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CLL Molecular Considerations
How I Adapt CLL Treatment to Evolving Molecular Considerations

Released: August 09, 2016

Expiration: August 08, 2017

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In the past few years, new discoveries and clinical trial data in chronic lymphocytic leukemia (CLL) have drastically changed our understanding of this disease and how we treat patients who are diagnosed with CLL. New targeted agents have provided a personalized approach to care of these patients to optimize their long-term outcomes, and it all starts with an accurate diagnosis of each patient—so let’s start at the beginning.

CLL is defined by monoclonal B‑cell lymphocytosis with a unique immunophenotype, including expression of CD5 and CD23. The nodal form of CLL is termed small lymphocytic lymphoma (SLL) and represents predominantly lymph node involvement with < 5 x 109 clonal lymphocytes/L. In the clinic, most patients are not purely leukemic and present on a continuum with a leukemic phase (blood and bone marrow involvement) and some adenopathy, that is, CLL/SLL. For both variants, CLL and SLL, the treatment approaches are the same. Of note, there is a variant of CLL that does not express CD23 and could be mistaken for mantle cell lymphoma.

Another type of monoclonal B‑cell lymphocytosis (MBL) comprises CLL‑like (CD5+, CD23+) monoclonal B-cells in the peripheral blood, but with < 5 x 109 cells/L and no detectable lymph node involvement by clinical exam or imaging. The low‑count form (< 0.5 x 109 cells/L) has a very low potential for evolution into CLL, and these patients can be followed by their primary care physicians. Patients with the high‑count form (> 0.5 x 109 cells/L) are at risk of progression to CLL (1% to 2% per year) and need to be monitored, typically every 6-12 months, depending on their absolute lymphocyte count.

CLL: Diagnosis
Diagnosis of CLL is established by flow cytometry testing for CD5, CD19, and CD23. Another useful marker detected by flow cytometry is CD200 and can distinguish CLL from MCL (particularly useful in cases that are CD23 negative). PET scans are not necessary for diagnosis. Bone marrow biopsy is generally not necessary; however, it should be performed to aid in the evaluation of cytopenias if present. If there is palpable peripheral adenopathy, a physical exam is often adequate and imaging may not be required. CT imaging is required if the differential diagnosis is MBL or if SLL is suspected.

Although imaging has a distinct role for patients who will begin treatment initiation, for an asymptomatic patient with no anemia or thrombocytopenia and a lymphocyte doubling time > 6 months (ie, does not meet the International Workshop Group on CLL iwCLL criteria for initiation of treatment), routine imaging at diagnosis is frequently not necessary.

CLL: Further Evaluation
For asymptomatic patients who do not meet the iwCLL criteria for treatment, further evaluation using FISH, IGHV mutation testing, and DNA sequencing is only prognostic and does not drive treatment decisions. However, further evaluation does become critically important when there is an indication for treatment, and patients should undergo cytogenetic analysis. The most common cytogenetic abnormalities are identified with FISH and include del(11q), del(13q), trisomy 12, and del(17p). Cytogenetic lesions can influence therapy. For example, patients with trisomy 12 and del(13q) generally will response to chemoimmunotherapy that includes an anti–CD20-based regimen. Patients with del(11q) who are treated with chemoimmunotherapy should have an alkylator included in the regimen (eg, FCR or BR). Finally, patients with known del(17p) or TP53 mutations generally do not respond to or have durable remission with conventional chemoimmunotherapy and should receive sequential treatment with tyrosine kinase inhibitors followed by the BCL2 inhibitor venetoclax for management of relapsed or refractory disease.

The role of IGHV mutation testing has long been considered purely prognostic: Patients with mutated IGHV have more favorable outcomes (longer time until treatment initiation, longer response duration to first treatment, and longer OS) vs those with unmutated IGHV. However, data from 300 patients with CLL treated with FCR at the M. D. Anderson Cancer Center suggested that the subgroup of these fit patients aged younger than 65 years with mutated IGHV can achieve long‑term disease‑free survival with this regimen. So, for young, fit patients who need therapy, IGHV mutation testing can be predictive and help shape treatment choices.

CLL: Additional Variables
Other prognostic variables include genetic abnormalities such as TP53, SF3B1, and NOTCH1, which are identified using next generation sequencing. Although del(17p) involves the loss of the TP53 tumor suppressor gene, FISH does not adequately identify all high‑risk patients with TP53 abnormalities. A focused DNA sequencing panel that includes TP53 can help identify these patients and thereby facilitate appropriate therapy selection. This testing is increasingly being done in most referral centers. The clinical relevance of these other abnormalities is as-yet unclear, and it is unnecessary for most community oncologists to conduct these tests. Clinical trials are currently using these biomarkers to determine any association with treatment benefit.

CLL: Initiating Treatment
Some patients with early-stage disease who do not have bulky disease or other indications for treatment may not need treatment immediately. However, for patients with the iwCLL criteria for treatment, which includes a lymphocyte doubling time of < 6 months, cytopenias due to bone marrow failure (hemoglobin < 11.0 g/dL, platelets < 100 x 109 cells/L), massive/symptomatic lymphadenopathy or organomegaly, and disease-related constitutional symptoms (disabling fatigue, unintentional weight loss, drenching night sweats, fevers unrelated to infectious complications), treatment should be considered.

For your patients with CLL who do need treatment, rapid advances in clinical discovery and availability of new treatment options have increased the complexity of these treatment decisions, and an individualized approach to treatment is paramount. To help, my colleagues (Drs. Awan, Coutre, Jones, and Keating) and I are developing a yearlong educational curriculum with online activities, decision support, and several more commentaries from CLL experts. An interactive treatment decision tool for CLL to provide treatment recommendations for individualized patient scenarios will be available soon. We hope that you will try this tool and will find it useful in your care of patients with CLL.

Please share your questions or thoughts on your current management approaches for patients with CLL in the comment box below.

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Which of the following factors is most helpful to guide choice of therapy for patients with CLL in your clinical practice?
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