Early use of Ibrutinib or is W&W still a needed strategy?

[ThreeWs]

I recently responded to this question posted on CLLSLLyahoogroups forum by C. M.

".... If these new drugs [kinase inhibitors] are so effective it makes sense not to "wait" for our white counts to rise and all the other side effects of the CLL. Are there any trials using Ibruitinib on CLL patients who have not had treatment?"

My reply, here expanded a bit, as follows: While it is unknown that allowing the increase of B-cancer cells, particularly in the peripheral blood, does not cause harm it is not apparent that any potential harm from accumulation is greater than current TX (treatment) options taken early in disease diagnosis. The question of Early Front-line use for kinase inhibition drugs like Ibrutinib or Idelalisib is not a slam-dunk based solely on their extraordinary efficacy to date. The following questions need to be considered if not answered and for which we need more time to gather appropriate data.

1) Ibrutinib in use today permanently and irreversibly blocks both BTK (Bruton's Tyrosine Kinase) and ITK (Interleukin 2 Inducible T-cell Kinase) for given cells on a daily basis. Keep in mind that these kinases are part of needed cell functioning activity under normal conditions so we do not know what stopping the pathology of cancer hijacked BTK and alteration of our T-cells by ITK inhibition does to beneficial kinase function as related to the overall function of the humoral or adaptive immune system.

2) Ibrutinib is not a cure and has produced very few CRs (Complete Remissions) as a monotherapy and if no longterm side effects arise, may have to be taken on a daily basis for the rest of a patient's life, so in patients who are in their 30s, 40s or 50s at a cost of ~$100,000.00 to $130,000.00 USD per year, do the math. Yes - Money matters, sad to say.

3) It is a different question as to being prescribed Ibrutinib when first diagnosed when a patient crosses the line from MBL(Monoclonal B-cell Lymphocytosis) to CLL, than giving Ibrutinib as a front-line therapy after a standard waiting period (W&W) when "B" symptoms appear, making TX necessary. Many years of high quality function can be the experience for many patients on W&W.

4) On the pro-early TX side of the argument, it is possible that early treatment might prevent clonal evolution leading to a more dangerous CLL from emerging but that is only speculation at this time. There should be some experimentation for this to be studied. What studies from about four and a half years of Ibrutinib use are telling us, is that frontline treated patients are doing better than chemo beat up patients even though both groups respond very well. In a time of rapid therapy development a strategy to argue for earlier Ibrutinib use could be made that by the time any potential bad side effect might show up a newer treatment - less toxic than chemo based options will be available. Gotta have faith for that one. In the oft chance that a longterm side effect could rear its head in the arena of humoral immune function, one could rationalize that any disfunction might easily be reversed by simply stopping the Ibrutinib therapy. This is unlike purine or alkylating agent damage that we know cannot be reversed once it shows up e.g. MDS (Myelodysplastic Syndrome) & secondary cancers likely to be more frequent with chemo.

5) On the anti-early TX side of the argument it is unknown whether permanent BTK/ITK blocking for prolonged years will inhibit the ability for a person to make novel antibodies to new biological threats that adults have not encountered in the past. If this speculation plays out I would imagine that younger patients would be more vulnerable to infections than older patients as a general rule. Even in the frontline treated monotherapy Ibrutinib patients there is not 100% PFS (Progression Free Survival) and relapses are occurring more frequently in chemo beat-up patients. The message applied to all treatment therapy is at this time to expect that the earlier one starts TX the sooner one may expect to relapse. Immune function under perpetual long term kinase inhibition may be analogous to turning an oil tanker around - It takes a long time but its direction can be reversed. Time and selective use of Ibrutinib will yield much need info as the years pass.

6) More Trials to include frontline use in previously untreated patients and other novel use combination Trials with Ibrutinib are coming up soon. This is difficult for those needing TX now but keep your eye on the website <Clinicaltrials.gov>

I am a lay-patient with no medical training and anything I write should be viewed in that context.

WWW - Ibrutinib monotherapy (280mg daily) lab-rat in the early Phase I R&R (Relapse & Refractory) Clinical Trial at OSU Medical Center under Dr. John Byrd - just past 30 months, PR (Partial Remission) still deepening as of last monitoring and feeling good with no apparent side effects to report.

[Newdawn Administrator]

Three W's, this is a very interesting question to pose particularly for us Watch & Waiters wondering if there's an alternative early intervention that may hold back or stem the strength of the eventual tide. I look forward to hearing the views of the more scientifically informed in our membership on this.

I confess to struggling with the meaning of this sentence however because there are a couple of double negatives in there that confuse the meaning for me;-

'My reply, here expanded a bit, as follows: While it is unknown that allowing the increase of B-cancer cells, particularly in the peripheral blood, does not cause harm it is not apparent that any potential harm from accumulation is greater than current TX (treatment) options taken early in disease diagnosis.'

Could you explain this sentence please as it sets the scene for the whole exploration of the proposal.

Many thanks,

Newdawn

[ThreeWs in reply to Newdawn]

There is no proof that W&W vs early TX increases the degree of pathology or risks shortening OS (Overall Survival) in the absence of B-symptoms. This is largely based on ALC (Absolute Lymphocyte Count) because the manifestation of our cancer as SLL (Small Lymphocytic Lymphoma) can cause separate categories of threats to health and function by dangerously enlarging liver, spleen or having internal nodes pressing on blood supply to kidneys. One pro-W&W idea, very relevant to this discussion, is whether W&W can actually provide an inhibitory effect via competition with potentially more dangerous clones (17p- or 11q-) from expanding when a patient has a dominant indolent clone (13q-) population at diagnosis. Enter kinase inhibitors and the unique properties for their efficacy. Because kinase inhibition from Ibrutinib or Idelalisib disrupts the homing/adhesion properties of all CLL cells regardless of clonal affiliation in the proliferation centers of the nodes, will this mean that clonal evolution with the emergence of 17p- and 11q- clones be less likely to occur? Research has yet to answer these questions but we do know that Chemo and mAb (Monoclonal Antibody) therapies will reduce the easier to kill indolent clones with results in many cases of harder to kill clonal populations becoming dominant leading to TX resistance.

One of the questions I have been seeking answers to, is how kinase inhibition over time may affect the quality or quantity of immunoglobulins which are so important to immune function. In my case I was always lucky to have a higher than expected IGG level given the high tumor burden I sustained during W&W. TX with FR brought IGGs down some but after failure from a severe life threatening reaction following cycle 2, I switched to HDRTX (High Dose Rituxan TX monotherapy) which also produced a life threatening severe reaction in which I observed a drastic reduction to my IGGs. Since being on Ibrutinib (30+months) I have not suffered any further reduction in IGG but do not know if the quality of function might be changing.

Hope this clarifies somewhat.

WWW

[Newdawn Administrator in reply to ThreeWs]

Yes, thanks, it clarifies the position WWW. Given your personal experience, it's not surprising that you are posing these important questions.

Interested to know other's views on this. What are the experts telling us thus far or is it too early to say?

Wishing you sincere good luck with your ongoing treatment WWW, you've had a tough time.

Newdawn

[AussieNeil Partner Administrator]

Thanks Three W's,

You've provided some food for thought on a subject of great interest to this community and I appreciate the considerable effort involved on your part putting your research and thoughts into words. If anyone is looking for some great ideas for experiments, you've also provided suggestions for some great papers!

With reference to your statement "While it is unknown that allowing the increase of B-cancer cells, particularly in the peripheral blood, does not cause harm it is not apparent that any potential harm from accumulation is greater than current TX (treatment) options taken early in disease diagnosis." this is indeed the crux of the matter. Until we had potential game changers like ibrutinib, we had no way of even exploring this unknown.

For those interested in reading more on what we currently know about high peripheral blood B-cell counts, read the pinned post "How high can you go? (And what does it matter?)", which includes some relevant references and videos:

healthunlocked.com/cllsuppo...

Neil

[Kwenda in reply to AussieNeil]

Many thanks WWW for this input. It is clearly written, not overly technical, and thus understandable for many readers here.

This is a subject that has been raised before on this forum, and will most certainly be raised again, as the news of ibrutinib and idelalisib filters out to readers on forums such as this.

I would suggest that it is worth pinning for easy recovery.

Dick

[AussieNeil Partner Administrator in reply to Kwenda]

I'm glad you found this post clearly written and not overly technical Dick, but I suspect you are in a small minority These are pretty technical musings by WWW and I expect it will be quite a while before we get any answers. After all, we are considering a revolution in how CLL is treated with perhaps a significant proportion of CLL patients actually being treated at diagnosis (after genetic tests confirm this is the best option), rather than being placed on Watch and Wait. While we are all hoping for one of the new drugs (such as Ibrutinib) to do for CLL what Imatinib/Gleevec did for Chronic Myelogeneous Leukaemia (CML), sadly the expert consensus is that Ibrutinib is not in the same league as Imatinib. While Ibrutinib looks to be considerably better than established treatments, it could be that Ibrutinib or one of the other new small molecule drugs currently on trial may provide a CURE for a significant proportion of CLL patients when used in combination with other drugs. That research is yet to be done though we are seeing trials in planning, like the trial of Ibrutinib + Rituximab versus FCR for first line fit patients able to tolerate FCR that are starting about now in the UK with FLAIR. There's some well considered hope that we may soon be in a position of having a choice between staying on a medication to control CLL for life (as imatinib did for CML) or going on say a 6 month course of some new combination treatment and actually being cured. It may not be that black and white; perhaps an assessment of CLL genetics, age and co-morbidities will determine which of these options is best for each patient. Frustratingly, we just don't know!

(For an article on how Imatinib was a game changer for CML, see webmd.com/cancer/news/20110... Unfortunately CLL is a much more complex blood cancer than CML.)

FYI, we have problem working with Pinned Posts in that the current implementation doesn't support their ordering. Until this is implemented, or we can categorise pinned posts, we've decided to minimise pinned posts to those that are immediately relevant to new members, hence Nick and I have decided not to pin this post.

Neil

[ThreeWs in reply to AussieNeil]

Neil,

The complexity of both CLL/SLL and the emerging therapies added to older therapies begs the question of whether our discussions can be simple. As you pointed out "Unfortunately CLL is a much more complex blood cancer than CML." To emphasize the complexity, I sat on a US Dept. of Defense research panel tasked with finding promising & novel basic research proposals addressing blood cancers. I was one of three patients on the panel with 12 doctor researchers as patient perspective advocates. My two fellow patients were CML Relapsed from Imatinib. People do relapse from a much simpler to define blood cancer and its "miracle" drug in CML so to not expect relapse in Ibrutinib patients at some time is not facing reality. This unknown begs the wisdom of assuming that frontline TX with kinase inhibitory drugs should begin before W&W plays out.

If patients are to become effectively proactive on their CLL journey, a basic understanding of the questions needed to be asked will demand effort in knowing the nature of the complexities. There is no simple way around plotting a path with any degree of certainty having CLL, unless a patient places unquestioned trust in his or her doctor and is willing to accept the outcome. I am not condemning this approach but it is not me and not what forums like this are about. By knowing as much as we can about the nature of our individual CLL and the mechanisms of how different classes of drugs affects both the cancer and our bodies we can gain what I call a Casino's edge with a better chance at a better outcome. Would you like to see more references citing medical research to accompany my posts or would that add too much of a technical flavor to discussions? One way might be to wait until statements are challenged to cite technical data. This might encourage a better level of discussion as when I was asked to clean up a confusing sentence in my recent post.

WWW

[Newdawn Administrator in reply to ThreeWs]

WWW, I am also a lay-patient without your impressive and advanced scientific knowledge which is why I asked for clarification of meaning in one of your sentences. Not because I was attempting to stifle discussion, quite the opposite, I was hoping to gain greater understanding of a potential treatment proposition that is critical to people like me on early W & W. We are all chasing the same hope.

I am certainly not an accepting or passive patient waiting unquestioningly for answers from my doctors but I suspect like many on this site, found the article pretty complex at times in terms of the technical content.

Of course it isn't always possible to coach the exploration of treatment proposals in simplistic language but please respect that there are many who require simpler clarification and explanation of terms. We are all at different stages in the CLL journey, many newly diagnosed and keen to know whether exciting propositions have any proven research basis. I was excited reading your proposition but wanted greater shared discussion as to what this means in reality, where are we in terms of this emerging therapy in W & W and is this a viable option I should be taking to my physician.

Because I believe many people on W&W feel this frustration acutely and could seize on this as an answer. It's why I wanted it to be opened up further, explained in less advanced terms and yes, discover the questions that need to be asked in order to be more pro-active on the CLL journey.

Simply to pin it at this stage wouldn't answer the questions for me, it's just a tantalising option that I'm keen to know has realistic application any time soon.

It is a difficult balance to achieve levels of technical and scientific information that all community members will understand but I'm quite prepared to admit when I need greater explanation of terms and hypothesises. I only asked for that request to be respected and not judged. This is a cancer support site as well as a valuable pool of scientific knowledge.

Your post opens up exciting proposals and challenges traditional treatment pathways. I hope people feel able to contribute but let's respect the right to ask questions without intellectual hostility.

Warmest regards,

Newdawn

[ThreeWs in reply to Newdawn]

Newdawn,

"intellectual hostility" Ouch!! that hurt. I feel like I am digging a deeper hole for myself though unintentionally. I attempted to acknowledge in a diverse population of patients, tolerance and respect for everyone to pursue what they seek to include those who are just looking for emotional support to those who have a need for more technical knowledge as to what is trying to kill them and what is out there to help them. I was being rhetorical and really wasn't judging you or directing that comment to you specifically. For the record let me state that I apologize if in any way someone interprets my posting as hostile, elitist or not trying hard enough to be passing on what I have learned in an understandable manner. Please put it down to an honest failure, on my part, to communicate. Another point which may be important to the success of members seeking answers on this forum is to make it very clear that there are no stupid questions and there is far less understanding achieved by those who are intimidated into being afraid to ask for clarification such as you did with my post. There is little that offends me and this "incident?" is viewed by me as a challenge to sharpen my ability to pass on what I think I know in better ways. Questioning deepens and expands the issues. We both agree.

Also for the record, if it can help new members with my posting, I will lay my lack of academic credentials on the metaphoric table. I barely made it out of high school. I sympathize with newly diagnosed members seeking answers. When I began my journey in Sept. 2006 I felt overwhelmed, having rarely ever been to a doctor's office in 63 years. In the intervening 8 years of my searching for answers, newer drugs with novel mechanisms of function have added to our choices but heightened the complexity for how we are to choose. At times I also would love questions answered in the simplicity of black and white but too often the waters remain muddy even in the presence of facts.

"Be patient toward all that is unsolved in your heart and try to love the questions themselves ..." Rainer M. Rilke

Be well and keep on asking questions and for clarifications.

WWW

[Kwenda in reply to ThreeWs]

After reading all of the above I was struck with the thought that this forum on Health Unlocked perhaps attempts to cover two different needs or types of people.

NewDawn wrote; ‘ This is a cancer support site as well as a valuable pool of scientific knowledge.’

We have those who are looking for what we might call and Wayne mentions, ‘emotional support ‘ in their journey with CLL.

Perhaps they have been recently diagnosed and were wondering if they were alone in this world.

Then we have others who are looking to research and understand their disease and are happy to read technical journals with a copy of a medical dictionary at hand.

Now there have been already comments on Health Unlocked about the technical nature of some postings, with humorous accounts of a men only page for those with a technical mind.

There used to be, and I believe they still may operate, two Yahoo forums. One was headed CLL and the other CLL Research.

Would it be a good idea to split up this Health Unlocked forum into two similar separate pages or forums.? Of course a cross link can be often available so that people can read further.

Failure to take this approach might discourage some visitors who are looking for ‘emotional support’ but end up first finding a page discussing chromosomal deletions and their relevance.

I am not sure that one single forum can ever be ‘ All things to all men ‘.

I might suggest that the administrators, at the very least investigate the idea.

Dick

[AussieNeil Partner Administrator in reply to Kwenda]

Hi Dick,

I think Bub (see reply below) has said it well. Those that like to explore the technical side of CLL need empathetic support too and there's no compulsion on anyone to read what doesn't interest them. Previously, a good suggestion was made that perhaps technical posters could preface their post with a warning that technical content was following. (I notice Mythbusters use this technique to good effect.)

Personally, I'm so glad that I can use multiple tabs in my browser so I can quickly check terminology or abbreviations with which I'm not familiar. Being able to quickly access reference information on-line has saved me a fortune in medical books plus desk space for them I just don't have!

For new or even established members that do develop an interest in the technical, there are now sufficient posts useful as background references for use by posters introducing a new topic or expanding our knowledge on existing topics. With Site Search working better now, those reference posts can be more readily found and links added to new posts, thereby increasing the audience that can benefit from the post, no matter their level of understanding.

Neil

[Newdawn Administrator in reply to ThreeWs]

Hi WWW and thank you for your open and humble response to me.

It seems that so much more is achieved when we collide at the level of fellow (scared) patients rather than academic foes

It's important for me to say that the message you were conveying in your original post wasn't lost on me and in view of your personal experience at the hands of alternative treatments, it's really not surprising that you extol the efficacy of ibrutinib. I've just been reading Dr. Koffman's blog and it's clear that it's proving to have superior results with relapsed and refractory patients including himself. And this delights me at my stage.

It probably would have been more productive and led to less misunderstanding if I'd simply read your post and said;

'Hey W, this sounds full of possibility, how far on do you think we are in using Ibrutinib as a first line treatment for W&W'ers, do I need to be proposing it to my doctors or are we jumping the gun at this stage!'

Because in reality that's what I was thinking in simplistic terms and it's why I wanted to delve deeper into the content for clarification. And I doubt whether I'm alone in that line of thought.

CLL is a funny cancer that doesn't make me laugh. The 'Nero fiddles whilst Rome burns' approach for W&W'ers defies traditional medicine. The 'what do you mean you'll keep watching me get worse' before you act doc is rather curious and baffling to many newly diagnosed. So any suggestion of meds at this stage is easy to seize on. But as I understand it, we are still at the drawing board stage in using Ibrutinib as an early game changer at dx stage. And it look forward to future trials at early stage CLL to change the landscape for newly diagnosed. It certainly would yield an enormous psychological impact for patients too.

And you are absolutely right in saying that there are no 'stupid questions' but regrettably some members still feel inhibited in asking them. I very much want that to change.

Every day I open the site to see another 'lifeboat of hope' sail in and I have to decide whether it's still taking in water, enthusiastically under repair or possibly able to safely deliver me to a safer destination'. We are inundated with complex scientific data and research and my learning curve has been so steep I've occasionally slid off with a bump!

But the one thing I value is the immense commitment and dedication by scientists, researchers and medics, including the 'experts' on this site who work hard to bring us hope, knowledge and possibility.

It's clear that knowledge apathy is a hazardous path to choose with this condition!

So I urge fellow members to keep asking the questions as I certainly will. The one thing that didn't escape me in your post W was the tough struggle you have experienced and I've very pleased that you are doing well at the moment. Long may it continue.

It is a challenge to balance complexity on a site where stages and understanding is so varied, so I'm glad you agree that the way forward is a totally permissable and unjudged policy of members being able to say, 'please explain, I don't understand'. Let's learn to love the questions.

Warmest regards,

Newdawn

[scaredandlost in reply to AussieNeil]

what is a pinned post? I am new here. Sorry for changing the subject.

[AussieNeil Partner Administrator in reply to scaredandlost]

Great posts covering important information are pinned for easier access. They can be found at the right of the post you are reading on a computer, or at the bottom of your smartphone/tablet screen.

healthunlocked.com/cllsuppo...

Neil

[Hidden]

I have read with much interest the exchanges on WWW's post. For bringing this information to us thank you WWW, also huge thanks to Newdawn for expressing so well the views of many of us, that perhaps do not have her communication skills.

I think there are many lurkers on this site that like me, never expected to have to get to grips with such technical knowledge, not being in the first flush of youth it is not always easy. But we learn as we go along, and we want to have this knowledge or we would not be using this site.

WWW brings 7 years of valuable experience with his mails, I am 3 years along my journey, and learning as I go, as I suspect quite a number of us are. We cannot underestimate the value to us of diverse technical and supportive mails.

As long as we are able to ask for clarification where we do not understand, and offer support to those of us who have just been diagnosed and who are understandably scared and new to this journey, I think it would be wrong to change the set up of this group.

To have two facilities, one technical and one empathatic would be divisive, there is room for both and I feel it would be a mistake to create a technical elite.

Bub

[Newdawn Administrator in reply to Hidden]

I totally support that position Bub, well said. It is possible for both needs to co-exist as long as the channels are open to ask questions and seek clarification. And I also applaud WWW's considerable efforts to do so on our behalf.

I hope the discussion has taken place in the spirit of respect and will yield a positive response to more open dialogue on highly technical matters.

Regards,

Newdawn

[HAIRBEAR_UK Founder Admin]

This is an interesting video of Dr Jennifer Brown - Dana-Farber Cancer Institute, Boston, USA

talking to ecancertv at ASH 2013 about the: "Phase 1 Study Of Single Agent CC-292, which is one of the new BTK inhibitor drugs a little further behind Ibrutinib and others. .

The video may be helpful.for some as In this brief interview Dr brown goes on to mention a bit about other inhibitors and touches on the question raised by the parent post of WWW about the importance of watch and wait in the era of these new therapies..

This may be useful to help explain some of the thinking of an expert CLL clinical researcher in this area.

Dr Brown touches on the dilemmas of moving away from watch and wait and the evidence required to enable research in this area to move forward to consider trialing this population.. ecancer.org/video/2571/nove...

[AussieNeil Partner Administrator in reply to HAIRBEAR_UK]

Thanks Nick, that 5+ minute video is well worth watching, though I found it frustrating because of the way it prevented me from revisiting sections without watching it all again. Rewind would have been nice...

[Kwenda in reply to HAIRBEAR_UK]

Dr Jennifer Brown’s videos are always instructive to watch. This video having additional information on how these now many new drugs might be used in the future. The reports on the trials of these new drugs will be fascinating to watch in the next few years.

Thanks Nick

[ThreeWs in reply to HAIRBEAR_UK]

Glad you drew attention to Dr. Brown's perspective. We should all be very attentive to the knowledge gained from multiple kinase inhibitor drugs. I had difficulty in understanding how two or more companies could get a patent on a drug that blocked the same kinase (BTK) in the case of Ibrutinib and CC-292? Turns out I had a naive concept of the variable ways in which a drug could be designed to do the job at hand. CC-292 it turns out is more highly selective in blocking BTK whereas Ibrutinib blocks not only BTK but ITK (Interleukin 2 Inducible Kinase), a kinase involved in regulating the ratio of T-lymphocyte CD4 and CD8 cells. This discovery has led to speculation for Ibrutinib's efficacy over that of CC-292 at similar dosage. The skewing of T-cell production in favor of CD8 cells or another way of saying it - the inhibition of CD4 cells has autoimmune function implications, for which knowledge gained, could greatly benefit those patients suffering from autoimmune conditions found in the CLL community. Many patients find themselves in a bind of not needing to treat the CLL but have a need to treat a threatening autoimmune condition like ITP (Idiopathic Thrombocytopenia Purpura), AIHA (Auto Immune Hemolytic Anemia) and more rare non-hemic autoimmune conditions like what happened to my kidneys.

Knowing how these drugs work or don't work may give some of us the "casino's edge" if and when we get faced with a choice of growing treatment options.

WWW

[Hidden in reply to HAIRBEAR_UK]

Thanks Nick.

Good to see the discussions and comments, I always find the videos helpful, Dr Brown's in particular for her clear diction. Whilst being a non contributor to these sometimes easier, sometimes harder technical discussions. I continue to learn, and appreciate those among us prepared to share their expertise and experience with us. Long may they all do so.

Thanks to all.

[Myrddin]

Clearly CLL is a cell division that has gone wrong. The longer the cells are allowed to continue dividing the greater the chance of some being produced that can not be effectively killed by current treatments. So there is a case for early intervention. The question is whether we have suitable treatments to justify treating earlier than now. The medical opinion at the Bart's meeting, where this question came up, was that we are not there yet because the medication is still being used in trials for individuals who have already had treatment. Trials to test early treatment may come but will be a while before we know the answer.

Certainly need technical information to be discussed here and there are medics ready to comment should the information be wrong. Anyone who does not want to read technical threads can skip as on any blog. There are other groups that are less technical but they miss out - that is why I am here. Need both.

[ThreeWs in reply to Myrddin]

Your logic on allowing a cancer like ours to continue without intervention is right on. The problem with jumping the gun with Ibrutinib as a TX (treatment) to be initiated at diagnosis is that we do not see a high number of CR (complete responses) in Ibru-patients, even in those not previously beat-up by prior therapies. If you begin seeing a single agent drug like Ibrutinib achieve a high number of CRs or better yet, MRD (Minimal Residual Disease) negative, I believe you will see a shift in thinking toward earliest possible TX.

The current hope for achieving an MRD neg response is a combo therapy of say, Ibrutinib and ABT-199 or maybe with one of the newer mAb (monoclonal antibodies). We might need to wait for a ROR-1 drug with cancer cell specificity. It will be interesting to see what the new BTK (Bruton's Tyrosine Kinase) Inhibitor does (ONO-4059) see Chris D's post (see link below - Admin). With all the new drugs coming out, something will work but in the meantime W&W has clinical value for our overall survival.

On a personal note: my remission is still classified as a PR (Partial Remission) but it is still deepening after 30+ months on Ibrutinib. We may just have to give the drug more time with some patients.

WWW

Post on (Bruton's Tyrosine Kinase) Inhibitor (ONO-4059) - Neil:

healthunlocked.com/cllsuppo...

[Cllcanada Top Poster CURE Hero in reply to ThreeWs]

Until I see a lot of clear data that early treatment does not cause clonal evolution ... this question is moot.

If new treatments prevent or slow this process... go for early treatment perhaps, but there is so much to be learned still...

~chris

[ThreeWs in reply to Cllcanada]

You are in the unenviable position of having suffered the duel blow of Shingles activation and Richter's following TX with FR. Some patients on Ibrutinib have also suffered the same fate. Treatment from any therapy may contribute to unfortunate events like these. We need to know who are the vulnerable patients and what drugs may be used at what stage of disease to diminish these debilitating events. I agree the learning curve is steep.

[Cllcanada Top Poster CURE Hero in reply to ThreeWs]

Not to mention the damage to my heart and nervous system The shingles followed round 3 of RCHOP which makes FR look like Koolaid...

Then there was 30 Gy in 10 fractions of radiotherapy to my L2 vertebrae, but that is a story for another day...

You make an important point... missed by many patients...Imbruvica (ibrutinib) does not prevent Richter's transformation, nor does it treat it in most cases. The rate of secondary cancers remains unanswered...

[ikahan]

Hi 3 W's, as you may remember my 64 yo husband is part of the early ibrutinib study with Dr Byrd at OSU for patients who are at high risk but are on watch and wait. When he started the trial he was unmutated, no 17P. his ALC was 40 k and he had a couple of internal nodes approx 1.5 cm , no visible , palpable nodes. platelets and HGB low normal . A BMB showed 20 - 30 % involvement. He was working full time , but feeling tired and having frequent sinus infections as well as shingles. His ALC has gone from 40 to 75 to 7 when we last checked about 2 months ago. Also no internal nodes and no infections . When we saw Dr Byrd last he told us that he will be able to stop ibr at the end of the trial Dec 2018 even if he is not yet mrd-ve. Dr Byrd believes that once the bone marrow is cleared of CLL his T cells will start working more effectively, and will keep the CLL under control for many years.

[ThreeWs]

Hi ikahan,

Thanks for posting this as I have not heard of this strategy. I wonder what definition of a "clear bone Marrow" is used. I often wondered if one BMB could possibly be sufficient to declare a patient was free from CLL marrow involvement.

Keep us posted.

WWW

[ikahan in reply to ThreeWs]

Hi - Dr Byrd's hypothesis is that ibrutinib will prevent clonal evolution when given early. After two years it can be stopped, even if there are still stem cells or very small CLL clones still present in the bone marrow. These clones can be controlled by the body's immune system (T cells), which are no longer impaired by the cancer cells.

[Justasheet1 in reply to ikahan]

If that’s the case why would anyone have gotten cancer in the first place? Are you sure you understood his position? I wish that was case.

Jeff

[ikahan in reply to Justasheet1]

HI Jeff, my husband has CLL in his family and was almost certainly born with CLL producing stem cells Yet he did not get CLL till he was 60 yo. So the immune system controlled it for a very long time. Then the cancer eventually took over a significant portion of bone marrow and overwhelmed the immune system. The ibrutinib reversed this and allowed the immune system to work again. There's a chance the stem cells will overwhelm the immune system again but hopefully this will take a very long time - at least 5 - 10 years.

[Justasheet1 in reply to ikahan]

I wish you both well. Dr Byrd certainly is an expert.