Report from my Scans and Lab at OSU

I am back home at last after a whirlwind tour of three states in five days.

My trip to Columbus for my OSU clinic visit at the James Hospital was enhanced by the hospitality of some new friends. The husband is also a CLL patient of Dr. Byrd and is enjoying an enduring and deep remission and who had his clinic appointment within twenty minutes of mine.

While waiting, I met a few people who teased me about my over sized poster in the lobby of the James, and a wife who insisted I meet her husband. Honestly I was touched when he told me that it was because of this blog that he drove from Kansas for the ibrutinib trial. He too is doing well with shrinking nodes and no ill effects.

For me, the news was good. All my blood tests were essentially within normal limits. My red and white blood cells and my platelets, my liver and kidney function and my electrolytes were all once again boring.

My scans showed stable disease. So after dramatic shrinking of my nodes over the first two scans in the first six months, there has been almost no change in the last nine months.

While my axillary nodes all shrank from three months ago, some significantly, and all my lymph nodes are a bit smaller than on the scan done last October, the actually measurements of my three index gut nodes were one mm bigger this time than than three months ago.

Since my whole GI tract was churning from the oral contrast (and is only now starting to recover), a one millimeter difference may be easily explained by the twisting of the gut, though radiologists usually choose to measure the index lymph nodes that are stabilized by their proximity to a major vein and less prone to changes in orientation.

Still one millimeter means nothing. In fact the summary says my nodes don't even meet the criteria for adenopathy (abnormal nodes). I can't agree with that cheery reading as I have one portal caval node that drains the liver that is 4 x 0.7 cm and that's an abnormally big node. None of the others are > 2 cm.

But they also say they are stable. If a patient, asked me about a one millimeter increase, I would offer them  my heartfelt reassurance that it meant nothing and was within the margin of error of the technology and the imperfect humans measuring them.

And that is what the radiologist stated. And they are famously over zealous in their reporting to avoid being blamed (and/or sued) for missing something, so I too am reassured.

Dr. Byrd advised that he sees this pattern of stable lymph nodes in many patients on ibrutinib and the nodes may start to shrink again in year two to three.

And of course, the report offers the added benefit that my every 84 day scanning surveillance has turned up nothing else suspicious in my thorax or abdomen or pelvis. No secondary cancers. Others have not been so fortunate.

I wish the nodes were all smaller. I wish they were all less that one centimeter, but I will take stable.

Patience.

Patience.

Next scan is not for six full months! That too is good news. I am nearly over the highest risk time for the very small risk of late relapse.

All in all, except for the mild gastric distress from the contrast media for the scan, a flash flood warning, and multiple delayed flights coming and going, a very good visit to Columbus.

I am happy and have much more exciting CLL news to share. More videos soon from ASCO.

Hope to get to report from the iwCLL workshop in Cologne, Germany and am definitely going to the LRF in Brooklyn, both in September.

More on Halting the Lenalidomide Trial

Please read my immediate prior post on this trial first if you have not already to best understand the context of this post.

I heard from a respected investigator and my person physician in my ibrutinib trial, Dr. John Byrd, involved in the halted trial of Revlimid (lenalidomide) versus Leukeran (chlorambucil) in the elderly with CLL. 

He said the Kaplan Meir curves were narrowing. Deaths are now 28 versus 36, but still with more in the lenalidomide arm. He also said "The cause of death was interspersed among many different causes." And he reiterated "We are very excited about lenalidomide as an immune modulating agent at lower doses" suggesting that we might find use for it at a low dose by not only considering its potential to control the CLL, but also to rebuild our damaged immunity. 

This is completely consistent with the additional information presented below from the well balanced reporting of the Myeloma Beacon News.

I have pasted the last half of their article on the topic, the part that is most pertinent to CLL.

Lessons learned?

1. Don't rush to judgement: Analyze all the data and don't generalize.
2. Don't throw out the baby with the bathwater: Immune modulating drugs may be an important piece in solving the CLL puzzle.
3. Expect the unexpected: Be prepared for something that you are are completely unprepared for.

Here is the last half  on the article. The full  article is available at this link but I jumped to the part that is more focused on CLL

As I said in my prior post, this is an evolving story.

Revlimid Leukemia Trial Halted – No Immediate Impact On Drug’s Use In Myeloma Expected

By Julie Shilane

Published: Jul 19, 2013 4:52 pm

The decision to halt the ORIGIN study was based on an analysis conducted in March that showed CLL pa­tients treated with Revlimid had a 92 percent increased risk of dying compared to those treated with chlor­am­bucil.  Specifically, 16 percent of patients treated with Revlimid had died at that point, compared to 9 percent of patients treated with chlorambucil.

Click on image to view a larger version of it.

The results from the March analysis show that a dif­ference between the overall survival curves started to emerge around 6 months after the start of treatment (see graph on the right).

Celgene told The Beacon that the gap in the sur­viv­al curves has since grown smaller, but has not closed, and that the death rates are currently 18 percent for Revlimid and 13 percent for chlor­am­bucil.  These findings, however, have not yet been reviewed or confirmed by the FDA.

The FDA also has not yet released any information about what factors may have increased the risk of death among Revlimid-treated patients.  A spokes­per­son from the agency told The Beacon, “The FDA is working with [Celgene] to gather the infor­ma­tion needed to better understand the nature of the deaths.”

Greg Geissman, a spokesperson from Celgene, provided some additional information to The Beacon.  He explained that secondary cancers have not contributed to the increased risk of death among patients treated with Revlimid in this study.  He added that secondary cancers were balanced between the two treatment groups, both in terms of the rate of patients developing secondary cancers and the number of deaths at­trib­ut­able to secondary cancers.

Geissman also stated, “As we understand, a preliminary observation shows a greater imbalance in deaths in patients over the age of 80 who have co-morbidities [additional medical conditions]. Our analysis will now look to understand further some of these dynamics and how they may have contributed to the imbalance.”

In addition to analyzing the potential impact of age and co-morbidities on the survival imbalance, Celgene stated that the company will analyze differences in how the patients were cared for at the various centers involved in the study.  The company indicated that the results from these analyses will be presented at an upcoming medical meeting.

The Mayo Clinic’s Dr. Kumar also explained that “Other studies of Revlimid in CLL have shown that these patients can have unique side effects compared to myeloma patients, such as tumor flare.”

A tumor flare reaction is a temporary worsening of symptoms soon after treatment begins.  It can be a sign that treatment is working, but it requires that patients be monitored closely during the first few weeks of treat­ment.

“Given that the [survival] curves start separating out close to a year, it is unlikely that [tumor flare] explains the increased mortality, but it clearly would be one of the aspects to be examined in the future,” explained Dr. Kumar.

“As we know more details about the cause of deaths in the Revlimid arm in the CLL study,” added Dr. Kumar, “we should certainly evaluate if there are specific patients with myeloma where there might be a concern.”

Lenalidomide (Revlimid) Associated with Excess Deaths in the Elderly

Honestly, I didn't see this coming. The IMIDs (immuno-modulating drugs such as lenalidomide or Revlimid) are touted as kinder gentler and safer therapy for the elderly.

Not so says this trial. 

What it found instead in an interim analysis was a significant increase in the number of deaths for those taking lenalidomide compared to those on the old school chemo drug, chlorambucil, an oral alkylating agent.

Now of course the details on the causes of the excessive deaths will help unravel this story, but for now it is a cautionary tale as why we need trials to test what seem to be safe and logical assumptions.

Does this mean if you are in another trial with lenalidomide, you should stop? Absolutely not, but you should discuss with your doctor what this means in your particular circumstance. Probably nothing if you are doing well.

Now this is a newsflash, and the full story is far from told, but since it is a popular non-chemo option out there, I wanted to share this ASAP.

Personally, I still believe there is a role for IMIDs in CLL (too many patients have done well with them), but my bigger belief is that we really have a very primitive understanding of how they work.

We have begun to crack the biology on B cell receptors pathways and BCL-2, but what exactly Revlimid is doing is murky. 

And usually our best results come when we have nailed the underlying basic science. Some drugs have come to us in the past from plain dumb luck, but most of the breakthrough today are based on meticulous pre-clinical basic research.

Here's the news:

GEN News Highlights : Jul 18, 2013

Celgene Halts a Phase III B-Cell CLL Trial Because of Deaths

Celgene today said that after a consultation with the FDA it will stop administering Revlimid® (lenalidomide) in its open-label, Phase III ORIGIN® trial because of patient deaths.

“An imbalance was observed in the number of deaths in patients treated with lenalidomide versus patients treated with chlorambucil,” Celgene said.

The trial, which FDA placed on clinical hold July 12, was intended to evaluate the efficacy and safety of lenalidomide versus chlorambucil as single agent in elderly patients 65 and older with B-cell chronic lymphocytic leukemia (CLL), plus comorbidities that precluded treatment with more aggressive standard chemo-immunotherapies.

The firm noted that, in this particular trial, there were 34 deaths out of 210 patients in the lenalidomide arm compared with 18 deaths out of 211 patients in the chlorambucil group. It added that “all other Celgene-sponsored chronic lymphocytic leukemia clinical trials with lenalidomide are continuing in accordance with their respective protocols.”

Revlimid is approved in the US for the treatment of patients with mantle cell lymphoma whose disease has relapsed or progressed after two prior therapies. The drug is also approved in the US, Canada Switzerland, Australia, and New Zealand, Malaysia, Israel, and “several Latin American countries”—according to Celgene—for the treatment of transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. In Europe, the drug is also approved for the treatment of similar patients with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. Revlimid is not approved as a CLL treatment.

ASCO 2013: Dr. Wierda on Prognostic Factors in CLL (Chronic Lymphocytic Leukemia)

The whole arena of prognostic factors in CLL is constantly evolving, but a few principles have remained constant over the years.

1: Most, if not nearly all the data is retrospective.

2: Dr. Wierda and many others are refining algorithms that will weight the many variables to better predict our future including such helpful information as the expected time to first treatment or our chances of a durable remission or ultimately our chances to live long and prosper.

3: The markers predict for groups, not individuals, but that doesn't mean we should be therapeutic nihilist and ignore what our FISH tests tell us about what options improve our odds.

4: Bad prognostics are not in themselves an indication for treatment (outside a clinical trial).

5: Good prognostics doesn't always mean that our CLL will be a non-event.

6: New prognostic factors are being discovered all the time, but few will be of much clinical import.

Here is the second part of my interview with Dr. Wierda from ASCO 2013.

I will let him fill in the details on all these topics and other aspects of this moving target.

Again my thanks to  my friends at Patient Power for sharing the work and supporting the effort to get the important news about CLL from ASCO out and available to all those of us who need it to inform our choices about how we handle our disease. Check in on their website on a regular basis as Andrew Schorr is frequently update his informative site.



In fairness, I must add that other researchers have published data supporting a possible relationship between Notch1 and Richter's Transformation (or Syndrome),

I quote from a letter in the British Journal of Haematology, 2012, 158, 415–429


"NOTCH1 mutations were associated with a ~5·8-fold increase in the crude hazard of transformation into a clonally related RS (Richter's Syndrome) "

This is from an editorial from haematologica | 2012; 97(3)

"In fact, the first studies reported a high frequency of NOTCH1 mutations in .... disease progression towards transformation into Richter’s syndrome."

Now this is not the same level of evidence as in a full article, and as such might not pass mustard for Dr. Wierda and others as proof positive of the correlation, but it convinced me that it is worthy of further study.

There is just too much data out there for anyone of us to be aware of it all.

And that's OK.

Flashback: I meet my Donor in 2009

This page, recently sent to me by a CLL friend  who lives across the country, is from the 2009 Annual Report of Ezer Mizion, a not for profit charity that among other good works, helped me find my bone marrow donor and a new friend in Israel. Ezer Mizion has a huge international bone marrow donor registry. All recruits  of the Israeli Defense Force are screened. in 2009 they found 642 matches and 138 transplants were done around the world.

We raised a lot of money that day in Manhattan. Yaakov and I have stayed in touch. We visited in Israel and my son, Will just met with Yaakov in Jerusalem last month.

I later spoke to the rabbi in Leeds, England that had lead the campaign to raise the money that ended up screening Yaakov and hundreds of others. They failed to find a donor for their congregant in need, but they found my donor. We never know the results of any kind act. We never know whom we might touch when we reach out our hand to give. Or to take.

And even though I never engrafted and it was not the cure that I hoped for, it did buy me enough time to make it to my present life changing clinical trial.

The months before my transplant was like crossing a minefield blindfolded, the months after, like tramping through a quagmire with no sleep, but all that is in the past, and today and the future are bright.

I am grateful for the friends that I have met along the way and especially to the selfless contribution of my blood brother, Yaakov.

As to my comments below, I am happy to report that I have not only met my first two grandchildren, I now plan to live long enough to meet their children.

By the way I got back the rest of my lab and even my IGG level after 6 weeks with no refilling of the tank, was still in the normal range, albeit barely. Looks like the 6 weeks between infusions is about as far as I dare stretch. 

Vitamin D3 level was high normal, just where I want it. I need to take 10,000 a day to get it there. Zinc level wasn't done. Lab error. Not worried.

Here's the article.

YAAKOV MEETS BRIAN

Cancer survivor, Dr. Brian Koffman (56) of California, spoke eloquently at an Ezer Mizion event of his bout with cancer. "It's great to be here," he began. "In fact for me it is great to be anywhere.
“I had been diagnosed with a particularly virulent form of cancer with a short leash and a tight grip. All my knowledge as a medical doctor offered no protection or control over the disease. It was like being on a roller coaster ride without the safety bar. My daughter recently got married. Would I be around to see my grandkids?
"Because of Ezer Mizion's efforts, I am alive. One thing I learned at the school that no one wants to attend: You need the right team. I was stretching out my arm as far as I could and Ezer Mizion reached across the ocean and gripped my fingertips and pulled me to safety."
Unknown to Dr. Koffman, waiting in the audience was Yaakov Fabian (24), the donor whose bone marrow donation had saved his life. An emotional meeting ensued between the two ‘blood brothers' and their spouses, who remained at each other's side for the rest of the evening.
This lifesaving transplant was made possible thanks to the generous sponsorship of the Leeds Jewry Donor Pool at Ezer Mizion’s Registry.

More Good Lab News

Our EHR (the electronic chart of all the medical records where I work and get my care) is down again, but before it crashed, I was able to view most of my lab results from 3 days ago.

Remember that I had gone a full six weeks between my lab tests and IVIG infusions to control by ITP, representing the longest period my veins haven't been probed for blood in the last seven years and the longest period ever between immunoglobulin infusions.

And the news was only good.

First the CBC.

For first time in many years, I have two blood counts in a row that showed no anemia. My hemoglobin was a robust 14.4.

My platelets were even better, an amazing 405,000. Although I have had a splenectomy, and they would be expected to be higher than in the reported average, this is still a super result, reinforcing the safety of the move to extend the time between infusions. It wasn't that long ago that I needed treatments every two weeks to keep my platelets in a safe range.

My absolute lymphocytes (ALC) was nice and low at 1.2. I want it low because those are the cells that make up my cancer. A high ALC usually means the leukemia has returned. My ANC (infection fighting neutrophils) was a healthy 6.2.

Blood chemistries showed that my liver and kidneys are doing a superior job of ridding me of any toxins or waste, and my sugar, minerals, and electrolytes are well balanced. Uric acid which often rockets up when taking cyclosporin as I do stayed well below the point when it comes out of solution and can cause the agonies of gout. This last result I particularly attribute to my vegan and nearly completely alcohol free diet.

Even my iron studies, consistently low in the past and likely one of the negative results of my longterm meatless diet, had inched their way into the bottom of the normal range, suggesting that using the cast iron skillet and eating more collard greens and molasses was slowly filling my empty tank.

And to top off the good times, my blood pressure was around 110/60 even with an IV in my arm.

When the computers are back up, I will check my Vitamin D, zinc and IGG levels.

I have grown accustomed to getting good lab results, but I never take them for granted and I am always grateful.

Next week, I am off to Ohio for my 84 day check in with yet another set of CT scans and more lab. On the way there, I am leaving early so that I can stop in the bay area to kvell (Yiddish for to feel proud and happy, especially applicable to one's offspring) over my granddaughters, and on the way home, I will be visiting friends in Missouri.

But that is the only travel planned for all of July! It is great to have some down time at home. Even with my boring labs, I still get tired and need my rest. Except for the fatigue, and the constant background noise about my impaired immunity and a host of other potential but G-d willing never going to happen concerns, my CLL is a non-event.

I believe that after this set of scans, I can go a whole six months between imaging, but not between visits to OSU and Dr. Byrd.  Enough scans already!

Starting late in August, American Airline will offer direct flights from LA to Columbus. It may be almost worth the unpredictable drive up the 405 from Newport Beach to LAX to avoid the stopover in Dallas or Chicago for my next trial visit. That could be nice.

I remain busy with prepping video and news material for the blog. Expect the second part of my ASCO 2013 Wierda interview on prognostic factors to be posted here soon.

ASCO 2013: Dr. Wierda Discusses Immune Therapies in CLL

In this first of several interviews from ASCO 2013, Dr. Bill Wierda of MDACC discusses immunity in general (or lack there of) in CLL and how that relates to the coming immune therapies.

He starts by explaining the basic difference between passive and active immune therapies.

His candid review of the trials so far points out the recurrent disappointments in the attempts to develop active immune therapies.

The story with passive immunity has had more success.

Monoclonal antibodies (mAb) such as rituximab or alemtuzumab were the pioneers of targeted immune therapy and have in many cases improved outcomes when added to chemotherapy without significantly increasing toxicity. Newer mAbs hold the promise of even deeper responses with few of the downsides of traditional chemotherapy and may even prove to work well without the addition of cytotoxic chemotherapy. Already useful examples include Rituximab and Revlimid or lenalidomide (R2) and the combo of HDMP (high dose methylprednisilone) + Ofatumumab. Powerful therapies with no chemo.

GA101 or obinutuzumab, a third generation anti CD20 mAB had received breakthrough status at the FDA and may be approved before the end of the year. The early data suggest this is both a potent and well tolerated treatment, hence the rush to get it to the clinic.

Passive immunity also includes the exciting CAR-T therapies that Dr. Wierda discusses. These are still in very early trials, but a few cases such as those out of U. Penn have seen spectacular saves when patients had all but ran out of all conventional options.

Immune modulating drugs (IMIDS) such as lenalidomide are in the early days of studies to figure out how they fit into the therapeutic landscape, but are clearly active in CLL and may improve some aspects of our impaired immunity,

This segues to another topic that gets Dr. Wierda really excited.

He tells of his research into ways to improve our immunity, to reconstitute our lost ability to fight off infections and to search and destroy the earliest microscopic cancers before they can grab hold and cause problems. Infections and secondary cancers are what kill those of us with CLL, and Dr. Wierda is fighting for ways not only to knock out our blood malignancy, but to also prevent us from dying not from our cancer itself, but from the damage the CLL (and its treatment) have already done to our ability to protect ourselves from infections and secondary malignancies.

This interview is from ASCO 2013 in June in Chicago.

It was great fun working with Andrew Schorr and the dedicated team from Patient Power in doing these interviews. I am grateful for their efforts and support and the willingness of the doctors to share their work at such a busy conference.

Look for more CLL interviews here over the next few weeks and keep checking Patient Power for other interviews that Andrew and I did on other cutting edge treatments for different cancers at ASCO in Chicago. Many of these have direct implications for how CLL may be treated in the future.

Here is Dr. Wierda:


Tomorrow it will be a full six weeks since my last IVIG infusion and blood draw. This is the longest I have gone without IVIG in the last six years and the longest I have gone without lab test since my first year with CLL.

I will report from the infusion center tomorrow.

Five Years Post "Failed" Hematopoietic Stem Cell Transplant

Granddaughter, Amira at the July 4th Parade

The last half of June and the first week of July are full of red letter days for me.

I had my hematopoietic stem cell transplant on July 1, Canada Day in 2008, a little over five years ago. I remember watching the fireworks on that 4th from the City of Hope hospital window on the 5th floor with my family and my IVs and my N95 mask.

About this time those five years ago, I was near the nadir for my blood counts and feeling about as healthy as a sticky asphalt road in Death Valley in a scalding August, with a convoy of overloaded 18 wheelers doing wheelies on my soft shoulder.

I ended up recovering quickly, but I never engrafted, and soon lost everything: the graft, my short lived MRD negative complete remission and any clarity that I ever had on what to do next.

My aggressive plan to deliver an early (first remission) knock-out punch to my CLL never even got cocked and ready.

But then again, it didn't knock me out either as it has done to so many others before. PC Venkat, my friend and the pioneering model for my shock and awe approach to CLL, passed away the day before I was admitted to City of Hope. That terrible news was both sad and sobering, but I went ahead with my plan to assault the same beachhead where he had fallen.

In hospital, I pushed to get ATG as part of my conditioning to cool my own immune system that never had been damaged by chemo or Campath. I failed and without it, my T cells at transplant time were still on active border patrol and as it turned out, more than up to the task of booting out the invading donor cells from my marrow. Later I pushed for more radical reinforcements, namely DLIs, but was told it would be too little too late. Either I should have a meaner and riskier second transplant, or.... Who knew.

Within six months, I had nearly simultaneously lost the graft and relapsed. Six months after that the ITP was back.

Not a good time.

But on the other hand, I have no graft versus host disease, because I have no graft. Actually the last check for my chimerism (measurement of more than one genetic fingerprint in an individual)  done years ago showed that I was still genetically in my marrow about 1% my wonderful Israeli donor (Yaakov). That is within the range of statistical error, but my wife swears it is Yaakov's lingering influence that has somewhat ameliorated my tone deafness.

Does that count as a partial remission?

My youngest son just visited him in Jerusalem. He is a gentle and generous young man.

Maybe losing the graft was for the best. GVHD (graft versus host disease) is tough and there can be worse, much worse outcomes. Only about half of those transplanted are still alive five years later to blog.

But I am doing well in my clinical trial and my life is most sweet these days. While it is possible that I might have been "cured" by today if I had been treated more aggressively those five years ago, it could just as easily been five years of misery with multiple hospitalization for some nasty mix of GVHD, sepsis, and relapse. Trading one disease, CLL, for another, GVHD.

I'll never know.

But it's hard to imagine a better life than the one I have now.

Sometimes it amazing how things work out and what looks like a disaster up close, from a distant turns out to be our saving grace.

I know how lucky that I am and for that I am deeply grateful.

Happy 4th!

Quick update: My talk to the San Diego CLL support group at UCSD yesterday was well attended and, I believe, well received. It was a great opportunity for me to meet others with my disease and share some of what I have learned over the last nearly eight years.

CLL Support Group on July 3, 2013 at 4 PM at the Moore Cancer Center

Please join me tomorrow at UCSD at 4 PM on the 2nd floor of the Moore Cancer Center in the "Commons" for my talk to the CLL support group based on my experience as a doctor turned patient dealing with cancer.

I plan to start with a brief overview of CLL, discussing in general terms diagnosis, lab tests, prognostic factors, symptoms, complications, management, and how treatment is changing. The last half of my talk will be about my personal experiences as a patient ending with my participation in OSU clinical trial with ibrutinib.

It will feature video clips from my interviews with Drs Kipps, Wiestner, Byrd and Pagel at past ASH meetings.

After my 45 minutes, we all have a chance to meet and exchange stories and information.

Hope you can make it.

Sydney Lilah Sowers

Sydney Lilah Sowers

Meet my beautiful very smart new granddaughter who is now about six weeks old.  She was named after my late father and her great grandfather, both of blessed memory, on her daddy's side.

It doesn't get any better than holding her in my arms. 

So many reasons to live.