Wednesday, January 21, 2009

Side Effects in easier language

After Paul's comment I have rewritten the last piece to make it more understandable by patients.

Recently, there has been some discussion among CLL patients about the side effects of drugs used to treat the disease. Are there any treatments that are side effect free?

Unless there were a perfectly targeted drug that killed silently and without fuss, it is inevitable that all effective drugs will have side effects. Whether the side effects really matter, is another question.

It is possible to classify side effects in a number of different ways: ones felt only by the patient versus ones that can be measured by an observer; ones that last for a limited time versus ones the patient is left with after the treatment stops; short or long lived; rare or common; caused by the treatment in everyone to some degree or only rarely and in particular patients.

Let's take the individual drugs that are used in CLL.

Chlorambucil (Leukeran) has been around the longest and has relatively few side effects compared to most of the others. It works by damaging the DNA of the CLL cell. This sets going a process known as ‘programmed cell death’. There are two programs on offer, and most chemo-drugs use the same program. It doesn’t just kill CLL cells; any cell that is dividing is at risk; this means the cells of the bone marrow, the immune system, the skin and hair, and the lining of the stomach and guts are in danger.

Compared to other anti-cancer drugs Leukeran is pretty free of side effects. Many patients take it and don’t notice anything different than if they were taking a sugar pill. The larger the dose the more likely it is that you will feel something, most commonly a metalic taste in your mouth. Some patients will feel sick, but it is very rare for it to make you vomit. Even if it does, most patients get relief by dividing up the dose during the course of the day or even taking the monthly dose over more days (14 instead of 7 for instance). You won’t lose your hair. Rashes are also rare – if you get one it is more likely to be due to a drug that you are taking at the same time like Zyloric (allopurinol), but some (very few) people are genuinely allergic to Leukeran.

What about the silent side effects that you can’t feel? It can certainly damage your bone marrow. Damaged bone marrow means you can’t make enough red cells, neutrophils (these are the white cells that eat bacteria) and platelets (needed to make the blood clot). The marrow can be damaged in two ways: either the stem cells are killed so that there aren’t enough of them to make the red cells, white cells and platelets, or the stem cells are damaged so that the red cells, white cells and platelets that are made don’t work properly. This second type of damage is known as the myelodysplastic syndrome (lets call it MDS so we don’t have to remember the long word). MDS can turn into acute leukemia (AML), so it is a worry.

Undoubtedly Leukeran can kill stem cells, but this is a slow process and it is pretty rare that it is a problem. It is hard to be sure because the very presence of the CLL seems to switch stem cells off so in any patient who has anemia (lack of red cells) , lack of white cells or platelets it might be due to remaining CLL cells in the bone marrow or due to the toxic effect of drugs. Nevertheless patients who have had a lot of Leukeran over a long period do run out of stem cells.

Leukeran also sems able to cause MDS. I have seen it in patients with ovarian cancer treated with Leukeran, but I have never seen it (or AML) caused by Leukeran in CLL. Neither has Danny Catovsky and between us we have seen more cases in the UK than anyone else. Occasionally untreated CLL develops MDS or AML, but we don’t know why. It is very rare.

Leukeran can also damage the immune system. Since the CLL cell is part of the immune system, you would expect it to, and it is true to say that all treatments that kill CLL cells also kill their ormal counterparts and thus make the poor immunity of CLL worse – at least temporarily.

Very simply, the immune system consists of B cells that make antibodies (CLL cells are B cells) and T cells that kill viruses and fungi, reject transplants and also control immunity. (They are like the conductor of the symphony orchestra). T cells are in fact very complicated; as well as helping B cells and other T cells to do their job, they are also the cells that switch off an immune response when it is no longer needed.

Leukeran kills both B cells and T cells, but again not so you’d notice – at least at first. This is because like the bone marrow, the immune system has a ‘full tank’ and it isn’t until you are running on empty that you begin to notice a problem. Drugs empty your tank at different rates, and Leukeran is one of the slowest.

Many years ago it was noticed that Leukeran could trigger a type of anemia called autoimmune hemolytic anemia (AHA). This is where the body makes an antibody to kill its own red cells. We now know that what happens is the T cells that are supposed to switch off an immune response are killed. AHA occurs in about 15% of patients with CLL and it is quite unusual for treatment with Leukeran to be the trigger, but almost any type of chemotherapy can do it.

The only other thing I want to say about Leukeran is that you can’t give it intravenously (iv). Some people see this as a disadvantage, though I think most people would rather take a pill than have a jab.

Because it has been around for so long (more than 50 years) Leukeran is the standard that other drugs are compared against.

There are other drugs that are chemically similar to Leukeran. They were all derived by chemists from Mustard Gas, which was used in the First World War to kill an injure soldiers. None of them are that toxic, but it is a warning that we are not dealing with sweeties. The most commonly used of these Leukeran lookalikes is cyclphosphamide. This has many trade names as it has been off patent for many years. We generally refer to it as Cyclo. Cyclo was invented by a wool chemist in Australia who was trying to alter the kinks in wool fiber. It is not usually used alone but as part of a combination (it is the ‘C’ in FCR, CHOP and CVP). It is very similar to Leukeran but it can be used iv as well as in pill-form. It has these differences. It is much more likelyto make you lose your hair. It is much more likely to make you feel sick and to vomit. It is less likely to kill stem cells but more likely to cause MDS. It tends not to supress T cells, but attacks B cells more. Because of this it tends to be a remedy, not a trigger of AHA. There don’t seem to be any comparisons with Leukeran on whether it makes you more likely to get an infection.

The other drug we have from mustard gas is bendamustine (Treanda). The publicity for Treanda suggests that it also has a chemical formula like fludarabine. This is partly true, but I have not seen any evidence that it acts like fludarabine. It is best to regard it as a Leukeran look-alike that has become very popular because the pharmaceutical company can make a big profit from it, which they can’t do with either Leukeran or Cyclo. There is also the dose thing. Increasing the dose of any of these drugs makes them both more effective and more toxic. So comparisons should be between equally toxic doses of the drugs. When this is done they all seem equally effective, but mostly they are compared with a low dose of Leukeran because doctors have often settled on a low non-toxic dose since they are not aiming to cure the disease, merely control it.

The list of side effects of Treanda given on the packet insert: nausea, vomiting, diarrhea, tiredness, itching, weight loss, headache, shortness of breath, fast heartbeat, dizziness, pale skin, confusion, hives, rash, difficulty breathing or swallowing, swelling of the face, excessive tiredness or weakness, fever, chills, cough, or other signs of infection, unusual bleeding or bruising and inferility in men are the same as are seen with all of this class of drug. Whether they occur or not is all about dose. The only controled trial comparing Leukeran with Treanda showed more benefit for Treanda but more toxicity. But the Leukeran results were particularly poor compared with other trials. I am waiting for a comparison with a bigger dose of Leukeran before I give a judgement.
Treanda can only be given iv.

Although fludarabine (Fludara) is not a member of the Mustard Gas family it still uses the same killing program kill CLL cells and in the test tube it has the same sensitivity pattern as Leukeran. It has roughly the same pattern of toxicity as Leukeran only more so. In the LRF CLL4 trial it was equally efficient as a larger dose of Leukeran than is usually used in clinical trials, but was more toxic, being more likely to allow a severe infection to take hold.
Fludara is much more toxic to T cells, knocking the T helper cell levels to about the same level as is seen in AIDS patients and for two years or more. As a consequence shingles is commoner and AHA more severe.

Shingles is caused by a herpes virus that we catch as chicken pox and thereafter lives in our nerve cells, but never comes out to harm us unless our T cells begin to fail. There are other viruses that are similar including CMV and EBV. These can also be reactivated after Fludara treatment (especially when it is given in combinations like FC or FCR) but this is rare. Another problem is lung infection with a fungus like aspergillus or pneumocystis. These are very difficult to treat once they get hold, and many people advocate using drugs to prevent these infections including, acyclovir, itraconazole and Bactrim.

A transfusion into someone who has had Fludara can be very dangerous. Fludara is used as an immunosuppresive drug to prepare a patient for a stem cell transplant. Blood transfusions are not matched for tissue type, just for red cell types. Therefore, white blood cells in the transfusion will recognise the patient as foreign and because they are not rejected by the patient’s damaged imune system they will try to reject the patient causing ‘transfusion related graft-versus-host disease’. This is uniformly fatal. For this reason, we recommend that patients who have ever had Fludara who need a blood transfusion should have the transfusoion irradiated to kill the white cells.

Fludara was originally just iv, but an oral preparation is now available even in the US, which was last to see the convenience of this.

Fludara is often used with cyclo. It is certainly more effective when they are used together, but also more toxic. We insist that a blood test is taken two weeks after the combination starts because the incidence of severe neutropenia is so great that G-CSF or prophylactic ciprofloxacin might be needed to protect the patient from a serious bacterial infection capable of killing the patient within a few hours. However, this combination is less likely to trigger AHA.

Prednisolone (or other steroids like dexamethasone and methyl prednisolone) is not a cytotoxic drug though it can kill CLL cells by the other program pathway. In high doses it kills even cells with the del17p (p53) lesion. But it has a whole set of different side effects. When given for a short time it causes fluid retention, diabetes, high blood presure and mood changes that are quite severe, but when continued for longer periods steroids cause muscle wasting and thinning of the bones as well.

Vincristine is a cytotoxic drug that is not very toxic to the bone marrow, and it is not much use against CLL either, even though it is used in the CVP and CHOP combinations. It does have quite unusual side effects though. It causes a peripheral neuritis. Everyone loses some nerve function; when you knock their ankle tendons with a hammer you don’t get the familiar twitch. Some people are get worse than this, even paralysis. More troubling is damage to the nerves of the stomach which cause bad bellyache and constipation.

Doxorubicin, also known as Adriamycin, causes hair loss and vomiting that are much worse than with any other CLL drug, but it is also toxic to the heart in a cumulative way. No more than 9 courses can be given else heart failure or abnormal heart rhythms will follow. If there is pre-existing heart disease even fewer courses are safe. Mitoxantrone (Novantrone) is a drug with similar qualities and similar side effects. It is used in FCR-M. We recommend that anyone having either Adriamycin or Mitoxantrone should have a heart Echo scan or MUGA scan first to see that their heart is working properly

The monoclonal antibody rituximab (Rituxin or MabThera) is not marrow suppressive and does not cause AHA. Its main side effect is an infusion reaction with flushing, shivering attacks, low blood pressure leading to fainting or collapse, changes in the pulse rate and possibly breathlessness. By giving the infusion more slowly this side effect can be avoided. Occasionally, patients become allergic to rituximab, but this is very, very rare.

Alemtuzumab (MabCampath or just Campath) is less well directed than rituximab since CD52 is also on T cells. It too can cause infusion reactions, but these can be avoided by subQ administration. Instead it causes local skin reactions at the injection sites. These can be unpleasant, but they are not serious. The main side effect is suppression of T cells so that infections with viruses and fungi become a problem. Bactrim and acyclovir prophylaxis is necessary, but because reactivation of CMV is a real possibility, it is necessary to do weekly tests for CMV antigen by PCR. Ganciclovir is given if two successive tests are raised, even if there are no symptoms. Untreated CMV can be fatal. The T cells recover about 6 months after stopping Campath.

Any effective treatment can cause tumor lysis syndrome (TLS). this means that release of toxins from the dying CLL cells are not cleared quickly enough and can damage or even kill the patient. The main toxins are potassium and uric acid. Prevention of TLS is by allopurinol for the uric acid and lots of fluids for the potassium.

Lenolidamide (Revlimid) is one of the drugs that cause TLS. It can also cause marrow suppression and it has a strange complication known as tumor flare, where a lymph node mass increases in size and may become painful. This can be suppressed by steroids, but it usually means that the treatment is working.

If there are any other side effects that I have not mentioned, please ask.


bob larkin said...

This is very helpful. When someone (like me) has been through most of these protocols with decent results, is there any guide post that says which protocol works best, or is least damaging, the second time around?

Anonymous said...

I have seen 2 individuals with significant problems secondary to gastroparesis and dysmotility following vincrsitine's use, as well as a few others with more traditional peripheral neuropathy.

I realize that it has been used to treat many types of lymphoma and in CLl patients with AIHA and ITP, but your description makes it seem as though you feel it has little role to play and brings more risk than reward.

Is that a fair assessment of your opinion?


Terry Hamblin said...

Yes, exactly. Clinical trials have shown that CVP has no advantages over chlorambucil.

Anonymous said...

Thank you Terry, for this post. It is very informative for the patient's. Tom has been on Revlimid/Rituxan trial at MDACC. He had to interrupt Revlimid at 10mg daily due to a diffuse erythema. The rash was everywhere and he looked sunburned. After two weeks off, he was restarted at 5mg every other day instead of daily. He now is showing a rash similar to petechiae. His platelets are in a good range. His Eoso# and % are high. Today he was told that perhaps this was CLL cells in his skin reacting to Revlimid and to stay on protocol. Skin involvement has been Tom's biggest problem with Relimid.

Jenny Lou

Irving Noble said...

Dr. Hamblin, I started my 4th chemo 8 days ago which is FC at a lower dose than I had 1 year ago. I am having a rough time with constipation which is making me feel unwell. I have been taking 6 capsules of Colace daily (stool softener) and now my doctor has had me add Senekot to my regimen. I had some good bowel movements yesterday a.m., but seem to be bunged up again. I am also taking Allopurinol, Ranitidine, and Sulfatrim. The first three days I was also taking Dexamethasone and Kytril. Last chemo I had a bowel blockage not having gone for over 9 days.
Drinking 8 x 8oz. water.
Any suggestions ?
Much appreciated.
Irv Noble, 74

Terry Hamblin said...


It sounds like you are taking the right sort of stuff to get your bowels moving. Fludarabine does have a neurotoxic effect in larger doses, but with so many drugs going in it is difficult to ascribe blame. Sometimes with constipation one has to resort to enemas.

Jenny Lou

Thanks for the information on Revlimid and rashes.

Anonymous said...

Dr. Hamblin --

Excellent article. Thanks.

Two questions:

1) There has been a recent discussion on the ACOR site about chemo treatments and low cholesterol/low HDL, and also about a potential interaction of Rituxan and statins. Do you have any comments on these issues?

2)Do we know anything about the relative effectiveness/toxicity tradeoff for patients with poor prognostic indicators (unmutated IgVH, high B2M, 11q del, ZAP 70 and CD 38 pos)?

Thanks again!


Terry Hamblin said...

I have written before about the cholesterol story> Statins and rituximab interact, but I think this is only a problem for lymphoma and not for CLL.

Prognostic factors do not affect outcome for CLL transplants.

Wayne said...

Thank you for this valuable perspective on drug toxicity.

If my memory has not failed me I believe that first time treatment patients react more acutely to Rituxan and subsequent infusions are easily tolerated for the majority. Would first time treated patients using Rituxan with Fresh Frozen Plasma get an amplified first infusion reaction from the FFP in the absence of no known patient allergies or co-morbidities?

Terry Hamblin said...

I think that is very likely. Since teh problem is complement, adding FFP would be like adding fuel to the fire.

Stephen Maryk said...

I was treated @ 5 weeek intervals with bendamustine, first 100mg/m2, then 50 mg/m2 with fairly severe side effects, followed by severe CMV infection that lodged in my GI tract. Endoscopy showed ulcerations of the esophagus, stomach and duodenum. Diarrhea was severe, I lost about 25 lbs (starting @ 155 lbs.) Biopsy showed CMV. I was hospitalized and treated with IV gancyclovir and am now @ home on Valcyte (oral gancyclovir). From peripheral blood evaluation the CLL seems in remission but Hematologist is thinking about doing marrow biopsy to be sure, I guess you gotta crack a few eggs to make an omelette but hear me, CMV is ROUGH.

Terry Hamblin said...

Bendamustine is not well known for reactivating CMV which is why it was detected late in your case. Early detection by twice weekly bood tests would have spare you the suffering.