Chronic Lymphocytic Leukemia Management

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. 

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. 

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 CLL 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 CLL:

• 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 CLL 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

Bruton’s Tyrosine Kinase (BTK) Inhibitors  

Acalabrutinib  

Acalabrutinib is a highly selective, irreversible, second-generation BTK inhibitor. It is recommended as one of the preferred first-, second- and subsequent-line therapy to CLL patients with or without del(17p)/TP53 mutation. It may be given in combination with Obinutuzumab. It is not recommended for CLL patients with BTK C481S mutations unresponsive to Ibrutinib therapy. 
 
Ibrutinib  

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

Pirtobrutinib  

Pirtobrutinib is a non-covalent, highly selective, third-generation BTK inhibitor. It is a first-line treatment option for older CLL patients with or without del(17p)/TP53 mutation with cardiac comorbidities who may only need one lifetime treatment of CLL. It is a second- or subsequent-line treatment option for CLL patients with or without del(17p)/TP53 mutation used for disease resistant or intolerant to prior BTK inhibitor-based regimens. It is also a therapy option for relapsed or refractory disease after prior BTK inhibitor- and BCL2 inhibitor-containing regimens for CLL patients with or without del(17p)/TP53 mutation if not previously used. 

Zanubrutinib  

Zanubrutinib is a second-generation, covalent BTK (cBTK) inhibitor. It is a preferred first-line therapy option for CLL patients with or without del(17p)/TP53 mutation. It is a preferred second- or subsequent-line therapy option for CLL patients with or without del(17p)/TP53 mutation. It is not recommended for Ibrutinib-refractory CLL patients with BTK C481S mutations. 

Cancer Immunotherapy/Immunomodulating Agent

Cancer immunotherapy should only be considered only when cBTK inhibitors and BCL2 inhibitors are not available or treatment with these targeted therapies is not feasible.

Lenalidomide  

Lenalidomide is a therapy for relapsed or refractory disease after prior BTK inhibitor- and BCL2 inhibitor-containing regimens for CLL patients with or without del(17p)/TP53 mutation if not previously used.  

Monoclonal Antibodies  

Alemtuzumab  

Alemtuzumab is recombinant, fully humanized, monoclonal antibody against the CD52 antigen. It is a treatment option in patients with del(17p)/TP53 mutation with relapsed or refractory disease after prior BTK inhibitor- and BCL2 inhibitor-containing regimens. 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 CLL patients with or without del(17p)/TP53 mutation as monotherapy. It is a first-line treatment option for CLL patients with or without del(17p)/TP53 mutation regardless of age and comorbidities when BTK inhibitor- and BCL2 inhibitors are not available. It is a treatment option for patients without del(17p)/TP53 mutation with relapsed or refractory disease after prior BTK inhibitor-based and BCL2 inhibitor-containing regimens. 

Other Antineoplastic Agents  
 
Duvelisib  

Duvelisib inhibits delta and gamma isoforms of phosphatidylinositol 3-kinase (PI3K). It is an alternative therapy for CLL patients with or without del(17p)/TP53 mutation with relapsed or refractory disease after prior BTK inhibitor-based and BCL2 inhibitor-containing regimens.  
 
Idelalisib  

Idelalisib is a PI3K delta (PI3Kδ) inhibitor. It is a therapy option for CLL patients with and without del(17p)/TP53 mutation with relapsed or refractory disease after prior BTK inhibitor-based and BCL2 inhibitor-containing regimens.  

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 BCL2 inhibitor-containing regimens.  
 
Venetoclax  

Venetoclax is a selective inhibitor of the anti-apoptotic protein BCL-2. It is a second- or subsequent-line treatment option for CLL patients with or without del(17p)/TP53 mutation who experiences disease relapse after a period of remission.
 
Combination Regimens

B-cell Lymphoma 2 (BCL2) Inhibitor-Containing Regimens  

Venetoclax with anti-CD20 mAb (Obinutuzumab, Rituximab) regimen is a first- (combination with Obinutuzumab), second- or subsequent-line treatment option for CLL 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 plus Acalabrutinib with or without Obinutuzumab is one of the preferred first-line treatment options for CLL patients with del(17p)/TP53 mutation and is an alternative first-line option for CLL patients without del(17)p/TP53 mutation with IGHV-unmutated disease. Venetoclax with Acalabrutinib combination is also used as a second- or subsequent-line treatment option for CLL patients with or without del(17p)/TP53 mutation. 

Venetoclax with Ibrutinib combination is a first-, second- and subsequent- line treatment option for CLL patients with or without del(17p)/TP53 mutation. Venetoclax with Zanubrutinib combination is the preferred first-line regimen for CLL patients with del(17p)/TP53 mutation, and as an alternative first-line treatment for CLL patients without del(17p)/TP53 mutation. It is also used as a second- or subsequent-line treatment option for CLL patients with or without del(17p)/TP53 mutation.
 
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 CLL patients without del(17p)/TP53 mutation ≥65 years old or <65-year-old patients with significant comorbidities when BTK inhibitors and BCL2 inhibitor containing regimens are not available or contraindicated or rapid disease debulking is needed. Bendamustine plus Rituximab combination is a treatment option for CLL patients without del(17p)/TP53 mutation for patients ≥65 years old or patients <65 years with significant comorbidities with relapsed or refractory disease after BTK inhibitor-based and BCL2 inhibitor-containing regimens. 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 first-line therapy for treatment-naive fit IGHV mutation-positive CLL patients without del(17p)/TP53 mutation <65 years without significant comorbiditiescomorbidities only when cBTK inhibitor and BCL2 inhibitor are not available or not feasible. 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 an option as a first-line treatment for patients with or without del(17)p/TP53 mutation and also used as a treatment option for relapsed or refractory CLL after prior BTK inhibitor-based and BCL2 inhibitor-containing regimens. If to be used in patients <65 years with significant comorbidities, benefits should outweigh outcome of treatment.
 
Ibrutinib plus Anti-CD20 mAb-based Combination  

Example combinations: Ibrutinib plus Obinutuzumab, Ibrutinib plus Rituximab  

Ibrutinib plus anti-CD20 mAb-based combinations are first-line options for CLL patients without del(17)p/TP53 mutation.
 
Obinutuzumab-based Combinations  

Obinutuzumab plus Chlorambucil  

Obinutuzumab plus Chlorambucil is an option as first-line treatment for CLL 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 BCL2 inhibitor-containing regimens are not available. Increased complete response rates and overall response rates were observed in patients given this combination, with minimal residual disease.

Acalabrutinib plus Obinutuzumab  

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

Venetoclax plus Obinutuzumab  

Venetoclax plus Obinutuzumab is the preferred regimen for first-line treatment of CLL patients with or without del(17p)/TP53 mutation. It is a second- or subsequent-line treatment option for CLL patients without del(17p)/TP53 mutation regardless of age and comorbidities.

Rituximab-based Combinations  

Rituximab in combination with Alemtuzumab is a treatment option in patients with del(17p)/TP53 mutation with relapsed or refractory disease after prior therapy using BTK inhibitor-based and BCL2 inhibitor-containing regimens. Rituximab plus Idelalisib is an option for patients with CLL with or without del(17p)/TP53 mutation with disease relapse or refractory disease after prior BTK inhibitor-based and BCL2 inhibitor-containing regimens. Lenalidomide ± Rituximab is a therapy option for CLL patients with or without del(17p)/TP53 mutation with disease relapse or refractory disease after prior BTK inhibitor-based and BCL2 inhibitor-containing regimens.
 
Second-Line or Subsequent-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 Subsequent-Line Therapy  

Second-line or subsequent-line therapy depends on the presence of del(17p)/TP53 mutation, the patient’s age, and the presence of comorbidities.  

Preferred regimens include Acalabrutinib¹, Pirtobrutinib (for patients with resistance or intolerance to prior cBTK inhibitor therapy), Venetoclax plus Obinutuzumab², and Zanubrutinib¹. Other recommended regimens include Ibrutinib¹, Venetoclax² (may be considered for relapse after a period of remission), Venetoclax plus anti-CD20 mAb² (for relapse after a period of remission [if previously used]), Venetoclax plus cBTK inhibitor (Acalabrutinib, Ibrutinib, Zanubrutinib), and Venetoclax plus Rituximab¹.

Therapy for Relapsed or Refractory Disease after Prior BTK Inhibitor- and BCL2 Inhibitor-Containing Regimens 

For patients with relapsed or refractory disease after BTK inhibitor- and BCL2 inhibitor-containing regimens, the preferred regimens include Lisocabtagene maraleucel ± Ibrutinib2 and Pirtobrutinib (if not given previously). Other recommended regimens include Alemtuzumab ± Rituximab2 (for patients with del[17p]/TP53 mutation), Bendamustine plus Rituximab⁴, Duvelisib², FCR², HDMP plus anti-CD20 mAb (Obinutuzumab or Rituximab)^2,3, Idelalisib ± Rituximab², Lenalidomide ± Rituximab², and Obinutuzumab².
 
¹Indicated as Category 1 by the NCCN.
²Indicated as Category 2A by the NCCN.
³Indicated as Category 2B by the NCCN.
⁴Indicated as Category 2B by the NCCN for patients ≥65 years old or <65 years old with significant comorbidities.

Supportive Therapy  

Autoimmune Cytopenias  

The most common forms in CLL 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 CLL patients. Treatment includes administration of corticosteroids; splenectomy, Rituximab, intravenous immunoglobulin (IVIg), or Cyclosporin may be considered for patients unresponsive to corticosteroid therapy. Thrombopoietin receptor agonists (eg 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 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 CLL patients should be considered.

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. A single-dose respiratory syncytial virus (RSV) vaccine is considered as well for all CLL patients.

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 CLL 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.

Non-chemoimmunotherapeutic regimens that may be considered include immune check point inhibitors (eg Atezolizumab plus Obinutuzumab plus Venetoclax, Nivolumab ± Ibrutinib, Pembrolizumab ± Ibrutinib, Tislelizumab plus Zanubrutinib), BTK inhibitor-based regimens (eg Acalabrutinib, Pirtobrutinib, Pirtobrutinib plus Venetoclax plus Obinutuzumab), bispecific antibody therapies (eg Epcortimab, Glofitamab), and CAR T-cell therapy (eg Axicabtagene ciloleucel, Lisocabtagene maraleucel, Tisagenlecleucel).

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). Abrupt discontinuation of BTK inhibitors can be associated with explosive disease flare with rapid rise in absolute lymphocyte count, enlargement of lymph nodes and accelerated clinical deterioration. 

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.

Prophylaxis prior to chemotherapy (especially with Lenalidomide, Obinutuzumab, Venetoclax, and chemoimmunotherapeutic agents) is recommended. This is 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)
• Pre-existing 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. Glucose-6-phosphate (G6PD) testing is recommended prior the use of Rasburicase. Tumor lysis syndrome is known to cause acute renal failure, cardiac arrhythmias, seizures, paralysis, and eventually death if left untreated. 

Venous Thromboembolism  

Venous thromboembolism is associated with Lenalidomide use in CLL patients. Prophylaxis with Aspirin therapy for patients with platelet count >50 x 10⁹/L is recommended. Prophylaxis is not recommended for patients currently undergoing anticoagulant therapy (eg Warfarin).  

Nonpharmacological

Observation

Observation is recommended for patients with early-stage, asymptomatic, low-risk CLL (Rai stage 0, Binet A) or some intermediate-risk CLL (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.  

Re-evaluation for the progression of the disease is recommended every 6-12 months for low- or intermediate-risk CLL and every 3-6 months is advised for patients with high-risk CLL. 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. 

Allogenic Hematopoietic Cell Transplantation 

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

Chronic Lymphocytic Leukemia