The influence of immunodeficiency, disease features, and patient characteristics on survival in plasmablastic lymphoma.

ABSTRACT: Plasmablastic lymphoma (PBL) is a rare and aggressive non-Hodgkin lymphoma associated with immunodeficiency, characterized by uncertain treatment approaches and an unfavorable prognosis. We conducted a multicenter, international, retrospective cohort study, aiming to characterize the clinical features, risk factors, and outcomes of patients with PBL. Data were collected from 22 institutions across 4 countries regarding patients diagnosed with PBL between 1 January 1999 and 31 December 2020. Survival risk factors were analyzed using both univariate and multivariate regression models. Overall survival (OS) was calculated using Kaplan-Meier statistics. First-line treatment regimens were stratified into standard- and higher-intensity regimens, and based on whether they incorporated a proteasome inhibitor (PI). A total of 281 patients (median age, 55 years) were included. Immunodeficiency of any kind was identified in 144 patients (51%), and 99 patients (35%) had HIV-positive results. The 5-year OS for the entire cohort was 36% (95% confidence interval, 30%-42%). In multivariate analysis, inferior OS was associated with Epstein-Barr virus-negative lymphoma, poor performance status, advanced stage, and bone marrow involvement. In an independent univariate analysis, the international prognostic index was associated with OS outcomes. Neither immunosuppression nor HIV infection, specifically, influenced OS. Among patients treated with curative intent (n = 234), the overall response rate was 72%. Neither the intensity of the treatment regimen nor the inclusion of PIs in first-line therapy was associated with OS. In this large retrospective study of patients with PBL, we identified novel risk factors for survival. PBL remains a challenging disease with poor long-term outcomes.

Personalised therapy in follicular lymphoma - is the dial turning?

Follicular lymphoma is the most common indolent lymphoma accounting for approximately 20%-25% of all new non-Hodgkin lymphoma diagnoses in western countries. Whilst outcomes are mostly favorable, the spectrum of clinical phenotypes includes high-risk groups with significantly inferior outcomes. This review discusses recent updates in risk stratification and treatment approaches from upfront treatment for limited and advanced stage follicular lymphoma to the growing options for relapsed, refractory disease with perspectives on how to approach this from a personalized lens. Notable gaps remain on how one can precisely and prospectively select optimal treatment for patients based on varying risks, with an anticipation that an increased understanding of the biology of these different phenotypes and increasing refinement of imaging- and biomarker-based tools will, in time, allow these gaps to be closed.

Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study.

BACKGROUND: Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have few treatment options. We aimed to establish the safety and recommended phase 2 dose of epcoritamab, a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells. METHODS: For the dose-escalation part of this phase 1/2 study, we enrolled adults (aged ≥18 years) with relapsed or refractory CD20+ B-cell non-Hodgkin lymphoma at ten sites across four countries (Denmark, the Netherlands, the UK, and Spain). Eligible patients received priming and intermediate doses followed by full doses of subcutaneous epcoritamab administered in 28-day cycles; each subsequent cohort involved escalation of the priming, intermediate, or full dose (0·0128-60 mg). The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Safety, antitumour activity, pharmacokinetics, and immune biomarkers were also assessed. This study is registered with ClinicalTrials.gov, NCT03625037, with the dose-expansion part ongoing. FINDINGS: Between June 26, 2018, and July 14, 2020, we enrolled 73 patients with relapsed, progressive, or refractory CD20+ mature B-cell non-Hodgkin lymphoma. 68 patients received escalating full doses (0·0128-60 mg) of subcutaneous epcoritamab. No dose-limiting toxic effects were observed, and the maximum tolerated dose was not reached; the full dose of 48 mg was identified as the recommended phase 2 dose. All 68 patients received at least one dose of epcoritamab and were included in safety analyses: common adverse events were pyrexia (47 patients [69%]), primarily associated with cytokine release syndrome (CRS; 40 [59%], all grade 1-2), and injection site reactions (32 [47%]; 31 grade 1). There were no grade 3 or higher CRS events. No discontinuations occurred due to treatment-related adverse events or treatment-related deaths. Overall response rate in patients with relapsed or refractory diffuse large B-cell lymphoma was 68% (95% CI 45-86), with 45% achieving a complete response at full doses of 12-60 mg. At 48 mg, the overall response rate was 88% (47-100), with 38% achieving a complete response. Patients with relapsed or refractory follicular lymphoma had an overall response rate of 90% (55-100), with 50% achieving a complete response at full doses of 0·76-48 mg. Epcoritamab induced robust and sustained B-cell depletion, and CD4+ and CD8+ T-cell activation and expansion, with modest increases in cytokine levels. INTERPRETATION: Single-agent subcutaneous epcoritamab for treatment of patients with relapsed or refractory B-cell non-Hodgkin lymphoma merits investigation in ongoing phase 2 and phase 3 studies. FUNDING: Genmab and AbbVie.

A phase II study to assess the safety and efficacy of the dual mTORC1/2 inhibitor vistusertib in relapsed, refractory DLBCL.

Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are unfit for or relapsed postautologous stem-cell transplantation have poor outcomes. Historically, mTORC1 inhibitors have produced responses in approximately 30% of patients in this setting. mTORC1 inhibitor efficacy may be limited by resistance mechanisms including AKT activation by mTORC2. To date, dual mTORC1/2 inhibitors targeting both the TORC1 and TORC2 complexes have not been investigated in DLBCL. This phase II trial investigated the oral dual mTORC1/2 inhibitor vistusertib in an intermittent dosing schedule of 125 mg b.d. for 2 days per week. Thirty patients received vistusertib and six received vistusertib-rituximab for up to six cycles (28-day cycles). Two partial responses were achieved on monotherapy. Durations of response were 57 and 62 days, respectively, for these patients. 19% had stable disease within six cycles. In the monotherapy arm, the median progression-free survival was1.69 (95% confidence interval [CI] 1.61-2.14) months and median overall survival was 6.58 (95% CI 3.81-not reached) months, respectively. The median duration of response or stable disease across the trial duration was 153 days (95% CI 112-not reached). Tumour responses according to positron emission tomography/computed tomography versus computed tomography were concordant. There were no differences noted in tumour volume response according to cell of origin by either gene expression profiling or immunohistochemistry. Vistusertib ± rituximab was well tolerated; across 36 patients 86% of adverse events were grade (G) 1-2. Common vistusertib-related adverse events were similar to those described with mTORC1 inhibitors: nausea (47% G1-2), diarrhoea (27% G1-2, 6% G3), fatigue (30% G1-2, 3% G3), mucositis (25% G1-2, 6% G3), vomiting (17% G1-2), and dyspepsia (14% G1-2). Dual mTORC1/2 inhibitors do not clearly confer an advantage over mTORC1 inhibitors in relapsed or refractory DLBCL. Potential resistance mechanisms are discussed within.

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.

Results of a multicentre UK-wide retrospective study evaluating the efficacy of pixantrone in relapsed, refractory diffuse large B cell lymphoma.

Relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in those unfit or ineligible for autologous stem cell transplantation is associated with a poor outcome and new treatment approaches are needed. Pixantrone is a novel aza-anthracenedione which is structurally similar to anthracyclines and is licenced in R/R DLBCL and National Institute for Health and Care Excellence (NICE)-approved following the PIX301 trial. No data exist post-NICE approval. We performed a UK-wide retrospective multi-centre study of 92 R/R DLBCL who received pixantrone. Eighty-five per cent had refractory disease and 72% had an international prognostic index (IPI) 3-5 at commencement of pixantrone. The median progression-free survival (PFS) was 2·0 months (95% confidence interval (CI) 1·5-2·4) and the median overall survival was 3·4 months (95% CI 2·7-4·5). The overall response rate was 24% (complete response 10%; partial response 14%). We demonstrate that pixantrone has limited activity in a cohort of high risk, predominantly refractory DLBCL. Multivariate Cox regression revealed that patients who relapsed >12 months after first line treatment, those with fewer prior lines of therapy and relapsed (non-refractory) DLBCL had improved PFS. The major population of unmet need are those with refractory DLBCL who are poorly represented within trials and in whom pixantrone appears less efficacious compared to relapsed DLBCL.

Automated prognostic pattern detection shows favourable diffuse pattern of FOXP3(+) Tregs in follicular lymphoma.

BACKGROUND: Histopathological prognostication relies on morphological pattern recognition, but as numbers of biomarkers increase, human prognostic pattern-recognition ability decreases. Follicular lymphoma (FL) has a variable outcome, partly determined by FOXP3 Tregs. We have developed an automated method, hypothesised interaction distribution (HID) analysis, to analyse spatial patterns of multiple biomarkers which we have applied to tumour-infiltrating lymphocytes in FL. METHODS: A tissue microarray of 40 patient samples was used in triplex immunohistochemistry for FOXP3, CD3 and CD69, and multispectral imaging used to determine the numbers and locations of CD3(+), FOXP3/CD3(+) and CD69/CD3(+) T cells. HID analysis was used to identify associations between cellular pattern and outcome. RESULTS: Higher numbers of CD3(+) (P=0.0001), FOXP3/CD3(+) (P=0.0031) and CD69/CD3(+) (P=0.0006) cells were favourable. Cross-validated HID analysis of cell pattern identified patient subgroups with statistically significantly different survival (35.5 vs 142 months, P=0.00255), a more diffuse pattern associated with favourable outcome and an aggregated pattern with unfavourable outcome. CONCLUSIONS: A diffuse pattern of FOXP3 and CD69 positivity was favourable, demonstrating ability of HID analysis to automatically identify prognostic cellular patterns. It is applicable to large numbers of biomarkers, representing an unsupervised, automated method for identification of undiscovered prognostic cellular patterns in cancer tissue samples.

Safety of bendamustine for the treatment of indolent non-Hodgkin lymphoma: a UK real-world experience.

ABSTRACT: Bendamustine is among the most effective chemotherapeutics for indolent B-cell non-Hodgkin lymphomas (iNHL), but trial reports of significant toxicity, including opportunistic infections and excess deaths, led to prescriber warnings. We conducted a multicenter observational study evaluating bendamustine toxicity in real-world practice. Patients receiving at least 1 dose of bendamustine with/without rituximab (R) for iNHL were included. Demographics, lymphoma and treatment details, and grade 3 to 5 adverse events (AEs) were analyzed and correlated. In total, 323 patients were enrolled from 9 National Health Service hospitals. Most patients (96%) received bendamustine-R, and 46%, R maintenance. Overall, 21.7% experienced serious AEs (SAE) related to treatment, including infections in 12%, with absolute risk highest during induction (63%), maintenance (20%), and follow-up (17%) and the relative risk highest during maintenance (54%), induction (34%), and follow-up (28%). Toxicity led to permanent treatment discontinuation for 13% of patients, and 2.8% died of bendamustine-related infections (n = 5), myelodysplastic syndrome (n = 3), and cardiac disease (n = 1). More SAEs per patient were reported in patients with mantle cell lymphoma, poor preinduction performance status (PS), poor premaintenance PS, and abnormal preinduction total globulins and in those receiving growth factors. Use of antimicrobial prophylaxis was variable, and 3 of 10 opportunistic infections occurred despite prophylaxis. In this real-world analysis, bendamustine-related deaths and treatment discontinuation were similar to those of trial populations of younger, fitter patients. Poor PS, mantle cell histology, and maintenance R were potential risk factors. Infections, including late onset events, were the most common treatment-related SAE and cause of death, warranting extended antimicrobial prophylaxis and infectious surveillance, especially for maintenance-treated patients.

Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study.

BACKGROUND: A standard of care and optimal duration of therapy have not been established for patients with multiply relapsed or refractory follicular lymphoma. The aim of this study was to evaluate epcoritamab, a novel CD3 × CD20 bispecific antibody, in the third-line and later setting of follicular lymphoma. METHODS: EPCORE NHL-1 is a multicohort, single-arm, phase 1-2 trial conducted at 88 sites across 15 countries. Here, we report the primary analysis of patients with relapsed or refractory follicular lymphoma in the phase 2 part of the trial, which included the pivotal (dose expansion) cohort and the cycle 1 optimisation cohort. Eligible patients were aged 18 years or older, had relapsed or refractory CD20+ follicular lymphoma (grade 1-3A), an Eastern Cooperative Oncology Group performance status of up to 2, and had received at least two previous lines of therapy (including an anti-CD20 monoclonal antibody and an alkylating agent or lenalidomide). Patients were treated with subcutaneous epcoritamab 48 mg in 28-day cycles: weekly in cycles 1-3, biweekly in cycles 4-9, and every 4 weeks until disease progression or unacceptable toxicity. To mitigate the risk and severity of cytokine release syndrome, in the pivotal cohort, cycle 1 consisted of a step-up dosing regimen of a 0·16-mg priming dose on day 1 and a 0·80-mg intermediate dose on day 8, followed by subsequent 48-mg full doses and prophylactic prednisolone 100 mg; in the cycle 1 optimisation cohort, a second intermediate dose of 3 mg on day 15, adequate hydration, and prophylactic dexamethasone 15 mg were evaluated during cycle 1 to further reduce risk and severity of cytokine release syndrome. Primary endpoints were independently reviewed overall response rate for the pivotal cohort and the proportion of patients with grade 2 or worse and any-grade cytokine release syndrome for the cycle 1 optimisation cohort. Analyses were done in all enrolled patients who had received at least one dose of epcoritamab. This study is registered with ClinicalTrials.gov, NCT03625037, and is ongoing. FINDINGS: Between June 19, 2020, and April 21, 2023, 128 patients (median age 65 years [IQR 55-72]; 49 [38%] female and 79 [62%] male) were enrolled and treated in the pivotal cohort (median follow-up 17·4 months [IQR 9·1-20·9]). The overall response rate was 82·0% (105 of 128 patients; 95% CI 74·3-88·3), with a complete response rate of 62·5% (80 of 128; 95% CI 53·5-70·9). The most common grade 3-4 treatment-emergent adverse event was neutropenia in 32 (25%) of 128 patients. Grade 1-2 cytokine release syndrome was reported in 83 (65%) of 128 patients; grade 3 cytokine release syndrome was reported in two (2%). Immune effector cell-associated neurotoxicity syndrome was reported in eight (6%) of 128 patients (five [4%] grade 1; three [2%] grade 2). Between Oct 25, 2022, and Jan 8, 2024, 86 patients (median age 64 years [55-71]; 37 [43%] female and 49 [57%] male) were enrolled and treated in the cycle 1 optimisation cohort. The incidence of cytokine release syndrome was 49% (42 of 86 patients; eight [9%] grade 2; none of grade 3 or worse), with no reported immune effector cell-associated neurotoxicity syndrome. INTERPRETATION: Epcoritamab monotherapy showed clinically meaningful activity in patients with multiply relapsed or refractory follicular lymphoma, and had a manageable safety profile. FUNDING: Genmab and AbbVie.

Safety and efficacy of zanubrutinib in relapsed/refractory marginal zone lymphoma: final analysis of the MAGNOLIA study.

The primary analysis of MAGNOLIA, an open-label, single-arm, multicenter, phase 2 study, demonstrated that the next-generation Bruton tyrosine kinase (BTK) inhibitor zanubrutinib provided a high overall response rate (ORR) in patients with relapsed/refractory marginal zone lymphoma (R/R MZL), with a favorable safety/tolerability profile. Presented here, is the final analysis of MAGNOLIA, performed to characterize the durability of response and longer-term safety and tolerability. Zanubrutinib (160 mg twice daily) was evaluated in 68 patients with R/R MZL who had received at least 1 anti-CD20-directed regimen. The primary end point was independent review committee (IRC)-assessed ORR. Secondary end points included investigator-assessed ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), health-related quality of life, safety, and tolerability. With a median follow-up of 27.4 months, the IRC-assessed ORR was 68.2% (95% confidence interval [CI], 55.6-79.1), with a 24-month DOR event-free rate of 72.9% (95% CI, 54.4-84.9). PFS and OS at 24 months were 70.9% (95% CI, 57.2-81.0) and 85.9% (95% CI, 74.7-92.4), respectively. The zanubrutinib safety profile was consistent with the primary analysis, with no new safety signals observed. Atrial fibrillation/flutter (n = 2 [2.9%]) and hypertension (n = 3 [4.4%]) were uncommon. Neutropenia (n = 8 [11.8%]) was the most common grade ≥3 adverse event. In this final analysis of MAGNOLIA, zanubrutinib demonstrated sustained clinical responses beyond 2 years, with 73% of responders alive and progression free. Zanubrutinib continued to demonstrate a favorable safety/tolerability profile with the additional time on treatment. This trial was registered at www.clinicaltrials.gov as #NCT03846427.

Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial.

219 HIV-negative adults ≤70 years with primary CNS lymphoma (PCNSL) were enrolled in the randomized IELSG32 trial. Enrolled patients were randomly assigned to receive methotrexate-cytarabine (arm A), or methotrexate-cytarabine-rituximab (B), or methotrexate-cytarabine-thiotepa-rituximab (MATRix; arm C). A second randomization allocated patients with responsive/stable disease to whole-brain irradiation (WBRT) or carmustine-thiotepa-conditioned autologous transplantation (ASCT). First results, after a median follow-up of 30 months, showed that MATRix significantly improves outcome, with both WBRT and ASCT being similarly effective. However, sound assessment of overall survival (OS), efficacy of salvage therapy, late complications, secondary tumors, and cognitive impairment requires longer follow-up. Herein, we report the results of this trial at a median follow-up of 88 months. As main findings, MATRix was associated with excellent long-lasting outcome, with a 7-year OS of 21%, 37%, and 56% respectively for arms A, B, and C. Notably, patients treated with MATRix and consolidation had a 7-year OS of 70%. The superiority of arm B on arm A suggests a benefit from the addition of rituximab. Comparable efficacy of WBRT and ASCT was confirmed. Salvage therapy was ineffective; benefit was recorded only in patients with late relapse re-treated with methotrexate. Eight (4%) patients developed a second cancer. Importantly, MATRix and ASCT did not result in higher non-relapse mortality or second tumors incidence. Patients who received WBRT experienced impairment in attentiveness and executive functions, whereas patients undergoing ASCT experienced improvement in these functions as well as in memory and quality of life.

Systemic ALCL Treated in Routine Clinical Practice: Outcomes Following First-Line Chemotherapy from a Multicentre Cohort.

INTRODUCTION: Brentuximab vedotin (BV)-CHP is the new standard regimen for first-line treatment of systemic anaplastic large cell lymphoma (sALCL). We undertook a retrospective analysis of consecutive patients diagnosed with sALCL, treated in routine practice, to serve as a benchmark analysis for comparison BV-CHP efficacy in routine practice. METHODS: Patients aged 16 years or older with sALCL treated in seven UK and Australian centres and from 14 additional centres from the UK Haematological Malignancy Research Network database (n = 214). Treatment allocation was clinician choice and included best supportive care (BSC). Main outcomes were time to treatment failure (TTF) and overall survival (OS). Multivariable analysis for predictors of both TTF and OS was also undertaken. RESULTS: The median age 52 years (range 16-93), 18% ECOG ≥ 3 and 40% of cases were ALK positive. CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) was employed in 152 (71%) of patients and CHOEP (CHOP + etoposide) in 4% of patients. For CHOP-treated patients overall response rate (ORR) was 65% and complete response (CR) 47%. Only 9% of patients underwent autologous stem cell transplant (ASCT). With 57 months median follow-up, 4-year TTF and OS were 41.2% (95% CI 33.1-49.1) and 58.9% (95% CI 50.3-66.5) respectively. Multivariable analysis showed ALK+ status was independently associated with superior TTF (HR 0.36, 95% CI 0.21-0.63) but not OS (0.44, 95% CI 0.18-1.07). DISCUSSION: We present a retrospective analysis with mature follow-up of one of the largest multicentre populations of sALCL available, comparable to similar large retrospective studies. ALK status remains a strong predictor of outcomes. CONCLUSION: These data serve as a robust benchmark for BV-CHP as the new standard of care for sALCL. Similar real-world evidence with BV-CHP will be desirable to confirm the findings of ECHELON-2.

A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial.

Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473.

Fractures are common within 18 months following first-line R-CHOP in older patients with diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) and osteoporotic fracture are both more common in older patients. Exposure to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) is likely to increase the risk of fracture, but evidence is lacking to define fracture incidence in this group. Data on consecutive patients with DLBCL aged ≥70 years treated with 1 to 8 cycles of full or attenuated R-CHOP were retrospectively collected across 10 UK centers (2009-2019). Patients were followed up from starting R-CHOP for a minimum of 6 months and censored at 18 months; at last follow-up if <18 months; or at progression or death. Of 877 patients identified, 148 were excluded: 121 had progression or died before 6 months; 23 had follow-up <6 months. Across 729 remaining patients, the median age was 77 years, and 68% had an Eastern Cooperative Oncology Group performance status of 0 to 1. Eighty-one fractures occurred within 18 months of follow-up; 42 were symptomatic, including 30 requiring hospital attendance or admission. The cumulative fracture incidence was 6.2% (95% confidence interval [CI], 4.7-8.2) at 6 months; 9.7% (95% CI, 7.8-12.1) at 12 months; and 11.4% (95% CI, 9.3-14.0) at 18 months. Multivariate analysis identified a predisposing history (osteoporosis, osteopenia, prior fracture, and rheumatoid arthritis [RhA]), DLBCL bone involvement at baseline, and receipt of prephase steroids as independent risk factors for fracture. There is a clinically relevant fracture risk and significant associated morbidity in older patients receiving R-CHOP. Careful attention to bone health is warranted in older patients receiving R-CHOP. Randomized studies are required to better define the most effective strategies to reduce fracture risk.

RIVA - a phase IIa study of rituximab and varlilumab in relapsed or refractory B-cell malignancies: study protocol for a randomized controlled trial.

BACKGROUND: Over 12,000 new cases of B-cell malignancies are diagnosed in the UK each year, with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) being the most common subtypes. Standard frontline therapy consists of immunochemotherapy with a CD20 monoclonal antibody (mAb), such as rituximab, delivered in combination with multi-agent chemotherapy. Despite being considered a treatable and potentially curable cancer, approximately 30% of DLBCL cases will relapse after frontline therapy. Advanced stage FL is incurable and typically has a relapsing and remitting course with a frequent need for re-treatment. Based on supportive preclinical data, we hypothesised that the addition of varlilumab (an anti-CD27 mAb) to rituximab (an anti-CD20 mAb) can improve the rate, depth and duration of the response of rituximab monotherapy in patients with relapsed or refractory B-cell malignancies. METHODS/DESIGN: Combination treatment of varlilumab plus rituximab, in two different dosing regimens, is being tested in the RIVA trial. RIVA is a two-stage open-label randomised phase IIa design in up to 40 patients with low- or high-grade relapsed or refractory CD20+ B-cell lymphoma. The study is open to recruitment in the UK. Enrolled patients are randomised 1:1 to two different experimental varlilumab to rituximab combinations. The primary objective is to determine the safety and tolerability of the combination and the anti-tumour activity (response) in relapsed or refractory B-cell malignancies. Secondary objectives will include an evaluation of the duration of the response and overall survival. Tertiary translational objectives include assessment of B-cell depletion, changes in immune effector cell populations, expression of CD27 as a biomarker of response and pharmacokinetic properties. Analyses will not be powered for formal statistical comparisons between treatment arms. DISCUSSION: RIVA will determine whether the combination of rituximab and varlilumab in relapsed or refractory B-cell malignancies is active and safe prior to future phase II/III trials. TRIAL REGISTRATION: EudraCT, 2017-000302-37. Registered on 16 January 2017. ISRCTN, ISRCTN15025004 . Registered on 16 August 2017.

A Phase 2/3 Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Lenalidomide Versus Investigator's Choice in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

Purpose: Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).Experimental Design: Patients with DLBCL who received ≥2 prior therapies were stratified by DLBCL subtype [germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC)] and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis [GCB vs. activated B-cell (ABC)] using gene expression profiling (GEP) were exploratory endpoints.Results: Stage 1: 102 DLBCL patients (by IHC: non-GCB, n = 54; GCB, n = 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks; P = 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively; P = 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively; P = 0.550).Conclusions: The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping. Clin Cancer Res; 23(15); 4127-37. ©2017 AACR.

Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial.

BACKGROUND: The International Extranodal Lymphoma Study Group-32 (IELSG32) trial is an international randomised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma. Results of the first randomisation have demonstrated that methotrexate, cytarabine, thiotepa, and rituximab (called the MATRix regimen) is the induction combination associated with significantly better outcome compared with the other induction combinations tested. Here, we report the results of the second randomisation that addresses the efficacy of myeloablative chemotherapy supported by autologous stem-cell transplantation (ASCT), as an alternative to whole-brain radiotherapy (WBRT), as consolidation after high-dose-methotrexate-based chemoimmunotherapy. METHODS: HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and an Eastern Cooperative Oncology Group performance status of 0-3 were randomly assigned to receive four courses of methotrexate 3·5 g/m2 on day 1 plus cytarabine 2 g/m2 twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m2 on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m2 on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after induction treatment, with adequate autologous peripheral blood stem-cell collection, and without persistent iatrogenic side-effects, were eligible for the second randomisation between WBRT (photons of 4-10 MeV; five fractions per week; fraction size 180 cGy; started within 4 weeks from the last induction course; group D) and carmustine-thiotepa conditioned ASCT (carmustine 400 mg/m2 on day -6, and thiotepa 5 mg/kg every 12 h on days -5 and -4, followed by reinfusion of autologous peripheral blood stem cells; group E). A permuted block randomised design was adopted for both randomisations, and a computer-generated randomisation list was used within each stratum. No masking after assignment to intervention was adopted. The primary endpoint was 2-year progression-free survival, with induction group and response to induction chemotherapy as stratification parameters. Analyses were done on a modified intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01011920. FINDINGS: Between Feb 19, 2010, and Aug 27, 2014, 227 patients were recruited from 53 centres in five countries. 219 of 227 enrolled patients were assessable. Of the 122 patients eligible for the second randomisation, 118 patients were randomly assigned to WBRT or ASCT (59 patients per group) and constitute the study population. WBRT and ASCT were both effective, and achieved the predetermined efficacy threshold of at least 40 progression-free survivors at 2 years among the first 52 patients in both groups D and E. There were no significant differences in 2-year progression-free survival between WBRT and ASCT: 80% (95% CI 70-90) in group D and 69% (59-79) in group E (hazard ratio 1·50, 95% CI 0·83-2·71; p=0·17). Both consolidation therapies were well tolerated. Grade 4 non-haematological toxicity was uncommon; as expected, haematological toxicity was more common in patients treated with ASCT than in those who received WBRT. Two toxic deaths (infections) were recorded, both in patients who received ASCT. INTERPRETATION: WBRT and ASCT are both feasible and effective as consolidation therapies after high-dose methotrexate-based chemoimmunotherapy in patients aged 70 years or younger with primary CNS lymphoma. The risks and implications of cognitive impairment after WBRT should be considered at the time of therapeutic decision. FUNDING: Agenzia Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Science Foundation.