Why I am keen on PCI-32765

This very nice blog post deals with the business as much as the scientific aspects of the enthusiasm about Bruton's Tyrosine Kinase (BTK) Inhibitors, specifically PCI-32765 in CLL and other B cell lymphomas.

It is a nice simple introduction to how the BTK inhibitors work and outlines the little but promising data presented at ASH 2011. The blog does not mention the 89% progression free survival in CLL.

I suspect we still don't have the whole story. In fact, I am sure we don't.

What do you think?

Am I and many others over excited about this little pill when the evidence is still pretty sparse?

Probably, but there doesn't seems to be much downside, and the other options of doing nothing or using an established therapy sure have their own very real problems.

And I can always move onto those options later if PCI-32765 doesn't work out. Moving in the other direction is not a likely option.

I am not going there. I have every reason to believe that I will be part of the vast group of dramatic responders, especially since my disease is so concentrated in my nodes and my 11q deletion has pretty much done everything by the book so far, which means my clone should melt away in this trial.

Can't wait to get started.

I see Dr. Kipps in three days to go over my bone marrow biopsy and get his final blessing on my plans.

Much News: Almost all of it Good on the CLL Front

At the beach and connecting by a tethered Iphone which is a whole other story.

In the midst of the sad visit to a long time patient getting compassionate hospice care, and in the process of digesting the loss of Dr. Hamblin, surely one of the kindest and brightest lights in the world of CLL, and in the aftermath of responding to a scare about a long time friend's daughter's cancer reoccurring, I got a bunch of good news.

The finding on my bone marrow are subtle, and the report is preliminary, but it is not bad. The CLL is now about 10% of the marrow, up from 3% only nine months ago, but it is not racing out of control. I take this news as neutral.

The health and cellularity of the marrow itself may be better than the last sample suggested when the report said my marrow had been damaged. There is some contradictory findings that I need Dr. Kipps to help me understand before I declare this a victory. Dr. Kipps may demand a recount.

The flow cytometry shows my clone is CD20 dim which means that ofatumumab (the other drug used with PCI-32765 in the OSU trial) may have some real therapeutic effect and all my infusions of rituximab have been cleared away. No CD20 positivity on my B cells might have given Dr. Byrd some pause as to my acceptability to a trial that relies heavily on an anti-CD20 antibody to clear the blood of the leukemia cells once they are flushed from the nodes by PCI-32765. I see this as one more obstacle removed on the road to Ohio.

FISH is still pending and has taken on a surprising new importance that I will explain in a follow-up post. (Hint: My 11q deletion may not be real).

My gastroenterologist called me to say that all 15 biopsies of my stomach and duodenum showed no metaplasia, no abnormal lymphocytes, and no H- Pylori. No hidden lymphoma or leukemic infiltrates. Another worry crossed of my list.

No wonder my tummy hurt that night. 15 biopsies!

And...... (drum roll, please)

My case manager at Blue Shield says that my consult with Dr. Byrd has been approved. Ohio State needs to call her and work out the details, but it's a go. Thank you, thank you.

So Columbus, here I come.

But wait, there's more!

A dear friend offered to take Patty and me to Italy next year for a month to stay at his rented villa. All expenses paid!

And my friend's daughter's imaging came back negative. No new cancer.

And finally my daughter and her boyfriend in Chicago are committed to switching to a plant based diet. And his employer is supporting it!

Sometimes we get an embarrassment of good fortune.

More good news in the marrow and the worst news on the ice

The Kings lost their 3rd game in OT, and are out of the playoffs again in the 1st round. They need a sniper, someone who can score. So sad.

I need a sniper too, something that can pick off my CLL clones and leave the rest of my body alone.

I may have a fair facsimile in my idiosyncratic mix of ciclosporin (CSP) and rituximab (R).

Dr. Kipps was very very very happy with my bone marrow report. His and my fears that the R was doing a good cosmetic job of cleaning up my blood and shrinking the nodes you could feel, while the marrow was loading up with cancer was not the case. In fact my marrow had less CLL than 3 months ago 3% by flow, and < 5% seen with special stains. The histology (the slide itself) looked normal to the hematopathologist.

That means no nodules of CLL like cells seen. And no excess blasts or increased marrow activity that might herald the dreaded MDS (See my friend's CarePage as he details his life saving transplant at MDACC for his CLL/MDS combo). (Update 8/2013: He is now long post transplant, disease-free, and doing great with a long cancer free life ahead of him.)

The cells lines for read and white and platelets were all just fine. The marrow's cellularity was a bit low, which Kipps think is from all the therapy I have had.

I guess I don't think of myself as having had that much therapy, if you don't count my transplant. (That's a joke.)

Anyway he is not worried and actually relieved that the marrow wasn't hypercellular like it usually is in MDS.

Also all my FISH studies for the common genetic irregularities associated with CLL and MDS were negative.

All this is old news.

The new news is that Kipps feel the ciclosporin is a big part of my success. He actually tried to get a study done on its efficacy in CLL. Apparently it doesn't help everyone and it is a generic drug, so funding would be tough.

But for me it works.

I think of it as the brakes on my ITP, but Kipps is reminding me of its antileukemic especially in combination with R.

The only bad news is my nodes have groin a bit again. All this has happened since I reduced the CSP.

Which also suggests it helps my CLL

So if I can find a dose that doesn't mess with my kidneys and still controls the CLL and the ITP, I may have the 1st piece of a winning strategy.

The second is also atypical: Maintenance Rituximab

I am going to wait for MR (more on that in the next post) before adding the R it has only been 4 months since my last dose, so my slowly growing nodes could be from the R starting to lose gas or from the reduced dose of the CSP or from both or neither.

I don't want my gut nodes to get gigantic and hard to treat, so I am thinking a course of "vitamin R" in June might be just what the doctor ordered. Kipps wouldn't say go for it, but he didn't say no either. Which is a lot for him considering this R+CSP is all unproven territory for a man who has built a world class reputation for elegantly clinical designed trials.

So all in all good news.

Watch the nodes with self examines in the shower, and a MR soon. BMB every 6-12 months.

Titrate to find the lowest dose of CSP that keeps things under control and add in some R every 6 months.

And the LA Kings sign a free agent snipe in July.

We have a plan.

The line is drawn, the die it is cast

Let's talk CLL. A bit technical again and a revisit to some prior tropes, but it helps me rethink the road ahead.

While in Washington, Dr Kipps' nurse was kind enough to email a PDF of my bone marrow biopsy report that was full of good news. Today Dr. Kipps called to review the findings and help map out our next move.

To start, the biopsy showed nearly normal cellularity of my marrow in all three lines of cells, so despite more than five years of CLL, and a transplant, my marrow that should be full to the 41% line is full to 39%. In other words 39% of the marrow is busy making blood. Pretty good. Plus the precursors for platelets are in the right numbers; not too many (that would suggest increased destruction), and not too few (that would suggest decreased production).

The biopsy also showed the CLL to be in the nodular form, which carries a better prognosis than a diffuse interstitial pattern. The down side is that nodules may not yield their cancer cells to the aspirate, so the flow cytometry that showed 3% cancer is probably a slight underestimate. The more accurate biopsy showed 5-10% CLL.

The fact that I am CD38 negative and there is no 11 q deletion or other FISH abnormality, while good news, is likely a function of the low number of cells that are being screened and doesn't mean much.

So do my doctors agree on where to from here?

There are surprising united on at least my next step, but after that, they diverge. Still, that is more than I expected. The future is hardly certain.

Dr. Kipps is the most reserved about more rituximab now. Drs. Forman and Sharma are ready to push ahead. Kipps is more ambivalent, but ultimately said and I paraphrase, why not give it a shot. While he admits it may shrink my nodes, he does not think it will get me to MRD negative in the marrow. That is not rituximab's strong suit, but with the cyclosporin, anything is possible. R seems to make everything work better. It is the ultimate helper drug. And there is little down side. Some immune suppression, but it is easy on the marrow, and resistance seems to be not much of an issue.

So I plan to start on more Rituxan in a week or so after I return from a 1/2 day visit to Atlantic City to lecture. I am pushing for the slightly higher dose used in the German study of 500 mg/M2 x 6 weeks. The more R, the better the response!

I will continue on my cyclosporine and my IVIG.

Three months after the last dose, it will be time to bite my nails and re-stage with a repeat bone marrow biopsy and CT scan.

If I am CR, MRD negative then, probably sometime in March 2011, I can expect a long glide, a long time until I will need more treatment. If my nodes are shrunk to less than two centimeters, maybe that's the time and place for a Campath chaser to clean up the marrow if it is not already MRD negative. Kipps likes that idea, but I have my doubts due to the infection issues. If I can achieve MRD negativity, the infection risk seems to be less. Maybe any detectable residual CLL screws up the immunity even more.

If my nodes are still up then campath is out (it is lousy with any node > 2 cm), so maybe FCR or PCR a trial or lenalidamide or who knows.

Then nail biting and re-staging again.

If I am not pretty much disease free, we try something else.

Then a second transplant when I am in a deep deep remission. Excellent survival odds and a better than 50/50 shot at a cure.

That's the big picture today. It is feeling more solid, more real, but there are still way too many turns in the road to expect to not have to reroute my path to that cure a few more times.

Still I feel confident of my ultimate success.

One step at a time.

Bone marrow biopsy report

Last CLL post for awhile. Biopsy was 3.55% donor DNA in the bone marrow. The T cells were 0% donor. What does that mean?

No other surprises.

Confirmed 5-10% CLL in the biopsy.

FISH studies pending.

On the whole good news.

Very latest news and it's good

The preliminary biopsy report shows about 5-10% involvement, with both a nodular and diffuse pattern. The chimerism was basically "host" both in the total and the T cell. This is good news. A miraculous disappearance of all the cancer would have been better, but I'll take this in a heartbeat. The CLL is not gone, but it is not taking off either. It's moving nice and slow, so so can I. Final results on Monday.

Not sure what "basically host" means and what the implications are in terms of using the same donor or finding a new one for a second transplant.

But there is no rush now to figure this out.

Either way, looks like the CLL is not forcing my hand. Except for the ITP, I wouldn't have much to worry about. If the ITP continues to stay controlled with only IVIG and clean living, I am on cruise control. Sweet.

Platelets were staying up, but I wasn't

At UCSD, my platelets have stayed up at a salubrious 231,000 a full 10 days after my low dose IViG. That is more very good news.

The other good news is that my FISH studies show that I have a normal male karyotype. My wife will vouch for that. No old familiar 11q del and no clonal evolution were found, though it might well be sampling error.

The recent bad news is that my previously clean as surgeon's sterile knife bone marrow is now 2.8% filled with CLL, and my nodes are growing, albeit very slowly. Bad to the bone, as my "game worn" CLL Patient Advocate states.

Adding it up, it means I have some time to make my big decisions about treatment. How long I have before I am forced into action is like guessing the time it takes to drive anywhere in LA. You can never really be sure. You are almost guaranteed to arrive too soon or too late.

Dr. Kipps was running behind (no surprise there. he works in patients like me all the time), so I missed my chance to hang-glide. He thinks he saved me an orthopedic consult and he might be right with my wobbly knees. As a result, my platelets may be floating in the normal range, but my crocs are still stuck on the ground. No time to jump off a cliff at the glider port .

Maybe next time. If I haven't started therapy.

I promised I would post soon on my reset plan, and my data collection is nearly done, but head is still murky trying to wrap around all these changes.

By the way, our time away at the Rancho Bernardo Inn was wonderful. They treated us like valued guests though we had snagged the cheap seats. It was a great chance to stop and sit and do next to nothing.

I could never understand my parents going on vacations to sit on the beach, and just veg out. Now, now, 4 plus years into a tough fight with CLL/ITP and 2 years short of 60, I am finally getting the attraction of having no attractions or distractions.

Very helpful to clear the brain.

Best to know

The bone marrow biopsy showed 2.8% of the cells were CLL. The three lines of cell growth were adequate including the platelet precursors (megakarocytes) so the platelet problem is a return of my ITP, which is the better of the two possibilities, the other being cancerous shut down of the bone marrow.

So the CLL and the ITP are back in the nodes and in the marrow playing their nasty games with my life, though the blood may still be clean.

Not the news I wanted to hear, but not unexpected. For me it is always better to know the enemy you are dealing with. It certainly makes my present situation more clear. What to come and what to do is less clear.

I am busy tonight with McGill events and projects with my children, and broken electric gates and overdue paperwork, so more later.

The biopsy news is rather cold and stark, and so my response must match.