Cancer, Chronic Lymphocytic Leukemia (CLL)


Article Author:
Hatem Kaseb
Alankrita Taneja


Article Editor:
Samip Master


Editors In Chief:
Wanda Wright
Cynthia Oster


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
7/4/2019 10:10:56 AM

Introduction

Chronic lymphocytic leukemia is a chronic lymphoproliferative disorder characterized by monoclonal B cell proliferation. It is the most common adult leukemia in Western populations.

Etiology

Chronic lymphocytic leukemia (CLL) is reported to have a genetic basis and is known to run in families (familial CLL). The age at diagnosis of the second-generation offspring is nearly 20 years younger as compared to the parent. Moreover, 17% of first-degree family members of patients with CLL had monoclonal B cell lymphocytosis, which is a precursor of CLL.[1][2][3]

Epidemiology

CLL comprises 25% to 30% of all leukemias in the United States. The disease has a slightly higher incidence in male populations as compared to female populations (1.3:1). However, studies have shown that women can have a more aggressive form of the disease as compared to men. It can affect adults as young as 30 years of age. However, the median age at diagnosis is 70 years. It has a racial predisposition and is most common in whites and least common in Asians. The incidence in African Americans is intermediate between the two.[4]

Pathophysiology

CLL is a monoclonal expansion of B cells. In all patients, it is preceded by an oligoclonal expansion of B cells termed monoclonal B-cell lymphocytosis. It is said to have a genetic basis, and certain genetic polymorphisms are known to predispose individuals to develop CLL.

Histopathology

Classical smudge cells are seen on peripheral blood smear; these are pathognomic of CLL. On peripheral blood flow cytometry, immunophenotypic analysis of the peripheral circulating lymphocytes can be performed which can help to diagnose CLL. The presence of B-cell antigens such as CD19, weak CD20 and CD23, T-cell antigen CD5 and low levels of surface membrane immunoglobulins which is usually IgM or both IgM and IgD and only one type of light chain suggesting the monoclonality of the lymphocytes. However, in some cases, biclonal CLL, expressing both light chains or different levels of expression of other immunophenotypic antigens, is also seen.

History and Physical

The presentation of CLL can range from asymptomatic to more severe complications due to the disease. Patients may be diagnosed after they are found to have incidental lymphocytosis on a complete blood count (CBC) done for an unrelated condition. Some patients may notice non-tender swelling of lymph nodes, particularly in the cervical region. The swelling comes and goes. Only 5% to 10% of patients present with the B symptoms of fever, weight loss, night sweats, and fatigue.

Some other presenting symptoms include hypersensitivity to insect bites, autoimmune hemolytic anemias, and recurrent infections.

The most common physical examination finding is lymphadenopathy. It could be localized or generalized and is firm, non-tender, and mobile when palpated.

Splenomegaly and hepatomegaly are other signs for which to look.

Skin examination is an important part of physical examination because skin cancers are a relatively frequent complication of CLL. Sometimes CLL cells infiltrate the skin resulting in a condition called leukemia cutis which can manifest as plaques, papules, nodules, among others.

Evaluation

The first step in evaluation is to perform a CBC which demonstrates lymphocytosis. There could be some degree of anemia and thrombocytopenia depending on the stage of the disease.[5][6][7][8]

A CT scan helps in evaluation to see the degree of lymphadenopathy and organ infiltration in the form of spleen and liver sizes.

As per Rai’s staging: 

  • Stage 0: lymphocytosis, 
  • Stage 1: lymphocytosis and lymphadenopathy, 
  • Stage 2: lymphocytosis and splenomegaly/hepatomegaly, 
  • Stage 3: lymphocytosis and anemia due to bone marrow infiltration of the tumor cells, 
  • Stage 4: lymphocytosis and thrombocytopenia due to bone marrow infiltration of tumor cells.

Bone marrow aspiration and biopsy, though not needed for diagnosis often are done as a part of a diagnostic workup or before treatment. These show more than 30% involvement by CLL cells for diagnosis of the disease. Reduction of lymphocytic infiltration to less than 30% on treatment indicates a complete response.

Flow cytometry can be performed on both peripheral blood and bone marrow aspirate to look for the classical immunophenotypic markers of CLL.

Lab studies which are of importance include serum lactate dehydrogenase (LDH) and beta-2 microglobulin (read with creatinine because it can normally be elevated in patients with elevated creatinine) which correlate with disease activity.

Serum immunoglobulins and free-light chains are also measured at baseline to look at immune deficiency and on treatment to look at immune reconstitution especially with the newer generation B-cell receptor signaling drugs.

Treatment / Management

Given that most patients with CLL are asymptomatic, treatment is not recommended for everyone. The recommendation for treatment depends on severe disease symptoms or rapidly progressing disease. Symptoms such as severe fatigue interfering with daily activities, B-symptoms, recurrent infections, or increased tumor burden are an indication for early treatment. Rapidly progressing disease such as an absolute lymphocyte count doubling time of fewer than 12 months is also an indication for early treatment.[9][10][11]

For patients who are not considered for treatment, regular follow-up at 3-month intervals is recommended. At the 12-month mark, depending on the symptoms and pace of disease, a decision whether treatment is needed can be made.

Symptomatic CLL is treated and despite many recent advances, remains to be an incurable disease.

For those patients for whom treatment is considered, a pre-treatment assessment should be done including gather information about age and general health, other features such as Tp53 abnormalities or adverse cytogenetics, relapsed disease, or treatment-naive status. There haven’t been studies comparing different treatment modalities, and an individual approach needs to be considered.

In patients younger than 70 years, fludarabine-based regimens are not recommended due to increased side effects. Single-agent ibrutinib is the most popular treatment in this age bracket. Drugs such as chlorambucil and CD20 antibodies can be added for patients with contraindications to ibrutinib such as bleeding tendencies or atrial fibrillation.

Those with a very aggressive form of the disease, such as patients with 17p deletion, especially in younger patients, HLA-matched donors should be recommended to get bone marrow transplant. Those without a matched donor or older in age can be given a trial of ibrutinib.

Pearls and Other Issues

It is important to differentiate CLL from other causes of lymphocytosis including other B-cell disorders which can present similarly. 

Reactive lymphocytosis: Certain infections can present with lymphocytoses such as pertussis and infectious mononucleosis. However, unlike CLL it is transient and is not monoclonal.

Monoclonal B-cell lymphocytosis (MBL): MBL is a condition which precedes CLL. It is characterized by a lymphocyte count of fewer than five times 10L. All cases of CLL are preceded by MBL, but all cases of MBL might not progress to CLL.

Other B cell disorders: Mantle cell lymphoma, splenic marginal zone lymphoma, follicular lymphoma, hairy cell leukemia. Even though these disorders can mimic CLL clinically, careful look at the immunophenotypic markers, morphology or specific genetic abnormalities such as translocation t(14;18) for follicular lymphoma, can lead us to the diagnosis.

Enhancing Healthcare Team Outcomes

CLL is a complex disorder that is best managed by a multidisciplinary team that includes an internist, hematologist, oncologist, nurse practitioner, and the primary care provider.

Given that most patients with CLL are asymptomatic, treatment is not recommended for everyone. The recommendation for treatment depends on severe disease symptoms or rapidly progressing disease. Symptoms such as severe fatigue interfering with daily activities, B-symptoms, recurrent infections, or increased tumor burden are an indication for early treatment. Rapidly progressing disease such as an absolute lymphocyte count doubling time of fewer than 12 months is also an indication for early treatment.

For patients who are not considered for treatment, regular follow-up at 3-month intervals is recommended. At the 12-month mark, depending on the symptoms and pace of disease, a decision whether treatment is needed can be made.

Symptomatic CLL is treated and despite many recent advances, remains to be an incurable disease. However, the use of newer biological agents appear to be making some improvement in lifespan. For symptomatic patients, the outlook is poor but those who are asymptomatic may have a normal life span.[12][13] (LEvel II)

 


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Cancer, Chronic Lymphocytic Leukemia (CLL) - Questions

Take a quiz of the questions on this article.

Take Quiz
Which is false about chronic lymphocytic leukemia (CLL)?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which is true of chronic lymphocytic leukemia?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 67-year-old female with chronic lymphocytic leukemia develops hemolytic anemia. Which of the following is appropriate nursing care?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is an indication for bone marrow transplant in a patient with chronic lymphocytic leukemia?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Cancer, Chronic Lymphocytic Leukemia (CLL) - References

References

Casola S,Perucho L,Tripodo C,Sindaco P,Ponzoni M,Facchetti F, The B-cell receptor in control of tumor B-cell fitness: Biology and clinical relevance. Immunological reviews. 2019 Mar;     [PubMed]
Chronic Lymphocytic Leukemia Treatment (PDQ®): Health Professional Version 2002;     [PubMed]
Patrussi L,Capitani N,Baldari CT, Abnormalities in chemokine receptor recycling in chronic lymphocytic leukemia. Cellular and molecular life sciences : CMLS. 2019 Mar 4;     [PubMed]
Little MP,Wakeford R,Borrego D,French B,Zablotska LB,Adams MJ,Allodji R,de Vathaire F,Lee C,Brenner AV,Miller JS,Campbell D,Pearce MS,Doody MM,Holmberg E,Lundell M,Sadetzki S,Linet MS,Berrington de González A, Leukaemia and myeloid malignancy among people exposed to low doses (<100 mSv) of ionising radiation during childhood: a pooled analysis of nine historical cohort studies. The Lancet. Haematology. 2018 Aug;     [PubMed]
Wierda WG,Byrd JC,Abramson JS,Bilgrami SF,Bociek G,Brander D,Brown J,Chanan-Khan AA,Chavez JC,Coutre SE,Davis RS,Fletcher CD,Hill B,Kahl BS,Kamdar M,Kaplan LD,Khan N,Kipps TJ,Ma S,Malek S,Mato A,Mosse C,Neppalli VT,Shadman M,Siddiqi T,Stephens D,Wagner N,Dwyer MA,Sundar H, NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2019. Journal of the National Comprehensive Cancer Network : JNCCN. 2019 Jan;     [PubMed]
Zelenetz AD, Chronic Lymphocytic Leukemia: Individualizing Treatment Approach. Journal of the National Comprehensive Cancer Network : JNCCN. 2017 May;     [PubMed]
Wierda WG,Zelenetz AD,Gordon LI,Abramson JS,Advani RH,Andreadis CB,Bartlett N,Byrd JC,Caimi P,Fayad LE,Fisher RI,Glenn MJ,Habermann TM,Harris NL,Hernandez-Ilizaliturri F,Hoppe RT,Horwitz SM,Kaminski MS,Kelsey CR,Kim YH,Krivacic S,LaCasce AS,Martin MG,Nademanee A,Porcu P,Press O,Rabinovitch R,Reddy N,Reid E,Roberts K,Saad AA,Snyder ED,Sokol L,Swinnen LJ,Vose JM,Yahalom J,Dwyer MA,Sundar H, NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2017. Journal of the National Comprehensive Cancer Network : JNCCN. 2017 Mar;     [PubMed]
Wierda WG, Updates to the management of chronic lymphocytic leukemia. Journal of the National Comprehensive Cancer Network : JNCCN. 2015 May;     [PubMed]
Gupta NK,Andreadis C, New meets old: a case study and review of novel therapeutics for the treatment of CLL in older patients. Journal of the National Comprehensive Cancer Network : JNCCN. 2014 Oct;     [PubMed]
O'Brien S, NCCN: New directions in chronic lymphocytic leukemia. Cancer control : journal of the Moffitt Cancer Center. 2001 Nov-Dec;     [PubMed]
Akhtar OS,Attwood K,Lund I,Hare R,Hernandez-Ilizaliturri FJ,Torka P, Dose reductions in ibrutinib therapy are not associated with inferior outcomes in patients with chronic lymphocytic leukemia (CLL). Leukemia     [PubMed]
O'Brien SM,Byrd JC,Hillmen P,Coutre S,Brown JR,Barr PM,Barrientos JC,Devereux S,Robak T,Reddy NM,Kipps TJ,Tedeschi A,Cymbalista F,Ghia P,Chang S,Ninomoto J,James DF,Burger JA, Outcomes with ibrutinib by line of therapy and post-ibrutinib discontinuation in patients with chronic lymphocytic leukemia: Phase 3 analysis. American journal of hematology. 2019 Feb 14;     [PubMed]
Gohil SH,Wu CJ, Dissecting CLL through high-dimensional single-cell technologies. Blood. 2019 Mar 28;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of CNS-Adult Health. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for CNS-Adult Health, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in CNS-Adult Health, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of CNS-Adult Health. When it is time for the CNS-Adult Health board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study CNS-Adult Health.