Neutropenia

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.