I have just listened to a podcast by Jesper Jurlander from the recent EHA meeting from Copenhagen. Remember that he was the man who introduced ranitidine for enhancing the effect of vaccination. He also has discovered the CLLU1 gene as a prognostic factor. This talk looked at prognostic factors in a new and interesting way. He first quotes from our 2002 paper drawing attention to the influence of age on prognosis. We looked at a large number of stage A patients who had a median survival of 15 years. However, if you ignored those patients who died from 'natural causes' the median survival was 24 years. At the age that most patients with CLL present, death from natural causes is increasingly common. Indeed in our study 40% of those who died, died from causes completely unrelated to their CLL.
The other interesting facts that he drew out were that CLLU1, despite being a very useful prognostic factor, didn't work at all for patients over 70. And he had an early report of the German fludarabine versus chlorambucil trial for over 65 year-olds. (Incidentally this report is misrepresented on the commercial report from ASH as showing an advantage for fludarabine). Interestingly there was no difference in progression-free survival and in terms of overall survival although there was no significant difference, there was a suggestion that the chlorambucil arm was doing rather better early on in the follow-up.
His final slide was to suggest a management strategy dependent on age. For older patients with good prognostic markers, 'watch and wait' is the strategy, with the likelihood that no treatment will be necessary, but if it is chlorambucil should suffice. Younger patients with good markers get 'watch and worry', and if they need treatment, probably FCR is first line. Younger patients with bad risk markers should be in trials looking at early treatment aiming at disease eradication with FCR followed by Campath or transplant. For older patients with bad markers the outlook is grim.
This approach is not encouraged by the recent CALGB 10101 trial of Campath consolidation following FR induction. Consolidation therapy with SC alemtuzumab (30 mg 3 times per week for 6 weeks) was started 3 months following induction treatment in patients with stable/responsive disease following induction. Six deaths were seen in patients most of whom were in CR. Five fatal infections were reported as follows: viral meningitis, Listeria meningitis, Legionella pneumonia, cytomegalovirus (CMV) infection and Pneumocystis jiroveci pneumonia (PCP), all in patients who achieved a complete response (CR) after induction therapy. In addition, a case of fatal EBV associated lymphoproliferative disorder was reported in a patient who achieved a partial response (PR) after induction therapy. Bayer Schering Pharma AG and Genzyme have subsequently been informed of an additional non-infection related fatality believed to be related to Transfusion Associated Graft Versus Host Disease (TAGVHD) in a patient who had received non-irradiated blood products. This was very different from the British experience of alemtuzumab and has reduced prospects for further studies of this type of consolidation.
The alternative approach - allograft - won't have been enhanced by the sad death of Harvey reported on the CLL Topics website.
Campath consolidation only after aggressive prophylaxis is the standard treatment as far as I am aware, because of the danger of infection that you cite. I personally know several people who have undergone both subcutaneous administration of Campath in the dosages you mention, as well as IV administration, after treatment, and the results have been very good.
ReplyDeleteThe patients I'm most familiar with, though, were in partial remission, with the regiment designed to put patients into a complete remission status. I believe that these several patients are alive and well and still in CR, after two-plus years.
I have read that clinicians are of course concerned about the suppressive nature of Campath and aggressively treat infections and, as I've mentioned, embark the patient on antibiotics, antifungals, and antivirals prior to administering Campath as their experience suggests.
The patients I'm most familiar with had Campath as part of a clinical trial.
As far as allogenic transplants go, the experience of one patient, or several, really cannot be used to make one's mind up about how to treat a particular case of CLL. Many factors come into play; it should also be noted that Mr. Venkat's death came after a dual cord blood transplant, which transplant specialists have less experience with, and which has proven to be somewhat problematic in patients (stem cell volume, resistance to disease, etc.). Mr. Venkat probably would have had a matched related or unrelated donor if one could be found, however, being non-Caucasian, he could not find a match.
Thanks for the post. All information about CLL is welcome.
His death (as well as those of many others after a transplant) does reinforce the idea that transplants have a high treatment-related mortality rate, and a not insignificant death rate persisting years later, mainly from disease relapse and graft vrs. host disease, which Dr. Hamblin has commented in this blog before.