Relapse patterns in early-PET negative, limited-stage Hodgkin lymphoma (HL) after ABVD with or without radiotherapy-a joint analysis of EORTC/LYSA/FIL H10 and NCRI RAPID trials.

In the H10 and RAPID randomised trials, chemotherapy+radiotherapy (combined modalities treatment, CMT) was compared with chemotherapy (C) in limited-stage Hodgkin lymphoma (HL), with negative early positron emission tomography (ePETneg). We analysed patterns of relapses in the H10 trial, validated findings in the RAPID trial and performed a combined analysis stratified by trial. The impact of radiotherapy (RT) on risk of relapse was studied using adjusted Cox models, with time-varying effects. In H10, 1,059 ePETneg patients were included (465 European Organisation for Research and Treatment of Cancer (EORTC) favourable [F], 594 unfavourable [U]). Among the F patients, 2/227 (1%) relapsed after CMT, 30/238 (13%) after C: of these relapses, 21/30 (70%) occurred in less than 2 years and 25/30 (83%) affected originally involved areas. Among the U group, 16/292 (5%) relapsed after CMT: 8/16 (50%) in less than 2 years, 11/16 (69%) in originally involved areas. After C 30/302 (10%) relapsed: 27/30 (90%) in less than 2 years, and 26/30 (87%) in originally involved areas. Similar results were observed in 419 ePETneg RAPID patients (241 F, 128 U, 50 unclassified): among F patients, 6/118 (5%) relapsed after CMT; 13/123 (11%) after C: 11/13 (85%) in less than 2 years and 11/13 (85%) affecting originally involved areas. In U patients, 3/65 (5%) relapsed after CMT and 5/63 (8%) after C. In both trials, omitting RT in ePETneg HL resulted in more early relapses, mainly affecting originally involved areas. RT significantly reduced risk of early relapses in the combined stratified analysis.

TLR9 expression in chronic lymphocytic leukemia identifies a promigratory subpopulation and novel therapeutic target.

Chronic lymphocytic leukemia (CLL) remains incurable despite B-cell receptor-targeted inhibitors revolutionizing treatment. This suggests that other signaling molecules are involved in disease escape mechanisms and resistance. Toll-like receptor 9 (TLR9) is a promising candidate that is activated by unmethylated cytosine guanine dinucleotide-DNA. Here, we show that plasma from patients with CLL contains significantly more unmethylated DNA than plasma from healthy control subjects (P < .0001) and that cell-free DNA levels correlate with the prognostic markers CD38, ß2-microglobulin, and lymphocyte doubling time. Furthermore, elevated cell-free DNA was associated with shorter time to first treatment (hazard ratio, 4.0; P = .003). We also show that TLR9 expression was associated with in vitro CLL cell migration (P < .001), and intracellular endosomal TLR9 strongly correlated with aberrant surface expression (sTLR9; r = 0.9). In addition, lymph node-derived CLL cells exhibited increased sTLR9 (P = .016), and RNA-sequencing of paired sTLR9hi and sTLR9lo CLL cells revealed differential transcription of genes involved in TLR signaling, adhesion, motility, and inflammation in sTLR9hi cells. Mechanistically, a TLR9 agonist, ODN2006, promoted CLL cell migration (P < .001) that was mediated by p65 NF-κB and STAT3 transcription factor activation. Importantly, autologous plasma induced the same effects, which were reversed by a TLR9 antagonist. Furthermore, high TLR9 expression promoted engraftment and rapid disease progression in a NOD/Shi-scid/IL-2Rγnull mouse xenograft model. Finally, we showed that dual targeting of TLR9 and Bruton's tyrosine kinase (BTK) was strongly synergistic (median combination index, 0.2 at half maximal effective dose), which highlights the distinct role for TLR9 signaling in CLL and the potential for combined targeting of TLR9 and BTK as a more effective treatment strategy in this incurable disease.

A national service for delivering CD19 CAR-Tin large B-cell lymphoma - The UK real-world experience.

CD19 CAR-T have emerged as a new standard treatment for relapsed/refractory (r/r) large B-cell lymphoma (LBCL). CAR-T real-world (RW) outcomes published to date suggest significant variability across countries. We provide results of a large national cohort of patients intended to be treated with CAR-T in the UK. Consecutive patients with r/r LBCL approved for CAR-T by the National CAR-T Clinical Panel between December 2018 and November 2020 across all UK CAR-T centres were included. 404/432 patients were approved [292 axicabtagene ciloleucel (axi-cel), 112 tisagenlecleucel (tisa-cel)], 300 (74%) received the cells. 110/300 (38.3%) patients achieved complete remission (CR) at 6 months (m). The overall response rate was 77% (52% CR) for axi-cel, 57% (44% CR) for tisa-cel. The 12-month progression-free survival was 41.8% (axi-cel) and 27.4% (tisa-cel). Median overall survival for the intention-to-treat population was 10.5 m, 16.2 m for infused patients. The incidence of grade ≥3 cytokine release syndrome and neurotoxicity were 7.6%/19.6% for axi-cel and 7.9%/3.9% for tisa-cel. This prospective RW population of CAR-T eligible patients offers important insights into the clinical benefit of CD19 CAR-T in LBCL in daily practice. Our results confirm long-term efficacy in patients receiving treatment similar to the pivotal trials, but highlight the significance of early CAR-T failure.

The architecture of neoplastic follicles in follicular lymphoma; analysis of the relationship between the tumor and follicular helper T cells.

CD4+ T-follicular helper cells are essential for the survival, proliferation, and differentiation of germinal center B cells and have been implicated in the pathogenesis of follicular lymphoma (FL). To further define the role of these cells in FL, we used multiparameter confocal microscopy to compare the architecture of normal and neoplastic follicles and next generation sequencing to analyze the T-cell receptor repertoire in FL lymph nodes (LN). Multiparameter analysis of LN showed that the proportion of T-follic-ular helper cells (TFH) in normal and neoplastic follicles is the same and that the previously reported increase in TFH numbers in FL is thus due to an increase in the number and not content of follicles. As in normal germinal centers, TFH were shown to have a close spatial correlation with proliferating B cells in neoplastic follicles, where features of immunological synapse formation were observed. The number of TFH in FL correlate with the rate of B-cell proliferation and TFH co-localized to activation induced cytidine deaminase expressing proliferating B cells. T-cell receptor repertoire analysis of FL LN revealed that follicular areas are significantly more clonal when compared to the rest of the LN. These novel findings show that neoplastic follicles and germinal centers share important structural features and provide further evidence that TFH may play a role in driving B-cell proliferation and genomic evolution in TFH Our results also suggest that targeting this interaction would be an attractive therapeutic option.

In vitro and in vivo evidence for uncoupling of B-cell receptor internalization and signaling in chronic lymphocytic leukemia.

B-cell receptor activation, occurring within lymph nodes, plays a key role in the pathogenesis of chronic lymphocytic leukemia and is linked to prognosis. As well as activation of downstream signaling, receptor ligation triggers internalization, transit to acidified endosomes and degradation of ligand-receptor complexes. Herein, we investigated the relationship between these two processes in normal and leukemic B cells. We found that leukemic B cells, particularly anergic cases lacking the capacity to initiate downstream signaling, internalize and accumulate ligand in acidified endosomes more efficiently than normal B cells. Furthermore, ligation of either surface CD79B, a B-cell receptor component required for downstream signaling, or surface Immunoglobulin M (IgM) by cognate agonistic antibody, showed that the two molecules internalize independently of each other in leukemic but not normal B cells. Since association with surface CD79B is required for surface retention of IgM, this suggests that uncoupling of B-cell receptor internalization from signaling may be due to the dissociation of these two molecules in leukemic cells. A comparison of lymph node with peripheral blood cells from chronic lymphocytic leukemia patients showed that, despite recent B-cell receptor activation, lymph node B cells expressed higher levels of surface IgM. This surprising finding suggests that the B-cell receptors of lymph node- and peripheral blood-derived leukemic cells might be functionally distinct. Finally, long-term therapy with the Bruton's tyrosine kinase inhibitors ibrutinib or acalabrutinib resulted in a switch to an anergic pattern of B-cell receptor function with reduced signaling capacity, surface IgM expression and more efficient internalization.

Results of a multicentre UK-wide retrospective study evaluating the efficacy of brentuximab vedotin in relapsed, refractory classical Hodgkin lymphoma in the transplant naive setting.

Relapsed or refractory classical Hodgkin lymphoma (cHL) is associated with a poor outcome when standard chemotherapy fails. Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate licensed for use at relapse after autologous stem cell transplant (ASCT) or following two prior therapies in those unsuitable for ASCT. There are limited data assessing the ability of BV to enable curative SCT. We performed a UK-wide retrospective study of 99 SCT-naïve relapsed/refractory cHL. All had received 2 prior lines and were deemed fit for transplant but had an insufficient remission to proceed. The median age was 32 years. Most had nodular sclerosis subtype, Eastern Cooperative Oncology Group performance status 0-1 and advanced stage disease. The median progression-free survival (PFS) was 5·6 months and median overall survival (OS) was 37·2 months. The overall response rate was 56% (29% complete response; 27% partial response). 61% reached SCT: 34% immediately post-BV and 27% following an inadequate BV response but were salvaged and underwent deferred SCT. Patients consolidated with SCT had a superior PFS and OS to those not receiving SCT (P < 0·001). BV is an effective, non-toxic bridge to immediate SCT in 34% and deferred SCT in 27%. 39% never reached SCT with a PFS of 3·0 months, demonstrating the unmet need to improve outcomes in those unsuitable for SCT post-BV.

Obinutuzumab Versus Rituximab Immunochemotherapy in Previously Untreated iNHL: Final Results From the GALLIUM Study.

The phase III GALLIUM trial assessed the safety and efficacy of obinutuzumab-based versus rituximab-based immunochemotherapy in patients with previously untreated follicular lymphoma (FL) or marginal zone lymphoma (MZL). At the primary analysis, the trial met its primary end point, demonstrating improvement in investigator-assessed progression-free survival (PFS) with obinutuzumab-based versus rituximab-based immunochemotherapy in patients with FL. We report the results of the final analysis in the FL population, with an additional exploratory analysis in the MZL subgroup. Overall, 1202 patients with FL were randomized 1:1 to obinutuzumab- or rituximab-based immunochemotherapy followed by maintenance with the same antibody for up to 2 years. After a median 7.9 (range, 0.0-9.8) years of follow-up, PFS remained improved with obinutuzumab- versus rituximab-based immunochemotherapy, with 7-year PFS rates of 63.4% versus 55.7% (P = 0.006). Time-to-next antilymphoma treatment was also improved (74.1% versus 65.4% of patients had not started their next antilymphoma treatment at 7 y; P = 0.001). Overall survival was similar between the arms (88.5% versus 87.2%; P = 0.36). Irrespective of the treatment received, PFS and OS were higher in patients with a complete molecular response (CMR) versus those with no CMR (P < 0.001). Serious adverse events were reported in 48.9% and 43.4% of patients in the obinutuzumab and rituximab arms, respectively; there was no difference in the rate of fatal adverse events (4.4% and 4.5%, respectively). No new safety signals were reported. These data demonstrate the long-term benefit of obinutuzumab-based immunochemotherapy and confirm its role as a standard-of-care for the first-line treatment of advanced-stage FL, taking into account patient characteristics and safety considerations.

Upfront autologous haematopoietic stem-cell transplantation versus carfilzomib-cyclophosphamide-dexamethasone consolidation with carfilzomib maintenance in patients with newly diagnosed multiple myeloma in England and Wales (CARDAMON): a randomised, phase 2, non-inferiority trial.

BACKGROUND: Standard-of-care treatment for patients with newly diagnosed multiple myeloma is bortezomib-based induction followed by high-dose melphalan and autologous haematopoietic stem-cell transplantation (HSCT) and lenalidomide maintenance. We aimed to evaluate whether an immunomodulatory-free carfilzomib-based induction, consolidation, and maintenance protocol without autologous HSCT was non-inferior to the same induction regimen followed by autologous HSCT and maintenance. METHODS: CARDAMON is a randomised, open-label, phase 2 trial in 19 hospitals in England and Wales, UK. Newly diagnosed, transplantation-eligible patients with multiple myeloma aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 received four 28-day cycles of carfilzomib (56 mg/m2 intravenously on days 1, 2, 8, 9, 15, and 16), cyclophosphamide (500 mg orally on days 1, 8, and 15), and dexamethasone (40 mg orally on days 1, 8, 15, and 22; KCd), followed by peripheral blood stem cell mobilisation. Patients with at least a partial response were randomly assigned (1:1) to either high-dose melphalan and autologous HSCT or four cycles of KCd. All randomised patients received 18 cycles of carfilzomib maintenance (56 mg/m2 intravenously on days 1, 8, and 15). The primary outcomes were the proportion of patients with at least a very good partial response after induction and difference in progression-free survival rate at 2 years from randomisation (non-inferiority margin 10%), both assessed by intention to treat. Safety was assessed in all patients who started treatment. The trial is registered with ClinicalTrials.gov (NCT02315716); recruitment is complete and all patients are in follow-up. FINDINGS: Between June 16, 2015, and July 8, 2019, 281 patients were enrolled, with 218 proceeding to randomisation (109 assigned to the KCd consolidation group [99 of whom completed consolidation] and 109 to the HSCT group [104 of whom underwent transplantation]). A further seven patients withdrew before initiation of carfilzomib maintenance (two in the KCd consolidation group vs five in the HSCT group). Median age was 59 years (IQR 52 to 64); 166 (59%) of 281 patients were male and 115 (41%) were female. 152 (71%) of 214 patients with known ethnicity were White, 37 (17%) were Black, 18 (8%) were Asian, 5 (2%) identified as Mixed, and 2 (1%) identified as other. Median follow-up from randomisation was 40·2 months (IQR 32·7 to 51·8). After induction, 162 (57·7%; 95% CI 51·6 to 63·5) of 281 patients had at least a very good partial response. The 2-year progression-free survival was 75% (95% CI 65 to 82) in the HSCT group versus 68% (95% CI 58 to 76) in the KCd group (difference -7·2%, 70% CI -11·1 to -2·8), exceeding the non-inferiority margin. The most common grade 3-4 events during KCd induction and consolidation were lymphocytopenia (72 [26%] of 278 patients who started induction; 15 [14%] of 109 patients who started consolidation) and infection (50 [18%] of 278 for induction; 15 [14%] of 109 for consolidation), and during carfilzomib maintenance were hypertension (20 [21%] of 97 patients in the KCd consolidation group vs 23 [23%] of 99 patients in the HSCT group) and infection (16 [16%] of 97 patients vs 25 [25%] of 99). Treatment-related serious adverse events at any point during the trial were reported in 109 (39%) of 278 patients who started induction, with infections (80 [29%]) being the most common. Treatment-emergent deaths were reported in five (2%) of 278 patients during induction (three from infection, one from cardiac event, and one from renal failure) and one of 99 patients during maintenance after autologous HSCT (oesophageal carcinoma). INTERPRETATION: KCd did not meet the criteria for non-inferiority compared with autologous HSCT, but the marginal difference in progression-free survival suggests that further studies are warranted to explore deferred autologous HSCT in some subgroups, such as individuals who are MRD negative after induction. FUNDING: Cancer Research UK and Amgen.

PET-guided treatment for personalised therapy of Hodgkin lymphoma and aggressive non-Hodgkin lymphoma.

FDG-PET scanning has a central role in lymphoma staging and response assessment. There is a growing body of evidence that PET response assessment during and after initial systemic therapy can provide useful prognostic information, and PET response has an evolving role in guiding patient care. This review provides a perspective on the role of PET response assessment for individualised management of patients with the most common aggressive lymphomas, Hodgkin lymphoma and diffuse large B-cell lymphoma.

Progress and pitfalls with the use of image-guided personalised approaches in lymphoma.

The use of 18F-FDG PET CT has become an essential part of the management of patients with lymphoma. The last decade has seen unrivalled progress in research efforts to personalise treatment approaches using PET as a predictive imaging biomarker. Critical to this success has been the standardisation of PET methods and reporting, including the 5-point Deauville scale, which has enabled the delivery of robust clinical trial data to develop response-adapted treatment approaches.(1, 2) The utility of PET as a predictive imaging biomarker in assessing treatment success or failure has been investigated extensively in malignant lymphomas. Considerable progress has been made over the last decade, in using PET to direct more personalised "risk-adapted" approaches, as well as an increased understanding of some of the limitations. Arguably the greatest success has been in Hodgkin Lymphoma (HL) where PET was initially demonstrated to be a powerful predictive biomarker (3) and is now routinely used in both early-stage and advanced HL to reduce or escalate the use of chemotherapy as well as guiding the delivery of more selective radiotherapy to patients.

Burkitt Lymphoma International Prognostic Index.

PURPOSE: Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches. METHODS: We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019. RESULTS: In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively. CONCLUSION: The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.

Author Correction: High-dose chemotherapy and autologous stem cell transplantation in enteropathy-associated and other aggressive T-cell lymphomas: a UK NCRI/Cancer Research UK Phase II Study.

In the original version of this article, the mention of 'ifosfamide 1500 mg/m2 days 1-3' should, in fact, read 'ifosfamide 1500 mg/m2 bd days 1-3'. This has now been updated in the original version of the article.

Favourable outcomes for high-risk Burkitt lymphoma patients (IPI 3-5) treated with rituximab plus CODOX-M/IVAC: Results of a phase 2 UK NCRI trial.

Introduction: Outcomes after frontline treatment of Burkitt lymphoma (BL) have improved with the introduction of dose-intense chemotherapy regimens, such as CODOX-M/IVAC. While rituximab has increased survival rates for most forms of high-grade B-cell lymphoma, there has previously been hesitancy about incorporating it into BL treatment, partly due to concerns about increased toxicity. Prospective data using the standard dose CODOX-M/IVAC regimen in combination with rituximab are lacking. We conducted a single-arm phase 2 trial to assess the efficacy and toxicity of R-CODOX-M/R-IVAC. Methods: Eligible patients were aged 18-65 years, with newly diagnosed BL with MYC rearrangement as the sole cytogenetic abnormality, and high-risk disease, defined by an International Prognostic Index (IPI) score of 3-5. Patients received two cycles of R-CODOX-M chemotherapy alternating with two cycles of R-IVAC, followed by two further cycles of rituximab alone. The primary endpoint was 2-year progression-free survival. Results: Thirty-eight patients were registered but after central pathology review, 27 patients had confirmed BL and commenced study treatment. Median age was 35 years, 14.8% patients had central nervous system involvement and 18.5% were HIV positive. Twenty-two (81.4%) patients completed four cycles of chemotherapy. There were two treatment-related deaths (7.4%). Two-year progression-free and overall survival rates were 77.2% (90% confidence interval [CI]: 56.0-89.0) and 80.7% (90% CI: 59.6-91.5), respectively. Conclusions: This prospective trial demonstrates excellent survival rates with R-CODOX-M/R-IVAC in a high-risk BL cohort. It provides reassuring evidence regarding the feasibility of this regimen and also provides a benchmark for future studies.

Positron Emission Tomography Score Has Greater Prognostic Significance Than Pretreatment Risk Stratification in Early-Stage Hodgkin Lymphoma in the UK RAPID Study.

PURPOSE: Accurate stratification of patients is an important goal in Hodgkin lymphoma (HL), but the role of pretreatment clinical risk stratification in the context of positron emission tomography (PET) -adapted treatment is unclear. We performed a subsidiary analysis of the RAPID trial to assess the prognostic value of pretreatment risk factors and PET score in determining outcomes. PATIENTS AND METHODS: Patients with stage IA to IIA HL and no mediastinal bulk underwent PET assessment after three cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine; 143 PET-positive patients (PET score, 3 to 5) received a fourth doxorubicin, bleomycin, vinblastine, and dacarbazine cycle and involved-field radiotherapy, and 419 patients in complete metabolic remission were randomly assigned to receive involved-field radiotherapy (n = 208) or no additional treatment (n = 211). Cox regression was used to investigate the association between PET score and pretreatment risk factors with HL-specific event-free survival (EFS). RESULTS: High PET score was associated with inferior EFS, before (P < .001) and after adjustment (P = .01) for baseline risk stratification. Only patients with a postchemotherapy PET score of 5 (uptake ≥ three times maximum liver uptake) had an increased risk of progression or HL-related death (hazard ratio, 9.4 v score of 3; 95% CI, 2.8 to 31.3 and hazard ratio, 6.7 v score of 4; 95% CI, 1.4 to 31.7). Patients with a PET score of 5 also had inferior progression-free and overall survival. There was no association between European Organisation for Research and Treatment of Cancer or German Hodgkin Study Group risk group and EFS, before or after adjusting for PET score (all P > .4). CONCLUSION: In RAPID, a positive PET scan did not carry uniform prognostic weight; only a PET score of 5 was associated with inferior outcomes. This suggests that in future trials involving patients without B symptoms or mediastinal bulk, a score of 5 rather than a positive PET result should be used to guide treatment escalation in early-stage HL.