Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 243
Filter
1.
Int J Hematol ; 119(6): 677-685, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38519820

ABSTRACT

Response determined by 18[F]-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)-CT after induction therapy can predict progression-free survival (PFS) in follicular lymphoma (FL). However, little prospective research has examined the significance of PET after second-line therapy. We conducted a prospective multicenter phase II trial (W-JHS NHL01) of bendamustine plus rituximab (BR) without rituximab maintenance for FL in first relapse. This study aimed to evaluate the usefulness of end-of-treatment (EOT)-PET for predicting PFS in FL patients in first relapse. EOT-PET examinations were performed between 6 and 8 weeks from the start of the last BR cycle. The primary endpoint was 1-year PFS. Key secondary endpoints were overall response rate (ORR), complete response rate (CRR), and 1-year overall survival (OS). Seventy-five patients were enrolled, and 8 were excluded from analysis. ORR was 86.6% and CRR was 59.7%. One-year PFS was 88.9% (95% confidence interval [CI] 80.7-94.3%) and 1-year OS in 75 patients was 97.3% (95% CI 89.6-99.3%). One-year PFS was significantly inferior in EOT-PET-positive patients (n = 9) compared with PET-negative patients (n = 58) (77.8% vs. 93.1%; p = 0.02). We confirmed that EOT-PET after second-line BR therapy could predict early progression in FL patients in first relapse.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Bendamustine Hydrochloride , Disease Progression , Fluorodeoxyglucose F18 , Lymphoma, Follicular , Positron-Emission Tomography , Rituximab , Humans , Lymphoma, Follicular/drug therapy , Lymphoma, Follicular/diagnostic imaging , Lymphoma, Follicular/mortality , Bendamustine Hydrochloride/administration & dosage , Rituximab/administration & dosage , Fluorodeoxyglucose F18/administration & dosage , Middle Aged , Aged , Male , Female , Prospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Adult , Japan , Positron-Emission Tomography/methods , Recurrence , Aged, 80 and over , Radiopharmaceuticals/administration & dosage
2.
Jpn J Clin Oncol ; 54(2): 153-159, 2024 Feb 07.
Article in English | MEDLINE | ID: mdl-37986553

ABSTRACT

OBJECTIVE: Minimal residual disease assessment of BCR-ABL messenger ribonucleic acid levels is crucial in Philadelphia chromosome-positive acute lymphoblastic leukemia for prognosis and treatment planning. However, accurately quantifying minor BCR-ABL transcripts, which comprise 70% of Philadelphia chromosome-positive acute lymphoblastic leukemia cases, lacks a national-approved method. METHODS: We developed the "Otsuka" minor BCR-ABLmessenger ribonucleic acid assay kit with exceptional precision (0.00151%). Minor BCR-ABL messenger ribonucleic acid levels were analyzed in 175 adults, 36 children with acute lymphoblastic leukemia and 25 healthy individuals to evaluate the kit's performance. RESULTS: The "Otsuka" kit showed high concordance with a commonly used chimeric gene screening method, indicating reliable detection of positive cases. Quantitative results demonstrated a robust correlation with both a laboratory-developed test and a diagnostic research product. The "Otsuka" kit performs comparably or even surpass to conventional products, providing valuable insights into Philadelphia chromosome-positive acute lymphoblastic leukemia pathology. CONCLUSIONS: The 'Otsuka" minor BCR-ABL messenger ribonucleic acid assay kit exhibits excellent performance in quantifying minor BCR-ABL transcripts in Philadelphia chromosome-positive acute lymphoblastic leukemia patients. Our results align well with established screening methods and show a strong correlation with laboratory-developed tests and diagnostic research products. The "Otsuka" kit holds great promise as a valuable tool for understanding Philadelphia chromosome-positive acute lymphoblastic leukemia pathology and guiding effective treatment strategies.


Subject(s)
Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Adult , Child , Humans , Fusion Proteins, bcr-abl/analysis , Fusion Proteins, bcr-abl/genetics , Real-Time Polymerase Chain Reaction , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , RNA
3.
Br J Haematol ; 203(3): 468-476, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37654088

ABSTRACT

To determine the prevalence and clinical relevance of glycosylphosphatidylinositol-anchored protein-deficient (GPI[-]) cell populations (paroxysmal nocturnal haemoglobinuria [PNH]-type cells) in patients with acquired aplastic anaemia (AA) or myelodysplastic syndrome (MDS), we prospectively studied peripheral blood samples of 2402 patients (1075 with AA, 900 with MDS, 144 with PNH, and 283 with other anaemia) using a high-sensitivity flow cytometry assay in a nationwide multi-centre observational study. PNH-type cells were detected in 52.6% of AA and 13.7% of MDS patients. None of the 35 patients with refractory anaemia (RA) with ringed sideroblasts or the 86 patients with RA with excess of blasts carried PNH-type cells. Among the 317 patients possessing PNH-type granulocytes, the percentage of PNH-type granulocytes increased by ≥10% in 47 patients (14.8%), remained unchanged in 240 patients (75.7%), and decreased by ≥10% in 30 patients (9.5%) during 3 years of follow-up. PNH-type granulocyte expansion occurred more frequently (27.1%) in the 144 patients who originally carried PNH-type granulocytes ≥1% than in the 173 patients with PNH-type granulocytes <1% (4.6%). This study confirmed that PNH-type cells are undetectable in authentic clonal MDS patients, and the presence of ≥1% PNH-type granulocytes predicts a higher likelihood of PNH-type cell expansion than with <1% PNH-type granulocytes.

4.
Int J Hematol ; 118(5): 609-617, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37668833

ABSTRACT

To investigate the real-world clinical outcomes and management of novel drug-containing therapies for newly diagnosed multiple myeloma (MM) patients, we retrospectively analyzed data on the first-line treatment for newly diagnosed transplant-ineligible MM patients from Kansai Myeloma Forum, a registry network in Japan. A total of 598 patients treated with novel drugs between March 2007 and February 2018 were analyzed. Regimens used were VD (n = 305), Rd (n = 103), VMP (n = 97), VCD (n = 71), and VRd (n = 22). Younger patients tended to receive VRd or VCD, whereas the regimen with the highest median patient age was Rd. More than three-quarters of patients in the Rd group received a reduced dose of lenalidomide. The Rd and VRd groups had a relatively high incidence of infection and skin complications, and the VMP group had the highest incidence of peripheral neuropathy. Overall response rate did not differ significantly between regimens. Multivariate analysis in all patients revealed several poor prognostic factors, such as poor performance status. Novel drug-containing regimens for newly diagnosed MM showed a durable response with manageable AEs in the real-world setting.


Subject(s)
Multiple Myeloma , Humans , Multiple Myeloma/diagnosis , Multiple Myeloma/drug therapy , Retrospective Studies , Bortezomib/therapeutic use , Induction Chemotherapy , Dexamethasone/adverse effects , Disease-Free Survival , Antineoplastic Combined Chemotherapy Protocols/adverse effects
5.
Jpn J Clin Oncol ; 53(10): 912-921, 2023 Oct 04.
Article in English | MEDLINE | ID: mdl-37486002

ABSTRACT

OBJECTIVE: This dose-escalation part of an ongoing Phase I study assessed the tolerability, safety and pharmacokinetics of mosunetuzumab in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). METHODS: Mosunetuzumab was administered intravenously, with step-up dosing in a 3 + 3 design, on Days 1, 8 and 15 of Cycle 1, and Day 1 of each subsequent 21-day cycle for up to 17 cycles to patients across five cohorts with different target doses (2.8, 6.0, 13.5, 27.0 or 60.0 mg). RESULTS: As of 5 July 2022, 23 patients had received mosunetuzumab. The median patient age was 63.0 years, 56.5% of patients were male, and 69.6% of patients had diffuse large B-cell lymphoma, 17.4% had transformed follicular lymphoma (FL) and 13.0% had FL. The median number of prior lines of therapy was 4. Mosunetuzumab was well tolerated and there were no deaths. The most common adverse events (any grade) were neutropenia/neutrophil count decreased (47.8%) and cytokine release syndrome (34.8%). Most cytokine release syndrome events were Grade 1/2 (one Grade 3), and most occurred within 24 hours of the first dose of mosunetuzumab. The apparent half-life of mosunetuzumab was 4.1-5.0 days. Two patients achieved a complete response, and 11 patients achieved a partial response. CONCLUSIONS: This study demonstrated that mosunetuzumab has an acceptable safety profile and antitumor activity in Japanese patients with relapsed/refractory B-cell NHL. The recommended Phase II dose of 1.0/2.0/60.0/60.0/30.0 mg was tolerable and there were no new or different safety signals compared with the global Phase I study.


Subject(s)
Antineoplastic Agents , Lymphoma, Follicular , Lymphoma, Non-Hodgkin , Humans , Male , Middle Aged , Female , Cytokine Release Syndrome/chemically induced , Cytokine Release Syndrome/drug therapy , East Asian People , Neoplasm Recurrence, Local/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/pathology , Antineoplastic Agents/therapeutic use , Lymphoma, Follicular/drug therapy
6.
Clin Pharmacol Ther ; 113(4): 904-915, 2023 04.
Article in English | MEDLINE | ID: mdl-36660902

ABSTRACT

Drug-target-drug complexes (DTDCs) are phenomena newly observed in patients who switch from the complement component 5 (C5) inhibitor eculizumab to crovalimab, a novel, anti-C5 antibody in development for paroxysmal nocturnal hemoglobinuria (PNH), because these agents bind to different C5 epitopes. In Part 3 of the four-part, phase I/II COMPOSER study, 19 patients with PNH switching from eculizumab received 1,000-mg crovalimab intravenously, then subcutaneous maintenance doses from Day 8 (680 mg every 4 weeks (q4w), 340 mg every 2 weeks, or 170 mg every week). Crovalimab exposure was transiently reduced, and size-exclusion chromatography and crovalimab-specific enzyme-linked immunosorbent assays revealed DTDCs in all 19 patients' sera. Additionally, self-limiting mild to moderate symptoms suggestive of type III hypersensitivity reactions occurred in two patients. Mathematical modeling simulations of DTDC kinetics and effects of dosing on DTDC size distribution using Part 3 data predicted that increased crovalimab concentrations could reduce the proportion of large, slow-clearing DTDCs in the blood. A simulation-guided, optimized crovalimab regimen (1,000 mg intravenously; four weekly, subcutaneous 340-mg doses; then 680 mg q4w from Day 29) was evaluated in Part 4. Confirming the model's predictions, mean proportions of large DTDCs in patients who switched from eculizumab to this optimized regimen decreased by > 50% by Day 22, and target crovalimab concentrations were maintained. No type III hypersensitivity reactions occurred in Part 4. Optimizing crovalimab dosing thus reduced the proportion of large DTDCs, ensured adequate complement inhibition, and may improve safety. Model-based dosing optimization to mitigate DTDC formation offers a useful strategy for patients switching to novel antibody treatments targeting soluble epitopes.


Subject(s)
Hemoglobinuria, Paroxysmal , Humans , Hemoglobinuria, Paroxysmal/drug therapy , Antibodies, Monoclonal , Complement Inactivating Agents/adverse effects , Complement C5
7.
Ther Adv Hematol ; 13: 20406207221104584, 2022.
Article in English | MEDLINE | ID: mdl-35785245

ABSTRACT

Background: Little is known about the real-world survival benefits and safety profiles of carfilzomib-lenalidomide-dexamethasone (KRd) and carfilzomib-dexamethasone (Kd). Methods: We performed a retrospective analysis to evaluate their efficacy and safety in 157 patients registered in the Kansai Myeloma Forum database. Results: A total of 107 patients received KRd. Before KRd, 99% of patients had received bortezomib (54% were refractory disease), and 82% had received lenalidomide (57% were refractory disease). The overall response rate (ORR) was 68.2%. The median progression-free survival (PFS) and overall survival (OS) were 8.8 and 29.3 months, respectively. Multivariate analysis showed that reduction of the carfilzomib dose and non-IgG M protein were significantly associated with lower PFS and reduction of the carfilzomib dose and refractoriness to prior bortezomib-based regimens were significantly associated with lower OS. A total of 50 patients received Kd. Before Kd, 96% of patients had received bortezomib (54% were refractory disease). The ORR was 62.0%. The median PFS and OS were 7.1 and 20.9 months, respectively. Based on the multivariate analysis, reduction of the carfilzomib dose and International Staging System Stage III (ISS III) were significantly associated with lower PFS. Grade III or higher adverse events were observed in 48% of KRd cases and 54% of Kd cases. Cardiovascular events, cytopenia, and infections were frequent, and 4 KRd patients died due to heart failure, arrhythmia, cerebral hemorrhage, and pneumonia. Conclusion: Our analysis showed that an adequate dose of carfilzomib is important for achieving the best survival benefits in a real-world setting. Adverse effects after KRd and Kd therapy should also be considered.

8.
Int J Hematol ; 116(5): 659-668, 2022 Nov.
Article in English | MEDLINE | ID: mdl-35821550

ABSTRACT

Darbepoetin alfa (DA) is used to treat anemia in lower-risk (IPSS low or int-1) myelodysplastic syndromes (MDS). However, whether mutations can predict the effectiveness of DA has not been examined. The present study aimed to determine predictive gene mutations. The primary endpoint was a correlation between the presence of highly frequent (≥ 10%) mutations and hematological improvement-erythroid according to IWG criteria 2006 by DA (240 µg/week) until week 16. The study included 79 patients (age 29-90, median 77.0 years; 52 [65.8%] male). Frequently (≥ 10%) mutated genes were SF3B1 (24 cases, 30.4%), TET2 (20, 25.3%), SRSF2 (10, 12.7%), ASXL1 (9, 11.4%), and DNMT3A (8, 10.1%). Overall response rate to DA was 70.9%. Multivariable analysis including baseline erythropoietin levels and red blood cell transfusion volumes as variables revealed that erythropoietin levels and mutations of ASXL1 gene were significantly associated with worse response (odds ratio 0.146, 95% confidence interval 0.042-0.503; p = 0.0023, odds ratio 0.175, 95% confidence interval 0.033-0.928; p = 0.0406, respectively). This study indicated that anemic patients who have higher erythropoietin levels and harbor ASXL1 gene mutations may respond poorly to DA. Alternative strategies are needed for the treatment of anemia in this population. Trial registration number and date of registration: UMIN000022185 and 09/05/2016.


Subject(s)
Anemia , Erythropoietin , Myelodysplastic Syndromes , Humans , Male , Adult , Middle Aged , Aged , Aged, 80 and over , Female , Darbepoetin alfa , Erythropoietin/therapeutic use , Anemia/etiology , Anemia/genetics , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/genetics , Mutation , Repressor Proteins/genetics
10.
Biochem Biophys Res Commun ; 603: 1-6, 2022 05 07.
Article in English | MEDLINE | ID: mdl-35259639

ABSTRACT

Anamorsin (AM) is an anti-apoptotic molecule cloned by us as a molecule that confers resistance against apoptosis induced by growth factor deprivation. AM-deficient mice are embryonic lethal, which impedes detailed analyses of the roles of AM in various types of adult cells. To overcome the embryonic lethality, we generated AM conditional knockout (AMflox/flox) mice and cell type-specific genetic modification became possible using the Cre-loxP system. CD19-Cre/AMflox/flox mice with AM deleted specifically in CD19+ B cells exhibited less B220+ B cells in their spleen, peripheral blood, and lymph node compared with control CD19-Cre mice. Using flow cytometry to categorize bone marrow and spleen cells into B cell subsets, we observed significantly less follicular type I cells, which are the most mature follicular B cells, compared with control CD19-Cre mice. These data suggest that AM has an important role in the generation of mature B cells.


Subject(s)
Antigens, CD19 , B-Lymphocytes , Animals , Antigens, CD19/genetics , Apoptosis , Cell Differentiation , Mice , Mice, Knockout , Spleen
11.
Int J Hematol ; 115(4): 470-480, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35146630

ABSTRACT

All Japanese patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with eculizumab were enrolled in post-marketing surveillance (PMS) between June 2010 and August 2019 to assess the long-term effectiveness and safety of eculizumab. The reduction in intravascular hemolysis, the change in hemoglobin (Hb) level, and the change in renal function were assessed to determine the effectiveness of eculizumab. The types and frequencies of adverse events (AEs) were assessed to determine its safety. A total of 632 patients were enrolled and the median treatment duration was 3.6 years. Treatment with eculizumab significantly reduced lactate dehydrogenase (LDH) levels and significantly increased Hb levels. These changes were maintained for up to 5 years of treatment. An estimated glomerular filtration rate ≥ 60 ml/min/1.73 m2 and higher LDH level at baseline were associated with increases in Hb levels during eculizumab treatment. The overall incidence of any AE was 69.92/100 patient-years. Hemolysis was the most common AE (6.43/100 patient-years). The incidence of infection-related AEs was 20.57/100 patient-years, and included meningococcal infection in three patients (0.12/100 patient-years). This long-term follow-up of patients with PNH demonstrated the sustained effectiveness of eculizumab and supports its well-established safety profile.


Subject(s)
Hemoglobinuria, Paroxysmal , Antibodies, Monoclonal, Humanized , Follow-Up Studies , Hemoglobinuria, Paroxysmal/drug therapy , Hemolysis , Humans , Japan/epidemiology , Product Surveillance, Postmarketing
12.
Exp Hematol ; 105: 10-17, 2022 01.
Article in English | MEDLINE | ID: mdl-34780812

ABSTRACT

Inflammatory and immune signals are involved in stressed hematopoiesis under myeloablation, infection, chronic inflammation, and aging. These signals also affect malignant pathogenesis, and the dysregulated immune environment which causes the resistance to treatment. On activation, various types of protein tyrosine kinases in the cytoplasm mediate the cascade, leading to the transcription of target genes in the nucleus. Adaptor molecules are commonly defined as proteins that lack enzymatic activity, DNA-binding or receptor functions and possess protein-protein or protein-lipid interaction domains. By binding to specific domains of signaling molecules, adaptor proteins adjust the signaling responses after the ligation of receptors of soluble factors, including cytokines, chemokines, and growth factors, as well as pattern recognition receptors such as toll-like receptors. The signal-transducing adaptor protein (STAP) family regulates various intracellular signaling pathways. These proteins have a pleckstrin homology domain in the N-terminal region and an SRC-homology 2-like domain in the central region, representing typical binding structures as adapter proteins. Following the elucidation of the effects of STAPs on terminally differentiated immune cells, such as macrophages, T cells, mast cells, and basophils, recent findings have indicated the critical roles of STAP-2 in B-cell progenitor cells in marrow under hematopoietic stress and STAP-1 and -2 in BCR-ABL-transduced leukemogenesis. In this review, we focus on the role of STAPs in the bone marrow.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Hematologic Neoplasms/metabolism , Hematopoiesis , Phosphoproteins/metabolism , Animals , Bone Marrow/metabolism , Bone Marrow/pathology , Hematologic Neoplasms/pathology , Humans , Signal Transduction
13.
Rinsho Ketsueki ; 62(10): 1488-1492, 2021.
Article in Japanese | MEDLINE | ID: mdl-34732621

ABSTRACT

COVID-19 is a viral infection characterized by a cytokine storm similar to that in acute respiratory distress syndrome (ARDS). Neutrophils and monocytes are known to play an important role in tissue damage in ARDS. COVID-19 has been reported to be more severe in patients with hematological malignancies; however, there are few reports of COVID-19 in patients with aplastic anemia. Moreover, how aplastic anemia affects COVID-19 remains unclear. Here, we report the case of a COVID-19 patient with aplastic anemia who had high serum IL-6 levels but did not progress to the severe form of COVID-19. We inferred that severe neutropenia and monocytopenia due to aplastic anemia could contribute to a mild form of COVID-19, although a risk of more severe secondary bacterial infections exists.


Subject(s)
Anemia, Aplastic , COVID-19 , Cytokine Release Syndrome , Humans , Interleukin-6 , SARS-CoV-2
14.
Intern Med ; 60(23): 3785-3788, 2021 Dec 01.
Article in English | MEDLINE | ID: mdl-34053991

ABSTRACT

Congenital mutations of the Wilms' tumor 1 (WT1) gene can lead to various abnormalities, including renal/gonadal developmental disorders and cardiac malformations. Although there have been many reports of somatic WT1 mutations in patients with acute myeloid leukemia and myelodysplastic syndrome, congenital WT1 mutations have not been reported in hematological disorders. We herein report a patient with early-onset clonal cytopenia of undetermined significance that was associated with a congenital mutation of WT1 and an acquired mutation of DNMT3A [encoding DNA (cytosine-5)-methyltransferase 3A].


Subject(s)
Clonal Hematopoiesis , DNA Methyltransferase 3A/genetics , Kidney Neoplasms , Wilms Tumor , Genes, Wilms Tumor , Humans , Mutation , WT1 Proteins/genetics , Wilms Tumor/genetics
15.
Br J Haematol ; 193(3): 659-668, 2021 05.
Article in English | MEDLINE | ID: mdl-33837967

ABSTRACT

A population of mesenchymal stem cells, termed CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells or leptin receptor-expressing cells, are the major cellular component of niches for haematopoietic stem cells (HSCs) in murine bone marrow. CAR cells are characterized by several salient features, including much higher expression of CXCL12, stem cell factor (SCF), forkhead box C1 (FOXC1) and early B-cell factor 3 (EBF3), which are essential for HSC maintenance, than other cells. However, the human counterpart of CAR cells has not been fully described. Here, we show the presence of cells expressing much higher CXCL12 than other cells in human adult bone marrow using a flow cytometry-based in situ technique that enables high-throughput detection of mRNA at single-cell resolution. Most CXCL12hi cells expressed high levels of SCF, FOXC1 and EBF3 and had the potential to differentiate into adipocytes and osteoblasts. Histologically, the nuclei of CXCL12hi cells were identified and quantified by EBF3 expression in fixed marrow sections. CXCL12hi cells sorted from residual bone marrow aspirates of chronic myeloid leukaemia patients expressed reduced levels of CXCL12, SCF, FOXC1 and EBF3 in correlation with increased leukaemic burden. Together, we identified the human counterpart of CAR cells, enabling the evaluation of their alterations in various haematological disorders by flow cytometric and histological analyses.


Subject(s)
Chemokine CXCL12/metabolism , Hematopoietic Stem Cells/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Mesenchymal Stem Cells/metabolism , Neoplasm Proteins/metabolism , Stem Cell Niche , Adult , Female , Forkhead Transcription Factors/metabolism , Hematopoietic Stem Cells/pathology , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Mesenchymal Stem Cells/pathology , Stem Cell Factor/metabolism , Transcription Factors/metabolism
16.
Int J Hematol ; 114(1): 53-64, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33765256

ABSTRACT

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication of transplantation. In addition to reactivation of Epstein-Barr virus in immunocompromised patients, impaired tumor immunity is suggested to be a risk factor for PTLD. However, it remains unclear whether immune suppressive tumor-infiltrating lymphocytes (TILs) correlate with the occurrence or prognosis of PTLD. We analyzed TILs in 26 patients with PTLD to elucidate the clinicopathological significance of the expression of PD-1 and FoxP3, which are associated with exhausted T-cells and regulatory T-cells (Tregs), respectively. Numbers of PD-1+ TILs in the PTLD specimens were significantly higher in patients who developed PTLD early after transplantation (P = 0.0040), while numbers of FoxP3+ TILs were not (P = 0.184). There was no difference in overall response rate regardless of the expression of PD-1 or FoxP3. FoxP3high patients tended to have a shorter time to progression compared with FoxP3low patients, especially in the case of FoxP3high patients with diffuse large B-cell lymphoma-subtype PTLD (P = 0.011), while PD-1high patients did not. These results suggest that T-cell exhaustion may be mainly associated with PTLD development, while immune suppression by Tregs may be dominant in enhanced progression of PTLD following disease occurrence.


Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Lymphocytes, Tumor-Infiltrating/pathology , Lymphoproliferative Disorders/etiology , Organ Transplantation/adverse effects , Programmed Cell Death 1 Receptor/analysis , Adult , Aged , Female , Forkhead Transcription Factors/analysis , Humans , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Large B-Cell, Diffuse/therapy , Lymphoproliferative Disorders/pathology , Male , Middle Aged , Retrospective Studies , Young Adult
17.
J Exp Med ; 218(5)2021 05 03.
Article in English | MEDLINE | ID: mdl-33666647

ABSTRACT

The cell-cycle status of hematopoietic stem and progenitor cells (HSPCs) becomes activated following chemotherapy-induced stress, promoting bone marrow (BM) regeneration; however, the underlying molecular mechanism remains elusive. Here we show that BM-resident group 2 innate lymphoid cells (ILC2s) support the recovery of HSPCs from 5-fluorouracil (5-FU)-induced stress by secreting granulocyte-macrophage colony-stimulating factor (GM-CSF). Mechanistically, IL-33 released from chemo-sensitive B cell progenitors activates MyD88-mediated secretion of GM-CSF in ILC2, suggesting the existence of a B cell-ILC2 axis for maintaining hematopoietic homeostasis. GM-CSF knockout mice treated with 5-FU showed severe loss of myeloid lineage cells, causing lethality, which was rescued by transferring BM ILC2s from wild-type mice. Further, the adoptive transfer of ILC2s to 5-FU-treated mice accelerates hematopoietic recovery, while the reduction of ILC2s results in the opposite effect. Thus, ILC2s may function by "sensing" the damaged BM spaces and subsequently support hematopoietic recovery under stress conditions.


Subject(s)
Bone Marrow Cells/metabolism , Fluorouracil/pharmacology , Hematopoietic Stem Cells/metabolism , Immunity, Innate/immunology , Lymphocytes/immunology , Animals , Bone Marrow/drug effects , Bone Marrow/metabolism , Bone Marrow Cells/cytology , Bone Marrow Cells/drug effects , Cells, Cultured , Gene Expression Profiling/methods , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/drug effects , Immunity, Innate/drug effects , Immunosuppressive Agents/pharmacology , Lymphocytes/drug effects , Lymphocytes/metabolism , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microscopy, Confocal , Reverse Transcriptase Polymerase Chain Reaction
18.
Hematol Oncol ; 39(3): 349-357, 2021 Aug.
Article in English | MEDLINE | ID: mdl-33724498

ABSTRACT

The plateau phase emerging during the treatment of multiple myeloma (MM) is known to last steadily for a certain period, even without treatment. Therefore, the treatment started at plateau phase is expected to be associated with a better outcome. In this study, this hypothesis was evaluated retrospectively for previously treated MM patients in Kansai Myeloma Forum database who received lenalidomide (LEN) with or without dexamethasone for the first time. Disease stability index (DSI) was defined as (maximum - minimum values of M protein during the 90 days before the start of LEN) divided by M-protein values at the start of LEN. The patients were classified into three groups: stable (S), DSI ≤ 0.25; increasing (I), DSI > 0.25 with increasing M protein; decreasing (D), DSI > 0.25 with decreasing M protein. In univariate analysis of 352 patients, DSI group "I", non-IgG type, serum albumin<3.5 g/dL, and age≥70 were statistically significant prognostic factors for both progression-free survival and overall survival. In multivariate analysis, the former 3 risk factors were statistically significant for poor overall survival. Thus, DSI is an independent prognostic factor for the treatment with LEN for previously treated MM.


Subject(s)
Databases, Factual , Lenalidomide/administration & dosage , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Adult , Age Factors , Aged , Aged, 80 and over , Dexamethasone/administration & dosage , Disease-Free Survival , Female , Humans , Male , Middle Aged , Risk Factors , Survival Rate
19.
Stem Cells ; 39(6): 723-736, 2021 06.
Article in English | MEDLINE | ID: mdl-33539590

ABSTRACT

Heterogeneity of leukemia stem cells (LSCs) is involved in their collective chemoresistance. To eradicate LSCs, it is necessary to understand the mechanisms underlying their heterogeneity. Here, we aimed to identify signals responsible for heterogeneity and variation of LSCs in human acute myeloid leukemia (AML). Monitoring expression levels of endothelial cell-selective adhesion molecule (ESAM), a hematopoietic stem cell-related marker, was useful to detect the plasticity of AML cells. While healthy human hematopoietic stem/progenitor cells robustly expressed ESAM, AML cells exhibited heterogeneous ESAM expression. Interestingly, ESAM- and ESAM+ leukemia cells obtained from AML patients were mutually interconvertible in culture. KG1a and CMK, human AML clones, also represented the heterogeneity in terms of ESAM expression. Single cell culture with ESAM- or ESAM+ AML clones recapitulated the phenotypic interconversion. The phenotypic alteration was regulated at the gene expression level, and RNA sequencing revealed activation of TGFß signaling in these cells. AML cells secreted TGFß1, which autonomously activated TGFß pathway and induced their phenotypic variation. Surprisingly, TGFß signaling blockade inhibited not only the variation but also the proliferation of AML cells. Therefore, autonomous activation of TGFß signaling underlies the LSC heterogeneity, which may be a promising therapeutic target for AML.


Subject(s)
Hematopoietic Stem Cells/metabolism , Leukemia, Myeloid, Acute/metabolism , Neoplastic Stem Cells/metabolism , Transforming Growth Factor beta/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , Cell Proliferation/physiology , Humans , Leukemia, Myeloid, Acute/genetics , Signal Transduction/genetics , Signal Transduction/physiology
20.
Eur J Haematol ; 106(4): 555-562, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33476404

ABSTRACT

OBJECTIVES: This study aimed to investigate real-world data of ixazomib plus lenalidomide and dexamethasone (IRd) therapy for patients with relapsed and refractory multiple myeloma (RRMM). METHODS: We retrospectively analyzed 122 patients treated with IRd at 16 centers from May 2017 to January 2019 by using the Kansai Myeloma Forum database. RESULT: At the start of IRd, the median age was 72 years, 66.7% of patients had IgG type, and the median number of prior therapies was 4, comprising bortezomib (85.4%) and lenalidomide (89.3%)-based regimens. Disease progression and adverse events accounted for treatment discontinuation in 46 and 32 patients, respectively. The median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 11.9 months. Sensitivity to bortezomib did not affect the PFS, whereas lenalidomide-refractory patients had significantly lower PFS than lenalidomide-sensitive patients, who were comparable to TOURMALINE-MM1 study. The patients with IgG type had significantly better PFS and OS than those with non-IgG type. CONCLUSION: This study presents the largest real-world data of patients treated with IRd in Asia. However, in real clinical practice, the patient background is different from the TOURMALINE-MM1 study, and IRd showed poor efficacy, especially in the non-IgG type and lenalidomide-refractory patients with RRMM.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Biomarkers, Tumor , Boron Compounds/administration & dosage , Dexamethasone/administration & dosage , Female , Glycine/administration & dosage , Glycine/analogs & derivatives , Humans , Kaplan-Meier Estimate , Lenalidomide/administration & dosage , Male , Middle Aged , Multiple Myeloma/diagnosis , Multiple Myeloma/etiology , Multiple Myeloma/mortality , Neoplasm Staging , Prognosis , Retreatment , Retrospective Studies , Treatment Outcome
SELECTION OF CITATIONS
SEARCH DETAIL
...