Richter transformation (RT) represents an uncommon (2% to 10%) but feared complication of chronic lymphocytic leukemia (CLL). The disease is characterized by rapid disease kinetics, a high-risk ...genetic mutational profile, chemoimmunotherapy resistance, and consequent poor survival. The typical overall survival (OS) from the pre-Bruton tyrosine kinase (BTK)/B-cell lymphoma 2 (BCL2) inhibitor CLL era is 6-12 months, and recent series of RT complicating progression on a BTK or BCL2 inhibitor in heavily pretreated relapsed CLL patients suggests an OS of only 3-4 months. Despite these sobering survival statistics, novel agents have the potential to impact the natural RT disease course. This article reviews recent therapeutic developments, focusing on inhibitors of BTK, BCL2, the PD1-PDL1 axis, and T-cell-activating/engaging therapies. Herein, I discuss the importance of randomized clinical trials in a disease where small single-arm studies dominate; industry engagement, including the role of registrational studies; and the need to integrate prospectively planned correlative biological studies embedded within future clinical trials to help discover which patient benefits most from each class or combination of novel targets.
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.
Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma in which immunochemotherapy, with or without high-dose therapy, and autologous stem cell transplantation remain standard ...frontline therapies. Despite their clear efficacy, patients inevitably relapse and require subsequent therapy. In this review, we discuss the key therapeutic approaches in the management of relapsed MCL, covering in depth the data supporting the use of covalent Bruton tyrosine kinase (BTK) inhibitors at first or subsequent relapse. We describe the outcomes of patients progressing through BTK inhibitors and discuss the mechanisms of covalent BTKi resistance and treatment options after covalent treatment with BTKi. Options in this setting may depend on treatment availability, patient's and physician's preference, and the patient's age and comorbidity status. We discuss the rapid recent development of anti-CD19 chimeric antigen receptor T-cell therapy, as well as the utility of allogenic stem cell transplantation and novel therapies, such as noncovalent, reversible BTK inhibitors; ROR1 antibody drug conjugates; and bispecific antibodies.
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Summary
High‐grade transformation of chronic lymphocytic leukaemia Richter syndrome (RS) is rare and represents a unique and uncommon clinical challenge. Clonally related diffuse large B cell type RS ...is a chemotherapy‐resistant and devastating disease. Patients are typically elderly, immunosuppressed and present with a rapidly deteriorating performance status. Historical outcomes suggest a median overall survival of approximately 8 months. RS remains is an area of high unmet clinical need. The molecular profile and treatment needs of patients are likely to change over time with the advent of novel B cell receptor inhibitors, monoclonal antibodies and BH3 mimetics. Herein, we summarise what is known regarding the molecular drivers of RS and the existing clinical trial data, including the recently published CHOP‐OR (cyclophosphamide, doxorubicin, vincristine, prednisolone and ofatumumab followed by ofatumumab maintenance in newly diagnosed RS) trial. We discuss novel agents in development with a focus on the second‐generation Bruton tyrosine kinase inhibitor acalabrutinib, checkpoint inhibition and the potential role of precision medicine in future trials of RS.
Richter transformation (RT) refers to the development of an aggressive lymphoma in patients with underlying chronic lymphocytic leukemia/small lymphocytic lymphoma. Aside from a small subgroup of ...patients with clonally unrelated and previously untreated chronic lymphocytic leukemia, the disease responds poorly to standard therapies and prognosis is dismal. Recent developments in the understanding of the biology of RT and the advent of several targeted agents may result in improved outcomes for these patients. The purpose of this review is to analyze recent data on the pathogenesis and treatment of RT. We reviewed studies addressing the pathophysiology of RT and analyzed the data for frontline chemoimmunotherapy and emerging targeted therapies likely to play a significant role in the future management of RT. Several biologic and clinical factors may help identify those who are unlikely to respond to conventional chemoimmunotherapy; where possible, these patients should be managed with a novel approach. Emerging therapies for the management of RT include chimeric antigen receptor T-cell therapy, noncovalent Bruton tyrosine kinase inhibitors, and T-cell-engaging bispecific antibodies. The use of less toxic and more effective targeted therapies may result in improved outcomes. Larger, prospective clinical trials are required to confirm efficacy and safety of novel agents for the management of RT, particularly when used in combination with other targeted therapies and in addition to chemoimmunotherapy regimens.
Summary
Mantle cell lymphoma (MCL) is a mature B‐cell lymphoma with a variable clinical course and historically poor prognosis. Management is challenging in part due to the heterogeneity of the ...disease course, with indolent and aggressive subtypes now well recognised. Indolent MCL is often characterised by a leukaemic presentation, SOX11 negativity and low proliferation index (Ki‐67). Aggressive MCL is characterised by rapid onset widespread lymphadenopathy, extra‐nodal involvement, blastoid or pleomorphic histology and high Ki‐67. Tumour protein p53 (TP53) aberrations in aggressive MCL are recognised with clear negative impact on survival. Until recently, trials have not addressed these specific subtypes separately. With the increasing availability of targeted novel agents and cellular therapies, the treatment landscape is constantly evolving. In this review, we describe the clinical presentation, biological factors, and specific management considerations of both indolent and aggressive MCL and discuss current and potential future evidence which may help move to a more personalised approach.
The transformation of chronic lymphocytic leukemia (CLL) to high-grade B-cell lymphoma is known as Richter syndrome (RS), a rare event with dismal prognosis. In this study, we conducted whole-genome ...sequencing (WGS) of paired circulating CLL (PB-CLL) and RS biopsies (tissue-RS) from 17 patients recruited into a clinical trial (CHOP-O). We found that tissue-RS was enriched for mutations in poor-risk CLL drivers and genes in the DNA damage response (DDR) pathway. In addition, we identified genomic aberrations not previously implicated in RS, including the protein tyrosine phosphatase receptor (PTPRD) and tumor necrosis factor receptor–associated factor 3 (TRAF3). In the noncoding genome, we discovered activation-induced cytidine deaminase–related and unrelated kataegis in tissue-RS affecting regulatory regions of key immune-regulatory genes. These include BTG2, CXCR4, NFATC1, PAX5, NOTCH-1, SLC44A5, FCRL3, SELL, TNIP2, and TRIM13. Furthermore, differences between the global mutation signatures of pairs of PB-CLL and tissue-RS samples implicate DDR as the dominant mechanism driving transformation. Pathway-based clonal deconvolution analysis showed that genes in the MAPK and DDR pathways demonstrate high clonal-expansion probability. Direct comparison of nodal-CLL and tissue-RS pairs from an independent cohort confirmed differential expression of the same pathways by RNA expression profiling. Our integrated analysis of WGS and RNA expression data significantly extends previous targeted approaches, which were limited by the lack of germline samples, and it facilitates the identification of novel genomic correlates implicated in RS transformation, which could be targeted therapeutically. Our results inform the future selection of investigative agents for a UK clinical platform study. This trial was registered at www.clinicaltrials.gov as #NCT03899337.
•RS is a rare complication of CLL with dismal prognosis, as well as an area in which effective therapies are sorely needed.•WGS and RNA expression profiling of paired CLL and RS samples reveals clinically targetable genes and pathways in RS transformation.
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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.
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