Navigating Chronic Lymphocytic Leukemia: The Critical Importance of the First 90 Days

Navigation Strategies to Improve Care, with Expert Commentary by

Emily Gentry, BSN, RN, HON-ONN-CG, OCN

Chelsea C. Passwater, DNP, RN, AGCNS-BC

Nikki L. Barkett, BSN, RN, OCN

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, with an estimated 21,250 new cases and 4320 attributed deaths in 2021.¹ There is a higher incidence of CLL in men compared with women (6.8 vs 3.5 cases per 100,000/year) and in white (7.3 [men] and 3.9 [women] cases per 100,000/year) compared with black (4.8 [men] and 2.4 [women] cases per 100,000/year) patients.²

Overview of the Disease State

CLL may have a stable course but can become aggressive with frequent episodes of relapse, or it may transform into an aggressive type of lymphoma, typically diffuse large B-cell lymphoma (DLBCL), known as Richter transformation.³ The natural history of CLL is variable, with survival estimates ranging from approximately 2 to 20 years.⁴ Most patients with CLL follow a “watch-and-wait” approach whereby the progression rate of disease is determined, and then the patient is assessed for symptom development periodically.⁵

Ms Passwater: It is important to note that patients may be in the watch-and-wait stage for a varied amount of time, depending on the specific nature of their disease. There is a lot of fear and anxiety from a patient perspective here. From a navigator perspective, it is critical to ensure that these patients are well educated about this period, so they understand the importance of follow-up and follow-through. Navigators can help ensure that patients do not fall through the cracks, complete timely follow-up, and understand the nuances of this watch-and-wait period.

CLL is a lymphoid malignancy that is characterized by the accumulation and proliferation of mature CD5+ B-cells in the bone marrow, blood, and lymphoid tissues.³ The presence in the blood of at least 5 × 10⁹/L monoclonal B-cells of typical phenotype is required for a diagnosis of CLL. If patients have <5 × 10⁹/L circulating CLL cells, they may be diagnosed with small lymphocytic lymphoma if they also have extramedullary disease, lymphadenopathy, or organomegaly, or with monoclonal B-cell lymphocytosis (MBL) if they do not.

CLL is preceded by high-count MBL, which is a premalignant state that is often unnoticed.⁶ Approximately 1% of cases of high-count MBL develop into CLL that requires therapy each year,⁷ with up to 10% of patients with symptomatic CLL who develop Richter transformation.⁸ In contrast, approximately 30% of patients with CLL do not require therapy and succumb to other causes, with 1% to 2% experiencing spontaneous disease regression.⁹

Transformation into aggressive lymphoma occurs in up to 10% and corresponds with DLBCL in more than 90% of cases, but Hodgkin lymphoma can also occur.¹⁰ Transformed DLBCL often carries CDKN2A deletions and MYC amplifications or translocations in addition to genomic alterations that were present in the original CLL, but it lacks common mutations found in primary DLBCL, indicating that this is a different biological category.⁸ Richter transformation can be seen in patients treated with Bruton tyrosine kinase (BTK) inhibitors. Although these tumors do not often acquire PLCG2 or BTK mutations, subclones with additional, independent mutations may emerge if they were present in the original CLL.^11,12

Two main clinical staging systems have been developed for CLL—the Rai staging system and the Binet staging system.^13,14 The Rai staging system divides patients into low-, intermediate-, and high-risk groups, which correspond with Rai stages of 0-I, II, and III-IV, respectively.¹³ Clinical features correspond with each Rai stage. Lymphocytosis only is present in Rai stage 0. In stage I, lymphocytosis and lymphadenopathy are observed. In stage II (intermediate-risk group), lymphocytosis, lymphadenopathy, and splenomegaly are present. In Rai stage III (high-risk group), lymphocytosis and low hemoglobin levels (≤11 g/dL) are present, and in stage IV (high-risk group), lymphocytosis and thrombocytopenia (≤100,000/mL) are present. The Binet staging system divides patients into low-, intermediate-, and high-risk groups, which correspond with Binet stages of A, B, and C, respectively, and clinical features correspond with each stage.¹⁴ In Binet stage A, <3 areas of lymphadenopathy are present, and in stage B, ≥3 areas of lymphadenopathy are present. Patients assigned Binet stage C have anemia (hemoglobin <10 g/dL) and/or thrombocytopenia (≤100,000/mL), regardless of the number of areas of lymphadenopathy.

Based on the availability of new information and therapeutic options for patients with CLL, there is an increased opportunity for patients’ personal preferences to be considered in the treatment decision-making process. Results have shown that an educational program contributed to improved patient activation, understanding of CLL, and desire and perception of shared decision-making.¹⁵

Ms Barkett: Individualized education is key, as CLL treatment varies for each individual (timing, course, when to start, etc). Health literacy is an important factor that must be considered when providing this education. Low health literacy is an independent risk factor for poor health outcome. As a navigator, it is important to educate patients/caregivers about the specifics of their CLL, ensuring patient/caregiver comprehension. Patients cannot expect to follow a textbook example of “how CLL is treated,” as each case is different based on patient age, comorbidities, and specifics related to the mutations/severity of their CLL. There are so many new options out there, and patients must be included in the shared decision-making process. The navigator can help with this education process and advocate for the patients based on their individualized wishes, needs, and goals for treatment. A big part of shared decision-making might include discussions regarding cost of treatments—the chronicity of CLL is very burdensome. All social determinants of health must be considered as factors in the final decision. For example, a patient with no transportation may need care closer to home or may opt for a treatment course that includes more oral oncolytics. All of these factors also play a role in patient adherence to their therapy. This is a key area that navigators can assess and follow the patient through. Networking with social work and community partners may be essential to assist patients with securing funding, resources, and even insurance to make their treatment as affordable as possible.

Genetics in CLL

Mutations in driver genes (eg, SF3B1, DDX3X, BIRC3, ATM) may be detected in patients with high-count MBL approximately 41 months prior to progression to CLL.^16,17 More commonly mutated genes in CLL include NOTCH1, TP53, and XPO1.^17,18 Patients with MBL and driver mutations experience a shorter time to first treatment.

Cytogenetics also play a role in CLL prognosis. Del(13q14) and trisomy 12 have been shown to confer a more favorable prognosis (median overall survival, 9.5-11 years), whereas del(11q22-23) and del(17p12) have been associated with a more unfavorable prognosis (median overall survival, 32 months-6.6 years).^19-21 Genetic sequencing results have also revealed favorable and unfavorable mutations that contribute to predicting prognosis, with more favorable genetics including NOTCH^wt, IGHV^mut, TP53^wt, and SF3B1^wt, and more unfavorable genetics including SF3B1^mut, IGHV^wt, TP53^mut, and NOTCH1^mut.^19-21

Ms Passwater: The new vocabulary and complexity of CLL can be overwhelming for patients and their caregivers. Navigators have an opportunity to provide patient education on therapy and cytogenetics to ensure the patient and family understand the disease process and treatment options.

Prognostic Factors and Predictive Models

The prognosis of patients with CLL was defined for many years using clinical parameters, including those in the Rai and Binet staging systems,^13,14 IGHV mutational status,²² and numerical aberrations determined by fluorescence in situ hybridization.¹⁹ The International Workshop on CLL (iwCLL) guidelines recommend evaluation of IGHV status and the presence or absence of TP53 aberrations in routine practice.²³ The more recent CLL International Prognostic Index (CLL-IPI) incorporates clinical and genomic/cytogenetic data, including age, clinical stage, beta2-microglobulin serum concentration, TP53 aberrations, and IGHV mutation status, into the prognostic score.²⁴ The CLL-IPI divides patients into low-, intermediate-, high-, and very high-risk groups. Median overall survival in the low-risk group was 93% at 5 years and 79% at 10 years. Median overall survival in the intermediate-risk group was 79% at 5 years and 39% at 10 years. Median overall survival in the high-risk group was 63% at 5 years and 22% at 10 years. Median overall survival in the very high-risk group was 23% at 5 years and 4% at 10 years. IGHV and TP53 have been shown to have the greatest impact on patient outcomes; therefore, simplified versions of the CLL-IPI using these 2 markers alone have been proposed.²⁵

The International Prognostic Score for Early-stage CLL (IPS-E) is a recently presented prognostic score designed to predict the likelihood that a patient with CLL will need treatment.²⁶ This is a 3-point system in which 1 point is assigned for each of the following: unmutated IGHV genes, absolute lymphocyte count higher than 15 × 10⁹/L, and palpable lymph nodes. Patients are assigned a risk category based on score, with low risk having a score of 0, intermediate risk having a score of 1, and high risk having a score of 2 to 3. Higher scores have been associated with increased risk for early treatment.

Indications for Treatment

CLL treatment is only indicated for patients who have active disease. The iwCLL criteria for treatment of active disease include the following²³:

• Progressive marrow failure (ie, new or worsening anemia, thrombocytopenia, or neutropenia)
• Massive, progressive, or symptomatic lymphadenopathy or splenomegaly
• Recurrent autoimmune complications
• Disease-related symptoms (eg, unintended weight loss, significant fatigue, persistent fevers, night sweats)
• Progressive lymphocytosis (increase of ≥50% over a 2-month period or lymphocyte doubling time <6 months)

Patients who do not meet these criteria should undergo age-appropriate cancer screening, annual dermatology visits for skin cancer screening, and appropriate vaccinations to reduce infection risk.²⁷ Patients with low- or intermediate-risk CLL should be monitored for disease progression every 6 to 12 months. Patients with high- or very high-risk CLL should be offered participation in early intervention trials and should be monitored for disease progression every 3 to 6 months.

Treatment

Treatment decisions are made based on individual aspects of the respective patients.²⁸ Initial therapy should be chosen to maximize efficacy and minimize overall toxicity, where the risk of treatment should be lower than the risk of disease. Although age is an important component of fitness, the chronologic age cutoff should be fluid to allow healthy older adults to benefit from more aggressive therapy and to spare younger patients with comorbidities unwarranted therapy-related risks. For all patients, treatment plans should be individualized based on clinical assessment and patient preference.

Not all patients require therapy for CLL. To date, the iwCLL recommends watchful observation for patients who have asymptomatic disease.²³ This recommendation is based on at least 2 randomized trials demonstrating that early therapy with chlorambucil monotherapy or fludarabine, cyclophosphamide, and rituximab (FCR) was not associated with prolonged overall survival in asymptomatic patients.^29,30 Both trials concluded that early therapy in asymptomatic patients was not associated with a prolonged overall survival.

For patients with symptomatic disease who require therapy, ibrutinib is often recommended based on clinical trial results.31-34 Ibrutinib has been shown to be superior in terms of response rate and progression-free survival, and has conferred longer overall survival.^31,32 Additionally, ibrutinib has been shown to be less toxic regarding severe adverse events or toxic deaths.

Ms Passwater: All oral oncolytics carry a stigma that they are “easier to tolerate” because they are a pill. This is simply not true. Adherence is a huge issue with this type of therapy—the navigator should assess and educate the patient, advocate for shared decision-making, and help monitor adherence to oral therapies.

Fit patients with mutated CLL without TP53 aberrations may be candidates for FCR, which can be completed in 6 months, whereas ibrutinib must be taken indefinitely. This option may be valuable for noncompliant patients or in patients for whom ibrutinib is contraindicated. With FCR treatment, caution must be taken in patients with NOTCH1 mutations because rituximab appears to have little added value.³⁵

Unfit patients may receive the frontline combination of venetoclax plus obinutuzumab (VO) based on trial results demonstrating superior response rates and progression-free survival, with a comparable safety profile.³⁶ VO was administered for 2 years, which may be appealing for older or unfit patients. The alternative BTK inhibitor acalabrutinib recently received FDA approval for frontline therapy.³⁷

Treatment for patients with relapsed/refractory disease depends on prior therapies used and the requirement for new treatment (eg, refractoriness vs intolerance). Ibrutinib is the gold-standard treatment for patients with relapsed/refractory disease^38-42; however, this is changing based on an increasing proportion of patients who receive frontline ibrutinib and the development of effective, alternative options.

Venetoclax may be considered for treatment of patients with relapsed/refractory CLL based on a superior response rate, progression-free survival, and overall survival.⁴³ Other possible treatments include PI3K inhibitors and alternative BTK inhibitors. The PI3K inhibitor idelalisib may have a role in patients with complex karyotypes,⁴⁴ those with a higher risk of progression and/or transformation following ibrutinib or venetoclax treatment,^12,45 or in older patients who generally do not tolerate ibrutinib.⁴⁶ Duvelisib is another FDA-approved PI3K inhibitor that exhibited a similar safety and efficacy profile.⁴⁷ The BTK inhibitor acalabrutinib is approved by the FDA for the treatment of relapsed/refractory CLL based on superior clinical trial results.⁴⁸

Despite the advances in available treatment options, some patients will fail to respond to initial therapy and should be considered for curative therapy. Currently, allogeneic hematopoietic cell transplantation is the only potentially curative option; however, it is associated with substantial morbidity and mortality. Although the number of patients referred for allogeneic hematopoietic cell transplantation has dropped significantly,⁴⁹ it should be recommended to young/fit patients who fail treatment with B-cell receptor/BCL-2 inhibitors, especially in those patients with TP53 aberrations or in the case of Richter transformation.^50,51

Treatment Considerations

For CLL, the chronic management strategy and drug administration schedule have contributed to a shift in the burden of treatment and adherence to the patient. As with chronic conditions, nonadherence has been associated with cancer progression and worse survival outcomes, and it also contributes to increased healthcare utilization and costs.^52,53 Therefore, adherence to therapy and identification of key drivers of medication use are paramount to the success of disease management and the development of adherence-promoting strategies to achieve improved patient outcomes.

Results from a retrospective database study revealed factors that may influence treatment adherence.⁵⁴ Patients enrolled in plans other than a preferred provider organization plan were more likely to be adherent, whereas patients who were aged 65 years or older, were residents of the southern United States, and had visited the emergency department during the 6-month period prior to oral oncolytic therapy initiation were less likely to be adherent. Adherent patients had a significantly lower likelihood of healthcare utilization and incurred lower medical costs but higher prescription costs; however, total costs were not significantly lower in these patients.

Ms Gentry: The correlation between adherence and healthcare costs for the CLL population is significant. With CLL treatment being provided in the outpatient setting and CLL patients taking oral therapies, navigators have an important role in providing care coordination, adverse event management, and barrier assessment to promote treatment adherence and patient care.

Because most patients are older than 65 years at diagnosis or requirement of therapy, many of these patients have multiple chronic comorbidities, such as renal insufficiency, arrhythmias, hypertension, or other conditions that limit quality of life and performance status.^55,56 Therefore, cooperative management with the primary care physician and/or other specialists is important for selecting appropriate treatment regimens.

Psychosocial Impact

Studies have shown that 10% to 15% of patients experience moderate to severe depression and anxiety symptoms at some point in their CLL journey.⁵⁷ Medical comorbidities, negative life events, and fatigue have been shown to predict symptoms. Among the most common impacts of CLL are worry, fear, depressed feelings, and work limitations.⁵⁸ Qualitative data obtained through social media applications are potentially useful in supporting concept identification for new instruments designed to assess patient-reported outcomes.⁵⁸ Because of the prolonged nature of the disease and treatment, studies have been conducted to assess parameters associated with the development of distress or depression. Subpopulations that may be at risk include those who live alone or have a high Charlson Comorbidity Index, whereas those at risk of distress are likely to be married or female.⁵⁹ Illness perceptions have been related to cancer-specific stress, depressive symptoms, and fatigue interference in patients with relapsed/refractory CLL.⁶⁰

Negative changes in sexuality, body image, and health-related quality of life in patients older than 45 years receiving treatment for hematologic malignancies are observed at 1 month following treatment, but these aspects recover to a great extent within 6 months.⁶¹ Patients receiving treatment for hematologic malignancies have reported a decreased importance of sexuality, sexual desire, and sexual ability after 1 month as well as more frequent distressing symptoms, such as feelings of tiredness.⁶² Oral targeted therapies are projected to improve survivorship among patients with CLL; however, they may impose a substantial financial burden.⁶³ Sustainable pricing strategies for these therapies are needed to avoid financial toxicity for patients. Notably, providing information related to even small out-of-pocket costs leads patients to change their selection for hypothetical treatments, which suggests that patients are sensitive to cost.⁶⁴

A study demonstrated the potential for optimizing the somatic, psychic, and spiritual end-of-life care following allogeneic stem cell transplantation.⁶⁵ Cooperation between the transplant team and the palliative care team is needed to realize the necessity of switching the curative concept into a palliative ambition in certain cases.

Ms Gentry: Providing psychosocial support to the patient diagnosed with CLL in the form of distress screening, identification of available community and national resources, and referrals for supportive care services, such as social work, behavioral medicine, pastoral care, nutrition, oncology rehabilitation, and financial navigators and advocates, is valuable in creating a comprehensive care plan.

A study of 12 participants describing their lives with CLL revealed the categories of “Living Under a Cloud of Illness,” “In the Beginning,” “Lens of Life,” “Preparing for Illness,” and “Advocating for Us.”⁶⁶ These findings may facilitate patient-centered care based on individual patient needs.

Caregiver Impact

Health-related quality of life of family caregivers has also been investigated. Compared with the general population, caregivers have been shown to have lower health utility scores.⁶⁷ CLL, low socioeconomic status, and minimal social support are associated with lower health utility scores of caregivers. A study of 123 relative caregivers demonstrated a significant association between poorer quality of life and increased care burden perception if they were caring for an older patient, if patients were dependent for daily activities, and if caregivers perceived having a low economic status.⁶⁸

Caregiving roles and tasks tend to change over time based on the patient’s condition and level of independence.⁶⁹ The caregiving role expands as a patient becomes sicker, particularly with in-home care delivery, and when patients approach the end of life. Some care transitions are more expected, with emergency department visits being potentially traumatic. Caregivers of patients with leukemia must be present for extended hospital stays, and they must manage adverse events and other complications of toxic treatments over the disease continuum.

Ms Passwater: Caregivers of CLL patients face significant responsibilities. CLL is a chronic illness. Caregivers may change during the course of the CLL journey. Healthcare providers generally do a poor job of assessing caregivers’ needs. For example, there are areas related to sexuality (spouses with CLL may have decreased sex drive, increased fatigue, and lack of desire to engage in activities) and caregiver burnout.

Ms Barkett: Due to the chronicity of the disease, caregivers juggle competing work priorities, financial concerns related to the cost of CLL, and resources such as gas, groceries, and other challenges. All of these must at least be acknowledged by the navigator, and if possible, supported with solutions.

References

1. American Cancer Society. Key Statistics for Chronic Lymphocytic Leukemia. www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/key-statistics.html. January 12, 2021. Accessed March 8, 2021.
2. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2017. National Cancer Institute; 2019. Posted to the SEER website, April 2020. https://seer.cancer.gov/archive/csr/1975_2017/results_merged/sect_13_leukemia.pdf.
3. Delgado J, Nadeu F, Colomer D, Campo E. Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies. Haematologica. 2020;105:2205-2217.
4. Scarfò L, Ferreri AJM, Ghia P. Chronic lymphocytic leukaemia. Crit Rev Oncol Hematol. 2016;104:169-182.
5. Gribben JG. How I treat CLL up front. Blood. 2010;115:187-197.
6. Landgren O, Albitar M, Ma W, et al. B-cell clones as early markers for chronic lymphocytic leukemia. N Engl J Med. 2009;360:659-667.
7. Rawstron AC, Bennett FL, O’Connor SJM, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008;359:575-583.
8. Rossi D, Spina V, Gaidano G. Biology and treatment of Richter syndrome. Blood. 2018;131:2761-2772.
9. Del Giudice I, Chiaretti S, Tavolaro S, et al. Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic features of 9 cases. Blood. 2009;114:638-646.
10. Al-Sawaf O, Robrecht S, Bahlo J, et al. Richter transformation in chronic lymphocytic leukemia (CLL) – a pooled analysis of German CLL Study Group (GCLLSG) front line treatment trials. Leukemia. 2021;35:169-176.
11. Kadri S, Lee J, Fitzpatrick C, et al. Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL. Blood Adv. 2017;1:715-727.
12. Miller CR, Ruppert AS, Heerema NA, et al. Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib. Blood Adv. 2017;1:1584-1588.
13. Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219-234.
14. Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48:198-206.
15. 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.
16. Puente XS, Beà S, Valdés-Mas R, et al. Non-coding recurrent mutations in chronic lymphocytic leukaemia. Nature. 2015;526:519-524.
17. Barrio S, Shanafelt TD, Ojha J, et al. Genomic characterization of high-count MBL cases indicates that early detection of driver mutations and subclonal expansion are predictors of adverse clinical outcome. Leukemia. 2017;31:170-176.
18. Winkelmann N, Rose-Zerilli M, Forster J, et al. Low frequency mutations independently predict poor treatment-free survival in early stage chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. Haematologica. 2015;100:e237-e239.
19. Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-1916.
20. Foa R, Del Giudice I, Guarini A, et al. Clinical implications of the molecular genetics of chronic lymphocytic leukemia. Haematologica. 2013;98:675-865.
21. Gaidano G, Rossi D. The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment. Hematology Am Soc Hematol Educ Program. 2017;2017:329-337.
22. Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848-1854.
23. 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.
24. International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta- analysis of individual patient data. Lancet Oncol. 2016;17:779-790.
25. Delgado J, Doubek M, Baumann T, et al. Chronic lymphocytic leukemia: a prognostic model comprising only two biomarkers (IGHV mutational status and FISH cytogenetics) separates patients with different outcome and simplifies the CLL-IPI. Am J Hematol. 2017;92:375-380.
26. Condoluci A, Terzi di Bergamo L, Langerbeins P, et al. International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia. Blood. 2020;135:1859-1869.
27. Parikh SA. Chronic lymphocytic leukemia treatment algorithm 2018. Blood Cancer J. 2018;8:93.
28. Jaksic B, Pejsa V, Ostojić-Kolonić S, et al. Guidelines for diagnosis and treatment of chronic lymphocytic leukemia. Krohem B-Cll 2017. Acta Clin Croat. 2018;57:190-215.
29. Dighiero G, Maloum K, Desablens B, et al. Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med. 1998;338:1506-1514.
30. Herling CD, Cymbalista F, Gross-Ophoff-Müller C, et al. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial. Leukemia. 2020;34:2038-2050.
31. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425-2437.
32. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432-443.
33. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379:2517-2528.
34. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:43-56.
35. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014;123:3247-3254.
36. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with cll and coexisting conditions. N Engl J Med. 2019;380:2225-2236.
37. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395:1278-1291.
38. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32-42.
39. Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015;16:169-176.
40. O’Brien S, Jones JA, Coutre SE, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016;17:1409-1418.
41. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371:213-223.
42. Chanan-Khan A, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17:200-211.
43. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018; 378:1107-1120.
44. Kreuzer KA, Furman RR, Stilgenbauer S, et al. The impact of complex karyotype on the overall survival of patients with relapsed chronic lymphocytic leukemia treated with idelalisib plus rituximab. Leukemia. 2020; 34:296-300.
45. Anderson MA, Tam C, Lew TE, et al. Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax. Blood. 2017;129:3362-3370.
46. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80-87.
47. Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib versus ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018;132:2446-2455.
48. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38:2849-2861.
49. Gribben JG. How and when I do allogeneic transplant in CLL. Blood. 2018;132:31-39.
50. Kharfan-Dabaja MA, Kumar A, Hamadani M, et al. Clinical practice recommendations for use of allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia on behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2016;22:2117-2125.
51. Dreger P, Ghia P, Schetelig J, et al. High-risk chronic lymphocytic leukemia in the era of pathway inhibitors: integrating molecular and cellular therapies. Blood. 2018;132:892-902.
52. Greer JA, Amoyal N, Nisotel L, et al. A systematic review of adherence to oral antineoplastic therapies. Oncologist. 2016;21:354-376.
53. Cutler RL, Fernandez-Llimos F, Frommer M, et al. Economic impact of medication non-adherence by disease groups: a systematic review. BMJ Open. 2018;8:e016982.
54. Dashputre AA, Gatwood KS, Gatwood J. Medication adherence, health care utilization, and costs among patients initiating oral oncolytics for multiple myeloma or chronic lymphocytic leukemia/small lymphocytic lymphoma. J Manag Care Spec Pharm. 2020;26:186-196.
55. Montserrat E, Moreno C. Chronic lymphocytic leukaemia: a short overview. Ann Oncol. 2008;19(Suppl 7):vii320-vii325.
56. Baumann T, Delgado J, Santacruz R, et al. Chronic lymphocytic leukemia in the elderly: clinico-biological features, outcomes, and proposal of a prognostic model. Haematologica. 2014;99:1599-1604.
57. Robbertz AS, Weiss DW, Awan FT, et al. Identifying risk factors for depression and anxiety symptoms in patients with chronic lymphocytic leukemia. Support Care Cancer. 2020;28:1799-1807.
58. McCarrier KP, Bull S, Fleming S, et al. Concept elicitation within patient-powered research networks: a feasibility study in chronic lymphocytic leukemia. Value Health. 2016;19:42-52.
59. Shreders AJ, Niazi SK, Hodge DO, et al. Correlation of sociodemographic and clinical parameters with depression and distress in patients with hematologic malignancies. Ann Hematol. 2018;97:519-528.
60. Westbrook TD, Maddocks K, Andersen BL. The relation of illness perceptions to stress, depression, and fatigue in patients with chronic lymphocytic leukaemia. Psychol Health. 2016;31:891-902.
61. Olsson C, Sandin-Bojö AK, Bjuresäter K, Larsson M. Changes in sexuality, body image and health related quality of life in patients treated for hematologic malignancies: a longitudinal study. Sex Disabil. 2016;34:367-388.
62. Olsson C, Sandin-Bojö AK, Bjuresäter K, Larsson M. Patients treated for hematologic malignancies: affected sexuality and health-related quality of life. Cancer Nurs. 2015;38:99-110.
63. Chen Q, Jain N, Ayer T, et al. Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States. J Clin Oncol. 2017;35:166-174.
64. Mansfield C, Masaquel A, Sutphin J, et al. Patients’ priorities in selecting chronic lymphocytic leukemia treatments. Blood Adv. 2017;1:2176-2185.
65. Busemann C, Jülich A, Buchhold B, et al. Clinical course and end-of-life care in patients who have died after allogeneic stem cell transplantation. J Cancer Res Clin Oncol. 2017;143:2067-2076.
66. Bell R. Developing a clinical program based on the needs of patients with chronic lymphocytic leukemia: preparing for illness episodes. J Adv Pract Oncol. 2017;8:462-473.
67. Yu H, Zhang H, Yang J, et al. Health utility scores of family caregivers for leukemia patients measured by EQ-5D-3L: a cross-sectional survey in China. BMC Cancer. 2018;18:950.
68. Deniz H, Inci F. The burden of care and quality of life of caregivers of leukemia and lymphoma patients following peripheric stem cell transplantation. J Psychosoc Oncol. 2015;33:250-262.
69. Dionne-Odom JN, Currie ER, Johnston EE, Rosenberg AR. Supporting family caregivers of adult and pediatric persons with leukemia. Semin Oncol Nurs. 2019;35:150954.