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State of the art treatment of chronic lymphocytic leukaemia

Blood Reviews, 1, 25, pages 1 - 9

Abstract

The management of chronic lymphocytic leukaemia is currently undergoing profound changes. Several drugs like bendamustine, alemtuzumab and rituximab have recently been approved for CLL treatment by regulatory agencies. New and very promising compounds like lenalidomide, ofatumumab, GA101, flavopiridol, or ABT-263 are currently investigated in clinical trials and are likely to further enlarge the therapeutic armamentarium in the next years. Latest results show that chemoimmunotherapies like FCR (fludarabine, cyclophosphamide and rituximab) may improve the life expectancy of CLL patients. This new paradigm will modify the way of CLL management in a radical manner. Finally, the development of new biological markers that describe distinct forms of CLL allows to enter the era of personalized therapy similar to other malignancies.

Keywords: Chronic lymphocytic leukaemia (CLL), Therapy, Treatment, Chemoimmunotherapy, Monoclonal antibodies.

1. Introduction

The introduction of new therapeutic and diagnostic tools has opened new perspectives for the management of chronic lymphocytic leukaemia (CLL). Most recently, the combination of monoclonal antibodies with conventional CLL therapies has significantly improved the outcome. However, these effective chemoimmunotherapies like FCR (fludarabine, cyclophosphamide and rituximab) cannot be given with the same success to all CLL patients. For example, FCR seems too toxic to be given to patients with comorbidities and is therefore reserved for physically fit patients. Similarly, patients with specific molecular features like a deletion 17p do not benefit as strongly from FCR chemoimmunotherapy and deserve the consideration of an early allogeneic stem cell transplantation. As a consequence the management of CLL has become increasingly personalized requiring a detailed knowledge of treatment options and diagnostic methods. This review attempts to summarize the current knowledge of CLL treatment and its application in clinical routine.

2. Components of CLL therapy

2.1. Alkylating antineoplastic agents

Chlorambucil has long been the most commonly used drug for CLL therapy. Especially due to its oral administration, chlorambucil is a convenient option for the palliative treatment of non-fit elderly patients. Eichhorst et al. conducted a randomized phase III trial comparing chlorambucil monotherapy to fludarabine monotherapy in elderly patients (> 65 years). 1 A total of 193 patients with a median age of 70 years were included in the trial. The results demonstrate that, although patients receiving fludarabine achieved higher response rates, OS and PFS were not prolonged. Indeed, the OS for patients receiving chlorambucil was 18 months longer without achieving statistical significance, though. Based on these results as well as on results of a trial conducted by the UK CLL Study Group including very fit elderly patients, 2 chlorambucil can still be regarded as an appropriate first-line option in elderly patients with substantial comorbidities. Chlorambucil monotherapy, however, only achieves a very low CR rate and is therefore no longer considered an appropriate option for younger or physically fit patients. Cyclophosphamide is another alkylating agent used in CLL therapy. It is generally utilized in combination regimen.

Bendamustine is a nitrogen mustard containing benzimidazole ring. In 2008, the agent was approved by the Food and Drug administration (FDA) for the treatment of CLL, the approval of the European Medicine Agency (EMEA) followed in 2010. The basis for these approvals were the results of a randomized phase III trial comparing bendamustine to chlorambucil as a first-line treatment in CLL patients. 3 The overall response rates (ORR) and median progression-free survival (PFS) achieved were 67% and 22 months in the bendamustine arm versus 30% and 8 months in the chlorambucil arm, respectively (both p < 0.0001).

2.2. Purine analogues

Fludarabine is the most extensively studied purine analogue in CLL. When used as monotherapy it achieves more and longer lasting complete remissions (CR) than alkylating agents.2, 4, 5, 6, and 7 Phase III studies comparing fludarabine monotherapy with chemotherapy combinations like CHOP (cyclophosphamide, doxorubicine, vincristine and prednisone) or CAP (cyclophosphamide, adriamycin and prednisone) demonstrated that fludarabine monotherapy was superior with regard to ORR and CR.8 and 9 However, fludarabine failed to improve overall survival when used as a single agent.1, 2, 5, and 10 Long-term results from the North American Intergroup Study C9001, suggested some weak trend towards improved survival following initial fludarabine treatment, appearing after 5–6 years (p = 0.07 (covariate adjusted)). 11

Other purine analogues utilized in CLL therapy are cladribine and pentostatine. Cladribine monotherapy elicited overall response rates of 45–70% as well as CRs between 5 and 10% in relapsed CLL. 12 Cladribine plus prednisone produced a higher CR rate than chlorambucil plus prednisone (47% versus 12%), without resulting in longer overall survival. 13 Cladribine in combination with cyclophosphamide was equally effective and safe as fludarabine plus cyclophosphamide for first-line treatment of progressive CLL in a phase III trial. 14 Pentostatine monotherapy seems to be less effective than fludarabine and cladribine in the treatment of CLL, obtaining OR rates of only 26–29%.15, 16, and 17

2.3. Monoclonal antibodies

Alemtuzumab is a fully humanized IgG1 antibody, targeting the CD52 cell surface antigen expressed on most B- and T-cell lymphomas. Monotherapy with alemtuzumab shows efficacy in relapsed and refractory CLL with overall response rates ranging from 33% to 53%, and a median duration of response between 8.7 and 15.4 months.18, 19, and 20 Patients with p53 deletion or mutations show satisfactory responses after treatment with the antibody.21 and 22 Therefore, alemtuzumab is a reasonable option for CLL patients with poor prognostic features.

The CAM 307 trial was a prospective randomized study that compared alemtuzumab to chlorambucil as first-line therapy for CLL 23 (see Table 1 ). Alemtuzumab showed superiority in terms of OR and CR (p < 0.0001) and PFS, with a 42% reduction in risk of progression or death (HR = 0.58, p < 0.0001, and a significantly longer median time to alternative treatment (TTP) (HR = 0.54, p = 0.0001). However, the CAM307 trial was not powered to answer the question, whether CLL patients benefit from alemtuzumab with regard to overall survival. Further hurdles for the widespread use of alemtuzumab in first-line therapy are its high toxicity, in particular immunosuppression and as a consequence severe infections. The subcutaneous administration of alemtuzumab seems as efficient as the intravenous route. The German CLL Study Group (GCLLSG) included 103 patients with fludarabine-refractory CLL in a prospective phase II trial. 24 Patients were subcutaneously treated with 30 mg alemtuzumab three times a week for up to 12 weeks. The overall response rate (ORR) was 34%, including 4% of complete responses (CR). The median PFS was 7.7 months, and the median overall survival (OS) was 19.1 months. Even more promising results were reported by Cortelezzi et al. 25 They included 49 pretreated CLL patients in a prospective phase II trial to determine the safety and efficacy of subcutaneous alemtuzumab at a low dose (10 mg three times per week for 18 weeks). The ORR was 53%, including 27% of CRs. After a median follow-up of 25 months, the median overall time to disease progression was 8 months (responders 12 months and non-responders 4 months), and median overall survival was 30 months. These results led to the initiation of a registration trial (CAM203) for subcutaneously administered alemtuzumab.

Table 1 Monotherapy — randomized trials comparing novel agents to chlorambucil.

Regimen Reference N Age (median) Advanced stage (%) a ANC, toxicity grades 3–4 (%) CR (%) OR (%) PFS (months)
F Rai 5 179 64 39 27 20 63 20
Clb 193 62 41 19 4 37 14
F Eichhorst 91 93 71 b 36 c 12 7 72 19
Clb 100 70 b 40 c 12 0 51 18
A Hillmen 23 149 59 34 41 24 83 14,6
Clb 148 60 33 25 2 55 11,7
B Knauf 92 162 63 28 c 23 31 68 22
Clb 157 66 29 c 11 2 31 8

a Rai III–IV.

b Study included only patients above 65 years.

c Binet C.

F = fludarabine, Clb = chlorambucil, A = alemtuzumab, B = bendamustine; ANC = absolute neutrophil count, toxicity grade 3 or 4.

Different trials addressed the question of the feasibility of alemtuzumab administration as consolidation or maintenance therapy in CLL. In all trials, fludarabine-based therapies were administered prior to alemtuzumab consolidation.26, 27, 28, and 29 Alemtuzumab maintenance therapy improved the quality of responses and led to prolonged progression-free survival compared to patients who did not receive a consolidation therapy. A phase III trial of the GCLLSG assessed the efficacy of alemtuzumab after induction therapy with fludarabine alone or in combination with cyclophosphamide. The trial was stopped early after randomization of 11 patients into the alemtuzumab arm due to severe infections in 7 of the 11 patients. 26 Interestingly, a long-term follow-up after 48 months of observation continued to show an improved progression-free survival in the alemtuzumab arm compared to the control arm without consolidation treatment (median PFS not reached versus 21 months, p = 0.004). 30 Byrd et al. investigated the impact of alemtuzumab after fludarabine treatment. 31 Patients with stable disease or better subsequently received 30 mg alemtuzumab three times weekly for 6 weeks either intravenously (IV) or subcutaneously (SC). After fludarabine induction therapy, the ORR was 55% including 4 CRs (5%). 39 patients received IV alemtuzumab for consolidation with an improvement in CR to 27% and ORR to 73%. 20 patients received SC alemtuzumab with an improvement of ORR to 69% and CR to 17%. Nine of the patients receiving alemtuzumab experienced cytomegalovirus (CMV) infection; one of those died. Another study included 12 previously treated CLL patients to receive alemtuzumab maintenance therapy. 32 The median chemotherapy-free interval was 13 months, and the median time to disease progression was 10 months. None of those patients experienced grade 3 or 4 toxicity. Alemtuzumab maintenance therapy seems to be feasible but requires close monitoring for CMV and other infectious agents. Furthermore, the interval between induction therapy and maintenance with alemtuzumab also seems to be of significance.

The monoclonal CD-20 antibody rituximab does not show satisfactory efficacy as monotherapy in CLL, unless very high doses are used.33, 34, 35, and 36 The data of a trial of the Spanish group using rituximab maintenance therapy are eagerly awaited.

2.4. Combination chemotherapy

The purine analogue fludarabine is most commonly used as backbone for combinatory regimen in CLL therapy. It was shown that exposure of CLL cells to the combination of fludarabine and cyclophosphamide in vitro resulted in synergistic cytotoxicity. 37 Fludarabine has been tested in a variety of combinatory regimen. Those regimens, however, turned out to be less effective and safe than fludarabine and cyclophosphamide (FC).5 and 38 Three phase III trials showed superiority of FC over F alone as first-line therapy, and concomitantly formed the basis for FC as the standard of care for younger patients.2, 39, and 40 Compared with fludarabine monotherapy, the combination of FC resulted in significantly higher CR rates as well as overall response rates. Furthermore, with FC-treatment a longer median progression-free survival and a longer treatment-free survival were achieved. Despite causing significantly more neutropenias, FC did not increase the number of severe infections. A recent analysis of the CLL4 trial of the GCLLSG suggested that compared to fludarabine alone, first-line treatment with FC may lead to improved overall survival (OS) of non-high-risk CLL patients (all patients not exhibiting a del(17p) or p53 mutation). 41

In 2010, the Polish Adult Leukemia Group (PALG) published the results of a randomized phase III trial suggesting that cladribine and fludarabine in combination with cyclophosphamide are equally effective and safe as first-line therapies for progressive CLL. 14 Of the 423 patients included in the study, 211 were treated with cladribine and cylcophosohamide (CC) and 212 with FC. Altogether, 395 patients were evaluable for analysis. The CR and OR rates were 47% and 88% in the CC arm and 46% and 82% in the FC arm (p = 0.25 and p = 0.11, respectively). CC treatment resulted in a median PFS of 2.34 years and FC in 2.27 years (p = 0.51). OS and grade 3/4 toxicities were also comparable. Both combinations displayed unsatisfactory activity in patients with del(17p). The results of the trial stand in some contrast to an earlier randomized phase III trial of the same group comparing efficacy and toxicity of cladribine alone to cladribine combined with cyclophosphamide or cyclophosphamide and mitoxantrone (CMC) in untreated progressive CLL. 42 No significant difference in toxicity and efficacy was found between treatment with CC and cladribine. Therapy with CMC induced higher CR rates compared to CC (p = 0.004), but was associated with a significantly higher rate of neutropenias and infections.

A further promising regime is the combination of FC with mitoxantrone. Bosch et al. evaluated the combination in two phase II studies in relapsed and treatment-naïve CLL patients.43 and 44 Of 60 treated patients with recurrent or resistant CLL, 30 (50%) achieved a CR, including 10 cases with negative minimal residual disease (17%) and 17 (28%) a PR. Treatment associated mortality was 5%. In a succeeding trial, sixty-nine patients under the age of 65 with active CLL received FMC as initial therapy. The overall response rate was 90%, including 26% MRD-negative CRs and 38% MRD-positive CRs. The median response duration was 37 months. Patients with del(17p) failed to attain a CR. In conclusion, FMC seems to be an effective therapeutic option with acceptable toxicity profile.

2.5. Chemoimmunotherapy

The addition of the monoclonal antibody rituximab to a chemotherapeutic backbone has created new perspectives especially for younger and physically fit patients. The current standard of care for this patient population is the combination of rituximab with FC (FCR). In cycle one, this regime usually includes 375 mg/m2 of rituximab on day 1, 25 mg/m2 of fludarabine on days 2–4 and cyclophosphamide at 250 mg/m2 on days 2–4. In cycles two to six 500 mg/m2 rituximab is administered on day 1, and 25 mg/m2 fludarabine and 250 mg/m2 cyclophosphamide on days 1–3. Rituximab should always be administered before chemotherapy. The regime was first evaluated in a phase II study by Schulz et al. enrolling 31 previously treated or untreated CLL patients. The ORR achieved was 87%, including 10 (32%) CRs. 45 A year later, Byrd et al. published the results of a randomized phase II trial investigating efficacy and safety of different administration schedules of fludarabine in combination with rituximab (CALGB 9712). 46 104 patients were randomized to receive either 6 cycles of fludarabine concurrently with rituximab followed 2 months later by 4 weekly doses of rituximab for induction therapy or sequential fludarabine alone followed 2 months later by rituximab consolidation therapy. During the induction portion of treatment, patients receiving the concurrent regimen experienced more grade 3 or 4 neutropenia (74% versus 41%). The overall response rate with the concurrent regime, however, was 90%, including 47% complete responses (CR), compared to an overall response rate of 77% (including 28% CRs) with the sequential regimen. In addition, all patients of the CALGB 9712 trial receiving fludarabine and rituximab were retrospectively compared with patients from the CALGB 9011 trial who had received only fludarabine. 47 Patients who had received the chemoimmunotherapy had a significantly better PFS (p < 0.001) and overall survival (p = 0.006) than patients receiving fludarabine monotherapy. Two-year PFS probabilities were 0.67 versus 0.45, and 2 year OS probabilities were 0.93 versus 0.81. Those promising results led to the initiation of two phase II trials by the MD Anderson Cancer Centre investigating efficacy, toxicity, and tolerability of FCR in CLL. The trial by Wierda et al. included 284 patients with relapsed and refractory CLL. A CR was achieved in 31%, the ORR was 75%. Median OS was 46 months (95% CI, 41–54 months) and median time to failure of therapy was 21 months (95% CI, 19–27 months). Grades 3 and 4 neutropenia occurred in 22% and 34% of treatment courses. 16% of patients experienced one or more episodes of pneumonia or sepsis during or following treatment. 48 , 49 In 2008, Tam et al. reported the long-term results of a trial including 300 patients treated with FCR as initial therapy.48 and 50 The ORR was 95%, with a CR in 72% of patients. Two patients (< 1%) died within 3 months of starting therapy. Six-year overall and failure-free survival was 77% and 51%, respectively. Median time to progression was 80 months.

FCR was subsequently evaluated in two recent prospective randomized phase III trials. 552 previously treated CLL patients were included in the trial by Robak et al. and randomly assigned to receive either FC or FCR. 51 After a median follow-up of 25 months, rituximab significantly improved PFS in patients with previously treated CLL (hazard ratio = 0.65; p < 0.001; median, 30.6 months for FCR versus 20.6 months for FC). Event-free survival, overall response rate, CR rate, duration of response, and time to new CLL treatment were also significantly improved. The rates of grade 3 or 4 adverse events and serious adverse events were slightly higher in the FCR–arm. The GCLLSG included 817 previously untreated CLL patients to randomly receive either FC or FCR (CLL8 trial). 52 FCR–treatment achieved a significantly higher overall response rate (FCR: 90% versus FC: 80%; p = 0.0001) and complete remission rate (FCR: 44% versus FC: 22%) compared to F–treatment. Median PFS was 51.8 months for FCR–treated patients versus 32.8 months for FC–treated patients (p < 0.0001). The three–year survival rate was 87% for FCR–treatment and 83% for FC–treatment (p = 0.012). FCR treatment was more frequently associated with hematologic adverse events, particularly neutropenia; however, this did not result in an increased infection rate. The results of these two large trials clearly show that physically fit patients significantly benefit from the addition of rituximab to chemotherapy, not only in terms of response rate and PFS, but in overall survival. FCR should therefore be considered the first-line option for this patient population.

The question whether immunochemotherapy is also an option for patients with limited physical condition has not been answered yet. Two phase II trials addressed this question by investigating regime modifications that should maintain efficacy while reducing toxicity. The first trial investigated a regime with low-dose fludarabine and cyclophosphamide, and high dose rituximab, including maintenance rituximab (FCR-Lite) in 50 previously untreated CLL patients. 53 The OR and CR rates were 100% and 77%, respectively. Median duration of complete response was 22.3 months. Grade 3/4 neutropenia was noted in 13% of cycles. A main objection, however, is that the median age of the evaluated population group was 58 years, although investigating a regime designed to be especially beneficial for patients with restricted physical condition.

The second trial conducted by Lamanna et al. investigated a sequential regime with fludarabine, high dose cyclophosphamide, and rituximab (F→C→R) in previously untreated CLL patients. 36 patients received therapy with fludarabine 25 mg/m2 on days 1 through 5 every 4 weeks for six cycles, followed by consolidation with cyclophosphamide 3000 mg/m2 administered every three weeks for three cycles, followed by consolidation with weekly rituximab 365 mg/m2 for four cycles. 54 There were 32 responses (89%), including 22 CRs (61%). Consolidation with cyclophosphamide improved responses in 13 patients (36%); nine patients (25%) further improved their responses with rituximab. The 5-year survival rate was 71%. Here again, it remains doubtful whether the results of the trial can be applied to a physically fragile patient group, as the median age of patients included in the trial was 59 years.

The GCLLSG recently started recruitment for a randomized phase III trial comparing efficacy and safety of the combinations chlorambucil + rituximab and chlorambucil + Ga101 to chlorambucil monotherapy in previously untreated patients with substantial comorbidities. GA101 is the first humanized and glycoengineered type II monoclonal CD20 antibody investigated in clinical trials. Compared to rituximab GA101 demonstrates in vitro an elevated antibody-dependent cytotoxicity as well as a markedly higher induction of direct cell death. In a phase I study by Morschhauser et al. GA101 showed a comparable safety profile to rituximab. 55 Of 13 treated high-risk CLL patients, 8 responded to therapy, including 1 CR and 7 PRs.

As previous phase II trials56 and 57 suggested that the replacement of fludarabine (F) by pentostatine (P) in the combination with cyclophosphamide (C) and rituximab (R) might lead to similar efficacy with less infectious complications than seen with FCR, a multicenter, randomized trial was conducted to compare FCR with PCR in 184 previously untreated or minimally treated CLL patients. 58 The PCR regime consisted of P: 4 mg/m2 day 1, C: 600 mg/m2 day 1 and R: 375 mg/m2 day 1, in a 21-day cycle. The FCR regime consisted of F: 20 mg/m2 days 1–5, C 600 mg/m2 day 1 and R 375 mg/m2 day 1, in a 28-day cycle. The infection rate in the FCR arm was 30.7% versus 33.7% in the PCR arm. CRs were achieved in 15 (17%) of FCR-treated patients and 6 (7%) of PCR-treated patients (p = 0.04), while the ORR was 57.5% with FCR versus 45% in PCR (p = 0.13). The results of this trial indicate that CLL patients do not benefit from PCR compared to FCR. Quite to the contrary, PCR tends to increase toxicity, while showing less efficacy. The low OR and CR rates achieved with FCR in this trial can probably be attributed to the reduced dosing of all three components compared to the established regime.

To assess whether the tolerability of PCR could be enhanced without sacrificing efficacy, Kay et al. conducted a phase II trial of the combination PR without C in 33 previously untreated CLL patients. 59 The OR rate was 76% with 9 CRs (27%). After a median follow-up of 14 months, 29 out of 33 patients were still alive. Four (12%) patients experienced grade 3 or higher hematologic toxicity. Comparison of these results, however, with those of a previous PCR trial showed that PR was inferior to PCR in terms of ORR (91% versus 76%) and CR rates (41% versus 27%). The median treatment-free survival was also notably longer in patients treated with PCR compared to PR (30 months versus 16 months). In conclusion, the results of this study suggest that cyclophosphamide is a substantial compound of the PCR regime and should not be eliminated.

A different combination was tested by the GCLLSG in two phase II trials: bendamustine plus rituximab (BR). 81 previously treated CLL patients were included in the first trial to receive 70 mg/m2 of bendamustine on days 1 and 2 and 375 mg/m2 of rituximab on day 0 of the first cycle, and 500 mg/m2 on day 1 rituximab during all subsequent cycles for up to six 28-day cycles. 60 Grade 3/4 neutropenia and thrombocytopenia occurred in 12% and 9% of all cycles respectively. OR rate was 77% with 15% CRs.

The second trial investigated the combination in 117 previously untreated patients. 61 The regime differed from the first trial in that bendamustine was administered in a dose of 90 mg/m2 on days 1 and 2 of each cycle. As of June 2009, the median observation time was 15.4 months. 114 patients were evaluable for toxicity, 110 for response and 113 for PFS. As anticipated, the most frequent adverse events were myelosuppression and infections. Grade 3/4 neutropenia occurred in 6.5% of all treatment cycles. The treatment-related mortality was 2.6%. ORR achieved was 90.9%, including 32.7% clinical CRs. 9.1% of the patients had a stable disease (SD), while none of the patients was progressive (PD). After 18 months, 75.8% of patients were still in remission, the median PFS has not been reached to date. 29 of 50 evaluable patients were MRD-negative in the peripheral blood after completion of the therapy, while seven of 25 patients were MRD-negative in the bone-marrow. Of seven patients with del(17p) only three achieved a partial response (PR). In conclusion, BR seems to be a safe and effective therapy. The GCLLSG is currently conducting a trial comparing FCR to BR in terms of safety and efficacy (CLL10).

Another approach to further improve the efficacy of immunochemotherapy is the addition of a fourth component, mitoxantrone, to the FCR regime. The results of two phase II trials investigating this option were recently published.62 and 63 The Spanish group included 72 untreated CLL patients age 70 or younger to receive FCR plus mitoxantrone 6 mg/m2 for up to six cycles supported by a colony stimulating factor. Patients who achieved response received maintenance with rituximab every three months for two years. The overall response rate achieved was 93%, including 46% MRD-negative CRs and 36% MRD-positive CRs. Severe del(17p) correlated with a lower CR rate. 62 Faderl et al. included 30 patients in their prospective phase II study. 63 A CR was achieved in 83% of patients, including 62% MRD-negative CRs; the overall response rate was 96%. After a median follow-up of 38.5 months, the median time to treatment-failure had not been reached. Grade 3/4 neutropenia occurred in 67% of patients and fever of unknown origin in 40%, despite prophylactic use of a colony stimulating factor. This, however, did not translate into an increase of therapy-associated infections compared with FMC alone. Faderl et al. compared these results with a historical group of FCR-treated patients and found no significant differences with respect to response or toxicity.

2.6. Treatment options for high-risk patients

In CLL, the term “high-risk” currently applies primarily to patients with del(17p) or patients that are refractory to first-line therapy. This 17p chromosome contains the coding sequence p53 that coordinates the cellular response to DNA damage. Patients displaying mutations that lead to defects of p53 have a significantly reduced overall survival compared to the statistical standard and do usually not benefit from fludarabine-based chemo- or chemoimmunotherapies. For this reason, different treatment strategies are needed for those patients. The question whether high-risk CLL patients in Binet stage A or asymptomatic B/Rai stages I and II benefit from early initiation of therapy has not been answered yet. Therefore, these patients should be included in clinical trials whenever possible. The GCLLSG has recently completed recruitment of a phase III trial investigating whether high-risk patients in Binet stage A benefit from early initiation of treatment with FCR (CLL7-trial).

For high-risk patients in symptomatic Binet B/Rai II stage or Binet C, Rai III–IV stage treatment should be initiated and should be followed by allogeneic hematopoietic stem cell transplantation if the physical fitness of the patient allows it. Alternative therapeutic options for these patients are still limited. Results of the CAM 307 trial by Hillmen et al. indicate that alemtuzumab monotherapy might show sufficient efficacy in CLL patients with 17p deletion. 23 11 patients of 149 assigned to the alemtuzumab arm displayed a del(17p), the ORR among this patient group was 64% (7 patients) and the median PFS was 10.7 months. In the chlorambucil arm 10 patients of 148 had a 17p deletion. Here, the ORR achieved was only 20% (2 patients) and the median PFS was 2.2 months. However, due to the low number of patients the difference was not significant (p = 0.08 for ORR and p = 0.4 for PFS).

A recent retrospective study confirmed these results. 64 A total of 105 consecutive, pretreated, otherwise unselected CLL patients, treated with alemtuzumab monotherapy were assessed for response, PFS and OS. The ORR in the total cohort was 43%, with CR and PR rates of 4% and 39%, respectively. 35 patients display a 17p deletion. In this subgroup the ORR achieved was 49%, of which all were assessed to be PRs. The investigators also differentiated response with regard to cumulative dose of alemtuzumab applied. Notably, in the subgroup with 17p deletion, the ORR was only 29% if less than 500 mg cumulative dose was applied and 62% if more than 500 mg cumulative dose was applied. The median PFS of all patients assessed in the study was 7.0 months. Interestingly the median PFS in 17p deleted patients (PFS = 7.0 months) did not differ statistically from patients with good risk cytogenetics, whereas 11q deleted patients had a significantly shorter PFS (2.7 months, p = 0.038). Median OS after initiation of alemtuzumab therapy was 32.8 in the total cohort of CLL patients, however only 19.1 months and 13.7 months were achieved in the subgroups with 17p deletion and 11q deletion, respectively.

Subcutaneous administration of alemtuzumab also seems to be feasible and safe in the high-risk population. Of the 103 pretreated CLL patients included in the CLL2H trial by Stilgenbauer et al., 31 were 17p deleted. 24 The ORR achieved in this subgroup was 39 (compared to 34% in the total cohort), median PFS was 5.8 months and median OS was 18.3 months (compared to PFS = 7.7 months and OS = 19.1 months in the total cohort). Response and duration of response (PFS and OS) in the subgroup with 17p deletion did not differ significantly from the total cohort.

Another promising approach is the combination of alemtuzumab with high dose methylprednisolone. Preliminary results of Pettitt et al. show good efficacy of this regime in CLL patients with p53 defects. 65 Further evaluations are needed.

In a retrospective analysis Robak et al. identified 20 previously untreated CLL patients with 17p deletion and assessed toxicity and efficacy of the CC regime (cladribine plus cyclosphosphamide). 66 16 of these 20 patients responded to CC therapy (ORR = 80%), including 10 patients who achieved a complete response (CR) and 6 patients with partial response (PR). The median PFS was 23 months (95% confidence interval, 5–41 months) and OS probability at 2 years was 52.5% (95% confidence interval, 26%–79%). Infections were the most common grade 3/4 adverse events and occurred in 6 patients (30%). These results suggest that it might be of interest to test the regime as backbone in combination with further components active in high-risk CLL patients.

Results of a phase I study suggest that the cyclin-dependent kinase inhibitor flavopiridol also shows adequate efficacy in high-risk CLL. 67 Of 12 patients with 17p deletion and 18 patients with 11q deletion, 5 and 13 patients, respectively, achieved a response (ORR = 42% and 72%). The immunomodulator lenalidomide also seems to show some efficacy in high-risk CLL. Sher et al. recently published an analysis of relapsed or refractory CLL patients enrolled in a phase II trial who had an 11q deletion or 17p deletion. 68 The ORR among those patients with high-risk cytogenetics was 38% with 19% of patients achieving a complete response. Median PFS was 12.1 months and the estimated 2-year survival probability was 58%. However, disappointingly, only one of the six patients displaying a del(17p) showed a partial response (PR), two patients only achieved stable disease (SD), one patient was progressive and two were not evaluable for response.

Allogeneic transplantation is the only CLL therapy with a potential to cure the disease. The crucial anti-leukaemic principle seems to be the graft versus leukaemia (GvL) effects induced by the donor stem cells. Recently, Dreger et al. published the long-term clinical and MRD results of the GCLLSG's CLL3X trial which investigated reduced-intensity conditioning stem cell transplantation (alloSCT) in high-risk CLL patients. 69 Conditioning was based on fludarabine and cyclophosphamide. 100 patients were included in the study, 90 of these proceeded to alloSCT. With a median follow-up of 46 months the 4-year non-relapse mortality, event-free survival (EFS) and OS were 23%, 42% and 65%, respectively. Notably, EFS was similar for all genetic subsets including patients with 17p deletion. A further important finding was that T-cell depletion with alemtuzumab had an adverse impact on EFS and OS. A further detailed review of alloSCT in CLL is beyond the scope of this article.70, 71, and 72

2.7. Newer treatment options

2.7.1. Lenalidomide

The immunomodulatory agent lenalidomide has shown activity in CLL in the relapsed/refractory as well as in the untreated setting. Activity in CLL was first demonstrated by Chanan-Khan et al. in a phase II study. 25 mg of lenalidomide was administered in this trial every 21 days of a 28-day cycle in 45 pretreated CLL patients. 73 The dosing schedule was modified after 29 patients were enrolled in the study due to two patients having tumor lysis syndrome. The new schedule stipulated a dose escalation beginning at 5 mg/day and a target dose of 25 mg/day. The ORR achieved was 47% including a CR in 9% of patients. The median progression-free survival was 19.4 months.

A subsequent study by Ferrajoli et al. adopted this dose escalation scheme and enrolled 45 patients with relapsed CLL. 74 The dosing started at 10 mg daily, followed by a 5 mg dose escalation every 28 days. The median dose administered due to toxicity at higher doses was 10 mg/day. ORR was 32% with 7% of patients achieving a CR. Notably, 13% of patients with del(17p) and 39% of patients with del(11q) responded to therapy. However, a recent retrospective analysis by Sher et al. demonstrated rather disappointing results of lenalidomide in a small subset of patients with 17p deletion. 68 A phase I/II dose defining trial is currently ongoing. Two trials of lenalidomide in previously untreated patients were presented at the ASH 2008.75 and 76 Both trials observed high toxicities, including tumor flare and tumor lysis syndrome, especially with higher doses. The OR rates ranged between 54 and 65%, so far no CR was achieved.

Ferrajoli et al. included 60 patients with relapsed CLL in a currently ongoing trial investigating the combination lenalidomide + rituximab. 77 37 patients are to date evaluable for response. The ORR was 68%, no CR was achieved. The results obtained suggest that the combination of rituximab and lenalidomide is superior to the single agent lenalidomide. Of special note is the observation that there was no increase in toxicity and that lenalidomide-associated tumor-flare reaction was even less frequent and less severe compared to lenalidomide alone.

Two trials investigated the combination of lenalidomide with fludarabine and rituximab. Brown et al. administered lenalidomide concurrently with fludarabine and rituximab. 78 The trial had to be closed due to significant myelotoxicity and idiosyncratic tumor flare. Another trial by Egle et al. is currently ongoing. The protocol combines 6 cycles of fludarabine (40 mg/m2) PO d1-3 and lenalidomide and rituximab (375 mg/m2 IV day 4 in cycle 1 and 500 mg/m2 IV day 1 in cycles 2–6). Lenalidomide is administered at a starting dose of 2.5 mg daily (days 7–21 in cycle 1) and escalated up to a dose of 25 mg/day from days 1–21 of the following cycles. 79 Following induction therapy, a maintenance phase with lenalidomide and rituximab for 6 months is planned. To date, 10 previously untreated patients have been enrolled in the trial. Preliminary efficacy data show that all patients achieved at least a PR after 2 cycles of therapy, except for one patient with Richter transformation. 50% of patients received a reduced dose due to not clearly dose-dependent skin and vascular toxicities.

To date lenalidomide and lenalidomide containing regimen should be reserved for clinical trials.

2.7.2. Flavopiridol

Flavopiridol, a synthetic flavon, targeting cyclin-dependent kinases, shows high activity in CLL patients with relapsed high-risk CLL.67 and 80 A phase II trial on relapsed CLL patients with genetically high-risk features achieved an overall response rate of 53%, including one CR. 81 Tumor lysis syndrome, however, was a common dose-limiting toxicity. Currently, a registration trial for flavopiridol in relapsed CLL is conducted in the United States and Europe.

2.7.3. Ofatumumab

The fully humanized monoclonal CD20-antibody ofatumumab is currently under investigation. The overall response rate achieved with 2000 mg dosing was 50%. 82 In patients with fludarabine- and alemtuzumab-refractory CLL and patients with fludarabine-refractory CLL with bulky disease, overall response rates of 58% and 47% were observed, respectively. 83 At present, the combination of ofatumumab (500 mg and 1000 mg, respectively) with FC in previously untreated CLL patients is investigated in a phase II trial. Preliminary data show an overall response rate of 77%, including a CR rate of 32% in the 500 mg dosing arm and an ORR of 73%, including a CR rate of 50% in the 1000 mg dosing arm. 84 Ofatumumab received FDA approval for the treatment of CLL patients refractory to fludarabine and alemtuzumab in October 2009.

3. Next questions

Future CLL research faces a multitude of questions:

  • 1. How can overall survival and quality of life of unfit patients be improved?
  • 2. How can overall survival be prolonged for patients with high-risk disease, particularly for patients with del(17p)?
  • 3. The role of the minimal residual disease (MRD) as treatment criterion for clinical trials and clinicians needs to be established.
  • 4. The role of “maintenance treatment” in CLL therapy needs to be determined.

Several trials showed that detectable MRD after therapy predicts relapse, shorter survival and progression-free survival.28, 43, 85, and 86 MRD might be a tool to identify those patients profiting from maintenance treatment, furthermore assessment of MRD might help to answer the question how long maintenance treatment should be applied. MRD might also be helpful as objective endpoints in clinical trials. The quantitative assessment of MRD in 471 patients included in the CLL8 trial of the GCLLSG receiving either FC or FCR demonstrated the clinical significance of MRD assessed by four-colour flow cytometry. 87 The analysis showed that MRD levels below 10−4 were correlated with longer PFS and that patients treated with FCR had, on average, lower MRD levels than patients treated with FC. For this reason, it is recommended to use standardized protocols of either four-colour flow cytometry or allele-specific oligonucleotide PCR (with a sensitivity of one CLL cell per 10,000 leukocytes) for MRD assessment in clinical trials. 88 These trials should assess the benefits and risks of therapies aimed at decreasing the number of CLL patients with detectable MRD levels before this strategy can be recommended for general practice. 89

4. Conclusion

4.1. Modern CLL treatment: towards tailored therapy

4.1.1. First-line therapy

To date, none of the available treatment options is adequate for all patients. Physicians ought to balance the need for aggressive therapy against the individual ability of their patient to tolerate the potential side effects. Treatment decisions should therefore be based on patient characteristics such as physical condition (fitness and comorbidities), which is independent of calendar age, genetic and other risk factors as well as the patient's Binet stage. Furthermore, it is important to distinguish first-line and second-line therapies. Table 2 suggests a treating algorithm for the choice of therapy in CLL. Three relevant considerations need to guide the therapeutic decision:

  • 1. The physical condition of the patient, implying fitness and burden of comorbidity, but independent of chronological age.
  • 2. The individual prognostic risk as determined by genetic profile (in particular the presence or absence of p17deletion) and other risk factors.
  • 3. Stage of disease (as assessed by Binet or Rai).

Table 2 Proposal of an algorithm for first and second-line therapy of CLL.

Stage Fitness Molecular cytogenetic First-line treatment
Standard Alternatives (partly tested in phase III trials)
Asymptomatic Binet A or B (Rai 0, I, II) Irrelevant Irrelevant None High-risk patients should only be treated in clinical trials
Binet C (Rai III–IV), or symptomatic disease (all stages) Go go No del(17p) FCR BR, FR, FA
Del(17p) FCR, A or FA followed by Allo SCT  
Slow go No del(17p) CLB CLB + R, CLB + GA101, B, dose reduced F, FC or FCR
Del(17p) A?  
 
Relapse Fitness Molecular cytogenetic Relapse therapy
Standard Alternatives
Early (< 1 year in case of chemotherapy; < 2 years in case of chemoimmunotherapy) = refractory disease Go go No del(17p) A or FA followed by Allo SCT BR, flavopiridol, lenalidomide
Del(17p) A or FA followed by Allo SCT Flavopiridol, lenalidomide
Slow go No del(17p) A BR, B, lenalidomide
Del(17p) A Lenalidomide
Late (> 1 year in case of chemotherapy; > 2 years in case of chemoimmunotherapy) Go go and slow go Repeat first line

Clb = chlorambucil, F = fludarabine, C = cyclophosphamide, A = alemtuzumab, R = rituximab, B = bendamustine, Allo SCT = allogeneic stem cell transplantation, and GA101 = novel anti-CD20 antibody.

For asymptomatic patients at an early stage (Binet A or B, Rai 0–II), the “watch and wait” strategy is still fully appropriate, since these patients do not benefit from an early initiation of treatment. At present, the question, whether there is a role for early treatment for patients with high-risk features (like a del(17p)) is still under investigation.

Patients with advanced (Binet C, Rai III–IV) or active, symptomatic disease should be treated. Among those patients, it is necessary to distinguish between patients with good clinical condition (“go go”), as defined by a normal creatinine clearance and a low score at the “cumulative illness rating scale” (CIRS), 90 and patients with relevant comorbidities (“slow go”). In addition, the presence of a del(17p) needs to be taken into account. “Go go” patients should receive FCR combination therapy. An alternative treatment option is BR. The CLL10 trial of the GCLLSG investigates whether FCR and BR are comparable in terms of safety and efficacy. To patients with limited physical condition and high comorbidity load (“slow go”) monotherapy with chlorambucil or bendamustine or a dose reduced regime containing fludarabine may be offered.

High-risk patients (p53 deletion or del(17p)) do usually respond poorly to chemotherapy. Alemtuzumab monotherapy or FCR achieves an ORR up to 50%. This response, however, is often of unsatisfactory short duration. Those patients should therefore be included in clinical trials investigating experimental regimen whenever possible. An allogeneic transplantation should be offered to eligible patients if feasible.

4.1.2. Second-line therapy

A review of all treatment options for relapsed or refractory CLL is beyond the scope of this paper. Table 2 , however, offers some guidance for the management of CLL patients with relapsed or refractory disease. In general, first-line therapy may be repeated in case the response achieved lasted more than one year (or more than 2 years if FCR or a similarly potent regimen was applied). Treatment decisions are more difficult for therapy-refractory patients or patients with p17 deletion. The principle in those cases is that therapy should be switched. Potential treatment options are:

  • - Alemtuzumab (as monotherapy or combination).
  • - Flavopiridol (in clinical trials).
  • - Lenalidomide (in clinical trials).
  • - Allogeneic stem cell transplantation with curative intent.

The decision for one of these options is strongly dependent on the physical condition of the patient. Furthermore, the current recommendations of an EBMT consensus group advise to offer an allogeneic stem cell transplantation to all physically fit patients with therapy-refractory disease or with 17p deletion as their life expectancy with conventional chemotherapy or immunochemotherapy is still very poor. 70

Conflict of interest statement

Dr. Natali Pflug has no conflicts of interest to disclose. Prof. Hallek receives: Grant Support and Speakers Honoraria from Roche and Mundipharma.

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Footnotes

a Klinik I für Innere Medizin, German CLL Study Group, University of Cologne, Kerpener Strasse 62, 50937 Köln, Germany

b Center for Integrated Oncology (CIO) Köln Bonn, University of Cologne, Kerpener Strasse 62, 50937 Köln, Germany

c Center of Excellence for Cellular Stress Responses in Aging–Associated Diseases (CECAD), University of Cologne, Kerpener Strasse 62, 50937 Köln, Germany

lowast Corresponding author. Klinik I für Innere Medizin, German CLL Study Group, University of Cologne, Kerpener Strasse 62, 50937 Köln, Germany. Tel.: + 49 221 478 4400; fax: + 49 221 478 5455.