Chronic%20lymphocytic%20leukemia Treatment

Treatment

Principles of Therapy

Choice of treatment for patients with chronic lymphocytic leukemia (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 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
- 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 (HCT), or (3) unresponsive to HCT

Pharmacotherapy

Alkylating Agents

Bendamustine

Treatment option for the first-line treatment of chronic lymphocytic leukemia (CLL) patients without del(17p)/TP53 mutation aged ≥65 years or <65 years with or without significant comorbidities in combination therapy with CD20 monoclonal antibody (Obinutuzumab, Ofatumumab, Rituximab)
- Bendamustine/Rituximab combination is a treatment option for relapsed or refractory disease after prior BTK inhibitor- and Venetoclax-based regimens for CLL patients without del(17p)/TP53 mutation regardless of age and 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

Cancer Immunotherapy

Lenalidomide

Second-line or third-line treatment option used for CLL patients (both with comorbidities and adequately functional) with or without del(17p)/TP53 mutation
Therapy for relapsed or refractory disease after prior BTK inhibitor- and Venetoclax-based regimens for CLL patients without del(17p)/TP53 mutation if not previously used

Monoclonal Antibodies

Alemtuzumab

First-line treatment option in patients with del(17p)/TP53 mutation
Less effective for bulky (>5 cm) lymphadenopathy

Obinutuzumab

A glycoengineered, humanized, type II antibody targeted against CD20
Approved for treatment-naive CLL patients with or without del(17p)/TP53 mutation as monotherapy
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
Studies showed higher overall response rates in patients given Obinutuzumab monotherapy

Ofatumumab

A fully human CD20 monoclonal antibody
Second-line or third-line treatment option for CLL patients with del(17p)/TP53 mutation regardless of age and comorbidities

Rituximab

Treatment option for first-line treatment for:
- CLL patients without del (17p)/TP53 mutation aged ≥65 years and <65 years old with significant comorbidities or patients with significant comorbidity or intolerant to purine analogs

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 second-generation Bruton’s tyrosine kinase inhibitor
Recommended as second-line or third-line therapy to CLL patients without del(17p)/TP53 mutation aged ≥65 years and <65 years old with significant comorbidities, aged <65 years without significant comorbidities, and 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)
Alternative second-line or third-line therapy of CLL patients with or without del(17p)/TP53 mutation regardless of age and comorbidities
May be used for relapsed or refractory CLL after at least 2 prior therapies

Ibrutinib

Irreversibly inhibits Bruton’s tyrosine kinase and inhibits CLL-cell migration, survival and proliferation
Preferred first-line and second-line/third-line treatment for CLL patients with or without del(17p)/TP53 mutation regardless of age and comorbidities

Idelalisib

A phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor
Second-line or third-line therapy option for CLL patients with and without del(17p)/TP53 mutation regardless of age and comorbidities
Combination with Rituximab is an alternative second-line or third-line therapy option for CLL patients with or without del(17p)/TP53 mutation regardless of age and comorbidities
- Therapy for relapsed or refractory disease after prior BTK inhibitor- and Venetoclax-based regimens for CLL patients without del(17p)/TP53 mutation if not previously used

Pirtobrutinib

A noncovalent, third generation Bruton’s tyrosine kinase inhibitor
Second-line or third-line treatment option for CLL patients without del(17p)/TP53 mutation used for relapse after a period of remission if previously used as a first-line therapy
Therapy for relapsed or refractory disease after prior BTK inhibitor- and Venetoclax-based regimens for CLL patients without del(17p)/TP53 mutation if not previously used

Venetoclax

A selective inhibitor of the anti-apoptotic protein BCL-2
Preferred second-line or third-line therapy regimen for CLL patients with del(17p)/TP53 mutation; may also be given in combination with Rituximab
Second-line and subsequent treatment option for CLL patients without del(17p)/TP53 mutation regardless of age and comorbidities
- Preferred first-line therapy option for CLL patients with or without del(17p)/TP53 mutation when given with Obinutuzumab
- Preferred second-line or third-line therapy regimen when given with Rituximab

Zanubrutinib

A second generation Bruton’s tyrosine kinase inhibitor
Preferred first-line therapy option for CLL patients with or without del(17p)/TP53 mutation with contraindication to other Bruton’s tyrosine kinase inhibitors
Preferred second-line or third-line therapy option for CLL patients with or without del(17p)/TP53 mutation regardless of age and comorbidities
Not recommended for Ibrutinib-refractory CLL patients with BTK C481S mutations

Chemotherapeutic Regimens

Bendamustine + CD20 Monoclonal Antibody-based Combinations

Eg Bendamustine + Obinutuzumab, Bendamustine + Ofatumumab, Bendamustine + Rituximab
First-line therapy option for CLL patients without del(17p)/TP53 mutation ≥65 years old, <65 years without significant comorbidities or <65-year-old patients with significant comorbidities and with IGHV mutation
Alternative second-line or third-line treatment option for CLL patients without del(17p)/TP53 mutation regardless of age and comorbidities
Showed longer progression-free survival rates compared to Bendamustine monotherapy

Fludarabine-based Combinations

First-line therapeutic regimens (eg FCR, FR) for younger (<65 years) fit CLL patients without del(17p)/TP53 mutation aged <65 years without significant comorbidities, and as second-line or third-line therapeutic option (eg FC + Ofatumumab, FCR) for patients without del(17p)/TP53 mutation <65 years old without significant comorbidities and with IGHV mutation

FCR (Fludarabine + Cyclophosphamide + Rituximab)

Treatment option as first-line therapy for treatment-naive fit CLL patients without del(17p)/TP53 mutation <65 years without significant comorbidities, advanced CLL patients and as second-line or third-line therapy option for CLL patients without del(17p)/TP53 mutation aged <65 years without significant comorbidities
- Preferred first-line therapy for IGHV-mutated CLL in patients <65 years without 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 cell transplantation

FR (Fludarabine + Rituximab)

Recommended as first-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

FC (Fludarabine + Cyclophosphamide) + Ofatumumab

Recommended second-line or third-line treatment option for CLL patients without del(17p)/TP53 mutation aged <65 years without significant comorbidities

Obinutuzumab-based Combinations

Obinutuzumab + Chlorambucil
- Treatment option as first-line treatment for CLL without del(17p)/TP53 mutation ≥65 years old and <65-year-old 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
High-dose Methylprednisolone (HDMP) + Obinutuzumab
- First-line, second-line or third-line treatment option for patients without del(17p)/TP53 mutation regardless of age and comorbidities

PCR (Pentostatin, Cyclophosphamide, Rituximab)

Treatment option for CLL patients without del(17p)/TP53 mutation aged <65 years old and ≥65 years without significant comorbidities, with symptoms (creatinine level >2 mg/dL or increased by 20% over baseline, with grade 2-4 toxicity)
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 in combination with Alemtuzumab is a first-line treatment option in patients with del(17p)/TP53 mutation
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
- First-line treatment option for CLL patients without del(17p)/TP53 mutation aged <65 years without significant comorbidities
Rituximab plus Idelalisib combination is recommended as a second-line or third-line therapy option for patients with CLL with or without del(17p)/TP53 mutation
Rituximab with HDMP is used as first-line, second-line or third-line treatment option for patients with or without del(17p)/TP53 mutation regardless of age and comorbidities
Venetoclax-Rituximab combination is a preferred second-line or third-line treatment regimen in patients with or without del(17p)/TP53 mutation regardless of age and comorbidities

Chemotherapy-free Regimens

Acalabrutinib ± Obinutuzumab

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

Ibrutinib + Obinutuzumab

First-line treatment option for patients with significant comorbidities and patients aged ≥65 years and <65 years old with significant comorbidities with CLL without del(17p)/TP53 mutation

Lenalidomide ± Rituximab

Second-line or third-line therapy option for CLL patients with or without del(17p)/TP53 mutation regardless of age and comorbidities

Venetoclax + Obinutuzumab

Preferred regimen for first-line treatment of CLL patients with or without del(17p)/TP53 mutation regardless of age and comorbidities
Second-line or third-line treatment option for CLL patients 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 first year of diagnosis
- Repeat complete blood chemistry (CBC), history and physical examination at 3- to 12-month intervals

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