ALBERT

Description: Introduction Despite recent developments on various transplantation procedures and supportive therapy, nonrelapse mortality (NRM) after allogeneic stem cell transplantation (allo-SCT) remains an essential issue. In choosing the appropriate regimen for allo-SCT, decision-making information that considers the complexity of different risk factors is vital. The Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), which was initially derived and validated by investigators at the Fred Hutchinson Cancer Research Center to predict NRM, has become a widely validated tool for predicting outcomes in many transplant settings (Sorror et al. Blood. 2005). It can also stratify patients for the risk of other outcomes, including overall survival and graft versus host disease. Patients with a high HCT-CI score tend to prefer allo-SCT with reduced-intensity conditioning. Conversely, for those who prefer allo-SCT with myeloablative conditioning (MAC) and has a low HCT-CI score, a prognostic indicator is unnecessary. Furthermore, the risk factors for NRM may differ among various conditioning regimens. Therefore, the current study aimed to establish a new prognostic model for patients specific to each MAC regimen before allo-SCT. Methods We performed a retrospective cohort study to develop prognostic models of NRM in patients conditioned with cyclophosphamide/total body irradiation (Cy/TBI) or busulfan/cyclophosphamide (Bu/Cy). We selected patients who had leukemia and lymphoma in remission or had untreated or stable myelodysplastic syndrome and experienced initial allo-SCT relapse between 2007 and 2017 in the Kanto Study of Group for Cell Therapy (KSGCT). The primary outcome measure was 2-year NRM. Furthermore, we evaluated variables such as patient age, albumin, liver function, renal function, respiratory function, ejection fraction (EF), C-reactive protein (CRP), stem cell source, donor type, antithymocyte globulin use, performance status, recipient/donor sexes, time interval from diagnosis to transplant, and HCT-CI score. To identify a set of variables for Cox proportional hazards, we used an Akaike Information Criterion (AIC)-based variable selection procedure. We assigned weights to individual parameters according to their prognostic significance in Cox proportional hazard models. The identified model's discriminative ability was assessed by Harrell's C-statistic calculated using the bootstrap method. Results Among the 555 patients analyzed, 338 received Cy/TBI, and 217 received Bu/Cy. In Cy/TBI and Bu/Cy, the median age was 39 (11-60) and 44 (18-62) years, the HCT-CI score ≤ 2 was observed in 82.1% and 87.6%, and 2-year NRM was found in 13.5% and 16.0% of the patients, respectively. Before transplantation, the most dominant parameters in Cy/TBI were abnormal liver function (AST/ALT or bilirubin 〉upper limit of normal) and albumin value 〈 4.5g/dL, whereas those in Bu/Cy were age 〉40 years, EF 〈 65 %, and CRP ≥ 0.2 mg/dL. Internal validation with bootstrap resampling showed good discrimination, with C-statistic values of 0.70 (95% CI: 0.69-0.71) in Cy/TBI and 0.68 (95% CI: 0.67-0.69) in Bu/Cy. Each of the abovementioned parameters, including age 〉40 years, was scored as 1 point. To evaluate the 2-year NRM, we divided the total scores into three risk groups. In the Cy/TBI group, the NRM was 6.9% in low (score 0-1, n = 186), 19.5% in intermediate (score 2, n = 127), and 35.3% in high (score 3, n = 25) scores. In the Bu/Cy group, the NRM was 8.3% in low (score 0-1, n = 93), 21.7% in intermediate (score 2, n = 98), and 29.8% in high (score 3, n = 26) scores (Figure). Higher scores were strongly associated with worse NRM and survival. Conclusions Our prognostic models for NRM estimation can distinguish patients with a high NRM risk. To our knowledge, these models are the first prognostic models used to estimate NRM for standard-risk patients specific to each MAC regimen. This new simple index may help predict NRM and choose an appropriate conditioning regimen before allo-SCT. Figure 1 Disclosures Nakasone: Takeda Pharmaceutical: Honoraria; Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical: Honoraria; Eisai: Honoraria; Chugai Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria. Fujisawa:Takeda Pharmaceutical Company Limited.: Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau; Novartis Pharma KK: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Janssen Pharmaceutical K.K: Speakers Bureau; NIPPON SHINYAKU CO.,LTD.: Research Funding. Nakaseko:Novartis Pharma KK: Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau. Kanda:Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Mochida Pharmaceutical: Honoraria; Mundipharma: Honoraria; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Shionogi: Research Funding; Otsuka: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Janssen: Honoraria; Astellas Pharma: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Pfizer: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria.

Description: Cytomegalovirus (CMV) infection is a major complication during allogeneic stem cell transplantation (allo-SCT). However, mechanisms of adaptive immunity that drive this remain unclear. To define early immunological responses to CMV after transplantation, we using next-generation sequencing to examine the repertoire of T-cell receptors in CD8+/CMV pp65 tetramer+ cells (CMV-CTLs) in peripheral blood samples obtained from 16 allo-SCT recipients with HLA-A*24:02 at the time of CMV reactivation. In most patients, TCR beta repertoire of CMV-CTLs was highly skewed (median Inverse Simpson’s index: 1.595) and, 15 of 16 patients shared at least one TCR-beta clonotype with ≥ 2 patients. The shared TCRs were dominant in 12 patients and, two clonotypes were shared by about half of the patients. Similarity analysis showed that CDR3 sequences of shared TCRs were more similar than unshared TCRs. TCR beta repertoires of CMV-CTLs in 12 patients were also analyzed after 2–4 weeks to characterize the short-term dynamics of TCR repertoires. In ten patients, we observed persistence of prevailing clones. In the other two patients, TCR repertoires became more diverse, major clones declined, and new private clones subsequently emerged. These results provided the substantive clue to understand the immunological behavior against CMV reactivation after allo-SCT.

Description: [Background] A marker chromosome (MAR) is a structurally abnormal chromosome that cannot be unambiguously identified or characterized by conventional chromosome analysis. MAR is considered to reflect genomic instability and is observed in 5% of acute myeloid leukemia (AML) patients. Although AML with MAR (AML/MAR+) was previously reported as refractory to chemotherapy, MAR is currently not considered associated with any specific cytogenetic risk category. Furthermore, the influence of MAR on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear. Thus, to understand the characteristics of AML/MAR+ and the influence on prognosis in patients with AML, we reviewed national survey data from Japan. [Patients and Methods] This retrospective study included 14,099 adult patients with AML evaluable for cytogenetic risk who received their first allo-HSCT between January 1986 and December 2017. All data were sourced from the registry of the Japanese Society for Hematopoietic Cell Transplantation. The median age at allo-HSCT was 48 y (range, 16-85 y). The median follow-up period was 1.4 y (range, 0-30 y). The definition of chromosomal abnormalities adhered to the International System for Human Cytogenetic Nomenclature guidelines; chromosomal gains and structural abnormalities had to be detected in at least two metaphases, and chromosomal losses in at least three metaphases to be acknowledged as clonal. Three or more chromosomal abnormalities were defined as "complex karyotype" (CK). Cytogenetic risk was classified as favorable (n = 2,246), intermediate (n = 9,236), or poor (n = 2,617) in accordance with the criteria provided by the National Comprehensive Cancer Network Guidelines (Version 1, 2016). We defined 1st/2nd/3rd remission (n = 8,039) as "remission" and underlying disease or primary induction failure (n = 5,960) as "non-remission". Some patients (n = 100) lacked disease stage data of pre-transplantation. For MAR evaluation, clinical phenotypes were compared, and overall survival (OS) and cumulated incidence of relapse (CIR) were calculated. These variables were validated using multivariate analysis. [Results] MAR was detected in 668 (4.6%) of the 14,099 patients. The median age of patients with AML/MAR+ was 55 y (range, 16-77 y), and so these patients were older than AML/MAR- patients (n = 13,431; age, 48 y; range, 16-85 y; P 〈 0.001). AML/MAR+ included more secondary AML than AML/MAR- (10.9% vs. 6.5%, P 〈 0.001). The frequency of MAR in poor-risk AML patients (n = 580, 22.2%) was significantly higher than in favorable- (n = 13, 0.6%) and intermediate-risk (n = 75, 0.8%) AML patients (P 〈 0.001). When the analysis was limited to poor-risk AML patients with CK (CK+AML, n = 1,368), the frequency of MAR was 42.1% (n = 576). Most cases of AML/MAR+ (n = 580, 86.8%) were categorized as poor-risk cases (vs. AML/MAR-, n = 2,037, 15.2%; P 〈 0.001). Moreover, almost all cases of poor-risk MAR (n = 576/580, 99.3%) reflected adjuncts of CK. Since AML/MAR+ has usually been considered poor-risk AML, especially CK+AML, we performed an evaluation focusing on these patients. First, among poor-risk AML patients, MAR was an independent risk factor of OS (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.20-1.56; P 〈 0.001) and CIR (HR, 1.41; 95% CI, 1.15-1.72; P 〈 0.001), based on the multivariable analysis adjusting for age, time of transplantation, performance status, disease stage, graft source, conditioning regimen, type of AML, and with/without CK. Next, in CK+AML, the 2-y-OS of CK+AML/MAR+ patients (n = 576) was 20.0% and thereby worse than that of CK+AML/ MAR- patients (n = 792, 33.2%; P 〈 0.001). The 2-y-CIR of CK+AML/MAR+ patients was 61.4% (vs. 48.2% in CK+AML/MAR- patients, P 〈 0.001). Furthermore, CK+AML/MAR+ patients who underwent transplant even in remission (n = 160) showed worse 2-y-OS (39.2%) and CIR (55.8%), than CK+AML/MAR- patients (n = 286, 54.5% [P = 0.004] and 37.8% [P=0.0011], respectively). In multivariable analysis adjusted for other prognosis factors, MAR was an independent risk factor of OS in CK+AML patients (HR, 1.40; 95% CI, 1.23-1.61; P 〈 0.001) and for CIR (HR, 1.44; 95% CI, 1.17-1.77; P 〈 0.001). [Conclusion] Cases of MAR almost exclusively reflected adjuncts of CK. MAR can be used to further stratify AML with CK after allo-HSCT. Disclosures Uchida: Sumitomo Dainippon Pharma: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka: Honoraria; Chugai Pharma: Honoraria; Novartis Pharma KK: Honoraria. Ozawa:Novartis Co., Ltd.: Honoraria. Kanda:Shionogi: Research Funding; Meiji Seika Kaisha: Honoraria; Sanofi: Honoraria, Research Funding; Mundipharma: Honoraria; Mochida Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Daiichi Sankyo: Honoraria; Shire: Honoraria; Alexion Pharmaceuticals: Honoraria; Takeda Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Novartis: Honoraria; Eisai: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Celgene: Honoraria; Otsuka: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Janssen: Honoraria; Astellas Pharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria. Ichinohe:Chugai Pharmaceutical Co., Ltd.: Research Funding; Zenyaku Kogyo Company, Limited: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria; Repertoire Genesis: Research Funding; FUJIFILM Wako Pure Chemical Corporation: Research Funding; Takara Bio Inc.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Research Funding.