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The Role of Alemtuzumab in the Management of Chronic Lymphocytic Leukaemia
in five of nine patients who did not respond to FC.
23
Patients with 17p and Alemtuzumab
11q deletions in the US Intergroup E2997 study experienced reduced PFS, Alemtuzumab is a monoclonal antibody that targets CD52. Since the CD52
although cytogenetics, IgV
H
mutational status, CD38 expression and p53 antigen is highly expressed on CLL B cells and normal T and B lymphocytes,
38
mutational status did not affect CR and ORR.
25
Preliminary analysis of the UK alemtuzumab may offer advantages over rituximab in CLL. It has been
LRF CLL4 study indicates that 17p deletion and 11q deletion were associated evaluated for first-line use alone, in combination with immuno-
with worse PFS and responses.
26
The combination of fludarabine, chemotherapy, as salvage therapy and as consolidation therapy.
39–45
cyclophosphamide and mitoxantrone (FCM) has also demonstrated efficacy
in a phase II trial. The study by Bosch et al. in patients less than 65 years of Defining a Role for Alemtuzumab
age with newly diagnosed CLL requiring therapy showed that FCM Alemtuzumab’s initial European indication was for the treatment of patients
treatment provided a CR of 64%, an ORR of 90% and median response with B-cell CLL (B-CLL) who have been treated with alkylating agents and
duration of 37 months.
27
No patients with 17p deletion detected by who have failed to achieve CR or PR or achieved only a short remission (<6
fluorescence in situ hybridisation (FISH) responded to treatment with FCM. months) following fludarabine therapy. This indication was recently
expanded to include first-line treatment of patients with B-CLL for whom
The Introduction of Targeted Therapies – fludarabine combination chemotherapy is not appropriate. In the US,
The Rituximab Era alemtuzumab was initially approved under accelerated approval regulations
Rituximab, a chimaeric anti-CD20 monoclonal antibody, has transformed for treatment of B-CLL in patients who had been treated with alkylating
the treatment of certain B-cell malignancies such as diffuse large B-cell agents and who had failed fludarabine therapy. Recently, the US labelling
lymphoma (DLBCL) and follicular lymphoma (FL). However, as single-agent was expanded and alemtuzumab was granted regulatory approval as a
therapy the standard dose of rituximab has relatively limited efficacy in single agent for the treatment of B-CLL in the first-line setting.
patients with CLL. Higher doses of rituximab or increased frequency or
duration of therapy are required to elicit comparable responses to those Alemtuzumab in Chemotherapy-refractory CLL
reported for other indolent lymphoid cancers.
28–31
The limited activity of Data from several small studies have demonstrated the activity of
single-agent rituximab in CLL may be due to low expression levels of CD20 alemtuzumab monotherapy in relapsed/refractory CLL.
15,39,42,45–47
In the
on the CLL cells.
32
largest of these studies, 93 patients who had received ≤7 previous therapies,
including at least one alkylating agent-based regimen, and who had failed
Immunochemotherapy with Rituximab fludarabine treatment were treated with alemtuzumab for a maximum of
In contrast to single-agent therapy, immunochemotherapy with rituximab 12 weeks.
42
Alemtuzumab monotherapy produced an ORR of 33%, with
has produced encouraging data. One of the most widely studied 2% CR and 31% PR. The median time to response was 1.5 months and the
immunochemotherapy regimens thus far has been the combination of median duration of response was 8.7 months. These and other studies
fludarabine, cyclophosphamide and rituximab (FCR). This regimen, noted that alemtuzumab was highly active in both blood and bone marrow,
pioneered by investigators from MD Anderson Cancer Center, has been but had a lesser effect in the presence of bulky lymphadenopathy.
15,40,42,48
shown to produce a high complete remission rate in both previously
untreated and relapsed CLL patients. Keating et al. evaluated the efficacy of Alemtuzumab as First-line Therapy
FCR in previously untreated patients with CLL requiring therapy in a phase II The CAM307 study compared chlorambucil with intravenous alemtuzumab
study. With a median of six cycles of FCR, OR and complete remission rates as front-line therapy for CLL.
41
This international, multicentre, open-label
of 95 and 70%, respectively, were achieved.
11
At a median follow-up of six phase III trial randomised 297 patients to receive either alemtuzumab at the
years, OS was 77% and PFS was 51%. Eighty-two per cent of patients in CR standard dose of 30mg intravenously three times per week for up to 12
achieved minimal residual disease (MRD)-negative status.
33
However, it weeks or chlorambucil 40mg/m
2
once every 28 days for up to 12 cycles. In
should be noted that MRD in the study was measured by the less sensitive the alemtuzumab group OR was 83% compared with 55% for the
two-colour flow cytometry and not the recently published, internationally chlorambucil group. Overall median PFS for the alemtuzumab group was
standardised high-sensitivity flow cytometry technique.
34
In previously 14.6 months compared with 11.7 months for the chlorambucil arm. No
treated patients with relapsed or refractory CLL, FCR treatment was differences in OS were observed. In patients who had the cytogenetic
associated with 25% CR, and nodular partial response (PR) and PR were deletion of 17p (p53), alemtuzumab therapy was associated with a three-
achieved in 16 and 32% of patients, respectively. The OR rate was 73%, fold increase in OR compared with chlorambucil. Of the biological
and molecular remissions were seen in one-third of patients achieving CR.
12
prognostic factors identified to date, deletion or mutation of the TP53 gene
Rituximab has also been investigated in other immunochemotherapy at chromosome band 17p13 is one of the most ominous predictors of
regimens, including with fludarabine alone
35
and with pentostatin plus survival and is associated with resistance to conventional chemotherapy.
8,9
In
cyclophosphamide.
36,37
These trials also produced encouraging data, an earlier series in the second-line setting by Lozanski et al.,
43
alemtuzumab
although the FCR combination has produced the strongest results to date. was shown to be effective in CLL patients with p53 defects. These data are
Clinical trials comparing FC, the most effective chemotherapeutic regimen in important as they identify alemtuzumab as one of the few agents with
terms of CR in phase III trials, with FCR are ongoing. The German CLL Study activity in this important sub-group of CLL patients who are refractory to
Group (GCLLSG) CLL8 phase III study, which was evaluating FC versus FCR chemotherapy. Sub-analysis of the CAM307 study also revealed that in
as first-line treatment, closed to recruitment ahead of schedule as the patients with 13q and 11q deletion, alemtuzumab treatment resulted in
primary end-point (PFS advantage) was met. Full results of the CLL8 study statistically significantly superior responses compared with chlorambucil.
are expected to be presented at the American Society of Haematology (ASH)
annual meeting in December 2008. The results of a randomised, open-label Maximal Disease Control in CLL
phase III study comparing the effect of FC versus FCR (REACH) for second- Notably, the study by Moreton et al.
15
demonstrated that patients who
line treatment are also anticipated. achieved CR and who were also negative for MRD, as measured by four-
EUROPEAN ONCOLOGY 47
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