New disease perspectives and goals of therapy in CLL

Transcription

1 New disease perspectives and goals of therapy in CLL

2 Contents Introduction 3 CLL overview 4 Patient population 4 Predisposing factors 4 Biology and pathophysiology 5 Clinical presentation 7 Clinical diagnosis and staging 7 Treatment initiation 9 Prognostic markers 10 Chromosomal aberrations 11 IgV H gene mutation status 12 Zeta-chain associated protein kinase 70 (ZAP-70) 13 CD38 expression 13 Prognostic markers in current practice 13 Evolving treatment expectations 15 Evaluating outcomes 16 Minimal residual disease (MRD) 16 Considering the patient 18 Managing older patients 18 Conclusions 19 2

3 Introduction The understanding and management of patients with chronic lymphocytic leukemia (CLL) have evolved significantly over the past several decades. Clinical management strategies for CLL have expanded beyond palliation to improvements in long-term outcomes. Prior to 1980, the opportunity to impact the course of the disease was limited because of the narrow spectrum of therapeutic options and the inability to adequately assess genetic, molecular, and prognostic features. 1 Advances in the knowledge of CLL biology, new treatment and supportive care strategies, and improved diagnostic and prognostic analyses have led to new treatment goals and a change in outlook for patients with the disease. 2 The following sections review patient characteristics, the pathophysiology of CLL, guidelines for diagnosis and staging, treatment options, and important goals of therapy. Additional topics of discussion include new molecular markers that are being evaluated as potential prognostic indicators. This monograph will also explore recent advances in the understanding of CLL biology and how this progress has led to an evolution in treatment goals and management of the disease. 3

4 CLL overview CLL is the most common leukemia in adults in Western countries and represents approximately 25% to 30% of all adult leukemias. 3,4 In the United States, an estimated 15,000 new patients were diagnosed with CLL in 2008, while the prevalence was approximately 95,000 that same year. 5 Patient population CLL is considered to be mainly a disease of the elderly, accounting for 40% of all leukemias in patients over the age of The median age of diagnosis in the United States is 72 years. Approximately 8.9% of cases are diagnosed between ages 45 and 54, and incidence rapidly increases at age Because the CLL patient population is often elderly, the majority of patients typically have a number of comorbidities, such as diabetes and heart disease, that may limit treatment options. 7,8 Patients with CLL vary in ethnicity, age, and gender. Geographic and ethnic differences are particularly important. In Asian countries, CLL represents only 5% of all leukemias. 3 In the United States, the incidence is highest in Caucasian individuals, followed by African Americans and Hispanics. Asian or Pacific Islander Americans and Native Americans (including Alaskans) have the lowest incidence of the disease. 5,9,10 Men are approximately twice as likely to be diagnosed with CLL as women, and most men present with later-stage disease. Conversely, women with CLL are more likely to present with early-stage disease and have a better prognosis than men, regardless of stage and age. 11,12 Predisposing factors Unlike other leukemias, there is no firm evidence linking environmental or occupational exposure with the incidence of CLL except for exposure to Agent Orange. 11,13,14 However, recent research has demonstrated an increased risk in first-degree relatives of patients with CLL. Therefore, a family history of CLL or other lymphoproliferative disorder may also be a CLL risk factor. 3,15 4

5 Biology and pathophysiology CLL is characterized as an abnormal proliferation of malignant B lymphocytes. 9 CLL was once thought to be a homogeneous disease, in which mature B cells accumulated largely due to a lack of normal cell death. Recently, however, CLL has been established as a heterogeneous disease of remarkable diversity. Differences in cell morphology, immunophenotype, cytogenetics, and molecular characteristics have been identified. This heterogeneity translates into varying clinical courses and responses to treatment. 16 Figure 1 provides a historical overview of some of the changes in how CLL biology is viewed. Lymphocytosis is a hallmark of CLL. 11 Malignant lymphocytes characteristically appear small and mature, although large atypical cells, cleaved cells, or prolymphocytic cells are also observed. 3,17 In CLL, malignant, long-lived lymphocytes accumulate in the blood, bone marrow, spleen, and lymph nodes. 4,11 The phenotype of CLL distinguishes it from other B-cell malignancies by the presence of B-cell markers (CD19, CD20, CD23, and CD43) along with CD5, an antigen normally found on T cells. Typically, CLL cells also express surface immunoglobulin (slg), CD79b, CD20, and CD22 at low density. 4,11 The phenotypic features of CLL are not only used for initial diagnosis, but they also play a role in the assessment of minimal residual disease (MRD), an important prognostic parameter defined as <1 CLL cell in 10,000 leukocytes. 17 CLL is often diagnosed as an indolent disease, with a progressive accumulation of malignant lymphocytes. It has a heterogeneous clinical course, ranging from one that does not require immediate treatment to a rapidly progressive disease that requires aggressive management. 18,19 Patients with advanced stage often present with anemia, neutropenia, and thrombocytopenia. 3 In approximately 2% to 6% of patients, the disease undergoes a transformation to large cell lymphoma, which is referred to as Richter s transformation. Prognosis after transformation is poor, with a median survival of approximately 6 months. 3 The range of CLL clinical presentations, combined with the often prolonged indolent course, creates unique challenges in diagnosis and staging. Historically, many patients were not diagnosed with CLL until they became symptomatic; today, there is greater early recognition of this disease due to improvements in patient care and routine laboratory analysis of peripheral blood. 1,20 5

6 Figure 1. Comparison of historical and current views of CLL biology 21 Historical view CLL is a clinically heterogeneous disease with a homogeneous cellular origin. CLL is a disease derived from naive B lymphocytes. Leukemic-cell accumulation occurs because of an inherent apoptotic defect involving the entire mass of leukemic cells. CLL is a disease of lymphocyte accumulation. Prognostic markers identify patients at various risk levels (low, intermediate, or high in the Rai staging categories, and A, B, or C in the Binet categories) with an acknowledged heterogeneity in clinical outcomes among patients in the low- and intermediate-risk categories. Current view CLL is a clinically heterogeneous disease originating from B lymphocytes that may differ in activation, maturity, or cellular subgroup. CLL is a disease derived from antigen-experienced B lymphocytes that differ in the level of immunoglobulin variable (v) gene mutations. Investigators believe leukemic cell accumulation occurs because of survival signals from the external environment. CLL is a disease of lymphocyte accumulation with a higher associated level of proliferation than was previously recognized. New molecular biomarkers are used in both diagnosis and prognosis to better assess patients. Adapted from Chiorazzi N et al. N Engl J Med. 2005;352:

7 Clinical presentation CLL is classified based on cell morphology, immunohistochemistry, and flow cytometry. The French- American-British classification system classifies CLL disease in the bone marrow into several groups, referred to as diffuse, nodular, interstitial, or a combination of these groupings, based on the percentage of abnormal cells. 3,11,22 This classification system is further described in Table 1. Table 1. Laboratory findings in CLL impacting classification 11 The French-American-British classification Typical CLL CLL/PLL Atypical CLL >90% of cells are small 11% 54% of cells are prolymphocytes Heterogeneous morphology; <10% prolymphocytes Marrow involvement Diffuse involvement Nodular, interstitial, or combination (nondiffuse involvement) Usually advanced disease; worse prognosis Associated with less advanced disease; better outcomes Clinical diagnosis and staging Today, approximately 40% of patients with CLL are diagnosed in the earlier stages of the disease and are often asymptomatic. Many of these patients have a long symptom-free period. The remaining 60% of patients present with a range of symptoms of which the most common are fatigue, enlarged lymph nodes, and weight loss. However, patients may also present with lymphadenopathy or splenomegaly. Patients with CLL have compromised immune systems and are susceptible to recurrent bacterial and viral infections. 3 Figure 2. IWCLL* update of the NCI-WG criteria for diagnosing CLL 17,23 Update of the NCI-WG criteria for CLL diagnosis A peripheral blood B-lymphocyte count of at least /L, with up to 55% of the cells being prolymphocytes The lymphocytes should be monoclonal B lymphocytes expressing B-cell surface antigens (CD19, CD20, CD23) with light chain restriction and the T-cell antigen CD5 Each clone of leukemia cells is restricted to expression of either kappa or lambda immunoglobulin light chains Variations of the intensity of expression of these markers may exist and do not prevent inclusion of a patient in CLL clinical trials *International Workshop on CLL. The International Workshop on CLL (IWCLL) update of the National Cancer Institute-sponsored Working Group (NCI-WG) has outlined specific criteria for diagnosing CLL, as detailed in Figure 2. A number of other B-cell malignancies cause increased circulating lymphocytes and thus need to be considered in the differential diagnosis. Advances in flow cytometry have allowed immunophenotyping to become a routine diagnostic tool used to differentiate CLL from other diseases, such as mantle cell and marginal zone leukemia/lymphoma, or other leukemias/lymphomas that may resemble CLL. 3,17,24 7

8 Table 2. Rai and Binet staging systems for classification of CLL 18,19,25 System Stage Definition Median survival Rai staging system Binet staging 0 (low risk) I (intermediate risk) II (intermediate risk) III (high risk) IV (high risk) A B C Lymphocytosis only Lymphocytosis and lymphadenopathy Lymphocytosis in blood and marrow with splenomegaly and/or hepatomegaly (with or without lymphadenopathy) Lymphocytosis and anemia (hemoglobin <11 g/dl or hematocrit <33%) Lymphocytosis and thrombocytopenia (platelet count <100,000/mm 3 ) Enlargement of <3 lymphoid areas (cervical, axillary, inguinal, spleen, liver); no anemia or thrombocytopenia Enlargement of 3 lymphoid areas Anemia (hemoglobin <10 g/dl or thrombocytopenia platelet count <100,000/mm 3 ), or both 11.5 years 11.0 years 7.8 years 5.3 years 7.0 years 11.5 years 8.6 years 7.0 years Table 2 summarizes the major staging systems used for the classification of CLL: the original Rai staging system, the modified Rai staging system, and the Binet staging system. 18,19,25 The original Rai system, published in 1975, consists of stages 0 through IV. It is based on the presence of lymphocytosis, lymphadenopathy, organomegaly, and cytopenias. 19 This staging system was later modified from a 5-tier to a 3-tier system that categorizes patients as having a low, intermediate, or high risk for disease progression. 17,25 The Binet system is also a 3-tier system, with categories A through C. It is based on a retrospective analysis of disease burden that correlates lymphocyte count and the degree of bone marrow infiltration with disease progression. 18 Both the Rai and Binet staging systems give a general indication of prognosis. These staging systems are static, do not take patient variability into consideration, and do not predict which patients will progress or require therapy. Moreover, survival within each stage may vary significantly, particularly in patients with Rai stage 0 and Binet stage A. 11 In these groups, a significant percentage of patients have indolent CLL, whereas others have more aggressive disease that may require earlier intervention. 3,16,26 The median survival of patients with Rai stage 0 disease is more than 12 years, and patients with Rai stages I and II have median survival rates of approximately 5 to 10 years. 19 8

9 Treatment initiation Criteria exist to guide oncologists in determining when to initiate treatment in patients with CLL. The updated IWCLL NCI-WG criteria on CLL focus on Rai and/or Binet stage when determining when to treat patients. According to the criteria, newly diagnosed patients with asymptomatic early-stage disease (Rai 0, Binet A) should be monitored without therapy [watch-and-wait approach] unless they have evidence of disease progression.... [P]atients [with] intermediate ([Rai] stages I and II) and high risk [disease] ([Rai] stages III and IV) according to the modified Rai classification or at Binet stage B and C usually benefit from the initiation of treatment.... Thus, treatment according to the NCI-WG criteria depends heavily on disease stage. However, even some later-stage patients, such as those with Rai stage III or IV or Binet stage C disease, can also be followed without therapy until they become symptomatic or their disease progresses. 17 The National Comprehensive Cancer Network (NCCN) provides more detailed guidance for treatment based not only on stage, but also on symptomatology. NCCN guidelines suggest first classifying patients based on the Rai staging system, then further classifying Rai low-risk and Rai intermediate-risk patients according to a list of conditions that influence treatment, including whether the patient has autoimmune cytopenia, recurrent infections, common B symptoms, threatened end-organ function, cytopenias, bulky disease, steady progression, or histologic progression, as described in Figure Figure 3. NCCN CLL indications for treatment 27 NCCN CLL indications Significant disease-related symptoms: Fatigue Night sweats Weight loss Fever without infection Threatened end-organ function Bulky disease (spleen >6 cm beneath costal margin, lymph nodes >10 cm) Lymphocyte doubling time 6 months* Progressive anemia Platelet count <100,000 cells/mm 3 Eligible for clinical trial *Absolute lymphocyte count alone is not an indication for treatment. Given incurability with conventional therapy, consider a clinical trial as first line of treatment. Adapted from National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin s Lymphomas. V

10 Prognostic markers The Rai and Binet staging systems are simple and reliable prognostic tools that form the basis of the decision to treat most patients. 11 However, there is considerable variation in outcome with each stage. Therefore, additional factors are more commonly being considered in predicting individual patient prognosis and stratifying patient risks. The World Health Organization (WHO) publications and NCI-WG criteria suggest a number of disease activity markers, such as b 2 -microglobulin, CD23, rapid lymphocyte doubling time, and serum thymidine kinase, for use in predicting patient outcomes. 4,17 In addition, recent advances have identified additional biologic markers, such as IgV H mutational status, chromosomal aberrations, and expression of zeta-chain associated protein kinase 70 (ZAP-70) and CD38, that complement the conventional prognostic factors previously described. 17 These additional biomarkers may be used in conjunction with staging to potentially predict outcome or level of tumor burden, as described in Table Table 3. Markers that identify poor prognosis in CLL 4,11 Routinely available markers Advanced Rai or Binet stage Atypical morphology Peripheral lymphocyte doubling time <12 months Serum markers: elevated thymidine kinase and scd23 Immunophenotyping: dim surface IgM/IgD, CD20+, CD22+, CD5+, CD19+, CD79a+, CD23+, CD43+ High β 2 -microglobulin level Diffuse marrow histology Poor response to chemotherapy Investigational markers Lack of IgV H gene mutation Expression of ZAP-70 protein FISH studies showing trisomy 12q, del 11q, del 17p, del 6q scd23=soluble CD23; FISH=fluorescence in situ hybridization. 10

11 Chromosomal aberrations No single genetic mutation or abnormality responsible for CLL development has been identified. Rather, the disease is characterized by a variety of chromosomal abnormalities. These may be detected in 40% to 50% of patients using chromosome banding and in approximately 80% of patients using fluorescence in situ hybridization (FISH) analysis. 3 The most common genetic aberration identified by FISH in untreated CLL patients is the 13q deletion, which is found in 55% of patients. 28 The next most common aberrations are 11q deletion, trisomy 12q, and 17p deletion, found in 18%, 16%, and 7% of patients, respectively. 28 Genetic aberrations are important predictors of disease outcome; specifically, deletions of 17p and 11q have been associated with poor survival. 28 In a study of 325 patients with CLL, chromosomal deletion at 17p predicted aggressive disease, with patients surviving an average of less than 3 years. Patients with the 11q deletion also had a poor overall prognosis, with a median survival of less than 7 years. Patients with a 13q deletion had a median survival of 11 years and, therefore, more favorable outcomes. 28 The impact of genetic abnormalities on overall survival (OS) of CLL patients is shown in Figure 4. Figure 4. Prognostic implication of chromosomal abnormalities 28 Prognostic implication of chromosomal abnormalities 100 Estimated survival probability p 13q single 40 17p 30 11q q Normal 10 13q single Overall survival (months) Adapted from Döhner H et al. N Engl J Med. 2000;343:

12 IgV H gene mutation status It has been suggested that there are 2 types of CLL, characterized by the presence or absence of a mutated immunoglobulin variable region (IgV H ), which follow distinct clinical courses. These are depicted in Figure 5. CLL patients can be divided into 2 prognostic groups based on mutation status. 29,30 The IgV H mutated group has an approximate survival of 25 years, while the IgV H unmutated group has a more aggressive clinical course and an approximate survival of 10 years. 30 Patients with IgV H gene mutations are also more likely to have a 13q deletion and a good prognosis, whereas those without IgV H gene mutations more frequently have trisomy 12q and a poorer prognosis. 31,32 Although there is an established correlation between IgV H mutation status and prognosis, assays to detect mutation status are not broadly available Thus, other laboratory tests are used as surrogate markers but are still under investigation. 33,34 Figure 5. Schematic of selected biologic differences between IgV H unmutated CLL B-cell clones and IgV H mutated CLL B-cell clones 37 Schematic of selected biological differences between IgV H unmutated and mutated CLL B-cell clones Median survival 8 to 10 years Median survival 25 years High CD38 Low CD38 p53 defects Unmutated lgv H Mutated lgv H Low ZAP-70 High ZAP-70 Poor-risk FISH (ie, 17p ; 11q ) Good-risk FISH (ie, 13q ) Adapted from Shanafelt TD et al. Blood. 2004;103: Blood: journal of the American Society of Hematology Copyright 2004 by AMERICAN SOCIETY OF HEMATOLOGY (ASH). Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY (ASH) in the format Internet posting via Copyright Clearance Center. 12

13 Zeta-chain associated protein kinase 70 (ZAP-70) ZAP-70 is a member of the Syk-ZAP-70 protein kinase family. This kinase is normally expressed in T and natural killer (NK) cells, and it plays a role in initiating T-cell signaling and in signaling through the B-cell receptor of CLL cells. 34,38 Recent research exploring ZAP-70 as a potential surrogate marker for IgV H gene mutation status has indicated that ZAP-70 overexpression is correlated with an unmutated IgV H and is predictive of poorer outcomes in CLL. 33,34,38,39 ZAP-70 expression may be measured by flow cytometry, Western blotting, quantitative reverse transcriptase-polymerase chain reaction (qrt-pcr), and immunohistochemistry. 38,39 Currently, assays examining ZAP-70 expression are inconsistent, with no clear guidelines for use. In addition, the correlation between ZAP-70 and outcomes, and its subsequent use as a marker for treatment decisions, remains subject to ongoing debate. 17 In an investigation evaluating ZAP-70 expression as a surrogate for IgV H mutation status, ZAP-70 expression correctly identified 91% of patients with unmutated IgV H genes, and no patient with mutated IgV H genes overexpressed ZAP Overall, there is a strong correlation between ZAP-70 expression and IgV H mutation; however, because ZAP-70 expression has been found to remain unchanged over time, some oncologists believe it to have independent prognostic value. 34,38,40 CD38 expression CD38 expression on CLL cells has been correlated with IgV H mutations. 29 Because CD38 cell-surface expression can be easily detected by flow cytometry, CD38 expression has been suggested as a surrogate marker for determining IgV H mutation status in CLL. 29 However, studies have not supported the role of CD38 as the desired surrogate. This work has indicated that the relationship between CD38 expression and IgV H mutation is not absolute and may be discordant in approximately 30% of cases. 34,41 Furthermore, CD38 expression may also fluctuate in patients, with karyotype evolution occurring in 15% to 40% of patients. 32 CD38 expression and IgV H mutation status are considered independent prognostic indicators. 34,41 In addition, CD38 correlation with outcomes and subsequent use as a marker for treatment remains subject to ongoing debate. 17,35 ZAP-70 and CD38 expression may ultimately provide complementary prognostic information; however, neither CD38 nor ZAP-70 assays are widely used outside of clinical trials. 17,34 Prognostic markers in current practice The recent IWCLL updated the NCI-WG criteria for diagnosis and treatment of patients with CLL to include standard prognostic indicators and possibly a CLL-relevant FISH panel in general practice (Table 4). Although still under debate, the current NCI-WG criteria further recommend that some of the newer molecular biomarkers, such as CD38, IgV H mutation status, and ZAP-70, as mentioned previously, be included in clinical trials

14 Prospective CLL studies that include the newly identified biomarkers will continue to refine the understanding of the clinical behavior and biology of this disease, and will be pivotal in the future refinement of new treatment strategies. Once these assays are perfected and incorporated into clinical practice, they are likely to guide patient management decisions. 35 Chromosomal abnormalities, IgV H mutation status, and ZAP-70 and CD38 expression may ultimately be combined with more established prognostic indicators, such as lymphocyte doubling time, to predict the clinical course of patients. 16 In addition, consideration of response to therapy and the eradication of MRD may be used to help predict patient outcomes. 42 These indicators may guide patient stratification into lowand high-risk populations, optimizing the clinician s ability to individualize treatment strategies to achieve greater clinical goals. 17 Table 4. IWCLL update of the NCI-WG recommendations for pretreatment evaluations of patients with CLL 17 Diagnostic test General practice* Clinical trial Tests to establish diagnosis Complete blood count and differntial count Always Always Immunophenotyping of lymphocytes Always Always Assessment before treatment History and physical, performance status Always Always Complete blood count and differential Always Always Marrow aspirate and biopsy Desirable Desirable Serum chemistry, serum immunoglobulin, direct antiglobulin test Always Always Chest radiograph Always Always Infectious disease status Always Always Additional tests before treatment Cytogenetics (FISH) for del 13q, del 11q, del 17p, trisomy 12q, Desirable Always del 6q in the peripheral blood lymphocytes IgV H mutation status, ZAP-70, and CD38 NGI Always CT scan of chest, abdomen, and pelvis NGI Desirable MRI, lymphangiogram, gallium scan, PET scans NGI NGI Abdominal ultrasound Possible NGI NGI=not generally indicated. * The use of accepted options for a patient with CLL who is not enrolled in a clinical trial. Adapted from Hallek M et al. Blood. 2008;111:

15 Evolving treatment expectations In the past 10 years, the CLL therapeutic landscape has dramatically evolved, as shown in Figure 6. Treatment options expanded from the use of alkylating agent monotherapy in the 1960s and 1970s to the introduction of purine analogs, and moved to combination therapy in the 1980s and 1990s. In the current decade, treatment strategies have expanded to include immunotherapy. 3,43 Figure 6. CLL treatment overview by decade 44 CLL treatment overview by decade Alkylating agents Purine nucleosides Purine nucleosides and alkylators Chemoimmunotherapy Adapted from Kay NE. Blood. 2006;107:848. Blood: journal of the American Society of Hematology Copyright 2004 by AMERICAN SOCIETY OF HEMATOLOGY (ASH). Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY (ASH) in the format Internet posting via Copyright Clearance Center. The expansion of the therapeutic landscape has shifted CLL treatment expectations to include both palliative care and symptom management as well as therapy with more response-driven intent. Recent treatment strategies have focused on achieving higher and better quality response rates and longer progression-free survival (PFS) As advances in CLL clinical research have continued to progress into the new millennium, treatment goals have included achieving longer survival as well as improved quality and duration of complete remission, with the hope of achieving MRD negativity. 50 As shown in Figure 7, oncologists have begun to expect CLL therapy to result in improvements in outcomes beyond response rates and into PFS and MRD negativity. As research continues to refine the treatment goals for patients with CLL, the progress in CLL achieved over the past 3 decades is likely to continue. 15

16 Figure 7. CLL treatment expectations by decade 51,52 Goals of treatment for CLL have evolved over time Palliation Palliation, higher response rates CR, FFP CR, PFS PFS, MRD-negative CR FFP=freedom from progression. Evaluating outcomes The NCI-WG recently updated the standard CLL response criteria (shown in Table 5). This update confirms the use of conventional biomarkers, defines new prognostic and predictive markers, and diagnostic parameters, and accommodates new treatment goals and options. 17 Until recently, response to therapy, or overall response rate (ORR), in CLL was determined using the 1996 NCI-WG response criteria defining complete remission, partial response (PR), stable disease (SD), and progressive disease (PD). 17,23 However, most current clinical trials have also included more sensitive evaluation techniques that have since become available. 17 These newer publications include reports on complete molecular remission as well as the standard designations of overall response (OR), complete response (CR), and PR. 17 The incorporation of MRD testing allows oncologists to more closely examine the quality of response to therapy. Improvements in PFS have been observed in patients who achieve CR, and even greater improvements for those achieving MRD negativity. 24,42 This has prompted reevaluation of treatment paradigms to include more vigilant monitoring of the depth of CR through MRD analysis. 42 Minimal residual disease (MRD) Today, MRD negativity is emerging as an important treatment assessment. Despite the growing consensus regarding the importance of MRD negativity and its possible correlation with long-term treatment outcomes, MRD assessment is not widely used. 3 MRD negativity is the eradication of disease to undetectable levels, defined as <1 CLL cell in 10,000 leukocytes. 17 Because MRD assessment leads to a more accurate prognosis, it has been added to the NCI-WG criteria for clinical trials as a goal of therapy. 17 Patients who achieve MRD negativity after therapy usually have a better prognosis than those with lowerquality responses to therapy. 53,54 In clinical studies, it has been reported that CLL patients achieving MRD-negative status generally had longer disease-free periods and better OS than MRD-positive patients. These findings stress the importance of eradicating disease at the molecular level. 53,54 MRD negativity may, therefore, become a decisive indicator of treatment success

17 Table revision of the NCI-WG criteria for response in CLL 17 Treatment goals in CLL Complete response (CR) Partial response (PR) Stable disease (SD) Progressive disease (PD) Progressive-free survival (PFS) Treatment failure Relapse Refractory Minimal residual disease (MRD) Definition At 2 months posttherapy: Absence of lymphadenopathy >1.5 cm, hepatomegaly, splenomegaly, and constitutional symptoms Normalization of CBC (neutrophils >1,500/µL, platelets >100,000/µL, hemoglobin >11 g/dl) Lymphocytes <4,000/µL Additional assessments in clinical trials: - Minimal residual disease (MRD) <1 CLL cell per 10,000 leukocytes - Bone marrow biopsy shows normal cellularity, lymphocytes <30% At 2 months posttherapy: A decrease in the number of blood lymphocytes by 50% from the value before therapy Reduction in lymphadenopathy (by CT scans in clinical trials or by palpation in clinical practice) as defined by - Decrease in lymph node size by 50% - No increase in any lymph node, and no new enlarged node(s) detected Normalization of CBC (neutrophils >1,500/µL or 50% improvement over baseline; platelets >100,00/µL or 50% improvement over baseline; hemoglobin >11 g/dl or 50% over baseline) No CR or PR, no progressive disease At least 1 of the following: Lymphadenopathy ( 50% increase) 50% increase in hepatomegaly or splenomegaly Transformation to a more aggresive histology (Richter s transformation) Occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL The time from study entry until objective disease progression or death Includes the following responses: Stable disease Nonresponse Progressive disease Death from any cause Patient achieved CR or PR but at 6 months shows evidence of disease progression Treatment failure or disease progression within 6 months of the last antileukemic therapy For patients who have achieved a CR, eradication of disease cells as determined by flow cytometry or PCR (<1 CLL cell per 10,000 leukocytes) Adapted from Hallek M et al. Blood. 2008;111:

18 Considering the patient Fine-tuning treatment and goals of therapy based on the unique characteristics of each patient is an important consideration in CLL management. Medical fitness, age, and the ability to tolerate aggressive therapy are critical and interrelated patient characteristics that should all be considered when choosing a treatment regimen. Medical fitness is receiving greater attention in CLL treatment planning. Medically fit patients have normal organ function, no additional health problems or only mild, nondebilitating health problems, and a good performance status. Conversely, medically unfit patients may present with a worse performance status or reduced organ function, as well as multiple or severe comorbidities that should be considered in treatment decisions. 55 Age is another critical factor when individualizing treatment goals. However, the effects of aging differ greatly among individuals, and treatment plans should account for this diversity. Younger patients typically have good medical fitness with few comorbidities. Conversely, the majority of CLL patients present at an older age and may have significant comorbidities. However, age does not automatically dictate medical unfitness. Therefore, regardless of a patient s age, the patient s medical history should be considered. Thus, a treatment algorithm should not be devised based exclusively on patient age. 3,8 Managing older patients The management of older patients with CLL involves identifying those who may tolerate and benefit from more aggressive therapy. 8 Data are emerging that confirm many patients over 65 are able to tolerate and benefit from more aggressive therapy. 56 However, many oncologists believe that the toxicity of some therapies is not well tolerated by patients 70 years or older. 2 While age has been defined as an important factor in selecting optimal treatment strategies, it should also be recognized that there is significant heterogeneity in the elderly population with regards to medical fitness and the risk of disease progression. Thus, a one-size-fits-all approach to the treatment of this patient population may not be ideal. Devising treatment strategies for elderly patients is also made difficult by the fact that this population is often underrepresented in clinical trials. In a recent review of available scientific literature pertaining to elderly CLL patients, Eichhorst et al concluded that medically fit patients with no or mild comorbidity and normal life expectancy should be treated intensively irrespective of their chronological age. 2 18

19 Conclusions Over the past 3 decades, an increased understanding of the biology of CLL, advances in diagnostic and prognostic analyses, new treatment strategies, and better supportive care have all led to improved patient outcomes. 1 The conventional view of CLL as a disease treated with palliation has now evolved to focus on improving long-term patient outcomes. 1,57 CLL treatments have expanded from alkylating agents, to combining purine analogs with alkylators, to the addition of immunotherapy. This increase in treatment options has resulted in a concomitant increase in complete response rates compared with prior generations of therapy. 1 Today, the goals of treatment for patients with CLL include high-quality responses, including CR with MRD negativity, duration of response, and PFS. 17 Oncologists have begun to refine and tailor treatment strategies for a more individualized approach that is based on patient characteristics. Ongoing scientific research in this field will continue to contribute to improved outcomes in CLL over the coming decades. 19

20 References: 1. Brenner H, Gondos A, Pulte D. Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century. Blood. 2008;111: Eichhorst B, Goede V, Hallek M. Treatment of elderly patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2009;50: Wierda WG, Keating MJ, O Brien S. Chronic lymphocytic leukemias. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer Principles & Practice of Oncology. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008: Müller-Hermelink HK, Montserrat E, Catovsky D, et al. Chronic lymphocytic leukaemia/small lymphocytic lymphoma. In: Swerdlow SH, Campo E, Harris NL, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008: Horner MJ, Ries LAG, Krapcho M, et al. SEER Cancer Statistics Review, Accessed May 15, British Society for Haematology. 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