Frontline therapies In CLL (Chronic Lymphocytic Leukemia)

In this lively ONCLIVE multi-part series of polite debates among four world class CLL experts (Drs. Byrd, Furman, Ma, and Kipps), I was struck by the conservative approach of the panelists to frontline therapy.

Almost all the discussion in this 13 minute segment is about chemo-immunotherapy (CIT).

Keep on mind that except for patients with 17p deletion where ibrutinib is approved, chemo-immunotherapy is all that is approved for frontline therapy. That said, we all know that many doctors including several on this panel would discuss with their patients other frontline options besides those they discuss on camera, namely FCR (fludarabine, cyclophosphamide and rituximab) or BR (bendamustine-rituximab) or chlorambucil and obinutuzumab.

Dr. Kipps points out the potential advantages of the chlorambucil and obinutuzumab in elderly patients with a less resilient bone marrow. This relatively gentle approach has achieved a 20% complete response rate and a 26.7 month mean progession free survival, much better than the other arms in the trial that lead to its approval. For the details of the study published in the NEJM please click on this link.

Drs. Byrd and Kipps talk glowingly about the very long term benefits of FCR in a small subset of patients with the best prognostic markers: mutated with no other bad prognostic indicators. This is a subject we have visited frequently visited in the past. Here Professor Hallek and I discussed this topic in this post in the context of the role of chemo-immunotherapy (CIT) way back at iwCLL 2013. I am still waiting for the published material on that low risk subgroup that is looking more and more as if they might be CURED!

In this ONCLIVE video, there is also debate on the need to complete all the cycles of FCR to get the full benefit. I fully agree with Dr. Kipps that the evidence suggests getting to MRD (minimal residual disease) negativity is what determines our prognosis and not the number of cycles it takes to get there. I quote from a Blood editorial by Sebastian Böttcher on the original research: "current investigation suggests that the number of treatment cycles also becomes irrelevant as long as MRD negativity can be attained." 
The full text of the original research is accessible here. The authors state in the abstract that:" MRD-negative patients had comparable PFS ( progression free survival) and OS (overall survival), independent of the number of courses received or interim staging. Early MRD eradication may be a desirable goal, prompting consideration of early discontinuation of treatment."

Dr. Furman hastened to point out the potential downside of chemo-immunotherapy and also that the group that did so well is a group that should do well with any therapy.

In this article from the British Journal of Hematology, we learn: "patients treated with purine nucleoside analogues (PNA) had a significantly increased risk of subsequent second LPD (5·2%) compared with patients who had not received PNA (1·9%; P = 0·008)"  PNA are drugs such as fludarabine and LPD are lymphoid cancers.  In fact, they go to stated that the only factor found to be associated with an increased risk of a secondary lymphoma for those us with CLL was prior treatment with chemotherapy.

That certainly does give one pause.

There is also some very interesting comparison of BR versus FCR, a subject that we extensively reviewed in this prior blog post with Dr. Jeff Sharman.  I appreciate Dr. Kipps' careful analysis of the different arms of the trial to ensure that we are really comparing apples to apples.

Give a listen and please share your comments.

Again, thank you ONCLIVE for bringing us this great panel discussion.

When Sportswriters Cover the Cancer Beat: The Uneven Reporting of the Bob McNair CLL (chronic lymphocytic leukemia) and Skin Cancer Story

The owners of the NFL team, the Texans, Bob McNair has come out and shared his successful battle with CLL and a very aggressive squamous cell (skin) cancer.  The newspapers in Texas were full of the good news, but they didn't quite get the CLL piece right.

Please take a look at this news report:

Texans owner McNair gets clean bill of health after cancer fight

Or check out:

Texans owner McNair healthy after 10-month cancer battle

where you will read:

"McNair's remarkable recovery has included ground-breaking experimental treatment for chronic lymphocytic leukemia (CLL)…"

I want some of whatever that is.

Here is my published comment in response to the article:

Good news. While Mr. McNair's skin cancer may be curable, not so with his blood cancer, CLL. At least not yet, however, it is often controllable with therapy. Since CLL weakens the immunity, it can make skin cancers more aggressive. The message here is that anyone with CLL and many other cancers needs to be particularly careful about their sun exposure and vigilant in checking their skin for any suspicious lesions. Sadly one cancer, especially CLL, can lead to another.

Turns out a few of the sportswriters got a bit scrambled in their understanding of the management of his slow moving CLL versus his aggressive skin cancer that spread well beyond the skin requiring extensive and repeated surgeries, radiation, chemotherapy and eventually skin grafting.

The press conference with Dr. Michael Keating out of MDACC (MD Anderson Cancer Center) tells a clearer story with the full transcript at this link. Dr. Keating has a long and broad view of what we CLL patients need and I am glad he is a leader on our Team CLL. I also love the way he can generated much needed publicity about our cancer that seems to spend most of its life in the shadows, avoiding the bright lights and headlines.

The ground-breaking experimental treatment mentioned in the report was pheresis or more commonly called apheresis and its experimental use is to increase our wimpy immune response and lower our high risk of secondary cancers and their reoccurrence. 

Dr. Keating explains it at the press conference:

"You’re all aware that there’s an increased instance of melanoma that occurs because of tanning beds and things like this, but the most common forms of skin cancers are Basil Cell cancer and Squamous Cell cancer and many people like Mr. McNair have more frequent visits to their dermatologists than to the other members of their families sometimes because they keep on coming back. So the one element of Chronic Lymphocytic Leukemia or CLL, which is the most common leukemia that we see in the western world, is that there is a complex suppression of the immune system and the only non-AFDA approved activity was part of an extension of a protocol where we could take immune cells out by a process called apheresis, where you go through a machine and you take white cells out and separate the immune cells and then stimulate them up a thousand fold so they go to one-hundred-million to one-hundred-billion and give them back and rebuild the immune system to try and prevent these events from occurring."

Looks as if the transcribers may have missed a few key words and phrases.

A few reflections on what we can learn from the news.

1: Another celebrity, Bob McNair, the owner of a proud NFL team, tells the world he has CLL and skin cancer. Of course I wish he had shared the CLL news earlier, perhaps even at the time of diagnosis in order to help remove the cancer stigma and demonstrate how well he continued to live his active life for many years post diagnosis. I recognize that sharing a cancer diagnosis is a complex and very personal decision. Still I wish he had told the world when he was in the battle and not after it was at least partially over, but still I am grateful for his thoughtful and generous comments to the media about his two cancers and the treatment. I have posted extensively on this subject and received many lively comments on the decision to share the news or shut up. This link will get get you started if you wanted to revisit that topic.

2: We CLL patients are all at heightened risks for skin cancers and even the usually well behaved ones can become very nasty with our suppressed immunity. We get more cancer and the cancers we get are more aggressive. We need to use our sunscreen and our hats and have a full body skin check (and that really means full body) at least once or twice a year. See this prior post on secondary cancer risk with CLL (and CT scans).

3: MDACC and others are working hard on ways to improve our immunity. We need that. Dr. Wierda talked about his immune boosting research last year in this post. Remember that it is secondary cancer and infections that kill the majority of us that arise as a result of our weakened immunity from the disease itself and its old school chemo treatments. No point of knocking the CLL back and then dying of a secondary problem.

4: Sportswriters should stick to covering sports. Or if not, get some help and fact checking. Many otherwise fine reporters when covering cancer go for the feel good story. I guess they get tired of writing about the bad news and dirty laundry the rest of the time. That's nice, but it is not the whole picture. I promise I won't write on sports (except maybe a little about my beloved LA Kings and ice hockey) if they won't write on CLL. You don't need a medical degree to be a good medical reporter, but it sure helps. If not, then please do your research or ask for help and please tell the whole story, the good and bad.

Saying No to Chemo: Non -Chemo Options for CLL, Part 1

This is probably the most common question that I am asked.

"I know that I need therapy, my CLL is taking off, but I don't want any chemo, so what are my options?"

The answer used to be "not much", but not so anymore. Today there are many choice and soon there will be even more.

But before I give my answer, let me give an important preamble and discuss what we are taking off the table when we veto the chemo option.

When fellow CLLers says no chemo please, I take it to mean that they don't want cytotoxic drugs that work by preferentially killing rapidly dividing cells.

For CLL in the USA, we are mostly taking about two classes of medications.

Number one and the backbone of most chemo cocktails is fludarabine that is a classic purine analog that kills by blocking DNA synthesis. Pentostatin and clardribine are similar adenosine analogs that work the same beat. What these cleverly designed drugs do is pretend to be purine, get themselves incorporated into the dividing DNA and completely gum up the work of replication. Nice.

The other class of pure chemo drugs we see a lot of are the direct descendants of the now banned World War I poison, mustard gas or nitrogen mustard. (The story of how its antileukemic powers were accidentally discovered is worthy of its own post). They destroy by attaching an alkyl group to any and all busy DNA, causing aberrant cross links and preventing it from making copies of itself. The more active the DNA, such as in a fast growing cancer, but also in our fast growing gut and skin, the more damage and the greater the kill. This is how the old standard therapy chlorambucil (AKA Leukeran) works. So too cyclophosphamide  (Cytoxan) the big C in FCR, and bendamustine (Treanda) an old communist drug but a new kid on this side of the Berlin Wall.

There are many many others cytotoxic drugs in oncology that play lesser roles in our disease such as vincristine (Oncovin), the V in CVP occasionally used for refractory CLL and just to confuse us, the O in R-CHOP used for Richter's Transformation and many lymphomas.

Oncologists carefully concoct these toxic cocktails with several goals in mind.

First they want to add to the killing power. Cancer is famously adaptive and will rapidly mutate itself right past a block on its road to lusty growth. Blocking it when it turns to either the left or right is a smart strategy. So too is capturing it in a pincer move with the lengthening lists of the toxic chemicals that make up the alphabet soup that we and others get IV to knock the socks off our cancer, and sometimes (but probably never in CLL) kill it for good.

But doesn't adding one drug on top of another inevitably lead to unacceptable toxicities?

Not necessarily so says our clever oncologists. They look for more than just complementary killing. They look for non-overlapping toxicities. CHOP is the poster boy example, a potentially curative cocktail for some lymphomas, where each of the chemo drugs interferes with the DNA in different synergistic ways AND where each drug has a different toxic target (the marrow or nerves or the heart).

Of course, it is never black and white, and dosing and individual sensitivities widely vary.

Hippocrates famously said that the difference between a medicine and a poison is the dose.

Never was this more true than with chemotherapy. Low dose oral chlorambucil is remarkably well tolerated, even in the elderly, but at the proven price of not doing much to extend the life of the patient.

Some chemo drugs are routinely used at low doses for relatively minor skin problems or auto-immune issues.

But the issue is more than the dose. It is also who is getting the dose.

Is there co-morbid heart disease or nerve damage from uncontrolled diabetes? Has the marrow been beaten up and is having a tough time rising again?

That is why it is so important that we stay well otherwise. Cancer is a hard enough fight without the handicap of a bad heart or bronchitic lungs.

Chemotherapy is not "targeted" in the strict sense, but it does preferentially cull the rapidly dividing cells and that is a good thing. In some cancers, it does such a strong job, it can cure. In CLL, while there are no chemo cures, it can and does give many of us years of healthy happy remission.

The majority of us that end up sitting in the infusion chairs for hours and hours report that while CLL chemo is annoying, it was much gentler that expected. No hair loss, little nausea. FCR or BR are wimpy protocols compared to some of the more potent stews used for more aggressive cancers. I know a surgeon who continue to operate all through his treatments with FCR.

Still cytopenias (low blood cell counts) are all too common including anemia, neutropenia with its high serious infection risk, and low platelets. So hand in hand with the chemo might come a partnering dose of a bone marrow stimulant for either red cells (EPOs), white cells (G-CSFs) or platelets (TPO mimetics) each carrying its own set of side effects and worries. Some of us even need transfusions to just keep going. More decisions. More risks. More time. More expense. More worries.

Long term, there also may be a price to pay. The marrow can only take so much before it gives up the ghost. When our marrow stops making enough of the three lineages of our blood cells, we are in dire straits and the only durable way out may be importing a new one AKA an allogeneic hematopoeitic stem cell transplant.

Chemo wallops our immune cells short term, risks of infections shoots up and may stays up for more than a year after fludarabine which is particularly nasty to our T cells.

Insist that your doctor offers you appropriate antimicrobial prophylaxis.

These drugs by design are mutagenic so we hold our breathe when we get our regular PAPs or mammos or PSAs or colonoscopies. We are getting them aren't we? Please see my earlier post on secondary cancers and do the right thing by yourself.

Infections and secondary cancers are the handle and the blade of the our grim reaper's scythe. So anything we can do to keep it reach short and its edge dull is good.

Eating right, exercise, love, sleep, and avoiding chemo are part of that prescription.

Still, when we face a clear and present danger, we must focus on our imminent needs and worry about tomorrow, tomorrow.

And until very recently, the best tools we had for staying alive when our cancer started to rage was a chemo cocktail, and I for one am grateful that these drugs were and are there in our time of need.

It was only a few years ago that we showed that for the first time a combination of chemo and immune therapy in FCR could prolong our lives. We know that those diagnosed with CLL in the 90s live longer than those diagnosed in the 80's, and much of the credit rests at the doorstep of chemotherapy and the modern management of its side effects.

So before we wave goodbye to chemo as some sort of poison concocted by the a cabal of international pharmaceutical companies, the military and medical industrial complex to keep cancer as a big profit center at our expense (believe me I encounter this line of thinking almost daily), let us calmly look at its risks and benefits.

Let's not throw the baby out with the bathwater.

If you have read any of my posts over the last few years, you have seen me vote with my feet and my blood. You know that I am a fan of the emerging small molecules and have tried to avoid chemo in my own personal journey.

All I am asking for is that we have some balance and keep our eyes wide open as we enter this brave new "post-chemo" world.

"Targeted therapies" while they might be compared a smart bombs or drone, they too like their battlefield equivalents, can pick off innocent target either that look like the enemy or are in the wrong place at the wrong time.

As I said, it isn't black and white.

More on non-chemo choices soon.

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]

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.

Lung Cancer and CLL

Seems like my last post on secondary cancer was old news.

Here is a review that I just discovered from 1979 in CHEST, a respected medical journal on lung disorders,  that examines the link between lung cancer and CLL. Seven percent or one out of every fourteen CLL patients had lung cancer too in this study. That was eleven times higher than the general population.

Another reason never to smoke.

http://journal.publications.chestnet.org/data/Journals/CHEST/21018/174.pdf

If you missed my last post on CLL, second at cancers, and CT scans take a look if you want a more nuanced and referenced discussion of these topics.

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.

One less worry

My PSA was rechecked. It had risen too quickly, but not too high over the last year. Like many things in medicine, it is not just the absolute number, but the rate of rise that shapes the result. 

The good news is that the result from this week has fallen compared to my last test on Dec 1, 2008, so prostrate cancer is off the table.  So am I am. That is another place I would not want a biopsy. Rolling up a sleeve is one thing for the doctor, but dropping your drawers is quite another.

I guess it is only the gallons of green tea and my anxiety that keeps me returning to the men's room.

Secondary cancers are an important cause of morbidity and  mortality in CLL. After skin cancer, prostrate cancer has a significantly higher attack rate in us guys.  A transplant also increases the rate of secondary cancer.

Listen, no one said this would be a risk free adventure.

I am relieved and thankful.