Objectives The aim of this retrospective study was to evaluate the safety and efficacy of SEAM regimen followed by auto-SCT in lymphoma. Patients and methods We retrospectively reviewed the records of patients with lymphoma who underwent auto-SCT with SEAM conditioning regimen from January 2010 to June 2018 at our centre. In total, 97 patients were analysed. Results The median time to neutrophil engraftment and platelet engraftment was 9.5 days (range, 7-15 days) and 12 days (range, 7-25 days), respectively. Grade 3-4 nausea/vomiting, mucositis and diarrhoea were observed in 21.6%, 36.1%, and 11.3% of patients, respectively. Treatment-related mortality at 100 days occurred in 2 patients (2.1%). After a median follow-up time of 53.9 months, the 3-year incidence of disease relapse or progression was 34%. The estimated progression-free survival and overall survival at 3 years were 62% and 75%, respectively. Compared with previous studies using BEAM as the conditioning regimen, this study shows that the SEAM regimen has a comparable efficacy and safety profile. Conclusions The SEAM regimen is feasible and might be an ideal alternative to BEAM regimen for lymphoma auto-SCT.

Background:Chimeric antigen receptor T cell (CAR-T) therapy has achieved remarkable effects in refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL). However, many patients receiving CAR-T therapy still eventually die of disease recurrence or progression due to target antigen loss or exhaustion of CAR-T cells. Therefore, maintaining the efficacy of CAR-T has become a particular research focus. As lenalidomide can regulate T cell function, we conducted a study to evaluate the efficacy of lenalidomide maintenance after CAR-T therapy in R/R DLBCL patients.Methods:Seven R/R DLBCL patients who received lenalidomide maintenance after CAR-T therapy and nine DLBCL patients that underwent CAR-T treatment alone were included. The clinical data of all subjects were collected to evaluate the efficacy of lenalidomide maintenance. In order to understand the possible mechanisms of lenalidomide in CAR-T therapy, CAR-T copies of peripheral blood were regularly detected by quantitative real-time polymerase chain reaction, and an in vitro test was also conducted.Results:Overall survival (OS) was significantly prolonged in the lenalidomide maintenance group. Furthermore, one case responding to CAR-T therapy initially but suffering a relapse shortly achieved complete remission again after lenalidomide exposure, with an increase in the number of CAR-T copies detected. The in vitro test showed that lenalidomide could delay the exhaustion of CAR-T cells.Conclusions:Lenalidomide maintenance after CAR-T therapy is a safe and effective choice for R/R DLBCL patients. We confirmed that lenalidomide maintenance can improve patients' OS, and the delayed exhaustion of CAR-T cells may contribute to this OS benefit.

Hepatosplenic γ δ T-cell lymphoma (HSTCL) is a rare subtype of peripheral T-cell lymphoma (PTCL) with aggressive clinical behavior. To date, no standard therapy for HSTCL has been established. This study analyzed the clinical features, treatment, and prognosis for patients with HSTCL to determine the best therapeutic approach. We reviewed the clinical characteristics, treatments, and responses to treatment of patients in our center between January 2001 and June 2021, and also reviewed related literature. Median patient age was 38 years (range 16–60 years) and the patients included eight males and six females. HSTCL in these patients typically presented with B symptoms (71.4%), splenomegaly (100%), and hepatomegaly (50.0%), but lymphadenopathy was extremely rare. In these patients, routine laboratory testing showed elevated lactate dehydrogenase (71.4%), liver dysfunction (42.9%), and decreased fibrinogen (35.7%). In the induction phase, five of the 14 patients received chemotherapy regimens containing anthracycline (CHOP, or CHOP plus bortezomib or Chidamide), and six were treated with non-CHOP chemotherapy. Seven patients responded to induction treatment, four of whom received allogeneic hematopoietic cell transplantation and then achieved a complete response in the consolidation phase. survival time of patients who received alloHCT range from 10 to 27 months. Hepatosplenic γ δ T-cell lacks a standard therapy and is often refractory to conventional chemotherapy regimens. Intensive induction chemotherapy followed by hematopoietic cell transplantation may improve the prognosis of HSTCL.

Background The use of T cells expressing chimeric antigen receptor (CAR T) engineered to target CD19 constitutes breakthrough treatment for relapsed or refractory B cell non-Hodgkin lymphoma (R/R B-NHL). Despite improved outcomes, high relapse rate remains a challenge to overcome. Here, we report the clinical results and the pharmacokinetics of bispecific CD19/22 CAR T in patients with R/R B-NHL. Methods We performed a prospective, single-arm study of bispecific CD19/22 CAR T cells in R/R B-NHL. We analyzed the safety and efficacy and investigated the kinetic profiles of the CAR T cells. CAR transgene levels were measured using quantitative polymerase chain reaction, and correlation analyses of pharmacodynamic markers and product characteristics, disease conditions, clinical efficacy and adverse events were performed. Results From August 2017 to September 2020, a total of 32 patients with CD19/22 CAR T administration were analyzed. The overall response rate was 79.3%, and the complete response rate was 34.5%. The progression-free survival (PFS) and overall survival (OS) rates at 12 months were 40.0% and 63.3%, respectively. Among patients who had a CR at 3 months, the PFS and OS rates at 12 months were 66.7% and 100%, respectively. Severe cytokine release syndrome (sCRS) (grade 3 and higher) occurred in nine patients (28.1%). Grade 3 or higher neurologic events occurred in four patients (12.5%). One patient died from irreversible severe CRS-associated acute kidney injury. Long-term CAR T cells persistence correlated with clinical efficacy (133 days vs 22 days, P = 0.004). Patients treated with more than three prior therapies and presenting extranodal organ involvement had lower maximal concentration (Cmax) values than other patients. Responders had higher Cmax and area under the curve values than non-responders. Tumour burden and Cmax were potentially associated with the severity of CRS. Conclusions This study demonstrates the safety and potential clinical efficacy of bispecific CD19/22 CAR T cells in patients with R/R B-NHL and highlights the importance of measuring kinetic parameters in PB to predict efficacy and safety in clinical applications of CAR T cell therapy. Clinical Trial Registration https://www.clinicaltrials.gov/ct2/show/NCT03196830, identifier NCT03196830.

Objective:To investigate the effect and prognostic factors of rituximab-containing chemotherapy regimen in treatment of patients with mantle cell lymphoma (MCL).Methods:The clinical data of 56 patients aged ≤65 years in the First Affiliated Hospital of Soochow University from June 2007 to November 2018 were retrospectively analyzed. Rituximab-containing chemotherapy regimen was used, and the effects of clinical features, treatment regimen and biological indexes on overall survival (OS) and progression-free survival (PFS) were observed.Results:The median age of 56 patients was 57 years old, including 43 males and 13 females. Among these cases, 24 patients received R-CHOP chemotherapy regimen; 29 patients received cytarabine-containing chemotherapy regimen, including R-hyper CVAD/R-MA regimen used in 15 patients and R-CHOP alternating with R-DAHP regimen used in 14 patients; and 3 patients received other treatment regimens. Among 56 patients, 19 patients received autologous hematopoietic stem cell transplantation (ASCT) consolidation therapy. The median OS time was 74 months, 2-year OS rate was 83.8%, 3-year OS rate was 70.9%, 2-year PFS rate was 72.0% and 3-year PFS rate was 49.7%. International prognostic index (IPI) high-risk and receiving ASCT or not during the treatment were independent influencing factors of OS and PFS in MCL patients. The overall response rate (ORR) in cytarabine-containing regimen group was higher compared with that in R-CHOP regimen group (93.1% vs. 83.3%), and there was no statistically significant difference ( χ2=0.465, P=0.495). In addition, there were no significant differences between two groups in both OS ( χ2=0.291, P=0.590) and PFS ( χ2=0.912, P=0.339). ASCT consolidation prolonged the median OS time (72 months vs.124 months, χ2=3.973, P=0.040) and the median PFS time (34 months vs. 90 months, χ2=3.984, P=0.046) in MCL patients achieving remission after induction therapy. Among patients in simplified MCL IPI (sMIPI) score middle-high risk group, compared with those not receiving ASCT, patients receiving ASCT therapy could obtain better OS and PFS (OS: χ2=5.037, P=0.025; PFS: χ2=6.787, P=0.009); among patients of sMIPI score low risk, there were no statistically significant differences in OS and PFS between the group receiving ASCT and not (all P > 0.05). Conclusions:Cytarabine-containing chemotherapy regimen has no predicatively satisfactory value in improving the prognosis and survival for MCL patients. For MCL patients who have achieved remission after reduction therapy and those in sMIPI score middle-high risk group, ASCT consolidation therapy can improve the prognosis and can be taken as the first-line consolidation treatment in young patients.

This study aimed to explore clinical indexes for management of severe/critically ill patients with COVID‐19, influenza A H7N9, and H1N1 pneumonia by comparing hematological and radiological characteristics.

Objective:To examine the efficacy of haploidentical stem-cell transplantation (haplo-SCT) for patients with refractory relapsed (R/R) non-Hodgkin lymphoma (NHL) by comparing with those contemporaneously undergoing HLA-matched SCT in myeloablative conditioning settings.Methods:Between January 2006 and December 2018, a total of 151 patients undergoing haplo-SCT ( n=81) or HLA-matched SCT ( n=70, sibling or unrelated) were enrolled. Median age of alloSCT was 30(5-59) years. And 150 patients received myeloablative conditioning (MAC) consisting of total body irradiation (12 Gy) plus cyclophosphamide or busulfan plus cyclophosphamide. Only one case had reduced intensity conditioning (RIC) with R-FBA (fludarabine, busulfan & cytarabina). It was followed by an infusion of granulocyte-colony stimulating factor-primed bone marrow (G-BM) and/or peripheral blood stem cells without in vitro T cell depletion. In haplo-SCT and HLA-matched unrelated donor for SCT, GVHD prophylaxis consisted of antithymocyte globulin, cyclosporine A, mycophenolate mofetil and a short course of methotrexate. Clinical efficacy, hematopoietic reconstitution and transplant-related complications were retrospectively analyzed. Results:Among them, 146(96%) patients engrafted with a median time to neutrophil and platelet recovery of 12 and 15 days respectively. During a median follow-up period of 19 months, 66 of them survived (43.7%) and 67 (44.4%) died (39 disease recurrence, 27 transplantation-related mortality). Between haplo-SCT and HLA-matched SCT groups, progression-free survival (PFS) rate was 49.4% and 50.5% ( P=0.577); overall survival (OS) rate 56.7% and 57.4% respectively ( P=0.963). The cumulative incidences of relapse (CIR) were 36.6% and 37.7% ( P=0.836) and those of cumulative incidences of non-relapse mortality (NRM) 22.0% and 24.7% ( P=0.530). And the cumulative incidences of chronic GVHD were 42.3% and 39.6% ( P=0.46) respectively. Conclusions:No inter-group difference exists in each major HSCT endpoint. Multivariate analysis reveals that occurrence of grade Ⅲ-Ⅳ aGVHD has a significantly worse prognosis. And primary chemorefractoriness is a strongest relapsing factor.

Background Among the growing number of patients with hematologic neoplasms hospitalized in the intensive care unit (ICU), the largest proportion of these patients are diagnosed with lymphoma. However, less attention has been paid in the past to identifying critically ill patients and assessing the prognosis of patients in ICU. Traditional critical care-related scores have shown limitations and inaccuracy in predicting mortality risk. Methods Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) were searched for in the Marketplace for Information in Intensive Care Medicine III (MIMIC-III) database. We searched mortality within 28 days as the primary endpoint. Logistics regression was used to screen risk factors. A calibration curve was used for internal validation, and the ROC curve and AUC were used to compare the new model with traditional scores. Results 405 patients with DLBCL are enrolled in the project. Multivariate analysis shows the patients with the level of lactate dehydrogenase (LDH) > 327 U/L had an increased risk of 28-day mortality in ICU than others (OR = 13.04, p<0.01). Notably, length of ICU stay, LDH, creatinine, white blood cell counts, and APS III score are independent prognostic factors for patients with DLBCL in the ICU. Then, all these independent prognostic factors are selected into our prediction model. The new model has good accuracy (C-index=0.863) and a calibration curve, which improves clinical status concerning established ratings such as IPI, NCCN-IPI score, SOFA, APS III, and LODS. The results of a multicenter external validation including 124 DLBCL patients also showed that the new model was more accurate than all other models. Conclusions The elevated level of LDH indicates a poor prognosis of patients with DLBCL in the ICU. Our risk score with crossed validation based on the level of LDH shows a significant prognostic value and may be a valuable tool for assessing the critically ill as well.

The aim of the study was to analyze the efficacy of posaconazole for the prophylaxis and treatment of invasive fungal diseases (IFDs) in patients with hematological malignancies. In this retrospective observational multi-center study, 762 patients from 25 Chinese hematological centers were enrolled. Inclusion criteria were patients with hematological malignancy or they had undergone hematopoietic stem cell transplantation and received at least 1 dose of posaconazole. The primary endpoints were the observation of breakthrough rates and the clinical efficacy of posaconazole prophylaxis. The secondary endpoint was the efficacy of posaconazole for the treatment of IFDs. Of the 762 enrolled patients, 456 (59.8%) were prescribed posaconazole prophylactically while 243 (31.9%) received posaconazole as an IFD treatment (12 proven, 61 probable, 109 possible, and 61 unclassified IFD cases) for >= 7 days. The overall IFD breakthrough rate (probable cases) for the >= 4 days prophylactic treatment (n = 445) group was 1.6% (95% Cl: 0.6%-3.2%), with breakthrough rates of 2.6% for acute myeloid leukemia/myelodysplastic syndrome patients undergoing chemotherapy and 2.2% for hematopoietic stem cell transplantation patients. For primary antifungal prophylaxis, the breakthrough rate was 1.9% and for secondary antifungal prophylaxis 0%. The overall effective IFD remission rate of patients treated for >= 7 days with posaconazole was 56.0% and the effective remission rate of proven/probable/possible IFD cases was 59.3%. The effective remission rate of posaconazole as salvage therapy was 50% (95% CI: 32.4%-67.6%) including 75% (CI: 19.4%-99.4%) for Aspergillus infections. The present retrospective study confirmed posaconazole as IFD prophylaxis and medication for hematological malignancy patients undergoing various treatments in China.

B-cell lymphomas that concurrently carry MYC, BCL2 and/or BCL6 gene rearrangements – so-called double-hit or triple-hit lymphomas – are rare entities associated with poor prognosis. B-cell lymphomas with translocations involving MYC, BCL2, BCL6 and CCND1 genes (quadruple-hit) are extremely rare, with limited cases reported to date.1-3 Herein we report a case diagnosed at an early stage and remaining disease-free for 15 months after the initial diagnosis. This study was approved by the Institutional Review Board of the First Affiliated Hospital of Soochow University. Written informed consent was obtained from the patient. The patient was a 76-year-old man suffering from pharyngeal obstruction for 2 months. A positron emission tomography scan showed multiple cervical lymphadenopathies (Fig 1A). The laboratory tests were unremarkable including a normal serum lactate dehydrogenase (LDH) level. Biopsy of the left cervical lymph node displayed effaced architecture by a diffuse infiltrate of medium to large lymphocytes. Tangible body macrophages were observed at lower magnification. At higher magnification, the tumour cells revealed a moderate amount of cytoplasm, round or slightly irregular nuclei, moderately dispersed chromatin and one or more small and occasionally prominent nucleoli (Fig 2A). By flow-cytometric immunophenotyping, 58·4% of the gated lymphoid events revealed a kappa immunoglobulin light chain restriction. These cells expressed pan-B markers such as CD19, CD20, and FMC7 with weak CD23 positivity. CD200, CD79b, CD5 and 10 were negative. By immunohistochemical (IHC) staining, the lymphoma cells were positive for CD20, CD79a, BCL6, cyclin D1, CD21, BCL2 and MYC. P53 was positive in occasional cells (Fig 2B–H). The Ki67 proliferative rate was 60% (Fig 2I). The tumour cells were negative for CD3, CD5, SOX11, MUM1, and EBER by in situ hybridisation. Examination of the bone marrow biopsy showed it to be negative for tumour infiltration. Given the over-expression of BCL6, MYC, cyclin D1, and BCL2, interphase fluorescence in situ hybridisation (FISH) analyses of these relevant genes were performed. Dual-color dual-fusion (D-FISH) probes (Beijing Jinpujia Medical Technologies, Beijing, China) were selected for MYC-IGH, CCND1-IGH and IHG-BCL2 rearrangements. In addition, a break-apart probe (BAP; Beijing Jinpujia Medical Technologies) was used for BCL6 rearrangement. The FISH analyses were performed on 4 μm paraffin-embedded tissue sections and it was considered positive if more than 15% of the tumour cells exhibited a fusion or break-apart signal. D-FISH of IGH-MYC (Fig 2J), IGH-CCND1 (Fig 2K) and IGH-BCL2 (Fig 2L) showed one fusion signal in 34% of 100 suspension cells, indicating MYC-IGH, CCND1-IGH and IGH-BCL2 rearrangements. Similarly, a BCL6 (Fig 2M) break was detected in 38% of 100 suspension cells, suggesting translocations of the genes. The FISH analyses were also repeated on tissue sections. Moreover, FISH analyses using BAP (Abbott Molecular, Des Plaines, IL, USA) of BCL2 (Figure S1A) and CCND1 (Figure S1B) revealed split signals on tissue sections, demonstrating a break of both genes. Therefore, according to the morphology, immunophenotype and FISH results, a final diagnosis of quadruple-hit pleomorphic mantle cell lymphoma (MCL) was favoured. Cytogenetic analysis was failed due to a lack of growth of metaphase cells after a short term of cell culture. However, we were able to perform Cytoscan 750k (Affymetrix, Santa Clara, CA, USA) single nucleotide polymorphism microarray (SNP-array) assay to assess genome-wide chromosomal copy number aberrations (CNAs). The SNP-array revealed apparent gains of whole chromosomes X, Y, 5 and 7, as well as segmental gains of chromosomes 1p36p23, 1q23q25, 1q25q31, 1q31q32, 1q41q42, 1q42q44, 2p25p16, 2p12p11, 2p11q12, 3p26q27, 6p25p12, 17q12q24, and 21q11q22 (Fig 2N). The genome-wide CNA pattern was suggestive for the presence of a complex hyperdiploid clone, with evidence of a chromothripsis-like pattern of 1q. Additionally, next-generation sequencing (NGS) was performed for somatic mutations with a targeted panel covering 222 genes, with an average sequencing depth of more than 1000 times. NGS revealed 12 nonsynonymous single nucleotide variants, one frameshift mutation, and one nonsense mutation, involving ARID1B, BCL2 (3), CCND1 (3), FOXO1, IL7R, MGA, PIM1 and SGK1 (3) genes (Table SI). No mutation was identified in the TP53 gene, which was consistent with IHC results. Deletions or mutations of the ARID1B gene have been observed in lymphoplasmacytic lymphoma.4 The Y24I mutation in FOXO1 gene has been identified in diffuse large B-cell lymphoma (DLBCL) and was associated with decreased overall survival.5 Mutations of the SGK1 gene were common in DLBCL and the PIMI gene mutation has been identified in DLBCL (leg type) and multiple myeloma.6 Interestingly, multiple mutations of BCL2 and CCND1 genes were also identified, which have rarely been reported to be co-existing with gene rearrangements. Of note, the CCND1 mutations have been reported in MCL.7 On the other hand, mutations in IL7R and MGA genes were not identified in the literature and the functional consequence remains unknown. Our patient received six cycles of lenalidomide in combination with R2-CHOP (one cycle standard R-CHOP on days 1–5, and 25 mg oral lenalidomide per day on days 1–14). He achieved complete remission after four cycles (Fig 1B) and was disease-free 15 months after initial diagnosis. Quadruple-hit lymphoma is rare and associated with a dismal prognosis.1-3 The prognosis of our patient was relatively good, and this may be due to an early-stage diagnosis, normal LDH level, and negative TP53 mutation.8 To further characterise the prognosis of our patient, MCL international prognostic index (MIPI) and biological MIPI (MIPIb) were evaluated, as described previously.9, 10 The patient was classified as high risk, both for the MIPI and MIPIb scores, with a predicted overall survival of 37 months. Thus, a longer follow-up is warranted to evaluate the clinical outcome. MYC gene rearrangement in MCL is rare, with limited cases reported to date.10-15 It was found to be associated with a higher median white blood cell, blastoid/pleomorphic morphology, medium-high MIPI risk and shorter overall survival.12, 15 Of note, these cases of quadruple-hit lymphoma showed high grade histological features. Therefore, testing of MYC protein in blastoid/pleomorphic MCL may help to identify those carry additional MYC gene rearrangements, and even quadruple-hit lymphomas. More cases with detailed clinical-pathological and biological data are needed to better characterise this entity. The authors would like to thank Sicheng Ai (New York University, New York, NY, 10003, USA) for his help in the preparation of the manuscript. WL, XC and JF designed the study and wrote the manuscript; MZ performed flow cytometric analysis; HS performed and analysed the next generation sequencing; XC and DW was involved in the clinical part and follow-up of the patient; GC performed the cytological analysis; YD and BH provided clinical data; ZZ and JP performed cytogenetic analysis; HH supervised the study and wrote the manuscript. This work was supported by grants from the Postdoctoral Science Foundation of Jiangsu Province (No. 1402080B), Translational Research Grant of NCRCH (No. 2020ZKMB02) and Suzhou Science and Technology Development Projects (No. SYS2019039 and SYSD2020104). The authors declare no relevant conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Isolated central nervous system involvement in multiple myeloma (CNS-MM) is rare and carries extremely poor prognosis. Chimeric antigen receptor T cell therapy (CART) targeting B-cell maturation antigen (BCMA) is demonstrated as a promising strategy in MM treatment, but the clinical safety and efficacy of BCMA-CART against isolated CNS-MM remain elusive. Here we report on a 56-year-old male with refractory isolated CNS-MM who received autologous BCMA-CART therapy and developed grade 4 neurological complications. Cerebrospinal fluid (CSF) analyses showed significant expansion of CART cells and a substantially elevated interleukin-6 (IL-6) level. Intravenous methylprednisolone was administered and the symptoms resolved gradually. Unexpectedly, the level of IL-6 in the CSF was maintained for another 3 days even after the relief of the neurological symptoms. A partial response was achieved and sustained for 5.5 months. This is the first report describing a patient with isolated CNS-MM treated using BCMA-CART therapy. The results demonstrated that BCMA-CART cells administered intravenously trafficked into the CSF, eradicated tumor cells, and induced severe but reversible neurological adverse events. This single-patient report suggests that BCMA-CART therapy can be considered as an alternative option for isolated CNS-MM. Clinical Trial Registration ClinicalTrials.gov, identifier NCT03196414.

Pulmonary computed tomography (CT) scans are commonly used as part of the clinical criteria in diagnostic workup of invasive fungal diseases like invasive aspergillosis, and may identify radiographic abnormalities, such as halo signs or air-crescent signs. We assessed the diagnostic utility of CT assessment in patients with hematologic malignancies or those who had undergone allogeneic hematopoietic stem cell transplantation in whom invasive aspergillosis was suspected. This post-hoc analysis assessed data from a prospective, multicenter, international trial of voriconazole (with and without anidulafungin) in patients with suspected invasive aspergillosis (IA; proven, probable, or possible, using 2008 European Organisation for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria) [NCT00531479]. Eligible patients received at least one baseline lung CT scan. Of 395 patients included in this post-hoc analysis, 240 patients (60.8%) had ‘confirmed’ proven (9/240, 3.8%) or probable (231/240, 96.3%) invasive aspergillosis (cIA) and 155 patients (39.2%) had ‘non-confirmed’ invasive aspergillosis (all nIA; all possible IA (de Pauw et al., Clin Infect Dis 46:1813–21, 2008)). Mean age was 52.3 and 50.5 years, 56.3 and 60.0% of patients were male, and most patients were white (71.7 and 71.0%) in the cIA and nIA populations, respectively. Median baseline galactomannan was 1.4 (cIA) and 0.2 (nIA), mean Karnofsky score was 65.3 (cIA) and 66.8 (nIA), and mean baseline platelet count was 48.0 (cIA) and 314.1 (nIA). Pulmonary nodules (46.8% of all patients), bilateral lung lesions (37.5%), unilateral lung lesions (28.4%), and consolidation (24.8%) were the most common radiographic abnormalities. Ground-glass attenuation (cIA: 24.2%; nIA: 11.6%; P < 0.01) and pulmonary nodules (cIA: 52.5%; nIA: 38.1%; P < 0.01) were associated with cIA. Other chest CT scan abnormalities (including halo signs and air-crescent signs) at baseline in patients with hematologic malignancy or hematopoietic stem cell transplantation, and suspected IA, were not associated with cIA. These findings highlight the limitations in the sensitivity of chest CT scans for the diagnosis of IA, and reinforce the importance of incorporating other available clinical data to guide management decisions on individual patients, including whether empirical treatment is reasonable, pending full evaluation. NCT00531479 (First posted on ClinicalTrials.gov on September 18, 2007)

Cytokine release syndrome (CRS) is among the most representative toxicities of chimeric antigen receptor T (CART) cell therapies against non-Hodgkin's lymphoma (NHL). However, the mechanism of CRS is not fully elucidated. Interleukin-6 (IL-6) has been reported as a key factor in the development of CRS. We here present a novel mechanism of CRS emphasizing a balance between IL-6 and soluble IL-6 receptors (sIL-6Rs), essential amplifiers for IL-6-mediated inflammatory responses. A 46-year-old male patient with transformed diffuse large B-cell lymphoma (Bcl-2+/C-Myc+) refractory to 3 lines of prior therapies was enrolled in our CART trial (NCT 03196830). Baseline findings included extensive disease, multiple lesions in the abdomen, bone marrow infiltration, and a large volume of chylous ascetics with malignant cells (ascitic IL-6 baseline level: 6,691 pg/ml). And the patient received a combination of CD19-BBζ CART (8 x 106 CAR+ cells/kg), CD22-BBζ CART (1 x 106 CAR+ cells/kg), and lenalidomide (25 mg, qod, Wang X, et al., Clin Cancer Res. 2018). The patient developed mild toxicities including fever, febrile, and rash on Day 3 which were completed reversed on Day 8 after supportive care without tocilizumab or steroids. Quantitative PCR analysis of the CAR transgene demonstrated rapid expansion of the CART cells in both peripheral blood and ascites. An efficacy assessment on Day 27 revealed that most lesions disappeared or significantly shrank, the ascites nearly completely disappeared, and no malignant cell in ascites or bone marrow was detected. The patient remained in remission for 10 months. The patient was graded as CRS grade 1 according to the ASBMT scale, and cytokine assays of peripheral blood at various time points before and after CART infusions revealed expected stable levels of cytokines, including IL-6, IL-1β, IL-12, IL-15, interferon-γ, monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory protein 1-alpha (MIP1α), IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF). In the ascites, however, soaring IL-6 levels were detected with a peak value of 18,516 pg/ml on Day 7, one of the highest IL-6 levels on our CART trials, whereas no compartmental CRS or other manifestation in local abdomen was observed. The trend of ascitic IL-6 coincided with that of CAR transgene numbers. Furthermore, sIL-6R levels in ascites were lower than in serum (p < 0.0001). Importantly, the ratios of IL-6:sIL-6R were 400 to 1000 fold higher in ascites compared with in serum, highlighting that sIL-6Rs were relatively depleted in the ascites. Indeed, the absolute levels of ascitic IL-6 were close to, or exceeded at some time points, those of sIL-6R, indicating that the bottleneck of the formation of IL-6/sIL-6R signaling complex might switch from IL-6 to sIL-6R in the ascites. Flow analysis demonstrated neutrophils account for 15-20% of the total cells in ascites compared with 40-75% in serum, indicating that lack of neutrophils might be a potential cause of the low sIL-6R levels. Additionally, although sgp130 levels in ascites were also lower than in serum, the absolute values were still overwhelming to those of IL-6 and sIL-6R. Lastly, the levels of MCP1, IL-8 and angiopoietin 2 were significantly elevated, and flow analysis revealed that approximately 25% of the ascitic cells were CD14+CD11b+, indicating monocytes/macrophages might be recruited and/or activated. The levels of MIP1α, GM-CSF, IL-1β, IL-12, IL-15, interferon-γ were low in ascites during the whole period. In conclusion, our data show that relative depletion of sIL-6R in ascites may completely abolish the development of local CRS in the presence of high IL-6. This is the first report to demonstrate the features of biomarkers in ascites after CART therapy, and to describe the impacts of disproportionately low sIL-6R on IL-6 signaling without drug intervention. These results imply that the unique microenvironments in exudates such as ascites may lead to distinct pathophysiological events following CART therapy, and IL-6:sIL-6R ratio should be considered as an indicative parameter in the toxicity management of CRS. Figure Disclosures No relevant conflicts of interest to declare.

BACKGROUND Autologous stem-cell transplantation (ASCT) is the standard treatment for R/R B-NHL, while chimeric antigen receptor T (CAR-T) therapy targeting CD19 emerges as an alternative strategy. Here we report a comparative analysis of the two strategies in a single center. METHODS We performed a prospective single-arm study of CAR-T therapy in 29 patients with R/R B-NHL and compared the outcomes with contemporaneous 27 patients who received ASCT. NHL was diagnosed by histopathological assessments, and the safety and efficacy were compared. RESULTS The CAR-T group exhibited better rates of CR (48.0% vs. 20.8%, P=0.046) and one-year OS (74.4% vs. 44.5%, P=0.044) compared with the ASCT group. Subpopulation analysis showed that patients with IPI scores ≥ 3 achieved significantly higher ORR and CR rates in the CAR-T group than in the ASCT group (ORR: 72.0% vs. 10.0%, P=0.002; CR: 38.9% vs 0% P=0.030, respectively). The most common severe adverse events in the CAR-T group were cytokine release syndrome, neurotoxicity and infection compared with cytopenia, gastrointestinal toxicity and infection in the ASCT group. Additionally, the incidence of non-hematologic severe adverse events (SAEs) was markedly lower in the CAR-T group than in the ASCT group (20.7% vs. 48.1% P=0.030). CONCLUSION CAR-T therapy exhibited superior clinical outcomes in safety and efficacy over ASCT in patients with R/R B-NHL, suggesting CAR-T may be a recommended alternative to ASCT.

Background Chimeric antigen receptor T cell (CART) therapy against blood malignancies exhibits unique pharmacokinetic profiles in vivo. There are reports of CART kinetics against acute or chronic lymphoblastic leukemia (ALL/CLL), but reports on CD19-41BBζ CART against relapsed or refractory non-Hodgkin's lymphoma (r/r NHL) are rare. Here we present a summary of the cellular kinetics of CART cells from 35 patients of aggressive or indolent NHL, highlighting the potential correlations between CART kinetics and clinical outcomes Methods Thirty-five consecutive patients with r/r NHL from a CART trial (NCT03196830) were analyzed. CART cells were administrated at doses of 5-10x106/kg in 3 split doses following lymphodepleting chemotherapies of fludarabine and cyclophosphamide. CART kinetic profiles in peripheral blood were determined by CAR transgene copies measured by quantitative PCR at various time points, and correlation analyses between kinetic and clinical factors were performed. Kinetic parameters included peak CAR transgene (Cmax), time to reach Cmax (Tmax), and area under the curve at day 28 (AUC0-28d) and day 70 (AUC0-70d) describing short-term and long-term persistence, respectively. Clinical factors included responses, adverse events, and disease characteristics. Results Correlation analysis between kinetic and efficacy profiles revealed that responders exhibited significantly higher AUC0-70d (but not Cmax and AUC0-28d) compared with non-responders, indicating that AUC0-70d rather than Cmax and AUC0-28d was correlated with clinical efficacy. This result was partially inconsistent with previous reports of CD19-BBζ CART in ALL/CLL patients (Mueller KT, et al., 2017), suggesting that CART might exhibit distinct kinetic profiles in NHL compared with ALL/CLL. Additionally, AUC0-70d was 7-fold higher in patients who maintained in remission for > 6 months after prior therapies compared with those who did not, and 278% higher in patients receiving < 3 prior lines of therapies than those > 3 lines, both of which were correlated with better durations of remission (DOR) and/or overall survival (OS). These results indicated that longer remission periods after and fewer lines of prior therapies were favorable factors of long-term persistence of CART cells, which subsequently led to improved clinical efficacy. Again, Cmax or AUC0-28d did not show any differences between groups. No difference in Tmax were achieved between any two groups Correlation analysis between kinetic and safety profiles revealed that patients with grade 3-4 cytokine release syndrome (CRS) had significantly higher Cmax than those with grade 1-2 CRS, indicating that CART expansion correlated with the severity of CRS. No correlation was observed between neurotoxicity and Cmax. Neither neurotoxicity nor CRS was correlated with Tmax, AUC0-28d, or AUC0-70d. Lastly, transient drops in CAR copies early after infusions were observed in 78% patients (24/35). A transient drop usually happened around Day 5, divided the whole expansion phase into two peaks, and created a trough value of <10% of the earlier peak. Interestingly, AUC0-70 was significantly higher in patients with transient drops than in those without, while Cmax, Tmax and AUC0-28 were nearly identical. Moreover, 75% patients (18/24) with transient drops were responders, compared with only 36% patients (4/11) without transient drops. Patients with transient drops also exhibited better DOR. This unique kinetic feature tended to be a favorable factor of efficacy, leaving the mechanism to be further explored. Conclusion Overall, significantly higher levels of long-term persistence were observed in patients who successfully responded to CART therapy in r/r NHL patients, indicating that the kinetics of CART cells could be used as predictive factors in clinical practice. This is the first summary of CD19-41BBζ CART against r/r NHL emphasizing different kinetic profiles between NHL and ALL/CLL. These results also imply that means to enhance long-term persistence of CART cells may be potential strategies of to improve response rates. Disclosures No relevant conflicts of interest to declare.

淋巴瘤是最常见的血液系统恶性肿瘤之一,其亚型众多,具有高度异质性.既往淋巴瘤的治疗多采取化疗、放疗及手术在内的常规方法,但难治/复发一直是临床面临的棘手问题.近年来,免疫治疗的突破性进展给淋巴瘤患者带来新的希望.综述了近年来靶向淋巴细胞分化抗原的单克隆抗体及耦联药物,免疫检查点阻断剂及嵌合抗原受体T细胞等多种免疫治疗方法在淋巴瘤中的应用现状及未来展望.

Primary testicular lymphoma (PTL) is quite rare. Immunohistochemical analyses show that the majority of cases are diffuse large B-cell lymphoma accounting for about 1–7% of all testicular malignanc...

Background: Pulmonary computed tomography (CT) scans are commonly used as part of the clinical criteria in diagnostic workup of invasive aspergillosis (IA). Other criteria for diagnosing IA include a combination of host, clinical and mycological factors, such as those recommended in the 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. Chest CT criteria include dense, well-circumscribed lesions(s) with or without a halo sign, air-crescent sign, or cavity. We assessed the diagnostic utility of these findings at baseline in a cohort of patients with hematological malignancy and suspected IA who received antifungal treatment.

OBJECTIVE To determine the plasma concentrations of voriconazole of inpatients,and access the association between the trough concentration and clinical efficacy and adverse drug reactions.METHODS A total of 103 measurements by high pressure liquid chromatography were performed in 64 patients.Clinical efficacy and adverse drug reactions were observed during the pharmacotherapy period.RESULTS Trough concentration was 1.5-5.5 μg·mL 1 in 39/64 cases (61％),the median was 2.62 (1.53-5.33) μg·mL-1;＜1.5 μg·mL-1 in 18/64 cases (28％),the median was 0.975 (0.16-1.49) μtg·mL-1;＞5.5 μg·mL-1 in 7/64 cases (11 ％),the median was 6.03 (5.58-9.38) μg·mL-1 Lack of response to therapy was more frequent in patients with voriconazole levels ＜ 1.5μg· mL-1 (61 ％) than in those with voriconazole levels ≥1.5 μg·mL 1 (12 ％)(P =0.050).Blood levels≥1.5 μg· mL-1 were reached after increasing the voriconazole dose,with complete or partial resolution of infection in all 11/18 cases.The incidences of adverse drug reaction with voriconazole trough blood levels ＞5.5 μg·mL-1 and ≤5.5 μg·mL-1 were 71％ and 28％.The risk of adverse drug reaction with voriconazole trough blood levels ＞5.5μg·mL-1 was significantly increased (P =0.034).21/64 cases (33％) occurred adverse reactions,and 9 cases improved after dose reduction,7 cases improved after treatment,5 cases discontinued voriconazole because of severe adverse reactions.CONCLUSION Voriconazole plasma concentration is largely different between individuals,while therapeutic drug monitoring improves the efficacy and safety of therapy in patients with invasive fungal infections.

Xiaofang Xiao , Haiwen Huang , Jia Chen, Yibin Jiang, Lihong Zhang, Yang Xu, Ting Xu, Xiaochen Chen, Caixia Li, Zhengming Jin, Jia Ruan and Depei Wu Department of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China; Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China; Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York–Presbyterian Hospital, NY, USA