chronic%20lymphocytic%20leukemia
CHRONIC LYMPHOCYTIC LEUKEMIA

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

Principles of Therapy

  • 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 immunoglobulin heavy chain variable (IGHV) mutation status
Indications for Initiation of Treatment
  • 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/functional extranodal involvement 
  • Presence of constitutional symptoms
    • Unintentional weight loss of ≥10% within a 6-month period
    • Significant fatigue (with ECOG PS score ≥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/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
    • Patients with del(17p) who are (1) unresponsive to 1st-line treatment, (2) responsive to 1st-line therapy but not eligible for allogeneic hematopoietic stem cell transplantation (HSCT), or (3) unresponsive to HSCT

Pharmacotherapy

Alkylating Agents

Bendamustine

  • Treatment option for the 1st-line treatment of chronic lymphocytic leukemia (CLL) patients without del(17p)/TP53 mutation aged ≥65 years or younger with significant comorbidities or <65 years without significant comorbidities in combination therapy with CD20 monoclonal antibody (Obinutuzumab, Ofatumumab, Rituximab)
    • Bendamustine/Rituximab combination is a treatment option for patients with relapsed/refractory CLL without del(17p)/TP53 mutation aged <65 years without significant comorbidities

Chlorambucil

  • Recommended for CLL patients intolerant of Ibrutinib or Chlorambucil-monoclonal antibody combination treatment, and as initial treatment for patients with impaired functional status for relief of symptoms
  • 1st-line treatment option for frail CLL patients without del(17p)/TP53 mutation, and fit CLL patients without del(17p)/TP53 mutation aged ≥65 years old and younger patients with significant comorbidities 

Cancer Immunotherapy

Lenalidomide

  • Treatment option used for refractory/relapsed chronic lymphocytic leukemia (both frail and adequately functional) with or without del(17p)/TP53 mutation
  • May consider as maintenance regimen for CLL patients without del(17p)/TP53 mutation after completion of 1st-line therapy, and for CLL patients without del(17p)/TP53 mutation with complete or partial response after therapy for relapsed/refractory disease

Monoclonal Antibodies

Obinutuzumab

  • A glycoengineered, humanized, type II antibody targeted against CD20
  • Approved for treatment-naive chronic lymphocytic leukemia patients as monotherapy or in combination with Chlorambucil
  • Studies showed higher overall response rates in patients given Obinutuzumab monotherapy

Ofatumumab

  • A fully human CD20 monoclonal antibody
  • Treatment option for CLL patients with or without del(17p)/TP53 mutation with relapsed/refractory disease aged
  • Used as maintenance treatment for patients without del(17p)/TP53 mutation with complete or partial response after receiving treatment relapsed or refractory disease

Rituximab

  • Treatment option for 1st-line treatment of the following:
    • CLL patients without del (17p)/TP53 mutation aged ≥65 years and younger with significant comorbidities or frail patients with significant comorbidity or intolerant to purine analogs
    • Relapsed/refractory CLL patients without del(17p)/TP53 mutation aged ≥65 years and younger with significant comorbidities or frail patients with significant comorbidity (dose-dense)

Other Antineoplastic Agents

  • Eg Acalabrutinib, Duvelisib, Ibrutinib, Idelalisib
  • There are ongoing studies investigating the use of these drugs for CLL and other types of cancer

Acalabrutinib

  • A 2nd-generation Bruton’s tyrosine kinase inhibitor
  • Recommended for refractory/relapsed CLL patients without del(17p)/TP53 mutation aged ≥65 years and younger with significant comorbidities, aged <65 years without significant comorbidities, and refractory/relapsed CLL patients with del(17p)/TP53 mutation
  • Not recommended for CLL patients with BTK C481S mutations unresponsive to Ibrutinib therapy

Duvelisib

  • Inhibits delta and gamma isoforms of phosphatidylinositol 3-kinase (PI3K)
  • Recommended for the treatment of relapsed/refractory CLL patients with or without del(17p)/TP53 mutation regardless of age and comorbidities

Ibrutinib

  • Irreversibly inhibits Bruton’s tyrosine kinase
  • Preferred 1st-line treatment for CLL patients with or without del(17p)/TP53 mutation as initial treatment and for relapsed/refractory disease

Idelalisib

  • A phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor
  • Treatment option for relapsed/refractory CLL with del(17p)/TP53 mutation, relapsed/refractory CLL without del(17p)/TP53 mutation ≥65 years and younger with significant comorbidities and <65 years without significant morbidities
  • Combination with Rituximab is recommended for relapsed/refractory CLL with del(17p)/TP53 mutation and relapsed/refractory CLL without del(17p)/TP53 mutation if eligible for Rituximab monotherapy

Venetoclax 

  • A selective inhibitor of the anti-apoptotic protein BCL-2
  • Preferred regimen for patients with refractory/relapsed CLL with del(17p)/TP53 mutation
  • Treatment option for relapsed/refractory CLL without del(17p)/TP53 mutation ≥65 years and younger with significant comorbidities and <65 years without significant morbidities

Chemotherapeutic Regimens

Acalabrutinib ± Obinutuzumab

  • Preferred 1st-line treatment for CLL patients with or without del(17p)/TP53 mutation regardless of age and comorbidities

Bendamustine + CD20 Monoclonal Antibody-based Combinations

  • Eg Bendamustine + Obinutuzumab, Bendamustine + Ofatumumab, Bendamustine + Rituximab
  • Treatment option as 1st-line regimen for CLL patients without del(17p)/TP53 mutation ≥65 years old, <65 years without significant comorbidities or younger patients with significant comorbidities and with IGHV mutation
  • Alternative treatment option for CLL patients without del(17p)/TP53 mutation with relapsed/refractory disease, <65 years without significant comorbidities
  • Showed longer progression-free survival rates compared to Bendamustine monotherapy
  • Bendamustine + Rituximab in combination with either Idelalisib or Ibrutinib may be considered in patients with refractory/relapsed disease positive for del(17p)/TP53 mutation

Fludarabine-based Combinations

  • First-line therapeutic regimens (eg FCR, FR) for younger (<65 years) fit CLL patients without del(17p)/TP53 mutation, and therapeutic option (eg FC + Ofatumumab, FCR) for patients without del(17p)/TP53 mutation with refractory/relapsed disease <65 years old without significant comorbidities and with IGHV mutation
  • FR (Fludarabine + Rituximab)
    • Recommended as 1st-line treatment option for CLL patients without del(17p)/TP53 mutation aged <65 years old without significant comorbidities
    • Studies have shown significant improvements in overall survival rate, complete remission, and progression-free survival when compared to Fludarabine monotherapy
  • FCR (Fludarabine + Cyclophosphamide + Rituximab)
    • Treatment option as 1st-line therapy for treatment-naive fit CLL patients without del(17p)/TP53 mutation <65 years without significant comorbidities, advanced CLL patients and for patients with relapsed/refractory CLL without del(17p)/TP53 mutation aged <65 years without significant comorbidities
      • Preferred 1st-line therapy for IGHV-mutated CLL in patients <65 years without significant comorbidities
      • Reduced-dose FCR is a treatment option for patients with relapsed/refractory CLL without del(17p)/TP53 mutation who are frail with significant comorbidity or aged ≥65 years and younger with significant comorbidities
    • May be considered for treatment-naive patients with adequate functional status, or relapsed patients with indications for treatment initiation
    • May be used as a debulking strategy prior to hematopoietic stem cell transplantation
  • FC (Fludarabine + Cyclophosphamide) + Ofatumumab
    • Recommended treatment option for relapsed/refractory CLL patients without del(17p)/TP53 mutation aged <65 years without significant comorbidities

Ibrutinib + Obinutuzumab

  • 1st-line treatment option for frail patients with significant comorbidities and patients aged ≥65 years and younger with significant comorbidities with CLL without del(17p)/TP53 mutation

Lenalidomide ± Rituximab

  • Treatment option for patients with relapsed/refractory CLL with or without del(17p)/TP53 mutation regardless of age and comorbidities
Obinutuzumab + Chlorambucil
  • Treatment option as 1st-line treatment for CLL:
    • In frail patients without del(17p)/TP53 mutation with significant comorbidity
    • Without del(17p)/TP53 mutation ≥65 years old and younger patients with significant comorbidities and with IGHV mutation
  • Increased complete response rates and overall response rates were observed in patients given this combination, with minimal residual disease

PCR (Pentostatin, Cyclophosphamide, Rituximab)

  • Treatment option for initial management of patients without del(17p)/TP53 mutation, <65 years old without significant comorbidities or those with relapsed/refractory disease
  • Reduced-dose PCR is a recommended treatment option for frail patients with significant comorbidity or aged ≥65 years and younger with significant comorbidities with relapsed/refractory disease without del(17p)/TP53 mutation
  • Efficacy comparable to FCR regimen but with lower complete remission rates
  • With less reports of myelosuppression compared to treatment with FCR

Rituximab-based Combinations

  • Rituximab combination with Chlorambucil may prolong progression-free survival in patients without del(17p)/TP53 mutation with significant comorbidities
  • Rituximab plus Ibrutinib was found to be more effective than FCR for patients ≥70 years without del(17p)/TP53 mutation particularly in those with unmutated IGHV based on the ECOG-American College of Radiology Imaging Network (ACRIN) study
    • 1st-line treatment option for CLL patients without del(17p)/TP53 mutation aged <65 years without significant comorbidities
  • Rituximab plus Idelalisib combination is recommended for relapsed/refractory CLL with or without del(17p)/TP53 mutation
  • Venetoclax-Rituximab combination is a preferred treatment regimen in both fit and frail patients with relapsed/refractory disease with or without del(17p)/TP53 mutation regardless of age and comorbidities

Venetoclax + Obinutuzumab

  • Preferred regimen for 1st-line treatment of CLL patients with or without del(17p)/TP53 mutation regardless of age and comorbidities

Non-Pharmacological Therapy

Observation

  • Recommended for patients with early stage, asymptomatic, low-risk chronic lymphocytic leukemia (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
  • Treatment should be initiated if with the presence of symptoms or disease progression
  • Reevaluation for progression of 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 2x/year within the 1st year of diagnosis
    • Repeat complete blood chemistry (CBC), history and physical examination at 3- to 12-month intervals
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