ASH 2015: Dr. John M Pagel on Idelalisib as Frontline Therapy in CLL (chronic lymphocytic leukemia)

We have just learned of the good news of the broad FDA approval in the USA of ibrutinib in the frontline setting for CLL.  

This step forward in CLL therapy only comes after years of research and is due in no small part to the brave patients who volunteered for these trials including the pivotal RESONATE-2 trial.

As a reminder, ibrutinib is a small molecule taken orally, a tyrosine kinase inhibitor or TKI, that inhibits the BTK pathway that is so important for  B cell communication. By doing so, it blocks a critical pro-survival signal in our CLL cells and helps control our disease. 

I will comment more on the significance of this frontline approval in a coming post, but to give some perspective, I want to reflect on the only other approved oral TKI for CLL, namely idelalisib that inhibits the PI3Kδ pathway. This pathway is also important for B-cell signaling in our CLL cells and blocking it also blocks the same strong survival signal. That is a big part of the reason why both these drugs work as well as they do. 

Researchers want to discover which CLL patient will get the most benefits with the least risks from these new therapies.

At ASH 2015 in December, many researcher were initially surprised by the amount of toxicity discovered when idelalisib was studied frontline or in the treatment-naive CLL population. 

Keep in mind that it is currently only approved for use in combination with rituximab in the relapsed and refractory CLL population, not frontline. This trial was to look at its safety and efficacy in this new setting.

I interviewed Dr. John Pagel of Swedish Hospital in Seattle, WA on the importance of this negative findings.  

It is a truism in science that we often learn as much or more from the trials that don't go as planned as from those that do.

Though most of the research on idelalisib presented at the ASH meeting was positive, the title of this abstract tells us there were significant issues:  Idelalisib Given Front-Line for the Treatment of Chronic Lymphocytic Leukemia Results in Frequent and Severe Immune-Mediated Toxicities.

Three quarters of the patients had grade 3 toxicities or severe problems. For 56% of them this was liver toxicities where the blood tests that measure liver inflammation were 5 to 10 times the upper limit of normal. These are much higher levels than generally seen when idelalisib is used in patients who have had prior treatments.

The good news is that with immune suppressive therapies including steroids, all the patients recovered.

The details of the trial are here.

Why then when ibrutinib is relatively benign in the frontline setting, did a somewhat similar drug have such unexpected problems.

Any drug may have effects on cells that are not their therapeutic target, resulting in unwanted side effects. One theory is that idelalisib lowered the balancing activity of the regulatory T cells or Tregs that are important in preventing auto-immunity. The PI3Kδ pathway is critical to the function not just of CLL cells but of the Tregs too. 

This is why we need to do research. This is why we need to laud the brave subjects who jump into these trials. Without them, we make no progress.

Here is my interview with Dr. Pagel on this subject from ASH 2015.



As Dr. Pagel emphasizes, idelasilib is a powerful drug that helps many patients with CLL. How and when to best use it is a matter of ongoing research.

Stay strong

Brian

Bad knees, Baker's Cysts, and Good Times with CLL (Chronic lymphocytic leukemia), plus our newsletter

I tripped walking into my medical office yesterday, scraping the front on my left knee just below the patella. I was tired, jet lagged having arrived home from Hobart, Australia less then 2 days earlier, was carrying a lot of stuff and was distracted talking on the phone with someone with CLL facing some tough choices. But I don't need any excuses. I fell because I have a bad knee. Actually two bad knees. Two very bad knees getting worse.

Happily my knees are slow to react to trauma. I was able to hobble through a busy day of patients, but by the end of the day I knew I was in trouble.

When I stress my knee (this is the second traumatic strain of my left knee in less than a month), there is no forgiveness, no flexibility, no resilience. There is only pain and swelling and loss of function.

In this case despite the anterior trauma, the back of my knee swelled up with a huge but benign Baker's cyst, a synovial swelling that restricts my ability to fully extend my joint and thus to walk without pain and a forward leaning posture reminiscent of the elderly osteoporotic women I met in my travels to Japan.

The good news is that it little hurts as long as I lie still with it raised, slightly flexed and packed in ice.

Which is what I did today. All day.

There is no definitive treatment for a Baker's cyst. The real treatment is to take care of the problem causing it, namely in my case, the end stage osteoarthritis of the knees. Blame street hockey or junior high football or my mother's arthritis.

My joints spaces are so narrowed medially that I have lost height due to a varus or bowlegged deformity that makes me look as if I have rounding up cattle all my life.

After a total of four surgeries, the only answer left on the (operating) table is to totally replace the knees.

I have scheduled the surgery twice now and backed off both times.

Why? Because if I vigorously exercise to stretch and strengthen my knees it partially ameliorates the pain. I am pretty good at that a home, but lousy when I am the road as I have been for 15 days in Australia.

If I use my walking sticks and acetaminophen and ice as I just did in Australia for two weeks, I can muddle through and still accomplish many miles of painful but manageable walking.

Until I fall or twist or the knees just give out on their own. And that's happening more these days.

So why have I cancelled the surgery twice now?

Due the increased bleeding risk with ibrutinib, by protocol I would have to be off my ibrutinib for one week before and three weeks after while I am on blood thinners post-op from my bilateral knee surgeries used to prevent blood clots. I have chosen to be part of the 15% or so brave or stupid patients that do both at once to get it over with and limit my time off my cancer therapy.

Here are the issues I would face:

1. Being off ibrutinib for more than 8 days almost triples (13% versus 31%) my risk of relapse. I'd be off for about a month. Here is the recent ASCO abstract that lays out the facts. 
2. Joint replacement surgery itself may be associated with an increased risk of blood cancers.  Makes sense when they are shoving titanium and glues up your hollowed out bone marrow. Reading this article will give you pause before you let an arthropod take a saw to your bones. 
3. I am at higher risk for peri-operative complications due my CLL including infections, bleeding and clots.
4. I have never lost a patient yet to osteoarthritis, but some patients who have relapsed from ibrutinib have had a poor prognosis. Here's the article from JAMA Oncology. 

Now if you dig into the studies that I am referencing, you learn quickly that the patients who went off ibrutinib for more that 8 days were generally much sicker and quite different than me and that whole study is being questioned, the total joint patients with subsequent blood cancer are still rare and a broad mix of surgeries, and the relapses post ibrutinib were clearly a different group than me.

It is important when you review any research that you critically assess if you belong to the group being studied. Except for the study on joint replacements (and even that is questionable), I don't belong to any of the study groups.

Still, as long as I can walk, I am staying away from the scalpel.

And odds are that I will be walking much better by tomorrow. The ice and rest has helped a great deal.

But there is another better option if time and circumstances allow. And they should.

We all know that as good as ibrutinib is, it is not a cure. Trials of dual and triple therapies are already opening in response to this unmet need, but I would only qualify today if I fail my ibrutinib.

I am pushing for trials that add in venetoclax (ABT-199) or a PD-1 inhibitor for that growing cohort of patients such as me who are doing well on ibrutinib or idelalasib, but who still have residual CLL. Don't wait for it to take off. Hit it while it's down by adding a second agent.

In my case under the cover of a second anti-CLL drug that doesn't effect bleeding, I would then replace my damaged knees and have control over my two biggest health issues, my cancer and my arthritis.

That's my plan and I am pushing hard to make it happen. These are good times for those of us with CLL and are options are getting better and better.

UPDATE: Knee still swollen with limited flexion on day three. Walking is not happening despite a night of elevation and ice. 80% better by day 7.

On a less personal note, the CLL Society was very busy in Australia with iwCLL 2015 being the only CLL group reporting from there, so stay tuned for some updates. Yours truly spoke in front of several hundred doctors on a panel with Dr. Michael Keating and other giants in CLL. Very humbling and very honored to have shared the patient's perspective in Sydney.

I'll be in Brooklyn Oct. 3-4 for LRF's 20th Annual North American Educational Forum on Lymphoma and would love to say hello. Drop me an email and we can try to connect.

Big news:

The CLL Society's inaugural newsletter is coming out later this month. It promises to be amazing with some wonderful articles written by fellow patients and caregivers and with some great surprises. If you haven't already, please sign up for it here. We won't share your info with anyone and you will be sure to be aware of all the upcoming posting from iwCLL and ASH and much much more. The newsletter will be quite different from this blog or  our CLL Society website, so please sign up here and don't miss it.

And if you are in the Seattle area, consider this meeting with John Pagel and a CLL patient and caregiver:

ADH 2014: Dr. Sharman on Cell Death in CLL (chronic lymphocytic leukemia), a patient meeting, a newsletter and iwCLL

Friends,

This week on the CLL Society website, in our Conference coverage section, we share the second part of an interview from ASH 2014 with Dr. Jeff Sharman with a discussion of the life and death pressures on our B cells and how that relates to ABT-199. We also cover the latest research on idelalisib and rituximab, and what research in general is still needed.

I'm heading off to the International Workshop on CLL in Sydney, Australia today and will be attending sessions and doing interviews while I'm there. I'll be posting new information upon my return. Stay tuned. We are also co-sponsoring a small patient meeting with Lymphoma Australia.

Also, we will be sending out our inaugural newsletter, the CLL Tribune at the end of September. Don't miss this special collection of research news, basic CLL information, fun facts and a wealth of wisdom and shared experiences from our fellow patients. If you are receiving this information through a CLL Society Alert email, you are already signed up to receive it. If you are reading this through another source, sign up to receive it here.

For those of you in the Seattle area, we just became aware of a patient meeting that will be held on Saturday, September 26, 2015 starting at 9:30 AM at the Sheraton Seattle Hotel. Two CLL patients will be sharing their personal stories, and Dr. John Pagel from the Swedish Hospital will be providing a talk on the basics of CLL. You can call 844-482-6815 to register. Complimentary breakfast and parking are provided and you are welcome to bring a guest. You can view the flyer for the event here.
Stay strong.

We are all this together

Brian Koffman

Volunteer Medical Director of the CLL Society

http://cllsociety.org
http://bkoffman.blogspot.com

ASH 2013: Dr. John Pagel Discusses the Risks and Benefits of ABT-199 and TRU-016 or otlertuzumab in CLL (chronic lymphocytic leukemia)

In the final segment of my interview with Dr. Pagel from ASH 2013, he discusses ABT-199 and TRU-016 or otlertuzumab (yet another mouthful for us to poor patients to learn and pronounce).

We have heard much already about ABT-199. Here is a link to a trial reported at last year's ASCO meeting and I have an interview pending from ASH 2013 with Dr. Seymour from Australia. At ASCO later this week, there will more news on ABT-199 with a new dosing schedule to reduce the risks of tumor lysis syndrome (TLS).

TRU-016 is another under reported therapy, a potent monoclonal antibody (MAb), much like rituximab, that is as of now only available in clinical trials. In my opinion it has not received the attention it deserves. Unlike rituximab or ofatumumab or even obinutuzumab that all target CD20, TRU-016 targets CD37. But like CD20, CD37 is also found on most mature B cells, both cancerous and benign and much less so on T cells making it is a good choice for fighting CLL. That's an important difference from Campath that binds to CD52 and destroys both B and T cells. With no T  or B cells to fight infection coupled with our already wimpy immunity, we are high risk for life threatening infections. TRU-016 did not increase infection risk in this small trial.

Here is the ASCO abstract that compares bendamustine with or without TRU-016. The number were very small, but for those who received TRU-016 there was responses in the two patients with 17p mutations but not in the two with 17p deletions. As expected, there were no responses to single agent bendamustine.

And here is Dr. Pagel:



I am hoping to sneak one or two more post before I take off for ASCO 2014 later this week.

ASH 2013: Dr. John Pagel Speculates on the Future of CLL (chronic lymphocytic leukemia) Therapies including the late breaking data on Idelalisib

In the second part of our interview at ASH 2013 we shift from discussing radio-immune therapy and listen as Dr. John Pagel starts by agreeing with many of us patients that our future could and should see less and less chemotherapy and more and more combinations of targeted therapies.

He then gives his perspective on the late breaking abstract at ASH on idelalisib (AKA CAL 101 AKA GS-1101) plus rituximab versus placebo plus rituximab that Dr. Furman and I also discussed in this prior post that also contains a link to the ASH abstract and the NEJM where it indeed did get published. This trial has been well reviewed in the past, but it was nice to note the agreement among the researchers involved in this large trial.

Here's part two of the three part interview.



More to come soon with the last section of Dr. Pagel's interview and a long three part interview with Dr. Byrd from the same ASH annual conference.

Then all the attention turns to ASCO 2014. ASCO covers all cancers, so CLL is a minor player compared to the big four of breast, colon, lung, and prostate, but there will be important new data on ibrutinib, idelalisib, ABT-199, ONO-4059, a new SYK inhibitor from Gilead and others.

I have several exciting interviews scheduled both in video and simple audio format that I will be posting and sharing with my friend Andrew Schorr on his patient friendly cancer website Patient Power as Andrew made the sensible decision not to fly from Barcelona to Chicago. Andrew's team will also be posting the latest news on several other types of cancer, some of which may have directly relevance to those of us with CLL.

ASH 2013: Dr. John Pagel Discusses Radio-Immune Therapy (RIT) in Chronic Lymphocytic Leukemia (CLL)

The big buzz at the ASH annual meetings for the last few years has rightly been targeted oral therapies such as ibrutinib and idelasib and other, but one therapy that in my opinion that has received short shrift is radio-immunotherapy or RIT.

In fact, it is so rarely used that since this video was recorded in December, 2013, Bexxar (Tositumomab) was pulled from the market in February, 2014 as it was prescribed fewer than 75 times in 2012.

Zevalin (Ibritumomab Tiuxetan) is still available.

At ASH 2013, I interviewed Dr. John Pagel out of the Seattle Cancer Care Alliance (the union of the Fred Hutchinson Cancer Research Center (the Hutch), UW Medicine, and Seattle Children's) who has a very patient friendly way of explaining how these drugs work and what their role might be. Dr. Pagel is also a kind and wise transplanter and as such has extensive experience with conditioning therapies that often include different forms and dosing of radiation to prepare for the transplant and that is another reason why I wanted to hear about his updated research on this important and neglected corner of CLL research. To understand how much or little we have moved forward in the last year, please check out my interview with Dr. Pagel done a year earlier at ASH 2012. As you can read, we are still dealing with the  some of the same old issues that are slowing our progress.

RIT makes most sense to me as a mop up  or "consolidation" therapy and as I have posted before, we desperately need that. I believe RIT should be explored as a final knockout punch to our CLL when it has been decimated and only a few active cells are hiding out in our marrow and our nodes.

I suspect that this research idea won't get much traction.

Dr. Pagel is too kind when he describes why these antibodies with their toxic payload are underutilized.

True they are expensive and tricky to administer, but they are usually a one or two time treatment. 

Sounds good to me. 

The real reason they are not used as much as they could be is that oncologists can not prescribe them. You need to consult a radiation oncologist and even then, the radiation oncologist you see may not offer that option or have much experience with RIT. It requires specialized set up for its administration and management. 

So basically it is a turf issue. 

Here is a link to the abstract that Dr. Pagel presented at ASH 2013.

And here is the interview. As I said as we talked, I love his analogies.

ASH 2012: Dr. Pagel discusses transplants for CLL and the Role of Radioimmunotherapy

In the final short segment of my ASH 2012 interview with Dr. John Pagel, he discusses the approach to hematopoietic stem cell transplants (HSCT) or what were once only bone marrow marrow transplants in CLL. Now, we more often harvest the primitive blood stem cells from the peripheral blood after they have been mobilized. Much easier for the donor who doesn't need multiple bone marrow aspirations.

What Dr. Pagel talks about the real possibility of cure for some patients, especially those who go in to transplant with their disease in a deep remission.

The news is that using a drug such as Zevalin (ibritumomab tiuxetan), a radioimmunotherapy (a radiolabeled monoclonal antibody) or RIT in high doses is getting the necessary deep remissions and improving the odds of that cure. Ibritumomab is similar to rituximab in that it latches onto and destroys any and all CD 20+ B cells (cancerous or not), but it differs in that it carries a radioactive payload to those cells and thus destroys not just the cell, but its nearby homeys. This is especially helpful in shrinking bulky cancerous nodes, but can be dangerous if there are too many B cells left in the marrow as the local radiation delivered can cause lingering damage to the future home of the new donor stem cells. Still, it is a lower dose, more "surgical" way in many settings to get the radiation precisely  to the desired sites (at the cellular level) than is an external ionizing radiation source, no matter how focused. And most CLL, at least to start out, is exquisitely sensitive to radiation, although it always come back, and often comes back meaner. 

There are significant expense and turf issues in the medical world that explain why RIT is a very much underused therapy. Briefly, it is very costly per treatment, but is usually used only once or sometimes twice, so the total cost is comparable to a full course of say FCR. More tricky is the role of the doctors administrating it. It can mean transfer of care from the medical to the radiation oncologist and many doctors are loathe to give up control of their patients. We can argue that it needs the services of both a medical and radiation oncologist and their support teams of pharmacists, nurses, and technicians. More turf issues.

But I digress. RIT is a great choice if we need a transplant and we can get buy in from our doctors and insurance.

And the other news is that the mortality curve seems to plateau around 3, not 5 years. After 3 years, we stop relapsing. The CLL doesn't come back.

In other words, if we can make it three years out with no evidence of the cancer returning, we can be pretty confident that we are, dare I say it, cured.

Transplants are risky business, but are a sensible option for those who are young with aggressive disease, who may not have the time or the option to wait for one of the new magic pills. And they can absolutely be curative.

You can't say that about any other CLL therapy. At least not yet.

Here is Dr. Pagel. Enjoy.

ASH 2012: Dr. John M. Pagel Part 1 Game changing medications including ABT-199, Ibrutinib, and GS-1101 for CLL

Here's a little New Year's Eve gift.

In the first of three segments of my interview with Dr. John Pagel,  he says some amazing things.

"this year from last year in CLL, it's game changing, it's night and day difference from where we're going and where we've come and what this field is evolving to, ...... evolving away from cytotoxic chemotherapy"

"this is an amazing wonderful time"

But enough of me quoting the scientist.

I will let the good doctor introduce himself and share some details about his personal experience and excitement concerning ABT199, ibrubinib, and GS1101.



As I attended more of the ASH science and education sessions, and as I interviewed more of the CLL champions, a more mature full screen story develops about the changes that are coming to the world of treatment.

Even a vegan can say that this isn't a case of too much sizzle, not enough steak. These changes are mighty and meaty.

This is really happening and it's happening fast.

In an upcoming post, I will outline some possible tactics for those of us whose urgent present need for treatment doesn't allow the luxury of waiting for the day in the not too distant future when we can go to our local pharmacy and pick up our bottle of pills to control our cancer along with our toothpaste and shampoo.

But first more, we have much more to learn from Dr. Pagel.

LIVE FROM ASH 2012

Let me use this post just to set the scene. I will bear news soon, all of it good, some of it incredible.

There is so much happening at ASH, often at the same time. There are several incidences when I have highlighted three different important presentations related to CLL for the same 15 minute slot that I would love to attend. That's not going to happen.

Add to this is that the conference center is so huge that it can take 20 minutes or longer to walk from one  lecture hall to another. I actually walk much more inside the building than the pleasant 15 minute walk through centennial park to the center from the hotel.

Add to that some 15,000 attendees, all of whom are in the halls between sessions with the proficient and helpful staff directing the heavy to and fro foot traffic through the long corridors and onto the narrow escalators.

So far one and a half days into it, I have interviewed Drs. Pagel, Kipps, and Steensma. Andrew Schorr interviewed me and I returned the favor, asking him about his coping with a secondary cancer. I have video from the press conference on ibrutinib given by Dr. Byrd.

So much more yet to happen.

Without my professional videographer, my oldest son, Ben, it would be impossible to pull this off.

The logistics are tricky. At the Georgia World Congress Center, we are constantly rejiggering the schedule, lining up the hematologists ( think herding cats), procuring the much in demand interview rooms, setting and resetting up redundant recording systems, doing the sound and video checks, and finally making sure the actual interviews runs on time. Rushing back to the hotel, Ben is recharging batteries, downloading the video cards, running our backups, and doing all the trouble shooting.

In between I am attending lectures and trying to find something vegan to eat.

The first sessions start at 7:30 AM and the last can finish at 8AM.

It makes for a long, busy but incredibly rewarding day.

I am so lucky to be here, to have my son's help and to have access to the generosity and wisdom of so many doctors.