Friday, December 19, 2014

Last chance for the CLL (chronic lymphocytic leukemia) Survey and the News About the Agreement between Gilead and Ono

We are taking down the survey at midnight tonight Pacific Time, so if you haven't completed it, please let us know what will be important to you in a CLL website and support groups.

Here is the link to the survey: https://cllsociety.questionpro.com

And thanks so much to the over 400 of you that completed the survey and the many who have made a donation to the CLL Society Inc. to jumpstart our process.

                                  


Finally I want to share this press release from Gilead:

ONO  AND  GILEAD  ANNOUNCE  EXCLUSIVE  LICENSE  AGREEMENT  TO  DEVELOP  BTK  INHIBITOR,  ONO-4059,  FOR  THE  TREATMENT  OF
B-CELL  MALIGNANCIES  AND  OTHER  DISEASES

-- Companies will Collaborate Jointly on Global Development of ONO-4059 --

Osaka, Japan, and Foster City, CA, December 18, 2014 - ONO PHARMACEUTICAL CO., LTD. (“ONO”) and Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the companies have entered into an exclusive license agreement for the development and commercialization of ONO-4059, ONO’s oral Bruton’s tyrosine kinase (BTK) inhibitor for the treatment of B-cell malignancies and other diseases.  Under the terms of the agreement, Gilead will pay ONO an upfront payment plus additional payments based upon achievement of certain development, regulatory and commercial milestones.  The companies will collaborate jointly on global development of ONO-4059.  Gilead will have exclusive rights to develop and commercialize ONO-4059 in all countries of the world outside of Japan, South Korea, Taiwan, China and the Association of Southeast Asian Nations (ASEAN) countries, where ONO retains development and commercialization rights.  
ONO-4059 is a selective, once-daily, oral inhibitor of BTK, which has been shown to play a role in the survival and proliferation of malignant B-cells.  ONO has presented preliminary Phase 1 data showing clinical activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) at several scientific conferences.  ONO and Gilead plan to develop ONO-4059 for the treatment of B-cell malignancies and other diseases as a monotherapy and in combination with approved and investigational agents, including combinations with kinase inhibitors in Gilead’s portfolio. 
“We are pleased to partner with Gilead to accelerate worldwide development and commercialization of ONO-4059,” said Gyo Sagara, ONO’s President, Representative Director and Chief Executive Officer.  “Our goal is to bring better therapeutic options as quickly as possible for the patients with B-cell malignancies or other diseases in the world, and we believe we can fulfill the goal by pursuing the development of ONO-4059 with Gilead.”
“With this agreement, Gilead now has compounds targeting four unique signaling pathways associated with B-cell malignancies – PI3K delta, Syk, JAK and BTK,” said Norbert W. Bischofberger, PhD, Gilead’s Executive Vice President, Research and Development and Chief Scientific Officer.  “In addition to evaluating ONO-4059 in combination with standards of care, we believe there is an opportunity to combine this compound with Gilead’s other kinase inhibitors with a goal of achieving more pronounced and more durable response rates.  We look forward to working with ONO to move the ONO-4059 development program forward as quickly as possible.”
About ONO PHARMACEUTICAL
ONO PHARMACEUTICAL, headquartered in Osaka, Japan, is an R&D-oriented pharmaceutical company committed to creating innovative medicines in specific areas. It focuses especially on the diabetes and oncology areas.  For more information, please visit the company’s website at http://www.ono.co.jp/eng/index.html.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need.  The company’s mission is to advance the care of patients suffering from life-threatening diseases.  Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.
Gilead Forward-Looking Statement
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including risks that the parties will be unable to develop and commercialize ONO-4059, as a potential monotherapy and in combination with other therapies, for the treatment of B-cell malignancies or other diseases.  These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements.  The reader is cautioned not to rely on these forward-looking statements.  These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2014, as filed with the U.S. Securities and Exchange Commission.  All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.
###

This is good news as we need more options and Gilead is a smart company that has a strong track record on getting new and important drugs approved. It also has other small molecules including idelalisib that might make sense in combination therapies. The market seems to approve of the move as this joint effort should increase the likelihood we will be seeing ONO-4059 become commercially available.

Ibrutinib is a great BTK inhibitor and has set the bar very very high in terms of its response rates and tolerability, but still it won't be the right choice for all patients due to some intolerance or adverse outcomes or lack of efficacy, so having another Bruton Tyrosine Kinase inhibitor option is something all patients should want.

And waiting in the sidelines is Acerta's ACP-196- no data to report yet, but the buzz about this new BTK inhibitor is very promising.

Abbvie, Janssen, Pharmacyclics and others are looking at new non-chemo combos in trials in the hope of going from control to cure. More on these trials and plans soon.

2014 was a great year for those with CLL. 2015 may be even better.

Happy Holidays to all.

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Wednesday, December 17, 2014

ASH 2014: Interview with Dr. Susan O'Brien and Dr. Bruce Cheson on CLL (chronic lymphocytic leukemia)

There is much to report from ASH 2014, and this sweet interview from Medscape offers a short synopsis of some of the highlights.

Over the coming weeks I plan to fill in the details with more comments and videos, but this is a nice and succinct place to start.

There are some priceless moments, thanks to the wise and dry humor of Dr. Cheson and the honest and patient centric attitude of Dr. O'Brien.

First, right up front, I really appreciate that Dr. Cheson points out just how out of date are even the most recent CLL guidelines that were developed only a few years ago.

Are you listening, community oncologists? The published CLL guidelines are out of date.

I am glad he also asked about the secondary malignancies with chemo-immunotherapy, a question too often swept under the carpet in many presentation on CLL treatment. We know there is a small but real risk of MDS or myelodysplastic syndrome (for an explanation of the relationship of MDS and CLL from Dr. Steensma, click here), a difficult to treat form of cancer that presents as bone marrow failure, that may come along as a late and serious complication with FCR (fludarabine, cyclophosphamide, and rituximab), but we don't have much data yet on the risk with BR (bendamustine and rituximab).  Because bendamustine is a DNA damaging alkylating agent similar to chlorambucil (Leukeran) and cyclophosphamide (the C in FCR), it is likely that MDS will also present as a late, but hopefully infrequent ugly complication after BR.

What we do know already is that now that we are living longer with our CLL, we are getting more secondary cancers (click here for a reminder of our risks), especially blood cancers.

Don't miss Dr. Cheson's hand gesture when Dr. O'Brien talks about the minority of patients that do so very well on FCR, a topic that we have visited here more than once (click here to hear Dr. Hallek at  iwCLL discuss who gets the most benefit from FCR).

Another highlight comes right after the honest discussion of the follow up important trial of the two old school chemo-immunotherapies that are duking it out for supremacy in the CLL world, namely the  FCR versus BR (for more on this trial from Dr. Sharman click here). After Dr. O'Brien's honest and upbeat response, Dr. Cheson asks her, quite properly in this era of new treatment options: Do we care?

Yet another interesting moment occurs when he asks Dr. O'Brien to choose between ibrutinib, idelalisib, and ABT-199: If they were all available: Which one would you pick?

She refuses to answer.

Their discussion on the meaning of minimal residual disease or MRD negativity in the era of novel therapies is both informative about what we know but even more so about what we don't know.

Only time and trials will help sort al this out.

Dr. O'Brien has her own hand gesture when she describes just how much above 50% was the progression free survival curve for ABT-199 at 18 months. We need more data. And more time to sort this all out.

I wish I had produced this video. I don't usually see the role of my blog to share what is already available on other websites, but this is good stuff and there was much in it that cried out for commentary and context. I wanted everyone who reads my blog to have the link with it here.

Please enjoy this Medscape Interview:

CLL: It's the Best -- and Most Confusing -- of Times



Thanks for your help and support.
                                          

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Monday, December 15, 2014

ESH 2014: Prof. Stephan Stilgenbauer Reviews Predictive and Prognostic Markers in CLL (chronic lymphocytic leukemia)

I was asked to present the patient's perspective in CLL at a satellite symposium to the annual congress of the Hellenic Society of Hematology held in Thessaloniki in northern Greece near the birthplace of Alexander the Great last month. The sponsors took a risk in inviting a patient to speak to a group of hematologists but my reception was warm and enthusiastic despite my inability to speak in the native language.

As a result of the positive response I received for my 30 minutes on the podium, I was asked if I could shoot a series of monologues that address various aspects of why it is so critical that our voices be heard by the professional community that treats us. I will posting those here and later our CLL website soon.  Check out the first monologue here filmed soon after I flew home. More monologues to follow on other topics.

The Hellenic hematology congress was co-incident with another valuable meeting in Thessaloniki organized by the European School of Hematology (ESH), ESH 2014: International Conference on New Concepts in B Cell Malignancies: From molecular pathogenesis to personalized treatment so I stayed in town for an extra few days to attend the CLL sessions and shoot some videos for the blog.

On a personal note, on my one half day free in Macedonia, I did rent a car and drove in the rain to see the amazing underground museum that includes the unspoiled grave of Philip II, father of Alexander the Great. Don't miss it. I loved my much too brief return visit to Greece.


 
Grave of Phillip II
My ESH videos were embargoed until after ASH, so I am only able to share them now.

The first video interview is with Prof. Dr. med. Stephan Stilgenbauer of the University of Ulm.

We revisit the topic of prognosis and predictive factors. Here is a link to an earlier post on another aspect of this subject with Dr. Bill Wierda from MD Anderson. Dr. Jeff Sharman gets into some of the same material in this helpful post from iwCLL 2013.

The first message that I gathered from Prof. Stilgenbauer is that the significance of all these factors must be reassessed in this era of novel therapies and that process has only just begun. How they may have predicted and prognosticated about treatment with FCR is not always going to match up as to their relevance for therapy with ibrutinib or idelalisib. 

This should be an active area or reassessment and research. One possible example seems to be that patients with 17p deletion respond differently when treated upfront with ibrutinib versus when treated after they have relapsed with 17p deletion. More predictive and prognostic factors will emerge if we look. 

My next take way: It is no longer sufficient to test only only for the deletion of the short (p for petite) arm of the 17th chromosome (17p deletion), but we also must ask our hematologists to check the function of the TP53 gene. TP53 has been called the guardian of the genome because when it is functioning well, it protects our genetic information from being miscopied and thus spawning a malignant offspring. When it is missing or dysfunctional, cancers are both meaner and harder to kill. Here is a nice overview on TP53 from the NIH. Dr. Stilgenbauer discusses the relation between TP53 and 17p deletion.

Finally we touch briefly on some of the new prognostic factors found in CLL with the advent of deeper probing of our cancer's genetic makeup with next generation sequencing. These include mutations in NOTCH1 (a signaling pathway between adjacent cells) and SF3B1 (a surprise finding, a important in gene splicing). Here's the original article from the NEJM that goes into much greater detail.

Here is Dr. Stilgenbauer.




More soon from ESH and ASH.

As I write and edit these recent blog posts, it has become increasingly clear to me that the scope of what needs to be done to teach about CLL had grown beyond the capacity of this meager blog.

That will be a major part of the mission of the nonprofit CLL Society Inc., to inform and support both the newbie and the cognoscenti of the CLL community through a new dedicated and more robust CLL specific website.

Please complete our survey to let us know what are your unmet needs by clicking this link: https://cllsociety.questionpro.com. It closes at the end of the week.

And thanks so much to the many of you that have already finished the survey and a big thanks to those of you that have generously supported us already with a tax deductible donation. It will all be used to extend and deepen our reach with more knowledge and support.

                                            

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Friday, December 12, 2014

ASCO 2014: Dr. O'Brien Discusses Improved Trial Designs, CT Scans and the role of Chemo-immunotherapy In Frontline Therapy in CLL (chronic lymphocytic leukemia)

I am back from ASH 2014 with some informative video interviews from Drs. Hillmen, Byrd, Burger, Wiestner, Kipps. Sharman, Roberts, Pagel, and Kay. The congress was a huge success and I will be reporting on the important abstracts and news over the next few months first here and then on our new website for the CLL Society Inc.

I also am very excited with the video interviews from ESH in Greece including ones with Furman, Porter, Hallek, Stilgenbauer, Wu, and Brown.

But first I have to share this fourth and final thoughtful audio interview with Dr. Susan O'Brien despite all its hisses and pops.

We pick up on the issue of ethical trial design from the third part of her interview on the issue of equipoise. If you missed part 3 or part 1 or 2, please enjoy by clicking on the numbers.

In this segment, Dr. O'Brien and I discuss the place of CT scans in clinical trials and in the real world of CLL therapy. Her answer is not black or white but is balanced and well considered.

Next Dr. O' Brien gives as a nuanced response to the question of what might be the possible role for chemo-immunotherapy in and out of trials.

Spoiler alert: Consider FCR frontline if you are young, healthy, mutated, and trisomy 12. But only under those circumstances>

 Here is Dr. O'Brien



More soon from ASH and ESH.

And thanks to the well over 300 of you that have completed our survey. If you haven't done it yet, please, take a few minutes to add your voice to the others as to what are your particular unmet needs in living with CLL. We are building the nonprofit CLL Society Inc. in response to those needs.

We will be taking the survey offline in one week on December 19, so please don't delay.

Here's the link.

And a very special thanks to those of you who have generously given a tax deductible donation to help us with our website construction and developing our CLL specific support groups.

More details to follow soon after we have analyzed the survey results.

We still are welcoming any contribution, large or small. At the suggestion of several of you, we have added a donate button at the top of the blog and on our placeholder website for the CLL Society Inc.

Thanks for all your help.

We are all in this together.

                                           

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Wednesday, December 3, 2014

ASCO 2014: Dr. Susan O'Brien Outlines Open Trials of Novel Agents and Equipoise in Trial Design for CLL (chronic lymphocytic leukemia)

In the third part of my interview at ASCO 2014, Dr. O'Brien points out the advantages of being in a clinical trial, including the real financial advantages of getting the trial drug for free. However do remember that the standard of care of drugs such as rituximab are not free. The labs and imaging are not usually free.

The one exemption are trials at the NIH where all costs are paid by our tax dollars. This is is the only way that most of those with no insurance or from out of country can afford  to be in a  clinical study.

Some of the active trials Dr. O'Brien asks us to consider is the phase 1 trial of the very promising second generation BTK inhibitor, ACP-196 that seems to be more selective and has longer binding. Nothing published yet, the early buzz is positive

TG Therapeutics has its next generation anti CD-20 monoclonal antibody and its PI3K inhibitor combined in a promising trial.

The CLL arm of trial of "Ublituximab + Ibrutinib in Select B-cell Malignancies" is already closed.

There is an ibrutinib versus ibrutinib plus rituximab trial at MD Anderson for relapsed patients. Free ibruinib!

The list keeps growing. Please check out clinicaltrials.gov when you are considering therapy. We need more options and the only way we get them is through trials, and the only way trials happen is if patients enroll (and their doctors recommend them).

Finally Dr. O'Brien eloquently addresses the issue of equipoise in clinical trials. This ASCO post article from 2013 should be mandatory reading for all patients and all trialists. Please listen carefully to all that she has to say, and how these breakthrough medication have changed how we should design future research. There are lives in the balance.

I love her blunt talk: "They will have to allow cross-overs."

Here is Dr. O'Brien. Again, my apologies for the poor audio quality.



If you haven't heard the prior two sections of the interview, please check them out.

Big news here in the next day or two.

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Tuesday, December 2, 2014

ASCO 2014: Dr. Susan O'Brien Speculates on Combinations with Ibrutinib to Get a Complete Remission in CLL (chronic lymphocytic leukemia)

In the second part of my audio interview, Dr. O'Brien of MD Anderson today and next year at UCI gives her opinion on one of my favorite topics, what combination of novel agents (and I am only  talking non chemo combos) might and might not do when added to ibrutinib as the backbone of a therapy. Can we get deeper responses? Can we get to cure?

The same speculations, and at this time it is all speculation, could be made for combos with idelalisib or ABT-199 or any of the novel agents in trial. The only way to find out is with research.

Here is just one example of one such interesting trial that was just posted today.

Dr. Susan O'Brien starts by rightly asks us to look at the data separately for the treatment naive group and the relapsed refractory gang.

Those lucky folks who got ibrutinib frontline may be on cruise control for a long long time and if so, why mess with a good thing by adding in another medication

Next please listen carefully as Dr. O'Brien does a good job of reminding us of what exactly we know from trials and what we think we know.  For example we know that obinutuzumab (Gazya) is a much better monoclonal antibody (mAb) than rituximab when used with chlorambucil or Leukeran to tray CLL.  What we think but don't really know is whether it is a better antibody when used in other combos for CLL. As I have reviewed in past posts about glyco-engineeered mAb such as Gazya there is good reason to expect that it is a better killer of B cells, but that has yet to proven.

I also agree with her that much of the benefit from adding a mAB to ibrutinib might be cosmetic, getting us a quicker response by blunting the rise in the absolute lymphocyte count seen early in treatment. When you look at the data further down the line, there is little difference in the already strong outcomes with or without an anti- CD 20 antibody aboard.

This interview will make more sense if you catch the first part of our conversation here.

Finally, another plea for your tolerance. The audio quality is terrible: full of hisses and pops. And don't worry, you have not gone through a time warp. I do repeat a few seconds on the interview just passed the seven minute mark. It's a good thing I don't make a living as a sound engineer.

I hope the quality of the information will allow you to forgive the lousy recording technique.

As I have said before the near future will be full not just of better recordings (made certain by my plan to engage recording professionals at the big congresses), but also I will be posting more focused CLL education.

Please stay tuned over the next few days.

I will need your help with an upcoming survey and will be posting some new kinds of material that I hope you will enjoy and learn from.

Here is Dr. O'Brien


A very busy and productive ASH 2014 is just a few days away. And trust me,  I am bringing a video professional for all my scheduled interviews.

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Monday, December 1, 2014

Good News from OSU About my CLL ( Chronic Lymphocytic Leukemia)

It is no fun to travel on Thanksgiving weekend across the country to OSU, spending hours in busy airports full of long lines of irritable flyers, but I am know that I am one lucky patient and I am grateful for my good care and my good drugs, even if it means crossing 3 time zones and leaving sunny beachy California for cold and wet Columbus, Ohio.

When I started on my ibrutinib trial two and half years ago there was a definite buzz about this new oral med that might change everything.

Well the game has changed, or more accurately is changing, and it is only going to get better with new non-chemo combos and second and third generation kinase inhibitors and monoclonal antibodies  (mAbs) offering us more and more options.

We aren't there yet, but we are moving fast (but not fast enough for those of us who need answers now) in the direction of long term disease control. Cure is still elusive, but there is now an active area of research on curing CLL, sometime inconceivable a few years back.

I am an example of the early changes.

Before ibrutinib and idelalisib and ABT-199 and now the second generation kinase inhibitors and the new mAbs came along in trials, someone like me with a failed transplant and a clone of 17p deleted bad boys had fewer choices than a vegan at a Texas BBQ stand.

Now 30 months into my ibrutinib adventure, I have a boringly healthy blood chemistry, and a mundane CBC (complete blood count) with a normal numbers of my red blood cells, my neutrophils, my platelets, and an absolute lymphocyte count of only 1.04

If you dig deep enough with PCR or sensitive flow cytometry, I suspect my cancerous clone is still lurking in the less that one percent of my B cells that still carried the signs of being part of the nasty cancerous clone gang when checked three months ago at OSU.

But as I said much to happy about it. And many reasons to give thanks.

Now with my personal good results locked in for another three months until I return for my next OSU clinic visit, I am off to ASH 2014 to bring the broader good news and to push the CLL researchers and pharmaceutical industry no to take their foot off the gas until we have a cure for us all.

Let me know if you have any burning questions for the researchers at ASH.

Life is good.

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