What is Neutropenia?
Neutrophils are crucial front-line troops in fighting infections, especially bacterial infections. Stem cell progenitors in your bone marrow produce baby neutrophils and after they have matured they are pushed out into open blood circulation. These potent infection fighting white blood cells cruise around in the blood, often entering your tissues and organs, always on the look out for lurking infectious pathogens. Unlike killer T-cells they are not “smart” troops in the sense that they cannot recognize specific markers on pathogens. Instead, they respond by homing in on inflammatory signals – a sure sign of some mischief going on, at least most of the time. Once at the site of inflammation they discharge their “weapons” and the hope is that in the process they kill any bacteria hanging around the area. Think of them as the run-of-the-mill police officers on the beat in the neighborhood (but not very highly trained and skilled detectives / criminologists – that role belongs to T-cells) and you get the picture.
When the number of neutrophils circulating in your blood is less than normal you are said to have neutropenia. The number to watch for on your monthly CBC (complete blood counts) is absolute neutrophil count (ANC). Some labs may not report the ANC as such. They may instead report the total white blood count (WBC) and the percentage of neutrophils in that mixed bag of white blood cells. For example, if your WBC is 25.6K, and your percentage of neutrophils is 15%, your ANC is 25.6K X 0.15 = 3.8K. We discussed this in detail in an earlier article on “Lymphocytes“.
Neutropenia is designated as mild, moderate or severe, depending on the ANC count. I would not get too excited if the neutropenia is mild. But a red flag goes up if you have ANC count below 0.5K. That is the scary terrain of severe neutropenia. Your risk of infections (especially bacterial infections) goes up with severity of neutropenia as well as how long it lasts.
- Mild neutropenia (ANC between 1.5K to 1.0K): minimal risk of infection
- Moderate neutropenia (ANC between 1.0K and 0.5K): moderate risk of infection
- Severe neutropenia (ANC less than 0.5K): severe risk of infection.
Age and race seem to play a role in defining “normal” ANC in people. As we age, our ANC seems to drop. Black and Hispanic people also tend to have lower ANC as a matter of course.
Neutropenic patients are prone to bacterial infections arising out of bacteria normally found on the skin (such as Staphylococcus aureus). Gastrointestinal and urinary tract infections are also common. In addition to bacterial infections, fungal infections of the mouth, genital area and skin are also more frequent in neutropenic patients. Since the infection may spread via the bloodstream to the lungs and other critical organs, severe prolonged neutropenia is not something to take lightly.
Causes of Neutropenia
Chronic neutropenia can be present in otherwise normal & healthy people due to a variety of genetic and inherited defects. While it is relatively uncommon, persons of Arabic or African descent and Yemenite Jewish people are more likely to have inherited chronic neutropenia. For the purposes of this article I will instead focus on the reasons why you as a CLL patient may become neutropenic – a case of acquired neutropenia.
Basically patients can be neutropenic for three reasons:
- Bone marrow is not producing enough neutrophils.
- Neutrophils are getting destroyed too quickly once they have been released into open blood circulation by the bone marrow.
- They are getting trapped in the spleen or other organs / tissues and therefore not available to carry out patrol duty in blood circulation.
As we have learned in previous articles about dropping red blood cells and platelet counts, a healthy bone marrow is needed for production of sufficient numbers of all blood cells, including neutrophils. If the marrow is too infiltrated with CLL cells, or stem cell progenitors (the grand daddies of all blood cells) have been damaged by too many drugs or radiation, production of brand new neutrophils can come to a screeching halt. If the problem is overcrowding due to CLL cells (often diagnosed by means of a bone marrow biopsy), the solution is creating more space in the marrow by appropriate chemotherapy to reduce the bone marrow infiltration. Damaged and dying stem cells are a lot harder to fix. If your stem cells have given up the ghost, there are few options other than stem cell transplant from a willing and matched donor – or becoming transfusion dependent and keeping your fingers crossed that your own stem cells gradually recover over time and get back to their job.
Many drugs are toxic to neutrophils. The list is very long and many chemotherapy drugs are on the list. This is one reason why neutropenia is such a common adverse effect in patients undergoing therapy. Fludarabine, cyclophosphamide, Campath and Revlimid are good examples of drugs that cause neutropenia. (I will have a lot more to say about Campath and neutropenia later in a next article). Even the easy going Rituxan has been tagged with delayed onset neutropenia. I have no doubt ofatumumab (trade name “Arzerra”, Humax-CD20) too will prove to have problems on this front as well, we just do not have long enough track record on this newly approved drug to confirm it.
Fortunately, autoimmune destruction of neutrophils (along the lines of AIHA and ITP in the destruction of perfectly good red blood cells and platelets, respectively) is not very common in CLL patients.
Increased sequestration and/or destruction of blood cells by the spleen (“hypersplenism”) can happen in some patients. Other organs can trap and destroy neutrophils too, especially the lungs.
Taking Care of Neutropenic Patients
Since there are so many reasons for neutropenia, it is essential that you work closely with your doctors to identify the causes and guard against risk factors. The more you understand about this problem, the easier it will be to have a meaningful conversation without wasting the precious consultation time. Here are some things to discuss with your physicians
- Review all drugs (and I mean all of them, including “herbal” and any over the counter drugs) you are taking and discontinue any that may be causing neutropenia. I know, this may not always be possible – if for example you are going through FCR or Campath therapy to control the underlying CLL. One more case of devil and the deep blue sea, I am afraid. Refractory and severe neutropenia is one of the most frequent reason why patients fail to complete all the scheduled cycles of chemotherapy.
- Your mouth is the single biggest source of all kinds of unfriendly bacteria. Use careful oral hygiene to prevent infections of the mucosa and teeth. We talked about the importance of oral hygiene in a previous article “A pain in the mouth”.
- Next only to your mouth, another place where bacteria flourish is at the other end of your GI tract. You really do not want tears in the skin and mucosal lining down there, providing an easy entry point for bacteria into your blood stream. Use stool softeners for constipation, so you don’t have to strain. Avoid rectal temperature measurements and rectal examinations. (Somehow, I don’t think this is really a big issue.)
- Use good skin care for wounds and abrasions. Use moisturizing lotions after your shower if you have dry skin that tends to crack. Even garden variety nicks and cuts (especially if you get the nicks or cuts while gardening or generally mucking about) pose extra risk in neutropenic patients.
- Severely neutropenic patients are advised to avoid fresh fruits, vegetables, and flowers to eliminate possible sources of infection. You can read more about neutropenic diet here, perhaps more than you want to know. Use common sense and good judgement.
- The 1997 guidelines of the Infectious Diseases Society of America for treating neutropenic fever recommended empiric broad-spectrum antibiotics be started immediately.
- The guidelines of the US Centers for Disease Control and Prevention (CDC) followed suit; it suggested adding vancomycin if Staphylococcus aureus infections are suspected. Delays in administering the first dose are associated with higher mortality. No particular antibiotic regimen has been found to be superior over another.
Hematopoietic Growth Factors
Last but by no means least, just in the last decade we have access to hematopoietic growth factors. We are talking about GCSF (“granulocyte colony stimulating factor”), a man-made version of the biological growth factor for increasing availability of neutrophils in the blood.
You probably know them by their trade names “Neupogen” (filgrastim) and Neulasta (pegfilgrastim). Neupogen has a longer track record, but many physicians have begun prescribing Neulasta since it is long lasting. Both are expensive and very powerful drugs. Typically they are administered to accelerate neutrophil recovery and shorten the duration of neutropenia, thereby preventing infections and hospitalizations.
Neupogen (scientific name ‘granulocyte colony stimulating factor’ or GCSF) activates and stimulates the production, maturation, migration, and potency of neutrophils. Like all growth factors, Neupogen and Neulasta can be double edged swords. Below are some of the precautions that I quoted from the manufacturer’s own website.
Precautions In The Use of Neupogen / Neulasta
- “Do not use 12-24 h before or 24 h after administering cytotoxic chemotherapy, because the sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy will increase. The safety and efficacy of Neupogen given simultaneously with cytotoxic chemotherapy have not been established.” In other words, watch out, newly minted neutrophils forced out of the bone marrow by Neupogen therapy are more likely to get killed by chemotherapy drugs.
- “Obtain CBC count before therapy, and monitor twice weekly during therapy to avoid excessive leukocytosis.” In plain English, you don’t want to over-do a good thing by getting too many neupogen shots or too high dosage, thereby forcing too many neutrophils out into the blood. A high ANC contributes to a high WBC, “excessive leukocytosis”. Keep track by frequent CBC blood tests.
- “Neupogen is a growth factor that primarily stimulates neutrophils. However, the possibility that Neupogen can act as a growth factor for any tumor type cannot be excluded”. WTF? Actually, you should not be surprised if you have been a dedicated reader of CLL Topics. We were among the first consumer / patient websites that raised the alarm about excessive use of growth factors such as Procrit and other erythropoietin drugs for increasing red blood cell counts. Now even the FDA agrees there is a “Dark side of EPO”. ALL GROWTH FACTORS POSE RISKS. Once again, make sure you understand the risks and rewards. But don’t throw the baby out with the bathwater, many experts believe Neupogen has an important role to play in protecting cancer patients; but more is not necessarily better either when it comes to using growth factors.
- “SPLENIC RUPTURE, INCLUDING FATAL CASES, HAS BEEN REPORTED FOLLOWING THE ADMINISTRATION OF NEUPOGEN. INDIVIDUALS RECEIVING NEUPOGEN WHO REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE”. This all caps citation is not my doing, the manufacturer has it that way on their website, bolded too for emphasis.
- “Acute Respiratory Distress Syndrome (ARDS) has been reported in patients receiving NEUPOGEN, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Patients receiving NEUPOGEN who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, NEUPOGEN should be withheld until resolution of ARDS or discontinued. Patients should receive appropriate medical management for this condition”.
I would like to add a special comment on the subject of ARDS and Neupogen use. It seems newly minted neutrophils that come screaming out of the bone marrow upon administration of Neupogen or Newlasta are very “hot”, very reactive. Think of them as killer cops on steroids, looking for trouble and eager and anxious to attack the enemy. Sometimes, all this killing rage can be mis-directed. Consider a situation where there is a tiny little infection or inflammation in the lungs. Nothing much, under normal circumstances it would not get much of a rise from mature neutrophils. But when neutrophils are ‘goosed’ by growth factors such as Neupogen and Neulasta, a tiny skirmish can quickly escalate into an over-the-top berserk response. The scenario is similar to “Keystone cops” firing their weapons in all directions and destroying healthy tissue in the process. Lung tissue right after such an uncontrolled neutrophil attack looks like bloody hamburger – and that is no exaggeration.
ARDS can kill patients, at the very least it can make them very sick indeed. One specific situation where this happens more frequently than I think it is recognized is in newly transplanted patients. There is a name for it: “pre-engraftment syndrome”. Newly transplanted patients are kept on a steady diet of Neupogen until their neutrophil counts are in normal range. But sometimes, the process gets out of control and the result is acute lung injury. Each wave of newly minted neutrophils rushes to the site of mayhem going on in the lungs, responding to the inflammatory signals of the raging battle. Pretty soon the situation can snowball out of control. To this day, I am convinced my husband PC’s death was exacerbated by this kind of a process.
Special Risk of Neupogen Use During Campath Therapy?
This is something I have wanted to write for a long time and it will be the sole focus of my next article in this series. I base my comments on highly credible published information. But I have not seen the dots connected quite in the same way by experts, so for now you will have to consider it as just my take on things – until we have some official confirmation of the logic. Since Campath therapy is notorious for causing neutropenia and many oncologists routinely use Neupogen in an attempt to prevent neutropenia, you can see this is going to be a controversial subject.
A happy Valentine’s day, from my family to yours.
16 comments on "Neutropenia"
This update is very important to me. I’m on Bendamustine and Rituxan. So far three two/day treatments. My last ANC was 1.0. I had one neupogen injection 5 days later.
Usually I’m on prilosec daily but because of interaction with Bendamustine, on zantac 150 twice daily.
I received an email from a member of CLL group that zantac lowered her count dangerously. I spoke to a pharmacist who could find no data on this. I will email my oncology nurse Monday. I appreciate the info on this from the member.
Chaya or anyone else, have you had any experience or heard about this.
Thank you
Rita Horwitz
The neutropenic diet was an eye opener! It wipes out many of my favorite foods. Good article.
And a happy valentines day to you, Chaya, and your family.
Jim
The following is highlighted in the article. “Fludarabine, cyclophosphamide, Campath, Revlimid are good examples of drugs that cause neutropenia.” Is Chlorambucil another good example, or is it different? I will be starting ChR in about a week.
Neupogen caused my spleen to enlarge rapidly and significantly whilst on FOLFOX treatment for a different cancer. The enlargement persisted until 3 years later after treatment with Chlorambucil/Rituxan. Yes, I had some neutropenia with the latter, but nothing significant.
Happy Valentine’s day Chaya, I know it must be mixed with sadness for you.
As usual another great education for me and I suspect most of us. Today’s article is especially pertinent to me since I just finish 6 cycles of chemo in which I was on Neulasta for each one. I take your series on blood elements with me when ever I see my hematologist. Thanks for publishing this article and, as always, I look forward to the next gem.
Tom
Through my many therapies since ’93, including ’05 transplant, my neuts have behaved well. Even during and after a heavy run of Campath (SubQ) 5/07 to 11/07, my neuts held steady. Now I am the “bull’e eye” of this heaven sent article. (Everything you do is heaven sent). I just finished another SubQ campath run (3/09 to 8/09) with another good response … except this time my neuts have crashed. They hit “critical to zero” ranges a number of times during the campath. I got lots of neupogen, especially July through August. While my other numbers look decent (even my platelets are over 100), my neuts are steadily sitting at .3 to .5. My Oncologist, who I love, seems content to let it ride, and especially seems reluctant to go the EPO route. He says, “Bob, your otherwise robust health and active schedulede makes me feel you have enough neuts in the tissue. Let’s just keep an eye on things”. I am still on daily bactrim and acyclovir, which probably props me up. In spite of my doc’s encouragement, my normal optimism, and the fact I have jumped a bunch of CLL hurdles since ’89, this neutropenia has me feeling my most vulnerable. I cannot thank you enough Chaya for everything you do. This topic is so PERFECTLY timed and helpful to me.
bob larkin
Chaya, Do you think that the whole handling of prophylatic post treatment medications are too driven by liability concerns and “one-size-fits-all” mentality? We patients are SO different in how we react to treatment and how the cancer affects our clincal health outside of the bulk of the disease I wonder if use of some non treatment medications may do more harm than good and whether the criteria for such use could be refined? I am not diminishing the serious threat that pathogens pose to the immune compromised patient by treatment or disease but wish there were a better way to gage the actual threat to a given patient, not by a universal number, but rather the patient’s own susceptibility to infection, based to some degree by clinical history in combo with the numbers.
Oddly and most welcome (so far) a Martian doctor might conclude that my having CLL has STRENGTHENED my immune system based on a history of past and post diagnosis infections. I raise this issue because it may be that my kidney failure event occurred in part or was exacerbated by post treatment medications. I was not thinking of the Neulasta in this case but for reader interest, my experience with Neulasta follows.
On the third day after completion of my 2nd cycle of RF labs showed I was neutropenic for the first time at .6k and my onc had me get a Neulasta shot.
I have talked with quite a few patients who had Neupogen shots and all had experienced bone pain in varying degrees. I braced myself for this discomfort but did not experience any pain and because Neulasta is longlasting it is only one shot, in most cases, whereas Neupogen often takes repeated shots to achieve the same result. The onc had to check with the insurance company for approval as I believe the Neulasta is quite a bit more costly.
While I am only one patient it worked very well for me. My labs showed a rise in ANC from .6 to 5.7 five days after the shot and a high spike of 9.7 nine days after the shot which then drifted down in succeeding tests.
Your reflections concerning lung involvement from new neutrophils are most valuable.
Dietary deficiencies can certainly cause neutropenia, anemia.
Rita, you ask a very important question that is worth answering in detail.
Zantac is taken by zillions of people world wide for controlling hyperacidity. It is a class of drugs called histamine H2-receptor antagonists. The generic name for Zantac is “ranitidine”.
Here is the problem in a nutshell. No one enjoys the heartburn associated with hyperacidity (strike 1, I have suffered from massive hyperacidity for decades now and take prilosec + Tums twice each day). But Stomach acid is there for good reason and the reason is to break down the food we eat so that nutrients in it can be absorbed properly as they makes their way through your gut. Reducing the level of stomach acid by means of drugs means the food breakdown is less efficient and that in turn means we may have nutritional deficiencies.
For example, some people on aggressive acid reduction therapies may be anemic due to poor iron absorption. Other nutrients also effected by this process are zinc and vitamin B12 (cyanocobalamin). Long term use of Zantac and similar drugs (along with the ubiquitous antacid tablets) could possibly reduce absorption of these nutrients sufficiently to cause vitamin B12-deficiency. This problem is made worse if patient has poor diet that has only marginal levels of vitamin B12 to begin with. Supplementation with vitamin B12 is often needed in vegans (strike 2, I have been a life long vegetarian).
Several other drugs (such as metformin used to control adult diabetes) can also add to the problem, as well as GI tract diseases such as Crohn’s disease and ulcerative colitis (Strike 3, I take metformin for diabetes and I was diagnosed with Crohn’s disease several years ago). I guess I should get B12 supplements, you think? I am so good at dishing out advice that I do not take myself :)
The B vitamins play a huge and very complex role in just about every cellular function. Vitamin B12 deficiency can lead to several cytopenias including anemia and neutropenia. Fortunately, it is also relatively easy to fix with proper supplements. Here is a useful quote from Wikipedia, as well as link to the full length article that you should read:
http://en.wikipedia.org/wiki/Vitamin_B12
“Vitamin B12 is normally involved in the metabolism of every cell of the body, especially affecting the DNA synthesis and regulation but also fatty acid synthesis and energy production. However, many (though not all) of the effects of functions of B12 can be replaced by sufficient quantities of folic acid (another B vitamin), since B12 is used to regenerate folate in the body. Most “B12 deficient symptoms” are actually folate deficient symptoms, since they include all the effects of pernicious anemia and megaloblastosis, which are due to poor synthesis of DNA when the body does not have a proper supply of folic acid for the production of thymine.[14] When sufficient folic acid is available, all known B12 related deficiency syndromes normalize”.
Recently I head from a good friend whose long standing neutropenia that required regular Neupogen shots became a whole lot better controlled after vitamin B supplements. Here is another quote from a Wiki article about how B12 deficiency can be corrected:
“B12 can be supplemented in healthy subjects by oral pill; sublingual pill, liquid, or strip; intranasal spray; or by injection. B12 is available singly or in combination with other supplements.
Vitamin B12 can be given as intramuscular injections of hydroxycobalamin, methylcobalamin, or cyanocobalamin. Body stores (in the liver) are refilled with half a dozen injections in the first couple of weeks and then maintenance with monthly to quarterly injections throughout the life of the patient”.
Traditionally B12 supplements have been given as an injection to ensure absorption. But in more recent times oral replacement (especially the sublingual form that melts under your tongue) are becoming more common. If sufficiently large doses are given, the oral route seems to work just fine and patients do not need the jab in the arm.
If you have any of the above mentioned reasons to suspect vitamin B deficiencies, it is easy enough to test for it by means of a blood test, then correct the problem with a very easy and cheap fix with almost no downside – talk to your doctor about it.
A family member I was caring for, developed rapid onset febrile neutropenia about five days after IV infusions of Cyclophosphamide and Prednisone. It was a “last try” for advanced cancer. After that came the pneumonia and sepsis which was battled until the last. With febrile neutropenia, watch for a fever rising pretty much by the hour. One hopes these side effects won’t occur but they can, and it is time to take rapid action, medically. Severe neutropenia is very serious.
Thank you for bringing this topic up, Chaya, and best wishes today.
Dear Chaya,
Thank you so much for the information and Updates. I should remember all this but when on chemo, I’m not responsible for much. I blame it on the steroid which does a number on me.
I have not eaten red meat for years. Once in a while chicken. And have an allergy to shellfish. Tuna and salmon in small amounts is all I do. I’m gun-shy after many problems.
I will contact my internist re:blood test tomorrow. I have had CLL for almost 16 years and my internist is the one that had an iron level drawn a few years ago. Lo iron. I was treated with medication, then.
Chaya, thank you so much for taking care of us and a personal thank you for taking care of me. And thank you for the note on my email.
Many Blessings,
Rita
Chaya: a little off subject here, but i’ve seen it suggested that green tea can cause a reduction in platlets. Have you come across any evidence of this
Ambrose
To Bob,
I was on bactrim for 2 1/2 years before my transplant and never had a problem with bactrim induced neutropenia. However, post-transplant, every time we have tried to restart bactrim, it has wiped out my neutrophils. It seems to be a fairly common response to bactrim in post-transplant patients. Even after stopping the bactrim, it took several weeks and some neupogen to get them back.
Bactrim is the first line choice since it cover both pneumocystis carinii and encapsulated bacteria. I was switched to dapsone and my neutrophils have done well since. Dapsone only covers pneumocystis so they have also recommended penicillin for coverage of encapsulated bacteria.
It is just a thought to consider discussing with your oncologist on the next visit if chronic neutropenia is making you feel uneasy. If you are interested in this approach or your oncologist wants to check it out in more depth, I would be happy to direct you to the protocol site.
Chaya,
As most above have been writing, this article is right on target with me at this time. I’m on Bendamustine and Rituxan with my third two/day treatment coming this week. Of particular note for me was the caution regarding using prilosec while infusing Bendamustine.
Your article cause my Wife and I to do more digging regarding what to watch for and/or avoid when engaged using Bendamustine. We found more than my VA care takers were advising us about. Vitamine E was also found was to be avoided when using Bendamustine as well as most over the counter pain pills including aspirin that thin the blood while using Bendamustine. One thing I came with as we started this third series was my demand for weekly CBCs which they resisted until I made it clear why I wanted this and my history/experience with my 1st two chemo treatments beginning in 2002.
I actually had one experience during my first set where my Neutrophils were ZERO and the lead Oncology Nurse assigned to me gasped outloud while reading the CBC that was being taken everyday during Fludarabine infusions and mid week one week and said loudly to her associates look at this! ZERO Neutrophils!
After this happen, all went silent and nurses with Doctors huddled and then she approach me and appologized for the out bursts but informed me why this was such an alarming situation. My Oncologist came out immediately and I was admistered a dose of Neulasta (pegfilgrastim)and since I was going to be out of town for the next three weeks following the infusion week camping at the coast and scheduled to get CBCs at clinics near where I was going, and I was experienced at self injecting medications due to weekly Avonex shots for my MS, I was given a couple of doses to use while gone.
Thank you Chaya, Thank you for keeping this web site going.
Frank Mazurkiewicz,
CLL now 10 years and MS 35 years
Steve,
I very much appreciate your input. I’ll definitely discuss this with my Oncologist. I’m seeing him on the 22nd. I will get back to you for the protocol site if he wants to see it. Again, thanks for taking the time and being so helpful.
Great information for all. Thank you Chaya.
Best wishes,
Monique
bob
I had 6 months of FRC and took Neulasta after every treatment. Never got down to dangerous levels but did have my counts drop consistently. 4 months after my last FRC session I still have low lymphocite counts but they are coming back up. Just found out yesterday that I have lesion on my stomach from the chemo, so the FRC was great at it put me into CR but did effect my stomach and immune system.
very good informative article, Chaya, Thank u.
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