Outcomes of Second Anti-CD19 CAR T-Cell Therapy (CART2) in Acute B Lymphoblastic Leukemia and the Impact of Allo-HSCT on Efficacy.

For patients exhibiting a suboptimal response to the first chimeric antigen receptor (CAR) T-cell therapy (CART1) or relapse after remission, secondary CAR T-cell therapy (CART2) for the same target may be an option. We retrospectively analyzed patients with acute B-cell lymphoblastic leukemia (B-ALL) receiving CD19 CART1 at our center (n = 84) to report the clinical outcomes of CART2 and to identify the factors that may influence the outcomes. Twenty-six patients received CART2 for suboptimal response or relapse post-CART1. The incidence of cytokine release syndrome (CRS) after CART2 was 65.4% (17/26), with 11 cases classified as grade 1 (42.3%), four cases as grade 2 (15.4%), and two cases as grade 3 (7.7%). Neurotoxicity was observed in one patient (3.8%) after CART2 infusion. Fourteen patients (53.8%) achieved complete remission (CR) after CART2. CART2 exhibited an inferior response rate (CART2: 53.8%, 14/26; CART1: 81.0%, 64/79; P = 0.006) and a lower incidence of severe CRS (CART2: 7.7%, 2/26; CART1: 30.4%, 24/79; P = 0.020) compared with CART1, with a median progression-free survival (PFS) and a median overall survival (OS) of 6.2 months and 11.2 months, respectively. In particular, patients who progressed after consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT) following CART1 and then received CART2 demonstrated promising outcomes with a response rate of 80.0% (8/10), a median PFS of 7.9 months, and a median OS of 25.1 months. After adjusting for the confounding factors, the response rate (85.7%, 6/7) of CART2 administered to this cohort was better than those who did not bridge to allo-HSCT receiving CART2 (28.6%, 2/7) or non-CART2 treatments (13.3%, 2/15). The median OS after CART2, which was not reached, was significantly better than the median OS after CART2 (3.9 months, P = 0.014) and non-CART2 treatments (6.0 months, P = 0.012) administered in patients who did not undergo consolidative allo-HSCT post-CART1. Our results indicated that, although less effective than CART1, a subset of patients can still benefit from CART2 with mild adverse effects. For patients who relapsed after consolidative allo-HSCT post-CART1, treatment with CART2 is a viable option.

[A Real-World Study of the Effect of rhG-CSF on Clinical Efficacy and Flow Cytometry MRD after Initial Induction Therapy for Acute Myeloid Leukemia].

OBJECTIVE: To investigate the effect of recombinant human granulocyte colony stimulating factor (rhG-CSF) on the clinical efficacy and flow cytometry (FCM) minimal residual disease (MRD) of patients with acute myeloid leukemia (AML) after initial induction therapy in the real world. METHODS: The clinical data of 44 AML patients who were diagnosed for the first time in the Department of Hematology, The Second Hospital of Anhui Medical University, and received the initial induction therapy were retrospectively analyzed. According to whether rhG-CSF was used after treatment, these patients were divided into control group and therapy group. The complete remission (CR) rate, duration of neutropenia, incidence of infection, duration of fever, cost of antibiotics drugs, length of hospital stay, FCM MRD, and relapse-free survival (RFS) time were compared between the two groups. RESULTS: The CR rate in the control group was 60%, and 74% in the therapy group (P=0.3429). The duration of neutropenia was (21.28±7.91) days in the control group and (14.79±3.07) days in the therapy group (P=0.0016). The duration of fever was (12.80±7.31) days in the control group and (9.11±7.48) days in the therapy group (P=0.0136). While, there were no statistically significant differences between the two groups in the incidence of infection, cost of antibacterial drugs, length of hospital stay and RFS time (all P>0.05). In addition, it is particularly noteworthy that among the patients who finally obtained CR in the therapy group, 66% of them had myeloid precursor cells detected by peripheral blood FCM (accounting for 2.25%±0.99%) at the time of the first release of neutropenia, which was easy to be misdiagnosed as MRD positive. CONCLUSION: rhG-CSF not only don't affect the clinical remission rate after the initial induction treatment of AML, but also significantly shortens the time of duration of neutropenia and fever, however, it may affect the analysis of peripheral blood FCM MRD detection results when the neutropenia is released for the first time.

Impact of Consolidative Unrelated Cord Blood Transplantation on Clinical Outcomes of Patients With Relapsed/Refractory Acute B Lymphoblastic Leukemia Entering Remission Following CD19 Chimeric Antigen Receptor T Cells.

Background: While chimeric antigen receptor (CAR)-T cell therapy is becoming widely used in hematological malignancies with remarkable remission rate, their high recurrence remains an obstacle to overcome. The role of consolidative transplantation following CAR-T cell-mediated remission remains controversial. We conducted a retrospective study to explore whether bridging to unrelated cord blood transplantation (UCBT) could improve the prognosis of patients entering remission after CAR-T therapy with different characteristics through subgroup analyses. Methods: We reviewed 53 patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) successfully infused with CD19 CAR-T cells and achieved complete remission (CR). In this study, 25 patients received consolidative UCBT (UCBT group) and 28 patients did not accept any intervention until relapse (non-UCBT group). Subgroup analysis on prognosis was then performed according to gender, age, number of previous relapses, tumor burden, presence of poor prognostic markers, and structure of CAR. Results: Compared with the non-UCBT group, patients who underwent consolidative UCBT had better median event-free survival (EFS; 12.3 months vs. 6.2 months; P = 0.035) and relapse-free survival (RFS; 22.3 months vs. 7.2 months; P = 0.046), while no significant difference was found in overall survival (OS; 30.8 months vs. 15.3 months; P = 0.118). Subsequent multivariate analysis revealed that bridging to UCBT was a protective factor for RFS (P = 0.048) but had no significant effect on EFS (P = 0.205) or OS (P = 0.541). In the subgroup analysis, UCBT has an added benefit in patients with specific characteristics. Patients who experienced ≥2 relapses or with sustained non-remission (NR) showed better RFS (P = 0.025) after UCBT. Better EFS was seen in patients with poor prognostic markers (P = 0.027). In the subgroup with pre-infusion minimal residual disease (MRD) ≥5% or with extramedullary disease (EMD), UCBT significantly prolonged EFS (P = 0.009), RFS (P = 0.017), and OS (P = 0.026). Patients with occurrence of acute graft-versus-host disease (aGVHD) appeared to have a longer duration of remission (P = 0.007). Conclusion: Consolidative UCBT can, to some extent, improve clinical outcomes of patients with R/R B-ALL entering remission following CD19 CAR-T therapy, especially in patients with more recurrences before treatment, patients with poor prognostic markers, and patients with a higher tumor burden. The occurrence of aGVHD after UCBT was associated with better RFS.

CD4+CD25+CD127low regulatory T cells associated with the effect of CD19 CAR-T therapy for relapsed/refractory B-cell acute lymphoblastic leukemia.

BACKGROUND: CD19-specific chimeric antigen receptor T-cell (CAR-T) therapy has shown promising clinical outcomes in relapsed/refractory acute B-cell lymphoblastic leukemia (R/R B-ALL) patients. However, some patients did not respond to this therapy or relapsed after remission. Regulatory T cells (Tregs) have shown great importance in promoting tumor escape, but little is known about their role in R/R B-ALL patients with CAR-T therapy. Our previous study has proved that higher Tregs before infusion was an independent high-risk factor for relapse-free survival (RFS). To further clarify the relationship between Tregs and the efficacy of CAR-T therapy, the present study tested the levels of CD4+CD25+CD127low Tregs in peripheral blood (PB) of R/R B-ALL patients at different stages of CD19 CAR-T therapy, and evaluate their impact on the efficacy and prognosis of CAR-T therapy. METHODS: From November 2015 to May 2019, 47 R/R B-ALL patients successfully received CD19 CAR-T therapy at our institution and followed up for at least 1 month. Among them, one patient did not tested for Tregs, so 46 patients enrolled in this study. We collected clinical information of them and dynamically detected the frequency of CD4+CD25+CD127low Tregs within CD4 + T cells at different time points (before infusion and at 1 week after infusion) by flow cytometry, and validated the relationship of circulating Tregs with clinical efficacy, OS, and recurrence of CAR-T therapy. RESULTS: Circulating Tregs of R/R B-ALL patients in pre-infusion group (median 6.67%) and in 1 week after infusion group (median 6.80%) were all higher than that of the healthy control group (median 5.04%), with statistical significance (P < 0.05). The frequencies of Tregs in not remission (NR) group at baseline (pre-infusion) and at 1 week after infusion were all significantly higher than those in remission group. With cut-off values of 11.54% (before infusion) and 13.56% (1 week after infusion), the specificity for Tregs were 94.6% and 100% , respectively. In remission group, 11 patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) after achieving remission by Sino 19 cell therapy. No significant differences of Tregs expression were found between transplantation and non-transplantation groups. Time-dependent Cox model showed that transplantation group had lower risk of relapse and death when compared with non-transplantation group (HR = 0.664 for RFS and HR = 0.364 for OS), however, no statistical significances were found (P = 0.403 and 0.106, respectively). Higher Tregs before infusion and at 1 week after infusion were significant associated with shorter RFS and OS by Kaplan-Meier analysis. Multivariate analysis showed that higher Tregs at 1 week after infusion was the independently factor for poor RFS (P = 0.032) and shorter OS (P = 0.025) in R/R B-ALL patients with CD19 CAR-T therapy. Besides, Tregs levels before and at 1 week after infusion were negatively correlated with the persistence time of Sino 19 cell. CONCLUSION: Higher circulating Tregs, especially 1 week after CD19 CAR-T cell infusion, was a poor predict indicator for CD19 CAR-T therapy in R/R B-ALL patients.

Influence of patient characteristics on chimeric antigen receptor T cell therapy in B-cell acute lymphoblastic leukemia.

CD19-specific chimeric antigen receptor T cell (CD19 CAR T) therapy has shown high remission rates in patients with refractory/relapsed B-cell acute lymphoblastic leukemia (r/r B-ALL). However, the long-term outcome and the factors that influence the efficacy need further exploration. Here we report the outcome of 51 r/r B-ALL patients from a non-randomized, Phase II clinical trial (ClinicalTrials.gov number: NCT02735291). The primary outcome shows that the overall remission rate (complete remission with or without incomplete hematologic recovery) is 80.9%. The secondary outcome reveals that the overall survival (OS) and relapse-free survival (RFS) rates at 1 year are 53.0 and 45.0%, respectively. The incidence of grade 4 adverse reactions is 6.4%. The trial meets pre-specified endpoints. Further analysis shows that patients with extramedullary diseases (EMDs) other than central nervous system (CNS) involvement have the lowest remission rate (28.6%). The OS and RFS in patients with any subtype of EMDs, higher Tregs, or high-risk genetic factors are all significantly lower than that in their corresponding control cohorts. EMDs and higher Tregs are independent high-risk factors respectively for poor OS and RFS. Thus, these patient characteristics may hinder the efficacy of CAR T therapy.

Hepatosplenic T-Cell Lymphoma in an Immunocompetent Male with Central Nervous System Invasion: A Rare Clinical Entity.

Hepatosplenic T-cell lymphoma (HSTCL) is a very rare non-Hodgkin lymphoma with an aggressive clinical course and poor prognosis. Patients of this disease usually presented with hepatosplenomegaly, which can be misdiagnosed or delayed. Bone marrow (BM) and peripheral blood (PB) are frequently involved, however, central nervous system (CNS) involvement is less common. Here, we are reporting an unusual case of hepatosplenic γδ T-cell lymphoma in a 64-year-old man with CNS involvement. Flow cytometry immunophenotyping was proved of great diagnostic contribution. © 2018 International Clinical Cytometry Society.