Treatment Guideline Chart

Chronic lymphocytic leukemia (CLL) is a malignant, chronic lymphoproliferative disorder characterized by proliferation and accumulation of monoclonal B-cells in the bone marrow, peripheral blood, lymph nodes, liver and spleen.

It is the most common form of adult leukemia in the Western world but rare in Asians.

Exact etiology is unknown but usually associated with genetic aberrations and lesions.


Chronic%20lymphocytic%20leukemia Treatment

Supportive Therapy

Autoimmune Cytopenias
  • Most common forms in chronic lymphocytic leukemia (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 intravenous immunoglobulin


  • Prevention of infectious complications by administration of intravenous immunoglobulin, 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 Bruton's tyrosine kinase inhibitor therapy
    • Coronavirus disease 2019 (COVID-19) vaccine for all CLL patients
      • 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 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

  • Increased risk of 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 PCR should be conducted every 2-3 weeks to measure cytomegalovirus (CMV) viremia

Hepatitis B Virus (HBV)

  • Increased risk for hepatitis B virus reactivation in patients undergoing treatment with anti-CD20 monoclonal antibody, 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 high incidence for resistance development
    • Adenofir, Telbivudine, and Tenofovir are acceptable alternatives
  • Viral load should be monitored using polymerase chain reaction (PCR) monthly during and every 3 months after treatment
  • Prophylactic regimen should be continued until 12 months after treatment

Richter’s Transformation

  • 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), and RCHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) may be given
    • For patients with history of 1 full dose of Rituximab IV therapy, SC 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 transplantation may also be considered for chemotherapy-sensitive transformed CLL

Tumor Flare Reactions

  • An immune response composed of splenomegaly, fever, rashes, painful lymphadenopathy, lymphocytosis and bone pain
  • Commonly occurs in patients given immunomodulating agents (eg Lenalidomide) and kinase inhibitors (eg Ibrutinib, Idelalisib)
  • Corticosteroid administration is recommended for 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

  • Cellular destruction secondary to chemotherapy causing 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
    • Consider for patients w/ 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
    • May give Allopurinol or Febuxostat for patients with low to intermediate risk, 2-3 days prior to initiation of chemotherapy then continued for 10-14 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
  • Known to cause acute renal failure, cardiac arrhythmias, seizures, paralysis and eventually death if left untreated

Venous Thromboembolism

  • Associated with Lenalidomide use in CLL patients
  • Prophylaxis with Aspirin therapy for patients with platelet count ≥50 x 1012/L is recommended
    • Not recommended for patients currently undergoing anticoagulant therapy (eg Warfarin)
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