Wednesday, April 27, 2016

Idelalisib: Implications

This is a few weeks old now, but it's a video of Dr. Bruce Cheson of Georgetown University, and most of you know how much I enjoy his videos.

Dr. Cheson discusses the announcement that some Idelalisib trials were being cancelled. As you can see, the usually entertaining Dr. Cheson starts out by saying "Today we have no music, we have no jokes. It is a serious discussion." And it is.

He discusses a second treatment that has had problems in its trials -- Acalabrutinib, which apparently has had success with CLL, but not with Follicular Lymphoma. I must confess, I don't know much about Acalabrutinib. It seems like it might be gone before it ever really got going enough for me to notice. It's a BTK inhibitor like Ibrutinib. That's about all I know.

The important message from Dr. Cheson comes at the end of the video. He was asked if the problems that these meant "the end for a chemo-free world." He says, "Absolutely not." There are treatments that work, and more being developed. As problems are being seen by researchers in trials, it's clear that future versions of these treatments will need to be more carefully developed and studied to try to take care of some of those problems.

Dr. Cheson has faith in the future, and that's good enough for me.

If you try to watch the video, you may be asked for a Medscape login. Medscape is great, and I recommend joining. But if you'd rather not, Dr. Cheson included a transcript of his video, which I have copied below.

*************************************

Hello again. This is Bruce Cheson from Georgetown University Hospital and the Lombardi Comprehensive Cancer Center, speaking to you for Medscape Hematology. Today we have no music, we have no jokes. It is a serious discussion.
Last week, I was in the splendid city of Rome giving a couple of presentations at the Second Postgraduate Lymphoma Conference. I was invited by my good friend Pier Luigi Zinzani, and was asked to give two talks: (1) on Bruton tyrosine kinase (BTK) inhibitors in follicular lymphoma, and (2) on how we're getting to a chemo-free world in patients with follicular lymphoma. That's a particularly favorite topic of mine, because I think that's really the goal of treatment.
Unfortunately, [because of breaking news] I had to make some very last-minute adjustments to both of these presentations. Regarding the chemo-free world, we've had an increasing number of very exciting drugs over the past few years, and I was to talk about these various drugs and how we put them together. Then we get this announcement from Gilead Pharmaceuticals about their PI3 kinase inhibitor idelalisib, a very active drug for chronic lymphocytic leukemia (CLL) and indolent lymphomas.
There are a number of new safety signals with that drug that have halted a number of their clinical trials, particularly those in combination with other agents. There have been cases of serious toxicities and fatalities, particularly pneumocystis and cytomegalovirus (CMV) reactivation. These events tend to be more common and more severe when you combine the drug with other agents within the first 6 or so months of treatment, and in patients who are less heavily pretreated. The trials, particularly those looking at upfront therapy, are gone.
This [safety signal] is consistent with some other observations with this drug that the hepatotoxicity and the diarrhea also are more common in the upfront setting. The drug also seems to induce a neutropenia.
So yes, it's a pill, and yes, it's targeted therapy. But yes, there are adverse effects that now require close monitoring, and the company is recommending prophylaxis for pneumocystis and frequent monitoring for CMV—and if either of these events occurs, that's it for the drug for that patient.
The second event related to my talk on BTK inhibitors. There's a great new drug out there, acalabrutinib (ACP-196). Unfortunately, whereas it seems to be fabulous in CLL, [in] the trials from Acerta Pharma, [efforts to pursue indications for acalabrutinib in combination with other drugs] in follicular lymphoma and other indolent lymphomas, such as Waldenström macroglobulinemia, are now terminated, [but Acerta is still conducting single-agent studies in those disease entities because acalabrutinib is showing promising activity with minimal toxicity]. And the company states they want to focus on getting the drug approved in CLL [in personal communications to Dr Bruce Cheson, as reported March 31, 2016]. That's their main objective, and it's a laudable one, but it also suggests that perhaps the drug is not as active as we would like to have it be in follicular lymphoma and the other indolent histologies. Too bad.
Someone in the audience asked me, is that the end for the chemo-free world? I said absolutely not. We have lots of new drugs coming along, venetoclax and others, which still offer this possibility for our patients. It's just a question of being careful, of developing newer and less toxic second- and third-generation drugs, and putting them together in an intelligent and safe fashion. Even though we have a couple of these drugs on the market, they should only be put together in the context of a carefully monitored clinical trial.
Bruce Cheson, signing off for Medscape Hematology, and I look forward to speaking to you again in the near future. Thank you.

Tuesday, April 19, 2016

For Marie: Survival and Statistics

A few weeks ago, a reader named Marie left a comment on a post from last October. I responded to it, and said I'd try to leave a longer response in a few days. I'm late with the longer response, but here it is.

*********************************

I have just been diagnosed with follicular lymphoma two weeks ago and I am losing my mind. I will be having another biopsy, blood tests, the bone marrow stuff (sorry I haven't yet learned the proper vocabulary),the scans etc. Then I will be waiting for reults... hmmm. I have found your blog on the internet and it keeps me from losing my mind completely. But I have noticed that most people affected by FL who comment on your blog (and seem to be doing quite well) are between 40 and 50. Any thoughts for us oldies (I'm 61) whose OS rates are always scary.

Best regards,
Marie 



Hi Marie. I'm guessing that the results from your tests are back now, and I hope they brought you some comfort -- as much comfort as you can get from hearing the details of your cancer. If you'd like to share the details, please do.

You are right -- Overall Survival rates are scary, for all of us, not just you "oldies." As I've said in this blog a bunch of times, the times that my cancer have made me truly sad have been when I looked at statistics. There's something about numbers that seems very definite and final. Numbers don't lie, right? Well, sure, except those times when they do lie.

It's not that numbers lie. They're just easy to read as something that isn't necessarily true. It's always more complex than the numbers make it seem. The one truth to looking at statistics is this: a number that says something about a large group of people is in no way a predication about your own life. Don't forget that. Ever.

Let's start with the idea that "OS rates for oldies are always scary."

There aren't many breakdowns of OS by age, and the one that I have seen that gave me the most encouragement (as a youngster) came from an ASH presentation from 2011. That makes it a little bit old (a whole lot has happened in 5 years), but it's about the best I have seen. While it focuses particularly on patients under 40, it does give statistics for OS for three age groups:

Under 40 have a median OS of 24 years.
41-59 year olds have a median OS of 16 years.
Over 60 have a median OS of 6 years.

Now, comparing those two groups (us youngsters with the 24 year OS -- I was diagnosed at 40 -- and you oldies with your OS of 6 years), and things look grim for the oldies. No wonder you're scared. Yikes!

But compared to us youngsters, you actually might be better off. Assuming the median OS, someone diagnosed at 61 would live to 67. But someone diagnosed  at 40? I'd only have until 64. So you have 3 years on me. (Don't brag about it.)

Now, before I start panicking anyone else (youngsters, oldies, or tweeners), let's remind ourselves of what median Overall Survival means. And let's remember, too, that a number that says something about a large group of people is in no way a predication about your own life. I told you not to forget that. Ever.

So let's assume that it is accurate that Follicular Lymphoma patients over 60 have a median OS of 6 years. But before we assume that it is accurate, remember that this number is more than 5 years old, and was calculated from patients from the 25 years prior, from 1986 to 2011, so a bunch of them never heard of Rituxan -- in other words, that number could very well be higher than 6 for a patient today.

But let's assume that it's accurate. The first thing to look at is the word "median." In statistical analysis, "median" means that half of the group is below that number, and half is above. So while there will be some people who have an OS of less than 6 years, the other half will have an OS of more than 6. How many more? Maybe 7, or 8, or 9, or 10, or 20, or 50. There's a lot that determines how long that will be, much of it having to do with the nature of your lymphoma (and maybe all of those tests you took shed some light on that). But the important thing to remember is, someone else's OS doesn't determine your lifespan.

Now, about that "Overall Survival" statistic. OS doesn't measure cause-specific survival, or death from cancer. It measures death from anything -- that's what "overall" means. It means that people with Follicular Lymphoma might have died within 6 years because of heart attack, being hit by a bus, whatever. Because FL is a slow-growing disease, the cause-specific survival is actually higher than it is for Overall Survival -- 9 years. You'd be more likely to die from something other than FL than you would from FL.

But none of those statistics really matters. Why? Because a number that says something about a large group of people is in no way a predication about your own life. I keep telling you that.

Again, all of this is based on patients who were diagnosed between 1986 and 2011. We've made advances since even then.

So what will our OS be, when someone calculates it 25 years from now? No idea. But, as a group, I can almost guarantee it will be higher than what we have now. The stuff we've learned about cancer, and especially Follicular Lymphoma, in just 5 years, is astounding. Stuff in the treatment pipeline now will only increase our OS in the future. And there is stuff that hasn't even been talked about yet at ASH or ASCO that will have an impact on our lives in the near future.

My advice is to stay away from statistics. But if you have to look at them, be sure to take a step back and think about what they really mean, and especially what they don't mean.

Marie, I hope your test results were as good as they could be, and you have created a plan with your oncologist and started on it. If you have something you'd like to share, I hope you will.

I wish you all some peace.



Tuesday, April 12, 2016

Reduced -Intensity Allo Transplant

Stem Cell Transplants are an option for Follicular Lymphoma, though one that scares a lot of people. Some research from the Annals of Oncology might make All STCs just a little bit less scary.

The article is called "Reduced intensity allogeneic stem cell transplantation for follicular lymphoma relapsing after an autologous transplant achieves durable long term disease control: An analysis from the Lymphoma Working Party of the EBMT."

(Before I go on, I need to comment on the Lymphoma Working Party, which is actually one of seven groups that policies for the European Society for Blood and Marrow Transplantation. But the name sounds like the LWP is a small political party that hopes to win just enough seats in a parliament that they could be asked to join a coalition and maybe get a minor cabinet ministry post for its troubles. For the record, if there was ever a political party made up of lymphoma patients, I would absolutely join it. Our slogan: "Lymphoma Working Party -- Because Politics Is In Our Blood!")

Anyway, that Annuls of Oncology article:

Stem Cell Transplants can be an effective option for Follicular Lymphoma. To put it simply: with an STC, the patient is given an aggressive treatment that basically wipes out her immune system (along with the cancer cells). Immune cells are then put back into the patient to replace it. There are two types of transplants. The first is an Autologous STC (or Auto STC), where the patient's own immune cells are removed before the aggressive treatment, and then put back afterwards. The second is an Allogeneic STC (or Allo STC), where a donor's cells are collected and then put into the patient after the aggressive treatment. Allo STCs have (at least) two big dangers: while the immune system is being replaced, there is a risk of infection, and no way to fight it off. Also, there is the chance that the patient's body will reject those foreign cells (this is known as Host Versus Graft Disease). With an Auto STC, there is no danger of rejecting the cells, since they are from the patient. But there is the danger that those cells going back in might not have been completely clean of cancer. Plus, there's that same danger of infection.

That's the very simple explanation. Read more about Stem Cell Transplants at Lymphomation.org.

It's definitely an aggressive treatment. The patient needs to be pretty healthy to handle that aggression. For patients who may not be able to handle such an aggressive treatment (because of age or poor health), there is the option of a Reduced-Intensity STC. The aggressive treatment that wipes out the immune system is a little bit less aggressive -- still enough to clear out most cancer cells, but not all of them. The donor immune cells might be able to clear out the rest.

The idea of a Reduced-Intensity Allo STC is fairly new -- new enough that not a lot of study has been done on it. This article tries to fix that.

The study looks at 183 patients who had a Reduced-Intensity Allo STC after having an Auto STC that failed. The results were pretty good -- the Overall Survival after 2 years was 63.3%, and after 5 years it was 51.1%. Given where these patients were -- they were close to running out of options -- those numbers are strong.

(The link above is for the abstract of the Annuls article. Healio's report on the study gives a lot more detailed statistical breakdown of the patients and the results, in case you're interested.)

The bottom line here is that the Reduced-Intensity STC has been shown to be an effective strategy for many patients. It's not right for everyone -- the more aggressive standard Allo STC will probbaly continue to be recommended for patients who are healthy enough, and who could benefit from an STC. But it will be interesting to see if the Reduced Intensity option becomes more commonly used for both sets of patients (those who are not healthy enough for an Allo STC, but maybe those who are, too).


Thursday, April 7, 2016

Dr. John Leonard on Follicular Lymphoma

About three weeks ago, OncLive published two pieces on Follicular Lymphoma, both featuring Dr. John Leonard.

He's a good guy to feature -- a legitimate Lymphoma Rock Star, he's the Richard T Silver Distinguished Professor of Hematology and Medical Oncology at Cornell Weill. He knows the cutting edge as well as anyone.

In the first OncLive piece, "Novel Agents on Horizen for Follicular Lymphoma," Dr. Leonard discusses clincial trial results for a few different treatments. But before he gets into that, he says something very comforting:

"Most patients will not die from follicular lymphoma, and that's very reassuring. About 80% of patients will die with their follicular lymphoma and not of their follicular lymphoma."
“Most patients will not die from follicular lymphoma, and that's very reassuring. About 80% of patients will die with their follicular lymphoma and not of their follicular lymphoma - See more at: http://www.onclive.com/conference-coverage/hematology-2016/novel-agents-on-horizon-for-follicular-lymphoma#sthash.mwHedDcv.dpuf
Novel Agents on Horizon for Follicular Lymphoma"
Richard T. Silver Distinguished Professor of Hematology and Medical Oncology, NewYork-Presbyterian Weill Cornell Medical Center. - See more at: http://www.onclive.com/conference-coverage/hematology-2016/novel-agents-on-horizon-for-follicular-lymphoma#sthash.mwHedDcv.dpuf
Richard T. Silver Distinguished Professor of Hematology and Medical Oncology, NewYork-Presbyterian Weill Cornell Medical Center. - See more at: http://www.onclive.com/conference-coverage/hematology-2016/novel-agents-on-horizon-for-follicular-lymphoma#sthash.mwHedDcv.dpuf
Richard T. Silver Distinguished Professor of Hematology and Medical Oncology, NewYork-Presbyterian Weill Cornell Medical Center. - See more at: http://www.onclive.com/conference-coverage/hematology-2016/novel-agents-on-horizon-for-follicular-lymphoma#sthash.mwHedDcv.dpuf


Let that sink in for a second.

I'm not big on statistics. The times when cancer has made me saddest have been the times I got caught up in statistics. My policy now is to only pay attention to statistics that make me happy. And that one makes me happy. It should make all of us happy.

As for the studies he cites:

  • There's Obinutuzumab (also known as Gazyva), an "next-generation" ant-CD20 monoclonal antibody, approved by the FDA in combination with Bendamustine, for patients who have previously had Rituxan. The study that led to the approval was the GADOLIN study, which found that the combination reduced the risk of disease progression by 52%, compared to Bendamustine alone.
  • R-Squared: In another study, Revlimid + Rituxin (R-squared) had a 75% response rate. Revlimid alone had a 44% response rate.
  • In another one, Idelalisib showed a 56% response rate.
None of these studies are new (I think I've discussed all of them here at some point), but together, they give a good sense of why that 80% of patients will do OK.

But what about the other 20%? Research from the last year or so has shown that this is a tougher population to work with, only because we know less about them. But there are already some trials with new treatments that are trying to address this group of patients.
  • Nicolumab, is in a phase 2 study.
  • Pembrolizumab (plus Rituxan) is also in a phase 2 study,
  • And in a small study of 30 patients, Pizilibumab had an overall response rate of 66% for patients who relapsed.
So while that 20% might be worrisome, there are some studies out there that are focused on it. As Dr. Leonard says, figuring out what makes this group different from others needs to be a priority, so more targeted treatments can be developed for their needs.

Dr. Leonard also thinks we need to ask bigger questions about the goals for patients -- are we going for a cure, or trreating FL like a chronic disease? -- and thinking about how we measure success, and how we consider quality of life for patients who may need treatment for a very long time.

All very interesting information.

And as I said, OncLive published a second piece a couple of days later, also featuring Dr. Leonard. This one is called "Dr. John Leonard on Treatment Options forRelapsed Follicular Lymphoma," and it has a short video in which Dr. Leonard discusses some of the options for patients who have already had treatment, particularly R-Squared. It doesn't get into much detail, but again, it's nice to hear a big list of our options.

Dr. John Leonard on Treatment Options for Relapsed Follicular Lymphoma - See more at: http://www.onclive.com/conference-coverage/hematology-2016/dr-john-leonard-on-treatment-options-for-relapsed-follicular-lymphoma#sthash.jjkVXQYO.dpuf

(Sorry for the strange change in font at the end. Not sure why it's doing that, and I can't seem to fix it....)

Sunday, April 3, 2016

Save Zevalin!

Karl Schwartz, who heads up Lymphomation.org, has written a letter to the U.S. Senate. He's hoping to save Zevalin, and he needs your help.

Zevalin is an example of RadioImmunoTherapy (RIT), an effective and underused category of treatments for lymphoma.

RIT uses radiation to kill cancer cells. There are lots of cancers that use radiation, but they are almost always "solid" cancers. These cancers involve tumors that will hold still so a beam of radiation can be aimed at them and kill the cells. That doesn't work with "liquid" cancers like lymphomas -- the cancer cells won't hold still. That's where RIT comes in.

With RIT, a small little bit of radiation is attached to something that seeks out individual lymphoma cells -- soemthing like a monoclonal antibody (like Rituxan) that will find a cell with a CD20 protein on it (like a B cell) and then deliver that little bit of radiation right to the cell. RIT has been around for a while, and it has been very effective for the people who have used it. (A couple of the better known are Betsy de Parry and Jamie Reno, both of whom are Follicular Lymphoma patients who have written about their experiences, and who had successful RIT treatments a long, long time ago.)

RIT works differently from other treatments, and a lot of people think that's an even better reason to keep it around. There's been a lot written in the cancer community lately about combining treatments to attack cancer in different ways, and RIT has been mentioned as a good thing to combine with for that reason.

But RIT isn't used as much as it could be, or should be. Even though it has been a very successful treatment, it's kind of complicated to use (or is thought to be complicated). Most of the time, it has to be administered by a nuclear medicine specialist, with a team of nurses. It has also, in the U.S., had some problems with the way doctors are reimbursed when they use it. These are things that don't have anything to do with its effectiveness, but more with how it can be a complicated process to get the treatment to patients.

All of that was enough for one of the RIT treatments, Bexxar, to be pulled from the market 3 years ago.  And now the other RIT treatment, Zevalin, is in trouble.

As Karl explains in his letter to Senator Shelley Moore Capito, who chairs the Clean Air and Nuclear Safety Committee, the Nuclear Regulatory Commission, which oversees nuclear medicine and radiation treatments for cancer, has changed its rules. It used to be that doctors who wanted to administer Zevalin had to have 80 hours of training. Now, they are required to have 700 hours.

That will certainly be enough to make Zevalin all but impossible to administer, since it will deter lots of oncologists from receiving the training. Most cancer patients get their treatments from "community oncologists" -- the folks we see in their offices. They won't have the time to get all of that training. Zevalin will die.

And that will be a shame. While we are all excited about the possibilities that we are seeing with new immunotherapy pathway treatments, Zevalin is a treatment that is 1) already proven to be effective, 2) targets lymphoma cells so side effects are diminished, and 3) works in a way that is different from almost any other treatment.

Karl's letter can be found here. It urges Senator Capito to look into what the NRC is doing with Zevalin. There is space for you to add your name and any comments you have. Please considering doing it. We really don't want to lose this arrow from our quiver.