Hope and Reality Check

Some of you wrote to me off-line, asking me to discuss in more detail the logic that Harvey used in opting to go for a mini-allo transplant. For example, why did he decide to participate in this cord blood transplant clinical trial, why not instead the vaccine trial at UCSD, or a new vaccine trial from Germany that is being discussed on some of the chat rooms?

This is an important question. None of us have a crystal ball, all of us have to make therapy decisions in the absence of complete information. The best we can try to do is make sound decisions that are not driven by mind-numbing fear or head-in-the-sand optimism that has little basis in reality. Hope and optimism that gives us the strength to carry on and live to fight another day are good things. Knee-jerk responses based on fear, or wishful thinking that is divorced from any sort of a reality check can be very dangerous – you may end up paying for it with your life. How does one tell the difference between the two? Aha! That is the million dollar question and I certainly do not claim to have cornered the market on wisdom. Best I can do is give you my two cents, free of charge of course, which makes it the best deal you are going to get today.

Time frames are important.

Technology that may well prove to be a resounding winner 10 years from now is of no use to a patient looking for options in the next few months. I have known too many patients who dithered too long, waiting for that miraculous no-risk cure while their CLL galloped out of control, and they were left with fewer good options at the end of it. Glowing press releases by researchers / companies involved and “human-interest” stories based on them repeated mindlessly by popular media does not do justice to this very important question. How long will it take before these sugar plums become proven, commercially available technology that can actually be of benefit to us? Press releases that jump the gun and gush about potential value ahead of solid clinical results reported in peer reviewed professional journals do not do patients any good. Sound bites do not take the place of good science that has been subjected to peer review. You may say I have become a little more cynical in my evaluations after being around the block for the last 6 years.

The CLL Sand-box

Just for example, let us consider a couple of recent examples in CLL clinical trials. The pivotal plenary article on results of early phase clinical trial “gene therapy” at UCSD was published in ‘Blood’ in November 2000. You can also read our reviews of the technology on CLL Topics website, all you have to do is type the words “gene therapy” into the search box at the top right hand side of the home page. Based on the encouraging results reported in the plenary paper, a second larger Phase-II trial was launched at UCSD a couple of years later.

Starting with recruitment of patients in the late 1990′s for the Phase – I trial, we are looking at a decade of actual clinical recruitment of patients for the “gene therapy”. Ten years after spike in interest in the “gene therapy” approach, are we there yet? Are we any closer to a proven, commercially available cure? If not a cure, at the very least is this approach available to general run of the mill patients as a way of mitigating and slowing down their CLL?

I am sorry to say, we are not. We have not even progressed to the level of large scale and Phase-III multi center clinical trials, an essential step before the technology can even be evaluated for FDA approval. Too many questions remain unanswered, too many dots that are yet to be connected. If you were a CLL patient back in 2000, holding your breath while waiting for the gene therapy to come of age and cure you with no fuss and no muss, I am afraid you would have been out of luck by now. If you had truly smoldering disease that needed no therapy all these years, why would you spoil a good thing and go into any sort of treatment? If you actually needed treatment back in 2000 or thereafter, I hope you bit the bullet and got the available therapy you needed.

Based on the early “gene therapy” work, a slightly modified version of the same technology and newly coined as a “vaccine trial” has been launched at UCSD. This is a very early phase clinical trial, with appropriately modest goals: “The main purpose of this clinical trial is to determine the safety and maximum tolerated dose of ISF35 in CLL patients. Recruitment will continue for 12 to 18 months, or until 28 patients are enrolled” says the press release. The goal of early phase trials is not to see if the technology actually works as hoped, it is correctly focused on patient safety. In the patient consent form of each and every early phase clinical trial is language to the effect that the trial is not meant to be of therapeutic value to the participant. Only time (and lots of it, I am afraid) will tell if this particular technology will finally progress to real-life viability.

Idiotype Vaccines

Another example to consider is the Genitope idiotype vaccine clinical trial. I had higher hopes for this approach, considering this technology had been in long term Phase-III clinical trials for non-Hodgkin’s lymphoma since 2000 and NHL is another B-cell malignancy that is a kissing cousin of CLL. Favrille was another company looking at a similar technology platform. The technology had already progressed from research bench to patient bedside in late stage, large multi-center trials. Both Favrille and Genitope were listed on the stock market, lots of money was riding on these bets. Once again, we are talking of efforts that spanned 10 or more years, the NHL trials have been going on for quite a while. Based on all of this, CLL Topics was delighted when we finally got Genitope to look at our patient pool as well, and a clinical trial was launched using our guys as participants. “Finally it is our turn” we wrote, back in March 2006, almost gushing with enthusiasm.

Two years after starting the CLL clinical trial, where are we? There is still hope lingering that Genitope will continue with the CLL version of their MyVax trial. But the company’s flagship trial of the same technology in NHL patients has run into massive problems. After many years and much money and effort, that late stage trial failed to show statistically significant advantage in their predetermined goals. Chances of getting FDA approval for MyVax are a lot grimmer now. Company finances and stock price took a huge hit as investors deserted a sinking ship in droves, and as we all know, money makes the world go around. Anecdotal reports from CLL patients participating in the CLL MyVax trial are ambiguous at best. No one has been cured, to the best of my knowledge. Some patients saw stabilization or even reduction in their lymphocyte counts. But heck, taking green tea extract EGCG seems to do that in quite a large percentage of patients with lot less fuss and hassle!

Cancer Vaccines: Where Do We Stand?

Let us take a broader view and look at the larger field of cancer vaccines in general. Ever since the “War on Cancer” was started by President Nixon back in 1971 (my how time flies while you are having fun), there has been no dearth of money or researchers looking at this holy grail, a way of curing an existing cancer with a quick jab in the arm. I won’t even try to put a dollar number on it, it will require too many zeros after. For all this effort, exactly how many cancer vaccines have been approved and made it into commercial availability? Are we any closer to curing cancer patients with vaccines?

This is the NCI page on cancer vaccines. Updated 6/2006.

  • Thus far, 2 prophylactic cancer vaccines have been approved targeting Hepatitis B, papillomavirus, both infectious agents, rather than the cancer itself. But since these two viruses are known to have a role in causing cancers, it is fair to list them here.
  • Other than these, zero therapeutic cancer vaccines have been approved.
  • Fifteen phase 3 are listed, some running since 1999-2000, including Genitope.

This is how I see the future, in my admittedly cracked and murky crystal ball:

  • Where vaccine research is concerned, the emphasis will always be much more on “solid” cancers. Makes commercial sense, the market is much larger for patients with breast cancer, lung cancer, prostate cancer etc. Blood cancers are small potatoes by comparison, and CLL is barely noticed compared to our larger siblings NHL, myeloid cancers and the like.
  • When it comes to vaccine trials, the fact that CLL is a “good cancer” makes it a less than attractive target. Our guys live too long (!!), and it takes too many years and too much money to prove statistical significance of the benefits of vaccines.
  • CLL is a cancer of the immune system. Vaccine approaches depend on corralling the immune system to fight the battle against cancer. Heck, our guys don’t respond worth a damn even to garden variety annual flu shots or pneumonia vaccinations! Getting our corrupted immune systems to wake up and initiate a take-no-prisoners crusade against home grown cancers is asking for a lot.
  • Commercially available and fully proven vaccine or gene therapy approaches to cure CLL patients are 10 years or more into the future. I am willing to bet money on it.

This is the biggest advantage of stem cell transplants, compared to vaccine approaches: transplants aim to throw out all the corrupted bums that are not doing the job, get a whole new crew in to fix the problem. Just like our general elections every four years, this is an expensive and time consuming process with lots of room for missteps. We can easily end up with more problems than we bargained for, and the new crew coming in may not be up to the job of cleaning out the mess left behind by the prior administration. GVHD in the process of getting GVL may very well prove to be a pact with the devil.

But transplant technology is here and now, accessible to most patients, and no pipe dream waiting for breakthroughs decades from now. Mini-allo transplant technology was developed on the sound basis of lessons learned with older full myeloablative transplant technology. Cord blood transplants in pediatric cancer patients has greatly benefited use of the same source of stem cells for adult patients. Are all the kinks worked out in transplant technology? Heck, no. There are real risks associated with any stem cell transplant procedure. People die, people get so sick they wish they had died. But some patients do survive, and get cured of their CLL, once and for all. If you are a refractory CLL patient looking at a decreasing set of therapy options, you are well advised to consider stem cell transplants.

Majority of transplants in this country and elsewhere are done in the context of clinical trials, and rightly so. Whether it is a new vaccine trial or a new fangled cord blood transplant, have no illusions about it, you are signing up for a clinical trial with a whole list of unknown or poorly understood risks and benefits.

Clinical trials are the life blood of progress in medical technology, and I think every patient who volunteers for a clinical trial is a hero that deserves our respect and admiration. But I am also a big fan of truly informed consent. You have a right to know exactly what you are signing up for. Patient consent forms written only with an eye to legal liability and ‘sold’ to the customer (patient) with a wink and a nod are a travesty of the process. You would not fall for that approach at the use car sales lot, surely you should make more of an effort to understand the detailed small print when it comes to your life?

And that, my friends, is the basis of Harvey’s decision. Stay tuned, this promises to be an interesting case history.