NE Oncology Issue – August 2010

Douglas A. Stewart, MD, FRCP(C),1 Christine Chen, MD, MEd, FRCP(C),2 Laurie H. Sehn, MD, MPH,3 Chaim Shustik, MD, FRCP(C)4

1Dr. Douglas A. Stewart, Chief, Division of Hematology and Hematological Malignancies, Department of Medicine and Professor, University of Calgary; Leader, Hematology/BMT Program, Tom Baker Cancer Centre, Calgary. 2Dr. Christine Chen, Assistant Professor, University of Toronto, Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto. 3Dr. Laurie H. Sehn, Clinical Assistant Professor, University of British Columbia and British Columbia Cancer Agency, Vancouver. 4Dr. Chaim Shustik, Professor of Medicine and Oncology, McGill University and Royal Victoria Hospital, Montreal.

Medical Writer: Anna Christofides MSc, RD, New Evidence

Canadian Reviewers: Neil Berinstein, MD, FRCP(C) (Sunnybrook Health Sciences Centre; Toronto, Ontario), Stephan Caplan, MD, FRCP(C) (Sir Mortimer B. Davis – Jewish General Hospital; Montreal, Quebec), Stephen Couban, MD, FRCP(C) (Dalhousie University and Queen Elizabeth II Health Sciences Centre; Halifax, Nova Scotia), John Kuruvilla, MD (University of Toronto and Princess Margaret Hospital; Toronto, Ontario), Wendy Lam, MD, FRCP(C) (University of British Columbia and British Columbia Cancer Agency; Vancouver, British Columbia), C. Pierre Laneuville, MD, FRCP(C) (McGill University and Royal Victoria Hospital; Montreal, Quebec), Loree Larratt, MD, FRCP(C) (University of Alberta Hospital; Edmonton, Alberta), David MacDonald, MD (Dalhousie University and Queen Elizabeth II Health Sciences Centre; Halifax, Nova Scotia), Khaled Ramadan, MBBCh, MRCPO, FRCPath (University of British Columbia and St. Paul’s Hospital; Vancouver, British Columbia), Michael Voralia, MD, FRCP(C) (University of Saskatchewan; Saskatoon, Saskatchewan).

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Background

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world, accounting for approximately 7% of non-Hodgkin’s lymphomas.1 In Canada, the median age at diagnosis is approximately 72 years, with less than 10% of cases diagnosed in patients under 50 years. Age-adjusted incidence rates are 7.5/100,000 person-years (p-yrs), with males representing approximately 57% of cases (male:female ratio = 1.3:1). The five-year relative survival is about 80% (95% CI: 73–86) in men and tends to be higher in women (85%; 95% CI: 78–92).2

Purpose of this document

There is no uniform standard of care for the treatment of CLL and at present, no national guidelines for managing CLL have been developed in Canada.3,4 In determining the optimal treatment for CLL, individual patient characteristics including performance status and disease stage must be considered.5 Based on these criteria, a number of patient subgroups therefore exist and should be included in treatment decisions.

Dr. Douglas Stewart, Dr. Chaim Shustik, Dr. Christine Chen, and Dr. Laurie Sehn drafted this document, which outlines a management approach to CLL. Topics addressed include initial diagnosis, staging and prognostic tests, indications for treatment, first- and second-line treatment options, new regimens, and associated management issues. The document was then reviewed by 10 Canadian hematologists who contributed further content to the document. The following paper describes a general consensus on CLL management, but does not reflect a true evidence-based guideline process with a systematic literature review. In addition, patient preference should always be considered in any treatment decision.

Diagnosing CLL

The World Health Organization (WHO) defines CLL and small lymphocytic lymphoma (SLL) as “a neoplasm composed of monomorphic small, round to slightly irregular B lymphocytes in the peripheral blood, bone marrow, spleen, and lymph nodes, admixed with prolymphocytes and paraimmunoblasts forming proliferation centers in tissue infiltrates.”1

According to the International Workshop on CLL (IWCLL) 2008 guidelines, the diagnosis of CLL requires ≥5 x 109 B lymphocytes/L in the peripheral blood for the duration of at least three months.5 In Canada, bone marrow biopsies and computed tomography (CT) scans are not routinely used in the diagnosis or management of CLL. Although CLL and SLL are considered together as similar entities, the term SLL is used to indicate neoplastic tissue infiltration in lymph nodes, spleen, or other organs associated with a circulating B lymphocyte count <5 x 109/L.

As many as 12% of healthy individuals >40 years of age may have low levels (<5 x 109/L) of circulating monoclonal B cells. These cells are phenotypically identical to CLL cells, but there is no evidence of tissue infiltration.6 This recently identified condition is referred to as monoclonal B-cell lymphocytosis (MBL).5 MBL progresses to CLL at a rate of 1%–2% of patients per year.7

Clinical features of CLL vary in their presentation, course, and outcome. Patients are often asymptomatic at diagnosis, but fatigue, autoimmune hemolytic anemia (AIHA), infections, splenomegaly, hepatomegaly, lymphadenopathy, or extra-nodal infiltrates may be present. Some patients may also exhibit a small serum monoclonal protein, an M-component. Although in rare cases patients may not have lymphocytosis at diagnosis, peripheral blood and bone marrow are usually involved as the disease progresses. Lymph nodes, liver, and spleen are commonly infiltrated, with other extra-nodal sites becoming involved in some patients.1

Although some CLL cases may have an atypical immunophenotype, the characteristic profile includes CD19/CD5/CD23/ CD43 positivity with weak CD20 and CD11c positivity and dim surface immunoglobulin expression with restricted light chain expression.1,8,9 (Table 1)

Staging and prognosis of patients with CLL

Clinical staging

Two widely accepted staging methods are used at diagnosis in both patient care and clinical trials: the modified Rai and the Binet systems, with the modified Rai system being the most commonly used in Canada. (Tables 2 and 3) These staging systems are relatively simple, relying solely on physical examination and standard laboratory tests.3,5,10

Prognostic tests

A number of predictive and prognostic markers have been identified that may predict for responsiveness to chemotherapy and survival, and may contribute to decisions in the optimal management of CLL. However, these tests may not be routinely available and, with the current state of knowledge, should not determine when to initiate first-line treatment outside the setting of a clinical trial.5

Cytogenetic testing

Interphase fluorescence in situ hybridization (FISH) can be used to identify cytogenetic abnormalities in more than 80% of patients.5 The most common are del(13q) in 14%–40%, deletions and/or trisomy in chromosome 12 in 11%–18%, del(11q) in 10%–32%, del(6q) in 2%–9%, and del(17p) in 3%– 27% of patients (the higher value for del(17p) occurring with disease progression and treatment).11 In general, patients with a normal karyotype or isolated del(13q) can be categorized as low risk with prolonged time-to-disease-progression and better chances of long-term survival, whereas patients with del(17p), and del(11q) are more likely to have a poor prognosis.11 Patients with trisomy 12 have a treatment advantage over those with del(17p) or del(11q), as they tend to respond better to fludarabine-based therapy. In addition, patients with del(11q) appear to benefit from the addition of cyclophosphamide to fludarabine (FC), and do particularly well with FC plus rituximab (FCR).11,12 Del(17p) leads to loss of the p53 tumour suppressor gene, which mediates cell death induced by alkylating agents and purine analogues. Hence, patients with del(17p) are typically less responsive to these agents, but may respond to agents such as alemtuzumab, flavopiridol, and lenalidomide.5,11 FISH analysis may therefore be useful in the selection of patients with high-risk disease who might benefit from allogeneic stem cell transplantation (allo-SCT). Such patients are at high risk of treatment failure and are likely to become refractory to treatment or to relapse early after fludarabine-based therapy.13 Though the prognostic value of FISH cytogenetics is best validated when performed at diagnosis, repeat analysis may be justified to identify additional genetic defects acquired with disease progression.5

IgVH mutational status and VH3.21 gene usage

Approximately half of all CLL patients have leukemic cells with somatic hypermutations in the immunoglobulin heavy chain variable region (IgVH) genes. Patients with IgVH mutations (mutated CLL) have improved survival as compared to those with unmutated IgVH (unmutated CLL).5,11 Patients with unmutated CLL exhibit faster disease progression, atypical peripheral blood cell morphology, adverse cytogenetic features, and clonal evolution.11 The VH3.21 gene is an unfavourable prognostic marker, regardless of IgVH mutational status.5 Sequencing of the genome required to determine IgVH mutational status is expensive, time-consuming, and not readily available for clinical purposes at most sites.

ZAP-70 and CD38 expression

In the course of identifying surrogate markers for IgVH mutational status, a small number of genes were identified that allow the separation of mutated and unmutated CLL. The most specific of these genes is the one that encodes for a 70-kD zeta-associated protein (ZAP-70). The majority of mutated CLL cases are ZAP-70 negative (defined as ≤20% positive cells), whereas unmutated forms are more often ZAP-70 positive (defined as >20% positive cells).11 Discordance of ZAP-70 expression and IgVH mutational status is reported in about 25% of CLL patients.14 ZAP-70 analysis is hampered by variation in technique, leading to inconsistent results across centres.

CD38 is an ectoenzyme involved in transmembrane signalling and cell adhesion, and can correlate with unmutated IgVH status, predicting a poor prognosis. Though easy to perform through flow cytometric techniques, CD38 is discordant with IgVH mutational status in a significant proportion of cases and variability in results over time are drawbacks for its use.5,14

Serum markers

Serum markers such as CD23, thymidine kinase (TK), and ß2- microglobulin (ß2M) may predict survival or progression-free survival (PFS).5 Even in cases of early stage disease, serum TK levels correlate with tumour mass and proliferative activity of CLL cells. In addition, high levels of CD23 are associated with diffuse bone marrow infiltration and rapid lymphocyte doubling time. Serum TK and CD23 assays are not routinely used in Canada. Alternatively, serum levels of β2M are easily available at most centres and correlate with both clinical stage and overall survival (OS).11

Assessing patient fitness

Patient fitness and co-morbidities should be considered in treatment decisions to determine whether aggressive treatments can be tolerated. Several systems exist for determining patient fitness, two of the most common being the Eastern Cooperative Oncology Group (ECOG) Performance Status and the Cumulative Illness Rating Scale (CIRS). In determining whether a patient can be categorized as fit, one of these scoring systems should be used.5

In 1982, ECOG developed a set of performance status criteria that categorizes patients into one of five categories from high to low levels of physical function. (Table 4) These categories were designed to assess how the patient’s disease affects daily living.15 The ECOG Performance Status categories are also commonly used within the context of CLL to assess treatment intensity and whether elderly patients could be included in specific clinical trials.5

A second system for assessing patient fitness is the Cumulative Illness Rating Scale (CIRS). The CIRS assesses co-morbidities in different organ systems by assigning points to various conditions, such as heart disease. The physician tabulates the number of points in a variety of body systems, where a low score indicates optimal health.16 This scoring system in combination with creatinine clearance (CrCl) has been used by the German CLL Study Group to assess patient fitness for eligibility in a phase III study evaluating the efficacy of FCR (rituximab, fludarabine, cyclophosphamide) versus FC (fludarabine, cyclophosphamide).17 See Appendix A for a detailed description of how to calculate the CIRS score.18

Categorizing patients into fitness types

Once a fitness score has been determined based on one of the systems discussed, it is possible to group patients into a fit or frail group. (Table 5)

Decision to treat and determining response in the management of CLL

The 2008 National Cancer Institute (NCI) guidelines support the initiation of treatment based on a combination of clinical staging, the presence of symptoms, and disease activity. These criteria are also supported by the 2008 National Comprehensive Cancer Network (NCCN) Guidelines on Non-Hodgkin’s Lymphomas.5,19 (Table 6)

To date, no studies have demonstrated a clear benefit of early treatment for asymptomatic CLL. However, a number of ongoing studies in otherwise healthy patients with poor prognosis are being performed, examining whether early intervention improves outcomes in this group. These studies by the German CLL Study Group and several U.S. cooperative groups will address whether early intervention with chemoimmunotherapy can improve long-term survival in high-risk patient groups. Whether or not treatment is indicated at the time of assessment, patients should continue to be evaluated for possible infections and disease-related complications, as outlined in the Managing complications and supportive care in CLL section.

Determining response to treatment

In assessing the response to treatment, a thorough physical examination and blood analysis should be performed. Although useful in clinical trials, imaging studies, including CT scans, are not an essential part of general practice.5,20 Patients in remission should be re-evaluated every 3–6 months to monitor disease status.21,22

Based on the results of the assessment, patients may be categorized as having a complete response (CR), a partial response (PR), progressive disease (PD), or stable disease (SD). (Table 7) Patients with a clinically beneficial response include those achieving CR and PR; treatment failure includes those with SD, non-response, PD, or death from any cause. Patients experiencing treatment failure during or within six months of treatment are identified as having refractory disease. Those demonstrating PD after ≥6 months of treatment, who have previously achieved a CR or PR, are identified as having relapsed disease.5

Common endpoints used in clinical trials

Overall survival

Overall survival (OS) is defined as the interval between diagnosis and death from any cause. Until recently, no phase III studies in CLL had shown a significant improvement in OS for one therapy over another.17,23 Lack of improvements in OS may be due to ineffective therapy, but may also be due to the natural history of the disease, as well as to the success of salvage therapies and the length of follow-up needed to show a significant effect. For example, in the case of follicular lymphoma, early study results of rituximab added to chemotherapy initially showed an improvement in progression-free survival (PFS) with no OS benefit. However, with longer follow-up, an improvement in OS was observed after 48 months.24–28

Progression-free survival

PFS is defined as the interval between the first treatment day to the first sign of disease progression, or death from any cause.5 The International Workshop in CLL (IWCLL) and a publication by Chakravarty and colleagues support the use of PFS as a primary endpoint of phase III clinical trials. Chakravarty, et al. suggest that in the absence of an effect on OS, clinical practice should be guided by trials demonstrating clinically significant improvements in PFS.29 For example, based on studies showing an improvement in PFS with no established survival benefit, fludarabine-based therapy became a preferred first-line treatment option over chlorambucil in many Canadian provinces.3,30

Minimal residual disease

Minimal residual disease (MRD) assessment in patients who have achieved a CR by standard criteria is typically performed using four-colour flow cytometry or allele-specific oligonucleotide polymerase chain reaction (PCR). With these techniques, one can identify residual CLL cells to a sensitivity of <1 CLL cell per 104 leukocytes.5 Recent studies have suggested that complete elimination of the CLL clone with achievement of an MRD-negative CR may be associated with an improved outcome and a longer PFS.5,31 However, whether treatments designed to eradicate MRD will improve clinical outcomes requires further clinical study.

First-line treatment options for CLL

Goals of therapy

The ultimate treatment goal in CLL is to achieve a long OS, while minimizing toxicities and improving quality of life (QoL). In the absence of an OS benefit, achieving a long PFS is a reasonable goal of therapy. However, for some frail patients, less aggressive treatments may be required; for others, supportive/ palliative treatment may be the best course.32 Considering the patient’s preference is always important in the determination of any treatment decision.

Chlorambucil

Chlorambucil is an oral antineoplastic nitrogen mustard that acts as an alkylating agent. For over 40 years since its discovery, chlorambucil has been used as a mainstay treatment for CLL. Many different dosing schedules have been used in CLL, including intermittent dosing from 40 mg/m2 every 28 days to 10 mg/m2 x 7 every 28 days, or continuous daily dosing of 0.1 mg/kg/day. In clinical trials, chlorambucil leads to overall response (OR) rates of 40%–70% and complete response (CR) rates ranging from 2%–7%. (Table 8) Median time-toprogression is approximately 1–1.5 years with this treatment. A convenient oral dosing and well-established side effect profile make chlorambucil a valuable option for frail patients or for those who decline or are unsuitable for more intensive intravenous therapy.33–36

Fludarabine

Fluarabine is a purine analogue that is typically administered intravenously, but is also available in an equally efficacious oral formulation in Canada and Europe. In patients refractory to traditional alkylating-agent therapy, fludarabine was shown to achieve OR rates of approximately 60%.37,38 Following the success of second-line treatment, fludarabine monotherapy was subsequently studied in treatment-naïve patients. The superior activity of fludarabine has been confirmed in randomized comparisons to alkylating agents. Studies showed prolonged PFS (median approximately 2 years), as compared to chlorambucil. Fludarabine also demonstrated superior clinical response, with response rates of 60%–80% and CR rates of 15%–40%.34,36,39,40 (Table 8) A Cochrane meta analysis of four randomized trials (Steurer, et al. 2006) supported the findings of superior PFS with fludarabine (Hazard ratio [HR] 0.70; 95% CI: 0.61–0.82).30 Recently, a long-term survival analysis of patients from a previous study by Rai, et al. (2000) has shown evidence of an OS advantage of F (63 months; 55–75 months) over chlorambucil (59 months; 51–70 months) (p = 0.04).23 Despite improved efficacy, rates of neutropenia are higher with fludarabine (41%) than with chlorambucil (28%) (p <0.0001), reflecting greater hematologic toxicity.34 Fludarabine is now used in preference to chlorambucil for first-line treatment in many provinces. However, chlorambucil remains a valuable option in frail patients, given the lower rates of neutropenia.

Fludarabine-cyclophosphamide (FC)

Studies of the combination of fludarabine and cyclophosphamide (FC) for second-line treatment in CLL have demonstrated good clinical response, with acceptable toxicity.41 These promising results in refractory settings led to the examination of FC in treatment-naïve patients.

Three randomized trials comparing fludarabine (F) or FC for frontline therapy in CLL have been published. A study by Eichhorst, et al. from the German CLL Study Group randomized 375 previously untreated patients to FC or F. The OR rate (95% vs. 83%), CR rate (24% vs. 7%), median PFS (48 vs. 20 months), and treatment-free survival (37 vs. 25 months) were higher with FC versus F, with no difference in OS.42 A study by Flinn, et al. from the U.S. ECOG randomized 278 patients to F or FC. FC achieved higher OR (74% vs. 60%), CR (23% vs. 5%), and median PFS (32 vs. 19 months), with no improvement in OS.43 Finally, Catovsky, et al. in the UK CLL-4 study randomized patients to chlorambucil, fludarabine, or FC. Patients treated with FC had better CR and OR rates than with fludarabine (CR: 38% vs. 15%, respectively; OR: 94% vs. 80%, respectively; p <0.0001 for both comparisons), which were in turn better than with chlorambucil (CR: 7%; OR: 72%; p <0.006 and 0.04, respectively). In addition, a statistically significant advantage in PFS was seen for the FC arm compared with the other arms (36% for FC versus 10% for both the fludarabine and chlorambucil arms; p <0.00005). FC was superior in all age groups, including patients over 70 years old. However, patients with del(17p) and del(11q) had inferior CR and OR rates, irrespective of treatment group.34 The above trials demonstrated that FC administered intravenously is more efficacious than fludarabine or chlorambucil as monotherapy, achieving higher CR rates (25%–40%) and longer median PFS (32–48 months). (Table 8)

Despite the improved efficacy of FC versus F, the UK CLL-4 and U.S. ECOG studies found higher neutropenia rates in the FC group; however, less hemolytic anemia was observed with FC (5%) than with fludarabine (11%) or chlorambucil (12%).34 A second study by Eichhorst, et al. (2007)44 showed no difference in quality of life (QoL) between treatment groups, while the FC group had a significantly longer PFS.

FC is now considered by many CLL study groups worldwide to be a standard first-line treatment. The FC combination is not approved in most provinces in Canada; however, its use as first-line treatment has been adopted by physicians as a common treatment option. The improvement in response seen with FC as compared to fludarabine or chlorambucil monotherapy makes FC a reasonable option in fit patients who are able to tolerate more aggressive treatment. In frail patients, less aggressive treatment options may be warranted to ensure side effects can be tolerated. In cases where a patient declines intravenous treatment, oral fludarabine or chlorambucil are alternatives.

Addition of rituximab to chemotherapy backbones

Rituximab is a chimeric monoclonal antibody that selectively targets CD20-positive B cells. Rituximab is currently indicated for use in non-Hodgkin’s lymphoma (NHL), where it is recommended as first-line treatment for CD20-positive, diffuse large B-cell NHL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and for untreated Stage III/IV follicular, CD20-positive, B-cell NHL in combination with CVP (cyclophosphamide, vincristine, prednisolone). Rituximab is also indicated for the treatment of patients with relapsed or refractory low-grade or follicular, CD20-positive, B-cell NHL and as maintenance therapy for patients with follicular NHL who have responded to induction therapy with either CHOP or R-CHOP.19,45

As a single agent in CLL, rituximab has only moderate activity, perhaps because of the dim CD20 expression on B-CLL cells. However, with higher doses than are typically used in lymphoma, the activity of single-agent rituximab in CLL is greatly enhanced.46 In a study by Byrd, et al. examining the efficacy of rituximab (375 mg/m2) monotherapy in CLL, the OR, CR, and PR rates were 45% (95% CI: 28–64), 3%, and 42%, respectively.46 Rituximab has been studied in a number of clinical trials evaluating its additional impact in combination therapy. The NCCN guidelines on CLL currently recommend the use of rituximab in combination with F, FC, or PC (pentostatin, cyclophosphamide) for fit patients. In frail patients, rituximab monotherapy may be a reasonable first-line option; however, results are moderate as mentioned above.19,45

Fludarabine-rituximab (FR)

Initial studies of rituximab combinations explored the addition of rituximab to fludarabine. Byrd, et al. (2003)47 conducted the randomized CALGB 9712 phase II study to determine the efficacy, safety, and optimal administration schedule for rituximab with fludarabine in previously untreated CLL patients. Patients were randomized to receive either six monthly courses of fludarabine concurrently with rituximab, followed two months later by four weekly doses of rituximab as consolidation therapy; or sequential fludarabine monotherapy, followed two months later by rituximab consolidation therapy. A total of 104 patients were randomized to the concurrent (n = 51) and sequential (n = 53) regimens. An OR rate of 90% and CR rate of 47% was observed in the concurrent group, as compared to an OR rate of 77% and CR rate of 28% in the sequential group.

In a subsequent retrospective analysis, Byrd, et al. (2005)48 compared the treatment outcome for patients given FR in the CALGB 9712 trial to patients given fludarabine monotherapy in the CALGB 9011 trial. Results showed statistically significant higher PFS and OS in patients who received fludarabine and rituximab, as compared with patients who received fludarabine alone.

Despite the lack of phase III studies, the Byrd, et al. phase II results suggest that adding rituximab to fludarabine improves PFS and OS, compared to F monotherapy.3 Based on the results of phase II trials, some Canadian centres have adopted the use of FR as the standard first-line treatment in both fit and frail patients. Further studies evaluating the FR regimen are currently underway, which may help to clarify its role in CLL patient subsets.

Fludarabine-cyclophosphamide-rituximab (FCR)

The successful addition of rituximab to fludarabine led to the development of other rituximab chemotherapy regimens. Phase II studies examining the addition of rituximab to FC (FCR) demonstrated a high CR and OR rate of ≈70% and ≈95%, respectively.37,49

The impressive results of phase II studies drove the design and execution of a phase III study by the German CLL Study Group (CLL-8 study) comparing the primary endpoint of PFS after treatment with FCR or FC.17 Study participants included 817 patients selected for minimal co-morbidity (CIRS <6). Patients were randomly assigned to receive 6 courses of either FC (F: 25 mg/m2 iv on days 1–3 plus C: 250 mg/m2 iv on days 1–3) or FC with the addition of rituximab (375 mg/m2 iv on day 0 of the first cycle and 500 mg/m2 on day 1 of all subsequent cycles). Prophylactic use of antibiotics or growth factors were used at the discretion of the treating physician, but were not specifically recommended in the protocol.

The median observation time was 37.7 months, at which point 761 patients were evaluable for response. The median patient age was 61 years, with a range of 30 to 81 years. Median PFS was reported as 32.8 months in the FC arm and 51.8 months in the FCR arm (HR 0.56; p <0.0001). The PFS shown in the FC arm was similar to that shown in previous studies using FC, which have reported a range of 32 to 48 months.42,43 Statistically significant differences were observed in OS between the two treatment arms. The OS rate at 37.7 months was 87.2% in the FCR arm versus 82.5% in the FC arm (p = 0.012). In both arms, the median OS has not been reached. Only patients in Binet stages A and B showed a superior OS after FCR treatment (Binet A: HR 0.19, p = 0.09; Binet B: HR 0.45, p <0.001; Binet C: HR 1.4, p = 0.168). Response rates were higher in the FCR group versus the FC group and are the highest rates of any chemotherapy regimen used to date. (Tables 8 and 9) Grade 3/4 hematological toxicity, neutropenia, and leukocytopenia rates were higher in the FCR versus FC arm (55.7% versus 39.6%, 33.7% versus 21.0%, and 24.0% versus 12.1%, respectively; p <0.0001).

Based on a high level of evidence from this phase III randomized trial, FCR is currently the best option for the first-line treatment of fit patients with CLL.17 Given that the dose of rituximab used in the FCR regimen for the phase III study was cycle 1–375 mg/m2 and cycles 2 to 6–500 mg/m2, in combination with 25 mg/m2 of fludarabine and 250 mg/m2 of cyclophosphamide on days 1–3 of each cycle, it is reasonable to recommend this dose of FCR in clinical practice. However, there is a lack of evidence to show that 500 mg/m2 per cycle is superior to 375 mg/m2 per cycle; a study comparing the efficacy of these two doses is needed to determine the optimal dose of FCR in CLL. Despite the improved efficacy, the potential toxicity of FCR suggests that frail patients may benefit from less aggressive treatments. In balancing toxicity with efficacy, FR remains a reasonable first-line option in CLL until results from randomized studies are available. For those patients who decline intravenous treatments, oral fludarabine and chlorambucil are reasonable options.

Other rituximab combinations

The addition of rituximab to other chemotherapy backbones in first-line treatment has been explored in a number of phase II studies. These studies have shown promising results using cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR); reduced-dose FCR (FCR-Lite); pentostatin, cyclophosphamide, and rituximab (PCR); rituximab with alemtuzumab (R-A); and rituximab with fludarabine, cyclophosphamide, and mitoxantrone (R-FCM).50–54 A study investigating R-chlorambucil in the first-line treatment of CLL is also being conducted, as well as a study comparing R-chlorambucil to R-bendamustine. The results of these and ongoing studies suggest that the benefits of adding rituximab may extend beyond FCR to other R-chemo regimens. As phase III data become available, these regimens may become valuable options for the first-line treatment of CLL.

Alemtuzumab for patients with del(17p)

In cases where FISH analysis has been performed and reveals the presence of del(17p), standard treatments which rely on the p53 pathway for activity may be less effective.5 Treatments with chlorambucil, fludarabine, and rituximab have shown poor response rates in patients with this cytogenetic abnormality.55 Alemtuzumab, a humanized anti-CD52 monoclonal antibody that acts via a p53 independent mechanism, may have beneficial results in patients with del(17p).56

Evidence of the beneficial role of alemtuzumab was first shown in the refractory setting. A study by Moreton, et al. found an overall response rate of 54% in fludarabine-refractory patients.57 A subsequent trial performed by Lozanski, et al. found a partial response in 40% of patients with del(17p) or p53 mutations.55 In the first-line setting, results of a randomized controlled trial (RCT) comparing alemtuzumab to chlorambucil were reported by Hillmen, et al. Of the 282 patients who underwent FISH cytogenetic analysis, 21 (7%) patients had del(17p). Patients with del(17p) who were treated with alemtuzumab had a PFS of 10.7 months compared to 2.2 months for patients who received chlorambucil. Although there was a trend of increased PFS in the del(17p) group treated with alemtuzumab, it did not reach statistical significance. Overall response rates for these two groups were 64% and 20%, respectively.58 Given the limited effectiveness of standard therapy in patients with del(17p), alemtuzumab may be considered a valuable alternative in this poor-risk group.

Current options for the first-line treatment of CLL

To date, only the phase III studies by Hallek, et al.17 comparing FCR with FC and by Rai, et al.23 comparing F to chlorambucil have shown evidence of improved OS with one regimen over another. The recommended regimens, as presented in Table 10, are therefore based on the results of studies also showing improvements in remission, with the understanding that the optimal sequence of treatments has not been adequately evaluated in clinical trials.

Individualizing patient treatment

In some cases, fit patients may require less aggressive therapy to minimize toxicities. In addition, certain frail patients with borderline performance status and normal organ function may be able to tolerate more aggressive therapies than F or chlorambucil. In these instances, FR may be a reasonable treatment option. For patients with del(17p), alemtuzumab may be preferable to standard options due to the poor response to standard therapies. In patients who decline intravenous therapy, oral chlorambucil or fludarabine are acceptable options, although these are associated with lower response durations.

Treatment for relapsed or refractory CLL

Second-line treatment options for relapsed and refractory patients with CLL

As defined earlier, patients experiencing treatment failure within six months of treatment are identified as having refractory disease. Those demonstrating PD after ≥6 months of treatment, who have previously achieved a CR or PR, are identified as having relapsed disease. Initiation of secondline treatment should be based on NCI criteria, as discussed in the Decision to treat and determining response in the management of CLL section.5

When initial remission is long, re-treatment with the initial regimen may be a reasonable option. When initial remission is short, however, a better response may be achieved by giving a different regimen as second-line treatment. A long remission may be arbitrarily defined as one that is over 1 year, and a short remission as one that is ≤1 year. These second-line treatment options are discussed in the following section.

Second-line options for frail patients

Fludarabine and chlorambucil
Where patients have not previously been given fludarabine or chlorambucil, these regimens may be reasonable options for second-line treatment. As discussed earlier, in patients refractory to traditional alkylating-agent therapy, fludarabine has achieved response rates of approximately 60% and may be a good second-line option.38 Data on the use of chlorambucil or other alkylators as second-line treatment after fludarabine is limited, but may also be reasonable.

Fludarabine-rituximab (FR)
Where not given previously, or after a long first remission, FR may be considered as a second-line option in otherwise healthy patients with borderline performance status or in fit patients requiring less aggressive treatment, as discussed in the First-line treatment options for CLL section.

Second-line options for fit patients

Fludarabine-cyclophosphamide-rituximab (FCR)
In a phase II study by Wierda, et al.59 FCR was evaluated in 177 previously treated patients. Treatment consisted of fludarabine (25 mg/m2 on days 2–4 of course 1 and days 1–3 of courses 2–6); cyclophosphamide (250 mg/m2 on days 2–4 of course 1 and days 1–3 of courses 2–6); and rituximab (375 mg/m2 on day 1 of course 1 and 500 mg/m2 on day 1 of courses 2–6). Courses were repeated every 4 weeks. The overall CR rate in this study was the highest reported in previously treated patients with CLL; however, low response rates were seen in fludarabine-refractory patients. (Table 11)

In a recent phase III study conducted by the German CLL Study Group (REACH study), FCR was compared to FC in previously treated patients.60 A median of one prior treatment had been administered, consisting of single-agent alkylator therapy (66%), purine-analogs (16%), or combination treatments (18%). Combination treatments administered were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), CVP (cyclophosphamide, vincristine, and prednisolone) or F-containing therapy. Patients with prior FC combination treatment or prior rituximab were not eligible. Treatment consisted of fludarabine (25 mg/m2 iv/day over 3 days for 6 cycles), cyclophosphamide (250 mg/m2 iv/day over 3 days for 6 cycles), and rituximab (375 mg/m2 iv for cycle 1 and 500 mg/m2 iv for cycles 2–6) for a total of 6 treatment cycles at intervals of 28 days. Patients with a CIRS >6, decreased kidney function, or who had previously received FC were excluded. PFS, the primary endpoint, was prolonged by a median of 10 months (a 50% improvement) in the FCR arm (30.6 months) compared with the FC arm (20.6 months) (p = 0.0002; HR 0.65 [95% CI: 0.51–0.82]). Response rates were also superior in the FCR versus the FC group. (Table 12) Median OS was not reached for FCR and was 53 months for FC (p = 0.29; HR 0.83).

The studies by Wierda, et al.59 and Robak, et al.60 show that FCR may be a reasonable second-line option in fit patients not previously given rituximab or FC. Re-treatment with FCR may also be reasonable in those experiencing a long remission after initial treatment. As previously discussed in the First-line treatment options for CLL section, frail patients should be given less aggressive treatments due to the potential toxicity of the FCR regimen.

Allogeneic stem cell transplantation (allo-SCT)
In the past 20 years, remarkable advances have been made in allogeneic stem cell transplantation (allo-SCT) for CLL. Traditionally, allo-SCT have been myeloablative, involving the depletion of bone marrow cells through administration of high doses of chemotherapy or radiation prior to transplantation. More recently, non-myeloablative techniques have been developed that require less intensive conditioning in an effort to reduce transplant-related mortality (TRM) rates.61

Myeloablative allo-SCT achieved promising results in chemosensitive patients, with OS and PFS rates of approximately 80% after 5 years.62,63 Unfortunately, the beneficial response of myeloablative procedures is tempered by high TRM rates of approximately 38%–50%.61,64 Registry data indicate that while one-third of patients will be cured after myeloablative allo-SCT, approximately two-thirds will not survive as a result of TRM or recurrent disease. Experimental studies using nonmyeloablative allo-SCT have achieved OS and PFS rates of 60%–72% and 52%–67%, respectively, with low non-relapse mortality rates of 15%–22% after 2 years.65,66 However, the risk of relapse may be higher with non-myeloablative versus myeloablative techniques.67

After the failure of first-line therapy, allo-SCT may be considered for patients <65 years with no response to therapy or early relapse (within 12 months), relapse within one year of fludarabine treatment or within two years of fludarabine-based combination therapy, or del(17p) abnormalities requiring treatment.13

Subsequent treatment options for relapsed and refractory patients with CLL

Alemtuzumab (Campath-1H)

Alemtuzumab is a humanized monoclonal antibody against CD52, which is expressed on all CLL cells. An initial phase II study in relapsed patients achieved an OR rate of 54% and CR rate of 36%. In addition, approximately 20% of relapsed patients were categorized as minimum residual disease (MRD) negative. A subsequent study showed a favourable response of approximately 40% in patients with del(17p) abnormalities.55,57 A phase III study in previously untreated patients (CAM307) has showed a reduction in the risk of progression of 42% with alemtuzumab versus chlorambucil (HR 0.58; p = 0.0001).OR rates (83% versus 55%) and CR rates (24% versus 2%) were higher in the alemtuzumab versus chlorambucil group.58

As a result of promising monotherapy results, alemtuzumab has been examined as part of a number of combination regimens. A UK phase II study (UKCLL02) examined alemtuzumab monotherapy in fludarabine-refractory patients, where patients not responding to alemtuzumab could be given concurrent fludarabine. Interim results presented at ASH 2005 in 36 evaluable patients showed OR rates of 44% in all patients combined.68 Another phase II study added alemtuzumab to FCR (R-FCA) to determine if efficacy could be improved in previously treated high-risk patients. Preliminary results presented at ASH 2008 showed OR and CR rates of 94% and 69%, respectively.50 Currently, an ongoing NCI phase III study is comparing FCA with FCR as first-line treatment for CLL, with the primary outcome being PFS at 36 months. A second phase III study is examining the efficacy of FA versus F in previously treated patients, with PFS also the primary outcome. Alemtuzumab may be a reasonable third-line option in fit patients who are fludarabine-resistant or as a method to debulk the disease in preparation for allo-SCT.

Fludarabine-cyclophosphamide-mitoxantrone (FCM)

In a phase II study by Hendry, et al., fludarabine, cyclophosphamide and mitoxantrone (FCM) was evaluated in 24 patients with relapsed or refractory CLL. Patients were treated with mitoxantrone (5 mg/m2 iv on day 1), fludarabine (25 mg/m2 iv for 3 days or 24 mg/m2 orally for 5 days), and cyclophosphamide (250 mg/m2 iv for 3 days or 150 mg/m2 orally for 5 days). Eighteen patients had previously received fludarabine, and most were heavily pre-treated, with 40% having >2 prior treatments. Results showed an OR rate of 78.5%, CR rate of 32%, and PR rate of 46.5%. Median duration of response was 19 months and median survival was 42 months.69 A second phase II study by Bosch, et al. examined FCM in 37 patients with recurrent or resistant CLL. Treatment consisted of up to six cycles of fludarabine (25 mg/m2 iv for 3 days), cyclophosphamide (200 mg/m2 iv for 3 days), and mitoxantrone (6 mg/m2 iv for 1 day). The CR rate was 50%, with 10 cases of negative MRD. The PR rate was 28% and the median duration of response was 19 months.70 FCM was later examined as front-line therapy in a phase II study by Bosch, et al. Sixty-nine patients <65 years received six cycles of fludarabine (25 mg/m2 iv for 3 days), cyclophosphamide (200 mg/m2 iv for 3 days), and mitoxantrone (6 mg/m2 iv for 1 day). The OR, MRD-negative CR, MRD-positive CR, nPR, and PR rates were 90%, 26%, 38%, 14%, and 12%, respectively. Patients with del(17p) failed to attain CR.71

Rituximab–high-dose methylprednisolone (R-HDMP)

Rituximab combined with high-dose methylprednisolone (R-HDMP) was evaluated in a phase II study by Castro, et al. in fludarabine-refractory CLL patients. Fourteen patients were treated with three cycles of rituximab (375 mg/m2 weekly for 4 weeks) in combination with HDMP (1 gm/m2 daily for 5 days). The OR and CR rates were 93% and 36%, respectively; median time-to-progression was 15 months.72 Recently, R-HDMP was examined in a second study by Castro, et al. as first-line treatment of CLL. Twenty-eight patients received HDMP (1 g/m2 each day for 3 days) together with rituximab and prophylactic antimicrobial therapy. The OR and CR rates were 96% and 32%, respectively.73

Other rituximab combinations

A number of other rituximab-containing regimens have been studied as second-line treatment for CLL. Results of these studies are presented in Appendix B. Future data from phase III studies should help determine whether these regimens are potential second-line options for fit patients. Studies examining less aggressive treatments, such as R-bendamustine and R-chlorambucil, are also underway and may provide additional options in frail patients, pending phase III study results.

Evolving therapeutic approaches for CLL

A number of new treatments for CLL are currently being evaluated in clinical trials. Therapies such as lenalidomide and flavopiridol, as well as new monoclonal antibodies such as ofatumumab, GA101, and lumiliximab have shown promising preliminary results. Completed and ongoing clinical trials evaluating these new therapies are presented in Appendix C. As discussed earlier, numerous rituximab combination regimens have been examined in clinical trials (see the First-line treatment options in CLL section and Appendix B). A number of ongoing studies are also exploring newer rituximab combinations for first- and second-line treatment and for maintenance treatment in CLL. These ongoing rituximab combination studies are also presented in Appendix C. Participating in ongoing and future clinical trials can help identify optimal treatment regimens for CLL, bringing us closer to reaching our treatment goals.

Recommendations for relapsed or refractory CLL

Recommendations for second-line treatment of CLL should consider individual factors such as co-morbidities and the length of the disease-free interval. When initial remission is greater than one year, re-treatment with the initial regimen is reasonable; in shorter remissions, treatment with a different second-line regimen is indicated. In frail patients, fludarabine and chlorambucil are reasonable second-line options where they have not been given previously, or in those experiencing a long remission from either regimen.36,38 In fit patients, FCR is an effective regimen in patients naïve to rituximab or FC; reuse of FCR may also be reasonable in patients experiencing a long remission after initial treatment.60 After the failure of first-line therapy, allo-SCT may be considered for patients <65 years with no response to therapy, with PD within one year of fludarabine treatment or within two years of fludarabinebased combination therapy, or with del(17p) abnormalities requiring treatment.13

Managing complications and supportive care in CLL

Prevention and management of infections

Patients with CLL often have compromised immune systems due to the disease itself and/or its associated treatments. Infections are therefore common, and prophylaxis is appropriate, depending on the type of treatment given. (Table 13) The use of live vaccines in patients with CLL is not inadvisable.3 However, the use of inactivated vaccines such as annual influenza and pneumococcal polysaccharide (PPV) every 5 years for patients in remission for more than three months is recommended.3,74,75

When infections occur, they should be diagnosed, treated, and reported. The etiology of any infection should be identified as bacterial, viral, or fungal, and the severity should be quantified as minor (requiring either oral antimicrobial therapy or symptomatic care alone), major (requiring hospitalization and systemic antimicrobial therapy), or fatal (death as a result of the infection).5 Where patients experience recurrent infections that require intravenous antibiotics or hospitalization, antimicrobials should be given as needed. In patients with recurrent infections and where serum IgG is <5 g/L, monthly intravenous immunoglobulins should be given at 0.3–0.5 g/kg; dose and interval should be adjusted to maintain a nadir level of more than 5–7 g/L.19

Autoimmune cytopenias

Patients with CLL are at increased risk of developing autoimmune cytopenias, such as autoimmune hemolytic anemia (AIHA), idiopathic thrombocytopenia purpura (ITP), and pure red cell aplasia (PRCA). AIHA will develop in approximately 11% of advanced-stage CLL patients.79 AIHA is diagnosed by the presence of at least one marker of hemolysis (increased indirect bilirubin not due to liver disease, increased lactate dehydrogenase without alternative etiology, increased absolute reticulocyte count, or increased bone marrow erythropoiesis in the absence of bleeding) with direct or indirect evidence of an autoimmune mechanism (positive direct antiglobulin for either IgG or C3d, cold agglutinins, or at least two markers of hemolysis in the absence of evidence of bleeding or hypersplenism).80 ITP is less common, occurring in 2%–3% of CLL patients at diagnosis or during early stage disease.79 ITP can be identified where platelet counts are ≤100 × 109/L with no evidence of hypersplenism, no evidence of increased platelet consumption due to other causes, and normal or increased megakaryocytes on bone marrow examination.80 PRCA is present in 6% of CLL patients who are tested.79 PRCA can be diagnosed when hemoglobin concentration is ≤120 g/L with reticulocytopenia and isolated absence of erythrocyte precursors in the bone marrow. Parvovirus infection must be ruled out, which can be done by using blood polymerase chain reaction (PCR) assay.80

ITP and AIHA, as a single abnormality caused by CLL, should be treated initially using glucocorticoids. Second-line options for AIHA include splenectomy, intravenous immunoglobulins, and/or immunosuppressive therapy with cyclosporine A, azathioprine, or low-dose cyclophosphamide. Good responses have also been obtained using rituximab or alemtuzumab.5 Most patients with PRCA will respond to treatment with corticosteroids, but prolonged high doses are usually needed; steroid-sparing agents such as cyclophosphamide may therefore be required. Rituximab may be an additional option for the treatment of PRCA, but success rates are lower than those seen for AIHA or ITP.80

Richter’s syndrome

The majority of Richter syndrome (RS) cases involve the transformation of CLL to an aggressive lymphoma, diffuse large B-cell lymphoma (DLBCL). The morphology of DLBCL consists of sheets of large neoplastic B lymphocytes clearly distinguishable from small lymphocytes, with sparse cytoplasm and clumped chromatin typical of CLL. Diagnosis of RS requires the pathologic identification of CLL transformation to aggressive lymphoma. Ideally, this should be determined by histology using a biopsy of the index lesion.81

Based on existing data, RS may be treated with cytoreductive chemotherapy appropriate for DLBCL, such as R-CHOP, with the goal of achieving a response. The role of consolidation therapies previously tested for CLL or DLBCL in patients responding to initial therapy, as well as the impact of new first-line therapies, may aid in the development of an ideal treatment approach in these patients.81

Tumour lysis syndrome

Tumour lysis syndrome (TLS) occurs when the release of large amounts of intracellular components of lysed malignant cells leads to a number of metabolic imbalances. Resulting hyperuricemia, hyperkalemia, hypocalcemia, and hyperphosphatemia may then lead to renal failure and cardiac arrhythmias. TLS usually occurs within 2–3 days after the initiation of therapy, with rare cases occurring after second-line treatment. Major risk factors include high tumour burden, high rate of proliferation, and disease that is highly responsive to therapy.82

Before the initiation of treatment, hospitalization should be considered for patients with white blood cell counts (WBC) >50,000/mm3 to ensure adequate hydration and monitoring. In patients with previous episodes of TLS, consultation with a nephrologist should be considered. Where overt uremic symptoms are present, dialysis may be necessary in order to prevent acute renal failure. In outpatients, frequent monitoring of serum electrolytes and uric acid is recommended as a preventative measure.82 Prophylactic allopurinol (300 mg/day orally) is necessary when a rapid lysis of large numbers of lymphocytes is anticipated (initial WBC >200 x 109/L). Allopurinol should also be given to patients with significant renal dysfunction or chronic hyperuricemia.3 In the advent of TLS, it may be necessary to interrupt treatment until symptoms are resolved. In hospitalized patients, cardiac activity should be monitored continuously and frequent monitoring of electrolyte levels is recommended.82

Blood product support

Transfusion-related graft-versus-host disease has been described in patients actively receiving fludarabine or alemtuzumab. The Canadian Blood Service recommends that patients on fludarabine or alemtuzumab should receive irradiated and CMV negative blood products.76,77

Conclusions

Over the last decade, the management of CLL has evolved considerably, with the introduction of treatments that extend progression-free survival (PFS) and dramatically improve response rates. The recent phase III study comparing FCR to FC is one of the first to show an improvement in overall survival (OS) of one regimen (FCR) over another (FC).17 These findings, as well as results showing the highest response rates to date in a phase III study, make FCR the best first-line option for fit patients. Another reasonable option for the initial treatment of CLL is fludarabine-rituximab (FR), which may result in a more favourable safety profile. A randomized study comparing FR to FCR and FR with lenalidomide is underway and will provide further insight into the balance between efficacy and toxicity of the FR regimen. In frail patients, less aggressive treatments such as fludarabine and chlorambucil remain valuable options for the initial treatment of CLL.

When initial remission is long (over one year), re-treatment with the initial regimen is a reasonable option; in shorter remissions, a different second-line regimen may yield a superior response. In frail patients, fludarabine and chlorambucil are reasonable second-line options where they have not been given previously, or in those experiencing a long remission from either regimen.36,38 In fit patients, results of a phase III study demonstrating a 50% improvement in PFS over FC show that FCR is an effective treatment choice in patients naïve to rituximab or FC; FCR may also be reasonable in those experiencing a long initial remission.60 After the failure of first-line therapy, allo-SCT may be considered for patients under 65 years with no response to therapy or early relapse (within 12 months), with progressive disease within a year of fludarabine treatment or within two years of fludarabine-based combination therapy, or with del(17p) abnormalities requiring treatment.13

Subsequent treatment with alemtuzumab, FCM, R-HDMP, and other rituximab combinations may be reasonable options based on results of preliminary phase II studies. Future studies on these and evolving new treatments such as lenalidomide, flavopiridol, ofatumumab, GA101, and lumiliximab may provide additional options for the treatment of patients with CLL.

Variability in patient characteristics such as performance status, disease progression, and individual preference should be considered in the development of treatment goals. In addition, the development of prognostic factors aiding in the stratification of patients into high- and low-risk groups may aid in decisions concerning optimal treatment strategies.5 Positive developments in the treatment of CLL and recent findings from a number of phase III studies move us closer to the creation of a Canadian guideline for its management.

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APPENDIX A: Calculating the fourteen-system modified Cumulative Index Rating Scale (CIRS)*

APPENDIX B: Studies evaluating rituximab-based regimens for second-line treatment in CLL

APPENDIX C. Completed and ongoing studies evaluating new treatment regimens in CLL