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Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults in the United States, accounting for about 35% of all leukemia cases.¹ In 2019, 20,720 patients were diagnosed with CLL, and the disease killed an estimated 3930 people.² The median age at diagnosis was 70, and 67% of new cases were in those ages 65 years and older. In the big picture, it is not a widely prevalent cancer, representing 1.2% of all new US cancer cases and 0.6% of all cancer deaths. It is seen more in men, with 6.8 new cases per 100,000, compared to 3.5 diagnoses for 100,000 women.²

Fortunately, there are many treatment options, and the 5-year survival rate is 85.1%, based on 2009-2015 data. The percentages of those who died from CLL are highest among those aged 75 years and older, at 68.7%, based on data from 2012-2016.² The median overall survival is 10 years, but that figure greatly depends on individual situations, and those with CLL have a shorter life expectancy than the general population compared to like ages and genders.³ In 2016, an estimated 178,206 people were living with CLL in the United States, and rates of death have fallen 2.9% annually on average from 2007 to 2016. Rates of new CLL cases has not changed significantly in the last decade.²

In CLL, cells in the bone marrow that will become lymphocytes only partly mature.⁴ As these cancerous cells multiply, they replace the normal lymphocytes, eventually moving into the bloodstream. This increases the white blood cell count, and they can spread to lymph nodes and organs like the liver or spleen. These cancerous cells are less effective at fighting infections. 

A CLL diagnosis requires at least at least 5000 monoclonal lymphocytes (per mm³) in the blood.⁴ CLL can be indolent or grow quickly, differentiating whether the person receives immediate treatment. CLL is often diagnosed as an incidental finding during a routine or unrelated blood test by finding a high number of lymphocytes. The person may not be experiencing symptoms. There are no routine screening tests for CLL.⁵ Symptoms, when present, can be vague and include weakness, fatigue, idiopathic weight loss, fever, chills, night sweats, swollen lymph nodes, bruising or bleeding easily, petechiae, and a feeling of fullness (from an enlarged spleen and/or liver).⁶

In the United States, staging is typically done using the Rai system, which uses three risk groups for treatment based on physical examination, bone marrow counts, and blood count. The physical exam portion includes levels of lymph node, spleen, and liver enlargement. Abnormal blood counts include lymphocytosis, which is a high number of lymphocytes not linked to other causes.⁵ Staging is partly determined by how close to normal red blood cell and platelet counts are. Rai stage 0 is low risk (median survival: 150 months). Rai stages I-II are intermediate risk (median survival: 71-101 months), and Rai stages III-IV are high risk (median survival: 19 months).⁷ People with indolent CLL tend to live longer and may be able to delay treatment.⁵ CLL is also described as asymptomatic, symptomatic or progressive, refractory, or recurrent.⁶

There are no known risk factors for CLL, other than exposure to chemicals like Agent Orange or benzene, and exposure to radon. Those with a family history of first-degree relatives with CLL have more than twice the risk for CLL than those without that history. Those with advanced age are at higher risk than younger ages. About 9 of 10 people with CLL are over age 50, and males have a higher risk for CLL than females. There is no known risk from lifestyle factors like diet or smoking.⁸ More than 80% of CLL cases show chromosomal abnormalities.³   

In the United States, CLL is more common in white males, at 7.3 per 100,000 persons (3.8 per 100,000 persons for white women), compared to 4.9 black males per 100,000 (2.4 black females per 100,000), and lower numbers for those of Asian, Hispanic, American Indian origin.⁵

CLL prognosis depends on a number of factors. Prognosis is best for those with a non-diffuse pattern of bone marrow involvement, a deletion of part of chromosome 13 (del(13p)) but no other chromosome abnormalities, less than 20% of CLL cells containing the ZAP-70 protein, less than 30% of CLL cells containing CD38, and CLL cells with a mutated gene for immunoglobulin heavy chain variable region (IGHV).⁵

Adverse prognostic factors include advanced age, a diffuse pattern of bone marrow involvement, deletions of part of chromosomes 17 (del(17p)) or 11 (del(11q)), trisomy 12 in CLL cells, lymphocyte doubling time of less than a year, high blood levels of beta-2-microglobulin, increased fraction of prolymphocytes in the blood, a high proportion (20% or 30% respectively) of CLL cells with proteins ZAP-70 or CD38, CLL cells with non-mutated gene for the IGHV mutation, and CLL cells without the TP53 gene.⁵ The international prognostic score (CLL‐IPI) incorporates genetic, biological and clinical variables to separate patients into distinct risk groups.⁹

Those with a deletion of the short arm of chromosome 17 (del(17p)) and/or the TP53 gene mutation predict chemoimmunotherapy (CIT) resistance and a shorter time to progression, even with most targeted therapies.⁹

Patients with CLL report experiencing a substantial disease burden, with the disease impacting energy levels in 68% of respondents, sleep patterns in 44%, and overall quality of life in 54% of respondents.¹⁰

Patients with CLL also have a higher risk of developing other cancers, compared to age- and gender-matched cohorts. CLL patients treated with fludarabine, cyclophosphamide, and rituximab (FCR) have a 2.38 times greater risk of developing a second cancer than the general population.³ 

Those with CLL have a higher risk of infections, partly because their immune systems do not function properly. CLL involves B lymphocytes that typically make infection-fighting antibodies. Some with CLL can get autoimmune hemolytic anemia from the antibodies attacking red blood cells or autoimmunity from the body attacking its normal blood cells, leading to low blood counts. The antibodies can also attack white blood cells, resulting in leukopenia.⁵  

A Danish study showed that those with comorbid conditions experienced higher rates of death during the follow-up period after treatment, at 56% compared to 42% with no comorbidities.¹¹

A study published in the Journal of Clinical Oncology in 2017 developed a simulation model for CLL management in the United States between 2011 and 2025, including CIT as standard of care before 2014, oral targeted therapies for patients with del(17p) and relapsed CLL from 2014, and  oral targeted therapies as a first-line treatment starting in 2016. They projected that treatment costs would rise from $0.74 billion in 2011 to $5.13 billion in 2025. They projected that per-patient lifetime costs for CLL treatment would change from $147,000 to $604,000 in that time period, as the move progressed to oral targeted therapies as first-line treatment. The out-of-pocket cost for Medicare enrollees would change from $9200 to $57,000 during that time.¹² 

Another study investigated the cost based on the number of adverse events (AEs), showing that the economic burden was substantial. This retrospective study included 7639 privately insured patients diagnosed with CLL between 2012 and 2015. Authors showed that the mean monthly all-cause cost of health care resource use (HCRU) increased as the number of AEs increased, from $905 for those with no AEs to $6032 for those with ≥6 AEs.¹³  

At the 61st American Society of Hematology’s Annual Meeting and Exposition in December 2019, research was presented about potential cost effectiveness of using a fixed duration course of venetoclax + obinutuzumab for one year, comparing it to time-limited CIT regimens and to treat-to-progression regimens like monotherapy ibrutinib or combination ibrutinib and CD20 antibodies.¹⁴ They found that the venetoclax + obinutuzumab combination for one year was significantly more cost effective than the treat-to-progression regimens, as therapies using novel agents have additional costs in later years and a drug holiday represented a cost savings. Analysis was thought to be preliminary and needed longer term clinical follow up and economic analysis.

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology recommend no treatment for those with early-stage disease and those without symptoms, ie, if Rai stage 0-II. Treatment should be considered once symptomatic or if they show evidence of progressive disease. Patients with Rai stages III-IV, who have progressive cytopenia, should be treated. Clinicians should consider treating patients who exhibit severe fatigue, night sweats, weight loss, fever without infection, threatened end-organ function, thrombocytopenia or progressive anemia, or steroid-refractory autoimmune cytopenia. Patients should also be considered for clinical trials.⁷ 

The NCCN recommends choosing a first-line treatment based on disease stage, the absence or presence for del(17p)/TP53 mutation and IGHV mutation status (if considering CIT), patient age, fitness or performance status, and any comorbid conditions.⁷ 

The preferred first-line therapy for all patients, including high risk cohorts with del(11q) or del(17p)/TP53 mutation and unmutated IGHV, is acalabrutinib ± obinutuzumab. Another first-line therapy option for patients (including those with del(17p)/TP53 mutation) is venetoclax + obinutuzumab, or ibrutinib, for an effective fixed-duration chemotherapy-free first-line option. Other recommended first-line options are alemtuzumab ± rituximab, or obinutuzumab. If relapsed/refractory to this therapy, NCCN recommends acalabrutinib, ibrutinib, venetoclax + rituximab, duvelisib, idelalisib + rituximab, or venetoclax. Other recommended options include alemtuzumab ± rituximab, HDMP + rituximab, idelalisib, lenalidomide ± rituximab, or ofatumumab.⁷ 

For patients who do not have del(17p)/TP53 mutation, are frail, and/or with significant morbidities, the preferred regimens include ibrutinib, acalabrutinib ± obinutuzumab, or venetoclax + obinutuzumab. Those younger than 65 without significant comorbidities could be offered the same options. The other recommended therapies differ for these two groups. The NCCN also recommends post-first-line CIT maintenance therapy including lenalidomide for high-risk patients.⁷

For patients ˂65 years with untreated IGHV mutated CLL, FCR is the preferred option for first-line treatment. This is a defined-treatment course, and the majority of these patients getting this treatment will have 10+ years of progression free survival (PFS), with potential cure.⁷ 

Those who have relapsed/refractory CLL without del(17p)/TP53 mutation could receive the preferred regimen of ibrutinib, idelalisib (± rituximab), acalabrutinib, duvelisib, or venetoclax ± rituximab. This is recommended both for patients with significant comorbidity and frailty, and for patients ˂65 without significant comorbidities. For patients with complete or partial response after relapsed/refractory treatment, NCCN recommends CIT maintenance therapy with lenalidomide or ofatumumab.⁷

If a patient has undetectable minimal residual disease (MRD) at the end of treatment, that is associated with long term survival. If there is a histologic transformation of CLL to more aggressive lymphomas, clinical trials are warranted, and prognosis is poor.⁷

While patients with CLL are fortunate to have many options, there are still questions to answer. Patients should be considered for clinical trials, whether as a first-line therapy or if pretreated. Trials are being conducted for chimeric antigen receptor T-cell therapy, bone marrow or peripheral stem cell transplantation, and for monotherapies and combination therapies. Targeted agents, however, have been seen as more potent than CIT in trials for relapsed patients for overall response rate, efficacy, complete remissions, progression-free survival, and MRD-negative remissions. The optimal sequencing of therapy combinations is still unknown, as is whether a combination is better than monotherapies.⁹                                     

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA A Cancer J Clin. 2020;70(1):7-30. doi:10.3322/caac.21590
2. National Cancer Institute. SEER Cancer Stat Facts: Chronic Lymphocytic Leukemia. Accessed April 8, 2020. https://seer.cancer.gov/statfacts/html/clyl.html
3. Chronic lymphocytic leukemia: an overview of diagnosis, prognosis, and treatment. Am J Manag Care. 2018. Published online January 7, 2019. Accessed April 8, 2020.
4. American Cancer Society. About Chronic Lymphocytic Leukemia: What is Chronic Lymphocytic Leukemia. Updated May 10, 2018. Accessed April 8, 2020.  https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is-cll.html
5. American Cancer Society. Early detection, diagnosis and staging: Can Chronic Lymphocytic Leukemia be found early? Updated May 10, 2018. Accessed April 8, 2020. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/detection-diagnosis-staging/detection.html
6. PDQ® Adult Treatment Editorial Board. PDQ Chronic Lymphocytic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated December 6, 2020. Accessed April 8, 2020. https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq
7. NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 4.2020 – December 20, 2019.
8. American Cancer Society. Causes, risk factors and prevention: What are the risk factors for Chronic Lymphocytic Leukemia? Updated May 10, 2018. Accessed April 8, 2020. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/causes-risks-prevention/risk-factors.html
9. Hallek, M. Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment. Am J Hematol. 2019;94(11):1266-1287. doi:10.1002/ajh.25595
10. Patient-Reported Disease Burden in CLL, DLBCL, and FL. J Clin Pathways. Published June 14, 2019. Accessed April 8, 2020. https://www.journalofclinicalpathways.com/news/patient-reported-disease-burden-cll-dlbcl-and-fl
11. Rotbain EC, Niemann CU, Rostgaard K, Da Cunha-Bang C, Hjalgrim H, Frederiksen H. Mapping comorbidity in CLL: impact on prognostic factors, treatment patterns and causes of death. Blood. 2019;134(suppl 1):4285. doi:10.1182/blood-2019-122673
12. 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(2):166-174. doi:10.1200/JCO.2016.68.2856
13. Kabadi, SM, Goyal, RK, Nagar, SP, Kaye, JA, Davis, KL. Treatment patterns, adverse events, and economic burden in a privately insured population of patients with chronic lymphocytic leukemia in the United States. Cancer Med. 2019;8(8):3803-3810. doi:10.1002/cam4.2268
14. Goodman A. Treating patients with chronic lymphocytic leukemia in 2020. ASCO Post.  March 10, 2020. Accessed April 8, 2020. https://www.ascopost.com/issues/march-10-2020/treating-patients-with-chronic-lymphocytic-leukemia-in-2020/