Chronic lymphocytic leukemia (CLL) is the most diagnosed leukemia in the Western world, accounting for approximately 25% of all new leukemia diagnoses. In recent years, remarkable progress has been ...made in our understanding of both the pathophysiology and genetics of CLL. While the disease generally affects older adults and initially follows an indolent course, cytogenetic and molecular profiling have helped to predict clinical outcomes. Greater prognostication, alongside the development of an increasing armamentarium of novel targeted therapies, has enabled us to provide more personalized management options for patients. 'Fast Facts: Chronic Lymphocytic Leukemia' covers the epidemiology, etiology, diagnosis and staging of the disease, and the molecular and genetic aspects that underpin treatment and prognosis. It provides a concise overview of treatment options, in both the front-line and relapsed/refractory settings, with particular focus on the novel targeted agents that have overcome many adverse prognostic factors, improving overall survival.
Summary
It has long been understood that the immune system has intrinsic anti‐tumour activity in humans, and that a key mechanism of tumour progression is the ability of a tumour to escape this ...immune surveillance. A number of attempts have been made to harness this anti‐tumour immunity in both solid tumour oncology and haematological malignancies with variable success. Examples include the use of allogeneic stem cell transplantation and donor lymphocyte infusion in haematological cancer and vaccine studies in solid tumours. Enhanced signalling of the Programmed cell death‐1 (PDCD1, PD‐1)/cytotoxic T‐lymphocyte‐associated protein 4 (CTLA4) ‘immune checkpoint’ pathway has emerged recently as a critical mechanism by which tumours can escape the natural anti‐tumour immune response. As such, novel therapies have been developed to help enhance this natural immunity by switching off the PDCD1/CTLA4 immune checkpoint pathway. The following review will discuss the pathobiology of these pathways and the exciting new data now available in lymphoid malignancies.
Summary
Patients with mantle cell lymphoma progressing on Bruton’s tyrosine kinase inhibitor (BTKi) have very poor prognosis and there is currently no standard of care. In this retrospective cohort ...study, patients progressing on BTKi received R‐BAC (rituximab, bendamustine, cytarabine). Overall response rate was 83% (complete response 60%) and 31% were bridged to allogeneic stem cell transplant (alloSCT). Median progression‐free survival was 10.1 months (95% confidence interval (CI) 6·9–13·3) and median overall survival was 12·5 months (95% CI 11·0–14·0). In those consolidated with alloSCT only one patient relapsed. R‐BAC demonstrates a high response rate in the post‐BTKi setting and in transplant eligible patients is an effective bridge to alloSCT.
With survival outcomes ever improving for patients with a wide range of lymphoma histologies, the focus on reducing long‐term complications of therapy has increased. Recently published, complimentary ...population and retrospective series have highlighted the importance of considering bone health in patients treated for lymphoma. Fracture‐related events or the requirement for secondary bone prophylaxis, likely linked to glucocorticoid‐induced osteoporosis (GIO) are substantial and clinically meaningful in a significant minority of patients following routinely employed steroid‐containing immunochemotherapy. In this review, we describe the pathophysiology of GIO, the risk of GIO in observational front‐line lymphoma studies and efficacy of prophylactic measures from several prospective clinical trials are summarized. Finally, areas of importance for future research are discussed and recommendations for GIO risk assessment and management in lymphoma are provided based on the current available literature.
Summary
Immune responses to primary COVID‐19 vaccination were investigated in 58 patients with follicular lymphoma (FL) as part of the PETReA trial of frontline therapy (EudraCT 2016–004010‐10). ...COVID‐19 vaccines (BNT162b2 or ChAdOx1) were administered before, during or after cytoreductive treatment comprising rituximab (depletes B cells) and either bendamustine (depletes CD4+ T cells) or cyclophosphamide‐based chemotherapy. Blood samples obtained after vaccine doses 1 and 2 (V1, V2) were analysed for antibodies and T cells reactive to the SARS‐CoV‐2 spike protein using the Abbott Architect and interferon‐gamma ELISpot assays respectively. Compared to 149 healthy controls, patients with FL exhibited lower antibody but preserved T‐cell responses. Within the FL cohort, multivariable analysis identified low pre‐treatment serum IgA levels and V2 administration during induction or maintenance treatment as independent determinants of lower antibody and higher T‐cell responses, and bendamustine and high/intermediate FLIPI‐2 score as additional determinants of a lower antibody response. Several clinical scenarios were identified where dichotomous immune responses were estimated with >95% confidence based on combinations of predictive variables. In conclusion, the immunogenicity of COVID‐19 vaccines in FL patients is influenced by multiple disease‐ and treatment‐related factors, among which B‐cell depletion showed differential effects on antibody and T‐cell responses.
The NCRI phase III PETReA trial provided a unique opportunity to investigate COVID‐19 vaccine responses in a well‐defined, uniformly treated cohort of patients with FL undergoing initial therapy. By analysing immune responses after the first (V1) and second (V2) COVID‐19 vaccine, we found antibody, but not T‐cell, responses to be impaired in patients with FL undergoing frontline therapy. Furthermore, upon relating vaccine responses to a range of clinical variables, we observed that both types of response are influenced by disease‐ and treatment‐related factors, and that some of these factors have differential effects on humoral and cellular immunity.
Summary
Idelalisib (IDL) is an oral first‐in‐class phosphatidylinositol 3‐kinase delta (PI3Kδ) inhibitor approved for chronic lymphocytic leukaemia (CLL) alongside rituximab (R) since 2014. However, ...little data exist on routine practice. The RETRO‐idel was a protocol‐led, retrospective study of 110 patients n = 27 front‐line (1L) who received IDL‐R. The primary end‐point was clinical overall response rate (ORR). The median (range) follow‐up of the whole cohort was 30·2 (0·1–51·9) months. The median (range) age was 72 (48–89) years. Tumour protein p53‐disruption was common 100% 1L, 32·5% relapsed/refractory (R/R). The best ORR (intention‐to‐treat) was 88·2% (1L 96·3%, R/R 85·5%). Overall, the median event‐free survival (mEFS) was 20·3 months and time‐to‐next treatment was 29·2 months. The mEFS for 1L patients was 18·7 months and R/R patients was 21·7 months. The 3‐year overall survival was 56·1% (95% confidence interval 45·7–65·3). IDL was discontinued in 87·3% (n = 96). More patients discontinued due to adverse events in the front‐line setting (1L 63·0% vs. R/R 44·6%) and due to progressive disease in R/R patients (20·5% vs. 3·7% in 1L). Lower respiratory tract infection/pneumonia were reported in 34·5% (Grade ≥3, 19·1%), diarrhoea in 30·9% (Grade ≥3, 6·4%), and colitis in 9·1% (Grade ≥3, 5·5%). Overall, these data describe clear efficacy for IDL‐R in routine practice. No new safety signals were identified, although careful management of known toxicities is required.
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