Chronic Lymphocytic Leukemia Management

Last updated: 28 October 2024

Content on this page:

Evaluation

Content on this page:

Evaluation

Evaluation

Chronic Lymphocytic Leukemia Staging Systems

Two staging systems are being used to predict patient outcomes. These staging systems are also used to assess patients to be included in clinical trials.  

Rai System  

Rai system is a staging system based on physical examination and CBC results used to assess the degree of tumor burden. 

Stage Description Risk Status1
0 Lymphocytosis >5 x 109/L and >40% lymphocytes in bone marrow Low
I Stage 0 with enlarged node(s) Intermediate
II Stage 0-I with splenomegaly, hepatomegaly, or both Intermediate
III Stage 0-II with hemoglobin (Hb) <11.0 g/dL or hematocrit (Hct) <33% High
IV Stage 0-III with platelets <100 x 109/L High
1Used in the modified Rai classification


Binet System  

The Binet system is based on the number of areas with lymph nodes >1 cm in diameter or organomegaly, and the presence of anemia or thrombocytopenia. The involved areas include the head and neck, axilla, groins including superficial femorals, spleen, and liver. 

Stage Description
A Hb ≥10 g/dL, platelets ≥100,000/mm3, and <3 enlarged areas
B
 Hb ≥10 g/dL, platelets ≥100,000/mm3, and ≥3 enlarged areas
C Hb <10 g/dL, and/or platelets <100,000/mm3, and any number of enlarged areas

Functional Status  

Functional status assessment is used to evaluate how a disease affects the daily activities of a patient. The commonly used performance status scoring systems include the Karnofsky performance status scale and the Eastern Cooperative Oncology Group (ECOG) performance scale (PS).

Principles of Therapy

The choice of treatment for patients with chronic lymphocytic leukemia is based on the disease stage, presence or absence of del(17p) or TP53 mutation, patient’s age, functional status, presence or absence of comorbidities, and IGHV mutation status.  

Indications for Initiation of Treatment  

The following are indications for the initiation of treatment in patients with chronic lymphocytic leukemia:

  • Progressive marrow failure manifested as worsening or development of anemia and/or thrombocytopenia
  • Symptomatic or massive splenomegaly of ≥6 cm below the costal margin with or without progression
  • Lymph node enlargement of ≥10 cm in diameter with or without symptoms or progression
  • Progressive lymphocytosis with ≥50% increase within a 2-month period or lymphocyte doubling time (LDT) of <6 months
  • Autoimmune anemia and/or thrombocytopenia that responds poorly to steroids and other therapeutic agents
  • Symptomatic or functional extranodal involvement 
  • Threatened end-organ function
  • Presence of constitutional symptoms such as unintentional weight loss of ≥10% within a 6-month period; significant fatigue (with ECOG PS score of ≥2, unable to work or carry out usual activities); fever ≥38°C of ≥2 weeks duration without known infection; night sweats of ≥1 month duration without known infection
  • Presence of hypogammaglobulinemia or monoclonal or oligoclonal paraproteinemia is not an indication for treatment initiation but should be assessed to determine if treatment is necessary 
  • Treatment timing should be based on the rate of disease progression 

Therapeutic Recommendations  

For early-stage disease (Rai stage 0, Binet stage A and B), treatment may be delayed with continuous monitoring every 3-12 months. For intermediate- to high-risk chronic lymphocytic leukemia patients, in patients with symptoms and signs of disease progression, treatment should be initiated at the earliest possible time.  

Enrollment in locally available clinical trials is recommended for all patients with indications for treatment which includes patients with del(17p) who are (1) unresponsive to first-line treatment, (2) responsive to first-line therapy but not eligible for allogeneic hematopoietic cell transplantation, or (3) unresponsive to hematopoietic cell transplantation. 

Pharmacological therapy

Alkylating Agents  

Bendamustine  

Bendamustine combined with Rituximab is a treatment option for the first-line treatment of chronic lymphocytic leukemia patients without del(17p)/TP53 mutation aged ≥65 years or <65 years with or without significant comorbidities in combination therapy with CD20 monoclonal antibody (Obinutuzumab, Ofatumumab, Rituximab). Bendamustine/Rituximab combination is a treatment option for relapsed or refractory disease after prior BTK inhibitor- and Venetoclax-based regimens for chronic lymphocytic leukemia patients without del(17p)/TP53 mutation regardless of age and comorbidities.  


Chronic Lymphocytic Leukemia_ManagementChronic Lymphocytic Leukemia_Management


Chlorambucil  

Chlorambucil combined with Obinutuzumab may be considered for CLL patients when BTK inhibitor and Venetoclax are not available or are contraindicated or rapid disease debulking is needed.  

Cancer Immunotherapy  

Lenalidomide  

Lenalidomide is a therapy for relapsed or refractory disease after prior BTK inhibitor- and Venetoclax-based regimens for chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation if not previously used.   

Monoclonal Antibodies  

Alemtuzumab  

Alemtuzumab is a first-line treatment option in patients with del(17p)/TP53 mutation. It may be given in combination with Rituximab. It is less effective for bulky (>5 cm) lymphadenopathy.  

Obinutuzumab  

Obintuzumab is a glycoengineered, humanized, type II antibody targeted against CD20. It is approved for treatment-naive chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation as monotherapy. It is a treatment option for patients without del(17p)/TP53 mutation with relapsed or refractory disease after prior BTK inhibitor-based and Venetoclax-based regimens. The combination with Chlorambucil is a first-line treatment option for chronic lymphocytic leukemia patients without del(17p)/TP53 mutation aged ≥65 years and <65 years old with significant comorbidities.    

Other Antineoplastic Agents  

Example drugs: Acalabrutinib, Duvelisib, Ibrutinib, Idelalisib, Pirtobrutinib  

There are ongoing studies investigating the use of these drugs for chronic lymphocytic leukemia and other types of cancer.  

Acalabrutinib  

Acalabrutinib is a second-generation BTK inhibitor. It is recommended as first-line therapy to chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation. It may be given in combination with Obinutuzumab. It is not recommended for chronic lymphocytic leukemia patients with BTK C481S mutations unresponsive to Ibrutinib therapy.   

Duvelisib  

Duvelisib inhibits delta and gamma isoforms of phosphatidylinositol 3-kinase (PI3K). It is an alternative second- or third-line therapy for chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation with relapsed or refractory disease after prior BTK inhibitor-based and Venetoclax-based regimens.  

Ibrutinib  

Ibrutinib irreversibly inhibits BTK and inhibits chronic lymphocytic leukemia-cell migration, survival, and proliferation. It is used as first-, second-, and third-line treatment for chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation regardless of age and comorbidities. It may be given in combination with Obinutuzumab, Rituximab or Venetoclax.   

Idelalisib  

Idelalisib is a phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor. It is a therapy option for chronic lymphocytic leukemia patients with and without del(17p)/TP53 mutation with relapsed or refractory disease after prior BTK inhibitor-based and Venetoclax-based regimens. The combination with Rituximab is an alternative first-line therapy option for patients with del(17p)/TP53 mutation if the other treatment options are unavailable or considered unsuitable for the patient.

Lisocabtagene maraleucel  

Lisocabtagene maraleucel is a CD19-directed genetically modified autologous T cell immunotherapy administered as a defined composition of chimeric antigen receptor (CAR)-positive viable T cells (consisting of CD8 and CD4 components). It is a treatment option for patients with or without del(17p)/TP53 with relapsed or refractory disease after prior BTK inhibitor-based and Venetoclax-based regimens.  

Pirtobrutinib  

Pirtobrutinib is a noncovalent, third-generation BTK inhibitor. It is a second- or third-line treatment option for chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation used for relapse after a period of remission if previously used as a first-line therapy. It is a therapy for relapsed or refractory disease after prior BTK inhibitor- and Venetoclax-based regimens for chronic lymphocytic leukemia patients without del(17p)/TP53 mutation if not previously used. 

Venetoclax  

Venetoclax is a selective inhibitor of the anti-apoptotic protein BCL-2. It is the preferred first-line therapy regimen for chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation when given with Obinutuzumab. It is a preferred second- or third-line therapy for chronic lymphocytic leukemia patients with del(17p)/TP53 mutation and may also be given in combination with Rituximab. It is a second- or third-line treatment option for chronic lymphocytic leukemia patients without del(17p)/TP53 mutation regardless of age and comorbidities. It is the preferred second- or third-line therapy regimen when given with Rituximab. 

Zanubrutinib  

Zanubrutinib is a second-generation BTK inhibitor. It is the preferred first-line therapy option for chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation with contraindication to other BTK inhibitors. It is the preferred second- or third-line therapy option for chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation, regardless of age and comorbidities. It is not recommended for Ibrutinib-refractory chronic lymphocytic leukemia patients with BTK C481S mutations.  

Chemotherapeutic Regimens  

Bendamustine plus Anti-CD20 Monoclonal Antibody (mAb)-based Combinations
 
Example combinations: Bendamustine plus Obinutuzumab, Bendamustine plus Rituximab  

Bendamustine plus anti-CD20 monoclonal antibody (mAb)-based combinations are first-line therapy options for chronic lymphocytic leukemia patients without del(17p)/TP53 mutation ≥65 years old or <65-year-old patients with significant comorbidities and with IGHV mutation. They are alternative second- or third-line treatment options for chronic lymphocytic leukemia patients without del(17p)/TP53 mutation for patients ≥65 years old or patients <65 years with significant comorbidities. They showed longer progression-free survival rates compared to Bendamustine monotherapy.  

FCR (Fludarabine plus Cyclophosphamide plus Rituximab)

Fludarabine plus Cyclophosphamide plus Rituximab (FCR) is a treatment option as first-line therapy for treatment-naive fit IGHV mutation-positive chronic lymphocytic leukemia patients without del(17p)/TP53 mutation <65 years without significant comorbidities, and as a second- or third-line therapy option for chronic lymphocytic leukemia patients without del(17p)/TP53 mutation aged <65 years without significant comorbidities. This combination may be considered for treatment-naive patients with adequate functional status or relapsed patients with indications for treatment initiation. It may be used as a debulking strategy prior to hematopoietic cell therapy. 

High-dose Methylprednisolone (HDMP) plus Anti-CD20 mAB-based Combination  

High-dose Methylprednisolone (HDMP) plus Obinutuzumab is a first-, second-, or third-line treatment option for patients with or without del(17p)/TP53 mutation regardless of age and comorbidities with relapsed or refractory disease after prior BTK inhibitor-based and Venetoclax-based regimens.  
  
Obinutuzumab-based Combinations  

Obinutuzumab plus Chlorambucil  

Obinutuzumab plus Chlorambucil is a treatment option as first-line treatment for chronic lymphocytic leukemia patients without del(17p)/TP53 mutation ≥65 years old and <65-year-old patients with significant comorbidities and with IGHV mutation when BTK inhibitors and Venetoclax are not available or contraindicated or rapid disease debulking is needed. Increased complete response rates and overall response rates were observed in patients given this combination, with minimal residual disease.

Acalabrutinib ± Obinutuzumab  

Acalabrutinib ± Obinutuzumab is the preferred first-line treatment for chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation regardless of age and comorbidities.  

Ibrutinib plus Obinutuzumab  

Ibrutinib plus Obinutuzumab is a first-line treatment option for patients with significant comorbidities and patients aged ≥65 years and <65 years old with significant comorbidities with chronic lymphocytic leukemia without del(17p)/TP53 mutation.  

Venetoclax plus Obinutuzumab  

Venetoclax plus Obinutuzumab is the preferred regimen for first-line treatment of chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation. It is a second- or third-line treatment option for chronic lymphocytic leukemia patients without del(17p)/TP53 mutation regardless of age and comorbidities at the presence of relapse after a period of remission if previously used as a first-line therapy.

Rituximab-based Combinations  

Rituximab in combination with Alemtuzumab is a first-line treatment option in patients with del(17p)/TP53 mutation. Rituximab plus Ibrutinib is a first-line treatment option for chronic lymphocytic leukemia patients without del(17p)/TP53 mutation aged <65 years without significant comorbidities. Rituximab plus Idelalisib is recommended as a first-line option for patients with del(17p)/TP53 mutation if the other treatment options are unavailable or considered unsuitable for the patient, and for patients with chronic lymphocytic leukemia with or without del(17p)/TP53 mutation with disease relapse or refractory disease after prior BTK inhibitor-based and Venetoclax-based regimens. Lenalidomide ± Rituximab is a therapy option for chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation with disease relapse or refractory disease after prior BTK inhibitor-based and Venetoclax-based regimens.

Venetoclax-based Combinations  

Venetoclax with anti-CD20 mAb (Obinutuzumab, Rituximab) regimen is a second- or third-line treatment option for chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation regardless of age and comorbidities at the presence of relapse after a period of remission if previously used as a first-line therapy.  

Venetoclax with Ibrutinib combination is a first-, second- and third- line treatment option for chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation and for those with disease relapse or refractory disease after prior BTK inhibitor-based and Venetoclax-based regimens.

Second-Line or Third-Line Therapy  

Relapsed disease occurs when disease progression appears ≥6 months after the initial complete or partial response. Refractory disease is when a patient fails to achieve a response or disease progression occurs within 6 months of the last treatment dose.  

Second-Line or Third-Line Therapy  

Second-line or third-line therapy depends on the presence of del(17p)/TP53 mutation, the patient’s age, and the presence of comorbidities.  
Patients without del(17p)/TP53 mutation may be given with Acalabrutinib1, Venetoclax plus Rituximab1, and Zanubrutinib1 as the preferred agents. Other recommended regimens include Ibrutinib1, Venetoclax2, and Ibrutinib plus Venetoclax3. The following may be used in special situations such as Venetoclax plus Obinutuzumab2 or Venetoclax plus other anti-CD20 mAb2 and Pirtobrutinib2 for patients with resistance or intolerance to prior covalent BTK inhibitor therapy. Acalabrutinib, Zanubrutinib, and Ibrutinib as continuous therapy are recommended in patients who experienced disease relapse after 36 months.

For chronic lymphocytic leukemia with del(17p)/TP53 mutation, Acalabrutinib1, Venetoclax plus Rituximab1, Venetoclax2, and Zanubrutinib1 are the preferred agents. Other recommended agents include Ibrutinib1 and Ibrutinib plus Venetoclax3. Lastly, the following regimens are used in special situations including Venetoclax plus other anti-CD20 mAb2 for those who relapsed after a period of remission if previously used, and Pirtobrutinib2 for patients with resistance or intolerance to prior covalent BTK inhibitor therapy.  

Therapy for Relapsed or Refractory Disease after Prior BTK Inhibitor- and Venetoclax-Based Regimens  

Chronic lymphocytic leukemia without del(17p)/TP53 mutation:

  • Bendamustine plus Rituximab2
  • Duvelisib2
  • FCR2
  • HDMP plus anti-CD20 mAb3
  • Ibrutinib plus Venetoclax3
  • Idelalisib ± Rituximab2
  • Lenalidomide ± Rituximab2
  • Lisocabtagene maraleucel2
  • Obinutuzumab2
  • Pirtobrutinib (if not previously given)


Chronic lymphocytic leukemia with del(17p)/TP53 mutation:

  • Alemtuzumab ± Rituximab2
  • Duvelisib2
  • HDMP plus anti-CD20 mAb2
  • Ibrutinib plus Venetoclax3
  • Idelalisib ± Rituximab2
  • Lenalidomide ± Rituximab2
  • Lisocabtagene maraleucel2
  • Pirtobrutinib (if not previously given)


1Indicated as Category 1 by the NCCN.
2Indicated as Category 2A by the NCCN.
3Indicated as Category 2B by the NCCN.


Supportive Therapy  

Autoimmune Cytopenias  

The most common forms in chronic lymphocytic leukemia patients include autoimmune hemolytic anemia, immune-mediated thrombocytopenia (also known as immune thrombocytopenic purpura), and pure red blood cell aplasia.  

Immune thrombocytopenic purpura is associated with poorer survival in chronic lymphocytic leukemia patients. Treatment includes administration of corticosteroids; splenectomy, Rituximab, intravenous immunoglobulin (IVIg), or Cyclosporin may be considered for patients unresponsive to corticosteroid therapy Romiplostim, Eltrombopag or BTK inhibitor-based therapy may also be considered for patients unresponsive to splenectomy, steroids, and IVIg.  

Infection or Reactivation  

Prevention of infectious complications by administration of IVIg, anti-infective prophylaxis, and vaccinations are recommended.  

Annual influenza vaccination (except live vaccines) and pneumococcal polysaccharide vaccine (PPSV23) every 5 years or to maintain protective serologic antibody levels based on serologic testing is recommended.  

Recombinant adjuvanted zoster vaccine is recommended for treatment-naive patients or those given BTK inhibitor therapy.  

The coronavirus disease 2019 (COVID-19) vaccine for all chronic lymphocytic leukemia patients should be considered. Consider COVID-19 prophylaxis with Tixagevimab and Cilgavimab.  

Immunoglobulin replacement therapy (monthly subcutaneous or IVIg) may be considered for patients with recurrent, severe infection despite prophylactic antibiotic therapy.  

Herpes virus with Acyclovir and Pneumocystis pneumonia prophylaxis with Acyclovir and Sulfamethoxazole/Trimethoprim respectively, are recommended for high-risk patients receiving Duvelisib or Idelalisib, purine analog, or Bendamustine-based chemoimmunotherapy and/or Alemtuzumab.  

Cytomegalovirus (CMV) Reactivation  

There is an increased risk of cytomegalovirus reactivation in patients receiving Alemtuzumab, Idelalisib, or Fludarabine-based chemoimmunotherapy. Prophylaxis with Ganciclovir may be considered in patients with increasing viral load during treatment. Quantitative polymerase chain reaction (PCR) should be conducted every 2-3 weeks to measure cytomegalovirus viremia.  

Hepatitis B Virus (HBV)  

There is an increased risk for hepatitis B virus reactivation in patients undergoing treatment with anti-CD20 monoclonal antibodies, Alemtuzumab, Ibrutinib, and Idelalisib. Prophylaxis with Entecavir is recommended for patients on immunosuppressive cytotoxic therapy with positive hepatitis B surface antigen (HBsAg), HBsAg negative but hepatitis B core antibody (HBcAb) positive, or elevated hepatitis B surface antibody (HBsAb) levels with increasing HBV DNA load. Lamivudine should be avoided due to the high incidence of resistance development. Adefovir, Telbivudine, and Tenofovir are acceptable alternatives. Viral load should be monitored using PCR monthly during and every 3 months after treatment. The prophylactic regimen should be continued until 12 months after treatment.  

Richter’s Transformation  

Richter’s transformation is the histologic transformation of chronic lymphocytic leukemia to a more aggressive form of lymphoma such as diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL).  
Chemoimmunotherapeutic regimens such as OFAR (Oxaliplatin, Fludarabine, Cytarabine, Rituximab), hyper- CVAD (Cyclophosphamide, Vincristine, Doxorubicin, Dexamethasone alternating with high-dose Methotrexate and Cytarabine) with Rituximab, DA-EPOCH-R (Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin with Rituximab), RCHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone), and Venetoclax plus RCHOP may be given.
 

For patients with a history of 1 full dose of Rituximab intravenous therapy, subcutaneous Rituximab plus human recombinant hyaluronidase may be used.  

For chemotherapy-refractory or del(17p)/TP53 mutation patients who are unable to receive chemoimmunotherapy, treatment options include Nivolumab with or without Ibrutinib, or Pembrolizumab with or without Ibrutinib.  

Hematopoietic cell transplant may also be considered for chemotherapy-sensitive transformed chronic lymphocytic leukemia.  

Tumor Flare Reactions  

Tumor flare reaction is an immune response composed of splenomegaly, fever, rashes, painful lymphadenopathy, lymphocytosis, and bone pain. They commonly occur in patients given immunomodulating agents (eg Lenalidomide) and kinase inhibitors (eg Ibrutinib, Idelalisib).  

Corticosteroid administration is recommended for the management of inflammation and lymphadenopathy. Prophylaxis with steroids may be considered for patients with bulky lymph nodes (>5 cm) prior to initiation of Lenalidomide treatment. Antihistamines may be used to manage pruritus with rashes.  

Tumor Lysis Syndrome  

Tumor lysis syndrome is cellular destruction secondary to chemotherapy which causes severe lymphadenopathy, hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and high LDH which may lead to acute renal failure. It is known to cause acute renal failure, cardiac arrhythmias, seizures, paralysis, and eventually death if left untreated.  

Prophylaxis prior to chemotherapy (especially with Lenalidomide, Obinutuzumab, Venetoclax, and chemoimmunotherapeutic agents) is recommended. This may be considered in patients with the following risk factors: 

  • Receiving Venetoclax chemoimmunotherapy, Lenalidomide, Obinutuzumab
  • Progressive disease after small-molecule inhibitor therapy 
  • Bulky lymph nodes 
  • Elevated white blood cell count (WBC)
  • Preexisting hyperuricemia 
  • Renal disease or renal involvement by tumor

Allopurinol or Febuxostat may be given for patients with low to intermediate risk, 2 to 3 days prior to initiation of chemotherapy then continued for 10 to 14 days. Rasburicase is recommended for patients with any high-risk features, urgent need for treatment initiation, when unable to achieve adequate hydration, and for patients with acute renal failure. 

Venous Thromboembolism  

Venous thromboembolism is associated with Lenalidomide use in chronic lymphocytic leukemia patients. Prophylaxis with Aspirin therapy for patients with platelet count ≥50 x 1012/L is recommended. Prophylaxis is not recommended for patients currently undergoing anticoagulant therapy (eg Warfarin).  

Allogenic Hematopoietic Cell Transplantation  

Allogenic hematopoietic cell transplantation should be considered in fit patients with high-risk chronic lymphocytic leukemia who experience disease relapse 24-36 months after first-line therapy, or patients with refractory chronic lymphocytic leukemia.  


Chronic Lymphocytic LeukemiaChronic Lymphocytic Leukemia



It may be considered in patients without significant comorbidities with chronic lymphocytic leukemia refractory to small-molecule inhibitor therapy (eg Acalabrutinib, Duvelisib, Ibrutinib, Idelalisib, Venetoclax). It may be considered as part of a clinical trial for young patients with del(17p)/TP53 mutation with good performance status and minimal comorbidities. Reports showed an increase in the progression-free survival rate compared to those given chemotherapy alone.  

Allogeneic hematopoietic cell transplantation is the preferred type of transplantation for chronic lymphocytic leukemia patients. It provides long-term disease control as shown in several prospective studies. It is not recommended as a treatment option for relapsed or refractory chronic lymphocytic leukemia after initial therapy with a purine-based regimen. 

Nonpharmacological

Observation

Observation is recommended for patients with early-stage, asymptomatic, low-risk chronic lymphocytic leukemia (Rai stage 0, Binet A) or some intermediate-risk chronic lymphocytic leukemia (Rai stage I-II, Binet B). Initiation of treatment in early-stage disease is not recommended and treatment should be initiated if with the presence of symptoms or disease progression.  

Reevaluation for the progression of the disease is recommended every 6-12 months for low- or intermediate-risk chronic lymphocytic leukemia and every 3-6 months is advised for patients with high-risk chronic lymphocytic leukemia. Patients should be assessed at least twice yearly within the first year of diagnosis. A repeat CBC, history, and physical examination should be done at 3- to 12-month intervals.