Aryl hydrocarbon receptor-targeted therapy for CD4+ T cell-mediated idiopathic pneumonia syndrome in mice.

We previously demonstrated that interferon γ (IFN-γ) derived from donor T cells co-opts the indoleamine 2,3-dioxygenase 1 (IDO1) → aryl hydrocarbon receptor (AHR) axis to suppress idiopathic pneumonia syndrome (IPS). Here we report that the dysregulated expression of AP-1 family genes in Ahr-/- lung epithelial cells exacerbated IPS in allogeneic bone marrow transplantation settings. AHR repressed transcription of Jund by preventing STAT1 from binding to its promoter. As a consequence, decreased interleukin-6 impaired the differentiation of CD4+ T cells toward Th17 cells. IFN-γ- and IDO1-independent induction of Ahr expression indicated that the AHR agonist might be a better therapeutic target for IPS than the IDO1 activator. We developed a novel synthetic AHR agonist (referred to here as PB502) that potently inhibits Jund expression. PB502 was highly effective at inducing AHR activation and ameliorating IPS. Notably, PB502 was by far superior to the endogenous AHR ligand, L-kynurenine, in promoting the differentiation of both mouse and human FoxP3+ regulatory CD4+ T cells. Our results suggest that the IDO1-AHR axis in lung epithelial cells is associated with IPS repression. A specific AHR agonist may exhibit therapeutic activity against inflammatory and autoimmune diseases by promoting regulatory T-cell differentiation.

Effects of food and ethnicity on the pharmacokinetics of venadaparib, a next-generation PARP inhibitor, in healthy Korean, Caucasian, and Chinese male subjects.

AIM: Venadaparib is a next-generation poly(ADP-ribose) polymerase inhibitor under development for treating gastric cancer. This study aimed to evaluate the effects of food and ethnicity on the pharmacokinetics (PKs) and safety of venadaparib after a single oral administration in healthy Korean, Caucasian, and Chinese male subjects. METHODS: In this randomized, open-label, single-dose, two-sequence, two-period, and crossover study, Korean and Caucasian subjects received venadaparib 80 mg in each period (fasted or fed state) with a seven-day washout. In an open-label, single-dose study, Chinese subjects received venadaparib 80 mg only in the fasted state. Serial blood samples were collected up to 72 h post-dosing. RESULTS: Twelve subjects from each ethnic group completed the study. The geometric mean ratios (90% confidence intervals) of the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable time point (AUClast) of venadaparib for the fed to fasted state were 0.82 (0.7457-0.9094) and 1.02 (0.9088-1.1339) in Koreans, and 0.77 (0.6871-0.8609) and 0.96 (0.9017-1.0186) in Caucasians, respectively. No statistically significant differences were observed in Cmax (P-value = 0.45) or AUClast (P-value = 0.30) among the three ethnic groups. A single venadaparib dose was well-tolerated. CONCLUSION: The overall systemic exposure of venadaparib was not affected by the high-fat meal, despite delayed absorption with a decreased Cmax in the fed state. The PK profiles were comparable among the Korean, Caucasian, and Chinese subjects. A single venadaparib 80 mg dose was safe and well-tolerated in both fasted and fed states.

Long-term efficacy and safety of tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: final analysis of phase IIb results.

Not available.

Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: Results of the multicenter KMMWP2201 study.

Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed at investigating this regimen's efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age: 63 years). The overall response rate was 90% in responseevaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, highrisk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2 to 3 months prior to start of KRd treatment significantly decreased PFS and overall survival (OS) in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e.delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AEs) were observed in 56% of the patients, and non-fatal or fatal AE's that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.

A Prospective Study of Preemptive Tenofovir Disoproxil Fumarate Therapy in HBsAg-Positive Patients With Diffuse Large B-Cell Lymphoma Receiving Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone.

INTRODUCTION: This prospective study aimed to investigate the efficacy and safety of preemptive antiviral therapy with tenofovir disoproxil fumarate (TDF) for HBsAg-positive patients with newly diagnosed diffuse large B-cell lymphoma receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. METHODS: We enrolled 73 patients from 20 institutions. The primary end point was the absolute risk of hepatitis B virus (HBV)-related hepatitis during preemptive TDF therapy and for 24 weeks after withdrawal from TDF. Hepatitis was defined as a more than 3-fold increase in serum alanine aminotransferase from baseline or an alanine aminotransferase level of ≥100 U/L. HBV-related hepatitis was defined as hepatitis with an increase in serum HBV-DNA to >10 times that of the pre-exacerbation baseline or an absolute increase of ≥20,000 IU/mL compared with the baseline. RESULTS: No patient developed HBV reactivation or HBV-related hepatitis during preemptive antiviral therapy (until 48 weeks after completion of R-CHOP chemotherapy) with TDF. All adverse events were grade 1 or 2. HBV reactivation was reported in 17 (23.3%) patients. All HBV reactivation was developed at a median of 90 days after withdrawal from TDF (range, 37-214 days). Six (8.2%) patients developed HBV-related hepatitis at a median of 88 days after withdrawal from TDF (range, 37-183 days). DISCUSSION: Preemptive TDF therapy in HBsAg-positive patients with diffuse large B-cell lymphoma receiving R-CHOP chemotherapy was safe and effective for preventing HBV-related hepatitis. However, a long-term maintenance strategy of preemptive TDF therapy should be recommended because of the relatively high rate of HBV-related hepatitis after withdrawal from TDF ( ClinicalTrials.gov ID: NCT02354846).

Oral HDAC inhibitor tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: phase IIb results.

Tucidinostat (formerly known as chidamide) is an orally available, novel benzamide class of histone deacetylase (HDAC) inhibitor that selectively blocks class I and class IIb HDAC. This multicenter phase IIb study aimed to investigate the efficacy and safety of tucidinostat, 40 mg twice per week (BIW), in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR) assessed by an independent overall efficacy review committee. Between March 2017 and March 2019, 55 patients were treated, and 46 and 55 were evaluated for efficacy and safety, respectively. Twenty-one of 46 patients achieved objective responses with an ORR of 46% (95% confidence interval : 30.9-61.0), including five patients with complete response (CR). Responses were observed across various PTCL subtypes. In angioimmunoblastic T-cell lymphoma, there were two CR and five partial responses (PR) among eight patients, achieving an ORR of 88%. The disease control rate (CR + PR + stable disease) was 72% (33/46). The median progression-free survival, duration of response, and overall survival were 5.6 months, 11.5 months, 22.8 months, respectively. The most common adverse events (AE) (all grades) were thrombocytopenia, neutropenia, leukopenia, anemia, and diarrhea. The grade ≥3 AE emerging in ≥20% of patients included thrombocytopenia (51%), neutropenia (36%), lymphopenia (22%), and leukopenia (20%). Importantly, most of the AE were manageable by supportive care and dose modification. In conclusion, the favorable efficacy and safety profiles indicate that tucidinostat could be a new therapeutic option in patients with R/R PTCL (clinicaltrials gov. Identifier: NCT02953652).

Sequential eradication of Helicobacter pylori as a treatment for immune thrombocytopenia in patients with moderate thrombocytopenia: a multicenter prospective randomized phase 3 study.

Due to several issues, standard treatments are not recommended for asymptomatic patients with moderate immune thrombocytopenia (ITP). Since platelet responses are reported in some patients with Helicobacter pylori (H. pylori)-positive ITP after eradication, we conducted a multicenter, phase 3 study to evaluate the safety and efficacy of recently established sequential eradication for these patients having moderate thrombocytopenia. Persistent or chronic ITP patients with platelet count (30 × 103 ~ 80 × 103/µL) and confirmed active H. pylori infection were randomly assigned to a treatment and a control group. The former received 10-day sequential treatment. Eradication was assessed by urea breath test at 3 months after treatment. Primary endpoint was the overall platelet response rate at 3 months in successfully eradicated treatment group and control group. Secondary endpoints were platelet response time, H. pylori eradication success rate, etc. The patient enrollment terminated early because of the change of national insurance and treatment guideline for H. pylori-positive patients in Korea during the study. Of the 28 H. pylori-positive ITP patients, 17 were randomized to the treatment group, and eradication was achieved for 15 (88.2%) at 3 months, and seven in control group after withdrawal. Statistically, significant difference in platelet response rates between the two groups were observed (p = 0.017). Our study verifies that H. pylori eradication was an effective ITP treatment for patients with H. pylori-associated moderate ITP. This sequential eradication regimen showed not only a high H. pylori eradication rate, but also a remarkable platelet response for ITP patients. Trial registration number and date of registration for these prospectively registered trials is ClinicalTrials.gov number, NCT03177629 and June 6, 2017.

Clinical Impact of Extranodal Metabolic Tumor Volume in 240 Diffuse Large B cell Lymphoma Patients with Extranodal Involvement.

The present study is to investigate whether extranodal (EN) metabolic tumor volume (MTV) would have a specific clinical meaning for survival in EN diffuse large B cell lymphoma (DLBCL) patients. Two hundred forty DLBCL patients with EN involvement received 18F-fluorodeoxygenase (FDG) positron emission tomography/computed tomography (PET/CT) were enrolled. Survival analysis revealed that low EN MTV (PFS [progression-free survival], HR = 0.278, 95% CI = 0.127-0.807, p = 0.001; OS [overall survival], HR = 0.320, 95% CI = 0.145-0.703, p = 0.003), low total MTV (PFS, HR = 0.194, 95% CI = 0.085-0.445, p < 0.001; OS, HR = 0.213, 95% CI = 0.092-0.491, p < 0.007), and high National Cancer Center Network-International Prognostic Index score (PFS, HR = 3.152, 95% CI = 1.732-5.734, p < 0.001; OS, HR = 2.457, 95% CI = 1.363-4.430, p = 0.003) were independently associated with survivals in the patients. Our data showed that EN MTV is a useful and novel prognostic parameter for predicting survival in DLBCL patients with EN involvement.

Busulfan, etoposide, cytarabine, and melphalan as a high-dose regimen for autologous stem cell transplantation in peripheral T-cell lymphomas.

Given the unsatisfactory survival in patients who received high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) for peripheral T-cell lymphomas (PTCLs), we conducted a prospective trial of busulfan (Bu), etoposide (E), cytarabine (A), and melphalan (M) (BuEAM), including IV Bu instead of carmustine (BCNU) as in standard BEAM, as a high-dose regimen in such patients. This study evaluated the efficacy and toxicity of BuEAM as a high-dose regimen for ASCT in patients with T-cell lymphomas. The high-dose chemotherapy at seven centers in Korea included Bu (3.2 mg/kg IV qd from day 6 to day 5), E (200 mg/m2 IV bid on day 4 and day 3), A (1 g/m2 IV qd on day 4 and day 3), and M (140 mg/m2 IV qd on day 2). Eighty-one patients were enrolled in this study. The main subtypes were peripheral T-cell lymphoma, not other specified (n = 32, 39.5%), NK/T-cell lymphoma (n = 22, 27.5%), and angioimmunoblastic T-cell lymphoma (n = 12, 14.8%). Upfront and salvage ASCTs were performed in 65 (80.2%) and 16 (19.8%) patients, respectively. The disease status of the patients before ASCT was 54 patients (66.7%) with complete response and 27 patients (33.3%) with partial response. The common grade-III toxicities were anorexia (8.6%), diarrhea (7.4%), and stomatitis (4.9%). No veno-occlusive disorder was noted. Fifty-six (69.1%) and seven (8.6%) patients achieved complete and partial response, respectively, after ASCT, although 17 patients (21.0%) showed progressive disease. At a median follow-up duration of 49.3 months, the estimated 3-year progression-free survival and overall survival were 55.2% and 68.2% in all patients. The BuEAM high-dose regimen for ASCT was well tolerated and seemed to be effective in patients with T-cell lymphomas.

Carfilzomib in addition to lenalidomide and dexamethasone in Asian patients with RRMM outside of a clinical trial.

Carfilzomib, lenalidomide, and dexamethasone (KRd) effectively improve survival in patients with relapsed and refractory multiple myeloma (RRMM). However, the outcome of KRd treatment in Asian patients reflecting a general RRMM population outside of a clinical trial has not been reported. Fifty-five RRMM patients who were treated with carfilzomib in combination with Rd from the time of the first approval of KRd in the Republic of Korea were analyzed. The median age was 61 years. The percentage of patients with an ECOG performance status ≥ 3, creatinine clearance < 50 mL/min, high-risk cytogenetics, and ≥ 4 lines of prior treatment were 9%, 22%, 31%, and 27%, respectively. Forty-one patients started treatment with KRd, whereas the remaining 14 patients (25%) were added carfilzomib during the Rd treatment. In the whole cohort, the overall response rate was 73% and progression-free survival was 8.8 months. The addition of carfilzomib in patients who were refractory or had disease progression during Rd treatment reattained a response in half of the patients. The advantage of carfilzomib with Rd was significant in patients in the first relapse. Toxicity profile was acceptable, excluding severe infections. Carfilzomib in combination with Rd is effective and has a reasonable adverse event rate in Asian patients with RRMM.

Clinical characteristics and prognostic factors of acquired haemophilia A in Korea.

INTRODUCTION: Acquired haemophilia A (AHA) treatment involves the haemostatic treatment for acute haemorrhage and immunosuppressive therapy (IST) to eradicate FVIII inhibitory antibodies. AIM: We assessed the clinical features of AHA and analysed treatment outcomes in Korea. We further identified prognostic factors affecting treatment outcomes. METHODS: Medical records of 55 patients with AHA from 18 institutions were reviewed retrospectively. Logistic and Cox regression analyses were performed to elucidate clinical factors affecting the achievement of complete remission (CR). The primary endpoint was time to CR after IST, and secondary endpoints were time to haemostasis, the achievement of CR, and overall survival (OS). RESULTS: Among the 55 patients, 50 (91%) had bleeding symptoms. Bleeding was severe in 74% of patients. Thirty-six (72%) patients received haemostatic therapy. Of the 42 patients who received IST, 23 (52%) received steroid alone, with a 52% response rate, and 10 (25%) received a combination of steroid and cyclophosphamide, with an 83% response rate. Five (16%) patients relapsed after a median duration of 220 days. There were eight deaths. In the Cox regression analysis, the FVIII inhibitor titre ≥ 20 BU/mL was the only significant prognostic factor affecting time to CR and haemostasis. No significant difference was observed in OS based on the inhibitor titre. CONCLUSION: The present study demonstrated the demographic data of AHA in Korea and showed that FVIII inhibitory antibody titre was a predictor of time to achieve CR after IST.

Pegteograstim prophylaxis for chemotherapy-induced neutropenia and febrile neutropenia: a prospective, observational, postmarketing surveillance study in Korea.

PURPOSE: This observational study aimed to evaluate the safety and efficacy of pegteograstim prophylaxis in patients with lymphoma and solid malignancies. METHODS: This study was conducted at 18 sites in Korea between November 2015 and August 2018. RESULTS: In total, 611 patients (female, 61.2%) with a median age of 58 (range, 18-88) years were included. Most patients had lymphomas (n = 371, 60.7%) and breast cancer (n = 230, 37.6%) and were administered R-CHOP21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone per 21 days) (n = 284, 46.5%) and AC (doxorubicin and cyclophosphamide) (n = 177, 29.0%). The total pegteograstim dose in the 611 patients was 14,970 mg (2495 doses), with each patient receiving an average daily dose of 6.0 mg. Neutropenia grade 4 occurred in 97 patients (15.9%), and febrile neutropenia (FN) occurred in 31 patients (5.1%). Among the 611 patients, 267 patients (43.7%) developed 882 adverse events (AEs), and 11 patients (1.8%) experienced 18 adverse drug reactions (ADRs). There were 62 patients (10.2%) who experienced 81 cases of serious adverse events (SAEs), with FN and pneumonia being the most frequent at 14 and 13 episodes, respectively, in 13 patients (2.1%). Meanwhile, 1 patient (0.2%) developed 2 episodes of serious ADRs (grade 1 and grade 2 hypotension). No safety concerns in the elderly and patients with liver and/or renal disease were identified. CONCLUSION: The prophylactic use of pegteograstim might have good overall safety and efficacy in patients with lymphomas and solid malignancies in routine clinical practice, even in those who are elderly and have liver and renal diseases.

Long-term data from a phase 3 study of radotinib versus imatinib in patients with newly diagnosed, chronic myeloid leukaemia in the chronic phase (RERISE).

In the phase 3 study RERISE, patients with newly diagnosed chronic myeloid leukaemia in chronic phase demonstrated significantly faster and higher rates of major molecular response (MMR) with twice-daily radotinib 300 mg (n = 79) or 400 mg (n = 81) than with once-daily imatinib 400 mg (n = 81) after 12 months. With ≥48 months' follow-up, MMR was higher with radotinib 300 mg (86%) or 400 mg (83%) than with imatinib (75%). Among patients with BCR-ABL1 ≤ 10% at three months, MMR and molecular response 4·5 (MR4·5 ) were achieved within 48 months by more radotinib-treated patients (300 mg: 84% and 52%, respectively; 400 mg: 74% and 44%, respectively) than imatinib-treated patients (71% and 44%, respectively). Estimated overall and progression-free survival rates at 48 months were not significantly different between imatinib (94% and 94%, respectively) and radotinib 300 mg (99% and 97%, respectively) or 400 mg (95% and 93%, respectively). The treatment failure rate was significantly higher with imatinib (19%) than with radotinib 300 mg (6%; P = 0·0197) or 400 mg (5%; P = 0·0072). Safety profiles were consistent with previous reports; most adverse events occurred within 12 months. Radotinib continues to demonstrate robust, deep molecular responses, suggesting that treatment-free remission may be attainable.

Long-term follow-up of abbreviated R-CHOP chemoimmunotherapy for completely resected limited-stage diffuse large B cell lymphoma (CISL 12-09).

The standard of treatment for completely resected limited-stage diffuse large B cell lymphoma (DLBCL) in patients without residual lesions has not yet been established. Previously, we designed a phase II trial to evaluate the safety and efficacy of three cycles of abbreviated R-CHOP in patients with completely resected limited-stage DLBCL and reported favorable survival outcomes. We present the long-term follow-up results to taking into account the importance of delayed relapse in patients with limited-stage DLBCL. With a median follow-up duration of 62.7 months (range, 60.2-75.5 months), the 5-year OS and DFS rates were both 95.0% (95% confidence interval, 85.59-104.11%). Only one patient experienced disease progression which was confirmed at 12.3 months, and one patient with primary intestinal DLBCL developed non-small cell lung cancer 6 years after treatment. The long-term results of our data support the use of three cycles of abbreviated R-CHOP for patients with completely resected limited-stage DLBCL. The study was reviewed and approved by the review boards of the participating institutes and registered at ClinicalTrials.gov , number NCT01279902, in August 3, 2010.

Correction to: Clinical outcomes in patients with diffuse large B cell lymphoma with a partial response to first-line R-CHOP chemotherapy: prognostic value of secondary International Prognostic Index scores and Deauville scores.

An additional affiliation for the first author was not indicated. Hyewon Lee is also affiliated with: Department of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, South Korea.

A phase II study of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin (ESHAOx) for patients with refractory or relapsed Hodgkin's lymphoma.

We assessed the efficacy and toxicity of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin (ESHAOx) combination chemotherapy in patients with refractory or relapsed Hodgkin's lymphoma (HL). This was an open-label, non-randomized, multi-center phase II study. The ESHAOx regimen consisted of intravenous (i.v.) etoposide 40 mg/m2 on days 1 to 4, i.v. methylprednisolone 500 mg on days 1 to 5, i.v. cytarabine 2 g/m2 on day 5, and i.v. oxaliplatin 130 mg/m2 on day 1. Cycles (up to six) were repeated every 3 weeks. In an effort to identify prognostic markers, the serum levels of cytokines including tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and vascular endothelial growth factor (VEGF) were measured at the time of study entry. A total of 37 patients were enrolled, and 36 were available for evaluation of tumor response. The overall response rate was 72.2% (26/36) (complete response, 33.3% [12/36]; partial response, 38.9% [14/36]). The median time to progression was 34.9 months (95% confidence interval, 23.1-46.7 months). The most common grade 3 or 4 hematological adverse events were neutropenia (16/37, 43.2%), followed by thrombocytopenia (10/37, 27.0%). Grade 3 or 4 non-hematological adverse events were nausea (3/37, 8.1%), anorexia (2/37, 5.4%), mucositis (1/37, 2.7%), and skin rash (1/37, 2.7%). There were no treatment-related deaths. High levels of TNF-α and CRP were significantly associated with poorer overall survival (p = 0.00005 for TNF-α, p = 0.0004 for CRP, respectively). The ESHAOx regimen exhibited antitumor activity and an acceptable safety profile in patients with refractory or relapsed HL. Trial Registration: ClinicalTrials.gov. Registered February 21, 2011, https://clinicaltrials.gov/ct2/show/NCT01300156.

The effectiveness and safety of lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma in real-world clinical practice: a study of the Korean Multiple Myeloma Working Party (KMMWP-151 study).

Although lenalidomide plus dexamethasone (RD) is a therapeutic option for relapsed/refractory multiple myeloma (RRMM), limited real-world clinical data exist. The purpose of this study was to estimate efficacy and safety of RD in RRMM patients of the clinical practice. Data from patients at 25 university hospitals in South Korea between October 2009 and December 2016 were collected retrospectively. We report the effectiveness and safety of RD in 546 RRMM patients in routine clinical practice in South Korea. Patients (median age, 65 years) typically received median 7 cycles of RD, and 184 (33.7%) patients were treated with 10 or more cycles of RD. Patients with renal impairment (CLCr < 40 mL/min; 10.4%), comorbid conditions (≥ 2; 12.0%), and poor performance status (≥ 2; 25.1%) were included. The overall response rate was 64.2%: complete response (13.1%), very good partial response (VGPR 19.9%). With median follow-up duration of 18.6 months, median PFS and OS were 11.2 months and 25.2 months, respectively. In multivariate analysis, less than 2 comorbid conditions, normal LDH, failed one chemotherapy prior to RD, and ≥ 10 cycles of RD therapy had significantly prolonged PFS (P = 0.007, P = 0.011, P = 0.007, and P < 0.001, respectively). Adverse events were acceptable. RD is effective and safe in real-life clinical practice, including patients with comorbidities. RD is an effective and safe treatment in a real clinical setting which includes patients with comorbidities. Early and continual use of RD treatment may improve RRMM survival outcomes.

Effect of Stem Cell Source and Dose on Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Idiopathic Aplastic Anemia: Data from the Korean Aplastic Anemia Trials.

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 <31 years (p = 0.010) and prior platelet transfusion <86 U (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.

Inhibition of acute lethal pulmonary inflammation by the IDO-AhR pathway.

The lung is a prototypic organ that was evolved to reduce immunopathology during the immune response to potentially hazardous endogenous and exogenous antigens. In this study, we show that donor CD4+ T cells transiently induced expression of indoleamine 2,3-dioxygenase (IDO) in lung parenchyma in an IFN-γ-dependent manner early after allogeneic hematopoietic stem cell transplantation (HSCT). Abrogation of host IDO expression by deletion of the IDO gene or the IFN-γ gene in donor T cells or by FK506 treatment resulted in acute lethal pulmonary inflammation known as idiopathic pneumonia syndrome (IPS). Interestingly, IL-6 strongly induced IDO expression in an IFN-γ-independent manner when deacetylation of STAT3 was inhibited. Accordingly, a histone deacetylase inhibitor (HDACi) could reduce IPS in the state where IFN-γ expression was suppressed by FK506. Finally, l-kynurenine produced by lung epithelial cells and alveolar macrophages during IPS progression suppresses the inflammatory activities of lung epithelial cells and CD4+ T cells through the aryl hydrocarbon receptor pathway. Taken together, our results reveal that IDO is a critical regulator of acute pulmonary inflammation and that regulation of IDO expression by HDACi may be a therapeutic approach for IPS after HSCT.

The effects of erythropoiesis-stimulating agents on the management of chemotherapy-induced anemia and tumor growth in diffuse large B-cell lymphoma patients.

Erythropoiesis-stimulating agents (ESAs), such as erythropoietin (EPO) and darbepoetin, may alleviate anemia in diffuse large B-cell lymphoma (DLBCL) patients. However, many cancer cells express EPO receptors (EPOR), through which exogenously administered ESAs potentially promote cancer cell growth. We conducted preclinical/phase II studies to investigate the safety and efficacy of ESAs for managing chemotherapy-related anemia in DLBCL patients. We examined EPOR expression in germinal center B-cell (GCB)- and activated B-cell (ABC)-DLBCL cell lines, and investigated the effects of ESAs on cell proliferation, and rituximab-mediated complement-dependent cytotoxicity (CDC). The clinical study enrolled 50 histologically confirmed DLBCL patients receiving rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-CHOP) who had hemoglobin levels <10.0 g/dl after a maximum of three R-CHOP cycles and received ≥4 doses of fixed-dose darbepoetin (360 µg) once every 3 weeks. EPOR mRNA was detected in all GCB-DLBCL cell lines, but little/none was detected in ABC-DLBCL cell lines. GCB-DLBCL and ABC-DLBCL cell proliferation was unaffected by EPO or darbepoetin. Rituximab-mediated CDC of DLBCL cell lines with/without EPOR expression was not affected adversely by EPO. In the clinical study, baseline mean hemoglobin was 9.19 g/dl; the overall mean change in hemoglobin was 1.59 ± 1.3 g/dl (16 weeks). Forty-eight percent of enrolled patients achieved a hematopoietic response. Our study shows that ESAs do not affect the growth of DLBCL cells or rituximab-mediated CDC under the experimental conditions that we used, and the appropriate use of ESAs may be effective and safe for DLBCL patients with anemia after R-CHOP.