Friday, March 28, 2008

Al Gore on the second ballot

Well, a boy can dream. I’ve always liked Al. Behind that stiff exterior lies a man with a good sense of humor and a good head on his shoulders. I’m not going to rehash the travesty that was the election of 2000; suffice it to say that the past eight years would have been infinitely better for our country had Gore been in charge.

Now there is an ever-so-slim hope that he might yet mount a white horse, Nobel Prize medallion around his
neck, sun block on his face to filter out the effects of ozone depletion, and ride to the rescue of the Democratic Party.

It looks like we m
ay need it.

Not that we don’t have two good candidates -- it’s just that the longer they stay in the arena, flailing away like punch-drunk prizefighters, the more battered and bloodied and uglier they become.

On th
e one hand we have Barack Obama, whose ability to inspire is equaled only by what we don’t know about him. The Rev. Jeremiah Wright affair should have been a wake-up call, at 3 a.m. or otherwise. Not the obnoxious things Wright said. Not the fine speech Obama gave on race relations. But the fact that Obama knew it was coming, had known it for a year, and did nothing to nip it in the bud.

"If Barack gets past the primary," Rev. Wright told the New York Times in April 2007, "he might have to publicly distance himself from me. I said it to Barack personally, and he said yeah, that might have to happen."

So my question is, what else does Barack know is coming? What other distancing does he have backup plans for? (I am just a tad uneasy about this Tony Rezko trial, for example.) Obama is an interesting figure. He’s bright, he’s personable, he's full of potential. But I fear he could also be full of surprises. After all, he’s a politician (which will come as a shock to those of you who think he’s the Second Coming of Kennedy). Politicians spin things for the best, and they hide things they think might hurt them.

Speaking as a Democrat, it matters when these things rear their heads and hurt us as a party. (Is there a New York governor in the house?!)

Which brings us to
Hillary Clinton, who has been well-vetted, and who we know, warts and all. Obama, who began this year on a pedestal, has nowhere to go but down. Clinton, who has endured often unfair sniping for almost two decades, has nowhere to go but up.

But that doesn’t mean she’s going anywhere, her campaign having blown it in the dozen or so states immediately following Super Tuesday, creating a pledged delegate shortfall that she can’t overcome without a miracle. (As Bill recently said, “It's the caucuses that have been killing us.”)

That won’t keep h
er from trying, of course. She plans on winning the nomination -- if not this time, then perhaps in 2012. It has been suggested, and not without some plausibility, that Clinton would rather see Obama lose the general election to John McCain than win it. This would, after all, make her the frontrunner for the party’s nomination four years hence, when Americans would be really, really, REALLY tired of Republican rule.

Is she that ambitious? I’d like to think not, but I don’t know. What I do know is that they’ll probably have to carry her out of the Denver convention in a straight jacket to get her to give up the fight. She has been waiting all her life for this, folks, and will not go gently into that good night.

Clinton’s recent approach to winning has been called the “Tonya Harding strategy” -- bash him on the kneecap and hope for the best. And the things that might still make her the nominee -- Obama’s inexperience or skeletons in his closet or a gaffe of some kind -- are the same things that the Republicans are counting on to help them win in November. So her strategy dovetails into their strategy, which is to create the perception that Obama is not ready to be president.
This is not helped, of course, by anything that Obama might do to confirm that he is unprepared or too risky to take a chance on.

So we hav
e a situation where two candidates, who are increasingly polarizing supporters on the other side -- witness the Carville/Richardson “Judas” dust-up -- will arrive in Denver without enough pledged delegates to win the nomination.

The superdelegat
es will have to come up with something, and I am not alone in wondering if Gore might be the answer. Back in the old days, conventions would sometimes select a dark horse on the second, third, fourth, or even later ballots.

Al Gore is hardly a d
ark horse. He is well known, experienced, a proven popular vote-getter, and more respected today than he was eight years ago. Al could mount that white horse, ride in to unite the party, and gain his rightful place in the Oval Office.

It probably
won’t happen, of course, because politics is not like the movies. It is not like fiction. It is stranger.

Saturday, March 22, 2008

Life's little annoyances 1

I have decided to embrace my inner curmudgeon and, from time to time, provide a list of some things that are annoying me. If you disagree with my choices, then you are annoying me also. Here, in reverse order of blood boilage, are today's nominees:

5. High fructose corn syrup. Does it have to be put into everything? (Well, apparently, yes.) Is it possible that there are people who might not want the empty calories, or who, if they are willing to risk the calories, might want the taste of real sugar? Here in Arizona you can get Coca-Cola made in Mexico with cane sugar; it tastes like Coke did when I was a kid, before the company switched to corn syrup in the US. . . Try finding a barbeque sauce, or a salad dressing, or even a can of soup or loaf of bread at your average supermarket that does not have corn syrup in it. It will be a miracle, and you should build a shrine.

4. Muzak. The other day I was at the dentist’s office and heard, in treacly, instrumental form, “Give me the beat boys/And free my soul/I wanna get lost in your rock and roll/And drift away.” Could there be a more grotesque irony? Satan himself could not have conjured up anything "better" to play in the waiting room in Hell. This beat didn't get me lost in anything, except laughter and a certain degree of existential despair.

3. Hotels where the windows are sealed shut. God forbid anyone would want some
fresh air, especially if the place has been renovated and the carpeting, paint, and luxurious particle board furnishings are outgassing their share of “sick building syndrome” fumes. What does the management think we’re going to do? Jump out the window when we get the bill?

2. Store loyalty cards. So now I have to carry a card for every supermarket I frequent if I want to get the sale price on merchandise at checkout. Ooh, I’m a member of the “Safeway Club.” How nice of Safeway to want to keep track of everything I have purchased, feed it into their computer, and target me with mailings. Why, it even tells the checker my name so they can add that "personal" touch and mispronounce it as they thank me for my purchase. (Sheesh, people, "Arenson" is not rocket science. It's "Air-in-sun," not "Arn-eson" or "Air-EN-son" or that pronunciation of people who just don't try, "Anderson.") Privacy? People have forgotten that one of the treasures of being an American is your ability to be anonymous. Think I'm paranoid? Read this and this and this.

1. Ads for TV programs inserted into other TV programs. Marge Simpson recently asked: “Can’t anyone just watch the show they’re watching?” Well, can’t we? It started with those jarring little logos that networks show on the bottom right of the screen. Now it has gotten way out of hand -- little people walking onto the screen amid flashing graphics to advertise their upcoming shows. Fans of Kids in the Hall will understand when I say "I want to crush their heads." Maybe in this age of multitasking and multimedia people are used to absorbing endless quantities of visual clutter. I want to throw a brick at the television.

Sunday, March 16, 2008

Here we go again . . .

Flame me all you want but I am here to make the point again: We Americans must do SOMETHING to guarantee access to health care for all, including those with preexisting conditions.

Dr. Terry Hamblin recently posted to his blog about problems with the UK's public health service, the NHS. (Follow this link and search for "Travails of the NHS.") He describes the messes that can be created when bureaucrats, including committees of doctors, attempt to decide on treatment without expert knowledge. If it were not so sad it would be funny: Terry quotes one doctor who read about CLL briefly and said: "I have been reading about this subject for two hours. I am now an expert in the condition."

What is the take-home lesson here? I think it is pretty clear: The best standard of care requires that doctors with (genuine) expertise in a given condition be allowed to make the decisions.

But a couple of
those who posted comments about Terry's piece drew another lesson, seen through the filter of their myopic glasses: "Cautionary tales such as this make me oppose national health systems being imposed in the US, " wrote one. "I'm not sure why there is such a hue and cry over the 'failure' of the American health care system when it is in many cases the envy of the world. . . . Changing to a bureaucratic-run system will be made at the peril of the patient."

Hmm. Somehow American veterans have managed to survive the bureaucracy at VA hospitals, and somehow elderly Americans have managed to cope with Medicare without keeling over in large numbers.

But those are asides. The essential point is this: The failures of bureaucracy do not mean that the US should not have a health care system that provides access to all. Access to health care is a moral issue independent of the manner in which it is instituted.

And bureaucracy is not the province of government-run care alone: We have all heard of -- and indeed, many of us have experienced -- cases in which bureaucrats working for health insurance companies in the US make ridiculous calls. They deny treatment, refuse to approve the right treatment, or reject an appropriate test. (Ask the family of Nataline Sarkisyan, or ask Hilary Skvov and then read this.) Indeed, the bozos making these decisions in the US often have no medical training at all; their job is counting beans. They could read about a given condition for two hours and still not know their asses from a hole in the ground, nor would they care. (A committee of doctors -- we should be so lucky!) In America, the fox guards the henhouse. The quality of our care may be excellent but getting access to it is another matter entirely -- even if you have insurance.

Ignorance is ignorance, be it in the public or private sectors. When it comes to patient care, doctors should be calling the shots. Coming up with a fair, workable system may be tricky but it is not impossible. We sent men to the moon, ferchrissakes. Americans want as much freedom of choice as possible, and as light a regulatory touch as possible, but they also want to be able to get the care they need. I have enough faith in my country to believe that we can finesse these matters and devise a system that works reasonably well for all.

None of this takes away from the fact that access to health care is a moral right in a civilized society. I will never forget the post I saw from a CLL patient who lost his job because of his condition and, having also lost his health care, was trying to combat his CLL with herbs. I am almost as sick and tired of those who use "bureaucracy" as an excuse to deny their fellow citizens coverage as I am of CLL.

Friday, March 07, 2008

Transplants and the treatment balancing act

If we’re smart, we CLLers look down the road and think ahead. A question we should be prepared to answer is this: Might I need a stem cell transplant at some point, or is there a reasonable possibility that I can ride this thing out without one?

Chances are, if you are younger than 60 and have unmutated chronic lymphocytic leukemia, you might well need a transplant if
you want to become the eccentric old codger you were meant to be. I, for one, look forward to spending my 80s with Marilyn and too many cats while yelling at kids to get off my lawn. I have no intention of letting CLL interfere with those golden years.

Further signs that y
ou might need a transplant -- and, by the way, transplants are now being done on patients well into their 60s if they are in otherwise good health -- are these: Risky abnormalities per FISH test, such as 17p, 11q, and perhaps Trisomy 12; ZAP-70 and/or CD38 positivity; clinical symptoms that show disease progression on many fronts; relapse from treatment, especially after a shorter-than-average remission.

For such young-uns wit
h uncooperative CLL, the stem cell, or bone marrow, transplant is a light at the end of the tunnel. For some, this light may have the characteristics of an oncoming train, but I prefer to look at it as a potential cure.

Harvey ponders the path to success

Anyone looking down this road should keep up with Harvey’s Journal at CLL Topics. Harvey is a somewhat hypothetical fellow who is about to undergo a cord blood transplant. A recent journal entry, Planning for Success, describes the logic of achieving a CR ("complete response") prior to transplant, as well as the ways in which our treatment choices over time can reduce our ability to achieve that CR. The facts presented led to a little surprise and consternation among some readers.

Chaya Venkat, the Topics writer who, like Elwood P. Dowd, enjoys the delusion that there is a Harvey in the house, cites a study from the Fred Hutchinson Cancer Center. It shows that entering a transplant with bulky disease puts you at a disadvantage: after two years, 14% of patients with lymph nodes less than 5 cm at transplant had relapsed, compared to 52% of those with nodes greater than 5 cm. She further cites another study from the Hutch, albeit with a small sample, showing that, in her words, “the risk of relapse in CLL patients going into the transplant with full blown CR was zero, none, nada.” If you think about it, that makes sense: the less CLL the new immune system has to fight, the better the odds of achieving a successful graft vs. leukemia effect.

Chaya also pro
vides data from a 2005 study by MD Anderson, which I have discussed in the past and which can be found in detail here. It shows the CR rates in previously treated patients who are given FCR, which is today’s gold standard of chemotherapy. While 70% of those using FCR as their first treatment get a CR, that number drops in previously treated patients: to 29% in those who have used single-agent Rituxan; to 28% in those who have used an alkalyting agent such as chlorambucil or cyclophosphamide; to 24% among those who have used fludarabine and cyclophosphamide together. Table 3 of the study has details on fludarabine sensitivity: 31% of those considered sensitive achieved CRs, as opposed to just 5% of those who were refractory to the drug. (A note here: Only seven patients in the study had used single-agent Rituxan. That's not a huge sample but it's the only one we've got.)

So what is a patient -- especially one who thinks they might need a transplant one day -- to do?

The treatment conundrum

The questi
on of which treatments to have, and in what order to have them, is much debated among patients -- I have written my share about it in this blog -- as well as their doctors. As Dr. Terry Hamblin has pointed out, the studies are just not there to show us what combination, and in what order, leads to the longest overall survival.

Chaya delineates the problem as it relates to transplant: “Getting that CR ahead of the transplant may prove to be more difficult than you thought. Waitin
g too long to make the transplant decision may end up costing you. If you become a truly refractory 'salvage' case, it may not be possible for you to get a good remission no matter what you try. Too few bullets left, and too strong an enemy, the window of opportunity to get a successful transplant may not last forever.”

Dr. John Byrd has been quoted as saying that your first treatment is the most important because your first remission will be your best. And if transplant success were the foremost goal, then we would all have transplants following our first treatment, and we would all insure that our first treatment is the one that gives us the best chance of a CR.

Indeed, the day may come when 1) we can predict a person's disease accurately enough, and 2) transplants are safe enough, to make that a routine course of action for those with aggressive disease.

But we are
not there yet, and transplants are still risky: There is a 20% chance that a transplant will shorten your life and another 20% chance of relapse, those statistics according to UK CLL expert Dr. Andrew Pettitt. (The good news, according to Pettitt, is that 60% are successful.) With the possible exception of 17p-deleted patients, those with the most aggressive CLL, most top doctors hesitate to recommend a transplant at first remission. They are more commonly recommended at second remission in patients with rather aggressive -- perhaps I should say "assertive" -- disease. Still other doctors, those who do not see the transplant glass as half full, recommend transplants only as a last resort, after any number of therapies have been tried. In all these instances, treatment with something as conditioning for the transplant will be required.

And if there is one thing we do know -- just look at that MD Anderson data -- it is that treatment with any drug(s) sets up a disease resistance situation where second treatment is likely to be less effective.

Acceptable (?) ris

So, if we assume that for most of us a transplant at the outset is too risky but may become a desirable risk later, how do we plan? How do we still get treated but avoid becoming salvage patients on whom nothing really works?

There are a couple of points worth noting here:

First, there is no guarantee of getting a CR with your first treatment, even if you use FCR. Thirty percent fail to get a CR in such cases.

according to MDA, 25% of pretreated patients achieve a CR with FCR. Who does the best? Single-agent Rituxan users (29%) and the fludarabine sensitive (31%).

How do you know how you will respond? You don't, but we can hazard a couple of guesses. If you are 17p deleted, you will have a harder time getting a CR. Those with huge lymph nodes may have trouble since it is that much harder to get rid of them. The NCI guidelines say you don't need to treat lymph nodes until they achieve a mass of 10 cm, but as a practical matter many patients report problems reducing nodes that big to an acceptable size. Keep that in mind if you, like me, have a largely node-centered disease (which is, by the way, a trademark of the 11q deletion).

Speaking of nodes, let us recall the data from the Hutch: 14% with nodes of less than 5 cm relapsed. 52% relapsed whose nodes were greater than 5 cm.

Given the risks of a transplant, and the fact that you may be able to keep the disease at bay for many years with treatment, does this data suggest what might be the reasonable standard, the compromise point, which one should aim for? In other words, preserving your ability, to the best of your ability, to reduce your nodes to below 5 cm (and perhaps to get a CR to boot)?

I think "yes" is a reasonable conclusion. I also think the data suggest that two things will be of particular help in preserving this ability: using Rituxan as your treatment of choice and maintaining your sensitivity to fludarabine.

(As always, my opinions are my own: There are wiser people who may well disagree with me. You could be reading the ravings of a madman here; remember that propensity for copious quantities of cats.)

The treatment blue plate special

Harvey the Hypothetical had six years of good quality of life (QOL) with the “soft glove” monoclonal antibodies Rituxan and HuMax-CD20 -- especially helpful as he had no donor match and had to wait u
ntil cord blood transplants could be made reasonably safe.

Rituxan and HuMax are not free lunches, as Chaya points out, but I think they at least qualify as the blue plate special. To paraphrase Churchill, they are the worst drugs to use, except for all the others. These monoclonals can plug the holes in the dike without being as immunosuppressive as the alternatives, without being mutagenic, and without building quite so much disease resistance. (Cases of especially aggressive disease, suc
h as the 17p deleted, are the exception here. Studies suggest that 17p-deleted CLL clones are pretty resistant to Rituxan, as well as to fludarabine; in these cases, the start-with-big-guns then straight-to-transplant-at-remission plan makes some sense.)

The MDA data show a CR of only 5% for the fludarabine refractory. It is possible to become flud
arabine refractory after your first treatment, although you may luck out and respond two, three, or more times. In the 2004 ASH Education Book, Dr. Byrd noted that "at the time of relapse from initial response to fludarabine, 40% can be retreated and will respond again to the same regimen." He went on to say that "ultimately, virtually all CLL patients who are treated become fludarabine-refractory." (It is generally accepted, by the way, that if you achieve a long remission the first time, your chances of a good response the second time are improved.)

So, are you better off playing for time by using single-agent Rituxan? Or should you start your treatment career with FCR, which obviously carries a greater risk of making you fludarabine refractory? (Of course, even Rituxan can make your disease somewhat resistant to fludarabine; CLL is not black and white. Our stock in trade is shades of gray.)

Let's look a little further at the MDA study: Let's add together the percentage who got either a CR or an NPR (nodular partial remission -- patients with no swollen lymph nodes who would have achieved a CR but for some nodules in the bone marrow). The responses were as follows: 58% in Rituxan users; 40% in those who had alkalyting agents; 39% in the FC group; 48% in the fludarabine-sensitive group; and just 16% among the fludarabine refractory.

The takeaway here is that those who did best -- and now we're talking half of previously-treated patients that managed to get rid of those pesky nodes -
- were those who had used single-agent Rituxan and those who were fludarabine sensitive.

So, if I were playing the odds, using Rituxan while trying to preserve fludarabine sensitivity by not using it is the way I would go. In fact, it is the way I had been going, until AIHA intervened and forced me to use cyclophosphamide and a touch of vincristine. (Not everyone should play it this way; Rituxan is still a soft-glove treatment and if you arrive at the treatment door needing something stronger to deal with the problems your disease is handing you, by all means use it.)

It is important to note that your previous treatment is not the only factor that influences your ability to get a CR or NPR with FCR. Do read the MDA article, which I linked to above; it goes into other significant factors, including age, stage, and number of previous treatments. For example, your chance of a CR with FCR is reduced significantly if you have had more than two previous treatments. (Does single-agent Rituxan, with its lighter touch, carry the same weight as other treatments, I wonder?)

Type A personalities, welcome to the seventh circle of hell

We can parse the data all we want, but it's important to remember that what Rowan and Martin of TV's Laugh In called the “fickle finger of fate” is also at play here. Harvey, for example, was not particularly fludarabine-sensitive out of the gate, while many patients are. None of us knows how we are likely to respond to drugs, despite what statistics may tell us.

The good news is that Harvey managed to get close to a CR with Revlimid, got those nodes down to well under 5 cm, which is also the cutoff point at which Campa
th will work on nodes. Since we’re talking hypotheticals here, he perhaps could have followed up with Campath to clear the nodes further, though this sets up a risk of immunosuppression, infection, and viral reactivation. HDMP was another option that he did not use that might have shrunk the nodes significantly. He could have opted for R-CHOP (or H-CHOP) or Hyper-CVAD. (One consideration, of course, is that the more immunosuppressive, toxic drugs you use to nuke the CLL with, the greater the chances of a side effect or complication. And transplants are complicated enough as it is.)

My point is that there are several ways to search for that node reduction and/or CR when the time comes (and, like all CLL treatments, each comes with its risks and rewards). And in the interim I think there is a reasonable middle gr
ound -- exactly the ground Harvey has trod. He got close to a CR after six years of good QOL with monoclonals, and he saved fludarabine for the end. That last gamble didn't work out as well as he hoped, but welcome to CLL.

Hindsight is 20/20: At the beginning of his CLL career, Harvey had only the favorable 13q deletion and was IgVH mutated to boot, so it seemed his disease course w
ould be rather indolent, in which case a transplant seemed unthinkable. It was only as time went on and clonal evolution to 11q occurred and his mutated status proved less significant than problematic clinical symptoms that the transplant option became more attractive. This concept -- “things can change” -- is important to keep in mind. It bolsters Chaya’s argument that one should not wait too long; I can tell you from personal experience, as well as the experience of many patients I know, that once the disease starts to progress, things do not get better. They get worse.

One of the biggest challenges of living with the "new normal" o
f CLL is that we are forever making decisions without knowing what our disease will do, or what the drugs will do. This is not a disease for Type A personalities. Fortunately, I have always been more of a roll-with-the-punches type of guy. My view is that we patients are dealing in real time, and we make the best choices we can. We should not fault ourselves for making one choice and then finding out that "had I known what I could not possibly have known I might have done things differently."

Chaya's journal entry gives us good food for thought. There is no such thing as a CLL treatment that is risk free or that will not have consequences down the road. No matter what you do, there is no treatment that will not make retreatment more difficult. It is all a matter of balancing the risks and the rewards, playing the odds, and a little luck.

And speaking of which, good luck to Harvey as he heads north to a cure! I confess to having seen him myself a few times. Must be chemo brain . . .