Jeffrey Crawford, MD: Hello and welcome to this CME/CE-certified clinical consult titled "Addressing Current Challenges in Preventing and Managing Neutropenia in Cancer."

My name is Dr Jeffrey Crawford. I am a professor of medicine and co-director of the Solid Tumor Therapeutics Program at Duke Cancer Institute in Durham, North Carolina.

It is my pleasure to introduce my guest, Dr LeAnn Norris, assistant professor in the Department of Clinical Pharmacy and Outcomes Sciences at South Carolina College of Pharmacy in Columbia, South Carolina.

LeAnn B. Norris, PharmD: Thank you for having me.

Dr Crawford: In our program today, we plan to address several different issues: patient- and treatment-related factors that help appropriately stratify patients in terms of risks for neutropenia; different myeloid growth factors and how they may be used to prevent or manage neutropenia in patients with cancer; and the pharmacoeconomic factors that affect myeloid growth factor utilization in patients with cancer.

Hematopoietic toxicity, particularly neutropenia, has really been the limiting factor in our ability to deliver chemotherapy over the years. Most of our regimens that are built around every 2 or 3 weeks are based on the fact that that is the time period for recovery of the myeloid compartment for the next round of chemotherapy. That is what has defined maximum tolerated dose for so many of our regimens. It has really been an interesting development over the last 25 years that as we learned more about chemotherapy regimens, we also learned how to integrate myeloid growth factors into their management.

From a clinical perspective, the biggest complication of chemotherapy that we see is not just neutropenia per se, but the complication of fever and infection that complicates neutropenia. For grade 4 neutropenia (a neutrophil count of less than 500 neutrophilic granulocytes/µL), there is an approximate risk of 10% of developing fever and therefore potentially infection for every 1 day that neutrophils are below that 500/µL count.^[1-3] It is therefore important to limit the days of severe neutropenia as much as possible.

Febrile neutropenia has multiple complications: patients must be hospitalized; they need intravenous antibiotics; severe infection may delay future treatment and reduce the patient's chance of getting the full benefit of chemotherapy in the future. Assuming a patient goes from neutropenia to infection, there is also the issue of not being able to deliver the full dose of chemotherapy on schedule. Patients are at risk from either mortality from the infection itself or reduced benefit and therefore mortality from less effective chemotherapy. It is therefore very important to manage the risk of neutropenia very carefully.

It is also important to remember that febrile neutropenia often develops in the first cycle event. We think of our chemotherapy adverse effects as happening in later cycles, but in this situation, it may happen in the very first cycle. Chemotherapy is metabolized differently in individual patients. While we dose by a body surface area measurement, we get very different outcomes in terms of neutrophils.

Until the emergence of myeloid growth factors, our management of neutropenia was basically dose reduction or antibiotics. Now, we have a whole host of myeloid growth factors we can think about for prevention. Can you talk about the different agents and how we might use them in the clinic?

Dr Norris: We refer to these agents as our colony-stimulating factors (CSFs) -- granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and pegylated G-CSF. We also have a newer biosimilar-type agent, tbo-filgrastim. These agents have changed the way we treat patients. A good 10 years ago, many more patients required admission to the hospital, had longer stays and higher costs in hospital stays, and required more antibiotic use. The use of these therapies has decreased that and has allowed us to be aggressive with our treatment.

Initiating these therapies in the first cycle can reduce the type of adverse effects patients have and reduce the length of their therapy. All of this is beneficial, especially in the curative setting in terms of increasing overall survival.

These therapies are fairly easy to use. Often the choice of therapy depends on your institution. In general, daily injections are reserved for the inpatient setting because of reimbursement issues. A lot of facilities prefer longer-acting therapy because it is easier in terms of injection -- it is a 1-time injection given 24 hours after chemotherapy. A lot of patients find that convenient. G-CSF and pegfilgrastim are probably the 2 that are used most often, as they have a category 1 recommendation by the National Comprehensive Cancer Network (NCCN) guidelines.^[1]

These therapies can add some additional adverse effects, but I think most patients and physicians would agree that the benefit outweighs the risk. Probably the most common adverse effect I hear about as a pharmacist is bone pain. We often manage bone pain with some sort of anti-inflammatory agent.^[5] There are some data looking at antihistamines because there is thought to be some antihistamine release with the bone pain that is associated with these therapies.^[6] Bone pain is not surprising based on the mechanism of action where the agent stimulates more cells to be produced and therefore causes the pain.

Some patients complain of flu-like symptoms, and some patients have no complaints at all. They would not even realize that they were taking an additional injection unless we mention it to them. A lot of patients would agree that the benefit outweighs the risk of using these therapies.

Dr Crawford: Do you counsel your patients on bone pain as a potential risk?

Dr Norris: I do counsel them on that, and I think that is an important adverse effect that they need to know about. Some patients associate the bone pain with the flu-like symptoms. When you think about having the flu, you often ache all over. It is important that patients understand what to expect and to know that they may or may not get the adverse effect. It can occur in a lot of patients, so it is critical to tell them in advance that it can happen, what to do if it does happen, and to make sure that they understand why they are taking this agent and what benefits it has. That is the most important aspect of the patient counseling.

Dr Norris: I personally do not have a lot of experience with using the newest product, tbo-filgrastim. Do you?

Dr Crawford: I have not used it directly, but as part of the NCCN panel, I did have an opportunity to look at the clinical trial data. Based on that, we were able to give it a category 1 recommendation.^[1] It is a very similar product to filgrastim, not identical, but that is true of other products that are in this category of biosimilars. Tbo-filgrastim is considered a biosimilar in Europe, while in the United States it went through the same biologic license application that filgrastim went through many years before. They had clinical data to support its use and they had 3 different clinical trials looking at lymphoma, breast cancer, and lung cancer, all of which showed comparability or noninferiority of use.^[7-9]

One of the things that this whole field builds on -- and what will become more common with a biosimilar pathway -- is the knowledge gained from an innovator product such as G-CSF or filgrastim, where you have a lot of experience. You know what the adverse effects are, you know what the benefits are, and you have surrogate markers. In this case, neutropenia was a surrogate marker for this agent, because we know there is such a tight relationship between neutropenia, duration of neutropenia, and febrile neutropenia. They did not have to show the same clinical end point that the original drug had to show, but they did have to show a lot about the experience with the drug in that clinical population. Conclusions are based on a much broader extrapolation from the other product and also all the safety data that they had to show about the similarity between the products.

Dr Norris: Where do you see its place in therapy? You stated it had a category 1 recommendation.

Dr Crawford: It gives us another option. There is the long-acting molecule pegfilgrastim and now there are filgrastim and tbo-filgrastim. I think the decisions between them will largely fall at the institutional level. If the data are as they appear to be, there should be relative interchangeability between filgrastim and tbo-filgrastim for the indication of chemotherapy-induced neutropenia. The decision of which agent is to be used preferentially will probably come at a pharmacy or hospital level and will be made largely based on cost.

Do you have other comments about the CSFs themselves that you want to make at this point?

Dr Norris: It is important to understand how they are used in the prevention of febrile neutropenia. Regimens patients are on should be assessed right away for whether or not they are high-risk for causing febrile neutropenia. A high-risk regimen is one that has a 20% or higher incidence of febrile neutropenia. CSFs are recommended in cycle 1 in patients who are receiving high-risk therapies.^[1]

For low-to-intermediate risk, the recommendation is that we consider the use of these therapies but also take into account other patient-specific risk factors.^[1] I know you have done a lot of research at Duke with those patient-specific risk factors.

Dr Crawford: I have been fortunate to be part of something called the Awareness of Neutropenia in Chemotherapy Study Group, with Gary Lyman and David Dale. We have been able to look at a large community setting of patients receiving chemotherapy and monitor their risk of neutropenia based on chemotherapy regimen, whether or not growth factors were used. It has been a very robust database that has taught us a lot over the years.

With that, we were able to show that patient risk factors are very important.^[10] The chemotherapy regimen dominates the risk to some extent and the NCCN and others have said that routine first cycle use of growth factor is appropriate if the risk based on the chemotherapy regimen is above 20%.^[1,2,4] Part of that risk must also take into account patient risk factors and that has not been as well delineated and is something that is still problematic in the management of chemotherapy-induced neutropenia. For example, we know that clinical trials that established the risk of neutropenia and febrile neutropenia are generally done in a healthier, younger population, while in practice, we are treating patients who are older with more comorbid disease and other problems. Because of that, their complication rate is higher in terms of toxicity.

What we saw in terms of what the patient risk factors are from this community-based registry study was that age was a factor. People over the age of 65 are more likely to have problems. Chemotherapy is clearly a factor. Giving a full dose of chemotherapy itself was a factor because that put patients at higher risk than dose reduction. Others risks included liver dysfunction, renal dysfunction, immunosuppression agents like prednisone, and previous chemotherapy or radiation. Those are all factors that have to be considered.

To be honest, we do not have a nice, well-described formula to assess risk. Our group published a risk model that looked carefully at the intermediate risk group -- those between 10% and 20% risk for whom we would not routinely use growth factors -- and divided the group into high- and low-risk based on patient risk factors.^[10] We then took those risk models and compared them with how oncologists in the community rated risk.^[11] For example, we presented community oncologists with a patient who is 71 with lymphoma and asked what they thought the patient's risk of febrile neutropenia was. The answers varied widely: some of them would say 10%, some would say 50%, and the model's risk was maybe 15%. We realized that we have a long way to go to have physicians understand how to use a model like that. We need to educate them better about what those risk factors are so we can incorporate that better in first-cycle decisions.

Dr Norris: I think there is a great opportunity for pharmacists there too. Some facilities have implemented templates into their computerized medical record that indicate up front when it is appropriate to initiate these therapies. But then there are those gray areas where you have patients who are receiving low-to-intermediate risk regimens. Having someone to assist with determining whether the patient has additional risk factors would be very helpful. Things can get overlooked -- for example, if the patient had previous chemo 1 or 2 years ago or what their liver or renal function is. The guidelines serve as a basis for us, but then we need to look at those other patient-specific risk factors to make the clinical decision about whether CSF is appropriate.

Dr Crawford: On the oncologist level, we do not make that decision that often and instead go ahead with the chemotherapy and put the patient at risk. By doing this, we often leave the pharmacist to clean up after us on a later cycle of treatment. The goal should be to prevent that very first event and use CSFs appropriately. We do not want to use a growth factor in low-risk patients just because we are not sure -- we clearly want to be able to identify appropriate candidates.

There will be a lot more work from a health services perspective and a rollout to make sure that both oncologists and pharmacists understand the risk in an individual patient when it is applied over and above just the chemotherapy regimen.

Dr Norris: I agree, and nurses should be educated too. I have often had nurses approach me in the clinic to ask, "Do you think this patient should be on growth factor?" It is great from the multidisciplinary standpoint that we can all become involved in the patient's care and make decisions.

Dr Crawford: That whole team approach will be very important, especially in making sure the patient is well educated. When patients go out the door, if they do not understand about bone pain, if they do not understand about some of the side effects particularly on daily G-CSF, if they stop taking it because they have bone pain, then they are going to lose the benefit from it.

Can you talk a little about the duration of treatment? There is the long-acting pegfilgrastim, which is given once after treatment. How many days do you take the daily G-CSF?

Dr Norris: Typically, pegfilgrastim has been shown to be equivalent to about 10 days of filgrastim. The interesting thing about pegfilgrastim is that it has neutrophil-mediated clearance, so that as your immune system improves, you get rid of the long-acting therapy. It has an extended length of activity that can be up to 10 or 14 days or so. It is mostly used with regimens that you administer every 3 weeks because of that recommendation of being really careful in the 14-day window. Patient adherence with daily filgrastim can be difficult, and not receiving the daily injections is related to more hospitalizations, which is related to more cost. But overall, either therapy would be appropriate -- it generally depends on the patient, adherence, and reimbursement and cost.

Dr Crawford: Pegfilgrastim is given once and then you get neutrophil recovery. As the recovery occurs, the molecules clear from circulation so you are okay to get the next dose of chemotherapy. That can happen on a 2- or 3-week basis. What would you do for a patient on a weekly regimen and neutropenia was limiting?

Dr Norris: Typically, I would recommend a daily filgrastim schedule. That has been my experience in the past. Would you say that has been your experience as well?

Dr Crawford: Yes. One of the issues is that you generally want to avoid co-administering the CSF on the same day as chemotherapy. There is some risk of stimulating the myeloid cells and thus counteracting the effect of chemotherapy. That said, there are a few studies with pegfilgrastim suggesting that you can do this, but I think it may lessen the full benefits.^[12] So if at all possible, you should try to avoid concurrent administration. That happens on a 2- or 3-week basis just by the normal clearance when you are using pegfilgrastim.

If you are using daily G-CSF, it is important for patients to understand they need to continue daily G-CSF until neutrophil recovery. Stopping short, say after 5 days, is often not enough and patients end up with febrile neutropenia. The NCCN recommends giving either tbo-filgrastim or filgrastim daily until you see recovery to a normal neutrophil count.^[1] It should be started a day after chemotherapy or possibly 2 or 3 days after -- somewhere in that interval of time.

In the decisions about how to pick between therapies, the convenience of pegfilgrastim would have some advantage for every-3-week regimens, while if you are dealing with shorter regimens, then daily G-CSF would be a consideration. But what about the pharmacoeconomics of all this? How does one decide from a pharmacy perspective whether the approach is cost advantageous?

Dr Norris: Medicare reimbursement for 1 dose of pegfilgrastim is approximately $2800. Reimbursement for filgrastim, depending on whether it is the 300 or the 480 dose, can range anywhere from approximately $280 to $400 dollars per vial. When you multiply that out by 10 days, depending on which dose you use, the cost can be fairly similar. Then, in addition to whether it is a 3-week cycle vs weekly regimen, therapy may be dictated by factors such as type of insurance and type of facility (ie, Veterans Affairs [VA] facility vs a private facility).

The other thing that is really important to stress when we talk about pharmacoeconomics of these therapies is that using them decreases the cost of hospital stays.^[1] They decrease the length of stay. They also decrease the use of antibiotics, which also decreases cost. When you talk about pharmacoeconomics with these therapies, it is important to not forget that aspect of cost.

Dr Crawford: When we set the 20% level as sort of a threshold for care, it was based on the clinical trial data supporting the fact that patients at that level had a significant reduction in risk with CSFs. However, as the economics have played out, it is clear that that the 20% is also a break-even point around overall economic cost. Obviously, the lower we can bring the cost of the drugs, the more favorable that becomes which I think is why we have started to see biosimilar drugs. Tbo-filgrastim is not technically a biosimilar in this country as it is in Europe, but there probably are some cost differences that will occur. More competition in the marketplace between the various filgrastims and other agents to come may help us better manage the cost going forward.

Dr Norris: The idea of more affordable biosimilar-type agents is very appealing. If we can reduce cost, then we can reach more patients and have an overall better clinical benefit.

Dr Crawford: Are there other potential discussion points that we should make? I think we have hit on a number of different areas today. We talked about factors influencing the pharmacoeconomics. We have talked about the importance of selecting a myeloid growth factor in the right patient at the right time. We have talked a little about the differentiation between the short and long-acting growth factors. We talked a little about GM-CSF but maybe not that much. What do you see in terms of the role of GM-CSF?

Dr Norris: I do not see a lot of use of GM-CSF. It does not have a category 1 recommendation in the NCCN guidelines.^[1] We see it mostly used in the bone marrow transplant setting. Some institutions have implemented GM-CSF into their treatment regimens but the 2 largest workhorses are certainly G-CSF and pegfilgrastim. Early on, physicians did not like to use GM-CSF because there were a lot of adverse effects, but they have since reformulated the product. Again, currently, the recommendation is either G-CSF or pegfilgrastim, and now the addition of the tbo-filgrastim.^[1]

Dr Crawford: To that point, tbo-filgrastim clearly has level 1 evidence around chemotherapy-induced neutropenia.^[1] At this point, we have not yet seen the data for its use in bone marrow transplant. There is some limited experience in mobilization and transplantation, but it does not have the level of evidence that filgrastim has at this point. We are going to need a little bit more data or experience before we feel comfortable and understand what its role would be in that setting as well as in severe chronic neutropenia. It will be interesting to see. I suspect there will be other, both short- and long-acting, CSFs coming along. It is going to lead to a lot of interesting discussion by the guidelines group and others about how we evaluate biosimilars vs innovator agents, and how much extrapolation we can do from one indication to another.

Dr Norris: One of the major take-home points is that the guidelines serve as a basis for our decisions. However, each patient should also be evaluated for additional risk factors such as age, performance status, etc. All those factors should be part of our decision making for whether or not patients are appropriate candidates for growth factors. As you stated, other healthcare professionals can also assist with that assessment.

Dr Crawford: Do you see any other barriers right now to the utilization of these agents for the management of chemotherapy-induced neutropenia overall?

Dr Norris: We need to ensure that we are using these agents the way that the guidelines suggest and that we are assessing every patient. Cost can add stress to these assessments, especially in a cost-containment system like the VA. That is a perfect example where you need to make the best decision for the patient but also try to minimize cost. We need to ensure that we are still assessing every patient up front to make the best patient decision.

Dr Crawford: I agree. Oncologists are not the best people to evaluate cost and health economics. Our decisions have to be made at the patient level: what is best for the patient, and then hoping that the institution, the payors, and others will help guide us in what agent to use and in what setting. If it is not the one we feel to be most appropriate in the given setting we have for the patient, we need to be able to deal with that and be advocates for our patients. The good news is we have multiple good choices now for management to prevent neutropenia. We still could do more work around the treatment part because these agents are less beneficial in the treatment setting than in prevention.

The take-home message I have is that the educational process at all levels -- for nurses, for pharmacists, and certainly for oncologists -- is about how to better assess risk. That will be so important in determining appropriate use and non-use of these agents going forward.

Dr Norris: I agree.

Dr Crawford: On behalf of Medscape Oncology, I would like to thank Dr Norris for participating in this educational activity that has been developed for hematologists, oncologists, pharmacists, and other specialists involved in the care of patients with cancer who receive myelosuppressive anti-cancer drugs.

Thank you also to the audience for participating in this educational activity. To proceed to the online CME/CE test, please click on the "Earn CME Credit" link on this page. Thank you.