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Abstract Central nervous system (CNS) involvement by mantle cell lymphoma (MCL) is rare and portends a poor prognosis. We describe the first patient to have a complete response with front‐line treatment with single‐agent acalabrutinib for MCL CNS.

Venetoclax is a standard treatment for patients with chronic lymphocytic leukemia (CLL) following covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy, despite relatively limited prospective data in this setting. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and re-establish BTK inhibition. An unanchored matching-adjusted indirect comparison (MAIC) was conducted to estimate the treatment effect of pirtobrutinib versus venetoclax monotherapy in patients with cBTKi-pretreated CLL. Data from patients with CLL who were venetoclax-naïve and pretreated with cBTKi received pirtobrutinib (N=146) in the phase I/II BRUIN study were compared with the only identified trial of patients with CLL receiving venetoclax after a cBTKi (N=91), as administered as monotherapy until progression. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-emergent adverse events. Both unweighted and weighted analyses were conducted. PFS and OS of pirtobrutinib and venetoclax were comparable in both unweighted and weighted analyses (weighted hazard ratios for PFS: 1.01, 95% confidence interval [CI]: 0.58-1.73, P=0.98 and OS: 0.64, 95% CI: 0.25-1.67, P=0.34). ORR was significantly higher for pirtobrutinib (80.2% vs. 64.8%, P=0.01). Grade ≥3 treatment-emergent adverse events were lower in weighted analyses for pirtobrutinib versus venetoclax (all P

Objectives There are no real-world data describing infection morbidity in relapsed/refractory myeloma (RRMM) patients treated with anti-CD38 isatuximab in combination with pomalidomide and dexamethasone (IsaPomDex). In this UK-wide retrospective study, we set out to evaluate infections experienced by routine care patients who received this novel therapy across 24 cancer centres during the COVID-19 pandemic.Methods The primary endpoint was infection morbidity (incidence, grading, hospitalization) as well as infection-related deaths. Secondary outcomes were clinical predictors of increased incidence of any grade (G2–5) and high grade (≥G3) infections.Results In a total cohort of 107 patients who received a median (IQR) of 4 cycles (2–8), 23.4% of patients experienced ≥1 any grade (G2–5) infections (total of 31 episodes) and 18.7% of patients experienced ≥1 high grade (≥G3) infections (total of 22 episodes). Median time (IQR) from start of therapy to first episode was 29 days (16–75). Six patients experienced COVID-19 infection, of whom 5 were not vaccinated and 1 was fully vaccinated. The cumulative duration of infection-related hospitalizations was 159 days. The multivariate (MVA) Poisson Regression analysis demonstrated that a higher co-morbidity burden with Charlson Co-morbidity Index (CCI) score ≥4 (incidence rate ratio (IRR) = 3, p = 0.012) and sub-optimal myeloma response less than a partial response (

Objectives: Daratumumab is the first anti-CD38 monoclonal antibody (Mab) used to treat myeloma in the newly diagnosed setting and in the relapsed setting. Isatuximab, another Mab targeting a specific epitope on the CD38 receptor, was recently approved in the UK in combination with pomalidomide and dexamethasone (IsaPomDex) to treat myeloma patients who received three prior lines of therapy. However, there is a lack of understanding of whether using a prior anti-CD38 Mab (e.g. daratumumab) can affect the efficacy of another Mab (e.g. isatuximab), when the latter is used to treat a subsequent relapse. Methods: We performed a UK-wide outcomes study of IsaPomDex in the real-world. In this case series, we report a detailed descriptive analysis of the characteristics and clinical outcomes of five IsaPomDex patients in UK routine practice (Patients I to V), with a prior exposure to daratumumab. Results: Age range was 51–77 years with two patients >70 and three patients

Abstract Background This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. Methods Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils 1. Baseline HR23B expression was assessed by immunohistochemistry. Results Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3–4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2–5.4) in solid-organ cancers and 2.6 months (95%CI 1.2–5.6) in lymphomas. HR23B status did not predict response. Conclusions CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. Trial registration ClinicalTrials.gov identifier NCT01977638 . Registered 07 November 2013.

The development of inhibitors of Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) has resulted in a paradigm shift in the treatment of chronic lymphocytic leukaemia (CLL) over the last decade. Observations regarding the importance of B-cell receptor signalling for the survival and proliferation of CLL cells led to the development of the first-in-class BTK inhibitor (BTKi), ibrutinib, for the treatment of CLL. Despite being better tolerated than chemoimmunotherapy, ibrutinib does have side effects, some of which are due to the off-target inhibition of kinases other than BTK. As a result, more specific inhibitors of BTK were developed, such as acalabrutinib and zanubrutinib, which have demonstrated equivalent/enhanced efficacy and improved tolerability in large randomized clinical trials. Despite the increased specificity for BTK, side effects and treatment resistance remain therapeutic challenges. As these drugs all bind covalently to BTK, an alternative approach was to develop noncovalent inhibitors of BTK, including pirtobrutinib and nemtabrutinib. The alternative mechanisms of BTK-binding of these agents has the potential to overcome resistance mutations, something that has been borne out in early clinical trial data. A further step in the clinical development of BTK inhibition has been the introduction of BTK degraders, which remove BTK by ubiquitination and proteasomal degradation, in marked contrast to BTK inhibition. This article will review the evolution of BTK inhibition for CLL and offer future perspectives on the sequencing of an increasing number of different agents, and how this may be impacted on by mutations in BTK itself and other kinases.

The optimum management approach for patients with relapsed or refractory follicular lymphoma remains uncertain. Autologous stem cell transplantation (autoSCT) is considered a standard option in suitable, younger patients with relapsed follicular lymphoma. AutoSCT is associated with very durable remissions in a minority of subjects, but also with significant, well-established toxicities. Although positron emission tomography (PET) status prior to autoSCT is an established prognostic factor in diffuse large B-cell lymphoma and Hodgkin lymphoma, no data exist in follicular lymphoma. We describe survival outcomes according to pre-transplant PET status, classified by the Lugano criteria into complete metabolic remission (CMR) versus non-CMR, in 172 patients with relapsed or refractory follicular lymphoma within a national, multicenter, retrospective British Society of Blood and Marrow Transplantation and Cellular Therapy registry study. The median number of lines of therapy prior to SCT was three (range, 1-6). The median follow-up after SCT was 27 months (range, 3–70). The median progression-free survival for all patients after autoSCT was 28 months (interquartile range, 23- 36). There was no interaction between age at transplantation, sex, number of months since last relapse, Karnofsky performance status or comorbidity index and achieving CMR prior to autoSCT. Superior progression-free survival was observed in 115 (67%) patients obtaining CMR versus 57 (33%) non-CMR patients (3-year progression-free survival 50% vs. 22%, P=0.011) and by pre-SCT Deauville score (continuous variable 1-5, hazard ratio [HR]=1.32, P=0.049). PET status was independently associated with progression-free status (non-CMR HR=2.02, P=0.003), overall survival (non-CMR HR=3.08, P=0.010) and risk of relapse (non-CMR HR=1.64, P=0.046) after autoSCT by multivariable analysis. Our data suggest that pre- SCT PET status is of clear prognostic value and may help to improve the selection of patients for autoSCT.

Data on outcome of patients with mantle cell lymphoma (MCL) and COVID-19 infection are limited. The European MCL (EMCL) registry is a centralized registry of the EMCL network, collecting real-world information about treatments and disease courses. During the COVID-19 pandemic, additional data on MCL patients with COVID-19 infection were collected, aiming to identify risk factors for mortality from COVID-19. In our retrospective, multicenter, international study, we collected data from 63 MCL patients with a median age of 64 years (range, 44–84) in 9 countries with evidence of a COVID-19 infection between February 2020 and October 2021. The overall mortality rate was high (44.4%), especially in hospitalized patients (61%) and in patients with need for intensive care unit care (94%). Patients receiving rituximab had significantly poorer survival than patients not receiving rituximab (P = 0.04). Our data highlight the importance of prevention strategies and underline the need for effective vaccination in this vulnerable cohort.

The management of myeloma in the elderly is shifting its focus towards reducing the risk of under-treating fit patients and the risk of over-treating frail patients. Frailty assessment is required in this patient group in order to individualise treatment decisions. In addition to the proven prognostic values of the International Myeloma Working Group (IMWG) frailty score and the revised Myeloma Co-morbidity Index (R-MCI), a new easy-to-use frailty-based risk profile score (high-risk (i.e. frail), medium risk (i.e. intermediate-fitness) and low-risk (i.e. fit)) named Myeloma Risk Profile (MRP) was shown to be predictive of survival in the clinical trial setting. In this retrospective real-world study, we set out to evaluate the frailty characteristics and clinical outcomes according to the different MRP scoring algorithm categories (frail vs. intermediate vs fit), in a high risk cohort of elderly newly diagnosed myeloma patients treated with the fixed-duration triplet therapy VCD (bortezomib with cyclophosphamide and dexamethasone). Clinical outcomes included: reason for treatment discontinuation, overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Out of 100 patients, 62 were frail, 27 were intermediate and 11 were fit, according to MRP scores. To enable meaningful comparisons between comparable numbers, subgroups analyses for ORR, OS, PFS, and AEs focused on frail (n = 62) versus intermediate or fit (n = 38) patients. The proportion of patients in each subgroup who were able to complete the planned course of treatment was (frail: 43.5% vs. intermediate or fit: 55.3%). A higher proportion in the frail subgroup discontinued therapy due to progressive disease (19.4% vs. 2.6%). Discontinuation due to toxicity was comparable across subgroups (14.5% vs. 15.8%), ORR in the total cohort was 75%, and this was comparable between subgroups (frail: 74.2% vs. intermediate or fit: 76.3%). There was a trend for a shorter median OS in the frail subgroup but without a statistical significance: (frail vs. intermediate or fit): (46 months vs. not reached, HR: 1.94, 95% CI 0.89–4.2, p = 0.094). There was no difference in median PFS between subgroups: (frail vs. intermediate or fit): (11.8 vs. 9.9 months, HR: 0.99, 95% CI: 0.61–1.61, P = 0.982). This cohort demonstrated a higher incidence rate of AEs in frail patients compared to those in the intermediate or fit group: patients with at least one any grade toxicity (85.5% vs. 71.1%), patients with at least one ≥G3 AE (37.1% vs. 21.1%). In conclusion, our study is to the first to evaluate clinical outcomes according to MRP in a high risk real-world cohort of patients treated exclusively with the proteasome inhibitor-based VCD therapy. Our study demonstrated a trend for worse OS in addition to worse AE outcomes in the frail group, but no difference in PFS with this fixed-duration therapy. MRP is an easy-to-use tool in clinical practice; its prognostic value was validated in the real-world in a large cohort of patients from the Danish Registry. Further evaluation of MRP in the real-world when continuous therapies are used, can further support the generalisability of its prognostic value in elderly myeloma patients.

Bimiralisib is an orally bioavailable pan-phosphatidylinositol 3-kinase and mammalian target of rapamycin inhibitor which has shown activity against lymphoma in preclinical models. This phase I/II study evaluated the response rate to bimiralisib at 2 continuous dose levels (60 mg and 80 mg) in patients with relapsed/refractory lymphoma. Fifty patients were enrolled and started treatment. The most common histologies were diffuse large B-cell lymphoma (n = 17), follicular lymphoma (n = 9), T-cell lymphoma (n = 8), and others (mostly indolent). Patients had been treated with a median of 5 prior lines of treatment and 44% were considered refractory to their last treatment. Mean duration of treatment (and standard deviations) with 60 mg once daily (o.d.) was 1.3 ± 1.2 months, and with 80 mg o.d. 3.7 ± 3.9 months. On an intention to treat analysis, the overall response rate was 14% with 10% achieving a partial response and 4% a complete response. Thirty-six percent of patients were reported as having stable disease. No dose-limiting toxicities were observed during the phase I portion of the study. Overall, 70% of patients had a grade 3 treatment emergent adverse events (TEAE) and 34% had a grade 4 TEAE; 28% of patients discontinued treatment due to toxicity. The most frequent TEAEs grade ≥3 was hyperglycemia (24%), neutropenia (20%), thrombocytopenia (22%), and diarrhea (12%). Per protocol, hyperglycemia required treatment with oral antihyperglycemic agents in 28% and with insulin in 14%. At 60 mg or 80 mg continuous dosing, bimiralisib showed modest efficacy with significant toxicity in heavily pretreated patients with various histological subtypes of lymphoma.

Abstract Background Transformation of chronic lymphocytic leukaemia (CLL) to diffuse large B-cell lymphoma (DLCBL) type Richter’s syndrome (RS) carries a dismal prognosis. Standard-of-care chemoimmunotherapy for de novo RS is inadequate with median survival of less than one year. Patients are frequently elderly or have co-morbidities limiting dose-intense chemotherapy. Treatment of relapsed/refractory (R/R) RS and RS emerging after CLL-directed therapy represent urgent unmet clinical needs. Agents targeting Bruton’s tyrosine kinase (BTK) deliver improved outcomes for patients with high-risk CLL and expand effective treatments to frailer patients. Acalabrutinib is an oral, second-generation BTK inhibitor with a favourable toxicity profile and demonstrated activity in CLL and B-cell lymphomas. Combination of acalabrutinib with standard-of-care CHOP-R chemoimmunotherapy offers a sound rationale to test in a prospective trial for de novo RS. Methods The prospective multicentre STELLAR study is designed in two elements, consisting of a randomised study to evaluate the safety and activity of CHOP-R chemoimmunotherapy in combination with acalabrutinib in newly diagnosed RS and single-arm studies of novel agents for other RS patient cohorts. Eligible patients with newly diagnosed DLBCL-type RS are randomised between six cycles of CHOP-R therapy and six cycles CHOP-R plus acalabrutinib, followed by acalabrutinib maintenance. The primary endpoint of the randomised component is progression free survival (PFS). Cohort 1 enrols RS patients with progressive disease following chemoimmunotherapy for acalabrutinib monotherapy. Patients with RS diagnosed while on ibrutinib may enrol in Cohort 2, a single-arm study of CHOP-R plus acalabrutinib. The primary endpoint for the single-arm studies is overall response rate (ORR). Secondary endpoints for all cohorts are overall survival (OS), quality of life and proportion of patients proceeding to stem cell transplantation. The study will be accompanied by exploratory analysis of the mutational landscape of RS and the relationship between dynamic changes in sequential circulating tumour DNA samples and clinical outcomes. Discussion The STELLAR randomised trial evaluates the role of CHOP-R plus acalabrutinib in newly diagnosed RS patients. The single-arm platform studies enable the incorporation of promising novel therapies into the protocol. The STELLAR study has potential to identify novel biomarkers of treatment response in this high-risk malignancy. Trial registration EudraCT: 2017–004401-40, registered on the 31-Oct-2017. IRSCTN: https://www.isrctn.com/ISRCTN52839057, registered on the 04-Mar-2019. ClinicalTrials.gov: NCT03899337, registered on 02-April-2019.

Central nervous system (CNS) relapse of diffuse large B-cell lymphoma remains uncommon but catastrophic. The benefit of standalone intrathecal prophylaxis in reducing CNS recurrence is unclear and remains controversial. No systematic review analysing the evidence for stand-alone intrathecal prophylaxis has been performed in the era of anti-CD20 monoclonal antibody therapy. A comprehensive search (01/2002-01/2019) was systematically performed using Ovid MEDLINE®, Ovid EMBASE® and Cochrane. Studies were selected from a total of 804, screened based on predefined inclusion/exclusion criteria, and were critically appraised. Three post hoc analyses (RICOVER-60, RCHOP-14/21, GOYA), one prospective database and 10 retrospective series were included. 7,357 rituximab/obinutuzumab-exposed patients were analysed. The median percentage receiving intrathecal prophylaxis was 11.9%. Cumulative CNS relapse incidence ranged from 1.9% at 6.5 years to 8.4% at 5 years. Median time (of medians) to CNS relapse was 10 months. 73% developed isolated CNS relapses, 24% concurrent CNS/systemic relapse, and 3% post-systemic relapse. Reported CNS relapse sites were: parenchymal (58%), leptomeningeal (27%), and both (12%). Event rates were low resulting in limited power within each study to provide robust univariable/multivariable analysis. Intrathecal prophylaxis was not a univariable or multivariable factor associated with a reduction in CNS relapse in any study. We found no strong evidence for the benefit, or indeed genuine lack of benefit, of stand-alone intrathecal prophylaxis in preventing CNS relapse in diffuse large B-cell lymphoma-treated patients using anthracycline-based immunochemotherapy. Current published study designs limit the strength of such conclusions.

We performed an observational study on the efficacy of ben-damustine and rituximab (BR) as first salvage regimen in chronic lymphocytic leukemia (CLL). In an intention-to-treat analysis including 237 patients, the median progression-free survival (PFS) was 25 months. The presence of del(17p), unmutated IGHV and advanced stage were associated with a shorter PFS at multivariate analysis. The median time-to-next treatment was 31.3 months. Front-line treatment with a chemoimmunotherapy regimen was the only predictive factor for a shorter time to next treatment at multivariate analysis. The median overall survival (OS) was 74.5 months. Advanced disease stage (i.e. Rai stage III-IV or Binet stage C) and resistant disease were the only parameters significantly associated with a shorter OS. Grade 3-5 infections were recorded in 6.3% of patients. A matched-adjusted indirect comparison with ibrutinib given second-line within Named Patient Programs in the United Kingdom and in Italy was carried out with OS as objective end point. When restricting the analysis to patients with intact 17p who had received chemoimmunotherapy in first line, there was no difference in OS between patients treated with ibrutinib (63% alive at 36 months) and patients treated with BR (74.4% alive at 36 months). BR is an efficacious first salvage regimen in CLL in a real-life population, including the elderly and unfit patients. BR and ibrutinib may be equally effective in terms of OS when used as first salvage treatment in patients without 17p deletion.