Multi-centers experience using therapeutic plasma exchange for corticosteroid/tocilizumab-refractory cytokine release syndrome following CAR-T therapy.

The chimeric antigen receptor T (CAR-T) cell therapy significantly enhances the prognosis of various hematologic malignancies; however, the systemic expansion of CAR-T cells also gives rise to severe cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Despite the successful application of corticosteroids and tocilizumab in alleviating severe CRS in most patients, there are still individuals who experience life-threatening CRS without responding to the aforementioned therapies. In our retrospective cohort, we conducted an analysis of clinical and laboratory parameters, including inflammatory cytokines, in 17 patients from three centers who underwent therapeutic plasma exchange (TPE) for refractory CRS with or without ICANS following CAR-T products treatment. Our findings demonstrate a significant improvement in both clinical symptoms and laboratory parameters subsequent to TPE treatment. The rapid decrease in temperature and levels of inflammatory indexes indicates the remarkable scavenging efficacy of TPE against cytokine storm following CAR-T therapy. In conclusion, TPE may serve as a valuable and safe adjunct to corticosteroids and tocilizumab in the management of severe CRS resulting from CAR-T cell infusion. We eagerly await further prospective studies to validate this finding.

The novel HLA-C*12:02:52 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-C*12:02:52 differs from HLA-C*12:02:02:01 by one nucleotide in exon 1.

Modified EASIX scores predict severe CRS/ICANS in patients with acute myeloid leukemia following CLL1 CAR-T cell therapy.

Chimeric antigen receptor T (CAR-T) cell therapy targeting CLL1 has been considered a potent weapon for patients with acute myeloid leukemia (AML). This study aims to evaluate the efficacy and toxicity of CLL1 CAR-T cell therapy in a larger cohort, with particular attention to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Among the 32 patients assessed for efficacy, complete remission occurred in 71.88% (23/32) of cases and undetectable minimal residual disease in 14 patients. The CRS developed in all patients, with 8 individuals experiencing ICANS. Severe CRS and ICANS were observed in 11 and 2 patients, respectively. Furthermore, the Endothelial Activation and Stress Index (EASIX) and its derivatives measured before and after CLL1 CAR-T cell infusion were employed for predicting the severe complications. Significant differences were observed in EASIX scores on the day before lymphodepletion (Day BL, P = 0.023), -1 (P < 0.001), +1 (P < 0.001), and +3(P = 0.014); sEASIX scores on Day BL (P = 0.007), -1 (P < 0.001), +1 (P < 0.001), and +3 (P < 0.001); and mEASIX score on Day -1 (P = 0.004) between patients with mild and severe CRS/ICANS. Additionally, there was a significant difference in mEASIX scores between responders and non-responders on Day BL (P = 0.004) and Day -1 (P = 0.044). Our findings indicate that pre- and post-infusion assessments of EASIX/mEASIX/sEASIX scores serve as reliable prognostic indicators for severe CRS/ICANS and treatment response following CLL1 CAR-T cell therapy, which can assist physicians in implementing preemptive treatment strategies for potential severe complications and screening patients who are suitable candidates for CLL1 CAR-T cell therapy. EASIX/mEASIX/sEASIX scores serve as reliable prognostic indicators for severe CRS/ICANS following CLL1 CAR-T cell therapy. The preinfusion mEASIX scores of CLL1 CAR-T cells can effectively predict treatment response.

Low-dose administration of prednisone has a good effect on the treatment of prolonged hematologic toxicity post-CD19 CAR-T cell therapy.

Introduction: Hematologic toxicity (HT) is a joint adverse event after CAR-T cells infusion. Some patients experience prolonged hematologic toxicity (PHT), which is challenging to treat. Methods: We collected clinical data from patients with relapsed refractory B-ALL treated with CD19 CAR-T cells. Patients with PHT who did not respond to erythropoietin, platelet receptor agonists, transfusion, or G-CSF and eventually received low-dose prednisone therapy were included in the analysis. We retrospectively analyzed the efficacy and safety of low-dose prednisone on PHT. Results: Among 109 patients treated with CD19 CAR-T cells, 78.9% (86/109) of patients were evaluated as PHT. Of these, 15 patients had persistent hematological toxicity after infusion (12 were grade 3/4 cytopenia, 12 were trilineage cytopenia and 3 were bilineage cytopenia), 2 developed cytopenia without apparent cause after D28. The initial prednisone dose was 0.5 mg/kg/day, and the median response time was 21 days (7-40 days). The recovery rate of blood count was 100%, and the complete recovery rate ranged from 60% to 66.67%. Especially exciting was that HT recurred in 6 patients after stopping prednisone. They were relieved again after the administration of prednisone. The median follow-up time was 14.97 months (4.1-31.2 months). Twelve-month duration of PFS and OS rates were 58.8% (±11.9%) and 64.7% (±11.6%). We did not observe any other side effects of prednisone apart from drug-controllable hyperglycemia and hypertension. Discussion: We suggest that low-dose prednisone is a beneficial and tolerable therapy for PHT after CAR-T cells. The trials have been registered at www.chictr.org.cn as ChiCTR-ONN-16009862 (November 14, 2016) and ChiCTR1800015164 (March 11, 2018).

Metagenomic Next-Generation Sequencing for Diagnostically Challenging Mucormycosis in Patients with Hematological Malignancies.

Background: 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.

The Value of Metagenomic Next-Generation Sequencing in Hematological Malignancy Patients with Febrile Neutropenia After Empiric Antibiotic Treatment Failure.

Background: 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.

Ibrutinib improves the efficacy of anti-CD19-CAR T-cell therapy in patients with refractory non-Hodgkin lymphoma.

The efficacy and side effects of the second-time humanized CD19 chimeric antigen receptor (CD19-CAR) T-cell therapy after unsuccessful first-time anti-CD19-CAR T-cell therapy and subsequent ibrutinib salvage treatment were observed in patients with refractory B-cell lymphoma. In our study, 3 patients with refractory mantle cell lymphoma (MCL) and 4 patients with refractory follicular lymphoma (FL) reached stable disease (SD), partial remission (PR), or progression of disease (PD) after first-time humanized anti-CD19-CAR T-cell therapy. They received ibrutinib as a salvage treatment and kept an SD in the following 7-16 mo, but their disease progressed again during ibrutinib salvage treatment. All 7 patients received a second-time humanized anti-CD19-CAR T-cell therapy, which was the same as their first-time anti-CD19-CAR T-cell therapy. In total, 3 MCL patients and 3 FL patients reached complete response (CR) with the second-time anti-CD19-CAR T-cell therapy combined with ibrutinib, whereas 1 FL patient reached PR. There were no differences in the transduction efficiency and proliferation between the 2 instances of anti-CD19-CAR T-cell therapy. However, the second-time anti-CD19-CAR T-cell therapy led to higher peaks of anti-CD19-CAR T cells and anti-CD19-CAR gene copies, but also to higher grades of cytokine release syndrome (CRS) and more serious hematological toxicity. The successful outcome of the second-time anti-CD19-CAR T-cell therapy might suggest that the previous ibrutinib treatment improved the activities of anti-CD19-CAR T cells.

Synergistic effect of programmed death-1 inhibitor and programmed death-1 ligand-1 inhibitor combined with chemotherapeutic drugs on DLBCL cell lines in vitro and in vivo.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL). Chemotherapy is one of the main treatments for cancer, but the antitumor effect of chemotherapeutic drugs is affected by the patient's immune status. The programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis is an important central checkpoint in tumor progression. The present study demonstrated a significant synergistic effect of PD-1 inhibitor and oxaliplatin, cisplatin, etoposide, cytarabine, ifosfamide and carboplatin. There was no difference in cytotoxicity between the groups with or without PD-L1 inhibitor. It was also observed that cytotoxicity of T cells combined with PD-1 inhibitor against DLBCL cells was inhibited by dexamethasone addition to the culture system at 24, 48 and 72 h. There was no difference in cytotoxicity between the group of dexamethasone added at 96 h and the group without dexamethasone at 96 h. Then, we selected a PD-1 inhibitor combined with a chemotherapeutic regimen in a Pfeiffer cell mouse xenograft model. At 21 days, the reduction in tumor size was more obvious in the DHAP combined with PD-1 inhibitor group (dexamethasone after 96 h of PD-1) compared with that in the DHAP (P=0.007), the PD-1 inhibitor (P=0.001) and the DHAP combined with PD-1 inhibitor (dexamethasone after 24 h of PD-1) (P=0.005) groups. However, the reduction in tumor size was more obvious in the GemOx combined with PD-1 inhibitor group compared with that in the GemOx group (P=0.037). Therefore, the present study demonstrated the synergistic effects of PD-1 inhibitor combined with chemotherapeutic regimens in DLBCL.

Clinical significance and prognostic value of Vav1 expression in Non-small cell lung cancer.

Vav1 has been reported to be involved in human cancers, however, the expression and clinical significance of Vav1 in NSCLC are not fully understood. In the present study, we examined the expression of Vav1 in 170 NSCLC patients who underwent radical resection by the immunohistochemical analyses. The association between the Vav1 expression and clinicopathological variables was analyzed. The multivariate Cox proportional hazards model was conducted to determine the prognostic value of Vav1 on the long-term survival. The results showed that the elevated Vav1 expression was correlated positively with lymph node metastasis (P<0.001), T stage (P<0.001) and poor histological differentiation (P<0.001). Patients with negative or low Vav1 expression had better prognoses than those with high Vav1 expression (P<0.001). Multivariate analysis indicated that Vav1 was independent prognostic factor for overall survival (OS) (HR 2.079, 95% CI 1.564 to 2.762, P<0.001) and disease-free survival (DFS) (HR 1.810, 95% CI 1.391 to 2.356, P<0.001). Our findings showed that overexpressed Vav1 was correlated with aggressive tumor behavior. Val1 was an independent factor for NSCLC prognosis, which may serve as a novel prognostic factor and potential target to improve the long-term outcome of NSCLC.