What is the appropriate evaluation and management approach for an older adult patient with Chronic Lymphocytic Leukemia (CLL)?

Evaluation of Chronic Lymphocytic Leukemia (CLL)

The evaluation of CLL requires a standardized diagnostic workup including history, physical examination, complete blood count with differential, blood smear microscopy, and flow cytometry, followed by mandatory testing for del(17p) and TP53 mutations before any treatment is planned, combined with systematic geriatric assessment to stratify fitness level. 1, 2

Diagnostic Workup

Essential Initial Testing

Use the same diagnostic methodology regardless of patient age to establish diagnosis and staging 1:

• History and physical examination focusing on lymphadenopathy (cervical most common), hepatomegaly, splenomegaly, B-symptoms (fever, night sweats, weight loss), and frequency of infections 1, 3

• Complete blood count with differential requiring sustained peripheral blood lymphocyte count ≥5,000/μL (≥5 × 10⁹/L) for diagnosis 2, 4, 5

• Blood smear microscopy to identify morphologically mature-appearing lymphocytes and exclude atypical or immature forms 1, 4

• Flow cytometry of peripheral blood to confirm characteristic immunophenotype: CD5+, CD19+, CD20+ (dim/low), CD23+, surface immunoglobulin low, CD79b low, FMC7 negative 2, 3, 5

• Staging using Binet or Rai classification based on physical examination findings and blood counts alone 1

Critical Pre-Treatment Testing

Before initiating any treatment, screen for del(17p) and/or TP53 mutations as these predict resistance to chemoimmunotherapy and mandate different treatment selection 1, 2:

• Del(17p) and TP53 mutations are associated with poor response to conventional chemo-immunotherapy and poor survival independent of age 1
• This testing is mandatory (Level of Evidence III, Strength of Recommendation B, 100% consensus) 1
• Reassess del(17p) and TP53 status before each new line of therapy, as these mutations can be acquired over time 2

Optional/Conditional Testing

• Bone marrow biopsy is NOT mandatory for diagnosis but may be performed in select cases 3, 5
• Imaging studies (chest X-ray, abdominal ultrasound, or CT scan) are used to assess degree of lymphadenopathy or organomegaly but are not required for diagnosis 3

Fitness Assessment

Clinical judgment supported by geriatric assessment must be used to stratify older patients into three fitness categories (Level of Evidence III, Strength of Recommendation B, 100% consensus) 1:

Three-Tier Fitness Stratification

1. Fit patients: Eligible for full-dose standard therapy, aiming for symptom control, complete remission, and prolonged survival 1

2. Vulnerable patients: Unfit for full-dose therapy but eligible for alternative therapy plus geriatric interventions, aiming for symptom control and long-term disease control 1

3. Terminally ill patients: Ineligible for anti-leukemic therapy, appropriate only for best supportive care aiming for symptom palliation 1

Systematic Assessment Tools

Perform geriatric assessment in routine clinical practice; when full assessment is not possible, use geriatric screening (e.g., G-8) (Level of Evidence II, Strength of Recommendation B, 100% consensus) 1, 2:

• Cumulative Illness Rating Scale for Geriatrics (CIRS-G) to quantify comorbidity burden; CIRS score >6 indicates significant comorbidities 1, 2

• Creatinine clearance (CrCl) estimation; CrCl <70 mL/min indicates significant renal impairment 2

• G-8 screening tool can be completed in approximately 5 minutes in busy clinics 1

• Activities of Daily Living (ADL) and Instrumental ADL using standardized instruments 1

• Assessment of comorbidities including coronary heart disease, heart failure, peripheral artery disease, chronic obstructive lung disease, diabetes mellitus—present in approximately 50% of newly diagnosed older CLL patients 1, 2

• Screening for geriatric syndromes including dementia, delirium, depression, falls, sarcopenia, frailty 1

Prognostic Significance

• Quality of life should be considered as a prognostic indicator of survival (Level of Evidence I, Strength of Recommendation A, 100% consensus) 1

• Presence of ≥2 comorbidities independently predicts worse clinical outcomes regardless of age or disease stage 2

• Social activity and nutritional status (≥5% weight loss in preceding 6 months) are associated with progression-free survival and overall survival 6

Critical Pitfalls to Avoid

Never initiate treatment based solely on elevated lymphocyte count, even when markedly elevated—absolute lymphocyte count alone is NOT an indication for treatment as symptoms related to leukostasis are exceedingly rare in CLL 2, 4

Do not rely on clinical judgment alone for fitness assessment—geriatric assessment can unmask vulnerability that otherwise remains undetected 1, 2

Always reassess del(17p) and TP53 mutation status before starting each new treatment line, as these may be acquired over time and fundamentally change treatment selection 2

Avoid unnecessary diagnostics that do not impact treatment decisions, particularly in terminally ill patients 1