One More Sunset

We walked up the beach at Crystal Cove and snapped this photo.

We are back home briefly, where we are getting ready for the family visiting tomorrow for the traditional Christmas meal of latkes (potato pancakes).

One small CLL Christmas present. Something special got a new official moniker. Her new name is Idelalisib but she called herself GS-1101 but everyone knew her as CAL-101. Reminds me of the Beatles' song Rocky Raccoon.

You heard it here first, though I am loathe to try to actually pronounce it or sing it.

I will have some interviews up my the end of the week and plan to review the good news from ASH on ABT-199 next.

To all those celebrating,

Merry Christmas 

ASH 2012: 189 The Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Promotes High Response Rate, Durable Remissions, and Is Tolerable in Treatment Naïve (TN) and Relapsed or Refractory (RR) Chronic Lymphocytic Leukemia (CLL) Including Patients with High-Risk (HR) Disease

Let's look in more detail at some of data on ibrutinib (PCI-32765) presented at ASH 2012.

There were many papers on ibrutinib, but I am going to start with #189 that looks at data in CLL/SLL that now goes out almost two years ("beyond 22 months") using the drug as single agent therapy.

Five cohorts were studied. Remember only patients needing treatment could enrolled in the trial.

For those for whom ibrutinib would be their first therapy ever for CLL, 26 got 420 mg and 5 got 820 mg. These were the treatment naive (TN) cohorts and all were older than 65.

The 820 cohort was closed before full accrual when it became apparent the lower dose had comparable activity and safety in the relapsed and refractory patients. What I believe this is saying is that once the target (the BTK pathway) is saturated with drug and fully blocked, there is no advantage to adding more drug.

In the relapsed and refractory (RR) groups, there were two cohorts. 27 and 34 patients respectively got 420 or 820 of ibutinib daily. All these patients had had to have failed at least two prior therapies  including a purine analog, usually fludarabine. As I said, before the different dosages made no difference in the outcomes.

The fifth cohort consisted of 24 addition high risk (HR) patients who had either 17p del or had relapsed in less than two years after FCR or an equivalent chemo-immunotherapy.They all received 420 mg daily.

In the combined two TN group, three patients had complete remissions (CR), nineteen had partial remissions (CR), three had PR with the now expected lymphocytosis, four patients had stable disease, and two patients could not be evaluated. In all, 29 of 31 patients and 100% of all evaluated patients were still on the trial drugs because it was helping them after almost two years.

That's a strong result, but let's look at the hard to treat patients, the RR and HR cohorts. This is the real test and where there is the greatest need for improved outcomes.

In the RR groups one patient out of 61 progressed. In the HR group, where seven were 17p del and eight were 11q del, one of 24 progressed. A detailed breakdown of the responses and all the data is available online here.

True in these two groups, there were only two CRs, but the results are better than the last interim report with more remissions. I bet there will be more CRs reported at ASH 2013 (in New Orleans) when we have yet another year of follow-up for this study. The data may be getting better the longer patients are on therapy.

Adverse events were usually not serious with diarrhea in 54% across cohorts being far and away the most common. That percent falls to about 3% after 6 months. Serious blood and infection issues can occur, but are very rare. Remarkably, IGA (an immunoglobulin used to fight infections especially in the mucus membranes) levels actually increased and IGM and IGG stayed stable. 7 of 116 patients quit the study due to side effects of the drug. All the problems seem to get less frequent after the first six months of treatment.

Drilling down into the data, the authors (my doctor, John Byrd was lead author) report that response rates were the similar for those with bad prognostics including 17p, high b2M, multiple prior therapies, and advanced disease stage.

This is a revolutionary change. Is it saying that the dreaded 17p del or having failed multiple therapies or being RAI stage IV makes no difference in our response rate? Seems so.

Old treatments in these tough to treat groups would be lauded if half the patients were doing OK after two years, but with ibrutinib, only two of 85 patients are reported as having progressed. And there are no significant side effects.

The Kaplan Meier curve tells it all. On the Y or vertical axis is the number of us still alive. On the X or horizontal axis is time. A flat line near the top is ideal. These results are nothing short of stunning.

Those old charts that showed a 45 degree or greater rush to mortality will soon be banished to the dustbin of medical history along with bloodletting for a sore throat or skull trephining for headaches.

We are living longer. And feeling better. Say goodbye soon to chemo for most of us. That's not just this wild-eyed patient talking. That is the emerging consensus from the CLL gurus.

Studies on ibrutinib were reported at last year's ASH, but the buzz has grown exponentially, not because the data is so much better which it is, but because it is looking as if this could be a durable treatment with no unexpected side effects and no growing issues of resistance so far.

I have been going to ASH meetings long enough to have seen more than one promising drug turn out to be a one hit wonder that makes big news one year and disappears the next, but ibrutinib is beginning to emerge as a solid therapy.

Hence the phase 3 trials. That's the acid test, the real proof.

Two years is too soon to close the book on CLL, but the data is way better than what we had last year, but we need bigger numbers and longer follow-up.

The phase 3 trials that are up and running already will tell us so much more. The sooner those are fully enrolled, the sooner I believe this game changing drug will be available to all of us who might need it.

If you are needing to consider therapy soon, I encourage you to check out clinical trials.gov to see if something there makes sense for you.

The life you save might be your own.

Sunset at Crystal Cove

This is the view of last night's sunset from our tiny but cozy cottage studio right on the sand at Crystal Cove. It is only 15 minutes from our home, but it is a world apart.

No internet (without tethering), no chores, no room to do much other than read and walk and look and listen to the sea.

There is so much more to life than CLL. It is moments such as these that paradoxically make me forget all my struggles and also remind me of why I went through them.

More from ASH coming, but right now, I am loving hearing the waves.

ASH 2012: Interview with Web Savvy Patient, Andrew Schorr

Andrew Schorr is a journalist, an advocate, and a very web savvy patient who has stared down CLL for about 16 years and it now winning his fight with myelofibrosis.

Through his helpful website, patientpower.info, he has provided a treasure trove of information for patients looking for answers.

Now he gets to be on the other side of the microphone in the hall outside the press rooms at ASH 2012. We learn from the interviewer turned interviewee about his strategies to navigate his disease. He outlines through his personal story and his decision process, the critical need for getting support from others with the disease, the primacy of expert advice, and the important role of clinical trials in saving his life.

In future posts, we will both share the interview he did of me about my ibrutinib trial.

Andrew and I have moved in the same CLL circles for several years now and I hope we keep doing it for many more to come.

Here is the interview:

Below is a photo of some of my local support group and our significant others at our holiday get-together. We don't look too bad for a bunch of patients with an incurable cancer, do we?

I would be lost without them.  If you have CLL, and don't have  support group, get one or join ours if you are local.

ASH 2012: Combinations of the PI3K∂ Inhibitor GS–1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Patients with Relapsed or Refractory CLL

GS1101(formerly CAL101) was the first oral, exciting small molecule to show outstanding results in CLL after the failure of many other small pathway blockers.

It had about an 18 month head start on ibrutinib (formerly PCI-32765), but its lead has shrunk considerably in the race to FDA approval.

It too blocks the pathway downstream from the BCR (B cell receptor) that tells the clone to survive and proliferate. Bench research presented at ASH seems to suggest that in some clones of aggressive CLL with a higher tendency to Richter's Transformation, BCR is promiscuous (couples and responses with any old stimulating antigen) or in another poster presentation, may be self stimulating, perpetually turned on and driving the disease with no outside help. Quoting from the conclusions in that paper " These findings suggest the possibility of self-recognition of BCRs within the CLL cell membrane or BCR interactions between neighboring CLL cells. This may potentially result in autostimulation of the leukemic cell independent of “exogenous” antigens and may account for self-sufficient signaling of some CLL-BCRs in driving disease progression. "

Either way, turned on BCR is not our friend.

This basic science work applies to any and all drugs that effect the BCR pathway, and it was work such as this that lead to the idea that compounds such as GS1101 and ibrutinib might someday have a major role to play in controlling CLL. We now know that PI3K∂ drives survival and proliferation of the cancers cells, so blocking it with GS1101 makes good sense. 

That kind of hard work leads to an understanding  of the basic cell biology that leads to a treatment hypothesis that leads to animal studies that leads to human trials that leads to a usable drug.  I am way oversimplifying the story and this ideal path is aborted 99% of the time long before it gives birth to a helpful medical compound, but I wanted to share some of the mostly unseen effort that makes these breakthroughs possible.  The medicine bottle at the pharmacy is just the tip of the iceberg. We owed so much to the medical chemists.

So what were the clinical results with GS1101 that were presented at ASH? 

The important  abstract 191:Combinations of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kdelta) Inhibitor GS–1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Results From a Phase I Study reported more good news: high response rates.

Here I am sharing an executive summary of the findings but you have a link to all the details included in the abstract. We must wait for the peer reviewed published paper as that is the true test of the validity of the research.

51 patients were studied in three different arms. These were not the easiest  of us to treat. All had relapsed after up to 10 prior therapies, 27 had refractory disease, more that half had bulky nodes, and nearly all had had prior B/R (bendamustine/rituximab).

In the group that was randomized to get B (bendamustine) with the GS1101, the intent to treat overall response rate (ORR) was 82%. Adding rituximab (the BR group) raised that to 87%.

But here is the number that excites me. Leave out the chemo (bendamustine) completely, and use only biological therapies with the combination of CD20 antibody, rituximab, and the new PI3K∂ inhibitor, the response rate was a very respectable 78% in these tough patients. 

Minimum follow-up was 40 weeks for each arm with the one year progression free survival numbers being very similar to the ORR.

Nodes shrunk rapidly in almost everyone. Disease related cytokines, elevated at the start of therapy fell, and that may explain why we feel so much better with these treatments. Elevated cytokines make us feel sick.

In the GS1101 + R (rituximab) group (only 19 patients), 21% (6 patients) got pneumonia, 32% had low neutrophils ( and 11% or two patients had febrile neutropenia) and 21% had low platelets. Only one patient had elevation of the liver enzymes. As expected, the blood work was considerably worse in the  two groups that received bendamustine. Surprising infections were lower in the BR group, but the sample was small with only 15 patients being followed.

The data are very encouraging, but we need much bigger numbers and longer time frames. That is the why we have the phase 3 trials, accruing right now. Check out clinicaltrials.gov for the details. My favorite would be the trial that offers either ofatumumab with or without GS1101 as a way to avoid a chemo arm.

But wait and discuss with your doctors the ibrutinib and ABT-199 trials too if you need to consider therapy soon. I will be reviewing those and some of the related important ASH abstracts here soon. Videos of my interviews with the experts at ASH are being rendered and prepared.

It is good to have choices. Not so long ago, we had almost none. 

Many reasons to be thankful and hopeful.

ASH 2012: Experimental Ibrutinib Promotes High Response Rate in Leukemia

Here are interviews with my doctor, Dr. John Byrd from OSU and Dr. Claire Dearden from the UK after the press conference announcing the news on ibrutinib.

I will be following up with more videos and text a that provide more details, but this is a nice overview of the enthusiasm with this BTK inhibitor.

The video is from Internal Medicine News with thanks and that tells you that the interest in this therapy extends beyond the hematology community.



http://youtu.be/LmyNurcH7JA?t=16s

Life and Death

My personal lab results can wait. The science can wait.

What can't wait is the rendering of my, our collective pain on this page.

Three crushing notices of death in the last week. 

We all lost Ravi Shankar who was still teaching and making music days before he passed at 92. We celebrate his life and remember his music and at least for me, those heady days in the late 60s and early 70s when he first touched my life. The scene was a concert at the faded regality of the Outremont Theater, in Outremont of course, an ethnically diverse neighborhood of Montreal, where I lived when in medical school. The very high audience applauded loudly for the tuning up. Mr Shankar commented that he hoped they would enjoy the music as much. And then we were transported by the foreign tonality and rhythms of his raga to new places, places of peace and beauty. And the applause was stronger. We had been taught to listen with new ears.

I am sure his friends and family wanted more time with the master, but he had traveled further than most and 92 years is not a life cut short.

Not so with Randy Shirley, a CLL warrior, cut down in his prime, killed in his battle to lead himself and others to a place of disease control. A husband, father, friend, and confidant to many others with CLL, Randy's fight ended suddenly after only three short years from time of diagnosis. It wasn't supposed to happen like this. The trial of biological therapy was supposed to be kinder and gentler. Doesn't that mean that you aren't supposed to die?  While we have no information, no connections, no data, no causes or effects, but the one thing I know for certain is that life offers no such guarantees. No Kaplan -Meir Curve is 100%. You pay your money and take your chances. And don't expect the rules to be fair. What's fair about a brave and generous soul being so alive one day and gone the next?

But the absences of guarantees and fairness doesn't begin to touch the abyss of meaningless terror for the 20 children and the 7 adults of Newtown, Connecticut. 20 children, 20 little children, gone for no reason. The horror is unimaginable for their families. There are no answers, nothing that will ever calm my soul or ease the burden of living in such a tortured world or explain away the craziness. Others may fine solace in their faith and I bless them for that, and join in their prayers, but for me personally, that never has unlocked any doors of salvation. I wish it did.

My answers, such as they are, have to do with living.

For me, one of the living, one touched from a distant by these deaths, I will push forward with greater urgency, using my sometimes empty words and my too often tentative grasps of the science and my too occasional prescient maneuvers to try to heal myself and the world.

I will not surrender to the sorrow or be bullied by the terror. I will not say no to the risks. Instead, I will continue to take the necessary chances. I will not stop pushing the limits. Instead I will demand better answers.

I will remember to savor every moment as if it might be my last. 

Some old Hassidic wisdom will help: "Life is a very narrow bridge. The important thing is not to be afraid." Rebbe Nachman of Bratslav.

Let me finish with some east/west music, a raga, to soothe my (our?) ragged souls.

We are all in this together. Especially when it hurts.

Randy Shirley: Another CLL Warrior Passes

I had hope to post the good news on GS-1101 from ASH 2012, but life and death have a way of intervening. I will get back to my sharing of the science tomorrow, but my blog has always also been about the journey, the wins and the losses. And sometimes I need to share the bad news too. Sometimes I need to mourn the loss of a friend. Randy Shirley, a fellow CLL battler, passed away yesterday at the age of 55.

Randy Shirley

From my friend Nancy O'Brien Simpson:

Randy Shirley has my kind of leukemia which is currently considered incurable. He was diagnosed October of 2009. Married to his best friend, Debbie, for 33 years with three daughters. He was an awesome poster on my FB leukemia support group. So happy, and brave, and cool! He was young and relatively healthy when he volunteered for a clinical trial (ABT-199). He unexpectedly passed away this morning. Devastating news. The volunteers in the clinical trials pave the way for the rest of us. Sometimes with their very lives. RIP Randy Shirley and thank you. Your presence will be missed so very much.

From me:

I was blindsided by the sudden death of this brave and good man. So sad to lose another CLL warrior. Rest in peace, Randy. The memory of your hope and generosity is a blessing to all of us who were lucky enough to know you. My deepest condolences to his family and friends.

From my friend, Pat Kennedy:

The CLL community has lost a great warrior. Like everyone else I was blindsided by this news. Randy was participating in a clinical trial and had just posted yesterday about how well he was doing. His motto, which you know if you knew Randy, was "Never,Ever Give Up!" and he never did, right to the end. RIP Randy!

From another person in the same trial:

I am not sure you are aware yet but Randy Shirley has passed away.  I just met him and his wife on Monday when I was in Seattle for my monthly blood draw at SCCA.  He said he felt better than he had in years. He was on 300 mg of the drug at the time.  Tuesday AM he began taking 1200 mg of ABT-199.  Sometime on Wednesday he passed away.  I contacted the clinical trial coordinator and they are completely shocked and do not have any information that they are releasing at this point.  So no details.  I am stunned with this news but I know you and Randy have been in contact and he spoke to me Monday about how helpful you had been to him.  Thought you would want to know.  I am lost for words.

Randy and I were in regular contact. He was so upbeat about his trial and his disease. It is way too premature to draw any conclusion about the cause of his death or its possible relationship to the trial drug ABT-199. We know nothing about what led to his unexpected demise. Believe me that in these tragic cases, there will be careful probing into what happened and what can be learned. Believe me that nothing will be swept under the carpet. Trials don't work like that. If there is an issue, it will be outed. The safety profile has been excellent for many others and I would still recommend this drug.

But first I need to mourn the loss of another friend.

ASH 2012: CLL Highlights

I am still traveling, now in Ohio staying with friends for my OSU clinic visit with Dr. Byrd tomorrow. I am expecting that my mildly elevated neutrophils on my last blood draw will turn out just be an unexplained blip. I have other results from that prior visit that I need to discuss here too, but my personal story needs to take a backseat to the wonderful news from ASH for now.

I also have a photo shoot with the doctor, so I need my rest to look my best. More on that later.

When I am home, I will report in much greater detail on ASH 2012, Atlanta, GA, but I want to rush the news out about the big picture as soon as possible, so let me share some overarching highlights as I see them without the stats and scientific explanations behind them.

1. There has never been a year like this for those of us with CLL.
2. There is a palpable excitement and consensus among all the CLL doctors that treatment is radically changing for the better: a paradigm shift in therapy with the end of most chemotherapy possible in the next few years.
3. These new players are mostly oral therapies and are NOT traditional killers of rapidly dividing cells as is traditional chemo, but rather targeted biological drugs.
4. The stars of this sea change are GS1101 (formerly CAL-101), ibrutinib (formerly PCI-32765). and probably the least publicized member of this triumvirate, ABT-199 (a Bcl-2 blocker with amazing but less mature results).
5. Responses rates with these drugs in all comers, including the worst of the worst (think 17p del and refractory patients), are nothing short of astounding with progression free survivals in some treatment naive cohorts at 96% at about two years.
6. Responses get better, not worse, the longer we take these meds.The Kaplan-Meir curves are not falling. Relapses are remaining rare events, al least in the short term. We need longer follow-up for sure, but there is no signal that trouble is brewing,
7. Side effects are minimal and may actually decrease the longer we are on the medications.
8. The bone marrow is spared and infections at least with ibrutinib are not increased. Blood counts may actually improve with treatment.
9. With ibrutinib, there is some reason to believe immunity might improve
10. The data keeps just keeps getting better and better.

Much more to share about CAR-T, "off the shelf" CAR-T, GA-101, lenalinomide, the benefits of ASA and curcumin, and new encouraging data on 11q del, but I am badly sleep deprived so I am quitting here. Plus I need my beauty sleep for my photos.

Trust me that when I do fill in the details you will feel the same excitement that I felt humming in the air in Atlanta.

There is never a good time to get CLL, but there has never been a better time to get CLL.

ASH 2012: 10 Minute Break from the Excitement of the End of the Chemotherapy Era in CLL

Since I last posted I have interviewed Dr. Wiestner and Byrd, two of the most important researchers in moving ibrutinib forward. I also taped a long discussion with Dr. Wierda about CAR-T therapy among other things. Dr. Furman who did the phase 1 ibrutinib trial is next, then meeting Dr. Jeff Sharman.

This afternoon more lectures on ibrutinib, lenalidomide, and the first one on CAR-T.

Squeeze in the poster sessions and exhibit halls. And a visit with my sister-in-law.

Let me just summarize the news from ASH on CLL. You may not have heard it here first, but let me shout it out loud and clear.

The days of chemotherapy for CLL are ending. 

Details to follow.

Real Live Time at ASH 2012

I am posting this from the lecture hall at ASH with Jan Burger from MDACC speaking on ibrutinib and rituximab.

Forgive typos and possible errors. This is unedited and I may have made mistakes, so it is not gospel.

Here it is as it happens:

Study was in high risk CLL either 17 p or 11q del or < 3 yr response to FCR

Prior trial of ibrutinib alone good responses including the high risk patients, so more research.

This trial added R to see if helped, weekly x 4, then monthly x 6 months

Ibrutinib was given orally daily.

Enrollment criteria were these HR patients
Most patients Rai 3 or 4
Had average of 2.5 prior RXs
B2M elevated
50% 17p
33% 11q
80% unmutated

FINDINGS

As expected ALC showed rise at first then fell after months
Hgb climbed
Only 2 patients off study, or 38 of the 40 patients are still on study
Dramatic shrinking of nodes within weeks.
At 3-6 months more than 50% decrease in node size. No difference in 17p responses.
Same with shrinking spleen
At 3-6 month, 1 CR, ORR was 83%, 2 with SD
ADVERSE EVENTS:
20% diarrhea
Bone achy, No increased infections.
BIOMARKERS
CCL3 CCL4  too high at start, fell with Rx

That's it.

38 out of 40 doing well in the highest risk patients. That's amazing.

LIVE FROM ASH 2012

Let me use this post just to set the scene. I will bear news soon, all of it good, some of it incredible.

There is so much happening at ASH, often at the same time. There are several incidences when I have highlighted three different important presentations related to CLL for the same 15 minute slot that I would love to attend. That's not going to happen.

Add to this is that the conference center is so huge that it can take 20 minutes or longer to walk from one  lecture hall to another. I actually walk much more inside the building than the pleasant 15 minute walk through centennial park to the center from the hotel.

Add to that some 15,000 attendees, all of whom are in the halls between sessions with the proficient and helpful staff directing the heavy to and fro foot traffic through the long corridors and onto the narrow escalators.

So far one and a half days into it, I have interviewed Drs. Pagel, Kipps, and Steensma. Andrew Schorr interviewed me and I returned the favor, asking him about his coping with a secondary cancer. I have video from the press conference on ibrutinib given by Dr. Byrd.

So much more yet to happen.

Without my professional videographer, my oldest son, Ben, it would be impossible to pull this off.

The logistics are tricky. At the Georgia World Congress Center, we are constantly rejiggering the schedule, lining up the hematologists ( think herding cats), procuring the much in demand interview rooms, setting and resetting up redundant recording systems, doing the sound and video checks, and finally making sure the actual interviews runs on time. Rushing back to the hotel, Ben is recharging batteries, downloading the video cards, running our backups, and doing all the trouble shooting.

In between I am attending lectures and trying to find something vegan to eat.

The first sessions start at 7:30 AM and the last can finish at 8AM.

It makes for a long, busy but incredibly rewarding day.

I am so lucky to be here, to have my son's help and to have access to the generosity and wisdom of so many doctors.

The Absolute Latest on Ibrutinib. Press Release from ASH 2012

Here is the official press release from the ASH 2012  press conference that I attended at 8 AM Atlanta time. I don't need to point out that it is 5 AM California time. This information from Drs. Byrd and Burger is no longer embargoed so I can now share. Video and links to follow but I wanted to rush this out. This should be seen as the beginning of a whole new paradigm in how we treat CLL. This is not an incremental change, but a sea change. The details, the drugs, the combos, the timing, all need to be worked out, but it is safe to say that the future of CLL treatment will be radically different than the past and that is a very good thing for the 70% of  those of us with CLL who will need treatment. A very good thing.

Enough from me.

The raw ASH press release:

New Investigational Agent Targets Gene Signaling Pathways to Improve Therapeutic Response for Patients with Chronic Lymphocytic Leukemia


December 8, 2012

EMBARGOED FOR RELEASE UNTIL: Saturday, December 8, 2012, 8:00 a.m. EST



(ATLANTA) - The promising investigational targeted therapy ibrutinib and its mechanism of silencing gene communication pathways critical to the development of cancer may be an effective way to combat chronic lymphocytic leukemia (CLL), according to studies presented today at the 54th Annual Meeting of the American Society of Hematology (ASH).



CLL is a blood cancer that causes abnormal white blood cells called lymphocytes to accumulate in the blood, bone marrow, and in the lymph nodes or other organs, causing these organs to enlarge. Approximately 15,000 Americans are diagnosed with CLL every year; nearly 70 percent of those affected are 65 and older.1, 2 For some patients with slower growing disease, physicians employ “watch and wait” strategies to minimize unnecessary treatment. However, patients with high-risk features such as rapidly progressing disease require prompt treatment to manage symptoms and reduce organ damage.



Ibrutinib is a specialized anti-cancer therapy that targets the Bruton’s tyrosine kinase (BTK, an enzyme important in the development of CLL). As an inhibitor of BTK, ibrutinib selectively targets leukemia cells, promoting their death and preventing them from growing while leaving normal cells unharmed. Studies suggest this design allows the drug to more effectively treat the disease, with encouraging early results in harder-to-treat patient groups such as elderly untreated patients and those whose disease has become resistant to other therapies or those who have experienced disease recurrence after receiving other therapies. Two studies will present efficacy and safety results testing the compound alone and in combination with other currently used therapies for CLL.



“The evidence collected to date on ibrutinib demonstrates that it may have the potential to improve long-term prognosis for patients who are not sensitive to standard treatment,” said Claire E. Dearden, MD, moderator of the press conference, Consultant Hematologist and Head of the CLL Unit at The Royal Marsden NHS Foundation Trust in London. “Equally important, the exciting efficacy and safety data that we are seeing for this drug in these studies underscore the significant progress we are making in our quest to better understand and attack the specific cellular targets responsible for CLL, particularly in these vulnerable patient populations.”



1 National Cancer Institute, “SEER Stat Fact Sheets: Chronic Lymphocytic Leukemia,” http://seer.cancer.gov/statfacts/html/clyl.html (Accessed October 2012). 2 Gribben, J.G., “How I treat CLL up front,” Blood 115, no. 2 (2009): 187-197.This press conference will take place on Saturday, December 8, at 8:00 a.m. EST.



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The Bruton’s Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Promotes High Response Rate, Durable Remissions, and is Tolerable in Treatment Naïve (TN) and Relapsed or Refractory (RR) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Patients including Patients with High-Risk (HR) Disease: New and Updated Results of 116 Patients in Phase Ib/II Study



[Abstract 189]



New research demonstrates that a novel investigational therapeutic agent called ibrutinib may be an effective and safe targeted treatment option for previously untreated, hard-to-treat, and relapsed patients with chronic lymphocytic leukemia (CLL).



Primary treatment for CLL includes a combined chemotherapy-based regimen with fludarabine and cyclophosphamide, along with the immune therapy rituximab. While rituximab is effective, it is generally not well tolerated among elderly patients. Treatment with this drug also compromises the immune system by attacking both cancerous and normal cells, putting patients at risk for a range of infections and increasing their risk of developing treatment-related acute myeloid leukemia.



To understand if ibrutinib may be effective for elderly CLL patients and to identify which patients might benefit most from the drug, researchers enrolled 116 CLL patient participants in several treatment cohorts: patients who were never treated (the treatment-naïve group), those who had received two or more prior therapies (the relapsed/refractory group), those who had relapsed within two years of treatment (the high-risk group), and those over age 65. Two oral dosing regimens (420 mg or 840 mg daily) of ibrutinib were used. The primary goal of the study was to determine the safety of the low and high doses; secondary objectives included efficacy, measures of the intensity of the drug’s effect in the body, and the long-term safety of administering this therapy continuously until relapse.



The study found that response to therapy was high across the cohorts, with largely manageable toxicities. Previously untreated elderly patients responded best to the agent, with 71 percent experiencing a complete or partial response at either treatment dose. The same response was observed in 67 percent of the relapsed patients and 50 percent of the high-risk patient cohort. After 22 months of follow-up, the disease had not progressed in 96 percent of previously untreated patients and 76 percent of relapsed and high-risk patients.



The treatment regimen was generally well-tolerated, as only non-severe side effects were observed, including diarrhea, fatigue, chest infection, rash, nausea, joint pain, and infrequent and transient low blood counts. Investigators found no evidence of cumulative toxicity or long-term safety concerns with a median follow-up of 16 months for treated patients. These results demonstrate ibrutinib’s potential as a highly active, well-tolerated first-line therapy for CLL.



“As we learn more about how to target specific essential survival signals and communications pathways in cancer, we are improving our ability to effectively treat the disease while avoiding the toxicities of chemotherapy and potential relapse,” said John C. Byrd, MD, lead author and Director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute in Columbus. “If we can replicate these high survival rates and good tolerability with ibrutinib through larger scale Phase III studies, we may find it to be an extremely valuable new therapy for not just elderly, but for all CLL patients.”



Dr. Byrd will present this study in an oral presentation on Sunday, December 9, at 5:00 p.m. EST at the Georgia World Congress Center in Thomas Murphy Ballroom 4, Level 5, Building B.


The BTK Inhibitor Ibrutinib (PCI-32765) in Combination with Rituximab is Well−Tolerated and Displays Profound Activity in High-Risk Chronic Lymphocytic Leukemia (CLL) Patients


[Abstract 187]


The combination of the novel investigational agent ibrutinib with an established therapeutic antibody, rituximab, may present a safer and more effective option than the current standard chemotherapy-based treatment regimen for patients with high-risk CLL.



While current chemotherapy-based treatment options for CLL patients are effective, they come with toxic side effects that are challenging for elderly patients. Physicians have long awaited new options that offer better tolerability. Ibrutinib is designed to selectively target leukemia cell growth, with the aim of effectively treating the disease without the toxicities of chemotherapy. Data from earlier studies of ibrutinib have shown it to be equally effective in both low- and high-risk CLL.



High-risk CLL patients typically have unfavorable responses to standard CLL therapies and a dismal outcome. Such patients are characterized by presence of chromosomal abnormalities (i.e., deletions of chromosome 17p or 11q) or short remissions (less than 3 years) after standard chemo-immunotherapy. To develop an alternative therapy regimen for this patient population, researchers explored the combination of ibrutinib and the anti-CD20 antibody rituximab in high-risk CLL.



In this Phase II study conducted at The University of Texas MD Anderson Cancer Center in Houston, ibrutinib was given in combination with rituximab to evaluate its potential to accelerate and improve CLL patient responses. Forty patients were treated with 420 mg of ibrutinib daily in combination with weekly rituximab for four weeks, followed by ibrutinib daily plus monthly rituximab until month six, followed by single-agent ibrutinib.



Positive responses to therapy were shown among the vast majority of treated patients. At four months of follow-up, the overall response rate was 85 percent and almost all (38 of 40) patients continued on therapy without disease progression. Of the 20 patients evaluable for early response, 17 achieved a partial remission. Patient health questionnaires also noted improvements in health and the quality of life of all treated patients.



Overall, the regimen was well-tolerated among participants, with little severe toxicity that was largely unrelated and short in duration. After treatment with ibrutinib-rituximab (iR) combination therapy, most cases of early lymphocytosis (increase in white blood cells that is a sign of infection), due to the ibrutinib-induced shift of CLL cells from lymph node tissues into the blood, peaked early and resolved; at four months of follow-up, only three treated patients had lymphocytosis that had not yet resolved. This shorter lymphocytosis duration, when compared to single-agent use of ibrutinib, is presumably related to the addition of rituximab.



“We know that high-risk CLL patients struggle with the effects of standard chemo-immunotherapy and eventually become resistant. For these harder-to-treat patients, ibrutinib in combination with rituximab appears to be a safer option with high efficacy and without the related risks,” said Jan Burger, MD, PhD, lead author and Associate Professor of Medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “Based on these promising results, we need larger-scale studies of ibrutinib-rituximab in high-risk CLL, with the goal of accelerating the development of this therapy for patients who most urgently need better options.”



Dr. Burger will present this study in an oral presentation on Sunday, December 9, at 4:30 p.m. EST at the Georgia World Congress Center in Thomas Murphy Ballroom 4, Level 5, Building B.



American Society of Hematology 54th Annual Meeting



The study authors and moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on efforts to reduce toxicity and improve survival for blood cancer therapy, strategies to increase the efficacy and safety of treatments for bleeding and clotting disorders, new targeted treatment for hard-to-treat blood disorders, and advances in stem cell technology and transplant strategies. For the complete annual meeting program and abstracts, visit www.hematology.org/2012abstracts. Follow ASH (@ASH_hematology) on Twitter (use the hashtag #ASH12 when posting tweets about the meeting) and on Facebook at www.facebook.com/AmericanSocietyofHematology for the most up-to-date information about the 2012 ASH Annual Meeting.





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The American Society of Hematology (ASH) (www.hematology.org) is the world’s largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 50 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. The official journal of ASH is Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, which is available weekly in print and online.

ASH Abstract: Long-Lasting Responses with Lenalidomide As Initial Therapy of Elderly Patients with Chronic Lymphocytic Leukemia (CLL)

Here's another abstract from ASH, # 3932.

I need to be reminded that most patients with CLL are elderly. The median age at time of diagnosis is about 71 or 72. I tend to be in touch with a skewed population sample as I suspect that those who follow my blog and are active on a list serve or Yahoo group might be a younger bunch. There are of course many many exceptions.

Our bone marrow becomes less resilient as we age (doesn't everything), so the standard approach of FCR can be hard and persistently dangerous low blood counts can delay or even prevent a full course the chemo-immunotherapy. And some elderly may not tolerate the adverse events as well, especially those who have picked up co-morbidities during their long lives.

That is why it is encouraging to see non chemo approaches to CLL, this time with the immune modulator, lenalidomide (the son of the infamous thalidomide that caused so many birth defects).

No-one is quite sure how it works, but that is a topic for another post.

The old good news is that it is a pill (no infusion needed) and the response rate is high with two out of three patients responding and a whopping 88% alive at two years. What is new this year that is being presented at ASH 2012 is that the researchers continued to follow this cohort and now three full years out (or longer) 31 of 60 are still responding. 29 of those 31 are in a CR (complete remission) with 4 MRD negative (minimal residual disease negative) CR. Very nice durable responses in a little over half of the patients for  at least 36 months! 

The median dose was low, only 5 mg a day, with a range of 2.5-10. That's good. This is one drug that is cheaper and safer at lower doses. Side effects that led to stopping the drug were the usual suspects: DVT (deep vein thrombosis) fatigue, secondary cancers (skin), and neuropathy.

Neutropenia resolved in 83% patients within a year. Hgb (100%), platelets (77%) and even immune globulin (IGG, IGM and IGA levels were higher than baseline in those who were long term survivors. T cell counts increased, More good news and a very different story than told by most chemo drugs.

The bad news is that it doesn't work for those who need it the most. Long term survivors "were more likely to have lower baseline levels of beta2-microglobulin, IL6, IL8, IFNγ and MIP1α and intermediate or favorable cytogenetic abnormalities."

In other words, those whom are favorable to treat, are favorable to treat. Those of us with poor prognostic factor live up to our billing, at least with this drug.

Remember also that everything has its price Lenalidomide is associated with potentially fatal blood clots, tumor lysis syndrome, painful and potentially fatal tumor flares, secondary cancers, suppressed blood counts, profound fatigue, diarrhea, neuropathies, and serious infections, so use with caution.

Still for half the population, this looks like a fine option. Better than chemo.

For the others. let's check for the news of trials of the tyrosine kinase inhibitors in the elderly.

On a personal note, my blood chemistries remain remarkably unremarkable with kidney and liver function all in the very healthy range. Low LDH and uric acid are also reassuring that nothing sinister is brewing in my blood.

Tonight, I am off to the beach, where there is no WIFI, but my cell phone works. I have mixed feeling about that.

From there I leave for ASH in Atlanta on Friday.  Much to share.

Life is good.

Dr. Richard Furman on Surprising Early Trial Results for Ibrutinib

We were all surprised, pleasantly surprised.

Dr. Furman did the first phase 1 study on ibrutinib. I remember him mentioning this trial to me years ago and it seemed to me such a long shot.

Not any more.

Thanks to those who had the courage to try something new. They were the real pioneers. We who are in the phase 2 and 3 trials are all in their debt.

And those who are eventually prescribed this drug or GS-1101 or others should look kindly on those of us who earlier make the decision, took a much lesser but still significant risk and entered a phase 2 or 3 trials.

Never quite normal. My latest lab shows a slightly high neutrophil count

Just once, it would be gratifying to get back a CBC (complete blood count) where every results was within normal limits. 

Just once.

Most of the time I am pretty close, but there is always some value that falls slightly out of the range of normal, causing my lab result to glow"red" in my electronic medical record.

I always disregard all the percentage of the white count and only focus on the absolute counts. Doing this is good medicine and gives me much less to ponder over. All patients should pay attention to the absolute counts, not the percentage.

Today my hemoglobin, my lymphocytes, and my platelets were all good. The size of my red cells (MCV or mean cell volume) remained a touch too big. This is probably a under-recognized consequence of having my spleen removed years ago, so I refuse to worry. I supplement my vitamin B12 as all vegans must (there is no source of B12 outside of animal products), my folate is fine and so it should be with my plant based diet, I don't drink, and my MCV is stable so I doubt it is a reflection of a damaged marrow. That list pretty much covers all the common causes of a macrocytic (big red cell) anemia that might apply to me, and besides I am not even anemic today.

What is new today is that my ANC or absolute number of neutrophils is a slightly high. Normal is under 8,000 (I usually run between 4,000 and 5,600), but today I'm 9,000. As a result my total white blood cell count is also raised at 12,300. 

A high ANC can be a sign of infection, usually bacterial. I have no infections that I know of other than a bit of a sore right nostril, that thankful has not bled in almost 2 weeks. Perhaps that could be enough.

Neutrophils also can jump up from any stress, physical or even emotional. That I alway have.

In my case, there is no cause for concern or worry, but it does demand monitoring to see if there is any trend.  One lab test means nothing. A level this close to the upper end of normal means nothing. 

Under react in my mantra, and this time it is easy.

Eight days from now, after a few days at the beach to relax and read and write, then the crazy busyness of ASH meeting in Atlanta, I will get my blood work all repeated at OSU.

This will all prove to be of no consequence, other than just once it would be great to get all normal results.

I guess it is just my fate, and that I suspect of the majority of my readers, never to be just like all the other kids.

Yet Another Reason to See the Dermatologist

I am trying to highlight more of the CLL literature in the lead up to ASH and even more so in the weeks that follow, but my blog will always continue to tell my personal story and add my commentary.

Stay tuned here for some more video interviews from ASH here starting a few weeks after the meeting next weekend.

Below is an interesting recent abstract from a surgical journal (not our usual source for CLL research) dealing with the association of melanoma with CLL.

What it is saying, among other things is that sometimes the CLL is an unexpected incidental finding when doing a lymph node biopsy for melanoma. Believe me, it is way better to find CLL in the node than melanoma. Having melanoma in a node is not good news.

It also says that those with melanoma have a much higher (10 fold) incidence of CLL compared to other cancers. Thanks for returning the favor, as we already know that those of us with CLL have a higher incidence of melanoma.

What goes around comes around.

We also already know from older research that those of us who develop a melanoma along with our CLL tend to have a more aggressive form of the skin cancer with a worse prognosis.

 Isn't this fun?

While this abstract doesn't address the risk of melanoma with CLL (it address the reverse), we still need to see our dermatologists regularly and avoid excessive sun.

No point in beating the CLL and then succumbing to a metastatic melanoma. There is no watch and wait for melanoma. Treatment is usually a full on wide ranging immediate assault. Early diagnosis can be life saving for us.

Ann Surg Oncol 2012 Nov 20. [Epub ahead of print]

A Collision of Diseases: Chronic Lymphocytic Leukemia Discovered During Lymph Node Biopsy for Melanoma.

Farma JM, Zager JS, Barnica-Elvir V, Puleo CA, Marzban SS, Rollison DE, Messina JL, Sondak VK.

Source

Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA, jeffrey.farma@fccc.edu.

Abstract

BACKGROUND:

In the United States in 2012, there were 16,060 new cases of chronic lymphocytic leukemia (CLL). Often CLL is clinically occult and first detected during pathologic evaluation of the sentinel lymph node biopsy (SLNB). We reviewed our experience of patients with the coexisting diagnosis of melanoma and CLL.

METHODS:

An institutional review board-approved review was performed on patients with CLL and melanoma treated from 1995 to 2009 at Moffitt Cancer Center and compared with the incidence of melanoma and CLL in our tumor registry patients with breast, prostate, lung, and colon cancer.

RESULTS:

Fifty-two patients (44 males; median age, 71 years [range, 46-88]) were identified with concurrent diagnoses of melanoma and CLL. Twenty-two patients (42 %) had CLL on SLNB for their melanoma. Thirty-two patients (62 %) were diagnosed with melanoma before CLL. Concomitant or prior cancer diagnoses included nonmelanoma skin cancers (N = 29), prostate (N = 6), colorectal (N = 2), and Merkel cell carcinoma (N = 2). Five of 20 patients (25 %) had metastatic melanoma found at the time of SLNB. Patients with melanoma had a tenfold increase of CLL diagnosis compared with colorectal cancer patients, an eightfold increase compared to prostate cancer patients, and a fourfold increase compared with breast cancer patients.

CONCLUSIONS:

We have confirmed an increased association of CLL and melanoma. This may be related to an underlying immunologic defect; however, there has been scant investigation into this phenomenon. Surgeons and pathologists should understand this occurrence and recognize that not all grossly enlarged or abnormal sentinel lymph nodes in melanoma patients represent melanoma.

PMID:

 

23179994

 

[PubMed - as supplied by publisher]

Another Reason to Exercise: It Lowers the Risk of Blood Cancers

I am just starting to review the abstracts from ASH and this one stood out.

It tried to determine if exercise lowered your risk of blood cancers. It also seems by the title (Regular Recreational Physical Activity and Risk of Hematologic Malignancies: Results From the Prospective Vitamins and Lifestyle (VITAL) Study) that they were researching the benefits of vitamins, but they did not report on that. I wonder why? Maybe I will get a chance to ask the investigators at ASH next week.

It is a big prospective study and that is good. They also controlled for most risks factors such as smoking and family history, also good. But the history was mostly self -reported which as first seems bad, but if you think about it, more people will likely exaggerate rather than minimize the amount of exercise they do. That would tend to weaken the effect of the actual amount of exercise and make finding any true relationship more unlikely.

What they did find is that in this group of 50-76 year olds, the more exercise, the less cancer. The reduction was big, more than a third for those getting their heart rates up 3.5 times a week or more. The negative association was strongest for myeloid cancer, cutting the rate in half for the those who exercised the most. Wow! But there was only a statistically insignificant trend for CLL and there was no effect for plasma cell cancers.

I wonder why the effects would be so so different for different cell lines.

What I can tell you that I already have CLL so I can't lower my risk. None of us with CLL can. We are at 100%, but although we already have CLL, most of us don't have a secondary myeloid cancer, at least not yet. The bad news is that our disease and its treatment, especially alkylating agents such as bendamustine, cytoxan, and chlorambucil and purine analogues (fludarabine) greatly increases our odds of these blood cancers. I will present some new papers on this topic later. Therefore anything I can do to that might lower my risk of these secondary cancers, these killers, is a no brainer.

Another reason for all of us to get moving. The more, the better.

Here's the abstract. The highlights are my addition.

87 Regular Recreational Physical Activity and Risk of Hematologic Malignancies: Results From the Prospective Vitamins and Lifestyle (VITAL) Study
Program: Oral and Poster Abstracts
Type: Oral
Session: 613. Acute Myeloid Leukemia - Pathophysiology & Clinical Studies: Basic
Tuesday, December 11, 2012: 8:30 AM
A103, Level 1, Building A (Georgia World Congress Center)
Roland B. Walter, MD, PhD1,2, Sarah A. Buckley, MD3* and Emily White, PhD4,5*
1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 2Department of Medicine/Division of Hematology, University of Washington, Seattle, WA 3Department of Medicine, University of Washington, Seattle, WA
4Department of Epidemiology, University of Washington, Seattle, WA
5Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
Background: Recreational physical activity (PA) provides numerous health benefits, including a reduction in cardiovascular and metabolic diseases and promotion of mental health. Increasing evidence from epidemiological studies also links PA to a reduced risk of major human cancers, particularly those of the colon and breast. On the other hand, previous case-control and cohort studies examining the relationship of PA and incident hematologic malignancies yielded inconsistent results. Given these conflicting findings, we used a large prospective cohort study to examine this association.
Patients and Methods: 65,322 men and women aged 50-76 years were recruited from 2000-2002 to the VITamins And Lifestyle (VITAL) study. The PA questionnaire at baseline asked about walking by intensity and two broader categories of activities (mild and moderate/strenuous exercise) by type over the past 10 years. For each activity, a corresponding metabolic equivalent (MET) intensity was assigned. Incident hematologic malignancies (n=666) after study enrollment were identified through December 2009 by linkage to the SEER cancer registry. Hazards ratios (HRs) for total incident hematologic malignancies and cancer subcategories associated with PA averaged over the previous 10 years before baseline were estimated by Cox proportional hazards models. Models were adjusted for age, sex, race/ethnicity, education, smoking, self-rated health, daily fruit and vegetable consumption, body mass index, fatigue, self-reported anemia, and family history of leukemia/lymphoma.
Results: After adjustment, there was a decreased risk of hematologic malignancies associated with any PA (HR=0.75 [95% CI: 0.61-0.94]) as well as any moderate/high-intensity activity (HR=0.72 [95% CI: 0.57-0.92]). The reduction in risk was greatest among the physically most active participants, both with regard to number of weekly episodes of activity (>4.8 episodes of all activities per week: HR=0.66 [95% CI: 0.51-0.86], P=0.005 for trend; >3.5 episodes of moderate/high-intensity activities per week: HR=0.60 [95% CI: 0.44-0.82], P=0.002 for trend) and metabolic activity (>13.625 MET of all activities per week: HR=0.71 [95% CI: 0.54-0.92], P=0.029 for trend; >11.2972 MET of moderate/high-intensity activities per week: HR=0.65 [95% CI: 0.48-0.89], P=0.005 for trend), respectively. To address the possibility of reverse causation, i.e. the possibility that study participants were physically less active as a result of a yet undiagnosed hematologic malignancy, we repeated these analyses after exclusion of the 146 incident cases that occurred within 2 years of baseline: the reduction in risk of incident hematologic malignancies among the physically most active participants in this study subset was relatively similar to that of the entire study cohort. When we stratified malignancies by WHO disease classification, we found that the association between PA and incident hematologic malignancy was strongest for myeloid neoplasms (HR=0.48 [95% CI: 0.29-0.79] for highest tertile of all PA, P=0.013 for trend; HR=0.40 [0.21-0.77] for highest tertile of moderate/high-intensity PA, P=0.016 for trend). There were also significant associations between episodes of moderate/high intensity PA and incident mature B-cell lymphomas other than chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or plasma cell disorders (>3.5 episodes per week: HR=0.59 [95% CI: 0.36-0.97], P=0.035 for trend) and between episodes of all activities and incident CLL/SLL (>4.8 episodes per week: HR=0.52 [95% CI: 0.26-1.03], P=0.023 for trend). No associations were found with incident plasma cell disorders.
Conclusion: Our study offers the strongest epidemiological evidence to date to suggest that regular recreational PA is associated with a dose-dependently reduced incidence of certain hematologic malignancies, with a greater than 50% reduction of risk for the development of neoplasms of myeloid origin for individuals within the top tertile of all or moderate/high-intensity activities. Our data also suggest a trend toward reduced risk for CLL/SLL and other mature B-cell NHLs except plasma cell disorders, although further studies in larger cohorts of participants will be required to assess these associations further. Together, our findings may thus suggest additional important health benefits attributable to regular PA.