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cancercontroljournal.org Vol. 22, No. 4, October 2015 Supplement

H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE, AN NCI COMPREHENSIVE CANCER CENTER

Chronic Lymphocytic Leukemia in the Elderly: Epidemiology and

Proposed Patient-Related Approach

Chronic Lymphocytic Leukemia in the Elderly,

Which Investigations Are Necessary: A Map for the Practicing Oncologist

Management of Chronic Lymphocytic Leukemia

in the Elderly

12902 Magnolia DriveTampa FL 33612-9416

Cancer Control is included inIndex Medicus/MEDLINE

Sponsored by:

October 2015, Vol. 22, No. 4 Supplement Cancer Control 1

Table of Contents

CanCer Control: Journal of the Moffitt CanCer Center (iSSn 1073-2748) is published by h. lee Moffitt Cancer Center & research institute, 12902 Magnolia Drive, tampa, fl 33612. telephone: 813-745-1348. fax: 813-449-8680. e-mail: [email protected]. internet address: cancercontroljournal.org. Cancer Control is included in Index Medicus®/MeDline® and eMBaSe®/excerpta Medica, thomson reuters Science Citation index expanded (SciSearch®) and Journal Citation reports/Science edition. Copyright 2015 by h. lee Moffitt Cancer Center & research institute. all rights reserved. Cancer Control: Journal of the Moffitt Cancer Center is a peer-reviewed journal that is published to enhance the knowledge needed by professionals in oncology to help them minimize the impact of human malignancy. each issue emphasizes a specific theme relating to the detection or management of cancer. the objectives of Cancer Control are to define the current state of cancer care, to integrate recently generated information with historical practice patterns, and to enlighten readers through critical reviews, commentaries, and analyses of recent research studies.DiSClaiMer: all articles published in this journal, including editorials and letters, represent the opinions of the author(s) and do not necessarily reflect the opinions of the editorial board, the h. lee Moffitt Cancer Center & research institute, inc, or the institutions with which the authors are affiliated unless clearly specified. the reader is advised to independently verify the effective-ness of all methods of treatment and the accuracy of all drug names, dosages, and schedules. Dosages and methods of administration of pharmaceutical products may not be those listed in the package insert and solely reflect the experience of the author(s) and/or clinical investigator(s).

EditorialWhy a Special Issue on Chronic Lymphocytic Leukemia? 2 Lodovico Balducci, MD

About the art in this issue:

Lisa Scholder is a multimedia artist whose canvas is the human body. Her technique involves applying body paint onto nude models, then digitally photo-graphing the painted body. The explosion of illuminating color on the human form is Scholder’s artistic trademark. All of the models shown in this issue are breast cancer survivors of varying ages and body types, and they are part of the Bodies of Courage project.

Scholder takes several hours to hand-paint the model with a crème-based paint and often incorporates other body-painted images in the final piece, which does not include the face of her model. Her artwork focuses on the abstract portrayal of the body infused with vibrant colors. Scholder’s late father-in-law, renowned Indian artist Fritz Scholder, had an unmistakable influence on her bold color combinations. Each model’s unique strength is represented with abstract and, at times, expressionist art forms on her body. The artist’s driving force is the self-empowerment that this process can bestow on her model, enabling her to see her body as a colorful, unique piece of art.

With no formal art training, she began body painting in 2000 and developed her distinct body painting and photography style. Her first public exhibition was in 2004, and she has progressed to gallery and art museum exhibitions.

“Bodies of Courage” is an Arts in Medicine project (www.bodiesofcourage.org) in partnership with the Faces of Courage Foundation (www.facesof-courage.org), which provides at no cost day outings and overnight camps for women, children, and families diagnosed with any type of cancer. Lisa Scholder and Peggie D. Sherry, the founder of Faces of Courage, began this project 5 years ago as a way to raise awareness and as an artistic therapy for cancer survivors. This project is an artistic testimony to the strength and determination of these survivors throughout their battles with cancer, their celebra-tion of life, and their reconnection with the beauty of their own bodies.

For information about the traveling gallery, please contact Peggie D. Sherry at [email protected] or (813) 948-7478. Further information on these projects is available at www.bodiesofcourage.org and www.facesofcourage.org.

Cover: Self Hug Sit. 12" × 18"

Articles: Color Sphere. 12" × 18" Yellow Star Port. 14" × 24" Sunflower. 16" × 24"

Articles

Chronic Lymphocytic Leukemia in the Elderly: 3 Epidemiology and Proposed Patient-Related Approach Lodovico Balducci, MD, and Dawn Dolan, PharmD

Chronic Lymphocytic Leukemia in the Elderly, 7 Which Investigations Are Necessary: A Map for the Practicing Oncologist Javier Pinilla-Ibarz, MD, PhD, and Josephine Emole, MD

Management of Chronic Lymphocytic Leukemia in the Elderly 17 Jacqueline C. Barrientos, MD

2 Cancer Control October 2015, Vol. 22, No. 4 Supplement

Editorial

The aging of the population, which has been called the “gray tsunami,”1 has at least three important im-plications for the practice of oncology:

• It is associated with increased incidence and prevalence of neoplastic diseases in general and in older individuals in particular.

• The ongoing prolongation of the average life expectancy of residents of developed countries has changed the impact of cancer on the survival of older patients. Whereas in the past most older individuals diagnosed with chronic lymphocytic leukemia (CLL) or prostate cancer might have died with the disease but of other causes, nowa-days they are more likely to die as a direct con-sequence of these neoplasms.2-3

• How to treat neoplastic diseases in older individ-uals is becoming a progressively more common concern among healthcare providers.4

CLL is an appropriate model to explore these issues, as age is universally recognized to be a poor prognostic factor for CLL,2 and novel agents prom-ise to modify the natural history of the disease.5-6 Some of these agents—including ibrutinib, idelalisib, obinutuzumab, and ofatumumab—lack major toxici-ties and therefore are particularly promising for older individuals. Aging represents a progressive loss in the functional reserve of multiple organ systems and for that reason is associated with reduced tolerance of stress. Consequently, some of the most effective treat-ments for CLL, such as the combination of fludarabine, cyclophosphamide, and rituximab (FCR) or bone mar-row transplant in 17p deleted/TP53-mutated disease may be contraindicated in the majority of individuals 70 years of age and older.5-6

After an overview of the epidemiology2 and treat-ment strategies6 for CLL, this special issue of Cancer Control examines the approach to CLL in older in-dividuals.5 As expected in a scientific treatise, new conclusions and new questions are offered.

The most important conclusions include:• CLL is lethal for the majority of older individu-

als who develop it before age 80, and there are reasons to believe that it may be lethal even up to age 85.2

• New agents—including obinutuzumab, ofatu-mumab, ibrutinib, and idelalisib—have improved the survival of older individuals, even among those affected with moderate comorbidity.2,5-6

• Ibrutinib is the only approved agent for patients

with 17p deleted/TP53-mutated disease, and it may be life-saving for older individuals with this type of CLL. Idelalisib is also promising in this context.The most important questions include:

• Should clinicians try to achieve a condition of minimal residual disease (MRD) in older CLL pa-tients? Is MRD predictive of survival in patients treated with novel agents compared with those treated with cytotoxic chemotherapy? How can the benefit of MRD best be determined in older individuals with limited life-expectancy and treat-ment tolerance?

• Can the novel agents achieve the same results, and with decreased toxicity, as FCR or benda-mustine plus rituximab (BR) in older individuals?

• What are the long-term complications of these novel treatments? Since treated CLL patients may have a life expectancy of longer than a decade, the late complications of treatment are particularly relevant to their survival and qual-ity of life.Overall, this supplement invites readers to feel a

sense of cautious optimism for the outcome of CLL in older individuals, and this optimism should be reinforced by the ongoing development of new, less toxic and more efficacious, albeit more expensive, treatment modalities.

Lodovico Balducci, MDSenior MemberProgram Leader, Senior Adult Oncology ProgramEditor, Cancer ControlH. Lee Moffitt Cancer Center & Research InstituteTampa, [email protected]

References 1. Wheelwright J. The gray tsunami. Discover Magazine. 2012. Avail-able at: http://discovermagazine.com/2012/oct/20-the-gray-tsunami. Accessed November 2, 2015. 2. Balducci L, Dolan D. Chronic lymphocytic leukemia in the elderly: epidemiology and proposed patient-related approach. Cancer Control. 2015;22(4 suppl):3-6. 3. Stephenson RA. Prostate cancer trends in the era of prostate-specific antigen. An update of incidence, mortality, and clinical factors from the SEER database. Urol Clin North Am. 2002;29:173-181. 4. Colloca G, Corsonello A, Marzetti E, et al. Treating cancer in older and oldest old patients. Curr Pharm Des. 2015;21:1699-1705. 5. Pinilla-Ibarz J, Emole J. Chronic lymphocytic leukemia in the elderly, which investigations are necessary: a map for the practicing oncologist. Cancer Control. 2015;22(4 suppl):7-16. 6. Barrientos JC. Management of chronic lymphocytic leukemia in the elderly. Cancer Control. 2015;22(4 suppl):17-23.

Why a Special Issue on Chronic Lymphocytic Leukemia?

Cancer Control 3October 2015, Vol. 22, No. 4 Supplement

More accurate tools to assess frailty and

physiologic age will play an increasingly

important role in the management of elderly

chronic lymphocytic leukemia patients.

Chronic Lymphocytic Leukemia in the Elderly: Epidemiology and Proposed Patient-Related Approach

Lodovico Balducci, MD, and Dawn Dolan, PharmD

Photo courtesy of Lisa Scholder. Color Sphere, 12" × 18".

Background: Chronic lymphocytic leukemia (CLL) occurs primarily in the elderly, and the majority of deaths attributable to CLL occur in persons 65 years of age or older. The greater number of comorbidities and reduced functionality associated with aging have also made successful treatment of CLL in the elderly more difficult.Methods: The authors reviewed current epidemiology and guidelines for treatment of CLL, as well as recently approved therapies and studies of physiological aging.Results: Determination of physiological age and performance of a thorough geriatric assessment play critical roles in the selection of optimal therapeutic approaches for older patients diagnosed with CLL.Conclusion: Older age, expressed via a frailty index, is a prognostic factor for poorer outcome in patients with CLL. However, several novel treatment options may result in reduced mortality and lessened treatment-related toxicity in older CLL patients. IntroductionChronic lymphocytic leukemia (CLL) is a disease of ag-ing. According to the most recent statistics, there are approximately 15,000 new cases of CLL in the United States every year, and half of them occur in individuals 71 years and older.1 Persons 65 years of age and older account for 60% of the annual deaths attributed to CLL and for 70% of the approximately 150,000 CLL patients currently alive. With the rapid aging of the popula-tion, the incidence and prevalence of CLL among older persons may be expected to continue to increase.2 In

addition, treatment advances that are prolonging the survival of the majority of patients will contribute to in-creased CLL survival in this population.3

This article reviews the influence of CLL on the life expectancy and the function of older individuals and appropriate treatment strategies for them.

CLL and Life ExpectancyContrary to a common impression, the majority of old-er CLL patients die of the disease rather than with it. Age has been shown to be an independent adverse fac-tor for survival in two prognostic models (Table 1).4,5 In a group of Israeli patients, Bairey et al6 demonstrat-ed that age greater than 80 years was associated with poorer CLL-specific survival vs younger individuals. In a review of 2,487 cases of CLL diagnosed at the Mayo Clinic between 1995 and 2008, Shanafelt et al7 report-ed that age at diagnosis was an independent prognos-tic factor for survival. Even patients with Rai stage 0 at diagnosis had a shorter survival than individuals of the same age without CLL, indicating that CLL is indeed a

From the Senior Adult Oncology Program (LB) and Pharmacy Service (DD), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.

Submitted: April 23, 2015; accepted October 26, 2015.

Address correspondence to Lodovico Balducci, MD, Moffitt Can-cer Center, 12902 Magnolia Drive, Tampa, FL 33612. E-mail: [email protected]

Dr Balducci is a consultant for and receives honoraria from Teva Pharmaceuticals. He also receives honoraria from Amgen, Astel-las Pharma, and Johnson & Johnson. Dr Dolan is a speaker for and receives honoraria from Eisai.


mortality risk for the elderly.Particularly relevant to this discussion is the study

by Goede et al,8 which randomized CLL patients with multiple comorbidities and mean age of 73 years to re-ceive chlorambucil, chlorambucil plus rituximab, or chlorambucil plus obizutunumab. The investigators found that the combination including obizutunumab led to greater overall survival and progression-free sur-vival. This important study further confirms that CLL is a cause of mortality in patients with advanced age and substantial comorbidity. All of the patients recruited into the study had well-established treatment indications.

These findings raise the question of whether poorer survival in older patients is due to the biology of the disease or to poorer treatment tolerance. Bulian et al5 and Shanefelt et al7 demonstrated that age was a prognostic factor for poorer survival independent of the absence of immunoglobulin heavy chain variable (IGHV) mutation and of the p17 de-letion. Moreover, whether age is associated more fre-quently with ZAP-70, CD38, q11 deletion disease, or more frequent Richter’s transformation remains un-determined at this time.

A recent study by the International Myeloma Study Group9 showed that the frailty index — which is derived from the preva-lence and severity of comor-bidity and functional de-pendence — was associated

with decreased tolerance of chemotherapy and poorer survival in patients with multiple myeloma. The find-ings of this study may imply that poor treatment toler-ance may be responsible for decreased survival even in older patients with CLL.

This brief review suggests the following con-clusions:

• CLL is a cause of death for older individuals, es-pecially for those aged 80 years and older. Older individuals may benefit from more effective, novel treatment of CLL.

• Age is associated with poor prognosis in CLL pa-tients, with age and prognosis correlated at least up to 85 years of age.

• Age does not appear to be associated with de-creased prevalence of either IGHV mutation or in-creased prevalence of p17 deletion. No information is available concerning the association of age with CD38, ZAP-70, 11q deletion, or risk of Richter’s transformation.

• Physiologic age, expressed as a frailty index, is as-sociated with poor treatment tolerance; this may explain, in part, the poorer CLL prognosis in pa-tients of advanced age.

Personalization of Treatment in Older Chronic Lymphocytic Leukemia PatientsThe assessment of physiological age, its influence on treatment tolerance, and personalized treatment of CLL are emerging as key issues in the management of CLL in older patients. Figure 1 illustrates the interac-tion of disease, age, and treatment in therapeutic deci-sion making. Aging involves a progressive decline in functional reserve and increased polymorbidity that combine to reduce a person’s life expectancy and tol-erance of stress.10 These changes are universal but oc-

Fig. — Treatment decision making in the elderly must account for the interactions of disease, age, and therapy, since aging involves a progressive decline in functional reserve and greater comorbidity, which combine to reduce life expectancy and tolerance of stress.

DiseaseAggressiveness

Effects on survival Effects on function

Decision

PatientLife expectancy

Functional reserve Treatment goals

TreatmentEffectiveness

ToxicityConvenience

Cost

Table 1. — Prognostic Models of Chronic Lymphocytic Leukemia

Factor MD Anderson

Prognostic Index4

Bulian Prognostic

Index5

Age P P

Sex P P

Beta-2 microglobulin concentration P P

Absolute lymphocyte count P Ï

Rai stage P Ï

Number of lymph node stations P Ï

Binet stage Ï P

Lack of IGHV mutation Ï P

17p deletion Ï P IGHV = immunoglobulin heavy chain variable.


cur at different rates in different individuals so that a person’s chronological age is a poor indicator of physi-ological age. The determination of life expectancy and functional reserve is essential to estimate the risks and benefits of CLL treatment for older patients. Table 2 presents the key factors to be considered in assess-ing a person’s physiological age. Laboratory tests have limited value for this purpose. Although the length of leukocyte telomeres decreases progressively with age, a high degree of interpersonal variability prevents the use of this test for the determination of individual physiological age.11

The “inflammatory index” was developed in a large cohort study, the Chianti study, and was vali-dated in the Baltimore Longitudinal Study. It is well established that aging is a progressive inflammatory process, as the concentration of different inflamma-tory markers increases in the circulation with aging.12 The concentration of these substances also predicts the likelihood of aging-related events, including death, dis-ability, and memory disorders. Varadhan et al12 found that the sum of the logarithm of the concentration of interleukin 6 (IL-6) plus the logarithm of the concen-tration of tumor necrosis factor α receptor 1 in the cir-culation more accurately predicted the risk of mortality at 10 years than any other combination of inflamma-tory markers. However, these data were obtained in patients who had not been diagnosed with cancer, and how cancer-induced inflammation may affect the pre-diction remains unclear. The expression of p16INK4a in mesenchymal tissues may reflect the tissue’s age, but to make this determination requires a biopsy. However, this has not yet been validated in a large group of indi-viduals.13

The best-validated estimate of physiological age at present derives from a comprehensive geriatric as-sessment that includes function, polymorbidity, poly-pharmacy, cognitive and emotional status, social sup-port, nutrition, and financial resources. A combination of these factors allows clinicians to predict the risk of mortality in older individuals up to nine years in the future.14 Two indices predicting the risk of cytotoxic chemotherapy-related toxicity are based on the geri-atric assessment.15,16 Other benefits of geriatric assess-ment include disclosure of other conditions that may interfere with cancer treatment such as undiagnosed diseases, drug interactions, memory disorders, depres-sion, malnutrition, and inadequate social support.17 For these reasons, National Comprehensive Cancer Network (NCCN) guidelines recommend that a com-prehensive geriatric assessment should be part of the initial evaluation of older cancer patients.17

Establishing the goal of treatment is important for every patient with an incurable disease but especially for older individuals whose treatment options may be more limited due to reduced functional reserve.18 A

realistic appreciation of the benefits and risks of treat-ment is essential to establish realistic goals. Prolonga-tion of an individual’s active life expectancy, ie, of func-tional independence, is a major goal for older cancer patients, and that goal may be of even greater impor-tance than the prolongation of survival.10

The risk of some forms of chemotherapy-related toxicity increases with a patient’s age.10,17 Among these risks, myelosuppression and neutropenic infections are the most common — and the most lethal. Most cli-nicians agree that myelopoietic growth factors should be used prophylactically in individuals 65 years and older who are receiving chemotherapy that has a dose-intensity comparable to that of CHOP (cyclophospha-mide, doxorubicin, vincristine, prednisone).17,19

The risk of chemotherapy-induced neuropathy and cardiomyopathy also increases with age. Periph-eral neuropathy may result from a number of chemo-therapy agents and may cause severe functional im-pairment.20

In a disease with prolonged survival, such as CLL, long-term toxicity is also important. In addition to neuropathy, such toxicities may include fatigue and memory disorders.21 Fatigue in older cancer patients is a harbinger of functional dependence and ultimately of mortality. Although there is no definitive proof that cy-totoxic chemotherapy may cause dementia in older in-dividuals, it may cause troublesome memory disorders that can precede progressive deterioration of quality of life and independence.21

ConclusionCLL is a disease of aging, and its incidence and preva-lence are expected to increase with the aging of the population. Moreover, age is a poor prognostic factor for CLL, independent of lack of IGHV mutation and of

Table 2. — Assessment of Physiologic Age

Laboratory AssessmentsLength of leukocyte telomeres

Inflammatory index

Tissue expression of p16INK4a

Comprehensive Clinical Geriatric Assessment Function expressed as performance status, activities of daily living (ADLs), and instrumental activities of daily living (IADLs)

Polymorbidity expressed as the number of diseases and as comorbidity index

Polypharmacy expressed as the number of drugs, potential drug interactions, and inappropriate prescriptions

Cognitive screening

Nutritional screening

Depression screening

Socioeconomic resources


17p deletion. The relation between aging and ZAP-70, CD38, 11q deletion disease, and Richter’s transforma-tion is unknown. CLL is the leading cause of death for older individuals who have been diagnosed with the disease. A number of new treatment options — including obizutunumab, ibrutinib, and idelalisib — may allow clinicians to prevent or delay CLL-related death in older individuals without life- or function-threatening toxicity.

References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29. 2. Centers for Disease Control and Prevention. National vital statistics system 2015. http://www.cdc.gov/nchs/nvss.htm. Accessed: October 21, 2015. 3. Keating M. Management strategies in chronic lymphocytic leukemia. http://www.medscape.org/viewarticle/456068. Accessed October 26, 2015. 4. Gentile M, Mauro FR, Rossi D, et al. Italian external and multicenter validation of the MD Anderson Cancer Center nomogram and prognostic index for chronic lymphocytic leukemia patients: analysis of 1502 cases. Br J Haematol. 2014;167:224-232. 5. Bulian P, Rossi D, Forconi F, et al. IGHV gene mutational status and 17p deletion are independent clinical molecular predictors in a com-prehensive clinical biologic model for overall survival prediction in chronic lymphocytic leukemia. J Transl Med. 2012;10:18. 6. Bairey O, Ruchlemer R, Rahimi-Levene N, et al. Presenting fea-tures and outcome of chronic lymphocytic leukemia in patients diagnosed at age of 80 and older. An ICLLSG study. Ann Hematol. 2011;90:1123-1129. 7. Shanafelt TD, Rabe KG, Kay NE, et al. Age at diagnosis and the utility of prognostic testing in patients with chronic lymphocytic leukemia. Cancer. 2010;116:4777-4787. 8. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlo-rambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370:1101-1110. 9. Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicity in elderly myeloma patients: an International Myeloma Working Group Study. Blood. 2015;25:2068-2074. 10. Balducci L. Systemic treatment of gastric and esophageal adeno-carcinoma in elderly patients. J Gastrointest Oncol. 2015;6:75-78. 11. Bendix L, Thinggaard M, Fenger M, et al. Longitudinal changes in telomere length and mortality in humans. J Gerontol A Biol Sci Med Sci. 2014:69:231-239. 12. Varadhan R, Yao W, Matteini A, et al. Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mor-tality in older adults. J Gerontol A Biol Sci Med Sci. 2014:69:165-173. 13. Choudhery MS, Badowski M, Muise A, et al. Donor age negatively impacts adipose tissue-derived mesenchymal stem cell expansion and dif-ferentiation. J Transl Med. 2014:12:8. 14. Yourman LC, Lee SJ, Schonberg MA, et al. Prognostic indices for older adults: a systematic review. JAMA. 2012:307:182-192. 15. Extermann M, Boler I, Reich RR, et al. Predicting the risk of che-motherapy toxicity in older patients: The Chemotherapy Risk Assessment Scale for High Age patients (CRASH) score. Cancer. 2012:118:3377-3386. 16. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy tox-icity in older adults with cancer. J Clin Oncol. 2011;29:3457-3465. 17. Hurria A, Wildes T, Blair SL, et al. Senior adult oncology, version 2.2014: clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2014;12:82-126. 18. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733-742. 19. Smith TJ, Katcheressian J, Lyman GH, et al. 2006 updates of rec-ommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24:3187-3205. 20. Mols F, Beijers T, Vredgeunhill G, et al. Chemotherapy-induced pe-ripheral neuropathy and its association with quality of life: a systematic review. Support Care Cancer. 2014;22:2261-2269. 21. Balducci L, Fossa SD. Rehabilitation of older cancer patients. Acta Oncol. 2013;52:233-238.


The findings of recent clinical

trials point toward improved patient

outcomes for older chronic

lymphocytic leukemia patients.

Chronic Lymphocytic Leukemia in the Elderly, Which Investigations Are Necessary: A Map for the Practicing Oncologist

Javier Pinilla-Ibarz, MD, PhD, and Josephine Emole, MD

Photo courtesy of Lisa Scholder. Yellow Star Port, 14" × 24".

Background: Chronic lymphocytic leukemia (CLL), the most prevalent leukemia in the Western world, is predominantly a disease of older individuals who also have other comorbidities as well as declining organ and bone marrow reserve. Although chemoimmunotherapy is the frontline therapy for fit CLL patients who can tolerate the therapy, many elderly patients cannot tolerate such intense therapy.Methods: The authors first reviewed the most recent findings concerning CLL cytogenetics, molecular biology, and prognostic models. They then surveyed recent and ongoing trials of novel CLL agents and strategies, with a focus on those most relevant to elderly patients.Results: Novel therapies, revised staging procedures, and careful assessment of individual patients’ frailty and functional status will allow clinicians to provide optimal care management for older CLL patients.Conclusion: Therapy for the elderly CLL population must be tailored to each patient’s fitness level and co-morbid conditions, with special consideration for the potential quality-of-life impacts of various treatment recommendations.

IntroductionChronic lymphocytic leukemia (CLL) is a monoclonal lymphoid malignancy characterized by a progressive accumulation of small, mature but functionally incom-petent neoplastic lymphocytes in the peripheral blood, bone marrow, and lymphoid organs.1 The malig-nant lymphocytes in CLL are usually of B-cell lineage (CD5+, CD10–, CD19+, CD20 dim, and CD23+).

CLL is the most prevalent leukemia, accounting for approximately 25% to 30% of all leukemias in the

Western world. The incidence of CLL is approximately 4.1 per 100,000 persons per year.2 In 2015, an estimat-ed 14,620 persons will be diagnosed with CLL in the United States, and an estimated 4,650 persons will die of the disease (representing approximately 0.8% of all cancer deaths).3 The median age at diagnosis of CLL is 72 years, with approximately 70% of patients being ≥ 65 years and 40% ≥ 75 years old. CLL is rare in persons younger than 25 years of age. The prevalence of CLL is higher in Caucasians and males.4

The clinical course of CLL can be variable. More than half of CLL patients are diagnosed at an early stage.5 Many CLL patients have an indolent course and neither develop symptoms nor require treatment for many years. For such patients, observation/watchful waiting is an appropriate management strategy. Other patients have a more aggressive course and die due to CLL within two to three years.6 Different prognostic features at diagnosis or at the time of progression of

From the Department of Malignant Hematology (JP-I, JE), H. Lee Moffitt Cancer Center & Research Institute, and the Department of Internal Medicine, University of South Florida College of Medicine (JE), Tampa, Florida.

Submitted August 10, 2015; accepted October 27, 2015.

Address correspondence to Javier Pinilla-Ibarz, MD, PhD, 12902 Magnolia Drive, Tampa, FL 33612. E-mail: [email protected]

Dr Pinilla-Ibarz is a consultant for and receives honoraria from Janssen and Pharmacyclics. He also receives honoraria from Gilead.


CLL account for the heterogeneous patient outcomes in CLL,7 and these features are predictors of progression-free survival (PFS) and overall survival (OS). Patients with certain poor prognostic features are also more likely to be refractory to first-line treatment or to re-lapse early, thereby requiring salvage therapy.

Treatment modalities for CLL had historically fo-cused on reducing tumor bulk, alleviating symptoms, and providing a good quality of life. Following its in-troduction in the early 1950s, chlorambucil became the mainstay of therapy for CLL. The advent of the anti-CD20 monoclonal antibody rituximab enabled combi-nation therapy with rituximab plus a purine analogue and resulted in improved response rates in CLL. When chemoimmunotherapy consisting of fludarabine, cy-clophosphamide, and rituximab (FCR) was shown to lead to a significant improvement in OS and PFS in a randomized phase 3 trial,8 FCR thereafter emerged as the standard therapy for physically fit patients and changed the goal of CLL therapy to obtaining a com-plete remission (CR). Since many elderly CLL patients may not tolerate such an aggressive therapy, there was need to tailor treatment goals for this population to the individual patient’s comorbidities and functional capac-ity. More recently, combination chemoimmunotherapy comprising either obinutuzumab or ofatumumab plus chlorambucil was approved by the US Food and Drug Administration (FDA) and may be more suitable for old-er patients with comorbidities.9,10

Diagnosis and WorkupAs many as one-quarter of CLL patients may be asymp-tomatic at diagnosis, when their disease is diagnosed incidentally upon detection of absolute lymphocytosis or enlarged lymph node(s). Other patients may pres-ent with nonspecific symptoms such as fatigue, mal-aise, decreased exercise tolerance, bleeding secondary to thrombocytopenia, or symptomatic anemia. Since CLL is characterized by impaired T-cell immunity and/or hypogammaglobulinemia, some patients may also present with recurrent viral or bacterial infections. Some patients with advanced disease at diagnosis may present with the classic “B symptoms” consisting of night sweats, fevers, and weight loss, but the onset of these symptoms in the setting of CLL relapse should raise suspicion of transformation to a high-grade lym-phoma, ie, Richter’s transformation.

Before making a diagnosis of CLL, the presence of monoclonal B-cell lymphocytosis of ≥ 5,000/mcL (5 × 109/L) in the peripheral blood must be established. Val-ues below this should be categorized as monoclonal B-cell lymphocytosis when there is no associated lymph-adenopathy. This distinction is important because patients with monoclonal B-cell lymphocytosis have a B-cell phenotype similar to CLL but with ˂ 5,000/mcL (5 × 109/L) monoclonal B-cells. This relatively new

entity has a rate of transformation to CLL of 1% to 2% per year.11,12 Diagnosis of small lymphocytic leukemia (SLL) requires the presence of lymphadenopathy and/or splenomegaly but ˂ 5 × 109/L clonal B lymphocytes in the peripheral blood. This review will refer to both CLL and SLL as CLL.

Once absolute lymphocytosis that meets the diag-nostic criteria for CLL is noted in the peripheral blood, a blood smear should be reviewed. Morphologically, CLL cells are small, mature-appearing lymphocytes with round nuclei, clumped chromatin, and scant cyto-plasm. A flow cytometry of peripheral blood should be performed to confirm the clonality of the lymphocytes, using the expression profile for cell surface markers, including kappa/lambda, CD5, CD10, CD19, CD20, and CD23. Classic immunophenotype expression pattern for CLL is CD5+, CD10–, CD19+, CD20 dim, CD23+, and low expression of surface immunoglobulins. Flo-rescence in situ hybridization (FISH) for t(11;14) is re-quired to rule out mantle cell lymphoma (MCL), which shares many immunophenotypic features with CLL, except that MCL is characterized by CD23 negativity.

Cytogenetic evaluation and FISH for del(17p), del(11q), trisomy 12, del(13q), and genetic analysis for immunoglobulin heavy chain variable region (IGHV) mutational status and TP53 mutation should be done to provide prognostic (and predictive) information. These tests are not absolutely necessary for the initial diag-nosis of CLL, but they should be implemented before initiation of therapy. Diagnosis of SLL requires a lymph node biopsy. A lymph node biopsy may also be neces-sary in a CLL patient to exclude transformation to high-grade lymphomas, especially in patients with rapidly enlarging lymph nodes.

Anemia and/or thrombocytopenia may occur at diagnosis in CLL due to marrow infiltration, autoimmu-nity against red cells and platelets, or hypersplenism. A bone marrow biopsy is not required to make a diag-nosis of CLL but should be done to evaluate these cyto-penias and before initiating CLL therapy.13 Reticulocyte count and Coombs tests are necessary for evaluation of immune hemolytic anemia and red cell aplasia, as both entities can be seen in CLL patients.

For patients with recurrent infections, IgG, IgA, and IgM levels should be measured. Computed tomog-raphy (CT) scans should not be routinely done at initial diagnosis or in asymptomatic patients, although they may be necessary to monitor disease progression in some patients with new symptoms. CT scans may also be necessary to evaluate patients with new-onset labo-ratory abnormalities if these abnormalities are suspect-ed to be secondary to lymph node enlargement.

Prognostic Factors and Risk StratificationTwo systems (Rai and Binet) have traditionally been used to stage CLL. Both staging systems were based


on clinical and laboratory features such as the pres-ence of lymphocytosis, lymphadenopathy, hepato-splenomegaly, anemia, or thrombocytopenia. Intro-duced by Rai and colleagues in 1975, the original Rai staging system classified patients into five clinical stages (0-IV).14 In 1981, Binet et al15 proposed a three-stage classification based on the overall lymphoid mass and presence of anemia or thrombocytopenia. In 1987, Rai modified the original Rai staging and classified patients into three risk groups: low, inter-mediate, and high risk.16

In addition to the two major clinical staging sys-tems, other prognostic factors have been proposed for better risk stratification of CLL, especially in ear-ly-stage patients. These additional prognostic factors include serum markers (thymidine kinase, beta-2 microglobulin),17-20 phenotype markers (CD38, ZAP-70, and CD49d), cytogenetic abnormalities (del(11q), del(17p), trisomy 12), and molecular characteristics (IGHV gene mutation) of the neoplastic B-cells. More recently the availability of next-generation technolo-gies has identified a limited number of genetic mu-tations (NOTCH1, SF3B1, BIRC3, TP53) that may be associated with poorer outcomes. Some of these prognostic factors have been valuable in predicting likely disease progression as well as outcomes in un-treated patients.21 Their utility in deciding when to initiate therapy or in predicting response to treatment has not yet been completely defined.

Immunoglobulin Heavy Chain Variable Region Gene Mutation Immunoglobulin expressed on B-cells consists of light and heavy chains. The extent to which the genes encoding for the heavy chain variable region have undergone somatic mutation can be used to distin-guish two groups of CLL patients: those with unmu-tated immunoglobulin heavy chain variable region gene (unmutated IGHV) and those with mutated genes (mutated IGHV). These two subsets have differ-ent propensities for progression, with the unmutated IGHV CLL cases having a higher tendency for rapidly progressive disease.22 In contrast, patients with IGHV genes of ˂ 98% nucleic acid homology with germ-line counterpart (mutated IGHV) tend to have a slower and more stable course, except for the 3-21 family of IGHV mutated genes that has been associated with a worse outcome. CLL cases with unmutated IGHV tend to be associated with del(11q) and del(17p), whereas those with mutated IGHV tend to have trisomy 12 and 13q14 abnormalities.23 The IGHV mutational status does not predict response to treatment but is typi-cally associated with shorter remission durations in patients with unmutated IGHV CLL treated with che-moimmunotherapy regimens compared with patients with mutated IGHV.24

CD38CD38 is a transmembrane glycoprotein that synthe-sizes cyclic adenosine diphosphate (ADP)–ribose from nicotinamide adenine dinucleotide and hydro-lyses cyclic ADP-ribose to ADP-ribose. Some studies have suggested that increased expression of CD38 on the surface of CLL cells is associated with inferior out-comes.25,26

Zeta-Associated Protein of 70kDa (ZAP-70)ZAP-70 is a cytoplasmic tyrosine kinase that is usu-ally highly expressed in natural killer cells and T-cells and is essential in receptor signaling in response to antigens. CLL cells with mutated IGHV genes usually do not express detectable levels of ZAP-70. In con-trast, CLL cells with unmutated IGHV genes have rela-tively high expression of ZAP-70.27 Higher expression of ZAP-70 (as assessed by flow cytometry) has been found to predict more rapid disease progression, short-er time from diagnosis to treatment, and shorter OS.27-29

CD49dCD49d (α4 subunit of integrin heterodimer α4β1), is a surface molecule which, along with the α4 integ-rin, acts as adhesion structure for extracellular matrix components and mediates cell-cell interactions.30 Ex-pression of CD49d promotes microenvironment-me-diated proliferation of CLL cells.31 Increased CD49d protein expression has been demonstrated in CLL cells from advanced Rai stage patients (stages III and IV).32 CD49d expression has also been described to be a prognosticator for time to treatment initiation and OS.33 Compared with other flow cytometry-based prognostic factors (CD38 and ZAP-70), CD49d has been suggested as the strongest predictor of OS and treatment-free sur-vival in CLL patients.34

CytogeneticsDeletion at 17p (del(17p)) is commonly associated with defects in TP53, a tumor suppressor gene that regu-lates a network that senses extracellular stress, onco-gene activation, and DNA damage; TP53 also enables the cell to react to such stimuli either by cell cycle ar-rest or apoptosis.35 The gene encodes the P53 protein, which plays a role in the cytotoxic activity of many che-motherapy agents. Not all cases with del(17p) have loss of P53 function,36 and a concordance rate of 94% has been suggested between del(17p) and TP53 mutation.37 Relatively few (approximately 4.5%) patients without del17p may have a TP53 mutation by sequencing.38 TP53 mutations in CLL predict for poor prognosis39 and poor response to purine analog–based regimens.40

CLL patients with 11q deletions tend to have a characteristic clinical profile: younger age at diagnosis, more advanced clinical stage, extensive lymphadenop-athy, and more frequent B symptoms.41 Patients with


11q deletions have been found to have more rapid dis-ease progression and poorer survival.41,42 Some studies have suggested that when treated with chemoimmu-notherapy (eg, FCR), CLL patients with 11q22 deletion have high rates of response, survival, and relapse-free survival; this suggests that alkylating agents may help overcome to some extent the adverse prognostic effect of del(11q).43 However, Fink et al44 observed that pres-ence of del(11q) was still associated with shorter PFS in patients treated with FCR in the CLL8 study.

Other MutationsRecent advances in next-generation sequencing technology have made it possible to identify oth-er frequently recurring mutations in CLL, among which genetic lesions affecting the NOTCH1, SF3B1, BIRC3, and MYD88 genes are particularly significant. NOTCH1 mutations are found in approximately 8.3% of CLL patients at diagnosis, are usually associated with unmutated IGHV, and are found in higher fre-quency during disease progression toward Richter’s transformation as well as in chemorefractory CLL.45-47 SF3B1 mutations occur in approximately 10% to 20% of patients, tend to occur in CLL with del(11q), and have been associated with a poorer prognosis.45,48 BIRC3 mutations have also been associated with a chemorefractory phenotype and tend to have a poor outcome, similar to that of patients with TP53 abnor-malities.49 Taking into account these novel recurrent mutations, Rossi et al50 have proposed a four-cat-egory prognostic model: high risk (patients harbor-ing del(17p)/TP53 mutation and/or BIRC3 mutation), intermediate risk (harboring del(11q), NOTCH1 mu-tation, and/or SF3B1 mutation), low risk (harboring trisomy 12 or normal karyotype), and very low risk (del(13q) as the sole abnormality). Although these mutations may provide prognostic information to the treating physician, at this time they do not guide ini-tiation of therapy or choice of treatment.

Serum markersSerum beta-2-microglobulin (β2m) has been found to correlate with clinical stage, marrow lymphocyte infil-tration, and bulky disease.51 High β2m levels are asso-ciated with poorer response to frontline standard che-motherapy.52

Prognostic ModelsMD Anderson Cancer Center Prognostic IndexAlthough the established prognostic factors have al-lowed better stratification of CLL patients and have in-creased clinicians’ understanding of disease biology, their associated assays are costly and not widely avail-able. The MD Anderson Cancer Center (MDACC) CLL group has proposed a simple prognostic system using routinely available clinical and laboratory character-

istics.18 In an analysis of the outcomes of 1,674 previ-ously untreated CLL patients who obtained care at MDACC from 1981 to 2004, investigators identified six factors — age, absolute lymphocyte count, sex, β2m, Rai stage, and number of lymph node regions — that correlated with OS. Using these six factors, they de-veloped a nomogram that predicted 5- and 10-year OS better than the clinical staging system. Based on the sum of the points assigned to each of the six factors, a prognostic index score was calculated to stratify un-treated CLL patients into three risk groups: low (score 1–3), intermediate (score 4–7), and high risk (score ≥ 8). The estimated median survival times by risk group were: not reached for low risk; 10.3 years (95% CI, 9.5 to 11.0 years) for intermediate risk; and 5.4 years (95% CI, 4.7 to 7.4 years) for high risk. Weaknesses of the study as identified by the authors were inclusion of pa-tients from a single institution and higher proportion of younger patients than the typical CLL cohort (me-dian age was 58 years in the study).

In 2009, Shanafelt et al53 performed an external validation of the MDACC prognostic index using the CLL database at the Mayo Clinic in Rochester, Minne-sota. With a median follow-up of 3.4 years, only age, β2m, number of nodal stations, and Rai stage were found to be independently associated with survival. Following another external validation of the MDACC prognostic index in a multicenter Italian/Swiss CLL population, Bulian et al54 proposed an alternative prog-nostic index using age, sex, Binet staging, and β2m. A third validation of the MDACC prognostic index in a multicenter Italian study by Gentile et al55 indicated that the six prognostic factors proposed by the MDACC remained a significant tool for predicting clinical course in CLL patients.

German Chronic Lymphocytic Leukemia Study Group Prognostic ScoreUsing data from three prospective randomized phase 3 trials conducted between 1997 and 2006 (CLL1 tri-al, CLL4 trial, and CLL8 trial), the German CLL Study Group (GCLLSG) evaluated the prognostic value of 23 clinical, biological, and genetic markers in CLL. Fol-lowing evaluation of 1,948 eligible CLL patients in the training data set, eight parameters were identified as independent predictors of OS: gender, age, Eastern Co-operative Oncology Group (ECOG) performance sta-tus, del(17p), del(11q), IGHV mutational status, serum thymidine kinase, and serum β2m. Total risk score was the sum of the risk scores of the eight individual factors (range, 0–14). The authors proposed four different risk categories for OS: low risk (score 0–2), intermediate risk (score 3–5), high risk (score 6–10), and very high risk (score 11–14). The five-year OS rates ranged from 95.2% (low risk) to 18.7% (very high risk; P < .001).56 The utility of this prognostic score was later validated


in an external cohort of 676 newly diagnosed CLL pa-tients at the Mayo Clinic.

Chronic Lymphocytic Leukemia-International Prognostic Index (CLL-IPI)More recently an international initiative to develop a more globally applicable prognostic score has been de-scribed as CLL-IPI.57 Data from eight phase 3 CLL trials in France, Germany, the United Kingdom, the United States, and Poland were analyzed to identify five inde-pendent variables that predicted for OS: age, clinical stage, del(17p) and/or TP53 mutation, IGHV mutation status, and β2m level. The researchers derived a prog-nostic index that separated patients into four groups: low (score 0–1), intermediate (score 2–3), high (score 4–6), and very high risk (score 7–10), with significantly different five-year OS of 93%, 79%, 64%, and 23%, re-spectively (P < .001) (Table 1). The reported advantage of the CLL-IPI over previous prognostic indices is that it combines the most important genetic risk factors (IGHV and del(17p)/TP53 mutation) with clinical stage, age, and β2m into an easily applicable prognostic score. This prognostic index is very likely to be used more widely, as it has been validated in multiple countries and is the simplest to use among the prognostic tools.

Indications for Therapy, with Special Considerations for the ElderlyMany patients with early-stage CLL do not require therapy and are best managed by observation only. With this approach, patients should be evaluated ev-ery three to six months for symptoms and laboratory changes and monitored for the emergence of more active disease. Patients having concerning symptoms or worsening lymphocytosis may require a more ex-tensive workup. Progressive disease should be treated according to the patient’s fitness and comorbidity bur-den, taking into consideration the presence of high-risk genetic factors.

Standard criteria for initiation of therapy in CLL

were initially established by the National Cancer Insti-tute CLL Working Group in 199658 and were updated by the International Workshop on CLL in 2008.13 Based on these criteria, CLL should be treated when there is progressive disease as evidenced by constitutional symptoms due to CLL, symptomatic or massive sple-nomegaly or lymphadenopathy, progressive marrow failure, rapidly progressive lymphocytosis, or autoim-mune cytopenias not responding to steroid therapy (Table 2).

In addition to these standard criteria for treatment initiation, elderly CLL patients should be evaluated in-dividually for comorbidity and/or functional activity prior to initiation of therapy.59-61 A consideration of the social environment and support for the elderly patient may also be an important part of therapeutic deci-sions.61 Based on data from the CLL4 and CLL5 trials, CLL patients with concomitant diseases who were treat-ed with chlorambucil, fludarabine, or fludarabine plus cyclophosphamide (FC) had a tendency toward inferi-or survival, independent of age.62 Comorbidities have been postulated to contribute to CLL-unrelated death, facilitate toxicity to CLL treatment, predispose to earlier progression of leukemic disease, and result in a high-er rate of CLL-related deaths.61 Elderly patients have a more limited bone marrow reserve vs younger patients

Table 1. — Chronic Lymphocytic Leukemia International Prognostic Index

Variable Risk ScoreGenetic abnormality Del(17p)/TP53 mutation 4

Serum β2m > 3.5 mg/L 2

IGHV mutation status Unmutated 2

Staging Binet B/C or Rai stage I- IV 1

Age > 65 years 1

IGHV = immunoglobulin heavy chain variable, β2m = beta 2 microglobulin.Low risk = score 0–1, intermediate risk = score 2–3, high risk = score 4–6, very high risk = score 7–10.

Table 2. — Standard Indications for Treatment Initiation for Chronic Lymphocytic Leukemia13

At least one of the following criteria should be met: Evidence of progressive marrow failure as manifested by the development, or worsening, of anemia and/or thrombocytopenia

Massive (> 6 cm below the left costal margin) or progressive or symptomatic splenomegaly

Massive nodes (> 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy

Progressive lymphocytosis with an increase > 50% over a 2-month period or lymphocyte doubling time (LDT) in ˂ 6 months

Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids or other standard therapy

Presence of ≥ 1 of the following disease-related symptoms: • Unintentional weight loss ≥ 10% within the previous 6 months • Significant fatigue (Eastern Cooperative Oncology Group performance score of ≤ 2; cannot work or unable to perform usual activities) • Fevers > 100.5°F or 38.0°C for ≥ 2 weeks without other evidence of infection • Night sweats for > 1 month without evidence of infection


and may recover more slowly from drug-related cytope-nias. Since many antileukemic agents are cleared by the kidneys or liver, age-related decline in renal and hepat-ic function may delay clearance of these medications, thereby necessitating dose reductions.

Tools for Assessing ComorbiditiesSeveral tools are available for assessment of comor-bidities, functional status, and risk of chemotherapy toxicity for elderly patients with cancer. The cumula-tive illness rating scale (CIRS) and the Charlson Index correlate closely with each other, and both have been found to be reliable tools for use in trials of older can-cer patients, eg, the CLL8 and CLL11 trials.59 The Che-motherapy Risk Assessment Scale for High-Age Pa-tients (CRASH) score is helpful for evaluating risk of hematologic and nonhematologic toxicities from che-motherapy in patients 70 years and older.63 Using the CIRS, the GCLLSG identified three categories of pa-tients for whom there should be different treatment ap-proaches: “GO GO,” “SLOW GO,” and “NO GO.”61

• Medically fit patients with no or minimal comor-bidities and normal life expectancy were desig-nated as “GO GO.” Irrespective of chronological age, CLL patients in this category should be con-sidered for intensive chemoimmunotherapy. How-ever, close monitoring of toxicities is still required for elderly patients in this category who are being treated with myelosuppressive agents. Where pos-sible, these patients should be treated in the con-text of a clinical trial.

• “SLOW GO” patients are less fit and have multi-ple or severe comorbidities as well as unknown life expectancy. CLL therapy for any patient in this category should be adapted to the patient’s comorbidity burden and individual risk assess-ment. Clinical trials remain a good treatment op-tion. In the absence of trials, reasonable first-line treatment options for patients in this category are chlorambucil plus obinutuzumab (National Com-prehensive Cancer Network [NCCN] category-1 recommendation);64 ofatumumab plus chloram-bucil; chlorambucil plus rituximab; obinutuzum-ab, rituximab, and chlorambucil monotherapy. Reduced doses of BR or FR are other options that can be considered, especially in the context of a clinical trial. Additional clinical trials and evi-dence-based therapeutic strategies are still need-ed for this group of elderly and comorbid CLL pa-tients.

• Patients designated as “NO GO” are frail and have severe comorbidities with very short life expec-tancy. The risks of antileukemic therapy outweigh the benefits for these patients, and therefore CLL treatment should not be offered except if deemed necessary for palliation of symptoms.

Management of High-risk CLL in the Elderly PatientThe presence of high-risk features is not itself an indi-cation to start therapy in any age group. In the elder-ly population, a more conservative approach may be even more important, to avoid possible toxicities due to therapy initiation.

In physically fit patients without high comorbidity burden and without very high-risk prognostic factors, chemoimmunotherapy with FCR is standard because this regimen has been shown to improve overall sur-vival. Bendamustine plus rituximab (BR) is also a rea-sonable option for some fit elderly patients with cer-tain comorbid conditions.65,66 However, these regimens may not be optimal for patients with higher-risk dis-ease — eg, those with del(17p).

CLL with del17p or TP53 MutationAll patients with CLL and del(17p) should be strongly considered for enrollment in a clinical trial. In the ab-sence of a clinical trial, appropriate first-line therapy for this subset of CLL patients includes ibrutinib, high-dose methylprednisolone plus rituximab, alemtuzum-ab with or without rituximab, or obinutuzumab plus chlorambucil. Patients who show good response to first-line therapy and are fit should be considered for allogeneic stem cell transplantation. Ibrutinib is the only therapy approved for use in patients with del(17p) and is indicated in the NCCN guidelines as a category-1 recommendation for patients age ≥ 70 years and with significant comorbidities and for patients ˂ 70 years who do not have significant comorbidities.

CLL with del(11q)CLL patients with del(11q) should receive an alkylat-ing agent-based regimen as frontline therapy when-ever possible. For patients 70 years or older, first-line options include obinutuzumab plus chlorambucil, ofa-tumumab plus chlorambucil, or bendamustine plus rituximab. In the relapse setting, ibrutinib (NCCN cat-egory-1 recommendation) or idelalisib plus rituximab should be considered as the main therapy.

Important Front-line Chronic Lymphocytic Leukemia Clinical TrialsAlthough chemoimmunotherapy regimens (FCR or BR) are excellent treatment options for younger pa-tients with lower-risk CLL, their application in elderly patients is limited by substantial toxicities such as in-fections and myelosuppression. In the last two de-cades, several new monoclonal antibodies have been introduced as therapy for many cancers, including CLL. In addition to rituximab, ofatumumab and obinutu-zumab now play pivotal roles in the treatment of CLL. Abnormal signaling of the B-cell receptor (BCR) path-way has been linked to the development and main-


tenance of B-cell malignancies, including CLL. This understanding has led to the development of phos-phatidylinositol 3 (PI3)-kinase inhibitors (idelalisib) and Bruton’s tyrosine kinase (BTK) inhibitors (ibruti-nib) for CLL therapy. The role of chemoimmunothera-py, monoclonal antibodies, and BCR inhibitors in the front-line treatment of elderly CLL patients will be re-viewed below.

The international, randomized phase 3 CLL8 trial demonstrated that the addition of rituximab to fluda-rabine-based chemotherapy improved both PFS and OS compared with fludarabine-only chemotherapy.8 In this trial, physically fit treatment-naive patients (aged 30 to 81 years, median age 61) with CD20-positive CLL were randomized to six courses of either FC (409 pa-tients) or FCR (408 patients). The investigators reported that FCR was associated with significantly improved re-sponse rates vs FC: overall response rate (ORR), 95% vs 88%, and CR, 44% vs 22%, respectively. At three years after randomization, FCR also resulted in higher PFS (65% vs 45%, P < .0001). In addition, OS was sig-nificantly improved in the patients receiving FCR com-pared with those receiving FC (87% vs 83%, P = .01). FCR was also more frequently associated with grades 3 and 4 neutropenia (34% vs 21% of patients, P < .0001) and leukopenia (24% vs 12%; P < .0001).

Bendamustine Plus RituximabIn a German phase 2 trial evaluating the combination of bendamustine plus rituximab (BR) as first-line ther-apy for CLL,67 117 patients aged 34 to 78 years (25.6%, 70 years or older) who had a WHO performance status of 0 to 2 and adequate renal and liver functions were treated with BR every 28 days for up to six courses. ORR was 88.0% (95% CI, 80.7% to 100.0%), with a CR of 23.1% and a PR of 64.9%. After a median follow-up of 27 months, median event-free survival (EFS) was 33.9 months, and 90.5% of patients were alive. Grade 3 or 4 infections occurred in 7.7% of patients, and grade 3 or 4 neutropenia, thrombocytopenia, and anemia were noted in 19.7%, 22.2%, and 19.7% of patients, re-spectively.

OfatumumabThe monoclonal CD20 antibody ofatumumab binds at a different epitope from the one recognized by ritux-imab. Ofatumumab has been approved for use in combination with chlorambucil for the frontline treat-ment of CLL in patient who cannot receive fludarabine-based therapy due to age or comorbidity. The approval of ofatumumab was based on the results of a phase 3 trial in which 447 patients were randomized to receive either ofatumumab plus chlorambucil or chlorambucil alone.9 Median age was 69 years; 82% of patients were ≥ 65 years, had at least two comorbidities, or both. The primary endpoint of mean PFS was reported as 22.4

months in the ofatumumab plus chlorambucil group vs 13.1 months in the chlorambucil group (hazard ratio = 0.57, P < .001). ORR was higher for ofatumumab plus chlorambucil vs chlorambucil (82% vs 69%, P = .001), and CR rate was higher (12% vs 1%). After a median follow-up of 29 months, median OS was not reached for either the ofatumumab plus chlorambucil group or the chlorambucil group. Grade ≥ 3 adverse events were experienced by 50% of patients receiving ofatumumab plus chlorambucil and 43% of patients receiving chlo-rambucil alone, with the most common adverse event being neutropenia. Grade ≥ 3 infections were reported in 15% and 14% of ofatumumab plus chlorambucil and chlorambucil-alone patients, respectively.

ObinutuzumabObinutuzumab is a humanized monoclonal antibody against CD20 whose binding properties differ from agents like rituximab and ofatumumab. Compared with rituximab and ofatumumab, obinutuzumab dem-onstrated elevated antibody-dependent cytotoxicity and markedly higher induction of lysosome-mediated cell death.68 The open-label, multicenter, three-arm CLL11 trial investigated the safety and efficacy of obinutuzumab plus chlorambucil vs rituximab plus chlorambucil or chlorambucil alone in previously untreated CLL patients with comorbidities.10 In this study, 781 CLL patients with median age of 73 years, creatinine clearance of 62 mL/minute, and baseline CIRS score of 8 were randomized to one of the three treatment arms. Treatment with obinutuzumab plus chlorambucil, rituximab plus chlorambucil, or chlo-rambucil monotherapy resulted in median PFS of 26.7 months, 16.3 months, and 11.1 months, respectively. OS was also prolonged by treatment with obinutu-zumab plus chlorambucil compared with chlorambu-cil alone (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P = .002). In the obinutuzumab plus chlorambucil group, grade 3 or 4 infusion-related reactions occurred in 20% of patients during the first infusion of obinutu-zumab, but there were no grade 3 or 4 reactions during subsequent infusions. Rates of grade 3 to 5 infection were 11% to 14% but did not differ significantly among the treatment groups. In combination with chlorambu-cil, obinutuzumab is now approved for frontline treat-ment of CLL, and the combination is recommended by the NCCN guidelines as a category-1 treatment of choice for older patients with comorbidities.

IbrutinibThe safety and activity of ibrutinib, an oral BTK inhibi-tor, in treatment-naive CLL patients aged 65 years and older were initially assessed in an open-label phase 1b/2 trial. Twenty-nine patients with CLL and two pa-tients with SLL (median age, 71 years; range, 65 to 84 years) were treated with 28-day cycles of once-daily


ibrutinib 420 mg. After a median follow-up of 22.1 months, 22 patients (71%) achieved an objective re-sponse (95% CI, 52.0 to 85.8); four patients (13%) had a CR; one patient (3%) had a nodular partial response; and 17 (55%) patients had a PR. An additional four pa-tients (13%) achieved PR with lymphocytosis, result-ing in an ORR of 84%. Median time to response was 1.9 months. Toxicities included diarrhea, nausea, and fatigue and were mostly of mild-to-moderate severity (grades 1–2). Three (10%) patients developed grade 3 infections, one patient developed grade 3 neutrope-nia, and one patient developed grade 4 thrombocyto-penia.69 Ibrutinib can cause increased lymphocytosis, which should not be mistaken for disease progres-sion in the early phases of therapy. With three years of follow-up, 81% of treatment-naive patients con-tinued on ibrutinib, and there were no relapses for more than two years. At a median treatment duration of 30 months, the ORR was 84%, with 23% attaining CR, 55% PR, and 6% PR with lymphocytosis. The esti-mated 30-month PFS rate was 96%, and the estimated 30-month OS was 97%. The most common grade ≥ 3 adverse events over the three years of follow-up were hypertension (23%), pneumonia (6%), neutropenia (3%), and thrombocytopenia (3%).70

IdelalisibIdelalisib, a selective oral inhibitor of PI3K-delta, is li-censed for use in combination with rituximab as treat-ment for patients who previously received at least one line of therapy. The activity of idelalisib has been eval-uated for use in elderly patients in several studies. As frontline monotherapy, it was evaluated in a phase 2 study of 37 treatment-naive CLL or SLL patients ≥ 65 years of age (median age, 70 years), requiring treat-ment per standard criteria and with measurable lymph-adenopathy.71 These patients received idelalisib 150 mg twice daily continuously for a median treatment peri-od of 4.8 months (range 0.9 to 8.5 months). Among 27 evaluable patients, ORR was 81%, with PR in 9 (33%) and PR with lymphocytosis in 13 (48%). The most fre-quent treatment-emergent adverse events (percentage, all grade/percentage, grade ≥ 3) were rash (27/3), up-per respiratory infection (16/0), constipation (14/0), cough (14/0), nausea (11/0), pyrexia (11/0), arthralgia (8/0), back pain (8/0), diarrhea (8/3), and pneumonia (8/5). Grade 3 or higher treatment-emergent labora-tory abnormalities were transaminase elevation (8%), anemia (5%), and neutropenia (20%). Similarly to pa-tients treated with ibrutinib, early lymphocytosis was observed in this study cohort.

Another phase 2 study evaluated the combination of idelalisib plus rituximab for the treatment of elderly CLL patients.72,73 Sixty-four treatment-naive patients ≥ 65 years of age (median age, 71 years; range: 65 to 90 years) with CLL or SLL were treated with rituximab

375 mg/m2 weekly × 8 and idelalisib 150 mg twice daily continuously for 48 weeks. Forty-three patients completed the 48-week primary study and 41 entered the extension study. The ORR was 97% (78% PR, 19% CR), with 3% of patients nonevaluable. Median time to response was 1.9 months (range 1.6 to 5.7 months). Median PFS was not reached (95% CI 37.3 months, undetermined). The most frequent grade ≥ 3 adverse events were diarrhea/colitis (42%), pneumonia (19%), rash (13%), dehydration (8%), urinary tract infection (6%), dyspnea (5%), and respiratory failure (5%). Grade 5 pneumonitis was reported in two patients (3%), and one patient with diverticulitis developed bowel per-foration. The median time to onset of grade ≥ 3 diar-rhea/colitis was 9.5 month, (range 3 to 29 months). In a phase 3 study of idelalisib plus rituximab in treatment-experienced CLL patients with significant comorbidi-ties, Furman et al74 reported that the median PFS was 5.5 months in the placebo group and had not been reached in the idelalisib group. Patients receiving ide-lalisib vs those receiving placebo had improved ORR (81% vs 13%, respectively) and OS at 12 months (92% vs 80%, respectively). Serious adverse events were re-ported in 40% of the patients receiving idelalisib plus rituximab and in 35% of those receiving placebo plus rituximab.

Response Assessment and Goals of Therapy for Elderly Chronic Lymphocytic Leukemia PatientsFollowing treatment for CLL, patients can be classi-fied as having CR, partial remission (PR), stable dis-ease, progressive disease (PD), or refractory disease.13 As proposed by Cheson et al,75 patients who are be-ing treated with idelalisib or ibrutinib and who have shown some clinical response in meeting the PR crite-ria but who have persistent lymphocytosis should re-ceive PR status.

Treatment goals in elderly CLL patients should aim for symptom control and improvement of quality of life rather than for induction of high CR rates. Be-cause aggressive therapy is typically not well tolerated in these patients, strong consideration should be given to health-related quality of life issues when choosing a treatment regimen.

Even when choosing to treat with BCR inhibitors (ibrutinib and idelalisib), the treating physician must remember that, although these medications may not be as myelosuppressive as chemotherapy, they are as-sociated with chronic adverse events. Among the most common important adverse events reported in stud-ies were low-grade bleeding, diarrhea, atrial fibrilla-tion, and rash (with ibrutinib) and hepatotoxicity, coli-tis, intestinal perforation, pneumonitis, and rash (with idelalisib), and patients should be evaluated frequently for these.


ConclusionCLL is the most prevalent leukemia in the Western world. It is also predominantly a disease of the elder-ly, with a median age of 72 years at diagnosis. Many patients are asymptomatic and may not require ther-apy for many years. Others have certain disease char-acteristics that confer higher risk of progression and therefore require therapy soon after diagnosis. Che-moimmunotherapy with FCR is the standard choice for younger CLL patients who are physically fit. Many elderly patients cannot tolerate intensive regimens and need individualized therapy based on their comor-bidities and functional status. Where indicated, certain elderly CLL patients — ie, those who are frail or have significant comorbidities — are better served by receiv-ing no treatment at all. Irrespective of the treatment option chosen for any particular elderly patient, clini-cians should consider quality of life issues as well as the need to manage acute and chronic adverse effects of medications. Enrollment in appropriate clinical tri-als remains the optimal frontline treatment choice for all elderly CLL patients.

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Dohner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-1916. 40. Dohner H, Fischer K, Bentz M, et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood. 1995;85:1580-1589. 41. Dohner H, Stilgenbauer S, James MR, et al. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by exten-sive nodal involvement and inferior prognosis. Blood. 1997;89:2516-2522. 42. Neilson JR, Auer R, White D, et al. Deletions at 11q identify a subset of patients with typical CLL who show consistent disease progression and reduced survival. Leukemia. 1997;11:1929-1932.


43. Tsimberidou AM, Tam C, Abruzzo LV, et al. Chemoimmunothera-py may overcome the adverse prognostic significance of 11q deletion in previously untreated patients with chronic lymphocytic leukemia. Cancer. 2009;115:373-380. 44. Fink AM, Böttcher S, Ritgen M, et al. Prediction of poor outcome in CLL patients following first-line treatment with fludarabine, cyclophospha-mide and rituximab. Leukemia. 2013;27:1949-1952. 45. Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med. 2011;365:2497-2506. 46. Fabbri G, Rasi S, Rossi D, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011;208:1389-1401. 47. Puente XS, Pinyol M, Quesada V, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475:101-105. 48. Quesada V, Conde L, Villamor N, et al. 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Incidence of chronic lym-phocytic leukemia and high-count monoclonal B-cell lymphocytosis using the 2008 guidelines. Cancer. 2014;120:2000-2005. 54. Bulian P, Tarnani M, Rossi D, et al. Multicentre validation of a prog-nostic index for overall survival in chronic lymphocytic leukaemia. Hematol Oncol. 2011;29:91-99. 55. Gentile M, Mauro FR, Rossi D, et al. Italian external and multicen-tric validation of the MD Anderson Cancer Center nomogram and prog-nostic index for chronic lymphocytic leukaemia patients: analysis of 1502 cases. Br J Haematol. 2014;167:224-232. 56. Pflug N, Bahlo J, Shanafelt TD, et al. Development of a compre-hensive prognostic index for patients with chronic lymphocytic leukemia. Blood. 2014;124:49-62. 57. Kutsch N, Bahlo J, Byrd JC, et al. The International Prognostic In-dex for Patients with CLL (CLL-IPI): An international meta-analysis. Pro-gram and abstracts of the 55th American Society of Clinical Oncology Annual Meeting and Exposition; May 29-June 2, 2015; Chicago, Illinois. Abstract 7002. 58. Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: re-vised guidelines for diagnosis and treatment. Blood. 1996;87:4990-4997. 59. Extermann M, Overcash J, Lyman GH, et al. Comorbidity and functional status are independent in older cancer patients. J Clin Oncol. 1998;16:1582-1587. 60. Balducci L, Extermann M. Management of cancer in the older per-son: a practical approach. Oncologist. 2000;5:224-237. 61. Eichhorst B, Goede V, Hallek M. Treatment of elderly patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2009;50:171-178. 62. Cramer P, Goede V, Jenke P, et al. Impact of different chemotherapy regimen in comorbid patients with advanced chronic lymphocytic leukemia: metaanalysis of two phase-III-trials of the German CLL Study Group. Pro-gram and abstracts of the 48th American Society of Hematology Annual Meeting; December 9-12, 2006; Orlando, Florida. Abstract 2840. 63. Extermann M, Boler I, Reich RR, et al. Predicting the risk of che-motherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer. 2012;118:3377-3386. 64. National Comprehensive Cancer Network (NCCN). NCCN Clini-cal Practice Guidelines in Oncology (NCCN Guidelines®). Non-Hodgkin’s lymphomas version 1.2015. ©National Comprehensive Cancer Network, Inc. 2014. All rights reserved. 65. Eichhorst B, Fink AM, Busch R, et al. Chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus bendamustine and rituximab (BR) in previously untreated and physically fit patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a planned interim analysis of the CLL10 trial, an international, randomized study of the German CLL Study Group (GCLLSG). Blood. 2013;122:526. 66. Eichhorst B, Fink AM, Busch R, et al. Frontline chemoimmuno-therapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) shows superior efficacy in comparison to bendamustine (B) and rituximab (BR) in previously untreated and physically fit patients (pts) with advanced chronic lymphocytic leukemia (CLL): final analysis of an inter-national, randomized study of the German CLL Study Group (GCLLSG) (CLL10 Study). Program and abstracts of the 56th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2014; San

Francisco, California. Abstract 19. 67. Fischer K, Cramer P, Busch R, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012;30:3209-3216. 68. Alduaij W, Ivanov A, Honeychurch J, et al. Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies. Blood. 2011;117:4519-4529. 69. O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lympho-cytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15:48-58. 70. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125:2497-2506. 71. Zelenetz AD, Lamanna N, Kipps TJ, et al. A phase 2 study of idelal-isib monotherapy in previously untreated patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Program and abstracts of the 56th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA. Abstract 1986. 72. O’Brien SM, Lamanna N, Kipps TJ, et al. A phase II study of the se-lective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor idelalisib (GS-1101) in combination with rituximab (R) in treatment-naive patients (pts) ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Program and abstracts of the 2013 Annual Meeting of the American Society of Clinical Oncology; May 31-June 4, 2013; Chicago, Illinois. Abstract 7005. 73. O’Brien S, Lamanna N, Kipps TJ, et al. Update on a phase 2 study of idelalisib in combination with rituximab in treatment-naïve patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lym-phoma (SLL). Program and abstracts of the 56th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2014; San Francisco, California. Abstract 1994. 74. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997-1007. 75. Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol. 2012;30:2820-2822.


Advances in knowledge of pathogenesis and

availability of novel therapies can improve

the management of chronic lymphocytic

leukemia, particularly in the elderly.

Management of Chronic Lymphocytic Leukemia in the ElderlyJacqueline C. Barrientos, MD

Photo courtesy of Lisa Scholder. Sunflower, 16" × 24".

Background: Because chronic lymphocytic leukemia (CLL) typically follows an indolent course, many patients do not need to initiate therapy until they reach a relatively advanced age, when frailty and reduced organ function can make some of the standard treatments difficult to tolerate and less effective. However, recent advances in the understanding of CLL biology and the approval of agents in novel treatment classes have of-fered significant advances in the management of the disease.Methods: The author reviewed current treatment goals in CLL management, including issues surround-ing complete remission (CR) and minimal residual disease (MRD); the findings of trials of treatments from novel drug classes, primarily kinase inhibitors and monoclonal antibodies; and current strategies for use of standard and novel therapies for treatment of individuals diagnosed with CLL, particularly elderly patients.Results: Several agents and regimens featuring improved clinical outcomes and tolerability are now avail-able or in advanced development for the management of CLL patients, including the elderly and those with high-risk disease. These include ibrutinib, idelalisib plus rituximab, and obinutuzumab plus chlorambucil.Conclusion: The availability of Bruton’s tyrosine kinase inhibitors and phosphatidylinositol 3-kinase inhibi-tors and other novel therapies will allow elderly CLL patients to receive more efficacious treatment with greater tolerability than available with traditional approaches for management of the disease.

IntroductionChronic lymphocytic leukemia (CLL) is the most preva-lent adult leukemia in the Western world, accounting for approximately 30% of all leukemias diagnosed in the United States. Approximately 14,600 new cases of CLL are expected to be diagnosed in the United States in 2015.1 CLL primarily affects the elderly, with the majority of patients being > 65 years of age at diagno-sis.2 Following diagnosis, most patients are monitored through a “watch and wait” approach, and therapy typ-ically is not initiated until symptoms develop. Manifes-tations of CLL include fevers, night sweats, weight loss, symptomatic lymphadenopathy, or bone marrow fail-ure (as evidenced by worsening anemia or thrombo-cytopenia).3 By the time most patients require therapy, the majority have multiple chronic comorbidities, in-

From the Department of Medicine, Hofstra North Shore-LIJ School of Medicine, New Hyde Park, New York.

Submitted: July 30, 2015; accepted October 26, 2015.

Address correspondence to Jacqueline C. Barrientos, MD, Hofs-tra North Shore-LIJ School of Medicine, CLL Research and Treat-ment Program, 410 Lakeville Road, Suite 212, New Hyde Park, NY 11042. E-mail: [email protected]

Dr Barrientos is on the Medical Advisory Board of Gilead, Cel-gene, Pharmacyclics, Janssen, and Genentech. She also receives grants/research support from AbbVie, Gilead, and Pharmacyclics.

Dr Barrientos’ work is supported in part by NIH/NCATS Grant #UL-1TR00457, the 2015 American Society of Hematology Harold Amos Medical Faculty Development Program (ASH-AMFDP) Fellowship, and the philanthropic contributions from the Karches Foundation, Marks Foundation, Jerome Levy Foundation, Leon Levy Founda-tion, and the Frank and Mildred Feinberg Foundation.

The author has disclosed that this article discusses unlabeled/unap-proved uses of the drug lenalidomide for the treatment of chronic lymphocytic leukemia.


cluding hypertension, arrhythmias, renal insufficiency, or other conditions that limit their quality of life and performance status.4,5 Therefore, patients typically re-ceive their first therapy at an age when they may be too frail to tolerate a regimen that may be associated with severe toxicities.

Over the last decade, the understanding of CLL biology has advanced considerably with the discov-ery of chromosomal abnormalities and genetic muta-tions that contribute to the heterogeneity of the disor-der and help predict its clinical course.6 Similarly, the discovery of the role of the microenvironment and of the signaling factors that play a key role in CLL patho-genesis has advanced clinicians’ understanding of the condition and has led to the development of agents that specifically target dysregulated pathways.7,8 With the approval of several new targeted agents having un-precedented clinical activity (particularly in patients with high-risk disease, poor prognostic markers, and inability to tolerate cytotoxic chemotherapy regimens), a transformation is occurring in the treatment of pa-tients with a CLL diagnosis.

Because of the aging of the population and in-creased life expectancy of the elderly, CLL will likely become a progressively more common cause of mor-bidity and mortality in older individuals. The goal of this review is to describe novel treatment approaches by highlighting agents recently approved by the US Food and Drug Administration (FDA) that will impact the management of CLL, particularly in the frail and the elderly.

Principles of Chronic Lymphocytic Leukemia TreatmentPrognostic FactorsThe clinical course of CLL is heterogeneous, hence the need for staging and prognostic assessment to de-termine the anticipated disease course. The prognosis of CLL is affected by disease stage, the patient’s cyto-genetic and molecular profile, and the patient’s func-tional ability to tolerate therapy.9 There is no evidence that initiation of therapy for asymptomatic early-stage disease (Rai 0–2 or Binet A) improves survival. Out-side of clinical trials, treatment of early disease is rec-ommended only if a patient develops B symptoms (fever, night sweats, unintentional weight loss) or dis-ease progression (eg, worsening lymphadenopathy or bone marrow failure).

Unfavorable genomic and molecular features in-clude the presence of unmutated immunoglobulin heavy chain variable (IGHV) gene, CD38 overexpres-sion, zeta-chain-associated protein kinase (ZAP)-70, and specific chromosomal aberrations, including 11q deletion, 17p deletion, and the presence of a TP53 mu-tation. A patient’s molecular profile affects treatment decisions: for patients with evidence of a 17p deletion

and/or a TP53 mutation, the treatment options are lim-ited. The only FDA-approved agent to treat a 17p dele-tion CLL patient, regardless of previous therapy, is the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib,10 al-though other agents have shown clinical activity in this patient population, including the monoclonal antibody alemtuzumab and the phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor idelalisib.11-13

Treatment ApproachesAlthough early intervention is considered crucial in most malignant diseases, this is not the case in CLL. The lack of evidence that CLL can be cured with cur-rently available modalities has resulted in a “watch and wait” approach for most patients. Except for allo-geneic bone marrow transplant,14 which is not an op-tion in the majority of individuals aged 70 years and older, current treatment approaches are not curative. The treatment of asymptomatic early-stage disease is not indicated even in the presence of high-risk disease (such as a 17p deletion or TP53 mutation). The addi-tion of immunotherapy to combination regimens of cytotoxic chemotherapy has demonstrated superior re-sponse and survival.15 Indeed, because of treatment ad-vances over the past few decades, CLL patients’ median survival from the time of diagnosis has increased from 96 months in 1980 to > 120 months in 2002.16

Although several treatments are available for CLL, the duration of response and of progression-free sur-vival (PFS) decreases and the risk of complications in-creases with every successive line of treatment (Fig). Therefore, practitioners should employ their clinical judgment in making treatment decisions, with the goal of achieving the most durable remission possible with the initial therapy, especially in older individuals, who are more susceptible to treatment complications and may not tolerate a second treatment regimen.

A remaining area of treatment controversy is whether minimal residual disease (MRD) should be pursued in addition to a clinical complete remission (CR). MRD is defined as < 0.1% of leukemic lympho-

Fig. — Regimens for chronic lymphocytic leukemia can have substantial toxicity and generally become less effective with recurrent treatment.

1stline

2ndline

3rdline

4thline

5thline

6thline

7thline

Drugs with new mechanisms of action are needed that have substantial single-agent activity and can be combined with current and emerging treatment options.

RemissionDuration

Res

pons

e


cytes in the bone marrow detected by oligonucleotide polymerase chain reaction (PCR) and four-color flow cytometry. The absence of MRD after fludarabine-based chemoimmunotherapy is associated with a more prolonged PFS and overall survival (OS), although out-comes in the setting of novel targeted agents have not yet been established. The duration of response while using a novel targeted agent may not necessarily cor-relate with the depth of response, and a remission may not be necessary to obtain durable clinical benefit for as long as continuous therapy is offered.

Whereas in younger or fit patients the aim may be to achieve a CR and MRD negativity with the use of chemoimmunotherapy, this approach traditionally has been poorly tolerated in patients with multiple comor-bidities. For elderly individuals, early detection of ab-sence of MRD may prompt early chemoimmunothera-py cessation, thereby substantially reducing the risk of treatment-related toxicity.17 Alternatively, frail patients may benefit primarily from a low-intensity approach in which the therapeutic endpoint is not CR or MRD, but rather duration of remission, tolerability, and quality of life. There is a clear need for greater representation of elderly and frail patients in randomized CLL clinical trials to assess the therapeutic goals of CR and MRD negativity in this patient population, particularly in the era of kinase inhibitor therapy. MRD negativity should be regarded as a treatment goal only in the setting of a clinical trial.

MedicationsTable 1 contains a list of the most common medications utilized in the treatment of CLL. Outlined here are tar-geted and immune-directed therapies that are impact-ing the way clinicians treat CLL.

The current CLL treatment paradigm is evolving based on the understanding of the disease’s patho-physiology. The B-cell receptor (BCR) regulates fun-damental proliferation and survival mechanisms for malignant B-cells. These functions are mediated by signals that are transmitted intracellularly downstream

through several kinases, including Lyn kinase, spleen tyrosine kinase (SYK), PI3K, BTK, and others. Target-ing these kinases, in particular the BTK and the PI3K signaling pathways, has shown remarkable clinical ac-tivity in patients with CLL and with other B-cell malig-nancies.7,18

Ibrutinib: BTK is a cytoplasmic tyrosine kinase involved in signaling of the BCR and chemokine re-ceptors. Ibrutinib is the first-in-class oral agent tar-geting the BTK pathway by forming a covalent bond with its active site, cysteine-481. It achieves target inhibition with once-daily oral dosing. In vitro and in vivo models demonstrate that ibrutinib inhibits survival, proliferation, and migration of CLL cells.18 Ibrutinib inhibits secretion of CCL3 and CCL4 by CLL cells, and at least part of this process occurs in a BCR-dependent manner.19 Use of ibrutinib (or any agent targeting the B-cell receptor pathway) results in rapid lymphocytosis accompanied by a marked reduction in lymphadenopathy, a “redistribution” phenomenon that is reversible upon temporary dis-continuation of the targeted agent.18 In a phase 1b/2 clinical trial, treatment with ibrutinib monotherapy in patients with relapsed or refractory CLL resulted in an overall response rate (ORR) of 71% and durable remissions (estimated PFS at 26 months: 75%) for all patient groups, including elderly patients and those with high-risk disease.20 In the phase 3 RESONATE trial for patients with relapsed or refractory CLL, ibru-tinib was evaluated against ofatumumab. Ibrutinib demonstrated improved PFS and OS vs ofatumumab, with outcomes independent of 17p deletion status.21 Minimal toxicities reported with ibrutinib included diarrhea, grades 1 and 2 pyrexia and infections, and grades 1 and 2 bleeding events.

Idelalisib: Idelalisib is a first-in-class inhibitor of PI3K, which plays a pivotal role in signal transduction involved in the growth, proliferation, differentiation, and survival of B-cells. A randomized, double-blind, placebo-controlled phase 3 trial of rituximab with or without idelalisib in CLL patients was discontinued

Table 1. — Medications Approved in the United States for the Treatment of Chronic Lymphocytic Leukemia

Drug Class

Alkylating Agents

Purine Analogues

Monoclonal Antibodies BTK Inhibitor

PI3Kδ Inhibitor

Chlorambucil Fludarabine Rituximab* (in combination with fludarabine and cyclophosphamide)

Ibrutinib Idelalisib (in combination with rituximab)

Cyclophosphamide Pentostatin Ofatumumab (as monotherapy or in combination with chlorambucil)

Bendamustine Obinutuzumab (in combination with chlorambucil)

Alemtuzumab

BTK = Bruton’s tyrosine kinase, PI3Kδ = phosphatidylinositol-3-kinase delta. *Also used in combination with bendamustine (BR regimen), but not FDA-approved for this combination.


early on the recommendation of an independent data and safety monitoring board after the combination regimen demonstrated clear superiority vs the mono-therapy arm. The reported ORR was 81% in patients receiving idelalisib plus rituximab vs 13% in patients receiving rituximab plus placebo.22 The most common adverse events associated with idelalisib included py-rexia, fatigue, and nausea. It is important to note that, although the drug was initially well tolerated, a severe noninfectious secretory diarrhea (grade 3 or 4) and/or colitis was reported as a late toxicity in 14% of study participants.23

Both ibrutinib and idelalisib have shown clinical activity in deletion 17p and/or in TP53-mutated dis-ease.10,13 Because of their excellent tolerability and ef-fectiveness, both ibrutinib and idelalisib appear partic-ularly suitable for the treatment of elderly individuals. Ongoing trials are evaluating these drugs’ usefulness both alone and in various combinations as frontline CLL treatment in frail and elderly patients.24,25

Obinutuzumab: Rituximab, ofatumumab, and obinutuzumab are monoclonal antibodies directed at the CD20 antigen and are used mainly in combination with other chemotherapeutic agents. Except for the possibility of severe or life-threatening infusion reac-tions and viral hepatitis reactivation, these agents are generally well tolerated. The most promising of these monoclonal antibodies that target CD20 is obinutu-zumab. Obinutuzumab differs from previous anti-CD20 monoclonal antibodies with respect to its gly-co-engineered crystallizable fragment (Fc) region and its type 2 CD20-binding mode. Glyco-engineering in-creases the binding affinity of the Fc portion of obinu-tuzumab to the Fcγ receptor III on innate immune ef-fector cells (such as neutrophils, natural killer cells, and macrophages); in turn, this results in improved antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis.26 Obinutu-zumab is indicated in combination with chlorambucil for use in treatment-naive CLL patients, based on the findings of a large phase 3 trial in which treatment-naive patients were randomized to receive either chlo-rambucil or chlorambucil plus rituximab or chloram-bucil plus obinutuzumab.27 In elderly (median age 73 years) patients with multiple debilitating comorbidi-ties, the combination of obinutuzumab with chloram-bucil was associated with a significant and clinically meaningful prolongation of PFS, increased CR, and an increased rate of MRD negativity, compared with the results obtained with the rituximab plus chlorambucil combination. Moreover, treatment with obinutuzumab plus chlorambucil resulted in a significant OS benefit compared with chlorambucil monotherapy, suggest-ing that the induction of deeper remissions (ie, MRD negativity) could translate into a survival advantage even in frail patients.26 Combination studies of obinu-

tuzumab with the novel inhibitors of B-cell receptors are planned.

Alemtuzumab: Alemtuzumab is a monoclonal antibody directed against the CD52 antigen and is ap-proved for use as monotherapy in CLL. Data from clini-cal trials suggest that the drug has good clinical activ-ity in patients with minimal nodal disease and in those with 17p or 11q deletions. Until the introduction of ibrutinib, alemtuzumab was the most commonly used agent in patients with 17p deletion or TP53-mutated disease.11,12 Alemtuzumab may still represent an option for patients whose CLL has failed to respond to other treatments. Alemtuzumab can have substantial toxicity, including fevers, pancytopenia, and severe viral or fun-gal infections, particularly reactivation of cytomegalo-virus. Concerns about its infectious complications con-tributed to its limited use in CLL patients. The drug was withdrawn from the US and European markets, but it is still available through manufacturer-sponsored patient access programs.

Lenalidomide: Although not FDA-approved, le-nalidomide is another targeted agent that has shown promising clinical activity in CLL patients.28,29 Unfortu-nately, the frontline study evaluating lenalidomide vs chlorambucil in CLL patients older than 65 years (ORI-GIN trial, NCT00910910) had to be halted due to safety concerns. The patients randomized to lenalidomide had a 92% increased risk for death compared with the patients receiving chlorambucil. Adverse effects of le-nalidomide use include neuropathy, thrombocytope-nia, and thrombotic events. At this time, the role of lenalidomide in the management of CLL is not well de-fined because of the availability of multiple other treat-ment options.

Treatment StrategiesCurrent recommended initial treatment of CLL includes a combination of cytotoxic chemotherapy plus a CD20 monoclonal antibody in young patients or fit elderly patients. The most common regimens are (1) fludara-bine, cyclophosphamide, and rituximab (FCR) and (2) bendamustine plus rituximab (BR). Recently, a large European phase 3 trial demonstrated the PFS superi-ority of FCR vs BR in patients with unmutated IGHV.30 In addition, FCR was associated with increased rates of complete remission and MRD negativity; in the set-ting of chemoimmunotherapy, this finding correlates with longer remission duration and possibly survival. The investigators recommended that, in fit patients without 17p deletion or TP53 mutation, FCR should be the preferred frontline treatment. It is important to note that the median age of the patients in both arms was 61 years, which is a decade younger than the me-dian age at CLL diagnosis and the patients that par-ticipated in the trials were fit with few comorbidities. The difference in PFS was not statistically significant


between the arms in patients ≥ 65 years old, suggest-ing that fit elderly patients may benefit from treatment with BR rather than FCR. FCR use was associated with increased risk of neutropenia, febrile neutropenia, and other complications that may be particularly severe and potentially lethal in older individuals (treatment- related mortality: 3.9% [FCR] vs 2.1% [BR]).

Despite the availability of combination regimens like FCR and BR, until very recently the frontline man-agement of older and unfit CLL patients had been lim-ited to the use of chlorambucil or rituximab monother-apy. The use of chemoimmunotherapy regimens was not an option until the recent report by Goede et al.27 The pivotal phase 3 study demonstrated the superior-ity of the combination of chlorambucil plus obinutu-zumab against chlorambucil alone in terms of PFS, CR, and OS. This registrational trial did not include age as an eligibility criterion; rather, it used the presence of a high cumulative illness rating scale (CIRS) score, which describes functional comorbidity and/or the presence of impaired renal function (patients of any age with a glomerular filtration rate of 30 mL to 69 mL/min). This study represents a major advance in the treatment of el-derly patients with CLL who lack a 17p deletion and es-tablishes a standard of care for the elderly and for frail patients with multiple medical conditions.

In another important phase 3 study evaluating the use of chemoimmunotherapy in elderly patients (medi-an age 69 years) with multiple comorbidities, Hillmen et al31 compared chlorambucil in combination with the anti-CD20 monoclonal antibody ofatumumab vs chlo-rambucil alone in patients for whom fludarabine ther-apy was inappropriate based on age or comorbidities. Patients receiving the combination treatment experi-enced a substantial improvement in PFS.

The only agent currently approved for use in pa-tients with a 17p deletion is ibrutinib. Although ide-lalisib (in combination with rituximab) has not been approved for this particular indication, clinical trials have shown clinical activity in patients with a 17p de-letion,13 and this would be a reasonable treatment ap-proach in patients unable to tolerate ibrutinib therapy. For eligible patients, evaluation for allogeneic bone marrow transplantation is recommended in any pa-tient with high-risk disease. Clinicians should make a decision only after carefully deliberating the advan-tages and disadvantages of continued therapy vs stem cell transplant. Conditions potentially favoring trans-plant include younger age and availability of a donor for a high-risk-disease patient carrying the 17p dele-tion or 11q deletion.32 The longest follow-up data of ibrutinib-treated patients having a 17p deletion (with a median of four prior therapies) reported a median PFS of 28 months. It is important to recognize that PFS with ibrutinib varies by interphase cytogenetic abnor-mality, with 17p deletion patients having a 30-month

estimated PFS rate of 48% (less than the 74% rate ob-served for 11q deletion patients and the 87% rate ob-served when neither of these genomic aberrations is present).33 More recent data suggest that complex karyotype may also be a risk factor.34,35 In fact, most patients with relapsed or refractory CLL who discontin-ued ibrutinib early were difficult to treat and had poor outcomes with relatively short survival.33,34 Published data regarding the sequencing of these new agents are relatively limited and anecdotal. Until greater clarity develops regarding which newer agents can be recom-mended as salvage therapy in patients whose disease progressed following ibrutinib therapy, transplantation will remain an important consideration for fit, trans-plant-eligible patients with a deletion 17p (or other high-risk characteristic), as transplant offers a poten-tially curative therapy.

For previously treated patients, ibrutinib as a single agent proved significantly more effective than ofatumumab in the open-label phase 3 RESONATE study in CLL patients with measurable nodal dis-ease who were not eligible for treatment with purine analog-based therapy and who had received ≥ 1 prior therapies.21 The outcomes of the 391 patients (median age 67 years) with relapsed CLL who participated in this trial were recently updated. The ORR with ibru-tinib was 90% vs 25% with ofatumumab; PFS was not reached at 15 months with ibrutinib and was reached at 8.1 months with ofatumumab.36 With longer follow-up, ibrutinib-treated patients maintained the improved OS. No significant difference in 12-month PFS was observed in ibrutinib-treated patients with or with-out 17p deletion or for those who developed lympho-cytosis compared with those without lymphocytosis. These dramatic results, which did not appear to be in-fluenced by patient age and were achieved with mini-mal toxicity, have established ibrutinib as the preferred second-line agent in CLL.

In another pivotal phase 3 study in patients ineligi-ble for cytotoxic therapy, the combination of idelalisib plus rituximab proved superior to rituximab alone in relapsed CLL. Of the 220 patients enrolled, 78% were 65 years and older.22 The median PFS duration was 5.5 months for rituximab and > 15 months for idelal-isib plus rituximab; OS was also greater with combi-nation therapy (92% in the idelalisib plus rituximab group vs 80% in the rituximab plus placebo group at 12 months). The results were independent of patient age or 17p deletion.13 The combination of idelalisib plus rituximab was well tolerated; adverse events re-ported included diarrhea, grades 1 and 2 pyrexia and infections, and grades 1 and 2 transaminitis.

As described, a number of new therapeutic op-tions are available in the frontline and second-line (or beyond) settings for CLL patients (Table 2). These novel agents are associated with prolonged survival in CLL


patients, including those with high-risk disease who historically have had poor survival rates. These target-ed therapies are particularly promising for patients 70 years and older, whose numbers will progressively in-crease and who already represent the largest cohort of CLL patients.

Management of Older Individuals with Chronic Lymphocytic LeukemiaBased on the findings reviewed in this article, this au-thor proposes that older CLL patients or patients with comorbidities should be considered for participation in a clinical trial if available or treated according to the therapy recommendations outlined in Tables 2 and 3. All individuals 70 years of age and older should under-go a comprehensive geriatric assessment before initia-tion of therapy to estimate cancer-independent mortal-ity risk and tolerance of chemotherapy and to identify conditions that may interfere with the treatment. These may include the potential for drug-drug interactions due to polypharmacy, poor access to nutrition, inad-equate social support, depression, memory disorders, and other coexisting illnesses or conditions that may necessitate interventions, as these may affect the thera-peutic effect of the proposed treatment plan. It is very important to individualize the patient’s therapy based

on the specific clinical presentation.In the near future, novel agents such as those

discussed in this article may be shown to have com-parable or even improved outcomes with greater tol-erability compared with FCR. Two large cooperative group trials in the United States are currently evaluat-ing whether the rational use of targeted agents such as ibrutinib in the frontline setting is superior in terms of duration of remission, survival, quality of life, and tol-erability in fit patients up to the age of 70 years (FCR vs ibrutinib plus rituximab [NCT02048813]) and in older patients with comorbidities (BR vs ibrutinib vs ibruti-nib plus rituximab [NCT01886872]). Several other on-going clinical trials are specifically accruing patients older than 65 years with the goal of improving current outcomes (more information can be obtained at www.clinicaltrials.gov).

Most importantly, in addition to the recently ap-proved agents, an array of promising new therapeu-tic interventions are undergoing evaluation in clini-

Table 2. — Frontline Regimens for Chronic Lymphocytic Leukemia

Patient Population Treatment Options

Patients < 70 years of age, or older patients without significant comorbidities and without del(17p)

Fludarabine + cyclophosphamide + rituximab (FCR) Bendamustine ± rituximab (BR) Fludarabine + rituximab (FR) Pentostatin + cyclophosphamide + rituximab (PCR) Obinutuzumab + chlorambucil Ofatumumab + chlorambucil

Patients ≥ 70 years of age or younger patients with comorbidities without del(17p)

Obinutuzumab + chlorambucil Ofatumumab + chlorambucil Bendamustine ± rituximab (BR) Cyclophosphamide ± rituximab ± corticosteroids Fludarabine ± rituximab (FR) Dose-reduced fludarabine + cyclophosphamide + rituximab (FCR) Chlorambucil ± rituximab

Patients with significant comorbidities who are unable to tolerate purine analogues

Obinutuzumab + chlorambucil Ofatumumab + chlorambucil Chlorambucil ± rituximab

Patients with del(17p) Ibrutinib Idelalisib + rituximab Clinical trial Alemtuzumab

Table 3. — Salvage Therapy for Relapsed Chronic Lymphocytic Leukemia

Patient Population Treatment OptionsPatients with short response to initial therapy who are < 70 years of age

Clinical trial Ibrutinib Idelalisib + rituximab Fludarabine + rituximab ± cyclophosphamide (if no prior FCR) Pentostatin + rituximab ± cyclophosphamide (if no prior FCR) Bendamustine ± rituximab Ofatumumab High-dose methylprednisolone + rituximab Lenalidomide ± rituximab Alemtuzumab ± rituximab OFAR (oxaliplatin, fludarabine, cytarabine, rituximab) R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone)

Patients with short response to initial therapy who are aged ≥ 70 years without del(17p)

Clinical trial Ibrutinib Idelalisib + rituximab Bendamustine ± rituximab Ofatumumab High-dose methylprednisolone + rituximab Alemtuzumab ± rituximab

Patients with del(17p) Clinical trial Ibrutinib Idelalisib + rituximab High-dose methylprednisolone + rituximab Alemtuzumab ± rituximab


cal trials, including second-generation BTK or PI3Kδ inhibitors, anti-apoptotic inhibitors, targeted tumor-specific cellular therapies, and others. The rational design of targeted agents appears to address elderly patients’ unmet needs with respect to improved effi-cacy and tolerability. With the introduction of these agents into the CLL armamentarium, clinicians may be able to exploit combination strategies that enable patients to achieve longer remissions, potentially al-tering the natural course of the disease. In fact, it may be possible to envision a future in which patients can receive chemotherapy-free treatment that is potential-ly curative.

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