11 minute read
ONCOLOGY Chronic lymphocytic leukemia
Chronic lymphocytic leukemia Updates in management
BY SANDEEP JAIN, MBBS, MRCP, FRCP
Chronic 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
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
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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.
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 Monitoring of response is done using careful physical, blood, and offer superior efficacy and avoid genotoxicity. BCL-2i-based therapy is also bone marrow examination. Partial response is defined as >50% decrease attractive as it offers fixed-duration therapy. in the absolute lymphocyte count, and >50% decrease in the size of lymph
For elderly patients or patients with significant comorbidities, improved PFS nodes and organomegaly. Complete response is defined as resolution of all but not overall survival has been demonstrated with lymphadenopathy, hepatomegaly, splenomegaly, both BTKi and BCL-2i-based therapies over CIT. and normal lymphocyte count with Hgb >11.0
BTKi are associated with increased risk examination. Patients who achieve complete of atrial fibrillation and bleeding. They are response should be evaluated for Minimal Residual contraindicated in patients on anticoagulation. BTKi-like ibrutinib is chronic therapy and can be expensive in the long run. Patients with del(17p) CLL is the most prevalent leukemia in adults. Disease (MRD) using multicolor flow cytometry or next-generation sequencing. Prospective clinical trials have shown that patients who achieve MRD, or TP53 are resistant to CIT and need treatment negativity defined as blood and bone marrow with with either BTKi or BCL-2i in which response <1 CLL cell in 10,000 leukocyte, have improved rate is similar in patients with del(17p) versus clinical outcomes. wild type. BTKi therapy is also associated with increased risk for infections, including invasive Selecting treatments for relapsed CLL fungal infections, and patients receiving therapy with BTKi should be Patients previously treated with CIT can be treated with either BTKi or carefully monitored for infections. BCL-2i with similar considerations. Patients who appear to have progressed
BCL-2i therapy is associated with significant risk of tumor lysis on BTKi should have careful evaluation to rule out other medical conditions syndrome (TLS). In the CLL14 regimen, allopurinol was started and the contributing to the presentation, such as an infection. Patients should also be first course of treatment was with obinutuzumab alone. Obintuzumab evaluated for the possibility of Richter’s transformation, a rare complication effectively decreased WBC count and reduced risk of TLS. Venetoclax where CLL suddenly transforms in a significantly more aggressive form is introduced with the second course and a ramp-up is done as per the of large cell lymphoma. When true progression on BTKi is confirmed, prescribing information. With these precautions, the risk of TLS is low. and platelets >100 along with normal bone marrow There is significant risk of neutropenia with venetoclax-based regimen. Chronic lymphocytic leukemia to page 244
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3 Chronic lymphocytic leukemia from page 23
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.
Conclusions
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.
3 The 2020 legislative wrapup from page 21
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employees contracting COVID-19 must provide positive test results, or, if a These bills will be compiled at the website of the state’s Office of the Revisor test is not available, must be diagnosed and documented by the employee’s of Statutes (www.revisor.mn.gov). To learn more about an individual House licensed physician, licensed physician’s assistant, or Senate bill, or to track bills that may carry or licensed advanced practice registered nurse. A forward during the 2021 session, visit www.leg. copy of the test or written documentation by the state.mn.us/leg/legis. employee’s health care provider must be provided to the employer or insurer. S.F. 1098 (Rosen)/H.F. 1246 (Morrison): Prescription Drug Price Transparency Act. This Committee meetings via Zoom videoconferencing became the norm. Tom Hanson, JD, an attorney with Winthrop & Weinstine, represents clients before the Legislature and regulatory bodies. Prior to joining the firm, he legislation requires drug manufacturers to submit certain pricing data to the Minnesota Department worked for the Republican Caucus in the Minnesota of Health (MDH) and requires MDH to publicly House of Representatives for eight years and served post certain data. Specifically, a manufacturer of for eight years in Gov. Pawlenty’s administration, a brand name drug whose price increases by 10% including four years as the Commissioner of or more in a 12-month period or 16% or more in a 24-month period, and/ Minnesota Management and Budget. or a generic drug whose price increases by 50% or more in a 12-month period, must submit information related to the increase, including the John Reich, director of government relations at Winthrop & Weinstine, has net yearly increase over the introductory price, total sales revenue for the extensive experience in lobbying and strategy management. Prior to joining the drug during the previous 12-month period, the manufacturer’s net profit firm, he worked for the DFL Caucus in the Minnesota House of Representatives attributable to the drug during the previous 12-month period, and other for five years and served for four years in Gov. Dayton’s administration. pricing information. A drug manufacturer that does not comply may be subject to a civil penalty not to exceed $10,000 per day. Lastly, MDH must issue an annual report to the Legislature on implementation.
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