Neutrophils: Defenders of your health
When it comes to keeping you safe from bacterial infections, there are no better troops than neutrophils. If you have too few neutrophils, you are said to be neutropenic. Most CLL patients will face the scary prospect of deep seated neutropenia at some point in their disease, especially if they are being treated with immune suppressive therapy.
Stem cell progenitors in your bone marrow produce baby neutrophils and after they have matured sufficiently they are pushed out into open blood circulation. Prudently, healthy bone marrow holds back reserves of almost-ready neutrophils nicely tucked away in the nooks and crannies of the bone marrow, ready to be released as it becomes necessary. Once released from the bone marrow these potent infection fighting white blood cells cruise around in the blood, often entering tissues and organs, always on the look out for lurking infectious pathogens.
Unlike killer T-cells neutrophils are not “smart” troops in the sense that they cannot recognize specific markers on pathogens. Instead, they respond by zeroing in on signs of inflammation – a sure sign of some mischief going on 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. They are the crucial first responders when trouble breaks out, but they are not very highly trained and skilled detectives / criminologists – that role belongs to T-cells.
Neutropenia comes in different flavors. Mild or transient neutropenia is not the end of the world so long as you are careful about avoiding infections. But most oncologists get concerned if you ANC is lower than 0.5K. ANC below this threshold puts you in the dangerous territory of severe neutropenia. Please read our earlier article on lymphocytes to learn more about ANC (absolute neutrophil count), how it is reported on your monthly CBC blood test, how to calculate it if the report does not spell it out.
Development of modern neutrophil growth factors such as Neupogen and Neulasta to reduce and shorten periods of severe neutropenia has saved lives, increased survival statistics, prevented hospitalizations and improved quality of life of many cancer patients. I want you to remember that important point as you read the rest of this article. Growth factors are powerful drugs. Their use may be associated with adverse effects in special circumstances and this article attempts to highlight situations where you may want to think twice before using them. But there is such a thing as throwing out the baby with the bathwater. Please be sure to discuss the pros and cons of Neupogen therapy with your doctors before you make decisions. As always, more is not necessarily better and do use caution before you pester your doctor for more shots or higher doses of Neupogen, just because it makes your monthly CBC look better.
How do Neupogen and Neulasta work?
Neupogen and Neulasta are brand named drugs that use man-made neutrophil growth factor G-CSF (granulocyte colony stimulating factor), mimicking a similar growth factor made by your own body. This growth factor works by giving the bone marrow marching orders to release neutrophils held in reserve in the bone marrow as well as start production of new baby neutrophils. Releasing already minted reserve troops happens quite quickly, often a matter of hours. As you can imagine, it takes longer to start from scratch and make new neutrophils ready for battle.
Neupogen was introduced first into the marketplace, followed by the longer-lasting Neulasta. We talked about “glycosylation”, addition of long strands of sugar molecules to drug molecules in our latest article on Epo. Addition of these sugar strands makes it harder for the body to get rid of the drug, which in turn makes its therapeutic effect last that much longer. A similar approach was taken to make Neulasta a longer acting drug. Neupogen shots are often given on a weekly basis, whereas the longer lasting Neulasta may be given only once a month or so. One of the less lovely side effects of these drugs is deep seated bone marrow pain – a consequence of goosing the bone marrow and forcing it to ramp up neutrophil production.
There is another use of Neupogen and Neulasta that you may not be aware of. The same feature of the drug that makes the bone marrow release reserve neutrophils nesting in there also causes flushing out of other cells residing in the bone marrow – of particular importance, the blood stem cells nicely tucked away in the bone marrow niches. A small number of blood stem cells are normally kept in open blood circulation, but the vast majority of them are kept safe within the bone marrow. When stem cell donors donate stem cells for allogeneic transplantations, they are often given one or more shots of Neupogen to increase the number of stem cells in the blood. There is an almost immediate increase in the number of stem cells circulating in the blood. This mass exodus of blood stem cells from the bone marrow gradually reverses over time (matter of several days) as all the cells kicked out of their comfortable homes mill around a bit in blood circulatin but eventually go back home.
Harvesting stem cells in sufficient numbers from the blood of donors becomes a much bigger challenge without flushing them out of the bone marrow and into open circulation. The same “flushing out” (also called “mobilization”) takes place also to other cell lines that happen to be sheltering in the bone marrow. A neupogen shot kicks out stem cells, reserve neutrophils, lymphocytes – you name it, any cell living in the bone marrow – out into the open. While this use of Neupogen has been hugely important in controlling neutropenia and making it easier for stem cell donors to mobilize sufficient numbers of stem cells, I worry that the same effect in CLL patients undergoing chemotherapy may pose unexpected problems. Read on.
Concurrent Use of Campath and Neupogen / Neulasta
Campath (also known as “alemtuzumab”) is a powerful and very valuable monoclonal antibody in our arsenal against CLL. It is one of the few drugs that works in patients with “Bucket C” cytogenetics with the poor prognosis 17p (p53) deletion, as well as those who have become refractory to fludarabine therapy. Chances are pretty good that the majority of CLL patients who have been through several chemotherapy regimens or with high risk disease will have to use this drug at some point or the other in our battle against CLL.
The single biggest drawback of Campath is that is not very specific. This monoclonal antibody targets CD52 marker – a marker carried by B-cells, T-cells, neutrophils and monocytes. That is just about the whole kit and caboodle of our cellular immune system. While it kills B-cells (and therefore CLL cells), Campath therapy also leaves patients with dangerously low levels of T-cells – the real “smart” troops of our immune system. T-cell levels after Campath therapy are at about the same level as advanced AIDS patients and this T-cell depletion lasts for almost a year or more!
Many of you may not be familiar with monocytes. If neutrophils are first responders to a crisis, think of monocytes as the instant responders. In neutropenic patients the very first cell line that the bone marrow is able to get out there onto the battle front are monocytes. Monocytes are the precursors of dendritic cells and macrophages – literally garbage monsters that can eat bacteria and other other pathogens alive. Dendritic cells are essential for alerting T-cells to the exact nature of the enemy. Without dendritic cells telling them what to fight, T-cells are blind and unable to mount an effective attack strategy.
So, to sum it all up, Campath kills B-cells, T-cells, neutrophils, monocytes and therefore macrophages and dendritic cells. Did I forget anything? Oh yes, a bit off topic, did you guys know that human sperm also carry the CD52 marker? Someone suggested a long time ago that Campath can be used as a male contraceptive since it leaves you guys shooting blanks. Frankly, I think it is a little excessive, treating people with Campath rather than giving them condoms.
The other thing you need to know about Campath is that it is a humanized monoclonal antibody. The good news about that is that the drug lasts for a long time in the body and therefore its therapeutic effects last for several months or more before last traces of it are gotten rid of. The bad news is also that it lasts for a long time in the body. During the many months while it lingers in your blood, it is busy killing B-cells. But equally likely, it is also killing neutrophils, T-cells, monocytes etc. That is why immune suppression due to Campath therapy is so deep and long-lasting.
Here is the million dollar question: is there something that can be done to improve the odds in our favor and give patients an improved level of immune protection while they are undergoing Campath therapy? Preventing neutropenia sounds like a good thing to do. How about giving patients Neupogen / Neulasta shots at the same time as they are getting Campath therapy? Sounds good, right? Not!
Leukemia. 2005 Apr 28; [Epub ahead of print]
Filgrastim(Neupogen) and alemtuzumab (Campath-1H) for refractory chronic lymphocytic leukemia.
Lin TS, Flinn IW, Lucas MS, Porcu P, Sickler J, Moran ME, Lucas DM, Heerema NA, Grever MR, Byrd JC.
The Division of Hematology-Oncology, The Ohio State University, Columbus, OH.
Alemtuzumab (anti-CD52; Campath-1H) is effective in fludarabine-refractory chronic lymphocytic leukemia (CLL), but is associated with infection and early onset neutropenia. To reduce toxicity, filgrastim (G-CSF) was administered concurrently with alemtuzumab. In total, 14 CLL patients (median age 59) with a median of 3.5 prior regimens (range 1-12) received i.v. alemtuzumab, stepped up from 3 to 30 mg the first week, then 30 mg thrice weekly for 12 weeks. Filgrastim (Neupogen) 5 mug/kg was administered daily 5 days before and throughout alemtuzumab therapy. Six patients developed cytomegalovirus (CMV) reactivation 3-6 weeks into treatment; six patients developed fever, three neutropenia, and one pneumonia. The patient with CMV pneumonia died; ganciclovir cleared CMV in the other patients. Five patients developed early neutropenia (weeks 2-5). Four patients developed delayed neutropenia (weeks 10-13) unassociated with CMV reactivation. Nine patients ceased therapy because of infectious and hematologic toxicity. Five partial responses were noted, all in patients with lymph nodes >5 cm, lasting a median of 6.5 months (range 5-13). Filgrastim and alemtuzumab were given concurrently with manageable infusion toxicity and clinical activity, but the efficacy of this regimen was limited by delayed neutropenia of unclear etiology and CMV reactivation. Filgrastrim (Neupogen) should not be administered prophylactically during alemtuzumab therapy outside clinical trials.
PMID: 15858611
This was a small study, only 14 patients, but has highly credible authors supporting the startling conclusions highlighted above.
- None of the patients were chemo naïve. But they were not exactly basket cases either, just your average, been-around-the-block-a-few-times CLL patients. While the patient number was small, the results were dramatic enough to justify pretty solid conclusions.
- A whopping 11 out of 14 patients developed grade 3-4 thrombocytopenia and / or anemia. If you are not familiar with the grading classification, grade3 is pretty darned serious and grade 4 is even more so.
- Six of the 14 patients developed full-blown CMV (cytomegalovirus) reactivation, and one of these patients died in hospital in spite of all efforts to contain the infection. As you should know by now, CMV activation is one of the most common opportunistic infections to watch for in Campath therapy. This trial of combining G-CSF with Campath was aimed mostly at controlling opportunistic infections, a task at which it failed spectacularly.
- Nine out of the 14 original patient cohort discontinued this therapy, and given the results above I am sure none of us are surprised at this very high drop-out rate.
- There were two important positive observations. Two of five patients with the feared 17p (p53) deletion, achieved a partial response. A similarly high response rate was noted in 5 out of 11 patients (46%) with lymph nodes greater than 5 cm. Typically, Campath does not work well with large lymph nodes, defined as larger than 5 cm.
The researchers were surprisingly blunt in their assessment: Filgrastrim (G-CSF: Neupogen, Neulasta) should not be administered prophylactically during alemtuzumab (Campath) therapy outside clinical trials. In other words, don’t attempt to do this on your own!
What is going on here?
This is how I see it, even though the researchers involved did not connect the dots quite as explicitly as I am about to. Campath kills all cells that carry the CD52 marker: T-cells, B-cells (CLL cells), neutrophils, monocytes (therefore macrophoages and dendritic cells). It has a hard time killing any of these cells if they are hidden safely away in large lymph nodes or deep within the bone marrow.
What happens when Neupogen is given concurrently with Campath? All those nicely hidden “reserve troops” of neutrophils, T-cells, monocytes are flushed out of the bone marrow and into open blood circulation, so many hapless victims to be mowed down by Campath. As any good general knows, it is important to keep fighting troops in reserve; throwing everything he has into an unwinnable fight is the surest way to lose the whole war. A more prudent strategy would be to keep the reserves safe where they are, live to fight another day.
The take home message? While neutropenia is a very important part of the immune suppression associated with Campath, it may not be a good idea to try to do an end run around it by giving Neupogen / Neulasta shots concurrently with the Campath therapy. Not only would this not reduce neutropenia and immune suppression, it might make things worse: neutropenia and immune suppression may become deeper and longer lasting if all the reserve troops are killed off as well.
What makes this a very complicated question is the fact that Campath lasts for a long time in the body- several months at least. How long are there trace amounts of Campath lurking around in the patient’s blood, enough to kill any neutrophil or T-cell that pokes its head out of the bone marrow? I do not know the answer to that question. Frankly, I am surprised more reports have not followed up this interesting lead about risk factors of concurrent use of Campath and Neupogen / Neulasta.
On the bright side, I speculate that the better than expected response in patients with bulky disease in this study is due to the Neupogen flushing out CLL cells out of the bulky lymph nodes and therefore making it easier for Campath to kill them. Normally Campath is not able to shrink bulky lymph nodes since it is not able to kill CLL cells tucked away in the lymph nodes.
Concurrent Use of Chemotherapy with Neupogen / Neulasta
Powerful chemotherapy combinations such as FCR and its analogs have revolutionized how we treat CLL patients. It is not an exaggeration to say they have added years to the life expectancy of our guys. But there is no denying that they also have serious adverse effect profiles. For example, FCR is contra-indicated for elderly CLL patients with decreased bone marrow reserve.
What exactly does “bone marrow reserve” mean? As we said above, majority of blood stem cells live in the bone marrow. As we age, the total number of blood stem cells we have available gradually decrease over time – unavoidable ravages of time. At any given time, a few of these blood stem cells may cruise the blood circulation for a while before going back home to their comfortable niches in the bone marrow where they are more secure and better protected.
Old fashioned chemotherapy drugs such as fludarabine and cyclophosphamide are not exactly friendly to stem cells. Any blood stem cells caught out in the open blood circulation are fair game, likely to get killed by these and similar chemotherapy drugs. But it is a little harder to kill stem cells hidden away in the nooks and crannies of the bone marrow. I am sure you can see how elderly patients with reduced numbers of stem cells to begin with can hardly afford to have more of them killed by chemo. What happens when there are too few blood stem cells left? Since these are the cells that create all other blood cells (red blood cells, platelets, neutrophils etc), lack of sufficient stem cells leaves patients with tough choices: transfusion dependency for the rest of their lives, or an allogeneic stem cell transplant to replace the dead stem cells with new healthy ones from a matched donor.
Where does this leave us when we consider Neupogen / Neulasta shots administered at the same time as fludarabine and cyclophosphamide infusions? Fortunately, neither F nor C last very long in the human body. And Rituxan is a very targeted monoclonal antibody, killing only mature B-cells that display the Cd20 marker. So, if Neupogen or Neulasta is given well past the time when F and C have been excreted out of the body, I would think there should be no problem similar to the Campath + Neupogen scenario we saw above.
But how many patients get Neupogen shots on the same day they are also scheduled to get fludarabine or cyclophosphamide, because it works better for every one’s schedule and convenience? And if this done, are we adding to the risk of precious blood stem cells getting flushed out into open blood circulation where they are more readily killed by the toxicity of fludarabine or cyclophosphamide? Especially in older patients with limited numbers of stem cells, is it prudent to withhold use of Neupogen or Neulasta for couple of weeks before and after latest round of F and C, to limit this potential damage to blood stem cells?
Frankly, I have not seen this potential risk addressed or highlighted in any professional articles. Unlike the concurrent use of Campath + Neupogen identified by the OSU researchers, this potential risk of using Neupogen concurrent with chemotherapy has not been addressed elsewhere. You have to judge for yourself the likelihood that I may be right. In any case, prudence is the better part of valor they say. Why not wait for a few days at least after your F and C infusion before you get your Neupogen shot? I am just saying.
Neutrophils on High Alert
Neupogen and Neulasta shots not only increase the numbers of neutrophils in the blood, they also increase the aggressiveness of the neutrophils. Think of them as cops on high alert, looking for trouble and only too eager to shoot-to-kill. This aspect of Neupogen-boosted neutrophils can be used to our advantage.
For example, combination of Neupogen + Rituxan is likely to work better than just Rituxan alone. Since Rituxan cannot do a whole lot of CLL cell killing by itself and needs an assist from the immune system, it makes sense that increased numbers of neutrophils will help and having these neutrophils goosed to maximum performance is even better. I remember pitching this concept to Dr. Mike Keating and Dr. Tom Kipps early in my CLL career. I am happy to report they followed up the suggestion. A variation on the theme, M. D. Anderson chose to use GM-CSF (granulocyte and macrophage colony stimulating factor; trade name “Leukine”) as the growth factor of choice, along with Rituxan in their clinical trial. Makes sense, this growth factor increases production and aggressiveness of neutrophils as well as macrophages. Reports out of M. D. Anderson suggest this approach has met with some success and in fact they recommend it as the therapy of choice for elderly patients with limited stem cell reserve. (Be sure to note, this is GM-CSF in combination with Rituxan. No chemotherapy drugs involved that can kill blood stem cells; Rituxan is the monoclonal of choice, therefore no risk of killing all other immune system cells as in the case of Campath).
Neutrophils on Rampage
While it is a good idea to have cops motivated, willing and able to apprehend criminals, no one wants over-zealous officers shooting first and then asking questions. As we pointed out in the section above, Neupogen induced and newly minted neutrophils are excellent partners for Rituxan targeted CLL cells. But as we also point out in the early parts of this review, neutrophils are not really smart troops. They are not very good at figuring things out for themselves, the way T-cells are.
Basically, neutrophils like to listen for tell-tale signals of inflammation – often a sign of something wrong, criminal elements at work and causing mayhem. Once they pick the scent of inflammation, they zero in on that spot and start shooting. Here is where the Keystone-Cops analogy comes in. Once they reach what they think is the crime scene, neutrophils shoot off their weapons in all directions, hoping to kill the bad guys. But in the process they can also do a lot of damage to surrounding healthy tissue – collateral damage of an over-zealous and not very smart bunch of defenders with itchy trigger fingers.
It has been known for some time that in some vulnerable patients Neupogen can cause lung damage. The scenario is easy to imagine. Some slight infection or inflammation in the lungs – a common thing in ill patients – precipitates the whole avalanche. A few Neupogen-goosed neutrophils latch on to the signals of inflammation in the lungs and zero in. In the process of shooting off their weapons they may cause a lot more damage to lung tissue; which in turn sets off even more pronounced signals of alarm and inflammation; which draws even more neutrophils-on-steroids to the melee. You get the picture. The abstract below reports how this can quickly get out of control – even become fatal. You can read the full text of the article by clicking on the link.
http://www.nature.com/bmt/journal/v36/n3/pdf/1705037a.pdf
Bone Marrow Transplant. 2005 Aug;36(3):245-50.
Respiratory status deterioration during G-CSF-induced neutropenia recovery.
Karlin L, Darmon M, Thiéry G, Ciroldi M, de Miranda S, Lefebvre A, Schlemmer B, Azoulay E.
1Medical Intensive Care Unit, Saint-Louis Teaching Hospital and Paris 7 University, Assistance Publique, Hôpitaux de Paris, Paris, France.
Exacerbation of prior pulmonary involvement may occur during neutropenia recovery. Granulocyte colony-stimulating factor (G-CSF)-related pulmonary toxicity has been documented in cancer patients, and experimental models suggest a role for G-CSF in acute lung injury during neutropenia recovery. We reviewed 20 cases of noncardiac acute respiratory failure during G-CSF-induced neutropenia recovery. Half the patients had received hematopoietic stem cell transplants. All patients experienced pulmonary infiltrates during neutropenia followed by respiratory status deterioration coinciding with neutropenia recovery. Neutropenia duration was 10 (4-22) days, and time between respiratory symptoms and the first day with more than 1000 leukocytes/mm3 was 1 (-0.5 to 2) day. Of the 20 patients, 16 received invasive or noninvasive mechanical ventilation, including 14 patients with acute respiratory distress syndrome (ARDS). Five patients died, with refractory ARDS. In patients with pulmonary infiltrates during neutropenia, G-CSF-induced neutropenia recovery carries a risk of respiratory status deterioration with acute lung injury or ARDS. Clinicians must maintain a high index of suspicion for this diagnosis, which requires eliminating another cause of acute respiratory failure, G-CSF discontinuation and ICU transfer for early supportive management including diagnostic confirmation and noninvasive mechanical ventilation.
PMID: 15937498
Is this risk of acute respiratory syndrome (ARDS) limited to ill cancer patients? It might surprise you to know that it is not. As we mentioned above, healthy stem cell donors are given Neupogen shots in order to flush out (“mobilize”) more stem cells for harvesting from their blood. As you would expect, this administration of Neupogen would also increase the numbers and aggressiveness of neutrophils – after all, that is the main function of this growth factor. The abstract below points out that a small percentage of these stem cell donors may also be at risk of Neupogen induced lung injury. Who knew.
Haematologica. 2005 Mar;90(3):ECR10.
Acute lung Injury in a healthy donor during mobilization of peripheral blood stem cells using granulocyte-colony stimulating factor alone.
Arimura K, Inoue H, Kukita T, Matsushita K, Akimot M, Kawamata N, Yamaguchi A, Kawada H, Ozak A, Arima N, Te C.Department of Hematology and Immunology, Kagoshima University Hospital, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan.
Abstract
Granulocyte-colony stimulating factor (G-CSF), a hematopoietic growth factor, is widely used to accelerate recovery from neutropenia after severe chemotherapy, both decreasing the risk of infection and mobilizing peripheral blood stem cells. Adverse effects occur with G-CSF use in approximately 30% of cases, comprised predominantly of bone pain, headache, and general fatigue. Pulmonary toxicity is very rare. Here, we describe a healthy donor for allogeneic hematopoietic stem cell transplantation who developed acute lung injury (ALI) after 4 days of G-CSF administration. Among the serum cytokines examined, only Interleukin (IL)-1beta level was elevated in this case. As a high level of IL-1beta was detected at the onset of ALI, on day 4 after G-CSF administration, and decreased to below the level of detection on day 11, it is possible in a certain part that IL-1beta was involved in the onset of G-CSF-related ALI in the present case. Granulocyte-colony stimulating factor (G-CSF) is commonly administered to healthy donors to mobilize peripheral blood stem cells (PBSC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adverse events from G-CSF use in healthy donors have been described in approximately 30% of cases, and are comprised predominantly of bone pain, headache, and general fatigue. Pulmonary complications caused by G-CSF include cough, dyspnea, and interstitial or alveolar pulmonary edema with mild-to-severe deterioration of blood oxygen level. Few cases of acute respiratory distress syndrome (ARDS) following G-CSF administration have been reported. The present report describes a healthy donor for allo-HSCT with acute lung injury (ALI) after 4 days of G-CSF administration. The cytokine-related mechanisms of G-CSF administration that contribute to ALI are discussed.PMID: 15753051
Last Words
This is a complex and important subject and I want to make sure my message is not garbled.
- Growth factors such a Neupogen, Neulasta, Leukine (GM-CSF) are true life savers. For the first time, clinicians have tools with which to control severe neutropenia. Longer life expectancies of many cancer patients are due to better control of neutropenia and therefore avoidance of fatal infections.
- But once again, these growth factors are potent weapons to be used with caution. Getting more shots of Neupogen than is clinically indicate just so that you are happy with your blood counts is foolish and dangerous.
- Equally foolish would be to throw away the baby with the bathwater. If your doctor suggests you need a Neupogen shot to address severe neutropenia, you are well advised to listen carefully; and discuss the pros and cons with him.
- I am particularly concerned about the lack of discussion among the experts on concurrent use of Neupogen with Campath as well as chemotherapy agents of known toxicity to stem cells. That last bit, the potential risk of concurrent use of Neupogen with chemotherapy is just me trying to connect the dots. It is up to you whether you consider that a credible risk assessment – or not.
I wonder how many of you remember a patient called Kurt Grayson. I gather he was quite a Hollywood star as well. He was my friend. Kurt believed in the combination of chlorambucil and Neupogen. I am afraid he belonged to the “more is better” school of thought when it came to Neupogen shots. Eventually, he died of Neupogen induced acute lung injury, ARDS. As I said, what you don’t know can easily kill you in this complex disease.
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28 comments on "Neupogen & Neulasta: Risks and Rewards"
Chaya
I was not familiar with most of this information. Thank you for organizing it and presenting it in an easily understandable format.
Jim
Chaya,
What about revlimid a neulasta? Coy has been getting neulasta every two weeks for the past year with revlimid therapy and ivig-also have constant cough and sinus drainage?!
Thanks,
Nancy
Nancy:
I do not know that there are any problems with concurrent use of Revlimid and Neulasta. Frankly I have not seen too many professional papers worrying about any of these combinations I discussed in my reveiw above. I am not sure I understand why that is the case.
Chaya,
Your dot connecting cannot be beat. It is so valuable to us all. This particular dot connecting is near and dear, as I am in my third round of Campath since relapsing from my ’05 transplant. The Campath has been working for me, but I know am playing russian roulette combining each treatment with neupogen when my neuts crash, which is often. One of my infusion nurses fought my Oncologist about combining the two. She did not want to do it. My Oncologist and I backed her down, telling her we’re willing to dance with the devil. I wish I knew an alternative, but when the neuts keep going near zero, I feel there is no choice.
I fondly remember Kurt. We conversed quite a bit (via email), including about his chlorambcil/neupogen crusade. He sure grabbed the bull by the horns. I miss him.
I am going to share your great report with my Oncologist. I should not do it, as I love the guy, and I know it will make him squirm some.
You are a treasure Chaya.
Bob Larkin
My husband was diagnosed 10 years ago and will soon be going on his 4th round of chemo, probably using Campath. Infrequently the past fifteen months his neutrophil count has dropped down in the 600 range. We noticed that his oncologist sparingly gives the Neupogen now and has decreased the dose. This is in contrast to how it was administered some years ago, but then his counts would go down to zero. He did have Neulasta prophylactically during chemo, but I used to say “the Neulasta never lasta” and he would end up getting doses of Neupogen, too. We felt comfort in the shot producing improved Neutrophil counts, so this article is timely for educating us, especially in view of what’s ahead. Thank you……..Donna
Thanks for this article, Chaya. I wonder if it explains the difference between the British and American results for the use of Campath as a drug to clear MRD? Those ‘grade 5’ complications that we just don’t see over here (ie deaths). Doctors here are much more reluctant to use Neupogen just for a cosmetic effect on the neutrophil count.
I remember seeing my first lung white out back in the 1980s before we had G-CSF. In those days we had to use granulocyte transfusions. When there was an underlying infection – be it CMV, pneumocystis or aspergillus, granulocyte infusions caused ARDS which was invariably fatal and we learned not to do it, pretty quickly.
I, too, remember Kurt. He was a nice guy, but headstrong.
Terry,
The use of Neupogen is just for the cosmetic effect? I thought no neutrophils was a sure road to infection, thus making the neupogen risk called for. Do you recommend stopping Campath when Neuts fall, or just forging ahead with no neupogen?
Bob Larkin
I’ve been waiting for your comments on neupogen, Chaya…thanks…it’s VERY enlightening!
And, apparently my hematologist keeps up to date on this information. As soon as I’m finished here, I’m jotting a note off to my former primary care physician (he moved from here in Rochester to New York City right after he got me set up with my current hematologist). I want to thank him for apparently locating the right team for me.
An anecdote follows, so only take it as such…
Looking back on my records, I was given neupogen more or less prophylactically one week after each of my PCR treatments. My ANC was around 1.5 after the treatments. The PCR Treatments were three weeks apart. My ANC would usually rise to about 3 or 4 after the neupogen, with one exception where it got up to 7.
Six weeks after the 4 months of PCR, they started giving me three shots of alemtuzumab each week for 10 weeks. I received no more neupogen during or after the alemtuzumab and my ANC stayed in the range of 0.9 to 2.5
The interesting thing is that in only twice during the entire treatment did my neutrophils go below 1.0! And that was only to 0.8 during the PCR treatment.
Another interesting point is that when I asked if I could get Neulasata instead of the Neupogen to avoid all the extra shots, my doctor said that we would only do that if we found we needed more than two or three neupogen shots…which I never did.
Looking back on her decisions then, I can now see that, in my case, Neulasta would probably have been overkill, and may have done more damage than help.
Keep the good information coming, Chaya…I forward a lot of these links to a friend who is a home health care nurse…this article was one that she may find appropriate for some of her patients.
Harley
Terry:
I too have wondered about the significant differences between US and UK results using Campath consolidation. I wish there was some way to dig out the details of Neupogen use in the two protocols.
Neupogen and Neulasta are used too much in this country and I hold both doctors and patients equally responsible for this over use. We have become a society that looks for a quick fix. A shot of Neupogen gets the ANC up nicely, no need to worry about infections, no need to be careful about social distancing or avoid eating at the grubby salad bar. And no need to worry about the astronomical cost of these growth factors since insurance will pay for it.
Patients pester doctors and doctors become enablers since it is far easier (saves time) than arguing with patients. Why look the gift horse in the mouth when the CBC report looks good? Just give the guy the Neupogen shot he wants, get him out of the office and usher in the next patient. Kurt was a case in point. As he got sicker, he insisted on double dose and double shots of Neupogen – he was wealthy, he could afford it. I remember sending him a couple of articles about potential links between ARDS and GCSF just weeks before he died. RIP, Kurt.
This is the same pattern that we saw with over-use of powerful antibiotics for situations that did not warrent them. All we need is just a bit more direct to consumer advertising on the TV to cook this goose to perfection.
Very helpful information, Chaya, as usual. The protocol at Georgetown University Lombardi Center for patients who need Neulasta during chemotherapy is to give the injection 24 hours after the last infusion for a cycle. This certainly does not seem optimal given your cogent analysis. Fortunately I survived 6 cycles recently under that protocol. I will discuss this with my hem-onc this week. For those of us who have histories of febrile neutropenia, perhaps 7 days into the cycle would be equally as effective and safer as well.
Your point hits home Chaya. I am educated, and I certianly now feel equally responsible. Now let’s see if I have the courage to turn down the neupogen I’m scheduled to get with my Campath this afternoon.
Bob Larkin
Very nice article. I was told, when I did PCR for my first round, that it is recommended that one wait 24 hours after infusion to get the Neulasta shot. However, my oncologist said that she didn’t think it made any difference whether or not I got the shot concurrently. Glad I waited. Sounds like even 24 hours may not be long enough, although that appears to be the standard waiting period.
Marshall Haith
Another fine article. Thank you Chaya!
My oncologist suggested taking Claritin (loratadine) the day before, the day of, and for 2 days after the Neulasta injection. It did help me to alleviate a lot of the bone pain associated with the treatment.
Here is a new twist on Campath marketing that might interest you.
http://www.bnet.com/blog/drug-business/genzyme-8217s-dilemma-its-cheap-cancer-drug-wants-to-cannibalize-a-potential-ms-blockbuster/4617
For Genzyme, the manufacturer of Campath, the CLL market is apparently not all that big – dollar wise. One full course of Campath for CLL comes out at about $50,000 a year at the pricing established today.
The problem for the company is that it has a new target: the lucrative market of Multiple Sclerosis. If recent trail results are real, much smaller doses of Campath can keep MS patients from deteriorating and in wheel chairs for as much as 4 years. Using the Campath pricing established for CLL, the lower dose MS therapy comes out to about just $10,000 per year. Since other competing MS drugs typically cost around $30,000 per year, Genzyme is having heartburn at being locked into their present pricing strategy since it is “the equivalent of giving it away for free to MS patients”.
What to do? How to get out of the CLL based pricing structure for Campath so the company can make bigger bucks in the MS marker? It seems Genzyme is thinking of withdrawing Campath from the CLL market so that it can establish a much steeper price for the MS market. If this strategy is put into practice down the road, if you are a 17p deleted patient with CLL and need Campath therapy, you may have the following choices:
1. Beg the company for free Campath on “compassionate use” basis.
2. Ask your doctor to get hold of it as if you were an MS patient, and pay the much higher costs (will insurance cover this scenario?)
3. Do without.
Ironic that not so long ago the company strong armed regulatory approval for acorss the board use of Campath in CLL, based on a straw-man comparison against chlorambucil. Tell me, do you think the company would spend any more money testing better protocols for use of Campath as a CLL drug, once they pull out of the CLL market altogether? And yet it is just one of three drugs (along with Revlimid and experimental drug flavopiridol) that works in the very high risk patients.
Chaya,
Thank you for this update. You are indeed a treasure.
Stay well,
Monique
Chaya… Thank you again for shedding light on a most critical issue.I do wish I had known all of this when I received treatment at MDA. Thanks to your very logical and well reasoned explanation of the risks involved,I now understand why some insurers will not pay if these meds are given within 24 hours of chemotherapy. Six to eight months after completing chemo at MDA, I was informed that my insurer had denied payment for several of these injections. The simple and incomplete reason for the denial was that the injections were given on the morning following chemotherapy with FCR. The denial letter stated that I was given the injections for “convenience” only. They were steadfast in refusing payment, despite subsequent letters submitted by my oncologist at MDA. My insurer told me that I “didn’t have a leg to stand on”, further informing me that had I had simply waited a mere 24 hours following chemo, I could have received the injection back home at the Medical Center in Little Rock. The costs would have been covered under my policy. I can say with great confidence that I did not choose to receive these injections out of mere convenience. As a man with 3 children in college, I would never have chosen to assume additional debt as a matter of convenience.
Despite the fact that I was not informed of the risks of giving these meds so close to the time of chemo, I was shocked to learn that no pre-approval was obtained (as I was told at my first interview and assessment at MDA) for a drug costing upwards of $10K per injection. We have appealed the insurer’s decision and have been denied. My outstanding indebtedness to MDA stands at $32K for these medications alone. I appreciate your explaining the rationale behind our insurer’s refusal to pay. Neither the insurer nor MDA has yet offered one. To others facing a similar situation, please ask more questions….the failure to inquire can be costly in more ways than you might imagine. John
There have been a lot of studies showing Neupogen will raise the neutrophil count in the trial arm that gets it, but serious infections are no different in either arm. There is also an interesting study showing that Vitamin B3 (nicotinamide) will enhance the G-CSF effect. It may be a much cheaper way of gaining the cosmetic effect.
FCR does lower neutrophil counts more than FC, but I think that this is consumption of neutrophils in the CD20-antiCD20 immune complex – they have an FCgamma receptor – rather than marrow suppression and therefore it does not warrant neupogen.
This is out of character for me, but what the heck. I’m stressed over some of the above, so I’ll push back at two of my heroes … and I do mean heroes. That’s what Terry and Chaya are to me. Somehow this has hit me hard and hurts. Did Terry ignore my question above because it is a “dumb question”, or maybe because he also sees me as one of those “irresponsible patients” looking a “gift horse in the mouth” for following my Hematologist/Oncologist’s protocol of Campath/neupogen. This shocks me. I have had just about all the treatments (including transplant), and it has never occurred to me that I am being irresponsible. On the contrary, like many others, I think positive and “do what I gotta do”. I don’t ever feel sorry for myself. I also thank the heavens and all the premium payers who have helped help me financially get through this. I don’t take lightly what it has cost everyone (myself, my former employer, my family, my insurers and my donor) to keep me alive. Maybe I’ve been at this too long, or my skin is thinning from tx and old age, but this got to me. I still love you Chaya and Terry.
bolark:
No, when used appropriately their use is not merely for cosmetic effect and I highlight that several times in the article. These drugs save lives, as I repeated several times. But just like using powerful broadspectrum antibiotics when they are not necessary, I believe there is danger in using these drugs inappropriately. You can agree or not, as you wish.
As for your oncologist’s protocol of concurrent Campath + Nuepogen, perhaps he was not aware of the warning article out of OSU. But in his defence, there has been very little published on this potential risk of concurrent Campath and Neupogen with the exception of the OSU article I cite. In any case, the game plan is different just ahead of a stem cell transplant. In that situation the target is to get rid of the host defences, immune suppression is not a concern.
We live and learn. Second-guessing therapy decisions after the fact is not of much use. My articles are not targeted at any one person. Since its publication 24 hours ago, this article has been read by thousands of people. I try to get the word out so that at least some of them can avoid the potential risks this article highlights. Please try not to shoot the messenger.
You and Terry are the last messengers in this world I should be shooting. Looking at my “rant” in the light of day (I did this during sleepless wee hours), makes me regret sending it. I have never done that before. I must be slipping. I go a long way back with both of you. I have benefitted much from that. Shame on me for not properly digesting the article, and for making it so unnecessarily personal.
Bob Larkin
No hard feelings Bob. This is a confusing disease and it gets to all of us at one time or another. Best wishes my friend.
Chaya,
I had Neulasta three or four days after treatment with Bendamustine/Rituxan and had no problems.
Thank you for a very informative article.
Blessings,
Rita Horwitz
Chaya,
This excellent article raises many further questions. One that comes to mind is that if Neulasta encourages release of stem cells which then may be killed off by chemo, how does a patient determine after treatment has ended whether their stem cell reserve has been irreversibly harmed? Bone narrow biopsy, perhaps?
dmackinnon:
Yes, a bone marrow biopsy may shed light on the health of the stem cells and the bone marrow environment after conclusion of therapy. Basically the pathologist would be looking for healthy hematopoiesis – sufficient numbers of all the different cell types beginning to grow back. A pathologist friend once described the difference between a healthy bone marrow versus a dead or dying bone marrow as the difference between a flourishing garden on a summer day versus a graveyard in the winter.
Pathology reports are only as good as the eyes that examine them. It is all too easy to miss important signs or mis-read the signals if the examination is cursory or inexperienced. The other problem with BMB is that it is examination of one specific spot in the bone marrow. If by chance the piece that was examined is not representative of the rest of the bone marrow, the results will be unrepresentative as well.
Thanks very much again for this Chaya. I’ve benefitted from GCSF, but I’ve never had Campath.
But I often feel, what if I am offered it in future? I have noticed small negative effects on my memory since having chemo(or is that just being over 60? :-) but I envisage a scene at some time in future when I have to react to an offer of a particular therapy, and I have to quickly zip through as many of your articles as possible for good advice on that new therapy. But if there’s a clear message from an article, like “Don’t combine Campath and GCSF”, why not use that as an aide memoire, and an index to the full article? Just an idea I’ve had, and I’m not necessarily asking CLLTopics to do it – any reasonably competent IT/CLL person could. Even me, given time and energy!
Comments welcome!
Lawrence
Cornwall, UK
Okay, so now my neutrophils have dropped to 1860 which was about a 50% drop in 6 months when they were 3410. I realize that 1500 is the cutoff. I have some small nodes in my neck. Lymphocytes are 9920 and have only gone up 1200 during that time. Platelets have also dropped from 127K to 118K. My exam shows some nodes in my neck which haven’t gotten any bigger and are 1 out of 10. I feel well. When I ask my oncologist if I should be concerned about the 50% drop in neutrophils he says not to worry, “that these are normal fluctuations in all patients”. He says I should come back and do blood again in 6 months. I called my PMD who decided to check my CBC in 3 months instead of 6. I realize my numbers may still be pretty strong, but it is the decided decline in neutros that doesn’t just seem like a “normal” fluctuation to me. I have never had treatment and was diagnosed in May 2010.
Am I being needlessly worried here in your opinion or what? I am feeling uncomfortable with increasing risk of infection etc. It is true that I am an anxious, compulsive type of person so it makes it harder to deal with this stuff objectively.
Thank you in advance for any light you can shed.
Howard
My company I work for is moving us to Kaiser Insurance. We have a top line PPO and pay a lot for it. We are worried about the move. When we called our insurance company and several others they all said my husband would be inelligible with CLL.. I thought California had a law that said there was no preexisting??
Any one have any ideas?
We have been insured since 1975 continuously.
Thanks in advance.
grey dove
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