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.

Celebrating My Two Year Anniversary Today on Ibrutinib for My CLL (chronic lymphocytic leukemia)

Much has happened in the last two years, most of it very good.

On a personal note, I swallowed my first 3 battleship grey capsules of PCI-32765 (it wasn't even called ibrutinib yet) on May 7, 2012 in a Phase I/II clinical trial at OSU with Dr. Byrd.

Two years later my lymph nodes have shrunk to less than 1/2 their size with the possibility that all that remains on the CT scans is the scarred shells of what used to be cancerous nodes.

Today, to find any CLL in my blood, you can no longer rely on the standard bloods test but must do the vey sensitive flow cytometry to find the < 0.3% of cells that are still clonal.

My latest bone marrow biopsy was 15 months ago in Feb. 2013 and even back then it showed only 4% CLL by flow cytometry down from between 10%-20% a year earlier.

I am clearly in a very deep and deepening remission.

I am very grateful.

On a community note, ibrutinib, the first in class signal blocker (BTK) for CLL, received breakthrough approval in the USA for anyone who has tried at least one prior therapy based on its outstanding safety and efficacy data in all patient groups, including those with 17p deletions and other hard to treat clones. But it is broadly available to any of us who have tried but not necessarily failed just one prior therapy.

Obinutuzumab, a potent 3rd generation monoclonal antibody (mAb) is now on the market and is getting complete remissions with the wimpy help of a touch of chlorambucil in clinical trials. Clearly it is this new mAB that is doing the heavy lifting.

Idelalisib, another  exciting targeted oral medication, should be approved later this year based on its stellar efficacy results in pivotal trials with few adverse events.

ABT-199 is proving to be perhaps the most potent oral agent yet in difficult to that patients.

ONO (ONO 4059) and Infinity (IPI 145) and others have very promising signal blockers well into development.

ROR1 trials are just beginning and should offer laser like focusing and very little off target damage.

CAR-T therapy has pulled a handful of patients from near death to deep remissions.

I was revising a 2012 CME (continuing medical education) on CLL program that I will be giving in Baltimore in June and realized just how far we (and I personally have) have come.

I am very grateful.

After  all, we are all in this together.

I think I''ll enjoy some  home made coconut milk yogurt to celebrate the amazing progress.

ASH 2013: Dr. Neil Kay on Why We Need a CLL (chronic lymphocytic leukemic) Expert and on Clonal Evolution

Dr. Neil Kay is Professor of Medicine at Mayo Clinic and also is fellow Canadian who had dedicated his career to helping those of us with CLL through research and direct patient care.

I interviewed him in New Orleans at ASH 2013.

His research has been wide and varied including the studies on EGCG (the active ingredient in green tea) that was sponsored by CLL Topics and Chaya Venkat that looked to see if there might be role for this specific extract from green tea as a gentler and more natural way to control our disease. Turns out it did have some significant efficacy, though its effect were not too powerful.

I miss what Chaya and what CLL Topics did for our community. Much of my work is an effort to pick up where she left off, but those are big shoes to fill.

In our interview form December 2013, Dr. Kay hits us with the cold facts that support my long time mantra of getting a CLL expert to head up your team. His published study has proven that we have better outcomes if we have a CLL expert on our team.

He and I discuss our shared vision of the perfect treatment team.

I can not overstate how important this is to our success in our long duet with our CLL, our nasty dancing bear of a partner. It can determine who will leads and who will follow, and how often we will get our toes stomped or worse, how often we will be forced to endure unwelcome advances by our disease.

The second topic we grappled with is more complex but worth the effort. It has to do with CLL clonal evolution.

Turns out p53 (often but not always related to a 17p deletion) is only half the story.

Turns out CLL is not a genetically stable disease. No surprise there. Especially true if you are unmutated or missing 17p.

Turns out the problem may be baked into the cancer from the start, to quote Dr. Kay it may be a "resident property of a patient who presents with CLL" and that treatment does not induce the new clones but allows what were once minor subclones to grow and become dominant. And that can spell problems for us as those clones are nearly always more aggressive and resistant to treatment.

The lessons from this research help inform us about the biology of how our cancer relapses and more importantly, about how it becomes refractory (resistant to therapy).

Dr. Kay admits that this research predates the new signal inhibitors such as ibrutinib and idelalisib and ABT-199 and more. How their use will impact the evolution of the CLL clones and subclones is a story that is not yet understood, but we can learn from this important research.

His explanation is crisp and clear. Understanding what his collaborative research has uncovered by looking at genetic evolution of CLL should help inform our decisions about when and how to treat our leukemia.

The second part of the interview will follow soon.