No abstract

Background and Case We herein present a case of the co‐occurrence of JAK2 ‐mutated essential thrombocythemia (ET) with chronic lymphocytic leukemia (CLL) harboring the recurrent and rare whole‐arm translocation, der(8;17)(q10;q10). The co‐existence of lymphoproliferative neoplasms and myeloproliferative neoplasms is suggested to be a rare event. Under this condition, the lymphoproliferative disorder presents a clinically indolent course with a low‐risk biological profile. However, the present case showed aggressive disease progression, reflecting a poor prognostic factor; that is, the loss of 17p caused by the whole‐arm der(8;17)(q10;q10) translocation. Conclusion The present case report emphasizes the importance of considering the involvement of a genetically poor prognostic factor, regardless of the co‐occurrence of CLL and ET.

An 80-year-old male was referred to our hospital with dyspnea on effort. He had a history of diffuse large B-cell lymphoma 2 years ago, for which he was treated with chemotherapy, including rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone. His laboratory data included a white blood cell count of 1.9 × 10 9 /L, a hemoglobin concentration of 10.5 g/dl, and a platelet count of 92 × 10 9 /L. His serum lactate dehydrogenase level was 196 U/L.

Background: Sinusoidal obstruction syndrome (SOS) remains a significant, potentially lethal complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although a liver biopsy is required to diagnose SOS accurately, it is not considered a mandatory evaluation due to its invasiveness. Therefore, the Seattle and Baltimore criteria with minor revisions have been widely used. However, the diagnostic accuracy of those criteria is insufficient. A noninvasive and more accurate diagnostic strategy is necessary. A number of studies have reported several candidate blood biomarkers for the diagnosis and prediction of SOS. However, which biomarkers or combination thereof are most useful for the diagnosis and prediction of SOS is unclear. We explored the best diagnostic and predictive biomarkers/combination among previously reported biomarkers for SOS using a stringent definition based on a liver biopsy. Methods: We performed this single-center prospective observational study in patients who received allo-HCT from April 2014 to February 2019. Seven biomarkers (PAI-1, P3P, ferritin, total bilirubin [T-bil], direct bilirubin [D-bil], brain natriuretic peptide [BNP], and protein C activity) were examined at pre-conditioning, at days 5 and 30, and at the onset of CTCAE grade ≥2 liver disorder after allo-HCT. We described how to diagnose definitive SOS (Fig. 1). A logistic regression (LR) model and the area under the receiver operating characteristic curves (AUC) were used to compare the seven biomarkers in the diagnosis and prediction of definitive SOS. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio for the SOS diagnosis and prediction were also calculated by the best cut-off values, using the Youden index. Results of statistical tests with a p < 0.05 were considered significant. Results: A total of 180 patients were included. The median age was 48 (range: 16-68) years old. Forty-eight patients developed CTCAE grade ≥2 liver disorders. Of these, 10 were diagnosed with definitive SOS. The results of LR and AUC analyses of the SOS diagnosis and prediction are shown in the Table. PAI-1, P3P, ferritin, T-bil, and D-bil were found to be significant diagnostic markers for SOS. Among these, PAI-1 showed the highest AUC (0.85; 95% confidence interval [CI], 0.67-1.00). Furthermore, PAI-1, P3P, ferritin, T-bil, D-bil, and BNP were significant predictors for SOS. Among these biomarkers, P3P showed the highest AUC (0.82; 95% CI, 0.67-0.97). To perform further comparisons using multivariable models in SOS prediction, we first constructed a base model including the times of allo-HCT, disease status, and conditioning intensity. The AUC of the base model was 0.66 (95% CI, 0.48-0.84). After adding P3P to the base model, the AUC significantly improved to 0.88 (95% CI, 0.76-1.00) (p = 0.049). In the kinetics analysis of biomarkers, notably, PAI-1 and P3P increased over the peri-transplant period only in patients with definitive SOS (Fig. 2). In contrast, those values in patients with liver disorders other than SOS or without liver disorders did not show significant kinetic characteristics in the allo-HCT period. Discussion: SOS is attributed to toxic injury of the sinusoidal endothelial cells. PAI-1 is a known endothelial factor, released when the endothelial cells are damaged. This could be why PAI-1 was considered useful for the SOS diagnosis. P3P has been shown to be a sensitive biomarker for liver fibrosis. Furthermore, fibrous alterations in the hepatic remodeling process are well-known significant features for patients with SOS. Thus, liver fibrosis may pathophysiologically be a risk factor for SOS, and P3P may allow clinicians to detect SOS-high-risk patients with high accuracy, even at the time of allo-HCT when preclinical liver fibrosis can exist. Conclusion: We demonstrated that PAI-1 and P3P were the most useful biomarkers for the diagnosis and prediction of SOS, respectively. Figure 1 Figure 1. Disclosures Okamura: NIPPON SHINYAKU CO.,LTD.: Honoraria. Koh: AstraZeneca: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; MSD: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria, Research Funding; Novartis: Honoraria; NIHON PHARMACEUTICAL CO., LTD: Honoraria; Asahi Kasei Corporation:: Research Funding; IQVIA Services Japan K.K.:: Research Funding. Takakuwa: Takeda Pharmaceutical Company Limited.: Honoraria; Bristol-Myers Squibb　Comapany: Honoraria; Sanofi K.K.: Honoraria; Celgene Corporation: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Novartis: Honoraria; AbbVie GK: Research Funding; Celgene Corporation: Research Funding. Nakamae: Novartis: Honoraria. Nishimoto: Otsuka Pharmaceutical Co., Ltd.: Honoraria; CSL Behring: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; "Bayer Yakuhin, Ltd ": Research Funding; Janssen Pharmaceutical K.K.: Research Funding. Nakashima: Amgen Astellas BioPharma K.K.: Honoraria; Amgen Inc: Honoraria; Novartis: Honoraria, Research Funding; JCR Pharmaceuticals Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Eisai Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; SymBio Pharmaceuticals Limited.: Honoraria, Research Funding; Astellas Pharma Inc.: Research Funding; Celgene Corporation: Research Funding; AbbVie GK: Research Funding. Nakamae: Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria; Simon-Kucher & Partners: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Novartis: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb　Company: Honoraria, Research Funding; Alexion: Research Funding; PPD-SNBL K.K: Research Funding; CMIC HOLDINGS Co., Ltd: Research Funding. Hino: Novartis: Honoraria, Research Funding; NIPPON SHINYAKU CO.,LTD.: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Sanofi: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; AstraZeneca: Honoraria; Astellas Pharma Inc.: Honoraria; MSD: Honoraria, Research Funding; CSL Behring: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Meiji Seika Pharma Co., Ltd.: Honoraria; Eisai Co., Ltd: Honoraria, Research Funding; Kyowa Kirin Co., Ltd: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria, Research Funding; Bristol-Myers Squibb　Comapany: Honoraria; Janssen Pharmaceutical: Honoraria; JCR Pharmaceuticals Co., Ltd.: Research Funding; ARKRAY: Research Funding; Asahi Kasei Corporation:: Research Funding; Abbott: Research Funding; TEIJIN PHARMA LIMITED.: Research Funding; SEKISUI MEDICAL CO., LTD.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Research Funding; TOSOH CORPORATION: Research Funding.

Background: Central nervous system (CNS) complications after allogeneic hematopoietic cell transplantation (allo-HCT) can be fatal. Although numerous studies have reported risk factors for CNS complications after allo-HCT, most defined CNS complication events as a composite endpoint, for example, composed of cerebrovascular disease, infection, posterior reversible encephalopathy syndrome (PRES), and metabolic encephalopathy. For a more precise and targeted approach, risk factor analyses for each individual CNS event are needed. Few studies have reported risk factor analyses for individual CNS complications. They have included analyses for cerebrovascular disease, viral encephalitis, HHV6 encephalitis, and noninfectious neurologic complications. To our knowledge, no pretransplant risk factor analysis for calcineurin inhibitor-induced encephalopathy (CNIE) and limbic encephalitis (LE) has yet been reported. Method: We retrospectively examined consecutive patients who underwent allo-HCT at our institute between January 2005 and November 2017. CNIE was defined as a patient who exhibited clinical symptoms of PRES or neurological manifestations of thrombotic microangiopathy during cyclosporin A (CSA) or tacrolimus (TAC) administration. LE was defined as a patient who displayed selective medial temporal lobe involvement in brain MRIs. As a rule, HHV-6 DNA polymerase chain reaction was performed on cerebrospinal fluid (CSF) for LE cases. Results: A total of 485 patients between 16- and 69-years-old (median, 46 years) were eligible for this study. They received myeloablative (n = 292) or reduced-intensity conditioning (n = 193) for allo-HCT. Diagnoses included AML/ALL (n = 292), MDS (n = 59), NHL (n = 93), and others (n = 41). HLA allele typing was performed at HLA-A, -B, -C, and -DRB1. Donor sources consisted of HLA-matched or -one allele mismatched sibling peripheral blood (PB) or bone marrow (BM) (n = 98)/HLA matched unrelated donors (n = 93) (hereafter referred to as HLA-matched donors), HLA-mismatched unrelated BM (uBM; n = 36), umbilical cord blood (uCB; n = 110), haploidentical PB (n = 118), and allele unknown uBM (n = 30). A total of 33 CNS events were identified: 11 CNIE (33 %), 14 LE (42 %), 3 transverse myelitis (9.0 %), 2 drug encephalopathy (6.0 %), 1 aseptic meningitis (3.0 %), 1 fungal brain abscess (3.0 %), and 1 acute epidural hematoma (3.0 %). The median follow-up time among the survivors was 1836 days (range, 45-4860 days) after allo-HCT. By landmark time analysis, the prognosis of those with any CNS complications within 30 days was significantly worse than those who did not (1-year OS, 37.5 % vs. 55.4 %, Log-rank p = 0.011). A multivariable time-dependent Cox model revealed that CNS complications were an independent prognostic factor for overall survival (Hazard ratio (HR) 4.49, 95 % CI, 2.30-8.76, p < 0.001), adjusted for age and disease risk index. CNIE cases included 6 CSA-induced and 3 TAC-induced cases, of which 4 patients (44 %) were alive. In the multivariable Cox models, MDS (HR 9.4 (vs. AML/ALL), 95 % CI, 2.2-40, p = 0.002) and HLA-mismatched uBM (HR 16 (vs. HLA-matched donors), 95 % CI, 3.0-81, p = 0.001) were significantly associated with CNIE development. LE included 7 HHV6-negative (2 alive), 5 HHV6-positve (1 alive), and 2 unknown cases (1 alive). Eleven of these patients were treated by methylprednisolone pulse therapy; all patients responded partially or effectively and four patients (36 %) achieved complete remission. In the multivariable Cox models, HLA-mismatched uBM (HR 7.5 (vs. HLA-matched donors), 95 % CI, 1.2-45, p = 0.028) was significantly associated with LE development. Conclusion: CNS complications were found to be an independent risk factor for OS after allo-HCT, as reported previously. MDS and HLA-mismatched uBM were risk factors for CNIE; the former may be partly explained by the fact that a subset of MDS may be predisposed to vascular endothelial damage (e.g. vasculitis), since CNIE may be triggered by endothelial dysfunction caused by CNI. Moreover, HLA-mismatched uBM was a risk factor for LE. Experimental data revealed that major histocompatibility complex class 1 protein was expressed in hippocampal neurons; thus, the limbic system may be targeted by alloimmune reactions more frequently in HLA-mismatched uBM settings, regardless of whether HHV-6 reactivation occurs. Disclosures Koh: Alexion: Honoraria; DAIICHI SANKYO COMPANY: Honoraria; MSD K.K: Honoraria; Takeda Pharmaceutical: Honoraria, Research Funding; NIHON PHARMACEUTICAL: Honoraria; Takeda Science Foundation: Research Funding; Chugai Pharmaceutical: Research Funding; Amgen Astellas BioPharma: Research Funding; Asahi Kasei Corporation: Research Funding; IQVIA Services Japan: Research Funding. Okamura:Eisai Co., Ltd: Honoraria; MSD K.K: Honoraria. Shiro:Bristol-Myers Squibb: Honoraria. Nanno:Eisai Co., Ltd.: Honoraria; MSD K.K: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Nakamae:Chugai Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Japan Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Inc.: Research Funding; Alexion: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Japan Blood Products Organization: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire Japan KK.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria. Nakashima:Novartis: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Eisai Co.,Ltd: Honoraria, Research Funding; Celgene Corporation: Research Funding; Amgen Astellas BioPharma K.K.: Honoraria, Research Funding; AbbVie Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Bristol-Myers Squibb: Honoraria. Nakane:Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.,: Honoraria; Mundipharma K.K.: Honoraria; Novartis: Honoraria; Janssen Pharmaceutical K.K.: Research Funding; MSD K. K,: Research Funding; Pfizer Japan Inc.: Research Funding; Bayer Yakuhin, Ltd: Research Funding. Hino:MSD: Honoraria, Research Funding; Mundipharma: Honoraria; Nihon Pharmaceutical Co., Ltd: Research Funding; Sumitomo Dainippon Parma: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ono Pharmaceutical: Honoraria, Other: Consulting fee, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Pfizer Japan Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria; Shire Japan KK: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consulting fee, Research Funding; Mochica Pharmaceutical Co., Ltd: Honoraria; Eisai: Research Funding; Janssen: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria, Research Funding; Daichi-Sankyo: Honoraria, Research Funding; Astellas Pharma Inc: Honoraria, Research Funding; Astellas Amgen BioPharma: Honoraria; Bristol-Myers Squibb: Honoraria; Taiho Pharama: Research Funding; Takeda Pharmaceutical Co., Ltd: Honoraria, Research Funding; Teijin: Research Funding; Alexion: Honoraria; Abbott: Research Funding. Nakamae:Takeda Pharmaceutical Co., Ltd.: Honoraria; Skire Japan KK.: Honoraria; Pfizer Japan Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceutical: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Kwowa-Hakko kirin Co., Ltd.: Honoraria; Japan blood Products Organization: Honoraria; Janssen: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Astellas Pharma Inc.: Research Funding; Alexion: Honoraria.