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Keywords:

  • alemtuzumab;
  • chronic lymphocytic leukaemia;
  • lymphoproliferative disorders;
  • minimal residual disease;
  • monoclonal antibodies

Summary

  1. Top of page
  2. Summary
  3. Alemtuzumab in CLL: mechanism of action
  4. Alemtuzumab in the treatment of relapsed/refractory CLL
  5. Alemtuzumab in other lymphoproliferative disorders
  6. Application of alemtuzumab in SCT
  7. Alemtuzumab in other non-malignant diseases
  8. Summary and conclusions
  9. Acknowledgements
  10. References

The humanized anti-CD52 monoclonal antibody alemtuzumab belongs to the family of Campath-1 antibodies, which were initially developed for their ability to prevent graft-versus-host disease (GVHD) and graft rejection in stem cell transplantation. Alemtuzumab is indicated for the treatment of chronic lymphocytic leukaemia (CLL) and has demonstrated considerable activity in relapsed/refractory disease and in previously untreated disease. It has been shown to induce minimal residual disease-negative responses as a single agent or as part of consolidation therapy in a meaningful proportion of patients with CLL and has shown promising activity in patients with high-risk cytogenetic markers. Alemtuzumab may also have significant activity in T-cell malignancies, such as mycosis fungoides and T-cell prolymphocytic leukaemia. Recent studies also have evaluated alemtuzumab as part of a conditioning regimen to prevent GVHD in stem cell transplantation. This article reviews our current understanding of alemtuzumab and discusses its emerging role in the treatment of CLL and other haematological malignancies.

The last two decades have seen significant development of new therapeutic agents for the treatment of haematological malignancies, including the widespread use of monoclonal antibodies. One such antibody is alemtuzumab, a humanized monoclonal antibody of the IgG1 subtype that is directed against human CD52 antigen. Alemtuzumab demonstrates single-agent activity in chronic lymphocytic leukaemia (CLL), both in relapsed/refractory disease (Keating et al, 2002a) and in previously untreated disease (Osterborg et al, 1996; Lundin et al, 2002; Hillmen et al, 2007), and it is currently approved for first-line treatment of CLL. Alemtuzumab has shows promising activity in patients with T-cell prolymphocytic leukaemia (T-PLL) (Dearden et al, 2001; Keating et al, 2002b), cutaneous T-cell lymphomas (CTCL) (Kennedy et al, 2003; Lundin et al, 2003) and peripheral T cell lymphomas (Enblad et al, 2004; Zinzani et al, 2005). In addition, there is increasing interest in the use of alemtuzumab as part of the conditioning regimen for stem cell transplantation (SCT) in an effort to reduce graft-versus-host disease (GVHD) and associated transplant-related mortality (Kottaridis et al, 2000; Chakraverty et al, 2002; Perez-Simon et al, 2002; Morris et al, 2004). In this article, we provide an overview of available clinical data on alemtuzumab therapy in CLL and other haematological malignancies and discuss emerging therapeutic roles of alemtuzumab in the treatment of these diseases.

Alemtuzumab in CLL: mechanism of action

  1. Top of page
  2. Summary
  3. Alemtuzumab in CLL: mechanism of action
  4. Alemtuzumab in the treatment of relapsed/refractory CLL
  5. Alemtuzumab in other lymphoproliferative disorders
  6. Application of alemtuzumab in SCT
  7. Alemtuzumab in other non-malignant diseases
  8. Summary and conclusions
  9. Acknowledgements
  10. References

Alemtuzumab belongs to the Campath-1 family of antibodies that target the human CD52 antigen, a 12-amino acid glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein of unknown function (Xia et al, 1993; Hale, 2001). CD52 is highly expressed on both normal and malignant lymphocytes (B and T cells) and is also found on monocytes, macrophages and eosinophils (Ginaldi et al, 1998; Hale, 2001), in addition to the male reproductive tract (Kirchhoff, 1996; Hale, 2001). Radioisotopic studies have estimated that approximately 5% of lymphocyte cell surfaces are covered by CD52 molecules (Osterborg & Dyer, 2001). Importantly, because CD52 antigen is not expressed on CD34+ hematopoietic progenitor cells, alemtuzumab does not interfere with early hematopoietic progenitor cell development (Gilleece & Dexter, 1993). Both antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity are recognized as primary mechanisms of action for the Campath-1 family of antibodies, including alemtuzumab (Heit et al, 1986; Golay et al, 2004; Nuckel et al, 2005). Caspase-independent apoptosis has also been demonstrated in B-cell lymphoma cell lines and primary CLL cells treated with alemtuzumab (Rowan et al, 1998; Stanglmaier et al, 2004; Mone et al, 2006).

Several parameters may influence the activity of therapeutic antibodies against CLL cells, including the expression level of target molecules. The level of CD52 expression in most normal and malignant B-cells (approximately 500 000 molecules/cell) is far greater than the level of CD20 expression in most mature B-cell malignancies (approximately 100 000 molecules/cell) or that in CLL cells (approximately 8000 molecules/cell) (Osterborg & Dyer, 2001). The difference in target molecule densities may contribute to the differential clinical activity of single-agent rituximab and alemtuzumab in CLL. Preliminary results suggest that resistance to fludarabine and rituximab is associated with downregulation of CD20 expression, but increased expression of CD52, and improved clinical responses to alemtuzumab (Ashraf et al, 2007). These results suggest that monitoring for CD20 and CD52 expression in patients prior to treatment may help identify those who would benefit from individual treatment strategies.

Another parameter that may affect the activity of therapeutic antibodies is the level of circulating soluble target molecule, which may be generated by the ‘antigen shedding’ process (Beum et al, 2006). Free soluble CD52 has been detected in plasma samples from patients receiving alemtuzumab, with levels found to correlate with Rai stage, β-2-microglobulin, and immunoglobulin mutation status. Patients with lower soluble CD52 levels had higher levels of plasma alemtuzumab (Albitar et al, 2004). A continuous infusion regimen of alemtuzumab therapy, which was intended to bind and deplete soluble CD52, has been evaluated (Ferrajoli et al, 2008).

Alemtuzumab in the treatment of relapsed/refractory CLL

  1. Top of page
  2. Summary
  3. Alemtuzumab in CLL: mechanism of action
  4. Alemtuzumab in the treatment of relapsed/refractory CLL
  5. Alemtuzumab in other lymphoproliferative disorders
  6. Application of alemtuzumab in SCT
  7. Alemtuzumab in other non-malignant diseases
  8. Summary and conclusions
  9. Acknowledgements
  10. References

Alemtuzumab was initially approved for the treatment of patients with CLL who had failed both alkylating agents and fludarabine therapy. Monotherapy with intravenous (IV) alemtuzumab produced overall response rates (ORR) of 33–54% in patients with advanced stage, relapsed and/or refractory CLL (Table I) (Osterborg et al, 1997; Keating et al, 2002a; Rai et al, 2002; Ferrajoli et al, 2003; Lozanski et al, 2004; Moreton et al, 2005). In the pivotal phase 2 study, 93 patients with fludarabine-relapsed or refractory disease were treated with IV alemtuzumab 30 mg three times weekly for up to 12 weeks. The ORR was 33% [2% complete response (CR), 31% partial response (PR)] (Keating et al, 2002a). The median overall survival (OS) was 32 months among responding patients and 16 months for the entire cohort. These results were encouraging because the median survival among patients with fludarabine-refractory CLL who received alternative salvage therapy was <1 year (Keating et al, 2002c). Alemtuzumab is effective in clearing CLL from the peripheral blood and bone marrow compartments, but induces lower responses in patients with bulky lymphadenopathy (>5 cm lymph node diameter) (Osterborg et al, 1997; Keating et al, 2002a; Moreton et al, 2005). The reason for this is not clear but may be related to decreased penetration of the antibody in bulky lymph nodes, or mechanisms protecting against antibody-mediated killing at that site. Subcutaneous (SC) administration of alemtuzumab produces similar efficacy in patients with relapsed/refractory CLL, compared with IV alemtuzumab. In a phase 2 study by the German CLL Study Group (GCLLSG), 109 patients with fludarabine-refractory CLL were treated with SC alemtuzumab three times a week for up to 12 weeks. An ORR of 33% was achieved (CR 4%, PR 27%). The median progression-free survival (PFS) was 7·7 months and the median OS was 19·1 months (Stilgenbauer et al, 2007). Because of the similar efficacy regardless of administration route, a registration trial (CAM203) is ongoing to support the regulatory filing for SC usage of alemtuzumab.

Table I.   Activity of single-agent alemtuzumab in relapsed/refractory CLL.
No. of patientsMedian no. of prior therapies (range)Fludarabine refractory, %Median age, years (range)Maximum treatment duration, weeksResponse rate, %Median response duration, months (range)Median OS, monthsReferences
  1. NR, not reported; TFS, treatment-free survival; PFS, progression-free survival; ORR, overall response rate; CR, complete response; PR, partial response; MRD, minimal residual disease; OS, overall survival.

  2. *One patient had T-cell prolymphocytic leukaemia.

  3. †Among all responders; study included patients with CLL (n = 42), T-cell prolymphocytic leukaemia (n = 18), cutaneous T-cell lymphoma (n = 6) and others (n = 12).

  4. ‡Alemtuzumab was administered subcutaneously.

93 (pivotal study)3 (2–7)48 refractory 52 relapsed66 (31–86)12ORR, 33 CR, 28·7 (2·5–22·6+)16 for all; 32 for respondersKeating et al (2002a)
2921 patients received at least two prior therapiesNR (three patients received prior fludarabine)57 (32–75)12ORR, 42 CR, 412 (6–25+)NROsterborg et al (1997)
24*3 (1–8) 54 refractory 17 relapsedNR16ORR, 33 CR, 015·4 (4·6–38+)27·5 for all; 35·8 for respondersRai et al (2002)
423 (1–9)9561 (35–75)12ORR, 31 CR, 518 (range NR)†12 for all; 25 for responders†Ferrajoli et al (2003)
363 (1–12)8161 (47–74)12ORR, 31 CR, 610 (3–36)NRLozanski et al (2004)
913 (1–8)48 (purine analog-refractory)58 (32–75)Until maximum response (median 9 weeks)ORR, 54 CR, 35TFS not reached for MRD− CR; 20 for MRD+ CR; 13 for PR; six for no responseNot reached for MRD− CR; 60 for MRD+ CR; 70 for PR; 15 for no responseMoreton et al (2005)
1093 (1–10)10063 (35–82)12‡ORR, 33 CR, 4PFS 7·7 19·1 Stilgenbauer et al (2007)

Toxicities occurring with alemtuzumab monotherapy are categorized as infusion-related, haematological, and infectious events, and guidelines are available for their prevention and management (Keating et al, 2004). In studies involving patients with relapsed/refractory CLL, the most common adverse events were infusion-related toxicities (e.g. fever, rigors, nausea, dyspnoea, hypotension), which were primarily grade 1 or 2 and resolved with continued therapy (Osterborg et al, 1997; Keating et al, 2002a; Rai et al, 2002; Ferrajoli et al, 2003; Moreton et al, 2005). Infusion-related reactions associated with SC administration were reduced (except for local injection site reactions) and severe reactions were rare (Stilgenbauer et al, 2007). Haematological toxicities with either IV or SC administration are generally transient and included thrombocytopenia (grade 3 or 4 in 27–50% of patients) and neutropenia (grade 3 or 4 in 34–67%) (Osterborg et al, 1997; Keating et al, 2002a; Lundin et al, 2002; Rai et al, 2002; Ferrajoli et al, 2003; Moreton et al, 2005). Infectious events are common in patients with refractory CLL (Perkins et al, 2002) and occur as a result of decreased immune function associated with CLL itself as well as immunosuppression induced by prior therapeutic regimens. Grade 3 or 4 infections were reported in 24–35% of patients with relapsed and/or refractory CLL treated with alemtuzumab (Osterborg et al, 1997; Keating et al, 2002b; Rai et al, 2002; Ferrajoli et al, 2003; Moreton et al, 2005). Cytomegalovirus (CMV) reactivation occurs in 10–30% of patients with relapsed and/or refractory disease treated with alemtuzumab (Keating et al, 2002a; Nguyen et al, 2002; Ferrajoli et al, 2003; Moreton et al, 2005), but deaths related to CMV are rare. The consensus guidelines on the management of patients treated with alemtuzumab stress the importance of screening or monitoring for CMV reactivation and to initiate therapy promptly with ganciclovir or its equivalent upon confirmation of reactivation (Keating et al, 2004). In a randomized trial, patients receiving alemtuzumab received prophylaxis with either valaclovir 500 mg orally daily or valganciclovir 450 mg orally twice daily, the use of prophylactic valganciclovir was highly effective for prophylaxis of CMV reactivation in patients receiving alemtuzumab (O’Brien et al, 2008).

Alemtuzumab as first-line treatment for CLL

Alemtuzumab monotherapy is highly active in patients with previously untreated CLL (Table II) (Lundin et al, 2002; Karlsson et al, 2006; Hillmen et al, 2007). A phase 2 trial investigated the activity and toxicity of SC alemtuzumab 30 mg three times weekly (following SC dose escalation from 3 mg) as a first-line therapy in 41 patients with symptomatic CLL, with an extended treatment period of up to 18 weeks (Lundin et al, 2002). The ORR among 38 evaluable patients was 87% (19% CR, 68% PR), and no apparent difference in response rates was observed among patients with advanced stage disease (81% ORR, 22% CR). However, CR was observed only among patients with minimal (<2 cm nodes) or no lymphadenopathy (Lundin et al, 2002). Consistent with the pivotal trial among relapsed/refractory patients, response rates by disease site showed significant clearance of malignant cells in the peripheral blood (95% CR) and bone marrow (45% CR, 21% nodular PR) while response was reduced in the lymph nodes (29% CR). Among patients who responded to alemtuzumab therapy, cumulative ORR by treatment duration and disease site suggested that although 12 weeks of therapy with SC alemtuzumab clears disease in the peripheral blood and lymph nodes (100% and 69% respectively), up to 18 weeks of therapy may be required to maximize response in the bone marrow (45% ORR at 12 weeks vs. 100% at 18 weeks) (Lundin et al, 2002). In a long-term follow-up analysis of the patients who responded to alemtuzumab therapy in this trial, the median time to treatment failure was 28 months (range 4 to 102+ months) (Karlsson et al, 2006).

Table II.   Activity of single-agent alemtuzumab in first-line treatment of CLL.
No. of patientsRai stage III or IV disease, %Median age, years (range)Treatment regimenResponse rate, %Median response duration, months (range)Median OS, monthsReference
  1. TIW, three times per week; IV, intravenous; SC, subcutaneous; TTF, time to treatment failure; NR, not reported; ORR, overall response rate; CR, complete response; OS, overall survival.

  2. *Median age calculated for all patients randomized to receive alemtuzumab or chlorambucil (N = 297).

1493460 (35–86)*IV alemtuzumab 30 mg TIW (up to 12 weeks)ORR, 83 CR, 24NR (not yet available)NR (not yet available)Hillmen et al (2007)
41 (38 evaluable)6866 (44–75)SC alemtuzumab 30 mg TIW (up to 18 weeks)ORR, 87 CR, 19TTF 28 for all (4–102+); 32 for responders (7–102+)NRLundin et al (2002)Karlsson et al (2006)

A recent phase 3 randomized study evaluated alemtuzumab versus chlorambucil in first-line treatment of 297 patients with progressive CLL. Patients in the alemtuzumab arm received IV alemtuzumab 30 mg three times weekly for up to 12 weeks (Hillmen et al, 2007). The results from this study showed significantly superior response rates for alemtuzumab compared with chlorambucil (ORR 83% vs. 56%; < 0·0001 and CR rates 24% vs. 2%; < 0·0001), and confirmed earlier efficacy results of first-line SC alemtuzumab therapy. On the basis of the phase 3 study results, the Federal Drug Administration (FDA) approved single agent alemtuzumab for first-line treatment of CLL.

As expected, infusion-related reactions were common with first-line IV alemtuzumab therapy, but most reactions were mild, with grade 3/4 reactions in only 14% of patients (Hillmen et al, 2007). Although the precise mechanism for infusion-related events is still unclear, it is believed that events such as fevers and rigors can be attributed to the intense cytokine release that occurs with IV administration of alemtuzumab. The most common grade 3 or 4 treatment-emergent adverse events were haematological toxicities, with grade 3 or 4 neutropenia and thrombocytopenia reported in 42% and 18% of patients respectively. The incidence of febrile neutropenia, however, was only 5% with IV alemtuzumab, which was comparable to the 3% incidence observed in the chlorambucil arm. Grade 3 or 4 infectious events occurred in 16% of patients (grade 3 in 15%) treated with alemtuzumab, with an additional 2% experiencing grade 3 or 4 CMV infection. The overall incidence of symptomatic CMV reactivation was 11%, which was similar to the 10% incidence reported with first-line SC alemtuzumab (Hillmen et al, 2007). In the phase 2 study of first-line therapy with SC alemtuzumab, infusion-related reactions (except for fever and local injection site reactions) were substantially reduced compared with IV delivery (Lundin et al, 2002). Reduced infusion reactions may be attributed to slower rate of absorption and accumulation in plasma. The incidence of severe haematological toxicities with SC alemtuzumab was similar to that seen with IV administration of alemtuzumab, and no patients developed febrile neutropenia. Interestingly, in the study with first-line SC alemtuzumab therapy, no bacterial infections grade >1 were noted, and only one case of severe fungal infection (Pneumocystis jiroveci pneumonia) was observed in a patient who could not tolerate anti-infective prophylaxis (Lundin et al, 2002). Although IV and SC delivery of alemtuzumab induce similar response rates, the toxicity profile is improved with the SC route because of the reduced incidence of common infusion-related reactions associated with IV administration.

Combination chemoimmunotherapy

The potential use of alemtuzumab in combination with chemotherapy in CLL was first indicated in a small study that treated patients who were refractory to single-agent therapy with both fludarabine and alemtuzumab (Kennedy et al, 2002). In this study, five of six patients treated with this combination achieved a response to therapy. These findings have been confirmed in larger studies treating patients with relapsed and/or refractory CLL (Table III) (Elter et al, 2005; Sayala et al, 2006). In a phase 2 trial of 36 patients, evaluating the activity of fludarabine and alemtuzumab administered concurrently on the first 3 d of a 4-week cycle, for up to six cycles (FluCam regimen), the ORR was 83% (30% CR, 53% PR), and six of the nine fludarabine-refractory patients and three of the four patients who had received prior alemtuzumab responded to combination therapy. The median OS for all patients was 35·6 months and has not yet been reached for patients achieving a response (Elter et al, 2005). Of note, among patients with autoimmune haemolysis (n = 7) or transfusion-dependent thrombocytopenia and/or anaemia (n = 9) prior to study initiation, all cases resulted in resolution of cytopoenia and independence from transfusions following therapy with alemtuzumab. Infusion-related reactions were the most common adverse events seen with FluCam treatment and were primarily grade 1 or 2 in severity and occurred during the initial infusions with alemtuzumab (Elter et al, 2005). Grade 3 or 4 haematological toxicities included leucopenia in 44% of 140 assessable treatment cycles, thrombocytopenia in 30% and neutropenia in 26%. Major infections (grade 3 or 4) were observed in 11% of patients, including two cases of grade 3 CMV reactivation. The incidence of symptomatic CMV reactivation (6%) was low, considering that 80% of patients were CMV-seropositive prior to treatment (Elter et al, 2005). Based on these promising results, a randomized, prospective, phase 3 study is currently under way comparing the efficacy and safety of FluCam with fludarabine. In another phase 2 study, in which single-agent SC alemtuzumab (30 mg three times weekly after dose escalation) was administered, patients with suboptimal responses (i.e., progressive disease at week 6 or stable disease at week 12) were eligible to receive alemtuzumab in combination with oral fludarabine (Cam Flud regimen) (Sayala et al, 2006). In the final analysis of 49 evaluable patients, alemtuzumab monotherapy (median duration, 18·8 weeks) produced an ORR of 45% (14% CR, 31% PR), which included five minimal residual disease (MRD)-negative CRs and one MRD-negative PR (in a patient who had persistent cytopenia). The combination regimen with CamFlud was administered to 17 patients, with a final ORR of 49% (16% CR) (Table III) (Sayala et al, 2006).

Table III.   Activity of combination therapy with alemtuzumab combination therapy in relapsed/refractory CLL.
No. of patientsMedian no. of prior therapies (range)Flu-refractory, %Median age, years (range)Treatment regimenResponse rate, %Median time-to-progression, monthsMedian OS, monthsReference
  1. Flu, fludarabine; C, cyclophosphamide; PD, progressive disease; SD, stable disease; TTP, time to progression; NR, not reported; TIW, three times per week; IV, intravenous; ORR, overall response rate; CR, complete response; OS, overall survival; MRD, minimal residual disease.

362 (1–8)2561 (38–80)Flu 30 mg/m2 IV, days 1–3 + alemtuzumab IV 30 mg days 1–3 of 4-week cycle, up to six cycles (FluCam)ORR, 83 CR, 3013 for all; 22 for patients with CR36 for all; not reached for patients with CRElter et al (2005)
50 (49 evaluable)NR10064 (41–79)Alemtuzumab SC 30 mg TIW monotherapy; if PD at week 6 or SD at week 12, alemtuzumab SC 30 mg TIW + Flu oral 40 mg/m2 days 1–3 every 4 weeks (CamFlud)Monotherapy: ORR, 45 CR, 14 MRD(−) CR, 10 CamFlud (addition of Flu in n = 17): ORR, 49 CR, 16NR21 for all; 25 for responders; 13 for no responseSayala et al (2006)
39 (20 evaluable)1NR64 (48–78)Flu 25 mg/m2 IV, C 200 mg/m2 IV, alemtuzumab SC 30 mg on days 1–3 every 28 d for up to six cyclesORR, 70 CR, 25NRNRElter et al (2008)
743 (1–6)4358 (39–79)C 250 mg/m2 IV (days 3–5), Flu 25 mg/m2 IV (days 3–5) Alemtuzumab 30 mg IV (days 1, 3 and 5) Rituximab 375–500 mg/m2 (day 2), every 28 d for up to six cyclesORR, 65 CR, 242619Wierda et al (2006)

The combination of fludarabine (F), cyclophosphamide (C) and alemtuzumab (Cam), the FCCam regimen, was evaluated in a recent phase 2 study. Thirty-nine patients with relapsed/refractory CLL received the FCCam regimen (F 25 mg/m2 IV, C 200 mg/m2 IV, alemtuzumab 30 mg SC given on days 1–3 every 28 d for up to six cycles). Of the 20 evaluable patients, the ORR was 70% (CR 25%, PR 45%). All patients with CR became MRD-negative (Elter et al, 2008). The FCCam regimen appeared to be highly effective in reducing bulky lymph nodes (>5 cm) (T. Elter and M. Hallek, unpublished data). The most serious side effects were thrombocytopenia and neutropenia. Infectious events included two CMV reactivation, one Herpes zoster reactivation and 12 fever of unknown origin (Elter et al, 2008).

The combination of cyclophosphamide, fludarabine, alemtuzumab and rituximab (CFAR) has been evaluated in previously treated CLL patients (Wierda et al, 2006). The CFAR regimen consisted of C 250 mg/m2, days 3–5; F 25 mg/m2, days 3–5; alemtuzumab 30 mg IV days 1, 3 and 5, and rituximab 375–500 mg/m2 day 2, repeated every 28 d for up to six cycles. Of 74 patients who completed treatment, the ORR was 65% and CR was achieved in 24% of patients. CFAR was active in patients with 17p deletion (ORR 44%) and in patients who had prior chemoimmunotherapy [CR 19%, PR 37% in 43 patients previously treated with fludarabine, cyclophosphamide and rituximab (FCR)]. Median survival was 19 months for all patients, >35 months for patients with CR, 18 months for patients with PR, and 7 months for non-responders. Residual disease in bone marrow was assessed in all patients using two-colour flow cytometry. Of 18 patients with CR, all were free of residual disease (Wierda et al, 2006).

MRD eradication and consolidation therapy with alemtuzumab

A patient with morphological CR may still have considerable residual disease and the presence of residual malignant cell clones because of suboptimal therapy probably underlies eventual disease relapse. Moreover, clonal selection by suboptimal therapy may result in enrichment of clones with resistant genotype (such as 17p deletion), leading to eventual chemoresistance. For example, in patients relapsing after FCR therapy, the frequency of 17p deletion was 24%, much higher than that in the overall patient population (7%) (Tam et al, 2008). Therefore, there is considerable interest in using agents that could further decrease or eliminate residual disease. Recent developments of sensitive four-colour flow cytometry technology make it feasible to detect small numbers of residual CLL cells (detection limit: one in 104–105 leucocytes) in bone marrow specimens. The presence of residual CLL cells (MRD-positive) in bone marrow of patients achieving CR was associated with significantly decreased event-free survival and OS, compared with patients with CR who were MRD-negative (Rawstron et al, 2001). Therefore, in CLL as in other haematological malignancies, the goal of therapy should be to effectively eliminate MRD, which may be of particular relevance to certain patient subgroups, such as patients with high-risk cytogenetic profiles.

In a study of 91 heavily pretreated patients with relapsed and/or refractory CLL, alemtuzumab was administered until maximum response (including MRD negativity) (Moreton et al, 2005). Compared with previously published trials of alemtuzumab in patients with relapsed and/or refractory disease, this trial had a relatively low enrolment of patients (12%) with bulky lymphadenopathy (>5 cm lymph nodes). MRD was evaluated using sensitive four-colour flow cytometry of blood and bone marrow (Rawstron et al, 2001). After a median of 9 weeks of treatment, the ORR was 54% (35% CR), with MRD-negative remission achieved in 20% of patients (Table I) (Moreton et al, 2005). Importantly, 18% of the purine analogue-refractory patients achieved an MRD-negative remission, and the ORR in this traditionally difficult-to-treat subgroup was 50%. As expected, none of the patients with bulky lymphadenopathy achieved CR or MRD negativity. Patients with MRD-negative remission had significantly longer treatment-free survival (< 0·0001) and OS (= 0·0007) (Fig 1A and B) suggesting that achievement of MRD negativity may translate into prolonged remission duration and improved survival (Moreton et al, 2005). These findings suggest that MRD assessment may be more important than achievement of CR in evaluating response to therapy. Toxicities were similar to those reported in other trials of patients with relapsed and/or refractory CLL treated with alemtuzumab, including transient infusion-related reactions (fever or rigors in 76%; grade 3 or 4 in only 13%), common haematological toxicities (grade 3 or 4 neutropenia in 48%; thrombocytopenia in 46%), and major infections in 24% of patients. Of 149 patients treated upfront with alemtuzumab, 11 patients achieved a MRD-negative CR and 25 patients achieved a MRD-positive CR. PFS was longer in patients with a MRD-negative CR than in patients with a MRD-positive CR (Hillmen et al, 2007). The CFAR combination regimen was also evaluated for MRD response in previously untreated patients. Of 21 evaluable patients, 15 patients (71%) had a CR, one patient (5%) had nodular PR (nPR) and four patients (19%) had a PR. All patients with CR or nPR and three of four patients with PR achieved MRD-negative response (Wierda et al, 2007).

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Figure 1.  Kaplan–Meier analyses for (A) treatment-free survival (TFS) and (B) overall survival (OS) in patients with relapsed and/or refractory chronic lymphocytic leukaemia treated with single-agent alemtuzumab. (A) Median TFS was significantly increased in patients achieving minimal residual disease (MRD)-negative response (not reached) compared with patients with MRD-positive complete response (CR) (20 months), partial response (PR) (13 months), or no response (6 months) (< 0·0001). (B) Median OS was significantly increased in patients with MRD-negative response (not reached) compared with patients with MRD-positive CR (60 months), PR (70 months), or no response (15 months) (= 0·0007). (Reprinted from Moreton et al, 2005, with permission from the American Society of Clinical Oncology.)

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Alemtuzumab has also been evaluated as consolidation therapy to eliminate MRD in patients responding to induction chemotherapy. As single-agent alemtuzumab has reduced activity in the lymph node compartment, initially debulking the tumour load with chemotherapy agents may optimize the activity of alemtuzumab and improve the initial response to chemotherapy while eliminating MRD. As summarized in Table IV, consolidation therapy with alemtuzumab improves the quality of remission and allows a substantial proportion of patients to achieve MRD negativity (O’Brien et al, 2003a,b; Wendtner et al, 2004; Montillo et al, 2006).

Table IV.   Activity of alemtuzumab as consolidation therapy in CLL.
No. of patientsPrior therapyInduction chemotherapyResponse to induction chemotherapyAlemtuzumab consolidation regimenResponse to alemtuzumab consolidation therapyReference
  1. PR, partial response; nPR = nodular PR; CR, complete response; PD, progressive disease; MRD, minimal residual disease; IV, intravenous; SC, subcutaneous; C, cyclophosphamide.

  2. *PR because of residual splenomegaly or lymphadenopathy.

58 (49 evaluable)Median 2 prior lines of therapy (range 1–7) Not specified7 CR 19 nPR 32 PR10 or 30 mg IV three times weekly for 4 weeks; if persistent MRD, four additional weeks of 30 mg9 nPR improved to CR; 12 PR improved to nPR or CR; 11 MRD-negative responses among 29 patients assessedO’Brien et al (2003a,b)
21No prior therapyFlu 25 mg/m2 IV, days 1–5 of 4-week cycle; or Flu 30 mg/m2 IV + C 250 mg/m2 IV days 1–3 of 4-week cycle (up to six cycles)Alemtuzumab: 1 CR  10 PR Observation:  2 CR  2 nPR  3 PR  3 PD30 mg IV three times weekly (up to 12 weeks)3 CR 8 PR* 5 MRD-negative responses among six patients assessedWendtner et al (2004)
34No prior therapyFlu 25 mg/m2 IV, days 1–5 of 4-week cycle; or Flu 25 mg/m2 IV + C 250 mg/m2 IV days 1–3 of 4-week cycle 12 CR  7 nPR  15 PR10 mg SC 3 times weekly for 6 weeks27 CR (19 MRD-negative) 4 nPR 3 PRMontillo et al (2006)

Consolidation therapy with alemtuzumab improved responses in 53% of patients (among 49 evaluable), including MRD-negative responses in 11 of 29 evaluable patients (38%) as assessed by patient-specific polymerase chain reaction (PCR) assay (O’Brien et al, 2003a,b). The most common adverse events were infusion-related toxicities that were all grade 1 or 2 in severity. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 30% and 14% of patients respectively. Infections occurred in 37% of patients, including CMV reactivation in 22% (O’Brien et al, 2003b) and three patients developed Epstein–Barr virus-positive large cell lymphoma, which resolved without chemotherapy in all three cases.

In a comparative phase 3 trial conducted by the GCLLSG, 21 patients were randomized to receive observation or alemtuzumab consolidation therapy following first-line fludarabine-based induction therapy. The 11 alemtuzumab-treated patients were more likely to achieve MRD-negative remissions (five of six patients assessed) compared with observation-only patients (0 of three patients assessed) (Wendtner et al, 2004). After a median follow-up of 31·3 months from start of first-line treatment, only one relapse had occurred in the alemtuzumab arm compared with seven in the observation-only arm (Fig 2). Infusion-related toxicities were common among the patients receiving alemtuzumab but were grade 1 or 2 in severity in all cases. This GCLLSG trial was halted early because of a high incidence of severe infectious events in the consolidation arm, which included seven grade 3 infections and one case of grade 4 pulmonary aspergillosis. The GCLLSG study was reopened as a dose-finding phase 1 and 2 trial to evaluate the optimal dosing regimen with consolidation therapy.

image

Figure 2.  Progression-free survival (PFS) in the randomized phase 3 study of the German CLL Study Group. Median PFS was significantly prolonged among patients randomized to receive alemtuzumab consolidation therapy (n = 11) compared with patients who were under observation only (n = 10) (not reached versus 27·7 months; = 0·033).

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Patients up to 65 years of age with MRD following initial response to first-line fludarabine-based therapies were treated with alemtuzumab 10 mg SC three times weekly for 6 weeks (Montillo et al, 2006). Following alemtuzumab consolidation, the quality of remission was improved in (53%) and the CR rate improved from 35% to 79% after induction therapy) and an MRD-negative CR was achieved in 56% of patients. Peripheral blood stem cells (PBSC) were successfully harvested in 92% of the 26 patients undergoing stem cell collection. Among 18 patients who underwent SCT, 17 remained in CR at 14·5 months after transplantation. In addition, nine patients (eight CR, one PR) who did not undergo SCT remained progression-free at a median follow-up of 17 months (Montillo et al, 2006). The use of alemtuzumab as consolidation therapy after fludarabine-based induction did not compromise PBSC collection and engraftment and is therefore feasible for patients undergoing autologous SCT. First-dose reactions were primarily grade 1 or 2 in severity, and only one grade 3 rash and one grade 3 fever were reported. Notably, no bacterial or fungal infections occurred in this study; although there were 18 cases of CMV reactivation, active infections were prevented in all cases by prompt ganciclovir treatment (n = 15) or by spontaneous resolution (n = 3). One patient with an MRD-negative CR died because of Richter’s transformation.

Alemtuzumab in CLL patients with high-risk cytogenetics

Cytogenetic studies using fluorescence in situ hybridization (FISH) analysis with chromosome-specific DNA probes have demonstrated that genetic abnormalities are present in approximately 80% of patients with active CLL, even among those with previously untreated disease (Dohner et al, 2000; Dewald et al, 2003). The most common chromosomal abnormality in CLL is monoallelic 13q deletion; followed by 11q deletion, 12q trisomy, and 17p deletion, with many patients having more multiple chromosomal abnormalities. Patients with deletions to chromosome 17p, including the tumour suppressor gene TP53, have the worst prognosis, with rapid disease progression (median 9 months from diagnosis) and significantly decreased OS (median 32 months from diagnosis) compared to patients with other genetic abnormalities or normal cytogenetics (Dohner et al, 2000). In studies evaluating various prognostic factors in a multivariate regression model, the presence of 17p deletion emerged as a strong predictor of decreased OS, independent of the immunoglobulin heavy chain variable region (IGHV) mutational status (Krober et al, 2002, 2006; Oscier et al, 2002). The outcomes were very similar among patients with Binet stage A disease, providing evidence of the significant negative impact of high-risk genetic abnormalities on survival outcomes even in patients with early stage CLL.

Several large, independent clinical studies have demonstrated that 17p deletion predicts for significantly decreased response rates, PFS and/or OS in patients with CLL receiving first-line fludarabine-based regimens (Byrd et al, 2006; Catovsky et al, 2007; Grever et al, 2007). Gene expression profiling suggests that fludarabine induces a p53-dependent response in CLL cells (Rosenwald et al, 2004), and resistance to fludarabine therapy is associated with dysfunctional p53. In contrast, alemtuzumab has considerable efficacy in patients with high-risk cytogenetic profiles and is capable of inducing responses in patients with relapsed and/or refractory CLL regardless of 17p deletion or TP53 mutation status (Stilgenbauer & Dohner, 2002; Lozanski et al, 2004; Osuji et al, 2005). Further, preliminary data from the CamFlud trial suggested that alemtuzumab-based therapy can induce MRD-negative CRs even among fludarabine-refractory CLL patients with 17p deletions (Sayala et al, 2006). Collectively, these studies point to the potential benefit of a risk-stratified treatment approach in CLL. Pending results of larger, prospective trials, alemtuzumab-based therapy represents a rational choice for the first-line treatment of CLL patients with 17p deletion and may be useful in other high-risk cytogenetic abnormalities.

Alemtuzumab in other lymphoproliferative disorders

  1. Top of page
  2. Summary
  3. Alemtuzumab in CLL: mechanism of action
  4. Alemtuzumab in the treatment of relapsed/refractory CLL
  5. Alemtuzumab in other lymphoproliferative disorders
  6. Application of alemtuzumab in SCT
  7. Alemtuzumab in other non-malignant diseases
  8. Summary and conclusions
  9. Acknowledgements
  10. References

Non-Hodgkin lymphoma (NHL)

Earlier in its development, alemtuzumab therapy demonstrated promising activity in patients with NHL (Hale et al, 1988); since then, several studies have evaluated alemtuzumab in the treatment of both low-grade and intermediate- to high-grade NHL. In a phase 2 multicentre trial by the European Study Group, patients with previously treated, relapsed (n = 25) or resistant (n = 25) low-grade NHL (Kiel classification) were treated with standard-dose alemtuzumab (Lundin et al, 1998). According to predefined criteria, the ORR was 20% (4% CR; achieved in only two of eight patients with mycosis fungoides) and an additional 48% of patients had stable disease. Consistent with previous studies of alemtuzumab in patients with CLL, rapid clearance of malignant cells from the peripheral blood and bone marrow were observed, with CR rates of 94% and 32% respectively, whereas the response in the lymph node compartment was minimal (Lundin et al, 1998). The median time to progression for all patients was 4 months; among the four patients with mycosis fungoides who achieved a response, the median time to progression was 10 months.

In another phase 2 study, patients with previously treated, non-bulky NHL were treated with standard-dose alemtuzumab for up to 14 weeks (Khorana et al, 2001). The study enrolled patients with various grades of NHL, including low-grade (n = 6; primarily follicular lymphoma), intermediate-grade (n = 8), and high-grade (n = 1; NHL transformed to lymphoblastic) NHL and mantle cell lymphoma (n = 3). Patients received a median of two prior chemotherapy regimens (range 1–4), and three patients had previously undergone autologous SCT. The ORR was 22%, with 17% CR (n = 3; all in patients with low-grade NHL, including a durable PCR-negative CR in one patient with follicular lymphoma). Although this study showed promising results, the trial was terminated early due to a high incidence of infectious complications. Alemtuzumab was further evaluated in a recent phase 1–2 study that enrolled patients with low-grade (n = 16; CLL in seven patients) and high-grade (n = 2) NHL (Uppenkamp et al, 2002). Patients were heavily pretreated and had received a median of three prior chemotherapy regimens (range 1–4) prior to alemtuzumab therapy. Based on predefined response criteria, the ORR was 44%; no patients achieved a CR, and responses (classified as major disease improvement or disease improvement) were observed primarily in patients with CLL. The median duration of response, however, was 3·5 months. The toxicities observed in patients with NHL treated with alemtuzumab were generally similar to those reported in previous studies in CLL.

T-cell malignancies

Alemtuzumab has been evaluated in patients with T-cell NHL, including T-PLL, CTCL and other peripheral T-cell lymphoma (PTCL). Currently, no approved standard of treatment exists for T-PLL, although alemtuzumab has demonstrated significant activity in patients with this malignancy (Table V). In studies that evaluated alemtuzumab in patients with primarily pretreated T-PLL, the ORR ranged from 51% to 76% (40–60% CR rates), and the median OS was 15–16 months among patients who achieved CR (Dearden et al, 2001; Keating et al, 2002b). In this patient population, toxicities were manageable and included infusion-related adverse events (grade 1 or 2) in nearly all patients, infectious events in 13–18%, and transient grade 3 or 4 haematological toxicities in only 8–13% of patients. Mycosis fungoides/Sézary syndrome is the most common form of CTCL, and the treatment of advanced, refractory disease remains a challenge. In a phase 2 study, 22 patients with advanced (primarily stage III or IV) mycosis fungoides/Sézary syndrome were treated with alemtuzumab 30 mg three times weekly for up to 12 weeks (Lundin et al, 2003). The ORR was 55% (32% CR, 23% PR) (Table V). Erythroderma improved in 69% of patients, with complete resolution in 38%. The CR rate for skin plaque/tumours was 30%. The median time to treatment failure was 12 months among patients who achieved a response. Consistent with previous reports of alemtuzumab therapy, the most common adverse event was infusion-related toxicity, which was primarily grade 1 or 2 in severity. Transient grade 4 neutropenia and thrombocytopenia occurred in 18% and 5% of patients respectively. Infectious events were common, but severe infectious events mostly occurred in patients with heavily pretreated (>3 prior lines of therapy) disease (Lundin et al, 2003). A separate study in a smaller group of patients with mycosis fungoides/Sézary syndrome (n = 8) reported less favourable outcomes (38% ORR, no CR) with alemtuzumab therapy (Kennedy et al, 2003). Patients with advanced PTCL have limited treatment options, and in patients with chemotherapy-refractory disease, the prognosis is poor. Alemtuzumab was evaluated in patients with advanced, relapsed and/or refractory PTCL with promising responses, including CR rates in 20% of patients (Enblad et al, 2004; Zinzani et al, 2005). A reduced dose of alemtuzumab (10 mg three times weekly) may be better tolerated in this heavily pretreated population, however, because standard doses were associated with a high incidence of infectious events.

Table V.   Activity of single-agent alemtuzumab in relapsed and/or refractory T-cell malignancies.
No. of patientsDisease typeMedian no. of prior therapies (range)Median age, years (range)Response rate, %Median response duration, months (range)Median OS, monthsReference
  1. DFI, disease-free interval; MF/SS, mycosis fungoides/Sézary syndrome; NR, not reported; ORR, overall response rate; CR, complete response; OS, overall survival; MRD, minimal residual disease; TTF, time to treatment failure.

  2. *Two patients were previously untreated.

  3. †Four patients were previously untreated.

  4. ‡Alemtuzumab was administered at a reduced dose of 10 mg three times weekly up to 4 weeks only.

39*T-PLLNR; 62% were refractory to prior therapy57 (34–78)ORR, 76CR, 60DFI 7 (4–45)10 for all; 16 for patients with CRDearden et al (2001)
76†T-PLL2 (0–5)60 (35–84)ORR, 51  CR, 409 for patients with CR (0·1–44)8 for all; 15 for patients with CRKeating et al (2002b)
22MF/SS3 (1–5)61 (38–77)ORR, 55  CR, 32TTF 12 for responders (5–32+)NRLundin et al (2003)
 8MF/SS7 (1–17)48 (30–62) ORR, 38  CR, 02·5 for responders (2–3·5)NR; 6 patients died at median 4 months after start of therapyKennedy et al (2003)
14PTCL2 (1–4)61 (53–79)ORR, 36  CR, 216 for patients with CR (2–12)NREnblad et al (2004)
10‡PTCL3 (2–4)65 (49–76)ORR, 60  CR, 207 (2–10)NRZinzani et al (2005)

Application of alemtuzumab in SCT

  1. Top of page
  2. Summary
  3. Alemtuzumab in CLL: mechanism of action
  4. Alemtuzumab in the treatment of relapsed/refractory CLL
  5. Alemtuzumab in other lymphoproliferative disorders
  6. Application of alemtuzumab in SCT
  7. Alemtuzumab in other non-malignant diseases
  8. Summary and conclusions
  9. Acknowledgements
  10. References

The Campath-1 family of monoclonal antibodies (e.g. Campath-1M, Campath-1G) was initially developed as T-cell depleting agents, and earlier studies have demonstrated considerable efficacy of these antibodies in preventing both GVHD and graft rejection in patients undergoing allogeneic SCT (Hale et al, 1983, 1998; Waldmann et al, 1984; Hale & Waldmann, 1994).

High-dose myeloablative therapies with SCT support have been extensively used in patients with various haematological malignancies, but elderly patients or patients with poor performance status are not suitable to receive such therapies because of the high risks for potential transplantation-related mortality. Recently, reduced-intensity (or non-myeloablative) conditioning regimens have been evaluated to reduce transplantation-related mortality while facilitating engraftment. Data from emerging studies suggest that incorporating alemtuzumab as part of a non-myeloablative conditioning regimen is effective in reducing severe GVHD and related mortality. Several studies evaluating a non-myeloablative conditioning regimen with alemtuzumab (20 mg days −8 to −4), fludarabine (30 mg/m2 days −7 to −3) and melphalan (140 mg/m2 day −2) in patients with haematological malignancies have demonstrated low incidences of grade 3 or 4 acute GVHD (<6% of patients) and chronic GVHD (<7%) with this regimen (Kottaridis et al, 2000; Chakraverty et al, 2002; Perez-Simon et al, 2002; Morris et al, 2004). The use of alemtuzumab-based conditioning regimens, however, is associated with potentially high incidences of infections and other complications. Among patients considered at risk for CMV reactivation (donor or recipient CMV-seropositive), 60–80% have developed CMV infection (symptomatic or asymptomatic) (Chakrabarti et al, 2002; Morris & Mackinnon, 2005; Delgado et al, 2006). Among patients receiving alemtuzumab-containing conditioning for SCT, the use of prophylactic ganciclovir prior to SCT, combined with acyclovir and high-dose valacyclovir significantly decreased the cumulative incidence of CMV reactivation compared with the use of acyclovir alone (29% vs. 53%; = 0·004) (Kline et al, 2006). In addition, no patients receiving the ganciclovir/valacyclovir treatment developed CMV disease compared with one patient in the acyclovir group. Other viral and fungal infections remain a common cause of morbidity and death. Infections, overall, have been reported as a cause of death in 8–22% of patients in recent clinical studies (Chakrabarti et al, 2002; Delgado et al, 2006). Other potentially life-threatening complications have been reported with the use of alemtuzumab-based conditioning regimens in SCT. In a study that assessed the use of alemtuzumab combined with total body irradiation and cyclophosphamide conditioning prior to autologous SCT in patients with CLL (the CLL3C trial of the GCLLSG), unexplained skin rashes developed in 12 of 16 patients and severe autologous GVHD was diagnosed in seven patients (Zenz et al, 2006). In addition, 69% of patients developed infectious events, which were primarily viral in origin. Because of the high incidence of complications observed in this study, the CLL3C trial was closed early and the investigators recommended against the use of alemtuzumab in combination with total body irradiation for autologous SCT. Currently, two registration trials are ongoing in Japan to evaluate the role of alemtuzumab in SCT. The results of these trials will further define the optimal use of alemtuzumab in this therapeutic setting.

Alemtuzumab in other non-malignant diseases

  1. Top of page
  2. Summary
  3. Alemtuzumab in CLL: mechanism of action
  4. Alemtuzumab in the treatment of relapsed/refractory CLL
  5. Alemtuzumab in other lymphoproliferative disorders
  6. Application of alemtuzumab in SCT
  7. Alemtuzumab in other non-malignant diseases
  8. Summary and conclusions
  9. Acknowledgements
  10. References

Because of its remarkable ability to deplete B and T cells, alemtuzumab is attracting interest as a new therapy for a number of immunological disorders, such as rheumatoid arthritis (RA) and multiple sclerosis (MS). In an earlier study of alemtuzumab in 41 patients with active and refractory RA, 20% patients had 50% Paulus response at 6 months and the majority of patients had symptomatic improvement (Isaacs et al, 1996). Alemtuzumab has also demonstrated encouraging activity in MS. A recent study evaluated alemtuzumab in 39 patients with aggressive relapsing MS. The mean annualized relapse rate was 0·19 after alemtuzumab treatment, compared with 2·48 pretreatment. Following treatment, 83% of patients had stable or improved disability (Hirst et al, 2008). An ongoing phase 3 randomized trial is comparing alemtuzumab with interferon beta-1 in patients with relapsing-remitting MS (ClinicalTrial.gov identifier: NCT00548405).

Summary and conclusions

  1. Top of page
  2. Summary
  3. Alemtuzumab in CLL: mechanism of action
  4. Alemtuzumab in the treatment of relapsed/refractory CLL
  5. Alemtuzumab in other lymphoproliferative disorders
  6. Application of alemtuzumab in SCT
  7. Alemtuzumab in other non-malignant diseases
  8. Summary and conclusions
  9. Acknowledgements
  10. References

In its earlier stages in the clinic, the Campath-1 family of antibodies was studied for its activity in preventing GVHD and graft rejection in patients undergoing SCT. Alemtuzumab has since emerged as an important agent in the treatment of CLL, with expanding roles within CLL as well as in other therapeutic areas, such as T-cell disease, and as part of the conditioning regimen in SCT. Ongoing research in CLL has indicated that eradication of MRD improves the quality of responses and disease-free survival and OS and may be the key to a potential cure in this disease. Alemtuzumab has demonstrated the ability to eliminate MRD in some patients, including those with high-risk profiles, such as heavily pretreated, fludarabine-refractory CLL. Moreover, alemtuzumab has demonstrated high response rates in patients with high-risk cytogenetic profiles, suggesting its potential role as a frontline treatment for these poor-prognosis subgroups. The ability to eliminate MRD with therapies such as alemtuzumab and the associated increase in survival is beginning to shift the focus of treatment for CLL from traditional palliative approaches toward the possibility of a cure. Alemtuzumab has also shown promising activity in T-cell malignancies, prompting the initiation of prospective studies that will better define the role of alemtuzumab in these disease areas. More recently, emerging studies suggest the potential role of alemtuzumab in reducing GVHD in patients undergoing SCT. Studies will continue to reveal the optimal application of alemtuzumab in CLL and in other therapeutic areas, shedding new light on how we will incorporate this ‘old’ agent into our practices.

Acknowledgements

  1. Top of page
  2. Summary
  3. Alemtuzumab in CLL: mechanism of action
  4. Alemtuzumab in the treatment of relapsed/refractory CLL
  5. Alemtuzumab in other lymphoproliferative disorders
  6. Application of alemtuzumab in SCT
  7. Alemtuzumab in other non-malignant diseases
  8. Summary and conclusions
  9. Acknowledgements
  10. References

J. G. G. has received honoraria as a speaker for Roche, Schering AG, Amgen and Genentech. M. H. has received clinical research support from Schering AG and from the Competence Network on Malignant Lymphoma funded by the German Ministry for Education and Research.

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  2. Summary
  3. Alemtuzumab in CLL: mechanism of action
  4. Alemtuzumab in the treatment of relapsed/refractory CLL
  5. Alemtuzumab in other lymphoproliferative disorders
  6. Application of alemtuzumab in SCT
  7. Alemtuzumab in other non-malignant diseases
  8. Summary and conclusions
  9. Acknowledgements
  10. References
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