Saturday, May 27, 2006

Steroids 3

After a long interval, I want to complete this subject with an essay on how steroids are used in CLL.

First, it goes without saying that where steroids are used in autoimmune diseases, they are also used in autoimmune disease associated with CLL. Thus for AIHA and ITP, and for paraneoplastic pemphigus steroids are used in a conventional way starting with a dose of 1 mg/kg and tailing off once the complication is controlled.

But steroids are also used as a treatment for CLL, either alone or in combination with chemotherapy or antibody therapy. Early studies showed no benefit from adding steroids to chemotherapy. The British CLL2 trial, for example, compared chlorambucil 20 mg/sq m for 3 days every 4 weeks with the same dose plus prednisolone 40mg/sq m for 5 days ever 4 weeks. There was no significant difference in response rates (74% v 80%) or in overall survival. After this study the recommendation was made that steroids only be used in patients with anemia or thrombocytopenia for the first or second course as anecdotally it was thought that such an approach afforded some protection from the potential marrow damaging affect of chlorambucil.

At the MD Anderson Cancer Center they don’t do comparative trials, but they compare successive phase II studies. The combination of fludarabine at 30 mg/ sq m/d for 5 days combined with prednisone at 30 mg/sq m/d for 5 days every 4 weeks was certainly no improvement on fludarabine alone, and may well have been worse, although with historical controls such a comparison lacks authority.

The use of high dose methylprednisolone with a dose of 1g/ sq m/ d for 5 days – about 30 times the dose that was used with chlorambucil in CLL 2 – was a development from the Royal Marsden Hospital, in London. They found that most patients responded to this, even those who were resistant to chlorambucil or fludarabine.

How does high dose methylprednisolone work? It seems to have a direct lympholytic effect that does not depend on the presence of steroid receptors, and does nor depend on the presence of p53.

Recently, two trials of high dose methylprednisolone (HDMP) and monoclonal antibody have begun. In Britain the combination of Campath and HDMP is being trialled, and in America HDMP plus rituximab. The logic of using Campath with HDMP is that both agents are effective in CLL with a crippled p53 pathway, the commonest cause of drug resistance. Rituximab is ineffective in these patients, but perhaps the combination is more effective. Both these studies are phase II trials, so we will not discover whether either combination is better than single agent treatment.

The suggestion has been made that steroids will render the effector cells used in ADCC ineffective. Although theoretically this seems to be a problem, in practice it does not seem to matter. Perhaps the other methods of killing that antibodies invoke synergize with the effects of the high dose steroids.

It is important to remember that high doses of steroids have major side effects. In diabetics there will be immediate loss of control of blood sugar and sometimes in pre-diabetics the existence of this precursor condition will be revealed. It is important therefore to monitor blood sugar. There is likely to be a change in psyche. Some patients are unable to sleep, others weep in an uncontrolled manner. Others are on a permanent high. Appetite is markedly increased. Blood pressure often goes out of controlled. Some patients will suffer bony collapse – crush fractures of the vertebrae are a possibility, and necrosis of the femoral head (hips) both occur, though usually only after repeated doses and with other auxiliary factors.

Infections are a real possibility. Reactivation of herpes infections such as zoster, herpes simplex and CMV, infections with Pneumocystis, Listeria monocytogenes, Aspergillus and other fungi, are a real possibility and therefore patients on these regimens need to be carefully monitored by doctors with experience of these complications.

In conclusion, steroids clearly have a role in CLL, but that role is not clearly defined. Apart from their use in the autoimmune complications, they are useful in displacing cells from relatively inaccessible sites like bone marrow and lymph nodes, and in high doses for their lympholytic effect which is active even in drug-resistant cases.


Anonymous said...

Terry: Thanks for this very clear and sensible review of the use of steroids in CLL. They clearly have a role to play in this disease, but like with everything else they are not a "free lunch".

I am particularly interested in the Campath + HDMP trial in the UK, for refractory and p53 deficient patients. Can you tell us more about it?

Chaya said...

That previous comment was from me, I am not quite sure how to comment so that it does not show up as anonymous.

Thanks for evrything Terry. You are the best thing that ever happened to CLL patients.


Jim McVey said...

I wondered if anonymous was Chaya.
The "Free Lunch" was the clue.

Chaya you are no slouch either and with Terry you make a formidable team.

ramez said...

My hematologist just put me on steroids as first treatment for low hemoglobin counts. With all the cautions that come with the drug I wondr lf it is worth it. This article is still so very helpful and Dr Hamblin is as Chaya described him: the best thing to happen to Cll sufferers.

Terry Hamblin said...

Most of the side effects of steroids come with prolonged use. When given in short bursts they are invaluable. When my arthritis gets really bad I take a quick 2 week burst with no side effects.

Anonymous said...

Dr. Kipps has been using HDMP and rituxan against CLL for some time now. The results have been good, but not superlative. There have been complete remissions but few molecular remissions, and people tend to relapse with depressing regularity (as with most other drugs).

The latest wrinkle is using a higher dose of rituximab with HDMP. That trial was supposed to start in January 2006, but has been delayed, and delayed and delayed.

Since no therapy is curative (except perhaps a transplant), it makes sense to use a therapy that is relatively free from serious side effects, but gives a good chance of a decent remission.

I don't know if the remissions will be particularly long, but most people seem to sail through the therapy.

The length of the steriod course was shortened from five days to three in untreated patients, to reduce the possibility of infection and other profound deleterious side effects.