British Journal of Haematology

ImportanceNew York City is a global epicenter for the SARS-CoV-2 outbreak with a significant number of individuals infected by the virus. Patients with multiple myeloma have a compromised immune system, due to both the disease and anti-myeloma therapies, and may therefore be particularly susceptible to coronavirus disease 2019 (COVID-19); however, there is limited information to guide clinical management. ObjectiveTo assess risk factors and outcomes of COVID-19 in patients with multiple myeloma. DesignCase-series. SettingFive large academic centers in New York City. ParticipantsPatients with multiple myeloma and related plasma cell disorders who were diagnosed with COVID-19 between March 10th, 2020 and April 30th, 2020. ExposuresClinical features and risk factors were analyzed in relation to severity of COVID-19. Main Outcomes and MeasuresDescriptive statistics as well as logistic regression were used to estimate disease severity reflected in hospital admissions, intensive care unit (ICU) admission, need for mechanical ventilation, or death. ResultsOf 100 multiple myeloma patients (male 58%; median age 68, range 41-91) diagnosed with COVID-19, 74 (74%) were admitted; of these 13 (18%) patients were placed on mechanical ventilation, and 18 patients (24%) expired. None of the studied risk factors were significantly associated (P>0.05) with adverse outcomes (ICU-admission, mechanical ventilation, or death): hypertension (N=56) odds ratio (OR) 2.3 (95% confidence interval [CI] 0.9-5.9); diabetes (N=18) OR 1.1 (95% CI 0.3-3.2); age >65 years (N=63) OR 2.0 (95% CI 0.8-5.3); high dose melphalan with autologous stem cell transplant <12 months (N=7) OR 1.2 (95% CI 0.2-7.4), IgG<650 mg/dL (N=42) OR=1.2 (95% CI 0.4-3.1). In the entire series of 127 patients with plasma cell disorders, hypertension was significantly associated with the combined end-point (OR 3.4, 95% CI 1.5-8.1). Conclusions and RelevanceAlthough multiple myeloma patients have a compromised immune system due to both the disease and therapy; in this largest disease specific cohort to date of patients with multiple myeloma and COVID-19, compared to the general population, we found risk factors for adverse outcome to be shared and mortality rates to be within the higher range of officially reported mortality rates.

ImportanceIn patients with hematologic malignancies, the immunogenicity of the standard 2-dose mRNA-1273 coronavirus disease 19 (COVID-19) vaccination schedule is often insufficient due to underlying disease and current or recent therapy. ObjectiveTo determine whether a 3rd mRNA-1273 vaccination raises antibody concentrations in immunocompromised hematology patients to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. DesignProspective observational cohort study. SettingFour academic hospitals in the Netherlands. Participants584 evaluable immunocompromised hematology patients, all grouped in predefined cohorts spanning the spectrum of hematologic malignancies. ExposureOne additional vaccination with mRNA-1273 5 months after completion of the standard 2-dose mRNA-1273 vaccination schedule. Main Outcomes and MeasuresSerum IgG antibodies to spike subunit 1 (S1) antigens prior to and 4 weeks after each vaccination, and pseudovirus neutralization of wildtype, delta and omicron variants in a subgroup of patients. ResultsIn immunocompromised hematology patients, a 3rd mRNA-1273 vaccination led to median S1 IgG concentrations comparable to concentrations obtained by healthy individuals after the 2-dose mRNA-1273 schedule. The rise in S1 IgG concentration after the 3rd vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. Specifically, patients with myeloid malignancies or multiple myeloma, and recipients of autologous or allogeneic hematopoietic cell transplantation (HCT) reached median S1 IgG concentrations similar to those obtained by healthy individuals after a 2-dose schedule. Patients on or shortly after rituximab therapy, CD19-directed chimeric antigen receptor T cell therapy recipients, and chronic lymphocytic leukemia patients on ibrutinib were less or unresponsive to the 3rd vaccination. In the 27 patients who received cell therapy between the 2nd and 3rd vaccination, S1 antibodies were preserved, but a 3rd mRNA-1273 vaccination did not significantly enhance S1 IgG concentrations except for multiple myeloma patients receiving autologous HCT. A 3rd vaccination significantly improved neutralization capacity per antibody. Conclusions and RelevanceThe primary schedule for immunocompromised patients with hematologic malignancies should be supplemented with a delayed 3rd vaccination. B cell lymphoma patients and allogeneic HCT recipients need to be revaccinated after treatment or transplantation. Trial RegistrationEudraCT 2021-001072-41 Key pointsO_ST_ABSQuestionC_ST_ABSCan a 3rd mRNA-1273 vaccination improve COVID-19 antibody concentrations in immunocompromised hematology patients to levels similar to healthy adults after the standard 2-dose mRNA-1273 schedule? FindingsIn this prospective observational cohort study that included 584 immunocompromised hematology patients, a 3rd mRNA-1273 vaccination significantly improved SARS-CoV-2 antibody concentrations to levels not significantly different from those obtained by healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. Pseudovirus neutralization capacity per antibody of wild type virus and variants of concern also significantly improved. MeaningThe primary COVID-19 vaccination schedule for immunocompromised patients with hematologic malignancies should be supplemented with a delayed 3rd vaccination.

There is limited information on the characteristics, pre-admission prognostic factors, and outcomes of patients with multiple myeloma (MM) hospitalized with coronavirus disease 2019 (COVID-19). This retrospective case series investigated characteristics and outcomes of 167 MM patients hospitalized with COVID-19 reported from 73 hospitals within the Spanish Myeloma Collaborative Group network in Spain between March 1 and April 30, 2020. Outcomes were compared with a randomly selected contemporary cohort of 167 age-/sex-matched non-cancer patients with COVID-19 admitted at 6 participating hospitals. Common demographic, clinical, laboratory, treatment, and outcome variables were collected; specific disease status and treatment data were collected for MM patients. Among the MM and non-cancer patients, median age was 71 years and 57% of patients were male in each series, and 75% and 77% of patients, respectively, had at least one comorbidity. COVID-19 clinical severity was moderate-severe in 77% and 89% of patients and critical in 8% and 4%, respectively. Supplemental oxygen was required by 47% and 55% of MM and non-cancer patients, respectively, and 21%/9% vs 8%/6% required non-invasive/invasive ventilation. Inpatient mortality was 34% and 23% in MM and non-cancer patients, respectively. Among MM patients, inpatient mortality was 41% in males, 42% in patients aged >65 years, 49% in patients with active/progressive MM at hospitalization, and 59% in patients with comorbid renal disease at hospitalization, which were independent prognostic factors of inpatient mortality on adjusted multivariate analysis. This case series demonstrates the increased risk and identifies predictors of inpatient mortality among MM patients hospitalized with COVID-19. Key PointsO_LIThere is an increased risk of inpatient mortality (34% vs 23%) in MM vs age-/sex-matched non-cancer patients hospitalized with COVID-19. C_LIO_LIAdverse prognostic factors at admission for inpatient mortality in MM patients include age >65 y, male sex, renal disease, and active MM. C_LI

ObjectiveTo evaluate immunological response to Covid-19 vaccines in immunocompromised haematology patients and compare with immunocompetent healthy controls DesignWe compared total Anti-SARS-CoV-2 spike antibody and T cell response in 45 immunocompromised haematology patients with 30 healthy adults following 2 doses of Covid-19 vaccine for 3 -5 months at 30 day intervals SettingSingle Centre, University Hospital, United Kingdom, March 2021-December 2021 Main Outcome measuresPeak quantitative total spike-specific antibody and cellular responses ResultsWe found O_LINon - significant difference in T cell and total Anti-SARS-CoV-2 S antibody response between study and control group patients C_LIO_LISix (13%) study group participants did not have detectable Total Anti-SARS -Cov-2 S antibodies at any time point throughout the study monitoring period. C_LIO_LIThree (7%) of the study group participants had no response, even after additional booster doses of Covid-19 vaccine. C_LIO_LIAll (100%) of the control group had detectable Anti-SARS-Cov-2 S antibodies after 2 doses of Covid-19 vaccine. C_LIO_LINo participant died or was hospitalised due to severe Covid-19 infection during the study period. This included study group participants who had no antibody response at any time point. C_LI ConclusionsThough there was a non - significant difference in T cell and total Anti-SARS-CoV-2 S antibody response between immunocompromised patients and healthy controls this did not result in any severe infection or Covid-19 related mortality in our study cohort. We did not identify any patient-specific factor (age, gender), specific haematological condition or treatment as determinant of response. Covid-19 vaccination was well tolerated without major side effects in both groups. What was already known about this topicprior to starting this study there were no studies to confirm immunological response following Covid-19 vaccination in immunocompromised haematology patients. During the conduct of our study there have been publications from researchers confirming blunted serological response in 62-66% of immunocompromised haematology patients compared to 74-95% in healthy controls. What this study addsOur study did not identify a significant difference in serological or T cell response between immunocompromised and healthy groups. Though 13% of immunocompromised patients had no response to Covid-19 vaccination none of them suffered from severe Covid-19 infection. We believe T cell response to Covid-19 vaccination has an important role in providing protective efficacy against Covid-19.

Patients with hematologic malignancies are a high priority for SARS-CoV-2 vaccination, yet the benefit they will derive is uncertain. We investigated the humoral response to vaccination in 53 non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or CLL patients. Peripheral blood was obtained 2 weeks after first vaccination and 6 weeks after second vaccination for antibody profiling using the multiplex bead-binding assay. Serum IgG, IgA, and IgM antibody levels to the spike specific receptor binding domain (RBD) were evaluated as a measure of response. Subsequently, antibody-positive serum were assayed for neutralization capacity against authentic SARS-CoV-2. Histology was 68% lymphoma and 32% CLL; groups were: patients receiving anti-CD20-based therapy (45%), monitored with disease (28%), receiving BTK inhibitors (19%), or chemotherapy (all HL) (8%). SARS-CoV-2 specific RBD IgG antibody response was decreased across all NHL and CLL groups: 25%, 73%, and 40%, respectively. Antibody IgG titers were significantly reduced (p < 0.001) for CD20 treated and targeted therapy patients, and (p = 0.003) for monitored patients. In 94% of patients evaluated after first and second vaccination, antibody titers did not significantly boost after second vaccination. Only 13% of CD20 treated and 13% of monitored patients generated neutralizing antibodies to SARS-CoV-2 with ICD50s 135 to 1767, and 445 and > 10240. This data has profound implications given the current guidance relaxing masking restrictions and for timing of vaccinations. Unless immunity is confirmed with laboratory testing, these patients should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals. Statement of Translational RelevanceNon Hodgkin lymphoma (NHL) and Chronic Lymphocytic leukemia (CLL) patients who are treated with anti-CD20 antibody therapy, BTK inhibitor therapy, or who are monitored with active disease, have decreased antibody response to SARS-CoV-2 vaccination and decreased antibody titers compared to healthy controls. Antibody titers do not boost following second vaccination, and very few patients generate neutralizing antibodies against SARS-CoV-2. This data is of particular importance, given the recent guidance from the CDC that vaccinated patients no longer need to be masked indoors as well as outdoors. Patients with NHL or CLL who fall into these categories should not consider their immunity from vaccination to be assured. If infected with SARS-CoV-2, they should be a high priority for monoclonal antibody directed therapy. Unless immune response to vaccination is confirmed with laboratory testing, they should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals.

Infections are increasingly recognized as a common complication of chimeric antigen receptor (CAR) T-cell therapy. The incidence of clinically-defined infection after CD19.CAR T-cell therapy for relapsed/refractory lymphoma ranges from 60-90% in the first year after CAR T-cell therapy and is the most common cause for non-relapse mortality. However, infectious risk after CAR T-cell therapy targeting other malignancies is not well understood. Herein, we report for the first time, infectious complications after CD30.CAR T-cell treatment for patients with Hodgkins lymphoma and peripheral T-cell lymphoma. Since CD30 is only expressed on a subset of activated T and B-cells, we hypothesized that CD30.CAR T-cell patients would have reduced incidence and severity of infections after infusion compared to CD19.CAR T-cell patients. We retrospectively evaluated all 64 patients who received CD30.CAR T-cells at a single institution between 2016-2021, and assessed infections within one year after cell infusion, comparing these data to a contemporary cohort of 50 patients who received CD19.CAR T-cells at the same institution between 2018-2021. 23 CD30.CAR T-cell patients (36%) and 18 CD19.CAR T-cell patients (36%) developed a microbiologically confirmed infection. Infection severity and bacterial infections were higher in the CD19.CAR T-cell group compared to CD30.CAR T-cell recipients who more commonly had grade 1 respiratory viral infections. Our data reflect expected outcomes for severity and infection type in CD19.CAR T-cell patients and provide a benchmark for comparison with the novel CD30.CAR T-cell product. Although our findings require replication in a larger cohort, they have implications for antimicrobial prophylaxis guidelines after CD30.CAR T-cell therapy. KEY POINTS1) The incidence of infections within the first year after CD30.CAR T-cell therapy was equivalent to that following CD19.CAR T-cell therapy 2) Viral infections were more common after CD30.CAR T-cell therapy but bacterial infections predominated after CD19.CAR T-cell therapy.

BackgroundImmunocompromised patients, including those with haematological malignancies, are among the high-risk group to develop severe coronavirus disease 2019 (COVID-19) complications. The effectiveness of passive immunotherapy with convalescent plasma (CP) on such patients diagnosed with COVID-19 has not been reviewed. Therefore, the aim of this review was to systematically appraise the current evidence for the efficacy of this therapy in haematological malignancies patients with COVID-19 infection. MethodsA comprehensive search was conducted up-to October 2021, using four databases: PubMed, Web of Science, Science Direct, and Scopus. Two reviewers independently assessed the quality of the included studies. Data collection analysis were performed using Microsoft Excel 365 and GraphPad Prism software. Results17 studies met the inclusion criteria; these records included 258 COVID-19 patients with haematological malignancies and treated with CP therapy (CPT). The main findings from the reviewed data suggests CPT may be associated with improved clinical outcomes including (a) higher survival rate, (b) improved SARS-CoV-2 clearance and presence of detectable anti-SARS-CoV-2 antibodies post CP transfusion, (c) improved hospital discharge time, and recovery after 1 month of CP therapy. Furthermore, treatment with convalescent plasma was not associated with development of adverse events. ConclusionOwing to its safety and beneficial effects in improving clinical outcomes, CPT appears to be an effective supportive therapeutic option for haematological malignancy patients infected with COVID-19.

BackgroundChronic lymphocytic leukemia (CLL) is a common adult blood cancer. There is no cure, but a third of people never require treatment and new targeted drugs have improved outcome. Understanding the experience of living with CLL is important for clinicians, health care providers and researchers. MethodsThis was an open internet-based survey of people with CLL, conducted by people with CLL. It was advertised via email and social media. Findings1,009 people completed the survey. Respondents were more likely to be women (526, 52% female; 482, 48% male) and were younger at diagnosis (574, 57% <71 years) than the general CLL population. For one third of respondents diagnosis was in the last five years. For 617 (61%) diagnosis was at a GP visit for another heath condition. 40% (406) reported no other health conditions. 558 (55%) respondents were currently on active monitoring, 261 (26%) were receiving treatment, and 190 (19%) in remission. Satisfaction with the speed of diagnosis, explanation of their CLL diagnosis and of the next steps in treatment was high. A quarter of respondents reported no current signs and symptoms of CLL, or side effects of treatment. Fatigue was reported by 578 (57%), three quarters of whom experienced this daily. Fatigue was reported to have a high impact on day-to-day life. Other common problems were bleeding and bruising more than normal (263, 26%) and getting infections often (228, 23%). From an emotional and a physical perspective, respondents reported their CLL had a higher impact on quality of life now than before the COVID-19 pandemic. Most respondents (829, 82%) received their treatment or monitoring at a hospital, for 253 (31%) contact was mostly/all remote. ConclusionsFatigue is a key problem for people with CLL. CLL impacts on the physical and emotional aspects of quality of life.

Despite the approval of multiple CAR T-cell products, access to this therapy remains limited in many developing countries. We conducted a single-arm, open-label, non-randomized, parallel phase 1/2 clinical trial (ClinicalTrials.gov identifier: NCT05333302) at two independent centers: the Vitebsk Regional Clinical Cancer Centre (VRCCC) and the Belarusian Research Center for Pediatric Oncology, Hematology, and Immunology (BRC POHI). The study enrolled patients with relapsed or refractory B-cell malignancies who received an in-house manufactured CD19 CAR T-cell product (BY19) following lymphodepletion with either fludarabine plus cyclophosphamide or cyclophosphamide plus fludarabine and decitabine. Seven patients at VRCCC and sixteen at BRC POHI received CD19 CAR T-cell therapy, comprising 17 patients with B-ALL, one with chronic lymphocytic leukemia (CLL), and five with non-Hodgkin lymphoma. The median age was 45 years (range: 38-56) at VRCCC and 13.5 years (range: 4-30) at BRC POHI. Cytokine release syndrome (CRS) occurred in 18 (67%) of the 27 infusions across both centers, predominantly mild cases. Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 12 (44%) patients, with severe ICANS (grade [&ge;]3) in 5 patients (18.5%). The overall response rate (ORR) was 80.0% (16/20), with a complete response (CR) rate of 75.0% (15/20) at the first assessment on day 28. The median progression-free survival (PFS) was 23 months, and the median overall survival (OS) was 55 months. At 12 months, PFS was 83.3% for non-Hodgkin lymphoma patients and 48.3% for B-ALL patients. Higher Cmax levels tended to correlate with better response rates; however, no clear advantage in PFS was observed. In conclusion, our in-house manufactured CD19 CAR T-cell product (BY19) demonstrates a safety and efficacy profile comparable to approved CD19 CAR T-cell therapies. This study underscores the translational potential of localized CAR T-cell manufacturing to expand global access to advanced immunotherapies, especially in middle-income countries. Additionally, incorporating decitabine into the lymphodepletion regimen shows promise in enhancing therapeutic efficacy and warrants further prospective investigation.

BackgroundPrimary extraosseous plasmacytoma (PEP) is a rare and localized form of plasmacytoma that is not well understood. This study aimed to investigate the clinical features and prognostic factors associated with PEP. MethodsUsing the Surveillance, Epidemiology, and End Results (SEER) database, patients diagnosed with PEP between 2000 and 2019 were extracted. Survival curves were calculated with the Kaplan-Meier method, and prognostic factors were identified based on the univariate and multivariate Cox regression analyses. A nomogram was constructed to predict survival at 3 and 5 years after diagnosis. ResultsA total of 1044 PEP patients were included in this study. The average age was 60.3 {+/-} 15.2 years, with 64.3% being male (male: female = 1.8:1) and 53.8% being over 60 years old. The most affected sites were the upper aerodigestive tract (42.6%). Most patients received radiotherapy (60.7%), followed by surgery (52.8%) and chemotherapy (15.1%). Overall survival (OS) rates were 88.3% at 1 year, 78.1% at 3 years, 70.7% at 5 years, and 56.0% at 10 years. Corresponding cancer-specific survival (CSS) rates were 92.1%, 85.8%, 82.5%, and 78.1%, respectively. Multivariate cox analysis indicated that age, race, marital status at diagnosis, radiotherapy, chemotherapy, and surgery were independent prognostic factors for OS, while age, race, radiotherapy, chemotherapy, and surgery were independent prognostic factors for CSS. Nomograms were further constructed to predict the possibility of OS and CSS with good performances. ConclusionsThe survival outcome of patients with PEP depends on several factors including age, race, marital status, and treatment options such as chemotherapy, radiotherapy, and surgery, which were also identified as independent predictors of OS for PEP. Patients who were younger, Asian or Pacific Islander, American Indian or Native American, and received radiotherapy or surgery had a more favorable prognosis, while those who underwent chemotherapy had poorer outcomes. This study provides valuable insights into the management of PEP.

AimsTo evaluate the association between platelet indices and platelet count severity in patients with primary immune thrombocytopenia during routine post-treatment follow-up. MethodsThis retrospective observational study included patients with primary immune thrombocytopenia followed at a single tertiary care center between 2011 and 2025. Demographic and laboratory data were obtained from medical records. Platelet count severity was categorized as less than 30 x 10^9/L, 30 to 100 x 10^9/L, and greater than 100 x 10^9/L. Platelet indices, including mean platelet volume (MPV) and platelet distribution width (PDW), were analyzed using the most recent complete blood count obtained during routine follow-up after treatment initiation. Continuous variables were summarized as median and interquartile range. Comparisons across platelet count categories were performed using the Kruskal-Wallis test with post hoc Mann-Whitney U testing. Correlation analysis and simple linear regression were also conducted. ResultsA total of 243 patients were identified, of whom 232 met the inclusion criteria. Platelet distribution width differed significantly across platelet count severity categories (Kruskal-Wallis p < 0.001) and demonstrated a strong inverse association with platelet count. Mean platelet volume also showed a statistically significant difference across platelet count groups (Kruskal-Wallis p = 0.007), although the association was weaker and less consistent compared with PDW. Regression analysis confirmed a significant association between platelet count and PDW. ConclusionPlatelet distribution width is more closely associated with platelet count severity than mean platelet volume in patients with primary immune thrombocytopenia during routine post-treatment follow-up. PDW may represent a useful adjunctive laboratory parameter when interpreted alongside platelet count in routine clinical practice.

IntroductionMyelodysplastic syndromes (MDS) are hematologic malignancies characterized by changes in haematopoiesis and a high risk for progressing into acute myeloid leukemia (AML). In this retrospective registry based real-world study, from two Finnish hospital data lakes we characterized specialised health care treated MDS patients, their treatment landscape, outcomes, and healthcare resource utilization. MethodsThis study consisted of adult patients with MDS diagnosed in either of two hospital districts in Finland: hospital district of Southwest Finland (HDSF) and Pirkanmaa hospital district (PHD). Two different time windows were used depending on data availability: 1.1.2010-31.12.2019 (HDSF) and 1.1.2012-31.12.2019 (PHD). Electronic health record data, including demographics, diagnoses, and medications was accessed via the respective hospital data lakes and dates and causes of death data was collected from Statistics Finland. ResultsWe identified 565 adult MDS patients, of whom 424 received active life-prolonging treatment at specialized healthcare and 141 were treated with watchful observation or supportive care at primary care. 72 patients were treated with azacitidine and 26 patients received allogeneic hematologic stem cell transplant. Median overall survival for the specialty healthcare treated patients was 27,5 months (95 confidence interval [CI] 24,1-35,2) and costs per patient year were 17 563{euro}. ConclusionThis hospital data lake-based analysis identified patient groups with differing disease severity and need for treatment. High-risk, azacitidine treated patients have suboptimal outcomes and high costs, highlighting the need for new therapeutic approaches to prevent disease progression and reduce disease burden.

BackgroundHaemophagocytic lymphohistiocytosis (HLH) is rare, results in high mortality and is increasingly being diagnosed. Little is known about what is driving the apparent rise in the incidence of this disease. MethodsUsing national linked electronic health data from hospital admissions and death certification cases of HLH that were diagnosed in England between 1/1/2003 and 31/12/2018 were identified using a previously validated approach. We calculated incidence rates of diagnosed HLH per million population using mid-year population estimates by calendar year, age group, sex and associated comorbidity (haematological malignancy, inflammatory rheumatological or bowel diseases (IBD)) associated with the diagnosis of HLH. We modelled trends in incidence and the interactions between calendar year, age and associated comorbidity using Poisson regression. FindingsThere were 1674 people with HLH diagnosed in England between 2003 and 2018. The incidence rate quadrupled (Incidence Rate Ratio (IRR) 2018 compared to 2003: 3.88 95% Confidence Interval (CI) 2.91 to 5.28), increasing 11% annually (adjusted IRR 1.11 95% CI 1.09 to 1.12). There was a rising trend in all age groups except those aged less than 5 years. There was a transition across the age groups with greater increases in those aged 5 to 14 years of HLH associated with rheumatological disease/IBD compared to HLH associated with haematological malignancy, with similar increases in HLH associated with both co-morbidities for those 15-54, and greater increases in associated haematological malignancies for those 55 years and older. InterpretationThe incidence of HLH in England has quadrupled between 2003 and 2018, increasing 11% annually. Substantial variation in the incidence occurred by age group and by HLH associated comorbidities with inflammatory rheumatological diseases or IBD associated HLH increasing more among the young and middle age groups, whereas in older age groups the largest increase was seen with haematological malignancy-associated HLH. Evidence before this studyThere is a paucity of population-based data on the epidemiology of HLH worldwide. The available evidence relies mostly upon a collection of cases series published in The Lancet in 2014 which described 2197 cases of HLH in adults reported in the literature to that point. Almost all of these were from tertiary referral specialist centres and/or described in small case series. The incidence of HLH has only been described in a few reports - and mainly this has focused on children with primary HLH. No previous studies have been large enough to examine trends in incidence by age, sex, underlying risk factors and calendar time. Added value of this studyThis study quantifies the incidence of diagnosed HLH for the first time in a nationwide manner for all age groups. It reports on 1674 patients with HLH from England and shows that there is substantial variation in the incidence by age group, associated disease and calendar time. The results imply reasons for the increase in HLH could be related to the increasing occurrence of haematological cancer, inflammatory rheumatological or bowel diseases and the treatments given for these conditions. This study has been carried out in partnership with the National Congenital Anomalies and Rare Diseases Registration Service and the methodology described can in future be applied to many rare diseases that as yet lack a way of quantifying crucial epidemiological metrics. Implications of all the available evidenceThe incidence of HLH is rising rapidly in people older than 5 years of age. This could be due to an increase in the biologic, immunomodulation or immunosuppressive therapy being used in people with haematological cancer and inflammatory rheumatological and bowel diseases. Further work should focus on how to minimise the risk of HLH occurring, or to improve treatment of this often fatal disease among those who need treatment for an associated comorbidity.

BackgroundWe report extended follow-up of TROG99.03, a randomised phase III trial in early-stage follicular lymphoma (ESFL) including new information on the role of adjuvant rituximab and translational studies. MethodsPatients with ESFL were randomised to involved-field radiotherapy (IFRT) or IFRT plus 6-cycles cyclophosphamide/vincristine/prednisolone (IFRT+CVP). From 2006 rituximab was added to IFRT+CVP (IFRT+R-CVP). Clinical and multi-omic parameters were evaluated. Findings were validated in two independent ESFL cohorts (99 and 60 patients respectively). FindingsBetween 2000-2012, 150 (75 per arm) patients were recruited. 48% were positron emission tomography (PET)-staged. Per protocol, at median follow-up 11.3-years, progression-free survival (PFS) remained superior for IFRT+(R)CVP vs. IFRT (hazard ratio [HR]=0.60, 95%CI=0.37-0.98, p=0.043; 10-year PFS 62% vs. 43%) respectively. Although no significant difference in overall survival was observed (HR=0.44, 95%CI=0.16-1.18, p=0.11, 10-year OS 95% vs 84%), patients receiving IFRT+(R)CVP experienced fewer composite (histological transformation and death) events (p=0.045). PFS of IFRT+R-CVP-treated patients compared with all other treatments lacking rituximab (IFRT alone plus IFRT+CVP) was superior (HR=0.36, 95%CI=0.13-0.82, p=0.013). Amongst PET-staged patients, PFS differences between IFRT+R-CVP vs. IFRT were maintained (HR=0.38, 95%CI=0.16-0.89, p=0.027) indicating benefit distinct from stage migration. FL-related mutations and BCL2-translocations were not associated with PFS. However, by multivariate analysis elevated CD8A gene expression in diagnostic biopsy tissue was independently associated with improved PFS (HR=0.45, 95%CI=0.26-0.79, p=0.037), a finding confirmed in both ESFL validation cohorts. CD8A gene expression was raised (p=0.02) and CD8+ T-cell density higher within follicles in ESFL vs. advanced-stage FL (p=0.047). Human leucocyte antigen class I specific neoantigens were detected in 43% of patients, suggesting neoantigen-specific CD8+ T-cells have a role in confining the spread of the disease. InterpretationAdjuvant R-CVP and elevated intratumoural CD8 expression were independently associated with sustained disease control after radiotherapy in ESFL. FundingCancer Council Victora; National Health and Medical Research Council; Leukaemia Foundation; Mater Foundation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly effective in healthy individuals. Patients with multiple myeloma (MM) are immunocompromised due to defects in humoral and cellular immunity as well as immunosuppressive therapies. The efficacy after two doses of SARS-CoV-2 mRNA vaccination in MM patients is currently unknown. Here, we report the case of a MM patient who developed a fatal SARS-CoV-2 infection after full vaccination while in remission after B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T treatment. We show that the patient failed to generate antibodies or SARS-CoV-2-specific B and T cell responses, highlighting the continued risk of severe coronavirus disease 2019 (COVID-19) in vaccine non-responders. In the largest cohort of vaccinated MM patients to date, we demonstrate that 15.9% lack SARS-CoV-2 spike antibody response more than 10 days after the second mRNA vaccine dose. The patients actively receiving MM treatment, especially on regimens containing anti-CD38 and anti-BCMA, have lower antibody responses compared to healthy controls. Thus, it is of critical importance to monitor this patient population for serological responses. Non-responders may benefit from ongoing public health measures and from urgent study of prophylactic treatments to prevent SARS-CoV-2 infection.

BackgroundHematopoietic cell transplant (HCT) outcomes are well characterized in clinical trials and international registries, but data remain scarce for patients who undergo transplantation abroad and return home for follow-up. While transplant centers typically report procedural details and early mortality for this cohort, long-term survival and chronic graft versus host disease (GVHD) outcomes are seldom captured, underscoring the need for comprehensive reporting. MethodsWe conducted a retrospective, multi-center study of all HCT recipients followed at all the three tertiary hospitals in Abu Dhabi, UAE, between 2009 and 2023. Patient demographics, transplant characteristics, overall survival (OS), and GVHD incidence were extracted from medical records. Kaplan-Meier OS estimates were calculated for diseases with [&ge;]20 cases; crude survival was reported for rarer indications. ResultsA total of 454 HCTs were analyzed: 350 (77.1%) allogeneic and 104 (22.9%) autologous. Adults undergoing allogeneic HCT were relatively young (median age 35.3 years), reflecting referral practices and the UAEs demographic profile. An unexpected female predominance was observed in pediatric malignancies and immune deficiencies. Matched unrelated donor (MUD) transplants were rare, and the trend remained low over time, underscoring reliance on matched related donor (MRD) and mismatched related donor (MMRD). The incidence of GVHD was high, approaching the upper range of international reports: 69.2% in adults and 45.7% in children. In adults with AML, acute GVHD was associated with an inferior 5-year OS (67.9% vs. 86.2%, p=0.036), whereas chronic GVHD did not significantly impact outcomes. In pediatric AML, both acute and chronic GVHD were linked to poorer survival (<50% at 5 years), while outcomes for B/T-ALL, thalassemia, and SCID exceeded 85-90% at 5 years regardless of GVHD status. ConclusionsHCT outcomes in this transplant tourism cohort were generally comparable to international benchmarks, yet notable for younger adult recipients, predominance of allogeneic over autologous procedures, limited use of MUDs, and a high incidence of GVHD. These observations highlight the urgent need to establish sustainable local transplant capacity, build donor registries, and implement aggressive GVHD prevention and treatment practices to improve outcomes in the UAE.

A growing understanding of the complexities of hematopoietic malignancies necessitates the existence of clinical recommendations that are sufficiently comprehensive. Although hereditary hematopoietic malignancies (HHMs) are increasingly recognized for conferring risk of myeloid malignancy, frequently utilized clinical recommendations have never been appraised for the ability to reliably guide HHM evaluation. We assessed established society-level clinical guidelines for inclusion of critical HHM genes and graded the strength of testing recommendations. We uncovered a substantial lack of consistency of recommendations guiding HHM evaluation. Such heterogeneity in guidelines likely contributes to refusal by payers to support HHM testing, leading to underdiagnoses and lost opportunities for clinical surveillance.

We report one of the largest non-Japanese cohorts of adult T-cell leukemia/lymphoma (ATL). A total of 175 cases were identified in Martinique between 1983 and 2013. The sex ratio was 1.01. The median age was 56 years. The overall incidence rate was 1.16/105 inhabitants/year, with a risk 1.29 times higher for men. The distribution of clinical types (acute, lymphoma, and chronic) was 62.9%, 29.1%, and 8%, respectively. Median survival time was 3.06, 8.13, and 45.16 months, respectively, for the acute, lymphoma, and chronic types (p <0.001). Survival was significantly higher for lymphoma type with skin lesions (median 13.96 months versus 6.06, p <0.002) and for the acute type without hypercalcemia (5.1 versus 2.4 months, p <0.01). Symptoms associated with hypercalcemia present in 46.9% of patients and skin lesions in 43.4% were the best-performing clinical signs for the diagnosis of ATL. However, only 16.9% had these manifestations. Strongyloides stercoralis infection was documented in 42.5% of patients. Twenty-three patients had an atypical phenotype, including 14 cases with CD4-CD8- and 4 with CD4+CD8+. Twenty-four patients did not express CD25 with no significant impact on overall survival. The hyperploidy, trisomy of chromosome 3 and rearrangements of chromosome 14 were the most frequent karyotype abnormalities.

While outcome for pediatric T lymphoblastic lymphoma (T-LBL) has improved with Acute Leukemia-type therapy, survival after relapse remains rare. Few prognostic markers have been identified and the value of Minimal Residual Disease (MRD) is less clear than in T-ALL. Mutations of NOTCH1 and/or FBXW7 (N/F) identify good prognosis T-LBL and both MRD and high-level Minimal Disseminated Disease (MDD) are reported to be of poor prognosis. We evaluated MDD status by 8-color flow cytometry (MFC) and/or digital droplet PCR (ddPCR) in 86 French pediatric T-LBL, of which N/F status was known for 65 (61 treated on the Euro-LB02 protocol). Both techniques gave identical results for MDD/MRD values above 0.1%, allowing compilation. While an MDD threshold of 1% had no prognostic significance, the 54% (44/82) of protocol-treated patients with MDD [&ge;]0.1% had a relatively favorable outcome (overall survival/OS; p = 0.026). MDD 0.1% status had no prognostic significance in the 68% of patients with N/F mutations, whereas low/negative MDD status (9/61) identified N/F germline patients at a high risk of relapse (5-year OS of 44.4% vs 90% for MDD [&ge;] 0.1%,p = 0.014; and a 5-year DFS of 50% vs 90.9% respectively, p = 0.041). Combining oncogenetic and MDD status allows identification of 85% of patients with an excellent outcome (5-year OS 91.9% and DFS 95%) and 15% of N/F germline/MDD< 0.1% patients who clearly require early alternative treatment (5-year OS 44.4%; p< 0.0001 and DFS 50%; p = 0.0001).

BackgroundAnti-Platelet Factor 4 (PF4) IgG antibodies that activate platelets via Fc{gamma}RIIa have been shown to be an important part of the pathophysiology of vaccine-induced immune thrombocytopenia and thrombosis (VITT). There is now extensive literature on its presentation and initial management. There is no literature however on what happens to these patients following discharge. MethodsWe collected clinical data and samples from seven patients presenting with VITT and followed them up for 82-145 days. We also collected clinical samples from them at last follow-up. Testing for anti-PF4/heparin antibodies was done using an anti-PF4/heparin enzymatic immunoassay. Flow Cytometry was used to look at Fc{gamma}RIIa levels on patient platelets. Light Transmission Aggregometry with patient serum and healthy donor / patient platelets was used to analyse platelet responsiveness, in the presence and absence of PF4. FindingsAll patients were discharged on direct oral anticoagulants. Two patients remain completely symptom free, three have ongoing headaches, two have residual neurological deficits. Two patients developed mild thrombocytopenia and worsening headache (but without cerebral venous sinus thrombosis) and were retreated, one of these with rituximab. All patients, except the one treated with rituximab, had similar anti-PF4 antibody titres at 80-120 days to their levels at diagnosis. Platelets from patients at follow-up had normal levels of Fc{gamma}RIIa and had normal responses to thrombin and collagen-related-peptide. Patient serum from diagnosis strongly activated healthy donor platelets in the presence of PF4. Serum from follow-up was much weaker at stimulating platelets, even in the presence of PF4. InterpretationThis study shows that despite similar PF4 antibody titres at diagnosis and during follow-up, there are further differences in patient serum, that are not apparent from currently used testing, that result in lower levels of platelet activation during the follow-up period. Further understanding of these factors are important in order to assess duration of anticoagulation for these patients. FundingThis work was supported by an Accelerator Grant (AA/18/2/34218) from the British Heart Foundation (BHF) and by a National Institute for Health Research (NIHR) grant. Key pointsO_LIPF4 antibody titres do not reduce up to 4-months post ChAdOx1 nCoV-19 in patients with VITT C_LIO_LIDespite similar PF4 antibody titres, diagnostic serum is more potent at activating platelets in the presence of PF4 than follow-up serum. C_LI