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Allogeneic hematopoietic cell transplantation (HSCT) has curative potential for Acute myeloid leukemia (AML). Given that the median age of acute myeloid leukemia (AML) patient is 68 years, the majority of HSCT candidates in AML are inevitably elderly patients. Advances in alternative donor HSCT and reduced intensity conditioning have expanded the opportunities for elderly patients to undergo HSCT. Previously, we reported HSCT outcomes of older adults with AML according to donor type, showing comparable outcomes among haploidentical donor (HID), matched unrelated donor (MUD) and matched sibling donor group, with especially superior survival in the MUD group ( Transplantation and Cellular Therapy2021; 27: 774.e1-774.e12.). Since donor age has been shown to be a significant factor in HSCT outcomes, we investigated the HSCT outcomes of older AML HSCT recipients from HID according to donor age, and compared to those of MUD HSCT recipients.

Introduction

CK1⍺ is a member of casein kinase 1 (CK1) family, a multifunctional serine/threonine kinase conserved in eukaryotes from yeast to humans. Substrates of CK1⍺ include various proteins important in cancer and regulate multiple survival pathways such as p53, Wnt, autophagy and NF-B signaling pathways. In particular, CK1- serves as an upstream regulator of p53 pathway through regulation of MDM2 and MDMX and degradation of CK1- may prevent MDM2 and/or MDMX mediated inactivation of p53 function, thus facilitate cell death.

Background:The development of the lymphoma treatment increased the number of patients with long-term survival. Due to the nature of lymphoma heterogeneous group of hematological malignancies, lymphoma treatment varies based on histopathological features. Various cytotoxic chemotherapy or radiotherapy could increase patients' risk of secondary cancer. Few studies evaluated the impact on survival of co-occurring cancers in mature lymphoid malignancies.

Genomic mutational profiles substantially influence selection of the treatment as they impact drug responses. However, the expected response to a specific treatment based on the data from a large group of the patients with the similar mutational profile is not always equal to the actual response observed at an individual basis. In this study, we measured ex vivosensitivity of the patient-derived AML cells to 21 different anti-cancer drugs and assessed their prognostic utility.

Introduction

Liver dysfunction is one of the dismal complications after allogeneic hematopoietic cell transplantation (Allo-HCT). Although most frequently suspected complications are hepatic graft-versus-host disease (GVHD) and toxic hepatitis, precise diagnosis can be challenging. In order to accurately diagnose hepatic dysfunction after allo-HCT, liver biopsies are occasionally done. However, even after attaining pathology, discerning between overlapping pathologic findings among different hepatic complications, still remains to be a challenge. We tried to review the pathologic findings of liver biopsies of patients with elevated liver enzymes after allo-HCT.

BackgroundAcute lymphoblastic leukemia (ALL) is frequently accompanied with the involvement of the central nervous system (CNS). The clinical prognosis for ALL patients with CNS disease is generally unfavorable, and prophylactic measures such as intrathecal chemotherapy are highly recommended. In adult ALL patients, hematopoietic stem cell transplantation (HSCT) presents a potential curative approach. However, there are currently only a few reports available on the risk factors and epidemiology of CNS relapse after HSCT. MethodWe conducted a retrospective single-center cohort study involving 1043 patients diagnosed with either acute lymphoblastic leukemia (ALL) or mixed phenotype acute leukemia (MPAL). These patients were treated at our center using the same treatment protocol between 2009 and 2022. During the remission induction phase, we utilized a modified hyper-CVAD regimen, along with six rounds of prophylactic intrathecal (IT) chemotherapy. High-risk patients who had suitable donors underwent allogeneic hematopoietic stem cell transplantation (HSCT) as part of their post-remission therapy. Diagnosis of central nervous system (CNS) leukemia was established when neurologic symptoms were observed in correlation with CNS lesions on imaging studies, or when leukemic blasts were detected in the cerebrospinal fluid (CSF). In our study, we examined the incidence, risk factors, and survival outcomes of patients who experienced CNS relapse after transplantation. ResultsAmong the entire cohort of 1043 patients, CNS involvement was observed in 3 (0.3%) patients at initial diagnosis and 12 (1.2%) during chemotherapy. We proceeded with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 755 consecutive patients. Among these 755 patients, 3 had CNS leukemia prior to transplantation. Among the group of 755 patients, a total of 224 (29.6%) experienced relapse. Of these relapses, 142 (18.8%) were bone marrow relapses alone, 54 (7.1%) were extramedullary relapses alone (with CNS involvement in 21 [38.8%]), and 28 (3.7%) had both bone marrow and extramedullary relapses (with CNS involvement in 13 [46.4%]). Overall, extramedullary relapse was observed in 82 (10.8%) patients, with CNS involvement in 34 (4.5%) cases, following allo-HSCT. The 5-year cumulative incidence of CNS relapse was 4.6%, which was significantly higher in patients with Philadelphia chromosome-positive (Ph-positive) ALL (9.4% vs. 1.0%, p <0.001), as well as those with a high leukocyte count at diagnosis (8.3% vs. 2.6%, p = 0.001). Among the Ph-positive ALL cases, a high leukocyte count (n=151) was associated with a higher prevalence of pre-HSCT minimal residual disease (MRD) > 0.1% (n=88), which exhibited a significantly increased incidence of CNS relapse (16.6% vs. 6.8%, p = 0.009). Factors such as age, number of intrathecal chemotherapy treatments, conditioning intensity, and dose of anti-thymocyte globulin did not have a significant impact. Among the 34 patients with CNS relapse, 21 (61.7%) had isolated CNS relapse, and 7 of them showed evidence of positive MRD. With the exception of one patient who refused further treatment, the remaining 33 patients received initial CNS local therapy, including intrathecal chemotherapy combined with radiotherapy in 27 (82.0%) cases, intrathecal chemotherapy alone in 6 cases, and radiotherapy alone in 4 cases. Out of these patients, 22 were treated with dasatinib or ponatinib, while 6 received salvage chemotherapy. The median overall survival for patients with CNS relapse was 11.2 months, which was 19.8 months for those with isolated CNS relapse and 10.9 months for those with CNS relapse accompanied by bone marrow relapse (p = 0.077). The subsequent 2-year cumulative incidence of CNS relapse was 30%. ConclusionBased on our findings, the current prophylaxis strategy employed for the prevention of post-HSCT CNS relapse in adult ALL appears to be effective. However, our data indicates that MRD-positive Ph-positive ALL requires distinct management due to its significantly elevated risk of CNS relapse. New strategies including prophylactic radiotherapy for this high-risk subgroup must be considered to prevent post-HSCT CNS disease.

In a previous study (SY Ahn et al, Cancer Res Treat 2023), we reported that the presence of only the basic leucine zipper in-frame mutation (bZIP in-f) CEBPAis associated with favorable outcomes in patients with CEBPAdouble mutations. However, when bZIP in-fCEBPAmutations were accompanied by certain mutations in chromatic/DNA modifiers, cohesion complex, and splicing genes, patients exhibited inferior overall survival (OS). FLT3-ITD or additional cytogenetic abnormalities is known to rarely co-occur with CEBPAmutation in patients with AML. In cases where both bZIP in-fCEBPAand FLT3-ITD coexist, there are conflicting aspects in risk stratification, and research on its prognostic significance is limited. Therefore, we aimed to evaluate the prognostic significances of the co-occurrence of bZIP in-fCEBPAmutation with unfavorable genetic abnormalities in acute myeloid leukemia.

Acute myeloid leukemia (AML) is the 2nd most frequent developing hematologic malignancy with deep heterogeneity, but unfortunately the majority of patients relapse even after allogeneic hematopoietic stem cell transplantation (HSCT) in complete remission (CR). We have developed allogeneic HSCT from familial mismatched/haploidentical donors (FMT) in adult patients with a single disease entity of AML lacking of both HLA-identical siblings and well-matched unrelated donors (WMUD) from the mid 1990s. Previously, several pilot studies of FMT performed with various total body irradiation (TBI)-based conditioning regimens (2~12 gray) with or without post-transplant cyclophosphamide (PT-Cy) as a graft-versus-host disease (GvHD) prophylaxis were reported. Here, we demonstrate about the encouraging outcomes of FMT using unmanipulated peripheral blood donor stem cells (PBSCs) and de-escalated dose of TBI (4~8 gray) containing conditioning regimen without T-cell depletion manner.

Background

Introduction

Introduction

Background:Haploidentical stem cell transplantation from a related mismatched donor (Haplo-SCT) has extended into adult patients with severe aplastic anemia (SAA) with advances in controlling graft failure and GVHD. However, because of concerns for morbidity and mortality, Haplo-SCT has been used as salvage treatment after the failure of immunosuppressive therapy (IST). In Haplo-SCT for SAA patients, the achievement of successful engraftment without GVHD is fundamental for better long-term survival with good quality of life. We optimized the dose of rabbit ATG and fractionated TBI (fTBI) with fixed dose of fludarabine (Flu, 150mg/m 2/day) using step-by-step dose de-escalation (Lee et al, Am J Hematol, 2018) and reached fTBI 600 cGy/Flu/intermediate-dose ATG (5 mg/kg). This protocol showed an overall survival rate of 91.0% after a median follow-up of 32.3 months in a study of 47 patients (Lee et al, BBMT, 2020). Here, we evaluated the feasibility of this protocol in both upfront and salvage setting for Haplo-SCT in adult patients with SAA.

Layered Ti3C2is attracting much attention as a promising electrode material for energy storage devices due to its excellent electrical conductivity and electrochemical properties due to its surface functional groups. Though various methods have been used to etch Ti3AlC2, the energy storage performance of Ti3C2mainly depends on exfoliation of aluminium, surface functional groups and intercalation of potassium. Hence, the optimization of Ti3AlC2etching process has been done by hydrothermal, stirring, and ultra-sonication methods which exhibits a different specific capacitance of 8.7 F g−1, 23.75 F g-1,and 141.45 F g−1respectively in 3 M KOH electrolyte at 2 mA constant current galvanostatic charge/discharge (GCD) analysis even though same etching time and quantity of MAX materials used. Surprisingly, all the samples show an increased specific capacitance up to 2000th cycles and a maximum value of around 170 % is reached and this value is maintained until 5000 charge-discharge cycle at 10 mA by GCD analysis. These electrochemical differences are investigated in terms TiAl bond termination and formation of O-Ti-O bonds due to the removal by Al during etching process. It is found from XPS analysis that -OH surface termination has occurred with F desorption and the interaction of K+ ion has increased the interlayer space between the individual layers. Moreover, the material has been phase transformed from Ti3C2to TiO2/Ti3C2hybrid crystal structure during the cycling stability test. The high dipole moment in TiO2/Ti3C2hybrid structure due to the decreased work function has increased the specific capacitance of MXene electrode material. To the best of the authors' knowledge, this has not been observed previously and reported.

Isolated nanodots of ZnO of at least 100 nm in size were deposited on transparent conducting substrate (Indium Tin Oxide coated quartz) by aqueous chemical growth technique. The nanodots have polycrystalline character and their crystallinity improves due to annealing in vacuum and oxygen atmosphere. The ultraviolet sensing property of the ZnO nanodot was investigated by current-voltage measurement. Under ultraviolet irradiation, the photo current was observed to be higher for the nanodots having higher volume density of point defects.

Only a few studies investigated prognostic values of next-generation sequencing-based measurable residual disease (NGS-MRD) detection in AML before or after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Moreover, NGS-MRD assessments were mostly performed only at pre-HSCT, and results were discordant.

Kim: Chugai: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Honoraria; BL&H: Research Funding; AbbVie: Honoraria; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AML Global Portal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Yuhan: Consultancy, Honoraria; Novartis: 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; Sanofi-Genzyme: Honoraria.

Fas-mediated apoptosis is a major physiologic mechanism by which activated T cells are eliminated after antigen-stimulated clonal expansion generates a specific cellular immune response. Because activated T cells are the major effectors of allograft rejection, we hypothesized that genetically modifying allogeneic bone marrow (BM) cells prior to transplantation could provide some protection from host T-cell attack, thus enhancing donor cell engraftment in bone marrow transplantation (BMT). We undertook studies to determine the outcome of lentiviral vector-mediated transduction of Fas ligand (FasL) into lineage antigen-negative (lin−) mouse BM cells (lin− BMs), in an allogeneic BMT model. FasL-modified lin− BMs killed Fas-expressing T cells in vitro. Mice that received transplants of allogeneic FasL+ lin−BMs had enhanced short-term engraftment, after nonmyeloablative conditioning, as compared to controls. We observed no major hepatic toxicity or hematopoietic or immune impairment in recipient mice at these time points. These results suggest potential therapeutic approaches by manipulating lymphohematopoietic stem-progenitor cells to express FasL or other immune-modulating genes in the context of BMT.

Fas-mediated apoptosis is a major physiologic mechanism by which activated T cells are eliminated after antigen-stimulated clonal expansion generates a specific cellular immune response. Because activated T cells are the major effectors of allograft rejection, we hypothesized that genetically modifying allogeneic bone marrow (BM) cells prior to transplantation could provide some protection from host T-cell attack, thus enhancing donor cell engraftment in bone marrow transplantation (BMT). We undertook studies to determine the outcome of lentiviral vector-mediated transduction of Fas ligand (FasL) into lineage antigen-negative (lin−) mouse BM cells (lin−BMs), in an allogeneic BMT model. FasL-modified lin−BMs killed Fas-expressing T cells in vitro. Mice that received transplants of allogeneic FasL+lin−BMs had enhanced short-term engraftment, after nonmyeloablative conditioning, as compared to controls. We observed no major hepatic toxicity or hematopoietic or immune impairment in recipient mice at these time points. These results suggest potential therapeutic approaches by manipulating lymphohematopoietic stem-progenitor cells to express FasL or other immune-modulating genes in the context of BMT.

Antihuman T-lymphocyte immune globulin (ATG) was shown to lower the incidence of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an unrelated donor. The type, dose, and duration of ATG treatment is a matter of ongoing controversy in allo-HSCT. Furthermore, there has been no phase 3 study to explore the role of ATG-thymoglobulin for the prevention of cGVHD in allo-HSCT from matched siblings, whereas results from a recent randomized trial of ATG-Fresenius was reported (NEJM 2016).

Kim: BMS: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Ilyang: Research Funding. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

Background

Kim: Pfizer: Research Funding; Ilyang: Research Funding; BMS: Research Funding; Novartis: Research Funding. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

Background

Background:in the 1970s, French-American-British (FAB) classification had been proposed and had been used for the classification of acute myeloid leukemia (AML) until cytogenetic risk classification was introduced. The FAB classification was based largely on morphologic features of leukemic blasts, and was useful to group AML. Morphology of leukemic blast is an endproduct of genetic changes in DNA/RNA levels in leukemic cells. Thus it is plausible that morphologic subtype can correlates with genetic changes in AML. The present study attempted to explore whether a specific somatic mutation correlates with morphologic subtype classified according to the FAB classification using mutation profile data by targeted deep sequencing in normal karyotype (NK) AML.

Background

Background

Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Jang: Kyowa Hakko Kirin Co., Ltd.: Research Funding.

No relevant conflicts of interest to declare.

Jang: Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Research Funding.

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Background:Vascular endothelial growth factor-C (VEGF-C) is a lymph-angiogenic growth factor and in general, transmits intracellular signals, resulting in cell proliferation and survival. Previous studies have reported that VEGF-C is important for cancer progression based on the autocrine VEGF-C loop promoting the invasion and metastasis of cancer cells as well as the spread of cancer cells by active recruitment of new lymphatics by tumor-derived VEGF-C. Acute myeloid leukemia (AML) blasts express VEGF-C and its receptors. A few studies demonstrated that high VEGF-C mRNA expression of AML blasts were related to increased in vitro and in vivo drug resistance and could predict adverse long-term outcomes. However, whether the expression of VEGF-C in the bone marrow (BM) and peripheral blood (PB) has a similar role in the pathophysiology of AML remains unclear.

So far, the cause of relapse or refractoriness in acute myeloid leukemia (AML) is regarded as the persistence of chemoresistant leukemic stem cells (LSCs). Even VEGF-C/FLT4 axis mediates blast proliferation and survival, understanding of the dynamic behavior of LSCs in bone marrow remains elusive. Especially, FLT4 endocytosis by VEGF-C is related to various biologic functions including signal activation. Based on our previous study, which addressed the potential of FLT4 as a marker for LSCs, we showed that surface FLT4 can be internalized by VEGF-C exposure in bone marrow (BM) derived LSCs. It resulted in resistant to chemotherapy, suggesting LSCs protection. In addition, data for apoptosis revealed that inhibition of FLT4 using MAZ51 with cytosine arabinoside (Ara-C) can effectually increase cell death under abundant VEGF-C in refractory patients. It indicated that targeting FLT4 allows investigators to establish advanced therapeutic strategy with conventional Ara-C in refractory patients with high VEGF-C. In clinic, low level of surface FLT4 in de novo AML-BM LSCs, but not PB cells were inclined to undergo refractory status after induction chemotherapy. To investigate whether FLT4 expressing CD34+CD38-LSCs can be protected by VEGF-C via internalization, FACS analysis, western blotting and immunocytochemistry were performed. Meanwhile, total 66 newly diagnosed (ND) AML patients were used to analyze for clinical correlation. (BM, n=37; PB, n=19). FACS analysis showed that surface FLT4 expressing CD34+CD38-LSCs in BM, but not PB, were significantly decreased by VEGF-C (In BM; without VEGF-C & with VEGF-C, 38.7±8.1% & 16.0±5.1%). Similar with surface FLT4 in PB cells, both intracellular FLT4 in BM and PB was highly sustained, regardless of VEGF-C (In BM; without VEGF-C & with VEGF-C, 62.9±17.2% & 69.7±14.9%, In PB; without VEGF-C & with VEGF-C, 77.4±15.6% & 70.4±21.8%). Immunocytochemistry and western blotting also showed internalization of surface FLT4 by VEGF-C treatment. FLT4+CD34+CD38-cells both in BM and PB were significantly higher in refractory patients than in post allogeneic stem cell transplantation (SCT) group, implying clinical correlation of FLT4 with refractory patients. Consistent with findings in ND-AML and refractory groups, FLT4+CD34+CD38-cells were highly sustained in complete remission group, showing drug resistant population (ND-AML, n=30; refractory AML, n=9; Complete remission AML, n=18; post-allogeneic stem cell transplantation, n=9). High level of VEGF-C was detected in refractory patients, compared to that of normal donors (Refractory AML, n=9, normal donors, n=7). Apoptosis results showed that high number of apoptotic CD45dimCD34+CD38-cells in MAZ51 (FLT4 antagonist) and Ara-C dual treatment under VEGF-C exposure, compared to no treatment of both MAZ51 and Ara-C (without VEGF-C; 0.5-1.3 folds, with VEGF-C; 2.7-43.3 folds) or single exposure either to MAZ51 or Ara-C (In Ara-C only; without VEGF-C; 1.0-9.5 folds, with VEGF-C; 0.1- 1.3 folds, In MAZ51 only; without VEGF-C; 1.1-1.7 folds, with VEGF-C; 1.3-39.3 folds), suggesting that Ara-C induced-blast apoptosis can be augmented by FLT4 inhibition even in the presence of VEGF-C in a sub-group of either refractory or relapsed AML patients. VEGF-C/FLT4 axis in AML is involved in PI3K and AKT pathway.

Background and Objectives

Introduction

Background:Acute promyelocytic leukemia (APL) is classified into a favorable-risk group and long-term overall survival (OS) is estimated at around 80%. Relapse rate of APL is lower than another acute myeloid leukemia (AML) subtypes, but we confront higher incidence of early deaths caused by fatal complications including bleeding events and differentiation syndromes (DS) during initial therapy. Recently, although arsenic trioxide (ATO) is introduced with a better survival outcome, the results were from data of low to intermediate-risk group. Thus, patients in high-risk group still show poor survival outcome with high probability of early complications and deaths. We calculated the incidence of DS and early deaths, and tried to find out affecting factors for those early events.