Chlorambucil plus rituximab

Don't read this if you are squeamish.

As readers will know I have long been an advocate of chlorambucil plus rituximab as a logical regimen to study in CLL.

Trying to cure CLL is a forlorn hope in many cases. The most successful regimens at producing molecular remissions - remissions in which the most sophisticated tests available cannot detect a single CLL cell in the body - are achieved with drugs like fludarabine and Campath which are very good at killing CLL cells, but also very good at killing T cells. What no-one has shown yet is that such intensive regimens have ever cured anyone, nor even whether the overall survival with such treatment is better than starting with chlorambucil.

It may be possible to cure people with a transplant, but this is a very high risk strategy. Most people's experience is that you kill more than you cure, and the follow up of mini-transplants, which are less toxic, is too short to know how successful they are.

CLL should not be thought of as just another cancer. As a cancer it is usually not much of a player. Very few CLL sufferers are ravaged by their tumor the way that melanoma attacks you. Melanoma is no respecter of territory it careers about the body setting up colonies wherever it lands. Great black tumors appear in the lungs, the liver, the bowel wall, the muscles, the heart, the spleen, the brain - it knows no bounds. CLL cells in most people obey the rules. They keep to the highway where lymphocytes are supposed to be. They rest in lymph nodes the liver and the spleen, causing traffic jams to be sure, but seldom spilling out into adjacent fields. This is why some doctors talk about a 'good cancer'. But CLL is more than just another cancer.

CLL is the tumor that causes the greatest disruption of the immune system. Until AIDS came along it was the only disease in adults that affected the immune system in a major way. The earliest work that I did on CLL showed that even the mildest cases, stage 0 with a lymphocyte count of less than 10, had impaired immunity. They were not able to respond to a new vaccine that they had not met previously. Everybody thinks that this is an antibody problem; after all, hypogammaglobulinemia - low levels of immunoglobulin in the blood - is a characteristic finding in CLL which is a B cell disease, and the B cells are responsible for making the immunoglobulin. But it is the T cells that instruct the B cells how to make the antibodies and T cells are at fault in CLL.

So to treat CLL with drugs that further damage T cells, seems to me to be risky, if not perverse. When fludarabine or Campath are used, it is necessary to protect against the kinds of germs that T cells are there to protect you from. Pneumocystis carinii and Herpes zoster require prophylaxis with Bactrim and val- or fam- cyclovir respectively. But the story doesn't end there. After fludarabine it is extremely difficult to get a stem cell harvest for an autograft. After fludarabine autoimmune hemolytic anemia may be triggered and sometimes this is so severe as to be untreatable. After fludarabine Richter's syndrome is more likely, probably because of reactivation of EB virus. After Campath, and sometimes after fludarabine in combination reactivation of CMV occurs. After fludarabine the risk of second cancers, especially skin cancers, is increased. After fludarabine secondary myelodysplasia seems to be commoner. I strongly suspect that this is because of its effect on T cells.

The first time I lectured about fludarabine I rejoiced that here was a drug with a major effect on lymphoma that was only minimally marrow toxic. I was reminded at the time by Professor Grant Prentice that its effect on T cells might be more significant. He was right. Fludarabine, like marriage 'is not by any to be enterprised, nor taken in hand, unadvisedly, lightly, or wantonly'. No doubt there are some for whom it is the right thing, but for many we must, like the dentist in 'Marathon Man', ask the question, "Is it safe?"

Don't you find it surprising that despite producing more and better responses and longer remissions than chlorambucil, it does not lead to a longer overall survival? Fludarabine's supporters put it down to crossover, the fact that once they fail chlorambucil, patients can try fludarabine later. But if that were the cause you would expect some to fall by the wayside in the changeover, and although it might not be significant, I would expect a small gap to be opening up at 5 years showing a small benefit for fludarabine. In fact, the small, but still statistically insignificant gap seems to be opening up in favor of chlorambucil. One possible reason for the failure of fludarabine based regimens to show superiority is the occurrence of late complications.

Rituximab is a different matter. Although as a single agent it does not seem to be all that good in CLL, in combination with virtually any chemotherapy, it adds value. It is so non-toxic. Sure it gets rid of the B cells, but not for ever as they are rapidly replenished from a CD20 negative source. Sure it causes infusion reactions, but these can be abolished by giving it more slowly. So adding it to chemotherapy improves the response and the overall survival. CHOP-R is better than CHOP; CVP-R is better than CVP; FCR is better than FC.

I have noticed that physicians have started using CVP-R for CLL. The logic behind this is that in follicular lymphoma CVP-R is better than CVP in the Robert Marcus trial. To many oncologists one low grade lymphoma is very like another and CLL is regarded as just another low grade lymphoma. I have no doubt that CVP-R will work in CLL, but CVP has been trialed in CLL and been shown to be no better than chlorambucil in terms of responses and survival, but worse in two respects: cyclophosphamide is more likely to cause you to lose your hair, and vincristine causes peripheral neuropathy. Everybody on vincristine loses their ankle reflexes, and some, especially older patients, never walk again.

Chlorambucil has been around since 1951. There is no money in it for the pharmaceutical companies. It is one sixteenth the price of fludarabine. Before fludarabine came along it had beaten off CVP, CHOP and CEP. The trials that showed it to be worse in some respects than fludarabine used a sub-optimal dose of chlorambucil. The latest CLL4 trial in Britain actually shows no difference between chlorambucil and fludarabine, though FC is better in every respect, except in overall survival.

Chlorambucil is not the perfect drug. It is marrow toxic, especially in higher doses. CLL does become resistant to it in a proportion of cases. It causes a rash in about 2% of cases. It does suppress T cells to a degree, though nothing like as much as fludarabine or Campath.

So why has nobody tried chlorambucil plus rituximab? There has been a small phase II trial in low grade lymphoma (unlike the Robert Marcus trial, this did include some patients with CLL). This trial was encouraging.

FCR has captured so much of the market and is so impressive up front that we have not been paying enough intention to late complications. Furthermore, the way it has developed, with initial courses given in Houston and subsequent courses and follow up taking place elsewhere in the US (indeed elsewhere the world) militates against the detection of late complications. Why was it that Houston, the greatest user of fludarabine, did not pick up the complication of triggering autoimmune complications as early as others? Because the follow-up was scattered to the winds.

The slow movement towards trying chlorambucil plus rituximab has come from patients, especially those who pay attention to the internet.

Here is a prediction. Changes in Big Pharma will bring about chlorambucil plus rituximab trials. Schering AG, a relatively small German company which markets both fludarabine and Campath, has been taken over by Bayer, one of the giants of the industry. This makes it much more unlikely that there will be joint trials between the Rituximab manufacturers and the fludarabine manufacturers in the future. There was always the possibility that Roche would take over Schering, but Bayer is too big a mouthful. So Roche, which handles rituximab outside the US, will be looking for another drug to use with rituximab. I predict they will hit on chlorambucil.

About 40% of patients with mutated IgVH genes will require some sort of therapy. Many of them will be elderly. The last thing they want is their immune systems completely scuppered. I predict that it will be in this group that we see the first trials.