Chronic Lymphocytic Leukaemia

The causes The causes of CLL are largely unknown. However, research has focused on some factors that may contribute to the development of malignancies, including genetic factors, impaired immune system and viruses. Scientists have established that CLL occurs in males more often than females and in white populations more often than Asian populations but the precise cause for this cannot be explained. Some families are more likely to have cases of CLL without having a defined genetic alteration.


2
Chronic Lymphocytic Leukaemia Subtype Report · LymphomaCoalition.org · © 2022 Lymphoma Coalition Overview Chronic lymphocytic leukaemia (CLL) is a mostly incurable cancer arising from the lymphocytes (white blood cells). 1 The clinical course of CLL is extremely variable, ranging from a slow-growing (indolent) disease not requiring treatment, sometimes never, to one that progresses rapidly (aggressive) and is resistant to treatment. 1 CLL typically affects older adults. Most cases of CLL are diagnosed in patients over the age of 55 years, with only approximately 10% of CLL cases being diagnosed in patients younger than 55 years.² Over the last decade, there has been significant progress in CLL therapy and many new treatment options are available. Mainly, the development of novel (new) targeted therapies has improved treatment outcomes for many patients. 3 Additionally, there are now more accurate tests that can reliably define high-risk disease and guide treatment choice. 3 The changing therapy landscape in CLL has made managing CLL more effective yet more challenging. 3 There is no gold standard first-or second-line therapy regimens or further lines of therapy for CLL, and optimal therapy sequencing has not been established. With so many treatment options now available, doctors and patients are having to make very complex treatment decisions.
Chronic Lymphocytic Leukaemia Subtype Report · LymphomaCoalition.org · © 2022 Lymphoma Coalition 3 The focus of this report is to: • Provide a current understanding of CLL • Explain the diagnosis and pre-treatment process Major gaps that must be addressed in the treatment and care of patients with CLL include: • First-line treatment requires optimisation to reduce the number of patients who develop disease relapse and need subsequent therapy.
• Therapy sequencing strategies must be optimized for existing and new treatments, in second line and beyond.
• Access to testing for genetic mutations, markers, and chromosomal abnormalities should be improved to ensure that all patients receive the best possible treatment.
• Access to targeted therapies must be improved globally as certain forms of CLL (e.g., del(17p) and/or TP53 mutation, unmutated IGHV) respond poorly to chemoimmunotherapy.
• There is a continued need for better treatment options with fewer toxicities in all lines of therapy.
• Improved treatment options are needed for the diffuse large B-cell (DLBCL) variant of Richter's Transformation.
• There is a promising role for minimal residual disease (MRD) testing in treatment response assessment for CLL, but this needs to be defined for routine use in the clinic.
• A consensus guideline for the management of patients with CLL during the Covid-19 pandemic (and future pandemics) must be established, and clarity surrounding Covid-19 immunisation and care strategies for this patient population are needed.
• Patients with CLL require more support to manage both physical/medical issues (especially fatigue) and psychosocial issues. Patients in active surveillance require more support for specific psychosocial issues (e.g., fear of disease progression, anxiety, depression).
• There continues to be room for improvement in patient-doctor communication.
Words highlighted in dark bold are defined in the glossary at the end of the report. Lymphocytes circulate in the body through a network referred to as the lymphatic system (figure 1). The organs and vessels of the lymphatic system work together to help fight infections throughout the body. CLL is characterised by the accumulation of mature, clonal B cells (many copies of the same abnormal B cell) in the blood, bone marrow, lymph nodes, and other lymphoid tissues. 1 These leukaemic B cells typically express a protein on their surface called CD5, which is not expressed on healthy B cells. 1 The CLL grow and survive better than normal cells, which means that over time, the clonal B cells begin to crowd out healthy blood cells (e.g., red cells, white cells, platelets) in the bone marrow. When there are large amounts of cancerous cells or not enough healthy blood cells, symptoms of CLL may begin to appear (e.g., fatigue, infections, bruising/bleeding). 6 CLL is often grouped together with small lymphocytic lymphoma (SLL) because they are considered different versions of the same disease based on current knowledge and technology. CLL and SLL are disorders of the same B cell, and they look the same under a microscope. The difference between CLL and SLL is where the cancer cells predominately collect.⁷ In CLL, cancer cells are mostly found in the blood and bone marrow.⁷ In SLL, cancer cells are mostly found in the lymph nodes.⁷ The clinical course of CLL is extremely variable. 1 Some people have CLL that grows slowly (indolent) and does not require treatment, while other people have CLL that progresses rapidly (aggressive) and is resistant to treatment. 4,[9][10][11] For some patients, CLL can change into a faster-growing (aggressive) cancer. This is call Richter's Transformation (RT), and it occurs in approximately 2% to 10% of patients with CLL. 13 Most often, CLL that undergoes RT will present as diffuse large B-cell lymphoma (DLBCL) (approximately 90% of RT cases). If not DLBCL, CLL sometimes transforms into Hodgkin lymphoma (approximately 10% of RT cases). 14 While it is possible for patients with CLL to develop acute leukaemia and myelodysplastic syndrome, it is uncommon. 15 INCIDENCE CLL is the most common adult leukaemia in the Western world 1-3,9 , accounting for 25-30% of all types of leukaemia. 12 Males are more commonly affected by CLL than females. 1,3 CLL typically affects older adults; the median age of diagnosis is 72 years. 2 Only about 10% of CLL patients are reported to be younger than 55 years. 2 Because CLL incidence rates rise with age, it is likely the prevalence and mortality of CLL will continue to increase due to the ageing global population. 1 A recent study (Dong et al.) used the Global Burden of Disease database to analyse international trends in the age-standardised incidence rate (ASIR) of CLL from 1990 to 2017. This study revealed the number of CLL cases globally more than doubled between 1990 and 2017, and most regions experienced a significant increase in the incidence rate of CLL. 16 The greatest increase was observed in East Asia, followed by Southeast Asia and Eastern Europe. 16 At a national level, more than 85% of all countries included in the analysis experienced an increase in CLL incidence between 1990 and 2017. 16 Additionally, the incidence of CLL was markedly higher in developed countries in 2017, with the highest incidences being observed in the United Kingdom, Denmark, and Slovakia (figure 2). 16 ASIR values are shown as 10^5 (values for every 100,000 population). For example, >2.00 means the age-standardised incidence rate of CLL was more than 2 for every 100,000 people in that country in 2017.

SIGNS AND SYMPTOMS
Many people with CLL have no early symptoms and only become aware of the cancer through a routine blood test that detects absolute lymphocytosis (an increase in the number of lymphocytes in the bloodstream beyond the normal range).³ Approximately 70% of patients present in an early phase of the disease. 14 However, CLL can have a range of presentations with some patients feeling well and being fully active, and others experiencing disease-related symptoms.
Those who do have symptoms may experience 3-4,11 : • Approximately 5 to 10% of patients present with typical B-symptoms, which are an array of symptoms including unexplained weight loss (more than 10% of body weight), drenching night sweats and fever without a known cause.³

RISK FACTORS
Despite extensive research, it is not certain what causes CLL. Recently, it has been reported that the the initiation of the changes underlying CLL may be acquired at the haematopoietic stem cell stage. 1 Haematopoietic stem cells are immature cells found in the bone marrow that can develop into all types of blood cells (e.g., white blood cell, red blood cell, platelets). In the development of CLL, it is suggested that the DNA (genetic material) of a developing haematopoietic stem cell is damaged, causing it to become cancerous and multiply. 1 Research has also shown that CLL can often be initiated by the addition or loss of large amounts of chromosomal material, which can be later followed by additional mutations that make the cancer more aggressive. 1  • Genetic factors: Genetic factors play a role in the development of CLL, with a six-to nine-fold increased risk for first-degree relatives of patients with CLL.² A family history of other blood and bone marrow cancers affecting B lymphocytes can can also increase a person's risk. 11 • Exposure to chemicals: Exposure to Agent Orange (used during the Vietnam war) has been associated with the development of CLL in some but not all studies. 11,15,18 Beyond this, CLL has generally not been associated with any other environmental or external risk factors. 10 The management of CLL is determined by the stage and activity of the cancer.

DIAGNOSIS
A complete blood count (CBC) with differential is the usual first step leading to a diagnosis. This routine test is often requested as an element of a check of a patient's general health status. The presence of at least 5,000 abnormal B cells per microlitre of blood (≥5,000 monoclonal B lymphocytes/µl) for at least three months is required to make the diagnosis. 1 However, in practice, if the lymphocyte count is slightly lower and there are other indications that the patient has CLL, clinicians will not wait another three months before retesting.
In 2016, the World Health Organization (WHO) modified its classification of lymphoid neoplasms. In 2008, it was unknown if monoclonal B-cell lymphocytosis (MBL) was a precursor of CLL. It is now clear that it is and that it precedes nearly all cases of CLL. The updated WHO guideline states that low-count MBL (peripheral blood monoclonal B lymphocyte count of <0.5 x 10 9 /L) must be differentiated from high-count MBL. Patients with high-count MBL are recommended to have yearly follow-up; those with low-count MBL rarely develop CLL. 19 As part of the diagnostic work-up, peripheral blood flow cytometry may be used to identify specific proteins that may be on the cell surface, such as CD5, CD19, CD20 and CD23, and to determine whether these cells are clonal. This is called immunophenotyping. 1,6 Specific diagnostic testing guidelines for CLL produced by the National Comprehensive Cancer Network (NCCN), the European Society for Medical Oncology (ESMO), and the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) can be found in Appendix I.

STAGING
The management of CLL is determined by the stage and activity of the cancer. Two widely accepted clinical staging systems are used to predict patient outcomes. 1 These staging systems use the results of physical examinations and blood counts. 1 In Europe, the Binet staging system is more widely used, whereas in North America, the Rai staging system is more commonly applied. Both systems recognise the importance of impairment of bone marrow function and define late-stage or high-risk disease through the presence of pronounced anaemia (low red blood cell count) or thrombocytopenia (low blood platelet count). In addition, both the Binet and Rai staging systems divide patients into three groups according to risk (table 1). 1 There is also a modified version of the Recently, there has been significant progress in CLL therapy, which has made these two clinical staging systems insufficient for classifying certain prognostic subgroups. 1 Numerous biological and genetic markers have been identified for CLL. These markers give prognostic information separate from the clinical stage. 1 To account for this, a new prognostic score called the CLL International Prognostic Index (CLL-IPI) was created (table 2). This score includes relevant clinical, biochemical, and genetic information and is a practical approach to treatment recommendation.³ Compared to the Binet and Rai clinical staging systems, the CLL-IPI more accurately identifies patients who do not require therapy. 1

PRE-TREATMENT TESTING
After CLL has been diagnosed, other tests that may have prognostic value and provide an overall idea of the patient's status prior to the start of treatment are conducted. These tests may include: • Physical exam and medical history • Genetic and cell protein tests (see next section) • Imaging (e.g., PET scan, x-ray, MRI, ultrasound) • Comprehensive metabolic panel, that provides information about a body's chemical balance and metabolism • Hepatitis B testing • Echocardiogram to check heart function, in select cases • Measurement of normal immunoglobin levels (for patients who develop repeated infections) • Bone marrow biopsy As CLL typically affects older adults, additional recommendations regarding other medical conditions and geriatric assessments should be followed to ensure patients receive the best therapy based on functional status, life expectancy, and predicted treatment tolerability. 21 While comprehensive geriatric assessment is recommended for patients 65 and older by the NCCN and by the International Society for Geriatric Oncology, there is still no consensus on an optimal validated tool for measuring the comorbidity burden in older patients with CLL. 21 For a full account of the pre-treatment testing recommended by the iwCLL, please see Appendix I.

PROGNOSTIC GENETIC MARKERS AND CHROMOSOMAL ABNORMALITIES FOR CLL
To help understand the concepts discussed below, please see Appendix II for a description of the biology basics relating to genetic markers, gene mutations, and chromosomal abnormalities.

Genetic Markers
Genes and their associated mutations are used to diagnose cancer and can also be prognostic about how the type of cancer may progress and/or predictive as to how the cancer may respond to available treatments.
The presence or absence of certain mutations can help guide the type of treatment a patient receives and predict how likely the cancer is to respond to certain drugs.
The following gene mutations and protein expressions have been identified in CLL and are currently used to determine best care: • IGHV (immunoglobulin heavy-chain variable): CLL is classified into two subgroups based on whether the CLL cells express a hyper-mutated version of the variable regions of the immunoglobulin heavy chain gene (IGHV). 12 The IGHV gene encodes antibodies that play a role in immune response. The developed of IGHV hypermutation occurs in the process of normal B cell development, specifically, when naïve B cells (a B cell that does not yet have a defined purpose) are changing into memory B cells (memory B cells provide protection against recurring infections). 12 -Patients whose CLL expresses a hypermutated IGHV have a more favourable prognosis than those with unmutated IGHV.
-Unmutated IGHV is associated with more aggressive disease, which often shows a shorter duration of response to chemotherapy-based treatment. 12 • TP53 (tumour protein 53): TP53 is an important tumour suppressor gene. 1 Patients with CLL which carries a mutation of TP53 have an inferior prognosis and the disease does not respond well to standard chemotherapy. 1,3 This mutation is detected in 4% to 37% of patients with CLL, with lower rates at initial diagnosis and increasing frequency with subsequent disease relapses. 1

Chromosomal Abnormalities
Identifying chromosomal abnormalities also plays a key role in understanding the prognosis of CLL and the likelihood of the CLL responding to different treatments.
A chromosomal abnormality can be a change in chromosome number (gains or losses of entire chromosomes), or a change in chromosome structure (irregular, missing, or extra part of DNA that makes up the chromosome).
There are four chromosomal abnormalities that are most frequently detected in CLL. Approximately 80% of patients with CLL carry at least one of these four abnormalities 22 , which include: 1) 17p deletion (del(17p)): Patients with CLL missing genetic material on the short arm of chromosome 17 are more likely to have an unfavourable prognosis. 3,22 The CLL of patients who carry this deletion is often resistant to traditional chemotherapy and chemo-immunotherapy. 1 This deletion is detected in only 5% to 8% of patients with CLL who have not received chemotherapy, but it becomes increasingly common when the disease recurs after multiple episodes of therapy. A patient may have both del(17p) and del(13q). 1 The 17p deletion nearly always includes the area where a major tumour suppressor gene (TP53) is located. 1 However, even if del(17p) is not present, it is still recommended to test separately for TP53 mutation.
2) 11q deletion: Patients with CLL who are missing genetic material on the long arm of chromosome 11 are more likely to have an unfavourable prognosis if treated with chemotherapy.³ Some of the poor prognostic features seem to be overcome by the use of chemoimmunotherapy (adding an anti-CD20 antibody to the chemotherapy). 1 The 11q deletion is found in approximately 25% of patients with advanced disease stages who have not received chemotherapy, and 10% of patients with early stage disease. 1

3) Trisomy 12:
Patients with CLL who have an extra copy of chromosome 12 are more likely to have an unfavourable prognosis when there is a coexisting NOTCH1 mutation. 22 Additionally, trisomy 12 increases the risk of Richter's Transformation, which has a poor prognosis. Trisomy 12 is detected in 10% to 20% of all CLL cases. 1

4) 13q14 deletion:
Patients with CLL missing genetic material on the long arm of chromosome 13 have a more favourable prognosis (i.e., a more benign course of disease) if the 13q deletion is their only genetic abnormality. 1,22 The 13q14 deletion is the most frequently observed chromosomal abnormality in CLL 12

INITIATING TREATMENT
Not all patients with CLL require treatment when they are first diagnosed. Instead, patients with asymptomatic early or intermediate stage disease are placed in active surveillance where they are re-assessed at one-to-threemonth intervals.³ When the patient's disease progresses or symptoms appear, treatment should be initiated. 1 The iwCLL guidelines define criteria for symptomatic or active disease. At least one of the following criteria should be met in order to initiate treatment 1,3 : • Evidence of progressive bone marrow failure with symptomatic anaemia (haemoglobin <10g/dL) or a low platelet count (<100 x 109/L) • Progressive lymphocytosis • Enlarged spleen (massive, progressive, or symptomatic) • Enlarged lymph nodes (massive, progressive, or symptomatic) • Symptomatic extranodal involvement (e.g., skin, kidney, lung, spine) • Autoimmune complications (e.g., anaemia, thrombocytopenia) that respond poorly to corticosteroids Within chemotherapy, different kinds of chemotherapy are used depending on the situation. These include purine analogues like fludarabine or pentostatin, and alkylating agents such as chlorambucil, cyclophosphamide or bendamustine.³ A patient may receive a purine analogue as part of their therapy if they are in good health and have good kidney function, but if their health is poor, they may receive an alkylating agent without a purine analogue.⁶ Chemoimmunotherapy includes the use of anti-CD20 monoclonal antibodies, immune system proteins made in a laboratory (such as rituximab, obinutuzumab or ofatumumab) in combination with chemotherapy.³ The antibodies attach to a specific target on cancer cells called CD20. Once attached, the antibodies kill the cells, block their growth, or keep them from spreading.⁴ Monoclonal antibodies can sometimes also be used alone without chemotherapy, but this is significantly less effective than their use in combination.
Targeted therapies are treatments that target the signalling pathways within a cell that promote the growth and/or survival of CLL cells. B C cell receptor (BCR) signalling plays a central role in CLL initiation and disease progression.⁸ There are three main classes of drug that can inhibit BCR signalling: • Bruton's tyrosine kinase (BTK) inhibitors (e.g., ibrutinib, acalabrutinib, zanubrutinib) • Phosphatidylinositol 3-kinase (PI3K) inhibitors (e.g., idelalisib, duvelisib) • Spleen tyrosine kinase (SYK) inhibitors (e.g., fostamatinib) The introduction of new therapy options in recent years has changed the treatment landscape for CLL and improved care for some hard-to-treat prognostic subgroups.

15
The B cell lymphoma 2 (BCL-2) protein is another target for CLL targeted therapies. BCL-2's role is to promote cell survival and inhibit the action of proteins that would otherwise cause cells to die. BCL-2 is overexpressed in CLL and helps CLL cells survive.³ Drugs that target this protein (e.g., venetoclax) directly reduce its function, and activate proteins that help with programmed cell death (i.e., killing CLL cells).³ A key feature currently directing the choice of therapy in CLL is the presence of either del(17p) (missing parts of chromosome 17) or mutated TP53 (tumour suppressor gene). As well, in patients who are less fit, the presence of comorbidities and the goal of treatment will play an important role in the choice of therapy. 15

FIRST-LINE TREATMENT
For the purpose of this review and to determine what treatment protocols should be accessible to patients with CLL, LC reviewed the information from both the NCCN and ESMO clinical practice guidelines for CLL.
In both guidelines, options for first-line treatment are grouped first by whether del(17p) or a TP53 mutation is present (table 3). The presence of del (17p) and/or TP53 are associated with decreased survival and impaired response to chemoimmunotherapy. 24 They are among the strongest predictive markers guiding treatment decisions in CLL, hence why the guidelines are organised this way. 24 .
For patients who do not have del(17p) or TP53, treatment recommendations are further subdivided for 'fit' and 'frail' patients. In the United States, fit patients are generally defined as those under 65 years of age who have a good performance status.
As was earlier noted, another major subgroup classification of patients with CLL is IGHV mutated vs unmutated. Though the NCCN and ESMO treatment guidelines are not organised based on this classification, IGHV mutation status does influence choice of therapy for CLL. Specifically, patients with mutated IGHV are better candidates for chemoimmunotherapy, while patients with unmutated IGHV are more likely to benefit from novel therapy approaches (e.g., targeted therapy).⁹ According to the NCCN guidelines, ibrutinib is the preferred first-line treatment for CLL, especially for older patients.⁶ Both guidelines suggest its use for CLL with and without del(17p) or mutated TP53. Ibrutinib is a BTK inhibitor, a targeted therapy that blocks Bruton's tyrosine kinase (BTK). This helps stop CLL cells from surviving and multiplying. There are newer BTK inhibitors that may have fewer or different side effects than ibrutinib (like acalabrutinib or zanubrutinib).
In both guidelines, targeted therapies are the preferred treatment for patients who have CLL with del(17p) or mutated TP53. Therapies that inhibit BCL-2 and PI3K (as described previously) can be considered, in addition to BTK inhibitors.
For CLL without del(17p) or mutated TP53, chemoimmunotherapy is a common treatment, especially for younger fit patients. 2,6 Patients who are younger than 65 years of age and healthy may be treated with fludarabine-based chemoimmunotherapy (e.g., FCR); however, with fludarabine treatment there is a risk of serious infections. 2,6 Bendamustine or chlorambucil combined with a CD20 antibody may be an option as they generally have a more tolerable side effect profile.
There are several Phase III clinical trials investigating BTK inhibitors (e.g., ibrutinib) as front-line therapy compared to chemoimmunotherapy. Ibrutinib (alone or in combination with CD20 antibodies) yielded a longer progression-free survival (PFS) when compared with fixed duration chemoimmunotherapy (FCR, bendamustine + rituximab , chlorambucil + obinutuzumab) in two Phase III trials. [25][26] However, currently patients need to take ibrutinib until the disease progresses or they have to stop taking the drug due to the impact of the side effects. Another Phase III trial compared ibrutinib plus rituximab versus FCR in young, fit patients and found that an overall survival (OS) benefit might exist for those treated with ibrutinib plus rituximab. 27 The final results of these trials may change current practice.

TREATMENT RESPONSE
Treatment response is assessed during and at the end of treatment using physical exams and blood tests.
There are four types of treatment response 6 : 1) Complete remission: No cancer symptoms, blood counts within normal range, enlarged lymph nodes and organs return to normal size and no detectable disease in the bone marrow with routine testing 2) Partial remission: Blood counts are returning to normal and the size of enlarged lymph nodes and organs has been greatly reduced or normalised, but there is still some disease present in the bone marrow 3) Stable disease: Less than partial remission, the cancer is not getting worse

4) Progressive disease:
The cancer is getting worse

Sometimes, even if a patient has achieved a complete clinical response (i.e., remission), a very small number of cancer cells can remain in the blood or bone marrow after treatment. This is called minimal residual disease (MRD). 6
Many studies have found that MRD status (positive or negative/undetectable) has prognostic significance among patients with CLL who achieve a complete or partial response to treatment. Specifically, MRD-negativity is associated with longer progression free survival (PFS) and overall survival (OS). [28][29][30] Over the last decade, MRD assessment has been increasingly implemented as a surrogate end-point in CLL clinical trials. 31 However, the role of MRD assessment in routine clinical practice has not yet been well defined. 28 There may be a role for MRD-guided treatment approaches in CLL, which may allow for more individualised therapy with better patient outcomes and fewer treatment toxicities. 28 For MRD treatment response assessment or MRD-guided treatment approaches to become clinical realities, the weaknesses that exist in current MRD assessment methods must be eliminated, and more sensitive methods developed that can detect MRD beyond the bone marrow and peripheral blood. 28 MRD testing methods have to become broadly applicable, accurate, reliable, fast to process and affordable before they can be widely adopted.

SUBSEQUENT TREATMENT
Most treated patients with CLL will develop relapsed disease and require subsequent therapy. 32 Disease relapse is when the cancer returns after it has been in remission for more than six months. When this happens, patients may not require treatment immediately. If treatment is needed, patients may receive the same or a different type of treatment than they were given before. 6 The goal of treatment would be to achieve remission again.
Refractory disease is when the cancer is not in remission at the end of treatment, or when the disease comes back within six months after treatment completion. 6 A different treatment is usually tried in these cases, and good results are often achieved. 6 Before starting subsequent treatment, the doctor should retest the cancer again to see if there have been any changes in genetic mutations. 31 For the purpose of this review and to determine which second-line and subsequent treatment protocols should be accessible to patients with CLL, LC reviewed the information from both the NCCN and ESMO clinical practice guidelines for CLL (table 4).
In both guidelines, options for second-line treatment are grouped first by whether del(17p) or a TP53 mutation is present (  For those with transformed HL, it has a good response rate to the chemotherapy regimen ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Because bleomycin exposure can cause serious pulmonary toxic effects, it can be omitted after two cycles of ABVD if an interim PET scan shows a negative Deauville score. 14 If the interim PET is positive, escalation to a different chemotherapy regimen called BEACOPP is an option for younger, healthy patients. For older, unfit patients, adding radiotherapy is an option. The HL variant of RT generally has a better prognosis as there is a better response to the available HL treatments. 14

21
Chronic Lymphocytic Leukaemia Subtype Report · LymphomaCoalition.org · © 2022 Lymphoma Coalition Access to targeted therapy regimens must be improved globally.

Therapy Access
To determine the availability of CLL therapies globally, Lymphoma Coalition (LC) looked at access to select chemoimmunotherapy and targeted therapy regimens in LC member countries. Therapies were chosen for inclusion based on current standards of care outlined in the NCCN and ESMO treatment guidelines for CLL. These included: Accessibility was defined as 'therapy being available to a patient through public healthcare'. If a treatment is marked as inaccessible, it means that the therapy is not funded in that country.
Detailed information on therapy access can be found in Appendix IV (by-country and grouped regionally).
When examined regionally (Europe, North America, South America, Asia-Pacific, Middle East, and Africa), though some data could not be found, all of the chemoimmunotherapy regimens appear to be readily accessible across all the regions.
There are a few exceptions, including: 1) Obinutuzumab-chlorambucil is not accessible in Columbia, Uruguay, or South Africa; 2) Bendamustine-rituximab is not accessible in South Africa; and 3) Bendamustine-rituximab is only accessible through special access programs in Czech Republic, Italy, Serbia, Australia, and New Zealand.

Generally, targeted therapies are less accessible across all regions.
The exception is ibrutinib monotherapy (used alone and not in combination with another drug) where New Zealand and South Africa were the only countries where this was inaccessible. Ibrutinib + rituximab as a combination therapy was largely inaccessible in countries where information could be found. This therapy was only accessible in Bulgaria, Germany, Netherlands, the United States, and Singapore. Acalabrutinib monotherapy and venetoclax + obinutuzumab combined therapy were also widely inaccessible across most regions. Many countries within Europe, North America and Asia-Pacific had access to venetoclax monotherapy but fewer have access to venetoclax + rituximab. Lastly, a greater majority of countries in Europe and North America had access to idelalisib + rituximab than countries in South America, Asia-Pacific, or Middle East and Africa.

Clinical Trials
There is significant clinical trial activity in the CLL space globally. As of January 2021 there were 241 Phase II and III clinical trials underway that involve CLL, of those, 133 (55%) are specific to CLL (no other subtypes included).
Research objectives in CLL include the optimisation of first-line therapy (56 trials), but the majority are focused on the development of effective salvage strategies for relapsed/refractory disease (158 trials).
Of the total trials involving CLL, 139 are researching combination therapies. Detailed information is available in Appendix V.
There is a large focus on targeted therapy in CLL, with 84% of trials researching this type of treatment. All patients who could benefit from a clinical trial should be able to access one.  (Table 2), as many trials occur in more than one country Given that CLL typically affects older adults, it is important that CLL clinical trials be designed to include older patients. There are many investigators interested in the treatment of cancer in older patients; however, it was not until recently that clinical trials in CLL began to focus on the older and less fit populations. 33 There is still variability among CLL clinical trials in terms of if they include and/or encourage the enrollment of older patients. 33 It is important that clinical trials match the age of the typical patient in order to more accurately predict how the therapy will perform and affect patients in the real world. Of the 133 CLL-specific clinical trials identified, 84% had no age requirements other than being 18 years and older. There were six clinical trials that had eligibility exclusively for patients aged 65 years and older. Fifteen clinical trials had age limits for participation (i.e., patients over a specified age cannot participate), which ranged from 65 years to 90 years.
There are several barriers that must be addressed to facilitate the participation of older patients in CLL clinical trials.
• Clinical trials must be made more accessible, both geographically (e.g., some older patients are less likely to travel to tertiary centres for care), and in terms of the number of hospital/clinic visits required.
• Many clinical trial designs inadvertently exclude patients with physiologic aging due to strict requirements (e.g., organ function). There is a continued need to embed function status and frailty assessments in clinical trial designs; however, the inclusion of strict organ function requirements in clinical trials should be thoroughly thought through, and only implemented where wholly justified. Reducing some of these organ function requirements might allow the enrollment of patients that more closely mimic the CLL population at-large.

COVID-19 AND CLL
Patients with cancer are more susceptible to Covid-19 not only because of their malignancy, but also because of their anti-cancer therapies (e.g., chemotherapy, targeted therapy, immunotherapy) that may result in a suppressed immune system. 34 Patients with CLL may be at particularly high risk for Covid-19 infection. CLL is associated with significant immune suppression, comorbidities, and advanced age, all of which act as compounding risk factors for Covid-19 infection. [37][38][39] Accumulating evidence also suggests that patients with cancer are at higher risk for a more severe course of Covid-19 once contracted. 41 Research has shown that compared to the general population, patients with CLL have an inferior immune response to  This means that they develop antibodies (anti-SARS-CoV-2 IgG) that help fight off the virus at a slower rate, and therefore might have a more severe disease course. 40 Two recent studies have shown that patients with CLL experience more complications, morbidities, and higher mortality rates due to Covid-19 than the general population ( Patients who undergo chemoimmunotherapy are likely to be at increased risk for clinical complications following Covid-19 infection. 37 In contrast, BTK inhibitors (e.g., ibrutinib, acalabrutinib) may have a protective effect and this is being explored in clinical studies with conflicting results. 37 For example, in

COVID-19 VACCINATION AND TREATMENT
CLL is associated with impaired humoral response to vaccination. 37,43 This means that the immune systems of patients with CLL, due to their disease or its treatment, are not good at making antibodies or mounting an immune response to existing vaccines.
A growing number of patients with CLL have long-term exposure to treatments that directly affect the immune system through depleting a patient's B cells, which are necessary for making antibodies ('humoral immunity'). This can further reduce a patient's ability to respond to vaccination. 43 It is important to remember the immune system has two responses to an antigen. One is to make and keep making antibodies to the antigen. This process creates a large burst of antibody aimed at destroying the antigen that gradually lessens as time goes on. The second is the development of memory cells whose role is to rapidly respond to a further encounter with the same antigen. It is possible for a small amount of antibody to be made (i.e., a poor humoral response) but immune memory response be very strong.
There is no evidence to suggest that Covid-19 vaccines are less safe in patients with blood cancer, though Covid-19 clinical trials have admittedly included few cancer patients. 46 LC encourages patients with CLL to discuss Covid-19 vaccine options with their healthcare teams.
Targeting 'passive immunity' in Covid-19 vaccine research is potentially a good approach for helping those who are less likely to benefit from vaccinations due to being immunocompromised. Passive immunity means that a person is given antibodies to a disease rather than producing them through their own immune system. 44 This is what is being explored in long-acting antibody (LAAB) trials. If a patient is given these antibodies, it should prevent the virus from entering their cells and infecting them or reduce the risk of severe Covid-19 if they are infected. If the antibodies work as promised, they should give protection for at least six months, without the patient's immune system ever having to learn how to make the antibodies itself. 45 This 'immune booster' approach may be a viable option for immunocompromised patients (with CLL and otherwise). 45

It is crucial that patients with CLL be eligible to receive Covid-19 vaccinations to reduce the risk or severity of Covid-19 infection. They should also receive priority access to any newly developed antivirals and treatments for Covid-19.
It is important to understand the patient experience and their quality of life, from diagnosis through to the point they are no longer experiencing effects from their disease or any adverse effects from treatment.

The Patient Experience
It is important to understand the experience of patients with CLL and their quality of life, from diagnosis through to the point they are no longer experiencing effects from their disease or any adverse effects from treatment. LC conducts a global survey of patients every two years that is distributed within the patient community. Through this survey, the impact of diagnosis, treatment and care can be better understood, and LC and its global members can bring the patient voice forward.
The LC 2020 Global Patient Survey on Lymphomas & CLL (GPS) results are used in this report to provide a sense of the experience of patients with CLL and SLL.
The LC 2020 GPS received 11,878 responses, including 9,179 patients and 2,699 caregivers. There was representation from respondents in over 90 countries around the world, of which 1,774 were identified as patients with CLL/SLL (19% of the total patient respondents).
Patients were asked questions about their understanding and awareness (including guidance and support), symptoms and treatment side effects, psychosocial concerns, communication with the doctor, and barriers to care.

UNDERSTANDING AND AWARENESS
When asked about their initial diagnosis experience, 89% of patients said they clearly understood they were being diagnosed with cancer but one in four were not told the specific subtype.
Two-thirds of patients reported not knowing if any genetic and biologic markers applied to them (table 6).
Understanding the characteristics of CLL/SLL is key given its chronic nature as well as its heterogeneity. If patients do not have a good understanding about their subtype and the chromosomal alterations associated with CLL/SLL, they are unable to seek the correct information that applies to their disease and will help them be better informed. Patients were asked whether they received and understood information on various topics around the time of diagnosis (table 7). While the majority of patients were given information about each topic, in all cases, less than half of patients reported completely understanding this information. Further, a fifth of patients were not given information on the process and stages of their care (21%) or on managing treatment side effects (20%). Though three in five patients said they received the right amount of information at diagnosis, a third reported not receiving enough. Most patients had the greatest need for information within the first month following diagnosis (52%). They wanted more information about their diagnosis and what is means (56%), treatment options (55%), and treatment side effects (33%).

Patients reported that their primary sources for information were doctors, websites, and patient organisations.
Most are confident in their ability to get the information they need from their doctor (83%) and are confident they can find reliable information about their CLL/SLL (75%). Access to credible, timely information is an important factor in a successful patient experience. It is critical that all parties work together to meet this need and provide patients with the information and support they need, right from the beginning of their experience.
The majority of patients reported receiving enough general support from doctors (81%) and from family/friends (81%) throughout their experience. However, only half (50%) received enough emotional support, and less than a third received enough practical or financial support (figure 4). Doctor support Family/friend support Practical Emotional Financial

Yes No Don't want/need
Patients were asked a series of questions about their role in healthcare decision-making. Most patients (90%) are involved as much as they want to be in decisions about their care.
• More than 75% of patients agreed or strongly agreed that they have good conversations with their doctor about their care and treatment plan (77%), seek clarification when they do not understand (91%), are confident in communicating concerns to their doctor (84%), and are confident in their ability to positively impact their health (78%).
• 82% say they always understand their doctors' advice and treatment plans.
• For those in treatment (or who had been treated in the past), almost a third (31%) had talked to their doctor about wanting to change their treatment to better meet their needs within the last two years, but only 3% of these patients chose a treatment that was not recommended by their doctor. 30% of patients got a second opinion about their most recent treatment.

However, more than a quarter of patients (28%) agreed or strongly agreed that they feel overwhelmed by managing their health and condition.
Patients were asked how confident they felt in managing their health problems day-to-day (if they had health problems) ( figure 5). Less than a third reported feeling very confident, and 12% reported not feeling confident (not very or not at all).

Figure 5. How confident patients felt managing health problems day-to-day
When asked more specific questions about managing their condition on a daily basis: • 77% of patients that have received treatment agreed or strongly agreed that they know what their prescribed medications do • 97% of those in treatment (or who had been treated in the past) agreed or strongly agreed that they understand how to take their medications at home • 81% of patients agreed or strongly agreed that they make the recommended lifestyle changes for their disease.
However, 30% of patients agreed or strongly agreed that they wait until health issues cannot be ignored before seeking help, and 16% disagreed or strongly disagreed that they are confident in their ability to keep their side effects from interfering with what they want to do.

Very confident 31%
Fairly confident 56% Not very confident 11% Not at all confident 2%

CLL SYMPTOMS AND TREATMENT SIDE EFFECTS
Patients were asked to identify any symptoms of CLL/SLL they had experienced ( figure 6). The top five reported symptoms were fatigue (65%), abnormal painless swellings (37%), and frequent or repeated infections, shortness of breath, and bruising/bleeding (29% each).    Though fewer patients in active surveillance reported CLL/SLL symptoms, at least 8% of these patients reported experiencing each symptom (ranging up to 58% for fatigue). This signals that despite not requiring treatment, these patients may require support to manage these symptoms.
Chronic Lymphocytic Leukaemia Subtype Report · LymphomaCoalition.org · © 2022 Lymphoma Coalition 34 This is further confirmed when examining how CLL/SLL symptoms impacted well-being (figure 8). Though a lesser proportion of those in active surveillance reported each impact category (compared to the rest of CLL/SLL patients), more than a fifth of those in active surveillance did report experiencing each impact.    Understanding cancer-related fatigue and the repercussions it may have for patients before, during, and post treatment is an important factor that must be addressed.
Patients who were in treatment, or who had been treated in the past, were asked which treatment-related side effects they had experienced. The top ten reported side effects are shown in figure 10. Patients were most commonly treated with chemoimmunotherapy (48%) and targeted therapy (32%). The medical issues (figure 10) reported by patients with CLL/SLL are commonly reported treatment-related side effects, highlighting the continued need for better treatment options with fewer toxicities. When patients were asked to rank the importance of outcomes relating to treatment, 'a cure' ranked first (58%), but 'quality of life' (45%) and 'fewer side effects to tolerate' (45%) ranked second and third, respectively.
Additionally, except for nausea and vomiting (mostly experienced while in therapy), each of the top treatmentrelated side effects were reported for eight or more years by at least 7% of patients who experienced them (table 8). Nearly a fifth (17%) of those who experienced fatigue reported experiencing it for more than eight years.
Side effects can impact quality of life and well-being. The majority of patients (60%) who experienced treatmentrelated side effects reported that their everyday activities were negatively impacted as a result: 38% were unable to work or adjusted their working pattern; 44% reported that their social life was negatively impacted; and 23% reported a negative impact on relationships.

PSYCHOSOCIAL CONCERNS
Psychosocial effects encompass the psychological and emotional well-being of the patient and how it impacts their day-to-day life. The chronic nature of CLL/SLL means all patients require more support to manage the coupled long-term psychosocial issues that impact well-being.
For this section, we again compared those patients in active surveillance (no treatment yet) (n=734) against the rest of the CLL/SLL population (n=1040).
Patients with CLL/SLL may spend several years living with the disease without treatment. More than a third (36%) of patients reported being in active surveillance (without treatment) for more than five years. Many patients live in constant fear of disease progression. Additionally, if active surveillance is not well explained and understood from the outset of diagnosis, it may seem like a risky or passive approach to a serious disease. All these factors can lead to a great deal of distress for patients.

Compared to the rest of the CLL/SLL population, a greater proportion of patients in active surveillance reported experiencing fear of lymphoma progression, anxiety, and depression (figure 11). Patients in active
surveillance require more support for these specific issues, as well as ongoing reassurance that their symptoms are being actively monitored and that treatment will begin when necessary.
Despite certain issues being more prevalent among those in active surveillance, more than 10% of patients in both groups reported experiencing each psychosocial issue ( figure 11). Fear of progression/recurrence, anxiety, and depression were high (<20%) in both groups. To note, patients in active surveillance were not asked if they experienced fear of cancer relapse as they had not yet been treated.
In supporting patients with these psychosocial issues, something that must be considered currently and going forward are the exacerbating effects of Covid-19. CLL/SLL diagnosis and treatment (including active surveillance), compounded by being high risk for COVID-19 infection and complications, can create high levels of psychological distress for patients (e.g., anxiety, depression). Additionally, patients with CLL/SLL during Covid-19 must manage stress related to less frequent touchpoints with their care team, potential treatment changes and/or delays, and the absence of traditional support systems due to social distancing protocols. Improved psychosocial supports must be designed with these factors in mind.

PATIENT-DOCTOR COMMUNICATION
In previous years, the LC GPS has shown that patients are more likely to communicate their medical issues with their doctors than their psychosocial issues. Additionally, when patients do communicate psychosocial concerns, they are often not met with adequate support from their healthcare providers.
In the LC 2020 GPS, nearly all patients with CLL/SLL (96%) who experienced treatment-related side effects reported discussing them with the doctor, of which 77% reported being helped (either definitely or to some extent). Patients who were helped by their doctors reported receiving medication (64%), being provided with further information (39%), and/or being referred to another source of support (15%).
Though fatigue was the top reported symptom and treatment-related side effect, compared to discussing treatment side effects generally, fewer patients who experienced fatigue reported specifically discussing it with their doctor (74%). Of those who did not discuss their fatigue, the top reported reasons for not doing so were believing nothing could help (32%), thinking they could handle it on their own (31%), and/or that the doctor never started a discussion about it (22%).
Patients who discussed their fatigue with their doctor were asked how the doctor helped ( figure 12). More than a third (35%) of patients reported that the doctor took no action after their discussion. Less than a fifth of patients reported that the doctor assessed their level of fatigue (17%), did a physical examination (17%), or asked about any contributing factors (14%).
All of the actions listed in figure 12 are taken from clinical practice guidelines (NCCN/ESMO) for cancer-related fatigue, all of which should be routinely implemented when a patient presents with fatigue. Additionally, only 17% of patients reported the doctor definitely followed-up with them about their fatigue. This represents a major gap in the care of patients with CLL/SLL.   As in past years, there was significantly less communication about psychosocial issues to the doctor. In the LC 2020 GPS, there was a focus on four issues for further questions about communication, including: depression, anxiety, changes in relationships, and fear of cancer relapse. Of patients who reported experiencing these issues, less than 60% reported discussing any of them with their doctor ( figure 13). Figure 13. Did patients discuss psychosocial issues that they experienced with their doctor?
x Of those who did not discuss these issues, the top reported reasons for not doing so were thinking they could handle it on their own, not thinking the issue was a big deal, and/or not wanting to bother the doctor.
Of those who did discuss these issues with the doctor, in all cases, patients reported the doctor was only able to help to some extent than definitely help ( figure 14). For changes in relationships, most patients reported the doctor was not able to help. Figure 14. Was the doctor able to help if patients discussed the issue with them?
x Less than 40% of patients who discussed these issues reported that their doctor definitely followed-up with them about it (depression 30%; anxiety 28%; changes in relationships 24%; fear of relapse 36%).

It is clear that a communication gap still exists surrounding psychosocial concerns; the two-way exchange of information between patients and their doctors continues to be impaired.
To encourage communication, the emotional impact of a cancer diagnosis must be acknowledged at the outset, and the emotional cues from the patients must be recognised and responded to throughout their experience. Additionally, it is imperative that physicians be educated on the importance of early access to emotional support for patients and be provided with the information on how to find these resources. 47 Healthcare providers cannot be expected to provide all the information and support patients need; however, patients must be directed to the appropriate resources. This can include other resources that are hospital or community-based, as well as patient organisations. There continues to be room for improvement here as less than 40% of patients reported being directed to another source of support by their doctor for any psychosocial issue.

BARRIERS TO CARE
There are many reasons why a patient may not be able to access treatment. The two main barriers reported by patients with CLL/SLL were financial difficulties (11%) and access to the most up-to-date treatment (6%). However, the majority of patients reported not experiencing any barriers to treatment (79%) ( figure 15).  Less than half of patients (48%) in Asia-Pacific reported experiencing no barriers to treatment, compared to 83% in the Americas and 90% in Europe.
The most reported barrier to treatment in Asia-Pacific was financial difficulties (39%), which was only reported by 5% of those in the Americas and 2% of those in Europe. This could be partially attributable to the 'out-ofpocket' healthcare systems that exist in many Asian countries. These systems create high stress and have large financial impacts for patients; many middle-class households in Asia face impoverishment after paying for cancer care. 48 Figure 16. Barriers to treatment reported by patients with CLL/SLL regionally (Middle East/Africa excluded due to low response) Chronic Lymphocytic Leukaemia Subtype Report * LymphomaCoalition.org * ©2021 Lymphoma Coalition Pg.
x The most reported barrier to treatment in the Americas and in Europe was gaining access to the most up-to-date treatments ( figure 16). The most up-to-date treatments are often accessed via clinical trials. In clinical practice guidelines for treating CLL/SLL (e.g., NCCN, ESMO), clinical trials are recommended for certain patients with CLL/ SLL in both first-and second-line therapy settings. However, when patients were asked if they were currently or had ever been in a clinical trial for their CLL/SLL, 82% said 'no'. When examined regionally, the greatest proportion of patients in Asia-Pacific had been (or were currently) involved in a clinical trial (Asia-Pacific 22%; Americas 20%; Europe 16%). Never being presented with an opportunity to take part was the most cited barrier to clinical trial participation globally (66%), and across the regions (Asia-Pacific 61%; Americas; 62%; Europe 69%).

Conclusions and Recommendations
It is likely that the prevalence and mortality of CLL will continue to increase because the global population is ageing. Therefore, it is important for major gaps in understanding, treatment, and care to be addressed.
Lymphoma Coalition firmly believes that if we, patient organisations, and other key stakeholders work together, we can jointly bring about positive change. Change will take time. There are steps we can take now that, once successfully implemented, will act as a solid foundation for future activities. Well-thought out, consistent effort over time will lead to improved patient experience.
The following are identified priorities from the Lymphoma Coalition's perspective.

RESEARCH PRIORITIES 1) There is still no cure for CLL.
The introduction of chemoimmunotherapy agents and targeted therapies have improved the outcomes of first-line treatment, but most patients with CLL relapse and require subsequent treatment. Of the clinical trials identified as involving CLL (globally), only 23% were first-line therapy trials. The optimisation of first-line treatment for CLL should remain a top priority given the potential to confer a greater benefit for a greater number of patients.

2) Clinical trials must be accessible for older patients.
Trials studying new treatment options or optimal therapy choices for patient with CLL must match the population of those diagnosed. This means the inclusion of older adults in trials, alongside tools to assess their function and frailty. Trial inclusion and exclusion criteria must also be carefully considered to ensure it does not unintentionally exclude the preferred patient population.

3) Therapy sequencing.
The introduction of novel, targeted therapies has changed the treatment landscape for CLL and improved care for some hard-to-treat prognostic subgroups. However, new challenges emerge when patients relapse on novel agents, and optimal sequencing strategies have not been established. Therapy sequencing strategies must be defined.

4) Reduced toxicity profiles.
Even new treatments can have an extensive side effect profile that can impact patients' quality of life. There is a continued need for better treatment options with fewer toxicities.

5) Minimal residual disease (MRD) assessment.
The role of MRD assessment in routine clinical practice for CLL needs to be better defined.

6) Treatment for Richter's Transformation.
Improved treatment options are needed for patients whose CLL undergoes Richter's Transformation (RT), especially for patients whose transformed CLL presents as DLBCL (90% of all RT cases). Generally, the DLBCL variant of RT has a poor prognosis because the disease responds poorly to the available DLBCL treatment regimens.

How LC can help:
While LC does not conduct or fund research related to medical care, we can do the following: • Provide input to the early-stage development and subsequent review of clinical trials to ensure the inclusion of patient-relevant priorities and removal of participation barriers.
• LC will partner with all relevant stakeholders to promote a regulatory change focused on reducing bureaucracy associated with clinical trials. This will encourage more doctors and patients to participate and will facilitate low-and middle-income countries to join clinical research.
• LC is committed to finding ways to bring the clinical trial to the patient in need, on a country-by-country basis.
• Through the Lymphoma and CLL Community Advisory Board, LC helps build research that answers questions and examines outcomes that are important to patients, their caregivers, and clinicians. LC can help to validate and integrate reliable Quality of Life and Patient Reported Outcomes (PRO) measurements to systematically capture meaningful health outcomes.

EQUITABLE TREATMENT PRIORITIES 1) Access to novel therapies.
Certain subgroups of patients with CLL (e.g., del(17p) and/or TP53 mutation, unmutated IGHV) respond poorly to chemoimmunotherapy. Yet targeted therapies were less accessible across all regions, with the exception of ibrutinib monotherapy. Access to targeted therapy regimens must be improved globally.

How LC can help:
• Continue to provide training to member patient organisations to increase their understanding of drug approval processes as well as advocacy techniques they can use to incite change locally, including the creation of an advocacy toolkit and member workshops. This will include how to effectively use both qualitative and quantitative data for an evidence-based approach to advocacy.
• Where extra support is needed, LC will provide individual mentoring to member groups to enable them to build and action their advocacy plans.
• Analyse data from the biennial Global Patient Survey on Lymphomas & CLL by disease status and geography so it can be used to support advocacy initiatives by members as well as inform the broader community.

2) Access to testing.
Numerous prognostic markers have been established for CLL. These can influence choice of treatment especially since therapy access is often limited to those with poor prognoses. Tests for mutations, markers, and chromosomal abnormalities are not readily accessible in all countries. This needs to change to ensure patients receive the best treatment. Additionally, increased patient education is needed around genetic markers and chromosomal abnormalities and how this impacts optimal treatment.

How LC can help:
• LC wrote a report on Genetic Markers in 2019. From this report, LC will create a quick reference sheet of biomarker tests used in CLL and their purpose.
• Include information on the importance of testing before every line of therapy for patients with CLL into an awareness campaign.
• Work alongside healthcare professional organisations to define minimum standards for testing and identify solutions for low-resourced communities.
• Use the above-mentioned advocacy initiative to help member organisations incite local change.

3) Pandemic response.
A consensus guideline for the management of patients with CLL during the Covid-19 pandemic and future infectious disease pandemics must be established. This must include clear indications for patients with and without a Covid-19 diagnosis. Additionally, it is crucial that patients with CLL be eligible to receive Covid-19 vaccinations, despite any doubts regarding immune response to vaccinations in this population, as well as priority access to any developed antivirals and treatments.

How LC can help:
• Track clinical practice guidelines related to Covid-19 from professional organisations and seek clarity on inconsistencies.
• Continue to create and compile Covid-19 resources for member patient groups to help them understand and manoeuvre through the latest research and recommendations.
• Advocate for access to vaccines, antivirals, and effective treatments in a timely manner for patients with lymphomas, including CLL.

IMPROVING PATIENT WELLBEING 1) Burden of fatigue.
Among patients with CLL/SLL who responded to the LC 2020 GPS, fatigue was the top reported symptom and treatment side effect affecting well-being, often for many years. Cancer-related fatigue and the repercussions it may have for patients before, during, and post treatment is an important factor that must be addressed.

How LC can help:
• LC champions the recognition of fatigue as a diminishing quality of life feature and will help to introduce active monitoring of fatigue in the lymphoma care pathway. This includes advocating for HCPs to follow the fatigue clinical practice guidelines established by NCCN and ESMO for each patient.
• Raise awareness of the impact of fatigue in an ongoing awareness campaign.
• Continue to recommend member patient organisations have information on fatigue available for patients, including resources to help patient's cope. LC published a toolkit related to fatigue in 2020.

2) Psychosocial impact.
A. Patients in active surveillance. The LC 2020 GPS showed that compared to the rest of the CLL/SLL population, a greater proportion of patients in active surveillance reported experiencing fear of disease progression, anxiety, and depression. Patients in active surveillance require more support for these specific issues, as well as ongoing reassurance that their symptoms are being actively monitored and that treatment will begin when necessary.
B. Need for ongoing support. The chronic nature of CLL means that many patients (not just those in active surveillance) will live with this disease for many years, and all patients require more support to manage the coupled long-term psychosocial issues that impact well-being.

C. Communication with doctors.
It was clear in the LC 2020 GPS that a communication gap still exists surrounding psychosocial concerns; the two-way exchange of information between patients and their doctors continues to be impaired. Healthcare providers cannot be expected to provide all the information and support patients need, especially in light of time limitations; however, patients must be directed to the appropriate resources (e.g., patient organisations, other hospital or community-based resources).

How LC can help:
• Encourage the use of the terminology active surveillance or active monitoring instead of watch-and-wait, to help communicate to patients at this stage that their healthcare team is diligently observing and reacting to their health status to determine when is the optimal time for them to progress to the next phase of treatment. This is a defined, clinically validated stage of the treatment pathway.
• Use the GPS data to highlight the specific needs of patients to both medical and patient advocacy communities, highlighting the importance of patients being connected as early as possible to both credible information and emotional support.
• Continue to recommend member patient organisations have credible information on fear of cancer recurrence (FCR) available for patients, including resources to help patients cope. LC published a toolkit related to FCR in 2020.
• Build an evidence-based framework of systematic questions to guide physician-patient communication that will facilitate a useful dialogue with patients about their emotional health, physical concerns and their individual treatment plan and personal care pathway, ensuring discussions with patients are conducted in a patient-centric manner.
• Connect doctors and clinics with local patient organisations who can provide additional information and support to patients, often without the time limitations experienced in clinic.

APPENDIX II: CELL BIOLOGY BASICS RELATING TO GENETIC MARKERS, GENE MUTATIONS, AND CHROMOSOMAL ABNORMALITIES
Human bodies are made up of trillions of cells, and most cells contain a complete set of genes. Each person has thousands of genes that act like a set of instructions, controlling growth and how bodies work. Genes are made of DNA and are carried on thread-like structures called chromosomes. Chromosomes are stored in the nucleus of a cell; usually, a person has 46 chromosomes in each cell, 23 inherited from their mother and 23 from their father. These structures are described in further detail below.

Cells
Cells are the basic unit of life. The human body is made up of trillions of cells which provide structure for the body, convert nutrients from food into energy, and carry out specialised functions. Cells contain the body's hereditary material.

Nucleus
The nucleus is the cell's command and information processing centre. It has 2 major functions: it coordinates the cell's activities (growth, maturation, division); and it stores the cell's hereditary material which is called DNA.

What is a Gene Mutation?
A gene mutation is a permanent change in the DNA sequence that makes up a gene. A gene mutation can range in size, affecting anywhere from a single DNA base pair (A&T, G&C) to a large DNA segment that involves multiple genes. Mutations can be hereditary (passed on from a parent) or acquired, meaning a change happens during a person's life that usually only affects certain cells. A person's health can be affected because mutations may lead to alterations in a protein's structure, changing the way the protein works, and affect the amount of proteins. Some mutations can change a cell from healthy to cancerous.

What is a Genetic Marker?
A genetic marker is a specific DNA sequence with a known physical location on a chromosome. It is described as an observable variation, which may arise because of a mutation or an alteration in the gene's location. Each chromosome has many genetic markers. While specific sequences may vary between individuals, there is enough consistency in the genetic code at that particular site on the genome to allow comparison between individuals. A marker can have functional consequences, for example, the function or expression of a gene can contribute directly to the development of a disease. A marker can also have no functional consequences but could be located very close to a functional variant (which does alter the function of a gene), which causes both the marker and the variant to be inherited together in the population at large.
Information taken from Lymphoma Coalition Genetic Markers report: lymphomacoalition.org/genetic-markers-in-lymphoma

Chromosome
A chromosome is a thread-like structure made up of DNA that is tightly coiled around proteins called histones. This is how DNA is packaged for storage in the cell nucleus. Each chromosome contains many genes and is divided into 2 'arms' by a constriction point called the centromere. The short arm is called the 'p arm' and the long arm is called the 'q arm'. The centromere can be located in different places on different chromosomes, this is what gives a chromosome its shape, and it can be used to describe the location of specific genes.

DNA
DNA, or deoxyribonucleic acid, is the hereditary material in humans. It is a double helix structure that resembles a twisted ladder. The information in DNA is stored as a code made up of 4 chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). The specific order of these bases determines the information available for building and maintaining an organism, much like how letters of the alphabet appear in different orders to form words and sentences. Each base is also attached to a sugar molecule and a phosphate molecule, and all 3 of these items together (base+ sugar+ phosphate) are called a nucleotide.

Nucleotides
Nucleotides are arranged in 2 long parallel strands that bind together to form the DNA double helix structure. These strands bind together through base pairing; A binds with T, and C binds with G to form the steps of the ladder, and the sugar and phosphate molecules form the vertical side pieces of the ladder.

Gene
A gene is the basic unit of heredity. Genes are made up of a segment DNA, and they can range in size from a few hundred DNA bases (A, C, G, T) to more than 2 million bases. Some genes act as instructions to make molecules called proteins. Genes are assigned a name and symbol; the symbol is a short combination of letters (and sometimes numbers) that represent an abbreviated version of the name.  Bruton's tyrosine kinase A protein kinase that plays a crucial role in oncogenic (cancerous) signalling pathways. Abnormal activation (or mutation) of Bruton's tyrosine kinase drives changes in cell growth, survival, movement, and metabolism, as well as helps cancer cells to evade the anti-tumour response. Bruton's tyrosine kinase is critical for the survival of cancer cells in various B cell cancers (including CLL).

Chimeric antigen receptor therapies
A treatment that modifies a patient's or a donor's immune cells to express a receptor on their surface. The receptor recognises and binds to specific structures (antigens) on the surface of cancer cells, and once bound, can destroy the cancer cell. In CAR T-cell therapy, it is the patient's own T cells that are modified.

Chromosome
Part of a cell that contains genetic information. All human cells contain 46 chromosomes (except for sperm and eggs).

Clinical trials
Clinical trials are research studies used to determine if a new therapy, surgery or behavioral intervention is safe and effective in people.

Comorbidities
The condition of having two or more diseases at the same time (e.g., cancer and diabetes).

Complete blood count (CBC) with differential
A measure of the number of white blood cells, red blood cells, and platelets in the blood, including the different types of white blood cells (neutrophils, lymphocytes, monocytes, basophils, and eosinophils).
A complete blood count also measures the amount of hemoglobin (substance in blood that carries oxygen) and hematocrit (the amount of whole blood that is made up of red blood cells). It is useful for diagnosing and monitoring many conditions.

Deauville score
A five-point scale used to stage and asses initial treatment response in certain lymphomas. The scale ranges from 1 to 5, where 1 is best (no uptake or no residual uptake) and 5 is worst (markedly increased uptake or any new lesion).

Flow cytometry
A laboratory test that measures the number of cells, the percentage of live cells, and certain cell characteristics (e.g., shape, size) in a sample of blood, bone marrow, or other tissue. This test also looks for the presence of tumour markers (e.g., antigens) on the surface of cells. Cells are stained with a dye that is light-sensitive, placed in a fluid, and then passed one at a time through a light beam. Measurements are taken based on how the cells react to the light beam.

Heterogeneity
Made up of elements or ingredients that are not alike.

Humoral response
A humoral response is when the body produces antibodies against a specific antigen (e.g. a virus).

Intubation
Inserting a tube into a patient's throat to help move air in and out of the lungs.

Lymphoid neoplasms
A neoplasm is an abnormal mass of tissues that forms when cells grow and divide more than they should, or do not die when they are supposed to. A neoplasm can be benign (non-cancerous) or malignant (cancerous). A lymphoid neoplasm arises from the malignant (cancerous) transformation of normal lymphoid cells at various stages of differentiation (cells changing from one type of cell to another). Lymphoid neoplasms include lymphoma, myeloma, and lymphoid leukaemia.

Median
The middle value in a set of measurements.

Memory B cells
Memory B cells are part of the adaptive immune system in the human body. Memory B cells provide protection against recurring infectious agents (they remember the virus or bacteria they fought previously). Memory B cells live in the body for a long time, even after all the viruses/bacteria from the first infection have been destroyed. They stay in ready-mode and are able to quickly recognise and attack any returning viruses or bacteria.

Monoclonal B-cell lymphocytosis (MBL)
A non-cancerous condition which causes an increased number of abnormal B cells called lymphocytes (white blood cells) in the blood. This condition is seen as a precursor (pre-cancerous) condition to CLL.
Naïve B cells B cells, or B lymphocytes, develop and mature in the bone marrow. A naïve B cell is one that has matured and entered the bloodstream but has not yet transformed into a new type of cell that has a specific purpose. Naïve B cells travel through the lymphatic system until they either become memory B cells or encounter the appropriate antigen and start the activation process.

NOTCH1 mutation
A mutation that is expressed in the NOTCH1 gene of some patients with CLL. Patients with CLL who express a mutation in the NOTCH1 gene are associated with an unfavourable prognosis (e.g., shorter treatment-free survival, increased risk for Richter's Transformation). This gene mutation is detected in approximately 10% of CLL cases at presentation. Patients with unmutated IGHV are more likely to have the NOTCH1 mutation.

Overall survival (OS)
The length of time from the date of diagnosis, or from the start of a treatment for a disease (e.g., cancer) that patients with the disease are still alive. Measuring overall survival in clinical trials is one way to see how well a new treatment works.

Passive immunity
Passive immunity means that a person is given antibodies to a disease rather than producing them through their own immune system.

PET scan
A positron emission tomography scan, or PET scan, is a procedure where a small amount of radioactive glucose (sugar) is injected into a vein, and then a scanner is used to make computerised pictures of areas inside the body where the glucose is absorbed. A PET scan can be used to find cancer cells in the body because they take up more glucose than normal cells.

Phase II clinical trial
The part of a research study where the therapy under review is administered to a larger group of patients (typically up to a few hundred) with the disease or condition for which the drug/therapy is being developed. Key focuses of Phase II clinical trials include initial assessment of effectiveness and further assessment of safety (of the drug/therapy), as well as determining the optimal dose or doses of a drug.

Phase III clinical trial
The part of a research study where the therapy under review is administered to many hundreds or thousands of participants from patient populations for which the drug/therapy is eventually intended to be used. Participants are assigned to receive either the drug/therapy being studied or are assigned to a control group where they will receive the current standard of care or a placebo. Phase III clinical trials are designed to determine whether or not the drug/ therapy being studied offers a treatment benefit, to provide more detailed safety data, and to serve as the basis for product labelling.

Phosphatidylinositol 3-kinase (PI3K)
The phosphatidylinositol 3-kinase (enzyme) pathway regulates various cell processes such as cell growth, proliferation, differentiation (a cell transforming into a new type of cell), survival, and intracellular (within a cell) trafficking. Mutational events that lead to the over activation of this pathway result in cancers.

Prognostic (prognosis)
The likely outcome or course of a disease, including the chance of recovery or recurrence.

Progression-free survival (PFS)
The length of time during and after the treatment of a disease that a patient lives with the disease without it getting worse. Measuring progression-free survival in clinical trials is one way to see how well a new treatment works.

Purine analogues
When a new cell in the human body is formed, it goes through a series of phases to become a fully functioning (mature) cell. This process is called the cell cycle. Chemotherapy drugs target cancer cells at different phases of the cell cycle. Purine analogue chemotherapy agents work best in the S-phase of cell division when cells are growing and dividing quickly. They work by preventing the continued growth of DNA of the cancer cell (DNA synthesis), which prevents cell division. They do this by replacing the natural substances (purines) that normally act as the building blocks in DNA molecules. In other words, they mimic the nutrients that the cancer cell needs to grow, tricking the cell into consuming them so eventually it starves to death.

Signalling pathways
A group of molecules work together to control one or more cell functions, such as cell division or death. When the first molecule in a pathway receives a signal, it activates another molecule. This process continues until the last molecule is activated and the cell function occurs. If the activation in the signalling pathway is abnormal, it can result in cancer.

Spleen tyrosine kinase
Spleen tyrosine kinase is required for various processes of B-cell development. It is also recognised as a promoter of cell survival in numerous cancer cell types, so it has attracted major interest as a target for novel anti-cancer therapies.

Surrogate end-point
Can be used in clinical trials as an indicator in place of something else to determine if the treatment works. For example, endpoints of 'shrinking tumour' or 'lower biomarker levels' can be used instead of stronger indicators like 'longer survival'. These endpoints are often used so that the results of a clinical trial can be measured sooner.