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 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
  • Further studies are needed to conclude the effect of Chlorambucil on the survival response rates of older patients when compared to Fludarabine

Cancer Immunotherapy

  • Eg 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
  • Further studies are needed to establish the efficacy of Lenalidomide for the treatment of chronic lymphocytic leukemia

Monoclonal Antibodies

Alemtuzumab

  • Should only be considered in patients with chronic lymphocytic leukemia with & without del(17p)/TP53 mutation when treatment with Ibrutinib is not favorable
  • 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 for chronic lymphocytic leukemia patients without del (17p)/TP53 mutation aged ≥65 years & younger with significant comorbidities
  • Also recommended for chronic lymphocytic leukemia patients intolerant to purine analogs & as 1st-line therapy for chronic lymphocytic leukemia patients without del (17p)/TP53 mutation, & in relapsed/refractory disease aged <65 years without significant comorbidities & ≥65 years & younger with comorbidities
  • 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 chronic lymphocytic leukemia patients without del (17p)/TP53 mutation with relapsed/refractory disease aged <65 years without significant comorbidities & in both frail & with adequate functional status ≥ 65 years & younger with comorbidities
  • 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 Ibrutinib, Idelalisib
  • There are ongoing studies investigating the use of these drugs for chronic lymphocytic leukemia & other types of cancer

Ibrutinib

  • Irreversibly inhibits Bruton’s tyrosine kinase
  • Preferred 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

Venetoclax

  • A selective inhibitor of the anti-apoptotic protein BCL-2
  • 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

Purine Analogs

Fludarabine

  • First-line treatment for treatment-naive, physically fit patients without del(17p)/TP53 mutation
  • Studies have shown that treatment with Fludarabine improves complete remission rate, partial remission rate & overall response rate
  • Fludarabine-based combinations are preferred therapeutic regimens for younger (<65 years) patients

Chemotherapeutic Regimens

Alemtuzumab-based combinations

  • Alemtuzumab + Rituximab
    • First-line treatment 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 + Rituximab

  • Alternative to Fludarabine-based regimens for chronic lymphocytic leukemia patients
  • With superior results (overall response rate) compared to Bendamustine monotherapy
  • With limited activity in patients with del(17p)

Fludarabine-based combinations:

  • Preferred therapeutic regimens for younger (<65 years) patients
  • Studies have demonstrated superiority of Fludarabine-based combination to Chlorambucil-based regimens in younger patients
  • FR (Fludarabine, Rituximab)
    • Recommended as 1st-line treatment 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, advanced chronic lymphocytic leukemia patients
    • Also considered for initial therapy in chronic lymphocytic leukemia with del(17p) with subsequent dose of Ibrutinib
    • 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
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

OFAR (Oxaliplatin, Fludarabine, Cytarabine, Rituximab)

  • Alternative combination regimen used for relapsed/refractory chronic lymphocytic leukemia
    • Without del(17p)/TP53 mutation <65 years old without 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

Ofatumumab + Bendamustine

  • Recently approved Ofatumumab-based combination to be used for treatment-naive chronic lymphocytic leukemia patients who have contraindications to Fludarabine-based treatments

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)

  • Treatment option for chronic lymphocytic leukemia patients:
    • Without del(17p)/TP53 mutation, <65 years old without comorbidities
    • Relapsed/refractory disease without del(17p)/TP53 mutation ≥65 years old & younger with significant comorbidities (reduced-dose)
    • Relapsed/refractory disease without del(17p)/TP53 mutation <65 years old without significant comorbidities
  • 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

RCHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone)

  • Treatment option for relapsed/refractory disease without del(17p)/TP53 mutation <65 years old without significant comorbidities

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 therapy for patients with del(17p)/TP53 mutation & as a treatment option for relapsed/refractory chronic lymphocytic leukemia with or without del(17p)/TP53 mutation ages ≥65 years old & younger with significant 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
Digital Edition
Asia's trusted medical magazine for healthcare professionals. Get your MIMS Oncology - Malaysia digital copy today!
DOWNLOAD
Editor's Recommendations
Most Read Articles
29 Nov 2017
Rapid onset opioids may allow for more effective treatment of breakthrough cancer pain as their pharmacokinetic profile closely mimics the pain’s time course
Christina Lau, 22 Oct 2015
A 21-gene expression assay can identify patients with early-stage breast cancer who can skip adjuvant chemotherapy without facing an increased risk of recurrence at 5 years.
Cathy Chow, PhD, 27 Aug 2015

HER2-positive breast cancer tends to be more aggressive, has worse patient prognosis, and responds less to treatment. A two-pronged approach to block the HER pathway via pertuzumab (Perjeta®, Roche), a first-in-class HER dimerization inhibitor, in combination with trastuzumab and chemotherapy, may offer more treatment options for HER2-positive metastatic breast cancer patients as well as those with early breast cancer. 

Saras Ramiya, 25 Oct 2017
The first patient-reported outcomes study on durvalumab treatment after chemoradiation in locally advanced non-small cell lung cancer (NSCLC) shows patients’ quality of life is similar to that of the patients who received placebo.