Current Treatment for Chronic Lymphocytic Leukemia

Comprehensive Review Current Treatment for Chronic Lymphocytic Leukemia Valentin Goede, Michael Hallek Abstract Within the past 15 years, the management of chronic lymphocytic leukemia (CLL) has shifted from palliative efforts to modern combination therapies that aim to induce durable remissions and prolong life. A widened spectrum of regimens and novel tools to predict response allows for the tailoring of first- and second-line treatment to a patient’s individual risk, age, and medical fitness. Herein, we review current treatment indications and therapeutic options, followed by evidence-based recommendations for the choice of therapy in primary and relapsed CLL. Supported by phase III trial data, combined chemotherapy with fludarabine and cyclophosphamide is considered the standard first-line regimen. In all probability, however, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab will become the standard therapy in the very near future. Patients at poor risk with genetic abnormalities, as well as elderly patients with medical impairments, require special attention because they often do not respond to these novel combination therapies. Salvage therapy (including hematopoietic stem cell transplantation) should be carried out in clinical trials whenever possible because no standard salvage regimen has been defined so far. Clinical Leukemia, Vol. 2, No. 4, 230-236, 2008; DOI: 10.3816/CLK.2008.n.030 Keywords: Alemtuzumab, Chemoimmunotherapy, Fludarabine, Rituximab, Stem cell transplantation

Introduction Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder that affects 3-4 of 100,000 persons per year, thereby accounting for one third of all leukemias of the Western world.1 Despite its significant contribution to the burden of hematologic malignancy in North America and Europe, treatment options were remarkably limited until the early 1990s. Since then, the spectrum of therapeutic options has been broadened remarkably, thus enabling the hematologist to tailor a patient’s treatment to his or her individual age, medical fitness, and risk of disease progression or relapse. Likewise, the traditional strategy of offering treatment solely to patients with advanced-disease stage has been challenged with the recent discovery of prognostic markers that allow a more precise anticipation of a patient’s course of disease and remission quality. However, paradigm shifts that result from this rapid development of novel therapeutic and diagnostic means have also complicated decision-making in clinical practice. This article summarizes the current state-of-the-art treatment of CLL by outlining indications for treatment and describing the outcome of available therapies. Recommendations on the choice of treatment in primary and relapsed CLL are given on the basis of the latest results of clinical trials.

Treatment Indications in Chronic Lymphocytic Leukemia Patients with newly diagnosed CLL are characterized by a highly variable course. Although some patients have asymptomatic, “smoldering” disease for many years, others experience early progression and require therapy. Initiation of treatment in patients with primary CLL who do not enter a clinical trial should solely rely on clinical criteria as proposed by the updated international guidelines.2,3 First Department of Internal Medicine (Hematology & Oncology), University of Cologne, Germany Submitted: Feb 1, 2007; Revised: Apr 18, 2008; Accepted: Apr 28, 2008 Address for correspondence: Valentin Goede, MD, First Department of Internal Medicine (Hematology & Oncology), University of Cologne, Kerpener Straße 62, 50937 Cologne, Germany Fax: 49-221-478-5134; e-mail: [email protected] Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1931-6925, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.

230

Clinical Leukemia • November 2008

000

Treatment should always be offered to patients with advanced disease stage and concurrent bone marrow failure (Rai stage III or IV, Binet stage C) because overall survival (OS) is reduced to 1-2 years with supportive treatment. However, immediate therapy in patients with early CLL (Rai stage 0-II, Binet stage A or B) has failed to prolong survival so far.4-6 Thus, according to the National Cancer Institute Working Group guidelines and outside of clinical trials, treatment of early-stage CLL should be restricted to patients who present with ≥ 1 of the following symptoms: severe B-symptoms (ie, weight loss of ≥ 10% within the previous 6 months, fever of > 38oC, or night sweats without evidence of infection), extreme fatigue not attributable to other health problems, complications from massive lymphadenopathy or splenomegaly, lymphocyte doubling time of < 6 months, or autoimmune anemia or thrombocytopenia that do not properly respond to corticosteroid therapy.2 Novel prognostic markers have been reported to be of potential usefulness in predicting disease-free survival and OS in early-stage CLL.7 For instance, chromosomal aberrations such as the 11q or 17p deletion,8 unmutated immunoglobulin VH gene status,9 overexpression of ZAP-7010,11 or CD38,12 and increased serum levels of thymidine kinase or ß2-microglobulin13,14 all have been associated with an unfavorable course of the disease. However, the presence of these modern risk factors generally does not allow initiation of treatment in early-stage CLL outside of a clinical trial. Ideally, patients with newly diagnosed CLL who present with a poor marker profile but do not present with symptoms or disease progression should be enrolled in prospective randomized trials that further address the question of whether immediate combination therapies are beneficial in patients with early-stage disease at high risk. Noticeable progress has been made in detecting post-therapeutic minimal residual disease (MRD) by flow cytometry or polymerase chain reaction. It has been proposed to treat MRD to improve the quality of remission or to preemptively neutralize disease relapse before the disease becomes clinically apparent.15 Additionally, the question of whether patients with a very unfavorable prognostic marker profile (ie, p53 dysfunction) and the poorest risk will benefit from a potentially harmful consolidation therapy after having had a first complete remission is still a matter of debate. At present, MRD treatment and risk-adapted consolidation therapy are experimental strategies that need further evaluation in prospective randomized trials. Outside of investigative trials, treatment of patients with relapsed CLL should not be started before they present with active or symptomatic disease defined by deterioration of blood counts, discomfort because of B-symptoms, lymphadenopathy or organomegaly, recurrent infections, or autoimmune cytopenia.2,16 Table 1 summarizes current indications for initial treatment, consolidation therapy, and salvage therapy in CLL.

Treatment Options in Chronic Lymphocytic Leukemia During the past years, treatment of CLL has rapidly developed from a palliative, mainly alkylator-based chemotherapy toward chemoimmunotherapy with purine analogues and monoclonal antibodies (MoAbs).17 Although conventional treatment approaches still have failed to result in definite cure of the disease, long-term

Table 1

Treatment Indications in Chronic Lymphocytic Leukemia Clinical Routine

Clinical Trial

Yes

Yes

Yes

Yes

Unfavorable marker profile

No

Yes

Favorable marker profile

No

No

Unfavorable marker profile

No

Yes

MRD positive

No

Yes

MRD negative

No

Yes

Yes

Yes

MRD positive

No

Yes

MRD negative

No

No

Treatment Initial Treatment Advanced-stage CLL (Rai III or IV, Binet C) Early-stage CLL (Rai 0-II, Binet A or B) Symptomatic Asymptomatic

Consolidation Therapy CLL in remission

Salvage Therapy Relapsed CLL Symptomatic/active Asymptomatic/inactive

Abbreviations: CLL = chronic lymphocytic leukemia; MRD = minimal residual disease

remissions have been observed with hematopoietic stem cell transplantation.18 Table 2 lists pivotal randomized phase III trials that illustrate recent improvements of CLL treatment.19-29

Alkylator-Based Chemotherapy Before the advent of purine analogues and MoAbs, the alkylating drug chlorambucil was widely applied as a single agent or in combination with prednisolone. Monochemotherapy with chlorambucil results in overall response rates (ORRs) of approximately 37%-72%, but complete remissions are rare (0-7%), and relapse generally occurs earlier than with purine analogues (median progression-free survival [PFS], 9-18 months).19, 20, 24, 28, 29 Bendamustine is another agent with an alkylator group that is active in relapsed or refractory CLL when applied alone or in combination with other cytostatic drugs (eg, mitoxantrone). Response rates in small trials have varied between 56% and 86%.30-32 Results from a randomized phase III trial indicate that bendamustine is safe and highly effective in patients naive to treatment.28 Bendamustine induced complete remissions in 30% and overall remissions in 68% of cases. Moreover, PFS was significantly longer than in the competing chlorambucil arm (22 months vs. 9 months).

Anthracycline-Based Chemotherapy Administration of CHOP (cyclophosphamide/doxorubicin/ vincristine/prednisone) or CAP (cyclophosphamide/doxorubicin/ prednisone) in previously untreated patients with CLL yields ORRs of approximately 58%-72%.21,22 However, in primary CLL, both

Clinical Leukemia • November 2008

231

Treatment for Chronic Lymphocytic Leukemia

Table 2

both treatment arms, 18-19 months). The toxicity of both treatments was comparable, except for myelotoxicity, which was Age, No. of Response more pronounced for fludarabine. Upon Study Arm ORR, % CRR, % Years Patients Duration relapse, patients of the chlorambucil arm more frequently received salvage therapy CLB 62 181 37 4 14 Months (TTP) Rai et al19 than patients treated with fludarabine F 64 170 63 20 25 Months (TTP) (26% vs. 12%) and responded well.20 CLB 70 105 59 0 18 Months (PFS) Taken together, these results and a recent Eichhorst et al20 F 70 101 86 8 19 Months (PFS) metaanalysis comparing fludarabine with CAP 62 48 60 17 7 Months (PFS) alkylator-based treatment regimens34 sugJohnson et al21 F 63 52 71 23 NR gest that the benefit of fludarabine alone might have been overestimated in the CHOP 63 357 72 30 30 Months (TTP) past. Moreover, future clinical research in 22 CAP 62 240 58 15 28 Months (TTP) Leporrier et al CLL should design specific trials for elderF 62 341 71 40 32 Months (TTP) ly patients with relevant comorbidity. F 59 164 83 11 20 Months (PFS) Phase II trials combining fludara23 Eichhorst et al FC 58 164 95 39 48 Months (PFS) bine with cyclophosphamide (FC regiCLB ND 384 72 7 9% at 5 years men) suggested an increased efficacy compared with fludarabine alone.35,36 F ND 194 80 15 14% at 5 years Catovsky et al24 Three recent phase III trials showed FC ND 196 94 39 33% at 5 years that first-line treatment with FC results F 61 137 50 6 18 Months (PFS) in increased CRRs (22%-39% vs. 6%Flinn et al25 FC 61 141 70 22 41 Months (PFS) 15%) and ORRs (70%-95% vs. 50%CCda ND 96 91 32 – 83%).23-25 Progression-free survival was Robak et al26 FC ND 100 85 34 – significantly prolonged with FC (41-48 months vs. 18-20 months), whereas no Cda 61 143 74 26 1.7 Years advantage in OS has been demonstrated 27 CCda 62 152 82 28 1.8 Years Robak et al so far. Toxicity with FC was higher than CMCda 59 139 79 40 1.4 Years with fludarabine monochemotherapy CLB 64 125 39 2 9 Months (PFS) but manageable. Combined treatment 28 Knauf et al B 64 139 68 30 22 Months (PFS) with FC has also been explored in preCLB 60 148 55 2 15 Months (TTT) viously untreated patients of advanced Hillmen et al29 age (≥ 70 years).37 Response rates were A 59 149 83 24 23 Months (TTT) favorable. However, rates of life-threatAbbreviations: A = alemtuzumab; B = bendamustine; C = cyclophosphamide; CAP = cyclophosphamide/doxorubicin/ ening adverse events were unacceptably prednisone; Cda = cladribine; CHOP = cyclophosphamide/doxorubicin/vincristine/prednisone; CLB = chlorambucil; CRR = complete response rate; F = fludarabine; M = mitoxantrone; ND = no data provided; NR = not reached; ORR = overall high, resulting in a high incidence of response rate; PFS = progression-free survival; RD = response duration; TTP = time to progression; TTT = time to treatment early treatment discontinuation. Chemotherapy with FC is also active in relapsed CLL.35,36,38 Again, in elderly patients, antileukemic regimens did not prove to be superior to monochemotherapy with activity might be counterbalanced by increased toxicity. However, the purine analogue fludarabine in terms of response induction, results of phase II studies on small cohorts of elderly patients sugremission duration, OS, and toxicity. A phase II study demongest that, while preserving antileukemic activity, rates of adverse strated antileukemic activity for the anthracycline epirubicin in events can eventually be reduced by the administration of FC at a primary and relapsed CLL when combined with fludarabine (FE lower dose.39 regimen).33 Besides fludarabine, the purine analogues cladribine and penPurine Analogue–Based Chemotherapy tostatin have also been demonstrated activity in CLL. Cladribine The discovery of the purine analogue fludarabine in the late 1980s has been successfully combined with cyclophosphamide (CCdamarks a new era in CLL treatment. Early phase III clinical trials demregimen), yielding response rates that are comparable with those onstrated that fludarabine is capable of inducing complete response with FC.26,27 rates (CRRs) of 20%-40% and overall remission rates of 63%-71% Antibody-Based Immunotherapy and in previously untreated patients,19,21,22 Compared with alkylatorChemoimmunotherapy based treatment with chlorambucil, the median PFS was extended The MoAb rituximab recognizes the CD20 membrane protein to 25 months, although no effect on OS was demonstrated.19 In a that is expressed on the cell surface of normal B cells and—with recent trial that exclusively enrolled patients aged ≥ 65 years, fludalower levels—on CLL cells. The binding of rituximab to CD20 rabine failed to prolong PFS compared with chlorambucil (PFS in

232

Results of Prospective Randomized Trials in Chronic Lymphocytic Leukemia

Clinical Leukemia • November 2008

Valentin Goede, Michael Hallek results in CLL cell death. Single-agent treatment with rituximab has only limited activity in CLL, unless very high doses are used.40,41 However, 2 pivotal phase II studies reported remission rates of 90%95% with 50%-70% of complete responses in patients naive to treatment when fludarabine alone or fludarabine plus cyclophosphamide were combined with rituximab (FR regimen; FCR regimen).42,43 Similarly, in phase II trials, rituximab has been successfully combined with pentostatin plus cyclophosphamide (PCR regimen)44 and with bendamustine (BR regimen) to treat primary CLL; CRRs and ORRs were well comparable to those with FR and FCR. Phase III trials are now under way to confirm these promising results. Alemtuzumab is a MoAb binding to the CD52 membrane protein expressed on T and B lymphocytes and on CLL cells. Binding of alemtuzumab is followed by CLL cell apoptosis. In contrast with rituximab alone, treatment with alemtuzumab alone is capable of exerting marked antileukemic activity. A recent phase III trial demonstrated that treatment of primary CLL with alemtuzumab significantly improves response rates (83% overall remissions, 24% complete remissions), PFS, and time to alternative treatment (23 months) in comparison with alkylator-based chemotherapy with chlorambucil.29 Single-agent use of alemtuzumab has also been applied as consolidation therapy after remission induction by chemotherapy with FC or fludarabine alone.45 Progression-free survival was significantly longer with alemtuzumab consolidation treatment than with observation alone (not reached vs. 21 months). However, occurrence of life-threatening infections because of sustained T-cell suppression (mainly cytomegalovirus reactivation) might neutralize the benefit of prolonged remission. Future clinical trials are warranted to further clarify the role and administration schedule of alemtuzumab-based consolidation therapy. Although single-agent treatment with alemtuzumab is active in relapsed CLL (31%-54% overall remissions),46-48 standard-dosed therapy with rituximab failed to exert sufficient antileukemic activity in pretreated patients. However, both antibodies have been successfully used in combination with cytostatic drugs (fludarabine, fludarabine/cyclophosphamide, pentostatin, bendamustine) to treat relapsed CLL (fludarabine/alemtuzumab [FluCam regimen], cyclophosphamide/fludarabine/alemtuzumab/rituximab [CFAR regimen], FCR regimen, PCR regimen, BR regimen).49-54 Of note, alemtuzumab was the first drug that has been convincingly reported to be active in patients refractory to fludarabine with lack of p53 function.55 Still, activity in these poor-risk patients is not a unique feature of alemtuzumab. For instance, flavopiridol has also been shown to yield responses in patients with p53 dysfunction.56

Hematopoietic Stem Cell Transplantation Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) have been applied in relapsed or refractory CLL. Although autologous HSCT does not seem to yield better results than modern chemoimmunotherapies, allogeneic HSCT proved to be capable of completely eradicating MRD followed by long-lasting remissions and long-term survival. Overall remission rates ≤ 90% and complete remissions in 40%-70% of patients have been reported.57-63 Five-year OS and event-free survival rates ranged between 30% and 70%.59-61,64 Particularly, in patients with poorest-risk

Table 3

Current Treatment of Primary and Relapsed Chronic Lymphocytic Leukemia

Treatment Criterion

Clinical Routine

Clinical Trial

FC

FCR, PCR, BR

First-Line Treatment Younger patient, medically fit patient* Poor-risk patient 17p deletion (lack of p53)

†

A

11q deletion

†

FCR, PtCR, A

CLB

dF, dFC, B, PtCR

Repeat first-line

–

Younger patient

†

FCR, BR, A, FA, FCA

Elderly patient

†

dF, dFC, B, CHOP

Poor-risk patient, refractory disease

†

A, FA, FCA, CFAR, aHSCT

Elderly patient, medically unfit patient Second-Line Treatment Late relapse (remission duration > 1 year) Early relapse (remission duration < 1 year)

*Category

includes patients with positivity for ZAP-70 or CD38, increase serum TK or

B2-microglobulin, unmutated immunoglobulin VH. †Enroll in clinical trial whenever possible. Abbreviations: A = alemtuzumab; aHSCT = allogeneic hematopoietic stem cell transplantation; B = bendamustine; C = cyclophosphamide; CLB = chlorambucil; d = dose-reduced; F = fludarabine; H = doxorubicin; O = vincristine; Pt = pentostatin; P = prednisone; R = rituximab

disease, durable remissions have been observed after allogeneic HSCT but not with any other treatment modality. Myeloablative conditioning is associated with a transplantationrelated mortality (TRM) of ≤ 30%-40% within 5 years after allogeneic HSCT, thereby offsetting the treatment modality’s potential to cure the disease.59-61 Nonhematologic toxicity and organ failure as well as graft-versus-host disease and infectious complications account for the high rates of TRM after myeloablative conditioning. Promising results came from more recent trials that used reduced-intensity conditioning (RIC), yielding lower rates of TRM (15%-20% within 2-5 years after transplantation) by decreasing organ toxicity without affecting graft-versus-leukemia activity.62-65

Current Treatment Recommendations First-Line Treatment of Chronic Lymphocytic Leukemia Historically, first-line treatment of CLL was performed with palliative intent. More recently, the broadened arsenal of therapeutic options opened new avenues toward a risk- and fitness-tailored treatment approach. Most younger patients are eligible for intense standard treatment because they usually have an excellent medical fitness and are not compromised by additional health problems. In addition, young (or physically fit) patients in need of treatment and with adverse genetic risk factors require special attention because they frequently do not respond to standard treatment. The majority of patients with CLL are of advanced age and represent a very heterogeneous group. Some elderly patients’ fitness is comparable to that of the young, whereas many other elderly are medically unfit and suffer

Clinical Leukemia • November 2008

233

Treatment for Chronic Lymphocytic Leukemia from declined organ function, comorbidity, and other impairments. Therefore, careful assessment of clinically relevant risk factors and additional health problems are essential to properly adapt first-line treatment of CLL to the patient’s individual needs (Table 3).

Standard Treatment Currently, combined chemotherapy with the FC regimen is still considered to be the standard treatment of primary CLL. As confirmed by several randomized phase III trials, the PFS by far exceeds the duration of remissions with alkylator-based or purine-analogue– based monochemotherapy (PFS of 41-48 months with FC versus 18-32 months or 9-18 months with fludarabine or chlorambucil, respectively; Table 2). The lack of OS improvement is probably not a result of lack of activity of FC itself. Recent data support the hypothesis that patients receiving FC as the first-line treatment might be less eligible for and benefit less from second-line therapies.24 Results from the latest phase II trials suggested that chemoimmunotherapy combining FC with the MoAb rituximab (FCR regimen) is even more active43,66 and will become the treatment of choice in the very near future. Both regimens are currently evaluated in a randomized fashion within the CLL8 trial of the German CLL Study Group (GCLLSG). The recruitment has already been completed. In January 2008, the data safety management board of the CLL8 trial protocol informed the sponsor that the available data indicate that the endpoint was reached and that FCR proved superior to FC. While we still await the careful analysis of these results and the examination of subgroups, this information suggests that FCR will be a new standard therapy for physically fit patients with CLL in the near future. More importantly, these patients should be included in clinical trials to further optimize treatment with FCR or with other chemoimmunotherapeutic regimens (eg, FR, PCR, BR) that might be equally active but less toxic.

Treatment of Patients at Poor Risk As indicated herein, several molecular prognostic factors have been characterized during the past 10 years.67 Among those, lack of p53 function, which is commonly detected by fluorescence in situ hybridization (17p deletion), is of high clinical importance. Patients requiring treatment and presenting with p53 dysfunction will respond poorly to monochemotherapy and combined chemo(immuno)therapy with FC and eventually FCR. Up to now, the MoAb alemtuzumab is the only drug that has been shown to be capable of overcoming p53-mediated refractoriness to standard therapeutic efforts.55 Currently, there is not enough evidence to exclusively recommend use of alemtuzumab as the standard first-line treatment in poor risk patients with lack of p53 function. Therefore, in these patients, initial therapy with alemtuzumab should be carried out within a clinical trial. Young and physically fit patients with p53 dysfunction might benefit from early allogeneic RIC-HSCT after having had a first complete response. Trials in which allogeneic RIC-HSCT is a regular component of the first-line treatment strategy for patients with p53 abnormalities are currently being conducted, but so far, there is no published evidence to generally recommend early allogeneic HSCT in these patients. The 11q deletion has also been associated with rapid progression from early-stage toward late-stage CLL and with shortened remission durations after chemoimmunotherapy.68 However, data

234

is still immature, and it is currently unclear which first-line regimen will be most suitable for this particular subgroup of patients. Interestingly, the response rates in the GCLLSG CLL4 trial for patients with 11q deletions were very high with FC. Nevertheless, patients presenting with 11q deletion and the need for therapy should be treated within clinical trials applying chemoimmunotherapy (eg, PCR, FCR, alemtuzumab).

Treatment of Elderly Patients Medically fit patients who do not suffer from concomitant diseases or decline of organ function should be eligible for standard CLL treatment, even at advanced age. Elderly patients with impaired medical fitness (comorbidity, low performance status), however, might be more vulnerable to intense chemo(immuno)therapy. In the past, elderly patients were underrepresented in clinical trials; thus, information on outcome is sparse. Although alkylator-based therapy with chlorambucil is no longer the treatment of choice in younger and medically fit patients, currently available results from trials suggest that chemotherapy with chlorambucil remains a preferable option in the elderly and in the medically unfit patient. Despite the fact that complete remissions are not observed with chlorambucil, in elderly patients, PFS and OS both are similar to fludarabine monochemotherapy.20 Moreover, treatment of elderly patients with FC or FCR is accompanied by substantial toxicity if not properly tailored to the patient’s burden of comorbidity and functional organ reserve.37 More recently, a regimen using pentostatin, cyclophosphamide, and rituximab has shown good antileukemic activity and relatively mild toxicity in elderly patients.69 It remains to be seen whether this more intense regimen should be used as the first or only the second treatment option in CLL patients with relevant comorbidity. Trials are currently under way to further elucidate the role of purine analogue–based chemotherapy (eg, with modified dosage) in elderly and medically unfit patients with primary CLL. Based on promising first results, other trials explore drugs such as bendamustine, lenalidomide, rituximab, and alemtuzumab as well as combinations of these agents in elderly and medically unfit patients. It is of utmost importance to include patients in these trials.

Second-Line Treatment of Chronic Lymphocytic Leukemia Treatment of relapsed CLL is far from being standardized. For patients with late relapses (response duration of ≥ 1 year; for modern chemoimmunotherapy, > 2 years is probable) re-administration of the first-line regimen is the treatment of choice. Patients with shorter disease-free intervals usually require therapy with alternative regimens. The choice of treatment depends on the nature and the numbers of previously administered therapies. However, genetic risk, age, and medical fitness must also be taken into account (Table 3). For example, early relapse after standard treatment with FC might be treated with FCR, BR, FluCam (FA), FCCam (FCA), or alemtuzumab alone, whereas in elderly patients, relapse upon chlorambucil might be followed by treatment with low-dose fludarabine, low-dose FC, bendamustine, or CHOP. Of note, patients who have refractory CLL (no response to first-line treatment) or relapsed CLL with lack of p53 function should

Clinical Leukemia • November 2008

Valentin Goede, Michael Hallek receive a salvage regimen that includes alemtuzumab. Subsequent allogeneic HSCT with RIC should be strongly considered in younger and medically fit patients with refractory or relapsed disease and p53 dysfunction. As long as possible, any patient with recurrent CLL should be treated within a clinical trial.

Future Perspectives In the near future, results from phase III trials will hopefully provide sound evidence for chemoimmunotherapy to be superior to the current standard treatment, thereby improving outcome and—of most importance—OS in CLL. In addition, treatment of elderly patients with CLL who mainly will not be eligible for intense chemoimmunotherapy must be refined by conducting separate trials that are specifically designed for this large group of patients with CLL. Finally, new insights in the biology of CLL and mechanisms of drug action will help to develop new substances that are clinically active and can be applied alone or in combination with already existing regimens. Recent results from the latest clinical trials are promising, and several agents such as lenalidomide or flavopiridol, MoAbs (eg, lumiliximab, ofatumomab), or gene therapy (using CD40 ligand gene transfer) have the potential of further improving treatment of CLL.

References 1. National Cancer Institute [Web site]. Surveillance Epidemiology and End Results Cancer Statistics Review, 1975-2005. Available at: http://seer.cancer. gov/csr/1975_2005/index.html. Access: November 4, 2008. 2. Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87:4990-7. 3. Hallek M, Cheson BD, Catovsky D, et al Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) updating the National Cancer Institute-Working Group (NCI-WG) 1996 guidelines. Blood 2008; 111:5446-56. 4. Shustik C, Mick R, Silver R, et al. Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation. Hematol Oncol 1988; 6:7-12. 5. Dighiero G, Maloum K, Desablens B, et al. Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med 1998; 338:1506-14. 6. Bergmann M, Eichhorst B, Busch R, et al. Early and risk-adapted therapy with fludarabine in high-risk Binet stage A CLL patients prolongs progression free survival but not overall survival: results of the CLL1 protocol of the German CLL Study Group (GCLLSG). Blood 2007; 110:607a (Abstract 2038). 7. Montserrat E. New prognostic markers in CLL. Hematology Am Soc Hematol Educ Program 2006; :279-84. 8. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343:1910-6. 9. Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94:1848-54. 10. Wiestner A, Rosenwald A, Barry TS, et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 2003; 101:4944-51. 11. Crespo M, Bosch F, Villamor N, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 2003; 348:1764-75. 12. Damle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94:1840-7. 13. Hallek M, Langenmayer I, Nerl C, et al. Elevated serum thymidine kinase levels identify a subgroup at high risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia. Blood 1999; 93:1732-7. 14. Hallek M, Touitou Y, Lévi F, et al. Serum thymidine kinase levels are elevated and exhibit diurnal variations in patients with advanced ovarian cancer. Clin Chim Acta 1997; 267:155-66. 15. Nabhan C, Coutré S, Hillmen P. Minimal residual disease in chronic lymphocytic leukaemia: is it ready for primetime? Br J Haematol 2007; 136:379-92. 16. Eichhorst B, Hallek M. Revision of the guidelines for diagnosis and therapy of chronic lymphocytic leukemia (CLL). Best Pract Res Clin Haematol 2007; 20:469-77. 17. Yee KW, O'Brien SM. Chronic lymphocytic leukemia: diagnosis and treatment. Mayo Clin Proc 2006; 81:1105-29. 18. Dreger P, Corradini P, Kimby E, et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Leukemia 2007; 21:12-7.

19. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000; 343:1750-7. 20. Eichhorst B, Busch R, Stauch M, et al. No significant clinical benefit of first line therapy with fludarabine (F) in comparison to chlorambucil (Clb) in elderly patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a phase III study of the German CLL Study Group (GCLLSG). Blood 2007; 110:194a (Abstract 629). 21. Johnson S, Smith AG, Löffler H, et al. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL. Lancet 2006; 347:1432-8. 22. Leporrier M, Chevret S, Cazin B, et al. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood 2001; 98:2319-25. 23. Eichhorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006; 107:885-91. 24. Catovsky D, Else M, Richards S, et al. The lack of survival differences in randomised trials in CLL may be related to the effect of second line therapies. A report from the LRF CLL4 trial. Blood 2006; 108:94a (Abstract 304). 25. Flinn IW, Kumm E, Grever MR, et al. Fludarabine and cyclophosphamide produces a higher complete response rate and more durable remissions than fludarabine in patients with previously untreated CLL: Intergroup Trial E2997. Presented at: the 46th Annual Meeting of American Society of Hematology; December 2004; San Diego, CA. Abstract 475. 26. Robak T, Blonski JZ, Gora-Tybor J, et al. Randomized comparison of cladribine with cyclophosphamide and fludarabine with cyclophosphamide in previously untreated progressive and symptomatic chronic lymphocytic leukemia: the interim analysis of PALG CLL3 Trial. Blood 2005; 106:212 (Abstract 2121). 27. Robak T, Blonski JZ, Gora-Tybor J, et al. Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2). Blood 2006; 108:473-9. 28. Knauf K, Lissichkov T, Aldaoud A, et al. Bendamustine versus chlorambucil in treatment-naive patients with B-cell chronic lymphocytic leukemia (B-CLL): results of an international phase III study. Blood 2007; 110:609a (Abstract 2043). 29. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007; 25:5616-23. 30. Kath R, Blumenstengel K, Fricke HJ, et al. Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia. J Cancer Res Clin Oncol 2001; 127:48-54. 31. Koppler H, Heymanns J, Pandorf A, et al. Bendamustine plus mitoxantrone--a new effective treatment for advanced chronic lymphocytic leukaemia: results of a phase I/II study. Leuk Lymphoma 2004; 45:911-3. 32. Bergmann MA, Goebeler ME, Herold M, et al. Efficacy of bendamustine in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase I/II study of the German CLL Study Group. Haematologica 2005; 90:1357-64. 33. Rummel MJ, Kafer G, Pfreundschuh M, et al. Fludarabine and epirubicin in the treatment of chronic lymphocytic leukaemia: a German multicenter phase II study. Ann Oncol 1999; 10:183-8. 34. Steurer M, Pall G, Richards S, et al. Purine antagonists for chronic lymphocytic leukaemia. Cochrane Database Syst Rev 2006; 3(CD004270). 35. O'Brien SM, Kantarjian HM, Cortes J, et al. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol 2001; 19:1414-20. 36. Hallek M, Schmitt B, Wilhelm M, et al. Fludarabine plus cyclophosphamide is an efficient treatment for advanced chronic lymphocytic leukaemia (CLL): results of a phase II study of the German CLL Study Group. Br J Haematol 2001; 114:342-8. 37. Ferrajoli A, O'Brien S, Wierda W, et al. Treatment of patients with CLL 70 years old and older: a single center experience of 142 patients. Leuk Lymph 2005; 46:S87. 38. O'Brien S, Moore JO, Boyd TE, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2007; 25:1114-20. 39. Marotta G, Bigazzi C, Lenoci M, et al. Low-dose fludarabine and cyclophosphamide in elderly patients with B-cell chronic lymphocytic leukemia refractory to conventional therapy. Haematologica 2000; 85:1268-70. 40. Huhn D, von Schilling C, Wilhelm M, et al. Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood 2001; 98:1326-31. 41. O'Brien SM, Kantarjian H, Thomas DA, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001; 19:2165-70. 42. Byrd JC, Peterson BL, Morrison VA, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 2003; 101:6-14. 43. Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005; 23:4079-88. 44. Kay NE, Geyer SM, Call TG, et al. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity

Clinical Leukemia • November 2008

235

Treatment for Chronic Lymphocytic Leukemia

45.

46. 47. 48. 49.

50. 51. 52. 53.

54. 55. 56. 57.

with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood 2007; 109:405-11. Schweighofer C, Ritgen M, Eichhorst B, et al. Consolidation with Alemtuzumab Improves Progression-Free Survival in Patients with Chronic Lymphocytic Leukemia (CLL) in First Remission - Long-Term Follow-Up of a Randomized Phase III Trial of the German CLL Study Group (GCLLSG). Blood 2006; 108:14a (Abstract 33). Moreton P, Kennedy B, Lucas G, et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 2005; 23:2971-9. Ferrajoli A, O'Brien SM, Cortes JE, et al. Phase II study of alemtuzumab in chronic lymphoproliferative disorders. Cancer 2003; 98:773-8. Rai KR, Freter CE, Mercier RJ, et al. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol 2002; 20:3891-7. Elter T, Borchmann P, Schulz H, et al. Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial. J Clin Oncol 2005; 23:7024-31. Kennedy B, Rawstron A, Carter C, et al. Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia. Blood 2002; 99:2245-7. Wierda WG, Obrien S, Ferrajoli A, et al. Salvage therapy with combined cyclophosphamide (C), fludarabine (F), alemtuzumab (A), and rituximab (R) (CFAR) for heavily pre-treated patients with CLL. Blood 2005; 106:720 (Abstract 719). Wierda W, O'Brien S, Wen S, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 2005; 23:4070-8. Fischer K, Stilgenbauer S, Schweighofer C, et al. Bendamustine in combination with rituximab (BR) for patients with relapsed chronic lymphocytic leukemia (CLL): A multicentre phase II trial of the German CLL Study Group (GCLLSG). Blood 2007; 110:913a (Abstract 3106). Lamanna N, Kalaycio M, Maslak P, et al. Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia. J Clin Oncol 2006; 24:1575-81. Stilgenbauer S, Döhner H. Campath-1H-induced complete remission of chronic lymphocytic leukemia despite p53 gene mutation and resistance to chemotherapy. N Engl J Med 2002; 347:452-3. Byrd JC, Lin TS, Dalton JT, et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 2007; 109:399-404. Brown JR, Li S, Kim H, et al. High levels of early donor chimerism and treatment-responsive disease predict improved progression-free survival following non-myeloablative transplantation for advanced CLL. Blood 2005; 106:166a-7a

236

(Abstract 560). 58. Michallet M, Michallet AS, Le QH, et al. Conventional HLA-identical sibling bone marrow transplantation is able to cure chronic lymphocytic leukemia. A study from the EBMT and IBMT Registries. Blood 2003; 102:474 (Abstract 1729). 59. Moreno C, Villamor N, Colomer D, et al. Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol 2005; 23:3433-8. 60. Pavletic SZ, Khouri IF, Haagenson M, et al. Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research. J Clin Oncol 2005; 23:5788-94. 61. Pavletic ZS, Arrowsmith ER, Bierman PJ, et al. Outcome of allogeneic stem cell transplantation for B cell chronic lymphocytic leukemia. Bone Marrow Transplant 2000; 25:717-22. 62. Schetelig J, Thiede C, Bornhauser M, et al. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol 2003; 21:2747-53. 63. Sorror ML, Maris MB, Sandmaier BM, et al. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol 2005; 23:3819-29. 64. Caballero D, García-Marco JA, Martino R, et al. Allogeneic transplant with reduced intensity conditioning regimens may overcome the poor prognosis of B-cell chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene and chromosomal abnormalities (11q- and 17p-). Clin Cancer Res 2005; 11:7757-63. 65. Dreger P, Brand R, Milligan D, et al. Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia 2005; 19:1029-33. 66. Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 2005; 105:49-53. 67. Binet JL, Caligaris-Cappio F, Catovsky D, et al. Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia. Blood 2006; 107:859-61. 68. Byrd JC, Gribben JG, Peterson BL, et al. Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol 2006; 24:437-43. 69. Shanafelt TD, Lin T, Geyer SM, et al. Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia. Cancer 2007; 109:2291-8.

Clinical Leukemia • November 2008