July 2020, Volume XXXIV, Number 4


Chronic lymphocytic leukemia

Updates in management

By Sandeep Jain, MBBS, MRCP, FRCP

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.


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, disease-related 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 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.

CLL is the most prevalent leukemia in adults.

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.

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 first line treatment is 88%. Thus, both BTKi and BCL-2i-based therapies offer superior efficacy and avoid genotoxicity. BCL-2i-based therapy is also attractive as it offers fixed-duration therapy.

For elderly patients or patients with significant comorbidities, improved PFS but not overall survival has been demonstrated with both BTKi and BCL-2i-based therapies over CIT.

BTKi are associated with increased risk of atrial fibrillation and bleeding. They are contraindicated in patients on anticoagulation. BTKi-like ibrutinib is chronic therapy and can be expensive in the long run. Patients with del(17p) or TP53 are resistant to CIT and need treatment with either BTKi or BCL-2i in which response rate is similar in patients with del(17p) versus wild type. BTKi therapy is also associated with increased risk for infections, including invasive fungal infections, and patients receiving therapy with BTKi should be carefully monitored for infections.

BCL-2i therapy is associated with significant risk of tumor lysis syndrome (TLS). In the CLL14 regimen, allopurinol was started and the first course of treatment was with obinutuzumab alone. Obintuzumab effectively decreased WBC count and reduced risk of TLS. Venetoclax is introduced with the second course and a ramp-up is done as per the prescribing information. With these precautions, the risk of TLS is low. There is significant risk of neutropenia with venetoclax-based regimen.

Monitoring of response is done using careful physical, blood, and bone marrow examination. Partial response is defined as >50% decrease in the absolute lymphocyte count, and >50% decrease in the size of lymph nodes and organomegaly. Complete response is defined as resolution of all lymphadenopathy, hepatomegaly, splenomegaly, and normal lymphocyte count with Hgb >11.0 and platelets >100 along with normal bone marrow examination. Patients who achieve complete response should be evaluated for Minimal Residual Disease (MRD) using multicolor flow cytometry or next-generation sequencing. Prospective clinical trials have shown that patients who achieve MRD, negativity defined as blood and bone marrow with <1 CLL cell in 10,000 leukocyte, have improved clinical outcomes.

Recent advances have substantially improved the outcomes for CLL patients.

Selecting treatments for relapsed CLL

Patients previously treated with CIT can be treated with either BTKi or BCL-2i with similar considerations. Patients who appear to have progressed on BTKi should have careful evaluation to rule out other medical conditions contributing to the presentation, such as an infection. Patients should also be evaluated for the possibility of Richter’s transformation, a rare complication where CLL suddenly transforms in a significantly more aggressive form of large cell lymphoma. When true progression on BTKi is confirmed, overall prognosis is poor. FISH and cytogenetic should be repeated, and BTK should be evaluated for mutations. BTKi should be continued while other treatment options are being considered, due to significant rebound effects. CIT is unlikely to be effective in this population. Treatment options include BCL-2i-based therapy, Phosphoinositide 3 kinase inhibitors (PI3K i), hematopoietic stem cell transplant, and clinical trials. Recent studies have shown that BCL-2i-based therapies can produce durable responses in patients with BTKi refractory disease and should be the preferred option. Patients who are refractory under both BTKi and BCL-2i therapy should be evaluated for clinical trial of newer therapies and/or hematopoietic stem cell transplant.

Supportive care and management of complications

Cytopenia can be seen in CLL related to therapy such as chemotherapy or drugs such as BCL-2i, which can cause neutropenia. Growth factors such as granulocyte colony stimulating factor (G-CSF) are effective and should be used in accordance with guidelines from the American Society of Clinical Oncology.

Cytopenias can be autoimmune in nature. There is an established relationship between CLL and autoimmune thrombocytopenia and autoimmune hemolytic anemia. These should be distinguished from cytopenias due to excessive bone marrow infiltration with CLL cells. In difficult cases, bone marrow biopsy is helpful in distinguishing autoimmune cytopenias from bone marrow dysfunction.

CLL is characterized by intrinsic immune dysfunction, which can be aggravated by the therapy for CLL. Infections are a frequent complication during management of CLL patients. Patients should be encouraged to complete routine vaccinations, as vaccinations achieve a reasonable rate of seroconversion and protection in immunocompromised cancer patients. Live vaccinations are contraindicated. Hypogammaglobulinemia is another well recognized complication of CLL. IVIG therapy has been shown to reduce the rate of recurrent infections, but is expensive and needs recurrent IV infusions. Therapy decisions should be individualized and reserved for patients with severe hypogammaglobulinemia and recurrent infections.


Recent advances have substantially improved the outcomes for CLL patients. Genetic tests have prognostic significance and, more importantly, help guide therapy and prevent patients from receiving toxic therapy, which has less chance of being effective.

Monitoring for MRD can help patients with prognostic information and improve the design of clinical trials as MRD negativity is a surrogate for improved clinical outcomes.

Multiple novel targeted therapies such as BTKi and BCL-2i are now available with impressive efficacy and better toxicity profile compared to CIT.

Sandeep Jain, MBBS, MRCP, FRCP, is board-certified in medical oncology, hematology, and internal medicine. His areas of special interest include myeloma, lymphoma, and lung cancer. Dr. Jain practices at Minnesota Oncology’s Burnsville clinic. 


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Sandeep Jain, MBBS, MRCP, FRCP, is board-certified in medical oncology, hematology, and internal medicine. His areas of special interest include myeloma, lymphoma, and lung cancer. Dr. Jain practices at Minnesota Oncology’s Burnsville clinic.