This supplement was supported by AbbVie Commercial.
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults in the United States, with 21,250 new cases and 4320 deaths estimated for 2021.1-4 The 5-year relative survival rate for CLL is 87.2%, which is indicative of the slow-moving nature of this cancer.4 Although this is good news, it also means that patients with CLL have to live with a chronic and incurable illness for a long time. This can be challenging both in terms of managing the practical aspects of treatment, as well as the possible mental health effects of the diagnosis.1 Healthcare providers play an important role in helping patients navigate their diagnosis, treatment plan, and health-related quality of life (HRQOL).1 In particular, oncology nurse navigators are essential members of the healthcare team as they eliminate barriers to timely care and coordinate the care patients receive across multiple treatment modalities and care path transitions.5
The understanding of CLL biology and the rapid development of targeted therapies have significantly changed the treatment landscape for CLL over the past few years.6 Until recently, chemoimmunotherapy (CIT), the combination of chemotherapy agents with anti-CD20 monoclonal antibodies, was the standard of care for patients with CLL.7 However, in 2016, the US Food and Drug Administration (FDA) approved the use of ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, in the frontline setting, representing the first chemotherapy-free option available to patients.8 Since then, other BTK inhibitors as well as phosphoinositide 3-kinase (PI3K) inhibitors, B-cell lymphoma 2 (BCL2) inhibitors, and other agents have also been approved and are recommended for the treatment of patients with CLL.3,9 The rapid development of various classes of therapeutic agents for CLL represents a challenge for healthcare providers in terms of clinical decision-making and communication strategies.
This article offers an overview of the current and evolving treatment landscape for CLL with an emphasis on HRQOL, communication strategies to optimize adherence, adverse event (AE) management strategies, ways of overcoming barriers to access care, survivorship support, and the impact of the coronavirus disease 2019 (COVID-19) pandemic.
What is CLL?
Cancers of white blood cells are called leukemias and are classified based on the type of cells affected, myeloid or lymphoid, and the speed of disease progression, acute or chronic.4 CLL is characterized by clonal populations of small, morphologically mature but immunologically immature B lymphocytes that progressively accumulate in the blood, bone marrow, and lymphatic tissues.1 CLL is more common in men, particularly among white and non-Hispanic men, and is most frequently diagnosed in people aged 65 to 74 years.4 The median age at diagnosis is 70 years and the median age at death is 82 years.4 In the United States, the incidence and mortality rates have been decreasing since 2005, while the 5-year relative survival rate has been increasing since 1975.4
CLL is typically diagnosed during routine blood work and most patients are asymptomatic at the time of diagnosis.1 Diagnosis is based on the presence of ≥5 × 109/L B lymphocytes in the peripheral blood, sustained for ≥3 months, with clonality confirmed by flow cytometry.3,10 Cell surface markers (CD5, CD19, CD20, and CD23), together with restricted expression of either the kappa or lambda immunoglobulin light chains, can be used to differentiate from other lymphomas.3,10 Other classical signs include enlarged lymph nodes, hepatomegaly, splenomegaly, anemia, and thrombocytopenia.1 Symptoms including weight loss, drenching night sweats, fatigue, and fever are also common.1 Small lymphocytic lymphoma (peripheral blood B lymphocytes <5 × 109/L and lymphadenopathy and/or splenomegaly) is considered to be the same disease and is treated in a similar manner.1 Disease-related complications, including autoimmune hemolytic anemia, idiopathic thrombocytopenia purpura, red-cell aplasia, infection, and transformation into a more aggressive form of the disease, can occur at any point, but are more common in advanced cases.1
There are 2 staging systems, the Rai and Binet systems, to classify patients with CLL (Table 1).3 These are used to estimate disease prognosis and help clinicians determine the appropriate time to begin treatment.1 In addition to these clinical markers, there are a number of biomarkers that provide additional prognostic information as well as guidance in therapy selection, with the most important ones being the IGHV mutational status, serum β2-microglobulin, and the presence of del(17p) and/or TP53 mutations.3,10 Other important cytogenetic abnormalities include del(11q), del(13q), trisomy 12, and t(11;14).9 Patients with a detectable del(17p) or a mutation of TP53, or unmutated IGHV status, have a worse prognosis.3
Treatment strategies for CLL
To ensure that patients experience less distress and are able to more fully engage in managing their care, it is important to foster an environment of open communication with patients and caregivers. Compared with patients with other malignancies, patients with CLL report a poorer quality of life.11 Therefore, a collaborative approach to decision-making that includes a discussion of patient values and wishes regarding treatment is crucial.1 Since CLL is often incurable, the goal of treatment is to slow disease progression, manage symptoms, improve HRQOL, and prolong survival.1,3 Due to this and to the complexity of the various treatments, patient counseling helps alleviate fears of possible side effects, answers questions about how treatment will impact patients’ lives, reinforces the rationale for initiating treatment, and serves as emotional support.1
Considerations around the watch-and-wait strategy
For patients with early-stage CLL (Binet A and B without active disease; Rai 0, I, and III without active disease), the standard treatment is a watch-and-wait strategy, with laboratory and clinical examinations carried out every 3 months during the first year and every 3 to 12 months afterward.3,10 Some patients may feel that nothing is being done, experience substantial anxiety, and find the checkups burdensome.1,11,12 In fact, compared with age-matched healthy controls, patients with early-stage CLL fared poorly in all functioning scales, and the 3 leading factors impacting quality of life were fatigue, financial difficulties, and worries/fears about health and functioning.11 Therefore, it is important to establish a trusting relationship with patients and to address their psychological distress by regular counseling regarding their disease and the evidence that supports the watch-and-wait strategy.1,11 It is equally important to address physical and financial concerns early.11
Several studies have shown that early treatment with chemotherapeutic drugs does not result in a survival benefit.13,14 In addition, a meta-analysis of clinical trials in 1999 found that cytotoxic treatment of early-stage disease can be safely deferred.15 Therefore, early-intervention therapy with antileukemia drugs, including targeted therapies, alone or in combination with monoclonal antibodies, is not indicated.10
Current therapeutic options for CLL
Most patients with intermediate- and high-risk disease benefit from the initiation of treatment.3,10 However, some can be monitored without therapy until there is evidence of active disease.3,10 Therapy should only be initiated if active disease is clearly documented.3,10 Criteria that indicate the presence of active disease include evidence of progressive marrow failure, massive/progressive/symptomatic splenomegaly or lymphadenopathy, progressive lymphocytosis, autoimmune complications, symptomatic extranodal involvement, and other disease-related symptoms.3,10
The various therapeutic agents currently available for the treatment of patients with CLL are shown in Table 2.16 Whenever possible, patients should be treated within a clinical trial both in the first-line setting as well as for relapsed or refractory disease.3 There are various treatment strategies recommended for the first-line setting, including time-limited CIT (fludarabine, cyclophosphamide, and rituximab [FCR] for fit patients with no TP53 mutation or del[17p] and any IGHV mutation status; chlorambucil plus obinutuzumab for unfit patients with no TP53 mutation or del[17p] and any IGHV mutation status); time-limited venetoclax plus obinutuzumab (for all patients with a TP53 mutation or del[17p], and unfit patients with no TP53 mutation or del[17p] and any IGHV mutation status); or continuous treatment with BTK inhibitors until progression (ibrutinib for all patients; acalabrutinib for all patients with a TP53 mutation or del[17p], and unfit patients with no TP53 mutation or del[17p] and any IGHV mutation status).3 Other options for patients with a TP53 mutation or del(17p) include monotherapy with venetoclax, and idelalisib plus rituximab.3
Treatment for relapsed disease should only be initiated if the patient is symptomatic.3,10 If the remission lasted >36 months, then the frontline therapy should be repeated, except for FCR due to increased toxicity rates and risk of secondary myeloid neoplasm.3 The preferred second-line regimens are venetoclax plus rituximab for 24 months, or a BTK inhibitor (ibrutinib, acalabrutinib, or another) as continuous therapy.3 Idelalisib plus rituximab is an alternative for all patient groups.3 Finally, venetoclax alone following CIT or BTK inhibitors can be used for patients with a TP53 mutation or del(17p) or those with a short remission duration (<36 months).3
For patients who are refractory to CIT, have a TP53 mutation or del(17p), but are fully responsive to novel inhibitory therapy, allogeneic stem-cell transplantation (allo-SCT) should be considered as an option for curative treatment if the risk of transplantation is low.3 Allo-SCT should also be considered for patients who are refractory to CIT and novel inhibitor therapy, including those at a higher risk of nonrelapse mortality and those with Richter’s transformation in remission after therapy and clonally related to CLL.3
When discussing treatment options with patients, it is important to keep in mind that the treatment goals of conventional therapy are symptom alleviation, reversing cytopenia, improving HRQOL, and prolonging overall survival.17 It is difficult to assess the overall survival benefit of the new therapeutic options as they have only become available very recently (ibrutinib was approved in 2016).17 Therefore, there is a lack of long-term survival data for many of the newer therapies.17 Instead, the relative clinical benefit of the various therapies has been estimated using the progression-free survival rate at a follow-up of ≥5 years.17 Another surrogate end point being evaluated in clinical trials is minimal residual disease (MRD).17
Implications of the new therapeutic options
Targeted agents, especially BTK inhibitors and the BCL2 inhibitor venetoclax, have changed the treatment landscape for patients with CLL as they provide effective options in the first- and second-line settings.18 This is particularly true for frail patients with comorbidities, as these agents are more effective and better tolerated than CIT.18 Targeted therapies have become the preferred first-line treatments for most patients.18 However, for young and fit patients with mutated IGHV, CIT is still a valid option.18
The availability of these new treatment options has created an opportunity for patient preferences to play a substantial role in treatment decisions.19 Oncology nurse navigators can help patients understand the choices they have available and the implications for HRQOL in the short- and long-term. When choosing between continuous or fixed-duration BTK inhibitors or BCL2 inhibitors, it is important to balance the tolerability of the regimen with improving survival, as well as patient preferences and HRQOL.18 Therefore, the approach should be individualized based on each patient’s comorbidities and risk profile, with young, fit patients benefiting the most from fixed-duration regimens.18 These regimens may also be indicated for patients with certain comorbidities to limit drug–drug interactions.18 Some patients may prefer the shorter treatment duration, particularly the reduction in chronic toxicities and fewer long-term outpatient monitoring visits.18 However, with fixed-duration regimens there is a need for more frequent hospital visits in the short-term and venetoclax ramp-up is associated with increased toxicity, which are important HRQOL factors to keep in mind.18
Continuous treatment may be a good option for older patients with comorbidities.18 Some patients find continuous therapy reassuring.18 However, there is a risk of poor long-term adherence to continuous therapy, which should be discussed at treatment initiation.18 In short, when deciding between continuous and fixed-duration regimens, patients have to balance the emotional impact of lifelong treatment versus stopping treatment before a cure can be declared, and possible low-grade AEs for the rest of their lives versus a higher-toxicity treatment with a fixed duration. The best practice is to have a conversation about compliance and setting patient expectations from the beginning.
Management of AEs
Despite the high efficacy of newer agents, AEs are one of the leading causes of treatment discontinuation.20 Therefore, to ensure compliance and safety with ongoing treatment, it is essential that the healthcare team is aware of common AEs and how to manage them.20 In addition, patients should be educated on the common or serious AEs and reminded to report any changes in medical problems to their healthcare teams.21 Common treatment-emergent AEs are summarized in Table 3.22-36
Fatigue is the most commonly reported symptom and may be associated with advanced disease and age.1It is important to assess and address possible sources of underlying fatigue such as stress, anemia, infection, dehydration, the presence of comorbid conditions, and insomnia, as this can help patients manage their symptoms and improve their overall quality of life.1
As mentioned above, patients with CLL are at an increased risk of infections, which can be exacerbated by treatment.1,10 Therefore, the use of corticosteroids and other immunosuppressive agents should be restricted.3 For patients with recurrent infections, antibiotics or antiviral prophylaxis is recommended.3 If possible, routine vaccinations (influenza and pneumococcus) should be performed before the initiation of treatment.3,10 However, live vaccines are contraindicated because of the risk of severe or fatal complications.10 Hematologic toxicities, such as cytopenias, are also common in patients with CLL, and it can be difficult to determine if they are caused by the treatment or the underlying CLL.10
In addition to vaccines, other supportive care strategies include administration of growth factors for patients under myelosuppressive CIT, and to support patients with prolonged cytopenias following treatment with alemtuzumab.10 Some patients with anemia might benefit from erythropoiesis factors as well.10 Finally, immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) should be treated with glucocorticoids initially.10 For AIHA, second-line treatment options include rituximab, splenectomy, intravenous immunoglobulins, and/or cyclosporine A, azathioprine, low-dose cyclophosphamide, or alemtuzumab.10 For ITP, second-line treatment options include rituximab, immunosuppressive agents, or thrombopoietin analogs.10
Nursing care and shared decision-making
Shared decision-making (SDM) is a process by which patients are informed of potential treatment options as well as the risks and benefits associated with these options and are able to incorporate their personal preferences and values into the decision-making process as they partner with their healthcare providers.19 For patients with CLL, education should include information on the disease, such as the natural course of CLL, symptom progression, available treatments, and treatment side effects as well as an emphasis on empowerment and SDM.1,19 A pilot study reported an improvement in patient knowledge, empowerment, and SDM of approximately 10% following education of patients with CLL and the oncology care team.19 Furthermore, patients reported high activation levels concurrent with the educational activities, which suggests that education may facilitate SDM through patient activation.19
However, CLL education can be challenging to do as the treatment landscape has evolved quickly in the past few years and there is a lack of recommendations regarding a standard sequencing of treatments.19 Oncology nurse navigators should explore potential barriers to care, such as the patient’s health literacy, language or cultural barriers, comorbidities, the patient’s support system (family and friends), and access to transportation, during the initial encounter with the patient.5 The most common barriers to care reported by patients with cancer are problems with medical communications, a lack of social support, and medical insurance concerns.37 Patients should be encouraged to reach out if they encounter any barriers acquiring their medications.21 Most patients will not be able to start a new therapy on the day the prescription is written.21 Prescriptions may require prior insurance authorization, delaying the start of therapy, and even when covered may have high copays that require the patient to apply for financial assistance.21 This needs to be taken into consideration when scheduling concomitant intravenous medication.21
Since many of the therapeutic options for CLL consist of oral therapies that are taken at home continuously with no defined end point, monitoring patient adherence to therapy is key for treatment success.21 Adherence is defined as the extent to which patients take medications as prescribed, and it is important to stress the adherence to the prescribed dose and the need for the medication to be taken at the same time(s) each day.21,38 Adherence should be assessed at each visit, with more frequent assessments being recommended during therapy initiation and when managing toxicities.21
SDM strategies should include methods to engage patients within community settings as they can provide a structure for educational and quality improvement opportunities.19 As mentioned above, patients with CLL can experience anxiety and lower quality of life. Nurses can identify patients at risk for psychological distress and poor diagnosis adaptation and help guide them to supportive care in the clinic and the community.1 As social support provides patients with an emotional and social network that can help them cope with the diagnosis and lifestyle changes, patients should be encouraged to involve their family and friends in their care, as well as joining support groups with other patients with CLL.1
Although long-lasting remissions are observed in a minority of patients treated with CIT, allo-SCT, and venetoclax-based combinations, it is not clear if these are equivalent to a functional cure and so, continued observation and follow-up are recommended for all patients.3 The follow-up should include a total blood cell count and palpation of lymph nodes, liver, and spleen every 3 to 12 months, with special attention to the appearance of autoimmune cytopenia, for totally asymptomatic patients.3 Active monitoring for secondary malignancies is also recommended.3
Patients with CLL typically have regular interactions with the healthcare system. While not on treatment, patients have regular laboratory and physical examinations to monitor disease progression.39 During treatment periods, patients go to healthcare facilities for treatment administration as well as for monitoring tolerability and response.39 The COVID-19 pandemic has disrupted access to healthcare globally, including for patients with CLL.40
For patients with CLL, the pandemic is also particularly worrisome as these patients are generally older and have a dysregulated immune system, putting them at a higher risk of severe COVID-19.41 Furthermore, many CLL therapies are associated with an increased risk of infection.41 On the other hand, the weakened immune system of patients with CLL may limit the COVID-19 inflammatory storm and the accompanying disease severity.41 Various studies have analyzed the incidence and mortality rates of COVID-19 in patients with CLL.40-42 To date, there is no evidence that indicates a higher incidence of severe COVID-19 in patients with CLL compared with other cancers.42 However, patients with CLL, both in the watch-and-wait and treated groups, and severe COVID-19 have a high mortality rate of approximately 30%.40,41 As is the case with the general population, the severity of COVID-19 increased with age in patients with CLL.41
It is important to encourage patients with CLL to maintain strict preventive measures (masks, hand-washing, and social distancing) as they have an increased risk of morbidity and mortality from COVID-19.41,43 The number of routine hospital visits and laboratory examinations should be limited and replaced whenever possible by online controls.41 The American Society of Hematology (ASH) recommends postponing CLL treatment initiation, if possible.44 This recommendation is shared by most experts worldwide.41 However, patients who require immediate therapy should receive the best available option considering disease and patient-specific factors.41,44 Preference should be given to regimens that can be administered in the outpatient setting and that require fewer hospital visits.41,44 Anti-CD20 antibodies and the initiation of venetoclax should be avoided.41,44 For patients already on therapy, the use of laboratories closer to home and telemedicine is recommended.44
Patients who test positive for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and have mild symptoms of COVID-19 should continue their CLL treatment.41,44 Decisions regarding treatment of patients who deteriorate or develop severe COVID-19 should be made on a case-by-case basis.41,44 In general, anti-CD20 antibodies should be discontinued.41,44 Stopping BTK inhibitors can result in a CLL flare that mimics COVID-19 symptoms, which can be reversed by reinstituting the BTK inhibitor.41,44 ASH recommends holding venetoclax therapy in patients with COVID-19.41,44
In general, ASH recommends COVID-19 vaccination of patients with a CLL/small lymphocytic lymphoma diagnosis.44 The immunodeficiency that is characteristic of CLL results in a poor immune response (20%-40%) to vaccines, including the COVID-19 vaccines.41 Patients in remission after treatment have the highest responses, followed by treatment-naïve patients.41 Patients on active treatment, particularly those on BTK inhibitors and venetoclax, had low responses to vaccination and none of the patients exposed to anti-CD20 antibodies in the 12 months prior to vaccination mounted a response.41 However, these studies only assessed the humoral response to the COVID-19 vaccines, and there is some evidence that T-cell responses are generally preserved.41 These results indicate that COVID-19 vaccination might be more effective if administered prior to treatment initiation.41
It is difficult to determine if the changes implemented during the COVID-19 pandemic will have a lasting effect in the standard of care for patients with CLL. For now, ASH recommends that standard treatment guidelines should be followed in areas where the COVID-19 pandemic is under control.44
The treatment landscape for patients with CLL is rapidly evolving. Studies are assessing MRD guidance for treatment discontinuation using either BTK inhibitors or BCL2 inhibitor combinations administered either continuously or as fixed-duration treatments.18 The use of MRD to guide clinical practice is an important knowledge gap at the moment.18 In addition, various studies are assessing the use of BTK inhibitors, PI3K inhibitors, BCL2 inhibitors, and novel agents (ARQ-531, LOXO-305) as monotherapies and in combination regimens.18 The use of chimeric antigen receptor T-cells in combination regimens is also being investigated.18 This highlights that the treatment landscape for patients with CLL is in a process of rapid change, and represents an opportunity for improved outcomes and HRQOL for patients.
On the other hand, this upgraded therapeutic toolbox also represents a challenge for healthcare professionals as many questions remain unanswered.45 Optimal treatment sequences as well as the most effective combinations will need to be defined with the goal of having time-limited and chemotherapy-free regimens that provide the longest remissions and potentially cure.45 Aspects of financial toxicity will need to be taken into consideration as patients start to be prescribed these agents outside of clinical trials.45
The COVID-19 pandemic has further complicated the management of patients with CLL and added a barrier to access to care. Furthermore, the full effect of the pandemic on this population is not clear. It is possible that some patients will be diagnosed with a more advanced disease because of delayed doctor appointments.
Oncology nurse navigators play a key role in multidisciplinary teams that serve patients diagnosed with CLL. Nurse navigators coordinate the care of patients with CLL by helping them cope with their diagnosis, providing patient education and promoting medical adherence, assisting in the management of AEs, and serving as a central point of contact for patients and their families and a conduit of information between other healthcare professionals and the patient. As such, these specialists are best suited to help patients overcome present and future barriers to care.
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- Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127:208-215.
- IMBRUVICA® (ibrutinib) approved by U.S. FDA for the first-line treatment of chronic lymphocytic leukemia. https://news.abbvie.com/news/imbruvica-ibrutinib-approved-by-us-fda-for-first-line-treatment-chronic-lymphocytic-leukemia.htm. Accessed November 14, 2021.
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- Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131:2745-2760.
- Youron P, Singh C, Jindal N, et al. Quality of life in patients of chronic lymphocytic leukemia using the EORTC QLQ-C30 and QLQ-CLL17 questionnaire. Eur J Haematol. 2020;105:755-762.
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- FDA approval sought for ublituximab/umbralisib combo in CLL. www.onclive.com/view/fda-approval-sought-for-ublituximab-umbralisib-combo-in-cll. Accessed November 14, 2021.
- Rai KR, Stilgenbauer S. Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia. UpToDate. www.uptodate.com/contents/selection-of-initial-therapy-for-symptomatic-or-advanced-chronic-lymphocytic-leukemia. Accessed November 22, 2021.
- Eyre TA, Hori S, Munir T. Treatment strategies for a rapidly evolving landscape in chronic lymphocytic leukaemia management. Hematol Oncol. 2021;doi:10.1002/hon.2943.
- Rocque GB, Williams CP, Halilova KI, et al. Improving shared decision-making in chronic lymphocytic leukemia through multidisciplinary education. Transl Behav Med. 2018;8:175-182.
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