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Meng Zhang,1,* Wenyi Lu,2,* Danni Xie,1 Jiaxi Wang,1 Xia Xiao,2 Yedi Pu,2 Juanxia Meng,2 Hairong Lyu,2 Mingfeng Zhao2 1First Center Clinic College of Tianjin Medical University, Tianjin, 300192, People’s Republic of China; 2Department of Hematology, Tianjin First Central Hospital, Tianjin, 300192, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mingfeng Zhao; Hairong Lyu, Department of Hematology, Tianjin First Central Hospital, Tianjin, 300192, People’s Republic of China, Email mingfengzhao@sina.com; 18802235939@163.comBackground: Metagenomic next-generation sequencing (mNGS) is a fast, sensitive and accurate diagnostic method for pathogens detection. However, reports on the application of mNGS in mucormycosis remain scarce.Methods: From January 2019 to December 2021, we recruited 13 patients with hematological malignancies who were suspected of mucormycosis and completed mNGS in D20. Then we retrospectively analyze the clinical data, diagnosis, therapeutic process, and outcomes. In order to evaluate the diagnostic value of mNGS in hematological malignancies patients with suspected mucormycosis.Results: All patients had high risk factors of Invasive Fungal Disease, including hematopoietic stem cell transplantation, immunosuppression, glucocorticoids, etc. The clinical presentations were pulmonary (n=9), rhino-orbito-cerebral (n=4). But the manifestations were nonspecific. All enrolled patients completed mNGS. And most (8/13, 61.54%) of the samples were from blood. Fungi can be detected in all specimens, including Rhizopus (n=7), Rhizomucor (n=4) and Mucor (n=2). In addition, 7/13 (53.85%) specimens were detected bacteria at the same time and virus were detected in 5/13 (38.46%). Histopathological examination was completed in 5 patients, 3 of which were completely consistent with the results of mNGS. After treatment, 6 patients were cured, while the other 7 patients died.Conclusion: mNGS may be a complementary method for early diagnosis, especially for patients who are not suitable for histopathology examination or unable to obtain culture specimen. mNGS can also help detect bacteria and viruses simultaneously, allowing for appropriate and timely antibiotic administration and thus improving patient outcomes.Keywords: metagenomic next-generation sequencing, mucormycosis, retrospectively, hematological malignancies, invasive fungal disease

Meng Zhang,1,2,&ast; Zhao Wang,2,&ast; Jiaxi Wang,1 Hairong Lv,2 Xia Xiao,2 Wenyi Lu,2 Xin Jin,2 Juanxia Meng,2 Yedi Pu,2 MingFeng Zhao2 1First Central Clinical College, Tianjin Medical University, Tianjin, 300192, People’s Republic of China; 2Department of Hematology, Tianjin First Central Hospital, Tianjin, 300192, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: MingFeng Zhao, Department of Hematology, Tianjin First Central Hospital, No. 24, Fukang Road, Nankai District, Tianjin, 300192, People’s Republic of China, Tel +16622082788, Email mingfengzhao@sina.comBackground: It was crucial to use empirical antibiotics in febrile neutropenia (FN) patients. However, most patients still died from infection due to poor efficacy. Metagenomic next-generation sequencing (mNGS) is a rapid microbiological diagnostic method. The value of mNGS in patients with FN remains to be studied, especially after empiric antibiotic treatment.Methods: We retrospectively analyzed the differences between mNGS and the traditional methods in 192 patients with hematological malignancies who have received empiric antibiotic treatment. Samples were collected when patient had chills or half an hour before peak body temperature. And we compared the differences between FN and non-FN patients, mainly including types of pathogens and the diagnostic value of different pathogens.Results: Despite receiving empirical treatment, the pathogen detection rate of mNGS was significantly higher than the traditional method (80.21% vs 25.00%, P< 0.001). And it has obvious advantages in detecting mixed pathogens infection (80.21% vs 4.17%, P< 0.001). Then, we found that mNGS saw more pathogens in the FN than in the non-FN group, especially fungus. 21/33 (63.63%) of FN patients was diagnosed with fungal infections. The fungal detection rate in FN was significantly higher than non-FN group (32.35% vs 12.22%, P=0.001). Besides, the sensitivity of mNGS was higher than the traditional methods in both FN and non-FN group (P< 0.001), but no significant difference in specificity (P> 0.05). In the FN group, empiric antibiotic treatment of 46/102 (45.10%) patients did not treat all the pathogens detected by mNGS. After adjusting the antimicrobial regimen according to the results of mNGS, the effective rate at 72 hours and 7 days was 22/46 (47.83%) and 24/102 (52.17%), respectively.Conclusion: mNGS had a significant impact on the diagnosis of infection and the second-line antimicrobial therapy in FN. mNGS plays a more important role in FN patients, especially in the diagnosis of fungal infections.Purpose: Firstly, we compared the difference between mNGS and the traditional methods in the diagnosis of infection. Secondly, we assessed the value of mNGS in FN patients by comparing it with non-FN patients, including types of pathogens and the diagnostic value of different pathogens. In order to show that mNGS plays a more important role in FN.Keywords: metagenomic next-generation sequencing, febrile neutropenia, infection, fever, empiric antibiotic treatment

A patient with relapsed mantle cell lymphoma (MCL) showed stable disease after receiving ibrutinib therapy as a salvage therapy, after the failure of his first chimeric antigen receptor (CAR)-T 19 cell therapy.The combined effects of CAR-T 19 cells from the patient and ibrutinib on JeKo-1 cell were explored in vitro and in vivo.The expression of programmed death-1 (PD-1) receptor on CD3+ T cells in the peripheral blood decreased from 82.95% in the first CAR-T 19 cell therapy to approx. 40% after 14 months of ibrutinib therapy. When the disease progressed again during the ibrutinib therapy, the patient was enrolled into the same clinical trial of CAR-T 19 cell therapy.The efficacy of CAR-T 19 cells increased after the ibrutinib therapy. The mRNA expression level of PD-1 in CAR-T 19 cells after ibrutinib therapy was lower than in CAR-T 19 cells before the ibrutinib therapy. Nevertheless, CAR-T 19 cell therapy combined with ibrutinib had no synergistic effect in a short term in vitro and in the JeKo-1 cell mouse model.We expect our results to provide evidence for the combination treatment of ibrutinib for MCL or even other types of B-cell lymphomas. Moreover, the improvement in CAR-T 19 cell function was based on long-term ibrutinib therapy.