Chronic Lymphocytic Leukemia Management

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).

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. 

Alkylating Agents  

Bendamustine  

Bendamustine combined with Rituximab is a treatment option for relapsed or refractory disease after prior BTK inhibitor- and B-cell lymphoma 2 (BCL2) inhibitor-containing regimens for CLL patients without del(17)p/TP53 mutation regardless of age and comorbidities. 

Chlorambucil  

Chlorambucil combined with Obinutuzumab may be considered for CLL patients when BTK inhibitor and BCL2 inhibitor-containing regimens are not available or are contraindicated or rapid disease debulking is needed.  

Bruton’s Tyrosine Kinase (BTK) Inhibitors  

Acalabrutinib  

Acalabrutinib is a second-generation BTK inhibitor. It is recommended as one of the preferred first-line therapy to CLL patients with or without del(17p)/TP53 mutation. It may be given in combination with Obinutuzumab. It is a preferred second- or subsequent-line therapy option for CLL patients with or without del(17)p/TP53 mutation, regardless of age and comorbidities. 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 noncovalent, third-generation BTK inhibitor. 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 BTK inhibitor. It is a preferred first-line therapy option for CLL patients with or without del(17p)/TP53 mutation with contraindication to other BTK inhibitors. It is a preferred second- or subsequent-line therapy option for CLL patients with or without del(17p)/TP53 mutation, regardless of age and comorbidities. It is not recommended for Ibrutinib-refractory CLL patients with BTK C481S mutations. 

Cancer Immunotherapy  

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 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 or contraindicated or rapid disease debulking is needed. 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. The combination with Chlorambucil is a first-line treatment option for CLL patients without del(17p)/TP53 mutation aged ≥65 years and <65 years old with significant comorbidities. 

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 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 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 preferred first-line therapy regimen for CLL patients with or without del(17p)/TP53 mutation when given with Obinutuzumab. It is a preferred second- or subsequent-line treatment option for chronic lymphocytic leukemia patients with or without del(17p)/TP53 mutation regardless of age and comorbidities when given with Obinutuzumab. It may also be given in combination with Rituximab.  
 
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 options for CLL patients with or without del(17)p/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.  

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 an alternative second- or subsequent-line treatment options 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 comorbidities, and an option for patients without del(17p)/TP53 mutation aged <65 years without significant comorbidities with relapsed or refractory CLL after prior BTK inhibitor-based and BCL2 inhibitor-containing regimens. 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 when BTK inhibitors and BCL2 inhibitor-containing regimens are not available or contraindicated or rapid disease debulking is needed. It is 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 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 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 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 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 Ibrutinib is a first-line treatment option for CLL 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 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 for CLL patients without del(17p)/TP53 mutation include Acalabrutinib¹, Pirobrutinib² (for patients with resistance or intolerance to prior covalent BTK inhibitor therapy), Venetoclax plus Obinutuzumab², and Zanubrutinib¹. Other recommended regimens include Ibrutinib¹, Venetoclax², Venetoclax plus Ibrutinib³, and Venetoclax plus Rituximab¹ or Venetoclax plus other anti-CD20 mAb². Acalabrutinib, Zanubrutinib, and Ibrutinib as continuous therapy are recommended in patients who experienced disease relapse after 36 months. 

For CLL with del(17p)/TP53 mutation, Acalabrutinib¹, Pirtobrutinib² (for patients with resistance or intolerance to prior covalent BTK inhibitor therapy), Venetoclax plus Obinutuzumab², Venetoclax², and Zanubrutinib¹ are the preferred agents. Other recommended agents include Ibrutinib¹, Venetoclax plus Ibrutinib³, and Venetoclax plus Rituximab¹. Lastly, Venetoclax plus other anti-CD20 mAb2 may be used in special situations such as for those who relapsed after a period of remission if previously used.

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

For patients with CLL without del(17p)/TP53 mutation, preferred regimens include Lisocabtagene maraleucel² and Pirtobrutinib² (if not given previously). Other recommended regimens include Bendamustine plus Rituximab^2,4, Duvelisib², FCR², HDMP plus anti-CD20 mAb (Obinutuzumab or Rituximab)³, Idelalisib ± Rituximab², Lenalidomide ± Rituximab², and Obinutuzumab².

For patients with CLL with del(17p)/TP53 mutation, preferred regimens include Lisocabtagene maraleucel² and Pirtobrutinib (if not given previously). While other recommended regimens include Alemtuzumab ± Rituximab², Duvelisib², HDMP plus anti-CD20 mAb (Obinutuzumab or Rituximab)², Idelalisib ± Rituximab², and Lenalidomide ± Rituximab².
 
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 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 CLL 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 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.  

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)
• 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. 

Venous Thromboembolism  

Venous thromboembolism is associated with Lenalidomide use in CLL 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 CLL who experience disease relapse 24-36 months after first-line therapy, or patients with refractory CLL.  

It may be considered in patients without significant comorbidities with CLL 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 CLL 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 CLL after initial therapy with a purine-based regimen.