White Blood Cell Growth Factors Guideline Update

Dr. Bishal Gyawali and Dr. Tessa Cigler share the new, comprehensive, evidence-based update of the ASCO guideline on the use of hematopoietic colony-stimulating factors in patients with cancer. They discuss recommendations on primary prophylaxis, secondary prophylaxis, and treatment of febrile neutropenia along with stem cell mobilization, efficacy, safety, duration, dosing, and administration of CSFs – including biosimilars. They highlight where it is appropriate to use a CSF, and importantly, when not to use a CSF. They touch on the significance of individual patient considerations and cost implications, and future work to refine the risk factors for the development of complications of febrile neutropenia. Read the full guideline, "White Blood Cell Growth Factors: ASCO Guideline Update" at www.asco.org/supportive-care-guidelines

TRANSCRIPT

This guideline, clinical tools and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-02938

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Bishal Gyawali from Queen's University in Kingston, Ontario, Canada, and Dr. Tessa Cigler from Weill Cornell Medicine in New York, New York, co-chairs on "White Blood Cell Growth Factors: ASCO Guideline Update." Thank you for being here today, Dr. Gyawali and Dr. Cigler.

Dr. Bishal Gyawali: Thank you very much for having me. It's a pleasure.

Dr. Tessa Cigler: Hi there. Nice to be here as well.

Brittany Harvey: Great. And then before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Cigler and Dr. Gyawali, who have joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then I'd like to dive into the guideline that we're here today to talk about. So first, what prompted an update to this guideline on the use of hematopoietic colony-stimulating factors in patients with cancer, and what is the scope of this updated guideline?

Dr. Bishal Gyawali: The last version of the guidelines from ASCO on this topic was back in 2015, so it has been more than a decade since ASCO had a guideline on the use of G-CSF in patients with cancer receiving treatment. So it was due for an update because there has been a lot more evidence based on not necessarily new drugs, but evidence for proper timing of these agents and the duration of these agents, as well as there have been a lot of new biosimilars, and there are questions about are these biosimilars equivalent or how do we choose among these different options. One is that content of the evidence that has evolved over time in the last decade, but also I think the last time we had these guidelines, the ASCO guidelines were not incorporated to have those evidence GRADE tables. So the quality of the ASCO guidelines itself has evolved over the years, so we wanted to have a new version of the guideline that includes not only the new evidence, but also contains those evidence GRADE tables that will help to quantify the benefits. And so I think it was high time, and even more than that, the newer ASCO guidelines for any guideline, they also include considerations of cost, access, equity, and all these factors that were not included in the previous version of the guideline. So I think it's only natural that with time the guideline should also evolve.

Dr. Tessa Cigler: I agree completely, and just as a framework, as we all know, neutropenia and its complications, including febrile neutropenia and infections, are still an important toxicity of many myelosuppressive chemotherapies. And these neutropenic complications do require prompt evaluation and treatment and often hospitalization, and we know that hematopoietic colony-stimulating factors, which I'm going to refer to as growth factors, can reduce the duration and severity of neutropenia and the risk of febrile neutropenia, so it remains an important topic in the practice of clinical oncology.

Brittany Harvey: Absolutely. It's an important topic for both clinicians and for patients who are receiving treatment for their cancer. And as you said, there was a substantial amount of literature to review here and updating everything to be in line with the GRADE evidence rating system, so there was a lot of work that you both put into this.

So then next, I'd like to review the key recommendations of this guideline by clinical question. So first, what factors did the expert panel identify that should influence the decision to administer primary prophylaxis of febrile neutropenia with a CSF?

Dr. Bishal Gyawali: Yeah, so I think that constitutes one of the most important recommendations in our guidelines about primary prophylaxis with G-CSF. And this is important because not only it's about when to use it, it's also about when not to use it, as in the ASCO "Choosing Wisely" campaign has also made some recommendations about this. So our guideline recommendations are also aligned with that.

So first of all, we recommend that primary prophylaxis with G-CSF is recommended when the risk of febrile neutropenia because of the chemotherapy regimen is equal to or more than 20% unless an alternative chemotherapy regimen with comparable efficacy and safety that does not need G-CSF is available. And the quality of evidence to make this recommendation is high, so we give a strong strength of recommendation for this. Having said that, even for patients where the risk of febrile neutropenia is not necessarily 20%, it's a little lower, but because of other patient-related factors, the patient is at a higher risk of complications from febrile neutropenia, such as age, comorbidities, and other factors, in such case primary prophylaxis with G-CSF should be offered. And we also make a recommendation that if G-CSF is not affordable or available, then antibiotic prophylaxis can also be offered, but the evidence quality for this is low, and the strength of recommendation is very conditional.

A couple of things to highlight here would be that, I think Dr. Cigler can attest to that, we ran into lots of problems about finding the data for the evidence base to say what are the patient-related factors that actually make them at a higher risk of febrile neutropenia, you know, like how did that 20% benchmark come about? Why 20%? Or when we say even if it's less than 20%, if based on other comorbidities, if the risk is higher, we tried to dig into that evidence. For example, we're talking about our "Box 1" in the guideline, what is the evidence for each item we have included under that "Box 1"? And we tried to do a lot of search to find the evidence for that, and some of them do have strong evidence, and that will tie into our future research ideas as well. And some of them actually don't have such solid evidence too, so that was one of the reasons why we ran into lots of problems about how do we quantify whether someone is at a high risk of febrile neutropenia and where that 20% benchmark comes from.

Dr. Tessa Cigler: And definitely, because there's not very clear data, our guidelines definitely leave room for physician discretion in all these situations.

Brittany Harvey: Absolutely. I find that in a lot of these guidelines the key point is that there's a lot of shared decision-making with patients after talking through what risk factors they may have and what is best for them in their individual clinical scenario.

So then moving on to secondary prophylaxis, what factors did the expert panel identify that should influence the decision to administer secondary prophylaxis of febrile neutropenia with a CSF?

Dr. Tessa Cigler: So for patients who've already experienced a neutropenic complication from a previous cycle of chemotherapy, the question is which patients should then receive prophylactic G-CSF for subsequent cycles of chemotherapy. And without a lot of evidence again to guide us, the panel really felt strongly that secondary prophylaxis should be used when a treatment delay or when a reduced dose of chemotherapy would be thought to compromise cure rates or survival outcomes. We do note that in many situations, certainly a dose reduction or a delay would be a very reasonable alternative or an additional strategy to G-CSF administration.

Dr. Bishal Gyawali: Yeah, I think it's more like if there is going to be compromise in outcomes without using G-CSF, as in if we can't maintain the dose intensity and that's going to lead to inferior outcomes, then we should. But if we can reduce the dose intensity and treatment frequency and still have the same outcomes, then I guess in simple words, we're just trying to say use it when it's absolutely needed, or you can also look into other alternatives that might not need G-CSF but you could maintain the same outcomes.

Brittany Harvey: Understood. It's helpful to review those options for clinicians and showing that there's not just one way to address potential neutropenic complications for later cycles of chemotherapy.

So then following those recommendations for prophylaxis, what does the expert panel recommend regarding CSFs for the treatment of febrile neutropenia?

Dr. Bishal Gyawali: This is an important question because this ties strongly with the "Choosing Wisely" campaign. In other words, primary and secondary prophylaxis we talked about when CSF should be used; here we make a sort of negative recommendation in that we say when CSF should not be used, because this is where we see most overuse or overtreatment with G-CSF. So first, we say that we should not be using a CSF routinely simply because a patient has neutropenia. If they are afebrile but they only have neutropenia, we recommend against using CSF just to boost neutrophil counts; that's not a meaningful metric. Then the second recommendation we make is CSF should not be routinely used as an adjunctive treatment with antibiotic therapy for patients with fever and neutropenia. So the first one was neutropenia, no fever, don't use it. The second one is okay, there is neutropenia and fever, but the treatment for that is use of antibiotic therapy, and so in such situations routinely we should not be using G-CSF just to boost the neutrophil count. And that is tied on to the third recommendation where if the patient has fever and neutropenia but is also at a very high risk for infection-related complications or who have other prognostic factors that we think will lead to poor outcomes for the patient, then in such situations, a CSF can be used as an adjunctive treatment. But we talk about the data in the manuscript, but the data show that the most that this will do is reduce the days of hospitalization by a couple of days. It actually does not have any data that it's going to improve the mortality rates.

So as of now, we use the word "may be offered," it's not "should be offered," it's "may be offered" if there are other factors that we think will make the patient at the very poor risk of mortality outcomes, and the evidence quality here therefore is low and our strength of recommendation is conditional. And we also have a box that lists those items that we think might be associated with poor prognosis for the patients, but again the data for those, are they really hard evidence? No. And that is also tied with our future research recommendation that we should study more about these factors that might lead to these poor outcomes.

Dr. Tessa Cigler: And again, allowing for discretion of the treating physician.

Brittany Harvey: Absolutely. It's just as important to know when not to use CSFs routinely, and those risk factor boxes that you mentioned are available in the full manuscript along with the full list of recommendations, and our listeners can refer to that; a link will be in the show notes of the episode .

Dr. Tessa Cigler: Just so you know, the panel, we really discussed those criteria a lot and agonized over them and gave you our best recommendations.

Brittany Harvey: Definitely, and it sounds like there was varying degrees of evidence to support a lot of those risk factors, and so it's really important that the evidence supports those, but also there was expert consensus of the panel in reviewing each of those factors individually to come up with recommendations that can be applicable for all clinicians.

Dr. Bishal Gyawali: If I may add, we're proud of our panel because I think our panel is quite inclusive of people representing different specialties within cancer care, as in we had radiation oncologist, we had infectious disease expert, pharmacists, and most importantly, we also had patient partners.

Brittany Harvey: Absolutely. Having a multidisciplinary panel is really important for each and every guideline.

So then, this is probably relevant now, but addressing a few more specific sections addressed in the guideline, what is the role of CSFs as adjuncts to progenitor cell transplantation?

Dr. Tessa Sigler: Great question, and so, as solid tumor oncologists, Dr. Gyawali and I really leaned heavily on our hematology experts within the panel. The panel decided that a CSF should be used alone after chemotherapy or in combination with a CXCR4 inhibitor to mobilize peripheral blood progenitor cells. Clearly the choice of mobilization strategy depends on the type of cancer and the type of transplantation. The panel noted that a CSF should be routinely administered after autologous stem cell transplantation to reduce the risk of severe neutropenia, and that a CSF may be administered after allogeneic stem cell transplant to reduce the duration of severe neutropenia. Again, this last recommendation has not a lot of evidence to support it, and so we kind of tempered our language that it may be administered or can be considered based on clinical judgment of the physician and the clinical status of the patient.

Brittany Harvey: And that really highlights the need for a multidisciplinary panel, because as you are solid tumor oncologists, you need the hematologists to make recommendations for all sorts of patients and make sure that these guidelines are comprehensive.

So then moving on to another smaller subset population, for patients receiving concomitant chemotherapy and radiation therapy, are CSFs recommended?

Dr. Bishal Gyawali: I think there is very little evidence for patients who are receiving radiation therapy alone, so there is no evidence to suggest the use of CSF in patients with radiation therapy alone. The bigger question is in patients who are receiving both chemo and radiation together, chemoradiotherapy. In those patients, up until now, the classical recommendation has been to avoid G-CSF use. I think in our updated guidelines we discuss a couple newer trials that are trying to address this issue, but in the totality of evidence, we still stick with the same recommendation as before, which is CSFs are not recommended in patients receiving concomitant chemotherapy and radiation therapy, especially those involving the mediastinum because the biggest evidence of harm is for these patients.

Dr. Tessa Cigler: I agree completely.

Brittany Harvey: Definitely. It's important to recognize when that balance of benefits and harms leans more towards harms, and so that this should not be recommended for those patients.

So there are several different CSFs that are recommended in the guideline, including biosimilars. So do the recommended CSFs differ in efficacy or safety?

Dr. Tessa Cigler: So as supported by evidence, and the panel all agreed, that the various forms of CSFs, including the biosimilars, really have the same evidence for efficacy and for safety, and that the choice of agent really should depend on cost, availability, accessibility, patient convenience, and sometimes disease subtypes and treatment regimens. But, in essence, these can be used interchangeably without concern for efficacy or toxicity differences.

Dr. Bishal Gyawali: I completely agree. I think in terms of efficacy outcomes, I don't think there is anything to choose between these agents. The choice between these agents would largely depend on different patient and treatment-related factors: cost, availability, affordability, feasibility. We even discuss things like where does the patient live, as in how frequently the patient can commit to the cancer center, and we also discussed things like even for the daily shots of filgrastim, patients can be taught and they can get it by themselves at home. So we discussed all these factors, but in a nutshell, the choice within these agents primarily depends not on efficacy factors, but simply based on all these other factors that are equally important but which can lead to informed decision-making about what is best for a given patient. But we mention it explicitly that the biosimilars, there is nothing to choose between them, especially the biosimilars; it's about price competition and what you can get at an affordable rate.

Brittany Harvey: Understood. It's great to have many different options for patients so that there's something that can work for them based off access, cost, and all these factors that you listed. As you mentioned, it may be easier for some patients to get their treatment at home rather than in clinic, and so having different options and reviewing those with patients is very important.

Dr. Bishal Gyawali: As we are having this conversation, I'm thinking that we might be a very unique guideline in that I don't think in many other settings you have this many options that you are asking about, you know, choices between equally good options and making decisions based on cost. I don't think there are any other areas in oncology where we have the privilege of making these decisions based on cost and convenience and all these factors, as well as we might be one of those guidelines where we have, as discussed before, so many recommendations about when not to do things and trying to promote judicial use of treatments.

Dr. Tessa Cigler: As you might imagine, our panel discussions were very lively.

Dr. Bishal Gyawali: Yes. But Dr. Cigler, do you recall any other guideline where there is so much discussion about when not to use things and how we have so many biosimilar options and we can choose the one that's most appropriate? I don't recall any other.

Dr. Tessa Cigler: I agree with you.

Brittany Harvey: It's certainly a unique guideline in that regard.

So we'll move into the last clinical question that the expert panel addressed. But what does the expert panel recommend for the initiation, duration, dosing, and administration of CSFs?

Dr. Bishal Gyawali: Yeah, I think there has been some new data in this regard that were not available in the previous guideline. For example, we have new trials testing a shorter duration of filgrastim injections compared to the standard of care. So we have some data, we call this 'de-escalation of treatment'. So we have more data supporting de-escalation of treatment. We have some data for lower dose of pegfilgrastim, we have data for lower duration of filgrastim, we have also some new data about timing of treatment, as in there has been some newer data presented about the relationship of timing of the drug and the frequency of adverse events from G-CSF such as bone pain. There is also the question about, for patients who don't live near the cancer center, can they get their pegfilgrastim shot on the day of chemo while they are in the cancer center? So all these questions that are very pragmatic and important questions, but were not answered before, we're glad that we had more evidence to talk about all these factors and give a more solid recommendation to our users of the guideline.

Brittany Harvey: Definitely. And listeners can review the full list of dosing and administration recommendations in Table 2 in the guideline, and that will be linked in the show notes of the episode.

So then I really want to thank you both for reviewing all of these recommendations. There's certainly a large amount of clinical questions and recommendations that you went through.

I'd like to next ask, in your view, what is the importance of this updated guideline and how will it impact both clinicians and patients?

Dr. Bishal Gyawali: I think the importance of this updated guideline is that, as mentioned before, we talk about newer data that have come up with regards to not just the most important two questions as in when to use it as primary prophylaxis and when to use it as secondary prophylaxis and when to use it as treatment, but also with regards to the duration and timing and dosing and multiple options and how these all factors as well as patient-related factors should be combined to make an informed decision, the most appropriate decision for the patient. And as mentioned before, we have the GRADE tables that were not in the previous version of this guideline. So I think even those users that are familiar with the 2015 guideline, I think they will find very novel content in this new updated guideline, and they will find it useful for their practice.

I would encourage the readers to not only read the headlines of the box recommendations, but also read the full text of these guidelines because we have worked really hard to incorporate the latest evidence and also interpret them contextually. The discussion regarding de-escalation, patient considerations, cost implications; usually, people just skip these portions when they read a guideline. But I think these are also one of the most important paragraphs in our guideline, so they have been written with very careful thought, and I think reading the whole guideline is very much worth your time.

Dr. Tessa Cigler: As you can imagine, I agree completely, having just spent several months thinking about these guidelines and all their nuances.

Brittany Harvey: Certainly, this guideline is definitely a very comprehensive update, and that nuance in the manuscript is really important for clinicians to understand and read through and understand when it's appropriate to make certain decisions.

So then to wrap us up, I'd like to ask, what are the outstanding questions and active research areas regarding the use of white blood cell growth factors in patients with cancer?

Dr. Tessa Cigler: As you all know from clinical practice and that we've said several times already in this podcast is that the risk factors for the development of complications of febrile neutropenia are still not clearly worked out. And one of the things that is, I think, really needed in clinical practice is the development of predictive algorithms or biomarkers to really allow us to understand who might be more at risk and to allow for the clinician to be able to tailor the use of G-CSF as needed.

Brittany Harvey: Yes, and so we'll look forward to future updates in this space to inform new recommendations and an updated guideline in the future.

So I want to thank you both so much for your work to develop this comprehensive guideline. It was certainly a lot of effort, and thank you for your time today, Dr. Gyawali and Dr. Cigler.

Dr. Tessa Cigler: Oh, my pleasure. It's nice to be here and to speak with you all.

Dr. Bishal Gyawali: Yeah, it was great to speak with both of you but also through you to the audience, and we had a great time. Thank you.

Brittany Harvey: And then finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

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