I have been meaning to write something about Campath for some time. I first started using this monoclonal antibody before it had been humanized, back in the mid 1980s. Then it was a rat IgM directed against CD52, an antigen present on all lymphoid cells and also on monocytes. It had marvelous complement killing activity and we were using it to lauder bone marrow in lymphoma autografts.
Subsequently, and IgG form has been produced and it has been humanized, though because it is now produced in Chinese Hamster Ovary cells, it does not have proper glycosolation (ie it does not have the correct sugar molecules attached) this is probably why it is not particularly good at penetrating large lymph node masses.
It was only when Campath got in the hands of Schering AG (Berlex in the US) that it was marketed as a treatment for CLL. It has several advantages. Most important, it is one of the few agents capable of killing CLL cells that have a damaged or absent p53. Second, it is capable of eliminating minimal residual disease from blood and bone marrow. Its major disadvantage is that it is very immunosuppressive, killing T cells as innocent bystanders, though not as permanently injurious as fludarabine. This makes it useful as a conditioning agent for bone marrow transplantation, but adds hazards when used to treat CLL.
Quite apart from its use as a drug to mop up residual disease and to treat resistant disease, Campath has been suggested as a first line treatment for CLL. At ASH last year Pete Hillmen presented the results of the CAM307 trial which compared Campath with chlorambucil as first line treatment for CLL. A total of 298 patients were randomized to receive one or other of the agents and the two groups were similar. The primary endpoint was progression-free survival and for this Campath was about 4 months better (p=0.0001). This was particularly true for patients with p53 abnormalities (10.7 months v 2.2 months) though for 11q deletions there was no significant difference. CR rate (24% v 2%) and overall response rate (83% v 55%) also favored Campath. Follow-up is too short to comment on overall survival.
Side effects were greater in the Campath arm, mostly infusion related (fever, chills, hypotension, urticaria) though giving it iv rather than sub q maximizes these effects. Chlorambucil caused more nausea and vomiting though giving it as a single dose once a month maximizes these effects. Asymptomatic CMV viremia occurred in 52% of the Campath patients and CMV infection in 16%. Grade 3/4 fever was commoner with Campath as was grade 3/4 neutropenia.
This really sounds good for Campath, but we have heard it all before. First, we have no evidence that the overall survival will be any different. Second, nobody has been cured. Third, the dose of chlorambucil used was 40 mg/sq meter, not the 70mg/sq meter that is normally given in the UK. Remember that the CALGB trial that showed fludarabine to be better than chlorambucil also used this low dose of chlorambucil, while the higher dose of chlorambucil used by the British CLL4 trial was shown to be equivalent in effect to that of fludarabine with fewer side effects. Also noteworthy is the fact that fludarabine and Campath or sold by the same company.
The final problem with this trial is that we do not know the long term outcome for these patients.
With this in mind Anders Osterberg has published some long term follow up results on 38 patients treated in Sweden with Campath as first line and compared the outcome with 75 historical controls from before the Campath era. These were treated with a variety of regimes including fludarabine, chlorambucil and CHOP. Demographically the two groups were very similar, although the Campath patients were slightly more likely to be stage III or IV. The results indicate a relatively high response rate to Campath compared to the various treatment the control group received, a significantly longer time to treatment failure and a rather lower (and not statistically significant) risk of infection. One important finding was the high rate of Richter's transformation in both Campath treated patients (16%) and historical controls (12%). Median overall survival was 28 months in the Campath treated group, compared to 17 months for the historical control group, although this was not significantly better.
As I have said before, when a regimen is introduced that produces a high rate of cure for CLL or a trial shows a better overall survival rate than what is achievable when starting with chlorambucil first line, then I will give it my backing. However, until that tile I believe in starting with treatment that does least harm to the patient’s immune system, and that treatment is not Campath