Since first being reported in 2010,1 CD19-directed chimeric antigen receptor (CAR) T cells have led a revolution in the treatment of B-cell non-Hodgkin lymphomas. ...the follow-up period was ...substantially extended, with a median of 40·3 months (IQR 37·8–43·8), and so the Article shows truly long-term patient outcomes. The findings reported by Schuster and colleagues8 show the long-term benefit of CD19-directed CAR T cells as a standalone therapy for some patients with non-Hodgkin lymphomas. ...emerging, not yet peer-reviewed, results showing the superiority of CD19-directed CAR T-cell therapies over standard-of-care autologous haematopoietic stem-cell transplantation in the second line will most likely change the treatment paradigm for patients with relapsed or refractory aggressive B-cell lymphomas in the near future.
Autologous T cells transduced with CD19-directed chimeric antigen receptors have recently been approved by several regulatory agencies for the treatment of relapsed and refractory leukemia and ...lymphoma, after demonstrating remarkable remission rate in advanced patients. The most common adverse events reported are cytokine-release syndrome (CRS), neurotoxicity, and hematologic toxicity. Here, we focus on early and late cytopenia occurring after CD19 CAR-T cells in 38 patients treated with CD19 CAR-T cells. Neutropenia, thrombocytopenia, and anemia occur frequently (94, 80, and 51%, respectively) after CAR-T cell infusion, and are associated with a biphasic nature, as in 93% of patients hematologic toxicity occurs after 21 days from cell infusion. Late hematologic toxicity was more common in patients with high grade CRS and in patients treated after a recent stem cell transplantation. Interestingly, since these events occur late after the lymphodepleting chemotherapy and after resolution of CRS, we found perturbations in SDF-1 levels to correlate with events of late neutropenia, likely associated with B-cell recovery.
Summary
The immunogenicity and safety of Pfizer‐BioNTech BNT162b2 mRNA vaccine in allogeneic haematopoietic stem cell transplantation (HSCT) recipients are unknown. We prospectively followed 152 HSCT ...recipients who were at least six months following transplantation and with no active acute graft‐versus‐host disease (GVHD). Blood samples were taken 2–4 weeks after the second vaccination and analyzed for receptor‐binding domain (RBD) antibodies and neutralizing antibodies (NA). 272 immunocompetent healthcare workers served as controls. At a median of 28 days after the second vaccination, 118 patients (77·6%) developed RBD immunoglobulin G (IgG) with a geometric mean titre (GMT) of 2·61 95% CI (confidence interval), 2·16–3·16. In the control group 269/272 (98·9%) developed RBD IgG, with a GMT of 5·98 (95% CI 5·70–6·28), P < 0·0001. The GMT of NA in HSCT recipients and controls was 116·0 (95% CI 76·5–175·9), and 427·9 (95% CI 354·3–516·7) respectively (P < 0001). Multivariate logistic regression analysis revealed that HSCT recipients with no chronic GVHD and no immunosuppressive therapy at the time of vaccination had significantly higher levels of NA following the second vaccination. Adverse events were minimal and were less common than in healthy controls. In conclusion; the BNT162b2 mRNA vaccination is safe and effective in HSCT recipients, especially those who are immunosuppression‐free. A significant fraction developed protecting NA.
The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in changes in management and imaging routines for patients with hematological malignancies. ...Treating physicians had to familiarize themselves with a new disease, with distinct imaging manifestations, sometimes overlapping with other infections prevalent in this patient population. In some aspects, infected hematological patients might exhibit a different disease course, and routine imaging in asymptomatic hematological patients may result in unexpected COVID-19 findings, implying covert infection, that should be further explored. Furthermore, some complications of hematological diseases and treatments may present with findings similar to COVID-19 manifestations, and treating physicians must consider both possibilities in the differential diagnosis. In this review, we aimed to present the influence the COVID-19 pandemic had on hematological malignancy imaging.
Patients with chronic lymphocytic leukemia (CLL) have a suboptimal humoral response to vaccination. Recently, BNT162b2, an mRNA COVID-19 vaccine with a high efficacy of 95% in immunocompetent ...individuals, was introduced. We investigated the safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with CLL from nine medical centers in Israel, Overall 400 patients were included, of whom 373 were found to be eligible for the analysis of antibody response. The vaccine appeared to be safe and only grade 1-2 adverse events were seen in 50% of the patients. Following the second dose, an antibody response was detected in 43% of the cohort. Among these CLL patients, 61% of the treatment-na ve patients responded to the vaccine, while responses developed in only 18% of those with ongoing disease, 37% of those previously treated with a BTK inhibitor and 5% of those recently given an anti-CD20 antibody. Among patients treated with BCL2 as monotherapy or in combination with anti-CD20, 62% and 14%, respectively, developed an immune response. There was a high concordance between neutralizing antibodies and positive serological response to spike protein. Based on our findings we developed a simple seven-factor score including timing of any treatment with anti-CD20, age, treatment status, and IgG, IgA, IgM and hemoglobin levels. The sum of all the above parameters can serve as a possible estimate to predict whether a given CLL patient will develop sufficient antibodies. In conclusion, the BNT162b2 mRNA COVID-19 vaccine was found to be safe in patients with CLL, but its efficacy is limited, particularly in treated patients.
Patients with plasma cell disorders (PCD) are at an increased risk for severe morbidity and mortality due to COVID-19. Recent data have suggested that patients with hematological malignancies, ...including those with PCD, have suboptimal antibody response to COVID-19 vaccination. We compared the antibody titers of 213 patients with PCD to those of 213 immunocompetent healthcare workers after the second vaccine dose of the BNT162b2 mRNA vaccine. Blood samples were taken 2-4 weeks after the second vaccination and analyzed for anti-receptor binding-domain immunoglobulin G (RBD-IgG) antibodies and neutralizing antibodies (NA). At a median of 20 days after the second vaccine dose, 172 patients (80.8%) developed anti-RBD-IgG antibodies with a geometric mean titer (GMT) of 2.7 (95% confidence interval CI, 2.4-3.1). In the control group 210 (98.9%) developed anti-RBD-IgG antibodies after a median of 21 days, with a GMT of 5.17 (95%CI, 4.8-5.6), p<0.0001. NA were observed in 151 patients with MM (70.9%) and in 210 controls (98.9%). The GMT of NA in patients with MM and controls was 84.4 (95% CI, 59.0-120.6), and 420.2 (95% CI, 341.4-517.1), respectively (p<0.0001). Multivariable logistic regression revealed that the number of prior therapy lines and age were significant predictors of poor humoral response among patients with MM. Injection site reaction, headache and fatigue were the most common adverse events after vaccination. Adverse events were less common in patients with MM than in controls. In conclusion, a significant percentage of patients with MM developed protecting NA to the BNT162b2 mRNA vaccine, which appears to be safe in this patient population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Autologous CD19 chimeric‐antigen receptor (CAR) T cells demonstrated remarkable remission rates in relapsed and refractory acute lymphoblastic leukemia (R/R ALL). Here, we report results from a phase ...1b/2 study of in‐house produced CD19 CAR with a CD28 costimulatory domain. Twenty‐one patients with R/R ALL were enrolled, and 20 infused. The median age was 11 years (range, 5‐48). Patients had a median of 4 prior regimens, including blinatumomab in 6 and prior stem–cell transplantation in 10. In total 8 patients had extramedullary (EM) leukemic involvement, and prior to lymphodepletion and CAR 7 had active lesions, a group underrepresented in previous trials. In vivo expansion of CAR T cells was observed in 18 patients. In total 16 patients developed cytokine release syndrome, and 11 patients developed neurotoxicity, with no toxic deaths. All responding patients were referred to an allogeneic hematopoietic stem‐cell transplantation. The remission rate was 90%, including resolution of all refractory EM sites. Four responding patients relapsed, 3 who had a PCR‐MRD positive remission at 28 days following CAR‐T cells and 1 patient 21 months after an MRD‐negative response. The estimated 1‐year event‐free survival and overall survival are 73% and 90%, respectively. Patients with R/R EM ALL may also benefit from CAR‐T cell therapy.
Second allogeneic hematopoietic stem-cell transplantation (HSCT2) is a therapeutic option for patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) relapsing after a first ...transplant (HSCT1). However, patients allocated to HSCT2 may be a selected group with better prognosis and the added efficacy of HSCT2 is not well established. We retrospectively analyzed 407 consecutive patients with relapsed AML/MDS after HSCT1. Sixty-two patients had HSCT2 (15%) and 345 did not. The 2-year cumulative incidence rates of non-relapse mortality and relapse after HSCT2 were 26% (95% confidence interval 95% CI: 17-39%) and 50% (95% CI: 39-65%), respectively. The 5-year overall survival rates were 25% (95% CI: 14-36%) and 7% (95% CI: 4-10%) in the HSCT2 and no-HSCT2 groups, respectively. Multivariate analysis identified female gender (hazard ratio HR=0.31, P=0.001), short remission duration after HSCT1 (HR=2.31, P=0.05), acute graft-versus-host disease after HSCT1 (HR=2.27, P=0.035), HSCT2 from a haplo-identical donor (HR=13.4, P=0.001) or matched unrelated donor (HR=4.53, P=0.007) and relapse after HSCT1 in earlier years (HR=2.46, P=0.02) as factors predicting overall survival after HSCT2. Multivariate analysis of all patients including HSCT2 as a timedependent variable identified relapse within 6 months after HSCT1 (HR=2.32, P<0.001), acute graft-versus-host disease before relapse (HR=1.47, P=0.005), myeloablative conditioning in HSCT1 (HR=0.67, P=0.011), female gender (HR=0.71, P=0.007), relapse in earlier years (HR=1.33, P=0.031) and not having HSCT2 (HR=1.66, P=0.010) as predictive of overall survival after relapse. In conclusion, HSCT2 is associated with longer survival compared to non-transplant treatments and may be the preferred approach in a subset of patients with relapsed AML/MDS after HSCT1.
We assessed the humoral and cellular response to the fourth BNT162b2 mRNA COVID‐19 vaccine dose in patients with CLL. A total of 67 patients with CLL and 85 age matched controls tested for serologic ...response and pseudo‐neutralization assay. We also tested the functional T‐cell response by interferon gamma (IFNγ) to spike protein in 26 patients. Two weeks after the fourth vaccine antibody serologic response was evident in 37 (55.2%) patients with CLL, 20 /22 (91%) of treatment naïve, and 9/32 (28%) patients with ongoing therapy, compared with 100% serologic response in age matched controls. The antibody titer increased by 10‐fold in patients with CLL, however, still 88‐folds lower than age matched controls. Predictors of better chances of post fourth vaccination serologic response were previous positive serologies after second, third, and pre‐fourth vaccination, neutralizing assay, and treatment naïve patients. T‐cell response improved from 42.3% before the fourth vaccine to 84.6% 2 weeks afterwards. During the time period of 3 months after the fourth vaccination, 14 patients (21%) developed COVID‐19 infection, all recovered uneventfully. Our data demonstrate that fourth SARS‐CoV‐2 vaccination improves serologic response in patients with CLL to a lesser extent than healthy controls and induces functional T‐cell response.
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