Thomas Elter, MD, Michael Hallek, MD, and Marco Montillo, MD
Dr. Elter is on the faculty of the Department of Internal Medicine, Center for Integrated Oncology Cologne-Bonn, at the University of Cologne, in Cologne, Germany. Dr. Hallek is Head of the Department of Internal Medicine, Center for Integrated Oncology Cologne-Bonn, at the University of Cologne, in Cologne, Germany. Dr. Hallek is also Head of the German CLL Study Group. Dr. Montillo is Deputy Director of the Chronic Lympho-proliferative Disorders Program, Department of Oncology/Haematology at Niguarda Ca’Granda Hospital, in Milan, Italy.
Address correspondence to: Thomas Elter, MD, Department of Internal Medicine, University of Cologne, Cologne, Germany; Phone: +49.2214785933; Fax: +49.2214783531; E-mail: thomas.elter@uk-koeln.de
Abstract: Over the past decade, the use of the monoclonal antibody alemtuzumab in chronic lymphocytic leukemia has expanded from administration as a single-agent therapy, into use in combination with fludarabine or rituximab, and further to use as a consolidation agent with the goal of eradicating minimal residual disease. Numerous clinical studies have shown that alemtuzumab is effective as first-line treatment and in patients who have relapsed disease or who are refractory to fludarabine. Despite improvements in response rates and survival compared with combination chemotherapy, there remains some hesitation to incorporate alemtuzumab into management because of known toxicities. Adverse events in patients treated with standard-dose, single-agent alemtuzumab occur at generally predictable time points during treatment and can be managed effectively; this outcome is less established when alemtuzumab is incorporated into combination regimens. Variability in alemtuzumab dosing, route of administration, and duration of therapy has led to inconsistent and sometimes adverse safety consequences. This article presents an overview of clinical studies with alemtuzumab as a single agent, in combination, or in consolidation, with discussion of toxicity and suggestions for ensuring that the efficacious outcomes following alemtuzumab therapy are not outweighed by safety concerns.
Introduction
Current treatments for patients with chronic lymphocytic leukemia (CLL) include a broad range of chemotherapeutic and immunotherapeutic options. These options range from single agents—such as alkylating drugs (eg, chlorambucil), purine analogs (eg, fludarabine, pentostatin, and cladribine, bendamustine [Treanda, Cephalon]), and monoclonal antibodies (eg, rituximab [Rituxan, Genentech/Biogen Idec] and alemtuzumab [Campath, Genzyme])—to combination chemotherapy, immunotherapy, or chemoimmunotherapy.1 Immunotherapeutic choices for CLL (eg, alemtuzumab, rituximab) provide a more targeted approach that, when combined with chemotherapy, demonstrates significantly improved patient outcomes compared with chemotherapy alone. This review focuses on the immunotherapy agent alemtuzumab, a monoclonal antibody that targets CD52-positive cells and is currently approved for use as a single agent in B-cell CLL.2
Alemtuzumab first received its indication in patients who had failed prior fludarabine therapy. In a multicenter, phase II study, patients given alemtuzumab achieved a 33% overall response and 16-month median overall survival.3 One additional phase III study of alemtuzumab has led to its expanded indication in the first-line setting, as a result of significantly improved efficacy endpoints over the standard first-line treatment chlorambucil.4 Combination studies with fludarabine also demonstrate enhanced patient response with the addition of alemtuzumab in relapsed or refractory disease.5,6
The efficacy of alemtuzumab is often negatively affected by known safety issues associated with treatment. As discussed in this review, the safety profile of single-agent, standard-dose alemtuzumab is predictable overall, and response to treatment is fairly consistent across clinical studies with standard dosing regimens. This outcome has been reiterated by physicians experienced with using alemtuzumab therapy over the past decade; management guidelines are consistently updated to ensure appropriate use of alemtuzumab.7,8 Their collective knowledge and practical experience have combined with emerging clinical study results to ensure appropriate guidance based on current treatment practices. Adverse events in patients treated with standard-dose, single-agent alemtuzumab generally occur at foreseeable time points during treatment and can be managed effectively to ensure maximal treatment with the goal of eradicating minimal residual disease. Because minimal residual disease is a major cause of relapse, its eradication is a critical achievement in the treatment of CLL. Patients receiving combination therapy containing alemtuzumab, however, demonstrate less consistent toxicity profiles, requiring further evaluation and standardization of dosing, administration route, and other factors to ensure an optimal risk-to-benefit ratio.
Proposed Treatment Guidelines for Alemtuzumab in CLL
The recommended position of alemtuzumab in treatment guidelines for each line of CLL therapy varies worldwide. Proposed treatment guidelines for patients with CLL were presented by the German CLL Study Group (GCLLSG) at the American Society of Hematology (ASH) meeting in December 2009.1 These guidelines recommend using alemtuzumab as a single agent or combined with fludarabine as first-line therapy in advanced-stage CLL for patients with poor-prognosis cytogenetics (ie, 17p deletion; Table 1). Alemtuzumab is the only drug approved by the US Food and Drug Administration that has reported activity for patients with leukemia cells that lack p53 function.
In the early relapsed or refractory setting, alemtuzumab alone or with fludarabine is recommended as standard therapy regardless of a patient’s molecular cytogenetic status. The GCLLSG guidelines propose alemtuzumab use early in the course of CLL treatment to improve overall disease management by eradicating minimal residual disease in the earliest possible course of therapy.1 Per the National Comprehensive Cancer Network (NCCN) guidelines, alemtuzumab used either as a monotherapy or within a combination regimen is a possible therapeutic option, but it is ranked behind a number of other chemotherapy/chemoimmunotherapy combination regimens (Table 1).9 Both sets of proposed guidelines give patients with good performance status the option of proceeding to allogeneic stem cell transplantation following combination therapy.
Alemtuzumab Dosing and Clinical Studies
The standard dosing schema for single-agent alemtuzumab is 30 mg/day (following initial dose escalation to minimize infusion-related toxicity) administered 3 times per week for up to 12 weeks.2 In relapsed or refractory CLL, standard-dose alemtuzumab monotherapy (intravenous [IV] or subcutaneous [SC]) given for 12 weeks consistently demonstrated 31–42% overall response rates (ORRs) and a complete response (CR) rate of 6% or less.3,10-13 Extended treatment at 30 mg for up to 16 weeks or low-dose (10 mg 3 times per week) alem-tuzumab showed similar or improved responses com-pared with standard-dose alemtuzumab monotherapy.14-17 Act-ivity was demonstrated in fludarabine-refractory patients, as well as in those with 17p deletion and/or p53 mutations. In the first-line setting, standard-dose alemtuzumab achieved improved ORRs of 83–87% (19–24% CR).4,18 These early studies established standard dosing for alem-tuzumab monotherapy. More recent studies have extended alemtuzumab into the first-line setting and have shown similar efficacy with IV or SC routes of administration, as discussed below.
The CAM307 and CLL2H studies of single-agent, standard-dose alemtuzumab showed responses and remission durations consistent with those in earlier phase II studies of standard-dose alemtuzumab.4,13 The CAM307 trial was the pivotal study of alemtuzumab (vs chlorambucil) for first-line treatment of CLL, leading to an expanded indication for first-line alemtuzumab.4 Patients receiving standard-dose IV alemtuzumab compared with oral chlorambucil (40 mg/m2 every 28 days, ≤12 cycles) showed superior ORR (83% vs 55%, respectively; P<.0001), CR (24% vs 2%, respectively; P<.0001), and progression-free survival (PFS; 14.6 vs 11.7 months, respectively; P=.0001), and prolonged median time to alternative treatment (23.3 vs 14.7 months, respectively).
In the CLL2H study of 103 relapsed or refractory CLL patients, alemtuzumab administered intravenously or subcutaneously achieved a 34% ORR (4% CR), with stable disease in 38% of patients.13 At a median follow-up of 37.9 months, median PFS was 7.7 months (95% confidence interval [CI], 5.1–10.0 months), OS was 19.1 months (95% CI, 15.8–29.0 months), and time to treatment failure was 5.6 months (95% CI, 4.4–8.9 months). Patient outcomes were similar regardless of genetic status (eg, 17p deletion, unmutated VH) or route of administration (IV vs SC). SC delivery was more convenient for patients; nearly all patients (96%) received the dosage on an outpatient basis. SC administration also showed an improved safety profile in terms of infusion-related skin reactions, and it provided a more cost-effective and flexible delivery mechanism. Both CAM307 and CLL2H showed consistent grade 3/4 adverse events stemming from the use of standard-dose alemtuzumab (Table 2).4,13 Toxicity was predictable and manageable, with milder infusion-related adverse events in the first-line setting, as well as after SC administration.
Studies of Combination Regimens With Alemtuzumab
Combination chemotherapy, immunotherapy, or chemoimmunotherapy regimens are increasingly becoming more common therapeutic choices for patients with CLL. A number of combination regimens have included alemtuzumab because of its cytotoxic activity independent of p53 pathways; this provides effective cytotoxic activity independent of poor-prognosis molecular cytogenetics (eg, 17p deletion).19,20 Translation of standard-dose, single-agent alemtuzumab into combination regimens has led to variable responses to treatment and alteration of the anticipated toxicity profile.
Initial investigations combined alemtuzumab and fludarabine based on synergistic activity demonstrated in vitro and in small clinical studies.5,21 These 2 agents have provided the foundation for a number of other investigated chemoimmunotherapy combinations in CLL, including alemtuzumab plus fludarabine (FluCam)5,6,22,23; fludarabine, cyclophosphamide, and alem-tuzumab (FCCam)24-26; and cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR; Table 3).27,28 Differences in line of therapy, dosing schema, administration route, and duration of therapy have led to some difficulty with the ability to interpret and compare study results with other combination treatment regimens. Nevertheless, alemtuzumab-based and fludarabine-based regimens have shown significant activity in both first-line and relapsed or refractory CLL. Across all studies, myelosuppression, infectious events, and cytomegalovirus (CMV) reactivation have constituted the majority of grade 3/4 adverse events.
Recently, 2 multicenter, phase III, randomized, con-trolled studies compared first-line FCCam with fludarabine, cyclophosphamide, and rituximab (FCR)29 or fludarabine and cyclophosphamide.30 Dosing and administration for the studies were similar (oral fludarabine 40 mg/m2 and cyclophosphamide 250 mg/m2), although there were variations in the initial dose escalation for alemtuzumab. In the first study, the French Cooperative Group on CLL and Waldenström’s macroglobulinemia (FCGCLL/WM) and the Groupe Ouest-Est d’Etudes Des Leucémies Aigües et Autres Maladies du Sang (GOELAMS) examined FCCam (alemtuzumab 30 mg SC, days 1–3) versus FCR (rituximab 375 mg/m2, day 0 of cycle 1, then 500 mg/m2, day 1 of subsequent cycles) in treatment-naïve patients (<65 years) who had good performance status and no 17p deletions.29 Following randomization of 165 patients, this trial was terminated prematurely because of excess mortality in the FCCam treatment arm. Preliminary study results were reported at ASH in 2009 for the first 100 patients. Three-quarters of all patients completed 6 cycles of therapy. Interim data suggest that FCR treatment showed enhanced response compared with FCCam (ORR: 96% vs 85%; P=.086); the data remain to be finalized. Grade 3/4 neutro-penia was a main cause of premature discontinuation; grade 4 neutropenia progressively increased from cycle 1 (28%) through cycle 6 (46%) in the FCCam treatment arm. In addition to elevated serious adverse events in the FCCam arm, 7 patients died of malignant transformation, infection-related events, and heart failure while experiencing neutropenia. These adverse events have triggered serious safety concerns with regard to the use of FCCam as first-line therapy.
In the second phase III, multicenter study, the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON68) compared FCCam with fludarabine and cyclophosphamide in high-risk adult patients of any CLL stage.30 Fludarabine and cyclophosphamide administration was similar to that in the FCGCLL/GOELAMS study; however, alemtuzumab was given at 30 mg SC on days -1, 0, and 1 of cycle 1, and day 1 of cycles 2–6. Following cycle 1, there was a two-thirds reduction in cumulative alemtuzumab concentration compared with the FCGCLL/WM/GOELAMS study. Safety data presented to date in a preliminary study report suggest an increased incidence of opportunistic infections (but not other types of infections) in the FCCam treatment arm.31
Studies of Nonchemotherapy Combination Regimens With Alemtuzumab
Immunotherapy combinations of alemtuzumab with the anti-CD20 antibody rituximab have been investigated to provide a dual-targeted approach in CLL patients and to minimize adverse events derived from chemotherapy-containing regimens. As detailed in Table 4, a number of studies with the combination of alemtuzumab and rituximab have been performed in relapsed or refractory patients,32-34 as well as in the first-line setting.35,36 Again, variations in the dosing regimens for alemtuzumab make the studies difficult to compare with one another. Dosing regimens for alemtuzumab are modified from the standard dosing regimen when used in an immunotherapy combination. In the relapsed/refractory setting, the combination regimen shows potentially improved response rates compared with single-agent, standard-dose alemtuzumab.
Studies of Consolidation With Alemtuzumab
Consideration of alemtuzumab as a consolidation treatment for CLL stems from alemtuzumab’s significant clearing of minimal residual disease. In the initial investigation of standard-dose alemtuzumab as consolidation therapy following initial chemotherapy with fludarabine alone or in combination with cyclophosphamide, 7 of 11 patients withdrew from the study due to severe infection.37 Although alemtuzumab consolidation was unfavorable from a safety perspective, it improved patient response to induction therapy, prolonged survival, and achieved min-imal residual disease negativity. Long-term follow-up of patients receiving alemtuzumab consolidation continued to show significantly prolonged PFS at a median of 48 months, compared with patients who received no further treatment after induction chemotherapy.38 Montillo and coll-eagues demonstrated an improvement in the quality of response following fludarabine-based induction with low-dose alemtuzumab (10 mg SC 3 times per week, ≤6 wk) consolidation, including an increase in CR rates from 35% to 79%, respectively.39 Over half of the CR patients (56%) achieved minimal residual disease negativity. Adverse events were anticipated (injection-site reactions and fever), and episodes of CMV reactivation were successfully managed with oral ganciclovir. In 92% of patients, peripheral blood stem cell collection was successful, enabling 18 of 24 patients to go on to autologous stem cell transplantation. In the Cancer and Leukemia Group B (CALGB) study 19901, patients who responded to or achieved stable disease with initial fludarabine (25 mg/m2 for 5 days, 4 cycles followed by observation) received alemtuzumab 30 mg 3 times per week IV or SC for 6 weeks.40 Both IV and SC ale-mtuzumab consolidation led to improved ORRs and CR rates, with decreased systemic adverse events following SC alemtuzumab. CMV infections occurred in 9 of 59 patients (15%), resulting in 1 death. Recommendations for future consolidation studies include frequent monitoring for CMV reactivation, with possible preemptive or prophylaxis treatment for CMV,40 as well as the use of alemtuzumab consolidation only in patients with remaining tumor burden after induction and at least 3 months following induction.39 Overall, these studies showed favorable responses and achievement of minimal residual disease negativity following alemtuzumab consolidation with low-dose alemtuzumab or an abbreviated course of standard-dose alemtuzumab. However, preliminary results of a CALGB study reported severe and life-threatening toxicity in patients treated with alemtuzumab consolidation following induction with fludarabine and rituximab (FR).41 In this trial, alemtuzumab-related infectious deaths in patients in CR after FR led to a protocol amendment allowing only patients in partial response after FR induction to receive treatment with alemtuzumab. Final study results suggest that alemtuzumab consolidation after FR, although limited by toxicity, improved CR and minimal residual disease negative rates; long-term follow-up remains to determine the potential impact on survival.42 Clinical trials are ongoing to determine optimal dose, route of administration (IV vs SC), and schedule for alemtuzumab in consolidation.
Safety: Alemtuzumab Administration, Pharmacokinetics, and Management
The inherently complex nature of antibody therapy and intrapatient variability in pharmacokinetics for alemtuzumab lends some difficulty in establishing a pharmacokinetic profile for alemtuzumab-treated patients.43 However, because there appears to be major variation in the pharmacokinetics for IV versus SC alemtuzumab, the clear advantage in the safety profile and convenience favors the SC over IV route of administration with the 3 times weekly administration scheme.44 For all combinations with a 4-week interval, we can presume from the results of pharmacokinetic studies conducted using the 3 times weekly administration that problems may result from using it as an SC administration instead of an IV administration, as sufficient plasma levels are not reached. In the majority of patients, initial infusion-related reactions (eg, fever, rash, rigors, nausea) in the first week of treatment are common and generally mild (grade 1/2). Prophylactic use of antihistamines and acetaminophen reduce these initial reactions. Hematologic adverse events are most common between weeks 2–8 of alemtuzumab treatment (thrombocytopenia weeks 2–4; neutropenia weeks 4–8), are reversible, and may be managed with growth factor support or transfusions. The inherent immunosuppressive nature of alemtuzumab leads to an increased susceptibility to infections, particularly opportunistic infections. The incorporation of antibacterial and antiviral prophylaxis significantly reduces the incidence of these infections.11 CMV reactivation is well documented in alemtuzumab-containing regimens. Upfront prophylaxis and frequent monitoring are recommended to aggressively manage any symptomatic CMV reactivations.45
Recently updated management guidelines for the use of single-agent alemtuzumab provide recommendations for adequate management of adverse events.8 A panel of practicing CLL experts who met at an advisory board meeting in Madrid, Spain reached a consensus on the following points8:
• Single-agent alemtuzumab may be a safe first-line treatment for CLL.
• Suitable patient populations for receiving alemtuzumab (first-line or following relapse or refractoriness) include those who are elderly, have 17p deletions, demonstrate pancytopenia due to infiltrated bone marrow, and have refractory autoimmune cytopenia.
• The standard dose should be 30 mg/day given 3 times per week, with a duration of 12 or more weeks; bone marrow evaluation of response is recommended at
week 12.
• Weekly monitoring for CMV reactivation is recommended; treatment is held if the patient is symptomatic.
• SC delivery is recommended to provide simplified and safer administration and to improve safety with efficacy equivalent to that of IV delivery.
Although these guidelines are effective for the use of single-agent alemtuzumab, incorporation of alemtuzumab into combination regimens or in consolidation is less standardized and requires further study in controlled clinical trials.
Conclusion
Continued clinical evaluation of alemtuzumab in CLL has provided a range of findings over the past 2 decades. As a monotherapy, standard-dose alemtuzumab demonstrates reproducible results in relapsed or refractory therapy, as well as first-line therapy. Adverse events are generally predictable and can be managed with prophylaxis and frequent monitoring to ensure that patients stay on therapy for optimal response. Initial therapy with alemtuzumab has demonstrated improved efficacy over chlorambucil, as well as prolonged duration of response, particularly in patients achieving an initial CR and minimal residual disease negativity. Combination regimens incorporating alemtuzumab show promising effects for overall response and response duration, but patient selection according to the mentioned guidelines is mandatory. In consolidation, low-dose alemtuzumab or an abbreviated course of standard-dose alemtuzumab provides a durable patient response by targeting minimal residual disease following induction therapy.
SC administration of alemtuzumab provides an improvement in infusion-related adverse events and enhanced convenience for a more cost-effective therapy. Although a direct pharmacokinetic comparison of the same schedule using 2 different routes of administration remains to be examined in clinical trials, it is suggested that if alemtuzumab is used outside the approved thrice-weekly schedule, it should still be given intravenously.
The overarching question for combination treatment of patients with CLL remains: What are the ideal dose and duration of alemtuzumab treatment so that its benefit-to-risk ratio provides beneficial clinical outcomes while minimizing significant adverse consequences? Although continued study is warranted to ensure standardization of alemtuzumab therapy in the combination and consolidation settings, the following recommendations are provided based on current studies of alemtuzumab monotherapy, in combination, or consolidation:
• Standard-dose alemtuzumab is safe when used early (ie, first-line or first relapse).
• Existing guidelines for use of alemtuzumab should be followed.
• For standard alemtuzumab dosing, SC administration is recommended to reduce adverse events.
• The IV route of administration may be considered preferable when it is not possible to obtain information regarding the patient’s pharmacokinetic profile or to establish the potential synergy of alemtuzumab when given in combination with other drugs.
• Weekly monitoring for CMV reactivation is important; preemptive or prophylaxis treatment for CMV symptoms may be warranted.
Acknowledgment
The development of this article was supported by Genzyme Corporation. The authors would like to thank Julie Kern, PhD, for editorial support.
References
1. Hallek M. State-of-the-art treatment of chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2009;440-449.
2. Campath (alemtuzumab) full prescribing information. Cambridge, MA: Genzyme Corporation; 2009.
3. Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002;99:3554-3561.
4. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616-5623.
5. 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;23:7024-7031.
6. Kennedy B, Rawstron A, Carter C, et al. Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia. Blood. 2002;99:2245-2247.
7. Keating M, Coutre S, Rai K, et al. Management guidelines for use of alemtuzumab in B-cell chronic lymphocytic leukemia. Clin Lymphoma. 2004;4:220-227.
8. Osterborg A, Foa R, Bezares RF, et al. Management guidelines for the use of alemtuzumab in chronic lymphocytic leukemia. Leukemia. 2009;23:1980-1988.
9. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphoma (version 3). Accessed October 14, 2009.
10. Osterborg A, Dyer MJ, Bunjes D, et al. Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. European Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic Leukemia.
J Clin Oncol. 1997;15:1567-1574.
11. Ferrajoli A, O’Brien SM, Cortes JE, et al. Phase II study of alemtuzumab in chronic lymphoproliferative disorders. Cancer. 2003;98:773-778.
12. Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004;103:3278-3281.
13. Stilgenbauer S, Zenz T, Winkler D, et al. Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2009;27:3994-4001.
14. 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;20:3891-3897.
15. 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;23:2971-2979.
16. Cortelezzi A, Pasquini MC, Sarina B, et al. A pilot study of low-dose subcutaneous alemtuzumab therapy for patients with chemotherapy-refractory chronic lymphocytic leukemia. Haematologica. 2005;90:410-412.
17. Cortelezzi A, Pasquini MC, Gardellini A, et al. Low-dose subcutaneous alemtuzumab in refractory chronic lymphocytic leukaemia (CLL): results of a prospective, single-arm multicentre study. Leukemia. 2009;23:2027-2033.
18. Lundin J, Kimby E, Bjorkholm M, et al. Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood. 2002;100:768-773.
19. Mone AP, Cheney C, Banks AL, et al. Alemtuzumab induces caspase-independent cell death in human chronic lymphocytic leukemia cells through a lipid raft-dependent mechanism. Leukemia. 2006;20:272-279.
20. Xia MQ, Hale G, Waldmann H. Efficient complement-mediated lysis of cells containing the CAMPATH-1 (CDw52) antigen. Mol Immunol. 1993;30:
1089-1096.
21. Smolewski P, Szmigielska-Kaplon A, Cebula B, et al. Proapoptotic activity of alemtuzumab alone and in combination with rituximab or purine nucleoside analogues in chronic lymphocytic leukemia cells. Leuk Lymphoma. 2005;46:
87-100.
22. Flowers C, Rosenthal H, Brown J, et al. Analysis of minimal residual disease from the phase 2 multicenter study of subcutaneous alemtuzumab combined with fludarabine for treatment of relapsed/refractory B-cell chronic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts). 2007;110:Abstract 3111.
23. Engert A, Gercheva L, Robak T, et al. Improved progression-free survival (PFS) of alemtuzumab (Campath®, MabCampath®) plus fludarabine (Fludara®) versus fludarabine alone as second-line treatment of patients with B-cell chronic lymphocytic leukemia: preliminary results from a phase III randomized trial. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 537.
24. Montillo M, Miqueleiz S, Tedeschi A, et al. Combined fludarabine, cyclophosphamide, and alemtuzumab (FCC), an active regimen for treated patients with chronic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts). 2007;110:Abstract 3133.
25. Elter T, James R, Stilgenbauer S, Ritgen M, Hallek M, Engert A. Chemoimmunotherapy with fludarabine, cyclophosphamide and alemtuzumab in patients with relapsed/refractory CLL: interim analysis of the CLL2L trial of the German CLL Study Group. Blood (ASH Annual Meeting Abstracts). 2008;112:Abstract 3170 and presented poster.
26. Elter T, James R, Stilgenbauer S, et al. Chemoimmuno-therapy with fludarabine, cyclophosphamide and alemtuzumab (FC-Cam) in patients with relapsed or genetic high-risk CLL: final analysis of the CLL2L trial of the German CLL Study Group. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 209.
27. Wierda WG, O’Brien S, Faderl S, et al. Combined cyclophosphamide,
fludarabine, alemtuzumab, and rituximab (CFAR), an active regimen for heavily treated patients with CLL. Blood (ASH Annual Meeting Abstracts). 2006;
108:Abstract 31.
28. Wierda WG, O’Brien S, Ferrajoli A, et al. Combined cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR), an active frontline regimen for high-risk patients with CLL. Blood (ASH Annual Meeting Abstracts). 2007;110:Abstract 628.
29. Lepretre S, Aurran T, Mahe B, et al. Immunochemotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus fludarabine (F), cyclophosphamide (C) and MabCampath (Cam) (FCCam) in previously untreated patients (pts) with advanced B-chronic lymphocytic leukemia (B-CLL): experience on safety and efficacy within a randomised multicenter phase III trial of the French Cooperative Group on CLL and WM (FCGCLL/MW) and the “Groupe Ouest-est d’Etudes Des Leucémies Aigües et Autres Maladies du Sang” (GOELAMS): CLL2007FMP (for fit medically patients). Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 538.
30. HOVON Web site. HOVON 68 protocol. A randomized phase III study in previously untreated patients with biological high-risk CLL: fludarabine + cyclophosphamide (FC) versus FC + low-dose alemtuzumab. http://www.hovon.nl/trials/trials-by-type/cll.html?action=showstudie&studie_id=6&categorie_id=8. Accessed April 4, 2010.
31. Polish Lymphoma Research Group Web site. Geisler C. HOVON68 CLL protocol: annual safety report 2008. http://www.plrg.pl/images/stories/badania/hovon/HOVON68CLL_Annual_Safety_Report_2008.pdf. Accessed April 4, 2010.
32. Faderl S, Thomas DA, O’Brien S, et al. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood. 2003;101:3413-3415.
33. Faderl S, Ferrajoli A, Wierda W, et al. Continuous infusion/subcutaneous alemtuzumab (Campath-1H) plus rituximab is active for patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Blood (ASH Annual Meeting Abstracts). 2005;106:Abstract 2963.
34. Nabhan C, Patton D, Gordon LI, et al. A pilot trial of rituximab and alemtuzumab combination therapy in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL). Leuk Lymphoma. 2004;45:2269-2273.
35. Frankfurt O, Hamilton E, Acharya S, Duffey S, Raji A, Rosen ST. A phase II trial of alemtuzumab and rituximab in patients with previously untreated CLL. Blood (ASH Annual Meeting Abstracts). 2007;110:Abstract 2056.
36. Zent CS, Call TG, Shanafelt TD, et al. Early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab. Cancer. 2008;113:
2110-2118.
37. Wendtner CM, Ritgen M, Schweighofer CD, et al. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission—experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004;18:1093-1101.
38. Schweighofer CD, Ritgen M, Eichhorst BF, et al. Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission: long-term follow-up of a randomized phase III
trial of the German CLL Study Group (GCLLSG). Br J Haematol. 2009;144:
95-98.
39. Montillo M, Tedeschi A, Miqueleiz S, et al. Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia. J Clin Oncol. 2006;24:2337-2342.
40. Byrd JC, Peterson BL, Rai KR, et al. Fludarabine followed by alemtuzumab consolidation for previously untreated chronic lymphocytic leukemia: final report of Cancer and Leukemia Group B study 19901. Leuk Lymphoma. 2009;50:
1589-1596.
41. Lin TS, Donohue KA, Lucas MS, et al. Consolidation therapy with subcutaneous alemtuzumab results in severe infectious toxicity in previously untreated CLL patients who achieve a complete response after fludarabine and rituximab induction therapy: interim safety analysis of the CALGB Study 10101. Blood (ASH Annual Meeting Abstracts). 2007;110:Abstract 755.
42. Lin TS, Donohue KA, Byrd JC, et al. Consolidation therapy with subcutaneous (SC) alemtuzumab after fludarabine and rituximab (FR) induction therapy improves the complete response (CR) rate in chronic lymphocytic leukemia (CLL) and eradicates minimal residual disease (MRD) but is associated with severe infectious toxicity: final analysis of CALGB study 10101. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 210.
43. Mould DR, Baumann A, Kuhlmann J, et al. Population pharmacokinetics-pharmacodynamics of alemtuzumab (Campath) in patients with chronic lym-ph-ocytic leukaemia and its link to treatment response. Br J Clin Pharmacol. 2007;64:278-291.
44. Hale G, Rebello P, Brettman LR, et al. Blood concentrations of alemtuzumab and antiglobulin responses in patients with chronic lymphocytic leukemia following intravenous or subcutaneous routes of administration. Blood. 2004;104:
948-955.
45. O’Brien SM, Keating MJ, Mocarski ES. Updated guidelines on the management of cytomegalovirus reactivation in patients with chronic lymphocytic leukemia treated with alemtuzumab. Clin Lymphoma Myeloma. 2006;7:125-130.