Understanding Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma

Symptoms, Staging, and Diagnostic Procedure

Symptoms

Many patients with CLL/SLL will live for years without any obvious symptoms. The disease might be detected during routine blood tests and/or a physical examination. Other patients may have symptoms that cause them to seek care from a doctor, and testing may lead to the diagnosis of CLL/SLL. Symptoms depend on the tumor location and may be mild.

Less frequent symptoms are often related to enlarged lymph nodes or spleen and may cause discomfort and a feeling of fullness after eating small amounts.

Diagnostic Procedure

Most cases of CLL/SLL are diagnosed based on abnormal blood test results in people who do not have any symptoms of the disease. The doctor might also suspect that a patient has CLL/SLL because of reported symptoms or results of the physical examination. The following tests are usually used to confirm the diagnosis:

• Complete blood count with differential, a test in which the number of the different blood cells are measured. The diagnosis of CLL is characterized by a high white blood cell counts, and sometimes low levels of red blood cell and platelet counts.
• Hematopathologic examination of blood smears and sometimes of a bone marrow biopsy.
• Immunophenotyping the lymphocytes (a type of white blood cell) in the blood and lymph nodes. In these tests, chemicals or dyes are used to understand if certain proteins on the outside of the cell (cell surface proteins) are present. This information distinguishes CLL from other types of leukemia. Classic markers found in CLL/SLL include CD5, CD19, CD23 and dimCD20.
• Histopathologic examination of a lymph node biopsy (needed for diagnosis of SLL if flow cytometry from the blood does not provide enough information).

Table 1. The Rai Staging System for CLL/SLL

Grade	Description	Risk Group
0	• Blood lymphocytosis (increased lymphocytes). • No lymph node enlargement, anemia (decreased red blood cells) and no thrombocytopenia (decreased platelets).	Low
I	• Blood lymphocytosis and enlarged lymph nodes. • No anemia and no thrombocytopenia.	Intermediate
II	• Blood lymphocytosis and enlarged spleen (splenomegaly) and/or enlarged liver (hepatomegaly). • No anemia and no thrombocytopenia.	Intermediate
III	• Blood lymphocytosis. • Anemia (hemoglobin less than 11 grams per deciliter).	High
IV	• Blood lymphocytosis. • Thrombocytopenia (platelets less than 100,000 per microliter).	High

Table 2. The Binet Staging System for CLL/SLL

Grade	Description	Match-Up with Rai Stages
A	• Less than three of five possible enlarged areas*. • No anemia and no thrombocytopenia.	Rai stages 0, I, and II
B	• Three or more of five possible enlarged areas*. • No anemia and no thrombocytopenia.	Rai stages I and II
C	• Any number of possible enlarged areas. • Anemia and/or thrombocytopenia.	Rai stages III and IV

Treatment is based on the severity of symptoms. When patients show no or few symptoms, doctors may decide to monitor the patient without treating the disease. This approach is called active surveillance, or watchful waiting. In this case, patients’ overall health and disease are monitored through regular check-up visits that may include laboratory tests (like a complete blood cell count) and physical examinations (like checking for any swelling). Sometimes, patients experience symptoms due to low red blood cell count (anemia). If patients begin to have symptoms or signs of disease progression, treatment is then prescribed. Early treatment has not been shown to make patients live longer, so it is important to maximize time off CLL treatment by deferring therapy until it is necessary. This means that many patients will never require treatment for their CLL.

First Treatment after Diagnosis

There are many current frontline (initial) treatment options for CLL/SLL. Treatments might differ in the presence of certain mutations (permanent changes in the DNA [deoxyribonucleic acid, the molecule that carries genetic information inside the cell]). An oncologist (doctor who specializes in treating cancer) or hematologist (doctor who specializes in treating blood cancers and other blood disorders) will run a variety of tests to confirm a person’s diagnosis and decide the appropriate treatment, if needed. The patient’s age, health status, and the benefits versus side effects of treatment are also considered for treatment decision.

Newer drugs and combinations have shown excellent activity in patients with all sorts of disease characteristics. Treatments for newly diagnosed CLL/SLL include:

Targeted therapy (drugs that target molecules that cancer cells use to grow and spread). These include inhibitors of proteins involved in cell signaling and growth like kinases (such as acalabrutinib, zanubrutinib, and ibrutinib) and B-cell lymphoma-2 (venetoclax).

Immunotherapy (drugs that help the body’s immune system fight cancer), including monoclonal antibodies (a protein made in the laboratory that binds to cancer cells and helps the immune system destroy them) such as obinutuzumab (Gazyva) and rituximab (Rituxan).

Chemotherapy (drugs that stop the growth of or kill cancer cells). This is rarely administered to newly diagnosed CLL/SLL patients but may be an option for certain patients.

Chemoimmunotherapy which is a combination of chemotherapy (drugs that stop the growth of or kill cancer cells) with immunotherapy (drugs that use the body’s immune system to fight cancer), such as FCR (fludarabine [Fludara], cyclophosphamide [Cytoxan], rituximab [Rituxan]), GC (obinutuzumab [Gazyva] and chlorambucil [Leukeran]), and BR (bendamustine [Belrapzo/Bendeka/Treanda], and rituximab [Rituxan]).

Occasionally, patients might also be treated with chemotherapy. Chemotherapy plays a limited role in the treatment of CLL nowadays. Treatment decisions depend on specific patient factors, like the ones mentioned above, and should be discussed extensively with the patient’s physician, ideally one that specializes in CLL. There are other combinations of treatments that may be suggested. These include chemoimmunotherapy and/or immunotherapy regimens, like the ones listed below:

• FCR (Fludarabine, cyclophosphamide, rituximab)
• GC (obinutuzumab and chlorambucil)
• BR (bendamustine and rituximab)
• Rituximab (Rituxan) or obinutuzumab (Gazyva) with corticosteroids such as dexamethasone and prednisone
• Obinutuzumab (Gazyva)

 Relapsed and Refractory CLL/SLL

Treatment may depend on the identification of specific markers (proteins found at the surface cancer cells) and whether these cells have certain mutations (permanent changes) in the DNA (deoxyribonucleic acid, the molecule that carries genetic information inside the cell). This will help doctors learn more about cancer and evaluate what the best treatment for you is.

Patients who have had a long response to a fixed duration treatment (e.g. venetoclax [Venclexta]) may be considered for retreatment with the same regimen.

An allogeneic SCT is a potentially curative option. However, most patients will do well with newer treatments that avoid the risk of complications of transplants. For more information on allogeneic SCT, view the Understanding Cellular Therapy publication on the Foundation’s website at lymphoma.org/publications.

Various other treatments are available or in development and should be discussed with your physician and/or a physician specialized in CLL.

Many new treatments (also referred to as investigational drugs) and combinations are currently being tested in clinical trials for patients with newly diagnosed or previously treated CLL/SLL. Results from these clinical trials may improve or change the current standard of care (the proper treatment that is widely used by healthcare professionals and accepted by medical experts). Table 1 (below) lists some of these investigational drugs that can be accessed through a clinical trial. For more information on clinical trials, view the Understanding Clinical Trials publication on the Foundation’s website at lymphoma.org/publication (Table 3).

Table 3. Investigational drugs for newly diagnosed and relapsed and refractory CLL/SLL

Agent (drug)	Class (type of treatment)	Type of Lymphoma
Lisaftoclax (APG-2575)	Targeted therapy; BCL2 inhibitor	Untreated CLL/SLL and relapsed/refractory CLL/SLL
Sonrotoclax (BGB-11417)	Targeted therapy; BCL2 inhibitor	Untreated CLL/SLL and relapsed/refractory CLL/SLL
Nemtabrutinib (MK-1026, ARQ 531)	Targeted therapy; BTK inhibitor	Untreated CLL/SLL and relapsed/refractory CLL/SLL
BGB-16673	Targeted therapy; BTK degrader	Untreated CLL/SLL
Daratumumab (Darzelex)	Immunotherapy; anti-CD38 antibody	Relapsed/refractory CLL/SLL
Tafasitamab (MOR00208)	Immunotherapy; anti-CD19 antibody	Relapsed/refractory CLL/SLL
Pembrolizumab (Keytruda)	Immunotherapy; PD-1 checkpoint inhibitor	Relapsed/refractory CLL/SLL
TL-895	Targeted therapy; tyrosine kinase inhibitor	Relapsed/refractory CLL/SLL
TQB-3909	Targeted therapy; BCL-2 inhibitor	Relapsed/refractory CLL/SLL
Atezolizumab	Immunotherapy; PD-1 checkpoint inhibitor	Relapsed/refractory CLL/SLL
Epcoritamab	Immunotherapy; bispecific antibody anti-CD3 and anti-CD20	Relapsed/refractory CLL/SLL
Bexobrutideg (NX-5948)	Targeted therapy; BTK degrader	Relpased/refractory CLL/SLL
Mirdametinib	Targeted therapy; MEK inhibitor	Relapsed/refractory CLL/SLL
Surovatamig (AZD0486, TNB-486)	Immunotherapy; bispecific antibody anti-CD3 and anti-CD19	Relapsed/refractory CLL/SLL

It is important to remember that scientific research is always evolving. Treatment options may change as new treatments are discovered, and current treatments are improved. Therefore, it is important that patients check with their physician or with the Foundation for any treatment updates that may have recently appeared. It is also very important that all patients with CLL consult with a CLL specialist to clear up any questions.

How to Be a Self-Advocate

Being a self-advocate and an active participant in healthcare decisions can be a positive experience. It may help patients regain a sense of control that they may have lost following the lymphoma diagnosis by making sure patients receive the best care. Patients and caregivers should remember they are partners in their treatment plan.

• Do not be afraid to ask your doctors or nurses questions about your care. An educated patient asking questions is not ‘being a challenge to your physician’ (or ‘being a difficult patient’).
• Learn more about lymphoma by asking your doctor for information and visiting reliable websites, such as the Foundation’s at www.lymphoma.org.
• Take advantage of counseling, support groups, nutritional counseling, fitness classes, expressive arts, and other services offered at your doctor’s office, cancer center, or hospital.
• Consider joining the Foundation’s Lymphoma Support Network, a nationwide peer support program that matches patients and caregivers with people who have had similar experiences. For information about the program, call (800) 500-9976 or email [email protected].
• Finally, it is important that patients not be afraid to talk with the healthcare team about nonmedical issues such as transportation, finances, insurance, working through treatment or taking time off, and childcare. There are nurses, social workers, physician’s assistants that are be able to provide the support and resources to help.

 Clinical trials are crucial in identifying effective drugs and optimal treatment doses for patients with lymphoma. They are not a “last resort” for patients. Every drug available today had to be tested in clinical trials before it was approved for general use, and all new and emerging treatments. There are four main types or phases of clinical trials. The phase is based on the study’s objective and the number of participants.

Patients interested in participating in a clinical trial should view the Understanding Clinical Trials fact sheet on the Foundation’s website (visit lymphoma.org/publications), talk to their physician, or contact the Foundation’s Lymphoma Resource Center for an individualized clinical trial search by calling (800) 500-9976 or emailing [email protected].

Measurable Residual Disease

Measurable residual disease (MRD), also known as minimal residual disease, refers to the small number of cancer cells in the body after completion of treatment. Typically, MRD tests detect cancer cells that remain in the blood or bone marrow. Testing for MRD is often done in clinical trials. Using very sensitive laboratory methods, one cancer cell can be detected among 1,000,000 healthy blood cells. An MRD-negative test means that there are no cancer cells detected within the sensitivity of the method used. Testing for MRD is mostly used as a prognostic marker (predicts the likely course of the disease) that provides useful information about long-term outcome after treatment. The prognostic value (the ability to predict how well the patient will do) of MRD may be dependent on the treatment the patient is receiving.

With certain CLL therapies, studies have found that patients with lower levels of MRD (fewer cancer cells remaining after the completion of treatment) have a longer remission. Patients receiving treatment with Bruton’s tyrosine kinase (BTK) inhibitors (a type of drug that works by blocking a specific protein called BTK, which the cancer cells use to survive and spread) may not reach a negative MRD status. However, the response to treatment can still last for a long period and maintain disease control for many years. For this reason, having detectable MRD does not necessarily mean the disease has relapsed or become refractory. This will help to make individualized decisions for your case. More recent studies are investigating whether undetectable MRD may result in a shorter course of treatment for patients. Patients should be encouraged to discuss MRD with their physician or a physician specialized in CLL/ SLL. If your doctor decides to test for MRD, it is important to discuss what your MRD status is and what it means.

Survivorship

As a cancer survivor, it is important that you practice self-care regularly to reset your physical and emotional well-being. Adopting routines of self-care will help you recharge your batteries and stay healthy. Talk with your healthcare team about developing a wellness plan to help you stay physically and emotionally healthy and improve your mood. Consider the following suggestions:

• Watch your health. Stay up-to-date with your own medical appointments and take any medications as prescribed.
• Exercise. Stay active with short periods of daily exercise (30 minutes of power walking, jogging or biking). If not possible, take the stairs instead of the elevator or park farther away than usual.
• Eat well. Include fruits and vegetables in your meals and maintain a balanced diet.
• Cut down on risk factors. Quit smoking and reduce alcohol intake.
• Sleep. Try to get 7 hours of sleep per night, or take naps when needed.
• Rest. Meditation, deep breathing and stretching can help you relax and reduce stress.
• Write it down. Keeping a journal with thoughts and feelings may help to let go of worries and fears.

View the Foundation’s Survivorship Series factsheet on the Foundation’s website atl ymphoma.org/publication for more info.

Long Term Follow-Up Care Plan

All lymphoma survivors should have a long term follow up plan (also called a “survivorship care plan”) after treatment ends. This plan is arranged by your healthcare team and includes a summary of the treatments you received, recommendations for follow-up care based on your medical history, and schedules for medical exams to check if the lymphoma has come back (recurrence). This allows your healthcare team to monitor your overall health and look out for long-term effects or other problems that may occur at any point after treatment. Your doctor will let you know how often you need to return for checkup appointments and which physical exams and blood tests are necessary. These checkups usually include a review of your medical history, physical exam and bloodwork, as well as specific exams or screenings recommended by your doctor (see Health Screenings to Consider on next page).

A follow-up care plan may also provide information to help you meet any emotional, social, legal, and/or financial needs. Your health care team can help you decide which doctor to see for your follow-up care plan (the same doctor who treated your lymphoma, a health care provider specialized in caring or cancer survivors, or your primary care provider [PCP]). Some clinics specialized in follow-up cancer plans offer comprehensive support to cancer survivors (called “survivorship clinics”). You can visit oncolink.org/clinics/search to check for survivorship clinics in your area.

Health Screenings To Consider

As a survivor, there are specific health screenings and exams that you may do at an earlier age than the general population. These will be adapted to the type of lymphoma you had and the treatment you received. For instance, due to the increased risk of secondary breast cancer from radiation therapy, women who received radiation therapy to the chest area during childhood, adolescence, or young adulthood should have clinical breast examinations yearly until age 25, then every six months thereafter. In addition, these women should receive yearly mammograms and breast magnetic resonance imaging (MRI) beginning at age 25 or eight years after completion of the radiation therapy, whichever comes last.

Other health screenings the physician may suggest include:

• Bone density scans
• Cardiovascular monitoring
• Chest or whole body imaging
• Screening for other cancers (e.g. colorectal or skin)
• Dental screenings
• Eye exams
• Lipid blood tests
• Thyroid function tests

Because everyone is different, survivors should talk with their physicians about which screenings are most appropriate and when they should be started.

Care Partners

There are many ways you can help a loved one with lymphoma, as follows:

• Be present. The most important thing that a care partner can do is to “just show up.”
• Be prepared. Talk with the healthcare team so that you know what to expect throughout the treatment, how to manage symptoms and when to ask for help.
• Listen. Each person asks for help in different ways, verbally (through words) and nonverbally, and some may require more comfort while others are more action oriented.
• Avoid “cheerleading”. Do not disregard your love one’s negative feelings (sadness, anger or worry).
• Organize the help. A rush of sudden help upon diagnosis can make the situation harder to manage and create unproductive tension.
• Set up remote access with computer and/or phone access. This is helpful for regular communication with your loved one.
• Offer rides. This is important for people with decreased mobility or limited resources.
• Take notes. If you go into the appointments, write down notes with the doctor’s plan, medications, potential side effects and other relevant information.

Patients and their care partner are encouraged to keep copies of all medical records. This includes test results as well as information on the types, amounts, and duration of all treatments received. Medical records are important for keeping track of any side effects resulting from treatment or potential disease recurrences. The Foundation can help patients manage this documentation.

View the Care Partners factsheet on the Foundation’s website at lymphoma.org/publication for more info.

• What is my exact diagnosis? What subtype of lymphoma do I have? May I have a copy of the report from the pathologist?
• What is the stage of my disease? In what area of the body is it specifically located?
• What are my treatment choices? Which do you recommend for me and why? Would choosing one treatment prevent me from getting a different kind of treatment later on? How are the different treatments administered?
• Do I need more than one type of treatment?
• What is the goal of treatment? What are the expected benefits of each type of treatment?
• How will we know if the treatment is working? What tests will I need to determine if treatment is working, and how often will I need to be tested?
• How long will the treatment last?
• What are the chances the treatment will be successful?
• What is a clinical trial? Are clinical trials available that are studying new treatments for my type of lymphoma? Would a clinical trial be appropriate for me? How would I benefit? Are there any drawbacks of participating in a clinical trial?
• Will I be able to work during treatment? Will I be able to drive or take public transportation during my treatment?
• Should I take care of other medical or dental issues before I start treatment?
• How much will the treatment cost? Will my insurance cover some or all of it? What will my out-of-pocket costs be?