Patients with hematological malignancies are at increased risk of severe COVID-19 outcomes due to compromised immune responses, but the insights of these studies have been compromised due to intrinsic limitations in study design. Here we present the PROSECO prospective observational study (NCT04858568) on 457 patients with lymphoma that received two or three COVID-19 vaccine doses. We show undetectable humoral responses following two vaccine doses in 52% of patients undergoing active anticancer treatment. Moreover, 60% of patients on anti-CD20 therapy had undetectable antibodies following full vaccination within 12 months of receiving their anticancer therapy. However, 70% of individuals with indolent B-cell lymphoma displayed improved antibody responses following booster vaccination. Notably, 63% of all patients displayed antigen-specific T-cell responses, which increased after a third dose irrespective of their cancer treatment status. Our results emphasize the urgency of careful monitoring of COVID-19-specific immune responses to guide vaccination schemes in these vulnerable populations.
SummaryChronic lymphocytic leukaemia (CLL) cells encounter T-cells and proliferate in response to T-cell signals in the lymph node microenvironment. In this report we determined interleukin 21 (IL21) function in CLL and showed that IL21 and interleukin 4 (IL4) act co-operatively to promote leukaemic cell proliferation without apoptosis or differentiation We further show that IL21 increased side population (SP) cells, which are associated with resistance to chemotherapy and increased self-renewal capacity in CLL. IL21 and IL4 are the major cytokines produced by the recently described CD4 + T follicular helper (Tfh) cell subset. Determination of Tfh cells in peripheral blood showed that patients had significantly increased numbers as compared to normal subjects although no association was found between Tfh numbers and IGHV gene mutational status or clinical stage. Our data suggests that the Tfh cytokines, IL4 and IL21, contribute to driving leukaemic cell proliferation in the lymph node microenvironment, and may contribute to the specific production of cells resistant to conventional chemotherapy. We suggest that increased circulating Tfh cells is a component of T-cell dysregulation in CLL. Our findings have implications for the therapeutic use of IL21.
The role of the microenvironment in high-grade lymphoma is not well defined. In this report, we employ immunohistochemistry to characterise programmed death-1 (PD-1/CD279) and FoxP3 expression in 70 cases of diffuse large B-cell lymphoma (DLBCL). PD-1 is a surface marker characteristic of follicular helper T-cells whilst FoxP3 is characteristic of Tregs. We demonstrate variable infiltration with CD4(+) T-cells (<10 to >50 % of all lymph node cells) and PD-1(hi) cells (0.1 to 1.5 % of all cells). CD4(+) T-cells can be distributed in clusters or more diffusely and PD-1(hi) cells, but not FoxP3(+) cells, are found in rosettes around lymphoma cells. Cases with high CD4(+) T-cell numbers tended to have higher numbers of both PD-1(hi) and FoxP3(+) cells. Cases with total CD4(+) T-cell, PD-1(hi) and FoxP3(+) numbers above the median associate with better clinical outcome. Overall, we demonstrate that infiltration by CD4(+) T-cells, including both FoxP3(+) and PD-1(hi) subsets, correlates with prognosis in DLBCL. In distinction to previous reported series, patients (91 %) were treated with rituximab-containing regimens, suggesting that the effects of CD4+ T-cell infiltration are maintained in the rituximab era. This work suggests that determinants of total CD4(+) T-cell infiltration, either molecular characteristics of the lymphoma or the patients' immune system, and not individual T-cell subsets, correlate with clinical outcome.
Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1,384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n=749) or at the end (n=635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT; 5.7% vs 5.8%, p=0.98, 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n=1,253). In patients with high CNS international prognostic index (n=600), 3-year CNS relapse rate was 9.1% with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX versus EOT, with 308/1573 (19.6%) i-HD-MTX treatments resulting in delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk versus i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.
Summary Peripheral T‐cell lymphomas (PTCL) comprise a heterogeneous group of aggressive lymphoproliferative disorders almost all of which are associated with poor clinical outcomes. Angioimmunoblastic T‐cell lymphoma (AITL) and some peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) have similarities to normal CD4+ T‐cell subsets in their gene expression profiles. A cell of origin model is, therefore, emerging and is likely to be refined in the future. Follicular helper (Tfh) T cells are now established as the cell of origin of AITL and about 20% of PTCL‐NOS. Sequencing studies have identified recurrent genetic alterations in epigenetic modifiers, T‐cell receptor signalling pathway intermediates or RHOA, most commonly a specific mutation leading to RHOA G17V. While PTCL‐NOS remains a diagnosis of exclusion, advances in genomics have identified subgroups expressing transcription factors TBX 21 (Th1‐like origin) and GATA3 (Th2‐like origin). These findings suggest new biomarkers and new therapeutic avenues including the hypomethylating agent azacytidine, or inhibitors of proximal T‐cell receptor (TCR) signalling and potentially certain monoclonal antibodies. The advances over the past few years, therefore, prompt stratified medicine approaches to test biologically based treatments and determine the clinical utility of the new disease classifications.
Summary Delayed lymphocyte and T‐cell immune reconstitution following bendamustine‐rituximab (BR) for indolent non‐Hodgkin lymphoma (iNHL) has been described, but no information is available for chronic lymphocytic leukaemia (CLL). We present a population‐based retrospective analysis of immune reconstitution and risk of infection following BR. Outcomes included timing/correlates of CD4+ recovery and risk of ≥grade 3 infections. Consecutively treated patients (1 April 2014 to 31 January 2017) were included (n = 295),with a median age of 65 years (range 33–92); 57% were 1st line treatments. Median cumulative bendamustine dose was 1080 mg/m2 (range 140–1440 mg/m2). CD4/CD8/CD19/NK subsets were available for 148 patients. Median follow‐up was 24 months. Median times to lymphocyte count (ALC) recovery (≥1 × 109/l) and CD4+ recovery (≥0·2 × 109/l) were 26 and 24 months, respectively. Bendamustine total dose >1080 mg/m2 (hazard ratio [HR] 0·4; 95% confidence interval [CI]: 0·2–0·8), end‐of‐treatment ALC ≤0·4 × 109/l (HR 0·53; 95% CI: 0·3–0·9) and CD4+ <0·1 × 109/l 1‐year post‐BR (HR 0·03; 95% CI: 0·008–0·15) were covariables for delayed CD4+ recovery. ALC‐recovery ≥1 × 109/l was an unreliable predictor of CD4+ recovery (negative predictive vale 74%, positive predictive value 86%, likelihood ratio 3·3). CD4+ lymphopenia >3 years was a significant risk factor for ≥grade 3 infections (Odds ratio 3·4; 95% CI: 1·4–6·9). CD4+ recovery after BR is unexpectedly delayed and late recovery is associated with risk of serious infections. Monitoring CD4+ following BR could identify patients at high risk of delayed infections.
SummaryBCL6 is a transcription factor that has essential B-cell and T-cell roles in normal antibody responses. It is involved in chromosomal translocations in diffuse large B-cell lymphoma (DBCL; including primary mediastinal B-cell lymphoma) and nodular lymphocyte predominant Hodgkin lymphoma, and is expressed in follicular lymphoma and Burkitt's lymphoma. The neoplastic T-cells of angioimmunoblastic T-cell lymphoma also express BCL6. BCL6 prevents terminal B-cell differentiation largely through repression of PRDM1. In the ''cell of origin'' classification of DLBCL BCL6 is associated with the germinal centre subtype, which carries a good response to modern treatments. More recently, specific BCL6 antagonists, including small molecule inhibitors, have been developed. These antagonists have demonstrated that DLBCL cells, in which BCL6 is transcriptionally active, are dependent on this gene for survival. BCL6 antagonists are active against primary DLBCL and may find future application in the treatment of lymphomas.
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