Three Year Anniversary on Ibrutinib for my CLL (chronic lymphocytic leukemia)

A Man and his Pills

On May 7, 2012, I swallowed my first three battleship grey pills of PCI-32765, later to be known as ibrutinib and finally Imbruvica when approved by the FDA for relapsed/refractory CLL in February, 2014. For us early adapters, most of whom like me, are still doing well in the subsequent extension trial, it is still the same grey pill and it is still called PCI-32765.

Clinical Trial NCT01217749 or PCYC-1109-CA out of Ohio State University (OSU) was a phase 1b/2 trial mixing the then very new BTK inhibitor with the then newest antibody, ofatumumab. I was in the last of three cohort. My group received the monoclonal antibody first so I actually started the trial a few months before I got to the ibrutinib. Details are described here.

Turns out that my cohort did the poorest as a bunch. Better to use the oral signal blocker first or even simultaneously to empty most of the cancer cells out of the marrow and nodes where the antibody can pick them off with no interference from their microenvironment enablers. That's why we do trials: do figure this stuff out.

But statistics predict for groups and here I am three years later in a deep deep remission. My absolute lymph count is at the low end of normal at 1000 and only 0.8% of those cells are clonal. If we do the math with just a few calculations we figure out that I only have 8 cancer cells in each microliter of blood. That not bad for someone who has a complex karyotype, 17p and 11q deletions, ZAP 70+, unmutated, CD38+, and a failed transplant.

Excellent disease control and a very deep remission, but not MRD negative. And certainly not cured.

For that elusive cure, I and most CLL patients will need a cocktail, preferably of target therapies. Fortunately some researchers agree and such trials are opening up.

During these last three years my blog has morphed from talking about my ups and downs in managing my CLL into a more universal story about the changing research and treatment paradigms in our disease.

Our newly launched nonprofit's CLL Society website: http://cllsociety.org will increasingly be taking on that educational role and my blog will return to being more my personal journey and the place for me to vent and pontificate.

Just this week, our website has several new articles: an article on the WHO statement on clinical trials, the news about the breakthrough therapy designation for ABT-199 or venetoclax for my fellow 17p deleted patients, and two cool interviews with Professor Roberts from Melbourne, part of our conference coverage,  which were done at ASH 2014. Dr. Roberts talks about the mechanism of action of and the early result with venetoclax or ABT-199, a drug that he helped develop in Australia.

Every Monday, Wednesday, and Friday we will be adding new videos and articles, so check back frequently. Already on some days, the one month old http://cllsociety.org is helping more folks affected by CLL than this venerable blog.

I have been asked by pessimists and worriers: How long and deep will the CLL Society's efforts at education, support, news, and advocacy continue? 

The answer is: As long as there is the need and the support for what we are doing, we will keep going.

Realistically, we desperately need to staff up in order to keep going at this pace and to expand what we are already doing. We have big plans that demand more than any one or two people can do, but we are just starting up and I am confident we will soon have the resources we need.

Stay strong.

We are all in this together.

Brian

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. 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. 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.

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.

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.

Zydelig: The Black Box Warnings for use in CLL (Chronic Lymphocytic Leukemia), SLL (Small Lymphocytic Lymphoma), and Follicular Lymphoma

Before you get very far into the Zydelig (CAL 101 or GS 1101 or idelasilib) label,  you come across a big bold black box warning.

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL PERFORATION

See full prescribing information for complete boxed warning.

• Fatal and/or serious hepatotoxicity occurred in 14% of Zydelig- treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig. (5.1)
• Fatal and/or serious and severe diarrhea or colitis occurred in 14% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig. (5.2)
• Fatal and serious pneumonitis can occur in Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig. (5.3)
• Fatal and serious intestinal perforation can occur in Zydelig- treated patients across clinical trials. Discontinue Zydelig if intestinal perforation is suspected. (5.4) 
  
  
  

That kind of warning should and does give most patients and doctors pause before proceeding. And that's a good thing. But we also need some perspective.

While black box warnings are the strongest language that the FDA can put on a label, it is focused on the worst of the worst and not necessarily on common problems.

Our old friend, the rather gentle giant in the CLL world, rituximab has multiple black box warnings (as it should):

From the Rituxan label:

WARNING: FATAL INFUSION REACTIONS, SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
See full prescribing information for complete boxed warning.

•   Fatal infusion reactions within 24 hours of Rituxan infusion; approximately 80% of fatal reactions occurred with first infusion. Monitor patients and discontinue Rituxan infusion for severe reactions (5.1).
  
•   Severe mucocutaneous reactions, some with fatal outcomes (5.2).
  
•   Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death (5.3).
  
•   Progressive multifocal leukoencephalopathy (PML) resulting in death (5.4).

Each one of those problems can kill us (PML has a 90% mortality rate, worse than Ebola) and if it doesn't cause our demise, leave us badly shaken and permanently damaged. But those concerns are thankfully relatively rare and it hasn't stop me or many others from enjoying the real benefits of rituximab.

Black boxes are found on many labels. Even common antidepressant medications come with a black box warning for the rare but obviously critically important issue of increased risk of suicide in those patients younger than 24.

For Zydelig, the serious liver issues and severe diarrhea and colitis occurred in one out of every seven patients in their trials. Not so rare. Colitis is miserable and can be fatal. Fortunately, the other, generally more life threatening, adverse events are less common.

Gilead have instituted a FDA mandated REMS (Risk Evaluation and Mitigation Strategy) program. Using this link and further links found on that webpage, you can see how serious the FDA and Gilead are about staying ahead of these potential problems for us patients.

They are being proactive. The fine print in the package insert gives strict guidelines on monitoring and what do based on what the patient's conditions and the lab test are telling the doctor. And most problems can be reversed if the patient and clinician are on their game and respond quickly and appropriately when there's a signal of an emerging problem. After a period off the drug, many of us can safely restart it at a reduced dose and continue to do get the benefits.

This is yet another reason to be choosy about who is managing your CLL. Please pick a doctor who is experienced with CLL and with the new medications so that he or she is on top of all the good and all the possible bad associated with them.

CLL is itself risky. Doing nothing is not an option for many of us.

FCR is no cakewalk. BR is not much better. Lenalidomide comes with a host of its own unique nasty issues.

But all of these drugs and and other drug combinations have saved lives. We can not afford to be therapeutic nihilists because we have no guaranteed safe choices.

Carefully read the label. Ask your doctor. Insist on the correct monitoring. Report any and all problems promptly.

Odds are heavily in our favor. Have perspective.

One place I do see as an advantage for idelalisib at this time is that there it has no warning on the label about bleeding in association with anticoagulants as there is with ibrutinib. By the way, Imbruvica has no black box warnings. The bleeding issues with Imbruvica are being studied more as they are not presently fully understood. Time will tell, but there is reason to believe that most of the bleeding/bruising problems may be simply increased bruising that is more a cosmetic than a health issue. Still, at this time, Zydelig has no such caution and Imbruvica does.

As I said in my last post, we are so lucky to have this choice of two new potent oral medicines that are targeted at our cancer.

To borrow from my dear friend and patient advocate, WWW: May our paths be well chosen.

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.

ASH 2013: Dr. Byrd on the New Data on Ibrutinib and Obinutuzumab in CLL (chronic lymphocytic leukemia)

In my final post from the last days of ASH 2013 (lots more to come from ASCO 2014), my doctor, Dr. John Byrd out of Ohio State (OSU) in the third part of our interview discusses the durability of the positive results with ibrutinib and the latest results with obinutuzumab. Here is the referenced ibrutinib trial. For the first part of my interview with Dr. Byrd, click here and for part two here. They are worth reviewing as we covered many of the novel up and coming therapies beyond the usual headline grabbers of ibrutinib and obinutuzumab that are the focus of this last segment of the interview.

Dr. Byrd reminds us that it is the usual suspects are the few unlucky ones who do relapse on ibrutinib, mostly those of us who have been heavily pretreated and/or are 17p deleted.

What is the happy surprise is that the side effects seem to get less common the longer we take Imbruvica and there is a hint (see this NIH research by Dr. Farooqui whom I subsequently interviewed at ASCO 2014), that our immunity improves. Certainly the number of infections diminishes over time.

Dr. Byrd also answers my questions on the exciting monoclonal antibody obinutuzumab (Gazyva) and the new study results presented at ASH.

There are many reasons to be excited about this antibody. Despite the fact that the trial was rigged by choosing the wimpy chlorambucil as its sparing partner, Gazyva is the first therapy when used with chlorambucil to show a survival advantage in the difficult to treat mostly elderly patents who have other medical problems (co-morbidities) such as kidney disease that may take many therapies off the table. This trial  is offering hope where there is a pressing need.

We get into some of the details of how the drug is different from other antibodies. Dr. Byrd discusses how its engineering was specifically directed to make it different and probably better than rituximab. We also discuss its potentially nasty and quick infusion reaction and why that may not be such a bad thing.

Enjoy Dr. Byrd.

Personal Update on my CLL (Chronic Lymphocytic Leukemia): The Good News

It's been a while since I posted on my personal medical news.

Today in Columbus, it was all good. CBC was happily and boringly normal. My Hgb still shows that I am no longer anemic. My ALC (lymphocytes) is 1.4 which is actually a bit high for me, but certainly a comforting level.

My ANC (neutrophils) was healthy. My platelets are a bit higher than normal again, but that is to be expected due my splenectomy. The spleen gleans the aging and decrepit platelets, so counts are higher when it's missing. I will take high platelets any day over the terrors of single digit counts when my ITP was raging. By the way, the accepted wisdom is that the high platelets associated with a splenectomy do not increase the risk of a blood clot, but ironically ITP which ravages the platelets does. You can both hemorrhage and thrombose with the same disease. Seems inflammation is the enemy. I refer you to the 19th century wisdom of Virchow's triad, a trusted nugget carried in the brain of all medical students. 

More on this particular topic soon with some personal revelations, but that is for another post.

My blood chemistries show my liver and kidneys are happy and healthy. The advantages of a vegan lifestyle.

Dr. Byrd would not agree to skipping my next CT scan in three months. The very few late relapses on ibrutinib that he has seen after 24 months (my two year anniversary of living with the TKI magic of ibrutinib aboard will be at 9:30 AM EST on May 7, 2014) are often subtle and begin in the nodes. With my pesky abdominal nodes, that does seem prudent despite my aversion to more diagnostic "radiation therapy". Getting the scan at the newer CT at OSU's Martha Morehouse may cut the rads by as much 60%.

Most relapses occur between 12 and 24 months, so my period of higher risk is thankfully coming to an end. 

Still my clonal instability and my small subclone of 17p deleted cells keeps me forever on alert.

What we really need is a trial for the many patients such as myself that are doing very well on ibrutinib, but are not in a complete remission (CR). How about adding in a PI3K inhibitor such as idelalisib or one of the newer ones following in its footsteps. Hit the cancer clone on two pathways at once. A pincer move. A classic chemotherapy technique, but instead on chemo, we box off the cancer with focused therapies. Next add a potent third generation monoclonal antibody (mAb) such as obinutuzumab once the rascally clonal B cells have been released from the nodes and marrow out into the open spaces of the blood stream where they are easy picking for the antibody. Finally, we add something to mess with Bcl-2, say ABT-199. All this done in a carefully orchestrated and timed dance to maximize efficacy and dodge tumor lysis (TLS) by adding the ABT-199 as the final coup de grâce to make sure the beast will never rise again, but also when the tumor load is low so the risk of TLS is mitigated.

You can't get to cure without first passing by CR and MRD (minimal residual disease) negative.

For me, this is not a theoretical discussion. This is my blood and marrow and proliferative centers in my node that are at stake.

The same applies to many others that are in similar circumstances with ibrutinib and other TKIs.

It may even make long term financial sense in that it may also be a way to limit the duration of therapy with this initial treatment intensification, but with a predicted end of treatment baked into the plan.

I don't want to wait until it's too late so I am hoping such a trial may come to pass, speedily, in my time.  

These and similar concepts are beginning to percolate out there.

What do you think?

I am wondering about bouncing such a plan off the powers that could make it happen. Right now it is a small population that would qualify for such a trial, but our numbers are growing fast.

Please give me your feedback.

"You may say I'm a dreamer, but I am not the only one."

More news, personal and general soon.

I wish a meaningful Passover to all my Jewish friends. May we all leave our personal Pharaohs behind and cross dry shod into the promised land.

Ibrutinib (Imbruvica) is Approved for CLL

No matter who we are or where we are in our lives with CLL, today is a great day.

Ibrutinib was approved as mono-therapy for CLL patients who have had at least one prior therapy.

That is a very broad indication and that's good.

What that means is that the majority of us who might benefit from ibrutinib because we need treatment for CLL for a second time can now get it outside of a clinical trial.

The obvious folks left out with this present indication are those with high risk treatment naive CLL such as those with 17p deletion who need front line therapy now.

Will it be used off label?

It already is. Patients have been getting it for CLL already before this approval.

Will it be used in combinations with chemo and mAbs (monoclonal antibodies)?

I am sure it will be. Lots of trials addressing this.

Will it be used up front for those with 17p deletion.

I sure hope so. These too has been and is being studied.

There are several stage three trials ongoing to address all these issues and more. This accelerated approval is just the first step, but it is a giant step. I am sure the indications and labeling will change and broaden as more data is collected and we learn more. The FDA is very conservative and not very speculative.

But from today forward, those of us in the USA facing the need for therapy for our CLL, ibrutinib has just become a real possibility, and probably a near certainty if we had at least one prior therapy. That is a pretty low bar to jump over.

And at least for those of us not on Medicare, the support to help patients afford the medication from Pharmacyclics is strong.

For those of us already in ibrutinib trials (especially continuation trials such as the one I am in), I am not sure what this will mean. Will our bodies and our blood still be wanted? Time will tell and I suspect some but not all trials will be terminated.

For those outside the USA, this is a positive step, but hardly a guarantee that Imbruvica will soon be a pharmacy near you. Politics and budgets are different in every country, and that is why we need active and informed patients and providers to advocate for our best choices

Still this is a day to celebrate. Time for victory dance.

Here is the official press release from Pharmacyclics.

Dosing of Ibrutinib and Other Oral Agents

"Poison is in everything, and no thing is without poison. The dosage makes it either a poison or a remedy."

PARACELSUS

Recently there has been some discussions among those of us who hang out at online at CLL forums such as ACOR and CLLSLL Yahoo Groups about the dosing of ibrutinib.

I am a strong believer in the power of these online communities to help us cope with our disease.

The problem inherent in peer to peer counsel is not the inaccuracy of the advice given as that also sadly too often occur in professional to patient counsel. The problem is more the lack of authority afforded any particular response. That said, if respect is earned, several regular contributors have earned my respect with their well reasoned and researched frequent comments online.

Often, especially with cutting edge therapies, the patient community is better informed about their rare disorder than the community healthcare professional who must handle the full spectrum of illness his or her chosen specialty demands.

For more on this subject see this article in BMJ  provocatively titled: What happens when patients know more than their doctors? Experiences of health interactions after diabetes patient education: a qualitative patient-led study

Case in point: Dosing of ibrutinib.

The only approved dose for ibrutinib is four tablets a day for mantle cell lymphoma (MCL), which by the way is usually a nastier disease than CLL. The Imbruvica dosing is right on the package insert.

So the community oncologist dutifully looks up what the dose to use for CLL, and finding no FDA sanctioned guidance, recommends using the MCL dose. After all,  the somewhat arbitrary dose of rituximab is the same across a wide spectrum of illness.  Arbitrary because, according to legend, the original dosing was based upon how much rituximab was available, divided by how many trial patients needed it. That worked out to be 375/M² and the rest is history.

The circumstances are less arbitrary with ibrutinib. We know that ibrutinib works by irreversibly blocking BTK through covalent binding to cysteine-481. We know that the sweet spot for getting that site fully saturated is somewhere between two and three 140 mg. capsules a day.

Moreover we know that mutation of cysteine-481binding site is an important cause of late resistance. Ibrutinib no longer fits, and the BTK pathway, and thus BCR signaling continues unabated. Not a good thing.

One sure way to increase the odds of that sinister development is to start with a low dose of ibrutinib that only partially blocks the site, but allows a significant population of lymphocytes to continue to express BTK. That is the last thing we want in cancer therapy. What we want is a SHOCK AND AWE approach to cancer. We don't want the cancer cells retreating, regrouping, and later coming back to get us by probing our weak points.

Worse yet, the up and coming second generation BTK inhibitors also seem to bind at the exact same site, so if we become resistant to oneBTK inhibitor, we may be resistant to them all. A strong incentive to get the full dosing the right from the start.

So when a doctor suggests slowly going from one to two to three or more capsules a day, it is OK for a patient to say: Can we please get a second opinion from someone with more experience with the particular drug? (Of course, there is always the possibility of the individual's extenuating circumstances that we just don't know).

Some drugs for good reasons such as allopurinol in gout needs very slow upward titration to prevent increased painful flares, but ibrutinib and most of the other TKIs should almost never be dosed that way.

Bottom line: The standard dose for CLL is three 140 mg. capsules once a day, for MCL four 140 mg. capsules once a day. Sometimes those doses can be adjusted due to adverse events or hepatic disease or concomitant medications that effect its clearance (more on that topic, specifically on the CYP3A4 pathway in another post). Short of end stage renal disease or dialysis where there is no data to go by, no dose adjustments are needed as less than 1% of the drug is excreted unchanged by the kidneys.

The right dose is more than important, it is mission critical.

iwCLL 2013: Dr. Michael Hallek Discusses Clinical Trials in Germany versus the USA and BR versus FCR

Happy New Year.

I am in Alameda, enjoying babysitting my 7 month old and 2 1/2 year old granddaughters. Needless to say, finding a second to get any work done is tough, but the joy of being with them makes my inefficiency a small price to pay.

Today, I am returning to share additional relevant interviews from iwCLL a few months ago.

In the first part of my interview on September 11, the last day of iwCLL 2013, Professor Hallek first discusses some of the differences in clinical trials on either side of the pond.

One subject Prof. Hallek does not mention is the greater willingness of European patients to be randomized in a trial. Canadians and Americans prefer more control in deciding their therapy, and that helps explain the generally lower accrual in North American studies that have two or more randomized arms. I admit that one reason I was drawn to my trial, the official title being,  An Open-label, Phase 1b/2, Safety and Efficacy Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, and Ofatumumab in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Prolymphocytic Leukemia, was that I was assured that I would be getting PCI-32765, AKA, ibrutinib, AKA, Imbruvica. Phase 3 trials rarely offer that certainty, unless there is a cross-over and that is a big ongoing issue.

Keep in mind that the  calculus of accrual is entirely different when we are looking at the new non-chemo agents, where trials offering some of the exciting new drugs have filled at record rates.

Also don't miss the professor's definition of young.

I like it.

Next, Prof. Hallek, presages with great accuracy what was going to be announced a few months later  in at an abstract presented in New Orleans at ASH 2013, namely that BR is gentler on the marrow, but less effective than FCR. His take on what to do with that data is the real gem in our conversation. Listen to how he describes tailoring of the therapy to the individual patient.

Dr. Jeff Sharman whose interviews have and will continue to pop up here, has a nice review of the ASH data on his excellent blog.

Here is Professor Hallek, who was very busy chairing iwCLL, so I very much appreciate his time.  Sadly when my flight to New Orleans was canceled, I had to also cancel my follow-up interview at ASH, but we get the full story here and from the abstract.

Many, myself included, wonder if the whole question of BR versus FCR is moot as the era of chemo-immunotherapy may be ending in CLL. We have spent many blog posts discussing this issue, and we aren't finished yet.

Here is Professor Hallek:



More soon.

iwCLL 2013: Dr. Jeff Sharman Discusses Two Issues: 17p deletion and Residual Disease in CLL

In Part 6 of my iwCLL 2013 interview with Dr. Sharman who has a lot of experience with several of the promising new CLL agents, we look at some more unknowns.

He reminds us about how thin and immature the data is when looking at 17p deleted patients treated with either idelalisib or ibrutinib, but, and it is a big but, how encouraging it is compare to the historical data. In other word, how much much better it is than standard therapy such as FCR.

Another take away message is when we are comparing studies, make certain we are comparing apples to apples. Results with treatment naive patients will be much better than that with a group of patients who had been a round the block a few times.

And sometimes the enemy of good is better. His advice is sound and I echo it. Most of these new drugs are a great leap forward in CLL therapy. At least for now when not one of the new oral meds is yet approved for CLL, don't be too picky about which one you can get. Do your homework, follow the literature (or my blog and other reliable online sources), check clinicaltrials.gov, and make the jump if appropriate.

Dr. Sharman also raises the question implicit in the observation that those treated earlier, before we are badly beaten up by chemo-immunotherapy or by the disease itself, do much better. Should we treat with these new agents earlier?  Only more trials will tell.

And he has an interesting historical take on the issue of the residual disease.

Here I might respectfully differ with the doctor. These drugs work so differently than traditional chemo or even monoclonal antibodies, that we may need to radically rethink our assumptions about what residual disease means in terms of prognosis.

I personally hope so. My next CT will be 21 months after I first swallowed a bruton tyrosine kinase inhibitor named at that time PCI-32765, soon better known as ibrutinib or now as Imbruvica. My nodes have changed little in the last few CT scans with gut nodes hanging around 4 centimeters, so the risks associated with residual disease are not a theoretical problem for yours truly. I may have reached my "maximum response", but maybe that is not such a bad thing. Again, only long term follow up with inform us.

Here is Dr. Sharman. Please see his other videos if you haven't already. Lots of good stuff in this segment.



Part 7 soon, and more interviews to come.

On a personal note, thank you all for your kind thoughts and prayers as I battle this nasty respiratory infection.

I think I have hit bottom, and am clearly getting better, albeit slowly with levaquin 500, a broad spectrum antibiotic, aboard. I am hardly well, but I am no longer getting worse. My fear of pneumonia is fading.

It's All Too Much: The Loss of a CLL Friend and the Approval of Ibrutinib for Mantle Cell Lymphoma

The world of CLL is unrelenting and demanding.

I tried to step away for a few days, but news, good and bad, swirled into the center of my vision, and if that didn't get my attention, it then whacked me off my seat with its wild and blunt force.

Like my six month old granddaughter saying with her fusses and her smiles, PAY ATTENTION TO ME, CLL craves to be the center of the universe.

We lost another CLL warrior today. A member of our Orange County support group, Susie Vercruse passed from complications from a stroke. This was not likely a direct CLL issue, as even with counts of a million or more lymphocytes, we don't get the dangerous hyperviscosity (the blood gets too thick) seen in other blood cancers than can lead to blood clots, but that doesn't ease the pain. I will miss her easy smile and friendly positive ways. Very sad.

And yesterday we gain a new warrior in our CLL battles. Well sorta. 

Ibrutinib or should I say now say Imbruvica was approved for relapsed and refractory mantle cell lymphoma (MCL).

This is very good news. It was as a friend in Houston said: a clean approval: No black box warnings concerning use with blood thinners (an early concern in some trials). 

The label says:

Five percent of patients with MCL had Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily.

The mechanism for the bleeding events is not well understood.
Consider the benefit-risk of ibrutinib in patients requiring antiplatelet or anticoagulant therapies.
Consider the benefit-risk of withholding ibrutinib for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding 

Importantly patients only have had to fail one prior drug before they can have access to Imbruvica (get used to that name). Often new and expensive treatments are held in reserve only for those who have failed all other therapies, not just one.

Also there are no restrictions as far as I can see on how it used, alone or in combination, unlike the more limited recent approval of obinutuzumab.

MCL is much rarer than CLL, less than 3,000 cases a year in the USA, and is generally a much nastier and faster moving cancer than most CLL, with until very recently, fewer good treatment options.

Both obinutuzumab and ibrutinib could benefit a ton of patient of patients "off label", which is an ethical and legal way that many cancer and other drugs are often used.

Of course, cost will be a big issue. At an estimated more than $90 a pill for Imbruvica, the annual price tag for those of us with CLL would be just a tad under $100,000 a year. It is a full third higher in MCL as they take four 140 mg tablets daily. To their great credit, I have read that Pharmacyclics will be offering some medication free to help patients while the insurance is being worked out and will offer co-pay support for others longer term.

These days, this is the typical cost of many new cancer drugs, and is actually lower than some. Some orphan drugs used to treat very rare disorders can cost $200,000 to $400,000 a year, making ibrutinib look like a bargain.

Still 99% of us will not able to pay for that, and insurance will likely balk or in the best case scenario, take a good arm wrestle to consent to lay out that kind of cash.

We need to hope from a very broad approval for Imbruvica for CLL, speedily to minimize these issue.

It is a brave new world we are entering, and there are no easy answers. Drugs are very very expensive to get to market and for every single chemical that succeeds in making it to market, scores and scores never make it to the pharmacy. 

We can't afford it and we can't afford not to do it. 

I will post more helpful interviews real soon from iwCLL 2013 (I promise), but as John Lennon said: Life is what happens to you, while you are busy making other plans.