Aisling Barrett

Survival in diffuse large B-cell lymphoma (DLBCL) has improved, raising interest in mortality from nonlymphoma causes in patients with DLBCL, which is known to be increased compared with the general population. We investigate excess mortality after DLBCL, quantifying both the absolute magnitude of the total nonlymphoma excess and the contributions of major disease groups. All 58 221 patients aged 18 to 79 years diagnosed with DLBCL as their first lymphoma in England during 1997 to 2020 were identified and followed for up to 25 years (median, 10.2 years). Absolute excess mortality rates (AERs) and standardized mortality ratios (SMRs) were estimated. A total of 30 596 patients died, 35.6% from lymphoma and 17.0% from other causes. The nonlymphoma mortality rate was 58% higher than that of the general population (SMR, 1.58; 95% confidence interval [CI], 1.55-1.61), with >100 excess nonlymphoma deaths per 10 000 person-years (AER, 103.8; 95% CI, 98.2-109.4). The nonlymphoma AER was substantial during the first year after diagnosis (AER, 369.1; 95% CI, 349.1-389.7). It subsequently fell but remained significantly elevated throughout follow-up, even beyond 10 years (AER, 93.7; 95% CI, 80.5-107.3). Disease groups with the biggest contributions to the AER were infection <1 year after diagnosis, constituting 29%; hematological causes excluding lymphoma (eg, leukemia) during years 1 to 4, 38%; and solid tumors thereafter, 31% in years 5 to 9 and 34% in years 10 to 25. Deaths from circulatory disease were elevated overall, but the SMR diminished in more recent calendar years of diagnosis. These insights may help guide treatment developments, interventions, and screening strategies toward reducing excess nonlymphoma deaths in the future.

Secondary central nervous system (CNS) large B-cell lymphoma (SCNSL) occurs in the de novo setting, as a CNS-isolated relapse, or synchronous (concomitant CNS and systemic) relapse. SCNSL is a devastating event without therapeutic consensus. Thus, we aimed to evaluate treatment outcomes in an international cohort. Progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR, estimated using competing-risk models) were reported. Prognostic factors were identified in a 6-month landmark multivariate analysis. Outcomes after thiotepa autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy (CAR-T) delivered at relapse were compared after propensity score matching (PSM). A total of 1139 patients were included in the analysis (de novo: 537; relapsed SCNSL: 602). Two-year PFS estimates were 40.4%, 43.9%, and 16.2% for de novo SCNSL, CNS-isolated relapse, and synchronous relapse, respectively. Patients with CNS-isolated relapse demonstrated low rates of systemic recurrence (24-month CIR, 6%). Thiotepa-ASCT correlated with longer survival in de novo SCNSL (PFS: hazard ratio [HR], 0.57; P = .005; and OS: HR, 0.62; P = .023) and CNS-isolated relapses (PFS: HR, 0.55; P = .002; and OS: HR, 0.39; P< .0001). ASCT (thiotepa or no thiotepa) also associated with improved survival in synchronous relapses (PFS: HR, 0.57; P = .023; and OS: HR, 0.48; P = .019). Higher survival with thiotepa-ASCT than CAR-T was observed after PSM (PFS: HR, 0.45; P = .005 and OS: HR, 0.41; P = .014). These data support thiotepa-ASCT in eligible patients, particularly de novo disease and CNS-isolated relapses. CNS-isolated relapse was infrequently associated with systemic recurrence, supporting treatment regimens adopted from primary CNS lymphoma.

The disease shift of chronic lymphocytic leukemia (CLL) to diffuse large B-cell lymphoma (DLBCL), so-called Richter transformation (RT), is a catastrophic clinical event. Rarely, survival can outperform expectations and accurate prognostication for patients may affect therapeutic choices. To date, prognosis has relied on readily available factors such as TP53 disruption, previous CLL treatment status, and performance score. Recently, a shared clonality assessment by immunoglobulin heavy-chain variable region gene (IgHV) sequencing of the CLL and RT has been considered therapeutically relevant, but this is infrequently performed. We performed a systematic review of peer-reviewed manuscripts where outcomes in relation to clonal relatedness and lack thereof (clonally related and clonally unrelated RT-DLBCL) were examined. Fifteen manuscripts that included 336 patients were found, of which 6 compared survival outcomes between the 2 groups in a statistically meaningful way. Two analyses showed no difference in survival outcomes with 4 studies reporting a significantly poorer prognosis with clonally related RT-DLBCL. In 2 of these studies, the baseline characteristics of clonally related and clonally unrelated groups were compared and the clonally related cases were enriched for underlying CLL, which was TP53 disrupted, IgHV unmutated, more heavily pretreated, and exhibiting stereotyped B-cell receptor VH CDR3 and RT-DLBCL, which was MYD88 wild type. We demonstrate that although clonal relatedness of the underlying CLL confers a poorer survival, this is not demonstrated in any study to be independent of other well-described clinical and genomic variables known to influence outcomes in RT-DLBCL. Further independent validation of this prognostic factor is required to help guide universal adoption into clinical practice.

Summary: This good practice paper (GPP) is intended to support clinicians in assessing patient fitness for bleomycin and in management of bleomycin pulmonary toxicity (BPT) where it occurs. Bleomycin, originally developed as an antibiotic in the 1960s, has been a cornerstone of therapy for classical Hodgkin lymphoma (CHL) since results of its use in combination with doxorubicin, vincristine and dacarbazine (ABVD) were first published by Bonadonna et al in 1975 1. The same author recognised high rates of respiratory morbidity in these patients 2, and bleomycin‐;related pulmonary toxicity (BPT) is now a well‐;recognised and feared complication with its use. ABVD and BEACOPP/ BEACOPDac (bleomycin, cyclophosphamide, etoposide, doxorubicin, vincristine and prednisolone, with procarbazine or dacarbazine) are standard first‐;line treatments in CHL patients, but considerable variation remains in assessing patient fitness for bleomycin both clinically and with respiratory investigations. A recent survey of British haematologists regularly using bleomycin revealed that 87.5% have no local protocols for assessing patients in an evidence‐;based fashion, with wide variations in practice captured in the same survey (personal data). A working group was established and a literature review undertaken with the goal of presenting practical recommendations for clinicians regarding bleomycin use based on available evidence and expert opinion.

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.

Since its initial description, classical Hodgkin lymphoma (cHL) portends a greatly improved prognosis and the goal of treatment in most patients is cure with minimisation of toxicity from treatment. Outcomes in older patients (>60 years old) lag behind those of their younger counterparts however, and cure remains achievable mostly for those who can tolerate full doses of conventional chemotherapy. This review addresses the difference in biology between younger and older patients with cHL and examines the impact of frailty and comorbidities on outcomes. The toxicities of conventional chemotherapy in anthracycline-fit and -unfit patients are examined, with a particular focus on pulmonary toxicity associated with bleomycin in older patients. New advances are discussed, including the possibility of using more targeted therapies such as the anti-CD30 antibody brentuximab vedotin (BV) and checkpoint inhibitors as a method of reducing dependency on conventional chemotherapy for those less well able to tolerate it. Treatment of older patients with cHL remains an area of unmet need in hematological research, and efforts to rectify this knowledge gap should continue.

Multiple myeloma (MM) is associated with an increased risk of venous thrombosis (VTE). In the United Kingdom Medical Research Council (MRC) XI study of patients treated with immunomodulatory therapy, the VTE rate was 11.8% despite 87.7% of the patients being on thromboprophylaxis at the time of thrombosis. In order to effectively prevent VTE events in MM patients, a better understanding of patient and disease risk factors that might predict thrombosis is required. We performed a retrospective cohort analysis of over 300 newly diagnosed MM patients at a tertiary referral centre to determine the VTE rate, predictive factors for VTE, value of the Khorana score for MM VTE events and long-term mortality outcomes. Fifty-four percent of the patients were receiving thromboprophylaxis at the time of the VTE event. The mortality odds ratio was 3.3 (95% CI, 2.4–4.5) in patients who developed VTE in comparison to age-matched controls with MM. A younger age at diagnosis and higher white cell count (WCC) were found to be predictive of VTE events. Our data suggest that standard thromboprophylaxis may not be effective in preventing VTE events in myeloma patients, and alternative strategies, which could include higher-intensity thromboprophylaxis in young patients with a high WCC, are necessary.

The introduction of the direct oral anticoagulants (DOACs) has led to their widespread use for stroke prevention and venous thromboembolism, but little is known about the numbers of patients switching from a DOAC to (or back to) a warfarin or the reasons for doing so. This study was an analysis of prospectively collected data from a 4-year period surveying a warfarin dose adjustment clinic in a large city centre hospital with the primary objective to identify these reasons. In our clinic with 1791 patients annually under review, 40 patients were identified as having switched from a DOAC to warfarin with the most common reasons for switching being bleeding, re-thrombosis and renal deterioration. Other reasons included medication interactions, side effects, antiphospholipid syndrome, valvular replacement or arterial embolism. Clinical events following warfarin commencement were also recorded. Overall, these data suggest that switching from a DOAC to warfarin is seldom deemed necessary by clinicians. However, as the number of patients receiving DOACs continues to increase, it is vital that health care professionals remain vigilant regarding medication interactions, bleeding risk and changing renal function.