144 results on '"Koji Nagafuji"'
Search Results
2. Adenovirus disease after hematopoietic cell transplantation: A Japanese transplant registry analysis
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Yoshihiro Inamoto, Wataru Takeda, Tsuneaki Hirakawa, Hirotoshi Sakaguchi, Nobuaki Nakano, Naoyuki Uchida, Noriko Doki, Kazuhiro Ikegame, Yuta Katayama, Masashi Sawa, Takuro Kuriyama, Nobuhiro Hiramoto, Shuichi Ota, Yukiyasu Ozawa, Keisuke Kataoka, Yoshinobu Kanda, Moeko Hino, Takafumi Kimura, Yoshiko Atsuta, Takahiro Fukuda, and Koji Nagafuji
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Adult ,Male ,Transplantation Conditioning ,Japan ,Lymphoma ,Hematopoietic Stem Cell Transplantation ,Humans ,Graft vs Host Disease ,Registries ,Hematology ,Middle Aged ,Child ,Adenoviridae - Abstract
We analyzed a Japanese registry database to elucidate the incidence, risk factors, and outcomes of adenovirus (AdV) disease after autologous and allogeneic hematopoietic cell transplantation (HCT) in contemporary real-world patients. We evaluated the cumulative incidence of AdV disease, as well as risk factors, survival, and treatment details, among 25 233 patients who underwent autologous HCT and 48 380 patients who underwent allogeneic HCT between 2005 and 2019. The 1-year cumulative incidences of AdV disease after autologous and allogeneic HCT were 0.18% and 1.52%, respectively, in children, and 0.49% and 2.99%, respectively, in adults. Among patients with AdV disease, renourinary infection was the most common manifestation, and viremia or disseminated disease occurred in 6% of those after autologous HCT and 19% of those after allogeneic HCT. In multivariate analysis, age ≥50 years and lymphoma were associated with AdV disease after autologous HCT, while patients age ≥50 years, male patients, lymphoma, HCT-specific comorbidity index ≥3, human leukocyte antigen-mismatched or haploidentical donors, cord blood, in vivo T-cell depletion, HCT from 2005 to 2009, acute graft-versus-host disease (GVHD), and chronic GVHD were associated with AdV disease after allogeneic HCT. The 1-year probabilities of survival after disease diagnosis were 65% in autologous HCT and 44% in allogeneic HCT. Regardless of the AdV disease burden, there was an increased risk of mortality after both autologous and allogeneic HCT. The most commonly used antiviral agents were cidofovir and vidarabine. The probabilities of improvement and survival with currently available agents were suboptimal. AdV disease after HCT remains a challenge. Better antiviral modalities are necessary.
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- 2022
3. Comparable survival outcomes with haploidentical stem cell transplantation and unrelated bone marrow transplantation
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Yoshiko Atsuta, Junichi Sugita, Hirohisa Nakamae, Yumiko Maruyama, Ken Ishiyama, Souichi Shiratori, Takahiro Fukuda, Mio Kurata, Naoki Shingai, Yukiyasu Ozawa, Masayoshi Masuko, Koji Nagafuji, Satoru Takada, Shinichi Kako, Yoshinobu Kanda, Junya Kanda, Tatsuo Ichinohe, and Takanori Teshima
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Leukemia, Myeloid, Acute ,Transplantation ,Recurrence ,Hematopoietic Stem Cell Transplantation ,Humans ,Graft vs Host Disease ,Hematology ,Unrelated Donors ,Cyclophosphamide ,Bone Marrow Transplantation ,Retrospective Studies - Abstract
We retrospectively compared outcomes of unrelated donor bone marrow transplant (UBMT) and HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide (PTCy-haploPBSCT) using the Japanese registry data. Recipients of first HCT for acute leukemia and myelodysplastic syndromes between 2012 and 2015 were included. The analyzed subjects comprised UBMT recipients with 8/8 matched HLA alleles (n = 1470), 7/8 matched alleles (n = 859), 6/8 matched alleles (n = 186), and recipients of PTCy-haploPBSCT (n = 133). In multivariate analyses with 8/8 matched UBMT as the reference, PTCy-haploPBSCT showed similar overall mortality, decreased risk of non-relapse mortality (NRM), increased risk of relapse, and decreased risk of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD. Adjusted probabilities for 8/8 matched UBMT, PTCy-haploPBSCT, and 7/8 and 6/8 matched UBMT groups at 2 years post-transplant were 61%, 60%, 58%, and 52% for overall survival, 23%, 28%, 21%, and 19% for relapse, and 20%, 7%, 24%, and 33% for NRM. PTCy-haploPBSCT was associated with remarkably low NRM, contributing to survival outcomes that were comparable to 8/8 matched UBMT. The higher relapse rate in the PTCy-haploPBSCT group might be associated with the higher proportion of high-risk patients. PTCy-haploPBSCT may be a viable alternative when HLA-matched related donors are not available.
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- 2022
4. Efficacy and Safety of Zanubrutinib in Japanese Patients with Mature B-Cell Malignancies
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Takayuki Ishikawa, Masahiro Takeuchi, Kazuyuki Shimada, Kohmei Kubo, Takeshi Kondo, Katsuya Fujimoto, Tomoaki Fujisaki, Koji Nagafuji, Rika Sakai, Shingo Kurahashi, Tatsuro Jo, Kazutaka Sunami, Senji Kasahara, Tomonori Nakazato, Haiyi Guo, William Novotny, Chris Tankersley, Motohisa Takai, Hui Yao, Jinhua Zhong, Hongjie Zhu, and Koji Izutsu
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
5. <scp> IKZF1 plus </scp> alterations are not associated with outcomes in Philadelphia‐positive acute lymphoblastic leukemia patients enrolled in the <scp>FBMTG ALL</scp> / <scp>MRD2008</scp> trial
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Yoshikiyo Ito, Hidetoshi Ozawa, Tetsuya Eto, Toshihiro Miyamoto, Tomohiko Kamimura, Ryosuke Ogawa, Naoyuki Uchida, Atsusi Wake, Tomoaki Fujisaki, Yuju Ohno, Ken Takase, Hirokazu Okumura, Yasushi Takamatsu, Noriaki Kawano, Koichi Akashi, and Koji Nagafuji
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Hematology ,General Medicine - Published
- 2023
6. Haploidentical transplantation with post-transplant cyclophosphamide versus single cord blood transplantation for myelodysplastic syndrome: A retrospective study from the Adult Myelodysplastic Syndrome Working Group of the Japanese Society for Transplantation and Cellular Therapy (JSTCT)
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Takaaki Konuma, Yoshimitsu Shimomura, Ken Ishiyama, Takahide Ara, Hirohisa Nakamae, Nobuhiro Hiramoto, Tetsuya Eto, Yumiko Maruyama, Koji Nagafuji, Jun Ishikawa, Naoyuki Uchida, Masatsugu Tanaka, Makoto Onizuka, Yasunori Ueda, Naoyuki Anzai, Takafumi Kimura, Yoshinobu Kanda, Takahiro Fukuda, and Yoshiko Atsuta
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Adult ,Transplantation Conditioning ,Japan ,Myelodysplastic Syndromes ,Transplantation, Haploidentical ,Hematopoietic Stem Cell Transplantation ,Humans ,Graft vs Host Disease ,Hematology ,Cord Blood Stem Cell Transplantation ,Cyclophosphamide ,Retrospective Studies - Published
- 2022
7. Alternating venetoclax/azacytidine and FLT3 inhibitor treatment for NPM1- and FLT3-mutated acute myeloid leukemia
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Shuki Oya, Hidetoshi Ozawa, Yoshimi Maehiro, Takayuki Nakamura, Yusuke Takaki, Toshinobu Fukuyama, Yoshitaka Yamasaki, Maki Yamaguchi, Kazutoshi Aoyama, Fumihiko Mouri, and Koji Nagafuji
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Cancer Research ,Oncology ,Hematology - Published
- 2023
8. Advantages of Higher Busulfan Dose Intensity in Fludarabine-Combined Conditioning for Patients with Acute Myeloid Leukemia Undergoing Cord Blood Transplantation
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Sho Shibata, Yasuyuki Arai, Tadakazu Kondo, Shohei Mizuno, Kaito Harada, Shigesaburo Miyakoshi, Naoyuki Uchida, Yumiko Maruyama, Tetsuya Eto, Yuna Katsuoka, Kosei Matsue, Kaichi Nishiwaki, Satoru Takada, Noriko Doki, Mitsuru Itoh, Koji Nagafuji, Toshiro Kawakita, Junji Tanaka, Takahiro Fukuda, Yoshiko Atsuta, and Masamitsu Yanada
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Fludarabine ,Transplantation ,Acute myeloid leukemia ,Cord blood transplantation ,Conditioning regimen ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology ,Busulfan - Abstract
The alkylating agent busulfan is commonly used as conditioning in allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). However, a consensus has not yet been reached regarding the optimal busulfan dose in cord blood transplantation (CBT). Therefore, we conducted this large nationwide cohort study to retrospectively analyze the outcomes of CBT in patients with AML receiving busulfan at intermediate (6.4 mg/kg i.v.; BU2) or higher (12.8 mg/kg i.v.; BU4) doses within a fludarabine/i.v. busulfan (FLU/BU) regimen. Among 475 patients who underwent their first CBT following FLU/BU conditioning between 2007 and 2018, 162 received BU2 and 313 received BU4. Multivariate analysis identified BU4 as a significant factor for longer disease-free survival (hazard ratio [HR], .85; 95% confidence interval [CI], .75 to .97; P = .014) and a lower relapse rate (HR, .84; 95% CI, .72 to .98; P = .030). No significant differences were observed in non-relapse mortality between BU4 and BU2 (HR, 1.05; 95% CI, .88-1.26; P = .57). Subgroup analyses showed that BU4 provided significant benefits for patients who underwent transplantation while not in complete remission (CR) and those age
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- 2023
9. CD33 rs12459419 SNP Regulated the Total CD33 Expression Level
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Shuki Oya, Hidetoshi Ozawa, Takayuki Nakamura, Toshinobu Fukuyama, Yusuke Takaki, Yoshitaka Yamasaki, Kazutoshi Aoyama, Maki Yamaguchi, Fumihiko Mouri, and Koji Nagafuji
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
10. Efficacy of prophylactic letermovir for cytomegalovirus reactivation in hematopoietic cell transplantation: a multicenter real-world data
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Katsuto Takenaka, Yuju Ohno, Ryosuke Ogawa, Yasuo Mori, Tetsuya Eto, Masanori Kadowaki, Koji Kato, Kentaro Kohno, Toshihiro Miyamoto, Ken Takase, Koji Nagafuji, Koichi Akashi, Tomohiko Kamimura, Yoshikiyo Ito, Takuya Harada, Fumiaki Jinnouchi, Goichi Yoshimoto, Takatoshi Aoki, Takuro Kuriyama, Hideho Henzan, Jun Odawara, and Toshiyuki Ueno
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Transplantation ,medicine.medical_specialty ,Cytomegalovirus reactivation ,Hematopoietic cell ,business.industry ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,Cytomegalovirus ,Hematology ,Acetates ,Cmv reactivation ,Antiviral Agents ,Letermovir ,Internal medicine ,Cytomegalovirus Infections ,Quinazolines ,Humans ,Medicine ,Cumulative incidence ,business ,Real world data ,Retrospective Studies ,medicine.drug - Abstract
A novel anti-cytomegalovirus (CMV) agent, letermovir (LMV), could reportedly improve the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) recipients because of its high potential to prevent CMV reactivation. Therefore, 685 Japanese allo-HCT recipients, of whom ~80% had a high risk of CMV reactivation, were retrospectively analyzed to assess the impacts of prophylactic LMV on the incidence of clinically significant CMV (csCMV) infection as well as their transplant outcome. By comparing 114 patients who received LMV prophylaxis for a median 92 days to 571 patients without prophylaxis, we observed that prophylactic LMV could significantly (1) reduce the 180-day cumulative incidence of csCMV infection (44.7 vs. 72.4%, p
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- 2020
11. Comparable survival outcomes with haploidentical stem cell transplantation and cord blood transplantation
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Junichi Sugita, Yoshiko Atsuta, Hirohisa Nakamae, Yumiko Maruyama, Ken Ishiyama, Souichi Shiratori, Takahiro Fukuda, Mio Kurata, Naoki Shingai, Yukiyasu Ozawa, Masayoshi Masuko, Koji Nagafuji, Naoyuki Uchida, Masatsugu Tanaka, Makoto Onizuka, Junya Kanda, Takafumi Kimura, Tatsuo Ichinohe, and Takanori Teshima
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Adult ,Transplantation ,Transplantation Conditioning ,Adolescent ,Hematopoietic Stem Cell Transplantation ,Graft vs Host Disease ,Hematology ,Middle Aged ,Young Adult ,Leukemia, Myeloid, Acute ,Recurrence ,Humans ,Cord Blood Stem Cell Transplantation ,Cyclophosphamide ,Aged ,Retrospective Studies - Abstract
HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) and umbilical cord blood transplantation (UCBT) are alternative to HLA-matched stem cell transplantation. We conducted a matched-pair analysis of PTCy-haplo and UCBT using the Japanese registry data. We identified 136 patients aged between 16 and 69 years who received PTCy-haplo as their first transplantation for acute leukemia or myelodysplastic syndromes. Control group included 408 UCBT recipients selected to match the PTCy-haplo group. Overall and relapse-free survival probabilities at 2 years were comparable between the PTCy-haplo and UCBT groups: 55% vs. 53% for overall survival (p = 0.46), and 47% vs. 48% for relapse-free survival (p = 0.79), respectively. The cumulative incidence of relapse was significantly higher (43% vs. 29%, respectively, p = 0.006), while the cumulative incidence of non-relapse mortality (NRM) was significantly lower (9% vs. 23%, respectively, p 0.001) in the PTCy-haplo group. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was lower in the PTCy-haplo group compared to the UCBT group (29% vs. 41%, respectively, p = 0.016), while those of grade III-IV acute GVHD and chronic GVHD were not statistically different between the two groups. Our results suggest that both PTCy-haplo and UCBT are viable alternatives to HLA-matched stem cell transplantation.
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- 2022
12. Beneficial tyrosine kinase inhibitor therapy in a patient with relapsed BCR-ABL1-like acute lymphoblastic leukemia with CCDC88C-PDGFRB fusion
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Kazutoshi Aoyama, Ritsuko Seki, Kensuke Sasaki, Yoshitaka Yamasaki, Takahiro Maeda, Takayuki Nakamura, Shuki Oya, Hidetoshi Ozawa, Yuichiro Semba, Koji Nagafuji, Fumihiko Mouri, Koichi Osaki, Toshihiro Miyamoto, and Satoshi Morishige
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Oncology ,medicine.medical_specialty ,Vincristine ,Neoplasm, Residual ,Oncogene Proteins, Fusion ,Fusion Proteins, bcr-abl ,PDGFRB ,Receptor, Platelet-Derived Growth Factor beta ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Maintenance therapy ,Recurrence ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Medicine ,Genetic Testing ,Molecular Targeted Therapy ,Protein Kinase Inhibitors ,Inotuzumab ozogamicin ,ABL ,business.industry ,Microfilament Proteins ,Intracellular Signaling Peptides and Proteins ,Imatinib ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Combined Modality Therapy ,Transplantation ,Treatment Outcome ,030220 oncology & carcinogenesis ,Retreatment ,Prednisolone ,Female ,business ,Biomarkers ,030215 immunology ,medicine.drug - Abstract
BCR-ABL1-like acute lymphoblastic leukemia (ALL) is a neoplasm of lymphoblasts committed to the B-cell lineage that lack the BCR-ABL1 translocation but show a pattern of gene expression very similar to that seen in ALL with BCR-ABL1 with poor prognosis. A 22-year-old female was diagnosed with common-B-cell-ALL positive for CD10, CD19, CD22, CD79a, CD34, HLA-DR, and TdT in January 2017, and achieved complete remission (CR) with induction therapy, followed by consolidation therapy and maintenance therapy. In March 2020, 6 months after the completion of maintenance therapy, she relapsed. Inotuzumab ozogamicin (IO) was administered, and on day 28, bone marrow evaluation showed a morphologic CR. She had an HLA-identical sibling, and transplantation in her 2nd CR was planned. Because her ALL had been identified as BCR-ABL1-like ALL with CCDC88C-PDGFRB fusion, she was treated with imatinib for 2 months accompanied by 2 intrathecal methotrexate therapies, and 1 course of l-asparaginase, vincristine, and prednisolone in an outpatient setting. MRD analysis revealed potent efficacy of 2 months imatinib therapy; IgH MRD decreased from 1 × 10−2 to 1 × 10−3, and CCDC88C-PDGFRB/104ABL from 37.3 to 0. It is earnestly desired that well-designed clinical trials of TKI in ABL class-mutant BCR-ABL1-like ALL be conducted in Japan.
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- 2020
13. Successful correction of factor V deficiency of patient‐derived iPSCs by CRISPR/Cas9‐mediated gene editing
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Fumihiko Mouri, Koichi Osaki, Koji Nagafuji, Ritsuko Seki, Kenji Kuboyama, Takayuki Nakamura, Shuki Oya, Kazutoshi Aoyama, Shinichi Mizuno, Maki Yamaguchi, Takashi Okamura, Hidetoshi Ozawa, Yoshitaka Yamasaki, and Satoshi Morishige
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Genetic enhancement ,Induced Pluripotent Stem Cells ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Genome editing ,Humans ,Medicine ,CRISPR ,Clustered Regularly Interspaced Short Palindromic Repeats ,Induced pluripotent stem cell ,Gene ,Cells, Cultured ,Genetics (clinical) ,Gene Editing ,biology ,business.industry ,Cas9 ,Factor V ,Cell Differentiation ,Hematology ,General Medicine ,Middle Aged ,Molecular biology ,biology.protein ,Female ,Factor V Deficiency ,business ,030215 immunology - Abstract
Background Factor V (FV) deficiency is a monogenic inherited coagulation disorder considered to be an ideal indication for gene therapy. To investigate the possibility of therapeutic application of genome editing, we generated induced pluripotent stem cells (iPSCs) from a FV-deficient patient and repaired the mutation of factor V gene (F5) using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9). Methods The patient's peripheral blood mononuclear cells were reprogrammed for iPSCs. The targeting vector was designed with homology arms against F5 containing the corrected sequence. Cas9 ribonucleoprotein (RNP) complex and targeting vector were electroporated into iPSCs. Gene-edited iPSCs were differentiated into hepatocyte-like cells (HLCs). Results The mutation of F5 in patient-derived iPSCs was repaired by CRISPR/Cas9. In concentrated culture supernatants of patient-derived iPS-HLCs, neither FV antigen nor activity was detected, while in those of gene-corrected iPS-HLCs, FV antigen and specific activity were 67.0 ± 13.1 ng/mL and 173.2 ± 41.1 U/mg, respectively. Conclusions We successfully repaired the mutation of F5 using the CRISPR/Cas9 and confirmed the recovery of FV activity with gene-corrected iPS-HLCs. Gene-edited iPSCs are promising for elucidating the pathophysiology as well as for a modality of gene therapy.
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- 2020
14. Measurable residual disease after the first consolidation predicts the outcomes of patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy
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Ryosuke Ogawa, Hiromi Iwasaki, Tetsuya Eto, Koji Kato, Ken Takase, Hideho Henzan, Goichi Yoshimoto, Toshihiro Miyamoto, Yasuo Mori, Naoyuki Uchida, Tomoaki Fujisaki, Tomohiko Kamimura, Mariko Minami, Koichi Akashi, Yoshikane Kikushige, and Koji Nagafuji
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Adult ,Male ,Acute promyelocytic leukemia ,medicine.medical_specialty ,Neoplasm, Residual ,Adolescent ,Anthracycline ,medicine.medical_treatment ,Tretinoin ,Gastroenterology ,Young Adult ,Leukemia, Promyelocytic, Acute ,Recurrence ,Internal medicine ,White blood cell ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Idarubicin ,Prospective Studies ,Aged ,Chemotherapy ,Hematology ,business.industry ,Cytarabine ,Middle Aged ,Prognosis ,medicine.disease ,Consolidation Chemotherapy ,Survival Rate ,Regimen ,Treatment Outcome ,medicine.anatomical_structure ,Female ,business ,Forecasting ,medicine.drug - Abstract
We stratified patients with newly diagnosed acute promyelocytic leukemia (APL) according to a white blood cell (WBC) count of ≥ 3 × 109/L (high risk) or
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- 2020
15. Health-related quality of life in peripheral blood stem cell donors and bone marrow donors: a prospective study in Japan
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Ritsuro Suzuki, Minako Iida, Katsumi Orihara, Yoshihisa Kodera, Ayumi Fujimoto, Takuya Yamashita, Heiwa Kanamori, Masayuki Hino, Koichi Miyamura, Shinichiro Okamoto, and Koji Nagafuji
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Male ,medicine.medical_specialty ,Health-related quality of life ,Stem cell donors ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Japan ,Quality of life ,Bone Marrow ,Risk Factors ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Risk factor ,Adverse effect ,Prospective cohort study ,Hematology ,business.industry ,Stem Cells ,Age Factors ,Odds ratio ,Tissue Donors ,medicine.anatomical_structure ,Health ,Adverse events ,030220 oncology & carcinogenesis ,Donation ,Peripheral Blood Stem Cells ,Quality of Life ,Tissue and Organ Harvesting ,Female ,Bone marrow ,business ,030215 immunology - Abstract
Understanding of the impact of stem cell donation on donors’ health-related quality of life (HRQOL) remains limited. A prospective observational study of eligible unrelated donors enrolled in the Japan Marrow Donor Program was conducted to compare HRQOL and adverse events (AEs) between peripheral blood stem cell (PBSC) and bone marrow (BM) donors. In total, 107 PBSC donors and 108 BM donors were enrolled. HRQOL scores for physical status were significantly lower in BM donors 1 week post-harvest (P
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- 2020
16. Effects of Haplotype Matching on Outcomes after Adult Single-Cord Blood Transplantation
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Toru Sakura, Satoko Morishima, Junya Kanda, Makoto Onizuka, Naoyuki Uchida, Hikaru Kobayashi, Junji Tanaka, Takakazu Kawase, Koji Nagafuji, Hidenori Tanaka, Yoshiko Matsuhashi, Hiroto Kojima, Shigesaburo Miyakoshi, Yasuo Morishima, Tetsuya Eto, Satoshi Takahashi, Tatsuo Ichinohe, Yoshiko Atsuta, and Takanori Ohta
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Transplantation ,medicine.medical_specialty ,Matching (statistics) ,Neutrophil Engraftment ,Multivariate analysis ,Platelet Engraftment ,business.industry ,Haplotype ,Hazard ratio ,Hematology ,Disease ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Cord blood ,medicine ,business ,030215 immunology - Abstract
It remains unclear whether the HLA haplotype of unrelated cord blood (UCB) should be matched to that of the patient in single UCB transplantation. Thus, using data from a Japanese registry, we analyzed the effect of haplotype matching on outcomes. Patients with hematologic diseases aged 16 years or older who had undergone their first transplant were included (N = 1347). The effects of haplotype matching and high-frequency HLA haplotype on outcomes were analyzed. Median patient age was 55 years. The cumulative incidences of neutrophil engraftment among groups with 0, 1, and 2 HLA haplotype matches were 79%, 82%, and 88%, respectively (P = .008). In a multivariate analysis, the group with 0 haplotype matches was marginally associated with worse neutrophil engraftment (P = .087) and significantly associated with platelet engraftment (P = .044) compared with the group with 1 haplotype match. Two-haplotype matches were associated with a higher risk of relapse. In the group with 1 haplotype match, the top 3 shared haplotypes were "A*24:02-B*52:01-C*12:02-DRB1*15:02" (HP-P1), "A*33:03-B*44:03-C*14:03-DRB1*13:02" (HP-P2), and "A*24:02-B*07:02-C*07:02-DRB1*01:01" (HP-P3). The presence of HP-P2 but not HP-P1 or HP-P3 was associated with a decreased risk of grades II to IV acute graft-versus-host disease (hazard ratio, .56; P = .001) but an increased risk of relapse (hazard ratio, 1.35; P = .045). HLA haplotype matching might be considered to improve engraftment. Two-haplotype matches should be avoided if the relapse risk is high. The haplotype itself may have an effect on the risk of acute graft-versus-host disease and relapse.
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- 2020
17. CRISPR/Cas9-mediated gene correction in hemophilia B patient-derived iPSCs
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Ahmad Mazahery, Koichi Osaki, Hidetoshi Ozawa, Shinichi Mizuno, Takayuki Nakamura, Fumihiko Mouri, Koji Nagafuji, Satoshi Morishige, Ritsuko Seki, Ken Ichi Yamamura, Takashi Okamura, and Kei Nomura
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Gene Editing ,Expression vector ,Cas9 ,Genetic enhancement ,Induced Pluripotent Stem Cells ,Genetic Therapy ,Hematology ,Biology ,Hemophilia B ,Molecular biology ,03 medical and health sciences ,Exon ,0302 clinical medicine ,030220 oncology & carcinogenesis ,medicine ,Humans ,CRISPR ,CRISPR-Cas Systems ,Induced pluripotent stem cell ,Gene ,030215 immunology ,Factor IX ,medicine.drug - Abstract
The clustered regulatory interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) system is an efficient genome-editing tool that holds potential for gene therapy. Here, we report an application of this system for gene repair in hemophilia B (HB) using induced pluripotent stem cells (iPSCs). We prepared targeting plasmids with homology arms containing corrected sequences to repair an in-frame deletion in exon 2 of the factor IX (F9) gene and transfected patient-derived iPSCs with the Cas9 nuclease and a guide RNA expression vector. To validate the expression of corrected F9, we attempted to induce the differentiation of iPSCs toward hepatocyte-like cells (HLCs) in vitro. We successfully repaired a disease-causing mutation in HB in patient-derived iPSCs. The transcription product of corrected F9 was confirmed in HLCs differentiated from gene-corrected iPSCs. Although further research should be undertaken to obtain completely functional hepatocytes with secretion of coagulation factor IX, our study provides a proof-of-principle for HB gene therapy using the CRISPR/Cas9 system.
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- 2019
18. Daratumumab plus bortezomib, melphalan, and prednisone in East Asian patients with non-transplant multiple myeloma: subanalysis of the randomized phase 3 ALCYONE trial
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Jae Hoon Lee, Hiroyuki Takamatsu, Ming Qi, Robin Carson, Kenshi Suzuki, Jianping Wang, Tomoaki Fujisaki, Wendy Crist, Koji Nagafuji, Chang-Ki Min, and Takayuki Ishikawa
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Adult ,Male ,Melphalan ,medicine.medical_specialty ,Prednisolone ,Population ,Gastroenterology ,Disease-Free Survival ,Bortezomib ,Multiple myeloma ,Prednisone ,Daratumumab ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,In patient ,Transplant-ineligible ,education ,Aged ,Aged, 80 and over ,education.field_of_study ,Hematology ,Asia, Eastern ,business.industry ,Antibodies, Monoclonal ,General Medicine ,Middle Aged ,medicine.disease ,Survival Rate ,VMP ,Original Article ,Female ,business ,medicine.drug - Abstract
In the ALCYONE trial, daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) reduced the risk of disease progression or death by 50% versus bortezomib, melphalan, and prednisone (VMP) in patients with transplant-ineligible newly diagnosed multiple myeloma. Here, we report a subanalysis of East Asian patients from ALCYONE. After a median follow-up of 17.1 and 15.9 months for Japanese (n = 50) and Korean (n = 41) patients, respectively, median progression-free survival for D-VMP versus VMP was not reached (NR) versus 20.7 months in Japanese patients and NR versus 14.0 months in Korean patients. The overall response rate for D-VMP versus VMP was 96% versus 92% in Japanese patients and 91% versus 61% in Korean patients. Using next-generation sequencing, minimal residual disease negativity at 10−5 sensitivity for D-VMP versus VMP was 33% versus 8% among Japanese patients and 17% versus 0% among Korean patients. Rates of any grade and grade 3/4 pneumonia were consistent with the rates observed for the global safety population. Similar efficacy and safety findings were observed in the combined Japanese and Korean subgroup and ≥ 75 years of age subgroup. In conclusion, D-VMP was safe and efficacious in East Asian patients, consistent with the global ALCYONE population. Electronic supplementary material The online version of this article (10.1007/s00277-019-03794-9) contains supplementary material, which is available to authorized users.
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- 2019
19. Cessation of nilotinib in patients with chronic myelogenous leukemia who have maintained deep molecular responses for 2 years: a multicenter phase 2 trial, stop nilotinib (NILSt)
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Hirohisa Nakamae, Junya Kuroda, Tatsuya Kawaguchi, Toshihiro Miyamoto, Jun Ishikawa, Yuzuru Kanakura, Takayuki Shimose, Koji Nagafuji, Norimitsu Kadowaki, Yutaka Imamura, Hirohito Yamazaki, Itaru Matsumura, and Koichi Akashi
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Adult ,Male ,Oncology ,medicine.medical_specialty ,03 medical and health sciences ,Myelogenous ,0302 clinical medicine ,Recurrence ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,medicine ,Humans ,Aged ,business.industry ,Remission Induction ,Imatinib ,Hematology ,Middle Aged ,medicine.disease ,Substance Withdrawal Syndrome ,Discontinuation ,Consolidation Chemotherapy ,Leukemia ,Pyrimidines ,Withholding Treatment ,Nilotinib ,030220 oncology & carcinogenesis ,Imatinib Mesylate ,Female ,business ,Sokal Score ,Tyrosine kinase ,030215 immunology ,medicine.drug ,Chronic myelogenous leukemia - Abstract
The aim of this multicenter phase 2 trial, Stop Nilotinib (NILSt), was to examine the safety and efficacy of discontinuation of nilotinib in patients with chronic phase (CP)-chronic myelogenous leukemia (CML). Patients with CP-CML who had achieved molecular response (MR4.5) after initiation of imatinib or nilotinib therapy received consolidation therapy with nilotinib 300–400 mg twice daily for up to 24 months. Patients who maintained MR4.5 at 24 months of consolidation therapy proceeded to discontinuation of nilotinib. The study enrolled 149 patients; 112 patients proceeded to consolidation therapy with nilotinib; 90 patients maintained MR4.5 with consolidation therapy, and 87 proceeded to discontinuation of nilotinib. The treatment-free remission (TFR) (MR4.5) rate at both 1 and 3 years after discontinuation of nilotinib was the same, at 60.9% (90% CI 51.6–69.7). Among 34 patients with molecular relapse, nilotinib was resumed in 33 patients; all of them attained MR4.5. There was no significant association between molecular relapse and age, sex, Sokal score, previous interferon-α exposure, duration of tyrosine kinase inhibitors treatment, or trough concentration of nilotinib. With nilotinib, it might be possible to avoid prognostic factors for TFR that exist with imatinib discontinuation. Cessation of nilotinib after two years of consolidation was safe and feasible. Trial registration UMIN000007141.
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- 2019
20. Prospective evaluation of minimal residual disease monitoring to predict prognosis of adult patients with Ph‐negative acute lymphoblastic leukemia
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Ryosuke Ogawa, Shouhei Yokota, Koichi Akashi, Tomoaki Fujisaki, Noriaki Kawano, Yasuhiko Miyazaki, Toshiro Kurokawa, Ken Takase, Hirokazu Okumura, Koji Nagafuji, Toshihiro Miyamoto, Atsushi Wake, Yasushi Takamatsu, Tomohiko Kamimura, Yuju Ohno, and Tetsuya Eto
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Adult ,Male ,Safety Management ,medicine.medical_specialty ,Neoplasm, Residual ,Adolescent ,Lymphoblastic Leukemia ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Philadelphia chromosome ,Gastroenterology ,Translocation, Genetic ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Transplantation, Homologous ,Medicine ,Philadelphia Chromosome ,Prospective Studies ,Aged ,Adult patients ,business.industry ,Hematopoietic Stem Cell Transplantation ,Induction chemotherapy ,Consolidation Chemotherapy ,Induction Chemotherapy ,Hematology ,General Medicine ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,medicine.disease ,Minimal residual disease ,body regions ,Clinical trial ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,business ,030215 immunology - Abstract
Objective We investigated whether minimal residual disease (MRD) status in adult patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) is useful for decision on clinical indications for allogeneic hematopoietic stem cell transplantation (HSCT). Methods We prospectively monitored MRD after induction and consolidation therapy in adult patients with Ph-negative ALL. Results Among 103 adult ALL patients enrolled, 59 were Ph-negative, and MRD status was assessed in 51 patients. The probability of 3-year overall survival (OS) and disease-free survival (DFS) was 69% (95%CI 54-80) and 50% (95%CI 36-63), respectively. Patients who were MRD-negative after induction therapy (n = 15) had a significantly better 3-year DFS compared with those who were MRD-positive (n = 30; 73% vs 41%, P = 0.018). Patients who were MRD-positive after induction but became MRD-negative after consolidation chemotherapy C in the first course (n = 11) showed a significantly worse 3-year DFS compared with patients who were MRD-negative after induction chemotherapy A in the first course (45% vs 73%, P = 0.025). Conclusions These results indicate that DFS of about 70% can be expected in MRD-negative patients after induction therapy, and the patients did not benefit from HSCT in 1CR. This study was registered with the UMIN Clinical Trials Registry (UMIN-CTR), number UMIN000001519.
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- 2019
21. Complete response following toxic epidermal necrolysis in relapsed adult T cell leukemia/lymphoma after haploidentical stem cell transplantation
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Ritsuko Seki, Koichi Osaki, Shuki Oya, Takayuki Nakamura, Fumiko Arakawa, Hiroshi Saruta, Marina Nishi, Maki Yamaguchi, Satoshi Morishige, Koichi Ohshima, Kazutoshi Aoyama, Yoshitaka Yamasaki, Fumihiko Mouri, and Koji Nagafuji
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Cyclophosphamide ,T-cell leukemia ,Antineoplastic Agents ,Antibodies, Monoclonal, Humanized ,Methylprednisolone ,Adult T-cell leukemia/lymphoma ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Mogamulizumab ,medicine ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Lenalidomide ,Aged ,business.industry ,Hematopoietic Stem Cell Transplantation ,Immunoglobulins, Intravenous ,Hematology ,Allografts ,medicine.disease ,Combined Modality Therapy ,Toxic epidermal necrolysis ,Lymphoma ,Transplantation ,Treatment Outcome ,surgical procedures, operative ,Pulse Therapy, Drug ,Stevens-Johnson Syndrome ,030220 oncology & carcinogenesis ,Transplantation, Haploidentical ,business ,030215 immunology ,medicine.drug - Abstract
Allogeneic hematopoietic cell transplantation (allo-HSCT) is considered the curative treatment option in patients with aggressive adult T cell leukemia/lymphoma (ATLL), but the treatment of relapse after allo-HSCT remains a major challenge. We report a case of ATLL that was treated with sequential mogamulizumab (MOG) and lenalidomide (LEN) for early relapse after allo-HSCT. A 73-year-old Japanese male with acute-type ATLL underwent haploidentical-HSCT with post-transplant cyclophosphamide. He attained a complete response. However, ATLL relapse was diagnosed by biopsy of skin lesions that appeared on day 67. Discontinuation of immunosuppressant therapy alone did not result in improvement of ATLL, however, the skin lesions disappeared after an immune response was induced by sequential MOG and LEN. Following MOG and LEN, very serious toxic epidermal necrolysis (TEN) developed requiring high-dose intravenous immunoglobulin and methylprednisolone pulse therapy. Although graft-versus-host disease exacerbated and progressed to TEN, a complete response was achieved after successful treatment of TEN. These agents may thus enhance anti-ATLL activity by immune modulation. Further investigation is necessary to determine the optimal use of MOG and LEN in relapsed ATLL after allo-HSCT.
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- 2019
22. Clinicopathological features of HCV-positive splenic diffuse large B cell lymphoma
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Kohta Miyawaki, Fumiko Arakawa, Koji Kato, Tetsuya Eto, Takeshi Sugio, Takuto Miyagishima, Joji Shimono, Koichi Akashi, Takanori Teshima, Koichi Ohshima, Koji Nagafuji, Hiroaki Miyoshi, and Kyohei Yamada
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Male ,Pathology ,medicine.medical_specialty ,Hepatitis C virus ,Hepacivirus ,Viral Nonstructural Proteins ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Humans ,B-cell lymphoma ,In Situ Hybridization ,B cell ,Aged ,Aged, 80 and over ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Splenic Neoplasms ,virus diseases ,Germinal center ,Hematology ,General Medicine ,Middle Aged ,Cell Transformation, Viral ,medicine.disease ,Hepatitis C ,digestive system diseases ,Lymphoma ,medicine.anatomical_structure ,B symptoms ,030220 oncology & carcinogenesis ,RNA, Viral ,Female ,Lymphoma, Large B-Cell, Diffuse ,medicine.symptom ,Splenic Lymphoma ,business ,Diffuse large B-cell lymphoma ,030215 immunology - Abstract
The hepatitis C virus (HCV) is a single-stranded RNA virus which is thought to be involved in the onset of B cell lymphoma. HCV-positive diffuse large B cell lymphoma (DLBCL) has been reported to clinically manifest in extranodal lesions (e.g., in the liver, spleen, and stomach). Here, we investigated HCV-positive and -negative primary splenic DLBCL (p-spDLBCL) and non-primary splenic DLBCL (ordinary DLBCL). Furthermore, to examine HCV lymphomagenesis, RNA in situ hybridization (ISH), RT-PCR (reverse-transcription polymerase chain reaction), and NS3 immunostaining of HCV viral nonstructural proteins were performed. HCV-positive p-spDLBCL patients presented fewer B symptoms (asymptomatic) and better performance status, with elevated presence of splenic macronodular lesions and more germinal center B cell (GCB) sub-group cases than HCV-negative p-spDLBCL patients. However, HCV-positive ordinary DLBCL patients were found to have more non-GCB sub-group cases than HCV-negative ordinary DLBCL patients. HCV-positive DLBCL patients showed 20.6% (7/34) NS3 positivity, 16.7% (1/6) HCV-RNA in situ positivity, and 22.2% (2/9) detection of HCV-RNA in tumor tissue by RT-PCR. Splenic samples were found to have a higher frequency of HCV detection than lymph node samples, thus suggesting that HCV may be closely related to lymphomagenesis, especially in splenic lymphoma.
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- 2019
23. Improved survival of patients with aggressive ATL by increased use of allo-HCT: a prospective observational study
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Masao Ogata, Atae Utsunomiya, Koji Kato, Kaoru Uchimaru, Ilseung Choi, Rika Sakai, Shinichiro Machida, Yoshitaka Inoue, Yasushi Sawayama, Takahiro Fukuda, Junya Makiyama, Tsutomu Takahashi, Ayumu Ito, Takashi Tanaka, Yoshihiro Inamoto, Shigeo Fuji, Nobuaki Nakano, Souichi Shiratori, Toshiro Kawakita, Tomohiko Kamimura, Koji Nagafuji, Ken Takase, and Hirohisa Nakamae
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medicine.medical_specialty ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Hematology ,medicine.disease ,Lymphoma ,Clinical trial ,Transplantation ,Leukemia ,hemic and lymphatic diseases ,Internal medicine ,Cord blood ,medicine ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Prospective Studies ,business ,Prospective cohort study ,Unrelated Donors ,Retrospective Studies - Abstract
Aggressive adult T-cell leukemia/lymphoma (ATL) is a hematological malignancy that is difficult to treat with chemotherapy alone, and allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy. We conducted a multicenter, prospective, observational study to clarify the treatment outcomes of aggressive ATL in the current era. Between 2015 and 2018, 113 patients aged 70 years or younger with newly diagnosed aggressive ATL were enrolled. The median age at diagnosis was 61 years. Treatment outcomes were compared with those of 1792 ATL patients diagnosed between 2000 and 2013 in our previous retrospective study. The inclusion criteria were the same in both studies. The prospective cohort demonstrated better overall survival (OS) than the retrospective cohort (2-year OS, 45% vs 29%, respectively; P < .001), with a much higher proportion of patients receiving allo-HCT (80% vs 34%, respectively; P < .001) and a shorter interval from diagnosis to allo-HCT (median, 128 vs 170 days, respectively; P < .001). Among the 90 patients who received allo-HCT (cord blood, n = 30; HLA-haploidentical related donors, n = 20; other related donors, n = 14; other unrelated donors, n = 26), the 2-year probabilities of OS, non-relapse mortality (NRM), and disease progression were 44%, 23%, and 46%, respectively. OS and NRM did not differ statistically according to donor type. Our results suggest that increased application of allo-HCT improved the survival of patients with aggressive ATL. The use of cord blood or HLA-haploidentical donors may be feasible for aggressive ATL when HLA-matched related donors are unavailable. This study was registered at the UMIN Clinical Trials Registry as #000017672.
- Published
- 2021
24. A case of lymphomatoid granulomatosis with central nervous system involvement successfully treated with IFNα
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Takekuni Nakama, Takayuki Nakamura, Yoshitaka Yamasaki, Hiroshi Koga, Koichi Osaki, Motohiro Morioka, Koichi Ohshima, Maki Yamaguchi, Takuya Furuta, Satoshi Morishige, Satoru Komaki, Shuki Oya, Fumihiko Mouri, Koji Nagafuji, and Kazutoshi Aoyama
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Pathology ,medicine.medical_specialty ,Lymphomatoid granulomatosis ,Erythema ,Biopsy ,Alpha interferon ,Central Nervous System Neoplasms ,Clonal Evolution ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Aged ,Hematology ,medicine.diagnostic_test ,business.industry ,Brain biopsy ,Interferon-alpha ,Lymphomatoid Granulomatosis ,medicine.disease ,Immunohistochemistry ,Magnetic Resonance Imaging ,Treatment Outcome ,030220 oncology & carcinogenesis ,Skin biopsy ,Prednisolone ,Female ,medicine.symptom ,Symptom Assessment ,business ,Tomography, X-Ray Computed ,Pyoderma gangrenosum ,Biomarkers ,030215 immunology ,medicine.drug - Abstract
Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disease affecting mainly extranodal sites such as the lung, central nervous system (CNS), skin, kidney, and liver. We report a case of low-grade LYG involving the CNS that was successfully treated with interferon alpha (IFNα). A 69-year-old woman developed necrotic erythema of the skin and was initially diagnosed with pyoderma gangrenosum based on skin biopsy. She showed a limited response to prednisolone. Approximately 6 months after the initial onset, low-grade LYG was diagnosed after detection of CNS lesions on brain biopsy. The whole blood EBV-DNA load determined by real-time polymerase chain reaction was slightly elevated. Two months into IFNα therapy, skin and CNS lesions had responded favorably and the EBV-DNA load decreased. IFNα plays an important role in treatment of LYG through its antiproliferative, immunomodulatory, and anti-EBV effects. To our knowledge, this is the first case report of successful treatment with IFNα in Japan. Further investigation is necessary to determine optimal use of IFNα for LYG.
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- 2021
25. Clinical features and chromosomal/genetic aberration in adult acute lymphoblastic leukemia in Japan: results of Fukuoka Blood & Marrow Transplant Group Studies ALL MRD 2002 and 2008
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Tomohiko Kamimura, Toshihiro Miyamoto, Atsushi Wake, Yasushi Takamatsu, Naoyuki Uchida, Tetsuya Eto, Satoshi Morishige, Tomoaki Fujisak, Hiromi Iwasaki, Yoshikiyo Ito, Koichi Akashi, Takahiro Maeda, Noriaki Kawano, Koji Nagafuji, Ryosuke Ogawa, Yasuhiko Miyazaki, Toshiro Kurokawa, Takanori Ohta, and Hirokazu Okumura
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medicine.medical_specialty ,Hematology ,business.industry ,Incidence (epidemiology) ,Cytogenetics ,hemic and lymphatic diseases ,Internal medicine ,Epidemiology ,Cohort ,medicine ,Adult Acute Lymphoblastic Leukemia ,Hypodiploidy ,Hyperdiploidy ,business - Abstract
Acute lymphoblastic leukemia (ALL) is a common neoplasm in children, but less frequent in adults. Since information on clinical features and genetics of adult ALL in Japan is limited, we analyzed 215 subjects aged 16–65 years with untreated ALL enrolled in the Fukuoka Blood & Marrow Transplant Group studies ALL MRD 2002 and 2008. The prevalence of ALL was bimodal, with the larger group aged 56–65 years. Immunophenotypic characterization showed B-lineage is more frequent than T-lineage ALL (78.6 vs 13.0%), with age-related differences. The proportion with BCR-ABL1 rearrangement increased progressively with age, up to 55.7% among subjects aged over 56–65 years. Rearrangements involving the KMT2A gene, ETV6-RUNX1, and TCF3-PBX1 were rare in this study cohort. The overall incidence of hyperdiploidy was only 1.7%, and there were no cases with hypodiploidy. Overall survival varied by age and cytogenetics. Older subjects and those with BCR-ABL1 tended to have inferior outcomes. In this epidemiological study of Japanese adult ALL, the majority of subjects had B-lineage ALL, the T-cell phenotype was most frequent in those aged 16–25, and BCR-ABL1 rearrangement was very common, with prevalence increasing with age. These types of adult ALL are potentially manageable with targeted therapies.
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- 2021
26. Antithymocyte Globulin Potentially Could Overcome an Adverse Effect of Acute Graft-versus-Host Disease in Matched-Related Peripheral Blood Stem Cell Transplantation
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Kotaro Miyao, Yachiyo Kuwatsuka, Makoto Murata, Koji Nagafuji, Takanori Teshima, Yuki Takeuchi, Souichi Shiratori, Yuho Najima, Naoyuki Uchida, Masatsugu Tanaka, Masashi Sawa, Shuichi Ota, Takahiro Fukuda, Yukiyasu Ozawa, Shinichi Kako, Toshiro Kawakita, Takahide Ara, Junji Tanaka, Yoshinobu Kanda, Yoshiko Atsuta, Junya Kanda, and Seitaro Terakura
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Leukemia, Myeloid, Acute ,Peripheral Blood Stem Cell Transplantation ,Transplantation ,Adolescent ,Recurrence ,Graft vs Host Disease ,Humans ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology ,Antilymphocyte Serum ,Retrospective Studies - Abstract
Previous Japanese studies have shown that bone marrow transplantation (BMT) is associated with better survival compared with peripheral blood stem cell transplantation (PBSCT) from a matched related donor (MRD). PBSCT recipients have shown higher incidences of severe graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) compared with BMT recipients. In recent years, the efficacy and safety of antithymocyte globulin (ATG) for PBSCT recipients has been evaluated worldwide. In the present study, we aimed to compare BMT and PBSCT recipients to identify current improvements and unmet needs among MRD PBSCT recipients. In addition, we evaluated the impact of ATG administration on the outcomes of PBSCT recipients. We retrospectively analyzed patients age ≥16 years with acute leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia who underwent their first BMT or PBSCT from an MRD between 2009 and 2018 in Japan. A total of 3599 transplantations were performed (BMT, n = 1218; PBSCT without ATG [PBSCT-ATG(-)], n = 2288; PBSCT with ATG [PBSCT-ATG(+)], n = 93). The PBSCT-ATG(-) group had a higher NRM (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.08 to 1.57; P = .005) and lower overall survival (OS) (HR, 1.16; 95% CI, 1.04 to 1.30; P = .011) compared with the BMT group. Furthermore, the PBSCT-ATG(-) group had higher incidences of grade III-IV, stage 2-4 gut, high-risk, and steroid-refractory acute GVHD compared with the BMT group. Acute GVHD had a negative impact on NRM and OS. The PBSCT-ATG(-) group also was associated with an elevated risk of chronic GVHD (HR, 1.89; 95% CI, 1.24 to 2.57; P.001) and extensive chronic GVHD (HR, 1.44; 95% CI, 1.23 to 1.68; P.001). The incidences of acute GVHD, chronic GVHD, and NRM and chronic GVHD-free relapse-free survival rates were comparable between the PBSCT-ATG(+) and BMT groups. The OS of patients with acute GVHD was similar in the 3 donor groups. Patients treated with reduced-intensity conditioning in the PBSCT-ATG(+) group had a higher relapse rate and lower OS rate compared with those in the BMT group. In this Japanese cohort, standard calcineurin inhibitor-based GVHD prophylaxis was not sufficient for recipients of MRD PBSCT because of the high incidence of severe acute GVHD. Prophylactic ATG was found to be a promising strategy against GVHD.
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- 2022
27. Outcome predictors after retransplantation in relapsed acute lymphoblastic leukemia: a multicenter, retrospective study
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Takeshi Sugio, Toshihiro Miyamoto, Toshiyuki Ueno, Takahiro Maeda, Koji Kato, Goichi Yoshimoto, Koji Nagafuji, Yoshikiyo Ito, Masanori Kadowaki, Takuro Kuriyama, Fukuoka Blood, Yasuo Mori, Koichi Akashi, Kensuke Sasaki, and Takatoshi Aoki
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Aged ,Retrospective Studies ,Univariate analysis ,Hematology ,Performance status ,business.industry ,Mortality rate ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,General Medicine ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Minimal residual disease ,Transplantation ,Survival Rate ,Treatment Outcome ,030220 oncology & carcinogenesis ,Retreatment ,Blinatumomab ,Female ,Neoplasm Recurrence, Local ,business ,030215 immunology ,medicine.drug - Abstract
Retransplantation is the only curative treatment option for patients with acute lymphoblastic leukemia (ALL) that has relapsed after allogeneic hematopoietic cell transplantation (allo-HCT); however, data in this setting remain scant. Hence, this multicenter, retrospective study aims to determine outcome predictors after retransplantation in relapsed ALL. We examined 55 recipients who underwent multiple allo-HCTs during 2006–2018. The 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality rates were 35.9%, 29.1%, and 23.6%, respectively. We observed a trend of better outcome in Ph + ALL (n = 22) patients compared with non-Ph ALL (n = 33) patients; the 2-year PFS was 40.9% versus 21.2%, indicating a beneficial effect of more potent second- or third-generation tyrosine kinase inhibitors. Univariate analysis revealed that late relapse after the previous transplant was the only significant predictor of better transplant outcome among Ph + ALL patients, whereas factors related to prolonged OS/PFS in non-Ph ALL patients were late relapse after the previous transplant, longer duration from disease relapse/progression to second or more allo-HCT, disease status at the transplantation, and good performance status. Nevertheless, further investigations are warranted to determine whether novel molecular-targeted agents with higher efficacy and fewer toxicities could exceed conventional chemotherapies as a bridging strategy to next allo-HCT and improve the outcomes of non-Ph ALL patients.
- Published
- 2020
28. Efficacy and safety of romiplostim in refractory aplastic anaemia: a Phase II/III, multicentre, open-label study
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Masashi Sawa, Akira Matsuda, Kinuko Mitani, Kensuke Usuki, Koji Nagafuji, Naoki Kobayashi, Keiya Ozawa, Yuji Yonemura, Itaru Matsumura, Jun Ho Jang, Koji Miyazaki, Tomoaki Fujisaki, Michihiro Hidaka, Kouki Enokitani, Yoshiaki Tomiyama, Satoshi Ichikawa, Shinji Nakao, Jong Wook Lee, Ko Sasaki, Hiroshi Kosugi, Masahiro Kizaki, and Nobuhiko Uoshima
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Adult ,Male ,medicine.medical_specialty ,Spasm ,Recombinant Fusion Proteins ,Receptors, Fc ,Gastroenterology ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Refractory ,Internal medicine ,Medicine ,Humans ,Platelet ,Red Cells and Iron ,Adverse effect ,Thrombopoietin ,Aged ,Romiplostim ,business.industry ,Anemia, Refractory ,Bone marrow failure ,Headache ,Anemia, Aplastic ,Hematology ,haematopoiesis ,Middle Aged ,medicine.disease ,Confidence interval ,aplastic anaemia ,Discontinuation ,Blood Cell Count ,Hematopoiesis ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,bone marrow failure ,business ,030215 immunology ,medicine.drug ,Research Paper - Abstract
A previous dose‐finding study has suggested that romiplostim is effective in patients with refractory aplastic anaemia (AA) and 10 µg/kg once weekly was recommended as a starting dose. In this Phase II/III, multicentre, open‐label study, romiplostim was administered subcutaneously at a fixed dose of 10 µg/kg once weekly for 4 weeks (weeks 1–4) followed by weekly doses (5, 10, 15 and 20 µg/kg) titrated by platelet response for up to 52 weeks (weeks 5–52). A total of 31 patients with AA who were refractory to immunosuppressive therapy (IST) and thrombocytopenia (platelet count of ≤30 × 109/l) were enrolled. The primary efficacy endpoint of the proportion of patients achieving any haematological (platelet, neutrophil and erythrocyte) response at week 27 was 84% [95% confidence interval (CI) 66–95%]. Trilineage response was 39% (95% CI 22–58%) at week 53. The most common treatment‐related adverse events (AEs) were headache and muscle spasms (each 13%). All AEs were mild or moderate except for three patients with Grade 3 hepatic AEs; no AEs necessitated romiplostim discontinuation. Two patients developed cytogenetic abnormalities, of whom one returned to normal karyotype at last follow‐up. High‐dose romiplostim is effective and well tolerated in the treatment of patients with AA refractory to IST.
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- 2020
29. Primary human herpesvirus 8-negative effusion-based lymphoma: a large B-cell lymphoma with favorable prognosis
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Koji Nagafuji, Yasunori Ueda, Tomohiro Kinoshita, Yasunori Ota, Go Yamamoto, Koichi Ohshima, Yasushi Terasaki, Naoko Tsuyama, Kosei Matsue, Yasuharu Sato, Masataka Okamoto, Shigeru Chiba, Shuichi Taniguchi, Daisuke Kaji, and Koji Izutsu
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medicine.medical_specialty ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Pleural effusion ,CHOP ,Gastroenterology ,Japan ,Internal medicine ,Medicine ,Humans ,B-cell lymphoma ,Aged ,Retrospective Studies ,Aged, 80 and over ,Lymphoid Neoplasia ,business.industry ,virus diseases ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Chemotherapy regimen ,Lymphoma ,Effusion ,Herpesvirus 8, Human ,Prednisolone ,Rituximab ,business ,medicine.drug - Abstract
Primary effusion-based lymphoma (EBL) presents as a malignant effusion in a body cavity. The clinicopathologic features and prognosis of primary human herpesvirus 8 (HHV8)–negative EBL remain unclear. We therefore conducted a retrospective study of 95 patients with EBL, regardless of HHV8 status, in Japan. Of 69 patients with EBL tested for HHV8, a total of 64 were negative. The median age of patients with primary HHV8-negative EBL at diagnosis was 77 years (range, 57-98 years); all 58 tested patients were negative for HIV. Primary HHV8-negative EBL was most commonly diagnosed in pleural effusion (77%). Expression of at least 1 pan B-cell antigen (CD19, CD20, or CD79a) was observed in all cases. According to the Hans algorithm, 30 of the 38 evaluated patients had nongerminal center B-cell (non-GCB) tumors. Epstein-Barr virus–encoded small RNA was positive in 6 of 45 patients. In 56 of 64 HHV8-negative patients, systemic therapy was initiated within 3 months after diagnosis. Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOP-like regimens with or without rituximab (n = 48) were the most common primary treatments. The overall response and complete response rates were 95% and 73%, respectively. Three patients did not progress without systemic treatment for a median of 24 months. With a median 25-month follow-up, the 2-year overall survival and progression-free survival rates were 84.7% and 73.8%. Sixteen patients died; 12 were lymphoma-related deaths. Thus, most EBL cases in Japan are HHV8-negative and affect elderly patients. The non-GCB subtype is predominant. Overall, primary HHV8-negative EBL exhibits a favorable prognosis after anthracycline-based chemotherapy.
- Published
- 2020
30. Clonally related diffuse large B-cell lymphoma and interdigitating dendritic cell sarcoma sharing MYC translocation
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Mitsunori Yamakawa, Koji Nagafuji, Satoru Miyano, Kenichi Chiba, Akifumi Takaori-Kondo, Noboru Yonetani, Yusuke Shiozawa, Sumie Tabata, Yuichi Shiraishi, Kenichi Yoshida, June Takeda, Daisuke Yamashita, Takayuki Ishikawa, Hiroko Tanaka, Seishi Ogawa, Yukihiro Imai, Keiichiro Uehara, Nobuhiro Hiramoto, Tetsuichi Yoshizato, Yasuhiro Kazuma, Yotaro Ochi, Yuichiro Ono, and Nobuyuki Kakiuchi
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0301 basic medicine ,Langerhans cell ,Hematology ,Dendritic cell ,Biology ,Histiocytic sarcoma ,medicine.disease ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Interdigitating dendritic cell sarcoma ,medicine ,Cancer research ,Neoplasm ,Online Only Articles ,Diffuse large B-cell lymphoma ,Histiocyte - Abstract
Interdigitating dendritic cell sarcoma (IDCS) is a rare neoplasm considered to derive from a dendritic cell. Recent studies have shown that B- or T-lymphoblastic leukemia/lymphomas can develop clonally related histiocytic/dendritic cell (H/DC) neoplasms, such as histiocytic sarcoma, Langerhans cell
- Published
- 2018
31. Risk Assessment in Adult T Cell Leukemia/Lymphoma Treated with Allogeneic Hematopoietic Stem Cell Transplantation
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Minoko Takanashi, Naoyuki Uchida, Michihiro Hidaka, Tatsuo Ichinohe, Yukiyoshi Moriuchi, Toshihiro Miyamoto, Makoto Yoshimitsu, Ilseung Choi, Yasuhiko Miyazaki, Koji Kato, Ryuji Tanosaki, Atae Utsunomiya, Koji Nagafuji, Yasuhiro Nakashima, Yoshifusa Takatsuka, Tetsuya Eto, Yoshiko Atsuta, Takahiro Fukuda, and Takashi Ishida
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,T-cell leukemia ,Hematopoietic stem cell transplantation ,Risk Assessment ,Disease-Free Survival ,Adult T-cell leukemia/lymphoma ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,Aged ,Retrospective Studies ,Transplantation ,Framingham Risk Score ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Allografts ,medicine.disease ,Lymphoma ,Survival Rate ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Immunology ,Cohort ,Female ,business ,Risk assessment ,030215 immunology - Abstract
Disease status at allogeneic hematopoietic cell transplantation (HCT) is an important pretransplant prognostic factor of HCT in adult T cell leukemia/lymphoma (ATL); however, other prognostic factors, including comorbidities, were not predictive in small cohort analyses. Several scoring systems (HCT-specific comorbidity index [HCT-CI]/modified European Group for Blood and Marrow Transplantation risk score [mEBMT]) have been adopted to predict HCT outcomes in other hematologic malignancies. We retrospectively evaluated HCT-CI and mEBMT to predict nonrelapse mortality (NRM) in 824 ATL patients registered in the Japan Society for Hematopoietic Cell Transplantation TRUMP database, from 2008 until 2013. A higher HCT-CI was associated with greater NRM when comparing HCT-CI 0 versus HCT-CI 1 to 3 and HCT-CI 0 versus HCT-CI ≥ 4. A higher mEBMT score was not associated with higher NRM when comparing mEBMT 0 to 3 with 4 to 6. Because ATL patients are older and consequently at risk of additional complications, we developed an optimized prognostic index for ATL (ATL-HCT-PI) using known risk factors: age, HCT-CI, and donor–recipient sex combination. The ATL-HCT-PI scores effectively predicted the 2-year NRM (22.0%, 27.7%, and 44.4%, respectively). Therefore, the newly developed ATL-HCT-PI, in combination with other risk factors, is more useful for predicting NRM in HCT for ATL patients.
- Published
- 2018
32. Hepatitis C virus infection is an independent prognostic factor in follicular lymphoma
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Koichi Ohshima, Tomohiko Kamimura, Tetsuya Eto, Koji Kato, Masao Seto, Kohta Miyawaki, Koji Nagafuji, Takeshi Sugio, Yoshitaka Imaizumi, Takanori Teshima, Takuto Miyagishima, Koichi Akashi, Takeharu Kato, Hiroaki Miyoshi, and Joji Shimono
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hepatitis C virus ,NS3 ,Prognostic factor ,medicine.medical_specialty ,Poor prognosis ,overall survival ,Hepatitis C virus ,Follicular lymphoma ,medicine.disease_cause ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,International Prognostic Index ,follicular lymphoma ,Internal medicine ,medicine ,Splenic marginal zone lymphoma ,Hematology ,business.industry ,virus diseases ,poor prognosis ,medicine.disease ,digestive system diseases ,Lymphoma ,Oncology ,030220 oncology & carcinogenesis ,business ,Research Paper ,030215 immunology - Abstract
// Joji Shimono 1, 9 , Hiroaki Miyoshi 1 , Takeharu Kato 2, 7 , Takeshi Sugio 3 , Kohta Miyawaki 3 , Tomohiko Kamimura 4 , Takuto Miyagishima 5 , Tetsuya Eto 6 , Yoshitaka Imaizumi 7 , Koji Kato 3 , Koji Nagafuji 8 , Koichi Akashi 3 , Masao Seto 1 , Takanori Teshima 9 and Koichi Ohshima 1 1 Department of Pathology, Kurume University, School of Medicine, Kurume, Japan 2 Department of Hematology, Sasebo City General Hospital, Sasebo, Japan 3 Department of Medicine and Biosystemic Science, Kyushu University Faculty of Medicine, Fukuoka, Japan 4 Department of Hematology, Hara Sanshin Hospital, Fukuoka, Japan 5 Department of Hematology, Kushiro Rosai Hospital, Kushiro, Japan 6 Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan 7 Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan 8 Department of Hematology, Kurume University, School of Medicine, Kurume, Japan 9 Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan Correspondence to: Hiroaki Miyoshi, email: miyoshi_hiroaki@med.kurume-u.ac.jp Keywords: follicular lymphoma; hepatitis C virus; poor prognosis; NS3; overall survival Received: July 23, 2017 Accepted: November 13, 2017 Published: December 11, 2017 ABSTRACT Hepatitis C virus (HCV) is a single-stranded RNA virus that not only affects hepatocytes, by B cells as well. It is thought that HCV is involved in the onset of B-cell lymphoma. The clinicopathological characteristics of HCV-positive diffuse large B-cell lymphoma (DLBCL) and HCV-positive splenic marginal zone lymphoma (SMZL) are known, but there has been no report on HCV-positive follicular lymphoma (FL). In this study, the clinicopathological characteristics of HCV-positive FL were examined in 263 patients with FL who were classified into a HCV-positive group with HCV antibody and negative groups without one. The number of patients with HCV-positive FL and HCV-negative FL was 10 (3.8%) and 253 (96.2%), respectively. The patients with HCV-positive FL commonly had more than one region of lymphadenopathy, Ann Arbor stage III/IV, hemoglobin
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- 2017
33. Prognostic factors for histiocytic and dendritic cell neoplasms
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Hiroaki Miyoshi, Fumiko Arakawa, Joji Shimono, Keisuke Kawamoto, Kensaku Sato, Koichi Ohshima, Daisuke Kurita, Eriko Yanagida, Koji Nagafuji, Reiji Muto, Yuya Sasaki, and Takuya Furuta
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0301 basic medicine ,medicine.medical_specialty ,Pathology ,Histiocytic sarcoma ,survival ,dendritic cell neoplasm ,histiocytic sarcoma ,BRAF ,03 medical and health sciences ,0302 clinical medicine ,Langerhans cell histiocytosis ,Internal medicine ,medicine ,Stage (cooking) ,prognostic factor ,Histiocyte ,Hematology ,business.industry ,Dendritic cell ,medicine.disease ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Follicular dendritic cell sarcoma ,Langerhans cell sarcoma ,business ,Research Paper - Abstract
// Joji Shimono 1, 3 , Hiroaki Miyoshi 1 , Fumiko Arakawa 1 , Kensaku Sato 1 , Takuya Furuta 1 , Reiji Muto 1 , Eriko Yanagida 1 , Yuya Sasaki 1 , Daisuke Kurita 1 , Keisuke Kawamoto 1 , Koji Nagafuji 2 and Koichi Ohshima 1 1 Department of Pathology, Kurume University, School of Medicine, Kurume, Japan 2 Department of Hematology, Kurume University, School of Medicine, Kurume, Japan 3 Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Correspondence to: Hiroaki Miyoshi, email: miyoshi_hiroaki@med.kurume-u.ac.jp Keywords: dendritic cell neoplasm; histiocytic sarcoma; survival; prognostic factor; BRAF Received: June 05, 2017 Accepted: September 21, 2017 Published: October 19, 2017 ABSTRACT Histiocytic and dendritic cell neoplasms are rare and poorly studied. We report the clinical characteristics and prognostic factors in such cases in Japan. We investigated the clinical characteristics and survival in 87 adult patients with histiocytic and dendritic cell neoplasms. Fifty patients had histiocytic sarcoma, 12 had Langerhans cell histiocytosis, 11 had follicular dendritic cell sarcoma, 8 had Langerhans cell sarcoma, 6 had interdigitating cell sarcoma and 1 had indeterminate dendritic cell sarcoma. The median follow-up period was 18.0 (range: 9.6-71.8) months, and median overall survival (OS) was 23.5 months . The 2-year OS rate was 49.2% . In the multivariate analysis, elevated lactate dehydrogenase (LDH) ( p =.004), ECOG performance status (PS) 2-4 ( p =.006), and Ann Arbor stage III-IV ( p =.008) affected OS. Stratification by elevated LDH, ECOG PS 2-4, and Ann Arbor stage III-IV allowed classification of patients into low risk, intermediate risk, and high risk groups. The same classification was applicable for HS and non-HS categories. In the rare neoplasms of histiocytic and dendritic cell sarcoma, ECOG PS, Ann Arbor stage, and LDH are important prognostic factors for predicting survival.
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- 2017
34. Clinicopathological features of primary splenic follicular lymphoma
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Masao Seto, Tetsuya Eto, Keisuke Kawamoto, Daisuke Kurita, Hiroaki Miyoshi, Joji Shimono, Koji Nagafuji, Takuto Miyagishima, Koichi Ohshima, Tomohiko Kamimura, Yuya Sasaki, and Takanori Teshima
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Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Splenectomy ,Follicular lymphoma ,Splenic Neoplasm ,Hepacivirus ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,International Prognostic Index ,medicine ,Humans ,Lymphoma, Follicular ,Survival rate ,Aged ,Aged, 80 and over ,business.industry ,Splenic Neoplasms ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Hepatitis C ,Lymphoma ,Survival Rate ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,Splenic Lymphoma ,business ,Generalized lymphadenopathy - Abstract
Follicular lymphoma (FL) is a low-grade lymphoma that is usually characterized by generalized lymphadenopathy. Extranodal invasion by FL generally involves the bone marrow, skin, and duodenum; splenic infiltration often occurs in the advanced stages. However, primary splenic FL is very rare. Hence, few studies have been performed on splenic FL, and its clinicopathological features have not been established. This study aimed to investigate the clinicopathological features of primary splenic FL, as compared to nodal FL. We analyzed 17 patients diagnosed with primary splenic FL and 153 control patients with systemic FL. Hepatitis C virus (HCV)-positive status was significantly more common in patients with splenic FL than in the control patients (p = 0.02). Ann Arbor stage III or IV (p = 0.0003) and high-risk FLIPI (Follicular Lymphoma International Prognostic Index) (p = 0.03) were significantly less common in patients with splenic FL than in the control patients; however, the overall and progression-free survival curves were not significantly different between the groups. Among the 17 patients with splenic FL, the progression-free survival was significantly worse in patients who underwent splenectomy without receiving postoperative chemotherapy than in those who did (p = 0.03). These results suggest that primary splenic FL should be considered different from systemic FL; accordingly, its management should also be conducted differently.
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- 2017
35. Comparison of clinicopathological characteristics between T-cell prolymphocytic leukemia and peripheral T-cell lymphoma, not otherwise specified
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Takeharu Kato, Junichi Kiyasu, Tetsuya Eto, Masao Seto, Ritsuko Seki, Hirohito Sone, Tatsuma Morikita, Koichi Ohshima, Eriko Yanagida, Tsuyoshi Muta, Hitoshi Suzushima, Yasuji Kozai, Noriaki Yoshida, Jun Takizawa, Keisuke Kawamoto, Koji Nagafuji, Koji Kato, Shinobu Tamura, and Hiroaki Miyoshi
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Adolescent ,Biopsy ,Receptors, Antigen, T-Cell ,Peripheral T-cell lymphoma not otherwise specified ,Aggressive lymphoma ,Immunophenotyping ,Diagnosis, Differential ,Leukocyte Count ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Neoplasm ,Neoplasm Metastasis ,Child ,Prolymphocytic leukemia ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Gene Rearrangement ,medicine.diagnostic_test ,business.industry ,Not Otherwise Specified ,Lymphoma, T-Cell, Peripheral ,Hematology ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Lymphoma ,Treatment Outcome ,030220 oncology & carcinogenesis ,Leukemia, Prolymphocytic, T-Cell ,T-cell prolymphocytic leukemia ,Female ,business ,Biomarkers ,030215 immunology - Abstract
Objectives T-cell prolymphocytic leukemia (T-PLL) is a very rare, aggressive T-cell neoplasm. Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is also a highly aggressive lymphoma. These two diseases can often be confused with each other; therefore, we aimed to determine the clinical and pathological differences between T-PLL and PTCL-NOS. Methods We analyzed 15 T-PLL and 91 PTCL-NOS patients and also compared clinical features between T-PLL and PTCL-NOS with leukemic presentation. Peripheral blood images and biopsy specimens were analyzed, and treatment responses were determined via imaging modalities. The clinicopathological characteristics were statistically compared. Results T-PLL cells were smaller in size than those of PTCL-NOS with leukemic presentation (P=.0068); moreover, PTCL-NOS cells with leukemic presentation were smaller than those of PTCL-NOS without leukemic presentation (P=.0017). Immunophenotypic patterns in T-PLL and PTCL-NOS were similar. Five-year overall survival rates of T-PLL and all PTCL-NOS patients were 57.5% and 36.8%, respectively. No significant differences were found in clinical manifestations or prognoses; T-PLL and PTCL-NOS with leukemic presentation had essentially equivalent characteristics. Conclusion T-PLL and PTCL-NOS may share common biological and clinical characteristics in Japanese patients.
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- 2017
36. Impact of Homozygous Conserved Extended HLA Haplotype on Single Cord Blood Transplantation: Lessons for Induced Pluripotent Stem Cell Banking and Transplantation in Allogeneic Settings
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Yasuhiro Sugio, Junya Kanda, Koji Nagafuji, Naoyuki Uchida, Takahiro Fukuda, Tetsuya Eto, Shunichi Kato, Yasuo Morishima, Yasushi Onishi, Nobuyoshi Arima, Tatsuo Ichinohe, Masami Inoue, Yoshiko Matsuhashi, Satoshi Takahashi, Makoto Onizuka, Yoshiko Atsuta, Makoto Murata, and Satoko Morishima
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Adult ,Male ,Adolescent ,Induced Pluripotent Stem Cells ,Graft vs Host Disease ,Locus (genetics) ,Human leukocyte antigen ,Cell therapy ,HLA Antigens ,Risk Factors ,Medicine ,Humans ,Typing ,Registries ,Allele ,Induced pluripotent stem cell ,Child ,Aged ,Biological Specimen Banks ,Retrospective Studies ,Aged, 80 and over ,Transplantation ,Neutrophil Engraftment ,business.industry ,Homozygote ,Infant, Newborn ,Infant ,Hematology ,Middle Aged ,Allografts ,Haplotypes ,Child, Preschool ,Hematologic Neoplasms ,Immunology ,Acute Disease ,Female ,Cord Blood Stem Cell Transplantation ,business - Abstract
Induced pluripotent stem cells (iPSCs) have been applied to clinical regenerative cell therapy. Recently, an iPSC banking system to collect HLA haplotype (HP) homozygous (homo) cells for iPSC transplantation in allogeneic settings was proposed, and tissue transplantation generated from iPSC through banking has just began. We analyzed 5017 single cord blood transplantation (CBT) pairs with HLA-A, -B, -C, -DRB1 allele typing data and found 39 donor HLA homo donor to patient HLA heterozygous (hetero) pairs. Of note, all 39 HLA homo to hetero pairs engrafted neutrophils, except 1 early death pair, and all 30 assessable pairs engrafted platelets. Acute graft-versus-host disease (GVHD) grades II to IV and grades III to IV occurred in 17 and 3 of 38 assessable pairs, respectively. Competing risk regression analysis revealed a favorable risk of neutrophil engraftment and higher risk of acute GVHD compared with HLA-matched CBTs. Thirty-seven of 39 homo to hetero pairs had conserved extended HLA HPs (HP-1, n = 18; HP-2, n = 8; HP-3, n = 7; HP-4, n = 4; HP-5, n = 1) that were ethnicity-specific, and at least 1 of 2 patient HLA-A, -B, -C, and -DRB1 alleles in each locus were invariably shared with the same donor HP in 35 pairs. These findings confirmed our preliminary results with 6 HLA homo CBTs, and a trend of high incidence of acute GVHD was newly observed. Importantly, they imply the possibility that HLA-homo iPSC transplantation provides favorable engraftment and accordingly imply the merit of banking iPSC with homozygous major conserved extended HLA HPs.
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- 2019
37. Comparison of calcineurin inhibitors in combination with conventional methotrexate, reduced methotrexate, or mycophenolate mofetil for prophylaxis of graft-versus-host disease after umbilical cord blood transplantation
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Koji Nagafuji, Takeshi Sugio, Tsuyoshi Muta, Goichi Yoshimoto, Ken Takase, Tomohiko Kamimura, Hideho Henzan, Shuro Yoshida, Hiromi Iwasaki, Toshihiro Miyamoto, Koichi Akashi, Yuju Ohno, Tetsuya Eto, Ryosuke Ogawa, and Takanori Ohta
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Male ,Neutrophils ,Graft vs Host Disease ,Kaplan-Meier Estimate ,Gastroenterology ,Leukocyte Count ,0302 clinical medicine ,Japan ,Cumulative incidence ,Aged, 80 and over ,Hematology ,Incidence ,Graft Survival ,General Medicine ,Middle Aged ,surgical procedures, operative ,Treatment Outcome ,030220 oncology & carcinogenesis ,Hematologic Neoplasms ,Toxicity ,Drug Therapy, Combination ,Female ,Cord Blood Stem Cell Transplantation ,Immunosuppressive Agents ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Calcineurin Inhibitors ,Infections ,03 medical and health sciences ,Young Adult ,Internal medicine ,medicine ,Humans ,Aged ,Retrospective Studies ,Neutrophil Engraftment ,Dose-Response Relationship, Drug ,Umbilical Cord Blood Transplantation ,business.industry ,Platelet Count ,Mycophenolic Acid ,medicine.disease ,Calcineurin ,Graft-versus-host disease ,Methotrexate ,business ,030215 immunology - Abstract
Umbilical cord blood transplantation (UCBT) is a curative treatment for hematological malignancies. However, appropriate prophylaxis against graft-versus-host disease (GVHD), aimed at obtaining rapid and stable engraftment and avoiding toxicity, remains controversial in UCBT. We retrospectively compared outcomes in 409 patients who received calcineurin inhibitors (CIs) plus conventional-dose methotrexate (conv-MTX/CIs, n = 77; methotrexate, 10 mg/m2 on day 1, 7 mg/m2 on days 3 and 6) with those who received CIs plus reduced-dose methotrexate (reduced-MTX/CIs, n = 209; methotrexate, 5 mg/m2 or 5 mg/body on days 1, 3, and 6) or CIs with mycophenolate mofetil (MMF/CIs, n = 123) for GVHD prophylaxis after UCBT. The cumulative incidence of neutrophil engraftment was significantly higher in the reduced-MTX/CI (82.3%) and MMF/CI (86.6%) groups than the conv-MTX/CI (71.4%) group (p = 0.014), although there were no differences in platelet recovery or infectious complications among the three groups. The incidence and severity of GVHD were comparable among the three groups, and there were no significant differences in transplantation-related mortality among the three groups. In conclusion, GVHD prophylaxis with reduced-dose methotrexate and MMF was closely associated with high incidence of neutrophil engraftment without an effect on the incidence and severity of GVHD, which was compared to GVHD prophylaxis with conventional-dose methotrexate.
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- 2019
38. Bortezomib-based strategy with autologous stem cell transplantation for newly diagnosed multiple myeloma: a phase II study by the Japan Study Group for Cell Therapy and Transplantation (JSCT-MM12)
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Toru Kiguchi, Junji Suzumiya, Ilsong Choi, Hiroyuki Takamatsu, Yoko Adachi, Toshiaki Yujiri, Naohito Fujishima, Toshihiro Miyamoto, Ryosuke Yamamura, Yasushi Takamatsu, Morio Matsumoto, Kazutaka Sunami, Tomonori Nakazato, Shin ichi Fuchida, Yoshiaki Kuroda, Koichi Akashi, Mine Harada, Koji Nagafuji, Eijiro Omoto, and Akio Maeda
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0301 basic medicine ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Cyclophosphamide ,Phases of clinical research ,Transplantation, Autologous ,Dexamethasone ,Bortezomib ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,Japan ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Lenalidomide ,Melphalan ,Multiple myeloma ,Aged ,business.industry ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Prognosis ,Combined Modality Therapy ,Neoadjuvant Therapy ,Thalidomide ,Transplantation ,Survival Rate ,030104 developmental biology ,030220 oncology & carcinogenesis ,Surgery ,Female ,business ,Multiple Myeloma ,medicine.drug ,Stem Cell Transplantation - Abstract
The Japan Study Group for Cell Therapy and Transplantation (JSCT) organized a phase II study to evaluate the efficacy and safety of a treatment protocol (JSCT-MM12) for multiple myeloma (MM) patients who were previously untreated and transplantation-eligible. Since bortezomib-based therapy is known to be effective for MM, the protocol is intensified more than the previous protocol (JSCT-MM10) and comprised the subsequent treatments: bortezomib + cyclophosphamide + dexamethasone (VCD) induction; bortezomib + high-dose-melphalan (B-HDM) conditioning with autologous stem cell transplantation (ASCT); bortezomib + thalidomide + dexamethasone (VTD) consolidation; and lenalidomide (LEN) maintenance. Sixty-four symptomatic patients aged between 20 and 65 years were enrolled for treatment and received three cycles of VCD, followed by cyclophosphamide administration for autologous stem cell harvest and B-HDM/ASCT, and subsequently two cycles of VTD, after that LEN for 1 year. Complete response (CR)/stringent CR (sCR) rates for induction, ASCT, consolidation, and maintenance therapies were 20, 39, 52, and 56%, respectively. The grade 3/4 toxicities (≥ 10%) with VCD treatment included neutropenia (27%), anemia (19%), and thrombocytopenia (11%). There was no treatment-related mortality. After median follow-up of 41 months, estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 64% and 88%, respectively. The high-risk group revealed lower CR/sCR, PFS, and OS than the standard-risk group. The study revealed that the treatment protocol consisting of VCD induction, B-HDM/ASCT followed by VTD consolidation, and LEN maintenance could produce highly beneficial responses and favorable tolerability in newly diagnosed MM. However, future study is required for improving treatment in the high-risk group.
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- 2018
39. Comparison of cyclosporine and tacrolimus combined with mycophenolate mofetil in prophylaxis for graft-versus-host disease after reduced-intensity umbilical cord blood transplantation
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Koji Nagafuji, Toshihiro Miyamoto, Takanori Teshima, Tomohiko Kamimura, Tetsuya Eto, Koichi Osaki, Hideho Henzan, Goichi Yoshimoto, Shuichiro Takashima, Ken Takase, Shuro Yoshida, Koichi Akashi, Hiromi Iwasaki, and Koji Kato
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Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,Mycophenolate ,Gastroenterology ,Disease-Free Survival ,Tacrolimus ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Aged ,Antibiotics, Antineoplastic ,Neutrophil Engraftment ,Hematology ,Umbilical Cord Blood Transplantation ,business.industry ,Incidence (epidemiology) ,Middle Aged ,Mycophenolic Acid ,Fetal Blood ,medicine.disease ,Treatment Outcome ,surgical procedures, operative ,Graft-versus-host disease ,Hematologic Neoplasms ,030220 oncology & carcinogenesis ,Anesthesia ,Cyclosporine ,Female ,Neoplasm Recurrence, Local ,business ,Immunosuppressive Agents ,030215 immunology - Abstract
Umbilical cord blood transplantation with a reduced-intensity conditioning regimen (RIC-UCBT) is used increasingly in patients who have comorbid organ functions and lack human leukocyte antigen-identical donors. We compared the outcomes in 35 patients who received mycophenolate mofetil plus cyclosporine (MMF/CSP, n = 17) or MMF plus tacrolimus (MMF/TAC, n = 18) for graft-versus-host disease (GVHD) prophylaxis after RIC-UCBT. Cumulative incidence of neutrophil engraftment was 94 and 89 % in MMF/CSP and MMF/TAC groups, respectively (p = 0.34). The incidence of pre-engraftment immune reaction did not differ between the MMF/CSP (41 %) and MMF/TAC (39 %, p = 1.00) groups; however, patients in the MMF/TAC group tended to have a lower incidence of grade II-IV acute GVHD than those in MMF/CSP group (28 vs 53 %, p = 0.11). Overall survival (OS) at 1 year was 43 and 60 % in MMF/CSP and MMF/TAC groups, respectively (p = 0.39). Progression-free survival, non-relapse mortality, and relapse rate were comparable between the two groups (p = 0.76, 0.59, and 0.88, respectively). In multivariate analyses, MMF/TAC GVHD prophylaxis was closely associated with improved OS, but not with incidence of engraftment and acute GVHD. These results suggest that more intensive GVHD prophylaxis with MMF/TAC decreased acute GVHD without affecting other clinical outcomes, resulting in improved OS after RIC-UCBT.
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- 2016
40. Graft-versus-Host Disease after HLA-Matched Sibling Bone Marrow or Peripheral Blood Stem Cell Transplantation: Comparison of North American Caucasian and Japanese Populations
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Sachiko Seo, Yoshinobu Kanda, Celalettin Ustun, Zhen-Huan Hu, Makoto Murata, Takahiro Fukuda, Koichi Miyamura, Shahrukh Hashimi, Ruta Brazauskas, Marcelo C. Pasquini, Yachiyo Kuwatsuka, Hisashi Sakamaki, Theresa Hahn, Wael Saber, Fumihiko Kimura, Giuseppe Milone, Ayami Yoshimi, Heiwa Kanamori, Junya Kanda, Koji Nagafuji, Carmem Bonfim, William A. Wood, Jignesh Dalal, Mahmoud Aljurf, and Yoshiko Atsuta
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Adult ,Male ,Risk ,medicine.medical_specialty ,Adolescent ,Graft vs Host Disease ,Lower risk ,Severity of Illness Index ,White People ,Article ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Recurrence ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Sibling ,Survival analysis ,Bone Marrow Transplantation ,Peripheral Blood Stem Cell Transplantation ,Transplantation ,Leukemia ,business.industry ,Histocompatibility Testing ,Siblings ,Mortality rate ,Hazard ratio ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Tissue Donors ,Surgery ,medicine.anatomical_structure ,Graft-versus-host disease ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Acute Disease ,Chronic Disease ,Female ,Bone marrow ,business ,030215 immunology - Abstract
The risk of acute graft-versus-host disease (GVHD) after HLA-matched sibling bone marrow transplantation (BMT) is lower in Japanese than in Caucasian patients. However, race may have differential effect on GVHD dependent on the graft source. North American Caucasian and Japanese patients receiving their first allogeneic BMT or peripheral blood stem cell transplantation from an HLA-matched sibling for leukemia were eligible. BMT was performed in 13% of the Caucasian patients and in 53% of the Japanese patients. On multivariate analysis, the interaction term between race and graft source was not significant in any of the models, indicating that graft source does not affect the impact of race on outcomes. The risk of grade III or IV acute GVHD was significantly lower in the Japanese patients compared with the Caucasian patients (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57 to 0.96), which resulted in lower risk of nonrelapse mortality in the Japanese patients (HR, 0.69; 95% CI, 0.54 to 0.89). The risk of relapse was also lower in this group. The lower risks of nonrelapse mortality and relapse resulted in lower overall mortality rates among the Japanese patients. In conclusion, our data indicate that irrespective of graft source, the risk of severe acute GVHD is lower in Japanese patients, resulting in a lower risk of nonrelapse mortality.
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- 2016
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41. A Fast and Accurate Diagnostic Method for Ph-like ALL Using the Ncounter System
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Kensuke Sasaki, Jumpei Nogami, Takeshi Sugio, Kohta Miyawaki, Yoshikiyo Ito, Toshihiro Miyamoto, Yuichiro Semba, Takahiro Maeda, Koji Kato, Koji Nagafuji, and Koichi Akashi
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Oncology ,medicine.medical_specialty ,ABL ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Immunology ,PDGFRB ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Fusion gene ,Internal medicine ,Acute lymphocytic leukemia ,medicine ,business ,Gene ,Fluorescence in situ hybridization - Abstract
Ph-like acute lymphoblastic leukemia (also known as BCR-ABL1-like ALL) is a new disease entity of B-cell ALL (B-ALL) that exhibits a mRNA expression profile similar to that of Philadelphia chromosome-positive ALL (Ph+ ALL). Ph-like signature is presumably driven by kinase-activating gene alterations. Thus, both gene expression pattern and DNA mutational status should be assessed to make a definitive diagnosis for Ph-like ALL. A variety of approaches combining multiple methods, including RNA sequencing (RNA-seq), Taqman low-density array (LDA), fluorescence in situ hybridization (FISH) and targeted DNA sequencing, are being tested; however, such multi-omics approaches are available only in limited institutions. Since Ph-like ALL patients generally exhibit poor response to standard chemotherapy, and tyrosine kinase inhibitors (TKIs) may benefit them when used in a timely manner, a fast, accurate and generalizable diagnostic method is critically needed. In the present study, we have developed a nCounter-based diagnostic method for Ph-like ALL and validated it using a cohort of Japanese adult B-ALL cases. To identify genes that are uniquely expressed (or not expressed) in Ph+ B-ALL, we first obtained publicly-available gene expression datasets comprising 1146 B-ALL cases and identified 82 differentially-expressed genes in Ph+ ALL cases. We then assessed expression levels of those genes in an independent cohort using the nCounter, which enables fast, sensitive and accurate RNA detection. We also tested whether nCounter-based methods can detect fusion transcripts relevant for Ph-like ALL pathogenesis using probes targeting ABL1, ABL2, CSF1R, PDGFRB, and JAK2. We analyzed 123 samples (Ph+ = 42, Ph- = 81, age 16 to 67) obtained from newly-diagnosed adult B-ALL patients enrolled in two clinical trials conducted by the Fukuoka Blood and Marrow Transplantation Group (FBMTG) (Nagafuji et al. Eur J Haematol 2019). Unsupervised hierarchical clustering successfully stratified 123 cases into two disease clusters: Ph+ and Ph- subgroups. As expected, Ph+ subgroup included almost all Ph+ ALL cases (40 out of 42 cases), while 18 out of 81 Ph- ALL cases (22%) were categorized into the Ph+ subgroup. We defined these cases as Ph-like ALL. To validate the nCounter-based Ph-like ALL classification, we performed RNA-seq and target-capture DNA sequencing of all Ph- ALL cases. As expected, we detected kinase-activating fusions/rearrangements, including CRLF2 rearrangements (7 cases), PDGFRB fusions (3 cases), JAK2 fusions (2 cases), EPOR rearrangements (2 cases), ABL1 fusion (1 case), and FLT3 internal tandem duplication (1 case) in 16 Ph-like ALL cases, while no genetic alterations were detected in 2 cases. Fusion genes involving PDGFRB were consistently detected by nCounter (3/3); however, detection of those involving JAK2 (1/2) and ABL1 (0/1) were inconsistent. JAK2 and/or RAS mutations were detected in 5 of 7 Ph-like ALL cases harboring CRLF2 rearrangements. Of note, CRLF2 protein expression was detected by FACS in all CRLF2-rearranged cases. We next assessed significance of the Ph-like signature on clinical outcomes using a cohort of 40 Ph- ALL cases, in which minimal/measurable residual disease (MRD) status, assessed by IgH and/or TCR rearrangements, as well as clinical data were available (Nagafuji et al. Eur J Haematol 2019). Ph-like ALL cases exclusively exhibited MRD positivity after induction therapy as compared to non-Ph-like cases (p=0.04), indicative of the chemo-resistant nature of Ph-like ALL as previously reported (Roberts et al. N Engl J Med, 2014 and Roberts et al. J Clin Oncol, 2017). As expected, Ph-like ALL cases exhibited significantly poor disease-free survival compared with non-Ph-like ALL cases (p=0.04); however, no significant difference was evident in overall survival (p=0.62) presumably due to the fact that all MRD-positive cases were subjected to allo-HSCT after induction therapy. These data indicate that MRD-based therapy stratification could overcome chemo-resistant nature of Ph-like ALL. Our data suggest that nCounter-based diagnostic method is fast and accurate to identify Ph-like ALL. Since Ph-like signature generally dictates poor clinical outcomes, and upfront TKI therapy may improve them, our method could facilitate precision medicine in the treatment of Ph- B-ALL. Disclosures Akashi: Sumitomo Dainippon, Kyowa Kirin: Consultancy; Celgene, Kyowa Kirin, Astellas, Shionogi, Asahi Kasei, Chugai, Bristol-Myers Squibb: Research Funding.
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- 2019
42. Favorable Outcomes of Newly Diagnosed Intravascular Large B-Cell Lymphoma Patients Treated with R-CHOP Combined with High-Dose Methotrexate Plus Intrathecal Chemotherapy: Results from a Multicenter Phase 2 Trial (PRIMEUR-IVL)
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Daigo Hashimoto, Tohru Izumi, Yachiyo Kuwatsuka, Motoko Yamaguchi, Keijiro Sato, Tomohiro Kinoshita, Yoshiko Atsuta, Jun Takizawa, Satoko Shimada, Yukio Kondo, Satoshi Kayukawa, Atsumi Yanagisawa, Kunihiro Tsukasaki, Kosei Matsue, Yoshihiro Kin, Shigeru Kusumoto, Daisuke Ennishi, Atsushi Wake, Masataka Okamoto, Koji Nagafuji, Hirokazu Nagai, Noriko Fukuhara, Takashi Tokunaga, Toshiki Uchida, Eiichi Ohtsuka, Yasumasa Sugita, Nozomi Niitsu, Yasufumi Masaki, Ritsuro Suzuki, Kazuyuki Shimada, Kana Miyazaki, Masaaki Yuge, Hitoshi Kiyoi, and Shigeo Nakamura
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medicine.medical_specialty ,Intravascular large B-cell lymphoma ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Chemotherapy regimen ,Lymphoma ,Internal medicine ,medicine ,Cytarabine ,Prednisolone ,Methotrexate ,Rituximab ,business ,Febrile neutropenia ,medicine.drug - Abstract
Introduction: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity characterized by selective growth of lymphoma cells in the lumina of small vessels. IVLBCL has been listed in the WHO classification, which improves recognition of the disease. However, no standard therapy has been established based on the results of prospective studies. We previously reported promising efficacy of rituximab (R)-containing chemotherapy for IVLBCL (JCO 2008) and a high incidence of central nervous system (CNS) recurrence (25% at 3 y) after R-chemotherapy (Lancet Oncol 2009, Cancer Sci 2010). To explore a more effective first-line treatment, we conducted a phase 2 trial of R-CHOP combined with CNS prophylaxis including R-high-dose methotrexate (R-HDMTX) and intrathecal chemotherapy with MTX, cytarabine (Ara-C), and prednisolone (PSL) (IT). Methods: Major inclusion criteria were untreated, histologically confirmed IVLBCL, age 20-79 y, ECOG PS 0-3, and no apparent CNS involvement at diagnosis. Patients received 3 cycles of R-CHOP followed by 2 cycles of R-HDMTX (3.5 g/m2; 2 g/m2 for ≥70 y) every 2 weeks, and 3 additional cycles of R-CHOP. IT (MTX 15 mg, Ara-C 40 mg, PSL 10 mg) was performed twice during the first 3 cycles of R-CHOP and twice during the final 3 cycles of R-CHOP (4 times in total). If patients achieved complete response (CR), they were observed without any therapy until relapse or disease progression. The primary endpoint was 2-y progression-free survival (PFS), and secondary endpoints included 2-y overall survival (OS), CR rate, cumulative incidence of CNS recurrence at 2 y, patterns of progression, and adverse events. The threshold 2-y PFS was estimated to be 35%, with expected 2-y PFS estimated to be 60%. With a statistical power of 90% and a one-sided, type I error of 5%, a projected sample size of 37 was calculated in anticipation of 10% ineligible patients. The trial was registered in the UMIN Clinical Trials Registry (UMIN000005707). Results: 38 IVLBCL patients were enrolled between June 2011 and July 2016. One patient was found to be ineligible after completion of the protocol treatment due to a past history of lymphoma. The protocol treatment was completed in 34 (89%) of 38 patients. The diagnosis of IVLBCL was histologically confirmed by central pathological review in all enrolled patients. The baseline characteristics of the 37 eligible patients were: male sex, 16 (43%); median age, 66 (range 38-78) y; ECOG PS >1, 15 (41%); stage IV, 37 (100%); serum LDH >ULN, 36 (97%); WBC Conclusion: This phase 2 trial met its primary endpoint and showed favorable outcomes with a low cumulative incidence of CNS recurrence and acceptable toxicity profiles. These results indicate that R-CHOP combined with CNS prophylaxis including R-HDMTX and IT could be a reasonable treatment option for untreated IVLBCL without apparent CNS involvement at diagnosis. Disclosures Shimada: Takeda Pharmaceutical: Honoraria; MSD: Research Funding; Otsuka Pharmaceutical: Research Funding; Janssen Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Eisai: Honoraria, Research Funding; Chugai Pharmaceutical: Consultancy, Honoraria; Kyowa Kirin: Honoraria, Research Funding; AstraZeneca: Honoraria. Yamaguchi:Ono Pharmaceutical: Research Funding; Teijin Pharma: Honoraria; MSD: Honoraria; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Sumitomo Dainippon Pharma: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Astellas Pharma: Research Funding; Sorrento: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Meiji Seika Kaisha: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Eisai: Honoraria; Chugai: Honoraria, Research Funding. Atsuta:Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Mochida Pharmaceutical Co. Ltd: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Matsue:Celgene: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Ono Pharmaceutical: Honoraria; Novartis Pharma K.K: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Kusumoto:Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding. Nagai:Eisai: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; AstraZeneca: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; Sanofi: Honoraria; Otsuka Pharmaceutical: Research Funding; SymBio Pharmaceuticals Limited: Honoraria, Research Funding; Solasia Pharma K.K.: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; IQVIA: Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; MSD: Honoraria; Novartis Pharma: Honoraria; Mundi Pharma: Honoraria, Research Funding; Bayer Pharma: Honoraria, Research Funding; AbbVie: Research Funding. Fukuhara:Mundi: Honoraria; Celgene Corporation: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Janssen Pharma: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Nippon Shinkyaku: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Zenyaku: Honoraria; AbbVie: Research Funding; Bayer: Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Miyazaki:Eisai: Honoraria; Chugai: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Celgene: Honoraria; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Takeda: Honoraria; SymBio Pharmaceuticals: Honoraria; Nippon Shinyaku: Honoraria; Janssen Pharmaceutical: Honoraria. Okamoto:Kyowa Kirin Co., Ltd.: Other: Scholarship donation; Chugai Pharmaceutical Co., Ltd.: Other: Scholarship donation; Takeda Pharmaceutical Co., Ltd.: Other: Scholarship donation; Taiho Pharmaceutical Co., Ltd.: Other: Scholarship donation. Uchida:Eisai: Honoraria. Tsukasaki:Daiichi Sankyo: Consultancy; Kyowa Kirin: Honoraria; Huya: Consultancy, Honoraria, Research Funding; Byer: Research Funding; Mundi Pharma: Honoraria; Ono Pharmaceutical: Consultancy; Eisai: Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Masaki:Tanabe Mitsubishi: Research Funding; Taiho: Research Funding; Kyowa Kirin: Research Funding; Astellas Pharma: Research Funding; Chugai Pharmaceutical: Research Funding; Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Eisai: Research Funding; Taisho Toyama: Research Funding; Daiichi Sankyo: Research Funding; Teijin: Research Funding; Takeda Pharmaceutical: Research Funding. Kiyoi:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Eisai Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; Perseus Proteomics Inc.: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding. Suzuki:Chugai Pharmaceutical Co.,Ltd.: Honoraria; Meiji Seika: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa Hakko Kirin: Honoraria; Celgene: Honoraria; Eisai: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Janssen: Honoraria; AbbVie: Honoraria; Novartis: Honoraria.
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- 2019
43. A Functional Analysis of SNP on Anthracycline-Induced Cardiotoxicity in a Uniform Genetic Background Using CRISPR/Cas9 Mediated Single-Base-Edited iPSCs
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Yoshitaka Yamasaki, Ritsuko Seki, Koichi Osaki, Maki Ymaguchi, Hidetoshi Ozawa, Shinichi Mizuno, Takayuki Nakamura, Shuki Oya, Fumihiko Mouri, Koji Nagafuji, Kazutoshi Aoyama, and Satoshi Morishige
- Subjects
Cardiotoxicity ,Immunology ,Single-nucleotide polymorphism ,Cell Biology ,Hematology ,Computational biology ,Biology ,Biochemistry ,chemistry.chemical_compound ,Genome editing ,chemistry ,medicine ,CRISPR ,SNP ,Doxorubicin ,Induced pluripotent stem cell ,DNA ,medicine.drug - Abstract
[Introduction] Anthracycline-induced cardiotoxicity (ACT) has been a major problem in leukemia therapy, and reported to be associated with several candidates of single nucleotide polymorphisms (SNPs). C242T polymorphism (rs4673) in the cytochrome b-245 alpha chain (CYBA) gene, which encodes superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase light chain subunit, is focused on as one of ACT related SNPs. Several clinical studies indicated that rs4673 T allele increases the risk of ACT, however, it is unclear how rs4673 affects ACT. Here, we established a series of induced pluripotent stem cells (iPSCs) with a genotype of C/C, T/T or C/T of rs4673 in a uniform genetic background by using CRISPR/ Cas9, and evaluated the effect of each SNP genotype on ACT in vitro. [Methods and Results] To edit the SNP site using CRISPR/Cas9, three guide RNAs (gRNAs) were designed to induce double strand break (DSB) near the target site. Cas9 nuclease and gRNA expression vectors were transfected into HEK293T cells using jetPEI (Polyplus-transfection SAS), and the genome editing activity was assessed by T7 endonucleaseⅠ(T7E1) assay to select more efficient gRNA for cleavage near the target site. The indel frequencies of sgRNAs 1,2 and 3 were 29.4%, 25.6%, and 18.6%, respectively. Furthermore, oligo-DNA (100 nt) to edit single-base in the SNP site was prepared. To generate Cas9/gRNA ribonucleoprotein (RNP) complexes, 1 μg of Cas9 protein and 0.2 μg of gRNA molecules were mixed. RNP complexes and 50 pmol of oligo-DNA were electroporated into human iPSC 201B7cells (Riken BioResource Center) using Neon electroporation device (Invitrogen),single-base-edited iPSCs (C/C and T/T from C/T genotype in rs4673) were established by homology-directed repair (HDR). Successful HDR events were verified by Sanger sequencing. These established iPSCs were differentiated into cardiomyocytes using PSC Cardiomyocyte Differentiation Kit (Thermo Fisher Scientific) in vitro. To facilitate nascent mesoderm induction, TBX6 was expressed transiently by a tetracycline-inducible lentiviral vector. Differentiated cardiomyocytes were revealed to be contracting and be positive for NK2 transcription factor related locus 5 (NKX2-5) and troponin T2 (TNNT2) by immunofluorescence staining.In order to evaluate the ACT depending on the difference of single base in rs4673, doxorubicin (DOX)was administered to each edited iPSC-derived cardiomyocyte. NADP+/NADPH before and after administration of DOX (1μM) in C/C cardiomyocytes was 1±0.18 and 0.93±0.14, respectively. On the other hand, it was 1±0.07 and 1.29±0.03 in T/T cardiomyocytes (p [Conclusion] SNPs are a factor of genetic diversity among individuals, and have been revealed to be associated with various traits and diseases by Genome-Wide Association Study (GWAS). However, the diverse genetic backgrounds often hamper to analyze the influence of each SNP on the trait. In this study, we analyzed the effects of rs4673 on ACT in a uniform genetic background by using CRISPR/Cas9 edited iPSCs. Our study showed that T/T cardiomyocytes activated NADP+/NADPH cycling after administration of DOX. These results suggest that rs4673T allele may increase the risk of ACT. Genome editing mediated single-base-alteration will provide us a novel system for functional analysis of SNPs. Disclosures No relevant conflicts of interest to declare.
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- 2019
44. Myeloablative and reduced-intensity conditioning in HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide
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Shuichi Taniguchi, Shuichi Ota, Mine Harada, Koji Nagafuji, Koichi Akashi, Miho Nara, Toshihiro Miyamoto, Keitaro Matsuo, Takanori Teshima, Junichi Sugita, Tatsuo Furukawa, Yasuhiko Shibasaki, and Yusuke Kagaya
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Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Cyclophosphamide ,Adolescent ,Human leukocyte antigen ,Gastroenterology ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Clinical endpoint ,Medicine ,Humans ,Prospective Studies ,Young adult ,Prospective cohort study ,Aged ,Transplantation ,Peripheral Blood Stem Cell Transplantation ,Neutrophil Engraftment ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,030220 oncology & carcinogenesis ,Reduced Intensity Conditioning ,Female ,business ,Immunosuppressive Agents ,030215 immunology ,medicine.drug - Abstract
We conducted two parallel prospective, multicenter, phase II studies to evaluate the safety and efficacy of HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide (PTCy-haploPBSCT) following myeloablative conditioning (MAC, n = 50) and reduced-intensity conditioning (RIC, n = 77). Event-free survival (EFS) at 1-year as for primary endpoint was 64% and 43% in the MAC and RIC groups, respectively. Neutrophil engraftment was achieved in 98% and 94% in the MAC and RIC groups, respectively. The incidences of grades II–IV and III–IV acute graft-versus-host disease (GVHD) were 18% and 8% in the MAC group, and 14% and 5% in the RIC group, respectively. Those of all grade and moderate to severe chronic GVHD at 2-year were 36% and 20% in the MAC group, and 27% and 20% in the RIC group, respectively. Overall survival (OS), EFS, nonrelapse mortality, and relapse rate at 2-year were 68%, 54%, 10%, and 36% in the MAC group, and 44%, 35%, 20%, and 45% in the RIC group, respectively. Notably, 83% and 86% of patients who survived without relapse stopped immunosuppressant at 2-year in the MAC and RIC groups, respectively. Our results indicate that both MAC and RIC are valid options for PTCy-haploPBSCT for adults with hematological malignancies.
- Published
- 2018
45. Is clinicopathological distinction of mucosa-associated lymphoid tissue lymphoma from Waldenström macroglobulinemia essential in MYD88 L265P mutation-positive cases?
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Koichi Ohshima, Shinya Kimura, Kensuke Kojima, Ritsuko Seki, Keisuke Kidoguchi, and Koji Nagafuji
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medicine.medical_specialty ,Hematology ,business.industry ,Mucosa-Associated Lymphoid Tissue Lymphoma ,Waldenstrom macroglobulinemia ,medicine.disease ,Lymphoma ,MYD88 L265P ,medicine.anatomical_structure ,Internal medicine ,Mutation (genetic algorithm) ,Cancer research ,Medicine ,Missense mutation ,business ,B cell - Published
- 2019
46. Effects of Prophylactic Foscarnet on Human Herpesvirus-6 Reactivation and Encephalitis in Cord Blood Transplant Recipients: A Prospective Multicenter Trial with an Historical Control Group
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Takahiro Fukuda, Koji Kato, Ilseung Choi, Kuniko Takano, Rika Sakai, Yukiyoshi Moriuchi, Nobuaki Nakano, Tadakazu Kondo, Masao Ogata, Yumi Jo, Tetsuya Eto, Yasuhiko Shibasaki, Kumi Oshima, Shinichi Kako, Koji Nagafuji, Nobuhiko Uoshima, Takehiko Mori, Toshimitsu Ueki, and Satoshi Yamasaki
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Foscarnet ,Adult ,medicine.medical_specialty ,Adolescent ,viruses ,Herpesvirus 6, Human ,Premedication ,Graft vs Host Disease ,Antiviral Agents ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Risk Factors ,Multicenter trial ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Encephalitis, Viral ,Prospective Studies ,Risk factor ,Prospective cohort study ,Aged ,Transplantation ,biology ,business.industry ,virus diseases ,Historically Controlled Study ,Hematology ,biochemical phenomena, metabolism, and nutrition ,Middle Aged ,Myeloablative Agonists ,medicine.disease ,biology.organism_classification ,Fetal Blood ,Treatment Outcome ,030220 oncology & carcinogenesis ,Cord blood ,DNA, Viral ,Human herpesvirus 6 ,Female ,Virus Activation ,business ,Encephalitis ,030215 immunology ,medicine.drug - Abstract
Cord blood transplantation (CBT) is a distinct risk factor for human herpesvirus-6 (HHV-6) reactivation and HHV-6 encephalitis. In a prospective multicenter trial we investigated the effects of prophylactic foscarnet (90 mg/kg i.v. infusion from days 7 to 27 after CBT) on the occurrence of HHV-6 reactivation, HHV-6 encephalitis, and acute graft-versus-host disease (aGVHD) in CBT recipients. Between 2014 and 2016, 57 patients were included in a foscarnet-prophylaxis group. Outcomes were compared with an historical control group who received CBT between 2010 and 2014 (standard-treatment group, n = 63). The cumulative incidence of high-level HHV-6 reactivation, defined as plasma HHV-6 DNA ≥ 104 copies/mL, at 60 days after CBT was significantly lower in the foscarnet-prophylaxis group than in the standard-treatment group (18.3% versus 57.3%, P
- Published
- 2017
47. Incidence and risk factors of hepatitis B virus reactivation in patients with multiple myeloma in an era with novel agents: a nationwide retrospective study in Japan
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Yutaka Tsukune, Tomonori Aoyama, Atsushi Isoda, Takaaki Miyake, Kazutaka Sunami, Makoto Sasaki, Yukiyoshi Moriuchi, Masaki Iino, Taro Kurihara, Kei Nakajima, Tomomi Takei, Aiko Igarashi, Takeshi Odajima, Koji Nagafuji, Hiroki Sugimori, Takayuki Shimizu, Norio Komatsu, Aya Nakaya, Koji Miyazaki, and Tsuyoshi Muta
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0301 basic medicine ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Hepatitis B virus ,Antineoplastic Agents ,medicine.disease_cause ,Transplantation, Autologous ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Japan ,Risk Factors ,Internal medicine ,Correspondence ,medicine ,Humans ,In patient ,Multiple myeloma ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Incidence (epidemiology) ,Incidence ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Hematology ,Middle Aged ,medicine.disease ,Hepatitis B ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Virology ,Transplantation ,030104 developmental biology ,Novel agents ,030220 oncology & carcinogenesis ,Female ,Virus Activation ,business ,Multiple Myeloma - Published
- 2017
48. Effects of conditioning intensity in allogeneic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia
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Koji Kato, Ken Takase, Koji Nagafuji, Goichi Yoshimoto, Shuichiro Takashima, Yuju Ohno, Shuro Yoshida, Tetsuya Eto, Koichi Akashi, Toshihiro Miyamoto, Tomohiko Kamimura, Takanori Teshima, Yoshikiyo Ito, and Hideho Henzan
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Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,medicine.medical_treatment ,Dasatinib ,Graft vs Host Disease ,Philadelphia chromosome ,Gastroenterology ,Young Adult ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Philadelphia Chromosome ,Protein Kinase Inhibitors ,Survival rate ,Aged ,Retrospective Studies ,Chemotherapy ,business.industry ,Remission Induction ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Allografts ,medicine.disease ,Combined Modality Therapy ,Minimal residual disease ,Surgery ,Transplantation ,Treatment Outcome ,Imatinib mesylate ,Imatinib Mesylate ,Female ,business ,medicine.drug - Abstract
We retrospectively analyzed the outcomes of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) who underwent first allogeneic stem cell transplantation (allo-SCT) at complete remission (CR) with myeloablative conditioning (MAC, n = 31) or reduced-intensity conditioning (RIC, n = 15) between 2001 and 2012. All the patients had received tyrosine kinase inhibitor (TKI)-based chemotherapy prior to allo-SCT. Overall survival (OS) rates (57 vs 63%, p = 0.53), leukemia-free survival rates (50 vs 65%, p = 0.29), and non-relapse mortality rates (39 vs 35%, p = 0.62) at 2 years were similar between the MAC and RIC groups. The minimal residual disease (MRD) status evaluated by sensitive polymerase chain reaction prior to allo-SCT did not influence the OS rate (77 vs 54%, p = 0.28) and leukemia-free survival rate (69 vs 51%, p = 0.48), irrespective of the conditioning intensity. Our data suggest that the RIC regimen may represent a sufficient intensity of therapeutic pre-transplant conditioning for patients with Ph+ALL who have maintained a hematological CR with TKI-combined chemotherapy.
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- 2015
49. Prospective randomization of post-remission therapy comparing autologous peripheral blood stem cell transplantation versus high-dose cytarabine consolidation for acute myelogenous leukemia in first remission
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Mine Harada, Hideho Henzan, Naoyuki Uchida, Toshihiro Miyamoto, Ryosuke Ogawa, Koji Nagafuji, Takanori Teshima, Kosei Matsue, Ken Takase, Takatoshi Aoki, Tomoaki Fujisaki, Koichi Akashi, Michihiro Hidaka, and Shuichi Taniguchi
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Antimetabolites, Antineoplastic ,Randomization ,medicine.medical_treatment ,03 medical and health sciences ,Myelogenous ,Young Adult ,0302 clinical medicine ,Autologous stem-cell transplantation ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Autografts ,Etoposide ,Aged ,Aged, 80 and over ,Mitoxantrone ,Chemotherapy ,Peripheral Blood Stem Cell Transplantation ,business.industry ,Remission Induction ,Cytarabine ,Hematology ,Middle Aged ,medicine.disease ,Consolidation Chemotherapy ,Leukemia ,Leukemia, Myeloid, Acute ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,business ,030215 immunology ,medicine.drug - Abstract
We prospectively compared outcomes of autologous stem cell transplantation (ASCT) versus high-dose cytarabine (HiDAC) consolidation as post-remission therapy for favorable- and intermediate-risk acute myelogenous leukemia (AML) in first complete remission (CR1). Two-hundred-forty patients under 65 years with AML-M1, M2, M4, or M5 subtypes were enrolled. After induction, 153 patients did not undergo randomization, while the remaining 87 who achieved CR1 were prospectively randomized to HiDAC (n = 45) or ASCT arm (n = 42). In the HiDAC arm, 43 patients completed three cycles of HiDAC, whereas in ASCT arm 22 patients completed two cycles of consolidation consisting of intermediate-dose cytarabine plus mitoxantrone or etoposide followed by ASCT. The three-year disease-free survival (DFS) rate was 41% in HiDAC and 55% in ASCT arm (p = 0.25). Three-year overall survival (OS) rates were 77 and 68% (p = 0.67). Incidence of relapse was 54 and 41% (p = 0.22). There was no significant difference in nonrelapse mortality between two arms (p = 0.88). Patients in the ASCT arm tended to have higher DFS rates and lower relapse rates than patients in HiDAC; however, there was no significant improvement in OS in patients with favorable- and intermediate-risk AML in CR1. Patients with AML are not benefited by the intensified chemotherapy represented by ASCT.
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- 2017
50. Prospective observational study on the first 51 cases of peripheral blood stem cell transplantation from unrelated donors in Japan
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Akinori Nishikawa, Tomonori Kato, Masaharu Nougawa, Kazuya Okada, Heiwa Kanamori, Tatsunori Goto, Masayuki Hino, Hirokazu Okumura, Masashi Sawa, Naomi Kawashima, Takashi Tanaka, Takahiro Fukuda, Junji Tanaka, Kazuteru Ohashi, Shigeru Chiba, Mitsune Tanimoto, Yasunori Ueda, Hiroatsu Ago, Yoshiko Atsuta, Koichi Miyamura, Shinichiro Okamoto, and Koji Nagafuji
- Subjects
Adult ,Male ,medicine.medical_specialty ,Time Factors ,Transplantation Conditioning ,Adolescent ,Graft vs Host Disease ,Disease ,Human leukocyte antigen ,Tacrolimus ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Japan ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Prospective Studies ,Aged ,Peripheral Blood Stem Cell Transplantation ,Hematology ,business.industry ,Incidence (epidemiology) ,Middle Aged ,Surgery ,Transplantation ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Hematologic Neoplasms ,Chronic Disease ,Feasibility Studies ,Observational study ,business ,Unrelated Donors ,Immunosuppressive Agents ,030215 immunology ,Follow-Up Studies - Abstract
The Japan Marrow Donor Program (JMDP) has facilitated unrelated peripheral blood stem cell transplantation (URPBSCT) since 2010. We conducted a prospective multicenter observational study to evaluate the feasibility of such transplantation. Between 2011 and 2014, 51 patients underwent URPBSCT from 8/8 allele-matched donors for hematological malignancies. The median age of the patients was 50 years; 21 had high-risk disease. Myeloablative conditioning regimens were used in 31 patients, and tacrolimus based graft-versus-host disease (GVHD) prophylaxis was used for all patients. The cumulative rate of engraftment was 96%. With a median follow-up period of 610 days for survivors, 100-day and 1-year overall survival rates were 86 and 59%, respectively. The cumulative incidence of non-relapse mortality and relapse at 1 year were 14 and 35%, respectively. The incidence of grade II to IV acute GVHD at 100 days and extensive type of chronic GVHD at 1 year were 25 and 32%, respectively. The probability of overall survival was comparable with that of bone marrow transplantation from HLA matched-unrelated donors in Japan, although the incidence of chronic GVHD was higher. Further follow-up with more patients is clearly warranted to establish the optimal use of URPBSCT together with the approaches of minimizing chronic GVHD.
- Published
- 2017
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