Case Report: Blinatumomab therapy for the treatment of B-cell acute lymphoblastic leukemia patients with central nervous system infiltration.

The treatment of B-cell acute lymphoblastic leukemia (B-ALL) with central nervous system (CNS) involvement poses a significant clinical challenge because most chemotherapeutic agents exhibit weak permeability to the blood-brain barrier (BBB). In addition, current anti-CNS leukemia treatments often bring short or long-term complications. Immunotherapy including chimeric antigen T-cell therapy and bispecific antibody have shown profound treatment responses in relapsed/refractory B-ALL. However, there is a lack of data on the efficacy of bispecific antibody in treating B-ALL with CNS involvement. Here, we report two ALL patients with CNS leukemia who received blinatumomab. Case 1 was diagnosed with chronic myeloid leukemia in lymphoid blast phase. The patient developed CNS leukemia and bone marrow relapse during the treatment with dasatinib. Case 2 was diagnosed with B-ALL and suffered early hematologic relapse and cerebral parenchyma involvement. After treatment with one cycle of blinatumomab, both patients achieved complete remission in the bone marrow and CNS. Furthermore, this is the first report on the efficacy of blinatumomab in treating CNS leukemia with both of the cerebral spinal fluid and the cerebral parenchymal involvement. Our results suggest that blinatumomab might be a potential option for the treatment of CNS leukemia.

Anti-CD19 CAR T-cell consolidation therapy combined with CD19+ feeding T cells and TKI for Ph+ acute lymphoblastic leukemia.

We conducted a single-arm, open-label, single-center phase 1 study to assess the safety and efficacy of multicycle-sequential anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in combination with autologous CD19+ feeding T cells (FTCs) and tyrosine kinase inhibitor (TKI) as consolidation therapy in patients under the age of 65 years with de novo Ph-positive CD19+ B-cell acute lymphoblastic leukemia. Participants were given induction chemotherapy as well as systemic chemotherapy with TKI. Afterward, they received a single cycle of CD19 CAR T-cell infusion and another 3 cycles of CD19 CAR T-cell and CD19+ FTC infusions, followed by TKI as consolidation therapy. CD19+ FTCs were given at 3 different doses. The phase 1 results of the first 15 patients, including 2 withdrawals, are presented. The most common adverse events were cytopenia (13/13) and hypogammaglobinemia (12/13). There was no incidence of cytokine release syndrome above grade 2 or immune effector cell-associated neurotoxicity syndrome or grade 4 nonhematological toxicities. All 13 patients achieved complete remission, including 12 patients with a complete molecular response (CMR) at the data cutoff. The relapse-free survival was 84%, and the overall survival was 83% with a median follow-up of 27 months. The total number of CD19-expressing cells decreased with an increasing CMR rate. CD19 CAR T cells survived for up to 40 months, whereas CD19+ FTCs vanished in 8 patients 3 months after the last infusion. These findings could form the basis for the development of an allo-HSCT-free consolidation paradigm. This trial was registered at www.clinicaltrials.gov as #NCT03984968.

Investigation of the risk factors to predict cytokine release syndrome in relapsed or refractory B-cell acute lymphoblastic leukemia patients receiving IL-6 knocking down anti-CD19 chimeric antigen receptor T-cell therapy.

CD19 chimeric antigen receptor-T (CAR-T) cell therapy has achieved remarkable results in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). However, the cytokine release syndrome (CRS) was presented in most patients as common toxicity and severe CRS (sCRS) characterized by the sharp increase in interleukin-6 (IL-6) could be life-threatening. We conducted a phase II clinical trial of ssCAR-T-19 cells, anti-CD19 CAR-T cells with shRNA targeting IL-6, in 61 patients with r/r B-ALL. This trial was registered at www.clinicaltrials.gov as #NCT03275493. Fifty-two patients achieved CR while nine patients were considered NR. The median duration of response (DOR) and overall survival (OS) were not reached (>50 months). CRS developed in 81.97% of patients, including 54.10% with grades 1 to 2 (grade 1, 31.15%; grade 2, 22.95%) and 27.87% with grades 3 to 4 (grade 3, 26.23%; grade 4, 1.64%). sCRS occurs earlier than mild CRS (mCRS). A multivariable analysis of baseline characteristics identified high bone marrow disease burden and poor genetic risk before infusion as independent risk factors for sCRS. After infusion, patients with sCRS exhibited larger expansion of ssCAR-T-19 cells, higher peak levels of IL-6, IL-10, and IFN-γ, and suffered more severe hematological and non-hematological toxicities compared with those with mCRS.

Phylogenetic analysis using E2 gene of classical swine fever virus reveals a new subgenotype in China.

Outbreaks of classical swine fever (CSF) have caused serious economic consequences in China. Phylogenetic analysis based on full-length E2 gene sequences showed that five classical swine fever virus (CSFV) isolates collected from Hunan province in 2011 and 2012, together with seven other isolates from neighboring provinces, Guangdong (5) and Guangxi (2), could be classified as a new subgenotype 2.1c, which may have been endemic in the south of China for at least fourteen years. Subgenotype 2.1c isolates share 90.2-94.9% and 89.9-93.8% nucleotide sequence similarity separately with those of subgenotype 2.1a and 2.1b in E2 gene, which are lower than the nucleotide identities between subgenotype 2.1a and 2.1b (91.1-95.7%). Further analysis based on a partial E2 gene sequence (216 nt) indicated that subgenotype 2.1c isolates are also circulating in Thailand. Alignment of E2 amino acid sequences showed that subgenotype 2.1c isolates exhibit a SPA → TPV substitution at positions 777 and 779 compared with subgenotypes 2.1a and 2.1b.

Complete genome sequences of classical Swine Fever virus isolates belonging to a new subgenotype, 2.1c, from hunan province, china.

Two isolates of a new classical swine fever virus (CSFV) subgenotype, 2.1c (HNLY-2011 and HNSD-2012), were recently isolated from pigs in Hunan Province, China. The most significant difference in the amino acid sequences of the polyproteins from subgenotypes 2.1a and 2.1b is an SPA → TPV amino acid substitution at positions 777 and 779 in the E2 protein.