ONCOLOGY
Chronic lymphocytic leukemia Updates in management BY SANDEEP JAIN, MBBS, MRCP, FRCP
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hronic lymphocytic leukemia (CLL) is characterized by an accumulation of small, mature lymphocytes in the blood, bone marrow, and lymphoid tissues. It is only distinguishable from small lymphocytic lymphoma (SLL) by the presence of leukemic cells in peripheral blood. CLL is the most prevalent leukemia in adults. According to the National Cancer Institute, an estimated 20,700 people were diagnosed with CLL in the United States in 2019. It is more prevalent in men than women and the median age of diagnosis is 70 years.
Diagnosis
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Common presentation is an asymptomatic adult who is found to have elevated absolute lymphocyte count on a blood test done for other indications. Manifestations of CLL include lymphadenopathy, organomegaly, diseaserelated cytopenia, and constitutional symptoms including fatigue, low-grade fever, unexplained weight loss, and night sweats. The diagnosis of CLL requires the presence of >5 X 109 clonal B lymphocytes, sustained for at least three months. The leukemic cells are characteristically small, mature lymphocytes
Other tests routinely performed include serum chemistry, serum immunoglobulins, and direct antiglobulin test. Fluorescence in situ hybridization (FISH) can be performed on peripheral blood lymphocytes, which is helpful in determining prognosis. Most common chromosomal aberrations include del(13q), trisomy 12, del(11q), and del(17p). Presence of isolated del(13q) is associated with a favorable prognosis. Patients with leukemic cells which carry del(17p) and del(11q) are associated with adverse outcomes. IGHV unmutated status is associated with early need to start treatment.
Staging and indications for treatment There are two widely accepted staging systems for CLL: Rai and Binet. Both are simple, inexpensive, and rely solely on physical examination and standard laboratory tests. Several trials comparing immediate versus deferred chemotherapy have established that there is no survival benefit from early treatment for indolent CLL, and it is universally accepted practice to defer start of treatment until patients become symptomatic, as defined by the International Workshop on Chronic Lymphocytic Leukemia.
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with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli. Smudge cells are commonly seen on peripheral smear. Diagnosis is confirmed by flow cytometry of peripheral blood. Bone marrow examination is not routinely performed in clinical practice, but may be required in clinical trials or to evaluate unexplained cytopenia. CLL cells co-express the surface antigen CD5 together with the B cell antigens CD19, CD20, and CD23. Consultation with a hematopathologist is recommended whenever possible.
JULY 2020 MINNESOTA PHYSICIAN
Factors affecting first-line treatment selection Multiple effective options are available when a decision is made to start treatment. Remarkable progress has been made in the last few years in the targeted therapy for CLL. Current treatment options include chemoimmunotherapy (CIT), a combination of chemotherapeutic agents with monoclonal antibody for CD20 such as rituximab or obintuzumab, Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib, acalabrutinib, and B-cell lymphoma-2 inhibitors (BCL-2i) such as venetoclax, or a combination of the above. Important considerations include age, comorbidities, del(17p) status, cardiac history, concomitant medications, renal function, financial considerations, and logistical access. For younger patients with no significant comorbidities and del(17p) wild-type status, the options include CIT, BTKi, and BCL-2i. The most effective CIT is FCR, a combination of fludarabine, cyclophosphamide, and rituximab. The median progression-free survival (PFS) with FCR is 55 months, however >90% patients with IGHV unmutated are expected to progress on follow-up. CIT such as FCR employs genotoxic therapy with an associated 3% to 5% risk of secondary hematologic malignancies such as myelodysplastic syndrome and acute myeloid leukemia. Both BTKi and BCL-2i-based therapies have superior PFS compared to CIT. The expected five years PFS for first-line BTKi ibrutinib-based therapy is 70%. The expected two years PFS for BCL2-i venetoclax-based 1-year fixed dose
