What are the typical presentation, diagnosis, and treatment options for an older adult patient with Chronic Lymphocytic Leukemia (CLL)?

Chronic Lymphocytic Leukemia (CLL): Overview

Presentation and Epidemiology

CLL predominantly affects older adults, with a median age at diagnosis of 72 years, and approximately 70% of patients diagnosed at age ≥65 years. 1

• Nearly 40% of patients are diagnosed at age ≥75 years 1
• The disease is characterized by progressive accumulation of morphologically mature, malignant B lymphocytes in blood, bone marrow, and lymphoid tissue 1
• Approximately half of newly diagnosed older patients present with major comorbidities including coronary heart disease, heart failure, peripheral artery disease, chronic obstructive lung disease, or diabetes mellitus 1
• The clinical course is highly variable—some patients have indolent disease while others progress rapidly to advanced disease requiring immediate treatment 1

Diagnosis

Diagnosis requires a sustained peripheral blood lymphocyte count ≥5 × 10⁹/L (5,000/μL) with characteristic immunophenotype CD5+, CD19+, CD20+ (low), CD23+, sIg low, CD79b low, FMC7–. 2, 3

The diagnostic workup includes: 1

• History taking and physical examination
• Complete blood count with differential
• Blood smear microscopy showing small, morphologically mature lymphocytes
• Flow cytometry of peripheral blood
• Staging via Rai (0-IV) or Binet (A-C) classification using physical examination and blood counts

Before initiating treatment, testing for del(17p) and TP53 mutation status is mandatory, as these predict resistance to chemoimmunotherapy and shorter progression-free survival. 1

Additional prognostic markers include: 1

• IGHV mutation status (important for selecting chemoimmunotherapy)
• CpG-stimulated karyotyping to identify high-risk patients

Fitness Assessment

Older patients must be stratified into three fitness categories before treatment selection: (1) fit patients eligible for full-dose standard therapy, (2) vulnerable patients requiring dose-attenuated therapy plus geriatric interventions, and (3) terminally ill patients appropriate only for best supportive care. 1

Assessment tools include: 1

• Cumulative Illness Rating Scale (CIRS) in combination with creatinine clearance (CrCl)
• CIRS score >6 or estimated CrCl <70 mL/min indicates significant comorbidities 1
• The presence of ≥2 comorbidities independently predicts worse clinical outcomes regardless of age or disease stage 1

Treatment Indications

Absolute lymphocyte count alone is NOT an indication for treatment—symptoms related to leukostasis are exceedingly rare in CLL. 1, 2

Treatment should be initiated for: 1

• Severe fatigue, weight loss, night sweats, or fever without infection
• Threatened end-organ function
• Progressive bulky disease (enlarged spleen or lymph nodes)
• Progressive anemia or thrombocytopenia
• Steroid-refractory autoimmune cytopenia
• Progressive lymphocytosis with >50% increase over 2 months or lymphocyte doubling time <6 months 2

Patients with low-risk CLL (Rai stage 0 or Binet A) or intermediate-risk CLL (Rai stage I-II or Binet B) without symptoms should be managed with "watch and wait" approach. 1

Treatment Options by Patient Category

Fit Patients Without del(17p)/TP53 Mutation

For fit patients <65 years without significant comorbidities, particularly those with mutated IGHV, fludarabine/cyclophosphamide/rituximab (FCR) remains standard therapy as it may have curative potential. 1, 3

For fit older patients (≥65 years): 1

• Bendamustine/rituximab (BR) or dose-attenuated FCR are less toxic alternatives with preserved efficacy
• Ibrutinib monotherapy (420 mg orally once daily) is established as first-line therapy based on RESONATE-2 and Alliance A041202 trials 1, 4
• Venetoclax plus obinutuzumab combination 3, 5

Vulnerable Patients Without del(17p)/TP53 Mutation

Vulnerable older patients should receive chlorambucil combined with a monoclonal anti-CD20 antibody (obinutuzumab, ofatumumab, or rituximab). 1

Alternative options include: 1

• Bendamustine/rituximab (BR)
• Dose-attenuated FCR
• Ibrutinib monotherapy

Patients With del(17p) or TP53 Mutation

All patients harboring del(17p) and/or TP53 mutation should be treated with ibrutinib as first-line therapy, regardless of fitness status. 1

• These patients are resistant to conventional chemoimmunotherapy 1
• Ibrutinib has demonstrated efficacy in this high-risk population 1
• Allogeneic stem cell transplantation may be considered in relapsing patients with these mutations 3

Relapsed/Refractory Disease

For relapsed disease with treatment-free interval >3 years, the initial treatment may be repeated; if relapse occurs earlier, therapy should be changed to an alternative regimen. 3, 5

For relapsed/refractory CLL: 1

• Ibrutinib or idelalisib plus rituximab (irrespective of del[17p]/TP53mut status) - Level of Evidence I, Strength of Recommendation A
• Venetoclax for patients who have failed kinase inhibitor therapy 1
• In the RESONATE trial, ibrutinib showed 90% overall response rate versus 25% with ofatumumab, with progression-free survival not reached at 16 months versus 8.1 months 1

Key Monitoring Parameters

Complete blood counts should be checked monthly during treatment to monitor for cytopenias. 4

For patients on watch and wait: 2

• Monitor blood cell counts every 3-6 months
• Exclude factors contributing to lymphocytosis other than CLL (e.g., infections) before initiating treatment

Critical Pitfalls to Avoid

• Never initiate treatment based solely on elevated lymphocyte count, even when markedly elevated 1, 2
• Always reassess del(17p) and TP53 mutation status before starting treatment, as these may be acquired over time 1
• Recognize that older patients (≥70 years) may not benefit from FCR and experience higher rates of grade 3-4 neutropenia, anemia, and infections 6
• Monitor for cardiac arrhythmias, hemorrhage, infections, and hypertension in patients receiving ibrutinib 4
• Assess comorbidities systematically using validated tools (CIRS, Charlson) rather than relying on clinical judgment alone, as geriatric assessment can unmask vulnerability that otherwise remains undetected 1