Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

Impaired neutralisation of SARS-CoV-2 delta variant in vaccinated patients with B cell chronic lymphocytic leukaemia.

BACKGROUND Immune suppression is a clinical feature of chronic lymphocytic leukaemia (CLL), and patients show increased vulnerability to SARS-CoV-2 infection and suboptimal antibody responses. METHOD We studied antibody responses in 500 patients following dual COVID-19 vaccination to assess the magnitude, correlates of response, stability and functional activity of the spike-specific antibody response with two different vaccine platforms. RESULTS Spike-specific seroconversion post-vaccine was seen in 67% of patients compared to 100% of age-matched controls. Amongst responders, titres were 3.7 times lower than the control group. Antibody responses showed a 33% fall over the next 4 months. The use of an mRNA (n = 204) or adenovirus-based (n = 296) vaccine platform did not impact on antibody response. Male gender, BTKi therapy, prophylactic antibiotics use and low serum IgA/IgM were predictive of failure to respond. Antibody responses after CD20-targeted immunotherapy recovered 12 months post treatment. Post-vaccine sera from CLL patients with Spike-specific antibody response showed markedly reduced neutralisation of the SARS-CoV-2 delta variant compared to healthy controls. Patients with previous natural SARS-CoV-2 infection showed equivalent antibody levels and function as healthy donors after vaccination. CONCLUSIONS These findings demonstrate impaired antibody responses following dual COVID-19 vaccination in patients with CLL and further define patient risk groups. Furthermore, humoural protection against the globally dominant delta variant is markedly impaired in CLL patients and indicates the need for further optimisation of immune protection in this patient cohort

SARS-CoV-2 vaccine responses following CD20-depletion treatment in patients with haematological and rheumatological disease: a West Midlands Research Consortium study

© 2021 The Authors. Published by Oxford Academic. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1093/cei/uxab018B cell depleting agents are amongst the most commonly used drugs to treat haemato-oncological and autoimmune diseases. They rapidly induce a state of peripheral B cell aplasia with the potential to interfere with nascent vaccine responses, particularly to novel antigens. We have examined the relationship between B cell reconstitution and SARS-CoV-2 vaccine responses in two cohorts of patients previously exposed to B cell depleting agents: a cohort of patients treated for haematological B cell malignancy and another treated for rheumatological disease. B cell depletion severely impairs vaccine responsiveness in the first 6 months after administration: SARS-CoV-2 antibody seroprevalence was 42.2% and 33.3% in the haemato-oncological patients and rheumatology patients respectively and 22.7% in patients vaccinated while actively receiving anti-lymphoma chemotherapy. After the first 6 months, vaccine responsiveness significantly improved during early B cell reconstitution, however, the kinetics of reconstitution was significantly faster in haemato-oncology patients. The AstraZeneca ChAdOx1 nCoV-19 vaccine and the Pfizer BioNTech 162b vaccine induced equivalent vaccine responses, however shorter intervals between vaccine doses (36m previously) vaccine non-responsiveness was independent of peripheral B cell reconstitution. The findings have important implications for primary vaccination and booster vaccination strategies in individuals clinically vulnerable to SARS-CoV-2