Questions and Answers Provoked by my Blog on CLL (chronic lymphocytic leukemia)

Here are best answers to some questions I recently received. Please email questions as it is difficult to respond this way. Remember I am not a hematologist, pathologist, or transplanter.

1: Please explain if CD 19 is present on both the normal B Cell and cancerous B cell as stated here, then how can CD 5, CD 19, and CD23 be what is used to diagnose CCL per Dr. Weird in a Patient Power interview? Also, are any of the 3 CD’s mentioned above also present in T Cells? on ASH 2012: Dr. Bill Wierda on CAR-T Therapies and "Off the Shelf" T-Cells

ANSWER: CD5 is usually only found on T cells. Its presence on monoclonal B cells is not expected and thus helps diagnose CLL.

Perhaps this chart will help. The information is gained from flow cytometry. Click on it to see a larger version.

2: Hello Dr. Kauffman, I am four years out from a CLL stem cell transplant. I wondering how long ones immune system is compromised after a transplant? Would I still catch pneumonia really easy? on Dr. Byrd Updating the trial data on ibrutinib for CLL (Chronic lymphocytic Leukemia)

ANSWER: Immune recovery post transplant is slow and complicated and varies from patient to patient and even within each patient themselves. Different immune component may recover at different rates. Suffice it to say, one can remain at increased infection and cancer risk for several years after transplant, but after about two years, much of the high risk period is behind you, that is assuming you are no longer on immunosuppressive drugs for graft versus host disease(GVHD) and you are well recovered. For example, routine vaccines are usually begun between 12 and 24 months post allogeneic stem cell transplant, suggesting that your humoral immune system is fairly robust by that time.

Below is some very basic outline of post transplant care.

3: In looking at the ASCO abstract, information is not provided as to the cause of treatment interruption. An interruption due to a drug complication or cll event may have a very different impact on PFS than a break in care for surgery. Is that data available? 

ANSWER: I wish I had that data too. I do understand that many of the patients were quite sick for multiple reasons and that's why they quit. Patients who go off drug for a week or so for a minor surgery as an example should expect better results.

ITP In CLL (Chronic Lymphocytic Leukemia): Personal And Clinical Reflections

Another great discussion courtesy of ONCLIVE with 4 top CLL experts, from left to right: Drs. Byrd, Furman, Ma, and Kipps.

This time they discuss immune thrombocytopenia (immune mediated low platelet count) or ITP.

ITP is where our immune system attacks our platelets. Just our luck, our wimpy inadequate immune system that can't alway respond to an infection or a vaccine or a secondary cancer, whips into high gear to attack its own cells.

In extreme cases it can lead to live threatening bleeding. It is well recognized complication of CLL occurring in < 5% of us, but as the doctors imply, I suspect many mild cases go unrecognized.

When the same process attacks our red blood cells, sometime leading to a dangerous anemia, it is called AIHA for the auto-immune hemolytic anemia. ITP is the platelet version of the same issue. Attacks on the neutrophils and multiple blood cells lineages also occur, but are more rare.

ITP is a subject near and dear to my heart.

About one year after my diagnosis with CLL, I remember being on call for my medical group and waking to the phone in the middle of the night. It was my exchange. I had asked my family doctor to order a CBC that morning because I had noticed some easy bruising and petechiae (tiny red dots caused by small hemorrhages often associated with low platelets) on my legs.

MEDICAL EXCHANGE: Dr. Koffman please.

ME: Yes. It's me.

MEDICAL EXCHANGE: We have a critical lab result ........ on Brian Koffman. A platelet count on 9.

ME: Thanks. I will definitely follow-up on this.

And I did. It was 6 they next morning and I was hospitalized for IVIG and steroids. It bounced up in 48 hours but because of my recurrently dangerously low platelets I would go on to five emergency admissions in the next year,  multiple outpatient infusions, and an urgent laparoscopic splenectomy where I lost half my blood. I failed steroids, rituximab, IVIG, cyclosporin and the splenectomy.

What finally worked post splenectomy was a combination of cyclosporin (an immune suppressing drug used today mostly to prevent rejection of kidney and other transplants) and rituximab that was recommended by Dr. Byrd. The combo's effects were nothing short of amazing, especially  considering that both drugs on their own had had no benefit in raising my counts. On the combo my platelets climbed from single digits to above normal (not uncommon when you have no spleen).

And the combination of cyclosporin and rituximab had the surprising and joyous bonus of reducing my bone marrow involvement with CLL down from 90% to 3%.

There are some case reports in the medical literature of cyclosporin having antileukemic activity, but it generally avoided due to the fact we are already immune suppressed and it can cause significant problems including renal disease, hypertension and aggressive gout.

It was my dangerous and refractory ITP more than my CLL that drove me to a first remission transplant.

That didn't work either, and my ITP was back one year post HSCT.

That were difficult times.

Despite the risks and side effects, it was only about none months ago, after almost two years on ibrutinib and with years of normal platelet counts under my belt, that I finally had the courage to taper off my cyclosporin. I feel it had helped save my life and I worried about stopping it.

But I did and I have done great since.

A few comments from one who's been there and done that. Yes, I know that one case is not data, but it can be a cautionary and instructive tale.

For obvious reason and because it is part of some of the guidelines, I would ask the doctors in the panel to add cyclosporin to their list of second line options for ITP. I would certainly use it well before the extremely immune suppressive alemtuzumab (CAMPATH) that knocks out both T and B cells for a very long time or splenic radiation that has a host of short and long term complications.

I would also remind us all that the surgery does not always go well, though laparoscopic is clearly the way to go. The research tells us that the best predictor of outcome is the experience of the surgeon. Though it didn't work for me, I have no regrets about my surgery.

I would also ask my colleagues to comment on just how difficult it can be to get us off steroids and not have the ITP return.

The data on ibrutinib is encouraging and makes sense from a biological point of view, but it is not 100% effective.

Overall, a very helpful and well considered discussion on a very important and scary topic. As we might expect, while there is much consensus, there is significant polite disagreement on how to proceed.



It is such a blessing to not have to live in fear of what my weekly or twice weekly blood test would reveal.  Showing up at the lab,  not  knowing whether I was OK or I was headed to the hospital.

That's all in my distant past now.

Still, as all of us with cancer know, we are always looking over our shoulder, wary of the return of our past tormentors,

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.

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 Gozdz^{1, 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