New Immune clinical trials and an explanation of cellular immunity in CLL ( chronic lymphocytic leukemia)

Friends, On the CLL Society website, we share two interesting articles: 1. An interview with Dr. John Gribben whom I interviewed at the CRC (CLL Research Consortium) Scientific Meeting in San Diego in April 2015. We discussed his approach to cellular immunity and T cell function in CLL. Please take a look here to see the interview. 2. A patient-friendly summary of three new Immune Antibody clinical trials from MD Anderson Cancer Center. These investigator-initiated trials are exploring how activation of the immune system may lead to killing of CLL cells. You can read more about these interesting trials here. This Fall has been incredibly busy so far, between traveling to Australia for the iwCLL meeting and an Australian patient support meeting, publishing our first issue of The CLL Tribune, and traveling to Brooklyn for the North American Educational Forum on Lymphoma hosted by the  Lymphoma Research Foundation. Now we're preparing to go to the American Society of Hematology Annual Meeting in Orlando, FL and putting together the next issue of The CLL Tribune, due out after ASH. If you haven't had a chance to peruse the first issue, you can access it here. If you have questions you like addressed in future newsletters, OR would be willing to answer 5 questions in our Reader Poll about the CLL Society website, OR would be interested in writing an article for future newsletters, please go to the Ask & Tell section. Our goal is to fulfill the unmet needs of the CLL community, so we always welcome your feedback and questions. SAVE THE DATE: If you live in the Los Angeles area, please consider attendinga post-ASH patient education forum and CLL Society LA support group launch in conjunction with City of Hope scheduled for Saturday, Dec. 12, 2015. A flyer with more details will be posted in the next week or 2. Finally, if you are reading this on blog and haven't already, please sign up here. Also, please forward this email to a fellow patient or caregiver who might benefit from knowing more about CLL. Another reason to make sure all the folks that might be helped sign on is that we will be posting a backlog of great lectures and interviews and articles on CLL over the next few months leading up to ASH and this alert is your best friend in knowing what new material we have posted. Stay strong. We are all this together Brian Koffman Volunteer Medical Director of the CLL Society http://cllsociety.org

My Chronic Lymphocytic Leukemia (CLL): More Good News

PLEASE NOTE I HAVE REVISED THIS AFTER RECEIVING THE HARD COPY OF MY FLOW CYTOMETRY REPORT. THE NEWS MAY ACTUALLY BE EVEN BETTER.

I still have CLL, but less of it.

It's in remission and it's actively retreating, but I still have residual disease.

Today I learned that my flow cytometry showed that I have a few cancer cells floating in my blood stream.

Here's how I know.

Essentially all B cells, good or bad, cancerous or benign, have a CD19 marker but are not supposed to have the CD5+ marker on their surface.  That's usually found only on T cells. Those that have both are my abnormal CLL cancer cells.

Flow cytometry which looks very deeply at thousands of cells was able to find only 28 of such cells per 10,000 cells. That means only 0.28% of my lymphocytes are clonal.

Let's do the math. I am a little shaky on my assumptions here, so please correct me if I'm wrong. Of every 10,000 lymphocytes that I have, only 28 are my CLL clone. That is an amount a microscope could never find, but the flow cytometry lasers can spot easily. If my nodes and bone marrow were clean (not likely but I can hope), I would be in a complete remission (CR), but minimal residual disease or MRD+. How important it is to be MRD- in the era of TKIs is a matter of debate.With FCR, it was very important in terms of prognosis.

There are 1,400 lymphocytes per millionth of each liter of my blood and of course there are a million microliters in every liter. We we all have about 5.6 liters of blood, so 1,400 x 1,000,000 x 5.6 x 0.028 = about 22,000,000 cancer cells lolling around in my blood stream. Sounds like a lot, but it's nothing.

Those millions and millions of peripheral white blood cells are not even the one that are proliferating. That's done mostly in the nodes, so my nodes are pumping out less cancer now. I know that because in October, the same count was 47. That's a 43% drop in the last 6 months, suggesting my CLL is still responding nicely to the ibrutinib.

After nearly two years, it is still working its magic inhibiting the B cell communication pathways needed to survive and reproduce.

That's truly great news.

Reassuring news.

Quite remarkable if we stop and think about it. Almost two years out and this gentle giant of a therapy is still dropping my leukemic cell count.

To get some perspective on my results, compared to my measly 220,000,00 cells in my entire blood stream, some of my friends with active disease can have half a million lymphocytes or more in each and every  millionth of a liter of blood and nearly everyone of those is a part of the evil clone's posse. 500,000 x 1,000,000 x 5.6 is a big number. The counts of almost anyone with active disease is several orders of magnitude greater than mine. My count of CD19/CD5+ cells is trivial in comparison.

The other good news is that my overall T cell count is climbing with appropriate CD4/CD8 ratios. This could mean my ability to fight off infections is improving and more importantly my bone marrow and the rest of my immune system is healing.

My CLL has always been more nodal, hidden in my belly, so the CT scan at the end of June will be critical, but this is a positive harbinger. Makes sense that if I harbored any significantly growing nodes that were resisting the ibrutinib, they would be pumping more cancer out into the blood and the exact opposite is happening. But the relationship between the size of the nodes and the CLL count in the blood is not always so tight. Still it is good news.

I will be posting more videos from ASH soon and am preparing to attend ASCO in Chicago at the end of May.

Large Granular Lymphocytic Leukemia: What We CLL Patients Can Learn from a Novel Therapy for a T Cell Cancer

This week in Blood there was a very interesting article published on a very rare form of blood cancer, LGLL or large granular lymphocytic leukemia.

The abstract stated:

T-cell large granular lymphocyte leukemia (LGLL) is a rare clonal disease often associated with rheumatoid arthritis (RA) and manifests chiefly as neutropenia and recurrent infections. Immunosuppressive agents are the mainstay of treatment, but long-term remissions are rare. We report 2 cases of LGLL in patients with RA successfully treated with rituximab, a monoclonal antibody specific of B cells and approved for treating RA. The first patient experienced a complete LGLL remission that was sustained during the 8-year follow-up after the first rituximab infusion. In the second patient, rituximab therapy was followed by immediate neutropenia recovery and then by marked shrinkage of the LGLL clone 1 year later. The paradoxical efficacy of this specific anti–B-cell drug on a monoclonal T-cell disease suggests that some cases of LGLL may be reactive manifestations of chronic autoantigen stimulation rather than true malignancies.

I added the bold because this jamming on of reactive pathways with all its nasty downstream consequences is similar to what we are trying to block with BTK and PI3K inhibitors in CLL. In CLL, we are trying to shut down the constitutively stimulated B cells by blocking their pro-survival communication, proliferative, and homing instincts.

Further down is the report we find:

As illustrated by our first patient, T-cell LGLL is frequently associated with concomitant low-grade B-cell dyscrasias, such as monoclonal gammopathy of unknown significance or chronic lymphocytic leukemia, suggesting that a common antigen may drive both T- and B-cell proliferation.

That is powerful talk. Yet to be proven, but worthy of more research.

Maybe that is why anti-T cells therapies such as ciclosporin help some in CLL, yours truly included. 

Everything in the complex immune system is so connected.

The whole Blood article is short and I recommend it.

This type of creative systemic thinking is exactly what will be needed to completely and finally shut done the monoclonal B cell factory that is CLL. We may need to read the green tea leaves in more than our CLL teacups to find our answers. We need to look at the research being done in other liquid and solid cancers. Some of the fantastic new immune therapies in metastatic melanoma as detailed in my prior post from ASCO 2013 immediately come to mind as future paths to pursue. 

Last, but not least, and while the issue may be just semantic and this is only two cases, all of us with  CLL would much prefer to live with a "reactive manifestations of chronic autoantigen stimulation rather than true malignancies", especially if such labeling leads to better therapeutic approaches and better outcomes.

I am off to Germany on Monday for iwCLL. Send me your burning thoughts and questions that I might share with all the CLL gurus gathered in Cologne.

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ASCO 2013: Dr. Wierda Discusses Immune Therapies in CLL

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

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

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

The story with passive immunity has had more success.

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

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

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

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

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

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

This interview is from ASCO 2013 in June in Chicago.

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

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

Here is Dr. Wierda:


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

I will report from the infusion center tomorrow.

What do Designer T cells mean to you and me?

The breakthrough in genetic engineering that lead to two of three patients with bad CLL getting a clean bill of health has generated world wide excitement, with good reason.

It's dramatic, it's a first, it's not chemo, it's mostly drug and big pharma money free , it's a doable technology for CLL that has possible applications for any cancer that can be recognized by its protein markers that protrude from their cell wall (in this case CD19), and it's still working a year later.

My bet is there will be a lot of money to move beyond this proof of concept to phase 1 trials, both at U Penn and other eager centers that can make the requisite designer genes.

That is mostly companies like Amgen and Genentech and a million start-ups, and universities, and big cancer centers such as MDACC, UCSD, Stanford, Dana-Faber, and others.

My bet is that these trials will not be hitting the local oncologists office anytime soon.

My bet is that the demand for this will outstrip the number of openings. It is a very personalized, hands on, and expensive therapy. My T cells won't work for you and vice versa.

My bet is that dosing will be critical as always in Phase 1 trials, but even more so here, where we know we have a very big bomb that can have quite a long fuse. Remember that the onset of the tumor lysis syndrome (TLS), the state where there is a very rapid and dangerous amount of cancer killed in a short time exceeding the kidneys' ability to handle all the debris, was quite delayed in the U Penn trial. Too high a cell dose, and the unpredictable TLS can kill you, too little, and the response is too feeble and the cancer continues to grow.

My bet is that choosing the right target is also critical. CD19, the target in the U Penn trial, is found on all B cells and its precursors, so this therapy wipes out nearly the entire immune army that produces antibodies. Does that mean you are cured of cancer, but may be at risk of dying from measles or chickenpox as the oldest soldiers (the memory cells) die off? We don't know, yet.

Are other targets better and more selective? Will they work as well without the immune risks? Again, that's what trials are all about- to answer these questions.

So what does this all mean to those of us with CLL?

Here's my best case scenario.

It means nothing today.

But I bet (when you have cancer you are always making bets with less than perfect knowledge), that in less than a year we will have limited opportunities to enter phase 1 trials on new iterations of the designer T cell therapies. This is too good a result and way too much fun for the MD/PHDs not to tinker with creating new cells to not work its way through the IRB committees quickly. Most trials will they likely be small and be restricted at first to those at the end of the present therapeutic rope, but as experience and safety data grows, in three years or so, bigger phase 1/11 trials now with pharma money may open for those looking at earlier or even front line therapy.

If all goes great, and and this is a big if, they can find a way to pay for this, we could have a new revolutionary treatment option in less than ten years. Maybe even seven or if a prominent senator is diagnosed with aggressive CLL, five.

That's the Cinderella story. The perfect fitting glass slipper and the lucky girl living happily thereafter.

But it won't be easy choosing what size or design is best, which virus is the safest to do the heavy lifting (the U Penn people used an HIV like virus with its reproduction genes disabled), what cancer center is best ready to handle possible TLS weeks out, what dose of T cells, what chemo if any is needed to clear the table before the gene therapy can begin, and a thousand other unknown unknowns.

So again for us patients, the trick is to stay alive, try to keep our powder dry by avoiding therapies that damage the marrow or immune system as long as possible, keep our ears to the ground for new research, assess whether we really need to do anything so don't get caught up in the hype and pressure and worry that we might miss the boat if we don't jump at this, and if we do need therapy, is what is available in a gene trial therapy the best choice?

The good news is that when we do need therapy, the choices are getting both better and tougher.

The devil we know such a FCR or Revlimid or Bendamustine or HSCT, or the devil that we are just getting to know such as the new small molecules such as CAL101, PCI 32765, ABT99 and more and more sharply focused cancer pathway blockades, or the completely unknown devil with his great promise, the new very sexy new kid in town - designer T cell therapy?

An exciting time for sure. I love these possibilities, but that is what they are possibilities. But so was Gleevec at one time.

For me, I am nervous about jumping too fast until I see more data, especially long term safety data. I am frightened that I will be, as Leonard Cohen said, "torn by what I have done and can't undo." Still the appeal is undeniable- the benefits of an allogenic transplant with much of the downside taken out of the equation.

So I plan to stay alive and follow my own advice given above.

But first I am going fishing in Missouri. And I don't even eat fish.

A major breakthrough in CLL therapy. There's a new serial killer in town.

They did it, they got the benefits of an allogenic transplant, namely a new population of T cells that alert the immune system in an ongoing way to search and destroy the cancerous B cells. A transplant sans transplant. The benefits without many of the most horrific risks.

Here's a link to a VIDEO that tells the story.

These T cells have been changed with the insertion of new genetic information by infection outside the body with an HIV type retrovirus that, when they are put back into the same patient, gives them the ability to recognize and attach to the CLL cells, to arouse a very robust inflammatory response (read that they initiate a killing frenzy of both cancerous and good B cells and its precursors), and most importantly to proliferate and stay around for at least a year.

Am I encouraged? You bet.

This has the potential to change everything. This has the real potential to cure CLL.

But at this point it all still potential and conjecture, and all therapies look great when they are brand new. There are may unknowns and concerns. Still, it is an exciting time to be a CLL patient.

More soon on what I think this means for anyone with CLL in general and for me in particular.

In the meantime, I am rooting for these new cops, this new "007" secret agents with their license to kill.

And all this was done with no pharma money!

Anyway you look at it, this is very good news.

"One more cup of coffee for the road" Bob Dylan

Sometimes the light's all shining on me
Other times I can barely see
Lately it occurs to me
What a long strange trip it's been

The Grateful Dead

This is strictly a medical post for the transplant crowd. Others are welcome to dip their spoons into the alphabet soup of engraftment seen in a reduced intensity stem cell transplant.

I face one more hurdle, before I can rest for a spell.  The HLA testing was redrawn today to see who is making my T cells. Hopefully this time my 14 tubes of blood will yield enough DNA to give the answer. The right answer, which is my donor. Go donor, go. The other blood lines are of much less import.

Here's the deal. After transplant, T cells hang around for a long time from that big bag dripped into my PICC line on July 1. That is why the long living T cell counts are higher than the other cell types earlier on because the transplanted monos and neutrophils die off pretty quickly.  The fact that my B cells are all donor 90 days out suggests these are mostly freshly minted B cells. My donor stem cells has taken up residence in the nooks and crannies of my marrow and are making at least some if not all of my blood now.  That's very good indeed. T cells DO NOT determine what the source of these B cells or neuts or monos will be. They just give the orders to them as to what is friend and what is foe. That is why they are so darn important. That is why T cell depleted transplants have more relapses in leukemia, but less GVH.

The T cell count does not always follow lock step with the other cells lines, but it's the boss so why should it. T cells originate in the bone marrow like all blood cells, but only become mature T cells in the thymus. 

If the T cells are 100% donor, then the chances of relapse are diminished. If they are steady, that  can be just fine too. If they are dropping, then that might or might not spell trouble. Here Dr. Forman and I do not agree.

Dr. Forman said my good news on my B cells was flirting. I think he mean it was tease. Let's hope the tease was just the preparation for the final act of consummation.

So one last hurtle. I am planning on going all the way, then I will rest.