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2097 Impact of Homozygous Conserved Extended HLA Haplotypes on Cord Blood Transplantation: Implications for Induced Pluripotent Stem Cell Banking and Transplantation

Program: Oral and Poster Abstracts
Session: 721. Clinical Allogeneic Transplantation: Conditioning Regimens, Engraftment, and Acute Transplant Toxicities: Poster I
Hematology Disease Topics & Pathways:
Biological, Diseases, Therapies, Clinically relevant, transplantation, stem cells
Saturday, December 1, 2018, 6:15 PM-8:15 PM
Hall GH (San Diego Convention Center)

Yasuo Morishima, MD, PhD1,2,3*, Satoko Morishima, MD, PhD4*, Makoto Murata, MD, PhD5, Nobuyoshi Arima, MD, PhD6*, Naoyuki Uchida, MD, PhD7*, Yuji Ohno, MD, PhD8*, Satoshi Takahashi, MD, PhD9, Yoshiko Matsuhashi, MD, PhD10*, Makoto Onizuka, MD, PhD11, Tetsuya Eto, MD, PhD12*, Yoshiko Atsuta, MD, PhD13*, Takahiro Fukuda, MD, PhD14*, Tatsuo Ichinohe, MD, PhD15, Shunichi Kato, MD, PhD16* and Junya Kanda, MD17

1Central Japan Cord Blood Bank, Seto, Japan
2Nakagami Hospital, Okinawa, Japan
3Aichi Medical University, Nagoya, Japan
4University Hospital of the Ryukyu, Nishihara, Japan
5Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan
6Medical Research Institute Kitano Hospital, Osaka, Japan
7Department of Hematology, Toranomon Hospital, Tokyo, Japan
8Kitakyushu Municipal Medical Center, Kitakyushu, Japan
9Institute of Medical Science, University of Tokyo, Tokyo, Japan
10Kawasaki Medical School Hospital, Kurashiki, Japan
11Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Japan
12Department of Hematology, Hamanomachi Hospital, Fukuoka, Japan
13Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan
14Hematopoietic Stem Cell Transplantation Division, National Cancer Center Hospital, Tokyo, Japan
15Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
16Tokai University School of Medicine, Isehara, Japan
17Department of Hematology and Oncology, Kyoto University Hospital, Kyoto, Japan

Induced pluripotent stem cells (iPSC) have the capacity to generate various tissues/organs, and clinical application in autologous settings in humans has just begun. However, autologous transplantation is hampered by the high time and cost required for the individual production of iPSC. To solve these issues, allogeneic iPSC transplantation (allo-iPS-T) from iPSC banking has been proposed. A candidate for this is iPSC induced from individuals with a homozygous HLA haplotype (HLA-homo), on the basis that HLA-homo iPSC might not be rejected by HLA haplotype-matched patients. Concerns have been raised over whether allo-iPS-T from HLA-homo iPSC induces immunogenicity in clinical settings. Cord blood transplantation (CBT) might be a suitable model for evaluating these concerns, because HLA mismatch CBT from donors with less than two HLA loci mismatches is common, and carries a high engraftment failure rate, with a range of 10% to 20%. Further, cord blood cells are reported to be good source for the production of iPSC. Here, we report an analysis of allogeneic immunogenicity which focuses on engraftment of unrelated transplantation from HLA-homo cord blood.

Using Transplant Registry of Japanese Data Center for Hematopoietic Cell Transplantation, we could analyze 5017 Japanese CBT pairs who were typed as HLA-A, -B, -C, -DRB1 alleles at the field 1 and 2 level, and transplanted single unit of cord blood for the first time. Patient age was ranged from 0 to 80 years old (median 50), Patient with AML was 1,113, ALL 884, MDS 514, other hematological malignancy 1,007 and non-hematological malignancy 374. 20 patients were transplanted in 1999-2004, 1,484 in 2005-2010 and 3,513 in 2011-2016. Donor HLA homo and patient HLA hetero combination (homo-hetero) was found in 39 pairs, hetero-homo in 40, homo-homo in 21, hetero-hetero with HLA allele match in HVG vector in 236, hetero-hetero with one allele mismatch in 569 and hetero-hetero with more than 2 allele mismatch in 4112 pairs.

Of note, all of 39 HLA homo-hetero pairs obtained neutrophil engraftment (500/μl) at 10-51 day (median 20) after transplantation except one early death pair. Platelet engraftment (20,000/μl) was also obtained in all evaluable 30 pairs. Acute GVHD with grade Ⅱ-Ⅳ and grade Ⅲ-Ⅳ occurred in 17 pairs and 3 pairs of 38 evaluable pairs respectively. Multivariate competing risk regression analysis including clinical factors revealed that homo-hetero pairs (n=39) showed a comparative neutrophil engraftment risk (HR=1.18 p=0.285) compared with HLA allele match hetero-hetero pairs (n=236), favorable risk compared with hetero-hetero pairs with HLA 1 allele mismatch (n=569) and favorable risk compared with hetero-hetero pairs with HLA more than 2 allele mismatch (n=4112). Also, these homo-hetero pairs showed comparative mortality (HR 0.95 P=0.85), platelet engraftment ((HR 1.10 p=0.597) and a tendency of higher risk of acute GVHD (grade 2-4) HR 1.63. p=0.065) compared with HLA allele match hetero-hetero pairs.

Further, we obtained detailed information on HLA alleles and haplotypes of HLA-homo. 37 of 39 homo-hetero donors had conserved extended HLA haplotypes (HP-1 n=18, HP=2 n=8, HP=3 n=7, HP-4 n=5, HP-5 n=1) which were ethnicity specific and highly conserved through the entire HLA region, and one of two patient heterogeneous HPs invariably shared the same HP as donor HLA-homo HP, and another non-shared patient HP was mismatched with 1 to 4 HLA alleles of HLA-A, -B, -C and -DRB1 loci in the GVH direction in 33 of these 37 pairs. The KIR2DL1 epitope was donor C1/C1 and patient C1/C1 in all homo-hetero pairs, making the KIR2DL ligand match combination.

In conclusion, CBTs from homo-hetero showed a favorable engraftment rate (100%), which confirmed our previous preliminary report for 6 homo-hetero CBTs. HLA alleles of HLA-homo donor were consisted of major conserved extended HLA haplotypes. Those results carry an important implication, namely the possibility that HLA-homo iPSC transplantation results in favorable engraftment, and banking of iPSC with major conserved extended HLA haplotypes is recommended, and patients possessing a single conserved common HLA haplotype have a higher chance of yielding HLA-homo iPSC and promising allo-iPS-T.

Disclosures: Ichinohe: Janssen Pharmaceutical K.K.: Honoraria; Mundipharma: Honoraria; Alexion Pharmaceuticals: Honoraria; Taiho Pharmaceutical Co.: Research Funding; Takeda Pharmaceutical Co.: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; MSD: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical Co.: Research Funding; Kyowa Hakko Kirin Co.: Research Funding; CSL Behring: Research Funding; JCR Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Zenyaku Kogyo Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Research Funding; Repertoire Genesis Inc.: Research Funding; Nippon Shinyaku Co.: Research Funding; Eisai Co.: Research Funding; Chugai Pharmaceutical Co.: Research Funding; Astellas Pharma: Research Funding; Novartis.: Honoraria.

*signifies non-member of ASH