Abstract: Mutations of CCAAT/enhancer–binding protein alpha (CEBPAmu) are found in 10% to 15% of de novo acute myeloid leukemia (AML) cases. Double-mutated CEBPA (CEBPAdm) is associated with a favorable prognosis; however, single-mutated CEBPA (CEBPAsm) does not seem to improve prognosis. We investigated CEBPAmu for prognosis in 1028 patients with AML, registered in the Multi-center Collaborative Program for Gene Sequencing of Japanese AML. It was found that CEBPAmu in the basic leucine zipper domain (bZIP) was strongly associated with a favorable prognosis, but CEBPAmu out of the bZIP domain was not. The presence of CEBPAmu in bZIP was a strong indicator of a higher chance of achieving complete remission (P & lt; .001), better overall survival (OS; P & lt; .001) and a lower risk of relapse (P & lt; .001). The prognostic significance of CEBPAmu in bZIP was also observed in the subgroup with CEBPAsm (all patients: OS, P = .008; the cumulative incidence of relapse, P = .063; patients aged ≤70 years and with intermediate-risk karyotype: OS, P = .008; cumulative incidence of relapse, P = .026). Multivariate analysis of 744 patients aged ≤70 years showed that CEBPAmu in bZIP was the most potent predictor of OS (hazard ratio, 0.3287; P & lt; .001). CEBPAdm was validated as a cofounding factor, which was overlapping with CEBPAmu in bZIP. In summary, these findings indicate that CEBPAmu in bZIP is a potent marker for AML prognosis. It holds potential in the refinement of treatment stratification and the development of targeted therapeutic approaches in CEBPA-mutated AML.

Abstract: Nucleophosmin1 ( NPM1 ) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1 ‐mutated AML. Although patients with NPM1 ‐mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A ( DNMT3A R882 mutations) were a strong predicative factor indicating poor prognosis in all AML ( p   〈  0.0001) and NPM1 ‐mutated AML cases ( p  = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3A R882 mutations and the co‐occurrence of internal tandem duplication in FMS‐like tyrosine kinase 3 ( FLT3 ‐ITD), NPM1 mutations, and DNMT3A R882 mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3A R882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3A R882 mutations and triple mutations on prognosis and according to the classification of NPM1 ‐mutated AML into three risk groups based on DNMT3A R882 / FLT3 ‐ITD genotypes, we achieved the improved stratification of prognosis ( p   〈  0.0001). We showed that DNMT3A R882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3A R882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status.

Abstract: Background The immunological effect of human leukocyte antigen (HLA) disparity has not been fully elucidated by the number and locus of HLA antigens or alleles. Several methods to predict epitopes recognized by the immune system have been developed to understand the immunogenicity of amino acid sequences in mismatched HLA pairs. We investigated the association between mismatching of HLA antibody-identified epitopes and hematopoietic stem cell transplantation (HSCT) outcomes. Patients and Methods This was a retrospective cohort study with 9,991 patients who underwent their first HSCT for hematologic malignancies from unrelated bone marrow donors in the Transplant Registry Unified Management Program (TRUMP). HLA epitope mismatches (EMM) were quantified using HLA-matchmaker (HLAMM). We conducted a multivariate analysis using Cox proportional hazard regression for the overall survival and the Fine-Gray regression model for competing risks. Statistical analyses were performed with Stata version 15.1 and R version 4.0.2. Results The median follow-up period for survivors was 6.3 years (interquartile range [IQR], 2.5-9.2 years). The most common indication for HSCT was acute myeloid leukemia (n=3,917, 39.2%), followed by acute lymphoblastic leukemia (n=1,913, 19.2%), and mature lymphoid malignancies (n=1,906, 19.1%). HSCT from HLA-matched, HLA 1 allele mismatched, and HLA 2 or more allele mismatched donors was received by 6,200, 2660, and 1131 patients, respectively. The number of EMM in recipient-donor pairs in our study population ranged from 0 to 37 in HLA class I (median, 0) and 0 to 60 in HLA class II (median, 1). Patients were categorized into two groups, low and high EMM, using the median value for each epitope matching as the threshold. Higher HLA class I EMM in the graft-versus-host (GVH) direction was associated with a significantly higher risk of grade III-IV acute GVHD (aGVHD) (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.21-2.36). Higher EMM for both class I and class II in the host-versus-graft (HVG) direction was associated with a significantly longer time to neutrophil engraftment (HR 0.78, 95% CI 0.65-0.95). In subgroup analysis limited to HLA 1 allele mismatch, class I high EMM group in the GVH direction had a significant association with higher risk for grade II-IV and grade III-IV aGVHD compared with both class I and class II low-EMM group (HR 1.69, 95% CI 1.16-2.47). Patients with HLA-C EMM accounted for 94.5% (n=1,603) of patients with HLA class I EMM. We further investigated the impact of HLA-C on severe aGVHD in relation to other known high-risk mismatch patterns. All killer immunoglobulin-like receptor (KIR)-ligand mismatched recipient-donor pairs (n=376) had HLA-C EMM. In multivariate analysis, patients with KIR-ligand mismatches and EMM did not show a higher incidence of grade III-IV aGVHD compared with KIR-ligand-matched patients with EMM (HR 0.96, 95% CI 0.74-1.25). In addition to the known high-risk mismatch patterns in the Japanese cohort (Kawase et al. Blood. 2007, Morishima et al. Haematologica. 2016), EMM was associated with a higher risk for grade III-IV aGVHD (Figure 1A, compared with HLA-C allele-matched patients (Match), HLA-C allele-mismatched patients without antigen mismatches, and EMM (group A): HR 0.78, 95% CI 0.41-1.48; HLA-C antigen-mismatched patients without EMM (group B): HR 0.56, 95% CI 0.28-1.15; HLA-C epitope-mismatched patients without high-risk mismatches (group C): HR 1.67, 95% CI 1.44-1.95; Patients with high-risk mismatches other than patient mismatched HLA-C*14:02 (group D): HR 2.01, 95% CI 1.50-2.69; Patients with patient mismatched HLA-C*14:02 (group E): HR 3.38, 95% CI 2.39-4.78). HLA-C epitope-mismatched patients without high-risk mismatches also showed a higher incidence of non-relapse mortality (NRM) and lower overall survival (OS) than HLA-C allele-matched patients (NRM (Figure 1B): HR 1.39, 95% CI 1.25-1.54; OS (Figure 1C): HR 1.20, 95% CI 1.10-1.30). Conclusion HLAMM-based epitope matching might be useful for identifying high-risk groups who can develop serious complications after HSCT from HLA-mismatched unrelated donors. In the HLA-C locus, epitope-mismatched recipient-donor pairs are non-permissive mismatched patterns along with known high-risk amino acid substitutions. Our findings might be helpful for clinicians in selecting permissive donors from alternative donor options. Figure 1 Figure 1. Disclosures Iwasaki: Amgen Astellas BioPharma: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Bristol-Myers Squibb Co: Honoraria; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co., Ltd.: Honoraria; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; NextGeM Inc: Patents & Royalties; Novartis Pharma K.K.: Honoraria; Ono Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees; TEIJIN PHARMA LIMTED.: Honoraria. Uchida: Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma Inc.: Honoraria. Kataoka: Ono Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria; Eisai: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; AstraZeneca: Honoraria; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Asahi Genomics: Current holder of individual stocks in a privately-held company; Shionogi: Research Funding; Teijin Pharma: Research Funding; Japan Blood Products Organization: Research Funding; Bristol-Myers Squibb: Research Funding; Mochida Pharmaceutical: Research Funding; JCR Pharmaceuticals: Research Funding; MSD: Research Funding. Kanda: MSD: Honoraria; Sanofi: Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding. Ichinohe: Daiichi Sankyo: Research Funding; Bristol-Myers Squibb: Honoraria; Chugai Pharmaceutical: Research Funding; CSL Behring: Honoraria, Research Funding; Eisai Co.: Honoraria, Research Funding; FUJIFILM Wako Chemicals.: Honoraria, Research Funding; Kyowa Kirin Co.: Honoraria, Research Funding; Ono Pharmaceutical Co.: Honoraria, Research Funding; Nippon Shinyaku Co: Research Funding; Otsuka Pharmaceutical Co.: Research Funding; Sumitomo Dainippon Pharma Co.: Honoraria, Research Funding; Taiho Pharmaceutical Co.: Research Funding; Takara Bio Inc.: Research Funding; Zenyaku Kogyo Co.: Research Funding; Celgene: Honoraria; Novartis Pharma K.K.: Honoraria; Repertoire Genesis Inc.: Honoraria, Research Funding; AbbVie Pharma: Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda Pharmaceutical Co.: Honoraria. Atsuta: Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria.

Abstract: Introduction: Selection of an appropriate donor is important for the success of allogeneic hematopoietic stem cell transplantation (allo-HCT). In general, an HLA-matched related donor (M-RD) and an HLA-matched unrelated donor (M-UD) are considered to be the first and second preferred donors in allo-HCT. On the other hand, the most suitable alternative donor remains unclear, when M-RD and M-UD are unavailable. In addition, the information on a suitable donor selection for elderly patients are limited. We hypothesized that the patient age might change the donor selection priority in allo-HCT, because related donor age, organ function, or endurance against graft-versus-host disease or infection differ between younger and older patients. Therefore, we conducted a nationwide, large retrospective study to investigate the donor selection priority in allo-HCT, classified according to patient age. Methods: We analyzed 17848 adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, or myelodysplastic syndrome who underwent a first all-HCT between 2007 and 2017 in Japan. We compared the transplant outcomes among M-RD (n=4106), HLA 1-antigen-mismatched related donor (1MM-RD) (n=592), HLA 2,3-antigen-mismatched related donor (23MM-RD) (n=882), M-UD (n=3927), HLA 1-locus-mismatched unrelated donor (1MM-UD) (n=2474), and unrelated cord blood (U-CB) (n=5867), in the whole cohort and in subgroups of patients aged & lt;50 years (n=8572) and those aged ≥50 years (n=9275). All P-values were two sided, and P-values & lt;0.05 were considered statistically significant. Results: Results of multivariate analyses of overall survival (OS), non-relapse mortality (NRM) and relapse are summarized in Table 1. For all patients, 1MM-RD, 23MM-RD, 1MM-UD, and U-CB were independent significant adverse factors for OS and NRM (hazard ratio [HR] 1.26, p & lt;0.001 and HR 1.93, p & lt;0.001 for 1MM-RD; HR 1.46, p & lt;0.001 and HR 2.15, p & lt;0.001 for 23MM-RD; HR 1.12, p=0.0032 and HR 1.68, p & lt;0.001 for 1MM-UD; and HR 1.19, p & lt;0.001 and HR 1.70, p & lt;0.001 for U-CB) compared to M-RD. On the other hand, there was no significant difference in OS between the M-RD and M-UD groups (HR 0.94, p=0.093), although NRM in the M-UD was inferior to that in the M-RD group (HR 1.27, p & lt;0.001). The risk of relapse in the 1MM-RD, 23MMRD, M-UD, 1MM-UD, and U-CB groups were significantly lower than that in the M-RD group. An interaction test revealed that the effect of M-UD on OS and NRM differed between the patient age & lt;50 years and ≥50 years (HR 0.88, p=0.055 and HR 0.78, p=0.019). Next, we compared transplant outcomes among these donor source within subgroups of patients grouped according to patient age. For the patients aged & lt;50 years, 23MM-RD, 1MM-UD, and U-CB were independent significant adverse factors for OS (HR 1.46, p & lt;0.001, HR 1.18, p & lt;0.001 and HR 1.20, p & lt;0.001), and 1MM-RD tended to be an adverse factor for OS (HR 1.19, p=0.052). On the other hand, OS in the M-UD group was comparable to that in the M-RD group (HR 1.02, p=0.72). For the patients aged ≥50 years, 1MM-RD, 23MMRD, and U-CB were independent significant adverse factors for OS (HR 1.29, p=0.0013, HR 1.42, p & lt;0.001 and HR 1.17, p & lt;0.001). 1MM-UD was not a significant adverse factor for OS (HR 1.07, p=0.18). Conversely, OS in the M-UD group was superior to that in the M-RD group (HR 0.89, p=0.012). In addition, we classified the M-UD group according to donor age (M-UD-Y, donor age & lt;50 years; M-UD-O, donor age ≥50 years). For the patients aged ≥50 years, OS in the M-UD-Y group was superior to that in the M-RD group (HR 0.86, p=0.035), although there was no significant difference in OS between the M-UD-O and M-RD groups (HR 1.08, p=0.70). However, for the patients aged & lt;50 years, OS in the both M-UD-Y and M-UD-O groups were comparable to those in the M-RD group (HR 1.02, p=0.73 and HR 1.04, p=0.82). The probabilities of adjusted OS at 3 years for the patients aged & lt;50 years and aged ≥50 years were 63.6% and 41.6% in the M-RD group, 58.4% and 38.8% in the 1MM-RD group, 52.3% and 30.4% in the 23MM-RD group, 63.6% and 46.8% in the M-UD group, 58.9% and 42.3% in the 1MM-UD group, and 60.1% and 40.3% in the U-CB group (Figure 1). Conclusions: Donor selection priority in all-HCT might be different according to patient age. In particular, young M-UD might be the first preferred donor for patients aged 50 years or older. We should reconsider donor selection priority in allo-HCT based on patient and donor age. Disclosures Kanda: Takeda: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Chugai: Honoraria; Kyowa Hakko Kirin: Honoraria; Otsuka: Honoraria; Bristol-Meyers Squib: Honoraria; JCR Pharmaceuticals: Honoraria; MSD: Honoraria; Daiichi Sankyo Company: Honoraria; NextGeM Incorporation: Patents & Royalties: 2019-011392. Kimura:JSPS KAKENHI: Research Funding. Ozawa:Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Astellas Pharma Inc.: Honoraria; Kyowa-Hakko Kirin: Honoraria. Atsuta:Kyowa Kirin Co., Ltd: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria. Kanda:Pfizer: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; CSL Behring: Research Funding; MSD: Research Funding; Pfizer: Research Funding; MSD: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Tanabe Mitsubishi: Research Funding; CSL Behring: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Otsuka: Research Funding; Tanabe Mitsubishi: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Taisho-Toyama: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Celgene: Consultancy, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Sanofi: Research Funding; Takara-bio: Consultancy, Honoraria; Taisho-Toyama: Research Funding; Taiho: Research Funding; Nippon-Shinyaku: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Mochida: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Takara-bio: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Nippon-Shinyaku: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding.

Abstract: Reduced-intensity conditioning (RIC) regimens have long-term outcomes that are generally comparable with those of myeloablative conditioning (MAC) because of a lower risk of nonrelapse mortality (NRM) but a higher risk of relapse. However, it is unclear how we should select the conditioning intensity in individual cases. We propose the risk assessment for the intensity of conditioning regimen in elderly patients (RICE) score. We retrospectively analyzed 6147 recipients aged 50 to 69 years using a Japanese registry database. Based on the interaction analyses, advanced age (≥60 years), hematopoietic cell transplantation–specific comorbidity index (≥2), and umbilical cord blood were used to design a scoring system to predict the difference in an individual patient's risk of NRM between MAC and RIC: the RICE score, which is the sum of the 3 factors. Zero or 1 implies low RICE score and 2 or 3, high RICE score. In multivariate analyses, RIC was significantly associated with a decreased risk of NRM in patients with a high RICE score (training cohort: hazard ratio [HR], 0.73; 95% confidence interval [CI] , 0.60-0.90; P = .003; validation cohort: HR, 0.57; 95% CI, 0.43-0.77; P  & lt; .001). In contrast, we found no significant differences in NRM between MAC and RIC in patients with a low RICE score (training cohort: HR, 0.99; 95% CI, 0.85-1.15; P = .860; validation cohort: HR, 0.81; 95% CI, 0.66-1.01; P = .061). In summary, a new and simple scoring system, the RICE score, appears to be useful for personalizing the conditioning intensity and could improve transplant outcomes in older patients.