What is the optimal treatment approach for a 70-year-old patient with Chronic Lymphocytic Leukemia (CLL), characterized by a chromosomal deletion 13q, unmutated Immunoglobulin Heavy Chain Variable Region (IGVH), and uveal lymphomatous involvement, presenting with double vision and fatigue, with normal hemoglobin (Hb), platelet count (PLT), and lactate dehydrogenase (LDH) levels?

From the Guidelines

For a 70-year-old CLL patient with unmutated IGVH, 13q deletion, rising WBC counts, and new onset double vision likely due to uveal lymphomatous involvement, I recommend starting with systemic CLL-directed therapy using BTK inhibitors like acalabrutinib, ibrutinib, or zanubrutinib, as suggested by the recent ESMO clinical practice guideline update 1.

Rationale for Systemic Therapy

The patient's disease progression, indicated by rising WBC counts, fatigue, and generalized lymphadenopathy, along with the new onset of double vision due to uveal lymphomatous involvement, necessitates a treatment approach that addresses both systemic and extramedullary disease components. BTK inhibitors have demonstrated efficacy in CLL with extramedullary involvement and good CNS penetration, making them a suitable choice for this patient.

Considerations for Treatment Choice

• The ESMO guideline update 1 emphasizes the importance of considering patient-related factors, such as comorbidities, preference, and expected treatment adherence, when choosing a therapy.
• Given the patient's age and potential for comorbidities, careful assessment of cardiac risk is necessary when planning to use a BTK inhibitor, as noted in the guideline update 1.
• The guideline also highlights the superiority of targeted therapies over chemoimmunotherapy in terms of progression-free survival for patients with unmutated IGHV status, supporting the choice of BTK inhibitors for this patient.

Monitoring and Adjustment of Therapy

Regular monitoring of blood counts, liver function, and cardiac status is necessary during BTK inhibitor therapy. If the response to BTK inhibitor therapy is inadequate after 2-3 months, consider adding low-dose orbital radiation therapy to address the localized ocular manifestation. Ophthalmologic monitoring should be performed regularly to assess the response of the ocular lesions to treatment.

Conclusion on Treatment Approach

The use of systemic CLL-directed therapy with BTK inhibitors is the preferred initial approach for this patient, given the disease's systemic and extramedullary components. This approach is supported by the latest clinical practice guidelines and evidence from recent studies 1, prioritizing the patient's morbidity, mortality, and quality of life outcomes.

From the FDA Drug Label

The most common adverse reactions in patients with CLL/SLL receiving IMBRUVICA (≥ 30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea.

The choice of therapy for a 70-year-old patient with CLL, Chr 13q, IGVH unmutated, and new onset double vision, likely due to uveal lymphomatous involvement, should be approached with caution.

• EBXRT may be considered for local control of the uveal involvement.
• CLL-directed therapy, such as ibrutinib, may be considered for systemic control of the disease.
• Combination therapy of both EBXRT and CLL-directed therapy may also be an option. However, the decision should be made on a case-by-case basis, taking into account the patient's overall health, disease status, and potential risks and benefits of each treatment option 2.

From the Research

Treatment Options for CLL

• The patient has CLL with Chr 13q, IGVH unmutated, and a slow rise in WBC count over the last year, with new onset double vision due to uveal lymphomatous involvement 3.
• The choice of therapy includes:
  • External Beam Radiation Therapy (EBXRT)
  • CLL-directed therapy, such as AVO (a combination of anti-CD20 antibody and chemotherapy)
  • Both EBXRT and CLL-directed therapy

CLL-Directed Therapy

• Studies have shown that ibrutinib, a B-cell receptor signaling pathway inhibitor, is effective in treating CLL, especially in patients with high-risk disease 4, 5.
• Ibrutinib has been compared to chemoimmunotherapy in older patients with untreated CLL, and has been shown to be superior in terms of progression-free survival 4.
• The combination of ibrutinib with bendamustine and rituximab has also been shown to be effective in patients with previously treated CLL 5.

Chemoimmunotherapy

• Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is a standard therapy for physically fit patients with advanced CLL 6.
• However, this regimen has been shown to have more toxic effects compared to bendamustine and rituximab, especially in older patients 6.
• The choice of chemoimmunotherapy regimen depends on various factors, including the patient's physical fitness, disease characteristics, and previous treatments 7.

Considerations for Treatment

• The patient's new onset double vision due to uveal lymphomatous involvement suggests that the disease is progressing and requires prompt treatment.
• The patient's age and physical fitness should be taken into consideration when choosing a treatment regimen.
• The potential benefits and risks of each treatment option should be carefully weighed, and the patient's preferences and values should be taken into account 3, 4, 5, 7, 6.