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.

 

Principles of Therapy

Indications for initiation of treatment:
  • Progressive marrow failure manifested as worsening or development of anemia &/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 &/or thrombocytopenia that responds poorly to steroids & other therapeutic agents
  • 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 I & II), treatment may be delayed with continuous monitoring every 3-12 months
  • For intermediate to high risk chronic lymphocytic leukemia patients, in patients with symptoms & 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 allogenic hematopoietic stem cell transplantation, or (3) unresponsive to hematopoietic stem cell transplantation

Pharmacotherapy

Alkylating Agents

Bendamustine

  • Recommended 1st-line treatment for both frail & adequately functional chronic lymphocytic leukemia (CLL) patients without del(17p)/TP53 mutation aged ≥65 years old & younger with comorbidities, & <65 years without significant comorbidities
    • May also be given as combination therapy with CD20 monoclonal antibody (Obinutuzumab, Ofatumumab, Rituximab) in refractory/relapsed disease
  • Monotherapy improved overall response rates & longer median progression-free survival but with reported toxicities

Chlorambucil

  • Recommended for chronic lymphocytic leukemia patients intolerant of Ibrutinib or Chlorambucil-monoclonal antibody combination treatment, & as initial treatment for patients with impaired functional status for relief of symptoms
  • First-line treatment option for frail CLL patients without del(17p)/TP53 mutation, & fit CLL patients without del(17p)/TP53 mutation aged ≥65 years old & younger patients w/ significant comorbidities 
  • Further studies are needed to conclude the effect of Chlorambucil on the survival response rates of older patients when compared to Fludarabine

Cancer Immunotherapy

Lenalidomide

  • Treatment option used for refractory/relapsed chronic lymphocytic leukemia (both frail & adequately functional) without del (17p)/TP53 mutation ≥65 years & younger with comorbidities & <65 years without significant comorbidities, with del (17p)/TP53 mutation with relapsed/refractory disease
  • Recommended maintenance regimen for CLL patients without del(17p)/TP53 mutation after completion of 1st-line therapy, & for CLL patients w/ or without del(17p)/TP53 mutation w/ complete or partial response after therapy for relapsed/refractory disease

Monoclonal Antibodies

Alemtuzumab

  • First-line therapeutic option for patients w/ del(17p)/TP53 mutation when treatment w/ preferred regimen (eg Ibrutinib) is not favorable, & option for patients w/ relapsed/refractory disease w/ del(17p)/TP53 mutation or those without del(17p)/TP53 mutation aged <65 years without significant comorbidities 
  • Studies have shown increased overall response rate & complete remission in previously untreated chronic lymphocytic leukemia patients when compared to Chlorambucil
  • Associated with increased incidence of infusion-related adverse effects, cytomegalovirus, & neutropenia, & is no longer commercially available

Obinutuzumab

  • A glycoengineered, humanized, type II antibody targeted against CD20
  • Recommended 1st-line treatment option for CLL patients without del(17p)/TP53 mutation aged ≥65 years & younger w/ significant comorbidities, frail CLL patients without del(17p)/TP53 mutation w/ significant comorbidities intolerant of purine analog treatment, those w/ refractory/relapsed disease, & patients w/ del(17p)/TP53 mutation
  • Approved for treatment-naive chronic lymphocytic leukemia patients in combination with Chlorambucil
  • Studies showed higher overall response rates in patients given Obinutuzumab monotherapy

Ofatumumab

  • A fully human CD20 monoclonal antibody
  • Recommended for CLL patients without del (17p)/TP53 mutation w/ relapsed/refractory disease aged <65 years without significant comorbidities & in both frail & w/ adequate functional status ≥65 years & younger w/ comorbidities, & patients with del (17p)/TP53 mutation w/ relapsed/refractory disease
  • Combination treatment with Chlorambucil is approved as 1st-line therapy for CLL patients without del(17p)/TP53 mutation in both frail & those with adequate functional status ≥65 years & younger with significant comorbidities
  • Used as maintenance treatment for patients with & without del(17p)/TP53 mutation with complete or partial response after receiving treatment relapsed or refractory disease

Rituximab

  • Recommended 1st-line treatment for chronic lymphocytic leukemia patients without del (17p)/TP53 mutation aged ≥65 years & younger with significant comorbidities & when combined with Methylprednisolone in patients with 17p deletion/TP53 mutation
    • Treatment option for patients with refractory/relapsed chronic lymphocytic leukemia aged <65 years without significant comorbidities without del (17p)/TP53 mutation when given in combination with high-dose Methylprednisone
  • Also recommended for frail chronic lymphocytic leukemia patients with significant comorbidities intolerant to purine analogs, chronic lymphocytic leukemia patients without del (17p)/TP53 mutation with relapsed/refractory disease aged ≥65 years & younger with comorbidities (dose-dense)

Other Antineoplastic Agents

  • Eg Acalabrutinib, Ibrutinib, Idelalisib
  • There are ongoing studies investigating the use of these drugs for chronic lymphocytic leukemia & other types of cancer

Acalabrutinib

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

Ibrutinib

  • Irreversibly inhibits Bruton’s tyrosine kinase
  • Preferred 1st-line treatment for chronic lymphocytic leukemia patients with del(17p)/TP53 mutation (initial & relapsed/refractory treatment), without del (17p)/TP53 mutation ≥65 years & younger with significant comorbidities (initial & relapsed/refractory treatment), & refractory/relapsed chronic lymphocytic leukemia aged <65 years without significant comorbidities without del (17p)/TP53 mutation

Idelalisib

  • A phosphatidylinositol-3-kinase (PI3Kδ) inhibitor
  • Treatment option for relapsed/refractory chronic lymphocytic leukemia with del(17p)/TP53 mutation, relapsed/refractory chronic lymphocytic leukemia without del(17p)/TP53 mutation ≥65 years & younger with significant comorbidities & <65 years without significant morbidities
  • Combination with Rituximab may be considered for relapsed/refractory chronic lymphocytic leukemia w/ CLL w/ del(17p)/TP53 mutation if eligible for Rituximab monotherapy

Venetoclax

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

Chemotherapeutic Regimens

Alemtuzumab + Rituximab

  • First-line treatment option for symptomatic patients with del(17p)/TP53 mutation
  • Treatment option for relapsed/refractory chronic lymphocytic leukemia with & without del(17p)/TP53 mutation or del(11q)

Bendamustine + CD20 Monoclonal Antibody-based Combinations

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

Fludarabine-based Combinations:

  • First-line therapeutic regimens (eg FCR, FR) for younger (<65 years) fit CLL patients without del(17p)/TP53 mutation, & therapeutic option (eg FC + Ofatumumab, FCR) for patients without del(17p)/TP53 mutation w/ refractory/relapsed disease <65 years old without significant comorbidities
  • FR (Fludarabine + Rituximab)
    • Recommended as 1st-line treatment option for chronic lymphocytic leukemia patients without del (17p)/TP53 mutation aged <65 years old without significant comorbidities
    • Studies have shown significant improvements in overall survival rate, complete remission, & progression-free survival when compared to Fludarabine monotherapy
  • FCR (Fludarabine + Cyclophosphamide + Rituximab)
    • Recommended 1st-line therapy for treatment-naive fit chronic lymphocytic leukemia patients without del(17p)/TP53 mutation <65 years without significant comorbidities, advanced chronic lymphocytic leukemia patients
    • 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
  • FR (Fludarabine + Cyclophosphamide) + Ofatumumab
    • Recommended treatment option for relapsed/refractory chronic lymphocytic leukemia patients aged 65 years without del (17p)/TP53 mutation
Obinutuzumab + Chlorambucil
  • First-line treatment for chronic lymphocytic leukemia:
    • Frail patients without del (17p)/TP53 mutation with significant comorbidity
    • Without del(17p)/TP53 mutation ≥65 years old & younger patients with significant comorbidities
    • With del(17p)/TP53 mutation
      • To be considered as last option considering that this combination is not as effective as other treatment options
  • Increased complete response rates & overall response rates were observed in patients given this combination, with minimal residual disease

Ofatumumab + Chlorambucil

  • Recommended for treatment-naive chronic lymphocytic leukemia patients who have contraindications to Fludarabine-based treatments
  • First line therapy for patients without del(17p)/TP53 mutation in both frail & those with adequate functional status ≥65 years & younger with significant comorbidities
  • Studies have shown that patients given Ofatumumab & Chlorambucil combination regimens had significantly longer progression-free survival rates, higher overall response rate, & superior complete remission rate

PCR (Pentostatin, Cyclophosphamide, Rituximab)

  • First-line treatment option for patients without del(17p)/TP53 mutation <65 years old without significant comorbidities
  • Relapsed/refractory disease without del(17p)/TP53 mutation <65 years old without significant comorbidities 
  • Reduced-dose PCR is a recommended treatment option for frail patients w/ relapsed/refractory disease without del(17p)/TP53 mutation
  • Efficacy comparable to FCR regimen but with lower complete remission rates & more reported adverse events
  • 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 Idelalisib combination may be used for relapsed/refractory chronic lymphocytic leukemia
  • Rituximab with high-dose Methylprednisolone is used as 1st line option for patients w/ del(17p)/TP53 mutation,for frail CLL patients without del(17p)/TP53 mutation, patients without del(17p)/TP53 mutation regardless of age & comorbidities, & a treatment option for relapsed/refractory CLL patients w/ or without del(17p)/TP53 mutation
  • Venetoclax-Rituximab combination is a preferred treatment regimen in both fit & frail patients w/ relapsed/refractory disease w/ or without del(17p)/TP53 mutation regardless of age & comorbidities

Non-Pharmacological Therapy

Observation

  • Recommended for patients with early stage, asymptomatic, low-risk chronic lymphocytic leukemia (CLL) [Rai stage 0, Binet A]
  • Initiation of treatment in early stage disease is not recommended
  • Treatment should be initiated if with the presence of symptoms or disease progression
  • Reevaluation every 3-12 months is advised for patients with stable disease
    • Patients should be assessed at least 2x/year within the 1st year of diagnosis
    • Repeat complete blood chemistry (CBC), history & physical examination at 3-month intervals
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