Pretransplantation predictors of survival in nonremission acute myeloid leukemia treated with haploidentical transplantation using steroid-based GVHD prophylaxis.

Haploidentical hematopoietic cell transplantation (HCT) using glucocorticoids for acute graft-versus-host disease prophylaxis (GC-haplo) may become a curative treatment option for nonremission acute myeloid leukemia (AML). This retrospective study aimed to identify pre-HCT predictors of survival in a cohort of 97 nonremission AML treated with GC-haplo in Hyogo Medical University Hospital between 2010 and 2020. Relapse and primary induction failure included in 70 (72%) and 27 (28%) patients, respectively. Sixty-one patients (63%) had undergone previous HCT. Multivariate analysis revealed that ≤ 6 months' duration between first complete remission (CR1) and first relapse (Rel1) (CR1-Rel1 interval) (hazard ratio 2.11, 95% confidence interval [CI] 1.15-3.89, P = 0.016) and serum albumin before starting the conditioning treatment of ≤ 3.5 g/dL (hazard ratio 1.80, 95%CI 1.09-2.96, P = 0.022) as risk factors for overall survival. Among three groups categorized according to serum albumin and CR1-Rel1 interval, the best 3-year overall survival was observed in patients with albumin > 3.5 g/dL and CR1-Rel1 interval > 6 months or primary induction failure (50.2%, 95%CI 28.9%-68.3%, P < 0.001), revealing that survival could be predicted using albumin and past CR duration in patients with very high-risk AML not in remission before GC-haplo.

Individualized rabbit anti-thymocyte globulin dosing in adult haploidentical hematopoietic cell transplantation with high-risk hematologic malignancy: Exposure-response analysis and population pharmacokinetics simulations.

Hematopoietic cell transplantation (HCT) for hematologic malignancies with non-remission disease and/or prior post-transplant relapse have poor relapse-free survival. We previously demonstrated the efficacy of haploidentical reduced-intensity HCT regimen with glucocorticoid-based graft-versus-host disease (GVHD) prophylaxis. We recently showed a possible association between rabbit antithymocyte globulin (rATG) exposure and acute GVHD (aGVHD) risk, leading to hypothesize that optimization of rATG exposure may further improve this regimen. We retrospectively examined the exposure-response association of rATG and key clinical outcomes post haploidentical HCT. We subsequently developed an individualized rATG dosing that optimizes rATG exposure using a previously developed population pharmacokinetic model. Of the 103 patients analyzed, the median age was 47 years (range: 17-70) and majority had a non-remission disease prior to HCT (88%). rATG concentration on day 0 of HCT (Cday_0 ) was the strongest predictor of Grade 2-4 aGVHD through day +100. Patients with Cday_0 ≥ 20 µg/mL had an approximately 3-fold lower risk of Grade 2-4 aGVHD (hazard ratio [HR]: 0.32, 95% confidence interval [CI]: 0.16, 0.62) and Grade 3-4 aGVHD (HR: 0.33, 95% CI: 0.16, 0.68) as well as an approximately 2-fold lower risk of overall mortality (HR: 0.47, 95% CI: 0.28, 0.77) and relapse (HR: 0.50, 95% CI: 0.26, 0.94). In conclusion, this reduced-intensity haploidentical HCT regimen with exposure-optimized rATG may provide a promising option to patients undergoing high-risk HCT for hematologic malignancy. The developed rATG dosing warrant prospective validation.

The Prognostic Impact of MYC Gene-Related Abnormalities on Multiple Myeloma Outcome through Fluorescence in situ Hybridization Analysis.

INTRODUCTION: Chromosomal abnormalities (CAs) have been identified as important factors in determining the biological features and prognostic value of multiple myeloma (MM). MYC gene-related abnormalities (MYC GAs) are one of the CAs, but their unfavorable impact has not been fully investigated in daily clinical practice. METHODS: This study retrospectively analyzed the prognostic impact of MYC GAs on 81 patients through fluorescence in situ hybridization analysis in our institute. RESULTS: MYC GAs were associated with poor overall survival (hazard ratio [HR], 3.08; 95% confidence interval [CI]: 1.23-7.73; p = 0.017), progression-free survival (PFS) (HR, 2.96; 95% CI: 1.58-5.53; p < 0.001), and time to next treatment (TNT) (HR, 2.11; 95% CI: 1.13-3.93; p = 0.018) in the median follow-up of 34.7 months. Furthermore, MYC GAs with an additional chromosome 8 (MYC-Ch8(+)) were associated with shorter PFS (HR, 3.15; 95% CI: 1.38-7.2; p = 0.0064), whereas MYC GAs without an additional chromosome 8 (MYC-Ch8(-)) were associated with shorter PFS (HR, 3.62; 95% CI: 1.51-8.68; p = 0.004) and shorter TNT (HR, 3.72; 95% CI: 1.41-9.81; p = 0.0078). CONCLUSION: These findings could help identify high-risk patients with MM. Further prospective studies are needed to confirm the significance of MYC GAs for the MM prognostic effect.

Increased SLAMF7high monocytes in myelofibrosis patients harboring JAK2V617F provide a therapeutic target of elotuzumab.

Monocyte-derived fibrocytes recently garnered attention because the novel pathogenesis of myelofibrosis (MF), and suppression of fibrocyte differentiation by serum amyloid P remarkably improved MF. We previously revealed that human fibrocytes highly expressed signaling lymphocytic activation molecule F7 (SLAMF7) compared with macrophages and that SLAMF7high monocytes in the peripheral blood (PB) of MF patients were significantly elevated relative to those in healthy controls (HCs). In this study, we evaluated SLAMF7high monocyte percentage in the PB of HCs, myeloproliferative neoplasm (MPN) patients with MF, and MPN patients without MF by using a cross-sectional approach. We found that MPN patients with MF who harbored JAK2V617F had a significantly elevated SLAMF7high monocyte percentage, which correlated positively with the JAK2V617F allele burden. In addition, the serum concentration of interleukin-1ra (IL-1ra) was significantly correlated with the SLAMF7high monocyte percentage and JAK2V617F allele burden. These findings suggest that both SLAMF7high monocytes and IL-1ra could be useful noninvasive markers of MF onset. Furthermore, the JAK2V617F allele burden of SLAMF7high monocytes was significantly higher than that of SLAMF7low monocytes and could be a potential target of elotuzumab (Elo), an anti-SLAMF7 antibody used for treating multiple myeloma. Elo independently inhibited differentiation of fibrocytes derived not only from HCs but also from MF patients in vitro. Elo also ameliorated MF and splenomegaly induced by romiplostim administration in humanized NOG mice. In conclusion, an increase of SLAMF7high monocytes with higher JAK2V617F allele burden was associated with the onset of MF in MPN patients harboring JAK2V617F, and Elo could be a therapeutic agent for MPN patients with MF who harbor JAK2V617F.

[Spontaneous resolution of refractory ascites in the late phase after cord blood transplantation in acute myeloid leukemia].

Patients with refractory ascites that develops >3 months after allogenic stem cell transplantation typically have a poor prognosis. We present the case of a 61-year-old man who developed refractory massive ascites approximately 3 months after cord blood transplantation (CBT) and showed complete and spontaneous remission from ascites after 18 months. The patient complained of severe bloating and needed weekly paracentesis to manage the fluid levels. Laboratory tests indicated that the ascites was caused by liver fibrosis. After the patient underwent Keisuke-Matsusaki cell-free and concentrated ascites reinfusion therapy (KM-CART), we were able to decrease the frequency of paracentesis treatments. We planned a transjugular liver biopsy, but the patient contracted pneumocystis pneumonia before the procedure could be performed. Although the pneumonia improved, the ascites worsened again. However, weekly paracentesis spontaneously stopped the progression of ascites and eventually resolved it completely, resulting in the patient's survival.

Transition-Metal-Free Synthesis of 2-Substituted Benzothiazoles from Nitrobenzenes, Methylheteroaryl Compounds, and Elemental Sulfur, Based on Nitro-Methyl Redox-Neutral Cyclization.

Greener and more sustainable chemical processes are required to address increasing environmental pollution and depletion of natural resources. This paper aims to develop greener and more sustainable modern synthetic chemical processes using redox-neutral cyclization. Redox-neutral cyclization has been shown to promote the efficient synthesis of 2-substituted benzothiazoles from easily available nitrobenzenes, methyl-heteroaryl compounds, and elemental sulfur in the absence of transition-metal catalysts. The 2-substituted benzothiazoles were obtained in reasonable yields through the sulfuration of electron-deficient C-H bonds with elemental sulfur. This synthetic methodology also affords a high atom economy without the use of any external oxidizing and/or reducing reagents.

[Bendamustine and rituximab combination therapy for recurrent indolent B-cell lymphomas: a retrospective single-institution study].

This retrospective study evaluated the outcomes of patients treated with combination of bendamustine and rituximab (BR) for recurrent indolent B-cell lymphoma from January 2011 to February 2018 in our department. The cohort included 36 males and 27 females, and majority of the patients (59%) were between 51 and 70 years of age. The disease types were follicular lymphoma (FL) and mantle-cell lymphoma in 42 (67%) and 15 (24%) patients, respectively. Median progression-free survival (PFS) was not reached in patients with FL who completed BR therapy. The analysis of patients who received BR therapy revealed that the number of CD4-positive lymphocytes remained around 200/µl even five years after the end of treatment. BR therapy was a useful treatment option for recurrent indolent B-cell lymphoma, especially in patients with FL, and completion of BR therapy appeared to be important for improved PFS. Furthermore, attention should be paid for potential infections for at least five years after BR therapy because cell-mediated immunodeficiency may become apparent after treatment.

[VEGF secretion from Epstein-Barr virus-infected cells as a cause of severe anasarca in a patient with angioimmunoblastic T-cell lymphoma].

A 69-year-old woman presented to National Defense Medical College hospital for suspected nephrotic syndrome due to weight gain of 30 kg in 3 weeks and bilateral lower leg edema. However, her urinalysis showed microproteinuria, which excluded nephrotic syndrome. Computed tomography revealed severe systemic edema, pleural effusion, ascites, and enlarged cervical and axillary lymph nodes. Histological examination of axillary lymph node specimen showed a typical architecture of angioimmunoblastic T-cell lymphoma. One course of CHOP chemotherapy regimen was administered which improved the lymph nodes and systemic edema. The patient achieved complete remission after 6 courses of CHOP. Because serum vascular endothelial growth factor (VEGF) level was elevated before the treatment and normalized after the treatment, increased vascular permeability mediated by VEGF was hypothesized to have caused the systemic edema. In addition, VEGF secretion from Epstein-Barr virus (EBV)-infected cells was likely associated with the patient's clinical condition because B lymphocytes stained with CD20 were positive for Epstein-Barr virus-encoded small RNAs (EBERs) and VEGF.

Three-Dimensional Sandwich Nanocubes Composed of 13-Atom Palladium Core and Hexakis-Carbocycle Shell.

Coordination of cyclic unsaturated hydrocarbons to transition metal generally gives bis-ligated sandwich complexes, which are a fundamental class of organometallic compounds. This sandwich structure may be extended to a higher-order three-dimensional one when more than two carbocyclic ligands surround an agglomerate of many transition metal atoms. Here, we report synthesis of three-dimensional sandwich nanocube compounds containing a close-packed transition metal cluster core. Reduction of a [Pd3(µ3-C7H7)2]2+ with tetraarylborate under neat conditions afforded [Pd13(µ4-C7H7)6]2+ containing a cuboctahedral Pd13 core with an octahedral ligand-shell.

Donor-derived cytomegalovirus-specific CD8+ T cells restricted to shared, donor-specific, or host-specific HLA after HLA mismatched hematopoietic stem cell transplantation.

Immune reconstitution after human leukocyte antigen (HLA)-mismatched (haploidentical) hematopoietic stem cell transplantation (haplo-HCT) can significantly influence long-term outcomes. The three possible HLA haplotypes after transplantation are: one carried by both the patient and the donor (shared HLA), one by donor only (donor-specific HLA), and one by patient only (host-specific HLA), and the donor T cells remain restricted to one of these three haplotypes. Understanding the presence of donor T cells restricted to each haplotype may provide more detailed insights into post-transplant immune response and potentially provide valuable information for the development of chimeric antigen receptor T cell or T cell receptor T cell constructs. In this study, patients or donors with HLA-A24 or HLA-A2 were tested with HLA-A*24:02- and A*02:01-restricted cytomegalovirus (CMV)-specific tetramers for detecting the respective HLA-restricted T cells. Sixty-four samples from 40 patients were assayed. More than half of the patients at day 90 and all patients by day 900 had shared HLA-restricted T cells. After day 90, half of the patients had donor-specific HLA-restricted T cells, but no host-specific HLA-restricted T cells were found. In the comparative analysis of the transplant types, shared HLA-restricted T cells were positive in all three categories: haplo-HCT (50%), 2-haplo-mis-HCT (75%), and spousal HCT (67%). Furthermore, donor-specific HLA-restricted T cells demonstrated positivity in haplo-HCT at 57% and in 2-haplo-mis-HCT at 60%, with a threshold of 0.01%. Donor-specific HLA-restricted T cells for spousal HCT were not examined due to the lack of an appropriate HLA combination for the tetramers. The presence of shared HLA-restricted T cells explains the host defense after HLA-haploidentical transplantation, while the presence of donor-specific HLA-restricted T cells may account for host defense against hematotropic viruses, such as CMV. However, this study failed to detect host-specific HLA-restricted T cells, leaving the host defense against epitheliotropic viruses unresolved, thus requiring further investigation.

Population Pharmacokinetics of Total Rabbit Anti-thymocyte Globulin in Non-obese Adult Patients Undergoing Hematopoietic Cell Transplantation for Hematologic Malignancy.

BACKGROUND AND OBJECTIVES: Rabbit anti-thymocyte globulin (rATG), a therapeutic polyclonal antibody against human T cells, is commonly used in conditioning therapy prior to allogeneic hematopoietic cell transplantation (HCT). Previous studies successfully developed an individualized rATG dosing regimen based on "active" rATG population PK (popPK) analysis, while "total" rATG can be a more logistically favorable alternative for early HCT outcomes. We conducted a novel popPK analysis of total rATG. METHODS: Total rATG concentration was measured in adult human-leukocyte antigen (HLA) mismatched HCT patients who received a low-dose rATG regimen (total 2.5-3 mg/kg) within 3 days prior to HCT. PopPK modeling and simulation was performed using nonlinear mixed effect modeling approach. RESULTS: A total of 504 rATG concentrations were available from 105 non-obese patients with hematologic malignancy (median age 47 years) treated in Japan. The majority had acute leukemia or malignant lymphoma (94%). Total rATG PK was described by a two-compartment linear model. Influential covariate relations include ideal body weight [positively on both clearance (CL) and central volume of distribution], baseline serum albumin (negatively on CL), CD4+ T cell dose (positively on CL), and baseline serum IgG (positively on CL). Simulated covariate effects predicted that early total rATG exposures were affected by ideal body weight. CONCLUSIONS: This novel popPK model described the PK of total rATG in the adult HCT patients who received a low-dose rATG conditioning regimen. This model can be used for model-informed precision dosing in the settings with minimal baseline rATG targets (T cells), and early clinical outcomes are of interest.

Association between the pharmacokinetics of rabbit anti-thymocyte globulin and acute graft-versus-host disease in patients who received haploidentical hematopoietic stem cell transplantation.

Anti-thymocyte globulin (ATG) is an important prophylactic drug against acute graft-versus-host disease (aGVHD) after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). This study analyzed the pharmacokinetics of rabbit ATG 2.5 mg/kg and its effect against aGVHD in 24 patients undergoing unmanipulated haplo-HSCT. All patients had hematological malignancies not in remission. The median absolute lymphocyte count (ALC) before rabbit ATG administration was 9.5/µL (range 0-41/µL). The grade ≥ II aGVHD group had a significantly lower median rabbit ATG concentration on days 0 (C0) and 7 (C7) and areas under the curve on days 0-7 (AUC0-7) and 0-32 (AUC0-32) than the grade 0-I aGVHD group. Among the four parameters, C0 was the most optimal for predicting aGVHD according to the receiver-operating characteristic (ROC) analysis (area under the ROC curve 0.893; 95% confidence interval 0.738-1.000). The high C0 (≥ 27.8 µg/mL) group had significantly lower cumulative incidence of grade ≥ II aGVHD on day 100 than the low C0 (< 27.8 µg/mL) group (13.8% vs. 88.9%, p < 0.001). In haplo-HSCT, the C0 of rabbit ATG is a good predictor of grade ≥ II aGVHD, even though ALC before rabbit ATG administration is not a predictor of aGVHD.

Allogeneic hematopoietic stem cell transplantation from a 2-HLA-haplotype-mismatched family donor for posttransplant relapse: a prospective phase I/II study.

HLA haploidentical hematopoietic stem cell transplantation (HSCT), i.e., HSCT from a 1-HLA-haplotype-mismatched family donor, has been successfully performed even as a second transplantation for posttransplant relapse. Is the haploidentical the limit of HLA mismatches in HSCT? In order to explore the possibility of HLA-mismatched HSCT from family donors beyond haploidentical relatives, we conducted a prospective phase I/II study of 2-HLA-haplotype-mismatched HSCT (2-haplo-mismatch HSCT). We enrolled 30 patients with posttransplant relapse (acute myeloid leukemia: 18, acute lymphoblastic leukemia: 11, non-Hodgkin lymphoma: 1). 2-haplo-mismatch HSCT was performed as the second to sixth transplantations. The donors were siblings (n = 12), cousins (n = 16), and second cousins (n = 2). The conditioning regimen consisted of fludarabine, cytarabine, melphalan, low-dose anti-thymocyte globulin, and 3 Gy of total body irradiation. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, methylprednisolone, and mycophenolate mofetil. All patients achieved neutrophil engraftment, except for a case of early death. The cumulative incidences of grades II-IV and III-IV acute GVHD were 36.7% and 16.7%, respectively. The overall survival at 1 year, relapse, and non-relapse mortality rates was 30.1%, 38.9%, and 44.3%, respectively. Considering the poor prognosis of posttransplant relapse, 2-haplo-mismatch HSCT can be an alternative option in a second or third transplantation.

Low mucosal-associated invariant T-cell number in peripheral blood of patients with immune thrombocytopenia and their response to prednisolone.

Mucosal-associated invariant T (MAIT) cells help protect against certain infections and are related to some autoimmune diseases. Immune thrombocytopenia (ITP) is a relatively rare hematological autoimmune disease associated with low platelet count. We designed a cross-sectional study wherein we examined peripheral blood samples of patients with ITP for the number of MAIT cells (CD3+TCR-Vα7.2+CD161+IL-18Rα+ lymphocytes) and their CD4/8 subsets (by flow cytometry) and levels of cytokines (by multiplex assays). The study cohort included 18 patients with ITP and 20 healthy controls (HCs). We first compared the number of MAIT cells between HCs and patients with ITP and then performed subgroup analysis in patients with ITP. The number of total MAIT cells in patients with ITP was significantly lower than that in HCs (p < 0.0001), and the CD4-CD8+ subset of MAIT cells showed the same trend. Moreover, patients with ITP refractory to prednisolone exhibited a significantly lower number of total MAIT and CD4-CD8+ MAIT cells than patients sensitive to prednisolone. The number of total MAIT and CD4-CD8+ MAIT cells was not correlated with the response to thrombopoietin receptor agonist treatment or with Helicobacter pylori infection. We found no relation between cytokine levels and response to prednisolone treatment, although the levels of IP-10 and RANTES showed a correlation with the number of total MAIT and CD4-CD8+ MAIT cells. In conclusion, total MAIT and CD4-CD8+ MAIT cells in peripheral blood were decreased in patients with ITP, correlating with their response to prednisolone.

Sudden blast phase in chronic myeloid leukemia developed during nilotinib therapy after major molecular response was achieved.

Sudden blast phase (SBP) is a rare event in which patients with chronic myeloid leukemia (CML) in complete cytogenetic response (CCyR) rapidly progress to the blast phase. Few patients on second-generation tyrosine kinase inhibitors (2nd TKIs) have been reported to develop SBP. Here, we report a 45-year-old man diagnosed with CML in the chronic phase in April 2008 and immediately started on imatinib therapy. He achieved CCyR 12 months after starting imatinib therapy. Imatinib was followed by treatment with the 2nd TKIs nilotinib and dasatinib from January 2011 to yield a better response. He achieved major molecular response (MMR) during dasatinib therapy in February 2012, but did not tolerate dasatinib well; hence, he was switched to nilotinib in July 2012. In December 2015, he presented at our hospital with fever and lumbago. A complete blood count revealed a white blood cell count of 30,500/µL with 60% blasts, leading to diagnosis of SBP. After dasatinib therapy and conventional chemotherapy, he again achieved MMR. This case demonstrates that SBP may occur after achieving MMR on treatment with 2nd TKIs. Continuous careful monitoring is required for the early detection of SBP, even in patients who have achieved MMR.