研究者業績

稲本 賢弘

イナモト ヨシヒロ  (yoshihiro inamoto)

基本情報

所属
藤田医科大学 医学部 造血細胞移植・細胞療法学 教授
学位
医学博士

J-GLOBAL ID
202401007871550018
researchmap会員ID
R000069858

論文

 46
  • Yachiyo Kuwatsuka, Hidemi Ito, Ken Tabuchi, Takaaki Konuma, Naoyuki Uchida, Yoshihiro Inamoto, Kazuki Inai, Tetsuya Nishida, Kazuhiro Ikegame, Tetsuya Eto, Yuta Katayama, Keisuke Kataoka, Masatsugu Tanaka, Satoshi Takahashi, Takahiro Fukuda, Tatsuo Ichinohe, Fumihiko Kimura, Junya Kanda, Yoshiko Atsuta, Keitaro Matsuo
    Bone marrow transplantation 59(9) 1295-1301 2024年9月  
    Prognosis for patients undergoing hematopoietic cell transplantation (HCT) has been improving. Short-term survival information, such as crude survival rates that consider deaths immediately after the transplantation, may not be sufficiently useful for assessing long-term survival. Using the data of the Japanese HCT registry, the net survival rate of patients who survived for a given period was determined according to age, disease, and type of transplant. We included a total of 41,716 patients who received their first allogeneic hematopoietic cell transplantation between 1991 and 2015. For each disease, age group, graft source subcategory, net survival was calculated using the Pohar-Perme method, and 5-year conditional net survival (CS) was calculated. Ten-year net survivals of total patient cohort were 41.5% and 47.4% for males and females, respectively. Except for myelodysplastic syndrome, multiple myeloma, and adult T-cell leukemia/lymphoma, 5-year CS for 5-year transplant survivors exceeded 90%. CS was especially high for aplastic anemia, of which was over 100% for children and younger adults receiving cord blood, suggesting that these patients have similar longevity to an equivalent group from the general population. These findings provide useful information for long-term survival, and can serve as benchmark for comparisons among registries, including other cancers.
  • Junya Kanda, Takaya Mitsuyoshi, Masatoshi Sakurai, Hisakazu Nishimori, Makoto Murata, Naoyuki Uchida, Noriko Doki, Yoshihiro Inamoto, Tetsuya Nishida, Masatsugu Tanaka, Yuta Katayama, Tetsuya Eto, Ken-Ichi Matsuoka, Satoshi Yoshihara, Masashi Sawa, Toshiro Kawakita, Gyungjin Jun, Mio Kurata, Tatsuo Ichinohe, Takahiro Fukuda, Takanori Teshima, Yoshiko Atsuta, Seitaro Terakura
    Transplantation and cellular therapy 30(9) 907.e1-907.e16 2024年9月  
    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapeutic option for patients with hematologic malignancies. However, the development of graft-versus-host disease (GVHD) after allo-HSCT remains a challenge. Although systemic steroid therapy is the established first-line therapy for acute GVHD (aGVHD) and chronic GVHD (cGVHD), many patients are unresponsive or resistant to corticosteroid therapy, and the response is insufficient. This study aimed to evaluate the clinical characteristics of patients who developed aGVHD and cGVHD after allo-HSCT. This noninterventional, retrospective study used large national registry data from the Transplant Registry Unified Management Program. The study included 29,690 patients with a hematologic disease who underwent their first allo-HSCT between January 2010 and December 2019. The primary study endpoints were the cumulative incidence of aGVHD and cGVHD. The secondary endpoints were overall survival (OS) and nonrelapse mortality (NRM) of patients with aGVHD and cGVHD and OS and NRM of patients who received second-line therapy for aGVHD. Of 29,690 patients who underwent allo-HSCT, the graft source was related bone marrow (RBM) in 2807, related peripheral blood (RPB) in 6167, unrelated bone marrow in 10,556, unrelated peripheral blood (UPB) in 774, and unrelated cord blood in 9339. The cumulative incidence of grade II-IV aGVHD at 100 days was high after the related and unrelated mismatched transplantation. The response rates for first- and second-line therapy for aGVHD were low in the RBM/RPB-mismatched (59.6%/61.6%) and UPB-mismatched subgroups (45.5%), respectively. The 3-year NRM in patients with aGVHD was high in the RPB and UPB mismatched subgroups (37.9% and 31.2%, respectively). Developing a novel treatment for steroid-refractory aGVHD is necessary to improve transplantation outcomes, particularly for patients undergoing HLA-mismatched allo-HSCT.
  • Justine Kahn, Ruta Brazauskas, Stephanie Bo-Subait, David Buchbinder, Betty K Hamilton, Hélène Schoemans, Allistair A Abraham, Vaibhav Agrawal, Jeffery J Auletta, Sherif M Badawy, Amer Beitinjaneh, Neel S Bhatt, Larisa Broglie, Miguel Angel Diaz Perez, Nosha Farhadfar, Cesar O Freytes, Robert Peter Gale, Siddhartha Ganguly, Robert J Hayashi, Peiman Hematti, Gerhard C Hildebrandt, Yoshihiro Inamoto, Rammurti T Kamble, Jane Koo, Hillard M Lazarus, Samantha J Mayo, Parinda A Mehta, Kasiani C Myers, Taiga Nishihori, Tim Prestidge, Seth J Rotz, Bipin N Savani, Raquel M Schears, Akshay Sharma, Elizabeth Stenger, Celalettin Ustun, Kirsten M Williams, Lynda M Vrooman, Prakash Satwani, Rachel Phelan
    The Lancet. Child & adolescent health 2024年8月29日  
    BACKGROUND: Continued advances in haematopoietic cell transplantation (HCT) for children with non-malignant diseases (NMDs) have led to a growing population of survivors in whom late occurring toxic effects remain a challenge. We investigated the incidence of and risk factors for post-transplant toxicities in a contemporary cohort of children and adolescents undergoing HCT for NMDs. METHODS: In this retrospective cohort study, we extracted data from the Center for International Blood and Marrow Transplantation Research (CIBMTR) database to analyse timing and incidence of effects and risk factors associated with late effects of HCT for treatment of NMDs at age 21 years or younger. Late effects of interest were avascular necrosis, cataracts, congestive heart failure, myocardial infarction, diabetes, gonadal dysfunction, growth hormone deficiency, hypothyroidism, renal failure requiring dialysis, and neurological events (stroke and seizure). Cumulative incidence of each late effect was calculated at 5 years and 7 years after HCT. Risk factors were evaluated in Cox proportional hazards regression analyses. Main exposures were primary NMD, age, sex, ethnicity and race, insurance, donor and graft type, myoablative conditioning, total-body irradiation exposure, graft-versus-host disease (GVHD), and transplant year. Primary outcomes were rates, cumulative incidence probability (95% CI), and risk-factors for organ-specific late effects. FINDINGS: Between Jan 1, 2000, and Dec 31, 2017, 7785 patients aged 21 years or younger underwent HCT. 1995 patients were ineligible or did not consent to be included. 5790 patients from 171 centres were included in the analysis. 3505 (60·5%) of 5790 patients were male and 2285 (39·5%) were female. 2106 (36·4%) patients were White, 771 (13·3%) were Hispanic, and 773 (12·7%) were Black. 1790 (30·9%) patients were non-USA residents. Median age at HCT was 5·5 years (range 0·0-21·0). 1127 (19%) of 5790 patients had one late effect, and 381 (7%) had at least two. At 7 years post-HCT, the cumulative incidence probability was 1·9 (95% CI 1·5-2·3) for cataracts, 4·9 (4·3-5·6) for diabetes, 2·6 (2·1-3·1) for gonadal dysfunction, 3·2 (2·7-3·8) for hypothyroidism, 5·0 (4·4-5·7) for growth disturbance, 8·1 (7·4-8·9) for renal failure, 1·6 (1·3-2·0) for avascular necrosis, 0·6 (0·4-0·8) for congestive heart failure, 0·2 (0·1-0·3) for myocardial infarction, and 9·4 (8·6-10·2) for neurological effects. Age 10 years or older at HCT, unrelated donor source, total-body irradiation, and GVHD were identified as risk factors for long-term effects. INTERPRETATION: The findings highlight the need for, and access to, multidisciplinary and lifelong follow-up for children undergoing HCT for NMDs. As more children undergo treatment with cellular therapies for non-malignant conditions, further analyses of post-transplant data could increasingly guide treatment decisions and subsequent long-term surveillance. FUNDING: National Cancer Institute, National Heart, Lung and Blood Institute, National Institute of Allergy and Infectious Diseases, Health Resources and Services Administration, and Office of Naval Research.
  • Tania Jain, Noel Estrada-Merly, M Queralt Salas, Soyoung Kim, Jakob DeVos, Min Chen, Xi Fang, Rajat Kumar, Marcio Andrade-Campos, Hany Elmariah, Vaibhav Agrawal, Mahmoud Aljurf, Ulrike Bacher, Talha Badar, Sherif M Badawy, Karen Ballen, Amer Beitinjaneh, Vijaya Raj Bhatt, Christopher Bredeson, Zachariah DeFilipp, Bhagirathbhai Dholaria, Nosha Farhadfar, Shatha Farhan, Arpita P Gandhi, Siddhartha Ganguly, Usama Gergis, Michael R Grunwald, Nada Hamad, Betty K Hamilton, Yoshihiro Inamoto, Madiha Iqbal, Omer Jamy, Mark Juckett, Mohamed A Kharfan-Dabaja, Maxwell M Krem, Deepesh P Lad, Jane Liesveld, Monzr M Al Malki, Adriana K Malone, Hemant S Murthy, Guillermo Ortí, Sagar S Patel, Attaphol Pawarode, Miguel-Angel Perales, Marjolein van der Poel, Olle Ringden, David A Rizzieri, Alicia Rovó, Bipin N Savani, Mary Lynn Savoie, Sachiko Seo, Melhem Solh, Celalettin Ustun, Leo F Verdonck, John R Wingard, Baldeep Wirk, Nelli Bejanyan, Richard J Jones, Taiga Nishihori, Betul Oran, Ryotaro Nakamura, Bart Scott, Wael Saber, Vikas Gupta
    Blood advances 8(16) 4281-4293 2024年8月27日  
    We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)-HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.
  • Masaharu Tamaki, Yu Akahoshi, Yoshihiro Inamoto, Kaoru Morita, Naoyuki Uchida, Noriko Doki, Masatsugu Tanaka, Tetsuya Nishida, Hiroyuki Ohigashi, Hirohisa Nakamae, Makoto Onizuka, Yuta Katayama, Ken-Ichi Matsuoka, Masashi Sawa, Fumihiko Ishimaru, Yoshinobu Kanda, Takahiro Fukuda, Yoshiko Atsuta, Seitaro Terakura, Junya Kanda
    Blood advances 8(16) 4250-4261 2024年8月27日  
    Chronic graft-versus-host disease (GVHD) is 1 of the major complications after allogeneic hematopoietic cell transplantation (allo-HCT). Although various risk factors for chronic GVHD have been reported, limited data are available regarding the impact of acute GVHD on chronic GVHD. We examined the association between acute and chronic GVHD using a Japanese registry data set. The landmark point was set at day 100 after allo-HCT, and patients who died or relapsed before the landmark point were excluded. In total, 14 618 and 6135 patients who underwent allo-HCT with bone marrow or peripheral blood (BM/PB) and with umbilical cord blood (UCB), respectively, were analyzed. In the BM/PB cohort, the risk for chronic GVHD that requires systemic steroids increased with each increase in acute GVHD grade from 0 to 2 (grade 0 vs 1 [hazard ratio (HR), 1.32; 95% confidence interval (CI), 1.19-1.46; P < .001]; grade 1 vs 2 [HR, 1.41; 95% CI, 1.28-1.56; P < .001]), but the risk was similar between acute GVHD grade 2 and grade 3 to 4 (HR, 1.02; 95% CI, 0.91-1.15; P = 1.0). These findings were confirmed in the UCB cohort. We further observed that the risk for severe chronic GVHD increased with each increment in the grade of acute GVHD, even between acute GVHD grade 2 and grade 3 to (grade 2 vs 3-4: HR, 1.70; 95% CI, 1.12-2.58; P = .025). In conclusion, the preceding profiles of acute GVHD should help to stratify the risk for chronic GVHD and its severity, which might be useful for the development of risk-adopted preemptive strategies for chronic GVHD.
  • Hamza Hashmi, Ambuj Kumar, Mohamed A Kharfan-Dabaja, Pashna N Munshi, Yoshihiro Inamoto, Zachariah DeFilipp, Bhagirathbhai Dholaria, Tania Jain, Miguel-Angel Perales, Paul A Carpenter, Mehdi Hamadani, Binod Dhakal, Saad Z Usmani
    Transplantation and cellular therapy 30(8) 750-759 2024年8月  
    Chimeric antigen receptor T cell therapy (CAR-T) has revolutionized the management of relapsed and/or refractory multiple myeloma (RRMM). However, CAR-T treatment failure is not uncommon and remains a major therapeutic challenge. There is substantial variability across transplantation and cellular therapy programs in assessing and managing post-CAR-T failures in patients with RRMM. The American Society for Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines conducted an online cross-sectional survey between September 2023 and December 2023 to determine myeloma, transplantation, and cellular therapy physicians' practice patterns for the surveillance, diagnosis, and management of CAR-T failure. The intent of this survey was to understand clinical practice patterns and identify areas for further investigation. Email surveys were sent to 1311 ASTCT physician members, of whom 80 (6.1%) completed the survey. The respondents were 58% white and 66% male, and 51% had >10 years of clinical experience. Most (89%) respondents were affiliated with a university/teaching center, and 56% had a myeloma-focused transplantation and/or cellular therapy practice. Post-CAR-T surveillance laboratory studies were commonly done every 4 weeks, and surveillance bone marrow biopsies and/or imaging surveillance were most commonly done at 3 months. Sixty-four percent of the respondents would often or always consider biopsy or imaging to confirm relapse. The most popular post-CAR-T failure rescue regimen was GPRC5D-directed immunotherapy (30%) for relapses occurring ≤3 months and BCMA-directed bispecific therapies (32.5%) for relapse at >3 months. Forty-one percent of the respondents endorsed post-CAR-T prolonged cytopenia as being "often" or "always" a barrier to next-line therapy; 53% had offered stem cell boost as a mitigation approach. Substantial across-center variation in practice patterns raises the need for collaborative studies and expert clinical recommendations to describe best practices for post-CAR-T disease surveillance, optimal workup for treatment failure, and choice of rescue therapies.
  • Koji Jimbo, Toyotaka Kawamata, Yoshihiro Inamoto, Ayumu Ito, Kazuaki Yokoyama, Aki Sato, Takahiro Fukuda, Kaoru Uchimaru, Yasuhito Nannya
    Blood advances 8(14) 3760-3770 2024年7月23日  
    Adult T-cell leukemia/lymphoma (ATL) is a poor prognosis hematological malignancy originating from human T-cell leukemia virus 1 (HTLV-1)-infected CD4+ T cells. Flow cytometric plots of CADM1 and CD7 in CD4+ T cells are useful for separating HTLV-1-uninfected T cells and ATL cells. They are indicators of clonal evolution of HTLV-1-infected cells and disease progression of asymptomatic carriers or indolent ATL. However, the impacts of the plots on the clinical course or prognosis of ATL, especially in aggressive ATL, remain unclear. We focused on the N fraction (CD4+ CADM1+ CD7-) reflecting ATL cells and analyzed the flow cytometric profiles and clinical course of 497 samples from 92 HTLV-1-infected patients who were mainly aggressive ATL. The parameters based on N fractions showed significant correlations with known indicators of ATL disease status (soluble interleukin-2 receptor, lactate dehydrogenase, abnormal lymphocytes, etc.) and sensitively reflected the treatment response of aggressive ATL. The parameters based on N fractions significantly stratified the prognosis of aggressive ATL at 4 different time points: before treatment, after 1 course of chemotherapy, at the best response after chemotherapy, and before allogeneic hematopoietic cell transplantation. Even after mogamulizumab administration, which shows potent effects for peripheral blood lesions, the N fraction was still a useful indicator for prognostic estimation. In summary, this report shows that CADM1 vs CD7 plots in CD4+ T cells are useful indicators of the clinical course and prognosis of aggressive ATL. Therefore, this CADM1 and CD7 profile is suggested to be a useful prognostic indicator consistently from HTLV-1 carriers to aggressive ATL.
  • Takanori Teshima, Yasushi Onishi, Koji Kato, Shuichi Taniguchi, Koichi Miyamura, Kentaro Fukushima, Jun Kato, Takayuki Ishikawa, Noriko Doki, Hirohisa Nakamae, Yoshinobu Maeda, Yoshihiro Inamoto, Masaya Okada, Akio Maki, Fumika Shimada, Takeshi Tajima, Monika Wroclawska, Robert Zeiser, Makoto Onizuka
    International journal of hematology 120(1) 106-116 2024年7月  
    Acute graft-versus-host disease (aGvHD) is a major complication after allogeneic hematopoietic stem cell transplantation in Japan and other countries. Nearly one-third of patients do not respond to standard systemic steroid therapy and no standard second-line treatment has been established in Japan. We report efficacy and safety findings of ruxolitinib versus best available therapy (BAT) from a subgroup analysis of the international, phase 3 REACH2 study in Japanese patients with steroid-refractory aGvHD. The primary endpoint was overall response rate (ORR) at day 28. Overall, 9 patients received ruxolitinib and 21 received BAT. The ORR at day 28 (88.9% vs 52.4%) and durable ORR at day 56 (66.7% vs 28.6%) were higher with ruxolitinib versus BAT. The estimated cumulative incidence of loss of response at 6 months was 12.5% with ruxolitinib and 18.2% with BAT. The median failure-free survival was longer with ruxolitinib versus BAT (2.73 vs 1.25 months). The most common adverse events up to day 28 in the ruxolitinib and BAT groups were anemia (55.6% vs 19.0%) and thrombocytopenia (44.4% vs 4.8%, respectively). Ruxolitinib showed better efficacy outcomes and a consistent safety profile compared with BAT in the Japanese subgroup, and the findings were consistent with overall study results.
  • Yoshihiro Inamoto, Koji Kato, Toshiro Kawakita, Yasushi Onishi, Ken-Ichi Matsuoka, Soichi Shiratori, Kazuhiro Ikegame, Nobuhiro Hiramoto, Masako Toyosaki, Yuta Katayama, Shun Murayama, Yuji Sasagawa, Yoshinobu Maeda, Kiyohiko Hatake, Takanori Teshima
    American journal of hematology 2024年6月27日  
    Belumosudil mesylate is a selective Rho-associated coiled-coil kinase 2 inhibitor with immunomodulatory and antifibrosis effects. This multicenter, open-label, single-arm study evaluated belumosudil 200 mg once daily as second or subsequent line of therapy (LOT) in 21 Japanese patients ≥12 years of age with steroid-dependent/steroid-resistant chronic graft-versus-host disease (cGVHD). The primary endpoint of best overall response rate (ORR) at 24 weeks after enrollment of the last patient was 85.7% (95% confidence interval [CI]: 63.7-97.0), and the lower limit of the 95% CI exceeded the pre-defined threshold of 25%. The Kaplan-Meier estimate of duration of response rate at 24 weeks was 75% (95% CI: 46-90); 13/18 responders (72.2%) had a sustained response for ≥20 weeks. The median time to response was 4.1 weeks (range 3.90-8.10); ORR was 47.6% at 4 weeks and 75.0% at 24 weeks; best ORR was 80% for joints/fascia, 66.7% for the mouth, and 54.5% for skin. Overall, 57.1% of patients had clinically meaningful symptom improvement at least once; the median duration of symptom improvement was 22.2 weeks (range 4.0-51.3). Corticosteroid dose reductions were recorded for 57.1% of patients. Median failure-free and overall survival were not reached. Treatment-emergent adverse events occurred in 85.7% of patients (most commonly diarrhea, 19.0%), of which 38.1% were drug-related. There were no drug-related discontinuations or deaths. In summary, belumosudil 200 mg once daily as second or subsequent LOT in Japanese patients with steroid-dependent/steroid-resistant cGVHD was effective, with no new safety concerns.
  • Catherine J Lee, Tao Wang, Karen Chen, Mukta Arora, Ruta Brazauskas, Stephen R Spellman, Carrie Kitko, Margaret L MacMillan, Joseph A Pidala, Sherif M Badawy, Neel Bhatt, Vijaya R Bhatt, Zachariah DeFilipp, Miguel A Diaz, Nosha Farhadfar, Shahinaz Gadalla, Shahrukh Hashmi, Peiman Hematti, Nasheed M Hossain, Yoshihiro Inamoto, Lazaros J Lekakis, Akshay Sharma, Scott Solomon, Stephanie J Lee, Daniel R Couriel
    Transplantation and cellular therapy 30(1) 97.e1-97.e14 2024年1月  
    The study aimed to determine the association of chronic graft-versus-host disease (cGVHD) diagnosis and severity with the development of subsequent neoplasms (SN) and nonmalignant late effects (NM-LE) in 2-year disease-free adult survivors following hematopoietic cell transplantation (HCT) for a hematologic malignancy. To do so, we conducted a retrospective analysis of 3884 survivors of HCT for hematologic malignancy in the Center of International Blood and Marrow Transplant Research database. We conducted a landmark analysis at the 2-year post-transplantation date, comparing first SN and NM-LE in survivors with and without cGVHD. The cumulative incidence (CuI) of SN and NM-LE were estimated through 10 years post-HCT in both groups, with death or disease relapse as a competing risk. Cox proportional hazards models were used to evaluate the associations of cGVHD and its related characteristics with the development of SN and NM-LE. The estimated 10-year CuI of SN in patients with GVHD (n = 2669) and patients without cGVHD (n = 1215) was 15% (95% confidence interval [CI], 14% to 17%) versus 9% (7.2% to 11%) (P < .001). cGVHD by 2 years post-HCT was independently associated with SN (hazard ratio [HR], 1.94; 95% CI, 1.53 to 2.46; P < .0001) with a standardized incidence ratio of 3.2 (95% CI, 2.9 to 3.5; P < .0001). Increasing severity of cGVHD was associated with an increased risk of SN. The estimated 10-year CuI of first NM-LE in patients with and without cGVHD was 28 (95% CI, 26% to 30%) versus 13% (95% CI, 11% to 15%) (P < .001). cGVHD by 2 years post-HCT was independently associated with NM-LE (HR, 2.23; 95% CI, 1.81 to 2.76; P < .0001). Multivariate analysis of cGVHD-related factors showed that increasing severity of cGVHD, extensive grade, having both mucocutaneous and visceral involvement, and receiving cGVHD treatment for >12 months were associated with the greatest magnitude of risk for NM-LE. cGVHD was closely associated with both SN and NM-LE in adult survivors of HCT for hematologic malignancy. Patients identified as having more severe involvement and both mucocutaneous and visceral organ involvement may warrant enhanced monitoring and screening for SNs and NM-LEs. However, caution is warranted when interpreting these results, as patients with cGVHD may have more vigilant post-transplantation health care and surveillance for late effects.
  • Marie Ohbiki, Yuri Ito, Yoshihiro Inamoto, Koichi Miyamura, Naoyuki Uchida, Takahiro Fukuda, Hiroki Fujiwara, Tetsuya Nishida, Masayasu Hayashi, Masatsugu Tanaka, Toshiro Kawakita, Kazuhiro Ikegame, Yuta Katayama, Takahide Ara, Tatsuo Ichinohe, Hitoshi Kiyoi, Keitaro Matsuo, Yoshiko Atsuta
    Transplantation and cellular therapy 29(12) 768.e1-768.e10 2023年12月  
    Allogeneic (allo-) hematopoietic cell transplantation (HCT) has evolved as a curative therapy for hematologic malignancies and diseases, with practice changes over the past 2 decades. This study aimed to evaluate the change in 5-year net survival (NS) of allo-HCT recipients in a population-based cohort over the past 2 decades, which allows the estimation of a more HCT-specific long-term survival rate by considering background mortality changes. This study included 42,064 patients with hematologic malignancies who underwent their first allo-HCT in Japan between 2000 and 2018 and were reported to the Transplant Registry Unified Management Program. We compared the 5-year NS after allo-HCT in 4 consecutive HCT periods (2000 to 2004, 2005 to 2008, 2009 to 2012, and 2013 to 2018). The 5-year NS of the latest period was estimated using the period analysis method. Adjusted excess hazard ratios (EHRs) for 5-year NS over the HCT period were analyzed using an EHR model. In addition to the analysis of all hematologic malignancies, adjusted 5-year NS for each major hematologic malignancy, including acute myelogenous leukemia, acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, adult T cell leukemia/lymphoma, chronic myeloid leukemia (CML), and malignant lymphoma, was analyzed. The probability of adjusted 5-year NS after HCT improved significantly over time: 35% in 2000 to 2004, 39% in 2005 to 2008, 45% in 2009 to 2012, and 49% in 2013 to 2018. The adjusted EHRs were .90 (95% confidence interval [CI], .86 to .93) in the 2005 to 2008 period, .77 (95% CI, .74 to .80) in the 2009 to 2012 period, and .65 (95% CI, .63 to .68) in the 2013 to 2018 period, with the 2000 to 2004 period as the reference. The 5-year NS improved among all hematologic malignancies, with a significant improvement in CML and ALL. The changes in 5-year NS from the 2000 to 2004 period to the 2013 to 2018 period ranged from 46% to 66% in CML and from 41% to 59% in ALL. In addition to the large improvement of 1-year NS, smaller but continued improvement in NS between 1 and 5 years after transplantation was observed. NS at 5 years conditional on being alive at 1 year increased from 64% in 2000 to 2004 to 73% in 2013 to 2018. Even after subtracting the background mortality in the general population, we found a significant improvement in long-term allo-HCT-specific survival rates for patients with hematologic malignancies over the past 2 decades in Japan.
  • Abraham S Kanate, Navneet Majhail, Zachariah DeFilipp, Binod Dhakal, Bhagirathbhai Dholaria, Betty Hamilton, Alex F Herrera, Yoshihiro Inamoto, Tania Jain, Miguel-Angel Perales, Paul A Carpenter, Mehdi Hamadani
    Transplantation and cellular therapy 29(10) 594-597 2023年10月  
    The American Society for Transplantation and Cellular Therapy (ASTCT) published its guidelines on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) and immune effector cell therapy (IECT) in 2020. Since then, we have witnessed rapid advancements in the field of IECT, resulting in several new chimeric antigen receptor T cell (CAR-T) products and disease indications being approved by the US Food and Drug Administration (FDA). To keep abreast of these practice changes, the ASTCT Committee on Practice Guidelines commissioned a focused update covering CAR-T therapy indications. Here we present updated ASTCT recommendations on indications for CAR-T therapy. Only FDA-approved indications for CAR-T were recommended and categorized as "standard of care," where the indication is well defined and supported by evidence. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.
  • Takashi Tanaka, Yoshihiro Inamoto, Ayumu Ito, Mizuki Watanabe, Wataru Takeda, Jun Aoki, Sung-Won Kim, Takahiro Fukuda
    Hematological oncology 41(3) 389-395 2023年8月  
    Patients with recurrent adult T-cell leukemia/lymphoma (ATL) after allogeneic hematopoietic cell transplantation (allo-HCT) have a dismal prognosis. We retrospectively evaluated the safety and efficacy of lenalidomide (LEN) in 11 consecutive patients with recurrent ATL after allo-HCT. The median time from allo-HCT to ATL recurrence was 111 days (range, 20-1476), and that from allo-HCT to the initiation of LEN was 162 days (range, 43-1560). The median initial daily dose of LEN was 10 mg (range, 5-25), and the median duration of LEN treatment was 37 days (range, 3-1078). Three patients (27%) achieved complete response and two (18%) achieved partial response (PR). The rates of complete or PR according to the involved site were 57% for skin and 50% for nodal or extranodal lesions. With a median follow-up of 1033 days (range, 601-1465) among survivors, the 1-year probability of overall survival (OS) after ATL recurrence was 55%. Grade ≥3 toxicities included cytopenia (n = 4), superficial vein thrombosis (n = 1), and deep vein thrombosis (n = 1). Graft-versus-host disease (GVHD) newly developed in five patients (45%) and worsened in four patients (36%). The median duration from the initiation of LEN to GVHD onset or worsening was 5 days (range, 1-9). GVHD was manageable in all patients. Seven patients received mogamulizumab (MOG) for recurrent ATL before LEN treatment. The overall response rates to LEN were 57% in patients who had previously received MOG and 25% in those who had not. The 1-year probabilities of OS after recurrent ATL were 71% in patients who had previously received MOG and 25% in those who had not. Although cytopenia and GVHD are common among patients with recurrent ATL after allo-HCT, LEN may improve survival. Administering MOG before LEN may augment treatment efficacy in the allo-HCT population.
  • Kayoko Tao, Yoshihiro Inamoto, Haruhi Furukawa, Rika Hosoba, Wataru Takeda, Akiko Maeshima, Jun Aoki, Ayumu Ito, Takashi Tanaka, Sung-Won Kim, Shinichi Makita, Suguru Fukuhara, Yasunori Kogure, Keisuke Kataoka, Koji Izutsu, Takahiro Fukuda
    International journal of hematology 118(2) 292-298 2023年8月  
    Patients with recurrent peripheral T-cell lymphoma (PTCL) after allogeneic hematopoietic cell transplantation (HCT) have dismal outcomes. Nodal PTCL with the T follicular helper phenotype (PTCL-TFH) is uniquely sensitive to histone deacetylase inhibitors compared to non-TFH phenotypes. We report the case of a 19-year-old man who experienced recurrence of PTCL-TFH shortly after allogeneic HCT and subsequently achieved durable remission with romidepsin. Before HCT, the patient had refractory disease after CHOP and ESHAP chemotherapies but achieved a partial response after two cycles of romidepsin as salvage treatment. HLA-haploidentical peripheral blood stem cell transplantation was performed using conditioning with fludarabine 180 mg/sqm, melphalan 80 mg/sqm, and total body irradiation 2 Gy, and graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide. One month after HCT, disease progression was observed in the lung. Romidepsin was readministered every 2 weeks at a reduced dose of 12 mg/sqm. After two cycles of romidepsin, the patient achieved a complete metabolic response without severe GVHD or other non-hematological toxicities. Romidepsin was discontinued after seven treatment cycles due to prolonged lymphopenia. The patient remains in complete remission 30 months after the last dose of romidepsin. Our experience suggests that romidepsin could be safely administered soon after allogeneic transplantation.
  • Yoshihiro Inamoto
    JACC. CardioOncology 5(4) 518-519 2023年8月  
  • Guru Subramanian Guru Murthy, Soyoung Kim, Noel Estrada-Merly, Muhammad Bilal Abid, Mahmoud Aljurf, Amer Assal, Talha Badar, Sherif M Badawy, Karen Ballen, Amer Beitinjaneh, Jan Cerny, Saurabh Chhabra, Zachariah DeFilipp, Bhagirathbhai Dholaria, Miguel Angel Diaz Perez, Shatha Farhan, Cesar O Freytes, Robert Peter Gale, Siddhartha Ganguly, Vikas Gupta, Michael R Grunwald, Nada Hamad, Gerhard C Hildebrandt, Yoshihiro Inamoto, Tania Jain, Omer Jamy, Mark Juckett, Matt Kalaycio, Maxwell M Krem, Hillard M Lazarus, Mark Litzow, Reinhold Munker, Hemant S Murthy, Sunita Nathan, Taiga Nishihori, Guillermo Ortí, Sagar S Patel, Marjolein Van der Poel, David A Rizzieri, Bipin N Savani, Sachiko Seo, Melhem Solh, Leo F Verdonck, Baldeep Wirk, Jean A Yared, Ryotaro Nakamura, Betul Oran, Bart Scott, Wael Saber
    Haematologica 108(7) 1900-1908 2023年7月1日  
    Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P<0.001; grade 3-4 HR=2.31; 95% CI: 1.52-3.52; P<0.001) and inferior GvHD-free relapse-free survival (GRFS) (HR=1.94; 95% CI: 1.49-2.53; P<0.001) as compared to fludarabine/busulfan. Hence, our study suggests that fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GvHD) and MAC (lower acute GvHD and better GRFS) in myelofibrosis.
  • Takanori Fukuta, Takashi Tanaka, Taiki Hashimoto, Kenji Isahaya, Yuko Kubo, Yoshihisa Yamano, Kaishi Satomi, Nobuyoshi Hiraoka, Nami Shirakawa, Ayumu Arakawa, Chitose Ogawa, Nao Nishimura, Jun Aoki, Ayumu Ito, Yoshihiro Inamoto, Sung-Won Kim, Takahiro Fukuda
    International journal of hematology 117(6) 933-940 2023年6月  
    Nelarabine is an effective treatment for T-cell acute lymphoblastic leukemia/lymphoma. Myelopathy is a rare but serious adverse event associated with this drug. Three patients who received nelarabine at the National Cancer Center Hospital from December 2014 to March 2021 developed myelopathy 20 days before, 12 days after, and 29 days after allogeneic hematopoietic cell transplantation (allo-HCT), respectively. Magnetic resonance imaging showed that two of the patients had lesions in the dorsal column or medulla oblongata, and one had no abnormalities in the head or spine. Despite treatment with intravenous immunoglobulin and methylprednisolone, all patients became unable to walk. One patient died on day 101 after allo-HCT due to progressive neurotoxicity. The other two patients showed spontaneous improvement in neurological symptoms, but one died of mucormycosis on day 476. Autopsy revealed spongiosis in the posterior funiculus in both patients who died, and also in the medulla oblongata in one patient. In the surviving patient, positron emission tomography on day 84 showed abnormal accumulation, suggesting continued inflammation. These cases demonstrated pathophysiological features of nelarabine-induced myelopathy and indicate that allo-HCT may worsen the condition. It is necessary to elucidate the underlying mechanism and establish diagnostic methods and therapies.
  • Takaaki Konuma, Kensuke Matsuda, Yoshimitsu Shimomura, Susumu Tanoue, Junichi Sugita, Yoshihiro Inamoto, Masahiro Hirayama, Takahide Ara, Hirohisa Nakamae, Shuichi Ota, Yumiko Maruyama, Tetsuya Eto, Naoyuki Uchida, Masatsugu Tanaka, Kazuya Ishiwata, Satoshi Koi, Satoshi Takahashi, Yukiyasu Ozawa, Makoto Onizuka, Yoshinobu Kanda, Takafumi Kimura, Tatsuo Ichinohe, Yoshiko Atsuta, Junya Kanda, Masamitsu Yanada
    Transplantation and cellular therapy 29(6) 365.e1-365.e11 2023年6月  
    The possibility that HLA mismatches could reduce relapse after alternative HLA-mismatched allogeneic hematopoietic cell transplantation (HCT) is an attractive concept for treating acute myeloid leukemia (AML). However, it remains unclear whether the prognostic effect of graft-versus-host disease (GVHD) on survival differs between recipients of single-unit cord blood transplantation (CBT) and recipients of haploidentical HCT using post-transplantation cyclophosphamide (PTCy-haplo-HCT) for AML. The objective of this retrospective study was to compare the effect of acute GVHD and chronic GVHD on post-transplantation outcomes between recipients of CBT and recipients of PTCy-haplo-HCT. We retrospectively evaluated the effect of acute and chronic GVHD on post-transplantation outcomes following CBT and PTCy-haplo-HCT in adults with AML (n = 1981) between 2014 and 2020 using a Japanese registry database. In univariate analysis, the probability of overall survival was significantly greater in patients who developed grade I-II acute GVHD (P < .001, log-rank test) and limited chronic GVHD (P < .001, log-rank test) among CBT recipients, but these effects were not significant among PTCy-haplo-HCT recipients. In multivariate analysis, in which the development of GVHD was treated as a time-dependent covariate, the effect of grade I-II acute GVHD on reducing overall mortality differed significantly between CBT and PTCy-haplo-HCT (adjusted hazard ratio [HR] for CBT, .73, 95% confidence interval [CI], .60 to .87; adjusted HR for PTCy-haplo-HCT, 1.07; 95% CI, .70 to 1.64; P for interaction = .038). Our data demonstrate that grade I-II acute GVHD was associated with a significant improvement in overall mortality in adults with AML receiving CBT but not in recipients of PTCy-haplo-HCT.
  • Yoshihiro Inamoto
    Blood 141(22) 2672-2673 2023年6月1日  
  • Keiji Okinaka, Yukihiro Akeda, Yoshihiro Inamoto, Shigeo Fuji, Ayumu Ito, Takashi Tanaka, Saiko Kurosawa, Sung-Won Kim, Ryuji Tanosaki, Takuya Yamashita, Chikako Ohwada, Keiji Kurata, Takeshi Mori, Masahiro Onozawa, Kuniko Takano, Hiroki Yokoyama, Katsuyoshi Koh, Koji Nagafuji, Kazutaka Nakayama, Toru Sakura, Tsutomu Takahashi, Kazunori Oishi, Takahiro Fukuda
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 29(4) 482-489 2023年4月  
    OBJECTIVE: This multicentre, phase 2, randomized, controlled study of allogeneic haematopoietic stem cell transplantation (allo-HSCT) recipients compared the immunogenicity of two anti-pneumococcal vaccine regimens: four doses of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) (3+1+1 experimental group), and three doses of PCV13 followed by PPSV23 (3+0+1 group). METHODS: Allo-HSCT recipients without active graft-versus-host disease at enrolment were eligible. The primary endpoint was the IgG response rate (≥0.20 mg/mL) for all eight measured serotypes at 5 months after the PPSV23 booster. RESULTS: Seventy-two recipients were randomized, and seventy recipients who received over one PCV13 dose were analysed. The mean ages were 47.2 years (standard deviation, 14.4) in the 3+1+1 group (n = 35) and 49.0 years (standard deviation, 14.3) in the 3+0+1 group (n = 35). There was no significant difference in the overall IgG response rate at 5 months after the PPSV23 booster between the 3+1+1 and 3+0+1 groups (100% (26/26) vs. 93% (27/29), respectively, relative risk (RR): 1.07; 95% confidence interval (CI): 0.97-1.19). This rate was high immediately before the PPSV23 booster in the 3+1+1 group (100% (26/26) compared with 81% (21/26), respectively, RR: 1.24; 95% CI: 1.03-1.49), but this difference disappeared 1 month after the PPSV23 booster (100% (26/26) vs. 97% (28/29), respectively, RR: 1.04; 95% CI; 0.97-1.11). No serious adverse events leading to study dropout occurred. DISCUSSION: We were not able to determine the efficacy of the experimental arm based on the IgG response rate at 5 months after the PPSV23 booster in allo-HSCT recipients.
  • Misato Tsubokura, Minoru Kojima, Saori Nakabayashi, Noriko Takahashi, Sayaka Takeuchi, Yu Aruga, Chiaki Ikeda, Naoki Maezawa, Koji Okazaki, Sanshiro Uchida, Mizuki Watanabe, Jun Aoki, Ayumu Ito, Takashi Tanaka, Yoshihiro Inamoto, Sung-Won Kim, Hiromichi Matsushita, Takahiro Fukuda
    Clinical case reports 11(4) e7023 2023年4月  
    We herein report a case of peripheral blood stem cell transplantation (PBSCT) involving a donor with EDTA-induced pseudothrombocytopenia (PTCP). The apheresis product was inspected for 24 h and there was no platelet clumping or thrombocytopenia. In the first 14 months after PBSCT, there has been no transfer of PTCP symptoms.
  • Takashi Sakai, Takahiro Uchida, Sachiko Iwama, Kentaro Sugisaki, Muneharu Yamada, Yoshihiro Inamoto, Takashi Oda
    Internal medicine (Tokyo, Japan) 62(2) 269-273 2023年1月15日  
    A 67-year-old woman who had undergone bone marrow transplantation 2 years previously for acute myeloid leukemia (AML) developed complications of chronic graft-versus-host disease (cGVHD). She thereafter also developed nephrotic syndrome, and membranous nephropathy (MN) was diagnosed by a renal biopsy. Although the causative antigens of the MN were not detected, immunofluorescence staining showed codominant deposition of immunoglobulins G2 and G3, a finding indicating secondary MN, thereby suggesting an association between MN and cGVHD. Rituximab treatment was initiated, and her nephrotic syndrome gradually improved without relapse of AML. Our present case suggests that rituximab is a safe and effective therapeutic option for cGVHD-associated MN.
  • Yoshihiro Inamoto
    [Rinsho ketsueki] The Japanese journal of clinical hematology 64(9) 1166-1175 2023年  
    Adenovirus disease can cause disseminated disease or lethal organ damage in patients undergoing hematopoietic cell transplantation (HCT). Renourinary infection is the most common in Japan. The 1-year cumulative incidences of adenovirus disease in children and adults were 0.15% and 0.49%, respectively, after autologous HCT, and 1.52% and 2.99%, respectively, after allogeneic HCT. The annual incidence remained above 100 cases. Viremia or disseminated disease after autologous and allogeneic HCT occurs in 6% and 19%, respectively, in patients with adenovirus disease. Age ≥50 years and lymphoma are associated with adenovirus disease after autologous HCT. Patient age ≥50 years, male patients, adult T-cell leukemia/lymphoma, lymphoma, HCT-specific comorbidity index ≥3, HLA-mismatched or haploidentical donors, cord blood, in vivo T-cell depletion, grades II-IV acute graft-versus-host disease (GVHD), and extensive chronic GVHD are associated with adenovirus disease after allogeneic HCT. No regulatory authority has approved an antiviral agent for treating adenovirus disease after HCT. More than half of the patients received only supportive care in Japan. The increased risk of mortality following developing adenovirus disease, even with a single-site infection, after both autologous and allogeneic HCT suggests an urgent unmet need for the development of safe and effective drugs.
  • 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, Koji Nagafuji
    American journal of hematology 97(12) 1568-1579 2022年12月  
    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.
  • Tomoyasu Jo, Yasuyuki Arai, Tadakazu Kondo, Shohei Mizuno, Shigeki Hirabayashi, Yoshihiro Inamoto, Noriko Doki, Takahiro Fukuda, Yukiyasu Ozawa, Yuta Katayama, Yoshinobu Kanda, Kentaro Fukushima, Ken-Ichi Matsuoka, Satoru Takada, Masashi Sawa, Takashi Ashida, Makoto Onizuka, Tatsuo Ichinohe, Yoshiko Atsuta, Junya Kanda, Masamitsu Yanada
    Cytotherapy 24(10) 1013-1025 2022年10月  
    BACKGROUND AIMS: In allogeneic stem cell transplantation, unrelated donors are chosen in cases where appropriate related donors are not available. Peripheral blood stem cells (PBSCs) are more often selected as a graft source than bone marrow (BM). However, the prognostic benefits of PBSCs versus BM transplants from unrelated donors have not been carefully examined in patients with acute myeloid leukemia (AML). This study compared outcomes of adult AML patients who underwent unrelated PBSC and BM transplantation, evaluating post-transplant complications, including engraftment, graft-versus-host disease (GVHD) and infections, and determined subgroups of patients who are most likely to benefit from unrelated PBSCs compared with BM transplants. METHODS: The authors analyzed 2962 adult AML patients who underwent unrelated PBSC or BM transplants between 2011 and 2018 (221 PBSC and 2741 BM) using the Japanese nationwide registry database, in which graft source selection is not skewed toward PBSCs. RESULTS: In 49.7% of patients, disease status at transplantation was first complete remission (CR1). In 57.1% of cases, HLA-matched donors were selected. Myeloablative conditioning was performed in 75.1% of cases, and anti-thymocyte globulin (ATG) was added to conditioning in 10.5%. Multivariate analyses showed a trend toward favorable non-relapse mortality (NRM) in PBSC recipients compared with BM recipients (hazard ratio [HR], 0.731, P = 0.096), whereas overall survival (OS) (HR, 0.959, P = 0.230) and disease-free survival (DFS) (HR, 0.868, P = 0.221) were comparable between PBSC and BM recipients. Although the rate of chronic GVHD (cGVHD) was significantly higher in PBSC patients (HR, 1.367, P = 0.016), NRM was not increased, mainly as a result of significantly reduced risk of bacterial infections (HR, 0.618, P = 0.010), reflecting more prompt engraftments in PBSC recipients. Subgroup analyses revealed that PBSC transplantation was advantageous in patients transplanted at CR1 and in those without ATG use. PBSC recipients experienced significantly better OS and/or DFS compared with BM recipients in this patient group. CONCLUSIONS: The authors' results confirmed the overall safety of unrelated PBSC transplantation for adult AML patients and suggested an advantage of PBSCs, especially for those in CR1. Further optimization of the prophylactic strategy for cGVHD is required to improve the overall outcome in transplantation from unrelated PBSC donors.
  • Catherine J Lee, Tao Wang, Karen Chen, Mukta Arora, Ruta Brazauskas, Stephen R Spellman, Carrie Kitko, Margaret L MacMillan, Joseph A Pidala, Jeffery J Auletta, Sherif M Badawy, Neel Bhatt, Vijaya R Bhatt, Jean-Yves Cahn, Zachariah DeFilipp, Miguel A Diaz, Nosha Farhadfar, Shahinaz Gadalla, Robert P Gale, Hasan Hashem, Shahrukh Hashmi, Peiman Hematti, Sanghee Hong, Nasheed M Hossain, Yoshihiro Inamoto, Lazaros J Lekakis, Dipenkumar Modi, Sager Patel, Akshay Sharma, Scott Solomon, Daniel R Couriel
    Transplantation and cellular therapy 28(10) 712.e1-712.e8 2022年10月  
    Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality of life among long-term survivors of pediatric HCT. Late effects (LEs) of HCT are well documented in this population, and cGVHD has been identified as a risk factor for subsequent neoplasms (SNs) and several nonmalignant LEs (NM-LEs); however, the reported correlation between cGVHD and LEs varies among studies. We compared LEs occurring ≥2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of LEs. This systematic retrospective analysis used data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large, representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant LEs and NM-LEs in those with a diagnosis of cGVHD and those who never developed cGVHD. The cumulative incidences of any first LE, SN, and NM-LE were estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD versus no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first LEs. The estimated 10-year cumulative incidence of any LE in patients with and without cGVHD was 43% (95% CI, 38% to 48.2%) versus 32% (95% confidence interval [CI], 28.5% to 36.3%) (P < .001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any LE (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.68; P = .001) and NM-LE (HR, 1.37; 95% CI, 1.10 to 1.70; P = .006), but not SN (HR, 1.30; 95% CI, .73 to 2.31; P = .38). cGVHD-related factors linked with the development of an NM-LE included having extensive grade cGVHD (HR, 1.60; 95% CI, 1.23 to 2.08; P = .0005), severe cGVHD (HR, 2.25; 95% CI, 1.60 to 3.17; P < .0001), interrupted onset type (HR, 1.57; 95% CI, 1.21 to 2.05; P = .0008), and both mucocutaneous and visceral organ involvement (HR, 1.59; 95% CI, 1.24 to 2.03; P = .0002). No significant association between cGVHD-specific variables and SN was identified. Finally, the duration of cGVHD treatment of cGVHD with systemic immunosuppression was not significantly associated with SNs or NM-LEs. cGVHD was more closely associated with NM-LEs than with SNs among survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SNs was strongly associated with the use of myeloablative total body irradiation. cGVHD-related characteristics consistent with a state of greater immune dysregulation were more closely linked to NM-LEs.
  • Suguru Fukuhara, Yuji Oshikawa-Kumade, Yasunori Kogure, Sumito Shingaki, Hirokazu Kariyazono, Yoshiya Kikukawa, Junji Koya, Yuki Saito, Mariko Tabata, Kota Yoshifuji, Kota Mizuno, Akiko Miyagi-Maeshima, Hiromichi Matsushita, Masanaka Sugiyama, Chitose Ogawa, Yoshihiro Inamoto, Takahiro Fukuda, Masato Sugano, Nobuhiko Yamauchi, Yosuke Minami, Makoto Hirata, Teruhiko Yoshida, Takashi Kohno, Shinji Kohsaka, Hiroyuki Mano, Yuichi Shiraishi, Seishi Ogawa, Koji Izutsu, Keisuke Kataoka
    Cancer science 113(8) 2763-2777 2022年8月  
    Identification of genetic alterations through next-generation sequencing (NGS) can guide treatment decision-making by providing information on diagnosis, therapy selection, and prognostic stratification in patients with hematological malignancies. Although the utility of NGS-based genomic profiling assays was investigated in hematological malignancies, no assays sufficiently cover driver mutations, including recently discovered ones, as well as fusions and/or pathogenic germline variants. To address these issues, here we have devised an integrated DNA/RNA profiling assay to detect various types of somatic alterations and germline variants at once. Particularly, our assay can successfully identify copy number alterations and structural variations, including immunoglobulin heavy chain translocations, IKZF1 intragenic deletions, and rare fusions. Using this assay, we conducted a prospective study to investigate the feasibility and clinical usefulness of comprehensive genomic profiling for 452 recurrently altered genes in hematological malignancies. In total, 176 patients (with 188 specimens) were analyzed, in which at least one alteration was detected in 171 (97%) patients, with a median number of total alterations of 7 (0-55). Among them, 145 (82%), 86 (49%), and 102 (58%) patients harbored at least one clinically relevant alteration for diagnosis, treatment, and prognosis, respectively. The proportion of patients with clinically relevant alterations was the highest in acute myeloid leukemia, whereas this assay was less informative in T/natural killer-cell lymphoma. These results suggest the clinical utility of NGS-based genomic profiling, particularly for their diagnosis and prognostic prediction, thereby highlighting the promise of precision medicine in hematological malignancies.
  • Geoffrey D E Cuvelier, Michelle Schoettler, Nataliya P Buxbaum, Iago Pinal-Fernandez, Marc Schmalzing, Jörg H W Distler, Olaf Penack, Bianca D Santomasso, Robert Zeiser, Klemens Angstwurm, Kelli P A MacDonald, W Taylor Kimberly, Naomi Taylor, Ervina Bilic, Bernhard Banas, Maike Buettner-Herold, Namita Sinha, Hildegard T Greinix, Joseph Pidala, Kirk R Schultz, Kirsten M Williams, Yoshihiro Inamoto, Corey Cutler, Linda M Griffith, Stephanie J Lee, Stefanie Sarantopoulos, Steven Z Pavletic, Daniel Wolff
    Transplantation and cellular therapy 28(8) 426-445 2022年8月  
    Alloreactive and autoimmune responses after allogeneic hematopoietic cell transplantation can occur in nonclassical chronic graft-versus-host disease (chronic GVHD) tissues and organ systems or manifest in atypical ways in classical organs commonly affected by chronic GVHD. The National Institutes of Health (NIH) consensus projects were developed to improve understanding and classification of the clinical features and diagnostic criteria for chronic GVHD. Although still speculative whether atypical manifestations are entirely due to chronic GVHD, these manifestations remain poorly captured by the current NIH consensus project criteria. Examples include chronic GVHD impacting the hematopoietic system as immune mediated cytopenias, endothelial dysfunction, or as atypical features in the musculoskeletal system, central and peripheral nervous system, kidneys, and serous membranes. These purported chronic GVHD features may contribute significantly to patient morbidity and mortality. Most of the atypical chronic GVHD features have received little study, particularly within multi-institutional and prospective studies, limiting our understanding of their frequency, pathogenesis, and relation to chronic GVHD. This NIH consensus project task force report provides an update on what is known and not known about the atypical manifestations of chronic GVHD while outlining a research framework for future studies to be undertaken within the next 3 to 7 years. We also provide provisional diagnostic criteria for each atypical manifestation, along with practical investigation strategies for clinicians managing patients with atypical chronic GVHD features.
  • Rachel Phelan, Annie Im, Rebecca L Hunter, Yoshihiro Inamoto, Maria Teresa Lupo-Stanghellini, Alicia Rovo, Sherif M Badawy, Linda Burns, Hesham Eissa, Hemant S Murthy, Pinki Prasad, Akshay Sharma, Elizabeth Suelzer, Vaibhav Agrawal, Mahmoud Aljurf, Karen Baker, Grzegorz W Basak, David Buchbinder, Zachariah DeFilipp, Lana Desnica Grkovic, Ajoy Dias, Hermann Einsele, Michael L Eisenberg, Narendranath Epperla, Nosha Farhadfar, Arthur Flatau, Robert Peter Gale, Hildegard Greinix, Betty K Hamilton, Shahrukh Hashmi, Peiman Hematti, Kareem Jamani, Dipnarine Maharaj, John Murray, Seema Naik, Sunita Nathan, Steven Pavletic, Zinaida Peric, Drazen Pulanic, Richard Ross, Andrea Salonia, Isabel Sanchez-Ortega, Bipin N Savani, Tal Schechter, Ami J Shah, Stephanie M Smith, John A Snowden, Amir Steinberg, Douglas Tremblay, Sarah C Vij, Lauren Walker, Daniel Wolff, Jean A Yared, Hélène Schoemans, André Tichelli
    Bone marrow transplantation 57(7) 1150-1163 2022年7月  
    Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GvHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies. They may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT. We provide a systematic review of male-specific late effects in a collaboration between transplant physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research, and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. The systematic review summarizes incidence, risk factors, screening, prevention and treatment of these complications and provides consensus evidence-based recommendations for clinical practice and future research.
  • Rachel Phelan, Annie Im, Rebecca L Hunter, Yoshihiro Inamoto, Maria Teresa Lupo-Stanghellini, Alicia Rovo, Sherif M Badawy, Linda Burns, Hesham Eissa, Hemant S Murthy, Pinki Prasad, Akshay Sharma, Elizabeth Suelzer, Vaibhav Agrawal, Mahmoud Aljurf, Karen Baker, Grzegorz W Basak, David Buchbinder, Zachariah DeFilipp, Lana Desnica Grkovic, Ajoy Dias, Hermann Einsele, Michael L Eisenberg, Narendranath Epperla, Nosha Farhadfar, Arthur Flatau, Robert Peter Gale, Hildegard Greinix, Betty K Hamilton, Shahrukh Hashmi, Peiman Hematti, Kareem Jamani, Dipnarine Maharaj, John Murray, Seema Naik, Sunita Nathan, Steven Pavletic, Zinaida Peric, Drazen Pulanic, Richard Ross, Andrea Salonia, Isabel Sanchez-Ortega, Bipin N Savani, Tal Schechter, Ami J Shah, Stephanie M Smith, John A Snowden, Amir Steinberg, Douglas Tremblay, Sarah C Vij, Lauren Walker, Daniel Wolff, Jean A Yared, Hélène Schoemans, André Tichelli
    Transplantation and cellular therapy 28(6) 335.e1-335.e17 2022年6月  
    Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GVHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies, such as prostate, penile, and testicular cancer. These effects may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT. Here we provide a systematic review of male-specific late effects in a collaboration among transplantation physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. We used a systematic review methodology to summarize incidence, risk factors, screening, prevention, and treatment of these complications and provide consensus evidence-based recommendations for clinical practice and future research. Most of the evidence regarding male GVHD is still based on limited data, precluding strong therapeutic recommendations. Therefore, we recommend systematic screening for male genital GVHD regularly and reporting of cases to large registries to allow for a better understanding. Future research also should address treatment, given the little published evidence currently available. Male-specific endocrine consequences of HCT include hypogonadism, which also may affect bone health. Given the scanty evidence, current recommendations for hormone substitution and/or bone health treatment are based on similar principles as for the general population. Following HCT, sexual health decreases, and this topic should be addressed at regular intervals. Future studies should focus on interventional strategies to address sexual dysfunction. Infertility remains prevalent in patients having undergone myeloablative conditioning, warranting the offer of sperm preservation for all HCT candidates. Most studies on fertility rely on descriptive registry analysis and surveys, underscoring the importance of reporting post-HCT conception data to large registries. Although the quality of evidence is low, the development of cancer in male genital organs does not seem more prevalent in HCT recipients compared with the general population; however, subsequent malignancies in general seem to be more prevalent in males than in females, and special attention should be given to skin and oral mucosa. Male-specific late effects, which likely are more underreported than female-specific complications, should be systematically considered during the regular follow-up visits of male survivors who have undergone HCT. Care of patients with male-specific late effects warrants close collaboration between transplantation physicians and specialists from other involved disciplines. Future research should be directed toward better data collection on male-specific late effects and on studies about the interrelationships among these late effects, to allow the development of evidence-based effective management practices.
  • Akio Onishi, Shigeo Fuji, Shigehisa Kitano, Akiko Miyagi Maeshima, Kinuko Tajima, Junko Yamaguchi, Ichiro Kawashima, Akihisa Kawajiri, Tomonari Takemura, Ayumu Ito, Takashi Tanaka, Keiji Okinaka, Yoshihiro Inamoto, Saiko Kurosawa, Sung-Won Kim, Wataru Munakata, Dai Maruyama, Kensei Tobinai, Takahiro Fukuda
    Annals of hematology 101(4) 799-810 2022年4月  
    The prognosis of patients with aggressive adult T cell leukemia-lymphoma (ATLL) is dismal even with intensive chemotherapy. Allogeneic hematopoietic stem cell transplantation (HSCT) is a promising option for patients with aggressive ATLL, but the posttransplant outcome remains unsatisfactory. Hence, to further improve clinical outcomes, novel therapeutic approaches are needed. The clinical significance of immune checkpoint protein expression has not been well-established in aggressive ATLL. This study aims to identify the association between the expression profile of immune checkpoint proteins on ATLL cells and clinical outcomes. This retrospective study cohort included 65 patients with aggressive ATLL diagnosed between 2001 and 2015 at the National Cancer Center Hospital, Tokyo, Japan. Formalin-fixed paraffin-embedded tissue was used to immunohistochemically determine the expression of immune checkpoint proteins and assess the impact of expression profile on the probability of overall survival from diagnosis or HSCT. The current analysis shows that cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) expressions were adverse prognostic factors in patients with aggressive ATLL. Experiments that assess the efficacy of immune checkpoint inhibitors are warranted to alleviate the adverse impacts associated with negative immune checkpoints.
  • Hemant S Murthy, Kwang Woo Ahn, Noel Estrada-Merly, Hassan B Alkhateeb, Susan Bal, Mohamed A Kharfan-Dabaja, Bhagirathbhai Dholaria, Francine Foss, Lohith Gowda, Deepa Jagadeesh, Craig Sauter, Muhammad Bilal Abid, Mahmoud Aljurf, Farrukh T Awan, Ulrike Bacher, Sherif M Badawy, Minoo Battiwalla, Chris Bredeson, Jan Cerny, Saurabh Chhabra, Abhinav Deol, Miguel Angel Diaz, Nosha Farhadfar, César Freytes, James Gajewski, Manish J Gandhi, Siddhartha Ganguly, Michael R Grunwald, Joerg Halter, Shahrukh Hashmi, Gerhard C Hildebrandt, Yoshihiro Inamoto, Antonio Martin Jimenez-Jimenez, Matt Kalaycio, Rammurti Kamble, Maxwell M Krem, Hillard M Lazarus, Aleksandr Lazaryan, Joseph Maakaron, Pashna N Munshi, Reinhold Munker, Aziz Nazha, Taiga Nishihori, Olalekan O Oluwole, Guillermo Ortí, Dorothy C Pan, Sagar S Patel, Attaphol Pawarode, David Rizzieri, Nakhle S Saba, Bipin Savani, Sachiko Seo, Celalettin Ustun, Marjolein van der Poel, Leo F Verdonck, John L Wagner, Baldeep Wirk, Betul Oran, Ryotaro Nakamura, Bart Scott, Wael Saber
    Transplantation and cellular therapy 28(4) 187.e1-187.e10 2022年4月  
    T cell prolymphocytic leukemia (T-PLL) is a rare, aggressive malignancy with limited treatment options and poor long-term survival. Previous studies of allogeneic hematopoietic cell transplantation (alloHCT) for T-PLL are limited by small numbers, and descriptions of patient and transplantation characteristics and outcomes after alloHCT are sparse. In this study, we evaluated outcomes of alloHCT in patients with T-PLL and attempted to identify predictors of post-transplantation relapse and survival. We conducted an analysis of data using the Center for International Blood and Marrow Transplant Research database on 266 patients with T-PLL who underwent alloHCT between 2008 and 2018. The 4-year rates of overall survival (OS), disease-free survival (DFS), relapse, and treatment-related mortality (TRM) were 30.0% (95% confidence interval [CI], 23.8% to 36.5%), 25.7% (95% CI, 20% to 32%), 41.9% (95% CI, 35.5% to 48.4%), and 32.4% (95% CI, 26.4% to 38.6%), respectively. In multivariable analyses, 3 variables were associated with inferior OS: receipt of a myeloablative conditioning (MAC) regimen (hazard ratio [HR], 2.18; P < .0001), age >60 years (HR, 1.61; P = .0053), and suboptimal performance status, defined by Karnofsky Performance Status (KPS) <90 (HR, 1.53; P = .0073). Receipt of an MAC regimen also was associated with increased TRM (HR, 3.31; P < .0001), an elevated cumulative incidence of grade II-IV acute graft-versus-host disease (HR, 2.94; P = .0011), and inferior DFS (HR, 1.86; P = .0004). Conditioning intensity was not associated with relapse; however, stable disease/progression was correlated with increased risk of relapse (HR, 2.13; P = .0072). Both in vivo T cell depletion (TCD) as part of conditioning and KPS <90 were associated with worse TRM and inferior DFS. Receipt of total body irradiation had no significant effect on OS, DFS, or TRM. Our data show that reduced-intensity conditioning without in vivo TCD (ie, without antithymocyte globulin or alemtuzumab) before alloHCT was associated with long-term DFS in patients with T-PLL who were age ≤60 years or who had a KPS >90 or chemosensitive disease.
  • Saiko Kurosawa, Takuhiro Yamaguchi, Ayako Mori, Mayumi Tsukagoshi, Ikue Okuda, Masako Ikeda, Takao Ueno, Yutaka Saito, Yukiko Aihara, Yuko Matsuba, Shigeo Fuji, Takuya Yamashita, Chitose Ogawa, Ayumu Ito, Takashi Tanaka, Yoshihiro Inamoto, Sung-Won Kim, Takahiro Fukuda
    Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 30(3) 2767-2776 2022年3月  
    PURPOSE: Advances in allogeneic hematopoietic cell transplantation (allo-HCT) have resulted in a growing number of transplant survivors; however, long-term survivors are at risk of developing late complications, and published guidelines recommend screening of this population. We conducted a single-center prospective study to evaluate the adherence to and usefulness of recommended screenings at a long-term follow-up (LTFU) clinic. METHODS: We included consecutive patients who received allo-HCT at our center from 2014, as well as post-HCT patients visiting our outpatient clinic. Visits and screenings were planned at 3 months, 6 months, and 1 year after allo-HCT, and annually thereafter. Outcomes were reported by physicians including the incidence of findings at each screening that led to interventions. RESULTS: Among the 216 participants, 95% visited the LTFU clinic, and 94% completed planned screenings. However, the rate of secondary cancer screenings targeting high-risk subjects was lower (38% to 68%). The overall percentage of screening results leading to interventions was 4.5%, with higher percentages (> 10%) for bone density testing, ophthalmological examinations, dental assessment, upper gastrointestinal endoscopy, and colonoscopy, with two patients diagnosed with secondary cancers. CONCLUSIONS: Although the overall screening rate was high, it should be possible to improve the detection rate of late complications by decreasing screening failures, especially the screening for secondary cancers limited for high-risk survivors. A nationwide effort to educate HCT survivors and health practitioners using standardized nationwide LTFU tools may be effective, along with the development of institutional, local, and nationwide networks to maintain effective follow-up systems.
  • Masatomo Kuno, Satoshi Yamasaki, Nobuharu Fujii, Yasushi Ishida, Takahiro Fukuda, Keisuke Kataoka, Naoyuki Uchida, Yuta Katayama, Maho Sato, Daishi Onai, Toshihiro Miyamoto, Shuichi Ota, Satoshi Yoshioka, Takahide Ara, Akira Hangaishi, Yoshiko Hashii, Makoto Onizuka, Tatsuo Ichinohe, Yoshiko Atsuta, Yoshihiro Inamoto
    American journal of hematology 97(2) 185-193 2022年2月1日  
    We compared characteristics of myeloid neoplasms (MNs) following allogeneic hematopoietic cell transplantation (HCT) versus autologous HCT using a Japanese HCT registry database. Among 43 788 patients who underwent allogeneic (n = 18 874) or autologous HCT (n = 24 914) for non-myeloid malignancies or non-malignant diseases, 352 developed MNs. The cumulative incidence of MNs was lower after allogeneic HCT than after autologous HCT (0.3% vs. 1.8% at 10 years, respectively, p < .001). Compared with autologous HCT, MNs following allogeneic HCT developed in younger patients (median, 42 vs. 57 years old, respectively) and sooner after HCT (median, 16 vs. 33 months, respectively). Approximately half of MNs following allogeneic HCT were donor-derived and occurred later than recipient-derived MNs (median, 26 vs. 6 months, respectively, p = .003). In multivariate analysis, reduced-intensity conditioning and cord blood transplantation were associated with MN development after allogeneic HCT. Overall survival was similar in patients who developed MNs following allogeneic versus autologous HCT (18% vs. 22% at 5 years, respectively, p = .48). Patient age ≥ 55 years, the presence of previous HCT, AML subtype, and chromosome 5 or 7 abnormalities were adverse factors for overall survival after MN diagnosis. Further research is warranted to elucidate the mechanisms of MN development following allogeneic HCT.
  • Toshihisa Nakashima, Yoshihiro Inamoto, Jun Aoki, Ayumu Ito, Takashi Tanaka, Sung-Won Kim, Hironobu Hashimoto, Takahiro Fukuda, Tetsuya Furukawa
    International journal of hematology 115(2) 158-162 2022年2月  
    Letermovir is commonly used for CMV prophylaxis after allogeneic hematopoietic cell transplantation (HCT). Pharmacokinetic studies have shown an increase in tacrolimus exposure among healthy volunteers who took letermovir. However, studies in HCT recipients are needed because these patients are typically using concomitant antifungals with different degrees of CYP3A4 inhibition that may further interact with tacrolimus pharmacokinetics. In this study, we retrospectively evaluated the kinetics of tacrolimus concentration after letermovir discontinuation by type of concomitant azole antifungal in 57 HCT recipients. The median fold change in tacrolimus concentration-to-dose (C/D) ratio after discontinuing letermovir was 0.64 (range 0.43-0.99) with fluconazole and 1.10 (range 0.59-1.73) with voriconazole (p < 0.001). The tacrolimus C/D ratio decreased ≥ 30% after discontinuing letermovir (p < 0.001) in 66% of patients on fluconazole and 9% on voriconazole. Among patients whose tacrolimus C/D ratio decreased ≥ 30%, three (9%) patients in the fluconazole group and one (4%) in the voriconazole group experienced worsening of GVHD. Careful monitoring of tacrolimus concentration is important after letermovir discontinuation to avoid worsening of GVHD due to decreased tacrolimus concentration.
  • Yi-Chen Sun, Yoshihiro Inamoto, Ruikang K Wang, Stephanie J Lee, Kai-Feng Hung, Tueng T Shen
    BMC ophthalmology 22(1) 38-38 2022年1月25日  
  • Yoshihiro Inamoto
    [Rinsho ketsueki] The Japanese journal of clinical hematology 63(5) 433-439 2022年  
    Chronic graft-versus-host disease (GVHD) affects various organs and causes significant morbidity and mortality after allogeneic hematopoietic cell transplantation. The 2005 National Institutes of Health consensus criteria for chronic GVHD have set international standards for endpoints and designing and reporting of clinical trials; these criteria were revised in 2014 to incorporate accumulated evidence and controversies. In addition, preclinical studies of chronic GVHD have identified treatment targets such as regulatory T cells, B-cell signaling, Th17 cells, Tc17 cells, follicular helper T cells, follicular regulatory T cells, and fibrosis-promoting factors. These efforts led to the approval of ibrutinib, belumosudil, and ruxolitinib by the U.S. Food and Drug Administration for treating chronic GVHD after failure of one or more lines of systemic therapy, and an increasing number of investigational agents that target different biological pathways of chronic GVHD are under development in clinical trials. To address challenges in a rapidly evolving field, a third National Institutes of Health consensus project was held in 2020, in which investigators, patient advocacy organizations, and pharmaceutical companies aimed to define basic and clinical research roadmaps that may lead to significant change in chronic GVHD management over the next 5 years.
  • Takuya Fukushima, Takashi Tanaka, Suguru Fukushima, Mizuki Watanabe, Jun Aoki, Ayumu Ito, Yoshihiro Inamoto, Sung-Won Kim, Akira Kawai, Takahiro Fukuda
    Physical therapy research 25(3) 162-167 2022年  
    PURPOSE: Physical activity (PA) interventions positively affect the physical function (PF) in patients with advanced cancer. However, patients must remain motivated during the intervention. We report a case wherein a smartphone application for PA intervention was useful in motivating the patient to improve adherence. METHODS: A 40-year-old woman underwent an allogeneic hematopoietic cell transplantation (allo-HCT) for an advanced extranodal natural killer/T-cell lymphoma. On day 6, she developed the posterior reversible encephalopathy syndrome. She was managed in the intensive care unit for 3 days, and her PF declined markedly. We initiated a smartphone-based PA intervention from day 35. She was instructed to maintain a PA diary for self-monitoring of the daily steps and to set a new step-count goal every week. RESULTS: The PA and PF improved within a short period thereafter. However, she developed severe acute graft-versus-host disease and was administered with high-dose systemic corticosteroids from day 49. The PA, PF, and quality of life (QOL) decreased again. The intervention was continued for 5 months with a high adherence. The PA, PF, and QOL improved gradually. She resumed independent activities of daily living and was discharged on day 202. CONCLUSION: Smartphone-based PA intervention may be effective against post-allo-HCT physical dysfunction.
  • Masachika Ikegami, Shinji Kohsaka, Takeshi Hirose, Toshihide Ueno, Satoshi Inoue, Naoki Kanomata, Hideko Yamauchi, Taisuke Mori, Shigeki Sekine, Yoshihiro Inamoto, Yasushi Yatabe, Hiroshi Kobayashi, Sakae Tanaka, Hiroyuki Mano
    Communications biology 4(1) 1396-1396 2021年12月15日  
    The clinical sequencing of tumors is usually performed on formalin-fixed, paraffin-embedded samples and results in many sequencing errors. We identified that most of these errors are detected in chimeric reads caused by single-strand DNA molecules with microhomology. During the end-repair step of library preparation, mutations are introduced by the mis-annealing of two single-strand DNA molecules comprising homologous sequences. The mutated bases are distributed unevenly near the ends in the individual reads. Our filtering pipeline, MicroSEC, focuses on the uneven distribution of mutations in each read and removes the sequencing errors in formalin-fixed, paraffin-embedded samples without over-eliminating the mutations detected also in fresh frozen samples. Amplicon-based sequencing using 97 mutations confirmed that the sensitivity and specificity of MicroSEC were 97% (95% confidence interval: 82-100%) and 96% (95% confidence interval: 88-99%), respectively. Our pipeline will increase the reliability of the clinical sequencing and advance the cancer research using formalin-fixed, paraffin-embedded samples.
  • Yoshihiro Inamoto, Robert Zeiser, Godfrey Chi-Fung Chan
    Blood cell therapy 4(4) 101-109 2021年11月25日  
    Allogeneic hematopoietic cell transplantation is a curative therapy for a variety of hematological diseases, but its success is hampered by acute and chronic graft-versus-host disease (GvHD). In the last five years, multiple novel therapeutic approaches for GvHD have entered the arena. The National Institutes of Health consensus criteria for chronic GvHD have set standards for designing and reporting clinical trials, and preclinical experiments of chronic GvHD have revealed the central roles of regulatory T cells, B-cell signaling, Th17 cells, Tc17 cells, follicular helper T cells, follicular regulatory T cells, and fibrosis-promoting factors. These scientific efforts and the resulting clinical studies led to the approval of ibrutinib, belumosudil and ruxolitinib for the treatment of refractory chronic GvHD. Recently, large randomized phase III trials showed that ruxolitinib was superior to the best available therapy for glucocorticoid-refractory acute GvHD (REACH2 trial) and glucocorticoid-refractory chronic GvHD (REACH3 trial). Furthermore, novel regenerative approaches, including IL-22, R-spondin, and glucogon-like peptide-2, and cellular therapies, such as the transfer of mesenchymal stem cells and regulatory T cells, are under intensive investigation. GvHD prevention using abatacept, dipeptidyl peptidase 4 inhibition, and post-transplant cyclophosphamide are also promising strategies that require further evaluation. In this article, we summarize the emerging knowledge of acute GvHD, chronic GvHD, and preclinical and clinical data of mesenchymal stem cells as GvHD therapy. In the next five years, basic and clinical studies will further advance the field, and dramatic changes in GvHD management will be encountered.
  • Yu Akahoshi, Shun-Ichi Kimura, Yoshihiro Inamoto, Sachiko Seo, Hiroyuki Muranushi, Hiroaki Shimizu, Yukiyasu Ozawa, Masatsugu Tanaka, Naoyuki Uchida, Yoshinobu Kanda, Yuta Katayama, Souichi Shiratori, Shuichi Ota, Ken-Ichi Matsuoka, Makoto Onizuka, Takahiro Fukuda, Yoshiko Atsuta, Makoto Murata, Seitaro Terakura, Hideki Nakasone
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 73(3) e620-e628 2020年12月20日  
    BACKGROUND: Despite a strong association between acute graft-versus-host disease (GVHD) and cytomegalovirus reactivation (CMVR), the joint effect of acute GVHD and CMVR on nonrelapse mortality (NRM) has not been well studied. METHODS: We evaluated the impact of CMVR on NRM stratified according to the development of acute GVHD using a landmark method. This study included 6078 patients who received their first allogeneic hematopoietic cell transplantation (HCT) with a pre-emptive strategy for CMVR between 2008 and 2017. RESULTS: The cumulative incidences of grade II-IV acute GVHD (G24GVHD), CMVR by day 100, and CMV disease by day 365 were 37.3%, 52.1%, and 2.9%, respectively. Patients with G24GVHD were associated with the subsequent development of CMVR, and the presence of CMVR also increased the risk of G24GVHD. In a landmark analysis at day 65, the cumulative incidence of NRM at 1 year was 5.4%, 10.0%, 13.9%, and 19.7% in patients with G24GVHD-/CMVR-, G24GVHD-/CMVR+, G24GVHD+/CMVR-, and G24GVHD+/CMVR+, respectively. In a multivariate analysis, CMVR was respectively associated with an increased risk of NRM by day 365 in patients without G24GVHD (HR [hazard ratio], 1.59, 95% CI, 1.24-2.05, P < 0.001) and with G24GVHD (HR, 1.34, 95% CI, 1.06-1.70, P = 0.014), but the interaction between G24GVHD and CMVR was not significant (P = 0.326). Subgroup analyses suggested that the joint effect of acute GVHD and CMVR might vary according to the baseline characteristics. CONCLUSIONS: These data regarding the close relationship between acute GVHD and CMVR should provide important implications for the treatment strategy after HCT.
  • Shigeo Fuji, Saiko Kurosawa, Yoshihiro Inamoto, Tatsunori Murata, Atae Utsunomiya, Kaoru Uchimaru, Satoshi Yamasaki, Yoshitaka Inoue, Yukiyoshi Moriuchi, Ilseung Choi, Masao Ogata, Michihiro Hidaka, Takuhiro Yamaguchi, Takahiro Fukuda
    International journal of hematology 111(3) 427-433 2020年3月  
    Patients with aggressive adult T-cell leukemia-lymphoma (ATL) have dismal outcomes with intensive chemotherapy. Early up-front allogeneic hematopoietic stem cell transplantation (allo-HSCT) is generally recommended. However, the choice of stem cell source, i.e., unrelated bone marrow transplant (UBMT) or cord blood transplantation (CBT), when an HLA-matched related donor is unavailable remains controversial. Thus, we undertook a decision analysis to compare the outcomes of two therapeutic strategies: chemotherapy followed by up-front UBMT at 6 months, and chemotherapy followed by up-front CBT at 3 months. Patients were stratified into low-, intermediate-, and high-risk groups according to the modified ATL-prognostic index. The model simulated life expectancy (LE) and quality-adjusted LE (QALE). LE following up-front UBMT was higher than that following up-front CBT in the low-risk group (2.63 vs. 2.28 years), but was comparable in the intermediate- (2.06 vs. 2.01 years) and high-risk groups (1.25 vs. 1.30 years). The Monte Carlo simulation for LE and QALE in each risk group showed that there was significant uncertainty in all categories. In conclusion, up-front UBMT was superior to up-front CBT in the low-risk group, but the strategies were comparable in the intermediate- and high-risk groups.
  • Yoshihiro Inamoto, Tomohiro Matsuda, Ken Tabuchi, Saiko Kurosawa, Hideki Nakasone, Hisakazu Nishimori, Satoshi Yamasaki, Noriko Doki, Koji Iwato, Takehiko Mori, Satoshi Takahashi, Hiromasa Yabe, Akio Kohno, Hirohisa Nakamae, Toru Sakura, Hisako Hashimoto, Junichi Sugita, Hiroatsu Ago, Takahiro Fukuda, Tatsuo Ichinohe, Yoshiko Atsuta, Takuya Yamashita
    Blood advances 2(15) 1901-1913 2018年8月14日  査読有り
    To characterize the outcomes of patients who developed a particular subsequent solid cancer after hematopoietic cell transplantation (HCT), age at cancer diagnosis, survival, and causes of death were compared with the respective primary cancer in the general population, using data from the national HCT registry and population-based cancer registries in Japan. Among 31 867 patients who underwent a first HCT between 1990 and 2013 and had progression-free survival at 1 year, 713 patients developed subsequent solid cancer. The median age at subsequent solid cancer diagnosis was 55 years, which was significantly younger than the 67 years for primary cancer patients in the general population (P < .001). The overall survival probability was 60% at 3 years after diagnosis of subsequent solid cancer and differed according to cancer type. Development of most solid cancers was associated with an increased risk of subsequent mortality after HCT. Subsequent solid cancers accounted for 76% of causes of death. Overall survival probabilities adjusted for age, sex, and year of diagnosis were lower in the HCT population than in the general population for colon, bone/soft tissue, and central nervous system cancers and did not differ statistically for other cancers. In conclusion, most subsequent solid cancers occurred at younger ages than primary cancers, emphasizing the need for cancer screening at younger ages. Subsequent solid cancers showed similar or worse survival compared with primary cancers. Biological and genetic differences between primary and subsequent solid cancers remain to be determined.
  • Anita J Kumar, Soyoung Kim, Michael T Hemmer, Mukta Arora, Stephen R Spellman, Joseph A Pidala, Daniel R Couriel, Amin M Alousi, Mahmoud D Aljurf, Jean-Yves Cahn, Mitchell S Cairo, Corey S Cutler, Shatha Farhan, Usama Gergis, Gregory A Hale, Shahrukh K Hashmi, Yoshihiro Inamoto, Rammurti T Kamble, Mohamed A Kharfan-Dabaja, Margaret L MacMillan, David I Marks, Hideki Nakasone, Maxim Norkin, Muna Qayed, Olle Ringden, Harry C Schouten, Kirk R Schultz, Melhem M Solh, Takanori Teshima, Alvaro Urbano-Ispizua, Leo F Verdonck, Robert Peter Gale, Betty K Hamilton, Navneet S Majhail, Alison W Loren
    Blood advances 2(9) 1022-1031 2018年5月8日  査読有り
    Optimal donor selection is critical for successful allogeneic hematopoietic cell transplantation (HCT). Donor sex and parity are well-established risk factors for graft-versus-host disease (GVHD), with male donors typically associated with lower rates of GVHD. Well-matched unrelated donors (URDs) have also been associated with increased risks of GVHD as compared with matched sibling donors. These observations raise the question of whether male URDs would lead to more (or less) favorable transplant outcomes as compared with parous female sibling donors. We used the Center for International Blood and Marrow Transplant Research registry to complete a retrospective cohort study in adults with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, who underwent T-cell replete HCT from these 2 donor types (parous female sibling or male URD) between 2000 and 2012. Primary outcomes included grade 2 to 4 acute GVHD (aGVHD), chronic GVHD (cGVHD), and overall survival. Secondary outcomes included disease-free survival, transplant-related mortality, and relapse. In 2813 recipients, patients receiving male URD transplants (n = 1921) had 1.6 times higher risk of grade 2 to 4 aGVHD (P < .0001). For cGVHD, recipient sex was a significant factor, so donor/recipient pairs were evaluated. Female recipients of male URD grafts had a higher risk of cGVHD than those receiving parous female sibling grafts (relative risk [RR] = 1.43, P < .0001), whereas male recipients had similar rates of cGVHD regardless of donor type (RR = 1.09, P = .23). Donor type did not significantly affect any other end point. We conclude that when available, parous female siblings are preferred over male URDs.
  • Ichiro Kawashima, Yoshihiro Inamoto, Akiko Miyagi Maeshima, Junko Nomoto, Kinuko Tajima, Tadahiro Honda, Takafumi Shichijo, Akihisa Kawajiri, Tomonari Takemura, Akio Onishi, Ayumu Ito, Takashi Tanaka, Shigeo Fuji, Saiko Kurosawa, Sung-Won Kim, Dai Maruyama, Kensei Tobinai, Yukio Kobayashi, Takahiro Fukuda
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 24(2) 294-300 2018年2月  査読有り
    Double-expressor lymphoma (DEL) is a diffuse large B cell lymphoma that exhibits co-expression of MYC and BCL2 proteins by immunohistochemistry. Patients with double-expressor lymphoma have a poor prognosis after standard chemoimmunotherapy or after high-dose chemotherapy with autologous transplantation, but the prognostic impact of DEL after allogeneic hematopoietic cell transplantation has not been well characterized. We retrospectively analyzed 60 consecutive patients with de novo diffuse large B cell lymphoma or transformed follicular lymphoma who underwent allogeneic transplantation at our center and had available immunohistochemistry data. Thirty-seven patients (62%) had DEL. The 2-year progression-free and overall survival rates were lower in patients with DEL than in those without DEL (20% versus 78%; overall P <.001 and 46% versus 77%; overall P = .016, respectively). The cumulative incidence of disease progression at 2 years was higher in patients with DEL (60% versus 13%; overall P = .005). The cumulative incidence of nonrelapse mortality did not differ statistically in the 2 groups. Even in patients with DEL and chemosensitive disease at transplantation, the 2-year progression-free survival rate was only 27% due to early disease progression. Multivariate analysis showed associations between DEL and increased risks of progression-free survival events (hazard ratio [HR], 4.58; 95% confidence interval [CI], 2.07-10.2; P <.001), overall mortality (HR, 2.29; 95% CI, 1.03-5.09; P = .042) and disease progression (HR, 3.60; 95% CI, 1.38-9.44; P = .009). Patients with DEL had poor outcomes after allogeneic transplantation. Innovative strategies are needed to improve outcomes in this population.
  • Yoshihiro Inamoto, Fumihiko Kimura, Junya Kanda, Junichi Sugita, Kazuhiro Ikegame, Hideki Nakasone, Yasuhito Nannya, Naoyuki Uchida, Takahiro Fukuda, Kosuke Yoshioka, Yukiyasu Ozawa, Ichiro Kawano, Yoshiko Atsuta, Koji Kato, Tatsuo Ichinohe, Masami Inoue, Takanori Teshima
    Haematologica 101(12) 1592-1602 2016年12月  査読有り
    Graft-versus-host disease-free relapse-free survival, which is defined as the absence of grade III-IV acute graft-versus-host disease, systemically treated chronic graft-versus-host disease, relapse, and death, is a novel, meaningful composite end point for clinical trials. To characterize risk factors and differences in graft-versus-host disease-free relapse-free survival according to a variety of graft sources, we analyzed 23,302 patients with hematologic malignancy that had a first allogeneic transplantation from 2000 through 2013 using the Japanese national transplant registry database. The 1-year graft-versus-host disease-free relapse-free survival rate was 41% in all patients. The rate was higher after bone marrow transplantation than after peripheral blood stem cell transplantation due to the lower risks of III-IV acute and chronic graft-versus-host disease. The rate was highest after HLA-matched sibling bone marrow transplantation. The rate after single cord blood transplantation was comparable to that after HLA-matched unrelated bone marrow transplantation among patients aged 20 years or under, and was comparable or better than other alternative graft sources among patients aged 21 years or over, due to the low risk of chronic graft-versus-host disease. Other factors associated with better graft-versus-host disease-free relapse-free survival include female patients, antithymocyte globulin prophylaxis (for standard-risk disease), recent years of transplantation, sex combinations other than from a female donor to a male patient, the absence of prior autologous transplantation, myeloablative conditioning, negative cytomegalovirus serostatus, and tacrolimus-based prophylaxis. These results provide important information to guide the choice of graft sources and are benchmarks for future graft-versus-host disease prophylaxis studies.

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