ASH: Vitamin D and Follicular Lymphoma

Another interesting ASH presentation -- this one is called "Vitamin D Insufficiency Is Associated with an Increased Risk of Early Clinical Failure in Follicular Lymphoma."

I'm very interested in Vitamin D and FL, mostly because I take some every day, on the advice of my doctor. It's kind of a controversial supplement, in that some doctors get very excited about patients taking it, and others are more skeptical, and there are lots of studies that suggest it's a problem not to have enough, and others that aren't quite so sure.

For me, despite my mom's Italian heritage, I'm mostly of fair-skinned Scottish-Canadian ancestry, so I try to stay out of the sun. And that means my body isn't making Vitamin D naturally, so I take a supplement.

Before I go any further, let me be clear: I'm not suggesting that anyone else should take Vitamin D. That's my choice, based on my doctor's advice. You should talk to your own doctor about whether it's a good idea for you.

Also, I'm NOT suggesting that there is any research that says Vitamin D will cure your Follicular Lymphoma. It's easy to get excited about these kinds of potentially easy solutions, but nothing is easy with Follicular Lymphoma, as we all know.

So, on to the study:

Researchers looked at 642 newly-diagnosed FL patients. They wanted to figure out if low Vitamin D levels in the blood could predict if a patient would have early clinical failure (measured by Event-Free Survival at 12 months, or EFS12) and Overall Survival, as well Lymphoma-Specific Survival (death caused by Lymphoma and not something else). They were interested to see if low Vitamin D levels were related to how successful specific treatments were, too.

They found that in the entire group, low Vitamin D levels were associated with inferior EFS12, OS, and LSS -- all three.

The same was true of patients who had Immunochemotherapy (something like R-CHOP or R-B) -- inferior for EFS12, OS, and LSS.

For patients who were observed (watch and wait), low Vitamin D was associated with low Overall Survival, but there was not enough of a connection to say it was associated with EFS12 or LSS.

There were not enough events or deaths to measure any connections for patients who had straight Rituxan. (That's bad for the study, but good overall.)

Their conclusion: "We confirm previous findings that vitamin D insufficiency is associated with adverse long-term prognosis among patients with FL treated with IC, and extend these findings to patients who are initially observed or treated with other therapies.  For the first time, we observed an association of vitamin D insufficiency with early clinical failure, suggesting a potentially modifiable factor to address in this subset of patients with poor outcomes.  Whether treating VDI improves outcomes in FL warrants assessment."

In other words, having low Vitamin D levels can make things worse for you. But that doesn't mean having sufficient or high levels will make things better.

So, it's an interesting study with no firm conclusions, other than to talk to your doctor about whether your Vitamin D levels are OK, and whether or not it matters.

 

ASH: A New Way to Think about Watching and Waiting

I'm fascinated by studies that ask whether or not Watching and Waiting is worth it for Follicular Lymphoma patients, even though they drive me crazy. It seems like these studies go back and forth with one another -- one will provide some evidence that Watching and Waiting is a better choice than being treated right away, and then a few months later, another study will say the opposite.

I don't think there is any right answer, but I keep reading them anyway, mostly because I want someone to tell me I was right to hold off on treatment for two years.

(Really, I don't need anyone to tell me I was right. I'm coming up on my 9 year diagnosiversary, and I'm still here. That's about as right as it gets. But I'd still like that decision to backed up by science, if that's possible.)

Since there doesn't seem to be any right answer to this question, I was pretty thrilled to see an ASH proposal that asked a different question: is there a better way to measure whether or not Watching and Waiting is an effective strategy?

The session is called "Intervention Versus Observation: What Is the Appropriate Endpoint? Assessment of Endpoints in Patients with Advanced Stage Follicular Lymphoma Who Are Initially Observed." Most research that compares the two options (watching and waiting vs. treating right away) by comparing Progression Free Survival or Time to First Next Treatment, these researchers suggest a better way to measure is Time to 2nd Treatment (TT2T).

Here's the logic: Imagine a trial that involves half of patients watching and waiting, and then measuring how long it takes to get to their first treatment. The other half involves patients getting Rituxan, and then measures how long it takes for them to get to their next treatment. Those two times are compared to see which approach works better.

But this is an unfair comparison. One group is measured by how long it takes to receive their first treatment, and the other is measured by how long it takes to receive their second treatment. What if we looked at that first (W & W) group and measured how long it took them to get to a second treatment?

More importantly, could TT2T be a replacement for measuring Overall Survival? In other words, studies that use that first treatment as a way of measuring success might be stopping their measurement too early. The big question with FL treatments is always "Dies this treatment improve Overall Survival (OS)?" Does TT2T give us a better idea (since it is measured over a longer period) of how well W & W might contribute to Overall Survival?

The answer, they say, is Yes. In a study of 264 FL patients, with a median follow up of almost 11 years, they found that the Time to First Treatment was 43.5 months -- just under 4 years. But the median Time to 2nd Treatment (TT2T) was 151.8 months -- almost 13 years. Median Overall Survival was not reached, so it will be more than 13 years. So the TT2T would seem to be a better measure of Overall Survival when comparing W & W with initial treatment.

The researchers think there needs to be more research before TT2T can be a replacement for OS, and I think there's some value on figuring out whether it can be (Overall Survival measures death by any cause at all, from cancer to heart attack to getting hit by a bus, while TT2T focuses only on how whether the lymphoma has progressed enough that treatment is necessary).

I like the statistics presented, too: 8 or 9 years is a long time between the first and second treatment, and it roughly follows the path that I seem to be on (2 years until first treatment, and almost seven years since and I still haven't needed a second one yet). My first treatment came exactly two years to the day from my diagnosis -- shouldn't that put me in that high risk group that needs treatment within 24 months? But my (not yet needed) second treatment puts me a very different group, one that has a slower-growing for of FL, and seemingly lower risk.

Mostly, I like that this gives us a different way to think about Watching and Waiting, and whether it is worth recommending as a strategy. In the end, that's an individual choice, one that involves an emotional assessment, and not just a scientific one. But it's ncie to have something else to add to the conversation.

I still feel like I made the right choice -- for me.

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Before I go, a note about terminology: The researchers use the term "Observation" instead of"Watching and Waiting." I had someone comment a while ago suggesting we stop using the "and waiting" part of that, and just call it "Watching" -- essentially the same thing as "Observation" -- because the "waiting" part brings on unnecessary stress. I use the "W & W" term mostly because it's the term I've been using for almost 9 years, and switching might be confusing to some people. I also think the "and waiting" is kind of unavoidable. We don't just watch -- we expect something to happen. I certainly did. So I respect the idea of going by a different term for a very good reason, but I'm sticking with W & W. It's a more accurate reflection of own experience.

ASH: R-Squared

More exciting news from ASH. The focus in in R-Squared, Rituxan + Revlimid (also known as Lenalidomide).

Researchers from Switzerland and the Nordic Lymphoma Group have been looking for a while at R-squared as a first treatment for Follicular Lymphoma. They reported positive results of a trial that looked at R-Squared's effect on Response, and found that it had a higher Complete Response rate than Rituxan alone, with manageable toxicity (basically, the side effects were outweighed by the results). They reported those results in articles in Blood and Hematological Oncology (sorry -- can't get a link working for that one).

The ASH presentation is a follow-up on those early results, and is called "Rituximab Plus Lenalidomide Versus Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in Need of Therapy. First Analysis of Survival Endpoints of the Randomized Phase-2 Trial SAKK 35/10."

Basically, they knew that R-Squared worked really well after 23 weeks (measuring for the percentage of patients who achieved a Complete Response). Now they want to know, is it effective beyond that point? Do those responses hold over time?

The answer is, Yes.

They used several different measures to figure this out. Half of the patients were given Rituxan alone, and half were give R-Squared.

The R-Squared patients had a better Complete Response duration; after 3 years, the median hadn't been reached, while it had been after 2.3 years for the Rituxan group.

The R-Squared patients had a better Progression Free Survival (the time it took for the lymphoma to get worse); after 3 years, the median hadn't been reached, while it had been after 2.3 years for the Rituxan group.

The R-Squared patients had a better Time To Next Treatment; after 3 years, the median hadn't been reached, while it had been after 2.1 years for the Rituxan group.

Overall Survival was great for both groups (93% for R-Squared and 92% for Rituxan only).

Lots of specialists are excited about R-Squared, and this study seems to give them more to be excited about. Interestingly, these results come from a phase 2 study. A phase 3 will involve a larger group of patients, and results will likely lead to the combination being approved as a first treatment for FL patients. That's always good news.

ASH: RCHOP + RIT + RM

More from the ASH abstracts.

This one has kind of a retro feel to it: "Sequential RCHOP, Radioimmunotherapy and Rituximab Maintenance Improves Early Outcomes in Advanced Stage Follicular Lymphoma: 5 Year Outcomes from SWOG 080."

This involves a Phase II clinical study involving 84 patients (at first) with stage 3 or 4 Follicular Lymphoma (or bulky stage 2), who have not yet had any treatment. Patients were first given six rounds of R-CHOP (Rituxan plus the chemo combo CHOP), then followed up with Zevalin (the RadioImmunoTherapy treatment), and then given Rituxan Maintenance for 4 years (once every 3 months).

Before I get to results, a couple of comments. As I said, this one has kind of a "retro feel" to it. Let me explain.

First, all of the big news these days focuses on treatments that are moving away from traditional chemotherapy like CHOP (and CHOP is about as traditional as it gets for Follicular Lymphoma). So it's interesting to see a successful trial involving chemo (and, as you'll see, it was successful). I've certainly expressed the opinion that CHOP trials are kind of outdated, and that resources could be better devoted to other things. But I've also said that CHOP still has a place in our bunch of treatments, and we certainly shouldn't get rid of it. (I'll say one or the other depending on my mood -- I'm fickle that way.) This trial also feels kind of retro because it involves RIT, which might be on its way out as an available treatment.

And finally, it feels kind of retro because I remember getting very excited, years ago, about a study that looked at R-CHOP and RIT (no maintenance) that was successful, and the researchers thought it was successful because the lymphoma was being attacked in 3 different ways. That combination approach always made sense to me -- cancer is too tricky to expect one treatment to wipe it out.

And this particular combination worked pretty dang well.

84 patients went through the R-CHOP and RIT. 59 of them had a Complete Response and 23 had a Partial Response, for an Overall Response Rate of 99%.

69 of those patients went through the last step and had Rituxan Maintenance, with 42 completing the full 4 years. The Overall Survival after 3 years is 96%, and after 5 years it's 94%.

Patients at various points in the trial experienced a variety of side effects, as they detail in the abstract. They had the most patients drop out of the trial during the Maintenance phase; they think 4 years is just too much time to be taking Rituxan.

But overall, those are some pretty good numbers. The researchers think this approach (RCHOP + RIT) could work well with "precision strategies" (which I assume are things like pathway inhibitors and immunotherapy), as a way of halting more high-risk lymphoma early on, with (I am guessing) those precision strategies to manage it from there.

So here's to retro treatments -- they still have a lot to offer us. Maybe this could be one of the many studies that show that RIT is worth saving?

ASH: Obinutuzumab (Two Studies)

Continuing with ASH commentary:

There are two sessions that will present results from the GALLIUM study, which looked at Obinutuzumab (also known as GA101 and Gazyva) plus chemotherapy as a first treatment for indolent lymphoma patients, comparing it to Rituxan + chemo.

Obinutuzumabis an anti-CD20 monoclonal antibody, like Rituxan. But it has been created differently. First, it is humanized, meaning it is created from  human cells (Rituxan has some mouse parts in it  -- sorry, some murine components). Some think humanized anibodies will cut down on the allergic reactions that Rituxan sometimes brings on (as it did for me). Obinutuzumabis also glycoengineered. Basically, it was made to have more sugar-related enzymes, which allows it to signal some T cells that will find and kill the cancer cells. There's more to it than that, but the bottom line is, Obinutuzumabwas created so it would be like Rituxan, but more effective.

The two studies from ASH focus on Follicular Lymphoma patients from the GALLIUM study (which is a phase 3 clinical trial that involves patients from several different countries).

The first one is called "Obinutuzumab-Based Induction and Maintenance Prolongs Progression-Free Survival (PFS) in Patients with Previously Untreated Follicular Lymphoma: Primary Results of the Randomized Phase 3 GALLIUM Study." (This was selected for the "Plenary Scientific Session," which makes it one of the top six presentations in the whole conference. A big deal.) The study compared Rituxan + chemo + R-maintenance with Obinutuzumab + chemo + Obinutuzumab maintenance. So we have a direct comparison between the two anti-CD20 treatments. The way of comparing was Progression-Free Survival (PFS) -- which treatment allowed patients to go longest without having their FL get worse?

The study is still going on, with not enough patients having reached the median yet (that's a good thing), but the researchers assume that the Obinutuzumab group has a PFS about 1.5 times longer than the Rituxan group, which could be as much as 3 years of Progression Free Survival. That's pretty significant (and the ASH Selection Committee giving the session a place of honor would seem to be saying the same thing). It's been tough to find something that works better than Rituxan. This might be it (when it combined with chemo -- either Bendamustine, CHOP, or CVP) and followed with maintenance. The researchers suggest this should be a new standard of care.

The other study involving Obinutuzumab and the GALLIUM study is "Minimal Residual Disease in Patients with Follicular Lymphoma Treated with Obinutuzumab or Rituximab As First-Line Induction Immunochemotherapy and Maintenance in the Phase 3 GALLIUM Study." This one uses the same patients to argue that Minimal Residual Disease (MRD) is a way ti measure how effective a treatment has been. Basically, by figuring out whether or not the treatment has cleaned up all of the cancer cells, we can tell how likely it is that the cancer will return.

To find MRD, researchers looked at either blood samples of bone marrow samples to see if there were any genetic markers on cells that would show that they were FL cells. The samples were taken at the mid-point of the treatment and at the end of the treatment (remember, this is still the GALLIUM study, so patients had either Obinutuzumabor Rituxan + chemo + maintenance). The tests that looked for genetic markers are sensitive enough that the researchers could be sure that the disease was present. (Compare this to something like a PET scan as a way of measuring how well a treatment worked. A scan might not light up, but there might be a small number of cancer cells still hanging around -- too small to light up a scan, but not too small that they won't multiply and bring the disease back. It's a more effective way of measuring success.) So there were really two things being measured here. First, the study showed that MRD was a good way of measuring how successful a treatment could be. And second, because they measured for MRD at the mid-point and the end, that showed that Obinutuzumab was more successful than Rituxan at clearing out cancer cells quickly.

Together, the two studies show that Obinutuzumab is really good when it is combined with chemo and followed with maintenance. It might be a good replacement for Rituxan in that situation. The same combo was already approved earlier this year as a second-line treatment for patients who already had Rituxan as part of their first treatment. It will be interesting to see what other combinations show positive results from here.

ASH: CAR-T

ASH abstracts are here! Woo hoo!

Every year at the beginning of December, the American Society of Hematology holds its annual meeting, and some of the most interesting and exciting research in lymphoma is shared. It's an exciting time for a Cancer Nerd like me. This year, there are about 60 presentations that are related to Follicular Lymphoma, and as I've done in the past, I'll try to read and comment on the sessions that are most exciting and interesting to me.

An important thing to mention: there is lots of good stuff at ASH every year, but it's usually not peer-reviewed. That is, it hasn't been looked at and approved by other experts in the area. That doesn't mean it isn't valid -- it just means it might turn out to be not as exciting as it seems at first. Also, a lot of the research is very early, in phase I or maybe phase II trials, with small numbers of patients. Same warning there -- it might turn out later that the research wasn't as exciting as it had seemed.

But that doesn't mean we can't get excited about what might come in the future, right?

So let's start with this one: "T Cells Expressing a Novel Fully-Human Anti-CD19 Chimeric Antigen Receptor Induce Remissions of Advanced Lymphoma in a First-in-Humans Clinical Trial."

This one was on my list, and then I got an email from William, who comments here sometimes. The paper is reporting on a trial that William's wife is a patient in, so he has an interest in sharing the good results that are being presented.

The paper discusses one of the many variations on CAR-T therapies that are being tested these days. As the abstract explains, some CAR-T types are made with murine components (researchers are too polite to say "mice," so they say "murine"). Like Rituxan, which is also made with murine components, the body can have a reaction to those non-human parts of the treatment. So the researchers reporting here created a fully-humanized CAR-T treatment to get rid of that problem, one that seeks out the CD19 protein on lymphoma cells. The treatment is called HuCAR-19.

Patients were given low-dose chemotherapy (Cyclophosphamide, the "C" in CHOP, plus Fludarabine), and then the HuCAR-19. Some patients were given a second dose if things hadn't cleared up.

This was a very small study (11 patients), and researchers were interested in the safety of the treatment as much as the results. They got good news on both ends: there were some safety issues, but they were treatable. The safety issue they were most concerned about was
Cytokine-Release Syndrome. With CRS, so many cells are being killed at once that the body has an inflammatory response, and it can have very serious consequences, including death. The researchers were aware of this, and had treatment available. The other thing they were looking for, a Response to the treatment, was also very good -- an 86% Overall Response Rate. So HuCAR-19 has shown to be safe and effective in this small study, making it worth examining in a larger study.

The patients, by the way, had several different types of lymphoma. Two patients had Follicular Lymphoma, and both had Responses to the treatment. that's good news, and certainly something for us to all keep an eye on, should a larger study of just FL patients come about.

Back to William: his wife Gretchen was, as he said in his email, their "star performer." If you look at the link, she's Patient 2 in the chart at the end: a Complete Response and no CRS! Congratulations, William and Gretchen! I hope things continue to go smoothly.

(And if there's anything important that I left out, please let me know in the comments.)

And one more thing -- this is more great advertising for clinical trials. New treatments can't happen if people don't volunteer to test them out.

More on ASH in the days to come. Lots to be (cautiously) excited about.

Cubbies and Cancer (or, Lester and Lymphoma)

I've told this story a few times before, but I'm going to tell it again:

When I was diagnosed, my kids were 6, 8, and 10 years old. My wife and decided quickly that, even with the kids at that young age, we wanted to be completely honest with them about everything that was going on. We knew that they would figure out that there was a problem, and we thought that what they imagined would be worse than the truth. So honesty was our approach.

So when we told them, I sat on the couch my arm around each of my sons. My oldest was old enough at 10 to really understand what was happening, and he tensed up at the word "cancer." I told him it was a kind of non-hodgkin's lymphoma. "You've heard of that before," I told him. "It's the kind of cancer that Jon Lester had."

And I felt his body immediately relax, and he let out a big sigh.

Jon Lester was a pitcher for my beloved Boston Red Sox. In fall 2006, he was diagnosed with Anaplastic Large Cell Lymphoma, a much more aggressive form of NHL that Follicular Lymphoma (though my son didn't need to know that).  He came back the next season, and pitched well, winning the clinching game of the World Series.

I was diagnosed about 3 months later.

And about 4 months after that, he threw a no-hitter. I woke my son up so he could watch the last inning.

If you're not a baseball fan, and the details don't mean much to you, that's OK. You probably get the message -- Jon Lester was a hero to me, and to my son, and he got us through some tough times, just watching him. I wore a shirt with Lester's name and number on it for all of my Rituxan treatments.

So I was sad when he left the Red Sox two seasons ago to pitch for the Chicago Cubs, but that was OK. He gave me what I needed, and I wished him well.

And the well-wishes worked! A couple of days ago, the Chicago Cubs won the World Series, breaking a streak that was even longer than the Red Sox's streak. Lester played a big role all season for the Cubbies. He wasn't the only hero, but he played a big role.


But even cooler than that?

Another of the Cubs' heroes was Anthony Rizzo. In 2008, Rizzo was playing for a Red Sox minor league team when he was diagnosed with Hodgkin's Lymphoma. Lester helped him through the experience.

And now they both have World Series rings, make lots of money, and give a bunch of it away to help with cancer research and to support families of cancer patients.

I haven't done a "Nodes of Gold" episode in a long time, so you can consider this one of them.

Of course, a World Series winner means there is a World Series loser, and in this case, that was Cleveland. And the Cleveland manager is Terry Francona, who managed the Red Sox when they won the World Series in 2004 and 2007.

He's the same Terry Francona who sent my kids a letter in March 2008, telling them that the Red Sox were cheering for me.

So no Red Sox victory this year, but plenty to celebrate anyway. And it brought back some nice memories of happy times.

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Something else to celebrate: abstracts for the ASH (American Society of Hematology) meeting are online. As usual, I plan to write about the ones that look promising or interesting to me.

Stay tuned.