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Current Approaches to Diagnosis and Risk Stratification in Chronic Lymphocytic Leukemia

Published Online: Jun 08,2017



Two clinical staging systems, the Rai and Binet systems, are used predominantly in the United States and Europe, respectively, to group patients with CLL into broad prognostic groups.23,24 Both systems combine the presence of specific physical parameters, such as lymph node involvement, enlarged spleen and/or liver and blood parameters, including anemia or thrombocytopenia, to determine tumor burden.


The Rai system, originally including 5 groups, has been modified to define low-risk disease (former stage 0) as lymphocytosis with leukemia cells in the blood and/or marrow. Intermediate risk disease (stage I/II) is defined as enlarged nodes in any site, and splenomegaly and/or hepatomegaly (lymph nodes being palpable or not), and high-risk disease (stage II/IV) as lymphocytosis and cytopenia (hemoglobin [Hb] level less than 11 g/dL and/ or platelet count of less than 100,000/μL) (TABLE 23,23).


The Binet staging system relies on determining the number of involved areas, ie, enlarged lymph nodes of greater than 1 cm in diameter or organomegaly, and the presence anemia or thrombocytopenia. Binet stages are low risk (stage A), with less than 3 palpable enlarged sites without cytopenia; intermediate risk (stage B), with 3 or more palpable enlarged sites without cytopenia, and high risk (stage C) in all patients who have Hb of less than 10 g/dL and/or a platelet count of less than 100,000/μL, irrespective of organomegaly (TABLE 3 24).


Available survival estimates linked with staging suggest similar survival to age-matched controls for patients with low-risk disease by Rai stage (median, 150 months), shorter survival for patients with intermediate-risk disease (median, 71-101 months), and poor survival for high-risk features (median, 19 months).1,3 However, these estimates reflect treatment with chemotherapy or chemoimmunotherapy, and life expectancies are increasing with newer small molecule inhibitor-based therapy.1,3




Newly diagnosed CLL is characterized by a highly variable clinical course, ranging from absence of symptoms for decades to the rapid development of symptoms or features of high-risk disease. Prognostic factors used for patient strati cation include patient factors and clinical features of the disease, and genetic, molecular, and biochemical characteristics of the CLL clone.3


In addition to staging and lymphocyte doubling time, traditional prognostic factors or clinical features associated with poorer outcome are male sex, ≥65 years, poor performance status due to medical comorbidities, high serum levels of beta-2 microglobulin (>3.5 mg/L), high absolute lymphocyte count (>50,000 cells/μL), and/or late-stage disease at diagnosis.25–27 Elevated serum β2 microglobulin is an independent prognostic indicator for treatment-free interval, response to treatment, and overall survival (OS) in response to first-line chemoimmunotherapy regimens,3,26 and—if remaining after 6 months of treatment—for inferior progres- sion-free survival (PFS) with ibrutinib (Imbruvica)-based therapies.28




The use of these diagnostic tests is encouraged by current treatment guidelines and managed care companies. John L. Fox, MD, MHA, the vice president of medical affairs of Priority Health, explained in an interview with the American Journal of Managed Care®, “The cost of the diagnostics themselves are really not an issue. Those are the upfront costs in trying to establish what the most appropriate therapy is for that particular patient.”29


Biological prognostic markers that reflect CLL cell characteristics and are used for risk stratification include cytogenetic abnormalities; IGHV mutational status; TP53 mutation; expression of ZAP-70, CD49d (also known as integrin alpha-4), or CD38; and mutations in NOTCH1, SF3B1, BIRC3, and MYD88.3 Among these, del(17p) and TP53 mutations are considered pertinent for treatment selection, and multiple other markers are considered of predictive value.


Del(17p), which causes the loss of 1 TP53 allele and is associated with inactivating mutations in the other allele in 80% of patients with CLL, is considered the most important prognostic marker in CLL, with predictive value on treatment. The presence of del(17p) and/or mutations in TP53 defines a group of patients with CLL not eligible for chemoimmunotherapy regimens due to poor outcomes.22,30 Targeted inhibitors of the B-cell receptor pathway and apoptosis inhibitors can produce high response rates in patients with del(17p) and are the preferred regimens in the first and subsequent lines of therapy.3 The deletion is relatively rare at diagnosis (approximately 7%)22 but frequent in relapsed/refractory disease, indicating acquisition or expansion of del(17q)-harboring CLL clones during treatment.31


Del(11q) has been linked to extensive lymphadenopathy, aggressive clinical course, and shorter median survival with traditional reg- imens (79 months).22 However, the presence of del(11q) is not an adverse prognostic marker for response for treatment with ibrutinib.32


Among cytogenetic abnormalities, del(13q) is the only one that confers a favorable prognosis and long median survival (133 months).22 Trisomy 12 has been linked to shorter survival.22


Unmutated IGHV (de ned as ≥98% homology with the germline gene sequence) re ects CLL originating from B cells that have not undergone a somatic mutation. The presence of unmutated IGHV predicts a more aggressive disease type and has traditionally been associated with significantly decreased survival compared with mutated IGHV, irrespective of disease stage.33,34 Recent analyses have con rmed unmutated IGHV as a predictor of shorter survival with chemoimmunotherapy regimens including udarabine and rituximab (Rituxan; FR), and udarabine, chlorambucil, and rituximab (FCR).35,36 In patients with mutated IGHV, FCR was associated with an improved survival in all cytogenetic groups except del(17p).36 Unmutated IGHV does not predict adverse outcomes with ibrutinib-based regimens.37


Among prognostic surface markers detected by flow cytometry or immunohistochemistry—including CD38, CD49d, and ZAP-70—CD49d is independent of FISH and IGHV.38 Multiple studies have associated CD38 and/or ZAP-70 expression with shorter PFS and OS, but despite positive correlations with the presence of unmutated IGHV, these markers are not considered appropriate surrogate markers—the latter due to discordance and variable expression during the course of disease.3 Expression of ZAP-70 may be a stronger predictor of time until treatment is needed than IGHV mutational status or CD38 levels 39,40; however, standardized detec- tion of this nuclear marker is hampered by technical issues and it’s use is not yet recommended outside clinical trials.3


NOTCH1, SF3B1, and BIRC3 mutations are observed in approximately 4% to 15% of patients with newly diagnosed CLL, and 15% to 25% of patients with CLL refractory to udarabine.3 These mutations have been associated with varying prognostic significance across studies, such that their impact on treatment selection remains to be established, particularly for targeted agents.


Del(17p) and TP53 mutations are currently the only disease-based predictive markers that affect treatment selection in CLL. With changing treatment options, particularly the inclusion of novel effective agents that prolong survival and have activity among patients considered high-risk in the era of chemotherapy-based regimens, the value of other prognostic markers continues to evolve.


As Steven E. Coutre, MD, professor of medicine (hematology) at the Stanford University Medical Center, summarized in an interview: “A FISH test from the peripheral blood identifies patients who are at higher risk of progression and, in some cases like with del(17p), identifies patients who respond differently to different therapies. And so, those are the kinds of insights that we’re looking for to help us better choose treatments for our patients. And I think that’s where the eld is going. Hopefully, we’ll be able to better tailor the choices we have toward specific patient groups."

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Current Approaches to Diagnosis and Risk Stratification in Chronic Lymphocytic Leukemia
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