Current and Investigational Therapies for Patients with CLL

There is remarkable clinical diversity in patients with chronic lymphocytic leukemia (CLL). Following diagnosis, some patients have smoldering, asymptomatic disease that may not progress for many years; others are diagnosed with advanced-stage disease, or early-stage disease that rapidly progresses, causing symptoms and/or bone marrow failure and requiring treatment. It is conceivable that elderly patients diagnosed with smoldering disease may not have an altered survival due to CLL. At the other end of the spectrum, young patients diagnosed with advanced or progressive CLL certainly will have shorter expected survival, owing to progressive CLL and lack of curative treatment. Prognostic factors for time to treatment and survival include mutation status of the immunoglobulin heavy chain variable gene (IgV_H); expression of ZAP-70; expression of CD38; plasma level of β2-microglobulin (β2M) and soluble CD23; and presence of chromosome abnormalities such as 17p deletion and 11q deletion by fluorescence in situ hybridization (FISH) analysis. Factors may help delineate patients with smoldering versus progressive disease, thereby providing tools to identify patients for whom early treatment clinical trials may be indicated. They also may prove useful in directing selection of treatment agents; however, prospective clinical trials to evaluate these issues are needed.

Studies from the Cancer and Leukemia Group B (CALGB) and the French cooperative group demonstrated immediate therapy did not prolong survival for patients with early-stage disease treated with chlorambucil.^1,2 However, these results may have been influenced by inclusion of patients with smoldering CLL and by ineffective treatment. To further address this issue, a large US Intergroup trial will be initiated comparing early versus delayed treatment with fludarabine with rituximab for high-risk patients defined as having an unmutated IgV_H gene (>98% homology to germline). Given available data for prognostic factors and status of therapies for patients with CLL, we continue to follow the 1996 National Cancer Institute-Working Group guidelines (NCI-WG) for initiating therapy in patients with active and progressive disease.³ Patients with advanced-stage (Rai stages III and IV) disease should receive treatment by these criteria. For patients with Rai stage 0-II disease, the following criteria are used to evaluate for active disease: symptoms, including progressive weight loss of greater than 10% body weight in the previous 6 months, extreme fatigue, fevers of greater than 100.5°F for longer than 2 weeks without evidence of infection, night sweats without evidence of infection; evidence for progressive marrow failure, specifically worsening anemia and/or thrombocytopenia; autoimmune phenomena (autoimmune hemolytic anemia [AIHA] and idiopathic thrombocytopenic purpura [ITP]) poorly responsive to corticosteroid therapy; massive splenomegaly (> 6 cm) or lymphadenopathy (> 10 cm); and progressive lymphocytosis with an increase of > 50% in the prior 2-month period or anticipated doubling time of less than 6 months. There is no specific white blood cell count (WBC) or absolute lymphocyte count (ALC) that is an indication to initiate therapy. Leukostasis syndrome is rare in patients with CLL. Early treatment with chemotherapy for patients without NCI-WG indications should be administered only in the context of clinical trial.

In addition to the diverse clinical course, there also is diversity in patient characteristics. The median age at diagnosis is over 70 years, an age at which clinically significant comorbidities exist. As a result, individuals over 70 tend to have health limitations as well as geographic and access limitations. Patients with CLL enrolled on clinical trials at academic institutions tend to be younger, with a median age of 58 to 62 years, thereby limiting our ability to generalize results to practice.

Historically, the approach to treatment has been palliation, based on the observations that no single treatment has been shown to prolong survival and that no standard-dose chemotherapy or regimen results in cure. This approach focuses on improving symptoms and maintains that treatment should be nontoxic and reduce bulk of disease, but does not need to result in complete remission (CR).

Clinical research has been aimed at developing new treatments that prolong survival and potentially cure patients with CLL. A response-driven approach is used, based on the observation that patients who achieve CR live longer than those who achieve partial remission (PR) or those who fail treatment. In general, clinical trials aim to increase the CR rate and demonstrate prolonged remission duration with the expectation that this will result in improved survival.

Response to treatment has been assessed in clinical trials by the NCI-WG criteria published 10 years ago.³ CR requires no evidence of disease on physical examination or microscopic examination of blood (ALC < 4000/μL) and bone marrow (< 30% lymphocytes, no nodules), and recovery of hemoglobin, neutrophil, and platelet counts. Recently, more sensitive tests to evaluate residual disease have become available, specifically multicolor flow cytometry and allele-specific polymerase chain reaction (PCR) for the immunoglobulin heavy chain variable gene (IgV_H). In some patients achieving CR by NCI-WG criteria, one or both of these methods can demonstrate residual disease, referred to as minimal residual disease (MRD), usually in the bone marrow. Patients free of MRD following treatment have a longer remission duration and longer survival.^4,5 Therefore, in addition to improving CR rates, investigators are focusing on eliminating MRD.

The initial treatment of patients with CLL represents the best opportunity to achieve CR. Generally, CLL B cells develop resistance with treatment, making response to subsequent treatment less likely and shorter remission durations.

Historic treatment consisted of an alkylating agent, most commonly chlorambucil, or alkylating agent–based combination (Table 1 ). This treatment usually results in PR and is intermittent and protracted. With alkylating agent–based therapy, the CR rate is less than 10%, the overall response (OR) rate is approximately 50–60%, and estimated median survival is 50–70 months.

Fludarabine is the most extensively studied purine analogue for the treatment of patients with CLL. Front-line, single-arm, phase II clinical trials demonstrated that single-agent fludarabine induced CR in 20–30% of patients and the OR rate was approximately 80%.^6,7 Randomized clinical trials have evaluated fludarabine versus single-agent chlorambucil or alkylator-based combinations for chemotherapy-naïve patients (Table 1 ).^8,–10 The US Intergroup trial randomized 509 patients to treatment with fludarabine, chlorambucil, or the combination.¹⁰ The combination arm was closed early due to unacceptable toxicity. The CR rate for patients in the fludarabine arm was 20% versus 4% in the chlorambucil arm (P < 0.001). In addition, the OR rates were 63% and 37% for the fludarabine and chlorambucil arms, respectively. The median remission duration for patients who received fludarabine was 25 months, nearly double that of patients on the chlorambucil arm. Despite a significantly higher CR rate and longer remission duration with fludarabine, overall survival (OS) was not different.

Two randomized studies, a European⁹ and a French Cooperative Group study,⁸ compared alkylating agent-based combinations with single-agent fludarabine for previously untreated patients (Table 1 ). Both demonstrated superior CR and OR rates and superior remission duration, but no OS advantage with fludarabine treatment. In the German CLL Study Group CLL5 trial, patients older than 65 years were randomized to receive chlorambucil for a maximum of 12 months versus 6 cycles of fludarabine 25 mg/m² days 1–5.¹¹ There were approximately 40 patients assessable for response in each arm, and there was a significantly higher CR rate with fludarabine (11%) versus no complete responders in the chlorambucil arm. There was a trend for improved OR rate with fludarabine. Despite a higher incidence of myelosuppression with fludarabine, there was no increase in the incidence of infection. Follow-up continues with this trial to evaluate remission duration, time to progression, and OS. Clearly, several randomized trials have demonstrated that fludarabine is a more active drug than alkylating agent–based treatment; the crossover design of these trials and low CR rates potentially impact the ability to appreciate a survival advantage for patients treated on the fludarabine arm.

Fludarabine inhibits excision repair of DNA inter-strand cross-links induced by cyclophosphamide, thereby potentiating activity and giving a rationale for combining these agents.¹² Phase II trials combining fludarabine and cyclophosphamide (FC) suggested increased efficacy compared to historical patients treated with fludarabine alone.^13,–15 In the German CLL Study Group CLL4 trial, previously untreated patients younger than 65 years with indications for treatment were randomized to receive 6 cycles of fludarabine at the standard dose versus fludarabine and cyclophosphamide at 30 mg/m² and 250 mg/m², respectively, daily for 3 days of each 4-week cycle (Table 2 ).¹⁶ There were 375 patients randomized and 328 were assessable for response; FC produced significantly higher CR (24%) and OR (95%) rates compared to fludarabine (7% CR; 83% OR). The median progression-free survival (PFS) for patients treated with FC was 48 versus 20 months for F (P = 0.001). The median treatment-free survival for patients treated with FC versus F was 37 versus 25 months (P = 0.001). The median OS was not reached in both arms. There was an increase in the incidence of myelosuppression with the FC combination; however, there was no increase in the incidence of infection.

Early results of the Intergroup E2997 and UK Leukemia Research Fund (LRF) CLL4 trials comparing FC to fludarabine were reported (Table 2 ).^17,18 In E2997, previously untreated patients were randomized to receive fludarabine at the standard dose versus fludarabine 20 mg/m² days 1–5 with cyclophosphamide 600 mg/m² day 1 (FC). The FC combination produced 22% CR and 70% OR rates and a median PFS of 41 months for 125 patients. This was in contrast to 6% CR and 50% OR rates and median PFS of 18 months for the 121 patients in the fludarabine arm. The incidence of myelosuppression was similar between the two arms albeit patients who received FC also routinely received G-CSF. The incidence of infection without neutropenia was 9% in the FC arm, higher than the 2% seen in the fludarabine arm (P < 0.02). The overall incidence of infection was not significantly different between the two arms. In the UK LRF CLL4 trial, 783 patients were randomized; 387 to receive initial treatment with chlorambucil 10 mg/m² × 7 days, 194 to fludarabine 25 mg/m² × 5 days, and 196 to fludarabine 25 mg/m² IV × 3 days with cyclophosphamide 250 mg/m² × 3 days or oral fludarabine 24 mg/m² and cyclophosphamide 150 mg/m², both × 5 days (FC). For 661 assessable patients, 8, 15, and 38% achieved CR and the OR rates were 69, 77, and 90% for patients treated with chlorambucil, fludarabine, and FC, respectively. PFS at 3 years was 23, 31, and 62% for patients treated with chlorambucil, fludarabine, and FC, respectively. Both studies indicated greater activity and longer PFS with the FC combination compared to single-agent fludarabine for chemotherapy-naïve patients with CLL.

Cladribine (2-CdA) and pentostatin (2-deoxycoformycin) also have single-agent activity in treating patients with CLL.¹⁹ Results of a large randomized trial comparing single-agent cladribine, cladribine with cyclophosphamide (CC), and cladribine with cyclophosphamide and mitoxantrone (CMC) as initial therapy demonstrated higher CR for CMC over the other treatments (Table 2 ).²⁰ Neutropenia was more common with CMC as was infection. There were no significant differences in PFS or OS for the three arms. There are no head-to-head randomized comparisons available for single-agent purine analogue.

Alemtuzumab is the humanized monoclonal antibody (mAb) targeting CD52, a highly expressed antigen on CLL B cells and normal T and B lymphocytes. Alemtuzumab was approved by the US FDA based on the pivotal trial demonstrating single-agent activity in fludarabine-refractory patients with CLL (Table 3 ).²¹ Other studies confirmed the activity of alemtuzumab in previously treated patients with CLL and when given by subcutaneous (SQ) administration.^22,–25 In a frontline trial of single-agent alemtuzumab (30 mg SQ thrice weekly for up to 18 weeks) in 41 patients, 19% and 87% achieved CR and OR, respectively.²⁶ This trial demonstrated efficacy for alemtuzumab in the front-line setting with successful clearing of disease from blood and bone marrow. Furthermore, subcutaneous administration eliminated the infusion-related side effects, although local injection-site reactions were noted. The skin reactions can be minimized by premedication and local measures such as icing, making the subcutaneous administration better tolerated than IV. Early results from a phase III multi-national randomized trial comparing frontline treatment with alemtuzumab versus chlorambucil (CAM307) were recently reported (Table 1 ).²⁷ Randomization resulted in 149 and 148 patients receiving alemtuzumab and chlorambucil, respectively. CR and OR rates were 22% and 85% versus 2% and 56% for patients treated with alemtuzumab versus chlorambucil, respectively. CMV reactivation occurred in 11% of patients treated with alemtuzumab. There was no excess mortality in either arm, and overall infection rates (excluding CMV) were similar despite more neutropenia with alemtuzumab; the incidence of anemia and thrombocytopenia was similar between the two treatments. Follow-up continues to evaluate PFS and OS.

Alemtuzumab is the only FDA-approved drug that reportedly has activity in treating patients with leukemia cells that lack p53 function.^28,29 Patients with 17p deletion lack p53 function and are resistant to treatment with standard antileukemia drugs such as chlorambucil, purine analogs, and rituximab.

Rituximab, the mAb targeting CD20, was approved by the US FDA for patients with relapsed low-grade non-Hodgkin lymphoma.³⁰ Relatively low levels of CD20 are expressed on CLL B cells, compared to normal B or neoplastic B cells of other lymphomas. In addition, soluble CD20 has been demonstrated in plasma of patients with CLL; this may inhibit the capacity of rituximab to bind to CLL B cells, thereby resulting in rapid clearance and negatively affecting pharmacokinetics.³¹ Standard-dose rituximab (375 mg/m² weekly for 4 weeks) has very limited activity for patients with CLL (Table 3 ).^30,32 Dose-intense³³ and dose-dense³⁴ single-agent rituximab has been shown to increase efficacy (Table 3 ).

Rituximab enhances the activity of purine analogue–based therapies and has been incorporated into combination regimens of chemoimmunotherapy (Table 4 ). Rituximab down-modulates expression of the anti-apoptotic protein bcl-2 and may sensitize leukemia cells to fludarabine-induced apoptosis. Furthermore, fludarabine downmodulates expression of complement-resistance proteins, CD46, CD55, and CD59 on malignant B cells, and renders them more susceptible to rituximab-induced, complement-dependent cytotoxicity. The randomized phase II multi-institutional CALGB 9712 trial evaluated the activity of concurrent versus sequential fludarabine and rituximab as initial treatment of patients with CLL (Table 4 ).³⁵ Induction consisted of 6 cycles of fludarabine 25 mg/m² days 1–5 of each 4-week course (sequential group) or fludarabine 25 mg/m² days 1–5 with rituximab 375 mg/m² on day 1 of each 4-week course (concurrent group). At the end of a 2-month observation period, responders and patients with stable disease in both groups received an additional 4 weekly doses of rituximab 375 mg/m². This trial demonstrated a significantly higher CR rate of 47% in the concurrent group versus 28% in the sequential group. The OR rate and PFS were not significantly different between the two groups. All patients in this study received rituximab, but the concurrent group received 2.5 times the cumulative dose given to the sequential group. Subsequently, an analysis of all patients treated in the CALGB 9712 trial compared to an historical group of patients treated with single-agent fludarabine in the randomized CALGB 9011 trial (no rituximab) demonstrated statistically significantly higher CR rate, OR rate, 2-year disease-free survival, and 2-year OS, favoring patients who received fludarabine and rituximab.³⁶ 

The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has been evaluated in both chemotherapy-naïve and previously treated patients with CLL (Table 4 ).^37,38 In this regimen, fludarabine and cyclophosphamide were given at 25 mg/m² and 250 mg/m², respectively, on days 1–3; rituximab was given 375 mg/m² day 1, course 1, and 500 mg/m² day 1, courses 2–6. Treatment was administered every 4 weeks for a total of 6 courses. In 224 previously untreated patients with CLL, the CR rate with FCR was 70% and the OR rate was 95%, with most patients having no detectable disease by two-color flow cytometry evaluation of the bone marrow at the end of therapy.³⁷ Over 40% of complete responders were free of disease in the bone marrow by PCR testing. The projected failure-free survival at 4 years was 69%. This was the highest response rate reported for any regimen in previously untreated patients with CLL. Large phase III randomized clinical trials of FCR versus FC are ongoing in Europe.

Rituximab has been combined with pentostatin and cyclophosphamide (PCR) for chemotherapy-naïve and previously treated patients with CLL (Table 4 ).^39,40 In a trial for previously treated patients, cyclophosphamide was given at 600 mg/m² on day 1, pentostatin 4 mg/m² on day 1, and rituximab at 375 mg/m² with each course beginning for course 2.⁴⁰ Courses were given every 3 weeks and all patients received G-CSF support. Thirty-two previously treated patients with CLL received this regimen and were assessable for response, 75% responded with CR in 25%. This regimen was well tolerated with the principal toxicity being myelosuppression. In a similar regimen for previously untreated patients, pentostatin was administered at 2 mg/m². Patients received a total of 6 courses and all received G-CSF support. A recent report of 33 previously untreated patients who received this regimen indicated that 43% achieved CR, 21% nodular PR, and 39% PR, for an OR rate of 97%. This regimen was well tolerated, with nausea and vomiting as the most common nonhematologic toxicity.

Synergy between fludarabine and alemtuzumab was first suggested in a series of 6 patients treated with the combination after being declared refractory to fludarabine and alemtuzumab used separately (Table 4 ).⁴¹ One patient achieved CR by NCI-WG criteria; 4 patients achieved PR. The FluCam regimen consists of fludarabine 30 mg/m² immediately followed by alemtuzumab 30 mg IV, both on days 1–3 of each 4-week course for a total of 6 courses.⁴² This regimen was evaluated in 36 previously treated patients with reported CR and PR rates of 30% and 53%, respectively. The median time to progression was 13 months and OS was 36 months. Therefore, FluCam is a promising regimen for previously treated patients with CLL.

Other combination regimens are being evaluated in clinical trials for treatment of relapsed and refractory patients (Table 4 ). No regimen has emerged as being remarkably superior. Work continues to identify active combinations for relapsed and refractory patients.

For patients with residual disease after purine analogue-based therapy, the marrow is the usual site of involvement. Eliminating residual disease may improve remission duration and overall outcome.^4,5 Because it has significant activity in clearing blood and bone marrow, several studies have evaluated the ability of alemtuzumab to eliminate residual disease following chemotherapy.^5,43,–46 One study evaluated a 4- to 8-week course of thrice weekly alemtuzumab 30 mg IV for recently treated patients who had achieved PR, nodular PR, or CR with residual marrow disease documented by 2-color flow cytometry.⁴³ The overall response (down-staging) in this trial was 46%, and residual marrow disease was cleared in most patients. Lack of response was most commonly associated with residual adenopathy. Molecular remission was achieved in some patients following treatment with alemtuzumab. In another study, thrice weekly alemtuzumab 10 mg SQ was given for 6 weeks beginning at least 2 months after completion of treatment with a fludarabine-based regimen. In 35 evaluable patients, alemtuzumab improved the CR rate from 20% post fludarabine, to 83%. In addition, 51% of treated patients pattern.⁴⁶ converted to a polyclonal IgV_H

The German CLL Study Group conducted a trial in patients who had received frontline fludarabine-based treatment and were then randomized to consolidation with alemtuzumab 30 mg IV thrice weekly for 12 weeks versus observation.⁴⁵ This trial was terminated early due to significant infection-related toxicity in patients who received alemtuzumab. There were 21 assessable patients, 11 received alemtuzumab, 7 of whom experienced infection including 4 with CMV reactivation and 1 each with pulmonary as-pergillosis, pulmonary tuberculosis, and herpes zoster. In the 10 patients randomized to the observation arm, there was 1 case of herpes zoster and 1 case of sinusitis. Six of 6 patients achieved a molecular remission in the blood after alemtuzumab, whereas all patients in the observation arm remained PCR positive. At 6 months, 2 patients randomized to receive alemtuzumab had achieved CR by NCI-WG criteria, whereas 3 patients in the observation arm had progressive disease. Longer PFS was seen in the patients randomized to receive alemtuzumab compared to the observation arm (P = 0.036). Therefore, alemtuzumab was highly effective at eliminating minimal residual disease with sustained responses and significantly improved disease-related outcome. A longer time than 2 months from fludarabine-based treatment to alemtuzumab may be required to safely administer alemtuzumab for consolidation. Studies to identify optimal dose and schedule of alemtuzumab consolidation continue.

A recent report of 91 previously treated patients with CLL who received alemtuzumab demonstrated eradication of residual disease in the blood and bone marrow in 20%.⁵ Minimal residual disease was evaluated by four-color flow cytometry and those patients who were negative for residual disease in the bone marrow had longer PFS and OS compared with those who had residual disease. The OS for the 18 patients who were free of detectable residual disease was 84% at 60 months. A focus of clinical investigation continues to be the elimination of minimal residual disease with the expectation that this will correlate with improved remission duration and survival.

Flavopiridol, a synthetic flavone, inhibits cyclin-dependent kinases (CDK) 1, 2, 4, and 9, potentially giving it anti-proliferative and apoptosis-inducing properties. Induction of apoptosis is via inhibition of gene transcription, profoundly affecting proteins with short transcript half-lives. Flavopiridol has substantial binding to human serum protein, which makes the therapeutic activity of the drug highly dose and schedule dependent. Response rates of up to 50% in heavily pretreated patients have been achieved with associated tumor lysis syndrome, indicating therapeutic activity.⁴⁷ A phase II trial is ongoing, and flavopiridol-based combinations are also being developed.⁴⁸ 

Lenalidomide, a thalidomide analogue, has immunomodulatory and anti-angiogenic activities and was FDA approved for treatment of patients with anemia due to myelodysplastic syndrome with the 5q deletion cytogenetic abnormality. The mechanisms of action and effects on the microenvironment are not well understood, but lenalidomide is being studied in CLL. In a phase II trial for relapsed/refractory patients with CLL, 29 patients received 25 mg daily for 21 or 28 days each cycle.⁴⁹ Myelosuppression was a significant toxicity as well as tumor flare, similar to that seen with thalidomide. There were 3 complete and 10 partial responders in 19 assessable patients; 2 of the CR patients achieved molecular remission. Work continues to identify an effective and tolerated dose.

Oblimersen is a synthetic, bcl-2–directed antisense oligonucleotide that downmodulates mRNA levels, resulting in reduced bcl-2 protein levels and inducing apoptosis in treated CLL B cells. It also makes treated cells more susceptible to apoptosis induced by fludarabine, dexamethasone, alemtuzumab, or rituximab. In a phase I/II trial, a maximum tolerated dose of 3 mg/kg/d × 7 days was identified and limited antitumor activity was demonstrated.⁵⁰ In a randomized phase III trial, 241 previously treated patients received FC alone or with oblimersen. Those who received oblimersen had a higher combined CR+nPR rate than those who received FC alone.⁵¹ 

Lumiliximab is a macaque-human chimeric anti-human CD23 mAb. Clinical activity was observed with no dose-limiting toxicities identified in a phase I trial of doses up to 500 mg/m² thrice weekly for 4 weeks.⁵² There were no CRs or PRs by NCI-WG criteria in this trial. Lumiliximab is currently being evaluated in combination chemoimmuno-therapy with FCR.⁵³ 

CD40 is a ubiquitously expressed B cell surface molecule with functional significance in CLL; ligation may provide survival and proliferation signals to the leukemia B cells.⁵⁴ A fully human anti-CD40 mAb (CHIR-12.12) has in vitro CD40-CD154 function-blocking activity, induces apoptosis, and mediates ADCC against CD40⁺ primary CLL B cells.^55,56 A phase I clinical trial of anti-CD40 mAb for previously treated patients with CLL is ongoing.

The rationale for vaccine strategies is to induce host cell–mediated immune responses against autologous malignant cells as a modality to eliminate tumor and provide lasting protection from recurrence. One vaccination strategy utilized ex vivo modified autologous leukemia cells.⁵⁷ A replication-defective adenovirus vector was used to transduce autologous CLL B cells to express the gene encoding CD154 (CD40 ligand). Upon expression of CD154, CD40 was crosslinked on transduced and bystander leukemia cells, inducing them to express co-stimulatory antigens, such as CD80 and CD86, thereby enabling both to present antigen to autologous T cells to induce a productive immune response. There were no dose-limiting toxicities and significant clinical responses, including reductions in leukemia cell counts and in the size of lymph nodes and spleen, were seen in a phase I clinical trial with this strategy. Cross-linking CD40 also induced changes that made the CLL B cells susceptible to apoptosis including expression or up-regulation of CD95 (Fas), as well as expression of bid, a pro-apoptotic protein that facilitates cross talk between mitochondria-dependent apoptosis and death receptors such as DR5.⁵⁸ Increased expression of bid may also make cells more susceptible to chemotherapy-induced apoptosis. DR5, a death-receptor for TNF-related apoptosis inducing ligand (TRAIL) was also expressed on CLL B cells following CD40 ligation. Prior to CD40 activation, CLL B cells were unaffected by ligation of CD95 or DR5. However, following ligation of CD40, the leukemia cells became sensitive to apoptosis induced by CD95 and/or DR5. Activated T cells express both Fasligand (CD178) and TRAIL and may function to kill CLL B cells through this mechanism. This potentially provides a second mechanism of action, in addition to adaptive T cell–mediated immunity. Work with this strategy continues in an ongoing phase I trial with a new chimeric CD154 construct.

There are several areas of focused clinical research for patients with CLL. At the forefront is the issue of how to evaluate and incorporate the new prognostic factors into patient management. Important issues include whether or not any prognostic factors can be used to identify patients at high risk for shorter survival, and whether early intervention in these patients can impact or improve survival. In addition, identifying factors to direct treatment, such as presence of 17p deletion and use of alemtuzumab, is another active area of investigation.

Intensive regimens are poorly tolerated by the elderly; there is more myelosuppression in this population with combination regimens. Developing effective, well-tolerated treatments, specifically for patients over 70 years of age, is another important focus.

Controlled prospective clinical trials demonstrating the benefit in prolonging survival by eliminating MRD are needed. Although methods are available for measuring MRD, these are technically complicated and are generally not available outside research institutions. Work will focus on identifying effective and active regimens to eliminate residual disease, as well as easy and improved methods for measuring residual disease.

Investigators are also focusing on understanding the immune defects that patients with CLL develop, with the intent of developing active and effective immunotherapies to correct these defects and to treat the disease. Currently, a potentially curative strategy is allogeneic stem cell transplant, which has a therapeutic basis in the immune response against the leukemia clone. For this and other reasons, immunotherapies hold promise for the eventual cure of this disease. Further clarifying the role of allogeneic stem cell transplant and optimizing the therapeutic benefit and minimizing toxicity also are focused areas of clinical investigation.

Identifying new, effective, and active drugs and combinations for patients with CLL, particularly relapsed or refractory disease, has historically been a focus of clinical investigation. Developing a better understanding of the biology of the disease, including a molecular basis, will enable us to identify effective and targeted treatments and potentially curative strategies. This continues as a priority for clinical research for patients with CLL.

New regimens combining chemotherapeutic agents with monoclonal antibodies have achieved higher CR rates than ever previously reported for patients with CLL. Treating to maximum leukemia cell reduction and eliminating residual disease after therapy may prolong PFS and OS. Ongoing investigations continue to develop more effective regimens as well as new agents with different mechanisms of actions for treating patients with CLL.