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colour flow cytometry, had a significantly prolonged PFS and OS. In this Immunochemotherapy with Alemtuzumab
study, 91 CLL patients were treated with alemtuzumab for a median period Currently, there are limited data regarding immunochemotherapy with
of nine weeks, initially at 3mg daily with titration upwards through 10mg alemtuzumab, and several trials utilising alemtuzumab immuno-
daily to 30mg three times weekly. The technique used to assess MRD in the chemotherapeutic regimens are ongoing in the first-line setting. Not
study was very sensitive, detecting one CLL cell per 10,000 normal cells. surprisingly, a number of studies are investigating the combination of
MRD was reduced to below the threshold of detection in 20% of patients the most effective chemotherapeutic agent with alemtuzumab. The
following alemtuzumab therapy. In those patients who achieved MRD combination of fludarabine and alemtuzumab has been investigated in a
negativity, OS was significantly prolonged, an observation that supports the phase II trial in patients with relapsed CLL.
The fludarabine and
contention that the achievement of MRD negativity is a desirable treatment alemtuzumab combination administered in a four-weekly dosing protocol
end-point in CLL, irrespective of what first-line treatment is given. achieved an ORR of 83% (30/36 patients), with 30% CR and 53% PR.
Importantly, 53% of evaluable patients were MRD-negative at three-month
The idea that further reduction of the tumour burden could be of clinical follow-up. The phase II UKCLL202 trial evaluated the combination of
benefit was the rationale for the several studies involving alemtuzumab as alemtuzumab and fludarabine (CamFlud) in fludarabine-refractory CLL
consolidation therapy after fludarabine-based induction regimens. A small patients. Subcutaneous alemtuzumab was given three times weekly for up
series conducted by O’Brien et al. showed that alemtuzumab at a reduced to 24 weeks (median 18.8 weeks) depending on six-weekly marrow
dose achieved additional significant responses in patients with residual assessments or until maximum response. Non-responders after 12 weeks of
disease after chemotherapy.
Similar results were reported by Montillo and alemtuzumab therapy then received fludarabine concurrently for three days
In both studies an improvement in response was reported in every four weeks. Seventeen patients received alemtuzumab plus
approximately half of the patients treated with alemtuzumab consolidation fludarabine: one patient achieved CR and two achieved PR.
therapy. Importantly, MRD negative status, as defined by negative
polymerase chain reaction (PCR) with consensus IgH primers, was achieved Future Directions
in one-third of the patients. There is a growing body of evidence that alemtuzumab is effective in CLL.
Alemtuzumab monotherapy has been shown to be effective in both first-
The GCLLSG trial (CLL4B) is the only randomised study to date to evaluate line and refractory CLL. Alemtuzumab is associated with risk of toxicity,
alemtuzumab consolidation versus observation following first-line especially with bacterial and viral infections,
although these infections
fludarabine or FC therapy. Although this trial was closed early due to an appear to be manageable with standard therapies.
unacceptable rate of infectious disease complications (seven of the 11 alemtuzumab is currently licensed for intravenous administration,
patients receiving alemtuzumab had severe infections), data from the evidence suggests that subcutaneous administration of alemtuzumab may
study showed a significant improvement in PFS for patients receiving reduce the incidence of non-haematological adverse events.
The increased incidence in infectious body of evidence also suggests that alemtuzumab may be useful as
toxicity between the German CLL Study Group experience and previous consolidation therapy and in immunochemotherapy regimens. The
consolidation studies may have been related to the relatively short time encouraging results seen thus far warrant larger randomised trials to
interval between initial chemotherapy and alemtuzumab consolidation in confirm the effectiveness of alemtuzumab in these settings, as well as
the German CLL Study Group trial (median two months, compared with phase II studies to establish the optimal timing, dose and delivery of the
five months in the Montillo study). Early data from the phase II US Cancer drug. The activity of alemtuzumab in patients with 17p deletions resulting
and Leukemia Group B study CALGB 10101, which is examining a in dysfunction of the p53 pathway is also of clinical importance, especially
regimen of fludarabine and rituximab for six cycles followed by with the increasing ability to stratify patients according to prognostic risk
subcutaneous alemtuzumab for six weeks as consolidation therapy, parameters such as genetic abnormalities. Thus, in CLL patients with p53
reported six infection-related deaths.
In this study, the median time deletion who do not have bulky nodal disease, alemtuzumab may offer
interval between initial chemotherapy and alemtuzumab consolidation appropriate benefits when used as earlier therapy. Furthermore,
was four months. Further ongoing studies evaluating alemtuzumab glucocorticoids may also be useful agents in this setting, and the
consolidation therapy will help to answer questions on optimal timing and effectiveness of combined methylprednisolone and alemtuzumab (CAM-
dosing of the agent in this setting. PRED) is currently under investigation.
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48 EUROPEAN ONCOLOGY
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