Thursday, July 17, 2014

ASCO 2014: Dr. Kipps Discusses Targeted Therapy and Obinutuzumab in the Treatment of CLL (chronic lymphocytic leukemia)

In the first brief section of my video interview from ASCO 2014, Dr. Tom Kipps, my personal doctor at UCSD, and mentions the buzz about ibrutinib (IMBRUVICA) at the meeting and then moves on to discuss obinutuzumab (GAZYVA) the new and exciting monoclonal antibody (mAb). He adds to what we learned from Dr. Byrd in this prior post from ASH 2013 and shares his subtly different take on how this powerful new addition to our CLL arsenal works.

My hunch is that it will prove to be much bigger step forward from rituximab (R) than was ofatumumab  (ARZERRA). That much anticipated next generation CD 20 mAb has disappointingly made at best some small incremental improvement for us CLL patients compared to the giant leap that we witnessed just a few years ago when the mother of all CD 20 antibodies, R was added to FC to give us the present "gold standard" of FCR. Ofatumumab does offer a possible helpful option for those of us who can not tolerate R.

Obinutuzumab is clearly proving to be a better antibody. As I covered in this more detailed post and interview from ASH 2013 with Dr. Brown, GAZYA is the first antibody that showed a clear survival advantage over rituximab albeit in combination with chlorambucil.

At ASCO 2014, we learned more. This abstract shows us that as a single agent in untreated patients, obinutuzumab had impressive response rates and even some complete remissions. This almost never happens with the other older CD 20 antibodies. I am pretty excited about all these results.

We already know that adding an antibody to almost any chemo agent makes that chemotherapy work better and explains why chemo-immunotherapy has become the backbone of the present treatment protocols in CLL/SLL and other lymphomas.

What we don't know yet is how this concept of adding a mAb will evolve in the coming era of oral therapies with small molecules such as ibrutinib and idelalisib and later on ABT-199. More on this in future posts.

Here is the first part of my interview with Dr. Kipps.

Listen to the lovely way that he describes how the different type antibodies works.



More to come soon on ROR-1.

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Tuesday, July 15, 2014

More Good News- Update on My Lab, CT Scans, and General CLL (chronic lymphocytic leukemia) Status

My blog has veered far away from the simple telling of my story to more telling of our stories with much B roll.

I am making plans to maybe bifurcate its content in the future, but for now it will continue its happy and diverse life as a personal health blog, a home for research news and video and audio interviews with leading researchers, and a whole bunch of personal analysis and advocacy on what it all means.

I am back from Ohio State where I am still seeing the research team every 3 months and getting CT scans every six months for my clinical trial on ibrutinib. I have riffed on this being too much radiation before in this prior post that includes links to some of the basic research of radiation exposure and its risks, but Dr. Byrd argues that the few relapses he sees on ibrutinib show up first in the nodes, so he wants to monitor me with the scans.

True enough. When I relapsed post failed hematopoeitic stem cell transplant in 2008, the nodes were my canary in the coal mine showing slight growth months before my lymphocyte counts started to move up and my platelets down.

So twice a year CTs are still the plot line for my clinical trial at OSU.

Since diagnosed in 2005, I have probably had about two dozen CT scans!

Add to that the equivalent of the 20 chest X-rays annually I get from flying over 100,000 miles a year, and my risk of secondary cancer is significant. This link with a NASA produced video tells the air travel part of the story.

If you really want to worry, take a look at this article from Medscape on CT scans in NHL.

But this post is not about the danger of CT scans, but about what my last one showed and happily that was stable disease.

I still have enlarged lymph nodes but they have changed little since October of 2012, or for the last 20 of my total of 25 plus months on ibrutinib. My largest sentinel gut node near my liver was about 10 cm at its peak, 7.3 x 3.3 cm just before starting ibrutinib, 4.4 x 0.7 cm in October, 2012 after about 6 months on the medication, then it shrunk to its shortest 3.9 x 0.7 three months later and when last measured on June 30, 2014 was 4.4 x 0.4 which actually represents its lowest volume. It has been fluctuating and when you account for the difficulty of measuring mobile objects in the mesentery and near the liver, is mostly stable since its dramatic shrinking in the first 6 months of therapy. Its a long hot dog shaped node instead of the more common bean shape. The same early dramatic shrinking in the first six months and slight ups and downs since has been the tale for my other smaller sentinel nodes on the scans.

So I have pretty stable disease.

What does this mean to still have enlarged nodes and a touch of CLL in my blood (see this prior post from last April on my flow cytometry report to understand more about my numbers and disease burden)?

The CLL does not proliferate in our blood, so the disease in our nodes and bone marrow are the source of all our problems and I will ignore the blood for now.

There is good reason to believe that these enlarged nodes are still full of CLL, but that it is not proliferating, thanks to the signal blocking from ibrutinib preventing it from getting the messages from its nurse like cells and others to be fruitful and multiply. So chock full of CLL, but it's dormant.

The other more positive interpretation is that these enlarged nodes are just the scarred down skeletons of the cancerous nodes they once were, and there is no residual disease to be found. Unfortunately, I am skeptical of this more PolyAnna hypothesis, and short of a biopsy which is not going to happen, there is not way to know for sure.

So what to do to avoid waking the Kraken?

Hope my genomic instability as evidenced by my 17p and 11q deletions and my complex karyotype will continue to behave with the ibrutinib aboard and not mutate so that my magical bullet no longer covalently binds BTK and blocks its activity?

Knock down the residual disease by adding a second or even a third agent?

Be reactive or proactive?

That is the question du jour faced by many of us now and more in the future whose CLL is controlled but it is not gone now with the new medications such as ibrutinib and idelalisib.

I have probed this recurring and unanswered question in more detail a prior post, and will soon be updating my thoughts on how to avoid being left stranded on third base and not getting home to a cure.

The rest of my news is also good.

My blood counts are boring and despite dropping my cyclosporin to a token dose of only 25 mgs once a day and stretching my 40 grams of IVIG infusions to every 7-8 weeks, my ITP also remains dormant. I think the possible immune stabilizing activity of ibrutinib and my low disease burden may be the factors  that have given me this long ride with high normal platelet counts. I have not been anemic for many months now and my neutrophils and the rest of the CBC are all copasetic. My blood chemistries are in the normal range and only my very low immunoglobulins, namely IGA, IGM, and IGG give proof to that fact that I still have a B cell leukemia, albeit a very sleepy and well behaved one.

More personal clinical and general CLL news soon, nearly all of it good.

I will be posting some of my interviews from ASCO 2014, plus sharing some exciting advocacy news. Busy times.

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Friday, July 11, 2014

ASH 2013: Dr. Byrd on the New Data on Ibrutinib and Obinutuzumub in CLL (chronic lymphocytic leukemia)

In my final post from the last days of ASH 2013 (lots more to come from ASCO 2014), my doctor, Dr. John Byrd out of Ohio State (OSU) in the third part of our interview discusses the durability of the positive results with ibrutinib and the latest results with obinutuzumab. Here is the referenced ibrutinib trial. For the first part of my interview with Dr. Byrd, click here and for part two here. They are worth reviewing as we covered many of the novel up and coming therapies beyond the usual headline grabbers of ibrutinib and obinutuzumab that are the focus of this last segment of the interview.

Dr. Byrd reminds us that it is the usual suspects are the few unlucky ones who do relapse on ibrutinib, mostly those of us who have been heavily pretreated and/or are 17p deleted.

What is the happy surprise is that the side effects seem to get less common the longer we take Imbruvica and there is a hint (see this NIH research by Dr. Farooqui whom I subsequently interviewed at ASCO 2014), that our immunity improves. Certainly the number of infections diminishes over time.

Dr. Byrd also answers my questions on the exciting monoclonal antibody obinutuzumab (Gazyva) and the new study results presented at ASH.

There are many reasons to be excited about this antibody. Despite the fact that the trial was rigged by choosing the wimpy chlorambucil as its sparing partner, Gazyva is the first therapy when used with chlorambucil to show a survival advantage in the difficult to treat mostly elderly patents who have other medical problems (co-morbidities) such as kidney disease that may take many therapies off the table. This trial  is offering hope where there is a pressing need.

We get into some of the details of how the drug is different from other antibodies. Dr. Byrd discusses how its engineering was specifically directed to make it different and probably better than rituximab. We also discuss its potentially nasty and quick infusion reaction and why that may not be such a bad thing.

Enjoy Dr. Byrd.

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Tuesday, June 24, 2014

EHA 2014: Encouraging News on the Pneumonia Vaccine in CLL ( chronic lymphocytic leukemia)

In all the excitement about the research being presented at ASH and ASCO and EHA on the new therapies for CLL, it is important to remember that infection, mostly respiratory, is still the final grim chapter for most of us. 50-80% of all deaths in CLL are from infections with pneumonia accounting for 40%. Streptococcus Pneumoniae (the bacteria formerly known as pneumococcus) is the leading bad actor. CLL is after all a cancer of the immune system. Dr. Wierda and others are working on ways to reboot our immunity as detailed in this prior post from ASCO 2013, but that is the future, not our present reality.

IVIG can help by relying on the kindness of thousands of strangers loaning their antibodies to offer us passive immunity. It is potent partial fix, but it is expensive and temporary, and like any infusion, especially a pooled blood product, it carries risks.

Vaccines offer the promise of the more potent active immunity, where we form our own more durable antibodies. The problem has been that they usually don't work. We are wimps at working antibodies. Our clonal B cells mess up our ability to form antibodies. whopping 85% of us have low levels of immunoglobulins and our cellular immunity is not so great either.

But there may be some good news from an abstract presented at the annual meeting of the EHA (European Hematology Association).

Many of patients are all too well aware of our dismal response rates to most killed vaccines. Live vaccine such as the one for shingles or herpes zoster are contra-indicated. Because of our impaired immunity, we just don't form adequate antibodies when given a flu or other shot. And worse, we run the risk after being jabbed with a live attenuated or weakened viral vaccine version of the very agent that we are supposed to be protected against running amuck in our immuno-compromised bodies.

The late CLL champion and researcher, Dr. Terry Hamblin, suggested dual dosing of killed vaccines with ramping up our antibody formation by taking weeks of a histamine 2 blocker between shots. Not much data to back up the idea. He did review a 2007 paper on an earlier conjugated killed vaccine Prevnar 7. His post offers a nice complement to this for those wanting more background on the pneumonia vaccines.

We all miss the wisdom of Dr. Hamblin.

The CDC has a protocol about the optimum order and spacing of the vaccines, but that is really just making the best of a bad situation. Bottom line: best to get the new conjugated vaccine first.

This abstract from EHA 2014 is important because it provides some hope and some data for us who are so immune compromised.


A little background. There are two major commercially available vaccines to prevent pneumonia is the USA.  Pneumovax 23 is based on asking our humeral immune system to recognize and be ready to attack based on presenting a polysaccharide (essentially a long sugar) that will trigger our plasma cells (B cell are the precursors to these cellular antibody factories) to fight against the 23 most common flavors of pneumococcus. Prevnar 13, the newer vaccine for adults, is conjugated to a protein and is more alerting to our immune systems, though it cover ten less serotypes.

The data is encouraging. While 100% of the control (normal immunity) population formed antibodies predictive of protecting against future infections, a still impressive 58% of CLL patients did the same. Compare that to the old vaccine results of from near zero to 25% response rates.

As one might expect based on all the prior research, those of us who do the best are those who are early in our disease with the higher levels of antibodies.

It is more complicated. As the name implies, Prevnar 13 only protects against 13 of the roughly 90 subtypes of Strep. Pneunomiae and obviously none of the infections caused by other pathogens. Moreover, as the vaccine is more widely used in different populations, the prevalence of the various subtypes causing us misery switches away from those covered by the vaccine. Those clever bacteria.

Another concern is that there is certainly no guarantee that just because our antibodies doubled that we will still have the immune resources to fight off a dangerous infections. We need more than antibodies. We need organized and functional T cells, something we are often sorely missing.

This study did not show that we got less infections. That would be a much longer and more robust trial. This trial just showed that we formed more protective antibodies with the new vaccine.

And that is a helpful step forward.

So here is the take away.

We should get vaccinated as soon as we are diagnosed. Prevnar 13 is the better choice for the first jab, or even the second.

I have pasted the actual abstract from the EHA below, as I found their web site cumbersome to navigate.

Abstract Submission
6. Chronic lymphocytic leukemia and related disorders - Clinical
ABSSUB-3908
EVALUATION OF IMMUNE RESPONSE TO 13-VALENT PNEUMOCOCCAL CONJUGATED VACCINE (PCV13) IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKAEMIA
Marcin Pasiarski1, Agnieszka Stelmach-Goldys1, Stanislaw Gozdz1, 2, Ewelina Grywalska3, Iwona Hus4, Jacek Rolinski* 3
1Department of Clinical Oncology, Holycross Cancer Center, 2Faculty of Health Science, The Jan Kochanowski University, Kielce, 3Department of Clinical Immunology, 4Department of Clinical Transplantology, Medical University of Lublin, Lublin, Poland

Background: Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder associated with severe impairment of the immune system in a substantial proportion of patients. This is directly linked with an increase in susceptibility to bacterial and viral infections. About 50 to 80% of patients diagnosed with CLL die from infectious complications. Most infections in CLL patients is caused by capsular bacteria: Streptococcus pneumoniae and Haemophilus influenzae. Patients with CLL who have low levels of antipneumococcal antibody are particularly at risk for severe and recurrent pneumococcal infections. In the U.S. and in many EU countries, vaccinations against Streptococcus pneumoniae are recommended for immunocompromised patients, such as patients with CLL. For many years, 23-valent pneumococcal polysaccharide vaccine (PPV23) was used. Antibody responses to PPV23 vaccine are inadequate in most patients with CLL, that induced response only in about 20-25 % of patients. Since 2012, in the prevention of pneumoccocal infections in immunocompromised adults, 13-valent pneumococcal conjugate vaccine (PCV13) has been used that efficacy in patients with CLL has not yet been studied
Aims: The aim of this study was to assess the efficacy of vaccination in patients with CLL using PCV13.
Methods: The study included 24 previously untreated patients with CLL in stage 0 - 2 according to Rai calssification and 15 healthy subjects as a control group. The percentage of plasma cells, defined as CD19+/++IgD/CD27, was analysed before vaccination and 7 days after the immunization, the level of specific anti-pneumococcal antibodies and the level of IgG and IgG1, IgG2, IgG3, IgG4 immunoglobulin subclasses were evaluated prior to vaccination and 4 weeks after vaccination.
Results: The positive response to vaccination was defined as at least a two-fold increase in specific anti-pneumococcal (anticapsular) antibody titers as compared to the titer prior to the vaccination. Such a criterion of response was fulfilled in 100% of healthy subjects and in 58.3% of the patients with CLL. The percentage of plasma cells after vaccination was significantly lower (p < 0.0001) in patients with CLL comparing  to the control group. Both in patients with CLL as well as healthy subjects, there was a statistically significant increase in the level of IgG2 subclass after vaccination (p = 0.0301). The patients with adequate antibody response to PCV13 had significantly less advanced stages of CLL, higher total IgG levels and IgG2 and IgG4 subclass levels. There was no no significant vaccine-related reactions, no increase in peripheral blood lymphocyte count  and no changes in laboratory markers of disease activity.
Summary/Conclusion: Protective immunization of patients with CLL using the PCV13 is safe and induces an effective immune response in a large proportion of patients. To achieve the optimal postvaccinal response it is recommended to the use the PCV13 as early as possible after the diagnosis of CLL with determination of post-vaccination antibody levels.


Keywords: Chronic lymphocytic leukemia, Infection, Vaccination

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