148

Center for Stem Cell Biology and Regenerative Medicine

Division of Stem Cell Transplantation
幹細胞移植分野

Professor
Yasuhito Nannya, M.D., D.M.Sc.
Project Professor Satoshi Takahashi, M.D., D.M.Sc.

教 授
特任教授

博士（医学）
博士（医学）

南高谷
橋泰

仁聡

We are studying the clinical promotion and medical development of hematopoietic
stem cell transplantation with a focus on cord blood transplantation. In addition todata on hematopoietic stem cell transplantation performed at the Department ofHematology/Oncology, we are analyzing various issues related to clinicaltransplantation using the Japanese transplant database. Basic studies include thedevelopment of efficient in vitro amplification of patient-derived primary cells andpreclinical studies on the use of virus-specific CTLs in post-transplant and otherimmunocompromised patients. Our goal is to make allogeneic transplantation asafer treatment option and extend it to older patients.

1.  Should a matched sibling donor still be considered the primary option for allogeneic hematopoietic cell transplantation in patientsover 50 years of age with myelodysplastic syndrome?
Takaaki Konuma1, Hidehiro Itonaga2, et., al
1 Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo,Tokyo, Japan.
2 Department of Hematology, Nagasaki University
Hospital, Nagasaki, Japan.
Human leukocyte antigen (HLA)-matched sibling
donors (MSDs) are the preferred choice for allogeneic
hematopoietic cell transplantation (HCT). However,as myelodysplastic syndrome (MDS) is most frequently diagnosed in the elderly, MSDs are also likely
to be of advanced age. It is unclear whether an MSD
should be considered the primary choice for allogeneic HCT in elderly patients with MDS. We retrospectively compared survival and other outcomes in 1787
patients with MDS over 50 years of age and receiving
allogeneic HCT between 2014 and 2020, using either
MSD (n=214), 8/8 allele-matched unrelated donor(MUD) (n=562), 7/8 allele-MUD (n=334), or unrelated

cord blood (UCB) (n=677) in Japan. In multivariate
analysis, compared to MSD transplants, the risk of relapse was significantly lower following 8/8MUD
transplants (hazard ratio [HR], 0.74; P=0.047), whereas non-relapse mortality was significantly higher following UCB transplants (HR, 1.43; P=0.041). However, donor type did not determine overall survival,
disease-free survival, or graft-versus-host disease(GVHD)-free, relapse-free survival, but chronic
GVHD-free, relapse-free survival was better after
UCB (HR, 0.80; P=0.025) and 8/8MUD (HR, 0.81;P=0.032) compared to MSD transplants. Our study
demonstrated that MSDs are not superior to alternative HCT methods, such as 8/8MUD, 7/8MUD, orUCB, in this population.
2.  Comparison of allogeneic transplant outcomes
between matched sibling donors and alternative donors in patients over 50 years of age
with acute myeloid leukemia: 8/8 allele-matchedunrelated donors and unrelated cord blood
provide better leukemia-free survival compared with matched sibling donors during
non-remission status
Takaaki Konuma 1, Satoshi Yamasaki 2, et al., rep-149
resenting for: the Adult Acute Myeloid Leukemia
and Donor/source Working Groups of the JapaneseSociety for Transplantation and Cellular Therapy
1 Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo,Tokyo, Japan.
2 Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Japan.
Acute myeloid leukemia (AML) is the most common indication for allogeneic hematopoietic celltransplantation (HCT). The increased availability ofalternative donor sources has broadened donor types
for older patients without HLA-matched sibling donors (MSD). It is uncertain if an MSD should be thefirst option for allogeneic HCT in patients with AML
over 50 years of age. The objective of this study was tocompare survival and other posttransplant outcomes
between MSDs, 8/8 allele-matched unrelated donors(MUDs), 7/8 allele-MUDs, unrelated cord blood(UCB), and haploidentical donors for patients with
AML over 50 years of age. We conducted a retrospective study to compare outcomes in 5,704 patients with
AML over 50 years of age and receiving allogeneic
HCT between 2013 and 2021, using either MSD, 8/8
allele-MUD, 7/8 allele-MUD, UCB, or haploidentical
donors in Japan. Complete remission (CR) andnon-remission at HCT were analyzed separately for
all analyses. In total, 3041 patients were CR, and 2663
patients were non-remission at the time of HCT. In
multivariate analysis, donor type did not determine
overall survival, irrespective of disease status at HCT.
Leukemia-free survival (LFS) was significantly betterfor 8/8 allele-MUD (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.64 to 0.93; P = 0.005) and UCB(HR, 0.76; 95% CI, 0.65 to 0.88; P = 0.001), but not for
7/8 allele-MUD (HR, 0.97; 95% CI, 0.79 to 1.19;
P=0.794), and haploidentical donor (HR, 0.86; 95% CI,
0.70 to 1.05; P=0.146) compared to the MSD group in
non-remission status. However, donor type did not
determine LFS among CR status. Relapse rates weresignificantly lower for 8/8 allele-MUD and UCB,
whereas non-relapse mortality was higher for UCB
compared to the MSD group among both CR andnon-remission status. Our registry-based study
demonstrated that MSDs do not lead to superior survival compared to alternative donors for patientswith AML over 50 years of age. Furthermore, 8/8 allele-MUDs and UCB provide better LFS comparedwith MSDs during non-remission status. Therefore,
MSD is not necessarily the best donor option for allogeneic HCT in this population.
3.  Development of ex vivo culture methods forprimary tumor specimens derived from patients of myeloid malignancies.
Chao Li1. , Kimihito Cojin Kawabata2. , SatoshiYamazaki3. 4. , Satoshi Takahashi1, 2, 5. , Yasuhito

Nannya1, 5.
1 Division of Hematopoietic Disease Control, IMSUT,
2 Division of Clinical Precision Research Platform,IMSUT
3 Division of Stem Cell Biology, Center for Stem Cell
Therapy, IMSUT
4 Division of Cell Regulation, Center of Experimental Medicine and Systems Biology, IMSUT
5 Department of Hematology/Oncology, IMSUT
HospitalHigh throughput drug sensitivity screening (DSS)
using patient-derived primary tumor specimens(PTS) are one of the most updated methods in current
precision medicine. Recently, we have developed anexperimental platform in which completely robotizedhandling of PTS is installed. They provide us with capability of conducting high throughput drug screening equipped with multicolor flow cytometry analyses upon ex vivo cultured PTS prepared onminiaturized 384-well-plate system. Even with thoseextremely modernized system, paucity of available
primary cells is a yet-to-be-solved issue, considering
numbers of candidate drugs, and types of clinicalquestions. The issue is more valid for PTS of myelodysplastic syndrome (MDS) , since the disease is characterized by its lower ratios of blast cells, and relatively lower cell numbers than highly proliferative acute
myeloid leukemia (AML) cells. In order to expand
possibility of those AML/ MDS PTS for more advanced applications, we have performed experiments
to side-by-side compare different ex vivo culture
methods. At Clinical Precision Research Platform, we
have already collected 159 different PTS aliquoted
into 1495 cryovials. They are ongoingly used either in
the automated DSS experiments, OMICS-analyses, orin this ex vivo culture assays. We have discoveredthat 1. Short-term culture protocols (up to 7 days) optimized for the current DSS assays make a few differences regardless of changed concentrations of serum
or other supplements for culture media. 2. Use of stromal feeder cells prevails other conventional stroma-free culture methods that are currently utilized
for normal hematopoietic stem cells. Moreover, 3. Recently, we installed the most updated culture methods to challenge for stroma-free, serum-free ex vivo
culture system optimized for PTS. The idea for theupdated culture media is derived from ongoing research projects by collaborators regarding normal hematopoietic stem cell culture. Initial data on this topic
is continuously fueling our research motivations, dayby day. Details of those findings will be followingly
updated.

150Publications1.		Kaito Y, Sugimoto E, Nakamura F, Tsukune Y,Sasaki M, Yui S, Yamaguchi H, Goyama S, Nannya
Y, Mitani K, Tamura H, Imai Y. Immune checkpoint molecule DNAM-1/CD112 axis is a novel
target for NK-cell therapy in acute myeloid leukemia. Haematologica.2023,
2.		Konuma T, Itonaga H, Ishiyama K, Hamamura A,Uchida N, Ozawa Y, Katayama Y, Sakurai M, Ueda
Y, Matsuoka KI, Kawakita T, Eto T, Ara T, Kanda J,Onizuka M, Fukuda T, Atsuta Y. Progress in survival following three decades of allogeneic hematopoietic cell transplantation for myelodysplastic syndrome: A real-world registry study inJapan. Am J Hematol. 2023, 98(4),E68-E71.
3.		Konuma T, Itonaga H, Shimomura Y, Fujioka M,Aoki K, Uchida N, Onizuka M, Jinguji A, Tanaka
M, Ueda Y, Katayama Y, Sawa M, Tanaka H, Na-kamae H, Kawakita T, Maruyama Y, Takahashi S,Ishimaru F, Kanda J, Ichinohe T, Atsuta Y. Single-unit unrelated cord blood transplantation versus HLA-matched sibling transplantation inadults with advanced myelodysplastic syndrome:
A registry-based study from the adult MDS working group of the Japanese society for transplantation and cellular therapy. Hematol Oncol. 2023,4.		Yanada M, Shimomura Y, Mizuno S, Matsuda K,
Kondo T, Doki N, Tanaka M, Fukuda T, Ara T,
Uchida N, Onizuka M, Sawa M, Ozawa Y, Hiramoto N, Ota S, Kanda J, Kanda Y, Ichinohe T,
Okamoto S, Atsuta Y, Konuma T. External validation and extended application of the transplantconditioning intensity score in acute myeloid leukemia. Bone Marrow Transplant. 2023, 58(10),1096-103.