Fifty to eighty percent of all deaths in chronic lymphocytic leukemia (CLL) are from infections, with pneumonia accounting for 40% of them. Streptococcus Pneumoniae (the bacteria formerly known as pneumococcus) is the leading bad actor. In all the excitement about the research being presented at the huge annual congresses of ASH (American Society of Hematology), ASCO (American Society of Clinical Oncology) and EHA (European Hematology Association) 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. CLL is after all a cancer of the immune system.
TAKE AWAY POINTS:
- Infections, especially pneumonia are the leading cause of death in CLL.
- Our response to vaccines is poor and gets worse over time.
- Still we should get all our “killed” vaccines as soon as possible after diagnosis.
- A new pneumonia vaccine, with new data and a new protocol from the CDC makes the best of a difficult situation.
- Live vaccines are contraindicated for all of us with CLL.
Dr. Wierda and others are working on ways to reboot our immunity as detailed in this prior blog post from ASCO 2013, but that is the future, not our present reality.
IVIG (intravenous immune globulin) 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.
Lenalidomide increases levels of our immunoglobulins and infections rate decrease after the first year on ibrutinib, but the data is not convincing these are paths to lower infection risks.
Vaccines offer the promise of the more potent active immunity, where we form our own more durable antibodies. Our problem has been that they usually don’t work for us. We are wimps at working antibodies. Our clonal B cells mess up the ability of the few remaining healthy B cells to form antibodies. Drugs such as rituximab make the situation worse by wiping out all the B cells, good or bad. A 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.
Because of our impaired immunity, we just don’t form adequate antibodies when given the flu vaccine or other jabs. And worse, after being jabbed with a live attenuated (a weakened version of the dangerous infectious agent) we run the real risk of that weakened but still alive virus running amuck in our immune-compromised bodies.
All live vaccines such as shingles (herpes zoster) or MMR or Yellow Fever are contraindicated in CLL.
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 this archived protocol that is still valid about the optimal order and spacing of the vaccines that is trying to make the best of a difficult 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 in 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 covers 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 infection. 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. Our immunity usually gets worse with time and treatment. Prevnar 13 is the better choice for the first jab, or even the second if we have already have received Pneunovax 23.
I have pasted the actual abstract from the EHA below, as I found their web site cumbersome to navigate.
6. Chronic lymphocytic leukemia and related disorders – Clinical
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 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.
Brian Koffman 6/24/14 Updated 3/17/15