripheral mononuclear cells at one month (88%, 46%, and 69% for HF-, MS- and UD-HCT respectively; p = 0.001). There was no significant difference in engraftment, chronic GVHD, leukaemia recurrence, non-relapse mortality, and patient survival. In patients with AML in CR who received HCT using ATG-containing conditioning, stronger donor-patient alloreactivity was observed in HF-HCT, in terms of increased acute GVHD and higher likelihood of complete donor chimaerism.

Clonal cytopenia of undetermined significance (CCUS) is characterized by persistent cytopenias with genetic aberrations, which do not meet the diagnostic criteria for myelodysplastic syndrome (MDS). We aimed to compare the clinical and genetic characteristics of CCUS with lower-risk MDS and identify patients with CCUS with a high risk of progression. We performed targeted sequencing of bone marrow (BM) samples from patients with idiopathic cytopenia of undetermined significance (ICUS) (n = 139) and MDS (n = 226). Overall survival (OS) of patients with CCUS (n = 78) was worse than non-clonal ICUS (n = 61) and superior to lower-risk MDS (n = 99). Patients with CCUS showed similar characteristics to those with lower-risk MDS, except for higher haemoglobin, lower BM cellularity, and less frequent SF3B1 mutations. Lower haemoglobin, DDX41 (biallelic germline and somatic), ETV6, and RUNX1 mutations were independent prognostic factors for worse OS. Lower haemoglobin and DDX41 mutations were also associated with lower progression-free survival. Patients with CCUS with high-risk features showed similar or worse OS than patients with lower-risk MDS. Our findings suggest that patients with CCUS having certain clinical or genetic features should be regarded and treated as lower-risk MDS despite lacking significant dysplasia or MDS-associated chromosomal abnormalities.

DDX41 mutations are associated with hematologic malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but the incidence in idiopathic cytopenia of undetermined significance (ICUS) is unknown. We investigated the incidence, genetic characteristics, and clinical features of DDX41 mutations in Korean patients with ICUS, MDS, or AML. We performed targeted deep sequencing of 61 genes including DDX41 in 457 patients with ICUS (n=75), MDS (n=210), or AML (n=172). Germline DDX41 mutations with causality were identified in 28 (6.1%) patients, of whom 27 (96.4%) had somatic mutations in the other position of DDX41. Germline origins of the DDX41 mutations were confirmed in all of the 11 patients in whom germline-based testing was performed. Of the germline DDX41 mutations, p.V152G (n=10) was most common, followed by p.Y259C (n=8), p.A500fs (n=6), and p.E7* (n=3). Compared with non-mutated patients, patients with a DDX41 mutation were more frequently male, older, had a normal karyotype, low leukocyte count, and hypocellular marrow at diagnosis. Three of the four ICUS patients with germline DDX41 mutations progressed to MDS. The incidence of DDX41 mutations in Korean patients was high and there was a distinct mutation pattern, in that p.V152G was a unique germline variant. ICUS harboring germline DDX41 mutations may be regarded as a hereditary myeloid neoplasm. Germline DDX41 mutations are not uncommon and should be explored when treating patients with myeloid malignancies.

OBJECTIVES We evaluated the prognostic impact of MK on postremission outcomes of AML patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) in the first complete remission (CR1). METHODS We retrospectively analyzed 465 adult patients with AML who had received HSCT in the first CR between 2000 and 2016. RESULTS In MK + AML, the median leukocyte count was significantly lower (P

Parainfluenza virus (PIV) infection is a significant cause of morbidity and mortality, especially in hematologic malignancy patients including hematopoietic stem cell transplantation (HCT) recipients. However, limited information is available for risk stratification in PIV-infected patients with hematologic malignancy with or without HCT. Patients with hematologic malignancy diagnosed with PIV from January 2009 to December 2018 were retrospectively included in a tertiary care hospital in Seoul, South Korea. Upper respiratory tract infection (URTI) was defined as the detection of PIV in a nasopharyngeal sample with URTI symptoms without new pulmonary infiltrates. Lower respiratory tract infection (LRTI) was defined as detection of PIV in either upper or lower respiratory tract samples with new pulmonary infiltrates, with or without hypoxia. PIV-associated mortality was defined as death with respiratory failure and persistent LRTI within 90 days after diagnosis. The study included 143 adult patients. Of these, 55 (38%) progressed to or initially presented with LRTI. Among these, 22 (40%) died from PIV-associated mortality. An immunodeficiency risk score was developed from associated risk factors using a multivariable Cox regression model. Patients were stratified into low (0–2), moderate (3–5), and high risk (6–8) groups with PIV-associated mortalities of 0%, 9%, and 67%, respectively (p

Genetic differences may be associated with the response to tyrosine kinase inhibitor (TKI) in patients with chronic myeloid leukemia (CML). In this study, we identified genetic alterations between rapid and slow responders (BCR/ABL1 International Scale at 6 months: ≤0.1 % vs. 0.1 %) of TKI treatment in chronic phase CML patients. Our analyses involved single nucleotide polymorphism (SNP), a Genome Wide Association Study and a Network-wide Association Study (NetWAS). Seventy-two patients from 16 institutions were enrolled and treated with a TKI, nilotinib. Gene Set Analysis identified genetic alterations in pathways related to the differentiation, proliferation, and activity of various innate immune cells. The NetWAS analysis found that genes associated with natural killer (NK) cells (PTPRCAP, BLNK, HCK, ARHGEF11, GPR183, TRPV2, SHKBP1, CD2) showed significant differences between rapid and slow responders of nilotinib. However, we found no significantly different genetic alterations according to the response in the SNP analysis. In conclusion, we found that rapidity of response to TKI was associated with pathway-associated genetic alterations in immune cells, particularly with respect to NK cell activity. These results suggested that the innate immune system at initial diagnosis had an important role in treatment response in patients with CML.

Background Scoring systems developed for predicting survival after allogeneic hematopoietic cell transplantation (HCT) show suboptimal prediction power, and various factors affect posttransplantation outcomes. Objective A prediction model using a machine learning–based algorithm can be an alternative for concurrently applying multiple variables and can reduce potential biases. In this regard, the aim of this study is to establish and validate a machine learning–based predictive model for survival after allogeneic HCT in patients with hematologic malignancies. Methods Data from 1470 patients with hematologic malignancies who underwent allogeneic HCT between December 1993 and June 2020 at Asan Medical Center, Seoul, South Korea, were retrospectively analyzed. Using the gradient boosting machine algorithm, we evaluated a model predicting the 5-year posttransplantation survival through 10-fold cross-validation. Results The prediction model showed good performance with a mean area under the receiver operating characteristic curve of 0.788 (SD 0.03). Furthermore, we developed a risk score predicting probabilities of posttransplantation survival in 294 randomly selected patients, and an agreement between the estimated predicted and observed risks of overall death, nonrelapse mortality, and relapse incidence was observed according to the risk score. Additionally, the calculated score demonstrated the possibility of predicting survival according to the different transplantation-related factors, with the visualization of the importance of each variable. Conclusions We developed a machine learning–based model for predicting long-term survival after allogeneic HCT in patients with hematologic malignancies. Our model provides a method for making decisions regarding patient and donor candidates or selecting transplantation-related resources, such as conditioning regimens.

BACKGROUND Scoring systems developed for predicting survival after allogeneic hematopoietic cell transplantation (HCT) show suboptimal prediction power, and various factors affect posttransplantation outcomes. OBJECTIVE A prediction model using a machine learning–based algorithm can be an alternative for concurrently applying multiple variables and can reduce potential biases. In this regard, the aim of this study is to establish and validate a machine learning–based predictive model for survival after allogeneic HCT in patients with hematologic malignancies. METHODS Data from 1470 patients with hematologic malignancies who underwent allogeneic HCT between December 1993 and June 2020 at Asan Medical Center, Seoul, South Korea, were retrospectively analyzed. Using the gradient boosting machine algorithm, we evaluated a model predicting the 5-year posttransplantation survival through 10-fold cross-validation. RESULTS The prediction model showed good performance with a mean area under the receiver operating characteristic curve of 0.788 (SD 0.03). Furthermore, we developed a risk score predicting probabilities of posttransplantation survival in 294 randomly selected patients, and an agreement between the estimated predicted and observed risks of overall death, nonrelapse mortality, and relapse incidence was observed according to the risk score. Additionally, the calculated score demonstrated the possibility of predicting survival according to the different transplantation-related factors, with the visualization of the importance of each variable. CONCLUSIONS We developed a machine learning–based model for predicting long-term survival after allogeneic HCT in patients with hematologic malignancies. Our model provides a method for making decisions regarding patient and donor candidates or selecting transplantation-related resources, such as conditioning regimens.

Background This study presents outcomes of management in graft failure (GF) after allogeneic hematopoietic stem cell transplantation (HCT) and provides prognostic information including rare cases of autologous reconstitution (AR). Methods We analyzed risk factors and outcomes of primary and secondary GF, and occurrence of AR in 1,630 HCT recipients transplanted over period of 18 years (January 2000–September 2017) at our center. Results Primary and secondary GF occurred in 13 (0.80%), and 69 patients (10-year cumulative incidence, 4.5%) respectively. No peri-transplant variables predicted primary GF, whereas reduced intensity conditioning (RIC) regimen (relative risk [RR], 0.97–28.0, P < 0.001) and lower CD34+ cell dose (RR, 2.44–2.84, P = 0.002) were associated with higher risk of secondary GF in multivariate analysis. Primary GF demonstrated 100% mortality, in the secondary GF group, the 5-year Kaplan-Meier survival rate was 28.8%, relapse ensued in 18.8%, and AR was observed in 11.6% (n = 8). In survival analysis, diagnosis of aplastic anemia (AA), chronic myeloid leukemia and use of RIC had a positive impact. There were 8 patients who experienced AR, which was rarely reported after transplantation for acute leukemia. Patient shared common characteristics such as young age (median 25 years), use of RIC regimen, absence of profound neutropenia, and had advantageous survival rate of 100% during follow period without relapse. Conclusion Primary GF exhibited high mortality rate. Secondary GF had 4.5% 10-year cumulative incidence, median onset of 3 months after HCT, and showed 5-year Kaplan-Meier survival of 28.8%. Diagnosis of severe AA and use of RIC was both associated with higher incidence and better survival rate in secondary GF group. AR occurred in 11.6% in secondary GF, exhibited excellent prognosis., Graphical Abstract

In hematopoietic stem cell transplant recipients, the incidence of tuberculosis in positive interferon-γ release assay (IGRA) without isoniazid prophylaxis (3.58/100 person-years) was higher than in negative or indeterminate IGRA (1.15/100 person-years; P = .01) and in positive IGRA with isoniazid prophylaxis (0/100 person-years; P = .09). The number needed to treat was 22 (95% confidence interval, 12–99) with positive IGRA results.

Objective: We aimed to evaluate the effect of stem cell source and dose on the survival of various donor subgroups, such as matched sibling donor (MSDs) and alternative donors (ADs), upon bone marrow (BM) or peripheral blood stem cell (PBSC) infusion in aplastic anemia (AA). Methods: We retrospectively investigated the effects of stem cell source and dose on allogeneic hematopoietic stem cell transplantation (alloHSCT) in AA. Results: A total of 267 patients were included in this analysis. The BM-treated group showed an association with low incidence of any-grade acute graft versus host disease (GvHD) (p < 0.001). A higher stem cell dose was related with a low incidence of extensive chronic GvHD in MSDs (p = 0.025). Multivariate analysis for overall survival (OS) revealed that only age at alloHSCT p = 0.010) and prior platelet transfusion p = 0.046) in MSDs and higher stem cell dose (hazard ratio = 2.596, p = 0.045) in ADs were favorable prognostic factors. Conclusion: PBSCs could be preferred in AD because high stem cell dose may be easily achieved to improve the OS at the expense of acute GvHD. However, BM stem cells are preferred in MSDs.

Our previous research indicated that a reduced-intensity conditioning regimen (fludarabine and melphalan at 100 mg/m2) was useful in allogeneic hematopoietic cell transplantation (HCT) for patients with lymphoma. This retrospective study evaluated the reduced-intensity conditioning regimen in allogeneic HCT for adult patients with hemophagocytic lymphohistiocytosis (HLH). Sixteen patients with HLH were evaluated, including 6 patients who were enrolled in a prospective clinical trial (NCT00772811) and 10 patients who received the same conditioning regimen (fludarabine at 30 mg/m2/day on days –6 to –2 and melphalan at 100 mg/m2 on day –2). The median age was 42 years (range, 18 to 64), and 12 patients had Epstein-Barr virus (EBV)-associated HLH. Donors were an HLA matched sibling for 10 patients, an unrelated matched volunteer for 4 patients, and a mismatched family member for 2 patients. After excluding 3 patients who died soon after HCT, 12 patients achieved an engraftment (neutrophil median, day 12; platelet median, day 16). Five patients experienced acute graft-versus-host disease (GVHD), including 1 case of grade II and 4 cases of grades III to IV. Chronic GVHD occurred in 3 patients (moderate, 1 case; severe, 2 cases). After a median follow-up of 33.8 months 1 patient progressed, 3 patients relapsed, and 9 patients died. Five deaths were unrelated to relapse or progression and were caused by infection (n = 3), bleeding (n = 1), and GVHD (n = 1). No deaths or relapses were observed at >124 days post-transplant. The overall survival rate was 48.6%, and significant differences were observed according to pretransplant ferritin level (P = .007) and cytopenia lineage (P = .021). Before allogeneic HCT 10 of 12 patients still tested positive for EBV DNA: 6 patients tested negative for EBV DNA after HCT, 2 patients had persistent EBV DNA, and 2 patients were unassessable because of early death. Conditioning therapy using a lower dose of melphalan combined with fludarabine appears to be promising in allogeneic HCT for adults with HLH. However, strategies are needed to reduce the risk of early death.

Methods for distinguishing catheter-related candidemia (CRC) from non-CRC before catheter removal remain limited. We thus evaluated the diagnostic performance of differential time to positivity (DTP) to diagnose CRC in neutropenic cancer patients with suspected CRC. Of the 35 patients enrolled, 15 (43%) with CRC (six definite and nine probable) and 17 (49%) with non-CRC were finally analyzed. Based on the receiver operating characteristic curve, the optimal cutoff value of DTP for diagnosing CRC was ≥1.45 hours with the sensitivity 80% (95% confidence interval [CI], 51–95) and specificity 100% (95% CI, 80–100), respectively.

Overcoming drug resistance is one of key issues in treating refractory acute myeloid leukemia (AML). The Toll-like receptor 4 (TLR4) signaling pathway is involved in many aspects of biological functions of AML cells, including the regulation of pro-inflammatory cytokine products, myeloid differentiation, and survival of AML cells. Thus, targeting TLR4 of AML patients for therapeutic purposes should be carefully addressed. In this regard, we investigated the possible role of TLR4 as a regulatory factor against fludarabine (FA) cytotoxicity activity. Here, we identified the differential expression of TLR4 and CD14 receptors in AML cell lines and examined their relationship to FA sensitivity. We found that the stimulation of TLR4 with lipopolysaccharide (LPS) in a TLR4-expressing cell line, THP-1, increased cell viability under FA treatment condition and showed that TLR4 stimulation overcame FA sensitivity through the activation of NF-κB, which subsequently upregulated several anti-apoptotic genes. The inhibition of TLR4/NF-κB signaling could partially or completely reverse LPS-induced cell survival under FA treatment conditions. Interestingly, we found that the expression of thioredoxin-interacting protein (TXNIP), a well-known tumor suppressor, was induced by FA treatment; however, it was suppressed by LPS treatment. Furthermore, the expression level of TXNIP was critical for FA-induced cytotoxicity or LPS-induced FA resistance of THP-1 cells. Our data suggest that TXNIP plays an important role in FA-induced cytotoxicity and TLR4/NF-κB-mediated FA resistance of AML cells. Therefore, TXNIP may be a potential therapeutic target for AML treatment.

Background and objectives There are limited data in real clinical practice on the diagnostic value of a bronchoalveolar lavage (BAL) fluid galactomannan (GM) assay in patients with suspected invasive pulmonary aspergillosis (IPA) who had negative serum GM results. Thus, we investigated the diagnostic performance of a BAL GM assay in patients with negative serum GM assay results who were suspected to have IPA. Methods This retrospective study was performed between May 2008 and April 2019 at a tertiary care hospital in Seoul, South Korea. All patients with suspected IPA whose serum GM assays revealed negative results who sequentially underwent BAL were enrolled in this study. Results A total of 341 patients with suspected IPA including 4 cases of proven IPA, 38 case of probable IPA, 107 cases of possible IPA, and 192 patients without IPA were enrolled. Of these 341 patients, 107 (31%) with possible IPA were excluded from the final analysis. Of 42 patients with proven and probable IPA who had initial negative serum GM results, 24 (57%) had positive BAL GM results (n = 24) or BAL fungal culture results (n = 8). In addition, BAL revealed evidence of other opportunistic infections including Pneumocystis jirovecii pneumonia (14% [26/190]), cytomegalovirus (CMV) pneumonia (5% [9/188]), and respiratory viral pneumonia (6% [12/193]). Conclusion Sequential BAL in patients with suspected IPA who had initial negative serum GM results provided additional diagnostic yield in approximately half of patients with evidence of another co-infection.

Core-binding factor (CBF)-acute myeloid leukemia (AML) generally have a favorable prognosis. However, approximately 50% of patients experience disease relapse during or after post-remission therapy. Retrospective studies on autologous hematopoietic cell transplantation (AHCT) have shown improved survival with decreased relapse rate in CBF-AML. In this prospective study, we evaluate the outcomes of AHCT following high-dose cytarabine (HiDAC) consolidation in patients with CBF-AML in first complete remission (CR). Adult patients with CBF-AML achieving first CR after induction chemotherapy were eligible for the study. High-dose chemotherapy before AHCT included intravenous busulfan (3.2 mg/kg/day, days − 7 to − 5) and etoposide (400 mg/m2/day, days − 3 to − 2). Twenty-nine patients, 17 with t(8;21) and 12 with inv(16), underwent AHCT following 2 or 3 courses of HiDAC consolidation. The estimated 5-year overall and disease-free survival rates were between 89.0% and 82.5%, respectively. The cumulative incidences of relapse and non-relapse mortality were between 17.5% and 0%, respectively. Presence of measurable residual disease (MRD) before AHCT and KIT mutation were significantly associated with relapse after transplantation. In conclusion, the post-remission strategy of AHCT following HiDAC consolidation in CBF-AML was feasible and efficacious. Assays for MRD and KIT mutation may guide selection of patients who will benefit from AHCT in CBF-AML in first CR.

Ultra-deep sequencing detects low-frequency genetic mutations with high sensitivity. We used this approach to prospectively examine mutations in the BCR/ABL1 tyrosine kinase from patients with newly diagnosed, chronic-phase chronic myeloid leukemia (CML) treated with the tyrosine kinase inhibitor nilotinib. Between May 2013 and November 2014, 50 patients from 18 institutions were enrolled in the study. We screened 103 somatic mutations and found that mutations in the P-loop domain were the most frequent (173/454 mutations in the P-loop) and noted the presence of the V299 L mutation (dasatinib-resistant/nilotinib-sensitive) in 98 % of patients (49/50). No patients had Y253H, E255 V, or F359 V/C/I mutations, which would recommend dasatinib rather than nilotinib treatment. The S417Y mutation was associated with lower achievement of a major molecular response (MMR) at 6 months, and the V371A mutation was associated with reduced MMR and MR4.5 durations (MMR for 2 years: 100 % for no mutation vs. 75 % for mutation, P=0.039; MR4.5 for 15 months: 94.1 % vs. 25 %, P=0.002). Patients with known nilotinib-resistant mutations had lower rates of MR4.5 achievement. In conclusion, ultra-deep sequencing is a sensitive method for genetic-based treatment decisions. Based on the results of these mutational analyses, nilotinib treatment is a promising option for Korean patients with CML.

Immune thrombocytopenia (ITP) is an autoimmune condition characterized by platelet destruction through antibody-mediated mechanism. ITP is one of the manifestations of a coronavirus disease, as well as an adverse event occurring after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several cases of ITP have been described after vaccination with two mRNA-based vaccines—BTN162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)—against SARS-CoV-2. Herein, we report a case of ITP occurring after vaccination with ChAdOx1 adenovirus vector nCoV-19 (AstraZeneca) vaccine in Korea. A 66-year-old woman presented with multiple ecchymoses on both upper and lower extremities and gingival bleeding, appearing 3 days after receiving the first dose of ChAdOx1 nCoV-19. Her laboratory results showed isolated severe thrombocytopenia without evidence of combined coagulopathy. She was diagnosed with ITP and successfully treated with high-dose dexamethasone and intravenous immunoglobulin. Clinical suspicion to identify vaccine-related ITP is important to promptly initiate appropriate treatment., Graphical Abstract

The prognosis of patients with acute leukemia relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) is dismal. We aimed to evaluate the outcomes and prognostic factors of the second HSCT (HSCT2) in acute leukemia patients relapsed after the first HSCT (HSCT1). We analyzed 80 patients who received HSCT2 for relapsed acute leukemia in two Korean institutes. All but four patients received HSCT2 from a donor other than matched sibling donor: an unrelated donor (URD) in 30 and a familial haploidentical donor (FHD) in 46. Forty-four patients (55.0%) were in complete remission (CR) or CR with incomplete count recovery (CRi) at HSCT2, and the median time from HSCT1 to relapse was nine months. The two-year overall survival (OS) and event-free survival (EFS) were 21.0% and 17.5%, respectively. The outcomes were similar between URD and FHD. Multivariate analysis demonstrated that disease status (active disease vs. CR/CRi) at HSCT2 and remission duration after HSCT1 were independent prognostic factors for OS and EFS after HSCT2. HSCT2 from URD or FHD was feasible in patients with acute leukemia relapsed after allogeneic HSCT. Also, our study confirmed two critical prognostic factors; disease status at HSCT2 and remission duration after HSCT1.

DDX41 mutations are associated with hematologic malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but the incidence in idiopathic cytopenia of undetermined significance (ICUS) is unknown. We investigated the incidence, genetic characteristics, and clinical features of DDX41 mutations in Korean patients with ICUS, MDS, or AML. We performed targeted deep sequencing of 61 genes including DDX41 in 457 patients with ICUS (n=75), MDS (n=210), or AML (n=172). Germline DDX41 mutations with causality were identified in 28 (6.1%) patients, of whom 27 (96.4%) had somatic mutations in the other position of DDX41. Germline origins of the DDX41 mutations were confirmed in all of the 11 patients in whom germline-based testing was performed. Of the germline DDX41 mutations, p.V152G (n=10) was most common, followed by p.Y259C (n=8), p.A500fs (n=6), and p.E7* (n=3). Compared with non-mutated patients, patients with a DDX41 mutation were more frequently male, older, had a normal karyotype, low leukocyte count, and hypocellular marrow at diagnosis. Three of the four ICUS patients with germline DDX41 mutations progressed to MDS. The incidence of DDX41 mutations in Korean patients was high and there was a distinct mutation pattern, in that p.V152G was a unique germline variant. ICUS harboring germline DDX41 mutations may be regarded as a hereditary myeloid neoplasm. Germline DDX41 mutations are not uncommon and should be explored when treating patients with myeloid malignancies.

The BCR-ABL1 fusion gene generating an oncogenic tyrosine kinase is a hallmark of chronic myeloid leukemia (CML), which can be successfully targeted by BCR-ABL1 tyrosine kinase inhibitors (TKIs). However, treatment-free remission has been achieved in a minority of patients due to evolving TKI resistance and intolerance. Primary or acquired resistance to the approved TKIs and progression to blast crisis (BC), thus, remain a major clinical challenge that requires alternative therapeutic strategies. Here, we first demonstrate that donor natural killer (NK) cells prepared using a protocol adopted in clinical trials can efficiently eliminate CML-BC blasts, with TKI resistance regardless of BCR-ABL1 mutations, and preferentially target CD34+CD38− leukemic stem cells (LSC), a potential source of disease relapse. Mechanistically, the predominant expression of PVR, a ligand for the NK cell-activating DNAM-1 receptor, in concert with ICAM-1, a ligand for NK cell adhesion, confer this susceptibility to NK cells, despite the lack of ligands for NKG2D, a principal NK cell activating receptor, as an immune evasion mechanism. With these mechanistic insights, our findings provide a proof-of-concept that donor NK cell-based therapy is a viable strategy for overcoming TKI resistance in CML, particularly the advanced, multi-TKI-resistant CML with dismal outcome.

Blood sampling via heparin-locked central venous catheter, including coagulation tests, is possible in accordance with the Clinical & Laboratory Standards Institute guidelines. However, differences exist between the test values of samples obtained from central venous catheter and those obtained from peripheral veins, even the guidelines are followed. To compare the coagulation time between blood samples from the heparin-locked central venous catheter and peripheral veins. In total, 72 hospitalized patients using heparin-locked Hickman catheters were enrolled. Blood samples for coagulation testing were simultaneously obtained via the peripheral veins and heparin-locked Hickman catheters. For sampling from the catheters, 0.9% sodium chloride flushing was performed and 10 or 23 ml of blood was discarded prior to collecting the coagulation test samples. Correlation, Bland-Altman plot, covariate, and regression analysis were performed for data analyses. Despite following the guidelines, the activated partial thromboplastin time test values differed. In the 10 ml of blood discard group, a correlation coefficient of 0.378 and a mean bias of 6.46 s were determined, while and in the 23 ml blood discard group, a correlation coefficient of 0.80 and a mean bias of 2.518 s were determined. Therefore, the volume of blood discarded from the heparin-locked Hickman catheters may affect the activated partial thromboplastin time test values.

This retrospective analysis compared anthracyclines (as part of an induction regimen) in 128 newly diagnosed FLT3-ITD-mutated AML patients. Induction regimens comprised high-dose daunorubicin (HD-DN; 90 mg/m2/d × 3d; n = 44), standard-dose daunorubicin (SD-DN; 45 mg/m2/d × 3d; n = 51), or idarubicin (IDA; 12 mg/m2/d × 3d; n = 33) in combination with cytarabine (100–200 mg/m2/d × 7d). Fifty-three patients showing persistent leukemia on interim bone marrow examination received a second course of induction chemotherapy comprising 2 days of daunorubicin (45 mg/m2/d) or IDA (8 or 12 mg/m2/d) in addition to 5 days of cytarabine. Complete remission (CR) rates were 77.3%, 56.9%, and 69.7% for HD-DN, SD-DN, and IDA, respectively (P = 0.101; HD-DN vs. SD-DN, P = 0.036; HD-DN vs. IDA, P = 0.453; IDA vs. SD-DN, P = 0.237). The HD-DN showed higher overall survival (OS) and event-free survival (EFS) than SD-DN and IDA: the differences between HD-DN and SD-DN (P = 0.009 for OS and P = 0.010 for EFS) were statistically significant. Results of in vitro studies using FLT3-ITD-mutated cell lines supported these findings. In conclusion, HD-DN improved the CR rate, OS, and EFS of FLT3-ITD-mutated AML patients. HD-DN also tended to yield better outcomes than IDA, though the difference was not significant. The superiority of HD-DN over IDA should be confirmed in future studies.

Although nilotinib has improved efficacy compared to imatinib, suboptimal response and intolerable adverse events (AEs) limit its effectiveness in many patients with chronic myeloid leukemia in chronic phase (CML‐CP). We investigated the 2‐year efficacy and safety of nilotinib and their relationships with plasma nilotinib concentrations (PNCs). In this open‐label, multi‐institutional phase 4 study, 110 Philadelphia chromosome‐positive CML‐CP patients were treated with nilotinib at a starting dose of 300 mg twice daily. Molecular responses (MRs) and AEs were monitored for up to 24 months. The 24‐month cumulative MR 4.5 rate was evaluated as the primary endpoint. Plasma samples were collected from 94 patients to determine PNCs, and the per‐patient mean was used to categorize them into four mean PNC (MPNC) groups. Cumulative MR rates and safety were compared between groups. With a median follow‐up of 22.2 months, the 24‐month cumulative MR 4.5 rate was 56.2% (95% confidence interval, 44.0%–8.3%), and the median time to MR 4.5 was 23.3 months. There were no significant differences in the cumulative rates of major molecular response, MR 4, and MR 4.5 between MPNC groups. One patient died due to acute viral hepatitis, and two developed hematological or cytogenetic relapse, while no progression to accelerated or blast phase was observed. Safety results were consistent with previous studies with no new safety signal identified. Across the MPNC groups, there was no significant linear trend in the frequency of AEs. Nilotinib is highly effective for the treatment of CML‐CP with manageable AEs. The measurement of PNC has no predictive value for patient outcomes and is thus not found to be clinically useful. This study is registered with clinicaltrials.gov, Number NCT03332511.

The prognosis of adult acute lymphoblastic leukemia is much worse than that of pediatric acute lymphoblastic leukemia, even when patients achieve complete remission. Early response to treatment can be an important alternative indicator of treatment outcomes. The purpose of our current study was to identify the prognostic value of the blast percentage of the induction interim bone marrow, which might predict relapse-free survival and overall survival in patients with adult acute lymphoblastic leukemia. A retrospective analysis was performed on 80 adult patients diagnosed with Philadelphia chromosome-negative acute lymphoblastic leukemia from 1994 to 2011. Complete remission was observed in 75 (93.8%) patients after induction chemotherapy. On multivariate analysis, a reduction of blasts to a level of 5% or less in the induction interim bone marrow and CD20 positivity were significant prognostic predictors of relapse-free survival (hazard ratio, HR = 2.88, p = 0.006, and HR = 2.67, p = 0.010) and overall survival (HR = 2.10, p = 0.033, and HR = 2.39, p = 0.013). The blast percentage of the induction interim bone marrow may be a useful prognostic factor to predict outcome.

Introduction: Allogeneic hematopoietic cell transplantation is an only potentially curative option for patients with higher-risk myelodysplastic syndrome (MDS). Owing to the advances in treatment strategies including reduced intensity conditioning, graft-versus-host disease (GVHD) prevention and supportive care, more elderly patients or those with comorbidities can proceed to allogeneic HCT. However, the long-term survival rate following allogeneic HCT is reported to be less than 50%, and non-relapse mortality (NRM) rate is still high reaching upto 30%. In this study, we aimed to evaluate the feasibility of using post-transplantation cyclophosphamide (PTCy) as a GVHD prophylaxis in allogeneic HCT for higher-risk MDS patients. We also compared the post-transplantation outcomes of PTCy group and those of historical control who received HCT using anti-thymocyte globulin (ATG). Methods: Patients with higher-risk MDS or MDS/myeloproliferative neoplasm (MPN) with bone marrow blast ≥ 5% were included in this study. Higher-risk MDS was defined by MDS with International Prognostic Scoring System >1.0 or bone marrow blast ≥ 5% at any time points before HCT. Conditioning regimen consists of busulfan (4-days for patients aged Results: Ninety-two and 144 patients received allogeneic HCT using PTCy and ATG, respectively. The median overall survival were 47.9 and 44.0 months, respectively (P=.383). Cumulative incidence of total and grade II-IV acute GVHD in PTCy and ATG group were 19.6% vs. 37.5% (P=.002), and 2.6% vs. 21.7% (P Conclusion: Allogeneic HCT using PTCy as GVHD prophylaxis in higher-risk MDS seems feasible in terms of low rate of acute GVHD and relapse incidence. Disclosures Choi: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board; AbbVie: Honoraria, Other: Advisory board.

Background: HM43239 is a novel FMS-like tyrosine kinase 3 (FLT3) inhibitor with potent in vitro and in vivo activity against both FLT3 mutated and wild-type AML. Preclinically HM43239 was highly active against FLT3 internal tandem duplication (ITD) mutated as well as resistance-conferring D835 and gatekeeper (F691) tyrosine kinase domain (TKD) mutated AML cell lines and xenograft models (AACR2021 abstract 1257). In addition to FLT3, HM43239 inhibits phosphorylation of spleen tyrosine kinase (SYK) known to be highly activated in AML and associated with resistance to FLT3 targeted therapy. We report data from an ongoing Phase 1/2 dose escalation and expansion FIH study assessing the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of HM43239 in pts with R/R AML. Methods: A phase 1/2 trial was conducted to evaluate HM43239 in pts with R/R AML who had received at least 1 prior line of therapy, including ≥ 1 prior FLT3 inhibitors (FLT3i). Pts with or without a FLT3 mutation (FLT3m) received HM43239 orally once daily until unacceptable toxicity or no clinical benefit (each cycle of ~28 days). Doses 20 to 160 mg had been evaluated at the time of this abstract. The dose escalation was initiated with an accelerated titration design followed by a 3+3 design. The 3+3 design kicked in after the first instance of a dose limiting toxicity (DLT) or moderate toxicity (MT, a grade 2 non-hematologic adverse event (AE) judged by the investigator to be at least possibly related to study drug) occurred. Parallel backfill expansion of cohorts deemed safe were initiated based on the observed safety and efficacy in the dose-escalation. AEs were graded per NCI-CTCAE (v4.03). Responses were evaluable according to the international working group (IWG) AML criteria including complete remission (CR) and composite CR (CRc). PK was examined after single and multiple dose (15 or 17 days) of 20 to 160 mg. Inhibition of FLT3 phosphorylation (pFLT3) was evaluated by a plasma inhibitory activity (PIA) assay and correlated with exposure levels. Results: Twenty-eight pts were enrolled at multiple international centers between March 2019 and June 2021: 13 in the dose escalation cohorts 20 - 160 mg and 15 in the dose expansion cohort at 80 mg. Patient characteristics are shown in Table 1. Median number of prior therapies for AML in this R/R pts was 2 (range, 1-7). Ten pts (36%) had FLT3m, 16 pts (57%) had FLT3 wild-type (FLTwt), and 2 pts (7%) were FLT3 unknown at enrollment. Most frequently reported FLT3m was ITD (21%) followed by TKD (11%), and ITD/TKD (4%). After 1 pt in the 80 mg dose escalation cohort showed a MT (Grade 3 nausea), the accelerated titration design was switched to the 3+3 design for 80 mg and higher doses. The most common drug related treatment-emergent adverse events (TEAEs) were diarrhea (14%), nausea (7%), vomiting (7%) and alanine aminotransferase increased (7%), and no drug related > Grade 3 TEAEs were observed to date. Five of 28 pts treated at all dose levels achieved CRc (17.9%) (Table 2). Best response was IWG CR in 4 pts and IWG CRi in 1 pt. All 5 CRc pts were treated at the 80 mg dose (n= 19) resulting in CRc of 26.3% at the 80 mg dose. Of 8 FLT3m pts at 80 mg, CRc was achieved in 3 pts (37.5%) and one had received prior FLT3i, gilteritinib. Of 11 FLT3wt pts at 80 mg, CRc was achieved in 2 pts (18%), including a relapsed TP53m AML who achieved CR and remained on study for 12 months before progressing. Among the remaining 4 CRc pts, three proceeded to hematopoietic stem cell transplantation (HSCT) remaining alive and in remission post HSCT at this time, and one remains in CR in Cycle 3 (Fig 1). The plasma concentration showed dose-dependent increase after single administration of 20 to 160 mg. After 17 days of treatment, steady-state was reached and PIA assay showed dose-dependent inhibition of pFLT3 with up to 90% at the dose levels ≥ 80 mg. Conclusions: HM43239 a preclinically potent FLT3 and SYK inhibitor showed a favorable safety profile with only mild AEs and no DLTs in this ongoing Phase 1/2 study. At 80 mg dose, HM43239 demonstrates clinical activity in both FLT3m (including a prior gilteritinib failure pt) and FLT3wt AML (including >1 year CR without HSCT in a relapsed TP53m AML). We continue to further evaluate doses above 80 mg to determine the optimal recommended Phase 2 Dose (RP2D). The dose escalation cohort of 160 mg and the dose expansion cohort of 120 mg are currently enrolling and updated response, safety, and PK/PD data will be presented. NCT03850574. Figure 1 Figure 1. Disclosures Daver: Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Trovagene: Consultancy, Research Funding; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Lee: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Arellano: Syndax Pharmaceuticals, Inc: Consultancy; KITE Pharma, Inc: Consultancy. Yoon: Hanmi Pharmaceutical: Current Employment. Lee: Hanmi Pharmaceutical: Current Employment. Kim: Hanmi Pharmaceutical: Current Employment. Lee: Hanmi Pharmaceutical: Current Employment. Jonas: AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy; 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie: Other: Travel reimbursement. Baek: Hanmi Pharmaceutical: Current Employment.

Background Idiopathic cytopenia of undetermined significance (ICUS) is characterized by a persistent and clinically significant cytopenias which does not meet the diagnostic criteria for myelodysplastic syndrome (MDS). In some patients with ICUS, disease evolution to MDS or acute myeloid leukemia after variable periods of time was observed in several studies. However, the incidence and predictive factors of progression as well as management guidelines for ICUS patients are not well established. We aimed to identify the clinical and genetic characteristics of ICUS in comparison with lower-risk MDS for understanding the pathophysiologic features and providing guidance for treating physicians. Methods We performed targeted deep sequencing including 61 myeloid neoplasm-related genes with a MiSeqDx sequencer (Illumina) using bone marrow (BM) samples obtained from the patients with ICUS (n=139) and MDS (n=226) between May 2009 and December 2019. The cut-off level of variant allele frequency (VAF) was set to 2.0% of mutant allele reads. Cloncal cytopenia of undetermined significance (CCUS) was defined as ICUS with ≥ 2% VAF of mutations and lower-risk MDS was defined as MDS with revised international prognostic scoring system ≤3.5. Results When we compared the overall survival (OS) of the patients according to the disease subtypes, OS of CCUS (77.0% at 5-year) was significantly better than that of higher-risk MDS (41.0%, P Conclusion In our study, CCUS and lower-risk MDS showed similar OS which was significantly better than higher-risk MDS and worse than non-clonal ICUS. The clinical and mutational characteristics were also similar except for the degree of anemia and the SF3B1 and STAT3 mutation. Our findings suggest that the patients with CCUS may be regarded and treated as the lower-risk MDS despite a lack of significant dysplasia or MDS-associated definitive chromosomal abnormality. Disclosures Choi: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Ingenium Therapeutics, Daejeon, Korea: Consultancy, Current holder of individual stocks in a privately-held company. Lee: Korean Society of Hematology: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Other: Advisory board; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board.

Background Allogeneic hematopoietic cell transplantation (HCT) has been more widely applicable to the patients with hematologic malignancies owing to the increased donor availability, advances in conditioning regimen, prevention of transplantation-related toxicities, and general supportive care. However, there is no comprehensive and uniform approach for decision making which incorporates transplantation-related factors including patients and donor selection, conditioning intensity, or prevention of graft-versus-host disease (GVHD). In this regard, we aimed to establish and validate a machine learning-based predictive model for survival after allogeneic HCT in hematologic malignancies. Method Data from 2,011 patients with hematologic malignancies (1,464 acute leukemia, 296 myelodysplastic syndrome, 100 chronic myeloid leukemia, 45 myeloproliferative neoplasm, 85 lymphoma, and 21 multiple myeloma) who received allogeneic HCT between December 1993 and December 2019 at the Asan Medical Center were retrospectively analyzed. Results The median overall and event-free survival of total patients were 4.2 year (95% confidence interval [CI], 2.9-5.4) and 1.5 year (95% CI, 1.1-1.8), respectively. To predict post-transplantation survival, the patients were classified into "survived more than 5 years" and "died before 5 years". Among four major machine learning models (random forest [RF], support vector machine, logistic regression, and feed forward neural network), we selected RF method according to the predictive power of each algorithm. Using the RF machine learning algorithm, we developed a post-transplantation survival predicting model with the training cohort of 1,408 patients (70%) and tested it with the validation cohort of 603 patients (30%). Of >200 variables, 33 were selected using recursive feature elimination, and the estimated area under the receiver operator characteristic curve and accuracy of the model was 0.812 and 0.73, respectively. We then evaluated the robustness of predictive power of the model using 10-fold cross-validation in validation cohort. In addition, risk scores were calculated from each patient in the validation cohort, and there was an agreement between the estimated predicted risk and observed risk. Conclusion In conclusion, the machine learning-based prediction model seems feasible assuming post-transplantation survival outcomes in hematologic malignancies. Our findings could be helpful for clinicians to select more appropriate donor in terms of age or type of human leukocyte antigen mismatch, conditioning regimen, and GVHD prophylaxis. Disclosures Lee: Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Lee:Hanmi: Research Funding.

Posaconazole prophylaxis is effective in decreasing the incidence of invasive fungal diseases (IFDs) in patients with acute myeloid leukemia (AML). However, the use of antifungal prophylaxis varies in real-life practice, and only a small number of studies have compared the incidence of IFDs between those receiving posaconazole prophylaxis and those without prophylaxis. We compared the clinical characteristics and outcomes of IFDs between patients with AML who received posaconazole prophylaxis and those without antifungal prophylaxis.We reviewed the medical records of adult AML patients who underwent induction chemotherapy between June 2016 and October 2019 at Asan Medical Center (Seoul, South Korea), where posaconazole prophylaxis is not administered in patients with gastrointestinal symptoms that may hinder sufficient absorption of oral prophylactic agents, and in patients with abnormal liver functions considering the possible exacerbation of adverse events. Patients who received posaconazole prophylaxis for ≥7 days were included in the prophylaxis group. Clinical characteristics and outcomes including the incidence of IFDs were compared between the 2 groups.Of the 247 patients with AML who underwent induction chemotherapy, 162 (66%) received posaconazole prophylaxis and 85 (34%) did not receive any prophylaxis. The incidence of proven/probable IFD was significantly higher in the no prophylaxis group than in the prophylaxis group (9.4% [8/85] vs 2.5% [4/162], P = .03). Of the 8 cases of IFDs in the no prophylaxis group, 7 were mold infections and 1 was invasive candidiasis. Of the 4 cases of IFDs in the prophylaxis group, 3 were mold infections and 1 was invasive candidiasis. Patients with posaconazole prophylaxis less frequently received therapeutic antifungal therapy (2.5% vs 9.4%, P = .03) and had a longer median, duration from chemotherapy to antifungal therapy compared with the no prophylaxis group (18 vs 11 days, P .99).Patients with AML who received posaconazole prophylaxis had a lower incidence of breakthrough IFDs compared with those who did not receive any prophylaxis. Invasive mold infection was the most common IFD regardless of antifungal prophylaxis.

To investigate the role of antithymocyte globulin (ATG)-containing reduced-intensity conditioning (RIC) in hematopoietic cell transplantation (HCT) from unrelated (UD) or haploidentical family donors (HFD), we conducted a phase 2 trial of 237 patients (age range, 16 to 69 years) with acute myeloid leukemia (AML) in remission. Patients undergoing UD-HCT (n = 93) or HFD-HCT (n = 59) received RIC comprising busulfan, fludarabine, and ATG, 9 mg/kg, whereas those undergoing HCT from matched sibling donors (MSD, n = 85) received myeloablative busulfan and cyclophosphamide conditioning or aforementioned RIC with ATG, 4.5 mg/kg. For graft-versus-host disease (GVHD) prophylaxis, cyclosporine and methotrexate were administered. The median follow-up period was 44.7 months after HCT for 161 survivors. For UD-HCT versus HFD-HCT, there were no significant differences in leukemia recurrence, nonrelapse mortality, relapse-free survival, grades 2 to 4 acute GVHD, and moderate-to-severe chronic GVHD. Furthermore, when the outcomes of UD-HCT and HFD-HCT were combined and compared with those of MSD-HCT, there were no significant differences in leukemia recurrence (3-year cumulative incidence, 30% versus 29%), nonrelapse mortality (3-year cumulative incidence, 7% versus 8%), relapse-free survival (3-year estimate, 63% versus 63%), and grades 2 to 4 acute GVHD (120-day cumulative incidence, 16% versus 13%). Moderate-to-severe chronic GVHD, however, occurred less frequently in UD/HFD-HCT (2-year cumulative incidence, 22% versus 40%; P = .006). The addition of ATG to conditioning regimen was a significant predictor for less chronic GVHD (subdistribution hazard ratio, .59). In AML in remission, UD/HFD-HCT after ATG-containing RIC achieved leukemia control equivalent to that of MSD-HCT. Despite HLA disparity in UD/HFD-HCT, chronic GVHD occurred less frequently after ATG-containing RIC, suggesting a strong GVHD-modulating effect of ATG.

Purpose We compared two induction regimens, idarubicin (12 mg/m2/d for 3 days) versus high-dose daunorubicin (90 mg/m2/d for 3 days), in young adults with newly diagnosed acute myeloid leukemia (AML). Patients and Methods A total of 299 patients (149 randomly assigned to cytarabine plus idarubicin [AI] and 150 assigned to cytarabine plus high-dose daunorubicin [AD]) were analyzed. All patients received cytarabine (200 mg/m2/d for 7 days). Results Complete remission (CR) was induced in 232 patients (77.6%), with no difference in CR rates between the AI and AD arms (80.5% v 74.7%, respectively; P = .224). At a median follow-up time of 34.9 months, survival and relapse rates did not differ between the AI and AD arms (4-year overall survival, 51.1% v 54.7%, respectively; P = .756; cumulative incidence of relapse, 35.2% v 25.1%, respectively; P = .194; event-free survival, 45.5% v 50.8%, respectively; P = .772). Toxicity profiles were also similar in the two arms. Interestingly, overall and event-free survival times of patients with FLT3 internal tandem duplication (ITD) mutation were significantly different (AI v AD: median overall survival, 15.5 months v not reached, respectively; P = .030; event-free survival, 11.9 months v not reached, respectively; P = .028). Conclusion This phase III trial comparing idarubicin with high-dose daunorubicin did not find significant differences in CR rates, relapse, and survival. Significant interaction between the treatment arm and the FLT3-ITD mutation was found, and high-dose daunorubicin was more effective than idarubicin in patients with FLT3-ITD mutation.

Background: We prospectively evaluated prognostic value of lymphocyte subpopulations in peripheral blood of allogeneic hematopoietic stem cell transplant (HSCT)-recipients. Methods: 113 allogeneic HSCT (47 sibling matched, 37 unrelated matched, 29 haploidentical)-performed patients diagnosed as AML (n=66), ALL (n=28) and MDS (n=19) were prospectively enrolled. 14 lymphocyte subpopulations were quantified by flow cytometry of PB at specific time-points after HSCT, and their prognostic impacts were analyzed. Results: At 1, 2, and 3 months post-HSCT, significant adverse impact on overall survival (OS) and/or event free survival (EFS) was exhibited by low levels of natural killer (NK) cells (≤32/µL and ≤90/µL at 1 and 2 months on OS and EFS); regulatory T cells (≤1/µL) on EFS at 2 months; and B cells (≤19/µL and ≤92/µL for OS and EFS at 3 months). At 12 months, low levels of T cells (≤1,180/µL), helper/inducer (H/I) T cells (≤250/µL), cytotoxic/suppressor (C/S) T cells (≤541/µL), and NK cells (≤138/µL) were associated with significantly higher risk of relapse. Low levels of T cells (≤879/µL) and C/S T cells (≤541/µL), and high level of naive thymic T cells (>115/µL) showed a significant association with poor OS; low levels of C/S T cells (≤541/µL) and NK cells (≤138/µL) showed a significant adverse impact on EFS. Conclusions: Low levels of NK cells, regulatory T cells, and B cells at early stage post-HSCT are adverse prognostic indicators. At late stage, low levels of T cells and their subpopulations, NK cells, and high level of naive thymic T cells are adverse prognostic indicators. This article is protected by copyright. All rights reserved.

CMV-specific cell mediated immune responses before and after hematopoietic stem cell transplantation (HCT) can categorize patients as at high or low risk of CMV development.We evaluated the usefulness of the CMV-specific T-cell ELISPOT assay for predicting the development of CMV infections after HCT in recipients with donor-positive and recipient-positive CMV serology (D+/R+ ).CMV pp65 and IE1-specific ELISPOT assays were performed before HCT (D0), and at 30 (D30) and 90 (D90) days after HCT.Of the 84 HCT recipients with D+/R+, 42 (50%) developed≥1 episode of CMV infection. Thirty-nine (64%) of 61 patients with Δ(D30-D0) pp6542 developed CMV infections compared with 3 (14%) of 21 patients with Δ(D30-D0) pp65≥42 (P0.001). Twenty-three (74%) of 31 patients with Δ(D30-D0) IE1-4 developed CMV infections compared with 19 (37%) of 51 patients with Δ(D30-D0) IE1≥-4 (P=0.001). pp65 Δ(D30-D0) ≥42 had 93% sensitivity for ruling out subsequent CMV infection, and pp65 Δ(D30-D0)42 followed by Δ(D30-D0) IE1-4 had 100% specificity for ruling in the subsequent CMV infection. In addition, 10 (53%) of 19 patients with Δ(D90-D30) pp6523 had relapsing CMV infections, compared with 3 (15%) of 20 patients with Δ(D90-D30) pp65≥23 (P=0.02). The sensitivity and specificity of Δ(D90-D30) pp65 were 77% (95% CI 50-92) and 65% (95% CI, 46-81).Dynamic change in the CMV-specific ELISPOT assay before versus after HCT appears to predict the subsequent development of CMV infection and relapsing CMV infection.

Hematopoiesis involves complex interactions between hematopoietic cells and the bone marrow (BM) microenvironment. The specific causes and mechanisms underlying dysregulated hematopoiesis are unknown. Here, BM biopsy specimens from patients with aplastic anemia (AA) and chronic myeloid leukemia (CML) and normal marrow were analyzed by semiquantitative immunohistochemistry to determine changes in the hematopoietic stem cell (HSC) compartment and BM microenvironment. HSC levels were lowest in AA and highest in CML. T and B lymphocytes were decreased in AA (p 0.01) and CML (p 0.01). Natural killer cells were observed in AA, but were absent in CML and healthy controls (p 0.01). Macrophages and mast cells were absent in CML. There were significant differences between AA and CML stromal cell components. No nestin