iwCLL 2013: Dr. John Byrd Discusses the Role of Novel Therapies versus Standard Chemo-Immunotherapy

In the first part of my interview from iwCLL 2013 in Cologne, Germany, my doctor for my ibrutinib trial out of Ohio State (OSU) gives us his take on two of the pressing questions facing us patients.

First, what is the going forward role of chemo-immunotherapy?

Remember that FRC offers those with specific favorable markers a 60% chance of a greater than a nine years MRD negative survival. That is beginning to smell like a cure, but at what price?

Based on his experience with over 400 ibruitinb patients, listen to Dr. Byrd's take. He calls upon the experience with imatinib (Gleevec) in CML to illustrate his point. Not every agrees with Dr. Byrd, but I do.

Next I ask about the vexing issue of residual disease with these new agents. Dr. Byrd is not worried. Hear his reasoning.



On a personal note, I am off to a very frantic ASH meeting tomorrow. Expect on the fly updates.

Still sick and miserable, but I am not I will recover.  Coughing less with a normal chest and sinus x-rays More of a head cold now. I also have been hampered by a cracked computer screen and broken eyeglasses, but the show must go on.

More News on Ibrutinib

The New England Journal of Medicine (NEJM) is arguably the most prestigious medical journal in the world. It is not easy to get your research into its pages and when you do, it is usually because you have moved the needle of medical science in an important way.

My daughter, when she was eleven years old, had a letter published in its pages that was picked up in the national news.

Check out  http://www.nejm.org/doi/full/10.1056/NEJM199204163261612

Dad has been published in CMAJ (Canadian Medical Assoc. Journal) and AFP (American Family Physician), but never in the NEJM.

The article on the ibrutinib where my doctor at OSU, Dr. John Byrd, is the lead author is considered groundbreaking news.

But for those of us who are living and breathing CLL everyday, this is hardly anything new.

However the rest of the world and the rest of the medical community doesn't think that much about CLL.

That is of course until it shows up in the NEJM.

Once it did, CNN and Time and Dr. Gupta were all over this CLL breakthrough.

Those of us who regularly read the updates here on my blog or in the CLLSLL Yahoo group or ACOR or at PatientPower long knew the broad outlines of this "breaking story".

But now it is vetted. Now we have the details. Now it is peer reviewed.

Now it is out in the world.

And it is pretty amazing. Please note that these great responses are independent of the usual bad risk factors.

This is an unprecedented improvement in the response rate for us who are the most difficult to treat CLL patients.

There was also an extremely important ibrutinib article on Mantle Cell Lymphoma and a thoughtful editorial on these changes in the same journal.

More on all this content and other news soon.

I have a presentation to give at UCSD to their local CLL support group on July 3 (Please join me at the Commons on the second floor of the Moore Cancer Center at 4 PM if you are interested), and then I am done with travel until my next trip to Columbus in mid July.

What that means is some free time to read, write, and edit the videos from ASCO to post here.

Here is the NEJM abstract on monotherapy. Exciting times. Enjoy.

Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia 

John C. Byrd, M.D., Richard R. Furman, M.D., Steven E. Coutre, M.D., Ian W. Flinn, M.D., Ph.D., Jan A. Burger, M.D., Ph.D., Kristie A. Blum, M.D., Barbara Grant, M.D., Jeff P. Sharman, M.D., Morton Coleman, M.D., William G. Wierda, M.D., Ph.D., Jeffrey A. Jones, M.D., M.P.H., Weiqiang Zhao, M.D., Ph.D., Nyla A. Heerema, Ph.D., Amy J. Johnson, Ph.D., Juthamas Sukbuntherng, Ph.D., Betty Y. Chang, Ph.D., Fong Clow, Sc.D., Eric Hedrick, M.D., Joseph J. Buggy, Ph.D., Danelle F. James, M.D.,
and Susan O’Brien, M.D. 

Background
The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton’s tyrosine kinase (BTK), an essential component of B-cell–receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells.
Methods
We conducted a phase 1b–2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg.
Results
Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%.
Conclusions
Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.)
n engl j med nejm.org 

Moving Sideways

Usually boring is the best way to be. No bumps in the road. No drama.

I saw Dr. Kipps last week and with his deeply delving fingers he was able to unearth some cervical nodes that no-one, not even the owner of this body, has ever felt.

But they were all small, less that one by one centimeter and maybe smaller than 90 days ago. When they are that size it is hard to tell if there's been any change.

My counts were still good. The neutrophils were back to normal after the jump up from my burst of methylprednisolone for the fluid behind my right eardrum. My platelets were over 400,000 and my Hgb was 13.8. All good stuff.

The CLL is still there but it is behaving itself. It's pretty stable, moving sideways at worst and more likely improving at a glacial pace.

The only trouble on the horizon is that my right ear is clogged up again. Seems that the steroid fix was only temporary so my family doctor suggested a trial of Afrin. It only helped a little and I needed to stop to avoid the rebound swelling that happens with extended use, so it's time to consult an ENT. I am less worried about it, as it is not progressive, easy to knock back, and mostly just annoying. Still time to check it out and make sure there is no structural problem. He may want to put a ventilation tube in, so I better get my surfing in first.

I am down to one infusion a month of IVIG here, and one more blood draw at OSU. That's more good news as my veins are pretty battered after so many years despite all my efforts to protect them.

Let me give you a sense of some of what I see happening in CLL just with people I know.

In this week alone, I learned that a friend, Chris Dwyer of CLL Canada has developed Richter's Transformation. Heard from another long time CLLer with both AIHA and ITP. After having curative surgery for lung cancer, some else is fighting to get back in the NIH ibrutinib trial which helped her knock back her CLL big time. I had dinner and a wonderful visit with a pal from the east coast who is doing great post transplant at MDACC for both CLL and MDS. Another long time local friend is considering the phase three trial of ibrutinib versus ofatumumab for his relapsed CLL. I said go for it. Talked with a young Asian woman who was diagnosed in her twenties. And this is supposed to be a disease of old white men. And I connected with two CLL widows. Not fair. It's not fair, any of this.

Sometimes the CLL is the least of our problems.

I am back in Ohio in a week. Let me know if you will there too.

L'Shana Tova to all my Jewish friends. May it be a year of peace and good health, May this be the year we see a cure to all cancers.

As for myself, at this time of self reflection and self improvement, I plan to double down of getting the word out about CLL to patients and providers alike.

I will be lecturing on CLL in Las Vegas next month to about 400 family doctors, and hope to be reporting from ASH again in Atlanta next December. But I have much bigger plans, Stay tuned

But first I need to visit my granddaughter.

And for something a big more upbeat than CLL, I am growing my own organic tea. We have two beautiful camellia sinensis, variety sinensis bushes each about two feet high. Tried my first cup. Picked a few leaves that had fallen off or been injured in transit, let them wilt in the shade for a hour, steamed them for a minute, dehydrated them at low heat, and then brewed the crispy leaves at 175 º for exactly 75 seconds. A rich smooth flavor, a lovely golden color, an almost silky taste in my cup. I am in heaven. Why didn't I try this before? I will need to let them get much bigger before I can harvest enough to meet my "habit" and must avoid for now picking the new tender growth that makes the best tea, but it's a good start.

It's always good to be starting something new.

A Personal Story of CLL and Secondary Cancer

Lynn is one of those fighting and beating two cancers, both CLL and a secondary lung cancer.

She has kindly permitted me to show how she has been coached by this double whammy.

She speaks to the advantages of the frequent CT scans and also give valuable information about her relatively benign experience of coming off the ibrutinib, also very helpful and encouraging.

Hi Brian,

Of course I follow your posts on various sites as well as your blog.  I think you saw that my end of 2nd cycle CT scan showed me with a right upper lobe and bronchus mass of 2.5 cm.  Biopsy revealed it was a cancer so I went off Ibrutinib and a great NIH surgeon, Dr. David Schrump, removed the upper right lobe and all of the tumor .. clean margins and nothing in the nodes removed, thus allowing me to avoid chemo.

During the first conscious sedation broncoscopy attempt to get a biopsy, the pulmonary doc couldn't get enough cells because of the easy bruising.  I mention this because I had lots of unexplained bruising while on Ibrutinib.  The second fully sedated biopsy didn't have the same bleeding issue and I had been off Ibrutinib for three days when that occurred.

I am VERY grateful I had the CT scan as part of my protocol.  My baseline showed nothing, and it was done in March while this tumor was present in July.  I think the tumor was perking just before I came to NIH and went on the protocol as I had a strange bronchitis with blood and then soon on the Ibrutinub I had lots of coughing with excessive bleeding.  Did the Ibrutinib allow it to bloom faster?  Who knows.  In a way, I'm glad it did so that it could be excised and considered a Stage I non-small cell adenomacarcinoma.  My surgeon said my tumor grew faster than would be expected for that type.

So .. I hope people won't throw out their CT scans.  I'm now a big believer and booster and hope that all should be aware of how important it is to find these secondary cancers.

I'm hopeful to eventually get back on Ibrutinib, one way or another.  It did wonders for me .. I started at 342k wbc and when I went off the drug, was around 114K and my counts kept going down, even after stopping taking it. In two cycles, my CLL marrow went from 80% to 50%. After my surgery and 12 hospital nights (got pneumothorax and had to return to the OR for pleuradesis) the WBC bottomed out at 13k with Hgb at 6.6 so got first ever transfusion of two units.  Now all climbing except for the neuts so have had several neupogen shots and hope tomorrow's CBC will show me out of neutropenic-ville.  Anyway, I'm sharing all this with you as I think it's important that you as both a patient and a thoughtful doctor hear from those of us on the "fringes" of these studies.  I don't think enough has been tracked of those who had to stop taking Ibrutinib and my story certainly is not one of rapidly increasing counts or nodes.  I'll keep you in my loop and love being in yours.

All the best,
Lynn

Here is my response:

Hi Lynn,

Thanks you again for reaching out, staying in touch, and sharing your story.

I am so glad your lung cancer was caught early. In most cancers the paradigm is a quick and aggressive pre-emptive strike, so unlike the hard-to-wrap-your-head-around paradigm for CLL where biding time is the prevailing wisdom .

In my post on secondary cancers, I pointed out that one possible reason for the high prevalence of secondary cancers in CLL is our greater surveillance. Not only CTs, but mammos, PAPs. colonoscopy, PSAs and skin exams find cancers earlier and more often.

Your neutropenia surprises me. That has not been a recurrent issue with ibrutinib or with lung cancer for the matter.

Also your WBC continuing to drop after treatment stopped is not what I have heard from others. Usually what I have heard is that the nodes bounce back up again, sometimes within days, but I haven't heard much about the counts so appreciate your good news.

I would like to share your email on my blog as I believe others would benefit from your experience and counsel.

Would it be OK for me to post your email on my blog?

Thanks and be well.

We are all in this together.

Brian

My last reply suggested that she push hard to restart the ibrutinib as she needed no chemo and has had curative surgery. In effect, she is back to square one dealing with a single cancer.

I am sorry for what she has had to endure, but thankful for her willingness to share her instructive, cautionary, and ultimately upbeat story.

Finally, her idea of sharing the experiences of those that needed to stop their ibrutinib or GS-1101 is brilliant and should be explored. Patients and hematologists alike will need to know and be prepared for what they might expect when the drugs are discontinued. My guess is that the longer that you are on them and the lower the disease burden, the less the rebound. We are just starting to look at these issues in CML with imatinib and the early results are encouraging.

Honestly, for right now I am just so happy to have something that works so well and is so free of side effects, that I don't plan to worry about how to stop for a long long time.

It's Always Something: Secondary Cancer Risk with CLL and CT scans

CLL is bad enough, but about half of us will get a secondary cancer and when we get them our overall survival is inferior. Skin cancers occur to more than one in three and a whopping 16.5% of us must deal with a melanoma.

Here is the gut of an abstract from ASCO this year:

546 CLL patients were included in the study. Median age was 62.5 years. 84 (43%) were Stage 0 and 62 (32%) were Stage 1 RAI at diagnosis indicating earlier disease. 266 (49%) patients had a second or secondary malignancy. A total of 304 cancers were identified. 14% of patients had more than one malignancy. Melanoma was identified in 44 (16.5%) patients and non-melanoma skin cancer was identified in 54 (20%). Lung cancer was identified as the most frequent solid tumor malignancy with 36 (13.5%) cases, followed by prostate (35), breast (21), colorectal (15), and bladder (14). 10 patients had a Richter’s transformation of their CLL. 26 patients developed either myelodysplastic syndrome or acute myelogenous leukemia. Conclusions: Second malignancies are frequent in CLL patients. Immunosupression, increased UV light exposure, longer life expectancy in low risk CLL, and tertiary cancer center referral bias are likely reasons for these increased rates.


And here's the conclusion of the one on how aggressive those secondary cancers can be:

Conclusions: Several common cancers, including breast, colon, and lung, have inferior overall and cancer-specific survival when there is coexistent CLL. 


And our risk is high even when compared to other B-cell cancers such as follicular lymphoma (FL)


Here's part of a Canadian abstract:


CLL patients had a 1.8-fold higher relative risk of a 2nd cancer (95% CI 1.29-2.41) compared to FL patients. SIR (Standardized Incidence Ratio) was 1.9 when non-melanoma skin cancers were excluded. Patients with FL had a similar incidence of second malignancies, as did patients with other invasive cancers. The most common second cancer among CLL patients was non-melanoma skin cancer, followed by cancers of the digestive organs, prostate, breast and lung. Malignancy was the leading cause of death in CLL patients. In patients with a 2nd cancer, cancers of the digestive organs, lung and brain were the most common causes of death. However, in patients without a 2nd cancer, CLL was the primary cause of death. After cancer, cardiovascular complications and infections were the most common causes of death in CLL patients.

And:

We demonstrated that CLL patients have a significantly increased risk of developing a 2nd cancer compared to FL patients, and this increase was similar in both genders and in all age groups. Thus, the poor relative survival of older men with CLL cannot be explained by an increased incidence of 2nd cancers. The increased incidence of malignancy in CLL may be related to the immune suppression in this disease or to an inherited predisposition to cancer.  

Five dear friends have had their CLL complicated by a secondary cancer is the last few months, two lung cancers, one breast, one prostrate, and one possibly renal.  Two are in ibrutinib trials and one is post transplant. Andrew Schorr, a well respected CLL patient and reporter has shared that he has developed MDS. I lost a friend a few years back to AML. And there are so many more.


Secondary cancers usually quickly vault into being the primary concern often demanding urgent therapy as the Canadian article notes. They are, after all, the leading cause of death in CLL.

I don't share this to depress you. I tell you because we are immune suppressed, many of us are on treatments that further compromise the ability of our immune systems to search and destroy potential and early cancers. A few of us must get EPO and other "growth" factors that might accelerate cancer growth. There is one possible positive. We often get more testing (see below re CT scans) that may facilitate finding new cancers sooner and more often.


And remember: we got CLL in the first place, which suggests at least a predisposition to one cancer. Maybe more?


So get your check-ups. See the dermatologist at least annually. Get our annoying choice of gender and age specific cancer screening tests: PAPs, mammos, PSAs, colonoscopies. We are not at normal risk. We are not the people at whom the recent relaxed recommendations for PSA screening were directed. We need to be more vigilant.


Next lab draw I get a PSA and I have a derm appointment scheduled. Colon is fine, thank you. It better be with all the fibrous veggies that I eat.


My news today from my ibrutinib/ofatumumab trial at OSU?  


Palpable nodes are slowly but surely getting smaller. Blood chemistries are completely normal including liver and kidney function and uric acid and LDH. ALC (absolute lymphocyte count) is down to a very normal 2.3, eosinophils are back to normal, platelets are just fine for someone with a history of ITP and single digit counts in the past at  a lofty 348,000, Hgb is almost normal at 13.0, reversing its prior slow downward drift. All good, very good.


So after four plus hours of my ofatumumab infusion, I will be leaving with my three bottles of ibrutinib. YEAH!


The trial protocol may be changing. Nothing is certain until there are written changes to the protocol approved by the independent IRB (Institutional Review Board) that is set up to safe guard us "subjects" from unethical or dangerous therapies.  


First the good news: After next month's and my last ofatumumab infusion, I probably only need to be here every 60 days. That makes perfect sense. 


Now the bad news which unfortunately is pertinent to today's topic of new cancers. I may no longer be able to opt out of the excessive CTs scan, every 60 - 90 days. Why do we need such frequent exposure to a proven cancer promoting procedure that is of questionable value in patients with CLL, already at higher risk for secondary malignancies? 


From the New England Journal of Medicine:


These considerations suggest that the estimated risks associated with CT are not hypothetical — that is, they are not based on models or major extrapolations in dose. Rather, they are based directly on measured excess radiation-related cancer rates among adults and children who in the past were exposed to the same range of organ doses as those delivered during CT studies. 


It is not that bad. The same journal does point out that the risk, while not insignificant, does dramatically decrease with age. Another advantage of being older; I am not likely to live the many decades it takes to get the secondary cancer. Dr. Rick Furman points out the data from that same article that states: " One article published (NEJM 2007;357:2277-2284) suggested that the increase risk for developing a cancer during their lifetime for a 40 year old was 0.02% from a single CT scan. Thus, it would take 50 scans to increase one's risk by 1% if they were 40 years old."


I don't want to overreact, but there is no safe minimum amount of radiation.  The radiation exposure from each set of three CT scans ordered here are roughly equivalent to 12 years of background radiation. Do I really need four or six a year? And it is reasonable to assume that the negative synergy of having CLL and a lot of ionizing radiation might make the risks higher for us.


As for the role and value in CLL, from an article that Dr. Bryd co-authored in JCO:
VOLUME 25 􏰆 NUMBER 35 􏰆 DECEMBER 10 2007.



"Current NCI-WG CLL response criteria are a significant predictor of PFS in previously treated CLL patients, with no additional benefit from the inclusion of CT scans."


But there are other ways to look at the issue.


Also from JCO earlier in 2007:
VOLUME 25 􏰆 NUMBER 12 􏰆 APRIL 20 2007

"In this series, an abnormal abdominal CT was a strong predictor of progression in patients with early-stage CLL. The inclusion of CT scans in the initial work-up of patients with early clinical stage on clinical grounds can, therefore, provide relevant clinical information. "

But those of us in this trial are much more similar to the previously treated patients in the first of those two study from JCO.

Finally, again from Dr. Byrd referring to the demands to include CTs in clinical trials in an ASH publication in March 2011:

"The current requirement for CT scans remains problematic to interpreting new study results, as essentially all prior CLL clinical trials did not include CT scans. More importantly, these imaging tests add significant cost and potential morbidity to the very special patients who volunteer to be part of clinical trials exploring new treatment approaches. Reconsideration of the CT requirement in the setting of implementing detailed lymph node and spleen physical exams might offer an opportunity to match our new clinical trial approaches to methods best supported by evidence-based tumor assessment."

I know I am in a trial. It is to get important potentially life saving information, but as Dr. Byrd says so eloquently, trials are for patients, not the other way around.


If push comes to shove, and the imaging is a must to do to in order to receive my meds, then the choice is simple: it is a small risk for a big gain.


Moreover, if it helps get the drug approved sooner, so all those waiting for these game changing meds can benefit, then it is a small theoretical risk for a huge payoff.


Finally, small molecules such as ibrutinib and GS-1101, because they unanchor the B-cells from the safe home in the nodes and send them out in droves onto the less protected environment of the blood stream,  the ALC can shoot up.  That is normally a sign of disease progression with old school therapies, but is not usually the case with these new new drugs. Hence, the need to document shrinking nodes to prove that the therapy is working is even more critical with these treatments.


Still, isn't twice a year enough?


I even opt out of the total body scanners at the airports where the risks are at best minor and more honestly, unknown at this time, so I hope I can continue to opt out of my CTs here. TSA staff can get by with just patting me down at the airport to check for contraband. Why is essentially the same procedure for palpable nodes done by team of medical professionals not sufficient?  


A while back, I suggested to Dr. Byrd that he do a trial that once and for all compares the response to therapy of palpable nodes to that of the nodes seen on CT to see if we can eliminate need for all the scans. Seems even more urgent now.


Finished the airport at Phoenix waiting for my delayed flight home.

The danger of getting advice from a non CLL expert

My search spiders, primed for anything CLLish, pointed me to a blog by a retired medical oncologist who shares with us his frustration with the limited therapies available for the many CLL patients he treated in the past and his excitement about finding an article reviewing new therapies.


I was pleased to read that an experienced seasoned general oncologist was turning his attention to our rare disease and was anxious to learn his insights.


I was soon disappointed.


He points out the realities when he practiced.


When I was in practice we didn’t have any very effective drugs. We had drugs that could eliminate most of the leukemia cells, but never cure the disease. Eventually, the leukemia would come back in spite of continuing treatment. So when I saw this article, I assumed that there were new treatments and drugs to offer these patients, because I had seen preliminary reports suggesting breakthroughs. Wrong! Yes many new drugs have been developed, but none are particularly effective. The only one that seems to be useful is a drug called Rituximab, which is an antibody directed against a molecule on the CLL surface. But even this drug saved only a few more people when it was added to standard treatment, treatment that is not much different than what I used. And in the key study where this was discovered, most of the patients were much younger than average.


 Later he concludes with this wet blanket for any fire we patients might have for the new therapies.


But for most patients, who are older and have active disease, a disappointment! No breakthroughs like the one for people with chronic myelocytic leukemia (see my article on Kareem and CML) where we have found drugs that are life-saving. Sorry.


What has he been reading? 


This is what happens when you have doctors who are not heavily involved in treating our disease. They may miss when the winds shift.  They are out of touch with the prevailing zeitgeist. 


They have been known to put their faith in gold standard across the board, whether appropriate or not. They too often rely on stale data, and they don't see the coming changes. Their care might be appropriate, compassionate, well meaning and competent, but it is not cutting edge. It is not the best that the present state of knowledge has to offer.


This oncologist blogger to his credit was making an effort, knows about the new prognostic markers, and warns us appropriately that none of the new therapies has yet been proven to extend life. He understands the disease, but doesn't see the import of the coming new therapies because he is not immersed in the research and patient care of CLL patients. He is waiting for the proof for the trials that show the new drugs will add years to our lives. 


That is a long wait, longer than some of have.


Here is what I wrote the doctor:


Contrary to your take, there has never been a more promising time for patients with CLL. Low toxicity  sea change therapies such as Ibrutinib, GS-1101 and other kinase inhibitors are entering phase III trials after extraordinary results in phase I and II trials. Lenilimamide, HDMP, ofatumumab, alemtuzumab, and bendamustine already ofter patients new alternatives for disease control and long symptom free remissions.  While I agree a trial that shows an advantage over the "gold standard" of FCR in survival is what we all want, it is unrealistic and unfair to ask patients to assume that all these game changing therapies will ultimately fail. I for one, like you am waiting for the proof, but I am very encouraged by the early data and like many patients with cancer, must make decisions with imperfect knowledge.


For a nice overview of the research on the new small molecules, please take a look at Blood June 19:
The B-cell receptor signaling pathway as a therapeutic target in CLL
Jennifer A. Woyach, Amy J. Johnson and John C. Byrd


Thanks


Brian Koffman MD -http://bkoffman.blogspot.com/


That is a great article that summarizes much of the recent research.  I recommend it


Truth is that the other blogger and I are both right. 


He is correct when he says that nothing is proven yet. CLL remains incurable for the most part. The best new therapies are just entering Phase III trials and that is a far cry from proving that will keep us alive a minute longer than placebo, let alone FCR.


But I am right too. Patients who were at the end of their therapeutic rope are seeing their lives extended. Patients too old or too sick or too refractory are being routinely salvaged with amazing consistency and minimal toxicity.


This is more than anecdotes. The reported data is getting stronger and stronger. The response rates and progression free survival numbers are to use a most non-medical term,  wonderful.


Could it all crash and burn in the phase III trial? Could every new drug and therapy in trial turn out to a loser? Of course that could happen. But that is not what I and many of my CLL friends and by the way, the smart money on Wall Street is betting. 


I think we got some winners here.


And I am not talking drugs or stocks or careers, but us patients. We are the winners if my vision of the future comes to pass. We will prove my colleague blogger wrong in his disappointment. And I think he will celebrate with us.


One final caveat. This well meaning clearly bright and thoughtful oncologist is out of the CLL loop. Make sure you doctor isn't also. That is why I beg you to get an opinion from a CLL maven. Picking the right team of doctors could save your life.

Control, Not Cure: A New Path Opens Up Four Years Later - Transplant Then, BTK Inhibitor (Ibrutinib) Now

Four years ago today, I was admitted to City of Hope for a first remission hematopoeitic stem cell transplant. It was and still is the only possible path to a cure for CLL.

The only way to say: "I used to have cancer."

At that time not only was CLL incurable outside of a high risk transplant, there were no options that had even been shown to prolong life.

Now we have proven that FCR can add years to our life. The same is probably (but not certainly) true for BR and perhaps other very effective chemo-immunotherapy cocktails.

But FCR is hard on the marrow and not a great choice if you are older or more frail or have an auto-immune history such as ITP (as I do) or AIHA or if you are 17 p deleted or otherwise F refractory.

As those or you who have followed me from the get-go know, I failed my transplant because I rejected the graft. I was too healthy from an immunity perspective. With no graft aboard, I never had any of the desired graft versus tumor effect. Within a year I had relapsed and needed treatment again for my ITP and later my CLL.

The transplant didn't cure me, but it didn't kill me either. What it did do was buy me time until the game changing new therapies showed up.

Because of the brave souls who entered into phase 1 trials of an unproven and radically different  approach to CLL, I was able to follow their trail into a more mature and certain trial for a tyrosine kinase inhibitor, in my case ibrutinib (formerly PCI-32765) that blocks a pathway that is jammed in the on position inside my cancerous clone. It keeps telling my cells to proliferate and never die.

Not a cure, but a promise of longterm control with a very manageable downside.

There are other similar small molecules and pathway blockers and promising new antibodies and immune modulators out there that are changing the way we will approach CLL in particular and cancer in general.

Four years after I entered hospital on my high stakes gambit to be rid of this cancer once and for all, I am shifting gears. My transplant failed and since I never engrafted, it is almost as if it never happened. All my benefits (and risks) were from my one week of high dose FCR conditioning.

Today I am amazingly healthy after seven years of a battle with a persistent and aggressive enemy, but  now I have a kinder gentler approach and it seems to be working. Let repeat today's theme: Control if not cure.

I have made the shift. I was lucky to be able to see how the paradigm was changing and make a move. 

I can now clearly envision a new future that was just a distant speck on the horizon four years ago.

I can live with that.

G-d willing, for a long, long time.

Virtual Cancer Buddy and brief update on Clinical Trial NCT01217749 (PCI-32765 and ofatumumab)

Well I am  finished my final weekly infusions of ofatumumab and so I now can put some energy into some projects dear to my heart.

This http://www.virtualcancerbuddy.com/ is near the top of the list.

Please go to the link and spend the two or three minutes letting me know what are the most important health data and web support tools that you would want to have with you at all times.

As some of you know, I like Chris D, and many others with CLL or cancer have a thumb drive in my pocket that has some medical history, but it would take a dedicated doctor or nurse to find it and open it and root through it if I wasn't able to guide them. And if I am able to guide them, they don't need it.

The idea is that this would be more accessible, simpler and more robust, but because it could contain more that just the dry spreadsheets and contact information it would be something that you would be constantly consulting and would be regularly updated.

It would be your boon companion, virtual cancer buddy.

Your feedback will help to design it.

Do you want easy access to the latest clinical trials?

Do you ache for a calming MP3 to help manage the stress?

Do you long for tools to aid on the difficult decision processes?

Do you wish you had easy access to reliable research information?

Would an integrated appointment reminder be important?

Do you want your advance directives accessible?

Would it help if it could Skype to others with cancer?

Where do want it? On your phone or ipad or computer or everywhere?

Please check out http://www.virtualcancerbuddy.com/ and see the whole list.

The plan would be to provide this as a free service to cancer patients and their caregivers as a value added service from their treating hospital or oncologist.

Thanks a bunch for your help.  The survey only takes a few minutes at the very most.



Next week I finally start PCI-32765 or ibrutinib. These last 8 weeks of ofatumumab have been a long prelude with only very modest results on my nasty but not enormous nodes. Truth be told, probably all the benefit came in the first two weeks. Not so the advisers events. The persistent and humbling myalgias that have me limping around the apartment at times are my only side effect now. That and a completely mucked up circadian rhythm that has me up to 3 or 4 AM most days.

I am glad for a the five week break from "ofa".

I am ecstatic that I get to taste the magic sauce next week.

I am looking forward to being home again with my family and friends and cat and showing off my shrunken lymph nodes from ibrutinib.

What is CLL? Dr. Adrian Wiestner from the NIH gives an answer.

This is pretty basic stuff for us experienced CLLers, but I think the clarity of the dual nature of CLL is particularly well presented.

It is a very short segment of a much longer interview at ASH 2011 with Dr. Adrian Wiestner who hails from the NIH and who has done and is doing very important research in CLL.

And is he is a great guy too.

Most primary care providers are clueless about CLL so I am putting together a program of videos and education programs to teach them how to better care for these patients. More to come.

Fighting the hidden enemy- My big mesenteric CLL nodes force my hand

The disconnect between how well I might look and feel and the growing burden of cancer in my gut challenges my intuitions of how the world and leukemia works. Fighting the hidden enemies is my new imperative, one I can not ignore or wish away.

My doctors Forman and Kipps disagree on most everything, EXCEPT that I need therapy. Soon.

I will be spending the next 2 to 3 months deciding what to do next.

Doing nothing is not an option. Or at least not a very wise option, though it is certainly the most appealing in the short term.

I will not let this decision consume me, but will try as best I can to detach myself from the process and argue as I would for a friend or patient.

I will try to be calm in the face of imperfect choices and incomplete data.

I will try to look beyond the immediate horizons to the best possible future.

I will decide and move on.

I will, in the words of Jon Kabat-Zinn: Meditate, Act and Be Aware

You give me reason to live, you give me a reason to live, you give me reason to live!

My daughter and granddaughter in the California Redwoods

Patty and I went on one of our best trip ever. It wasn't exotic China, not romantic Italy, not Zen Japan, not super natural New Zealand, not historic Prague or musical Vienna or friendly OZ, not ancient Israel and Egypt, not the castled United Kingdom, not magical Peru, not the grand Grand Canyon, but gritty occupied Oakland because that's where my daughter, son-in-law, and granddaughter live.

That young lady with the pink bib in the picture is another reason to soldier on.

I have no bucket list. As I have said before, I have way too much joy in each day and way too many things left undone to imagine that a list of the top 10 or top 100 or 1000 checked off would signal it's OK to check out.

But seeing that four month old under the marriage chuppah might be a moment when I can say that I have seen enough.

Nah, make that holding my first great grandchild. I should be in my 90s or close. If I live long enough to see that baby's bat mitzvah, I would be around the century mark.

In any case, CLL would be a remote memory. What a blessing that would be.

But now CLL is front and center. Tomorrow I have my MRI to see if my CLL is trying to launch a sneak attack from inside enemy lines, my mesenteric or gut nodes. If they have grown too big despite another course of rituximab, I need to knock them back to size while I still can. If they become "massive" ( >10 cm) they become harder to kill. In these large niches, they have more supportive infrastructure such as nurse cells and they are just tricker to reach with what ever toxic cocktail I have planned for their last meal.

That means choosing a new treatment strategy that keeps one eye on my ITP, and another on my sleepy bone marrow and my third eye on a future transplant redux- probably my only chance to live long enough to see a fourth generation.

I wish there was another way, but I am not convinced. Kinase inhibitors such as CAL 101 or immunomodulators such as Revlimid might buy some time, but not a cure. They don't promise me another 30 years. Only a second transplant gives me a 50/50 shot at getting really old. But a transplant demands a big price for that shot of redemption and a second transplant demands even more.

I have been catching up on hours and hours of reading about my disease and transplant. CLL remains thankfully a hot research arena. Much is changing fast, but is it fast enough? I doubt it, at least for me and those of us who might need treatment soon.

Those who have followed me on some or part of my six year journey know this is a repetitive loop- my anxiety before a scan or bone marrow biopsy, my cogitation over my next move, my lament about the slow progress and the constricted choices, and my hunger for life.

Thanks for joining me on the trip. The CLL community and others facing similar challenges are among the many gifts in my life

I've got too many reasons to live and one very young, and beautiful new one.

It's the Nodes, Stupid

I am not big on sharing studies here. There are other sites that I have listed before that are much better at that than this blog,

I share this to share with you some of what gets me excited. Most of the research that I read on CLL, and that is several articles everyday, are not immediately pertinent and nearly all are downright dull.

However for me, this recent study answers the questions as to where my cancer, chronic lymphoid leukemia, is doing most of its growth. And from that it is my opinion, we learn where it must wiped cleaned or there is no chance for a cure.

What this research says to me if that the cancer is most active in the nodes and the spleen, essentially a big node. That fits completely with my own experience. My CLL (after my transplant) came back in my nodes first, my hidden nodes deep in my guts. This is most obvious in those like me with 11q del that tend to have bulky nodes, but is true for all with CLL.

This has important implications for me and any CLLer. If I want a cure, which I sure as heck do, I need to get rid of all the proliferative centers in all the nodes.

Hopefully this small step will be followed soon, with the article that announces the path to the cure.

Proliferative index and expression of CD38, Zap-70, and CD25 in different lymphoid compartments of chronic lymphocytic leukemia patients

Original Research

(423) Article views

Authors: Olga Khoudoleeva, Eugeny Gretsov, Natasha Barteneva, et al

Published Date January 2011 , Volume 2011:3 Pages 7 - 16 DOI 10.2147/PLMI.S14752

Olga Khoudoleeva¹ Eugeny Gretsov¹ Natasha Barteneva²,³ Ivan Vorobjev^1
1Hematology Scientific Center, Russian Academy of Medical Sciences, Moscow, Russia; ²Immune Disease Institute and Program in Cellular and Molecular Biology, Children Hospital of Boston, Boston, MA, USA; ³Department of Pathology, Harvard Medical School, Boston, MA, USA

Abstract: Recent studies of chronic lymphocytic leukemia (CLL) show that malignant B cells proliferate at a rate similar to normal B lymphocytes. This is in apparent contradiction to the very low proliferation rate found in blood specimens from CLL patients. To address this problem, we studied the expression of Ki-67, CD38, CD25, and Zap-70 in different compartments of CLL patients. Using triple-color flow cytometry, we examined the expression of CD38, CD25, Zap-70, and Ki-67 antigens in the peripheral blood, bone marrow, spleen, and lymph nodes biopsies of patients with CLL, splenic marginal zone lymphoma (SMZL), and nonmalignant diseases. In parallel probes of lymph node/spleen biopsies and blood taken from one and the same patient, Ki-67 expression was 17 times higher. Among the whole cohort, we also found significantly higher Ki-67 expression in biopsies from lymph nodes and spleen (4.95% ± 0.55%), compared with bone marrow (1.88% ± 0.32%) and peripheral blood (0.45% ± 0.03%,). We show for the first time that proliferation of B lymphocytes in CLL patients is associated primarily with lymph nodes/spleen. Malignant cells in the blood represent only a subpopulation of nonproliferating and less-activated B cells in this disease.

Keywords: chronic lymphoid leukemia, CD38, Zap-70, Ki-67, bone marrow, lymph node