I am off to ASH 2015 to learn everything I can about CLL and I have a miserable cold.

I got my biannual cold that seems to come just as I am planning to get on the plane to the be the only family doctor among 30,000 or so hematologists and researchers from around the world.

Despite my aches and cough and runny nose, I am looking forward to learning all that I can on CLL, absorbing it and sharing it here and on the CLL Society website.

Highlights include the first data on an ew BTK inhibitor, ACP-196 (NEWS BREAK: now officially called acalabrutinib), more on other exciting drugs in development including venetoclax (ABT-199) and several promising new signal blockers and more on SYK inhibitors and new antibodies and new combos and more on approved drugs such as ibrutinib and idelalisib and obinutuzumab and ofatumumab and more smartly focused material on chemo and on new understandings of how CLL is treated in the real world and how it might be treated soon and so much more.

Plenty of interviews scheduled with experts from around the world, many whom are old friends and some who are new to me, but have published important research.

Hundreds of great abstracts (I have reviewed about 200 so far) and many oral presentations and press conferences.

I am also meeting with other patient advocates and friends from around the world to share best practices.

I will try to share some live updates from ASH 2015 because it is so exciting, but mostly I like to digest the research over a few weeks so that it can be understood and put in meaningful perspective.

The only thing missing is lots of sleep.

So now I am going to bed. Flight tomorrow AM.

Biologic and Immune Therapies for CLL (chronic lymphocytic leukemia)

Hi Friends,

This week’s update on the CLL Society website http://cllsociety.org is my unscripted recordings on biologic or immunotherapies.

I start by reviewing my take on the good and bad of the well known and novel antibodies directed against our B cells by targeting its surface marker CD20. These include rituximab (Rituxan), ofatuzumab (Arzerra), and obinituzumab (Gazyva). Among other topics,  I discuss the difference between type I and type II monoclonal antibodies.

I also cover other antibodies, new and old, IMIDS (immune modulating drugs) such as lenalidomide (Revlimid) vaccines, and more.

To listen please, visit the treatment section (found under the Basics tab) of the CLL website by clicking here: http://cllsociety.org/cll-101/treatment/

Please let us know if this helps. I am particularly proud of this recording as it was done live and spontaneously with no notes. I think is ends up being more focused, ironically similar to the drugs discussed.

We plan on bringing more of this type of content. Your feedback on the website or to me by email informs what we add and how we will grow the website. Although there is only myself, my wife (both unpaid) and a wonderful RN, Betsy Dennison as the team, we listen carefully to all comments to help brings what’s needed to best manage our cancer. 

Smart patients get smart care™.

As always, all our content is free and easily accessible to anyone but if you want you may sign up for our weekly alerts to know when we post new content, 1 to 3 x a week, and for our inaugural newsletters which will be amazing. We understand the importance of privacy and don’t share any personal info.

Our website traffic has grown phenomenally in its first 10 weeks. Over a 1000 page views on our busy days. We also hope it will be a launching site for anyone with CLL as we have links to nearly all the quality sites on our front page.

The artwork in the background of the video is again my son, Will Koffman’s tribute to Durer’s Four Horsemen of the Apocalypse.  Will rendered the entire work using only bleach on black cotton.

Nothing much new to report on the personal level with my CLL. Still get tired. Still traveling way too much (over the next 2 weeks I will be in Dallas, Seattle, Las Vegas and Poland to teach and to learn) and still doing too much and getting too sleep. Really it is a bit crazy.

I am waiting on my more granular lab results from OSU. Despite my best intentions, I always worry when I am waiting for my results.

Thanks.

Stay strong.

We are all in this together.

Brian

Volunteer Medical Director, CLL Society Inc.

http://cllsociety.org

BKOFFMANMD@GMAIL.COM

This Week in CLL: (chronic lymphocytic leukemia) Chemotherapy, News of the Helios Trial, New Drug Approvals and the High Cost of Cancer Medications

The annual humongous meeting of ASCO (American Society of Clinical Oncology) 2015 in Chicago did offer those of us with CLL ( chronic lymphocytic leukemia) a few interesting abstracts and one excellent education session, but this week we wanted to share some news unrelated to ASCO on our website.

This week on the CLL Society website we are posting news and educational material that relates in one way or another to chemotherapy, alone, in combos, and in trials.

We are adding another of my treatment monologues. This time I discuss what really is chemotherapy and how does it fit into the rapidly changing treatment paradigms for CLL. Spoiler alert: The key point here is that everything is changing, very fast. You can find that link here in the treatment section of the CLL Society website.

This is a good basic primer on what chemo is and isn't. The feedback from the earlier readers has been most gratifying. Please let me know what you think.

Just to emphasize the point of change coming, on June 4, 2015 the results of the final analysis of the Phase III RESONATE-2 were released comparing ibrutinib to chlorambucil in over-65 treatment-naïve patients, excluding those patients with deletion 17p. The big news is not that ibrutinib met its primary endpoint of better progression free survival (PFS) and secondary endpoints of better overall survival (OS) and overall response rate (ORR) as we might have predicted that based on the significant difference in the usual historical efficacy of the two drugs tested in prior trials. What is important about this Phase III trial for patients is that it is an important step towards getting FDA approval of ibrutinib as frontline therapy for those of us over 65.  The official press release can be found here and my commentary will be up on the CLL Society website on Wednesday, June 10, 2015 in the news section.

Finally, we share the good news that Quebec, home to my alma mater, McGill University, and often the leader in new therapies in Canada, is the first province to approve the use of obinituzumab (O) or Gazyva in combination with that same chlorambucil (C). On June 2, 2015, there was similar approval for patients in England and Wales. These two approvals on both sides of the Atlantic were based on the trial reported in NEJM in 2014 that demonstrated the superiority of the C-O over C-R (rituximab) or C alone in frailer patients with co-morbidities. That story and links to the original research can be found in the news section on Friday, June 12, 2015.

In our ongoing emphasis to consider clinical trials when making treatment decisions, we fielded another survey to explore search functions that CLL patients would want available in a CLL-specific Clinical Trials Search Engine. We're thankful to those patients and caregivers that took the time to complete the survey at the CLL Society booth during the CLL Patient Education and Empowerment Meeting prior to the CLL Clinical Research Consortium held in San Diego, CA from April 22-23, 2015. You can view those results in the Survey Results and Clinical Trials sections of the website on Friday, also.

One last thing: If you want to share your experience about how the high cost of our cancer meds impacts your care in a way that might make a difference, please contact me to discuss how we can get the word out.

On a personal note, I am still waiting for my final lab results form OSU, so I have nothing new to share.

I don't think I can keep up the pace of 4 new posts a week, but we will try to bring you the latest news and fill in the missing gaps as best and as fast as we can.

Thanks

Stay strong

We are all in this together.

Brian Koffman

Volunteer Medical Director of the CLL Society

Blogger 

E- cancer advocate

Husband, father and grandfather

Frontline therapies In CLL (Chronic Lymphocytic Leukemia)

In this lively ONCLIVE multi-part series of polite debates among four world class CLL experts (Drs. Byrd, Furman, Ma, and Kipps), I was struck by the conservative approach of the panelists to frontline therapy.

Almost all the discussion in this 13 minute segment is about chemo-immunotherapy (CIT).

Keep on mind that except for patients with 17p deletion where ibrutinib is approved, chemo-immunotherapy is all that is approved for frontline therapy. That said, we all know that many doctors including several on this panel would discuss with their patients other frontline options besides those they discuss on camera, namely FCR (fludarabine, cyclophosphamide and rituximab) or BR (bendamustine-rituximab) or chlorambucil and obinutuzumab.

Dr. Kipps points out the potential advantages of the chlorambucil and obinutuzumab in elderly patients with a less resilient bone marrow. This relatively gentle approach has achieved a 20% complete response rate and a 26.7 month mean progession free survival, much better than the other arms in the trial that lead to its approval. For the details of the study published in the NEJM please click on this link.

Drs. Byrd and Kipps talk glowingly about the very long term benefits of FCR in a small subset of patients with the best prognostic markers: mutated with no other bad prognostic indicators. This is a subject we have visited frequently visited in the past. Here Professor Hallek and I discussed this topic in this post in the context of the role of chemo-immunotherapy (CIT) way back at iwCLL 2013. I am still waiting for the published material on that low risk subgroup that is looking more and more as if they might be CURED!

In this ONCLIVE video, there is also debate on the need to complete all the cycles of FCR to get the full benefit. I fully agree with Dr. Kipps that the evidence suggests getting to MRD (minimal residual disease) negativity is what determines our prognosis and not the number of cycles it takes to get there. I quote from a Blood editorial by Sebastian Böttcher on the original research: "current investigation suggests that the number of treatment cycles also becomes irrelevant as long as MRD negativity can be attained." 
The full text of the original research is accessible here. The authors state in the abstract that:" MRD-negative patients had comparable PFS ( progression free survival) and OS (overall survival), independent of the number of courses received or interim staging. Early MRD eradication may be a desirable goal, prompting consideration of early discontinuation of treatment."

Dr. Furman hastened to point out the potential downside of chemo-immunotherapy and also that the group that did so well is a group that should do well with any therapy.

In this article from the British Journal of Hematology, we learn: "patients treated with purine nucleoside analogues (PNA) had a significantly increased risk of subsequent second LPD (5·2%) compared with patients who had not received PNA (1·9%; P = 0·008)"  PNA are drugs such as fludarabine and LPD are lymphoid cancers.  In fact, they go to stated that the only factor found to be associated with an increased risk of a secondary lymphoma for those us with CLL was prior treatment with chemotherapy.

That certainly does give one pause.

There is also some very interesting comparison of BR versus FCR, a subject that we extensively reviewed in this prior blog post with Dr. Jeff Sharman.  I appreciate Dr. Kipps' careful analysis of the different arms of the trial to ensure that we are really comparing apples to apples.

Give a listen and please share your comments.

Again, thank you ONCLIVE for bringing us this great panel discussion.

Obinutuzumab in CLL (chronic lymphocytic leukemia): Rituximab with an Attitude

This second  OncLive video with Drs. Byrd, Furman, Kipps, and Ma was actually the first, the lead-in to my prior post. In fact the last few minutes of this video are the first few minutes of the video with the same doctors seen on my the recent post discussing ibrutinib.

Obinutuzumab is a powerful antibody directed against CD20 as is rituximab and ofatumumab but it seems to promise better responses as part of a therapeutic combination at least in some circumstances In this case when used with chlorambucil (a gentle form of chemotherapy or alkylating agent similar to cyclophosphamide, the C in FCR), it clearly delivered significantly deeper and longer responses than the other arms of the trial.

While the video session is clearly aimed at the oncology doctors, and our eyes may glaze over when there is a detailed discussion concerning the choice of the best steroid to use to abrogate the potential severe infusion reactions associated with this potent antibody, it is worthwhile to listen and catch the data on obinutuzumab.

It is nice to listen the experts for once discussing the real world concerns about cost and insurance.

It is also good to hear Dr. Kipps point out the critical role of the infusion nurses in keeping us well and safe.

Here is the results from the abstract published in the NEJM with Valentin Goede as the lead author. It is a study that randomized patients to one of three possible therapies: chlorambucil alone, or combined with either rituximab or with obinutuzumab. The trial patients were all untreated and would generally be considered to be too sick due to renal disease or other problems to risk more robust chemo-immunotherapy such as FCR.

Here is part of abstract results:

Obinutuzumab plus Chlorambucil in
Patients with CLL and Coexisting Conditions 

RESULTS

The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and CIRS score of 8 at baseline. Treatment with obinutuzumab–chlorambucil or rituximab–chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression-free survival (median progression-free survival, 26.7 months with obinutuzumab–chlorambucil vs. 11.1 months with chlorambucil alone;... and 16.3 months with rituximab–chlorambucil vs. 11.1 months with chlorambucil alone;

Please note that the impressive 10 month improvement in the mean progression free survival noted with obinutuzumab–chlorambucil compared to rituximab- chlorambucil. Comparison to chlorambucil monotherapy is not helpful as it is rarely used this way in the USA because of its known lack of efficacy.

CIRS score is a marker of the degree of co-existing illness.

It is important to remember that a benefit demonstrated with one combination is no guarantee that the antibody would demonstrate a similar benefit in any other combos. Assumptions can be dangerous in cancer care.

I am waiting for the published data that Dr. Kipps that show the results of the combination bendamustine and obinutuzumab.

Lastly, what we all really want (if we can't get a cure) is a durable remission. The mean progression free survival was a little over two years (26.7 months) for the mostly elderly treatment naive patients.

Is that enough for you?  Two years is nice respite, especially for a pretty gentle therapy used in a delicate population, but I wanted a longer time before half the group had to live with the reality of their cancer progressing again.

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.

ASCO 2014: Dr. Sharman Reviews the Results and Implication of a Single Agent Obinituzumab Poster in CLL (chronic lymphocytic leukemia)

Another audio interview from ASCO 2014, this time with the ubiquitous Dr. Jeff Sharman, who with his work heading up a large national CLL/NHL research group, has brought us several important clinical results that has advanced our understanding of treatment options and provided directions for further research.

Here he is part of a group with Dr. Joe Flynn as the lead author, studying two different doses of the  fully humanized monoclonal type II antibody directed against CD20 (same target used by rituximab and oaftumumab) known as obinituzumab, also known as (AKA) GA101and AKA Gazyva used in this trial as single agent.

The abstract shows a strong trend to a better response with the higher dose, especially as regards complete responses. This is not surprising when we know from a dose escalation trial of rituximab published in 2001 from Dr. Susan O'Brien (mentioned in the interview by Dr. Sharman), that when it comes to antibodies, more is better.

Makes sense based on what we know about how these antibodies work. There are billions of B cells and only so much antibody. When they are all "bound up", there are none left.

There is also research now looking to see if there is similar dose response relation with CAR-T therapy: the more chimeric T-cells, the better, though the story here is much more complicated as it seems CAR-T cells are serial killers.

Dr. Kipps and I also discussed this same paper and the difference between Type 1 and Type 2 antibodies here. Dr. Jennifer Brown discusses earlier research on GA101 at ASH 2013 and the different types of antibodies here. And here are the details of its FDA approval and some of my comments only published only a little more than a year ago.

And if that's not enough background, here is an editorial from Blood 2012.

What a great year it has been for those of us touched by CLL! We are all on a fast moving train and while cure is still a distant light in the tunnel, long lasting low toxicity disease control for most of us may be a whistle stop that we blown past some time without even noticing some time last year.

Here's hoping.

Enjoy the audio interview with Dr. Sharman.


Thank you for putting up with all the pops and hisses again. I promise that they will be a thing of the past once I finish uploading the audio from ASCO 2014 and move forward to ASH 2014 and beyond.

Stay tuned as we have big plans that I will be announcing here soon that will improve our options for education and support for all of us with CLL and related B cell lymphomas in the near future.

ASCO 2014: Dr. Kipps on ABT-199 and more on CLL (chronic lymphocytic leukemia): "Cancer is not an alien from outer space, cancer is us"

More mural work from my son, Ben Koffman

In this final segment of my three part interview from ASCO 2014, my doctor, Dr. Kipps out of the Moore Cancer Center at UCSD, explains as only he can about the competing roles of Bcl-2 and BIM in our malignant B cell clone and how ABT-199 resets that balance in our favor in our malignant B cells.

Here are links to part one and part two of the same interview. They will help set up and give perspective on this longer final segment.

Before you turn off when you hear mention of yet another B cell pathway, please listen to his helpful buttress explanation that explains why this therapy, especially in combinations with other agents, promises a possible cure with no cytotoxic chemotherapy with little collateral damage.

This specific cell death mechanism is particularly active in our malignant B cells. Accordingly, it makes sense as an even more potent target than is blocking B cell communication though the the B-cell receptor (BCR). Blocking BCR activity is likely a major mechanism for the outstanding success of the two newly approved targeted oral agents, idelalisib and ibrutinib. ABT-199 works differently. It works directly on the cell's life and death pathway.

As those who have read my prior post know too well, ABT-199's very potency is its weakness too. It can kill the cancer so fast there is a risk that the kidneys can't keep up with the flood of intracellular toxins spilling out of the millions and millions of lysed (broken down) cancer cells. Tragically, at least two deaths have occurred from this tumor lysis syndrome (TLS), and as a result the whole ABT-199 trial strategy was stopped and than revamped, but it's now back and better.

In other posts, I discussed one tragic death that happened in the trial and argue strongly then that its development be continued and I am so glad that has happened.

But when ABT-199 gets out of trials and into the larger community, I worry that TLS may start to reoccur if the education of the community doctors and their patients is not strong enough.

That, my friends, is one of my major goals here and elsewhere: to inform my fellow patients and providers of the changing landscape in managing CLL so we can make smart decisions and get the care we need.

But ABT-199 has gotten some patients to MRD negative status and even allowed durable disease control long after the med is stopped. That is very exciting and appears to be significantly different from the usual results seen with idelalisib and ibrutinib.

In the past I have argued of reducing the tumor burden with Imbruvica or Zydelig, perhaps with a mAB (monoclonal antibody) such as obinituzumab or rituximab, and then cleaning up any residual disease with ABT-199.

I am happy to say that is now a research direction that is being actively pursued.

It's too early to predict how ABT-199 will fit in the mix, but I predict it will play an important role in the future. The bar already has been set high with the robust responses already seen with the first two approved TKIs. It is not unreasonable to dream that the significant extra kick from ABT-199 or one of the new agents could push us to cure.

So  happy to see more research. We must keep pushing for more evolved therapies that offer cure, not just disease control. (Not that I am complaining about the recent advances that have positively changed my life and that of of so many other CLL patients.)

Later I will comment on the recently announced combination of the PD-1 immune checkpoint inhibitor nivolumab (Opdivo) and the oral BTK inhibitor ibrutinib (Imbruvica) in a phase I/II trial for patients with non-Hodgkin lymphoma (NHL). This is another promising and bold path that has me pretty excited.

But before, we move on, Dr. Kipps has more news for us patients from ASCO 2014.

In the last few minutes of the interview, Dr. Kipps takes a step back and forces us to consider a different perspective on the nature of cancer in general and CLL in particular. He reminds us of cancer's primitive embryonic nature and how ROR1, an embryonic antigen, might be a major player not just in CLL but in other metastatic cancers such as prostrate or ovary too. Thinking about cancer and CLL in this way opens us the possibility for new avenues of research and therapy. The anti-ROR1 mAB is a step in that direction.

When I saw, Dr. Michael Keating from MDACC at the AACR hematology meeting last month in Philadelphia,  he told me he is betting on ROR1 as the path to cure.

When Drs. Kipps and Keating agree, it is worth listening. And considering a ROR1 trial.

Please enjoy my interview with Dr. Kipps.



More soon. (By the way, my ASCO 2014 goatee is long gone.)

This is my crazy season of traveling and teaching, so please forgive my tardiness in posting.

I will be at the LRF conference this Saturday, Oct. 25, 2014 in Manhattan Beach, so please join me and say hello. If you have never attended a LRF conference, they are worthwhile on so many ways. Do come and learn and meet fellow patients.

We are all in this together.

ASCO 2014: Dr. Furman Gives us Perspective on Resistance with Ibrutinib in CLL (chronic lymphocytic leukemia)

More of My Son, Ben's Mural Work

ASCO 2014 was only a few months ago, but happily the CLL world is a fast moving place.

Since this video interview with Dr. Rick Furman of Weill Cornell, recorded and edited by Andrew Schorr and his team at Patient Power, idelasilib has been approved for CLL (see this post for discussion of its labeled indication) as predicted by Dr. Furman, and ibrutinib was approved for frontline therapy in 17p deleted patients (see this post).

YEAH to both!

Also in the intervening months, new mathematical models that consider evolution of resistant sub clones have been published by Dr. Burger out of MDACC and a high powered mathematical team headed by Dr. Natalia Komorova out of UCI. (I plan to interview Dr. Komorova as we are practically neighbors in Orange County, CA). Similar research, but this time using deep genetic analysis of the cancer's evolution over time by Dr. Cathy Wu from Dana Farber was presented at AACR 2014 Hematologic Malignancies Conference last week. (I also plan to post on her important research soon.)

The issue of ibrutinib resistance may be becoming an increasingly important issue. More and more of us are doing great with our BTK inhibited, but we still have residual disease and if you are similar to me with bad markers such as clonal diversity, 17p deletion, 11q deletion, and have a history of having been heavily pretreated (I have the first three for sure and many would say the 4th with my bone marrow transplant), then the fear of a resistant sub clone starting to act out, while still not the case for most of us even with the worst of the worst disease, is based on a growing reality of a droopy Kaplan-Meier (KM) Curve. Below are KM plots from OSU published in NATURE at the start of the year that show the downward drift in progression free and overall survival for those of us that are 17p deleted. As you can see the curves are way better than anything else out there, but they are hardly perfect.

This whole resistance issue might be largely obviated in the future by moving the new therapies up to frontline status. Dr. Furman and I both agree that is the direction we need to encourage with appropriate trials and struggles with insurers to pay for these drugs in all treatment naive patients.

Dr. Furman also mentions two exciting new BTK inhibitors, ACP-196 and ONO-4059. Click on the drugs' names to be linked to their phase 1 trials. We are just in the first chapters, but it is looking that the stories they will tell should have very happy endings. Please consider trials that offer these drugs among your treatment options.

Here is my ASCO 2014 interview with Dr. Rick Furman.



As there is a small but significant cohort of FCR patients that do great for years and years, there is a much much larger cohort of patients taking ibrutinib and other small molecules, now based on more than on more than four years of data, that should continue to do well year after year.

I am so happy for all these patients.

But I worry about the minority who won't do well, who will relapse. I am not giving up on my plea: Don't leave us stranded on 3rd base- Get us to the home plate of a cure with a follow up therapy.

We discuss obinutuzumab and ABT-199 as mop up therapies and I think those are smart choices. Maybe it will be cirmtuzumab, a new ROR1 mAB discussed in my recent post with Dr. Kipps from the very same meeting. We will only find out with clinical trials.

Dr. Byrd: "We are at an incredibly exciting time for patients and their families with CLL (chronic lymphocytic leukemia)" Let's all bake a cake of cure.

Cake of Cure

OK team, we have taken the first giant step in this moon shot. We've safely landed in a new world of disease control with no chemo. Now get us home.

The real work is just beginning.

We need potent combos of these new wonder drugs to help us stay in the land of remission forever, get off the daily meds, and maybe, just maybe find our decades from now that we have been cured.

We need more trials, trials that use NO chemotherapy. Trials that use drugs from different pharmaceutical companies. Abbvie links with Infinity Pharmacyclics is already working with TG Therapeutics in a clinical trial.We need more of these alliances that break down commercial barriers for the benefit of the patients.

We need brave patients to volunteer. While all of this sound so positive, let's not forget that when Gilead ran a sensible and necessary trial combining its Syk inhibitor, GS-9973 and its better known PI3k inhibitor, idelalisib or Zydelig (click here for the abstract), they concluded: "Despite promising activity in CLL, the combination of GS-9973 and Idelalisib resulted in an unexpectedly high rate of pneumonitis and resulted in stopping dosing of the combination These data need to be considered when designing future investigations combining inhibitors of B cell receptor signaling."

So we can't take anything for granted. These trials need to be carefully designed and monitored. But they are our best path to a cure.

It demands patients and providers and industry and the FDA all fighting together to "bake a cake of cure" for  CLL.

I like it.

Please enjoy this upbeat and realistic one minute video of my doctor, Dr. John Byrd out of OSU.



More soon on ROR1 including an exciting new trial,  and also on challenging paper on new mathematical modeling of ibrutinib resistance.

Good times indeed. Let's have our cake (vegan of course) and eat it.

Want to avoid chemotherapy or taking an expensive medication foreverfor your CLL (chronic lymphocytic leukemia)? I may have a clinicaltrial for you.

METHYLPREDNISOLONE

I and many others have railed against chemotherapy for our CLL. It may give us a long remission, or not.  Your mileage will vary and those of us with anything but the best prognostics can be pretty sure that we will relapse too soon for our liking with a nastier clone. FCR may even cure a few very select low risk patients, though that is yet to be proven. But at what cost?  Possible bone marrow damage and immunosuppression leading to low blood counts, infections, and secondary cancers.

Many of us also worry about the risks and cost of being on a life long medication no matter how targeted and patient friendly it might be. This fear is not so much based on any evidence of a problem (as there are not many problems and the data generally keeps getting better as the years roll along), but more based on the opposite: the lack of evidence with any of the new oral agents about their real long term safety, because no one had been on them for more than five years at this time.

So that is why this trial at UCSD with Dr. Januario Castro deserves our consideration. Besides being the innovator in the research on HDMP, Dr. Castro is a super nice guy. Still, entering any trial is a huge decision and by its very nature is full of unknowns.

A PHASE IB/II STUDY OF OBINUTUZUMAB (GA101) IN COMBINATION WITH HIGH-DOSE METHYLPREDNISOLONE (HDMP) IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS. (GA101 & HDMP)

The team of Drs. Kipps and Castro and more recently Choi has been a leader for years in innovative less toxic treatments for CLL. HDMP especially in combination with rituximab or ofatumumab has proven efficacy in all flavors of CLL including those of us with the stubborn 17p deletion. Here is link to an article on HDMP+R in frontline therapy. I quote:" With over 3 years of follow-up median progression-free survival was 30.3 months with only 39% of patients requiring additional therapy, and an overall survival was 96%." Similar results have been published here with HPMP + ofatumumab.

There are reasons to believe that this new trial may do even better. Obinutuzumab is a more potent mAb (monoclonal antibody) than its predecessors.  Remember that when it was combined with chlorambucil it proved superior to ritximab: This abstract from NEJM states: "Treatment with obinutuzumab–chlorambucil, as compared with rituximab–chlorambucil, resulted in prolongation of progression-free survival." Its 20.7% complete response rate in combination with wimpy chlorambucil is also encouraging, so it suggests that adding Gazyva to another cytotoxic agent, in this case HDMP makes good sense.


Not that either HDMP or obinutuzumab are without their risks. HDMP can cause a short term increase chance of serious infections, diabetes, fluid retention and psychiatric issues to mention but a few of the possible adverse events. Gazyva can be associated with scary infusion reactions. One definitely needs a team that has experience with this heavy weight arsenal. USCD certainly does. And the good news is that neither therapy is myelosuppressive and neither should have long term sequelae.

The rap against HDMP, justified or not, is that the remissions have not been that durable. This trial hopes to squash that story. But no one knows. That's why it's called a trial.

So are you interested?

The best news is that unlike other trials for attractive therapies where inclusion criteria may be fairly narrow, this trial welcomes nearly all comers. See below. I especially like: A. Documented refusal to be treated with chemotherapy agents.  Do you think patient advocates may have been a factor in kicking open the gate that wide? Here are some of the inclusion criteria copied from clinical trials.gov.

Laboratory parameters as specified below:

• Hematologic: Hemoglobin > 8 g/dL (may be post-transfusion); platelet count > 40 x103/mm3 (may be post-transfusion). Absolute neutrophil count > 1.0 109 cells/mm3 (Growth factor use is allowed).
• Hepatic: Total Bilirubin < 3 x ULN, and ALT and AST < 3 x ULN
• Renal: Creatinine clearance > 30 mL/min (Calculated according to institutional standards or using Cockcroft-Gault formula. Subjects with requirement of hemodialysis will be excluded).

Subjects can be enrolled and treated under this protocol regardless of their CLL treatment history or number of previous treatments. In addition, subjects with history of allogeneic stem cell transplant can be enrolled and treated unless they have active manifestations of graft vs. host disease (GVHD) or chronic illness or infections that will prevent them from completing the study.

Previously untreated subjects that meet ANY of the following criteria: A. Documented refusal to be treated with chemotherapy agents. B. Subjects that are not candidates for treatment with chemotherapy based on poor performance status (ECOG ≥ 2), advance age (> 65 years), Cumulative Illness Rating Scale (CIRS score) ≥ 6 or cytopenias.

These are extraordinarily liberal rules for eligibility for any trial.

I don't know where HDMP+OB will fit in. No-one does. That's why we need this trial. It is particularly attractive to anyone who want to avoid chemo (who doesn't), is willing to document their reluctance, and does not qualify for other non-chemo trials. But it also should appeal to any of us with 17p deletion or any of us who just want to have six months of non-chemo treatment and then hopefully coast for a long long while.

Finally to be clear, I don't have any personal connection with this trial other than my history of being a patient at UCSD. Moreover, while I believe that for some of us, it is worthy of careful review for the reasons I have detailed, the decision about entering any trial must be personal and cautiously weighed. Thankfully there are growing numbers of non-chemo and chemo options out there.

It's all a gamble: hope as I am doing to ride a TKI (ibrutinib) into the happy ever after sunset or whack the CLL hard monthly for half a year and pray that it is so far gone that it ain't ever coming back.

Sunset at Corona del Mar

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Forbes says: "With So Many Terrific New Drugs For Chronic Lymphocytic Leukemia (CLL), Why Worry?" I say it's a Tempest in A Teapot

Hydra (mythical monster that grows two heads when you cut off one)

Elaine Schattner wrote a provocative and helpful editorial in Forbes: With So Many Terrific New Drugs for Chronic Lymphocytic Leukemia, Why worry? I recommend we all read it, but that we also read it critically.

It has to do with her concerns about the dangers of unnecessary treatment.

My friend and fellow cancer advocate Andrew Schorr wisely reminds of us a friend with CLL who has done very well without treatment for nearly 18 years.

We know that about three out of every ten of us diagnosed will follow a very indolent (slow) course and never need treatment.

And so the author cautions us to avoid unneeded therapy. Good counsel. Never take a treatment that's not needed. All drugs and I mean all drugs have side effects. 

Her concern and motive for her editorial is that thousands of us will rise up demanding that our hematologists offer us the new expensive therapies just because they are so darn safe and effective when we would be better off doing nothing, just watching and waiting. Hordes of CLL patients will ignore the carefully tuned 2008 iwCLL guidelines on treatment, and demand an immediate prescription NOW before we are in troubled waters.

I believe it's a false concern. 

A powerful and practical reason that Ms. Schattner is worrying over nothing is that these expensive drug are not yet approved frontline  with the notable exception of ibrutinib in 17p deleted patients as detailed in this recent post). It is highly unlikely our medical insurance is going to pay for an off label use of a pricey therapy when there is ZERO data to support it. And of course, there are vanishingly few of us that could afford the out of pocket cost of at least several thousand dollars per month for any of the new star therapies (in order of appearance on the CLL stage): ofatumumab, obinutuzumab, ibrutinib and idelalisib. And of course, even frontline approval is not the same as approval (and insurance coverage) when there is no indication to treat.

That said, I am sure that there will be a few patients among us who will think it is the height of craziness to sit on our hands. We should strike the cancer while is still in its infancy well before it has the time to achieve its typical mature persistence and wily ways, making it such a formidable foe, making a cure still a dream for almost all of us. Kill it before it grows into a multi headed hydra.  

But a quick review of the facts should dissuade us from this tempting but false path. There is absolutely no evidence that early intervention helps. In this oft quoted article from 1988, Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation, and this one from the NEJM in the same year show we learned that there was no survival advantage to early intervention. And there are certainly risks. Studies such as these reinforces the importance of knowing the data and also knowing where there is no data.

Wait you say: Chlorambucil may have been state of the art in 1988, but today we have better therapies. Might not the results be different if we looked again using today's drugs? 

Good question. The same sort of trial was set up with FCR, but died on the vine due to lack of enrollment.

That is why trial such as this closed trial on using lenalidomide or this new one using ofatumumab are so important and need our support.

Although prognostic factors such as FISH and ZAP 70 and mutation status tell us much about a group of individuals and little about the individual members of that group, wouldn't we all want to jump out of the high risk frying pan and get far far away from the heat in the kitchen to a calm and cool place of low risk if we could do so by intervening early?

That's is exactly why we need more studies to answer if it is possible to save more lives by using the new mAbs such as ofatumumab and obinutuzumab and the new TKIs such as ibrutinib and idelalisib and others in the pipeline before we traditionally need treatment. There is good reason to believe it just might be so, but without data…. it's only conjecture.

So what do I recommend?

I believe all these drugs should be moved towards more frontline therapy for all patients with the help of well designed trials,  not just those of us with high risk prognostic factors.

I believe these drugs should be studied in those of us with high risk unstable disease BEFORE we need treatment. 

And maybe I am about to sound like a doctor when I say this: I also believe that outside of a clinical trial, there is absolutely no role for these drugs for patients who don't meet criteria for treatment.

The Forbes editorial ends with some sage advice:

“As with other malignancies, the best way to prevent overtreatment is to assure that doctors are current in their education, knowledgeable of “lesser” treatment approaches, and not motivated by financial incentives to give therapy. And for patients, the best prophylaxis is to know that not all conditions carrying a malignant label warrant treatment. Patients might ask, “What’s the least toxic therapy you can give, so that I’m likely to stay alive with the quality of life I want, with this particular form of cancer?”

That's precisely what we are trying to do here. Educate doctors and patients about low toxicity options.

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Approval of Imbruvica Frontline for 17p deleted CLL (Chronic Lymphocytic Leukemia) and Important Trials

It's old news (July 28, 2014), but worthy of some reflection that ibrutinib ( PCI-32765 or Imbruvica) was approved frontline in CLL for those of unfortunate enough to have a deletion of the short (petite or p) arm of chromosome 17.

The p53 gene lives on the 17p arm so when it's deleted, there's missing p53. Without functional p53, cancer cells don't die very easily of apoptosis, the programmed death pathway built into all cells that allows them to suicide when they get too old to function, or in the case of our leukemic cells, become increasingly aberrant and dysfunctional. Without  the tumor suppressing p53 gene, the "guardian of the genome", protecting and repairing our DNA and if that fails, then starting to fire up the self destruction pathway, our cancer continues to grow and mutate and get weirder and more aggressive and difficult to treat.

Most chemotherapy works with the help of p53, first damaging the DNA itself, but then needing the p53 to take it from there by recognizing the overwhelming damage and then persuading the injured cell to die. No p53, and we get just the  chemo induced DNA damage, but the cell can live on and even reproduce faulty clones of itself. That is one reason 17p deletion carries such a bad prognosis.

Until we had ibrutinib (and now also idelalisib or Zydelig), our choices for treating 17p deleted CLL were poor- There were and are a few other therapies that do their killing independent of p53 induced cell suicide. Campath works if you don't have any big nodes, but comes with high infection risks. HDMP (high dose methylprednisolone) + R (rituximab) and flavoperidol and even lenalidomide helped some.

No great choices, until now.

I quote from the press release about the trial that lead to the ibrutinib approval:

At baseline, the median age of these patients was 67 years, 58% of whom had at least one tumor  >  5 cm, and 32% of whom had the del 17p mutation. Patients receiving IMBRUVICA demonstrated a statistically significant improvement in progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) as compared to patients treated with ofatumumab. The median PFS and OS has not been reached on the IMBRUVICA arm. There was a 78% statistically significant reduction in the risk of progression or death as assessed by an independent review committee (IRC) according to the modified IWCLL criteria (HR 0.22, 95% CI, 0.15 to 0.32). In addition, the analysis of overall survival demonstrated a 57% statistically significant reduction in the risk of death for patients in the IMBRUVICA arm (HR 0.43; 95 CI, 0.24 to 0.79). This was observed despite a total of 57 patients who were initially randomized to ofatumumab crossing over to receive IMBRUVICA prior to the analysis. For previously treated del 17p CLL patients, there was a 75% reduction in the risk of progression or death as assessed by an IRC (HR 0.25, 95% CI, 0.14 to 0.45).

Ibrutinib seems to do well on all the folks like me with a missing 17p chromosome on our FISH test, and probably even better for the treatment naive 17p deleted patient. Here is another abstract from the NIH on the subject.

This is good news, right now for just those 17p deletion frontline, but I hope it is only the beginning.

I believe these drugs and others in the pipeline need to be available to all appropriate treatment naive patients, not just those with 17p deletion.

It shouldn't be that most of us have to fail chemo first before being offered less toxic options. The ibrutinib data from the earliest trials suggest those who get ibrutinib upfront before any chemo do the best.

That is why there are some really important clinical trials out there to consider for those who will soon be needing their first treatment for their CLL. Here are a few of my favorites.

With ibrutinib or Imbruvica:

Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia

Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

With idelalisib or Zydelig or CAL101: 

A Study of Idelalisib (GS1101, CAL101) + Ofatumumab in Previously Untreated CLL/SLL

A Study of Idelalisib and Rituximab in Elderly Patients With Untreated CLL or SLL

Efficacy and Safety of Idelalisib in Combination With Rituximab in Patients With Previously Untreated Chronic Lymphocytic Leukemia With 17p Deletion (Havasu)

Efficacy and Safety of Idelalisib in Combination With Bendamustine and Rituximab in Subjects With Previously Untreated Chronic Lymphocytic Leukemia

With ABT-199 or GDC-0199:

A Study of GDC-0199 (ABT-199) in Combination With Obinutuzumab in Patients With Chronic Lymphocytic Leukemia

This is by no means a complete list. There are at least 222 trials when you search untreated CLL on Clinicaltrials.gov.

These trials are critical so we can finally prove, as I suspect, that moving these drugs upfront and avoiding chemo all together, is our best course for a long and healthy life.

There are a few other exciting early trials using ROR1 for relapsed disease that Dr. Kipps will be discussing in my next post, an interview from ASCO. ROR1 may prove to be the holy grail of a marker that is truly unique to the CLL cells, making it the perfect target for an anti-cancer drug.

UC-961 (Cirmtuzumab) in Relapsed or Refractory Chronic Lymphocytic Leukemia

This is with a very exciting and very specific antibody developed by Dr. Kipps' team at UCSD. It should be opening very soon.

Autologous ROR1R-CAR-T Cells for Chronic Lymphocytic Leukemia (CLL)

This is from Dr. Wierda's team at MDACC and CLL Global Alliance, building on the promising work out of U. Penn with CART-T cells directed at the much less specific CD19.

Both these are phase 1 trials with all the risks and possible breakthroughs that come with being early to a new therapy. My ibrutinib trial, though later in development, was still a phase 1/2 trial.

There are growing choices out there for those of us facing therapy for the first time, and for those who have relapsed. 

Clinical trials are the only way our knowledge can grow, and the only way these drugs will ever become widely available.

And clinical trials are for many of us, especially in frontline settings, the only path to getting these new agents. 

Speaking of new drugs being available, July 28 was also the date that the FDA gave final approval for Ibrutinib for those who have received one prior therapy. The accelerated conditional approval six months ago had been based on phase 2 data, the final approval looked at the big phase 3 RESONATE trial data.

More from Dr. Kipps on ROR1 soon from our interview at ASCO 2014.

ASCO 2014: Dr. Kipps Discusses Targeted Therapy and Obinutuzumab in the Treatment of CLL (chronic lymphocytic leukemia)

In the first brief section of my video interview from ASCO 2014, Dr. Tom Kipps, my personal doctor at UCSD, and mentions the buzz about ibrutinib (IMBRUVICA) at the meeting and then moves on to discuss obinutuzumab (GAZYVA) the new and exciting monoclonal antibody (mAb). He adds to what we learned from Dr. Byrd in this prior post from ASH 2013 and shares his subtly different take on how this powerful new addition to our CLL arsenal works.

My hunch is that it will prove to be much bigger step forward from rituximab (R) than was ofatumumab  (ARZERRA). That much anticipated next generation CD 20 mAb has disappointingly made at best some small incremental improvement for us CLL patients compared to the giant leap that we witnessed just a few years ago when the mother of all CD 20 antibodies, R was added to FC to give us the present "gold standard" of FCR. Ofatumumab does offer a possible helpful option for those of us who can not tolerate R.

Obinutuzumab is clearly proving to be a better antibody. As I covered in this more detailed post and interview from ASH 2013 with Dr. Brown, GAZYA is the first antibody that showed a clear survival advantage over rituximab albeit in combination with chlorambucil.

At ASCO 2014, we learned more. This abstract shows us that as a single agent in untreated patients, obinutuzumab had impressive response rates and even some complete remissions. This almost never happens with the other older CD 20 antibodies. I am pretty excited about all these results.

We already know that adding an antibody to almost any chemo agent makes that chemotherapy work better and explains why chemo-immunotherapy has become the backbone of the present treatment protocols in CLL/SLL and other lymphomas.

What we don't know yet is how this concept of adding a mAb will evolve in the coming era of oral therapies with small molecules such as ibrutinib and idelalisib and later on ABT-199. More on this in future posts.

Here is the first part of my interview with Dr. Kipps.

Listen to the lovely way that he describes how the different type antibodies works.



More to come soon on ROR-1.