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.