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Hello from Boston, Massachusetts. Oliver Freudenreich here, or Dr. F as my patients call me, for the Psychopharmacology Institute. In this Quick Take, we will look at an article together regarding clozapine specifically about the efficacy and safety of using colony stimulating factors, like filgrastim, in a clozapine rechallenge when you’re dealing with somebody who developed agranulocytosis or neutropenia.
For those of you who are prescribing clozapine, here’s the feared scenario. Let’s imagine you just started somebody on clozapine ,and after a few months he is on a good dose and clinically improving. Then, on a Friday afternoon, you get a call from the laboratory that his ANCs are 900. You repeat it, and now it’s 800. So, you stop clozapine and stabilize the patient more or less on chlorpromazine. Now, once you end up with a patient who developed agranulocytosis or severe neutropenia while on clozapine, you’re a bit behind the 8-ball clinically since discontinuation is usually not a good option. You’re using this medicine as a last resort, if you will, for treatment-resistant schizophrenia usually. So, I think we often rechallenge at some point. We go very slowly in titrating clozapine back up and hope for the best. And now, once you run into problems again, then you are in the territory that the paper addresses.
You basically wonder, “Should I rechallenge?” If you do, you should add a colony stimulating factor, like GCSF, this time to boost your patient’s bone marrow production of neutrophils. This manuscript specifically addresses the question of whether you should use GCSF if you want to increase the chances of success for a clozapine rechallenge or continuation when you have a patient on agranulocytosis or neutropenia on clozapine.
Let me emphasize 3 things about clozapine and agranulocytosis before moving on to the paper itself. One, it can happen. It’s rare, probably below 1%, but common enough so that if you work in a clozapine clinic, you will absolutely see it. Two, for it to be clearly related to clozapine, it must occur within the first 6–12 months. Now, this has to do with the presumed pathophysiology, which is either a toxic or an immune reaction to clozapine, or both. Now, never say never in medicine, but if somebody’s ANC is decreasing after years on clozapine, I think it’s unlikely for this to be clozapine or at least clozapine alone. There’s substantial differential diagnoses with dropping neutrophils, like infections, and making the etiological connection between clozapine and agranulocytosis or neutropenia is not always cut and dried. And 3, I already alluded to this as my 8-ball example, you cannot simply move on to a different antipsychotic if agran happens.
So, the question of rechallenge is very real. It’s a clinical dilemma. And so, I’m thankful for this paper by my namesake, Olivier Corbeil and his colleagues, which really asked the question if you can have a more successful rechallenge or ongoing treatment in the face of these blood dyscrasias. The paper itself is basically a literature review of the cases and case series published with this question in mind, and those reviews of published cases are of course not great because they’re unselected and not systematic. You never know what gets published or does not get published, so the reporting bias is a real concern.
In the end, the authors came up with 34 articles with a total of 59 cases. Not very impressive numbers, but it is what it is. There were 3 key findings. First, about between 70% or 80%, three-fourths of cases were successfully rechallenged or continued on clozapine. Now, consecutive case series, which may be a little bit less biased, had a lower success rate of 60%. Rule of thumb here is, well, you have at least a 50% chance of success based on this paper. Key finding 2, there were no clinical predictors of success or failure, like the severity of episode or time course of the episode of agranulocytosis. The third key finding was that filgrastim was the most widely used GCSF analog. Probably not a big difference between prophylactic use of filgrastim or as-needed use. That means you could give it as a single dose once your ANC drops below a prespecified threshold, like 1000 cells/uL. Filgrastim was also well-tolerated with only minor complaints, and the most common dose, if you’re interested, was 300 mcg per day.
The authors in their discussion also mentioned lithium, which I used to use to manage benign ethnic neutropenia before the REMS registry created a special category that really alleviated this problem of BEN patients. So, this problem is really not a big problem anymore. Lithium is a poor man’s GCSF, as it mildly stimulates the bone marrow. It goes beyond just demarginalization, which I think mistakenly some people assume is the main mechanism of action. You know this to be true if you have someone in lithium and monitor white blood cells. Typically, most patients on chronic long-term lithium treatment have a WBC of about 10,000 or so. It really mildly stimulates the bone marrow to put out more neutrophils.
So, other than the sample size, the main weakness of the paper is that the etiology of the lower ANC is unclear because they really mixed agranulocytosis and neutropenia. Only about 60% of cases fell into the consensus time frame for clozapine-induced agranulocytosis—so, early in the course of treatment but definitely within the first year. I think this just shows the confusion between benign ethnic neutropenia, natural fluctuations, and other causes of temporarily low neutrophils. In this report, 50% of cases were given GCSF after the second episode, meaning that they actually had tried to rechallenge initially without GCSF. This is a very important clinical point. In general, the risk of agranulocytosis after a firm diagnosis of clozapine-related agranulocytosis is very high, probably about 80%. In a review of all clozapine rechallenges after major adverse events from 2018 by Peter Manu, the authors looked at NMS, myocarditis, agranulocytosis, and neutropenia. And only 18% were successfully rechallenged for agranulocytosis compared with 63% after neutropenia, suggesting that those 2 entities are really very different clinical beasts.
So, here’s my clinical bottom line. Given that the stakes from clozapine discontinuation are so high, it is worthwhile to think how to best support your subsequent treatment efforts with clozapine after an episode of agranulocytosis or neutropenia. This may come in the form of maximum medical support with GCSF, particularly if there’s uncertainty about the etiology of your low ANCs. I am skeptical that if you are dealing with a very toxic and a very fulminant immune reaction to clozapine within the first few months that GCSF can prevent this from happening again. If I decide, though, I’m not so clear I want to give it a try. I want to maximize my chances of success, so I would probably use GCSF and I would probably use it as needed and not necessarily prophylactically. And if I use this strategy, I have at least a 50% chance of being able to continue clozapine. Not such bad odds. So, GCSF probably really helps if you just need to boost your bone marrow a little bit, but you’re not dealing with the catastrophic destruction of neutrophils or neutrophil precursors in the bone marrow from an immune reaction triggered by clozapine. It is unclear how long you would need to provide GCSF support but probably at least 1 year.
And one last comment before I let you go. I would definitely work this out with hematology at least in my setting to make sure I’m not off base with my treatment plan and also for the initial workup and diagnosis. A clozapine rechallenge is a high-risk medical intervention, and you need buy-in from all stakeholders, including patients, family members, and even group home staff who can help you implement and monitor this. And all of them need to know about the potential risks and really sign off on it.
Abstract
Clozapine Rechallenge or Continuation Despite Neutropenia or Agranulocytosis Using Colony-Stimulating Factor: A Systematic Review
Olivier Corbeil, Laurent Béchard, Émilien Fournier, Maude Plante, Marc-André Thivierge, Charles-Émile Lafrenière, Maxime Huot-Lavoie, Sébastien Brodeur, Anne-Marie Essiambre, Marc-André Roy, Marie-France Demers
Objectives: Rechallenge/continuation of clozapine in association with colony-stimulating factors (CSFs) following neutropenia/agranulocytosis has been reported, but many questions remain unanswered about efficacy and safety. This systematic review aims to assess the efficacy and safety of rechallenging/continuing clozapine in patients following neutropenia/agranulocytosis using CSFs.
Methods: MEDLINE, Embase, PsycInfo, and Web of Science databases were searched from inception date to July 31, 2022. Articles screening and data extraction were realized independently by two reviewers, according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 systematic review guidance. Included articles had to report on at least one case where clozapine was rechallenged/continued using CSFs despite previous neutropenia/agranulocytosis.
Results: Eight hundred forty articles were retrieved; 34 articles met the inclusion criteria, totaling 59 individual cases. Clozapine was successfully rechallenged/continued in 76% of patients for an average follow-up period of 1.9 years. There was a trend toward better efficacy reported in case reports/series, compared with consecutive case series (overall success rates of 84% and 60%, respectively, p-value = 0.065). Two administration strategies were identified, “as-needed” and prophylactic, both yielding similar success rates (81% and 80%, respectively). Only mild and transient adverse events were documented.
Conclusions: Although limited by the relatively small number of published cases, factors such as time of onset to first neutropenia and severity of the episode did not seem to impact the outcome of a subsequent clozapine rechallenge using CSFs. While the efficacy of this strategy remains to be further adequately evaluated in more rigorous study designs, its long-term innocuity warrants considering its use more proactively in the management of clozapine hematological adverse events as to maintain this treatment for as many individuals as possible.
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Reference
Corbeil, O., Béchard, L., Fournier, É., Plante, M., Thivierge, M., Lafrenière, C., Huot-Lavoie, M., Brodeur, S., Essiambre, A., Roy, M., & Demers, M. (2023). Clozapine rechallenge or continuation despite neutropenia or agranulocytosis using colony-stimulating factor: A systematic review. Journal of Psychopharmacology, 37(4), 370-377.
Related References
Manu, P., Lapitskaya, Y., Shaikh, A., & Nielsen, J. (2018). Clozapine rechallenge after major adverse effects: Clinical guidelines based on 259 cases.
American Journal of Therapeutics, 25
(2), e218-e223
