What is the initial workup and treatment approach for an older adult with a suspected diagnosis of Chronic Lymphocytic Leukemia (CLL) and potential comorbidities, including previous cancers, autoimmune disorders, or infections?

Initial Workup for Chronic Lymphocytic Leukemia (CLL)

Diagnostic Confirmation

The diagnosis of CLL requires a sustained peripheral blood lymphocyte count ≥5,000/μL (≥5 × 10⁹/L) maintained for at least 3 months, combined with characteristic immunophenotyping showing CD5+, CD19+, CD20 (dim), CD23+, surface immunoglobulin (dim), and light chain restriction. 1, 2

Essential Initial Laboratory Tests

• Complete blood count with manual differential to assess absolute lymphocyte count and identify cytopenias 1, 3
• Peripheral blood smear with morphologic evaluation looking specifically for small, morphologically mature lymphocytes (not atypical or immature forms) 1, 3, 4
• Flow cytometry of peripheral blood to confirm the composite immunophenotype: CD5+, CD19+, CD20 (dim)+, CD23+, surface Ig (dim)+, CD79b (low), FMC7- 1, 2, 4
• Comprehensive metabolic panel including LDH, β2-microglobulin, bilirubin 1
• Serum protein electrophoresis and direct antiglobulin test (Coombs test) to screen for autoimmune complications 1

Mandatory Genetic Testing Before Treatment

Before initiating any treatment, testing for del(17p) and TP53 mutation status is absolutely mandatory, as these predict resistance to chemoimmunotherapy and guide treatment selection toward BTK inhibitors. 1, 2, 5, 6

• FISH analysis with 4-probe panel for del(17p), del(11q), trisomy 12, and del(13q) 1, 7
• TP53 mutation analysis by sequencing 2, 5, 7
• IGHV mutational status should be determined before first treatment, as mutated IGHV predicts better outcomes and influences treatment choice 5, 6, 7

Physical Examination and Staging

• Careful palpation of all lymph node areas (cervical, axillary, inguinal), liver, and spleen to assess organomegaly 1, 3
• Binet or Rai staging using physical examination findings and blood counts 1, 5, 6
• Chest X-ray and abdominal ultrasound or CT scan if lymphadenopathy or organomegaly is suspected 1

Optional Diagnostic Procedures

• Lymph node biopsy is recommended whenever an enlarged, accessible peripheral lymph node is present, primarily to exclude transformation to aggressive lymphoma (Richter transformation) or to differentiate from mantle cell lymphoma 1
• Bone marrow biopsy is not required for diagnosis but may be performed to define complete remission during response evaluation 1

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Comorbidity Assessment in Older Adults

Approximately 50% of newly diagnosed older CLL patients present with major comorbidities including coronary heart disease, heart failure, peripheral artery disease, chronic obstructive lung disease, or diabetes mellitus, which directly impact treatment selection and outcomes. 2

Fitness Stratification (Mandatory Before Treatment)

All 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, and (3) terminally ill patients appropriate only for best supportive care. 1, 2

• Cumulative Illness Rating Scale (CIRS) combined with creatinine clearance (CrCl) assessment 2
• CIRS score >6 or estimated CrCl <70 mL/min indicates significant comorbidities that require treatment modification 2
• Presence of ≥2 comorbidities independently predicts worse clinical outcomes regardless of age or disease stage 2

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Treatment Indications

The absolute lymphocyte count alone is NEVER an indication for treatment—symptoms related to leukostasis are exceedingly rare in CLL, and early treatment of asymptomatic disease does not improve survival. 2, 4, 8

Watch-and-Wait Strategy (Standard for Asymptomatic Patients)

For patients with early-stage disease (Binet A/B or Rai 0-II) without symptoms, the standard approach is observation with monitoring every 3 months. 1, 3, 4

• Monitor complete blood count with differential every 3 months 1, 3, 4
• Physical examination at each visit assessing lymph nodes, liver, and spleen 1, 3
• Special attention to autoimmune cytopenias which may develop during observation 1

Criteria for Initiating Treatment

Treatment should be initiated when patients develop any of the following 1, 2:

• B-symptoms: severe fatigue, unintentional weight loss >10% in 6 months, night sweats, or fever without infection 1, 2
• Progressive cytopenias not caused by autoimmune phenomena (hemoglobin <10 g/dL or platelets <100,000/μL) 1
• Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly causing discomfort or organ dysfunction 1
• Rapid disease progression with lymphocyte doubling time <12 months 1
• Autoimmune cytopenias poorly responsive to corticosteroids 1

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First-Line Treatment Approach

Patients with del(17p) and/or TP53 Mutation (Any Fitness Level)

All patients harboring del(17p) and/or TP53 mutation should be treated with a BTK inhibitor (preferably second-generation: acalabrutinib or zanubrutinib) as first-line therapy, regardless of fitness status, as these patients are resistant to chemoimmunotherapy. 1, 2, 9, 10, 7

• Ibrutinib 420 mg orally once daily administered continuously until disease progression 9
• Second-generation BTK inhibitors (acalabrutinib, zanubrutinib) are preferred over ibrutinib due to improved safety profiles 8, 6, 7

Fit Patients Without del(17p)/TP53 Mutation

For fit older patients (≥65 years) without del(17p)/TP53 mutation, treatment choice depends on IGHV mutational status. 2, 7

Mutated IGHV

• Time-limited therapy with venetoclax plus obinutuzumab should be considered as first therapeutic option (1 year fixed duration) 6, 7
• Overall survival 82% at 5-year follow-up 8

Unmutated IGHV

• Both continuous BTK inhibitor monotherapy and finite BCL2 inhibitor combination therapy are valid options that must be evaluated considering potential toxicities, drug interactions, and patient preference 7
• Bendamustine plus rituximab (BR) or dose-attenuated FCR are less toxic alternatives with preserved efficacy 1, 2

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, 2, 4

Very Frail or Terminally Ill Patients

In terminally ill patients, supportive treatment should be considered rather than active CLL therapy. 7

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Management of Complications

Autoimmune Cytopenias

• Most patients with autoimmune cytopenias respond to corticosteroids as first-line therapy 1
• Rituximab administration is a reasonable treatment option for patients not responding to corticosteroids before considering splenectomy 1
• Treatment of underlying CLL is recommended for patients with resistant autoimmune cytopenias 1

Infection Prevention

Infections are a common complication in CLL patients; therefore, immunosuppressive agents such as corticosteroids should be restricted to the minimum necessary. 1

• Prophylactic intravenous immunoglobulin does NOT improve overall survival and is only recommended in patients with severe hypogammaglobulinemia and repeated infections 1
• Pneumocystis prophylaxis with co-trimoxazole during treatment with purine analogue-based or bendamustine-based chemoimmunotherapy 1
• Pneumococcal vaccination and seasonal influenza vaccination recommended in early-stage CLL 1
• Do NOT prescribe unnecessary antimicrobial prophylaxis in patients with stable disease, as this promotes antibiotic resistance without proven benefit 3, 4

Secondary Malignancies

CLL patients have a 2- to 7-fold increased risk of developing secondary malignancies (mostly solid cancers, but also myelodysplastic syndromes or acute myeloblastic leukemia), requiring lifelong surveillance. 1

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Relapsed/Refractory Disease

Treatment Selection Based on Prior Therapy

For relapsed/refractory CLL, ibrutinib or idelalisib plus rituximab are recommended (irrespective of del[17p]/TP53 mutation status) with Level of Evidence I, Strength of Recommendation A. 1

• If relapse occurs >3 years after initial therapy, the first-line treatment may be repeated 5, 6, 7
• If relapse occurs <3 years or disease is refractory, therapy should be changed to an alternative regimen 5, 6
• Venetoclax for patients who have failed kinase inhibitor therapy 1
• Pirtobrutinib (noncovalent BTK inhibitor) shows >70% overall response rate after failure of covalent BTK inhibitors and venetoclax 8

Double-Refractory Disease (BTK and BCL2 Inhibitor Failure)

• CAR-T therapy with lisocabtagene maraleucel was associated with 45% complete response rate in patients with multiple relapses 8
• Allogeneic hematopoietic stem cell transplantation should be considered in patients failing several lines of therapy and remains the only potential cure for CLL 1, 8, 10

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Critical Pitfalls to Avoid

• Never initiate treatment based solely on elevated lymphocyte count, even when markedly elevated—absolute lymphocyte count alone is NOT a treatment indication 2, 4
• Always reassess del(17p) and TP53 mutation status before starting treatment, as these may be acquired over time 2
• Do NOT use G-CSF for chronic stable leukopenia in CLL patients—it should be reserved only for febrile severe neutropenia or specific chemotherapy-related scenarios 3
• 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 2
• Do NOT assume early treatment improves outcomes—watch-and-wait for asymptomatic patients is evidence-based and does not compromise survival 4, 8