When it is time to treat, what is your best option for frontline therapy?

FCR (fludarabine + cyclophosphamide + Rituxan) has become the “gold standard” for treating chemo-naïve CLL patients. This powerful chemoimmunotherapy regimen pioneered at M. D. Anderson gives very high percentage of responses – and even more important to us chickens, it gives high percentage of remissions with no trace of minimum residual disease.  Which in turn means patients often stay disease free for long period of time without relapsing. We will be discussing all the pros and cons of FCR protocol at our upcoming Workshop on August 14th, 2010.

But is there a way of improving on FCR? For example, can we drop the ‘mouse juice’ of Rituxan and use instead the fully humanized monoclonal ofatumumab (“Arzerra”, Humax-CD20)? Lord knows we went to enough trouble to get FDA approval for this new monoclonal antibody. It seems to cause fewer problems of hypersensitivity in patients (it does not have any snippets of mouse protein in it, being a fully humanized monoclonal antibody) and it seems to work better than Rituxan, on account of hanging on more tightly to the CD20 marker.

And I think some of our guys can benefit from getting into a maintenance regimen of ofatumumab after they are done with the usual 6 monthly cycles of “F+O” or “FC+O”. This approach of a maintenance regimen was used effectively in the recent FCR-Lite protocol. Can we combine the normal six cycles of F+O or  FC+O with continued maintenance of ofatumumab – a way of getting more patients into deep and long lasting remissions? Is this going to remain nothing more than my “Dream Protocol” since insurance companies are likely to balk at paying for all those expensive ofatumumab infusions?

Standard of Care at the NIH

Many of you have volunteered for the NIH “Natural history of CLL” study. We reviewed that study earlier and I strongly urge you to read our review as well as the extensive comment section that follows. The natural history trial monitors patients from the time of enrollment to the point where their disease has progressed and requires treatment.

The feedback I got from all our members who were accepted into the trial has been rave reviews. What is not to like? World class experts, detailed monitoring, patient friendly staff, all of it  paid for by your tax dollars – no money out of your pocket and no hassles with your insurance company. I admit, it is a bit of a drag if you are not in the Bethesda, MD area and have to schlep your way here for periodic appointments. On the bright side, they do try to help with even that, put you in touch with generous volunteers who will put you up for free if you need to stay overnight. And if you happen to come to MD, you can come and visit me, buy me lunch. I swear I am a cheap date, given I am a vegetarian and don’t do three martini lunches.

When it is time to treat

So, the million dollar question we discussed back and forth in the comments section of our earlier review was this: what happens when the patient has progressed and needs therapy? What are the therapy options available at the NIH? I am not surprised that most of our members who are in the natural history trial would like to continue being monitored and treated by the same team.

I am delighted to report that it is now possible that many of our guys to have their cake and eat it too -  continue being looked after by the NIH team, and at the same time have access to the “Dream Protocol” we discussed above. From my admittedly biased perspective as a CLL patient advocate, I cannot think of a better way to spend our tax dollars – especially in these tough times when many of our members are financially challenged and insurance companies have not quite become patient-friendly.

More therapy if you need it, less if you don’t

How smart is that? Simple concept when you think about it, risk adjusted therapy. I am glad to see it put into practice in this important clinical trial.

In a nutshell, patients enrolled in this clinical trial will be treated with 6 monthly cycles in the “induction” phase of the protocol. Those with good prognostics (as in good FISH results) and low risk disease will get just F + O. No cyclophosphamide for these guys. Patients with high risk disease (11q and 17p deletions by FISH test) will get six cycles of F+C+O.

I wish I had a dollar for each time our members raised the question of F+C+R versus just F+R. Which is better? Do we really need to add  cyclophosphamide? Well, that depends on whether the patient asking the question is a high risk case or a low risk case. Addition of cyclophosphamide makes sense if the patient needs it to tame a high risk version of CLL. Many experts feel that addition of cyclophosphamide to FR is helpful in treating high risk patients with 11q or 17p deletion. But why take on the extra toxicity of cyclophosphamide if you don’t need it? I am glad to see this clinical trial takes that particular issue into consideration, tailoring the drug combo to suit the needs of the individual patient. Patients will get six cycles of F+O if they have good FISH prognostics; they will get F+C+O if they have either of the two bad chromosomal abnormalities, 11q or 17p deletions, as detected by FISH test

Consolidation after induction

At the end of the 6 cycles, patients who still have minimum residual disease (“MRD” positive, tell-tale signs of remaining CLL in their blood or bone marrow), will be given maintenance therapy with ofatumumab infusions in a “consolidation phase”. There will be four extra infusions of ofatumumab, given every alternate month. Once again, the emphasis is on giving more therapy for those who need it, not to those who do not need it. Makes sense, does it not?

I like ofatumumab consolidation a whole lot better than the previous attempts by other researchers using Campath (alemtuzumab) consolidation to mop up remaining CLL in patients who fail to achieve MRD negative status after FCR or R+HDMP (high dose methylprednisolone) etc. Campath is a hugely immune suppressive drug that causes long term depletion of T-cells, with high risk of opportunistic infections – especially viral infections. And yet, not everyone gets squeaky clean MRD negative remission after FCR, and chances are good that the same will be true of FC+O as well. Getting more of these not-quite-done patients into deeper remissions is very tempting, if it can be done without paying too much of a price by way of toxicity. Ofatumumab maintenance may be that perfect Goldilocks scenario - not as immune suppressive as Campath, but hopefully more effective than the Rituxan maintenance attempted in earlier FCR-Lite protocol.

NIH clinical trial protocol

You can read all the official details of the trial at the link below.

NCT01145209

The inclusion criteria are pretty straightforward. The trial is open to patients whose CLL has come to the point where it needs therapy, for the first time. Patients with hepatitis or HIV infections or where the CLL has transformed to other forms of lymphoma etc are not eligible. Active autoimmune disease (AIHA and/or ITP) are also grounds for exclusion, as is any serious chronic medical condition such as COPD, cardiac issues etc. You do not have to be in the prior natural history of CLL trial in order to be eligible to volunteer for this one. Please read the clinical trial protocol details carefully to get all the details.

Let me point out the bad news right up front. The trial is open to only 46 patients. Bummer.  I would like to see several hundred patients inducted into this trial.  First come, first served. Contact information etc is given in the clinical trial citation. Please don’t make pests of yourselves by swamping their phone lines, but if this trial is of interest to you I think you should not dither too long before sending them a detailed, thoughtful, to the point and clear email expressing your interest. You need to be patient since they can screen patients only so fast.  If your situation is such that you need to be in therapy right away, I think it will be a good idea to let them know that in your introductory email - perhaps they will get you to the front of the line and schedule you early.

I like the careful prophylactic protection offered patients in this trial. Bactrim to protect against bacterial infections, acyclovir to prevent herpes zoster (shingles, in layperson terms).  If patients become neutropenic (it is almost guaranteed a certain percentage of patients will become neutropenic), growth factors such as Neupogen and / or Neulasta will be used at the discretion of the medical team and as needed.

The trial calls for three bone marrow biopsies. The first one is before starting therapy. If you are already enrolled in the earlier NIH trial on the natural history of CLL and had a bone marrow biopsy done as part of that trial, you may be able to skip the first BMB of this new trial. The second BMB is in the middle of the 6 monthly induction period, to see how you are responding to the therapy. The last one is at the end of the six month induction phase, to see how well things worked out, whether there is still minimum residual disease lurking around in the bone marrow and therefore whether you need to be in the maintenance (“consolidation”) phase.I am not a big fan of BMBs, not unless they are done for good and solid reasons.

I have to admit I cannot argue with the logic of the need for these three BMBs in the protocol.

Folks, this is a research clinical trial. The results from this trial will influence what becomes the next and improved definition of a “gold standard” for CLL. You will be doing a huge service to future generations of CLL patients by participating in this trial. The results will be that much more valuable if they are detailed and credible. So, please consider putting up with the very real pain-in-the-butt involved in getting a BMB. I promise you it is not as bad as you think it will be, but it is no simple blood-draw pin prick either. Think of all the good you are doing as you present your backside to the sharp needle.  Scratch that altruistic and idealistic itch you have had all your life.  Do it for the fat lady.

Along the same lines, I am very pleased that Dr. Ron Taylor of the “Shaving Reaction” fame will be joining Dr. Adrian Wiestner in doing detailed research analysis of the samples collected. (Dr. Clifton Mo of the NHLBI is the principal investigator, working under the supervision of Dr. Adrian Wiestner). I think very highly of both of both Dr. Taylor and Dr. Wiestner, and however it turns out, we will be able to trust the results coming out of this clinical trial. By the way, Glaxo Smith Kline will be providing all the boat loads of ofatumumab free of charge for this trial, and they will also be picking up the tab for Dr. Taylor’s research. Hey, every little bit helps.

Last but not least, if you are lucky enough to be inducted into this trial do be sure and let us know how it works out for you.  I am counting on you guys to keep the rest of us informed, OK?