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First-line Treatment for Chronic Lymphocytic Leukaemia – The Time for Alemtuzumab?
been shown to give better complete remission (CR) rates and
Table 1: Prognostic Markers in Chronic Lymphocytic Leukaemia
progression-free survival (PFS) compared with the cyclophosphamide,
doxorubicin and prednisone (CAP) regimen and with chlorambucil in
Characteristic Favourable Poor
randomised trials.
26–29
Although all patients eventually relapsed, the
Clinical stage Binet A, Rai 0/I Binet C, Rai III/IV
conclusion drawn from these studies was that fludarabine was one of
Gender Female Male
Lymphocyte morphology Typical ‘Atypical’, increased
the most active single agents in CLL and should form the building
pro-lymphocytes
block of subsequent therapies. Since then, combinations of
Lymphocyte doubling time >12 months <12 months
fludarabine and cyclophosphamide (FC) and, more recently,
Bone marrow biopsy Nodular/interstitial Diffuse
fludarabine, cyclophosphamide and mitoxantrone have been Serum markers (β2M, LDH, Normal Raised
investigated. These agents gave high RRs in single-institution studies
thymidine kinase, CD23)
and showed higher CR rates and longer PFS than single-agent purine
Cytogenetic abnormalities None, 13qdel (sole) 11q del, 17p del
analogues.
30,31
In a small fraction of patients these combinations
IgVH genes Mutated Unmutated
CD38 <30% >30%
eradicated minimal residual disease (MRD). As with many
ZAP 70 <20% >20%
malignancies, eradication of MRD translates into longer PFS and long-
term survival.
31
antibody-dependent cellular cytotoxicity and/or induction of apoptosis.
In the last two years, three large phase III studies comparing In patients with relapsed or refractory CLL after fludarabine and
fludarabine alone versus combination FC therapy for CLL patients alkylator therapy, alemtuzumab induced a 33% ORR, including some
requiring their first treatment have reported the superior objective CRs, with additional clinical benefit seen in patients with stable
response rate (ORR), CR and PFS seen with the FC combination.
32–34
disease.
39
A number of other small studies have confirmed the activity
These trials included more than 1,000 patients overall, and in one of alemtuzumab in patients with fludarabine-refractory CLL. In one of
study one-third of the patients were over 70 years of age and had these studies a proportion of patients achieved eradication of MRD,
similar RR and toxicity to those in the younger age group.
34
This has and this was associated with improved survival.
40
Importantly,
shifted the standard of care for CLL towards the use of FC combination alemtuzumab is particularly active in those patients who have a TP53
therapy for younger patients (<65 years of age) and for fitter older deletion detected by FISH and who typically are resistant to
patients without significant co-morbidities. Despite these encouraging conventional fludarabine-based treatment.
41–43
results, patients with disease refractory to standard chemotherapy
have a particularly poor prognosis, and currently there is no accepted Another approach to the use of alemtuzumab is based on the concept
standard treatment. that this monoclonal antibody may be effective at purging residual
disease in patients who achieve a maximal response after fludarabine-
Immunotherapy in Chronic Lymphocytic Leukaemia based induction treatment. Results from a preliminary study in nine
Over the past two decades significant advances in the development of patients were encouraging, since all but one patient achieved CR and
monoclonal antibodies have improved treatment results in a number 33% became polymerase chain reaction (PCR)-negative for IGVH.
of haemopoietic malignancies. In CLL, two antibodies have been Several studies using different schedules and doses have shown the
studied: rituximab, a chimeric human–mouse anti-CD20, and feasibility of this approach, with improved responses in 50–60% of
alemtuzumab (campath-1H), a humanised anti-CD52 antibody. patients.
44–47
One study randomised patients to receive consolidation
with alemtuzumab compared with observation and demonstrated
Rituximab has proven efficacy for patients with B-cell lymphomas, improved PFS for the treatment arm.
48–49
especially when used in combination with chemotherapy. In CLL, when
used as a single agent it is less effective, probably because of the lower As yet, there is rather little published data on completed trials of
expression of CD20 in this disease. However, in combination with purine alemtuzumab in combination regimens in either the refractory or first-
analogues and alkylating therapy in the fludarabine and rituximab (FR) line setting. Preliminary data suggest that fludarabine-based
or fludarabine, cyclophosphamide and rituximab (FCR) regimens, results combinations are effective (ORR ~80% in relapsed CLL) and well
have been very promising.
35,36
As first-line therapy, FCR has induced tolerated; it remains to be seen how these compare with rituximab-
remissions in >90% of patients, with CR seen in 70%.
36
based regimens.
Alemtuzumab was the first of this class of drug to receive approval in Alemtuzumab as First-line Therapy
the US and Europe for use in the treatment of patients with refractory Results from a phase II trial of alemtuzumab as first-line therapy for
CLL. More recently, it has been approved for the first-line treatment of B-CLL showed an ORR of 81%. Moreover, seven patients achieved CRs
patients with B-cell CLL (B-CLL) for whom fludarabine-based and 26 partial responses.
50
In this study, alemtuzumab was administered
chemotherapy is not appropriate. subcutaneously for up to 18 weeks.The long-term follow-up report on
these patients showed a median time to treatment failure of 28 months
Alemtuzumab in Chronic Lymphocytic Leukaemia in the alemtuzumab group compared with 17 months in the matched
Alemtuzumab is a recombinant monoclonal antibody against CD52, a historical controls who received various chemotherapy agents as first-
surface protein highly expressed on most normal and malignant B and line therapy.
51
T lymphocytes
37
but not on haemopoietic stem cells.
38
Once bound to
CD52, alemtuzumab induces cell death by one or more of the CAM307, an international, multicentre, open-label phase III trial,
following mechanisms: complement-dependent cellular cytotoxicity, compared alemtuzumab with chlorambucil in previously untreated CLL
EUROPEAN ONCOLOGY 51
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