Association between N-acetylcysteine treatment and in-hospital mortality in adult patients with acquired thrombotic thrombocytopenic purpura: a cohort study.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a fatal hematologic disease. Despite the currently high standards of care, some patients who develop refractory or recurrent disease still have a poor prognosis. Although N-acetylcysteine (NAC) is recommended for the treatment of aTTP, its use in aTTP treatment is still controversial. We aimed to evaluate the association of NAC with mortality in patients with aTTP. This was a retrospective cohort study of patients with aTTP with in-hospital mortality as the primary outcome and time to platelet recovery and neurological recovery as secondary outcomes. We used multifactorial COX regression analysis to check for an association of NAC with mortality. Moreover, we performed a sensitivity analysis check the stability of our results. Finally, 89 patients with aTTP were enrolled. After adjusting for potential confounders, we found NAC to be associated with 75% lower in-hospital mortality (HR = 0.25, 95% CI = 0.1-0.64). The results of sensitivity analyses performed remained stable as the risk of in-hospital mortality in patients reduced in patients with comorbid neurological symptoms (HR = 0.23, 95% CI = 0.06-0.89). However, NAC use did not affect the time to platelet recovery (HR = 1.19, 95% CI = 0.57-2.5) or neurological recovery (HR = 0.32, 95% CI = 0.08-1.25) in patients with aTTP. NAC treatment reduces in-hospital mortality in patients with aTTP but does not shorten the time to platelet recovery or neurological recovery.

Efficacy and safety of chimeric antigen receptor T cell therapy in relapsed/refractory diffuse large B-cell lymphoma with different HBV status: a retrospective study from a single center.

Background: Chimeric antigen receptor T cell (CAR-T) therapy is an effective salvage treatment in relapsed or refractory(r/r) diffuse large B-cell lymphoma (DLBCL), but the impact of hepatitis B virus (HBV) infection has not been studied. Methods and results: Here, 51 patients with r/r DLBCL receiving CAR-T therapy were enrolled and analyzed at the First Affiliated Hospital of Soochow University. The overall response rate and the complete remission rate (CR) of CAR-T therapy were 74.5% and 39.2%, respectively. With a median follow-up of 21.1 months after CAR-T, the probabilities of overall survival (OS) and progression-free survival (PFS) at 36 months were 43.4% and 28.7%, respectively. These patients were divided into three cohorts including chronic HBV infection group (n=6), resolved HBV infection group (n=25) and non-HBV infection group (n=20). Bone marrow involvement was significantly higher in the HBV infection group(P<0.001), other basic characteristics before CAR-T therapy were comparable. Subgroup analysis showed that HBV infection status did not affect the efficacy of CAR-T therapy in CR rate, OS or PFS, and there was no significant difference in CAR-T related toxicities between three cohorts. Only one cirrhosis patient with chronic HBV infection experienced HBV reactivation. Conclusions: CAR-T therapy was effective and can be used safely in r/r DLBCL with HBV infection under proper monitoring and antiviral prophylaxis.

CAR-T cell therapy followed by allogenic hematopoietic stem cell transplantation yielded comparable outcome between Ph like ALL and other high-risk ALL.

It was previously believed that patients with Ph-like ALL had poorer prognosis compared with other B-ALL subgroups due to resistance to conventional chemotherapy and lack of targeted drugs. CAR-T therapy has been successfully applied in the treatment of relapsed and refractory B-ALL. Currently, there are few data on whether CAR-T therapy can alter the outcome of Ph-like ALL. Here we included 17 Ph-like, 23 Ph+ and 51 other B-ALL patients, who received autologous CAR T-cell therapy and subsequently allogenic stem cell transplantation. Patients in the Ph-like group and B-ALL-others group were younger that those in the Ph+ group (P=0.001). Ph-like and Ph+ ALL patients showed higher white blood cell counts at diagnosis (P=0.025). The percentage of patients with active disease before receiving CAR T-cells infusion was 64.7%, 39.1% and 62.7% in the Ph-like, Ph+ and B-ALL-others groups. The response rates to CAR-T therapy were 94.1% (16/17), 95.6% (22/23) and 98.0% (50/51) in the Ph-like, Ph+ and B-ALL-others groups. Measurable residual disease negative CR was achieved in 64.7% (11/17), 60.9% (14/23) and 54.9% (28/51) in the Ph-like, Ph+ and B-ALL-others groups, respectively. The estimated rates of 3-year overall survival (65.9%±16.5%, 59.7%±10.5% and 61.6%±7.3%, P=0.758) and 3-year relapse-free survival (59.8%±14.8%, 63.1%±10.5% and 56.3%±7.1%, P=0.764) were comparable among the Ph-like, Ph+ and B-ALL-others groups. Estimated 3-year cumulative relapse rate was 7.8%±0.6%, 23.4%±0.9% and 29.0%±0.4% (P=0.241). Our findings suggest that CART followed by allo-HSCT results in a comparable prognosis in Ph-like ALL and other high-risk B-ALL.Trial registration ClinicalTrials. gov, NCT03275493, Registered on September 7, 2017, prospectively registered and NCT03614858, Registered on August 3, 2018, prospectively registered.

Decitabine-primed tandem CD19/CD22 CAR-T therapy in relapsed/refractory diffuse large B-cell lymphoma patients.

Chimeric antigen receptor T cell (CAR-T) therapy has emerged as highly effective in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but only about 40% patients have achieved sustained responses. Here, we conducted a phase II clinical trial testing efficacy and toxicities of CAR-T therapy in R/R non-Hodgkin's lymphoma patients (NCT03196830). Among enrolled patients, 33 R/R DLBCL patients pretreated with DFC (decitabine, fludarabine plus cyclophosphamide) lymphodepletion chemotherapy and infused with tandem CD19-CD22 based CAR-T cells were drawn out for efficacy and toxicities of CAR-T therapy evaluation. With a median follow-up of 10.9(0.6-29.0) months, the best overall response and complete remission (CR) rates were 90.9% and 63.6%, respectively. The median progression-free survival (PFS) was 10.2 months and overall survival (OS) was undefined. The 2-year OS and PFS rates were 54.3% and 47.2%, respectively. No severe grade 4 cytokine release syndrome (CRS) was observed and grade 3 CRS was observed in only 7 patients; 3 patients developed mild immune effect or cell-associated neurotoxic syndrome. All toxicities were transient and reversible and no CAR-T-related mortality. Further subgroup analysis showed that achieving CR was an independent prognostic factor associated with favorable PFS and OS. The 2-year OS and PFS for patients who achieved CR within 3 months (undefined versus undefined P=0.021 and undefined versus undefined P=0.036) or during the follow-up period were significantly longer than those who did not (undefined versus 4.6 months P < 0.0001 and undefined versus 2.0months P<0.001). While severe CRS was also an independent prognostic factor but associated with inferior PFS and OS. The 2-year OS and PFS for patients with grade 3 CRS were significantly shorter than those with grade 0-2 CRS (4.1 months versus undefined P<0.0001 and 1.7 months versus undefined P=0.0002). This study indicated that CD19/CD22 dual-targeted CAR-T therapy under a decitabine-containing lymphodepletion regimen may be a safe, potent effective approach to R/R DLBCL patients.

Dual epigenetic agents plus rituximab-gemcitabine-oxaliplatin as salvage treatment in relapsed/refractory diffuse large B-cell lymphoma patients failure of salvage chemotherapy.

Refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) patients' failure of salvage chemotherapy had extremely worse prognoses. Herein, 14 R/R DLBCL patients failed to salvage chemotherapy were exposed to dual epigenetic agents (Chidamide 30 mg biw*2w and Decitabine 10 mg/m2 qd*d1-d5) and sequential R-GemOx (rituximab 375 mg/m2 qd d6; gemcitabine 1 g/m2 d7, d14; and oxaliplatin 100 mg/m2 d7) for further salvage chemotherapy. Finally, 11/14(78.6%) patients achieved overall response with 6/14(42.9%) achieving complete remission and 2-year overall survival (OS)/progression free survival (PFS) rate was 42.7%, extremely higher than reported previously. Further subgroup analysis demonstrated that 2-year OS/PFS rate was significantly higher in patients achieved complete/partial remission or with low international prognosis index (IPI 0-2) than that in patients with steady disease or high IPI (3-5). Common grade 3-4 adverse events were hematological toxicities. All toxicities were transient and reversible. Our report implicates that combination of dual epigenetic agents and R-GemOx is a safe and promising alternative for R/R DLBCL patients.

Successful treatment of acquired amegakaryocytic thrombocytopenia with eltrombopag and immunosuppressant.

Acquired amegakaryocytic thrombocypenia (AAMT) is an extremely rare hematologic disorder and standard treatment strategy has not been established. We described herein two cases of AAMT who were fully responded to eltrombopag and immunosuppressant. Patient 1 was refractory to steroid, IVIG and recombinant human thrombopoietin (rhTPO). Patient 2 did not respond to high dosage of steroid, IVIG, rhTPO and rituximab. Moreover, his AAMT progressed to aplastic anemia in 5 months. Both patients took eltrombopag and immunosuppressant, then they achieved long-term remission without obvious side effects. Our findings suggest that this combination can be a valuable alternative in AAMT.

Radiation Priming Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma With High Tumor Burden.

Chimeric antigen receptor T-cell (CAR-T) therapy demonstrates impressive efficacy in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, CAR-T therapy-related severe cytokine release syndrome and neurological toxicity limit its clinical application in R/R DLBCL patients with high tumor burden. Here, we conducted a phase II clinical trial testing the efficacy and toxicities of CAR-T therapy in R/R non-Hodgkin lymphoma patients (NCT03196830). Among the enrolled patients, 10 R/R DLBCL patients with high tumor burden were analyzed. Before CAR-T therapy, 4 were treated with intensive combined chemotherapy (C-CAR-cohort), and 6 were exposed to radiotherapy (R-CAR-cohort). Patients in the R-CAR-T-cohort showed a higher overall response rate (100% vs. 25%, P=0.033) and less severe cytokine release syndrome (0% vs. 100%, P=0.0048) and neurotoxicity (0% vs. 75%, P=0.033) incidences than patients in the C-CAR-T-cohort. Furthermore, one case who responded to CAR-T therapy initially and who suffered a relapse shortly was exposed to radiation and achieved complete remission, with an increase in the number of CAR-T copies detected. This study demonstrates that radiotherapy is an optimal debulking regimen to managing R/R DLBCL patients before CAR-T therapy and a promising alternative salvage therapy for patients who suffer a relapse after CAR-T therapy by fuelling CAR-T copies.

Anti-CD19 chimeric antigen receptors T cells for the treatment of relapsed or refractory E2A-PBX1 positive acute lymphoblastic leukemia: report of three cases.

Patients with relapsed or refractory E2A-PBX1 positive acute B lymphoblastic leukemia (B-ALL) receiving anti-CD19 chimeric antigen receptor T cells (CAR-T) were retrospectively assessed to evaluate the efficacy and safety of disease burden on outcomes and to identify predictive variables. Of the three case patients, case 1 relapsed after hematopoietic stem cell transplantation. After being treated with anti-CD19 CAR-T, the patient showed minimal residual disease (MRD), and his fusion genes turned negative. Case 2, who suffered refractory leukemia, received anti-CD19 CAR-T treatment in an attempt to remove the MRD before transplantation. She showed MRD, and her fusion genes turned negative. Case 3 received anti-CD19 CAR-T treatment because of relapse after allo-SCT at the molecular level. After infusion, she developed severe pneumonia accompanied with the indication that the leukemia had progressed. Our findings suggest that anti-CD19 CAR-T cells therapy with a remarkable MRD eradicating ability might be an effective option for patients with relapsed and refractory E2A-PBX1 positive B-ALL.

Successful treatment of secondary poor graft function post allogeneic hematopoietic stem cell transplantation with eltrombopag.

Poor graft function (PGF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Current treatment strategies include the use of growth factors, CD34+-selected stem cell boost, mesenchymal stem cell transfusion, and second allo-HSCT, but these treatments are not effective in all patients. Eltrombopag, an oral thrombopoietin receptor agonist, which showed promising results in severe aplasia anemia, may be an alternative choice for PGF patients. Therefore, we treated 12 patients who responded poorly to standard treatments for secondary PGF after allo-HSCT with eltrombopag. The median duration was 116 (35-1000) days from transplantation to PGF diagnosis and 59 (30-180) days from PGF diagnosis to eltrombopag treatment. Eltrombopag was started at a dose of 25 mg/d for 3 days and then increased to 50 or 75 mg/d. Median treatment duration was 8 (2-23) weeks. Ten patients (83.3%) responded to the treatment: 8 achieved complete response (CR), and the remaining 2 achieved partial response. In the 10 responding subjects, median platelet count was 18 (5-27) × 109/L vs 74 (30-117) × 109/L prior to and after treatment. Neutrophil count was 0.51 (0.28-0.69) × 109/L vs 1.84 (0.78-4.90) × 109/L. Hemoglobin was 88 (63-123) vs 101 (78-134) g/L. In the 8 patients who achieved CR, the time from eltrombopag initiation to achieving CR was 29 (10-49) days; the response lasted until the last follow-up in all 8 CR subjects (10-18 months). The 12-month overall survival rate was 83.3%. There was no treatment-related mortality and no evidence of cataract, thrombosis, or any other grade 3/4 toxicities.