Monday, November 18, 2013

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.


Thursday, November 14, 2013

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

Monday, November 11, 2013

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.

Saturday, November 9, 2013

ASH Follicular Lymphoma Abstracts are Here!

It's the most wonderful time of the year!

(For a cancer nerd!)

The abstracts for the annual American Society of Hematology conference are available online.

 The ASH conference will be held in New Orleans this year from December 7-10. (I have some very fond memories of a trip to New Orleans when my wife and I were first married. Shrimp and oyster po' boys. The St. Charles street car. Cross-dressers singing Cher songs....stories for another time.....)

Anyway, the ASH conference is often when some of the most interesting research about Follicular Lymphoma (and other blood diseases) makes its debut. In a quick search, I found 169 results for "Follicular Lymphoma," and I'll spend the next week or so looking through them to see what's interesting.

One that stands out right away: "Follicular Lymphoma In Young Adults: Clinical Characteristics and Early Treatment Outcomes." I consider myself still young, especially in Follicular Lymphoma terms, given that the median age of those diagnosed is about 67. Alas, "young adults" in this sense means those under 40. I was 40 years and 6 months when I was diagnosed. But I'm young at heart, so I'm interested in what they have to say.

The study looked at 410 patients who were newly diagnosed with FL; 55 of them were under 40, and the rest were between 40 and 65 (referred to as "older patients," which I'm trying hard not to be offended by). The researchers were interested in how different the lymphoma was -- if there were physical differences, or different outcomes.

They found a few differences: 10 year Overall Survival for the Young Adult group was 89.3%; for the older folks, it was 74.2%. Now, Overall Survival measures death from any cause, whether disease-related or being hit by a runaway streetcar in New Orleans. So it's probably not too surprising that a 39 year ols has a better 10 year survival chance than a 65 year old.

So they measured lymphoma-related survival, too, and found a lower probability of death in the young folks (4%) than in the older folks (15.3%). However, this was not found to be statistically significant (which means they probably didn't have enough patients to look at to really find a trend that they could be confident about).

And here's another fascinating tidbit: the Watch-and-Waiters did much better than those who had treatment right away. (But don't read too much into that. If anything, it just validates that W & W is still an OK choice; it doen't mean it's right for everyone.)

Their conclusion: the physical characteristics of Follicular Lymphoma are pretty much the same, no matter the age of the patient. But younger patients seemed to have a better Overall Survival, and it's going to take more research to figure out why that is true.

Interesting stuff. I'll keep reading and post more soon. (And try to provide a warning for why we should be optimistic, but not too excited, about positive stories from ASH.)

Thursday, November 7, 2013

Dr. Cheson on Follicular Lymphoma

Apparently, Matt Lauer and Al Roker got live prostate exams on the Today Show this morning, to raise awareness during Prostate Cancer Month. This is a link from a news story yesterday that said it was going to happen.  I'm not including a link to the actual show, because I don't really care to watch Al Roker get a prostate exam. Besides, "I'd rather watch Al Roker get a prostate exam" sounds too much like a Jay Leno punchline.

There -- I've done my part to promote prostate cancer awareness.

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Lymphoma Rock Star Dr. Bruce Cheson gives us the State of the Art in managing Follicular Lymphoma, in an interview with Clinical Oncology News. Dr. Cheson is Head of Hematology at Georgetown University Hospital in DC, and he's a very visible expert on Follicular Lymphoma, appearing online to explain things clearly. (And frankly, I need something from someone like him, given my last couple of posts. This interview comes at a good time.)

It's not a long interview, so I'll give you what are for me the highlights:

Dr. Cheson was asked the difference between FLIPI and FLIP-2, and how a score influences his treatment decisions. FLIPI stands for Follicular Lymphoma International Prognostic Index, and it was designed to help doctors gauge patient outcomes, and thus how aggressively to treat. It's a funny index; it's best to think of it as an estimation of where you are, not a prediction of what will happen. The difference between the two is FLIP-2 is a more recent creation, and takes into account he difference that Rituxan has made on treatment. What the FLIPI indexes will not tell you, though, is when to treat.

For that decision, Dr. Cheson consults the GELF criteria (the name comes from the Groupe d’étude des Lymphomes Folliculaires, a French study group for Follicular Lymphoma). GELF lays out some of the physical properties that might make it a good time to treat (things like lymph node size and some blood counts).

The "when" question, of course, assumes that treatment isn't necessary immediately, which again brings up the issue of Watch and Wait. Dr. Cheson gives his take on the W & W controversy, one that I agree with. First off, he wisely mentions that importance of taking psychological and emotional factors into consideration. Physical factors aside, some patients want to be treated right away. Others, conversely, feel better knowing they can hold off treatment. GELFs and FLIPIs mean nothing until the doctor understands how it affects the patient emotionally.

From there, Dr. Cheson reviews the research on Watching and Waiting. His conclusion? He still uses it for patients in certain situations. 

Dr. Cheson closes with a discussion of curability, mostly with regards to Stage I and II disease, which are diagnosed only about 15% of the time. But he has some thoughts on the curability of later stage disease, too, that are worth considering. (No, Follicular Lymphoma is still not curable, but Dr. Sheson suggests we might re-think what that means in the long term.)

Overall, it's a nice summary of where we are with Follicular Lymphoma, from a well-known expert. There's a part 2 for next month, with his thoughts on front-line treatments and maintenance therapy. Looking forward to that one.

Tuesday, November 5, 2013

Non-Hodgkin's Lymphoma (Mostly) Explained

Patients Against Lymphoma (the organization behind Lymphomation.com) posted this video to their Facebook feed today.

It's from MedCram, which creates videos aimed at Medical students (the narrator of the video refers to exams a lot -- not sure I like med students watching videos to "cram".....).

This is part 1 of a two part series; it focuses on NHL, mostly laying out the different types, with part 2 focusing on Hodgkin's.

It's a good introduction to NHL,  aimed at future medical professionals. But a few things bothered me.

First off, I'm not crazy about the division of NHL in low-grade, intermediate-grade, and high-grade lymphomas. Calling them "grades," first of all, is confusing, since each type of NHL has its own grading. My understanding is that the NHL community has been moving away from these terms, preferring "indolent" and "aggressive." I can see where three categories is better than two -- DLBCL and Burkitt's are very different lymphomas, and probably shouldn't be lumped together under "aggressive." A guide from the Leukemia and Lymphoma Society just cuts out "intermediate" completely, and calls them "'indolent' or 'low grade'," and "'aggressive' or 'high grade'."

My point is, this is potentially confusing to patients. If this is intended for future medical doctors, it would be nice to have some consistency in terminology. Makes it easier for everyone to understand.

Another, similar issue: Follicular Large Cell Lymphoma is listed as an Intermediate Grade Lymphoma. Honestly, I've never heard this term before. And, in fact, the World Health Organization classification from 2011 (its most recent) does not recognize this as a separate type of NHL. As far as I can tell, the narrator is using this term to describe transformed Follicular Lymphoma, but he never uses that term (or discusses transformation at all, which seems like it should be kind of a big deal).

Again, maybe we should have different names for the different ways Follicular Lymphoma presents itself. But for now, we don't. It just creates confusion. Maybe this is why we have problems communicating with our doctors sometimes?

Which brings me to the part that bothers me most. It's a throw-away comment the narrator makes, so quick you might miss it if you aren't listening carefully. He describes the two types of B cell lymphomas as being from follicles (like Follicular Lymphoma) or as diffuse (like DLBCL). Follicle lymphomas a "good"; diffuse are "not good." He uses this term again to describes "less proliferative" (good) and "more proliferative" (bad) types of NHL. Low-grade/indolent = good.

I have a problem with this. I've heard lots of patients who are told, sometimes by doctors and sometimes by patients, that they got "the good kind of lymphoma." What makes it good? This is entirely a matter of perspective. Aggressive lymphomas are not "the good kind," since they need to be treated immediately, unlike some indolent lymphomas. On the other hand, most aggressive lymphomas are, under some circumstances, curable, unlike most indolent lymphomas. I'd say that makes aggressive lymphomas "good." I'd say there's nothing good about knowing that, even when Rituxan or Bendamustine  has knocked back my Follicular Lymphoma, it's probably coming back at some point. Not good.

I refer you to the very funny (if you like cancer humor) subplot from Curb Your Enthusiasm when Larry tries to figure out if Hodgkin's or Non-Hodgkin's is "the good kind." When a sitcom explains this better than a medical exam preparer, I think we have a problem.

All of that said, I think the video did do a good job of explaining some basic stuff about NHL -- cleaved cells, maturity of cells, etc. But there are some details that matter, especially when those details affect the way a doctor communicates with a patient about her disease.

The really big lesson is, if you're in medical school, and you have exams coming up, and you have to cram for an exam on lymphoma, and a video is your only option, then please, please find a video made by a lymphoma expert, not someone described as "Board certified in Internal Medicine, Pulmonary, Critical Care, and Sleep Medicine."  You owe us, your future patients, at least that much.

Sunday, November 3, 2013

Make-A-Wish

Saw this and thought it was pretty awesome:

The Greater Bay Area Make-A-Wish Foundation, which, of course, grants wishes to sick kids, is helping a 5-year-old Leukemia patient fulfill his wish to be Batman.

Their website lists the schedule for his special day, November 15, and the city of San Francisco is pitching in to help. The actual Chief of Police will be calling for his help in the morning. He will rescue a woman in trouble, battle the Puzzler, get a call at lunch to catch a bank robber, and more. The day ends with the mayor giving Batkid the key to the city to thank him for his help.

The website also lists the times and ways that people in the San Francisco area can take part in the fun, being part of the crowd that calls for help, or clapping when the mayor hands him his key.

It sounds like a great day, and a great reminder that very small gestures can sometimes have a big impact.