In patients who are fludarabine refractory or have a p53 dysfunction the available treatments are limited. The first drug that comes to mind is alemtuzumab (Campath). Although Campath does not require intact p53 to kill CLL cells, it is very poor at eliminating bulky disease. Why this should be is unclear, since in the first |Lancet paper on the treatment of two patients with CLL with Campath, bulky disease was not a problem. However, Campath is made differently now and it may be that the new system is not as good at attaching sugars to the molecule. Hence the new alemtuzumab may be ineffectively glycosylated. A new version of Campath is being developed.
Another drug that deals with p53 deficient CLL cells is high dose steroids (either methylprednisolone or dexamethasone). These drugs also deal with bulky disease, but they are likely to produce severe steroid side effects, such as high blood pressure, fluid retention, alteration in body shape (a melon on cocktail sticks), thin skin, thin bones, diabetes and most important in this context, immunodeficiency.
This is why many doctors are reluctant to combine high dose steroids with alemtuzumab. Fungal, viral and bacterial infections are all likely and must be guarded against. Prophylactic cotrimoxazole (either Bactrim or Septrin) is needed to prevent pneumocystis, aciclovir (or similar) to prevent herpes simplex and zoster, and one of the many antifungals to prevent candida and aspergillus. Twice weekly screening for reactivated CMV is also necessary.
However, in my experience, when used in specialized centers this is the most effective treatment available.
There are advocates for high dose steroids with rituximab and some evidence that this combination may also be effective in bulky fludarabine resistant disease. We await a head to head comparison.
Lenalidomide (Revlimid) is reported to be effective in drug resistant CLL though the numbers of drug resistant and p53 defective patients treated in clinical trials is still very few. The other agent with this property is Flavopiridol, but this is notoriously difficult to administer and available in very few centers.
Clinical trials of other drugs that may be useful, like acadesine, are continuing, but as yet treatment for this difficult problem remains uncertain.
3 comments:
A very timely post. I am on a flavopiridol trial at UC San Diego under the supervision of Dr. Thomas Kipps. I have the 11q deletion and have bulky lymph nodes in my abdomen.
So far the treatment was been successful, leading to a diminished spleen size and smaller lymph nodes in the abdomen. Since I have few options, anything short of a transplant to keep me alive is welcome.
There are side effects from the treatment, though. After eight weekly doses, I've ended up in the hospital six times. (To be fair, the first two were planned.)
I look forward to the new formulation of Campath, since the HDMP+R, followed by Campath, has given excellent results in Dr. Kipps' shop. It is my feeling just from listening in the infusion room at UCSD that they are giving this regime to many, if not most, of the CLLers who need treatment. I know personally of two people who did the HDMP+R followed by Campath who are CLL-free several years out, with some restoration of immunity!
FCR can't claim that, that I'm aware of.
It is not a mild regime, and infections are a possibility. I myself underwent the HDMP+R in 2006, but developed the 11q del with massive abdominal nodes, eliminating me as a candidate for further treatment.
I understand that in other facilities, the success rate has been lower, and complications including death have been higher. I myself ended up in the ER after the first of three cycles with a neutrophil count of zero, and a temperature that reached 105 degrees.
It did give me a partial remission that lasted two years, which is not bad for someone like me who now has bad prognostic indicators.
Thanks for the post.
(I've posted on my experience with flavopiridol elsewhere.)
Barry B.
Terry,
Hope you are much better and feeling healthy!
Tom was on Revlimid for 9 months as one of 36 trial rats at MDAnderson for relapsed CLL using Rituximab once monthly and 10mg Revlimid daily--every day. He was taken off trial 3 weeks ago because it has not shown to be working for him. His last BMB did show double 13q deletion, 17p deletion, (but only 15%) and TP53 deletion. Have you ever heard of the double 13q deletion in CLL?
He is now being watched for a lung infection--getting better--and is on monthly solumedrol infusions....Rituximab is also on hold because of his lung involvement.
Jenny Lou Park
Yes, double 13 deletion is seen not uncommonly. One paper suggests that it has a worse prognosis than a single del 13, but that came from a rather unknown center. In our very large series it makes no difference to prognosis.
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