Dr, Bill Wierda on the Importance of Clinical Trials in CLL

I’m home from the European Hematology Association Congress in Copenhagen. 

I received very positive feedback on my lecture and the preliminary data from our Reader Poll with many requests for more information. We plan to follow up with another survey, Seems the 1000 plus hematologists to whom I presented the data and the folks from industry really want to know what we patients think and want.

I attended several lectures on CLL, reviewed dozens of abstracts, and had some great interviews with world experts that I look forward to sharing with you in the near future. 

After the last long day, I finally got out of the convention center long enough to walk along the harbor and see the famous The Little Mermaid statue.

This week in the Clinical Trials/The Basics section of our website we’ve posted an interview with Dr. Bill Wierda of MDACC where we talked about the value of clinical trials and how he approaches the discussion with patients about joining a clinical trial. You can read a summary of our discussion and watch my interview with Dr. Wierda here. http://cllsociety.org/2016/06/dr-william-wierda-clinical-trials-cll-chronic-lymphocytic-leukemia/

In the meantime….

Stay strong.

We are all in this together.

Brian Koffman, MD

Volunteer Medical Director of the CLL Society

http://cllsociety.org

New Immune clinical trials and an explanation of cellular immunity in CLL ( chronic lymphocytic leukemia)

Friends, On the CLL Society website, we share two interesting articles: 1. An interview with Dr. John Gribben whom I interviewed at the CRC (CLL Research Consortium) Scientific Meeting in San Diego in April 2015. We discussed his approach to cellular immunity and T cell function in CLL. Please take a look here to see the interview. 2. A patient-friendly summary of three new Immune Antibody clinical trials from MD Anderson Cancer Center. These investigator-initiated trials are exploring how activation of the immune system may lead to killing of CLL cells. You can read more about these interesting trials here. This Fall has been incredibly busy so far, between traveling to Australia for the iwCLL meeting and an Australian patient support meeting, publishing our first issue of The CLL Tribune, and traveling to Brooklyn for the North American Educational Forum on Lymphoma hosted by the  Lymphoma Research Foundation. Now we're preparing to go to the American Society of Hematology Annual Meeting in Orlando, FL and putting together the next issue of The CLL Tribune, due out after ASH. If you haven't had a chance to peruse the first issue, you can access it here. If you have questions you like addressed in future newsletters, OR would be willing to answer 5 questions in our Reader Poll about the CLL Society website, OR would be interested in writing an article for future newsletters, please go to the Ask & Tell section. Our goal is to fulfill the unmet needs of the CLL community, so we always welcome your feedback and questions. SAVE THE DATE: If you live in the Los Angeles area, please consider attendinga post-ASH patient education forum and CLL Society LA support group launch in conjunction with City of Hope scheduled for Saturday, Dec. 12, 2015. A flyer with more details will be posted in the next week or 2. Finally, if you are reading this on blog and haven't already, please sign up here. Also, please forward this email to a fellow patient or caregiver who might benefit from knowing more about CLL. Another reason to make sure all the folks that might be helped sign on is that we will be posting a backlog of great lectures and interviews and articles on CLL over the next few months leading up to ASH and this alert is your best friend in knowing what new material we have posted. Stay strong. We are all this together Brian Koffman Volunteer Medical Director of the CLL Society http://cllsociety.org

Dr. Byrd on trial design and getting drugs to market for CLL ( chronic lymphocytic leukemia)

This week on the CLL Society website, we share an interview with my trial doctor, Dr. John Byrd out of Ohio State University, discussing how CLL drugs get to market and what the implications are for patients in terms of clinical trial design, especially in phase 1 trials for chronic lymphocytic leukemia.

We met at the CRC (CLL Research Consortium) Scientific Meeting in San Diego in April 2015. The CLL Society also co-sponsored a patent forum the day before the science meeting began.

There are several take-aways from my interview, however one that is critical is that we be well-informed, not just about the drugs we might be taking, but also of the details of the clinical trial design itself.

Please take a look at cllsociety.org/2015/09/crc-... to see the interview and important related links.

The CLL Society’s inaugural newsletter will be emailed out midweek and we are really excited about it: Dr. Byrd is has written a long Q+A on ibrutinib; Dr. Jennifer Brown gives practical advice on idelalisib; I cover the basics of just what is CLL/SLL and more in a monolog and transcription; plus several patients including WWW have written diverse and helpful articles. If you are interested, please sign up at cllsociety.org/newsletter-s... .

Another reason to sign up is that we will posting a backlog of great lectures and interviews and articles on CLL from CRC and my time at iwCLL over the next few months leading up to ASH and getting the alert is your best friend in knowing what new material we have posted. As always all our content is free and doesn’t demand any of of your information to be seen.

Save the date: We are planning a post-ASH patient education forum and CLL Society LA support group launch in conjunction with City of Hope on Dec. 12, 2015. More details to follow.

Exciting times, but us patients still have to keep encouraging on the researchers. We aren’t to cure yet. We need to keep pushing.

Stay strong.

We are all in this together.

Brian

Phase 1 Trials and My Advice on How to Survive and Be Your Own Best Advocate with CLL (chronic lymphocytic leukemia)

 Friends,

This week we have published helpful information from two patients on the CLL Society website.

The first is a thoughtful well-referenced editorial by Cynthia Havstad on the personal value of enrolling in a Phase 1 trial

Cynthia recently enrolled in a trial of a novel antibody directed against ROR1. This promising and very specific target is the culmination of decades of works by Dr. Kipps and his team at UCSD. For the background on why therapies directed against ROR1 are so exciting and details the trial, click here to watch my interview with Dr. Kipps. The link to the actual trial is found here.

To read Cynthia's helpful own story about her experience in considering a trial so early in a new drug's development and her actual experience please click here.

Without researchers such as Dr. Kipps and brave and smart patients such as Cynthia, we would not be making the amazing progress that we are in treating CLL.

The second patient we present this week is yours truly sharing my full 24 minute video from the CRC 2015 conference. My topic was pretty fundamental: Being our Own Advocate and Staying Alive with CLL (chronic lymphocytic leukemia).

It's a dense presentation.

First I briefly share my own 10-year history with CLL.

Self advocacy's risk (yes there are risks) and benefits are outlined.

Next I catalogue my advice in term of my personal three steps for mindful survival.

1. PREPARE
2. ACT 
3. BE AWARE

I tried to keep my counsel very practical and even a little fun, sharing my survival tips learned over my 10 years of struggles with an aggressive brand of CLL.

Some of these are broad overarching principles of dealing with a catastrophic illness, and some are very focused suggestions on getting the most out of a doctor's visit or a phone call with our insurance.

They include:

• Put together your team (this is number one)
• Become or find an expert.
• Think laterally.
• You always have time to make a decision, but you don't have forever.
• Risk is impossible to eliminate.
• You have to make decisions with imperfect and contradictory advice.

Lots more but it would be best if you can set aside 24 minutes and perhaps have a pad and paper handy.

The link to my video lecture is here. 

Enjoy.

Please, please, please if you have your own survival and advocacy tips, share them with us at the CLL Society Community using http://cllsociety.org/contact-us/

We welcome your feedback.

As always, all our content is free with no requirement to sign in, but if you want to receive alerts about what's new so you don't miss any important fresh content, please sign up at http://cllsociety.org/newsletter-sign-up/

Thanks

Stay strong

We are all in this together.

Brian Koffman

Volunteer Medical Director of the CLL Society

ESH 2014: The Future Role of FCR and new data on venetoclax and rituximab in CLL (chronic lymphocytic leukemia) and my latest lab results

I thought I sneak in one last post from LAX before I board my plane to Wroclaw, Poland via Munich.

It is mostly about the new posts on the CLL Society's website and our nonprofit's news, but I wanted to share that my latest lab results from my visit to the infusion center for IVIG remains most boring with a low normal hemoglobin, a high normal platelet count and an absolute lymphocyte count of 1.2.  YEAH! Of course that really matters is the count of clonal B cells and that takes flow cytometry, but at least I know that nothing major is happening. Slow and steady makes me happy.

This week on the CLL Society website we bring the second part of our interview with Professor Michael Hallek of Koln, Germany, the director of the German CLL Study Group and a major CLL researcher and thinker.

He starts by discussing his “fast boat” adaptive trial strategy (similar in many ways to that of Prof. Hillmen in the UK), essentially looking for the most tailored therapy based on not just predictive factors, but also on how we patients actually respond in trials. He is looking for what I call that perfect Goldilocks’ mix of “ as much as necessary, as little as possible” therapy.

In the second half of the interview, he makes a cogent argument for the ongoing use of FCR frontline in select patients. While many of us are not fans of chemo-immunotherapy (CIT), Professor Hallek has strong data to support his perspective. Listen with an open mind.

Please give a look here in our section on conference coverage from 2014.

We also share my comments and background on an important oral abstract presented at the 20^th Congress of the European Hematology Association (EHA), June 11-15, 2015 on venetoclax (ABT-199 or GDC-199) and rituximab. In relapsed patients, the total response rate, the complete response rate, the MRD- rate and the ability for some to be able to remain disease free after stopping the drug is important data that you can find here in our 2015 conference coverage section.

We have a significant backlog of important educational material mostly from large conferences such as ASH 2014 and others from 2015 that we plan to post over the next few months.

In a first step to speed up the process, our first high school intern volunteer, the granddaughter of the CLL Society's attorney, has joined us online to help her earn her community service hours by helping us catalog all the videos that we have produced and are storing on the web.

We are working hard to expand what we offer to the tens of thousands of online readers and to actuate our ambitious plans for patient-centric, physician-curated live education and support. One volunteer medical director (yours truly), his unpaid wife and one part-time RN can’t do it all, although I have to say we have made some amazing progress in our mission to meet the unmet needs of the CLL community in the less than 90 days since our nonprofit’s website launched. Our website is #1 in organic Google searches for CLL Society despite having no search engine optimization in place. We are too busy trying to get our content up.

There is so much more we must do. Your suggestions, help, support, donations, ideas, and feedback are what guide us and keep us going.

We remain forever committed to open content for all with no need to sign in or share any of your personal information to see a video or to get the help you need. If you haven’t done so already, we encourage you to please sign up to receive alerts regarding new postings and for our quarterly newsletters (first one will be published in September) and to share with other patients, caregivers or concerned family or anyone whose life is touched by CLL.

The CLL Society will be at iwCLL in Australia in September to cover the news and we are planning an amazing patient meeting the day before the researchers' meeting in Sydney with Lymphoma Australia. 

Stay strong.

We are all in this together.

Brian Koffman

Volunteer Medical Director, CLL Society

ASH 2014: Professor Hillmen Discusses the Trials Acceleration Program for CLL (Chronic lymphocytic leukemia)

In this week's new postings on the CLL Society website on Monday, Wednesday, and Friday (May 11th,13th, and 15th), Professor Peter Hillmen from Leeds, England outlines the sorry state of traditional trial design and the problems it creates, or more accurately the problems that it doesn't solve, for us CLL patients. Professor Hillmen heads up CLL research in the United Kingdom.

There are so many new CLL drugs and so many more possible combinations that need to be explored. And that can take a long, long time. Sadly, too long for some of us.

But Dr. Hillmen offers a practical, agile solution that is now happening in the United Kingdom.

During the three-part interview, Professor Hillmen outlines a consolidated strategy called TAP (Trials Acceleration Programme) to get us the answers we need more quickly. Trial design, surrogate markers and how well they translate with novel therapies, and statistics are explained during the course of our interview done in December 2014 at the ASH (American Society of Hematology) Annual Meeting in San Francisco.

I understand if your eyes begin to glaze over when we start to discuss trial design and statistics, but just as it is important that we know about the drugs we are getting, it is equally important that we know about trials we are getting. Proper trial design and proper rendering of the results can change and save lives.

But I will let Professor Hillmen explain it here in a direct link. His excitement and pride are palpable. Please check the CL Society website again on Wednesday and Friday for the 2nd and third parts of our interview.

As we have discussed extensively in the issue of equipoise and crossovers, trial designs must reflect the needs of the patients.

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.

                                           

ASCO 2014: Dr. Byrd: Ibrutinib in the Real World of CLL (chronic lymphocytic leukemia)

In this short second half of my interview from the final minutes of ASCO 2014, Dr. Byrd, my clinical trial doctor at OSU, discusses some of the potential  pitfalls in receiving ibrutinib outside of a trial from a provider who perhaps has little or no experience with the drug.

That is one of the reasons I push so hard that we patients be well informed and engaged so we can be be sure we are getting the best possible care.

It is also a push to strongly consider a second opinion, especially when we are considering therapy  with a doctor where the bulk of the practice and research is devoted to the care of CLL patients.

Ibrutinib and some similar other targeted oral medications (kinase inhibitors) are quite safe and easy to use, but do have some unusual characteristic effects.  For example it is common to experience a rapid climb in the lymphocyte count at the start of therapy. You and your doctor need to appreciate that it is not dangerous or a sign of progression or even really an adverse event. It is just a redistribution of the lymphocytes from the nodes to the blood whether there are more vulnerable and more likely to die.

Again, please pardon the pops and hisses in my part of the audio during the interview.

I have several great videos on tap from Greece (ESH International Conference on New Concepts in B Cell Malignancies: From molecular pathogenesis to personalized treatment) but they are embargoed until after ASH.

And of course, I will be attending ASH 2014 next week with my one man video production team to bring the latest news, commentaries, and explanations.

I go as as doctor, a patient, a reporter and I hope as your advocate. It can get pretty crazy: a scheduling nightmare and long demanding days.

On a personal note, my labs remain stable even though I have been off cyclosporin for my auto-immune platelet issues (ITP) for almost two months. The one fly in the ointment is that my white count and absolute neutrophils are a bit high. That usually means an infections, but I feel well. Could be just stress and lack of sleep. It's happened before and returned to normal, never leaving a clues as to why it bumped it. With CLL, I have learned to accept that things just happen and I may never know why.

Here is Dr. Byrd.



Happy Thanksgiving.

ASCO 2014: Dr. Farooqui on Trials at the NIH, ABT-199, and Issues of Long Term Oral Therapies in Chronic Lymphocytic Leukemia (CLL)

In my last video interview from ASCO 2014 (several audio only interviews to come), with help from my friends at Patient Power, I interviewed Dr. Mohammed Farooqui from the NIH on the research and trials ongoing at the NIH, his enthusiasm about ABT-199 and the questions he and others are researching on longterm use of the novel oral meds.

Do keep in mind that all trials at the NIH in Bethesda are all free, with or without insurance. They even help with your airfare and hotel, and they are open to any one in or out of the USA.

The natural history trial on CLL is still actively recruiting and deserves our support. The care one will get at the NIH will be world class. A win-win situation.



It is not surprising to hear the honest response about getting adequate accrual in a chemo-immunotherapy trial is more difficult these days. I have heard similar concerns from other researchers. Now that ibrutinib and idelalisib are approved and available outside of trials, many of us are no longer considering clinical trials, especially where there is a computer randomly deciding whether we get the drug of our choice. Even trials offering an option of free ibrutinib and idelalisib are enrolling more slowly.

Dr. Farooqui also shares my excitement about ABT-199. Complete responses (CR), let alone minimal residual disease (MRD) negative responses, are rare with the two approved (though that may be changing as Dr Burger has some research showing CR and MRD negative responses with ibrutinib and mAb therapy- more on this important data point later), but CR and MRD- do occur in combination trials with ABT-199. 

I keep trying to get an answer to my question that is so pertinent for me and many others: what does it mean to walk around with residual disease (or not). There is still no answer and it will only be revealed with more time and more research. Dr. Farooqui does nicely lay out the possibilities.

Soon I will be posting some great audio only interviews from ASCO 2014 with Drs. O'Brien, Byrd, and Sharman. Next month I will be reporting from both ASH 2014 and early next week from the International Conference on New Concepts in B Cell Malignancies: From molecular pathogenesis to personalized treatment but this is your last chance to see me with a goatee on camera.

I have not been home for more than a few days at a time in over a month. After next week, I will have been at six medical conference, in two continents, in 6 different cities, lecturing on five different topics from alternative medicine to gout to CLL. ASH in San Francisco, a short vacation in Yosemite and maybe a quick turn-around trip to London to speak on CLL are on tap before the years' end.

This crazy schedule needs to stop.

And it will.

My plan and commitment to you is that in the very near future my focus will narrow from teaching about a variety of medical topics to only focusing on my passion to spread the news about CLL and related B cell lymphomas. I have big plans and I will need your help and support to make them come true. More to follow soon.  (There is a hint of the exciting news to come in the interview).

ASCO 2014: Dr. Kipps Discusses ROR1 and Information about a New ROR1 Monoclonal Antibody (cirmtuzumab) Trial in Relapsed and Refractory CLL (chronic lymphocytic leukemia)

Mural Detail by my son Benjamin Koffman

I am just back from a very exciting AACR (American Association for Cancer Research) Hematologic Malignancies Conference that was focused on pre-clinical research pointing the way to better therapies in the future for CLL and all blood cancers.

I will be sharing some of the most promising and clinically relevant research from that meeting in Philadelphia over the next several weeks, but first I wanted to post this timely video from ASCO earlier this year with Dr. Tom Kipps out of UCSD as there is now a chance to see how a new promising therapy using cirmtuzumab, an antibody directed at RORI will work in the real world, converting years and years of research into the first in human clinical trial.

If you haven't seen the lead up to our discussion on this brand new and very specific mAb (monoclonal antibody) targeting ROR1, then please revisit this prior post to catch the first part of our interview done in collaboration with my friend Andrew Schorr and his Patient Power team.

Remember that Dr. Kipps is a cutting edge researcher in the field of immunology and this is an immune  therapy. At the AACR meeting in Philadelphia, when I asked the father of FCR, Dr. Michael Keating out of MDACC how I might cure my own CLL, he quickly said ROR1 therapy (both MDACC and UCSD are working on CAR-T directed at ROR1- See this post with Dr. Wierda from back at ASH 2012). For many blood and cancers in general, the path to a cure means inviting an immune therapy onto the team and ROR1 is a very promising and specific target in CLL.

For more background on ROR1 by Dr. Kipps, see this, also from ASH 2012. It's a ton of long and hard bench science to bring these therapies to the bedside. Dr. Kipps has been excited about this for years and it is finally coming to fruition.

I will let Dr. Kipps tell the update of the story.



I love his push for a cure and I love his pneumonia analogy.

Now the trial for relapsed and refractory CLL patients opened recently, not too much later than the hoped for June start date mentioned at ASCO and this new ROR1 antibody, cirmtuzumab is already being used. A few patients have begun the experimental therapy, and though it is way too early to know much of value, so far so good.

Here's the link at clinical trials.gov and here is a news article on the trial.

What I like about this trial that it is an immune therapy with the promise of very little off target damage. I also like that it is so time limited- you get the 4 infusions over 8 weeks are you are done.

The downside risk. This is a Phase 1 first in human trial. Nuff said!

The dose escalation is also a potential turn off in Phase 1 trials as they are always about safety first. The hope is to find the highest dose that is not toxic called the dose limiting toxicity or DTL.

We know from our experience with the tragedies with too rapid a dose escalation with ABT-199 resulting in fatal tumor lysis syndrome (TLS) that slow and easy is the only way to go. Please see this and this and sadly this if you are not familiar with this tragic and instructive story.

The negative consequence of this emphasis on safety is the risk that those in the first few cohort may get too low or a sub-therapeutic dose.

That's why I like that this trial design. I quote from the trial site: "There is intra-patient dose escalation in the first 3 cohorts, followed by the standard 3+3 design for the next 5 cohorts."

What that means is those in the first three groups get a low dose and if they experience no problems a higher and higher dose. After that the dose is fixed for each three patient cohort.

The whole topic of Phase 1 trial design to minimize risk and maximize benefit is complicated and I am no expert, so I welcome comments from those more savvy. This is a link to a nice review article that will help if you want to dig a bit deeper.

Safety comes first and only then is drug efficacy studied more formally in later trials, but that doesn't mean there can be no measurable benefits from this kind of trial. My ibrutinib trial is sort of a phase 1 trial (1b/2) and I see no reason not to expect that this study with reveal positive results and that cirmtuzumab will eventually become an important new weapon in our arsenal to fight CLL.

For relapsed and refractory patients, admission criteria are pretty standard and there is no mention of prior transplant excluding admission to the trial.

ROR1 has been a long long time in coming.

Is it the future? It looks promising and safe in the lab and animal models, but only the clinical trials will tell us for sure.

As I have said before, the science only advances when one of patients facing a tough therapeutic decision decides that joining a clinical trial makes more sense for a host of potential reasons than standard of care. I did and it turned out to be a good bet.

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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