Fast Facts: Chronic Lymphocytic Leukemia

Lindsey E. Roeker, Parag Jasani, Toby A. Eyre

Description

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. Table of Contents • Epidemiology and etiology • Molecular biology and genetics • Diagnosis, staging and prognosis • Management • Research directions

Sujets

• Hermatology
• Medical
• Médecine
• Oncology
• General officer
• Hematology
• General

Informations

• Publié par: S. Karger AG
• Date de parution: 07 juin 2023
• Nombre de lectures: 0
• EAN13: 9783318072303
• Langue: English

Extrait

Fast Facts: Chronic Lymphocytic Leukemia
First published 2022
Second edition 2023
Text 2023 Toby A Eyre, Parag Jasani, Lindsey E Roeker
2023 in this edition S. Karger Publishers Ltd
S. Karger Publishers Ltd, Merchant House, 5 East St Helen Street, Abingdon, Oxford OX14 5EG, UK
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ISBN 978-3-318-07160-3
Eyre TA (Toby)
Fast Facts: Chronic Lymphocytic Leukemia/
Toby A Eyre, Parag Jasani, Lindsey E Roeker
Medical illustrations by Graeme Chambers, Belfast, UK.
Typesetting by Amnet, Chennai, India.
Printed in the UK with Xpedient Print.
This publication was made possible by a contribution from BeiGene. BeiGene did not have any influence over the content and all items were subject to independent peer and editorial review.
Contents
List of abbreviations
Introduction
Epidemiology and etiology
Molecular biology and genetics
Diagnosis, staging and prognosis
Management
Research directions
Useful resources
Index
List of abbreviations
AE: adverse event
AF: atrial fibrillation
AIHA: autoimmune hemolytic anemia
alloSCT: allogeneic (hematopoietic) stem cell transplantation
Bcl-2: B-cell lymphoma 2
BCR: B-cell receptor
BCRi: B-cell receptor (pathway) inhibitor
BR: bendamustine and rituximab
BTK: Bruton tyrosine kinase
CAR: chimeric antigen receptor
CBC: complete blood count
CK: complex karyotype
CLL: chronic lymphocytic leukemia
CLL-IPI: CLL International Prognostic Index
CMV: cytomegalovirus
DLBCL: diffuse large B-cell lymphoma
ECOG: Eastern Cooperative Oncology Group
EMA: European Medicines Agency
FCR: fludarabine, cyclophosphamide and rituximab
FDA: (US) Food and Drug Administration
FISH: fluorescence in situ hybridization
GBD: Global Burden of Disease (study)
Ig: immunoglobulin
IL: interleukin
IPS-E: International Prognostic Score for Early-stage CLL
ITP: immune-related thrombocytopenia
IVIG: intravenous immunoglobulin (replacement therapy)
iwCLL: International Workshop on CLL (response criteria)
LDH: lactate dehydrogenase
LDT: lymphocyte doubling time
MBL: monoclonal B-cell lymphocytosis
M-CLL: mutated CLL
MRD: measurable residual disease
MSC: mesenchymal stromal cell
NF- B: nuclear factor kappa B
NGS: next-generation sequencing
NK: natural killer (cell)
NLC: nurse-like cell
ORR: overall response rate
OS: overall survival
PCP: Pneumocystis carinii pneumonia
PET: positron emission tomography
PFS: progression-free survival
PI3K: phosphoinositide 3 kinase
R/R: relapsed or refractory
RT: Richter transformation
SHM: somatic hypermutation
SLL: small lymphocytic lymphoma
SYK: spleen tyrosine kinase
TLS: tumor lysis syndrome
TNF: tumor necrosis factor
U-CLL: unmutated CLL
Introduction
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.
Herein, we cover the epidemiology, etiology, diagnosis and staging of the disease, and the molecular and genetic aspects that underpin treatment and prognosis. Importantly, we provide 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.
We also consider the role of allogeneic hematopoietic stem cell transplantation, which offers curative potential in selected young high-risk patients for whom targeted agents may eventually fail, and we provide guidance on the management of common complications associated with CLL, including tumor lysis syndrome, infection, autoimmune cytopenias and Richter transformation.
While huge strides have been made in the management of CLL, new approaches are still being developed to enhance the depth and durability of treatment responses. We look at these, and other important research directions, in the final chapter of the book.
We hope that this resource will provide all members of the multidisciplinary team who care for patients with CLL with a strong foundation for understanding, diagnosing and managing CLL in the present and future.
1 Epidemiology and etiology
Definitions
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are monoclonal B-cell malignancies characterized by an accumulation of mature CD5+ B lymphocytes. CLL and SLL are leukemic and lymphomatous manifestations of the same biological entity. For patients with a persistent level of more than 5000 clonal B lymphocytes per microliter in the peripheral blood for at least 3 months, the diagnosis of CLL is made regardless of lymph-node involvement. For patients with SLL, clonal B lymphocytes drive lymphadenopathy and/or splenomegaly, but the number of clonal B lymphocytes in the peripheral blood is fewer than 5000 per microliter ( Figure 1.1 ). 1 , 2
Monoclonal B-cell lymphocytosis (MBL) is a premalignant condition characterized by fewer than 5000 clonal B lymphocytes per microliter in the peripheral blood with no lymphadenopathy, splenomegaly or disease-related cytopenias. 1 Population-based screening studies show that the prevalence of MBL increases with age; it occurs in 0.2-0.3% of people under 40 years of age, but 5-9% of those over 60 years old. 3 , 4 MBL carries a 1-2% risk of progression to CLL requiring therapy per year. 5 , 6

Figure 1.1 Defining features of CLL, SLL and MBL.
Epidemiology
CLL is the most diagnosed leukemia in the Western world, accounting for approximately 25% of all new leukemia diagnoses.
Incidence and prevalence. Data from the Global Burden of Disease (GBD) study for 2019 reported 20 723 and 27 560 new cases of CLL in high-income North America and Western Europe, respectively. Globally, there were 103 467 people diagnosed with CLL in 2019. 7 In the UK, there were around 3800 new cases per year in 2016-2018. 8 Given the chronic nature of CLL, prevalence is much higher: for example, there were 200 766 people living with CLL in the USA in 2019. 9
For the general population, the incidence is approximately 5 per 100 000 per year, though there is a male predominance in newly diagnosed patients. 7-9 In the USA, CLL is most frequently diagnosed in White individuals compared with other ethnicities ( Figure 1.2 ). 9 The same has been shown in England, where 86% of cases of CLL in 2013-2017 occurred in White individuals compared with 1.9% in Asian and 0.9% in Black individuals. 10

Figure 1.2 Rates of new cases in the USA per 100 000 men and women by race/ethnicity. Adapted from age-adjusted National Cancer Institute Surveillance, Epidemiology, and End Results data, 2015-2019. 9 * Non-Hispanic.

Globally, age-standardized incidence of CLL increased by 155% between 1990 and 2019. 7 However, in the USA, age-adjusted rates for new CLL diagnoses have been falling on average by 2.1% each year over the past decade. 9
Incidence rises with age, and the median age at diagnosis is around 70 years. The GBD data showed that, worldwide, the highest incidence of new CLL cases was in people aged 60-75 years. 7 US data have suggested racial differences in age at diagnosis, as Black patients were diagnosed at a median age of 67 years compared with 70 years for White patients. 11
Mortality. Globally, 44 613 people died of CLL in 2019, with 6696 and 10 043 deaths in North America and Western Europe, respectively. 7 In the UK, there were around 980 deaths from CLL every year in 2017-2019. 8 Worldwide, the number of deaths from CLL increased by 107% between 1990 and 2019, but the age-adjusted mortality rate decreased on average by 0.34% per year, with the USA having the most significant decrease over time. 7
Risk factors
Environmental. The underlying risk factors leading to CLL development are not completely understood. Agent orange exposure and residential radon exposure have been linked to the development of CLL. 12 , 13 Certain professionals, including farmers and workers in the rubber industry, have been noted to have a higher incidence of the disease than expected, although exposure associations have been inconsistent or not definitively proven. 14 - 17 While many potential links between environmental exposures and CLL development have been investigated, other significant associations have not been discovered.
Genetic. Familial risk has been described: 5% o