Giving Thanks

This past Monday, I had the privilege of reading something I wrote to a small audience. I won 2nd prize in a memoir writing contest -- and a $50 Barnes and Noble gift card to go with it. The memoir had to be 500 words or less, and, long-winded as I can be, I came in a exactly 499 words -- after a whole lot of trimming.

And when I say I read in front of a small audience, I mean just that; I think there were more boxes of free pizza than there were people in attendance. So I ended up with some extra pizza, in addition to that gift card -- plus the applause I got from the audience.

Anyway, every year on Thanksgiving Day, I try to write something about what I'm thankful for. This year, I thought I'd share my 500 word memoir. It's a story I've told before, just not necessarily in this particular form. It is called, appropriately for this day, "The Gift":

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"The Gift"

When I first took up running, an experienced friend told me, “Some people who run are running away from something, and some are running toward something.”

When I started running, it was toward something: better health. I wanted to be around for my wife and kids.

Soon, I realized I was running away from something. For a few moments in the mornings, I could block everything out, just listening to music or the rhythm of my breath.

On my 40^th birthday, my wife bought me a treadmill. She knew I enjoyed running outside, but she worried about cars not seeing me, or slippery ice, or twisting an ankle far from home. A beautiful treadmill, it sat idle for a month; cool June morning runs were just too tempting.

Then it stayed idle because of a bout of bronchitis. The doctor gave me a prescription, and I asked her when I could run again, and she said, “A couple of weeks.” When I felt better, I finally tried the treadmill. The hiss of the belt and the grinding of the motor and the pounding of my feet were loud, even with my iPod at full volume. I missed the outdoors, and I couldn’t wait to get back to the peace.

The bronchitis never really went away, and I was back at the doctor’s office twice in two months for stronger antibiotics. On the rare days that I could breathe well, my run was on the treadmill. Tree pollen and car exhaust made it too hard to run outside.

Then late in the summer, the bronchitis turned to pneumonia. What should have been peaceful, cool fall morning runs were half run/half walks on the treadmill. To make matters worse, my oldest child, an early riser like me, started to join me in the basement, wanting to talk about the highlights on ESPN, turned up loud, joining the motor and my pounding feet to disturb my peace. Eventually, all that noise got to him, too, and he stopped coming downstairs in the mornings.

The pneumonia cleared, but a follow-up CT scan showed some swollen lymph nodes in my chest. A few months later, more nodes, more tests, and a biopsy that came back fast and grim: Follicular Lymphoma, an incurable blood cancer. Still limping from the biopsy, I asked the doctor when I could run again. “Two weeks,” he said.

Back to the treadmill.

I worried about myself, but I worried more about my wife and kids, and I watched and listened for clues about how they were feeling. One night, my ear to the door to my sons’ room, I heard the older one talking to the younger one. “I’m telling you, he’s OK.”

“How do you know?”

"I heard him running on the treadmill. He’s fine.”

Sometimes when we run, we are running toward something. Sometimes, we’re running away from something.

And sometimes we run because we want to stay, blissfully, even for a little while, right where we are.

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I wrote a version of this story about 5 years ago and submitted it to the magazine Runner's World, which often publishes short memoirs about running. They rejected it, of course, which was fine. That version was more focused on running, naturally, and did a lot more explaining about what I considered to be a gift.

When I wrote the piece for the memoir contest, I thought about renaming it "The Treadmill." That would make a lot of sense for a story about having Follicular Lymphoma. It feels like being on a treadmill sometimes, at least for me. Lots of watching and waiting. Rituxan gave me a Partial Response almost four years ago, so there's still come FL cells floating around in there, but not enough, apparently, to need treatment. No scan in more than three years, so I'm not getting better, but I'm not getting worse.

Just walking on a treadmill.

And "the gift" in the title is definitely my birthday treadmill. But that story wasn't just about the treadmill itself; it was about the way I was able to connect to my kids. And that's a gift.

I know lots of people who choose to look at cancer as a gift, at least indirectly -- cancer let them get their priorities in order, pay more attention to their health, or get closer to people they care about. Plenty of others think it's crazy to think of cancer in any way positive.

I guess, if I had to choose one or the other, I'd lean toward cancer not being much of a gift. (Of course, Follicular Lymphoma is the gift that keep son giving -- hah!). I'd never re-gift it, but if I had been given the choice, you can be dang sure I would have politely declined.

Still, on the other hand, I can see where, indirectly, it can result in some good. And if this memoir is as much about my kids as it is about a treadmill, I'd say my cancer has given me some things. I think my kids, now 16, 14, and 12, have become better people because of my cancer. They seem to me to be less fearful. They have seen what it is like to face something difficult and do what is necessary. They certainly aren't fearless, but they are a little less fearful.

And more importantly, they're a little more compassionate. They notice people who need help, and they provide it when they can. Small things, usually, but they can see the big results that can come from small actions. At a time when lots of young people are focusing more on themselves, they are, at least a little bit, looking at others. That makes me very happy.

So, what am I thankful for?

My treadmill. And the relative good health to keep using it. And my wife, for taking care of me.

My kids, who are growing up into fine people.

My extended family, who I wish I had more time to spend with.

And finally, for being able to share whatever gifts I have with all of you. I thank you for the feedback you give me. It means a lot.

Thanks for reading. Enjoy your day.

ASH: Dr. Cheson's Preview

Hard to believe it's almost December. All of the signs are out there: 20 degree weather in Connecticut, Salvation Army bell ringers in front of Stop & Shop, and now our first ASH expert preview -- this one from Lymphoma Rock Star Dr. Bruce Cheson of Georgetown University.

Medscape Hematology has a video from Dr. Cheson with some of the things he's excited about at ASH. The video is accompanied by a transcript (though if you don't have a Medscape account, you can't read beyond the first page).

Dr. Cheson's big theme seems to be that, while there are reports of studies involving traditional chemotherapies (including R-CHOP and Bendamustine), the real excitement is from newer, non-chemo agents. He seems especially high on Ibrutinib, and mentions several studies. He also discusses briefly some Kinase inhibitors.

It seems like CLL (Chronic Lymphocytic Leukemia) is the big winner at ASH this year, with a bunch of important and exciting studies being discussed (Dr. Jeff Sharman addressed these in his excellent blog about 10 days ago).

Unfortunately, Dr. Cheson doesn't devote a lot of time to Follicular Lymphoma (I guess I found more to be excited about there than he did). He does mention Rituxan maintenance, though reluctantly ("Maintenance won't seem to go away....I'm not a big fan....").

 The video is a little under 9 minutes, but worth it, even for a Follicular Lymphoma patient, just to see how excited he is about going to ASH. One quote from him kind of sums it up for me: "Great new drugs which will be changing the landscape of Non-Hodgkin's Lymphoma."

So sayeth the Rock Star.

ASH: The Psychological Effects of Blood Cancer

OK, another paper from ASH -- this one not focused on treatment, but on its long-term after effects.

The paper is called "Psychosocial Factors and Impact Of Cancer In British Long-Term Haematological Cancer Survivors," and it looks at the psychological (rather than the physical) effects of cancer, and how being a long-term survivor affects Quality of Life.

The study looked at 718 long-term (that is 5+ years) survivors of a variety of blood cancers, including 128 Follicular Lymphoma survivors. The researchers were particularly interested in "psychological distress (depression, anxiety), functioning, and fatigue" in this group, and how that compared to the general population. The study accounted for a number of different factors that would impact how people felt.

They found that the blood cancer survivors had a worse Quality of Life than the general population, with 15% at a distress level that would make them clinically depressed, 18% with high fatigue, and 10% with moderate to severe impairment in functioning. Interestingly, higher positive scores were obtained by the Acute Leukemia patients over Lymphoma patients, and lower positive scores were obtained by patients who were Caucasian, had high education levels, did not have a partner, were depressed, and didn't have much social support. (The low scores for lack of partner and social support make sense. I guess the higher education level does, too -- maybe more apt to spend all day looking up cancer information online and not liking what we see? Not sure about being Caucasian or having lymphoma. Interesting.)

The overall results are not terribly surprising. I'm sure they are even higher among people who are survivors of less than 5 years, since that magical 5 year mark means that most cancer patients are fairly safe from relapse. (Not so much for most Follicular Lymphoma survivors, of course, though there are certainly some very long-term survivors who might dare call themselves cured.

The study brings up two questions for me in particular.

The first has to do with health care availability and its effects on Quality of Life. The paper looks at British patients only; I wonder if their Quality of Life is better knowing that they will have access to health care if they relapse. In other words, would Americans taking the same survey be more likely to be depressed, knowing that they may not be covered, or that they have lost coverage? I'm aware that the law has changed now to eliminate denial for pre-existing conditions, but with so much uncertainty surrounding the ACA, I wonder if that is affecting log-term survivors. And I wonder if any other cultural factors would influence the way the results played out in the U.S.

I also wonder how things differ among patients with different types of lymphoma. Obviously, there are physical differences between indolent and aggressive lymphomas, but I wonder what the psychological differences are, too. Every now and then, I read exchanges between patients of the two types about who has it worse -- the one that is curable but aggressive, with more toxic treatments, or the one that is not curable but slower growing, with a potentially less disruptive quality of life, and the potential to transform? (As an indolent lymphoma patient, I have a harder time representing the concerns of the aggressive lymphoma patients, because I haven't lived through their fears.)

I tend to think cancer sucks either way, and neither of us has it very good. Fears linger, even after a successful treatment, whether the doctor calls "Cure" or not. And cancer also hardens some us, too, whether it's aggressive or indolent.

That's the study I'd really like to see: the psychological affects on long-term lymphoma survivors, and their effect on quality of life. Not so we can lord it over one another and say, "See, I told you we had it worse," but more because I'd like to see more of a dialogue on how it's bad for all of us, and more importantly, how we can help each other out.

The conclusion of the study is this: "The impact of cancer on survivors’ lives is influenced by a variety of factors. By using a simple means of screening for medical comorbidity, depression and fatigue the group that needs most support could be identified early, allowing appropriate interventions to improve QOL-related measures and promote well-being by addressing both negative and positive impact of cancer."

Wouldn't it be great to be able identify early the people who will need the most help? The best thing I ever did for myself as a cancer patient was to find a group online who was supportive, knowledgeable, and encouraging. Having them there has been a major factor in my own Quality of Life. It would wonderful if others were able to find that, too.

ASH: Why Revlimid + Rituxan Works (Maybe)

 Another interesting paper to be delivered at ASH in a few weeks: "Correlative Analysis and Clinical Update Of a Phase II Study Using Lenalidomide and Rituximab In Patients With Indolent Non-Hodgkin Lymphoma," by researchers at UC-Davis.

This study looks at the combination of Revlimid and Rituxan. Revlimid is also known as Lenalidomide, which is how this paper refers to it. However, the combination is often known as R + R, or R2, or R squared, so I'm going with Revlimid, because then I can say R + R and not have to type Lenalidomide over and over because I'm both lazy and a horrible typist.

Anyway, the study provides an update on a phase 2 study of patients using R + R, but goes a little farther by also providing an analysis of what's going on in the body to give some hint as to how and why R + R works. There are several trials studying this combination, including one reported on last month that showed that Revlimid might help Follicular Lymphoma patients who have become resistant to Rituxan. But, as these researchers note, there's still little sense of why it works. Knowing why might help identify patients for whom the treatment will work best.

First, the straight numbers: It's aphase 2 trial, so there were a relatively small number of patients involved (just 30 who had been treated previously with Rituxan, with 22 of those being Follicular Lymphoma patients, and another 15 who had not received any treatment. So 45 in total.

Results: for those who had been previously treated, the Overall Response Rate was 74%, including 12 patients 44% who a Complete Response; 3 of those CRs lasted for more than 4 years. Of the previously untreated patients, the Overall Response rate was 92%, with 42% reaching a Complete Response.

Those numbers are fairly well in line with previous reports on R + R for Follicular Lymphoma patients, which is great. I expect there will be a phase 3 trial at some point.

The second part of it all was what made things so interesting. To try to figure out why the combination worked, they took blood samples and measured levels of cytokines in the blood before treatment, then at 15 days after receiving the Revlimid (and before receiving the Rituxan), and then at 30 days and 60 days.

Now, cytokines are a fairly large group of substances that do a bunch of things in the body, mostly signaling other things that they should get to work. So by measuring levels of particular cytokines in the blood, they were hoping to see if certain activities were being signaled to begin, and thus giving them some sense of how Revlimid works.

They measured for 10 different cytokines that are usually associated with immune response in some way; basically, they signal the body to defend itself. They found that six of them didn't respond in any significant way, but four other responded big time, particularly at Day 15, before Rituxan was given.

I'm not sure the specifics really matter, but these are the substances that increased so much:

• IFN-y, or Interferon Gamma, which stops viruses from multiplying, but which also stimulates the immune system to act.
• GM-CSF, or Granulocyte Macrophage Colony-Stimulating Factor, which encourages white blood cells to grow.
• CXCL10, or C-X-C Motif Chemokine 10, which binds to cells to help T cells and Natural Killer cells find their targets.
• And IL-2, or Interleukin 2, which helps to keep white blood cells in check, and helps the body figure out which cells belong there and which should be attacked.

As I said, for our purposes, the specific substances and the things they do probably don't matter much. What does matter is that the researchers found them, and can begin to consider the significance of them.

What also seems especially significant to me are two things:
First, these substances were especially present in the patients who achieved a Complete Response.
Second, the levels for these substances went up before Rituxan was given, so they might say a lot about Revlimid, rather than the combination. But that doesn't mean the combination isn't great, only that these particular substances increased with Revlimid. That might very well have prepped the lymphoma cells for the Rituxan, which is why the combination works so well.

And the combination does seem to work, at least for a specific group of patients. It will be interesting to see what a larger phase 3 trial ends up with.


 

ASH: Rituxan vs. Watching and Waiting

Another interesting abstract from ASH: "Frontline Rituximab Monotherapy Induction Versus a Watch and Wait Approach For Asymptomatic Advanced Stage Follicular Lymphoma: A Cost-Effectiveness Analysis," from several Canadian researchers. The whole "do I treat or do I wait?" debate has been going on for a while, and we don't have a definitive answer. This paper provides another perspective (though, not, I would argue, a definitive answer.)


I am, of course, a watch-and-waiter, so my bias tends to be toward this approach, if it makes sense medically and emotionally for the patient. The argument I received for watching and waiting is essentially the same that most patients hear: starting treatment right away has not been shown to increase overall survival. If there are a limited number of treatments available to Follicular Lymphoma patients, it makes sense to hold off for as long as possible before starting to chip away at that list. Also, if watching and waiting works, there's no sense in starting a treatment that could potentially result in side effects, even if they are minimal ("Do no harm," as Dr. R puts it -- choose the treatment that will give the most benefit with the least damage.)

The authors of this paper take a different look at this controversy, focusing on cost. Now, watch and wait also has that cost advantage: no treatment = no outlay. But they look at this from a different angle.

They note that the studies that have looked at watching and waiting vs. treatment all looked at some form of chemotherapy as the treatment being compared. None looked at Rituxan as an immediate first treatment. They found that a study from 2010 showed that while there was no overall survival benefit to Rituxan instead of W & W, there was a benefit in Time to Initiation of Next Treatment. In other words, Watch and Waiters needed to be treated sooner than those who took Rituxan.

The researchers developed a hypothetical model, using data from published studies. Essentially, they created fake 60 year old patients (yes, I know "fake" is a loaded term, but I also know that not all Folliuclar Lymphoma patients are 60 years old) and ran a model of what was likely to happen to them over the course of several years. They looked at the patient in 6 month intervals: based on published data about FL patients, and various median times to treatment, what is likely to happen 6 months after diagnosis? Would they need treatment? And after 6 more months, what would happen? And six months after that?

Based on this hypothetical model, they determined when these patients would likely need a first treatment, a second treatment, Rituxan Maintenance, salvage treatment, palliative care, etc -- basically running through their entire post-diagnosis lives. They ran the model with patients who began by watching and waiting, and who began by getting Rituxan right away. All of the patients received Bendamutine + Rituxan, then Rituxan Maintenance, with a maximum of 3 different treatments. Overall, they ran the model on 10,000 patients. They focused on how much all of that care would cost, based on actual Canadian health care system figures.

The results showed very little difference in Overall Survival, as was the case with other studies (and considering the data was based on actual studies, it is to be expected). So there is no arguing that one is better than the other in terms of effectiveness.

However, because the Rituxan patients required more time until treatment, the overall average monetary cost was lower for them: $59,061 for the Rituxan patients, and $74,531 for the Watch and Waiters. They argue that there is a lot of money being spent for no real benefit.

This is certainly one more variable to consider in choosing between the two strategies. While it is a simulation, it's based on data from actual patients, which does lend it some credibility. And I'm certainly in favor of reducing costs, as long as care is not comprimised.

It will be interesting to see what the reaction is for this one. I don't think treatment strategies would change based just on cost alone (that doesn't seem to be an issue right now, anyway), though it could be one more factor that tips the scales for some individual doctors in making a recommendation to patients. I think any effects from this are going to be pretty subtle.

Ibrutinib

A quick break from all of that good ASH Follicular Lymphoma news:

Yesterday, the FDA announced that it has granted accelerated approval for Ibrutinib for Mantle Cell Lymphoma.

The accelerated designation came because the approval was based on results from a phase 2 clinical trial, rather than the usual phase 3 trial, which would have involved a wider pool patients. The results were certainly impressive: a 68% overall response rate, with 21% achieving a complete response. The response was decently long-lasting, with a median of 17.5 months.

Ibrutinib is a kinase inhibitor, a funky new class of treatments that targets kinases, which are enzymes that act to do things like phosphorylation, which is a process that I don't feel like looking up right now and describing. Let's just say that kinases work to make some complex things happen within cells, including some that encourage the growth of cancer. A kinases inhibitor like Ibrutinib stops those things from happening. (What more do you need to know?)

Ibrutinib is still not approved for Follicular Lymphoma, though a trial is currently under way that looks at Ibrutinib in Follicular Lymphoma patients who had already received a different treatment. Another small study showed that Ibrutinib works very well with R-CHOP, achieving a 100% response rate in 15 patients. I think there are others, too. As far as I can tell, there's nothing at ASH this year reporting on any Ibrutinib studies for Follicular Lymphoma.

So, not directly good news for Follicular Lymphoma, but I like hearing that treatment under consideration for FL is doing well elsewhere. There's no guarantee it will work for Follicular Lymphoma, of course, but I still like to hear those success stories.

More ASH stuff coming up.

Bruton's tyrosine kinase (BTK) inhibitor

ASH: Rituxan Maintenance for Follicular Lymphoma

Sometimes ASH or ASCO or some other lymphoma-nerd conference is kind of a dud -- nothing really new or exciting to be discussed (at least, nothing I find exciting, which is what really matters).

This year's ASH conference is an exception. There's some good stuff that's going to come out of it, and as we get closer to the actual conference, we're going to see lots of press releases from research centers and drug manufacturers touting the good things that they reported on. I try not to get too optimistic about things. I'm all about hope, but hope, by definition, always contains just a little bit of doubt. If we were really sure of something, we wouldn't need to hope.

So read everything I say as optimistic realism.

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I predict that this particular paper is going to get a whole lot of discussion in the weeks ahead. It's called "Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy." The study is being led by Dr. Gilles Salles from Lyon, France. At the conference, this session is being held in La Nouvelle Ballroom AB at the Ernest N. Morial Convention Center. I've never been to this Convention Center, but I've been to enough conferences to know that the "ballroom" talks, especially when the ones that they take out the room divider for (it's in ballroom "AB," not "A" or "B"), are expected to attract a whole bunch of people.

Not surprising, given the topic -- Rituxan Maintenance. The PRIMA study (it stands for Primary RItuximab and MAintentance) is the major study of Rituxan Maintenance, and it is taking place in mostly European Study Centers (over 200 different hospitals and research centers in 25 countries). As the title of the paper indicates, it has been going on for almost 10 years now.

Here are the basics of the PRIMA study:  It looked at 1217 Follicular Lymphoma patients who were given one of three chemotherapies along with Rituxan (The chemos were CHOP, CVP, or FCM, which is a Fludarabine combo).  Of those patients, 1019 has a partial or complete response to the chemo + Rituxan combo. These were assigned to one of two arms: 505 patients were given Rituxan Maintenance; 519 got no further immediate treatment.  The R-Maintenance consisted of a dose of Rituxan every 8 weeks for 2 years. The first major update for the study was published in The Lancet (a major British medical journal) in 2010: after 36 months, Progression Free Survival for the R-Maintenance group was 74.9%; for the other group, it was 57.6%.  The conclusion: R-Maintenance works.

Now, the important thing to remember is that PRIMA is not the only study of R-Maintenance (though I believe it is the largest).  Other studies have shown less success, or at least less dramatic benefit. Lymphoma Rock Star Dr. Bruce Cheson offered a nice summary of some of these studies after last year's ASH conference. The basic complaint: still not enough evidence that the large number of doses of Rituxan is worth the expense, since there appears to be little Overall Survival benefit to R-Maintenance.

So now we have this year's ASH presentation. It reports on those same 1019 patients, but with three additional years of data. Here's the upshot: After 73 months (a little over 6 years), the Progression Free Survival rate for the R-Maintenance group is 59.2%, and for the other group, 42.7%. That's down some from 3 years ago, but that's certainly to be expected. The key number is the difference between the two groups. It has stayed roughly the same -- about a 17% difference. And the difference was even bigger for older patients (doesn't define what that means), female patients, and those with lower FLIPI scores.

Three other important points: 1) there seems to be no difference in the two groups for rate of transformation (which seems really small, though I need to look into that more); 2) there is no difference in Overall Survival (around 88% after 6 years); and 3) when patients did need a second treatment, there was no difference in the effectiveness of that treatment (in other words, the R-Maintenance didn't make the treatments less effective).

It will be interesting to see how people respond to this paper. It certainly does make a case for the effectiveness of R-Maintenance after chemo. But, as Dr. Cheson pointed out last year, there are some other studies that call into question whether r not it's worth it. My guess is the lymphoma community is going to be split: those who already believe that R-Maintenance is the way to go will praise it; skeptics will call on us to wait until some of those other studies (like the RESORT study) also present longer-term results, for comparison.

Or, maybe this will be enough, and we'll have some consensus that R-Maintenance is the way to go. (History, however, suggests that we will still be debating this next year. After all, the superior numbers for Bendamustine haven't stopped lots of oncologists from preferring R-CHOP as a first treatment.)

I'm kind of looking forward to what happens next.

I'll have something else from ASH in a few more days.