 Chemotherapy-induced neutropenia [CIN] is a serious consequence of cancer chemotherapies, many of which are heavily myelosuppressive, and chemotherapy-induced neutropenia does put a substantial toll on patients with cancer.

The most important clinical implication of CIN is febrile neutropenia [FN]. Fever in the setting of neutropenia, typically with a neutrophil count less than 1000 [per μL], or even more so less than 500 [per μL}, should prompt an evaluation for an infection. Even when we don’t find an infection, febrile neutropenia, fever greater than 100.5 [°F], approximately, that lasts with neutropenia should be treated as an infection unless proven otherwise.

Febrile neutropenia can lead to a hospitalization. It can lead to sepsis, and it can lead to exacerbation of multiple comorbidities. In extreme cases, it can even lead to mortality, and we do see that even in today’s era where we have effective antibiotics. It does happen. We find that patients get chemotherapy-induced neutropenia, or CIN, depending on the degree of myelosuppression of the chemotherapy regimen that they’re receiving. If one looks at the NCCN [National Comprehensive Cancer Network] guidelines, for example, there are nice lists of example regimens that have a high risk of CIN and the consequence of febrile neutropenia. Typically, that’s considered high risk if that risk is greater than 20% for febrile neutropenia. And many regimens that we use today continue to have that high risk. Even more are in the intermediate group, which based on the chemotherapy itself, has a risk of 10% to 20% of FN and a higher risk of CIN.

There are other factors that impact the chance of getting febrile neutropenia besides the intensity of the chemotherapy alone, and some of them are things like age. Patients who are over the age of 65 have a higher risk of developing CIN and FN. Those patients are at particular high risk, as are patients who have extensive bone marrow involvement, who have had prior chemotherapy and prior radiation therapy, who have had CIN in a previous cycle of therapy either with the same regimen or a previous regimen, and also the patients who have substantial comorbidities like diabetes and renal dysfunction or liver dysfunction.

When you put all that together, there are many patients who are at high risk of FN, even with the intermediate range myelosuppressive regimens.

For regimens that are low risk, under 10%, we typically don’t consider them at high enough risk to consider any prophylaxis against CIN.

The frequency of CIN depends on the myelosuppressive intensity of the chemotherapy. It varies from disease to disease, not by the disease per se, but by which chemotherapy regimen they’re getting. Combination chemotherapy with drugs that are highly myelosuppressive like taxanes or combinations of platins, like carboplatin, and a taxane tend to be higher. Regimens with anthracyclines tend to be higher. But it depends on the specific dosing and schedule of the regimen.

Regimens that are given at less frequent intervals, for example a 3-week regimen, is more likely to make a patient susceptible to CIN. But it’s mostly about the regimen and about the patient’s risk factors, and the disease risk factors themselves.

Facts About Chemotherapy-Induced Neutropenia

: CIN [chemotherapy-induced neutropenia] affects cancer care in several ways. First of all, if a patient develops chemotherapy-induced neutropenia, there may be a delay in recovery of the [neutrophil] counts, and therefore the patient may not start their next scheduled dose on time. If this happens multiple times, the patient will not receive the full dose of therapy on schedule, and we’ve learned over the years that that’s an important component of outcome.

For patients who receive, particularly in a curative setting, chemotherapy that’s less than 85% of the calculated dose when you start, based on the clinical trials that prove the efficacy of that regimen, the outcome for patients who receive less than full dose on schedule can be compromised. What we mean by that is that patients may have increased mortality in a curative setting if they get less than 85% of the planned dose on schedule. If there is a dose delay, if the physician modifies the dose, which frequently happens when a patient develops CIN and then febrile neutropenia, they may get a reduction in their dose in subsequent cycles of therapy.

The combination of dose modifications and dose delays can reduce the total dose of curative therapy given, which can lead to a poorer outcome.

In rare cases, patients may have to discontinue therapy completely if they had a severe complication of CIN. The severe complications of CIN include an unplanned visit to the clinic to get hydration or antibiotics, or even more commonly emergency department visits, admissions to the hospital for febrile neutropenia, which require IV [intravenous] treatment including IV antibiotics, and treatment of those patients who can become very sick.

For the patients in my experience who do have an episode of febrile neutropenia and prolonged hospitalization, they may often not continue their chemotherapy, and therefore, not get the benefit out of that type of treatment.

Chemotherapy-Induced Neutropenia: Impact on Cancer Care

 The first component in monitoring and preventing CIN [chemotherapy-induced neutropenia] in practice is to understand the myelosuppressive intensity of the chemotherapy that you’re giving to a patient, and it’s also important to look at a list of potential patient and disease factors that might impact that more negatively as well.

You might have a regimen that has an intermediate risk of CIN and FN [febrile neutropenia] in that 10% to 20% range, but you might have that patient being elderly with multiple comorbidities and extensive bone marrow involvement. You know that patient has a higher risk of CIN.

We also need to know by the regimen when the CIN occurs. It’s not an immediate event. Remember, the chemotherapy is impacting the hematopoietic stem cells in the bone marrow that are constantly making neutrophils. It takes many days for a neutrophil to go from a committed stem cell to a fully mature neutrophil and to be released from the bone marrow into the circulation where it can fight infection. Chemotherapy slows that process, and therefore, depending on the chemotherapy you get, that could be anywhere from around 8 days to about 14 days after the chemotherapy when it hits its nadir, the lowest point in the neutrophil count.

It is important to think about monitoring patients, particularly in their first cycle of therapy, to see how low they go and whether or not they develop CIN. Now, mild CIN is usually not of great consequence, but severe CIN with a neutrophil count of less than 1000 [per μL], which is grade 3, or less than 500 [per μL], which is grade 4, is where we start to see the risk for fever and infection developing.

We’ve known for decades now that the risk of febrile neutropenia is directly related to the depth of the nadir, how low the white blood cell count, particularly the neutrophil count, goes and how long it stays low. In patients treated even in the 1960s, this relationship with low neutrophil count and duration of neutropenia was established. If you have a neutrophil count below 500 [per μL], but it lasts for several days, that risk goes up substantially. If you have a neutrophil count that goes down to zero, which can happen with chemotherapy, that risk is high almost immediately, within a day or two. And even if you have a neutrophil count that’s below 1000 [per μL], if it lasts for several days or longer, those patients are at risk for getting febrile neutropenia. It’s the product of the time of neutropenia and the depth of neutropenia that gives you the risk of febrile neutropenia and infection and complications.

Monitoring for Chemotherapy-Induced Neutropenia

: It’s interesting that when you do careful analysis of various chemotherapy regimens across the board, the cycle that is at greatest risk for CIN [chemotherapy-induced neutropenia] and FN [febrile neutropenia] is the first cycle of any regimen. That may be because the bone marrow has not been primed to expand its neutrophil precursors until there is an insult to it, which occurs with myelosuppressive chemotherapy. Therefore, it’s important for clinicians to think about prophylaxis against neutropenia before they start a new regimen, not afterward.

In fact, about 50% of episodes of febrile neutropenia occur with the first cycle of therapy regardless of which treatment you’re giving. A clinician should be evaluating the risk of myelosuppression from the chemotherapy, along with the patient risk factors, along with tumor risk factors, to make a decision whether prophylaxis against CIN should be given with the first cycle of any new regimen.

If a patient is to get a myelosuppressive chemotherapy, the clinician should think about prophylaxis against CIN, and we have prophylactic measures that are effective. Keeping the neutrophil count high, above that 1000 [per μL] point, through the entire cycle of therapy and avoiding the nadir count, which occurs with myelosuppressive chemotherapy at some predictable time, usually in the middle of the cycle, is the goal, because if we can do that effectively then the patient will not be at risk for febrile neutropenia. The patient will not be at risk for all the complications of neutropenia, including hospitalization potentially, and the patient will not be at risk for a dose delay or a dose modification. Therefore, the resource utilization could be dramatically lower if prophylaxis is appropriately employed prior to initiating a new regimen of myelosuppressive chemotherapy.

Considerations for Chemotherapy-Induced Neutropenia Prophylaxis

 We have had effective prophylaxis against CIN [chemotherapy-induced neutropenia] for the past 30 years, with the advent of recombinant growth factors, predominantly G-CSF, granulocyte colony-stimulating factor. Studies done in the early ’90s with highly myelosuppressive chemotherapy showed that we could reduce, but not eliminate, CIN with the delivery of G-CSF given after chemotherapy that was heavily myelosuppressive. We also in early days used GM-CSF [granulocyte-macrophage colony-stimulating factor], but in the clinic that’s rarely used today because of other toxicities, and it probably doesn’t work as well as a broader growth factor stimulant, not just of granulocytes.

For the last 30 years, we’ve had either short-acting G-CSF, which is administered daily after chemotherapy, usually starting at least 24 hours after chemotherapy and continued until the [neutrophil] count recovery, which is typically around 10 days afterward. We give G-CSF as a daily injection, and for the last 20 years we’ve had a long-acting version of G-CSF, which is pegfilgrastim, which allows dosing much more conveniently, only once because it has decreased clearance through the kidneys and is self-regulated. Once the white blood cell count comes back, it metabolizes the drug. Giving G-CSF has revolutionized the approach to CIN because [it can give patients prophylaxis] against CIN when they’re getting a myelosuppressive regimen, with an appropriate G-CSF dose.

The NCCN [National Comprehensive Cancer Network] has a growth factor guideline committee, and it recommends prophylaxis with G-CSF for any patient who is receiving a myelosuppressive regimen where that risk of febrile neutropenia [FN] would be at least 20%, and particularly when it’s in a curative regimen. In a palliative regimen, another alternative would be to reduce the dose in subsequent cycles, although it must be noted that that might decrease the efficacy, even in a palliative setting.

For FN risk greater than 20% by chemotherapy, it’s recommended. For patients in the intermediate range, which is considered 10% to 20% risk from the chemotherapy itself, patient risk factors should be taken into account, and based on the clinician and patient’s decision together, consider growth factor prophylaxis starting with the first cycle of therapy, importantly. For regimens that have less than a 10% risk, the NCCN does not recommend growth factor support, even if there are patient risk factors, because it’s relatively low.

Chemotherapy-Induced Neutropenia Prophylaxis: Standard of Care

 While colony-stimulating factors like G-CSF [granulocyte colony-stimulating factor] have revolutionized the approach to chemotherapy-induced neutropenia [CIN] and febrile neutropenia by giving us an effective prophylaxis, it’s not perfect. First of all, for the more myelosuppressive regimens, its use in reducing neutropenia is about a 50% reduction. As the myelosuppression goes down, it tends to be more effective, but even in regimens that are not considered in the high-risk range, in some patients receiving G-CSF support, they still get febrile neutropenia. It’s not 100% effective by any means. And again, as the myelosuppression risk goes up in general, the ability of current dosing of G-CSF tends to be less effective.

In addition, G-CSF is not given on the same day as a chemotherapy administration, and the standard is to give it between 24 and 72 hours after the chemotherapy. That in some cases necessitates an additional visit for the patient to get the growth factor, although there are devices that can be put on the patient’s body to administer the dose about a day later.

Also, and importantly, there are [adverse] effects with G-CSF administration, and the No. 1 [adverse] effect is bone pain. This is an on-target effect because what the G-CSF is doing is stimulating the myeloid precursors in the bone marrow, and as they start to expand, they can cause bone pain.

Many clinicians prescribe a long-acting antihistamine, to be taken daily with the G-CSF or afterwards for several days after the cycle. While anecdotally that’s been shown in some cases to help the bone pain, it’s never been proven to my knowledge in a randomized, double-blind, placebo-controlled study to actually work. We do it because it’s low risk, but it clearly does not help a lot of people. A lot of people still have bone pain, and our patients come in sometimes with severe bone pain even to the point where they might need narcotics or even refuse the chemotherapy at full dose with the G-CSF in the next cycle because it was so severe.

This is a remaining issue that needs to be solved. Finally, there are patients, as I mentioned, who still get CIN despite getting appropriate growth factor prophylaxis with G-CSF either long acting or daily standard filgrastim, and those patients need more protection than the current standard will deliver.

CIN Prophylaxis: Treating With G-CSFs

 We have room for new agents in helping us reduce the incidence of CIN [chemotherapy-induced neutropenia] and FN[febrile neutropenia]. There is a new agent called plinabulin, which has shown some interesting and exciting results as an add-on agent for reducing CIN. This agent is different. It’s not a colony-stimulating factor. It appears to be an immune and stem cell modulator, and it has a different mechanism of action than our standard growth factors, which we use in the clinic today.

In a randomized, phase 2 study comparing plinabulin to G-CSF [granulocyte colony-stimulating factor] in moderately myelosuppressive chemotherapy, it showed similar benefits in reducing the duration of severe neutropenia after patients received doses of docetaxel as the single agent. Based on that data it went into phase 3 trials. One of those phase 3 trials is called PROTECTIVE-2, and we saw some of the top-line results, which are exciting.

PROTECTIVE-2 is a study looking at plinabulin given on day 1 after chemotherapy with pegfilgrastim given as standard on day 2 after myelosuppressive chemotherapy in patients with breast cancer receiving a triplet combination of drugs called TAC, for docetaxel, doxorubicin, and cyclophosphamide. We know that this regimen is heavily myelosuppressive, and although pegfilgrastim by itself can reduce the incidence of CIN, it does not completely abrogate it, nor does it abrogate the risk of febrile neutropenia. Those patients in particular with severe myelosuppression do require an additional agent.

The primary end point of PROTECTIVE-2 was to show a reduction in the incidence of grade 4 neutropenia after TAC [docetaxel, doxorubicin, and cyclophosphamide] with the addition of plinabulin to pegfilgrastim, and the top-line results showed that this primary end point was met and was highly statistically significant.

In addition, a secondary end point of the duration of severe neutropenia in the first 8 days after chemotherapy, when plinabulin will be working before G-CSF has a chance to kick in if you will, was also achieved and was highly statistically significant. We have exciting preliminary data that suggest that this combination of plinabulin plus pegfilgrastim can reduce further the risk of CIN that is severe, and therefore the risk of FN, when using the combination approach. We await the final results of this study. This drug did receive breakthrough designation by the FDA.

If plinabulin is approved by the FDA, we would now have a new regimen of likely combination with plinabulin given on day 1 and pegfilgrastim given on day 2 after highly myelosuppressive chemotherapy with the potential benefit of completely doing away with the risk of severe CIN, or at least markedly reducing it from where we are today after highly myelosuppressive chemotherapy.

Plinabulin With G-CSF Treatment for CIN Prophylaxis

 As I mentioned, the NCCN [National Comprehensive Cancer Network] has a guideline committee for the use of myeloid growth factors after myelosuppressive chemotherapy to reduce the incidence of CIN [chemotherapy-induced neutropenia] and FN [febrile neutropenia].

In the spring after the COVID-19 [coronavirus disease 2019] pandemic was becoming full blown, the NCCN modified their guidelines and recommend the use of prophylactic G-CSF [granulocyte colony-stimulating factor] in patients who were receiving intermediate-risk regimens in that 10% to 20% risk range. A lot of different chemotherapies are in that risk range that may or may not get a prophylactic G-CSF regimen along with it.

Based on that, we received reimbursement for patients receiving growth factors even for those intermediate-range myelosuppressive regimens, which was not always a given prior to this emergency usage of G-CSF as recommended by NCCN. The reason they recommended it in the intermediate-range group is we did not want patients receiving chemotherapy for cancer to have to make additional visits, either to the clinic or even worse to the hospital where resources were so strained by the COVID-19 pandemic and have to be admitted for preventable neutropenia and complications. In my own clinic, we did implement this, and we have seen a reduction in the incidence of moderate or severe CIN while giving growth factors to these patients who frequently need it. This has been a savings all around. We have not increased morbidity to our patients. We have not exposed them to the possibility of getting COVID-19 in the hospital. And we’ve reduced the stress on the hospital system, particularly now as we’re talking in late November 2020, where COVID-19 is unfortunately spiking and threatening to overwhelm our hospital resources and our health care workers. We do not need to have patients who could be prevented from being in the hospital because of febrile neutropenia, if they got prophylaxis to not have had it. That’s what we’re doing currently. The NCCN and ASCO, [the American Society of Clinical Oncology] by the way, which released similar guidelines, did a great service to the cancer community by modifying their guidelines.

Where in the past we might have asked patients to come back in for a complete blood count at their time of nadir, at day 8, or at day 10, or at day 12, or 14, or even come in a couple of times to get blood counts, each time they come to the clinic, they’re coming to a situation where they may be exposed to others with COVID-19. Based on essentially the ongoing mandate to reduce exposures, particularly for vulnerable populations, and patients with cancer are among the most vulnerable populations given that they have impaired immune systems to begin with and many of them are older, these are exactly the type of individuals we don’t want to increase exposure for any means to the potential of getting COVID-19. Reducing their need to come in for a blood count check is one way to do that, and by giving patients G-CSF prophylaxis beforehand, that does away with the need to have them come back and check their neutrophil count.

We do ask patients to monitor their fever, and if they don’t feel well, they should certainly take their temperature, particularly during that time when they might be at highest risk for chemotherapy-induced neutropenia and febrile neutropenia. The COVID-19 pandemic has also complicated matters for patients who do get neutropenia and fever because we frequently don’t know if that’s standard FN due to their chemotherapy and we’re treating them that way, or whether it could be COVID-19 and the first manifestation of it. This leads to more care and distress in trying to determine that. And we’re testing those patients for COVID-19 when they come in with fever and neutropenia, just to make sure we’re not missing that as well.

New Directions in Chemotherapy-Induced Neutropenia