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Narrative Review: Initial Management of Newly Diagnosed, Early-Stage Chronic Lymphocytic Leukemia

Tait D. Shanafelt, MD; John C. Byrd, MD; Timothy G. Call, MD; Clive S. Zent, MD; and Neil E. Kay, MD
[+] Article and Author Information

From Mayo Clinic College of Medicine, Rochester, Minnesota, and Ohio State University, Columbus, Ohio.


Grant Support: Salary support from National Cancer Institute (K12 CA90628) (Dr. Shanafelt) and partial salary support from the University of Iowa/Mayo Clinic Lymphoma SPORE (CA97274) (Drs. Shanafelt and Zent). Dr. Byrd is a clinical scholar of the Leukemia and Lymphoma Society. The authors thank Mr. Edson Spencer and Mr. Robert Donner for continued philanthropic support.

Potential Financial Conflicts of Interest: Grants received: C.S. Zent (Berlex, Genentech); Grants pending: T. Shanafelt (Berlex Corp.).

Requests for Single Reprints: Tait D. Shanafelt, MD, Department of Internal Medicine, Division of Hematology, Mayo Clinic College of Medicine, 200 First Street, Rochester, MN 55902.

Current Author Addresses: Drs. Shanafelt, Call, Zent, and Kay: Department of Internal Medicine, Division of Hematology, Mayo Clinic College of Medicine, 200 First Street, Rochester, MN 55902.

Dr. Byrd: Ohio State University, B302 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210.


Ann Intern Med. 2006;145(6):435-447. doi:10.7326/0003-4819-145-6-200609190-00007
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Chronic lymphocytic leukemia is one of the most common malignant lymphoid diseases in the western world and is frequently diagnosed by internists. There have been clinically significant changes in method of diagnosis, prognostic tools, supportive care, and treatment over the past 2 decades. Most patients with chronic lymphocytic leukemia now have Rai stage 0 or I disease at diagnosis. Patients with early-stage disease are a heterogeneous group: Approximately 30% to 50% will have accelerated disease progression, and the remainder may live for decades and possibly never require therapy. Recent insights into the biological characteristics of leukemic B cells have led to the discovery of new prognostic tools (immunoglobulin variable-region heavy chain gene mutation status, cytogenetic abnormalities assessed by fluorescent in situ hybridization, and Z-chain–associated protein kinase-70 protein expression) that can identify patients with early-stage disease who are at high risk for early disease progression. These tools allow physicians to individualize counseling, follow-up, and management on the basis of disease risk. In addition, new treatments developed over the past 2 decades (purine nucleoside analogues, monoclonal antibodies, and combination chemoimmunotherapy regimens) have dramatically improved response rates and appear to prolong survival. In this review, the authors discuss the current work-up of lymphocytosis and highlight how to use recently identified prognostic tools to stratify risk in patients with newly diagnosed, early-stage chronic lymphocytic leukemia. Recommendations for patient counseling, follow-up, supportive care, and initial treatment are presented for each risk category.

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Figure 1.
Evaluation of lymphocytosis.

Adapted from reference (24). CBC = complete blood count; CMV = cytomegalovirus; EBV = Epstein–Barr virus; HTLV = human T-cell leukemia virus; NHL = non-Hodgkin lymphoma; TB = tuberculosis.

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Figure 2.
Use of prognostic tests to risk stratify patients with early-stage disease.

FISH = fluorescent in situ hybridization; IgVH = immunoglobulin variable-region heavy chain gene. *Fever, weight loss, night sweats, and fatigue not due to another cause (see text). †If available at center. ‡Less than or equal to 2% mutated compared with germline sequence. §Although high Z-chain–associated protein kinase-70 expression may be used to characterize patients with early-stage disease as high risk in the future, this assay cannot be recommended for routine clinical use until it can be standardized and shown to have reliable intralaboratory reproducibility.

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Figure 3.
How the authors select first-line therapy in patients with chronic lymphocytic leukemia (CLL) who require treatment and are not participating in clinical trials.

Data on FR, FCR, and PCR are from references (83, 84), and (85), respectively. FCR = fludarabine, cyclophosphamide, and rituximab; FR = fludarabine and rituximab; PCR = pentostatin, cyclophosphamide, and rituximab. *Patients with poor performance status directly due to CLL rather than comorbid disease can be treated similarly to patients with performance status 0–2. †If used to treat disease-related symptoms.

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