Early evaluation of CAR-T cell therapy response in R/R DLBCL patients using 18F-FDG PET/CT.

OBJECTIVE: CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy provides a durable response in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). The role of fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for early evaluation of response in patients with that immunotherapy was evaluated. SUBJECTS AND METHODS: Three separate 18F-FDG PET/CT examinations of 53 patients (29 males, 24 females; median 62 years old) with R/R DLBCL were conducted; before bridging therapy [time of decision (TD)], before CAR-T (tisagenlecleucel, n=37; lisocabtagenemaraleucel, n=16) infusion [time of CAR-T infusion (IT)], and one month (M1) after CAR-T infusion. Response was evaluated based on the Deauville 5-point scale and Lugano criteria. RESULTS: Among 21 patients (39.6%) with complete metabolic response (CMR) at IT-PET, 20 were able to continue CMR, while one showed progression at M1-PET. Among 32 patients (60.4%) with non-CMR at IT-PET, 12, 8, 4, and 8 showed CMR, partial metabolic response (PMR), (non-metabolic response (NMR), and progressive metabolic disease (PMD), respectively, at M1-PET as compared with IT-PET. Evaluations of M1-PET as compared with baseline TD-PET indicated 32, 7, 5, and 9 patients with CMR, PMR, NMR, and PMD, respectively. After a median 10.1 months, 26 patients showed progression and 13 had died from DLBCL. The 32 who achieved CMR showed significantly longer progression-free (P<0.0001) and overall survival (P<0.0001) periods as compared to the 21 non-CMR patients. CONCLUSION: Fluorine-18-FDG PET/CT findings obtained one month after CAR-T cell therapy showed accuracy for early response evaluation and prediction of progression in patients with R/R DLBCL.

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.

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.

Balance Function after Balance Exercise Assist Robot Therapy in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: A Pilot Study.

Objectives: This study compared the balance function in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with their balance function after subsequent training sessions with a Balance Exercise Assist Robot (BEAR). Methods: In this prospective observational study, inpatients who underwent allo-HSCT from human leukocyte antigen-mismatched relatives were enrolled from December 2015 to October 2017. Patients were allowed to leave their clean room after allo-HSCT and underwent balance exercise training using the BEAR. Sessions (20-40 min) were performed 5 days per week and consisted of three games that were performed four times each. A total of 15 sessions were performed by each patient. Patient balance function was assessed before BEAR therapy according to the mini-balance evaluation systems test (mini-BESTest), and patients were divided into two groups (Low and High) based on a 70% cut-off value for the total mini-BESTest score. Patient balance was also assessed after BEAR therapy. Results: Fourteen patients providing written informed consent fulfilled the protocol: six patients in the Low group, and eight patients in the High group. In the Low group, there was a statistically significant difference between pre- and post-evaluations in postural response, which a sub-item of the mini-BESTest. In the High group, there was no significant difference between pre- and post-evaluations in the mini-BESTest. Conclusions: BEAR sessions improve balance function in patients undergoing allo-HSCT.

Peritransplantation Glucocorticoid Haploidentical Stem Cell Transplantation Is a Promising Strategy for AML Patients With High Leukemic Burden: Comparison With Transplantations Using Other Donor Types.

Using a murine haploidentical bone marrow transplantation (BMT) model, we recently showed that peritransplantation administration of glucocorticoid (GC) redistributed donor T cells from the gastrointestinal tract to bone marrow, which resulted in a significant reduction of graft-versus-host disease (GVHD) while promoting graft-versus-leukemia effects. Furthermore, in a retrospective clinical study of patients with acute myelogenous leukemia (AML) undergoing transplantation in non-remission, we also showed that haploidentical stem cell transplantation (haplo-SCT) using peritransplantation GC administration led to a significantly lower relapse rate and better overall survival rate compared with haplo-SCT using post-transplantation cyclophosphamide. In the present study, using the same dataset of patients undergoing GC haplo-SCT, we retrospectively compared with patients with AML undergoing transplantation in non-remission using 3 other donor types: matched sibling donor (MSD), matched unrelated donor (MUD), and umbilical cord blood (UCB). For GC haplo-SCT, 44 patients underwent peripheral blood stem cell transplantation in a single center (Hyogo College of Medicine), with the conditioning treatment consisting of fludarabine, melphalan, anti-thymocyte globulin (2.5 mg/kg), and TBI 3 Gy. Methylprednisolone was given from the start of conditioning treatment, and the GVHD prophylaxis consisted of tacrolimus and methylprednisolone (1 mg/kg). The transplantation outcomes were compared with data of 1889 patients undergoing MSD-SCT (n = 449), MUD-BMT (n = 493), or UCB transplantation (UCBT) (n = 947) in non-CR, which were extracted from the Transplant Registry Unified Management Program data, the largest data registry in Japan. For donor engraftment, significantly faster neutrophil and platelet engraftment was achieved with GC haplo-SCT compared with allo-SCT using the 3 other donor types. Neutrophil engraftment was achieved at a median of 10 days for GC haplo-SCT, and 20 days for MSD-, MUD-, and UCB-transplants. Platelet engraftment was achieved at a median of 19.5 days for GC haplo-SCT, 42 days for MSD-SCT and MUD-BMT, and 43 days for UCBT, respectively. The incidence of grade II-IV acute GVHD was lower after allo-SCTs using MSD (hazard ratio [HR] = 0.465, P = .003), MUD (HR = 0.524, P = .010), and UCB (HR = 0.647, P = .067) compared with GC haplo-SCT. There was no significant difference in the incidence of chronic GVHD between GC haplo-SCT and allo-SCT using the other 3 donor types. Regarding relapse, GC haplo-SCT was associated with a significantly lower risk compared with MSD-SCT (P < .001) or MUD-BMT (P = .004). GC haplo-SCT tended to have a lower risk compared with UCBT (P = .063). Especially, all the 43 evaluable GC haplo-SCT recipients achieved CR after transplantation, whereas 23.9%, 22.8%, and 27.0% of patients who underwent MSD-SCT, MUD-BMT, and UCBT could not achieve CR after transplantation, respectively. Regarding non-relapse mortality, GC haplo-SCT was associated with a significantly higher risk compared with MUD-BMT (P = .014), and tended to have a higher risk compared with MSD-SCT (P = .061). There was no significant difference between GC haplo-SCT and UCBT (P = .600). Allo-SCTs using MSD (HR = 2.548, P < .001), MUD (HR = 2.134, P = .005), and UCB (HR = 2.376, P = .001) lead to significantly higher overall mortality compared with GC haplo-SCT; the adjusted overall survival at 3 years was 19.8% for MSD, 26.1% for MUD, 28.0% for UCB, and 65.1% for GC haplo. Thus GC haplo-SCT is a promising treatment option for patients with AML with a high leukemic burden.

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.

Peritransplant glucocorticoids redistribute donor T cells to the bone marrow and prevent relapse after haploidentical SCT.

Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes, with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities, but it typically requires intensive immunosuppression with posttransplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here, we demonstrate in preclinical models that glucocorticoid administration from days -1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the BM, promoting donor T cell residency. This results in significant reductions in GVHD while promoting potent GVL effects; relapse in recipients receiving glucocorticoids, vehicle, or PT-Cy was 12%, 56%, and 100%, respectively. Intriguingly, patients with acute myeloid leukemia not in remission who received unmanipulated haplo-SCT and peritransplant glucocorticoids also had an unexpectedly low relapse rate at 1 year (32%; 95% CI, 18%-47%) with high overall survival at 3 years (58%; 95% CI, 38%-74%). These data highlight a potentially simple and effective approach to prevent relapse in patients with otherwise incurable leukemia that could be studied in prospective randomized trials.

Impact of the use of hydroxyethyl starch in granulocyte apheresis using Spectra Optia.

OBJECTIVES: To determine the impact of the use of hydroxyethyl starch (HES) in granulocyte apheresis using Spectra Optia. BACKGROUND: Granulocyte transfusion (GT) is a therapeutic option for neutropenic patients with severe bacterial or fungal infections. Recent studies in emergency medicine have shown the potential risk of using HES, which is routinely used in granulocyte apheresis to increase yield by sedimenting red blood cells. We hypothesized that the use of a newer device (Spectra Optia) would spare the need for HES. METHODS: We retrospectively compared granulocyte apheresis with HES (HES group, n = 89) and without HES (non-HES group, n = 36) using Spectra Optia. RESULTS: The granulocyte yield was significantly higher in the HES group (7.3 × 1010 vs. 2.0 × 10, p < 0.01) and was attributed to the difference in collection efficiency (36% vs. 7.7%, p < 0.01). The absolute neutrophil count on the following morning of GT was significantly higher in the HES group than in the non-HES group (2460/µl vs. 505/µl, p < 0.01). There were no significant differences in the occurrence of adverse events between the HES and non-HES groups. The renal function was unchanged in both groups after apheresis. CONCLUSIONS: We demonstrated that the advantage of using HES remained unchanged in granulocyte apheresis using Spectra Optia.

Relationship Between Corticosteroid Dose and Muscle Oxygen Consumption in Recipients of Hematopoietic Stem-Cell Transplantation.

INTRODUCTION: After hematopoietic stem-cell transplantation (HSCT), patients exhibit decreased muscle strength and muscle oxygen consumption. Furthermore, total corticosteroid dose affects the reduction in muscle strength after HSCT. However, to date, no studies have investigated the relationship between corticosteroid dose and muscle oxygen consumption and saturation in these patients. The purpose of this study was to investigate the relationship between steroid dose and deoxyhemoglobin (ΔHHb) and muscle oxyhemoglobin saturation (ΔSmO2) in patients undergoing HSCT. METHODS: This study included 17 men with hematologic disease who underwent allogeneic HSCT. We evaluated ankle dorsiflexor muscle force, ΔHHb, and ΔSmO2 in skeletal muscles by near-infrared spectroscopy (NIRS) in patients before and after HSCT. RESULTS: Peak ankle dorsiflexion, ΔHHb, and ΔSmO2 decreased significantly after transplantation as compared to measurements taken before transplantation (p < 0.01). The change in peak ankle dorsiflexion from before to after HSCT was not significantly correlated with total steroid dose. However, ΔHHb and ΔSmO2 from before to after HSCT were significantly correlated with total steroid dose (p < 0.01). CONCLUSION: This study showed that higher corticosteroid doses are associated with diminished skeletal muscle O2 consumption and skeletal muscle O2 demand relative to supply. Therefore, rehabilitation staff, nurses, and physicians should take note of these findings in patients undergoing HSCT. Moreover, physiotherapists should be carefully measuring muscle oxidative metabolism on skeletal muscle when planning physical exercise in such patients.

Muscle oxygen extraction and lung function are related to exercise tolerance after allogeneic hematopoietic stem cell transplantation.

PURPOSE: This study aimed to investigate the relationship between exercise intolerance, muscle oxidative metabolism, and cardiopulmonary function following allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a sterile isolation room setting. METHODS: This was a prospective observational cohort study conducted in a single center. Fourteen patients with hematopoietic malignancies who had undergone allo-HSCT were included in this study from June 2015 to April 2020. Patients received donor HSCT after high dose-chemotherapy and total-body irradiation. Physical activity was limited during treatments. Outcome measures included body anthropometric measurements, exercise tolerance tests using the ramp protocol, pulmonary function tests, and near-infrared spectroscopy (NIRS) measurements. Data of pre- and posttransplant measurements were compared using the paired t test or nonparametric Wilcoxon U test. Associations were assessed using the Pearson or nonparametric Spearman correlations. RESULTS: NIRS showed reduced muscle consumption and extraction of oxygen in the posttransplant period compared to the pretransplant period (ΔStO2 min pre: -18.6% vs. post: -13.0%, P = 0.04; ΔHHb max pre: 4.21µmol/l vs. post: 3.31µmol/l: P = 0.048). Exercise tolerance had reduced following allo-HSCT (Peak workload pre: 70.3 W vs. post: 58.0 W: P = 0.014). Furthermore, exercise intolerance was associated with pulmonary function, muscle oxygen consumption, and muscle oxygen extraction (all P <0.05). CONCLUSION: This analysis revealed that exercise intolerance following allo-HSCT was associated with pulmonary dysfunction and muscle oxidative dysfunction. These findings could help identify the physical function associated with impaired tissue oxygen transport leading to exercise intolerance following allo-HSCT.

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.

Decrease in voriconazole concentration-to-dose ratio after letermovir initiation: a retrospective, observational study.

Letermovir is used to prevent cytomegalovirus infection in hematopoietic stem cell transplantation (HSCT) recipients. Although this agent decreases voriconazole exposure in healthy individuals, the effect of coadministration of letermovir and voriconazole in HSCT recipients is unknown. This retrospective, observational, single-center study was conducted between January 2016 and July 2019 to examine the voriconazole concentration-to-dose ratio over three periods: (A) (days -7 to -1 [day 0: day of HCST]), (B) (days 4-10), and (C) (days 11-17). Forty-two HSCT recipients administered voriconazole were divided into the following two groups based on letermovir coadministration: letermovir (n = 15) and control (n = 27). The percent change (-33.2%, p < 0.05) in the voriconazole concentration-to-dose ratio from periods A to C in the letermovir group was significantly lower than that in the control group. Therefore, frequent therapeutic drug monitoring of voriconazole concentrations and subsequent dose adjustments should be performed regularly in HSCT recipients.

Tacrolimus Concentration after Letermovir Initiation in Hematopoietic Stem Cell Transplantation Recipients Receiving Voriconazole: A Retrospective, Observational Study.

Letermovir (LMV) is a new antiviral drug used to prevent cytomegalovirus infection in hematopoietic stem cell transplantation (HSCT) recipients. It has been reported to increase tacrolimus (TAC) exposure and decrease voriconazole (VRCZ) exposure in healthy participants. However, VRCZ inhibits the metabolism of TAC. Thus, the effects of LMV on TAC exposure in patients receiving VRCZ are unknown. This retrospective, observational, single-center study was conducted between May 2018 and April 2019. The TAC concentration/dose (C/D) ratio, VRCZ concentration, and VRCZ C/D ratio for 7 days before and for the first and second 7-day periods after the initiation of LMV administration were evaluated. Fourteen HSCT recipients receiving VRCZ were enrolled. There was no significant difference in the TAC C/D ratio for 7 days before and for the first and second 7-day periods after initiating LMV administration (median: 866 [IQR: 653-953], 842 [IQR: 636-1031], and 906 [IQR: 824-1210] [ng/mL]/[mg/kg], respectively). In contrast, the VRCZ C/D ratio and concentration for the first and second 7-day periods after LMV initiation were significantly lower than those before initiating LMV administration (mean 1.11 ± 0.07, 0.12 ± 0.08, and 0.22 ± 0.12 [µg/mL]/[mg/kg] and 0.7 ± 0.5, 0.8 ± 0.5, and 1.3 ± 0.7 µg/mL, respectively; n = 12). This can be explained by the increase in TAC concentration caused by CYP3A4 inhibition due to LMV and by the decrease in TAC concentration ascribed to the decrease in VRCZ concentration by CYP2C19 induction due to LMV. These results suggest that it is unnecessary to adjust the dose of TAC based on LMV initiation; however, it is necessary to adjust the dose of TAC based on conventional TAC concentration measurements.

Relationship Between Muscle Oxygen Saturation and Exercise Load in Patients with Malignant Hematopoietic Disease.

Our previous research confirmed that patients with malignant hematopoietic disease already had a low hemoglobin level before allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, no study has determined whether a correlation exists between exercise load, hemoglobin level, and muscle oxygen saturation (SmO2), during exercise. Therefore, the purpose of this study was to investigate whether near-infrared spectroscopy (NIRS)-derived SmO2 is associated with exercise load, as determined by a dynamometer, before allo-HSCT. This study included 19 male patients who received allo-HSCT in Hyogo College of Medicine Hospital (Japan) between November 2009 and October 2012. Patients performed isometric repeated dorsiflexion at 50% maximum voluntary contraction for 180 s to determine exercise load, and SmO2 was evaluated during exercise at the same time using NIRS (BOM-L1TRW, Omega Wave, Inc., Japan). The hemoglobin level was also evaluated before allo-HSCT. Patients with hematopoietic disease before allo-HSCT already had a low hemoglobin level. There was a significant correlation between exercise load and ∆SmO2; however, the hemoglobin level was not correlated with exercise load. In these patients, exercise load might be affected by muscle oxygen consumption rather than by the hemoglobin level. This finding shows that NIRS can used to assess fatigue in patients with malignant hematopoietic disease.

Relationship Between Exercise Capacity and Muscle O2Hb Saturation in Patients Before Hematopoietic Stem-Cell Transplantation.

Patients with hematological malignancy might already have decreased muscle oxygen saturation at rest and exercise capacity before undergoing hematopoietic stem cell transplantation (HSCT). However, to date, no studies have investigated the relationship between exercise capacity and muscle oxygen saturation at rest in these patients. Therefore, purpose of this study was to investigate the relationship between exercise capacity and muscle oxygen-hemoglobin (O2Hb) saturation (SmO2) at rest and patients' hemoglobin level before undergoing HSCT. METHODS: This study included 60 men with hematologic disease who underwent allo-HSCT. Patients performed a 6-minute walk test (6MWT) to determine exercise capacity, and muscle O2Hb saturation at rest was evaluatabed using near-infrared spectroscopy (BOM-L1TRW, Omegawave Inc., Japan); hemoglobin levels in hematological malignancy patients before undergoing HSCT were also evaluated. RESULTS: There was a significant correlation between the 6MWT and muscle O2Hb saturation at rest in hematological malignancy patients (p < 0.05). Additionally, the 6MWT was significantly correlated to the hemoglobin level (p < 0.05). Furthermore, muscle O2Hb saturation at rest was significantly related to hemoglobin level (p < 0.05). CONCLUSION: In patients with hematological malignancy, a relationship exists between exercise capacity, muscle O2Hb saturation, and hemoglobin level before they undergo HSCT. Therefore, rehabilitation staff, nurses, and physicians should recognize these relationships in patients who undergo allo-HSCT. Moreover, physiotherapists may need to promote muscle oxidative metabolism through exercise to increase exercise capacity in these patients.

Safety and efficacy of amnion-derived mesenchymal stem cells (AM01) in patients with steroid-refractory acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation: a study protocol for a phase I/II Japanese trial.

INTRODUCTION: Regenerative medicine and cell therapies have been gaining much attention among clinicians. Therapeutic infusion of mesenchymal stromal cells (MSCs) is now a leading investigational strategy for the treatment of acute graft-versus-host disease (aGVHD). Bone marrow MSCs are approved for manufacture and marketing as a cell therapy for aGVHD. Our non-clinical studies confirmed that human amnion-derived MSCs had immunomodulatory activity equal to or higher than that of human bone marrow MSCs. This study will aim to evaluate the safety and efficacy of amnion-derived MSCs (AM01) in patients with steroid-refractory aGVHD. METHODS AND ANALYSIS: This study will be a multicentre, single-arm, open-label trial (an interventional study). This clinical trial will begin with a low-dose group, and when safety has been confirmed in at least three cases in the low-dose group, treatment will begin for the high-dose group, for which the safety will also be verified. The primary endpoint is to assess the safety of intravenous infusion therapy of AM01 within 24 hours after intravenous infusion of AM01. The secondary endpoint is to explore the efficacy of intravenous infusion therapy with AM01. ETHICS AND DISSEMINATION: The institutional review boards of all participating hospitals approved this study protocol (latest V3.3.0, 3 August 2018). Final data will be publicly announced. A report releasing the study results will be submitted for publication to an appropriate peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000029945.

Low incidence of HHV-6 reactivation in haploidentical hematopoietic stem cell transplantation with corticosteroid as graft-vs-host disease prophylaxis compared with cord blood transplantation.

BACKGROUND: Human leukocyte antigen (HLA) mismatch and the administration of immunosuppressive agents are considered risks for human herpesvirus 6 (HHV-6) reactivation after stem cell transplantation (SCT). However, the incidence of HHV-6 reactivation in HLA-mismatched related SCT remains unknown. METHODS: We monitored plasma HHV-6 DNA loads weekly using real-time quantitative polymerase chain reaction for 5 weeks after SCT and compared serum IL-6 levels in HLA-mismatched SCT groups. RESULTS: Compared with detection in all 11 umbilical cord blood transplantation (CBT) patients (100%), plasma HHV-6 DNA was detected in only 3 of 42 haplo-SCT patients (7.1%) despite the use of methylprednisolone and antithymocyte globulin as graft-vs-host disease prophylaxis and a reduced-intensity conditioning regimen, respectively. Correspondingly, serum IL-6 levels in haplo-SCT patients were significantly lower than those in CBT patients. No HHV-6-associated encephalitis developed in either groups. CONCLUSIONS: Neither HLA disparity nor the use of methylprednisolone and antithymocyte globulin were risk factors for HHV-6 reactivation in our haplo-SCT patients. Rather than increasing risk, the administration of immunosuppressive agents potentially prevented HHV-6 reactivation after haplo-SCT by suppressing IL-6 production.